Johns Hopkins University

NIH Research Projects · FY 2025 · 2025-09

Smart assistive technology (SAT) for individuals with severe vision loss is becoming affordable, thanks to miniaturization of display hardware (head-mounted or phone screen) and more powerful AI software, driven by demand in the consumer market. Unfortunately, these developments do not take into account visually impaired users’ perspective on: 1) ergonomics, i.e., non-visual access to all device functions; and 2) relevance, i.e., functionality that meets their needs and enhances independence. The most often heard complaint is that the device or app overwhelms the user with information, so pertinent information is too hard to find. In this application, four organizations — the Low Vision divisions at Johns Hopkins (JHU) and the Chicago Lighthouse (CLH), Applied Universal Dynamics Corp (AUD) and the Pritzker Institute at the Illinois Institute of Technology (IIT) — are joining forces to address this problem. We are uniquely positioned to do so, through our combined expertise in smart systems design and integration (AUD), clinical and rehabilitative knowledge of the user population (JHU and CLH), and the opportunity to extend the user base to visual prosthesis users (IIT). With the users’ lived experience in mind, we propose to reduce the information overload by defining a gaze-contingent region of interest (RoI) specific to each user’s gaze and remaining visual field, so the AI- supported system will operate on targets within this RoI. In the R61 phase of the project, we will use a head- mounted display (HMD) with built-in eyetracking as the platform; in the R33 phase, a glasses frame with built-in camera and eyetracking will be used, with a smart phone or belt pack computer running the AI engine. The R61 phase will encompass 3 Aims: 1) Formulate user requirements by surveying SAT users (interviews and discussions), and recruit an expert user panel for ongoing feedback; 2) Design and build an HMD-based prototype (H1) for clinical tests, with a software upgrade (H2) based on initial outcomes and feedback; 3) Conduct user training and collect ongoing feedback and performance data for evaluation and re- design. The R33 phase will create the glasses-based system and enhance processing power and customization, through 3 additional Aims: 4) Integrate the glasses frame camera and eyetracker with a speech- enabled belt pack computer (G1), with an upgrade in Year 4 (G2) suitable for take-home use; 5) Enhance user- specific solutions by adding individualized and task-specific RoI adjustments, and add search and hazard warning functions for users with narrow fields; 6) Conduct user training and collect ongoing feedback and performance data for evaluation and G2 upgrades, followed by a 3-month take-home study with performance tests (pre vs, post). The resulting gaze-contingent AI-supported low vision adaptive technology (GALVAT) will be highly adaptive to users’ individual needs and greatly contribute to their functional visual independence.

