Emory University

NSF Awards · FY 2025 · 2025-10

With support from the Chemical Structure and Dynamics (CSD) program in the Division of Chemistry, Professor Michael Heaven at Emory University and Professor Richard Mawhorter at Pomona College are conducting gas phase high-resolution molecular spectroscopy measurements of candidate molecules to probe their potential to advance the search for physics beyond the standard model (BSM). The remarkably successful standard model cannot explain the imbalance of matter and anti-matter in the universe. Violations of molecular symmetry properties, detected by precision spectroscopic measurements, can provide critical tests of proposed BSM theories. One challenge for this approach is that the molecules must be cooled to nearly absolute zero (ultracold) to achieve the required measurement accuracy. A second challenge is that the BSM effects will be largest for molecules that include a heavy atom. Such molecules usually exhibit congested and complicated spectra. Consequently, many theoretically promising molecules have not been characterized in laboratory studies. Professors Heaven, Mawhorter and their students will carry out experimental studies of three classes of heavy element-containing molecules. The objectives are to identify the most promising candidates for BSM measurements and to obtain the spectroscopic data needed for the design of the experiments as well as to determine how to accomplish the cooling, state preparation and state read-out. The educational impact of this program is that it provides excellent training for graduate students, and research experience opportunities for undergraduate students. The experiments involve advanced instrumentation, and interpretation of the results requires the application of high-level theoretical methods. Several laser-based spectroscopic instruments will be applied. The available techniques include laser induced fluorescence, dispersed laser induced fluorescence, two-photon ionization and anion photodetachment. The first group of molecules to be examined is YbNH2, YbCH3 and YbSH. Preliminary data for YbNH2 and YbCH3, and calculations for YbSH indicate that they are promising for direct laser cooling. Electronic transition energies, fluorescence branching ratios and low energy metastable states will be characterized. The second group of molecules, YbF- and the group IIA oxyfluoride anions (OMF-) may be cooled using external electric fields and then converted to neutral molecules by means of photodetachment. For this scheme the bond dissociation energy of the anion must exceed the electron affinity of the neutral. Tests for this condition will be conducted using anion photodetachment spectroscopy. Lastly, diatomic molecules consisting of Cu, Ag or Au bound to Yb will be examined. These molecules may be formed at ultracold temperatures by photoassociation. The spectroscopic data needed for the design of such ultracold synthesis experiments will be sought using laser ablation techniques to generate the target molecules at higher temperatures (5-20 K). This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-10

Today’s information technology hardware uses the silicon transistors developed 70 years ago. However, applications such as Artificial Intelligence (AI) can be optimized by different types of elements naturally modelling neurons in human brain. The project will advance such elements implemented by magnetic heterostructures, where information is carried by coherent microwave-frequency magnetization dynamics. In the proposed project, these dynamics will be driven by the Rashba spin-orbit torque – a torque exerted on the magnetization due to the spin-orbit interaction at electrically biased interfaces between materials. The material properties of the interfaces will be engineered to maximize the device efficiency, while the geometry and the magnetic properties of the devices will maximize the dynamical coherence. The heterostructures will be incorporated into a new device architecture enabling the detection of voltage transverse to the current, which will produce larger signals and will be compatible with a wider range of materials than the usual longitudinal voltage detection. By integrating engineering with the fundamental questions about the mechanism driving magnetization dynamics, the project will impact both the nanomagnetic technologies and the scientific understanding of spin-dependent phenomena at interfaces. The project will also include innovative undergraduate STEM course development, and PI-STEM teacher partnership with a local elementary school, adding much-needed hands-on activities and engagement to the science curriculum. Magnetic nano-oscillators driven by spin Hall effect (SHE) - the spin Hall nano-oscillators (SHNO) – find applications in microwave generation, neuromorphics, and magnonics. However, they suffer from low coherence due to small oscillation volume, large Joule dissipation due to the high resistivity of efficient SHE materials such as heavy metals, and small output signals produced by anisotropic magnetoresistance (AMR). The goal of the proposed research will be to develop approaches that can overcome these limitations. First, heterostructures with large interfacial spin-orbit torques (SOTs) driven by the interfacial Rashba effect will be developed, without SHE source metals. By obviating the need for current to pass through metallic SHE sources, Joule dissipation will be reduced and the output power of oscillators will be increased. Large built-in effective interfacial electric fields – the basis for the Rashba effect – will be achieved by engineering graded oxidation or nitridation of the interfaces. Second, the net magnetic anisotropy will be minimized by magnetic heterostructure engineering. This will enable oscillation of large magnetic volumes, resulting in increased coherence. Third, larger output will be generated using anomalous Hall effect (AHE) instead of AMR, which will be compatible with a wider range of materials including antiferromagnets. The SOTs in the developed heterostructures and devices will be characterized by the nonlinear harmonic mixing technique, SOT-ferromagnetic resonance, and by microwave spectroscopy. In addition to magnetic nano-oscillators, the developed approaches will benefit other applications of SOTs, such as magnetic random access memory and magnetic memristors. The project will contribute to training of high-tech and academic workforce, integrate outreach to elementary school, and develop a novel freshman hands-on course providing a pipeline for increased STEM major enrollment. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-10

NON-TECHNICAL SUMMARY The history of spin glasses is a fascinating study into the intellectual power of statistical physics and its far-reaching consequences, especially for the understanding of complex materials. Once devised as an abstraction of some rare materials with peculiar magnetic properties, they have become a foundation for the study of complexity in some of the hardest computational problems in the sciences and engineering: from memory and learning in neural networks such as the brain or in artificial intelligence, to the structure and dynamics of a very broad range of real amorphous materials – granular, colloidal, polymeric, or magnetic. Their wide-ranging importance has been recognized with the 2021 Nobel Prize in Physics. An "Ising" spin glass is a simple model in which the spin variables can take on merely two values, up or down (+/-), similar to a bit (0/1) in a computer. By coupling each pair of these variables with a randomly selected positive (enhancing) or negative (suppressing) bond, it becomes an elementary model of a glass, i.e., a disordered amorphous material that fails to condense into a regularly ordered, crystalline state on cooling. Since finding such ground states is among the hardest known computational problems in science, their low-temperature properties are still poorly understood. While a mean-field theory of spin glasses that is mathematically tractable but ignores spatial embedding is well developed, results for real glasses that exist in 2 or 3 dimensions (thin films or bulk materials, respectively) are in contradiction with this theory. This project applies exact and approximate algorithms to find ground states of Ising spin glasses and explore the low-temperature properties of disordered materials. The methods to be developed will allow us to bridge the gap between the mean-field theory and those real-world materials. Specifically, the algorithms that will be developed can interpolate the behavior of physical quantities characterising the spin glass ground state between the finite-dimensional case and the regime described by the theory. Gaining such insights is a worthwhile goal because the very complexity that makes these materials hard to study in turn allows to employ them for efficient storage and processing of information at many levels. Broader impacts will include the applicability of the abovementioned algorithms to computationally-hard optimization problems in other fields of science & engineering, and training two Ph.D. students annually. TECHNICAL SUMMARY In this project, the research team will focus on applying exact algorithmic as well as efficient heuristic methods the PI is currently developing to explore the low-temperature properties of the complex energy landscape associated with Ising spin glasses. The scaling of finite volume corrections will be employed to study as-of-yet-elusive geometric aspects of low-energy excitations of finite-dimensional glasses, both with and without an external field. In its own right, a direct measurement of the structure and the energetics of droplet excitations near the ground state, a fundamental task for these glassy materials, will provide essential input for many ongoing theoretical and experimental studies. In particular, this project will allow calculation of their fractal exponent and, in the process, determine their energy barriers with significantly improved accuracy. The self-overlaps of systems in an external field at zero temperature will be measured; such overlaps have been the focus of much recent theoretical work. The efficiency of the computational methods will allow to make direct connection between real-space systems and mean-field theory at the upper critical dimension to test recent theoretical predictions. These are unique capabilities of the algorithm that will provide transformative results for the study of spin glasses. Its development entails a foray into the non-equilibrium dynamics of spin glasses and relaxation in complex energy landscapes, generally. The insights gained from these investigations will motivate and guide theoretical inroads towards extending exact solutions of spin glass models beyond mean-field limits to structured systems. The efficient heuristic methods for hard combinatorial problems that will be developed in this project are of broader utility within the science and engineering community. They have the ability to find good solutions for many technical problems, such as in scheduling, routing, and packing. Our alternative heuristic approach will challenge the dominance of commercial solvers, supplying researchers with a publicly-available option. In the process, these research projects provide the training of PhD students who are the bedrock of an innovation-driven society intent on sustaining its competitive edge in science and technology. STATEMENT OF MERIT REVIEW This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-10

