Univ Of North Carolina Chapel Hill

NIH Research Projects · FY 2025 · 2022-08

Abstract Triple-negative breast cancer (TNBC) is a unique type of breast cancer that does not express or overexpress estrogen receptor (ER), progesterone receptor (PR), and HER2. During the past several decades, the standard care of TNBC remains the highly toxic chemotherapy with little progress in more effective treatments. To address the urgent unmet need to develop targeted therapies specific for TNBC, we developed a totally protein-based nanoplatform called ProNano that is composed of two recombinant proteins, including the first an elastin-like polypeptide (ELP) nanocore that displays multiple calmodulin-binding short peptides on the surface, and the second a recombinant calmodulin protein genetically fused with a highly stable and modular protein domain possessing either tumor homing or therapeutic features. The docking of the ELP nanocore with a TNBC- targeting module together with a functional module with therapeutic feature results in bifunctional ProNanos that can be used for tumor-homing delivery of therapeutic agents for the combination therapy for TNBC. Three specific aims will be pursued in this project. The first specific aim is to develop a ProNano platform that allows tunable targeting of TNBC cells based on their surface antigen expression profiles. The second specific aim is to develop a bifunctional ProNano platform that allows tumor-specific blockade of the aberrant Wnt signaling for the treatment of TNBC. The third specific aim is to develop a bifunctional ProNano platform that allows tumor- specific inhibition of the ENPP1-catalyzed hydrolysis of extracellular cGAMP for combination immunotherapy of TNBC. The bifunctional ProNano platforms developed in this project have several major advantages over conventional nanoplatforms, including all protein components each can be precisely and genetically engineered, oriented and self-assembled introduction of both tumor homing and/or therapeutic moieties at desired ratios without need of any chemical conjugation, and use of highly stable and easily expressed modular polypeptides with no or low immunogenicity. Although we focus on the targeted treatment for TNBC, the ProNano platforms developed in this project can be easily adapted to address other cancer types simply by changing the tumor targeting module.

NIH Research Projects · FY 2025 · 2022-07

ABSTRACT Despite significant gains in the control of Plasmodium falciparum (PF) globally, Plasmodium ovale (PO) and Plasmodium vivax (PV) may be expanding to fill the niche left behind. These malaria species are more difficult to control due to early commitment to transmissible life cycle stages (gametocytes), allowing transmission prior to treatment, and by the formation of dormant liver stages (hypnozoites) which are resistant to blood stage antimalarial drugs and can cause recurrent infection at a later date (relapse). PO and PV are more prevalent in Africa than previously recognized. PO, known to be endemic, is a rising cause of malaria infections in multiple countries. PV, long thought absent from Africa, has persisted despite the dogma that the lack of Duffy protein, the main red cell (RBC) invasion ligand, renders Africans immune to infection. Despite the growing evidence of their increased burden, almost nothing is known about key biologic parameters that govern PO and PV transmission in Africa. Largely due to the lack of field diagnostics and molecular tools, studies of PO and PV in most of Africa have almost exclusively been limited to cross-sectional prevalence surveys or convenience sampling from clinics, without any attempt to gain a deeper understanding of the basic transmission biology and relapse patterns of these species. This proposal leverages technical advances in the field, including field deployable molecular diagnostics, high throughput genotyping and single cell sequencing, to provide the first robust studies of these fundamental knowledge gaps in PO and PV biology in Africa. Through community and clinic-based surveillance, we will identify PO and PV infected individuals in Dschang Cameroon, a site co- endemic for all 4 major species of human malaria in Africa and which has the most extensive epidemiologic data concerning PV infection in Central Africa. By combining human, vector and genomic studies, the proposal will provide key information about transmission biology (Aim 1), relapse patterns (Aim 2) and, for PV, the ability to overcome the mechanisms that restrict RBC invasion (Aim 3). Filling in these gaps will lead to the design of more appropriate interventions for relapsing malaria by defining the infectious reservoir and the contribution of relapse to the reservoir (Aim 1A, 2A and 2B), as well as defining vectors for targeted intervention (Aim 1B). This work will provide insight into the mechanisms by which PV and PO in Africa may prove resilient in the face of continued elimination efforts targeting PF and at the same time generate tools (e.g. point-of-care diagnostics and diversity markers) to track these species. Together, these findings will help shape the design of new malaria control strategies for relapsing malarias.

NIH Research Projects · FY 2025 · 2022-07

PROJECT SUMMARY African-American women across the US experience alarmingly higher rates of maternal mortality than their white counterparts. Factors associated with social determinants of health (SDoH), including education, housing, transportation, and nutrition are recognized as potentially contributiing to this disparity in maternal health outcomes, along with clinical risk factors including hypertension and heart disease. However, the complex associations among these factors, along with the causal role they play in increased risk for maternal mortality, are not well understood, nor are there comprehensive health care interventions that take these combined factors into account to provide decision and communication support for patients, providers, and community support workers. The Analytics and Machine-learning for Maternal-health Interventions (AMMI) initiative, a collaborative effort from researchers at UNC- Chapel Hill, Duke, and Wake Forest, aims to address these gaps by developing a machine learning- enhanced health technology framework to reduce downstream risk of maternal mortality in African- American women. By integrating data across the three institutions that includes both clinical and SDoH factors, and by building machine learning applications grounded in this data, AMMI’s goals are to: 1) clarify and track contributions of biological, clinical, and SDoH factors toward specific maternal morbidities associated with eventual mortality, 2) conduct efficient and accurate risk predictions to determine whether patients fall into defined target risk groups, and 3) translate these risk predictions into interventions appropriate for providers, patients, and community support organizations. A key focus of the initiative is to create an advanced technology infrastructure supporting connectivity and communication among these three types of stakeholders, with the goal of building trust and awareness based on automatically curated decision support aids and ultimately mitigating patient risk. To this end, Aim 1, focused on establishing system requirements, begins with the formation of a stakeholder group that brings together patient, provider, and community support organization representatives to engage in design and evaluation with AMMI researchers throughout the project. Aim 2 focuses on systems development, including the creation of 1) a custom-built clinical and SDoH data mart, 2) clinical decision support software using machine learning algorithms, and 3) three user-facing apps aimed at providers, patients and community support personnel, and AMMI researchers. Aim 3 focuses on pilot-level deployment of the system, integrating the AMMI apps through Epic to provide informational interventions to providers, patients, and community support personnel. Aim 4 engages stakeholders in formative and summative evaluation during and after the deployment phase (Aim 3), including both testing of the software function and measurement of the impact of AMMI interventions on end users.