NIH Research Projects · FY 2025 · 2025-09

Project Summary: During development, sensory neurons differentiate into subtypes with distinct morphologies, gene expression, and functions. In the retina, the diversity of photoreceptor subtypes is critical for vision and the ability to interact with the environment. This proposal aims to advance our knowledge of cell fate specification by examining how photoreceptors are patterned during development in flies and mosquitoes. In the fly eye, stereotypical and stochastic patterns are overlaid during development. The stereotypical structure of the eye results from a wave of morphogenesis, driven by Hedgehog (Hh) signaling, which promotes expression of Decapentaplegic (Dpp). Overlaid on the regular morphology of the eye, two R7 photoreceptor subtypes are stochastically patterned, controlled by stochastic ON/OFF expression of the transcription factor, Spineless (Ss). My preliminary studies show that Hh signaling coordinates stereotyped and stochastic patterning in the fly eye, requiring activity of the receptor Patched (Ptc), but not Cubitus Interruptus (Ci), the canonical transcriptional effector. I hypothesize that Hh functions through an unidentified transcriptional factor to promote (1) dpp transcription and stereotypical morphological patterning and (2) ss transcription and stochastic R7 subtype patterning. To test this hypothesis in Aim 1, I will analyze the transcriptional and chromatin dynamics of dpp and ss regulation. I will generate a single-nucleus multiomics dataset to identify putative transcription factors mediating Hh signaling and examine their functions in the eye. This aim will address how signaling mechanisms that drive stereotypical patterning are co-opted to produce stochastic patterns during development. Mosquitoes are a disease vector that pose an increasing risk to human health and welfare. In mosquitoes, vision is critical for host-seeking, mating, and foraging behaviors, yet the mechanisms that establish patterning of the mosquito eye are not known. In contrast to the fly eye, R7 subtypes are found in stereotypical stripe patterns in the dorsal and ventral regions of the mosquito retina. I hypothesize that the gene network giving rise to stereotypical PR subtype specification is vital for mosquito survival behaviors. To test this hypothesis in Aim 2, I will generate a single-nucleus multiomics atlas of retinal development in An. gambiae, identify factors with cell-type-specific expression and roles in fly eye development, and validate their expression using IHC and RNA FISH. I will determine roles for Drosophila R7 patterning genes in An. gambiae. Finally, I will determine the functional roles of R7 subtype specification in behavior using host-seeking assays. In my lab, I will dissect the regulatory networks involved in mosquito retinal development, focusing on patterning and cell fate specification. Using the atlas, I will define the roles of ~30 key regulators previously characterized in flies, and compare their functions across species, including Ae. aegypti. I will also identify and test novel regulators of mosquito eye development. These studies will provide the first mechanistic dissection of eye development in mosquitoes, generate insights into evolution of the underlying mechanisms, and establish my independent research program.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT/SUMMARY Pregnancy-related outcomes, and disparities in these outcomes, remain poor and have worsened in recent years. At the same time, the lack of safe and affordable housing has become a national crisis. Despite the strong potential for housing insecurity to impact the perinatal period, there is a paucity of evidence connecting these two areas. The Care, Housing Assistance, Medicaid, and Perinatal (CHAMP) Health Outcomes Study is a highly innovative investigation of the association between housing security and perinatal and infant outcomes. It focuses on the role of federal housing assistance which, through a variety of programs, including Housing Choice Vouchers, public housing, and multifamily housing, limit household spending on rent and utilities. By increasing housing affordability and stability, improving housing quality, changing neighborhood context, and connecting residents with health and social services, federal housing assistance has the potential to improve the quality of care that pregnant individuals receive and, more broadly, shed light on the intersection of pregnancy and housing. The study makes use of a novel dataset linking national Medicaid claims for the years 2016-2023 with U.S. Department of Housing and Urban Development data on the receipt of federal housing assistance. Because individuals who receive housing assistance may be fundamentally different from those who do not, the study makes use of an innovative ‘pseudo’ waitlist control design that leverages the limited supply of housing assistance relative to demand and the random timing of the receipt of housing assistance. The first aim examines the overall relationship between receipt of federal housing assistance and pregnant and postpartum individuals (including pre- and post-natal care and morbidity) and newborns (including low birth weight, preterm birth, and neonatal intensive care admission). The second aim investigates whether these relationships vary across a range of factors including race and ethnicity, neighborhood socioeconomic context, and type of housing assistance. The final aim uses qualitative methods to elicit narratives and perspectives on how housing assistance can support perinatal and infant health through interviews with policy and program officials, practitioners, and people with lived experience.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Mary Rooney, PhD, MPH is a junior faculty member at the Johns Hopkins Bloomberg School of Public Health Department of Epidemiology at the level of Assistant Research Professor. She seeks a K01 Mentored Research Scientist Development Award to become an independent research scientist in the area of diabetes prediction and -omics. This research proposal details a 5-year plan to refine current prediabetes definitions to better predict who will develop diabetes and its complications using clinical factors, novel proteomic biomarkers, and polygenic risk scores. The specific aims of this research are to: 1) harmonize datasets and pool participant-level data from 13 epidemiologic cohorts; 2) refine prediabetes definitions by integrating information on clinical factors, novel proteomic biomarkers, and genetic susceptibility; and 3) quantify the associations of clinical, proteomic, and genetic risk stratification groups with risk of diabetes complications. Short-term career goals include advanced training in multiple -omics research, leading a meta-analysis within a consortium and the development and validation of diabetes risk prediction equations. The proposed mentored research and career development activities fill training gaps needed to facilitate Dr. Rooney’s transition into a successful independent researcher. A more precise approach to diabetes risk stratification can inform clinical and public health strategies for the screening and primary prevention of diabetes and its complications.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY - OVERALL The overall goal of this proposal is to create a Rare Disease Clinical Research Consortium (RDCRC) to facilitate collaborative clinical and translational research, patient advocacy and education, and training clinicians and researchers focused on thrombotic microangiopathies (TMAs). TMAs are a group of rare disorders characterized by thrombocytopenia, microangiopathic hemolysis, and ischemic organ injury due to microvascular thrombosis. They include immune-mediated thrombotic thrombocytopenic purpura (iTTP), congenital TTP (cTTP), complement-mediated TMA (CM-TMA or aHUS), and multiple causes of “secondary” TMA. iTTP is caused by autoantibody-mediated deficiency of ADAMTS13 (a key regulator of coagulation) and cTTP is caused by a genetic deficiency of ADAMTS13. Acute outcomes of TMA have improved dramatically with advances in pathogenesis and treatment. While it was previously believed that TMA survivors return to their baseline level of health after recovery from an acute episode, collaborative efforts from our group and others have established that iTTP and cTTP survivors experience increased rates of stroke and other cardiovascular events, cognitive impairment, depression, and earlier mortality that is attributable primarily to cardiovascular causes. There is little data on the long-term outcomes of CM-TMA, but our preliminary studies show high rates of hypertension and cardiac disease. We will leverage the existing United States TMA consortium with high volume clinical sites, experienced investigators, and close collaboration with patient advocacy groups to evaluate outcomes across the lifespan to define unmet treatment needs, answer pressing clinical questions, and to establish clinical trial readiness for interventional trials of novel treatment strategies. The RDCRC focused on collaborative clinical research in the TMAs will undertake prospective longitudinal registries of adults and children with cTTP, iTTP (Project 1), and CM-TMA (Project 2) with acute and remission clinical data, comorbidities, treatments, and outcomes including relapse, cardiovascular and cerebrovascular disease, and pregnancy outcomes. Project 1 will also prospectively evaluate cognitive function and silent cerebral infarction in cTTP and iTTP. In project 2, we will use a novel cell-based assay to evaluate the role of persistent complement dysregulation in clinical remission in CM-TMA sequelae including relapse, progressive renal impairment, and cardiovascular disease. We will develop a pilot core for evaluating and funding novel clinical research proposals, and a career enhancement core to provide training focused on TMAs to foster the development of future generations of TMA experts. Finally, we will collaborate with patient organizations, scientific and medical societies, and industry partners to provide information regarding diagnosis, treatment, clinical and basic research in TMAs to medical professionals, scientists, families, and other lay persons.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Crohn’s disease (CD), and the related condition of ulcerative colitis, are chronic inflammatory bowel diseases (IBD) that impact 3.1 million Americans. While anti-cytokine therapies have revolutionized care, clinical remission is only achieved in 40% of patients with CD – a therapeutic ceiling that has not changed in 20 years. These data underscore the need for new treatment strategies. We are focused on understanding the role of defective N-glycosylation in CD as an innovative strategy to study pathophysiology and develop new therapeutics. Depending on the ancestral background, 7-25% of patients with CD carry a pathogenic, missense mutation in the manganese (Mn) transporter ZIP8 (ZIP8 A391T). ZIP8 regulates systemic Mn homeostasis via enteric and hepatobiliary Mn absorption. ZIP8 391-Thr causes a relative Mn insufficiency that impairs Mn-dependent N- glycosylation. Our central hypothesis is that CD is exacerbated by aberrant N-glycosylation in patients with ZIP8 391-Thr and that this defect can be targeted by specific, safe therapy. Supporting this hypothesis, blood Mn levels are 15% lower and complex, branched N-glycans are decreased in plasma in ZIP8 391-Thr carriers. Further, we uncovered an ileal microbiota signature that implicated altered bile acid homeostasis in ZIP8 391- Thr carriers. We generated a knock-in (KI) mouse model (Zip8 393T-KI) that recapitulates findings of these human studies. Promising human trials have shown that defects in N-glycan branching can be safely restored by raising levels of the rate-limiting metabolite UDP-N-acetylglucosamine (GlcNAc) via supplementation, sparing risks related to direct Mn supplementation. Our preliminary data in Zip8 393T-KI mice have demonstrated that GlcNAc supplementation restores N-glycan branching deficits in the gut and rescues defects in bile acid homeostasis, intestinal permeability, and colitis susceptibility. Thus, our objective is to use the Zip8 393T-KI mice to study the molecular impact of decreased N-glycan branching in the ileum and develop aberrant N- glycosylation as a therapeutic target in CD. In Aim 1, we will elucidate how ZIP8 391-Thr impacts systemic Mn homeostasis to impair Mn-dependent processes. We will use study of bile acid homeostasis, determined by the activity of the key ileal glycoprotein, apical sodium-dependent bile acid transporter (Asbt), as a model to determine the impact of decreased N-glycan branching. These mechanistic studies will be complemented by the unbiased approach of glycoproteomics to expand our understanding of the proteins and pathways perturbed by ZIP8 391-Thr and decreased N-glycan branching with studies in Zip8 393T-KI mice and ileal biopies from healthy individuals and patients with active CD. In Aim 2, we will prospectively “glyco-phenotype” patients with CD to inform on the spectrum of N-glycan branching defects in patients with CD, and we will test the efficacy of oral GlcNAc supplementation in patients with CD and ZIP8 391-Thr in a randomized, placebo-controlled, cross-over study. Together, these studies will assess the impact of aberrant N-glycosylation in CD and accelerate progress towards targeted, genotype-specific, glycosylation-directed therapies.