This project aims to advance machine learning methods for discovering cause-and-effect relationships in complex systems. While much of modern data science focuses on identifying patterns and correlations in data, such associations cannot explain why events happen or how changing one factor might influence another. Causal discovery addresses this fundamental challenge by revealing the mechanisms behind observed phenomena, enabling more informed decisions, reliable predictions, and targeted interventions across fields such as healthcare, economics, engineering, and public policy. Despite recent AI advancements, determining causality from complex, large, noisy or incomplete datasets remains challenging. This research tackles that challenge by developing new theoretical models and analytical tools that target both specific causal inference and broader causal structure discovery. By integrating approaches from statistics, computer science, and mathematics, this work seeks to create AI systems that are more transparent, interpretable, and scientifically grounded. The anticipated outcomes are expected to significantly advance multiple fields by fostering interdisciplinary collaborations and paving the way for future discoveries in causality and data-driven problem-solving. To address the challenges of causal discovery and inference in the presence of missing, incomplete, or limited data, the project is organized around three closely connected research thrusts: (1) Causal Inference in the Presence of Unmeasured Confounders, which will focus on identifying causal effects as functions of observed data and estimating them robustly in the presence of hidden variables; (2) Differentiable Causal Graph Learning from Partially Observed Data, which will develop scalable, optimization-based methods for learning causal structures when data are noisy or partially missing; and (3) Causal Inference and Modeling Amid Insufficient Data via Large Language Models (LLMs), which will leverage the vast scientific knowledge embedded in literatures and databases to guide discovery when observational data are sparse. The proposed LLM-powered framework will extract relevant insights from external sources to validate assumptions or suggest modifications to the structure of causal models, enabling a novel fusion of data-driven algorithms and knowledge-based reasoning. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-10

Part 1: This project employs modern social science methods to investigate the micro-foundations of deterrence, providing rigorous, causal evidence on the effectiveness of different strategies. Deterrence is a critical component of security, yet there remains significant uncertainty about when and how defensive actions can prevent conflicts from escalating. By integrating quasi-experimental designs, randomized controlled trials, and artificial intelligence data collection and analysis, the project generates insights into how resolve is built, communicated, and interpreted in real-world contexts. These findings not only contribute to academic debates but also inform decision makers in the United States and allied nations about the conditions under which deterrence strategies succeed or fail. This project empirically tests key aspects of deterrence theory with attention to causal inference. First, it examines the effects of a real policy reform, using a quasi-experimental design to assess how the reform shapes resolve. Second, a field experiment evaluates how participation in civil defense training programs influences perceptions of national identity, efficacy, and deterrent capability. Third, the project leverages survey experiments to measure the credibility of deterrent signals, as well as whether key actors in potential aggressor states accurately perceive these signals. Lastly, the project uses artificial intelligence to collect and analyze data to assess the structure and timing of deterrence-related communication, including official statements and mass sentiment across digital platforms. The theoretical frameworks and methodological innovations are broadly applicable to many conflict-prone regions. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY According to the CDC, approximately 1.7 million people in America develop sepsis, an uncontrolled bacterial infection, each year where the financial burden is estimated to be $62 billion annually in hospitalizations and nursing care. Sepsis is a global threat with no specific treatment options. A key feature of sepsis is the breakdown of endothelial cell barrier function. Endothelial cells line blood vessels and act as the primary barrier for exchange of fluid, waste, and nutrients between the blood and tissue. Baseline permeability of the endothelial barrier is vessel dependent, where permeability is low in arterioles and high in post-capillary venules. Endothelial barrier permeability is regulated through the apical junctional complex composed primarily of tight junctions and adherens junctions. Tight junction proteins, specifically claudins, directly regulate permeability of the endothelial barrier where claudin11 is expressed in a venous specific manner, making it a focus of this study. Maintenance of vascular homeostasis is important in preventing the pathologic consequences of disease, including sepsis, which occurs from a dysregulated inflammatory response to infection. This dysregulated immune response induces changes in endothelial barrier function making the molecular mechanisms underlying endothelial barrier function crucial for development of novel therapeutics. Recent work has demonstrated that TNF, a contributing factor to inflammation in sepsis, causes a defect in venous endothelial barrier function that is mediated through a pannexin1-dependent pathway. The central hypothesis of this proposal is that the tight junction protein cldn11 forms a signaling hub with pannexin1 that regulates barrier function in response to inflammation. I will test this hypothesis in two aims: Aim 1 will investigate protein composition changes in response to pro- inflammatory cytokines using BioID; Aim 2 will examine changes in vessel permeability in response to pro- inflammatory cytokines measured by changes in transendothelial resistance, immunoblot, and immunofluorescence. A long-term goal of this project is to identify potential therapeutic targets that promote endothelial cell barrier function that would otherwise be compromised as a result of inflammation and sepsis.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Alarming increases in both type 1 and type 2 diabetes have been observed among youth in the United States over the past decade. There is an urgent need for a comprehensive surveillance system to monitor the prevalence, incidence, and complications of diabetes among youth and young adults, while evaluating disparities and contributing factors. However, national surveys lack sufficient data on youth and young adults to support rigorous diabetes surveillance. The recent development of the EPIC COSMOS database—which includes EHR records from over 289 million unique individuals, encompassing more than 60% of U.S. residents across all 50 states—offers an unprecedented opportunity to build a nationwide young-onset diabetes surveillance system. The rich data elements within COSMOS—including demographics, biomarkers, diagnoses, prescriptions, and social determinants of health—allow for accurate identification of diabetes cases and examine disparities in risk factors, complications, and medication use in diabetes. Given our strong experience as a leading user of the COSMOS network, we propose to develop a nationwide diabetes surveillance system based on this database, in response to CASSIDY’s RFA (Component A). The detailed aims are as follows: Aim 1: Refine the DiCAYA CP algorithms for automated identification of prevalent and incident cases of type 1 and type 2 diabetes among youth and young adults. Aim 2: Estimate the prevalence and incidence of type 1 and type 2 diabetes. Aim 3: Assess the risk factors for diabetes complications, the onset of acute and chronic complications, and the use of diabetes medications among youth and young adults with diabetes. Dissemination: We will work closely with the CDC and coordinating center to (1) adopt a CDM for data analysis and sharing across centers, and (2) disseminate study results through EPIC stakeholders and nationally by contributing to the CDC’s National Diabetes Statistical Report and high-impact scientific publications.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Neurodevelopmental disabilities among autistic people are an increasing public health concern in the U.S. Current prevalence estimates indicate that 1 in 31 school-aged children have autism, and the increase in recent decades strongly supports environmental factors as key contributors. However, there have been no systematic studies of complex environmental exposures contributing to the likelihood of developing autism. Leveraging a powerful untargeted high-resolution mass spectrometry (HRMS) approach and two large, multi-site autism studies from the U.S. that already include extensive genetic, omics, questionnaire, targeted exposure, and phenotype data, we will create the largest exposome database for autism and an Autism Exposome Atlas well-powered for foundational discovery analyses of non-genetic factors driving autism outcomes, including the role of critical developmental periods and familial studies supporting differentiation between shared environmental and genetic influences. The exposome represents cumulative life-long environmental exposures that produce biological response signatures influencing health; exposome characterization is widely recognized as the greatest unmet challenge in children’s environmental health. Our team is at the forefront in developing critical advances in HRMS methodologies and algorithms for chemical detection, high-dimensional approaches for biomarker selection, and advanced mixtures statistics that address the complexity of the real-life environment. We are thus poised to conduct cutting-edge exposomic research on environmental drivers of autism-associated health outcomes. In support of the Autism Data Science Initiative (ADSI) Tasks II and III, we will apply these approaches to establish dynamic exposome-metabolome signatures of autism outcomes. We will leverage children and parent biospecimens collected from participants enrolled in the Early Autism Risk Longitudinal Investigation (EARLI) and the Study to Explore Early Development (SEED) cohorts to 1) Develop a comprehensive database of environmental, dietary, and chemical biomarkers that influence autism development; 2) Assemble a unified Autism Exposome Atlas through comprehensive and high- throughput chemical exposome profiling of 7,812 blood samples (including autism cases and their parents) for profiling of environmental, dietary, pharmaceutical, and endogenous metabolite biomarkers; 3) Identify exposome biomarker profiles of autism development, and 4) Integrate exposure and biological response pathways to uncover mechanisms underlying autism across different windows of susceptibility. Our results will identify critical exposome biomarkers for autism and determine how exposure and biological response contribute to neurodevelopment and symptom heterogeneity. We will develop a transformative Autism Exposome Atlas providing a centralized and organized resource for evaluating familial and cross-sectional exposome signatures and corresponding functional relationships with underlying biological response signatures. Assembly of the Autism Exposome Atlas will accelerate identification of key environmental predictors of autism and provide the evidence needed to prioritize public health interventions to support child neurodevelopment and improve health and well-being among autistic people.