NIH Research Projects · FY 2025 · 2022-07

PROJECT SUMMARY Background: Chronic pain impacts a fifth of American adults. Integrative pain management (IPM) interventions including mindfulness-based stress reduction, yoga, and other methods have demonstrated improvements in pain and function, and are now included in clinical guidelines for chronic pain conditions. Despite evidence of efficacy, IPM is not reaching low-income populations at greatest risk for chronic pain and related opioid overdose. Low-income communities rely on safety-net healthcare facilities to access care, of which Federally Qualified Health Centers (FQHCs) are the primary providers. The Integrative Medical Group Visit (IMGV) for chronic pain is one of a few promising IPM interventions developed specifically for safety-net settings. The challenge now is to examine effectiveness and implementation of IMGV in FQHC settings, to address chronic pain and risks associated with opioid use. Goals and Objectives: Dr. Roth’s long-term career goal is to become an independent investigator evaluating effectiveness and implementation of IPM interventions to reduce the burden of chronic pain, particularly in low-income communities. This K01 career development award will allow Dr. Roth to gain advanced skills in conducting trials that can identify successful implementation strategies for IPM interventions. Career Development Activities: The K01 application will provide structured didactic and hands-on training that will build on Dr. Roth’s training in community-based participatory research and foundational implementation science skills, through training in cluster-randomized trial designs, cost measurement and evaluation, and conducting a multi-site pilot study with FQHCs. The plan will engage Dr. Roth in robust training activities including mentorship, coursework, research projects, publishing and presenting, workshops and seminars, grant-writing, and responsible conduct of research. Mentors: Dr. Roth’s mentorship team consists of accomplished scientists from implementation science, clinical integrative health research, intervention epidemiology, health economics, and FQHCs. Environment: Dr. Roth will benefit from a comprehensive research training program and infrastructure based at the UNC School of Medicine’s Program on Integrative Medicine, the top-ranked UNC Gillings School of Public Health, and the North Carolina Translational and Clinical and Sciences Institute. The North Carolina Community Health Center Association will provide training in working with FQHCs. Research: Dr. Roth’s proposed K01 research project will address the limited access to IPM in FQHC settings serving low-income patients. Dr. Roth will first engage key stakeholders through implementation mapping to identify and refine implementation strategies (Aim 1). She will then pilot measures of effectiveness and implementation for IMGV in two FQHCs (one rural, one urban) in North Carolina (Aim 2). This award will prepare Dr. Roth to submit a future competitive grant application for a hybrid type 2 effectiveness-implementation trial of IMGV for chronic pain in FQHC settings.

NIH Research Projects · FY 2025 · 2022-07

Project Abstract The COVID-19 pandemic caused by SARS-CoV-2 has resulted in swift and catastrophic losses of human lives globally. Acute respiratory distress syndrome (ARDS) is one of the most detrimental outcomes of COVID-19 infection that can lead to the rapid deterioration and death of patients. ARDS is primarily caused by the cytokine storm which unleashes a plethora of inflammatory cytokines during the late stages of COVID-19. The master cytokines that are thought to be responsible for much of the damage are interleukin 1 (IL-1), interleukin 6 (IL-6) and tumor necrosis factor (TNF). Currently two clinical trials have shown the efficacy of IL-1 inhibitor in COVID- 19 patients. However, in many cases, the mechanism and impact of these cytokines during SARS-CoV-2 infection are poorly understood. An in-depth mechanistic understanding of cytokine induction is important because this understanding will significantly impact the design and success of ARDS treatment. This application focuses on the role and mitigation of the inflammasome complex which leads to the proinflammatory cytokine, IL-1β, in ARDS. The inflammasome is a protein supramolecular structure that leads to caspase 1 activation, which then cleaves pro-IL-1β and pro-IL-18 to mature IL-1β and IL-18. In addition to the release of IL-1β and IL- 18, caspase 1 cleaves gasdermin D to cause inflammatory pyroptotic cell death, thus leading to a cascade of cell death and inflammation. The inflammasome is comprised of a receptor or sensor, with the most prominent ones represented by NLRP1, NLRP3, NLRP6, NLRC4 and AIM2. It also includes an adaptor molecule ASC (apoptosis-associated speck-like protein containing a CARD), and the effector caspase-1. Each receptor or sensor can be activated by specific pathogen products called PAMPs or cell damage associated molecules called DAMPs. Single cell RNAseq data from COVID-19 patients show dramatic increases of inflammasome sensors in the bronchial alveolar lavage of severe COVID-19 patients. In addition, we find a bidirectional feed- forward loop of inflammasome activation and inflammatory cytokine induction involving myeloid cells and airway stromal cells. This proposal will test the hypothesis that this two way amplification loop is important in COVID- 19.

NIH Research Projects · FY 2025 · 2022-07

PROJECT SUMMARY How our brain achieves coherent perception by integrating information from parallel sensory pathways distributed across space and time remains a central question in neuroscience. In the auditory system, sound information reaches the cortex via the lemniscal (“primary”) and non-lemniscal (“secondary”) pathways. The non-lemniscal pathways have often been described as slower integrators of multi-sensory information, in contrast to the roles of the lemniscal pathways as fast and reliable relays for sound inputs. However, the contribution of the non-lemniscal pathways in driving fast cortical responses and how they interact with the lemniscal pathways during sound processing are still matters of debate. Our preliminary electrophysiology experiments show that layer 6 (L6) of not only the primary but also the secondary auditory cortex receives sound inputs whose latency can be shorter than the L4 lemniscal inputs. Surprisingly, our retrograde tracing demonstrates that this short-latency L6 input originates from the non-tonotopic parts of the auditory thalamus, supporting the role of the non-lemniscal pathway in fast sensory processing. Building on this exciting finding, we will combine anatomical tracing, in vitro/in vivo electrophysiology, optogenetics, and behavior to delineate this non-classical pathway and determine how it interacts with the lemniscal pathway to regulate cortical sensory processing. Specifically, we will examine the hypothesis that short-latency non-lemniscal inputs onto L6 regulate cortical sound processing in a timing-dependent manner and control the tuning and temporal fidelity of sound responses. To achieve this goal, this project aims to (1) Delineate the anatomy of the fast non- lemniscal pathway from the cochlear nucleus to the auditory cortex using both anatomical tracing and in vivo unit recordings, (2) Determine the synaptic impact of the non-lemniscal input onto cortical cell types by performing targeted whole-cell recordings in cortical slices while simultaneously activating L6-targeting thalamic inputs, and (3) Identify the roles of the fast non-lemniscal input in cortical sound processing in vivo by optogenetically manipulating thalamic inputs onto L6 during unit recordings in the mice performing sound- guided behaviors. Through our research, we seek to provide a more holistic understanding of auditory processing across the two major ascending pathways. Since parallel thalamocortical inputs onto L4 and L6 are conserved across sensory modalities, results from this project will provide insights into the generalizable principles underlying the cortical circuitry of sensory integration. Ultimately, these studies will help the future development of targeted treatments for not only hearing disorders but also other sensory integration dysfunctions.