NIH Research Projects · FY 2025 · 2025-09

Cardiovascular diseases and pulmonary fibrosis remain leading global health challenges, with cardiovascular diseases accounting for 17.9 million deaths annually and pulmonary fibrosis carrying a median survival time of only 3 to 5 years post-diagnosis. Despite current treatment options, patients with pulmonary fibrosis continue to experience high mortality rates. A major challenge to developing targeted treatments is the limited understanding of the molecular and biophysical mechanisms driving these diseases, specifically, how a cell initiates membrane asymmetry, establishes polarity, and enables directional migration—the fundamental biological processes involved in developing and maintaining cardiovascular and pulmonary systems. My recent findings reveal that phosphatidylinositol 4-phosphate 5-kinase (PIP5K), which synthesizes phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), undergoes dynamic partitioning and reciprocally inhibits Ras small GTPase activity during cell migration. Therefore, we target PIP5K and our overall hypothesis is that PIP5K and its effector Arf GTPase regulate cell migration through differential diffusion-driven dynamic partitioning, modulating Ras activity and downstream signaling pathways on specific membrane regions. The proposed hypothesis will be addressed in three specific aims. Aim 1 will determine how dynamic partitioning and binding affinity of PIP5K contribute to symmetry breaking and polarity establishment in migrating cells. I will measure PIP5K diffusion coefficients with photo-conversion techniques and single-molecule imaging under varying conditions. I will investigate how actin and actomyosin networks influence PIP5K partitioning using CRISPR-based gene disruption and pharmacological inhibitors. These experimental data will be integrated into stochastic simulations of an excitable network to validate models of symmetry breaking. Aim 2 seeks to identify and characterize the binding partners of PIP5K to understand its role in regulating Ras activity. I will use TurboID proximity labeling and Mass Spectrometry to map PIP5K’s interactome, with validation through co-immunoprecipitation and genetic perturbation. Functional studies will investigate how these partners influence PIP5K and Ras activities during cell migration. Aim 3 focuses on elucidating the roles of Arf GTPases in regulating cell migration and PIP5K functions. Using optogenetic tools and CRISPR, I will study how Arf GTPases and their regulators (ArfGEFs and ArfGAPs) modulate PIP5K localization, Ras signaling, and cytoskeletal dynamics. Biochemical assays will explore interactions between Arf proteins and PIP5K and their joint regulation of Ras activity. This study will provide valuable insights into how PIP5K, Arf, and Ras form a signaling cascade to regulate cell migration and polarity through the Ras/PI3K/Akt pathway and potentially uncover novel therapeutic targets for cardiovascular and pulmonary diseases. This project aligns with NHLBI’s mission to advance research on heart, lung, and blood diseases, improving public health through innovative science.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Native American (NA) toddlers and preschoolers experience a high rate of preventable developmental delay (DD) which contributes to decreased kindergarten readiness and often results in the need for special education services. In addition, children with DD are at high risk for preventable health issues, such as obesity and behavior problems. Varying environmental factors, such as poverty, decreased opportunities for structured play, increased caregiver stress, and low print exposure can contribute to DD. One of the most effective ways to address this type of DD is through caregiver coaching intended to boost the frequency of quality, language- rich interactions between caregivers and their young children. Evidence shows DD, especially in the areas of language and social-emotional skills, can be both prevented and remediated through increased language nutrition (LN) exposure. LN is defined as early language exposure that is rich in quality and quantity and delivered through social interactions at home. LN is crucial for a young child's development and strongly associated with future literacy, academic achievement, and better health. An ideal opportunity to deliver LN programming to NA families today is through Tribal Home Visiting programs. The “+Language is Medicine (+LiM)” intervention that will be tested in this study combines cultural adaptations of two evidence-based language interventions: It Takes Two to Talk and Enhanced Milieu Teaching. The current +LiM training package equips tribal home visitors to model and coach primary caregivers through home-based education to use responsive and reciprocal early communication and language acquisition strategies--emphasizing traditional language learning, when possible—to support their children's development. This randomized controlled trial intends to test the effectiveness of the +LiM intervention with caregivers and children ages 9 to 24 months living on the Navajo Nation. We will evaluate +LiM versus a beneficial control condition (Family Spirit Nurture—which promotes optimal early childhood feeding) on preventing early childhood DD, using a Hybrid Type I Effectiveness-Implementation approach. We will track toddler's development before, during, and after the +LiM intervention is delivered. An additional aim is to co-design promising implementation strategies to support integration of +LiM at scale across the Navajo Nation and other communities. This aim will be accomplished through collaboration with +LiM participants and national stakeholders to understand barriers to and facilitators of +LiM implementation across the country. This study is responsive to Program Announcement PAR-20-238 and focuses on key areas of interest including the development, adaptation, and testing the effectiveness of health-promotion and disease-prevention interventions in NA populations. Our overall objective is to rigorously test the +LiM intervention designed to be embedded in tribal home visiting programs so that we can detect early signs of DD in NA toddlers and prevent these delays from progressing.