NIH Research Projects · FY 2025 · 2025-09

Wildfires have become more frequent and intense over the last four decades. Due to the burning of both biomass and human-made structures during wildfires, the particulate matter generated from wildfire smoke (WFPM) tends to have smaller particle sizes and contain a unique mixture of chemicals that may be more toxic than urban background PM2.5, which is mostly generated from the fossil fuel combustion. Of particular concern is the presence of more polar and higher oxidative organic compounds, such as polycyclic aromatic hydrocarbons (PAHs), which could lead to a host of adverse consequences including effects on human fertility. As wildfires become more pervasive, it is imperative to understand how they affect female reproductive function. To address this knowledge gap, we propose to develop a transdisciplinary consortium to explore a set of integrated aims using population, clinical, and experimental approaches to investigate the association between wildfire smoke and female fertility. Aim 1 will utilize population-level data from the National Assisted Reproductive Technology (ART) Surveillance System, which includes over 220,000 ART cycles initiated in Western US states from 2001 to 2019, to evaluate the impact of WFPM on probability of cycle cancellation, clinical pregnancy, and live birth. Aim 2 will leverage a unique clinical biorepository of ART patients at UCSF who underwent oocyte retrieval during a period of pristine air quality (May-Jul 2020) and record-setting wildfires (Sep-Nov 2020) to determine the impacts of WFPM on ovarian reserve, oocyte and embryo quality, and the chemical composition of the follicular fluid. Finally, Aim 3 will use a state-of-the-art, lab-based wildfire simulator to experimentally evaluate the effects of whole-body WFPM on ovarian function and reproductive outcomes in mice. Moreover, an established ex vivo 3D ovarian follicle culture system will be used to investigate the toxic mechanisms of human relevant exposure levels of WFPM on folliculogenesis and oogenesis. We expect the clinical and biological insights gained from this proposal will provide valuable information for individual- and population-level prevention, clinical decision making, future risk assessments and policy decisions, with the longer-term goal of reducing female infertility.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Dengue virus (DENV) causes the most common mosquito-borne viral infection in the world, accounting for up to 400 million infections and 20,000 deaths each year. Billions of people live in areas conducive to DENV transmission, and DENV infection is a leading cause of febrile illness in returned travelers. Vaccination represents an essential countermeasure for combating emerging and reemerging infectious diseases like DENV. A major challenge is that DENV comprises genetically and antigenically diverse viruses classified into four serotypes (DENV1-4). Furthermore, as reported in trials for CYD-TDV, vaccination may increase the risk of disease due to DENV infection in some recipients, likely due to antibody-dependent enhancement (ADE). Therefore, generating a humoral immune response that is durable and broadly effective in preventing disease caused by DENV is a critical and unmet goal of DENV vaccine development. To address these gaps, we propose to study DENV immunity induced by heterologous vaccination with the two currently available DENV vaccines within the rigorous framework of a Phase 2b clinical trial. We hypothesize that boosting with Butantan-DV 9 months after a TAK-003 prime will optimally expand DENV serotype-specific and cross-reactive memory B cells, leading to broad durable immunity similar to that following secondary infection with wildtype DENV. This innovative trial will address the significant outstanding question in the DENV vaccine field of whether heterologous prime-boost vaccination is a viable approach to pursue for DENV vaccine programs. As part of per- protocol safety monitoring, we will scrutinize the possibility of vaccine-induced risk of ADE by performing in vitro assays to measure ADE antibodies and conduct unscheduled study visits to thoroughly evaluate any participants experiencing a suspected DENV infection. Immunogenicity in the four study groups will be studied across three specific aims focused on 1) magnitude, specificity, durability, and breadth (across serotypes and within serotype variants) of NAb measured in serologic assays, 2) magnitude, specificity, and kinetics of memory B cell responses and the evolution of the B cell repertoire for two years following vaccination (B cell trajectory), and 3) frequency, specificity, and kinetics of T cell response following vaccination. This study will have immediate and wide-ranging impact, as it addresses a critical need in the DENV field to provide practical and actionable data while delving deeper into immunological mechanisms that may underlie optimally protective adaptive immune responses to DENV elicited by vaccination. In addition to providing data that could justify larger efficacy trial and inform near future public health policy on DENV vaccination, this study will further provide proof-of-concept upon which to build an expanded initiative to examine heterologous vaccination approaches for DENV more broadly, including mixing vaccine platforms, schedules, and antigen composition.