NIH Research Projects · FY 2025 · 2022-07

Project Summary/Abstract - There is an urgent need to create sustainable systems to facilitate the success of early career investigators as it pertains to the mission of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Thus, we propose a comprehensive program to facilitate the success of early career scientists engaged in research that is directly responsive to the mission of NIDDK and that builds on the extensive infrastructure already in place within and across our institutions. We draw upon established collaborations through our NIDDK-funded University of North Carolina at Chapel Hill Nutrition Obesity Research Center (UNC-NORC) (P30DK056350, MPIs Mayer-Davis/Shaikh) and our North Carolina Diabetes Research Center (NC-DRC) (P30DK124723, PI McClain) to Duke University, North Carolina Agricultural and Technical State University (NC A&T), University of North Carolina at Chapel Hill (UNC), North Carolina Central University, Wake Forest University School of Medicine and Winston-Salem State University. Led by MPIs Dr. Saame Raza Shaikh (UNC), Dr. Kimberly Truesdale (UNC), and Dr. Marc Cook (NC A&T), we propose the Supporting Promoting, and Launching the Expansion of Nutrition, Diabetes, and Obesity Researchers in North Carolina (SPLENDOR-NC) program. We aim to build on established infrastructure to develop key program components and a rigorous evaluation plan (Year 1) that ensures continuous quality improvement (Years 2-5) of SPLENDOR-NC that will support the success of early career scientists in the conduct of research in nutrition, obesity, diabetes, and related conditions. We will establish three cohorts of scholars (total n=20) (Year 2, Years 3-4) and execute programmatic activities (Years 2-5). Scholars will be selected competitively and will include senior post-doctoral scholars and early career faculty members across our six institutions. Each scholar will have a dedicated primary mentor and mentoring team as well as access to carefully curated programs for professional development that will unfold over the two-year program. The required deliverable for our program is an NIH proposal (K or R-level, as appropriate to career stage) for which substantial training and mentoring will be provided. Finally, we will offer a robust P&F Program (Years 1-5) with two levels of funding that will 1) enable collection of preliminary data to support external proposal submissions (up to $50,000 per award) and 2) enhance research success by providing targeted support for equipment, lab supplies, trainings, etc. (up to $10,000 per award). Building on our substantial existing NIDDK infrastructure and research funding, SPLENDOR-NC will markedly improve the research workforce, preparing scholars to make substantial scientific contributions via independent NIH research funding in the critical areas of nutrition, obesity, diabetes, and related conditions for years to come.

NIH Research Projects · FY 2025 · 2022-07

Perovskite Based Foldable and Sensitive X-ray Imaging Detectors for Trauma Care Project Summary/Abstract X-ray imaging techniques including plain x-ray, tomosynthesis and computed tomography are the most common and indispensable imaging modalities for screening and diagnosis. Trauma care needs the rapid deployment of medical diagnostic devices and data collection to examine the injury of patient in complicated environments, such as outside the hospitals or imaging-centers. Portable medical imaging devices such as X- ray imaging devices are notably critical to address these needs. Since almost all present X-ray detectors are made of the combination of scintillators with photodetector arrays, the portability of X-ray detectors is limited by the rigid ceramic scintillators. Exposure to ionizing radiation is known to increase the risk of cancer due to the damaging of DNA by X-ray. The current detectors are not sensitive enough so that a large dose is need to achieve enough signal to noise ratio in imaging. The overall objective of this project is to yield a new generation of X-ray detectors that are foldable, sensitive by overcoming the limitation of state-of-the-art detectors using metal halide perovskites to directly convert X-ray into electrical signal. Direct conversion detectors have better resolution than indirection ones, because it doesnot have the issue of nondirectional light emission in scintillators. Perovskites are promising X-ray detection material by combining the strong stopping to X-ray and excellent charge extraction capability. These detectors will be made to be like Yoga mats so that they can be folded for easy carrying and quickly rolling-out or wrapping the point of care for inspection. A perovskite filled membrane (PFM) structure will be used for multiple layer structure construction which have been demonstrated to have the high sensitivity and easy to upscaled to large area for practical applications. Our specific objectives are: (Aim1) establishing perovskite compositions, stacking structure and material fabrication process to develop sensitive PFMs with large mobility-lifetime product, low noise, and excellent uniformity over a practical X-ray imaging device area; (Aim2) developing a material design and process to integrate the X-ray detection perovskite films into readout electronics with a robust mechanical connection and uniform electronic connection using several soft materials based bonding techniques, The proposed technology has the potential to offer: (1) a factor of 10- 100 X patient imaging dose reduction; (2) increased imaging resolution; and (3) a flexibility and light weight detector. The project leverages a recently discovered application of lead halide perovskites for ionization radiation detection with demonstrated significantly higher sensitivity compared to the current mammography detectors; Reducing the imaging dose will decrease the risk of radiation-induced cancer for patients, making the screening process safer. Increasing the resolution will potentially lead to improved detection and analysis of features in injury or sickness. The light-weight foldable detectors enable new applications in field for trauma care.

NIH Research Projects · FY 2025 · 2022-07

PROJECT SUMMARY Essential tremor (ET) is a common neurological disorder and a leading cause of functional and psychological disabilities that can be difficult to suppress with oral medications, many of which have considerable side effects limiting adequate dosing. As a result, up to 20% of ET patients cannot achieve satisfactory control of their symptoms and must consider interventional options. Focused ultrasound ablation (FUSA) of the ventral intermediate nucleus (Vim) is an FDA-approved and Medicare-reimbursed procedure for ET resistant to medications that can selectively ablate the brain area associated with tremor without the need for surgical incisions or anesthesia. The success of Vim-FUSA depends on the ability to accurately ablate 70% of the Vim volume without lesioning neighboring structures, a goal that is complicated by technical challenges in three critical phases of the procedure: planning (identifying the Vim location and extension); delivery (ablating the Vim volume with adequate accuracy); and monitoring (confirming Vim ablation with reliable intraoperative imaging). We propose to advance Vim-FUSA with the support of 3-D tractography, a neuroimaging technique to visually represent nerve tracts within the brain. We hypothesize that 3-D tractography Vim-FUSA will improve the Vim ablation compared to standard Vim-FUSA and prove safe and feasible in the clinical setting. We also hypothesize that intraoperative magnetic resonance (i-MR) monitoring will differentiate ablated tissue from immediate perilesional edema and accurately predict the Vim-FUSA clinical outcomes. Aim 1. Estimate and characterize the improvement in Vim ablation achieved with 3-D tractography Vim-FUSA vs. standard Vim-FUSA in an experimental controlled animal study. Through an experimental animal study, we will characterize the Vim ablation delivered with 3-D tractography Vim-FUSA in one hemisphere (experimental group) vs. standard Vim-FUSA in the opposite hemisphere (control group). Aim 2. Test safety, feasibility, and preliminary efficacy, and estimate effect size of 3-D tractography Vim-FUSA in a phase-II, two-groups, pre-post interventional human study. In a human study, we will test the safety and feasibility of ablating 70% of the Vim volume while checking for side effects with intraoperative clinical testing. Tremor assessments will be videotaped at baseline and 12 weeks and compared, in a blinded fashion, with age-sex matched controls randomly selected from the video repository of the two FDA-regulated studies of standard Vim-FUSA at baseline and 12 weeks. Aim 3 (Exploratory). Assess the accuracy of i-MR in differentiating tissue ablation from immediate perilesional edema and its utility in predicting Vim-FUSA clinical outcomes. In the experimental animal study, we will estimate and compare the accuracy of conventional and non-conventional i-MR in differentiating tissue necrosis from perilesional edema. In the interventional human study, we will evaluate the utility of i-MR in predicting Vim-FUSA clinical outcomes.