NIH Research Projects · FY 2025 · 2025-09

In 2022, 2.3 million newborns died in their first 28 days of life. Over half of these deaths occurred among small vulnerable newborns (SVN), who are born preterm (<37 weeks’ gestation), small-for-gestational-age (SGA, <10% centile), and/or low birth weight (LBW, <2,500g). The highest rates of SVNs occur in South Asia, where 52.1% of newborns are affected, and global and regional progress in reducing these outcomes has stagnated over the last decade. Periodontal disease has been implicated in observational studies as a factor associated with preterm, SGA, and LBW births. Yet randomized controlled trials evaluating the impact of periodontal interventions on incidence of SVN types have produced inconsistent results. Meta-analyses of previous trials have reported that many studies failed to eliminate the periodontal disease exposure or suffered from methodological flaws that threatened their internal validity, and some only delivered interventions later in gestation, potentially too late to disrupt hypothesized pathways. The study proposed in this application offers an opportunity to address such issues in innovative ways, including by 1) enrolling a large sample, 2) identifying participants in the 1st trimester for early intervention initiation, and 3) utilizing a low-cost package of interventions, including an antiseptic oral rinse, to reduce gingival inflammation. The study area, located in Nepal’s Terai region, has high rates of SVN types and neonatal mortality and is broadly representative of rural settings in much of South Asia. The study is a cluster-randomized controlled trial (n=2,280) to evaluate a package of oral health interventions delivered early in the first trimester until delivery on the incidence of SVNs in rural Sarlahi District, Nepal. The intervention package will include an oral health examination, daily antiseptic oral rinse, intensive oral hygiene education and instruction, and provision of a manual toothbrush, toothpaste, and dental floss. The trial will map and census the area, randomize clusters to intervention or control, establish surveillance to identify incident pregnancies, collect baseline data in both arms on a range of factors, deliver the intervention package until the pregnancy outcome, and visit participants within 72 hours of birth to assess incidence of SVNs and other outcomes. In a biospecimen sub-study (n=200), we will collect venous blood, gingival crevicular fluid, and plaque in early and late pregnancy to explore relationships between subgingival inflammation, circulating inflammation, and SVN types. The specific aims are to: 1) Determine the effect of a package of oral health interventions in pregnancy on the incidence of SVNs at birth and preterm birth, SGA birth, and LBW birth; 2) Explore relationships between subgingival inflammation, circulating inflammation, and incidence of SVNs.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Tuberculosis (TB) is the leading single-agent cause of infectious mortality worldwide, including among people with HIV (PWH). TB survivors also continue to experience sequelae including post-TB lung disease (PTLD) and higher mortality. It remains uncertain, however, how much of these post-TB sequelae reflect TB itself versus underlying pre-TB risk factors and lung disease. For example, if a substantial burden of PTLD reflects pre-existing lung damage due to smoking – itself a risk factor for TB – then preventing TB may have minimal effect on this burden, and we should prioritize efforts to augment smoking cessation (including among people at risk for TB). By contrast, if PTLD development instead reflects lung damage incurred while TB diagnosis was delayed (e.g., because people who smoke may delay seeking care for a cough), then efforts to detect TB more rapidly – or prevent TB in the first place – are even more essential. Such questions can only be answered by evaluating lung function and respiratory symptoms both before and after people develop TB. Performing such a study is challenging, however, because typically no more than 1 in 500 people develop TB each year. Thus, a large population must be followed after an initial lung function evaluation to obtain a sufficient sample size for analysis. This proposal leverages a unique opportunity to create such a prospective cohort, as 9,000 people from a district in rural southwestern Uganda (Rakai district) are already being recruited into a cohort study involving lung function testing. These participants can be followed for TB and paired with an additional 20,000 people from an ongoing decades-long community-based cohort study in the same area (the Rakai Community Cohort Study) to create a novel prospective population-based cohort for evaluating pre-TB and post-TB lung function in an HIV-endemic African setting. In Specific Aim 1, we will characterize trajectories of lung function before and after the development of TB disease, including among key subgroups (e.g., PWH). This aim will enable us to infer the fraction of post-TB lung function deficits that are attributable to TB itself versus reflective of underlying lung vulnerability. In Specific Aim 2, we will identify pre-TB characteristics and biomarkers that are associated with a higher burden of future PTLD – both through higher risk of developing TB and higher risk of experiencing PTLD if TB develops. This aim will enhance our understanding of PTLD pathophysiology and identify key subpopulations that might benefit from interventions to prevent TB or mitigate its consequences. In Specific Aim 3, we will use population modeling techniques to project the likely long-term impacts of different interventions on the population burden of post-TB illness. These results will enable policymakers to better prioritize those interventions most likely to have the greatest impact when delivered to specific key populations. In summary, the proposed study will make use of a novel “window of opportunity” to better understand lung function in TB survivors – before they develop TB in the first place. This understanding will facilitate a more effective response to averting and/or mitigating the tremendous burden of post-TB illness worldwide.

NIH Research Projects · FY 2025 · 2025-09

Summary Efforts towards an HIV cure have elucidated the marked variation in the HIV reservoir and the immune responses between different individuals. Sex has emerged as a factor that is associated with differences across the spectrum of HIV from acquisition through pathogenesis and HIV reservoir dynamics. Although the mechanisms are incompletely defined, the sex steroid hormone 17β-estradiol has been shown to interact with HIV replication and maintenance of latency. Levels of this hormone vary dramatically over the lifespan, introducing periods of potential reservoir disruption that are unique to women. In addition, natural aging has sex-specific features, which may be partially linked to sex steroid hormone exposure, and this has intersections with HIV reservoir maintenance and immunity. Despite these data, there is a marked underrepresentation of women in studies relevant to HIV cure. This is in part due to the limited number of cure studies in Africa where the majority of women living with HIV reside; this has also meant that the majority of virologic assays have not been developed for non-subtype B viruses. In this proposal, we will address the knowledge gaps around sex-specific features of HIV reservoir with specific attention to aging across the reproductive lifespan in a cohort of Ugandans living with HIV. We will accomplish this with three specific aims: 1. Analyze the impact of pregnancy on HIV reservoir and immunity 2. Assess HIV reservoir and immunophenotype across the menopausal transition in comparison to chronologically age-matched men 3. Estimate epigenetic age in women and men living with HIV and assess for relationships with sex and HIV reservoir activity. We have assembled a multidisciplinary team, led by co-Principal Investigators Dr. Eileen Scully (Johns Hopkins University) and Dr. Ronald Galiwango (Rakai Health Sciences Program), who together have the expertise and infrastructure to recruit participants and perform the advanced analyses to accomplish these aims. The study will substantively advance the understanding of the non-subtype B reservoir in women across the reproductive lifespan and the intersections between sex, reservoir and aging with multiple potential implications for curative efforts.