NIH Research Projects · FY 2025 · 2025-09

Abstract: Although vast majority and in many regions of the world, the overwhelming majority of women and adolescent girls experience periodic menstruation; how this immune-mediated tissue remodeling process compromises cellular immunity generated against sexually transmitted pathogens, including Chlamydia trachomatis (C. trachomatis) and Neisseria Gonorrhoeae (N. gonorrhoeae), is poorly understood. C. trachomatis and N. gonorrhoeae are the causative agents of the most costly and common bacterial sexually transmitted infections (STIs), with the highest incidence of C. trachomatis infections occurring in women and adolescent girls of reproductive age. Genital infections by these STI pathogens can lead to severe health complications, including congenital transmissions, ectopic pregnancies, infertility, and chronic pelvic pain. Moreover, these infections increase the risk of acquiring more severe secondary infections, including human immunodeficiency virus type- 1 (HIV-1). Taken together, these facts emphasize the critical need for an effective vaccine to prevent infections of the female reproductive tract (FRT). Memory T cells that become localized in the cervicovaginal and uterine mucosa through a recent infection or from vaccination provide optimal immune protection against bacterial STI pathogens, leading to more rapid bacterial clearance and reducing disease severity. Therefore, generating long- lived resident memory T cells in the reproductive tract mucosa that will recognize and respond against C. trachomatis and N. gonorrhoeae is a promising approach to strengthening immunity. Previous scientific research investigations into understanding tissue-resident memory T cell durability demonstrate that local environmental molecular signals can provide critical support that determines tissue-resident memory T cell development, regionalization, and prolonged viability at sites such as the lung, skin, and gut. Yet, despite the fact that genital chlamydial and gonorrheal reinfections in women are common and there is no available vaccine, we have a very limited understanding of how the tissue remodeling events of menstruation alter the reproductive tract environment to drive T cell immunity. Therefore, a major challenge for developing prophylactic strategies, including vaccines that can prevent genital chlamydia infections, is to determine how to support long-lived and durable tissue-resident memory T cells in the reproductive tract under menstrual cycle regulation. The goals of our proposal are to acquire critical insights into the mechanism(s) by which menstruation regulates immune protection and identify strategies that can support optimal memory T cell durability against chlamydial and gonococcal infections in the reproductive tract throughout this process.

NIH Research Projects · FY 2025 · 2025-09

Heavy drinking is common among young adult men, which increases likelihood of engaging in sexual behaviors with risk for HIV. Text messaging – a ubiquitous technology – is starting to be used to address alcohol/HIV risk, but more theory-based work is needed to rigorously develop and test the content of text messages to optimize behavior change. Thus, in this K99/R00, the applicant will, in the K99 phase, develop and refine, and then, in the R00 phase, test the efficacy of an interactive text messaging program to reduce heavy drinking and HIV risk utilizing construal level theory (CLT) to define intervention targets. Both prior evidence and theory inform this proposal. Specifically, CLT suggests that individuals can think about a behavior or behavior change (e.g., drinking less) abstractly (e.g., why the person wants to drink less) or concretely (e.g., how the person will limit their drinking). Interventions and experimental manipulations based on CLT use the why/how paradigm to ask participants a series of why/how questions intended to induce abstract or concrete thinking, respectively. Evidence suggests that abstract thinking may enhance motivation to change whereas concrete thinking may facilitate effective implementation of behavior change; however, CLT has largely been applied to facilitate weight loss and reduced smoking. Despite its applicability and potential, CLT has yet to be applied to alcohol and HIV research. In this proposal, the applicant seeks to develop and test CLT-based why/how text messages to induce abstract/concrete thinking, respectively, about alcohol and HIV risk and in turn reduce alcohol use, risky sexual behaviors, and negative consequences of drinking, at the day-level. During the K99 phase, the applicant, working with an advisory panel of young adult heavy drinking men, will develop and refine the text messaging protocol (Aim 1; months 1-9). We will then conduct a series of pilot tests and exit interviews (2 rounds of n=12 participants) to iteratively assess and improve feasibility and acceptability of the intervention (Aim 2; months 10-24). During the R00 phase, participants (N=240) will first complete baseline assessment and GamePlan – an existing brief alcohol/HIV intervention to enhance motivation to change with demonstrated promise. Participants will then be micro-randomized at the day-level (i.e., randomized every day) for 8 weeks to receive (1) CLT-concrete messages; (2) CLT-abstract messages; (3) control messages; or (4) no messages. Participants will complete assessments daily and at the end of the intervention. These aims are in line with the applicant’s goals to acquire training in (1) developing and testing behavioral interventions (Dr. Christopher Kahler); (2) conducting micro-randomized trials (Dr. Stephanie Goldstein), and (3) analyzing intensive longitudinal data (Dr. Jennifer Merrill), and to facilitate a successful transition to independence. This project will enable the applicant to work with a highly skilled, experienced team, and provide data for a future R01 to test the effectiveness of the intervention on a larger scale, as well as provide critical theoretical information regarding potentially novel mechanisms of behavior change in alcohol/HIV research.