NIH Research Projects · FY 2025 · 2022-07

Project Summary/Abstract Alzheimer’s Disease and Alzheimer’s Disease Related Dementias (AD/ADRD) are on the rise in the United States. Estimates project a 40% increase in AD among older Americans by 2025. This increase, along with its associated economic, social, and health burdens, are likely to have disproportionate impacts, as Black adults have the highest incidence of dementia of any racial/ethnic group in the U.S. Moreover, Black Americans experience higher rates of established biological risk factors for AD/ADRD, including hypertension, diabetes, stroke, inflammation, and biological aging. The expected growth in AD diagnoses, expenditures, and burdens, as well as potentially widening racial inequalities, make it imperative to investigate early risk factors for the development of AD/ADRD and racial inequalities in AD/ADRD. Structural forms of racism are likely important drivers of racial inequalities in AD/ADRD risk. Yet, much of the research in this area focuses on downstream factors, such as exposure to stressors and discrimination, or specific domains of structural racism at one point in time. Missing are longitudinal studies of structural racism and aging-related health inequalities across multiple geographic contexts. Further, there is limited knowledge of how public health and policy interventions addressing structural racism can be utilized to reduce racial inequalities in AD/ADRD. Causal modeling techniques provide opportunities to assess the impact of structural interventions on documented inequalities in biological risk factors for AD/ADRD using observational data. The purpose of this project is twofold: 1) to create a public-use, comprehensive data repository of multilevel and repeated contextual measures of structural racism; and 2) use the new contextual data in combination with existing contextual and individual-level longitudinal data from the National Longitudinal Study of Adolescent to Adult Health (Add Health) to examine specific pathways linking structural racism and AD/ADRD biological risk among early midlife U.S. adults. Specifically, we will investigate whether structural racism across educational, residential, and criminal justice contexts independently and jointly shape Black-White disparities in biological risk factors for AD/ADRD, including hypertension, diabetes, inflammation, epigenetic aging, and two novel biomarkers of AD/ADRD risk (neurofilament light and total tau). We will also use simulation models to compare the effects of hypothetical population-based policy changes and targeted interventions on racial inequalities in biological risk factors of AD/ADRD risk. Findings from this study will advance our understanding of how structural racism shapes AD/ADRD risk early in the life course. Results from simulation models will also inform the development of population-level, early interventions aimed to slow the progression of AD/ADRD risk and reduce health inequalities in these outcomes.

NIH Research Projects · FY 2025 · 2022-07

Project Summary/Abstract Having Alzheimer's disease or a related dementia, being ambulatory, and awakening in the night constitute a recipe for a dangerous fall. Add a lighting system that promotes postural stability, and the fall may be avoided. That is exactly what our recent NIH R21 exploratory/developmental randomized crossover trial did, and exactly what we found -- a 34% decrease in falls due to a novel lighting intervention. The proposed project will build on that preliminary effort; if the results are as promising as suggested, this pragmatic passive lighting system has the potential to reduce falls and related sequelae for countless persons with Alzheimer's disease and related dementias, and to become a new standard of care. Falls are the primary cause of fatal and non-fatal injuries among persons 65 years of age and older. Dementia is a major risk factors for falls, and assisted living (AL) communities are the primary provider of residential care for ambulatory older adults with dementia, making AL a critical setting in which to reduce falls. Forty-two percent of the more than 811,000 AL residents across the U.S. have moderate or severe dementia, 84% are ambulatory, and more than a third experience a fall in a six-month period, putting them among the 15% of AL residents who suffer a hip fracture or other serious fall-related injury each year. Falls are responsible for one- third of all hospitalizations of AL residents, and the resulting injuries may lead to a cascade of events, including worsening function, nursing home transfer, and death. A significant number of these falls occur in the bedroom during the evening and night, when AL staff are not present, thereby limiting their ability to intervene. However, the cause of many of these falls -- impaired nighttime vision and related postural instability -- suggests a promising avenue for intervention. Specifically, an intervention that does not require staff effort, and that targets orientation and postural stability in the evening and night when lighting is poor and residents may not be fully awake, has great potential to reduce falls in AL. This project will test the effectiveness of a novel intervention consisting of unobtrusive, low-intensity, horizontal and vertical lights that outline the bathroom or entry way doorframe in residents' rooms and provide visual cues to promote postural stability. The lighting system is particularly attractive and pragmatic because it is low cost, requires no staff involvement, and can be easily installed in new buildings or retrofitted to existing buildings. Specifically, this pragmatic crossover trial will enroll 390 AL residents with dementia and follow them for one year, comparing the incidence of nighttime falls during the lighting condition to the incidence of falls during the control condition; secondarily, it will determine whether and to what extent the intervention effect is modified by resident- and environmental-level risk factors, and satisfaction with the lighting system. We expect that the lighting system holds great promise to constitute a new standard of dementia care and falls reduction, appropriate for use in all settings in which persons with Alzheimer's disease and related dementias reside.

NIH Research Projects · FY 2026 · 2022-07

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NIH Research Projects · FY 2025 · 2022-07

Project Summary Alcohol abstinence is a key feature of the drinking experience, and relapse – by definition – is shifting from an abstained state to consumption. Many questions remain unanswered in the literature regarding the physiological mechanisms and neural signatures of abstinence, and understanding these substrates will be essential for developing prevention and treatment studies for Alcohol Use Disorders (AUD). The focus of the F99/K00 proposal is an investigation of central and autonomic nervous system effects associated with alcohol abstinence – in essence, how the brain responds to a period of imposed abstinence and how autonomic function impacts those responses. Before we can understand how neural processes associated with abstinence contribute to relapse in AUD patients, we need to understand what comprises a typical response, and the range of potential responses in otherwise healthy drinkers. Typically, physiological research examining alcohol drinkers focuses solely on brain function, discounting the interplay between central and peripheral nervous system measures. This study examining autonomic nervous system function, through the peripheral metric Heart Rate Variability (HRV), in addition to examine differences in functional brain network organization in everyday drinkers during a period of typical alcohol consumption and a period of abstinence. By examining the relationship between these central and peripheral measures, this study aims to capture a more complete understanding of the neurobiology associated with alcohol abstinence. At the time of this submission, the applicant, under the guidance of the sponsor, has completed all research design and data collection relevant to the study. Still remaining are analyses investigating the relationship between HRV and functional brain network connectivity during alcohol cue exposure following abstinence (F99 Phase), which will require hands‐on and didactic training analyzing HRV and brain network data. Following the completion of the F99 portion of this proposed project, the study will be expanded during a postdoctoral following to include more advanced analyses of brain network and HRV dynamics (K00 Phase).

