Ohio State University

NSF Awards · FY 2024 · 2024-08

The formation of hierarchies in task groups is a ubiquitous process, but these hierarchies are not always stable. Group hierarchies can evolve with the contributions of members. If a comparatively low status group member makes a positive contribution to the group, for example, they are likely to increase their standing in the overall group. Conversely, if a relatively high status group member makes a poor contribution, they are likely to decrease their standing. This research systematically varies moderator interventions to study their effects on the contributions of various group members to evaluate whether group moderators can enhance or flatten the emergence of hierarchies in task groups and what the effects of this are for task success. Drawing on existing research on status dynamics, moderators intervene in task discussions to enhance the standing of comparatively low status group members.   To study these processes, the research uses experimental and computational methods. First, moderator interventions are experimentally varied. In a control condition, moderators do not intervene in the emergence of the group’s status hierarchy. In two experimental conditions, moderators use cues and interventions from the extant literature on status dynamics to enhance the perceived standing of comparatively low status group members. Influence over the group is measured and used to evaluate whether moderator interventions are successful in mitigating task irrelevant characteristics from shaping the power and prestige order of the group. Also examined is what this means for task success. The research further develops a computational pipeline that uses Natural Language Processing to track the group’s status hierarchy. The group’s conversation for status-relevant information is coded and machine learning algorithms “learn” the codes that humans assign to the text. This enables automatically coding of subsequent conversations for status-relevant information. Collectively, the work evaluates new moderator interventions to make task groups more egalitarian, and develops computational tools to automate the coding of hierarchy formation in task groups. 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 2024 · 2024-08

In this project funded by the Chemical Mechanism, Function and Properties Program of the Chemistry Division, Professor Claudia Turro of the Department of Chemistry and Biochemistry at The Ohio State University, in collaboration with Professor Jeremy Kodanko at Wayne State University, aims at understanding the steps that take place at very early times (femtosecond to picosecond) after a transition metal complex absorbs a photon of light. These ruthenium complexes are important in applications that include solar energy conversion and the delivery of drugs for phototherapy. The project will also focus on the design of new transition metal complexes that release a wider range of ligands, especially those that coordinate strongly, with visible or low energy near-IR light. These systems can have potential applications in drug delivery. The investigation of complexes that exhibit dual-reactivity will be a major goal of the proposed work. The basic knowledge gained regarding photoinduced ligand exchange will also aid in the design or complexes that require the ligand exchange process to be eliminated in order to increase the lifetime of the 3MLCT (triplet metal-to-ligand charge transfer) state, an important factor in solar energy conversion. This collaborative team is also well positioned to provide the highest level of education and training for students underrepresented in science. The major focus of this collaborative project is to understand the basic principles that govern the photophysical processes in Ru(II) complexes at early times, including the factors that control efficient photosubstitution. Focus is on dual-activity compounds which generate cytotoxic singlet oxygen and simultaneously undergo ligand exchange. The mechanism by which two different photoactive states are populated in these complexes remains unknown and is counter to the rules of photochemistry developed for organic molecules. In addition, the photoinduced drug release using Ru(II) complexes is highly dependent on the identity of both the leaving and ancillary ligands, a point that will be investigated. It is hypothesized that fast population of the metal-centered 3LF (triplet ligand field) state is required for ligand exchange to take place, but it is yet unknown if ligand exchange also occurs directly from the lowest-energy 3MLCT state. The basic knowledge gained regarding photoinduced ligand exchange will also aid in the design of complexes that require the ligand exchange process to be eliminated in order to increase the lifetime of the 3MLCT state, a factor important in solar energy conversion. The proposed work includes ultrafast studies, electronic and vibrational, as well as the synthesis of new complexes for improved ligand dissociation and for dual action. 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 · 2024-08

Obstructive sleep apnea (OSA) is a major public health problem that is commonly seen in primary care clinics where a majority of outpatient office visits occur. Prior studies suggest that OSA is severely under-diagnosed in primary care practices, but these studies relied on patient reported symptoms rather than objective diagnosis. Consequently, the prevalence of OSA and rate of under-diagnosis of OSA among primary care practices are not currently known. Given the recent studies implicating the excessively sleepy OSA symptom subtype to the development of cardiovascular events, it is also important to ascertain the prevalence and underdiagnosis rate of this OSA subtype among patients seen at primary care clinics. In addition to estimating prevalence, it is equally important to evaluate the factors contributing to the likelihood of underdiagnosis across different primary care practices. Barriers to OSA diagnosis include patient factors related to lack of awareness and understanding of the disease, physician perceptions of OSA risk and knowledge about the heterogeneous presentation of OSA, and system and practice-specific factors such as time constraints. The growth of electronic health records (EHRs) in recent years also provides the unique ability to identify these undiagnosed and untreated cases via the application of automated algorithms. Our preliminary data suggest that combining readily available data in EHRs including comorbidities using machine learning techniques offers an opportunity to develop a reliable OSA phenotypic risk score that would facilitate OSA case identification in primary care. New paradigms for identification of OSA and its subtypes centered on primary care and using data from the EHR, including comorbidities and patient symptoms, are needed to meet the high prevalence of OSA. In Aim 1, using a two-stage sampling strategy in primary care practices, we will determine the prevalence of OSA and its subtypes, and robustly estimate the rate of OSA under-diagnosis in primary care clinics. In Aim 2, we intend to develop a root cause analysis of the underdiagnosis of OSA problem in primary care practice setting using a systems engineering framework. We will elicit the barriers and facilitators of the OSA diagnostic process within the work system of the primary care practice setting using stakeholder engagement methods with multi-level stakeholders. Using these results, we will survey primary care providers and staff to estimate the frequency and priority rank-order of OSA diagnostic process barriers and facilitators within the primary care work system. In Aim 3, using a novel machine learning pipeline, we will develop an efficient and accurate tool for determining OSA risk in primary care participants recruited in Aim 1 and an efficient tool to determine OSA subtype that could be employed within the context of primary care practice. This proposal will ultimately lead to increased identification of OSA and its subtypes in primary care clinics and prioritize treatment of patients that will most benefit from therapy which may reduce the burden of significant health problems that are associated with this very common condition.