NIH Research Projects · FY 2025 · 2025-09

Respiratory control has long been linked to brainstem circuits, but growing evidence in animals and humans shows that higher-order brain regions actively shape breathing. This shift has major implications for treating respiratory diseases where lung pathology is irreversible and central mechanisms are suspected—such as in COPD, asthma, interstitial lung disease, neuromuscular and cardiac conditions, aging, and palliative care. This project aims to define how higher brain regions interact with brainstem circuits to produce disordered breathing. We focus on dyspnea, a persistent sensation of breathing discomfort that drives ~10% of the population to seek care and rivals chronic pain in prevalence. Patients describe it as “feeling suffocated” or “like air is more precious than water.” Dyspnea arises when the brain’s drive to breathe is out of sync with incoming sensory feedback. Current brain-targeted treatments—opioids and benzodiazepines—carry serious risks: ventilatory suppression, dependence, and respiratory failure. Our goal is to guide safer treatments by identifying cortical mechanisms that shape the perception of dyspnea without impairing ventilation. Existing human studies (EEG, fMRI) lack the spatial and temporal resolution to access deep sources or resolve the sensory and affective components of dyspnea. We overcome this using intracranial EEG (iEEG) from patients with implanted electrodes (for epilepsy treatment), and leverage on our recent work showing that brain oscillations in these regions track the breathing cycle—so-called respiratory-related brain oscillations (RRBO). We propose three aims: Aim 1: Determine causality between RRBO and the breathing cycle. Aim 2: Validate RRBO as a neural marker of dyspnea by identifying sensory and affective signatures in interoceptive cortex. Aim 3: Use direct electrical stimulation (DES) to reduce dyspnea by targeting key regions in secondary interoceptive cortex.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Despite the remarkable viral sequence diversity observed within an individual during chronic HIV infection, the majority of new transmission events are established by a single HIV viral variant, aka the Transmitted Founder virus (T/F). Regardless of transmission route, replication of this T/F rapidly spreads from the mucosal site of transmission to distant tissue compartments within days of infection, including the gut mucosa, which contains a substantial proportion of the body’s lymphocytes. Viral replication within the gut mucosa contributes to loss of both gut barrier structural integrity and immunological homeostasis early in HIV infection. Ongoing translocation of microbial products across the damaged gut barrier into systemic circulation is thought to be a major contributor to the persistent inflammation described in persons living with HIV. This chronic inflammation a top research priority, as it has been associated with poor long-term health outcomes in persons living with HIV (PLHIV) highly relevant to the NIDDK, including the development of hyperglycemia and type 2 diabetes mellitus, metabolic dysfunction-associated steatotic liver disease, and chronic kidney disease. As T/F replication within the gut is responsible for the primary damage to the gut barrier in PLHIV, and, damage to the gut barrier is associated with poor health outcomes in PLHIV, we therefore hypothesize that differences in T/F replicative capacity within gut tissues is an undefined and under-appreciated factor which could contribute to an apparent sex-bias in comorbidity development between women and men living with HIV. That is, in addition to hypothesizing that T/Fs will display a broad range of replicative capacity within gut tissues (gvRC), we also hypothesize that gut tissues from women are a unique immune environment that will support higher levels of T/F replication, than tissues donated by men. To explore these concepts, in Aim 1, we will use the ex vivo rectal explant challenge model to define the gvRC of a unique collection of Subtype A, C, A/C T/F infectious molecular clones (n=24) in gut mucosal tissues donated by women and men (n=20/sex). In Aim 2, we will identify associations between gut resident immune cells in donated tissues and gvRC, and, critical clinical metrics such as increased rate of CD4 T cell decline, or elevated set-point viral-load, in the individuals from whom these T/F were isolated, while considering significant sex-based outcomes within Aim 1. Successful execution of these aims will lay the groundwork for future studies which seek to better understand the influence of sex on early viral and immunological events within the gut mucosa, with the goal of identifying novel targets for sex-appropriate biomedical interventions for PLHIV.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT The sexually transmitted infection (STI) epidemic in the United States (US) is escalating, particularly among Black and Southeastern women. Most alarmingly, syphilis cases have increased a staggering 937% and congenital syphilis cases have increased 755% in the past decade. In pregnant women, STIs can cause severe adverse reproductive health outcomes including stillbirth and preterm birth. Treatment delays for STIs are common as current test modalities do not produce same-day results. Treatment delays increase risk of onward STI transmission to others, including mother to child, and reproductive complications. Effective and scalable methods to improve timely STI treatment during pregnancy are needed to reduce extreme rates of maternal and neonatal morbidity and mortality. Point-of-care testing (POCT) for STIs may reduce treatment delays in pregnant women, but STI POCTs have not yet been implemented for this high-need population due to questions about uptake, effectiveness, implementation, and cost. Multidisciplinary experts in obstetrics, STI, clinical trials, and implementation science from Emory University propose the MATCH-POINT study, a Type 1 effectiveness-implementation randomized hybrid study to answer these critical questions. We will evaluate the impact of two highly sensitive and specific POCTs for syphilis, gonorrhea, chlamydia, and trichomoniasis on time to STI treatment among pregnant women (Aim 1). The MATCH-POINT study will also evaluate POCT implementation processes (Aim 2), costs, and cost-effectiveness (Aim 3). Study evaluation will be guided by the RE-AIM framework. This will be the first study to evaluate the impact and implementation of POCTs for these STI among pregnant women in the US; there are no US data on syphilis POCT among pregnant women, and the evidence base for gonorrhea, chlamydia, and trichomoniasis among pregnant women is extremely limited. The study will be conducted at Grady Memorial Hospital in Atlanta, Georgia. Similar to other large, safe-net hospitals in the US Southeast, Grady Memorial Hospital cares for primarily under resourced women with a high prevalence of STIs during pregnancy and high maternal and child morbidity and mortality. MATCH-POINT study findings will be used to refine STI POCT implementation strategies and make recommendations to key stakeholders at the Georgia Department of Health for scalability to under resourced pregnant women throughout the US Southeast.

NIH Research Projects · FY 2025 · 2025-09

GLP-1 receptor agonists (GLP-1RAs), initially approved for diabetes management, have demonstrated efficacy in reducing cardiovascular and renal diseases, reversing non-alcoholic fatty liver disease (NAFLD), and enabling significant weight loss in individuals with or without diabetes. With rising obesity rates, these developments offer significant benefits to over half of the US adult population. However, the high cost of GLP-1RAs (> $15,000 annually) has led major healthcare payers to limit coverage, particularly for weight management. Policymakers have historically aimed to maximize treatment uptake among high-benefit user groups to improve health outcomes. However, identifying 'high-benefit users' of GLP-1RAs is challenging due to substantial variability in treatment benefits, influenced by a complex interplay of clinical characteristics and genetic factors. There is a significant lack of robust data to support precision policy design, necessitating targeted research that integrates clinical and genetic data. Preliminary analysis of NIH’s All-of-Us (AoU) data shows significant variability in GLP-1RA benefits linked to genetic factors. We now propose to expand the use of AoU data for more intricate analyses that comprehensively examine obesity-related cardiometabolic diseases. The OBJECTIVE of this study is to use clinical and genetic data that inform precision health policy design for GLP-1RA Coverage. Aim 1: To develop an agent-based microsimulation model for obesity-related cardiometabolic complications. Aim 2: To develop predictive models for the magnitude of GLP-1RA treatment response in preventing various cardiometabolic complications. Aim 3: Integrate the models from Aim 1 and Aim 2 to conduct large-scale simulation experiments on a nationally weighted sample and develop a scoring system using the simulation-proliferated data to inform precision health policy for GLP-1RA coverage. Dissemination Aim: To develop a large language model for presenting the scoring system.  This project is significant because it fills in a critical knowledge gap that impacts half of the US population, generating critical information to inform both clinical treatment choices and policy-level decisions. This project is also novel due to its state-of-the-art microsimulation approach and the application of ML and generative AI.