NIH Research Projects · FY 2025 · 2025-09

Food insecurity is common among adults with obesity and is associated with less favorable outcomes in behavioral weight loss (BWL) interventions. There is a lack of evidence on treatment strategies that are effective in addressing both food insecurity and obesity. The primary objective of this proposal is to improve obesity treatment among adults with food insecurity by enhancing patients' capacity to afford and obtain nutritious foods during BWL. To achieve this objective, we will conduct a randomized controlled trial with a 3-group, parallel design that enrolls 300 adults with obesity and food insecurity. Participants will be assigned to one of three groups: BWL-Alone (n=100), BWL with food supplementation via either food vouchers (BWL+VOUCHER; n=100), or home-delivered, medically tailored groceries consistent with BWL recommendations (BWL+HOME; n=100). Food vouchers and HOME provisions will be provided for the initial 24 weeks of treatment. All groups will receive BWL treatment for 52 weeks in accordance with treatment guidelines. Assessments will occur at baseline and at weeks 12, 24 (conclusion of food supplementation), and 52 (completion of BWL treatment). Our primary aims are to assess whether BWL+VOUCHER and BWL+HOME yield greater weight loss (percentage of initial weight) at 24 weeks compared to BWL-Alone. Secondary objectives are to examine differences in percent weight loss between BWL+HOME vs BWL+VOUCHER at week 24, and to assess changes among groups from baseline to 52 weeks. Additional secondary goals are to investigate changes in health-related quality of life and self-reported and objective measures of dietary quality across treatment groups. Our exploratory aim is to conduct an economic analysis to evaluate the cost-effectiveness of each intervention. The anticipated outcome of this study is to provide evidence of feasible food support interventions applicable within healthcare systems to improve nutrition in people with obesity.

NIH Research Projects · FY 2025 · 2025-09

Continuous glucose monitoring (CGM) systems have revolutionized glycemic control in people with type 1 diabetes. Prediabetes and type 2 diabetes are heterogenous conditions with significant variation in etiology and rates of disease progression.1-3 Standard glycemic measures such as hemoglobin A1c (HbA1c) do not capture certain elements of glycemia (e.g., variability, hypoglycemia) that are predictive of progression and complications.4-6 CGM systems comprehensively capture glucose patterns and are ideal for precisely identifying high-risk subgroups in persons with and without diabetes. Nonetheless, few studies have conducted standardized CGM assessments and evaluated associations of CGM-defined glucose patterns with progression of glycemia and clinical outcomes outside of type 1 diabetes. Emerging studies of CGM-defined subtypes (or “glucotypes”) are small, focus on patients in clinical settings, use older CGM devices, lack diversity and external validation, do not examine the underlying determinants of subtypes, and have not linked subtypes to progression of glycemia and clinical outcomes.7-13 There is also a paucity of data on glucotypes in persons without diabetes. We proposed to use CGM and novel machine learning (ML) methods to identify clusters of persons with and without diabetes at high risk for poor outcomes.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Diabetic foot ulcers (DFU) affect over 4 million adults with diabetes in the US. Adults with diabetes have a 30% likelihood of developing a DFU during their lifetime and DFUs are associated with substantial morbidity and mortality. More than 80% of all lower extremity amputations are the result of a DFU. The majority of DFUs have a neuropathic etiology and appear on the plantar surface of the foot as the result of decreased sensation and repetitive trauma. Prompt prevention and treatment of DFU is critical to decreasing amputation rates and improving limb outcomes in patients with diabetes. Even after healing is achieved, DFU recurrence is common. Up to 50% of adults with a history of DFU will develop a recurrent ulcer within one year of healing, and approximately 70% of affected adults will develop a recurrent DFU within 5 years. The standard clinical approach to DFU prevention includes regular foot examinations and offloading therapy, where patients with healed DFU are given special shoes or insoles to redistribute plantar pressure points away from a previously affected area of the foot. Even in a setting with proactive surveillance and offloading programs, one-year ulcer recurrence is typically greater than 30%. Interactive sensory insoles (Orpyx Medical Technologies Inc.) is a novel foot overload warning device designed to monitor gait parameters including plantar pressure, plantar temperature, and step count in adults with diabetes. Unlike standard offloading therapy, interactive sensory insoles provide real-time cues for pressure offloading to patients via a smartphone application, and transmit data to healthcare providers via a HIPAA-compliant dashboard for concurrent remote patient monitoring. We have completed a feasibility trial of interactive sensory insoles and demonstrated excellent usability and patient engagement. However, it is unclear if this technology can reduce the risk of DFU recurrence in adults with recently healed ulcers. We propose to assess the efficacy of using interactive sensory insoles for the prevention of recurrent DFU in a single-blinded randomized controlled trial. Primary Aim 1: Determine whether use of an interacgtive sensory insole with real-time patient feedback and remote patient monitoring can reduce plantar DFU recurrence compared to standard offloading alone among adults with a recently healed DFU. Secondary Aim 2: Assess patient-reported outcomes related to the use of interactive vs. non-interactive sensory insoles. Exploratory Aim 3: Assess DFU-related healthcare charges for patients randomized to using interactive vs. non-interactive sensory insoles. Impact: There is a critical need for better DFU prevention strategies, particularly for high-risk patients with prior DFU. Existing clinical paradigms with basic foot offloading and annual foot exams only minimally decrease the risk of recurrent DFU. Study results will provide actionable data about the efficacy of using patient-interactive sensory insole technology to monitor and prevent DFU formation in adults at high risk for diabetic foot complications, potentially changing the way DFU prevention is approached moving forward.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT. The COVID-19 pandemic exacerbated adolescent mental health problems and worsened disparities in their prevalence. While universal evidence-based school mental health programs are an effective way to reduce and prevent youth mental health issues, few such programs are, in fact, used in schools. Translation of research into practice averages 17 years, and most evidence-based programs are never sustainably adopted in real-world settings due to implementation barriers. RAP (Relax, Aware, Personal rating) Club is an evidence-based intervention to improve mental health among 8th grade students. Due to its trauma- informed approach and combination of mindfulness and cognitive behavioral skills, RAP Club is appropriate for 8th graders who have been exposed to chronic stress and trauma. Our team’s randomized control trial (RCT) in 29 urban public schools showed that, compared with an active control condition, RAP Club reduced symptoms of post-traumatic stress (PTSD), depression, and anxiety, as well as behavior problems, during the transition into high school. In the RCT, RAP Club sessions were delivered by research staff, which is not a sustainable or scalable delivery model. Thus, the objective of this type II hybrid effectiveness-implementation study is to test RAP Club’s delivery by school personnel, using a randomized factorial experiment to identify the most effective implementation approaches. We will examine the performance of two factors: (1) facilitator expertise (school personnel with versus without mental health expertise) and (2) supervision level (standard versus enhanced). Using a 2x2 factorial design, we will test four conditions that represent all combinations of these two factors. This design will allow us to identify the conditions that improve student mental health, strategically balanced by data on their implementation constraints (e.g., cost). We will test the impact of each of these four conditions on student PTSD symptoms (primary outcome) and anxiety symptoms, depressive symptoms, and behavior problems (secondary outcomes) at post-test and 4- and 12-month follow-ups (Aim 1: Effectiveness outcomes). For each of the four conditions, we will also evaluate cost, cost-effectiveness, and fidelity of implementation, as well as feasibility and acceptability (Aim 2: Implementation outcomes). Potential moderators of the effectiveness and implementation outcomes will be explored for each of the four conditions, including characteristics of schools (size, % low-income students), students (sex, trauma exposure), and facilitators (sex, years in profession) (Exploratory Aim 3: Potential Moderators). Findings will be used to create a toolkit that presents effectiveness and implementation data for each of the four conditions to guide education leaders in selecting strategies that maximize their current resources. Use of a factorial design to test program implementation strategies offers a novel and efficient model for streamlining translation of research into school- based practice. Findings will advance the science on school mental health interventions and will boost RAP Club’s potential for widespread adoption.