NIH Research Projects · FY 2025 · 2024-08

ABSTRACT Many cancer drugs increase cardiovascular (CV) events, including hypertension, thrombosis, and cardiomyopathy. Damaged endothelial cells (ECs) caused by chemotherapy can trigger the development and progression of cardiovascular disease (CVD). ECs represent a critical target for improving the management of chemotherapy-induced CV toxicity. The lysosomal pathway is critical to maintaining EC homeostasis. However, the role of lysosomes in chemotherapy-induced EC dysfunction and whether rescuing lysosomal function is a potential strategy to treat CV toxicity remain to be fully explored. Our preliminary data suggest that the chemotherapeutic drug doxorubicin (DOX) impairs lysosomal function in ECs. TFEB is a master regulator of autophagy and lysosome biogenesis. Our previous studies demonstrated that endothelial TFEB protects against atherosclerosis, increases glucose uptake, and improves blood flow recovery after ischemic injury, underscoring the critical role of EC TFEB in regulating CV hemostasis. Our preliminary data suggest that EC- TFEB transgene regulates DOX-induced cardiac dysfunction in mice. TFEB controls lysosomal malfunction, apoptosis, oxidative stress, and inflammation induced by DOX in human ECs. Our RNA-seq data identified multiple lysosomal-associated pathways in ECs treated with DOX. Based on the solid rationale and preliminary data, we will define the role of endothelial TFEB in CV dysfunction induced by cancer treatment. By taking advantage of our EC-specific transgenic (Tg) and knockout (KO) mouse models and the combined expertise of the assembled team, three Specific Aims are proposed. Specific Aim 1: Define the role of endothelial TFEB in cancer therapy-induced EC dysfunction and EC-cardiomyocyte interaction in vitro; Specific Aim 2: Define the role of EC TFEB in cancer therapy-induced CV toxicity in vivo; Specific Aim 3: Elucidate the mechanisms mediating the effects of EC TFEB on cancer therapy-induced cardiac dysfunction in vivo. Understanding endothelial TFEB’s role and underlying mechanisms in cancer therapy-induced CV toxicity would set a profound foundation to define endothelial TFEB as a potential therapeutic target to treat CV complications caused by cancer therapy.

NIH Research Projects · FY 2025 · 2024-08

Modified Project Summary/Abstract Section While some barriers and facilitators to parent presence and participation (PPP) in the neonatal intensive care unit (NICU) have been identified, comprehensive descriptions of factors influencing PPP and changes in these factors over time are lacking. To improve outcomes for preterm infants and their parents, the factors influencing PPP must be identified. PPP is critical to improving clinical outcomes and neurodevelopment for preterm infants. The purpose of the proposed study is to comprehensively determine barriers and facilitators affecting PPP in the NICU and effects of PPP on infant outcomes. Using a non-experimental, longitudinal design, the following specific aims and subaims will be accomplished: (Aim 1) determine barriers and facilitators affecting PPP and changes in barriers and facilitators over time; (Subaim 1) predict barriers and facilitators of PPP for various groups of parents; (Aim 2) determine the effect of PPP on infant clinical outcomes and neurodevelopment; (Subaim 2) determine the mediation effect of parent-infant responsiveness on the relationship between PPP and infant clinical outcomes and neurodevelopment; (Aim 3) determine the moderation effect of PPP on the relationship between infant stress exposure and infant clinical outcomes and neurodevelopment. Parents with an infant born less than 32 weeks gestational age will be enrolled. Parents will complete surveys throughout their infant’s hospitalization to identify barriers and facilitators influencing PPP and to quantify their experiences of parent-staff engagement in the NICU. PPP will be quantified by parent-report, electronic health record documentation, and NICU visitation logs. Infant clinical outcomes, including length of NICU stay and achievement of oral feeding competence, will be measured throughout hospitalization and at discharge. Neurodevelopment will be assessed at 3-months corrected age using the Test of Infant Motor Performance and 12-months corrected age using the Bayley Scales of Infant and Toddler Development, 4th Edition. Parent-infant responsiveness at discharge and 3-months corrected age will be determined as will the moderating effect of PPP on infant stress exposure throughout hospitalization. The study focuses on modifiable factors that may affect PPP. The study will provide data to support the development of NICU interventions to promote PPP, thus improving outcomes for preterm infants and their families. This proposal addresses the research priority area of the NICHD’s Pregnancy and Perinatology Branch to advance the science of preterm birth and its consequences while incorporating the NICHD’s aspirational goal to enhance the healthy development of preterm infants.

NIH Research Projects · FY 2025 · 2024-08

Disasters have increased in number, intensity, costliness, and human impact, including public health. Over the same period, drug-related morbidity, mortality, and dependence have increased dramatically. While research has shown that experiencing a disaster affects physical and mental health, the literature on disasters’ effects on substance use outcomes is often limited to single disasters (e.g., Hurricanes Katrina and Sandy), based on convenience or opportunistic samples that are difficult to generalize across disasters, and with equivocal findings. This research study will use quasi-experimental methods and a robust disaster database to examine the impact of disasters on aggregate-level mortality and individual-level substance use over an extended period, including examining intervening mechanisms through which disasters are hypothesized to operate using a Big Events conceptual model. For disaster data, we will employ a currently underutilized dataset within public health research: the Federal Emergency Management Agency’s Disaster Declaration Database, a temporally-specific and geocoded dataset containing all disaster declarations in the U.S. dating back to 1964. We will combine this information with county-level mortality data from the Centers for Disease Control and Prevention and drug arrest data from the FBI Uniform Crime Reports, individual-level data on use, distress, and treatment gaps from the National Survey on Drug Use and Health, and control variables from the U.S. Census Bureau. Taking advantage of the exogenous nature of disasters, often used as a statistical instrument, we will employ quasi-experimental methods to estimate the main effects of disaster occurrence as well as the mechanisms though which disasters operate, including psychological distress, treatment disruption, and drug market disruption. In addition to county fixed-effects in aggregate analyses, both levels of analysis will incorporate temporal and spatial variability in order to understand how disaster effects diffuse over both dimensions. Finally, we will conduct these analyses by characteristics of both the county and individual. Our proposed research provides an opportunity to test the effects of two phenomena that have greatly impacted public health. We will also contribute in additional ways. First, the examination of mechanisms through which disasters operate will identify which resources need immediate redress in the face of disaster to curb adverse substance use outcomes. Second, the identification of the effects of disasters on substance use outcomes can assist in knowing where and how resources can be deployed. Finally, we will create and make publicly available a county by month database of nearly 50 years of disaster data for future researchers to use to examine additional public health outcomes.