NIH Research Projects · FY 2025 · 2022-07

PROJECT SUMMARY This is an application for a K23 award for Dr. Monica M. Diaz, a neurologist at the University of North Carolina at Chapel Hill School of Medicine. Dr. Diaz is establishing herself as an investigator in patient-oriented clinical research at the intersect of brain health and HIV in Latin America. Dr. Diaz has been based at least half- time in Peru since 2019 where she developed a mentored pilot study assessing HIV-associated neurocognitive disorder (HAND) in older people living with HIV in Peru. The K23 award will provide Dr. Diaz with the necessary support to develop expertise in 5 key areas: 1) Qualitative research methods and analysis, 2) clinical tool validation in international settings, 3) neuropsychological assessments, 4) advanced biostatistical skills, 5) implementation science frameworks and methodology. Dr. Diaz has assembled a team of core mentors (Dr. Gwenn Garden [expert in neurocognitive disorder assessments], Dr. Victor Valcour [expert in international assessments of HAND] and Dr. Clare Barrington [mixed-methods/qualitative research expertise in Latin America] who will guide Dr. Diaz in achieving her training goals and career development. Supporting Dr. Diaz and her core mentors are three collaborators: Dr. Maria Marquine (neuropsychologist with expertise in HAND in Latinos), Dr. Michael Hudgens (biostatistician with expertise in HIV observational data) and Dr. Patricia Garcia (implementation science expert on HIV in Peru). This multi-disciplinary mentorship team embedded within a highly collaborative training environment is crucial for Dr. Diaz’s development into an independent investigator with the goal of optimizing diagnostics and treatments for brain health in people with HIV in Latin America. HAND is a pressing issue in low-and-middle-income countries with increasing access to antiretroviral therapy, highlighting the urgent need to optimize diagnostics and prediction of HAND for early interventions. Dr. Diaz’s research plan outlined in this application leverages pilot data that demonstrated that nearly 30% of people living with HIV in Lima had HAND, yet diagnostics for HAND are limited in Latin America given a lack of regional normative data and experts in neuropsychological testing. The proposed research includes a prospective cohort of patients with HIV and HIV-negative controls from two socioeconomically-distinct HIV clinics in Lima. The study seeks to adapt and validate a tablet-based cognitive screening tool currently optimized for early Alzheimer’s screening to detect HAND in Peru (Aim 1). Known modifiable risk factors for cognitive impairment, including social determinants of health, will be used to build a predictive statistical model for HAND in Peru that can identify intervenable factors (Aim 2). These two tools will be implemented, evaluated and optimized through iterative rounds of interviewing with HIV care providers (Aim 3). This K23 award will provide Dr. Diaz with the mentorship and expertise necessary to become an independent investigator to improve brain health of underserved populations with HIV in Latin America. This proposal is a crucial step toward developing a large prospective study identifying frequency and risk factors for HAND in Latin America as a future R01 grant.

NIH Research Projects · FY 2025 · 2022-07

The objective of the proposed research is to improve the response to incident HIV infection by engaging the networks of people at most affected by HIV through a combination of Partner Services, social network recruitment, and HIV genetic cluster detection. Despite marked advances in HIV treatment and prevention, HIV incidence has not substantially declined in the Southern United States (US), highlighting the need for innovative methods to detect and respond to ongoing HIV transmission. While Partner Services can be highly effective, case finding remains limited even for persons diagnosed soon after HIV acquisition (acute or recent infections). Partner Services can also be limited in investigations across jurisdictional boundaries and in rural areas. We hypothesize that leveraging the social networks (social contacts rather than only drug sharing or sexual partners) of networks with recent HIV transmission will lead to improved engagement in HIV services (prevention or care). However, such strategies must be responsive to the barriers and facilitators to engagement in these services including a better understanding of social support networks. This project involves a multidisciplinary team including robust public health partnerships and active community engagement to address HIV prevention needs and build on existing resources. We will develop and implement an enhanced social network strategy (eSNS) for networks of people with new HIV diagnoses, including acute incident infection, in the high-burden Charlotte region (Mecklenburg County, North Carolina), situated on the border of South Carolina. Both areas are priority regions in the Ending the Epidemic (EHE) initiative. In the eSNS intervention, new diagnoses will receive rapid response Partner Services for elicitation of social and sexual contacts; selected contacts will be recruited and coached to recruit their peers to engage in HIV services. Aim 1 will employ regional genetic and contact network analysis of incident and prevalent HIV in North and South Carolina, to evaluate important connections (bridging) between states and between urban and rural areas. This granular data (contact, spatial, genetic) will expand epidemiological understanding of the epidemic to inform development of the eSNS and enhance local EHE strategies. To further inform eSNS development, Aim 2 will use a mixed methods approach to examine the barriers and facilitators of engaging members of networks with recent HIV transmission. Aim 3 will then evaluate the eSNS with effectiveness and implementation outcomes. Effectiveness outcomes (increase in testing, pre-exposure prophylaxis referral, and HIV care engagement) will be evaluated with regression point displacement design comparing outcomes pre/post intervention in Charlotte and in comparison, with the Raleigh region receiving standard of care partner services. Overall, the results of this project will lead to critical information to guide new strategies in Partner Services and in EHE responses to increase HIV care and prevention engagement among people with HIV in the Southern US.

NIH Research Projects · FY 2025 · 2022-07

Optogenetics has primarily employed light gated ion channels (derived from lower organisms) to trigger or inhibit the neuronal action potential. Analogous studies in the cardiovascular field have used these photoresponsive foreign proteins to regulate contractility and pacing. However, light gated ion channels are unable to interrogate the intracellular mechanisms that control behavior and homeostasis. As a consequence, we have developed a protein engineering strategy for creating light responsive analogs of endogenous proteins. The proposed research program is focused on the design, construction, and validation of optogenetic signaling for proteins that contribute to myocardial homeostasis, and the application of this technology to unravel the mechanisms that drive cardiac hypertrophy and fibrosis. Aim 1: Optogenetic Engineering to Access the Biochemical Pathways of Hypertrophy and Fibrosis. We will employ a novel optogenetic engineering strategy to create light responsive signaling cascades localized at specific intracellular sites, with a focus on cAMP-mediated signaling pathways. Aim 2: Light Guided Mapping of the Signaling Domains that Mediate Hypertrophy. The optogenetic constructs outlined in Aim 1 will be used to explore the impact of signaling events at distinct intracellular locations on cardiomyocyte behavior, with an emphasis on hypertrophic relevant responses. Aim 3: Light Guided Mapping of the Intercellular Communication that Mediates Fibrosis. Optogenetic analogs of endogenous proteins will be used to assess intercellular crosstalk between two distinct cardiac cell types. Light- triggered activation of engineered signaling pathways offers the opportunity to tease apart a collaborative signaling network that has been observed between these distinct cell populations.