NIH Research Projects · FY 2025 · 2025-09

Glycans, sugar structures on glycoproteins and glycolipids, are abundant on cell surfaces where they regulate cell physiology, often by interacting with glycan-specific binding proteins. Deciphering the “glycan code” of cell regulation is a key goal for glycobiology with great potential to impact human health in many clinical areas including cancer diagnosis and therapy, immune system disorders, and nervous system diseases. This “Focused Technology Research and Development” application, based on recent advances by our team, merges bioortho- gonal chemistry and deep learning tools to experimentally and computationally explore the glycan interactome. Our approach focuses on a subset of the human glycome, gangliosides, which offer great technical advantages for these efforts. Gangliosides, sialic acid-bearing glycans carried on ceramide lipids, are embedded in the outer leaflet of the plasma membrane of all human cells with their glycans facing outward. They function in diverse regulatory pathways involved in cell-cell adhesion, signal transduction, and ion transport. Ganglioside expression is linked to human diseases including cancer, diabetes, neurodegeneration, and infectious diseases. As probes of the glycan interactome they have the great advantage of being “stand-alone” functional units, each with a well- defined glycan structure. They are chemically accessible and readily deliverable to live cells. We capitalized on these properties to synthesize proof-of-concept bifunctional ganglioside probes bearing photoaffinity diazirines and click alkyne tags. We delivered these to human cancer cell lines, captured their ganglioside-protein interactome, and characterized it by proteomic mass spectrometry. The next phases of technology development constitute the focus of the current application. Aim 1: Human gangliosides are quantitatively dominated by just eight glycan structures, each carried on a ceramide lipid. Our proof-of-concept study focused on three of these (GM3, GM1, GD1a) representing a range of glycan sizes. Each was derivatized individually with minimally disruptive bifunctional diazirine-alkyne tags on the ceramide lipid, the sialic acid, and (where feasible) the terminal galactose. The current proposal extends the repertoire and scale of synthesis to embrace cancer-associated gangliosides GM2, GD3, and GD2 and major brain gangliosides GD1b and GT1b, completing the eight-ganglioside set. These will be validated using human cancer and neural cells. The outcomes will be used to evaluate and optimize deep learning computational tools designed to independently identify glycan-protein interactions. Aim 2: Gangliosides with bifunctional probes installed on their glycan sialic acid moiety capture proteins via a covalent bond to each protein’s glycan binding site. Subsequent protein depolymerization, tagged peptide capture, and release for mass spectrometric identification will allow us to catalog glycan binding sites simultaneously on numerous glycan-interacting proteins in a single experiment. The sites will be computationally compared to deep learning all-atom models optimized for glycan-protein binding.