NIH Research Projects · FY 2025 · 2025-09

1 Project Summary/Abstract 2 Adductor laryngeal dystonia (AdLD) is a neurological voice disorder causing involuntary laryngeal spasms of 3 the larynx, leading to communication impairments. AdLD is diagnosed based on perceptual features, which 4 lack reliability and can present similarly to primary muscle tension dysphonia (pMTD). However, treatment for 5 the two disorders is vastly different. Misdiagnoses of AdLD delay treatment by 5–6 years, imposing financial 6 and quality-of-life burdens. No automated, clinically feasible objective diagnostic measures exist for 7 distinguishing the two disorders. Automated estimates of creak, defined as irregularly spaced vocal pulses 8 often perceived as vocal fry, show promise as a diagnostic marker for AdLD. Preliminary studies demonstrated 9 automated creak detection effectively differentiates AdLD from MTD with high diagnostic accuracy (AUC = 10 0.86). Understanding creak's physiological origins is critical. In typical speakers, creak occurs at the end of 11 breath phrases due to low subglottal pressure. In AdLD, creak occurs throughout the breath phrase, 12 suggesting distinct underlying mechanisms. Recent advances in accelerometer-based subglottal pressure 13 (ACC-Ps) estimation allow detailed physiological analysis during connected speech, making it feasible to study 14 in AdLD, pMTD, and controls. In the proposed study, a single experiment will record simultaneous speech, 15 ACC-Ps, and respiratory kinematics in speakers with AdLD, MTD, and controls reading aloud. An automated 16 creak detector will analyze speech data. Our first aim is to investigate the underlying physiology of creak in 17 speakers with AdLD by measuring subglottal pressure in connected speech. Our second aim will evaluate 18 discriminative accuracy of creak that occurs early in the breath group phrase, called early-phrase creak, 19 between speakers with AdLD, speakers with MTD, and controls. We will benchmark the discriminative 20 performance of early-phrase creak against standard clinical measures used to measure voice. The dataset 21 collected in this project will serve as pilot data for an R01 application to develop creak-based diagnostic tools, 22 which may improve differential diagnosis of AdLD and MTD, thus mitigating the current delay in diagnosis and 23 treatment of this debilitating voice disorder.

NIH Research Projects · FY 2025 · 2025-09

PROPOSAL SUMMARY/ABSTRACT My long-term career goal is to broaden our understandings of molecular and cellular mechanisms governing hematopoietic cell fate decisions both in normal and pathogenic conditions as an independent investigator. A central question of my research is how broadly expressed transcription factors regulate a distinct set of genes in different developmental programs, as transcription factors’ ability to provide precisely required functional inputs in each cellular context is essential for life-long production of healthy blood cells. To address this, I propose to determine molecular mechanisms driving dynamic functions of Runx transcription factors in early thymic T cell development and megakaryocyte differentiation, two vastly different programs relying on Runx activities. Also, I aim to exploit a novel cell culture technique recapitulating the connection between bone marrow progenitor stages and early thymic progenitor stages. This will establish a new opportunity to define the roles of transcription factors in this developmental window, which was previously challenging due to lack of in vitro system. My preliminary studies suggest that Runx factors possess notable ability to switch their DNA binding sites in a context-specific fashion both within the same developmental trajectory at different stages as well as across different cell types. These dynamic Runx binding sites are closely associated with the genes that are sensitive to Runx functions. Importantly, redistribution of Runx factors occurs across large genomic domains and multiple peaks appear and disappear coordinately. Also, cell type-specific Runx binding sites harbor distinct sets of other transcription factor motifs, suggesting that a unique ensemble of collaborators may be present in each cellular context. Thus, I hypothesize that 3D chromatin reconfiguration responds to or causes context-specific Runx binding site choices, and these dynamic Runx functions are driven by distinct co-factors in each program. To address this, I will determine whether developmental changes of 3D chromatin structure require or instruct Runx functions during early T cell development (AIM 1, mentored phase). Also, I will define which functional collaborators physically interact with Runx factors in early T cell development and megakaryocyte development and test which co-factors are necessary to guide cell type-specific Runx DNA binding (AIM 2A). Additionally, I will define the impact of cell type-specific partners on Runx functions independently of chromatin state by experimentally introducing mismatched-co-factors to non-native developmental context (AIM 2B). Finally, I will establish a novel in vitro system recapitulating the developmental transition from bone marrow progenitor phases to early thymic progenitor stages. I will exploit this system to test whether the principles underlying dynamic Runx functions apply to the activities of another multilineage-expressed transcription factor, c-Myb. Together, the studies in this proposal will show how globally expressed transcription factors execute context- specific functions in different developmental pathways in normal hematopoiesis, and how malfunction of these principles can cause hematologic pathologies, such as leukemia. 1

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Achieving substantial reductions in TB incidence will require innovative strategies for halting TB transmission, which have been hampered by a critical knowledge gap of where, when, and by whom transmission is occurring. We and others have shown that only 9-30% of TB cases can be linked to a close contact, suggesting most transmission occurs outside of household settings and with more limited (or casual) contact. Because individuals have more community contacts than household contacts, there is greater opportunity for exposure and infection outside the home, despite a lower intensity of the interactions. Thus, implementing effective measures to prevent transmission requires a comprehensive understanding of when someone becomes infectious and where they are encountering the largest number of susceptible individuals. It is increasingly clear that TB exists along a dynamic spectrum between latent TB infection and active TB disease, with several intervening states characterized by absence of symptoms in the setting of Mtb replication and host response. It is estimated that asymptomatic TB may account for up to half of bacteriologically confirmed TB globally, yet there is limited understanding of infectiousness during this stage. Recent studies have shown that cough may not be necessary for TB to be transmitted. TB bacilli detected in bioaerosols generated by less forceful respiratory maneuvers, such as tidal breathing, are associated with incident TB in close contacts. Since asymptomatic TB remains undiagnosed for an average of two years—during which time people maintain their normal activities and social mixing behaviors—this may explain the large proportion of transmission occurring in community settings. Understanding social contact patterns during early stages of TB has important implications for determining where and when TB is spread. There are limited data on asymptomatic TB transmission; however, research on contact patterns during the COVID-19 pandemic demonstrated community transmission by asymptomatic cases, in part because social contact patterns are unchanged while feeling well. Asymptomatic spread is an established paradigm for several infectious diseases but is yet to be characterized for TB. We will conduct a prospective cohort study of 1,000 close contacts to determine the onset of infectiousness (Aim 1) and measure social contact patterns (Aim 2) along the spectrum of TB disease. Aim 3 will utilize these data to model the proportion of TB transmission that occurs during early-stage disease, particularly in community settings. We have been conducting community-wide TB screening, diagnosis, and transmission research for over two decades, leading to transformative findings that shaped patient care and policy. Our team brings together global leaders in field-based epidemiologic research, transmission science, aerobiology, multi-omics, and modeling to examine fundamental questions in TB transmission science. Together these findings will provide critical information to guide interventions that will more effectively reduce TB incidence