NIH Research Projects · FY 2024 · 2024-08

Project Abstract Despite high global vaccination rates, pertussis caused by the gram-negative bacterial pathogen Bordetella pertussis (Bp) is re-emerging in vaccinated individuals. This is correlated with the switch in the 1990s from whole cell (wPV) to acellular vaccines (aPV). wPV elicit TH1/TH17 polarized immune responses and clear Bp from the entire respiratory tract. In contrast, aPV elicit TH2 polarized immunity and do not prevent nasal colonization. Thus, aPV immunized individuals serve as reservoirs for transmission to vulnerable populations. While the importance of CD4+ T cells for long-term protection against Bp infection is established, the antigens recognized by the T cells remain undefined. Using high dimensional mass spectrometry and functional T cell assays we identified several new antigens from Bp that generate tissue-resident memory T cell responses in mice and are recognized by CD4+ T cells from wPV immunized people. In this application we will test the efficacy of a subunit vaccine containing these antigens and the TH1/TH17 polarizing adjuvants Bordetella Colonization Factor A (BcfA) and double mutant heat-labile toxin (dmLT). These adjuvants activate immune responses through different mechanisms and elicit mucosal immunity. We hypothesize that these vaccines will elicit long-lived TH1/TH17 tissue-resident T cell responses in the nose and lungs, and clear Bp from the nose, thereby reducing the likelihood of Bp transmission by vaccinated individuals. Specific Aim 1: To test the ability of an intranasal subunit booster vaccine containing new T cell recognized antigens to reduce Bp colonization in aPV primed adult mice. We will test an intranasal (i.n) booster vaccine containing the TH1/TH17 polarizing adjuvant BcfA, admixed with detoxified pertussis toxin and three new T cell antigens, in mice previously immunized intramuscularly (i.m) with an approved aPV. The systemic and mucosal T cell and antibody responses will be quantified, along with the phagocytes recruited to the respiratory tract, and the Bp bacterial load in the nose and lungs. Specific Aim 2: To test the immunogenicity and protective efficacy in infant mice of a subunit vaccine delivered by a heterologous immunization regimen. We will test the novel T cell antigens combined with the adjuvants dmLT and BcfA, separately and together. Vaccines containing dmLT will be tested by the i.d route and vaccines containing BcfA will be tested by the i.d or i.n route. Immune responses, bacterial load and the longevity of protection will be determined. IMPACT: There is a critical need for next generation pertussis vaccines that elicit mucosal immunity and prevent nasal colonization. The proposed experiments will test a vaccine formulation containing novel MHC Class II presented antigens that will provide sustained protection against Bp infection as a booster and as a pediatric vaccine. These foundational studies will lead to a safe and effective next generation pertussis vaccine that will prevent transmission and thereby reduce the burden of the disease pertussis.

NIH Research Projects · FY 2025 · 2024-08

Project Summary Half of heart failure (HF) patients die suddenly, termed as sudden cardiac death (SCD), while HF affects over 5 million people in the United State alone. The current ACC/HF/AHA guidelines recommend implantable cardioverter-defibrillator (ICD) therapy for the secondary prevention of SCD and primary prevention in HF patients. However, significant mortality benefits in ICD implanted HF patients was not shown in randomized clinical trials. Therefore, development of effective therapies is urgently needed. HF myocardium exhibits electrophysiologic pathological remodeling that underlies the development of non-reentrant mechanisms (triggered activity) as well as slowing of conduction in nonischemic HF human hearts that underlie development of reentry. Sarcoplasmic reticulum (SR) Ca2+ mishandling impairs excitation-contraction coupling, to play a key role in triggered arrhythmia in HF. Our group recently discovered a previously unknown form of kinase-on-kinase crosstalk where JNK2 enhances CaMKII gene expression and activity, CaMKII-regulated SR Ca mishandling (leak/overload), arrhythmic Ca activities, and triggered delayed afterdepolarization (DADs) in the heart. We further demonstrated a JNK2-specific action (independent of CaMKII) in SR Ca overload via enhanced SERCA2 Ca uptake, which exacerbates the JNK2-CaMKII-evoked diastolic SR Ca leak and arrhythmogenesis. In addition, we found that JNK2 downregulates gap junction Cx43 gene expression and impairs cell-to-cell communication, which promotes reentrant substrate to sustain triggered activities. Our pilot studies show that JNK2 is markedly activated and upregulated in explanted failing left ventricles (LV) from dilated cardiomyopathy (DCM) patients compared to healthy control hearts suggesting that JNK2 could be an unexplored contributor to SCD in HF. Although our preliminary data suggest a key implication for JNK2 in the mechanisms leading to SCD, the upstream pathway leading to this upregulation of JNK2 remains unknown. Importantly, downregulation of the Potassium Channel Interacting Protein, KChIP2, has been linked to arrhythmias and SCD. In the absence of KChIP2 there is enhanced susceptibility to ventricular arrhythmias, while restoring KChIP2 expression in a rodent model of hypertrophy delayed the progression to HF and reduced arrhythmias. Importantly, we demonstrated that KChIP2 is found in the nucleus where it can act as a transcriptional repressor suggesting it could contribute to arrhythmia mechanisms through transcriptional regulation of cardiac genes. Our preliminary data suggest that KChIP2 can bind and repress the expression of JNK2. Thus, our central hypothesis for this proposal is that the KChIP2-JNK2 axis plays a critical role in mechanisms leading to arrhythmias and SCD. This proposal will aim on answering two important questions: 1) how does KChIP2 regulate JNK2 expression? 2) how does the KChIP2-JNK2 axis promote SCD in HF? Importantly, we will test therapeutic interventions of overexpression of KChIP2 and/or inhibition of JNK2 as novel anti-arrhythmia strategies for HF patients.

NSF Awards · FY 2024 · 2024-08

The intimate link between form, or shape, and function is ubiquitous in science. In biology, for instance, the shapes of biological components are pivotal in understanding patterns of normal behavior and growth; a notable example is protein shape, which contributes to our understanding of protein function and classification. This project, led by a team of investigators from the USA and the UK, will develop ways of modeling how biological and other shapes change with time, using formal statistical frameworks that capture not only the changes themselves, but how these changes vary across objects and populations. This will enable the study of the link between form and function in all its variability. As example applications, the project will develop models for changes in cell morphology and topology during motility and division, and changes in human posture during various activities, facilitating the exploration of scientific questions such as how and why cell division fails, or how to improve human postures in factory tasks. These are proofs of concept, but the methods themselves will have much wider applicability. This project will thus not only progress the science of shape analysis and the specific applications studied; it will have broader downstream impacts on a range of scientific application domains, providing practitioners with general and useful tools. While there are several approaches for representing and analyzing static shapes, encompassing curves, surfaces, and complex structures like trees and shape graphs, the statistical modeling and analysis of dynamic shapes has received limited attention. Mathematically, shapes are elements of quotient spaces of nonlinear manifolds, and shape changes can be modeled as stochastic processes, termed shape processes, on these complex spaces. The primary challenges lie in adapting classical modeling concepts to the nonlinear geometry of shape spaces and in developing efficient statistical tools for computation and inference in such very high-dimensional, nonlinear settings. The project consists of three thrust areas, dealing with combinations of discrete and continuous time, and discrete and continuous representations of shape, with a particular emphasis on the issues raised by topology changes. The key idea is to integrate spatiotemporal registration of objects and their evolution into the statistical formulation, rather than treating them as pre-processing steps. This project will specifically add to the current state-of-the-art in topic areas such as stochastic differential equations on shape manifolds, time series models for shapes, shape-based functional data analysis, and modeling and inference on infinite-dimensional shape spaces. 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 2024 · 2024-08