NIH Research Projects · FY 2025 · 2025-09

In the United States (US), there are more than 300,000 lower extremity musculoskeletal injuries each year. In patients with severe injuries, 20-40% will develop an infection. Patients at highest risk for infection have open injuries where the bone breaks through the skin causing skin and muscle damage that require soft tissue reconstruction with a flap. A flap is vascularized tissue that is moved from one area of the patient's body to the injury site to reconstruct the damaged soft tissues. Prior studies have optimized many aspects of lower extremity trauma care for severe injuries. Despite extensive prior work, the timing of the flap surgery has not been rigorously evaluated. In the US, the mean time from injury to flap surgery is 10 days and infection rates are 20- 40%. There is evidence to suggest that an alternative approach of early flap coverage might reduce the risk of infection. Studies have shown that when the time between injury and the flap surgery was 72 hours or less, infection rates were reduced. Mechanistically, this makes sense. Faster soft tissue reconstruction of the open wound requires early high-quality debridement at specialized centers and leads to early antibiotic delivery and the prevention of nosocomial contamination. The existing data and this rationale led the United Kingdom (UK) to develop guidelines for early flap coverage. Following guideline implementation, infection rates dropped to less than 10%. Despite this success, practice outside of the UK has not changed. We believe this is due to inadequate evidence to motivate surgeons and hospitals to mobilize the resources required to change the time to flap from 10 days to less than 72 hours. Resources required include timely transport of patients to specialized centers and a re-prioritization of operating room and surgeon availability. In existing studies, the time from injury to flap is highly influenced by several confounding factors, namely, injury severity and practice environment which are not adequately controlled for in non-randomized studies. While the existing retrospective and non-comparative data are promising, given the resources required to change, higher quality evidence is needed. The proposed trial will address this knowledge gap. This is an international randomized controlled trial of 356 patients with severe fractures and/or dislocations below the knee that require flap surgery for initial injury management. Patients will be randomized 1:1 to accelerated flap surgery within 72 hours of injury versus standard of care flap surgery timing. The trial's overarching objective is to determine if accelerated flap timing reduces infection. The primary outcome is a 6-month composite clinical status outcome, hierarchically assessed as: 1) mortality, 2) amputation, 3) re-operation, and 4) days in the hospital. This trial will test three specific aims: 1) to determine if accelerated flap surgery leads to improved clinical status at 6 months, 2) to determine if accelerated flap surgery leads to improved clinical status at 12 months, leads to improvements in the individual components of the composite outcome at 6- and 12-months, and 3) to determine if accelerated flap surgery improves quality of life over 6 months and over 12 months.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Unsupervised Machine Learning to Identify Novel Clusters of Systemic Sclerosis Pulmonary Hypertension Patients Pulmonary hypertension (PH) is a common devastating complication of systemic sclerosis (SSc), an autoimmune condition characterized by fibrosis and inflammation of the skin and internal organs, particularly the lungs and blood vessels. SSc patients can have PH related to numerous etiologies, most notably pulmonary fibrosis/interstitial lung disease (ILD, termed group 3 PH) and/or a primary pulmonary vasculopathy (pulmonary arterial hypertension [PAH], group 1 PH). Since SSc patients have varying degrees of ILD and patients with ILD-PH and PAH can have identical pressures on right heart catheterization, it is challenging to precisely classify individual patients using our existing scheme (i.e., group 1 vs group 3). This has important implications for PH treatment choices and therefore further study is needed to improve our classification system. The Pulmonary Vascular Disease Phenomics Program (PVDOMICS) is an NHLBI-funded project aiming to deeply phenotype PH patients. The current project will be a secondary analysis of the PVDOMICS dataset and the Johns Hopkins PH Registry to accomplish the following Specific Aims: Aim 1: Use unsupervised machine learning to identify distinct clusters of SSc pre-capillary PH patients, incorporating echocardiography, cardiac MRI, invasive cardiopulmonary exercise testing, clinical characteristics, and biomarkers. Aim 2: Evaluate transplant-free survival and hospitalization rates in the newly identified clusters. Principal component analysis and K-means clustering will be used to determine the novel clusters, independent of our current classification scheme. Cox regression and receiver operating characteristics curve analysis will be used to determine if the newly discovered clusters differ based on clinically relevant outcomes and have improved discrimination and calibration compared to the traditional classification system. Successful completion of these aims will establish novel methods for phenotyping SSc-PH patients that transcend our current paradigm of group 1 vs group 3 classification. The potential clinical relevance of the cluster-based classification method in patient-centered outcomes will be established. The long-term objective of this project is to generate data to plan prospective phenotyping studies testing personalized treatment strategies based on SSc-PH cluster assignment, which has the potential to change the paradigm of how we classify and treat this complex subset of pulmonary hypertension patients.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Older persons with HIV (PWH) face a higher risk, greater burden, and faster progression of age-related comorbidities, including cardiovascular diseases, metabolic disorders, renal dysfunction, obstructive lung disease, liver cirrhosis, and cancers, compared to those without HIV. These comorbidities lead to polypharmacy, adverse outcomes, and premature death. Understanding the cascade of comorbidity events and the natural history of these conditions among PWH is essential to guide secondary prevention and early interventions. The MACS/WIHS Combined Cohort Study (MWCCS) has significantly advanced HIV care by providing insights into HIV transmission, risk factors, and AIDS and non-AIDS outcomes among PWH using an interval cohort design. We propose to enrich this data source by establishing an electronic health record registry nested within the MWCCS (Aim 1) to study comorbidity burden and cascade among people with and without HIV. Furthermore, we will leverage existing cohort-wide biobehavioral data and the newly linked EHR data to develop predictive models of the comorbidity cascade among people with and without HIV (Aim 2). The proposed R21 work directly responds to PAR-24-092 by studying the aging and comorbidities of HIV using multidisciplinary approaches. Advanced clinical informatics tools, statistical learning models, and leveraging existing MWCCS infrastructure and biobehavioral measurements will shed light on aging and comorbidities in PWH. It will identify high-risk individuals prone to high comorbidity burden, thus paving the way to eventually be able to provide guidance on clinical decision making and care. Notably, this transformative initiative will serve as a pilot platform, leveraging MWCCS infrastructure, real-time EHR data, and existing cohort biomarkers. The data pipeline developed through this project will provide a scalable foundation for expansion to other MWCCS study sites in the near future, significantly broadening the scope and impact of ongoing research in HIV, aging, and comorbidity.