NIH Research Projects · FY 2024 · 2022-07

Project Abstract/Summary The goal of this proposed F32 postdoctoral fellowship is to provide the applicant with a multi-disciplinary training experience in genetic epidemiology and nutrigenetics analysis. The applicant will engage in advanced scholarly activities to understand genetic and nutrigenetic influences on the susceptibility to, and severity of, developmental delays and traits that the constitute fetal alcohol spectrum disorders (FASD) continuum. The overarching aim of this application is to characterize the effect of maternal nutrition, maternal and child genetic predisposition, and maternal diet-by-genetic interaction as it relates to the child's physical dysmorphology, neurodevelopmental abilities, and FASD diagnosis. This application capitalizes on previously collected biological samples (circulating plasma concentrations) and genetic data from pregnant women in the Western Cape Province of South Africa whose offspring have been followed since birth with standardized dysmorphology and neurodevelopmental assessments. This project will (1) determine whether maternal nutrient status mediates the relationship between alcohol exposure and child growth, dysmorphology, and neurocognitive outcomes; (2) develop a polygenic risk score associated with FASD diagnosis; and (3) determine whether there is a choline-related diet-by-gene interaction which partially explains the susceptibility and severity of an FASD diagnosis. Key components of the training plan include advanced instruction in genetic epidemiology and nutrigenomic theory and applied statistical analysis. Specific skills to be mastered during this fellowship include: (1) quantitative analytic skills in the genetics of complex diseases; (2) advanced training in nutrigenetics data analysis; and (3) enhancement of leadership and grantsmanship skills. The proposed fellowship will enable these goals through carefully selected coursework, research experiences, seminars, and workshops. Collectively, these will provide an unparalleled opportunity to gain the advanced skills before applying the methods and techniques to important, yet largely unanswered questions about the etiology of FASD. This application provides a rich training environment to carry out the research plan. The proposed research plan will facilitate the applicant's transition into an independent investigator by establish the applicant's expertise in genetics and nutrigenetic analysis and applying this expertise to determining nutritional, genetic, nutrigenetic influences on the susceptibility and severity of an FASD diagnosis, an area of research remains vastly uncharacterized within the field of FASD.

NIH Research Projects · FY 2025 · 2022-07

Abstract Biology is driven through the action of proteins. We know that structure often provides the foundation for proteins’ function, but in recent years it has become clear that protein function is also critically dependent on dynamics, or movements of structure. How dynamics enables function is now a central question in protein biology that limits our basic understanding of proteins, as well as applications in drug discovery and protein design. While there are many types of functions that dynamics – or conformational flexibility – promotes, two functional archetypes for dynamics are enzyme catalysis and allostery. The mechanistic bases for these two phenomena, pervasive as they are, remain largely mysterious and have attracted much attention for the likely role of dynamics. The Lee laboratory has focused on studying dynamics and allostery in proteins using NMR and other biophysical methods for nearly 20 years. The approach outlined in this proposal is to combine investigation of natural allosteric enzymes (Areas 1 and 2) with efforts to engineer allosteric regulation into signaling proteins using optogenetics (Area 3). In the last five years, the lab has developed two complementary systems for NMR and biophysical studies of dynamics and allostery that are highly amenable for addressing these mechanistic questions and, importantly, developing approaches to study intersubunit allosteric communication. The two systems are the enzymes chorismate mutase (CM) and thymidylate synthase (TS), both symmetric homodimers that are functionally allosteric. CM (from yeast) is a classically allosteric protein, exhibiting all the hallmarks of traditional allostery: sigmoidal activity curve; symmetric quaternary structure; tense (“T”) and relaxed (“R”) conformations; and small molecule allosteric effector ligands that either up- or down-regulate activity. In contrast to CM’s positive cooperativity, TS is negatively cooperative because it is half-the-sites reactive. Work will be on the E. coli (ecTS) and human (hTS) forms, which, despite their similarities show very different behaviors. The human TS is the target of anticancer drug 5-fluoro-uracil (5-FU). CM, ecTS, and hTS all have outstanding features for study by solution NMR since they are highly soluble, stable, and yield excellent spectra. The goals for the next five years fall into three main areas: (1) Through the use of NMR spectroscopy, molecular dynamics simulations, calorimetry, x-ray crystallography, and biochemistry, the structural and dynamic properties of these enzymes will be related to functional behaviors of key interest, such as: allosteric communication; how apo state conformations compare to T and R conformations; protomer asymmetry in singly liganded states; and the nature of the transition state. (2) We will advance the study of protein homodimers by NMR by introducing a technology for chemical conjugation of protomers using click chemistry. Mixed labeled dimers produced this way will facilitate NMR study of interprotomer interactions, such as allostery, and improve NMR structure determination of homodimers. (3) For engineered GTPases that have been artificially placed under optogenetic control, the allosteric mechanisms will be determined using an NMR approach.

NIH Research Projects · FY 2025 · 2022-07

PROJECT SUMMARY This is a competing renewal application for the North Carolina Occupational Safety and Health Education and Research Center (NC OSHERC). Our unique Center builds upon the strengths of the occupational health and safety (OHS) education and research programs at the University of North Carolina at Chapel Hill, Duke University, and North Carolina State University. Nearly 62% of US adults are employed, and work exerts an independent, powerful influence on their health and safety. As we conducted needs and strengths assessments in preparation for this Center proposal, we saw how the COVID- 19 pandemic created a massive re-shaping of work, work conditions, and worker health, particularly related to safety, mental health, and well-being among essential and underserved workers. This observation has strengthened our joint efforts with both our regional Education and Research Center colleagues and other OHS partners to serve the emerging needs of occupational health professionals and the diverse workforce. The guiding mission of the NC OSHERC is to provide high- quality education and research training in the OHS sciences for the protection and promotion of worker health and well- being and to prevent occupational illness and injury in North Carolina, the southeast region, and the nation. To fulfill this mission, our goals are to (1) train future leaders to meet the nation’s OHS research needs and NIOSH priority goals and (2) bridge the gap between the innovative research being conducted in OHS within the regional universities and the needs of the region’s workforce. We will accomplish these goals through interdisciplinary OHS training, research, and service. The proposed education and research program’s specific aims are to: 1. Train practitioners, educators, and researchers in the academic disciplines of occupational exposure science and industrial hygiene, occupational medicine, safety and ergonomics, occupational epidemiology, and Total Worker Healthâ, with a specific focus given to training diverse, underrepresented, and minority practitioners and researchers. 2. Provide interdisciplinary learning experiences through coursework, practice and field projects, research activities, and seminars. Academic training and targeted research training programs guide trainees to develop skills in scientific inquiry and research to practice (r2p) to mitigate and eliminate hazards and improve working conditions. 3. Provide outreach and continuing education training programs to meet the needs of practitioners and OHS stakeholders. 4. Fund pilot research projects to support the development of young investigators and advance OHS science. The NC OSHERC is uniquely positioned to increase capacity and address the future challenges of OHS training, research, and preparedness in the Southeast and the nation by training diverse OHS practitioners and professionals in the challenging interdisciplinary OHS field and by fostering greater collaboration between academic researchers, local, state, and federal occupational professionals, as well as business and industry sector stakeholders. The NC OSHERC’s overall program responds to mandates in the OSHA Act, section 2(b)(5) and addresses the National Occupational Research Agenda (NORA) 2019 – 2024 priorities and critically important OHS issues in the NORA sector and cross-sector areas.