The GENETIS and Nebulous projects aim to provide a nexus point for collaborations from astrophysics, other areas of science, and industry to design instruments for optimal scientific outcomes that may not be achievable with human engineering. Initially, they have focused on genetic algorithms and have already evolved antennas for neutrino astrophysics applications. This group travel award supports attendance by team members at a “Blue Sky Studies” workshop and follow-up GENETIS meeting to be held at CalTech in Pasadena, CA, August 12-14. The goal of this workshop is to develop a plan for broadening and streamlining the use of AI for the design of instruments, with a focus on applications in astrophysics. By standardizing tools developed by the GENETIS and Nebulous projects, the expectation is that the design phase of experiments will become more efficient, while also increasing scientific impact. The meeting will create a prioritized roadmap for developing AI for instrument design, understanding the needs of future missions and experiments, and the limitations of AI. GENETIS has an exemplary record as a launch pad for diverse undergraduate and graduate students, including those from minority-serving institutions. This interdisciplinary team adds new perspectives to every aspect of the work and provides rich learning opportunities for early career researchers. 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 2024 · 2024-08

A research collaboration between the University of Hawai’i and Ohio State University will continue to operate the All-Sky Automated Survey for Supernovae (ASAS-SN), which is a network of 20 telescopes deployed at four sites around the globe with a scientific goal to provide a survey of the bright transient and variable astronomical sky. ASAS-SN is the first project to image the entire visible sky on a nightly basis to a visible magnitude of g~18, making the data public. The project discovers and observes approximately 300 supernova per year, and is also an important resource for other science such as active galactic nuclei and blazar flares, tidal disruption events, Galactic and Local Group novae, cataclysmic variables, and other transients. ASAS-SN triggers on events from other NSF-supported facilities, such as astrophysical neutrinos from IceCube and gravitational wave events from LIGO to search for the optical counterparts that are crucial to fully exploring them. ASAS-SN will continue to provide a critical training ground for the next generation of time-domain astronomers and the investigators plan future Citizen Science projects to classify detected objects. Targeted observations of multimessenger alerts can reach g~20 over 100s of square degrees in a few hours. It is a unique all-sky optical counterpart to other facilities searching for neutrinos, gravitational waves, and gamma rays. The depth of ASAS-SN is nearly perfectly matched to many spacecraft (TESS/Swift for imaging, and HST/CXO/JWST for spectra). Because ASAS-SN transients are bright and promptly announced, they frequently become the best-studied sources in any transient class. Many ASAS-SN sources and transients can be studied in detail for long periods of time, whereas fainter transients cannot. ASAS-SN discovers and recovers ~300 SNe per year, with ~3300 total projected by 2027, the majority with spectroscopic classifications. It will be the largest such sample for studies of rates and correlations by type or with host properties. ASAS-SN provides public databases of 600,000 homogeneously classified variable stars as well as continuously updated light curves of more than 100 million g < 18 sources. This enables new science across many sub-fields of astronomy. ASAS-SN also provides the community with a unique tool to obtain an up-to-date optical light curve for any point on the sky. 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 2024 · 2024-08

Data in science and engineering are often managed by software libraries that store data and data-describing metadata together. These “self-describing” data, file formats, and software libraries, such as HDF5 and netCDF, offer standardized, machine-independent, and portable file formats that support flexible and performant organization of large amounts of data. As a result, numerous scientific, engineering, and industry applications use these formats for storing and analyzing their data. With many critical fields using self-describing formats, these data as well as their corresponding data management software libraries have become critical cyberinfrastructure that must be secured to perform accurate and reproducible science. Unfortunately, existing data management software libraries were designed decades ago, before cybersecurity was a major concern, so there has never been a targeted testing and evaluation of the trustworthiness, integrity, and resilience of these libraries. This project is exploring strategies to integrate both well-known and advanced security algorithms into prominent data management libraries. The research performed in in this project will be a foundational step towards building next generation secure data management cyberinfrastructure for the rapidly changing landscape of science and AI, where security, privacy, and trustworthiness are critically required. This project will apply comprehensive testing, evaluation, issue identification, hardening, and validation to correct security deficiencies in self-describing file formats and libraries. The specific R&D tasks include: (1) assessing and fixing file format vulnerabilities, (2) protecting data access libraries, (3) exploring security solutions for metadata and data, and (4) constructing a security framework, called S2-D2. The S2-D2 project will have a direct impact on securing data in a variety of scientific domains. Additionally, bolstering the HDF5 library with robust security will make it more usable in applications that require increased security, such as the financial and medical fields. This award by the NSF Office of Advanced Cyberinfrastructure is jointly supported by the NSF National Discovery Cloud for Climate (NDC-C) initiative. 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 · 2024-08