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Sudden onset immune-mediated neurologic syndromes can result in devastating long-term morbidity and mortality in children and adults. These conditions include rare and poorly understood neuroinflammatory diseases, such as autoimmune encephalitis (AE), new onset refractory status epilepticus (NORSE), and Rasmussen syndrome. ARISEN (Autoimmunity, Rasmussen's, Inflammation & Status Epilepticus research Network) is the first U.S. based multi-center registry including these diseases, which are thought to be caused by the immune system attacking the brain and can cause high risk for death and long-term neurological problems. Clinical trials have been lacking in these diseases, and we do not know the natural history, long term outcomes or optimal treatments in these disorders. Moreover, the diagnosis can be delayed, which can be catastrophic for patient outcomes. The goal of ARISEN is to address roadblocks in developing novel therapeutics for rare neuroinflammatory conditions to lead to improved clinical trial readiness, treatments, and long-term outcomes, including patient and caregiver reported outcomes. These rare conditions require a multi-center clinical research approach to interrogate the natural history and immunopathogenesis. To study these diseases, ARISEN (Autoimmunity, Rasmussens, Inflammation & Status Epilepticus research Network) is a synergistic effort between two consortia: CONNECT (CONquering Inflammation and Epilepsies ConsorTium), the first multi-center prospective pediatric focused U.S.-based registry for AE and Rasmussen's, and the NORSE Institute which recruits children and adults. Our central hypothesis is that these syndromes result in long-term sequelae, including risk for refractory seizures and poor neuropsychological outcomes, that may be mitigated by an improved understanding of their pathogenesis and natural history (Project 1) and optimal outcome assessment measures, including patient and caregiver reported outcomes (Project 2). We will also search for. novel biomarkers to aid in earlier diagnosis, more timely therapeutic intervention, and inform clinical trials by improved characterization and targeted treatment of the underlying immune dysregulation (Project 3). This grant would allow for the collection of electroencephalograms, magnetic resonance imaging, and longitudinal biospecimens to be used for future studies. MPIs Drs. Gombolay and Murray will co-direct the administrative core. Dr. Gombolay has led the CONNECT AE registry for five years, and Dr. Murray has 22 years of experience as PI of large-scale federally-funded patient cohorts, including an encephalitis cohort. The ARISEN pilot core will fund proposals that will utilize ARISEN, develop new resources, and foster collaboration to tackle the unmet needs in these diseases. The Career Enhancement Core will train the next generation of scientists in these conditions by providing educational sessions, mentorship, access to the registry, and funding support. ARISEN's multidisciplinary team of clinical experts and patient advocacy groups will begin to address the critical obstacles to future clinical trials, including improving treatments and outcomes for these patients and their caregivers.