NIH Research Projects · FY 2025 · 2022-06

PROJECT SUMMARY/ABSTRACT The current COVID-19 pandemic is disproportionately affecting Black and Latino individuals and increasing existing health disparities. These racial/ethnic populations are facing magnified stress and lack access to patient- oriented health services. Thus, utilization of Digital Health Platforms (DHP) has the potential to address reach, delivery, effectiveness, scalability, and sustainability to decrease COVID-19 related stress in these populations. The proposed study builds on our previous DHP, the Biofeedback Assisted Resilience Training (BART), that targeted improving physiological metrics of Heart Rate Variability (HRV) as a measure of autonomic regulation to manage stress in service members. Now, we incorporate UNC Health patient portal (UNCH- PHRs), Mindfulness-Based Stress Reduction program tailored for COVID-related stress, wearable heart rate sensor, and mobile health app (mHealth) to collect physiological and psychological scales of mental health, into our DHP model to deliver a culturally sensitive Stress Management Intervention Leveraging Electronic health records (SMILE). The overall objective of this proposal is to investigate effectiveness and sustainability of our DHP model, to delineate mindfulness-related mechanisms of action by measuring changes in psychological self-reported metrics and autonomic balance using HRV, and to examine associations between COVID-19 related stress and mental health outcomes, resilience, and HRV. Understanding these interrelationships with a focus on racial/ethnic groups is of utmost importance to provide personalized treatment. The central hypothesis is that SMILE will mitigate COVID-19 related stress. We will test our central hypothesis with a 3-arm randomized controlled trial. Participants will be randomized to one of three arms: 1) an internet-delivered, instructor- administered Mindfulness-Based Stress Management training (MTIA), 2) self-administered Mindfulness training through the commercially available mHealth app Headspace (MAPP), or 3) Waitlist control (WLC). The DHP will capture progress at various points of the study (baseline, weekly during the 08 weeks and at 3-months follow- up). Our rationale is that our DHP model enables access to a wide range of populations, facilitating the promotion and delivery of targeted DHP interventions, such as mindfulness, while collecting psychophysiological metrics to assess treatment efficacy and predictors of mental health. The broader impact is that our proposed DHP could be used to assess new treatment effects and increase health equity for racial/ethnic populations.

NIH Research Projects · FY 2025 · 2022-06

7. PROJECT SUMMARY/ ABSTRACT In traditional predictive genetic testing single gene variants are analyzed to determine whether an individual is at high risk of developing a disease. The vast majority of diseases, however, are polygenic—caused by many different genes. Polygenic risk scores (PRS) have been heralded for their promise to predict risk for these more complex diseases like heart disease or diabetes by measuring the contribution of hundreds or thousands of genetic variants at once. Yet beyond prediction of health or medical outcomes, the realm of `sociogenomics' is developing polygenic scores (PGS) measuring genetic contributions to social traits and behavioral factors, such as income, educational attainment, sexuality, and optimism. Proponents of sociogenomic PGS cite the potential for this research to increase understanding of the interplay between genetic and environmental factors, to account for genetic factors in social science research, and to create personalized social interventions akin to personalized medicine. But others worry that sociogenomic PGS findings could lead to discrimination and an exacerbation of existing social disparities. In order to understand the ethical, legal, and social implications of sociogenomic PGS research and its outcomes, this project addresses the following research questions: 1) What are the current trends in the development of sociogenomic PGS and what are the possible applications of scores in social settings?; 2) How do various stakeholders perceive the benefits and risks of sociogenomic PGS?; and 3) How well do existing laws, policies, or governance protect against the potential harms of sociogenomic PGS while also promoting their potential benefits? Answering these questions requires both empirical research and legal analysis. Using horizon scanning methodologies, Aim 1 maps the landscape of sociogenomic PGS, their potential applications, and how sociogenomic research findings are presented to and consumed by the public. Aim 2 enlists those involved in the pipeline of sociogenomics research (biobank participants whose genetic data may be used to develop PGS, PGS researchers who develop the scores, and social scientists who may use the scores in their research studies) to examine and assess their attitudes toward the range of harms and benefits of sociogenomic PGS, and the implications of varying applications of PGS. Both of these efforts will inform Aim 3, which consists of a legal and policy analysis of how current legal rules protect against potential misuse and/or promote possible benefits of sociogenomic findings. The product of this project will be a set of case studies designed to help policy makers and researchers anticipate and mitigate the potential harms of employing sociogenomic PGS in various social settings while still identifying and maximizing potential benefits.

NIH Research Projects · FY 2024 · 2022-06

Modified Project Summary/Abstract Section Improved linkage to and uptake of pre-exposure prophylaxis (PrEP) is critical to end the HIV epidemic in the United States (US). Despite PrEP’s high efficacy, less than 20% of PrEP-eligible people have received a prescription and gaps in uptake expose differences by region and subgroups. In 2018, the US South accounted for more than half of all new HIV diagnoses but only one-third of PrEP users. PrEP use in North Carolina (NC) similarly lags, with uptake lowest among the highest incidence populations, including men who have sex with. Among NC counties with the highest rate of HIV diagnoses, four have rural designation and nine are small or medium metropolitan areas. NC’s HIV epidemic thrives alongside rising sexually transmitted infections (STI), which are also frequently concentrated in rural areas. Despite behavioral risk overlap of incident STIs and HIV, in NC, PrEP is only offered at a few, primarily urban health department (HD) affiliated STI clinics. The lack of robust healthcare infrastructure in rural areas and lack of PrEP knowledge among providers and rural persons vulnerable to HIV present unique challenges for HIV and STI prevention. Leveraging HD-affiliated STI clinics as an on-ramp to PrEP is an ideal opportunity to capitalize on STI service encounters and increase PrEP access. A pathway to PrEP that utilizes existing clinic infrastructure to identify potential PrEP users, adapts services to ameliorate clinic constraints, and tailors PrEP engagement tools to specific client needs is a compelling strategy to improve PrEP access, uptake, and persistence in rural NC. This multilevel intervention to link PrEP and STI services, addresses barriers at policy, clinic, provider, and user levels. The strategy builds capacity and confidence via clinic training; facilitates patient handoff to navigators for linkage to financial support; and uses an evidence-based digital health platform, connecting users to peer educators, PrEP resources, and telehealth providers. The overarching objective is to parlay episodic STI service encounters into linkage to convenient, continuous PrEP care in NC. This objective will be accomplished in four aims. In Aim 1, investigators conduct a randomized trial at eight rural and peri-urban HDaffiliated STI clinics, enrolling persons into the above-described intervention or control based on enrolling clinic group assignment. The primary outcome is PrEP uptake within 3 months of clinic visit. In Aim 2, investigators conduct a cost-effectiveness analysis, including a budget impact analysis, examining cost per new PrEP initiation. If pre-defined go/no-go criteria are met, Aim 3 will proceed by engaging key stakeholders to refine the intervention, using an Intervention Mapping framework and informed by effectiveness outcomes and cost levers. Finally, in Aim 4, the refined intervention will be expanded to all eight clinics to examine impact on PrEP uptake and finalize cost estimates. If successful at increasing PrEP use and cost effective for increasing PrEP uptake and averting HIV infections, this intervention can be adapted and scaled up to STI clinics across NC and other rural and peri-urban areas in the US.