PROJECT SUMMARY/ABSTRACT The development of healthy molar teeth with elongated roots, mineralized dentin, and sensory innervation re- quires coordinated efforts between neuronal and mesenchymal tissue. During the first week of development, mouse molars begin all three developmental processes of secreting a dentin matrix, initiating root elongation, and secreting chemoattractants to guide sensory afferent penetration into the pulp tissue. Research has shown that disrupting pulp mesenchyme signals during this period can have drastic effects on one or more of these processes. These coordinated processes are conserved in humans and pose clinical challenges for pediatric dentists and endodontists attempting to ensure the long-term vitality of an infected or damaged immature tooth. The long-term goal of this project is to understand the cellular mechanisms that protect teeth via dental tissue crosstalk. The objective is to determine the mechanisms that regulate the development of a tooth into a miner- alized, anchored, sensory organ. Our central hypothesis is that Sema7a signaling from differentiating odonto- blasts regulates tooth mineralization, root elongation, and innervation. This hypothesis was formulated because our mouse model of conditional Tgfbr2 deletion in tooth mesenchyme demonstrated reduced mineralization, root elongation, and innervation coinciding with reduced Sema7a RNA expression in the DP and aberrant lo- calization of SEMA7a in the apical regions of the developing teeth. Guided by our previously generated data, we will test our hypothesis with the following two specific aims: 1) To determine the impact of global and condi- tional deletion in dental pulp mesenchyme of Sema7a on dentin mineralization, root elongation, and tooth in- nervation; and 2) Isolate the role(s) of SEMA7a signaling to DP neuronal and mesenchymal populations with in vitro assays. Under the first aim, we will analyze tooth morphology, including the dentin volume, density, and thickness, root length, and tooth innervation using the Sema7a-/- mouse model in addition to a conditional knockout mouse with Sema7a deletion induced by the osterix-promoter driven Cre recombinase induced at postnatal day 3. For the second aim, we will utilize a co-culture model with primary dental pulp cells and tri- geminal neurons to assess whether SEMA7a regulates the processes of odontoblast differentiation, matrix deposition and neurite outgrowth. The research proposed in this application is innovative because it a) investi- gates a previously unrecognized chemoattractant involved in the process of tooth development during the criti- cal window of time during the initiation of matrix deposition, root elongation, and tooth innervation; and b) pro- poses to be the first study to examine tooth development in models with global and conditional deletion of Sema7a. The proposed research is significant because it is expected to advance the understanding of how these three developmental processes are regulated during a critical window of time during postnatal tooth de- velopment. Ultimately, such knowledge has the potential to bolster regenerative endodontics to treat injuries and disease states, and to ensure the proper development and long-term retention of healthy teeth.

NSF Awards · FY 2024 · 2024-08

This doctoral dissertation project examines naturally shed deciduous (milk) teeth to assess how stress affects tooth formation in males and females during early life. Because deciduous teeth’s growth and development is mostly impacted by maternal health, the study focuses on teeth from individuals whose mothers have well documented health information. Results obtained establish: (1) the extent to which teeth formed during this period record documented stressors, and (2) whether there are sex differences in the degree to which the deciduous dentition reflects these stressors. Because teeth record stress during development, they are often used in the study of health and growth in human ancestors as well as past human populations. Thus, results from this study improve current interpretations of stress evidence in past and present populations. This study provides training for graduate and undergraduate students in a STEM field and increases representation in science. Fluctuating dental asymmetry, which reflects developmental stress, is assessed based on 3D and 2D dental measurements from µCT scans. Additionally, histological sectioning of antimeres are analyzed to evaluate the width and asymmetry of the neonatal line. Results obtained reveal the types and magnitude of stressors documented in dental asymmetry, and test whether fluctuating asymmetry and the neonatal line in deciduous teeth reflect a theorized sex difference in vulnerability to stress during early development. This project builds on existing work on fluctuating dental asymmetry, but it is the first one to use µCT scans in a clinical sample, making it possible to assess the relationships between known medical stress data and dental measurements. 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 2026 · 2024-08

PROJECT SUMMARY/ABSTRACT Problem statement: The investigation and manipulation of complex biological systems require lab-on-a-chip (LOC) systems that can perform spatially resolved, localized sensing (e.g., detection of biomarkers) and actuation (e.g., micropatterning, and electrical stimulation) on a single entity (e.g., within the surface of a soft tissue). Faradaic electrochemistry involving reduction/oxidation (redox) reactions is commonly used as the driving force for these operation modalities and processes. However, array-type electrodes prepared by conventional lithography-based technologies have limitations in their flexibility as the dimensions, designs, and locations are tailored to specific tasks, making it difficult to adjust the regions of measurement/manipulation of dynamic cellular processes as required. Additionally, redesigning these electrodes requires time-consuming, expensive, and highly sophisticated fabrication and read-out procedures. Furthermore, the predetermined geometry may limit the achievable density of effective working sites due to the use of conductive pads/interconnects within the electrode arrays. As a result, there is a need to explore novel LOC systems with improved resolution, flexibility, and adaptability to shift the paradigm of spatially resolved biosensing and actuation applications. Hypothesis: This project aims to develop a photoelectrochemistry-enabled multi-utility lab-on-a-chip (LOC) system, known as the "optoelectronic micro-gadget" (OMG), for sensing and actuation by utilizing cross- disciplinary expertise in electrical engineering, optoelectronics, and analytical chemistry. The OMG system will be based on a monolithic, flexible silicon thin film (thickness < 10 μm) and a reconfigurable focused laser beam for spatially resolved photoexcitation. The working principle is that, when the semiconductor thin-film contacts a redox solution, a space-charge region develops at the interface due to the Fermi energy level mismatch. A photoexcitation will result in the generation of electron-hole pairs that are delivered to the semiconductor- electrolyte interface, causing charge transfer and triggering redox reactions that can be used for amperometric sensing and actuation in the localized spot. The hypothesis is that the flexible OMG system can achieve accurate light-induced sensing and actuation within a single entity of curvilinear surfaces at a cellular or sub-cellular dimension scale, and thus can serve as a powerful tool for biomedical investigation supporting multiple operation modalities such as biosensing, micropatterning, pH regulation and electrical stimulation. The study will include the following aims: Aim 1: Develop flexible photoelectrodes supporting light-induced redox reactions. Aim 2: Integrate the photoelectrodes with an optical system and test the feasibility of conducting spatially resolved, localized photoelectrochemistry. Aim 3: Evaluate performance/multifunctionality of “OMG” for applications in neuroscience & other fields.