NSF Awards · FY 2025 · 2025-09

Many types of disease can be treated with ablation, a medical procedure which applies energy to destroy small regions of tissue that do not behave normally. Ablation therapy can be used to treat conditions like arthritis, uterine fibroids, and cancer. It can also treat disruptions of the heart’s regular rhythm, such as atrial fibrillation. Ablation procedures can be difficult to perform, and sometimes multiple treatments may be necessary. A deeper understanding of exactly how the settings associated with the ablation procedure affect the biological tissue could lead to better results. This project aims to improve the understanding of radiofrequency ablation’s interactions with heart tissue through a combination of theory, multi-physics and machine-learning models, and experiments. To ensure the experiments reflect the differences in tissue structures and properties of real patients, tissue from human hearts no longer needed after being replaced by transplants will be used when possible. Medical doctors will help assess the practical significance of the project’s results. This study has the potential to lead to improved ablation treatments and patient outcomes, and the new methodology can be extended, with minor adaptations, to other types of diseases. Educational components include training of graduate and undergraduate students, contributions to undergraduate and graduate courses, and engagement of the general public with interactive programs available through a website. Radiofrequency ablation (RFA), used for a wide variety of physiological systems, faces limitations from an imprecise understanding of ablation and tissue interactions, along with challenges in optimizing the procedure given the many parameters associated with ablation and patient variability. This project aims to develop and validate a detailed multi-physics mathematical RFA model with an unprecedented level of accuracy and analysis. It will focus on cardiac tissue, but the tools can be adapted for other biological tissues and ablation therapies. First, the novel computational model will include advanced methods of domain decomposition and model reduction to address the multi-physics nature of the problem and will incorporate important physiological parameters of ablation-tissue interactions. Second, the model will be enhanced by rigorously integrating the sizes, thicknesses and thermal profiles of ablation lesions in cardiac tissue from varying thermal doses, contact angles, and pressures and by comparing with experiments. This project will be enhanced by using optical-mapping methods during ablation in live hearts, including live human explanted hearts from patients undergoing heart transplants, to simultaneously quantify the extent and sensitivity of the ablation at different tissue depths in real time as a function of ablation parameters. This information will enable continuous refinement of the computational model and accurate sensitivity analysis. Finally, simulations and experiments will be integrated to assess how ablation lesions will effectively terminate disorganized electrical wave propagation during fibrillation. The mechanistic RFA model will provide highly accurate predictions of ablation parameter effects on the success rate of terminating cardiac fibrillation. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Systemic lupus erythematosus (lupus) is a chronic, multisystem, autoimmune disease that disproportionately affects women (approximately 8 to 1), and it is typically diagnosed during the reproductive years. Preeclampsia, a serious pregnancy complication characterized by high blood pressure, is 3 times more common in women with lupus compared with other women, but there has been limited research into how medical management of lupus during pregnancy could prevent preeclampsia and other hypertensive disorders of pregnancy (HDP). Hydroxychloroquine (HCQ) is a lupus maintenance drug that women are recommended to continue during pregnancy, but for women with well-controlled lupus who are not taking HCQ prior to pregnancy, recommendations are less clear. HCQ helps manage lupus symptoms during pregnancy; it may also decrease the risk of HDP although the current literature is inconsistent, likely due to small sample size in prior studies. On the other hand, women who conceive with active lupus often need to change their treatments to drugs that are considered safe during pregnancy. There is limited evidence that suggests use of high dose corticosteroids may increase the risk of preeclampsia, but less is known about other drugs, such as azathioprine, or about the effects of different treatments on HDP more broadly. Of additional concern, in the general population, history of HDP has been associated with hypertensive-related outcomes, such as kidney and cardiovascular disease, postpartum and later in life. This relationship is of particular concern for women with lupus who are already at substantially higher risk of hypertensive-related outcomes during their reproductive years compared to the general population. Pregnancy itself may even increase the risk of these outcomes among women with lupus. Thus, pregnancy history may serve as an important marker to identify women with lupus at the greatest risk of hypertensive-related outcomes. We will address current gaps in knowledge through the following aims: 1) To what degree does HCQ decrease the risk of HDP among women with well-controlled lupus before pregnancy, 2) Which approaches to medical management of lupus decrease the risk of HDP among women with active lupus before pregnancy, and 3) To what degree does pregnancy history predict hypertensive-related outcomes, including kidney and cardiovascular disease, outside of pregnancy? We will address these aims using 17 years of data from Merative™ MarketScan® Research Databases, which will include around 4,700 pregnancies to women with lupus. The data include de-identified, individual-level enrollment records and inpatient, outpatient, and drug claims data for a cohort of privately insured individuals. The proposed work is directly aligned with the goals for this request for applications. Expected outcomes from the proposed work will 1) contribute evidence directly relevant to treatment decisions for women with lupus during pregnancy, and 2) provide insights into the role pregnancy history may play in identifying women with lupus at high risk for future hypertensive-related outcomes.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT The prevalence of end-stage renal disease (ESRD) in the U.S. has grown exponentially in recent years, now reaching over 800,000 people, most of whom have multiple chronic illnesses, and most of whom require dialysis to sustain life. In-center hemodialysis (HD), which requires travel to a dialysis facility 3 times a week for a ~4-hour treatment session, has been the most common form of dialysis for many years. However, over the past 10 years there has been a national push to increase the uptake of home dialysis, i.e., peritoneal dialysis (PD) and home hemodialysis (HHD). During this time, home dialysis has nearly doubled from 7.5% to 13.4% of patients on dialysis. Recently, the Centers for Medicare & Medicaid Services (CMS), the largest primary payer for ESRD treatment, launched payment policies to incentivize the uptake of home dialysis and kidney transplantation with a goal of reaching 80% of the incident ESRD population. But the latest national data show that a majority of patients who tried home dialysis in 2018-2019 switched to in-center HD or died by the end of their second year, suggesting there are very significant challenges in coping with home dialysis. While there is a clear need for interventions and policies to support those who manage dialysis at home, we lack in-depth knowledge of the patient and family caregiver experiences when their home is medicalized by dialysis at home. The everyday experiences, including the workload associated with home dialysis superimposed on existing multimorbidity is largely unknown, as are the facilitators and barriers to long-term success in home dialysis. To address this critical gap, we propose a prospective longitudinal cohort study with 221 home dialysis patients and their caregivers to characterize the quality of their everyday life experiences to understand how they incorporate dialysis into their daily routines, with a focus on how these experiences and life satisfaction change over time. For Aims 1 and 2, we will use the Day Reconstruction Method with repeated measures at baseline and every 2 months. We will characterize the quality of everyday life experience and life satisfaction among home dialysis patients and their caregivers over 12 months (Aim 1). We will examine how the quality of everyday life experience and life satisfaction affect patient and caregiver outcomes, including self-rated overall health (patients and caregivers), complications (e.g., access infection, peritonitis, sepsis), patients’ healthcare resource use (ED visits and hospital admissions), burnout (patient and caregiver), and whether the patient continues on home dialysis or not (Aim 2). For Aim 3, we will use qualitative interviews to explore the perspectives of patients and caregivers who convert to in-center HD about the circumstances that led to the decision to discontinue home dialysis. Findings from our research will contribute to the development of data- based interventions and policies to enhance day-to-day living quality and well-being for those on home dialysis. Such knowledge can increase the uptake of home dialysis as a high-quality, high-value care option that is well- aligned with the care and life priorities and capacities of patients and caregivers.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Access to substance use disorder (SUD) treatment remains inadequate for many groups, particularly those in Southern jails. Black individuals and people experiencing homelessness are disproportionately represented in carceral populations, yet they lack equitable access to medications for opioid use disorder (MOUD), including methadone and buprenorphine (3-8). Further, these populations are rarely prescribed MOUD upon release from incarceration, when the risk for death from overdose is highest.(8) MOUD can be lifesaving, yet represents one part of the recovery ecosystem; medications with a similar effect size are not yet available for individuals with a non-opioid SUD including stimulants.(9-11) An individualized yet scalable approach matched to individual needs and substance use, is required.(12-14) Peer recovery coach (PRC) models which engage individuals with lived experience to conduct motivational interviewing and a warm handoff to medical, behavioral, and community-based services, are associated with improved SUD-related outcomes and can be delivered via telehealth.(15-19) Nonetheless, there is less research assessing the implementation and effectiveness of PRCs in jails, except for linking persons with HIV to community care upon release, despite the heightened vulnerabilities individuals with SUD face as they transition from carceral settings.(20-22) The proposed JCOIN II Innovation Hub will implement and rigorously evaluate a PRC program at three high- throughput jails in the Atlanta, Georgia area. The Innovation Hub will adapt and evaluate an established SUD virtual peer recovery (telehealth) model (LINCS UP) to the jail setting. Project implementation will be guided by the EPIS framework and developed in collaboration with an established community advisory board including individuals with a history of SUD and justice involvement. Outcomes will be measured across the RE-AIM framework.(23) PRC effectiveness will be evaluated through a stepped wedge cluster randomized clinical trial. Primary outcomes will include engagement in addiction care while in jail and successful linkage to community- based care upon release. Secondary outcomes will include, but are not limited to ongoing substance use, recovery capital, overdose events, mortality, and recidivism. Finally, the Innovation Hub will conduct a cost effectiveness analysis of the jail PRC program. Following consensus recommendations, this analysis will include cost considerations from both healthcare and societal perspectives.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Red blood cell (RBC) transfusion is an essential part of the management of sickle cell disease (SCD). The effectiveness of transfusion therapy to treat acute disease complications and prevent chronic disease progression have unique considerations in SCD that are dependent upon post-transfusion RBC survival. For many individuals with SCD who receive acute or chronic transfusions, transfusion survival and thus effectiveness is suboptimal. The NHLBI State of the Science in Transfusion Medicine symposium identified optimization of RBC transfusion outcomes for recipients with SCD as a key clinical and research priority. The proposed research will evaluate the impact of donor and recipient factors on the survival of transfused RBCs in recipients with SCD and will examine mechanisms contributing to RBC clearance in both the recipient and the donor. Based on our preliminary data, we hypothesize that RBC components from donors with G6PD deficiency or with alpha-thalassemia trait will have decreased post-transfusion in vivo survival as compared to normal donor RBCs. We have previously demonstrated that recipients with SCD have a much higher likelihood of receiving transfusion from donors with these RBC conditions that are common among healthy donors with African ancestry. We additionally hypothesize that recipients with past RBC alloimmunization responses will have faster clearance of transfused RBCs via mechanisms of spleen and hepatic phagocytic activity. We propose an experimental, interventional, controlled trial with a paired study design that will allow recipient and donor factors to be assessed independently without confounding. Through large-scale next generation sequencing (NGS) genetic screening of at least 10,000 African American blood donors through LifeSouth Community Blood Centers, we will create a database of eligible blood donors including blood type, RBC minor antigen genotype for matching to recipients, G6PD, and alpha-thalassemia hemoglobinopathy status. Pairs of minor antigen-similar blood donors (G6PD deficiency to normal, and alpha-thalassemia to normal) will be recruited for donation, with transfusion directed to pairs of recipients with SCD (alloimmunized vs. non- alloimmunized). Biotin-labeling will be used to measure post-transfusion RBC survival kinetics. Our aims are to (1) determine differences in post-transfusion survival for RBC components from donors with and without G6PD deficiency or alpha-thalassemia trait, and (2) to determine differences in the clearance of transfused RBCs in recipients with SCD with and without past alloimmunization. We will conduct the project through the Georgia Comprehensive Sickle Cell Center at Emory University-affiliated Grady Memorial Hospital. Our project has the potential to improve the management of RBC transfusion therapy, with focus on tangible areas such as donor screening and selection, and identification of recipients at increased risk of suboptimal transfusion survival and efficacy.