NIH Research Projects · FY 2025 · 2022-06

PROJECT ABSTRACT Weight gain is disproportionately high among young adults (YAs) with average weight gain of 30 lbs. occurring between ages 18-35 and is associated with an early worsening of CVD risk factors. Primary prevention of weight gain is important because weight loss is difficult to achieve, access to programs is limited, and initially successful people regain weight over time. Weight gain is a serious problem in the Department of Defense, our nation’s largest employer, with more employees than Walmart or Amazon. The military, comprised largely of YAs, has growing rates of obesity and yearly weight gain. Many people believe that young, active-duty men and women are fit, lean, and healthy because of the military lifestyle and protected from obesity. Unfortunately, obesity rates in active U.S. military personnel have mirrored those of civilians. Furthermore, inability to maintain a healthy weight results in early discharges and threatens the readiness of well-trained Airmen to be deployed. Overweight in the military is now considered a threat to national security. Few weight gain prevention (WGP) trials have been done in military populations, and previous trials with YAs have mixed results and poor external validity. Our proposal is designed to address the major public health problem of weight gain in the military, as well as address notable gaps in pragmatic mHealth and WGP trials. The SNAP- M intervention will be adapted, with partners and key stakeholder from the US Air Force, from our evidence- based WGP intervention for YAs, the Study of Novel Approaches to weight gain Prevention (SNAP). SNAP tested 2 self-regulatory interventions in 599 general population YAs and found that both reduced weight gain over 2-3 years compared to controls. This project proposes to make 1) critical adaptions to SNAP to facilitate translation and 2) conduct a Pragmatic Hybrid Type 1 Effectiveness Trial of the SNAP-M intervention using a 2-group randomized controlled trial (RCT) design in 454 Air Force Airmen recruited from 4 military installations with the primary outcome of mean weight change from baseline to 2 years. We will compare the groups on key outcomes and examine potential moderators of treatment effect. Additionally, we will apply a RE-AIM Framework to determine reach and representativeness, and potential for organizational-level adoption, implementation, and maintenance of SNAP-M, if successful. The proposed research fills key research gaps in an underserved population in critical need of weight gain prevention with completely remote delivery suitable for YAs in the military.

NIH Research Projects · FY 2025 · 2022-06

ABSTRACT Among young adults (18-24 years), a concerning 10-20% develop advanced but asymptomatic atherosclerotic lesions, yet cardiometabolic disease (CMD) prevention is understudied. In the U.S. two-thirds of young adults attend college, during which they adopt poor lifestyle behaviors that contribute to CMD risk. For example, college-based young adults (CBYA) engage in sedentary behavior (SB), defined as very low intensity behaviors in a seated, reclined, or supine postures, for ~7 hr/day. National and international public health agencies have recently called on the research community to better understand how to implement SB-reduction strategies. However, while CBYA present a captive but understudied population, we have scant understanding as to how to target this multi-dimensional behavior. Our long-term goal is the primary prevention of CMD in CBYA. To support this goal, the overarching aim of this proposal is to develop an evidence-based, multi-level intervention to target SB reduction. This longitudinal observational study will recruit a cohort of 500 CBYA (18-24 years) from a representative state college population. On each of the two visits (12 months apart) we will measure traditional and novel CMD risk biomarkers and administer participant questionnaires to collect information on lifestyle behaviors (diet, chronotype, substance use) and socio-ecological (individual, intra-individual, inter-individual) predictors of SB. Over the next 7 days, SB quantity will be captured using a thigh-worn inclinometer, and physical activity and sleep behaviors using accelerometry. SB context (television, transportation, academic/occupational, leisure computer, other) will be measured using ecological momentary analysis. Aim 1 will identify whether total SB (T-SB) or context-specific SB (CS-SB) is more strongly associated with CMD risk. The degree to which SB confers CMD risk likely depends on the context in which it occurs. For example, in the general adult population, television viewing is more strongly associated with CMD than other CS-SB. The reasons are unknown but may include the greater likelihood of co-occurring unhealthy behaviors (e.g., processed foods) while watching television. Therefore, Aim 2 will identify how much CMD risk is explained directly by SB, versus indirectly mediated by co-occurring lifestyle behaviors. Aim 3 will then identify multi-level intervention targets. To date, the existing longitudinal research has predominantly focused on non-modifiable socio-demographic variables. We will use a socioecological model to identify modifiable predictors. Last, will use the Intervention Mapping protocol to design an intervention implementation and evaluation plan. This innovative proposal will enhance our understanding of the importance of CS-SB and co- occurring behaviors to CMD risk. The final product will be an evidence-based CS-SB reduction intervention to target primary CMD prevention in CBYA. The likelihood of future high impact is enhanced by: college campuses are relatively contained are well-suited to multi-level interventions; behaviors adopted during college track into older adulthood; and our experienced multi-disciplinary team.

NIH Research Projects · FY 2025 · 2022-06

Injury-related fear after anterior cruciate ligament (ACL) injury significantly contributes to decreased return to sport, decreased physical activity engagement, and increased ACL reinjury risk in previously high functioning, physically active individuals. Injury-related fear is also associated with poor jump-landing movement patterns in patients after ACL reconstruction (ACLR). Unfortunately, current rehabilitation practices do not specifically address injury-related fear in patients after ACLR. Virtual reality mindfulness meditation is a mental practice that involves focusing your mind on your experiences in the present moment and has been used to address depression, anxiety, and chronic musculoskeletal pain. Additionally, mindfulness meditation has led to positive changes in brain activity in individuals with depression, anxiety, and chronic musculoskeletal pain. Patients after ACLR exhibit poor brain activity similar to individuals with depression, anxiety, and chronic musculoskeletal pain; thus, patients after ACLR may also benefit from mindfulness meditation. To evaluate the effect of virtual reality mindfulness meditation on patients after ACLR, we will determine the effect of virtual reality mindfulness meditation to 1) decrease self-reported injury-related fear, 2) improve poor jump-landing movement patterns, and 3) improve brain activity in women 9-months post-ACLR when compared to a virtual reality sham group. Injury-related fear and poor jump-landing movement patterns have been associated with ACL reinjury risk. Women were selected for this study as previous literature has demonstrated sex differences in brain activity and women also have a higher incidence of ACL injury and ACL reinjury risk. All patients in the study will complete an 8-week advanced rehabilitation training program to improve lower-body muscle strength, power, and flexibility. Patients in the intervention group will complete 8-weeks of virtual reality mindfulness meditation + the advanced rehabilitation training program. Patients in the sham group will complete 8-weeks of the virtual reality sham + the advanced rehabilitation training program. The central hypothesis is that women 9-months post ACLR who undergo virtual reality mindfulness meditation will demonstrate decreased injury-related fear, improved jump-landing movement patterns, and improved brain activity. The findings from this proposal will address a gap in knowledge about effective psychological interventions to address psychological and biological factors associated with ACL reinjury risk. This proposal also positions an aspiring independent clinician scientist training to learn neuroimaging techniques and complex movement pattern data collection and analyses. With this training, the primary investigator will examine the efficacy of virtual reality mindfulness meditation to mitigate injury-related fear, decrease ACL reinjury risk, and improve quality of life in patients after ACLR throughout her career as a clinician scientist.