NIH Research Projects · FY 2024 · 2024-08

Project Summary Mycobacterium tuberculosis (M.tb) causes tuberculosis (TB), a serious lung disease that affects over one third of the global population and results in ~1.5 million deaths every year. TB treatment includes a combination of three or more anti-TB drugs over a prolonged period (6–9 months). In the last few decades, multidrug-resistant TB and extensively drug resistant TB strains have emerged due to mismanaged use of anti-TB drugs, (e.g., not completing the full course of the TB regimen, using the wrong dose or length of administration time, and/or the use of poor-quality drugs). We propose that shortening the treatment period for clearance of M.tb would assist to eradicate TB and preventing the development of drug resistance in active and latent TB. We discovered that, the need for long treatment period is partly due to suppression of the host innate immune response by M.tb, which involves the efflux of endogenous anti-microbial substances and administered TB drugs from host macrophages. Specifically, when macrophages are infected with M.tb, expression of the macrophage drug efflux pump MDR1 increases, resulting in various endogenous and exogenous chemical substances, including TB drugs, being expelled from macrophages to benefit the survival of the bacteria. Thus, M.tb co-opts these host pathways. Overall, the mission of my laboratory is to identify molecules in the host that will enable us to create a novel host-directed therapy for TB. Toward that end, we were the first to discover the link between M.tb pathogenesis and macrophage MDR1 expression and function during infection. Elevated MDR1 alters the macrophage innate immune response and subsequent efflux of antimicrobials reduces the effectiveness of macrophages M.tb killing. We hypothesize that M.tb-dependent upregulation of MDR1 expression in human macrophages is mediated by heat shock factor protein 1 (HSF1). The aims of the proposed research are to 1) Define the role of MDR1 in M.tb survival in macrophages; 2) Determine whether HSF1 activation or MDR1 inhibition shortens the sterilization period of M.tb by TB drugs; and 3) Identification of endogenous antimicrobials produced by macrophages in response to M.tb infection. We will use human monocyte-derived macrophages, biochemical and genetic techniques, and a mouse model to accomplish our aims. Our basic research discoveries will jump-start the development of new drugs to treat tuberculosis.

NIH Research Projects · FY 2025 · 2024-08

TITLE Biochemical properties and implications of NRAS mutant-specific BRAF interactions in melanoma ABSTRACT Extracellular growth factors promote cellular proliferation, motility, and survival through a complex network of signal transduction pathways. Thus, mutations in these pathways can cause inappropriate cellular proliferation and lead to diseases, such as cancer. RAS, an intracellular hub for multiple signaling pathways, is mutated in 20-30% of all human cancers. While the three RAS isoforms (H-, K-, and N-RAS) share a high degree of similarity, each RAS-driven cancer type is enriched for mutations in a specific RAS isoform, codon (12, 13, or 61), and amino acid. We do not fully understand the mechanism driving this observed selectivity, although each RAS mutant has distinct biochemical and functional properties. Elucidating the mechanisms underlying these mutational preferences could help identify the features of oncogenic RAS required to initiate cancer in different tissue types. To address this knowledge gap, we have focused on the selection of specific NRAS mutants in melanoma. Our work has shown that common melanoma-associated NRAS mutants (Q61R, K) promote MAPK signaling through increased activation of BRAF homo- and hetero-dimers. New molecular dynamics simulations suggest that conformational properties, specific to the NRAS mutants that drive melanoma, facilitate BRAF binding. Here, I will test the hypothesis that structural differences between NRAS mutants determine their ability to outcompete autoinhibitory BRAF interactions, drive enhanced MAPK>ERK activation, and alter the potency of RAF inhibitors. To test my hypothesis, I will use a variety of in vitro biosensors, cell-based signaling assays, and mouse models to define the mutant-specific features of NRAS that facilitate BRAF interactions (Aim 1) and how the structural determinants of different NRAS mutant-BRAF interactions influence BRAF inhibitor sensitivity (Aim 2). Successful completion of these studies will enhance my knowledge of structural biology, therapeutic development, and mouse models of cancer. I will also identify mutant-specific NRAS-BRAF interfaces to guide the design of novel therapeutic approaches for NRAS-mutant cancers and provide information relevant to the clinical implementation of next-generation RAF inhibitors.

NSF Awards · FY 2024 · 2024-08

Languages vary in the interpretation of allowable quantities for words like "some." For example, in a hypothetical scenario like the following: four dogs want to cross a bridge and then four out of those four dogs cross it, some languages do not permit a logical interpretation that "some dogs crossed the bridge" is true, instead reserving a strict and informative meaning of "some but not all." In those languages the scenario would need to have at most three out of the four dogs cross in order to use the quantifier "some." This doctoral dissertation research project examines whether bilingual children are able to maintain this semantic distinction when input from their two languages differ on permissible interpretation. A secondary objective is to investigate what more general cognitive processes support these semantic distinctions. Previous research with monolingual children has shown that their vocabularies and their executive function abilities predict their semantic interpretations. However, less is known on whether the vocabulary of one language, the other, or a combination of both affects semantic interpretations during bilingual acquisition. The outcomes of this dissertation project can help inform theories on the structure of the bilingual mind. To investigate this topic, researchers use stop-motion video scenarios paired with sentences using quantifiers like "some" that are presented to bilingual child participants as descriptions of the video scenario. Participants complete vocabulary measures in each of their two languages along with a combined measure in order to analyze which measure leads to successful prediction of children's interpretations. Because quantifiers like "some" have two possible interpretations, children's executive function is also measured, since prior work with monolingual children has shown that executive function does affect a child’s ability to pay attention to the correct interpretation. 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 · 2024-08

PROJECT SUMMARY Adults with Down syndrome (DS) are twice as likely to be obese (BMI > 30kg/m2) than their peers without DS. The health consequences of excessive adiposity include greater risk for cardiovascular diseases, cancers, type II diabetes, etc. These alarming health implications highlight the importance of identifying accurate methods for body composition and physical activity (PA) analysis since an early detection and intervention could help alleviate the burden of diseases that occur later in life. Unfortunately, many methods used for assessing body composition and PA may be perceived as threatening and burdensome by individuals with DS. Particularly, the need to visit a research laboratory or clinical testing center may induce discomfort, as our team has noted in previous research conducted in adults with DS. The MPI’s can attest firsthand that many subjects with DS find body composition testing as threatening when using devices such as dual energy X-ray absorptiometry (DXA). Several subjects with DS that visited our laboratory had difficulty remaining motionless during the 5-to-10- minute DXA scanning procedure. We overcame those issues by having a parent or guardian available to offer verbal encouragement during the scan. Nonetheless, the emergence of wearable technology may offer the opportunity to measure body composition and PA in a comfortable environment. As a result, the utilization of wearable technology for body composition and PA may overcome problems commonly observed by researchers in validation studies. This multi-site cross-sectional study will include 50 adults with DS (18-60 years of age). Body composition will be measured via the InBody Band 2 (biompedance-based smartwatch) and compared against a criterion DXA scan. Further, the validity of wearable PA trackers will be examined via the following devices: wrist – Samsung Galaxy Watch 4, InBody BAND 2; waist – ActiGraph GT9X, thigh – activPAL Micro 4; and ankle – StepWatch 4. The wearable PA trackers will be validated against a criterion measure that consists of directly observed, hand tallied step count (with video recording for step count verification). This project relates to the mission of NIH since knowledge gained will be useful in promoting the health of a special population that has an increased risk of obesity by identifying whether a wearable technology can be used in weight management and PA interventions. In addition, this study is responsive to NOT-OD-21-092, which will study the validation of at-home diagnostic tools including actigraphy and wearable technologies in individuals with DS.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY Our proposed project is designed to investigate the immunopathological basis of NK cell-mediated pancreatic insufficiency which may lead to the future occurrence of diabetes mellitus (DM) among people living with HIV (PLWH). Furthermore, we plan to explore HIV/antiretroviral therapy-induced endoplasmic reticulum (ER) stress as a contributory pathophysiological phenomenon which would render pancreatic tissue more susceptible to immune-mediated destruction in this population, with attempts to mitigate this through low-cost, ER stress- inhibiting medication. Our comprehensive analysis of the altered immunophenotype among PLWH has revealed several subsets of activated, pro-inflammatory NK cells dominating the circulation. We have also successfully demonstrated direct effects of these altered NK cells among PLWH in contributing to the ongoing risk of other non-communicable diseases (NCDs) like atherosclerotic cardiovascular disease at a very young age. Based on our previous research findings and existing literature, we have gathered sufficient evidence to back our proposed studies. Our epidemiological findings have collectively predicted an increased risk of DM in an expanding HIV population dominated by young adults in Sri Lanka, a lower-middle income country (LMIC) in South Asia, which relies heavily on an active workforce for sustenance of its fragile economy. We strongly believe that our proposed work and its main outcomes may broaden our understanding of the NK cell-mediated immunopathogenesis of such NCDs and socioeconomically acceptable therapeutic/preventive strategies which could be implemented in these critical populations in the future. We also believe that our exploratory study would create a significant impact and ignite further research in this field of study. By conducting this project in an LMIC setting like Sri Lanka, we hope to foster a network of research collaborations between two diverse settings, with plans to strengthen the research infrastructure related to HIV and its comorbidities in Sri Lanka. Through our proposed scientific techniques such as high-dimensional flow cytometry, novel immunohistochemical techniques, transcriptomics and epigenomics, we hope to carryout exchange of knowledge and expertise and between our study settings and help build necessary infrastructure in Sri Lanka in an effort to lay the groundwork for future collaborations on HIV related research in this setting.

NSF Awards · FY 2024 · 2024-08

This project encompasses a research program in the field of ergodic geometry, which concerns the long-term behavior of dynamical systems arising naturally in geometry, particularly in situations where the geometry of the system leads to rich dynamics best studied from a probabilistic point of view. The most natural dynamical system in geometry is the geodesic flow: given an initial position and direction, a particle flows at unit speed along the path that locally minimizes distance. This flow has special importance because of its relationship with the geometry and topology of the underlying space. The shape of the space will often produce geodesic flows with interesting dynamical behavior. Consider, for example, a torus with more than one hole, which can be visualized as a pretzel. Paths in the torus that start close together will usually separate and follow different and unpredictable trajectories around the holes. Typically, such trajectories will eventually look independent of the way they started. This is a model situation in which the dynamics and geometry can be understood using tools of ergodic theory. The PI will pursue research on ergodic geometry in two main directions which take advantage of the interplay between geometric and dynamical techniques. In one direction, the PI studies a variety of new problems in the geodesic flow setting that have become tractable due to recent advances in the state-of-the-art. In another direction, the PI expands on this approach by implementing the ideas of ergodic geometry in a broader class of smooth dynamical systems beyond geodesic flows. This award will also support the training of graduate students, and the participation of undergraduate students in the Ohio State REU program in dynamical systems. This project has three parts. The first part of the project comprises the next phase of the PI’s research on geodesic flows. Problems include thermodynamic formalism for CAT(0) spaces and rates of mixing for a broad class of geodesic flows and reference measures. The second part of the project concerns thermodynamic formalism for a panorama of smooth dynamical systems with non-uniform properties, focusing on dynamics ‘beyond’ rational maps. Complex dynamics has strong analogies with the theory of geodesic flows in negative curvature, and the PI furthers the analogy by importing some novel ideas to that setting. The third part of the project will involve the development of symbolic dynamics for non-compact geodesic flows on manifolds in dimensions 3 and higher. The project includes substantial mentoring and research opportunities for early-career mathematicians. 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 · 2024-08

PROJECT SUMMARY/ABSTRACT Pseudomonas aeruginosa, Candida albicans, and Candida auris are opportunistic pathogens of great concern due to their broad arsenal of virulence factors and resistance to antimicrobial drugs. These pathogens are among the most common agents in hospital-acquired infections and are often co-isolated from lung and wound infections. Furthermore, these infections are often in the form of mixed-species biofilms, which can provide additional protection against antimicrobial compounds. The antimicrobial resistance crisis of the last few decades in combination with the rise of difficulties in discovery of drugs with novel mechanisms of action have resulted in urgent needs for alternative treatments. Bacteriophage (phage) therapy and antimicrobial peptides (AMPs) present as encouraging approaches. Phage therapy has been used to combat bacterial infections for over a century and is an exciting alternative approach to combat drug resistant bacteria. Phage therapy employs bacterial viruses as antibacterial agents yet provides no remedy for fungal infections. There also are no known lytic viruses that infect Candida spp. Therefore, the present study aims to develop novel treatments against P. aeruginosa and Candida spp., using combinations of phages and antimicrobial peptides, with focus on the treatment of dual-species biofilms. In addition to developing combination treatments utilizing antimicrobial peptides and phages, we propose to genetically engineer P. aeruginosa phages to produce AMPs to enhance peptide access to targeted Candida spp. within mixed-species biofilms. This approach alleviates two potential concerns with the current state of AMP application: low bioavailability due to peptide instability in body fluids and excessive toxicity if higher systemic doses are required. Dual-species biofilms will be generated in vitro, subjected to these treatments, and analyzed to determine remaining live biomass using metabolic studies. Differentially fluorescently labeled strains will also be used for confocal microscopy to determine strain-specific responses to these treatments. Suitable antimicrobial peptides will be identified against single- and dual-species populations growing planktonically and in biofilms. Phage engineering will involve using a CRISPR-Cas9 system to edit phage genomes to encode anti-Candida and anti-biofilm AMPs. The phage engineering approach provides not only novel alternative treatments, but also a new phage engineering pipeline, expanding the use of phages as cargo delivery vehicles to infection-specific sites. To our knowledge, this is the first study investigating engineering phages to produce AMPs to treat mixed-species populations, and thus may also serve as a template for the treatment of mixed-species infections beyond P. aeruginosa and Candida spp.

NSF Awards · FY 2024 · 2024-08

A goal of probability theory is to understand and predict the behavior of large random systems that are present in everyday life, such as traffic models, percolation, polymers, and the molecular structure of solids. Because a rigorous treatment of such random systems is still out of the reach of probability theory, mathematicians and physicists instead consider idealized models with the same large-scale behaviors that are amenable to standard mathematical analysis. In this project, the PI will use multivariate special function techniques to construct and study random idealized systems that are “solvable,” meaning they can be analyzed through well-honed, yet sophisticated, ideas from representation theory and combinatorics. At the same time, these models are ubiquitous in nature, because of their origins in random matrices, plane partitions and quantum algebras. This project will provide training activities and outreach efforts aimed at undergraduate and graduate students through research opportunities and lecture series led by the PI. This project is centered around two interrelated topics: (i) Continuous and discrete Boltzmann distributions from statistical physics. These can be regarded as one-parameter generalizations of random matrix eigenvalues and random partitions. The goal is to describe, using novel versions of free probability, the large-scale asymptotics of random particle ensembles at various temperature limit regimes. The main tool will be the Dunkl transform, which depends on multivariate Bessel functions. (ii) Asymptotic representation theory and its relations with beta-ensembles. The open problems to be considered are infinite-dimensional versions of the classification of irreducible representations and the problem of noncommutative harmonic analysis. Prior work employed q-orthogonal multivariate polynomials to unveil links between representations and novel discrete quantized analogues of beta-ensembles, yielding connections with measures from topic (i). 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 · 2024-08

ABSTRACT Heavy, problematic alcohol use is highly prevalent within individuals receiving medications for opioid use disorder (MOUD) and contributes to increased risk of opioid overdose and poorer MOUD treatment outcomes. The recently proposed CANUE model (Catastrophizing, Anxiety, Negative Urgency, and Expectancy) suggests that emotional pain (or psychological distress) is a robust proximal antecedent to alcohol and opioid use via negative reinforcement. More importantly, the CANUE model posits that several modifiable risk factors influence ‘self- medication’ of emotional pain with alcohol during MOUD. Two key factors implicated in this model are anxiety sensitivity (AS) and intolerance of uncertainty (IU) which are theorized to independently and synergistically interact to amplify the negative reinforcement cycle of addiction and play a unique role in alcohol use during MOUD. Along these lines, our team has developed a brief, digitally-enhanced, virtual psychotherapeutic intervention called IMPROVE: Managing Physical Reactions to Overwhelming Emotions. IMPROVE is associated with large reductions in IU and AS in college students with elevated anxiety. The overall objective of this proposal is to further develop and refine IMPROVE to be used as a brief intervention to reduce alcohol use among individuals engaged in MOUD. We will also use this planning project to collect preliminary data on whether changes in AS/IU targets are linked to changes in alcohol use. This R34 study will lay the groundwork for a large-scale clinical trial of IMPROVE to reduce heavy drinking and enhance MOUD outcomes. The current study will leverage the infrastructure of our university-based addiction treatment center and a community partner to complete two study phases. In Phase One (Aim 1; Year 1) we will adapt IMPROVE’s content, delivery, and digital tools using the Delphi method with key experts and stakeholders. We will also develop an implementation protocol through field usability sessions. Aim 1 will yield a customized, feasible, and acceptable IMPROVE package ready for implementation. In Phase Two (Years 2-3) we will conduct a pilot randomized control trial of the adapted IMPROVE protocol as compared to our active control intervention on drinking behavior in individuals receiving MOUD. Heavy alcohol users receiving MOUD will be assigned to IMPROVE or a control health promotion intervention (N=40 per arm). All participants will complete daily ecological momentary assessments (EMA) delivered to participants’ mobile phones to capture real-world alcohol use before, during, and after the intervention. We will evaluate the impact of IMPROVE (vs. control) on daily alcohol use (primary) and MOUD adherence (secondary), and explore treatment-related changes in the antecedents of drinking behavior (Aim 2). Phase Two will also include a multimodal battery of self-report and objective lab-based measures of AS and IU involving startle eyeblink potentiation and event-related potentials via electroencephalography (EEG). This will allow us to examine whether IMPROVE changes IU and AS, and to assess if changes in these targets are associated with changes in alcohol use (primary) and MOUD adherence (secondary) (Aim 3).

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY Ableist discrimination is pervasive in healthcare and negatively affects the US organ transplant system, resulting in patients with intellectual or developmental disabilities (IDD) often being unjustly excluded from life-saving transplantation. To address this inequity, thirty-nine states have passed laws prohibiting disability-based discrimination in organ transplantation. Currently, we do not know the extent to which anti-discrimination laws mitigate ableism against patients with IDD, nor do we know which patient factors compound with ableism to exacerbate disparities in transplantation access. Focusing on kidney transplantation, the most commonly transplanted solid organ in the US, we will leverage our team’s unique expertise in IDD, transplant equity, population-level claims data, and policy evaluation to achieve our specific aims: (Aim 1) determine the efficacy of state laws prohibiting ableist discrimination in closing the equity gap between kidney transplant candidates with vs. without IDD; (Aim 2) identify patient factors that compound with ableism to disproportionately reduce kidney transplant access and increase dialysis time for patients with vs. without IDD; (Exploratory Aim 3) compare reasons for exclusion among patients with vs. without IDD to understand how ableism impacts access to kidney transplantation. We will achieve these aims through the synergistic use of national Medicare claims data and local electronic health records (EHR) data. In Aim 1, we will use staggered adoption difference-in- difference models to assess the impact of anti-discrimination laws on kidney transplant access for propensity score matched samples of patients with and without IDD. In Aim 2, we will use multi-level regression and time- to-event models with interaction terms and contrast statements to quantify the compounding effects of comorbidities and social determinants of health with ableism for patients with IDD relative to propensity-score matched patients without IDD. Last, in Exploratory Aim 3, we will leverage EHR data from four large academic transplant centers to compare the stated reasons for kidney transplant denial between patients with and without IDD. Findings will have practical applications for healthcare providers, regulatory agencies, and legislators responsible for mitigating ableism against people with IDD in organ transplantation. This study is responsive to RFA-HD-24-007 in that we will “examine the impact of existing efforts to address ableism (e.g., laws) on the health of individuals” with IDD and how patient factors mediate the “impacts of ableism on health.” This project will have a high public health impact yielding new, actionable information to further mitigate ableism against people with IDD in organ transplantation and improve equitable access to this life-saving care.