NIH Research Projects · FY 2025 · 2025-09

Project Summary: Vascular abnormalities are associated with neurodegenerative diseases, including Alzheimer’s disease (AD), the AD-related dementia (ADRD) Amyotrophic Lateral Sclerosis (ALS)/Frontotemporal Dementia (FTD), and ALS. One mechanism contributing to neurodegeneration is the failure of the vasculature to release signaling factors that promote neuronal survival. Efforts to develop these factors as therapies have lapsed due to unwanted angiogenic effects upon delivery. Preliminary studies here identify a novel pathway in vascular endothelial cells that releases a protein required for neuronal survival with minimal angiogenic function. The six-transmembrane enzyme Glycerophosphodiester phosphodiesterase 2 (GDE2 or GDPD5) acts at the cell surface to cleave the glycosylphosphatidylinositol (GPI)-anchor that tethers some proteins to the membrane. GDE2 distribution and function are disrupted in ALS, ALS/FTD, and Alzheimer’s Disease but are not affected in Huntington’s disease (HD), suggesting some specificity of GDE2 dysfunction across neurodegenerative diseases. GDE2 is normally expressed in neurons, oligodendrocytes, and vascular endothelial cells. Genetic ablation of GDE2 in vascular endothelial cells, but not neurons or oligodendrocytes, results in spinal motor neuron loss. Further, conditioned medium from cultured vascular endothelial cells (veCM) from Gde2 knockout (KO) mice fails to rescue cell death in in vitro cell viability models. These observations suggest that GDE2 vascular function is required for neuronal survival. The GPI-anchored protein Glypican (GPC) 6 is a substrate of GDE2 that overlaps with GDE2 expression in vascular endothelial cells, is linked to ALS and Alzheimer’s Disease via GWAS, and shows abnormal expression and release in ALS models and postmortem brain of patients with ALS and the ADRD ALS/FTD. veCM from vascular endothelial cells with GPC6 knockdown has limited neuroprotective activity in cellular survival models, and genetic ablation of GPC6 in vascular endothelial cells leads to spinal motor neuron loss in vivo. Further, GPC6 delivery is sufficient to promote motor neuron survival in vitro and in vivo, with minimal angiogenic effects. These observations suggest the hypothesis that vascular GDE2 activity releases GPC6, which selectively acts on neurons to promote their survival, and that the disruption of this pathway contributes to neurodegenerative pathologies in disease. This proposal will test this hypothesis with three Aims. Aim 1 will determine if pro-survival roles for GDE2 vascular function apply to cortical areas and if its functions are neuro-selective. Aim 2 will define the mechanism of GPC6 neuroprotective function and assess its angiogenic activity. Aim 3 will determine if the failure of GPC6 release contributes to neurodegenerative changes using mouse models of ALS and the ADRD ALS/FTD. Outcomes from these studies are expected to provide new molecular insight into the physiological contributions of the vasculature to neuronal survival, which could clarify vascular-dependent involvement in disease pathogenesis in ALS, ADRDs, and Alzheimer’s Disease and identify new candidates for therapeutic development.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY / ABSTRACT The objective of this project is to conduct a mixed methods study characterizing clinician communication around glycemic management (glycemic treatment and glycemic goals), identifying and quantifying the most effective communication practices. A large proportion of people with diabetes in the U.S. do not achieve glycemic goals, and suffer worse outcomes and likely more stigmatizing and judgmental language in clinical settings. While there is strong evidence that high quality clinician communication (defined as informative, compassionate, motivating and free of stigmatizing and judgmental language) improves diabetes outcomes, no studies to date have directly observed diabetes communication within clinical visits, and there are no validated tools for measuring the quality of this dialogue. Therefore, the specific communication practices that are most helpful (or harmful) for people with diabetes are not known, creating a major barrier to developing and implementing interventions that harness the power of clinical communication to improve diabetes care. Further, existing evidence-based communication interventions are high intensity and difficult to disseminate, creating a need for pragmatic interventions achievable within primary care practice. We hypothesize that changing clinician communication practices in simple, pragmatic ways is likely to improve diabetes self-management, which should in turn lead to improved glycemia and lower complications. In Aim 1, we will characterize clinician communication around glycemic management in 121 primary care visits for people with diabetes and HbA1c ≥8.0%. We will utilize data from the Black Box of Cultural Competence (Black Box) study, an observational cohort that audio-recorded routine primary care visits between people with diabetes and their primary care provider in the Veterans Affairs health system. We will use qualitative content analysis to identify features of good and poor communication quality, and use conversation analysis (a method of parsing the linguistic details of interactions) to evaluate the responses of people with diabetes, identifying the specific communication approaches and language that have the strongest positive and negative impact. In Aim 2, we will develop and psychometrically validate an instrument to quantitatively rate clinician communication quality around glycemic management, and determine its association with diabetes self-management abilities. These aims lead directly to our next steps: developing primary care interventions to improve diabetes outcomes. Identifying the most effective communication strategies will lead to efficient interventions that optimize clinicians’ language through targeted changes, and increase the ability of the healthcare team to support people with diabetes. Further, a validated instrument to measure the quality of glycemia management communication can serve as an important surrogate outcome for clinical interventions. Ultimately, we will leverage the power of clinical communication to improve outcomes for people with diabetes.

NIH Research Projects · FY 2025 · 2025-09

I am a Research Associate and the Core Manager of the Biostatistics Shared Resource in the Sidney Kimmel Comprehensive Cancer Center (SKCCC) at Johns Hopkins University. This Core offers comprehensive biostatistical support to members of the Cancer Center, including standard study design and analysis to more innovative methods development and validation. In my role as Core Manager of the Shared Resource, I oversee and coordinate the biostatistical services provided in the Core and support the mentoring of junior statisticians. To this application, I bring my expertise in population-based health services outcomes research supporting the mission of the Cancer Prevention and Control program, primarily leveraging the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, a program linking Medicare claims to those enrolled in the SEER cancer registry. The SEER-Medicare program is currently at an important point where new data is being made available, opening new and previously unavailable avenues for research. There is an increasing need for expertise that builds on this crucial data linkage. In this application, I highlight key areas of research that illustrate my expertise with this data and unique position possessing the skills needed to execute the statistical methodology required to successfully complete future projects. I will specifically discuss 1) prior projects using large datasets, focusing on SEER-Medicare data, 2) an extension to SEER-Medicare which links administrative housing data, 3) future data linkages that are currently on the horizon, 4) methodological considerations for using observational data linkages, and 5) how my role will enable me to effectively partner with investigators to answer high priority questions using real data, supporting the research mission of the Cancer Prevention and Control program in the Cancer Center. With the support of this R50 award, I will be able to manage the use of these resources in a more coordinated manner by leveraging data across multiple projects while training junior statisticians. It would also allow me to master my skills as a critical team member supporting the Cancer Prevention and Control program’s goals to answer real world questions on drivers of cancer-related care.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY: This is a submission for a National Institutes of Health R21/R33 award aiming to develop and validate an innovative, inexpensive multi-modal digital stethoscope capable of simultaneous automated lung sound and respiratory rate analysis, and mobile phone interoperability with an electronic health (eHealth) DHIS2 platform for real-time LRI and antibiotic surveillance in LMICs (R21 period), and then evaluation of the multi-modal digital stethoscope and eHealth system using an individually randomized controlled trial (R33 period). The lower respiratory infection (LRI) pneumonia is the leading infectious cause of death among children globally and in sub-Saharan Africa, but appropriate, accurate and user-friendly LRI diagnostics suitable for low-income and middle-income countries (LMICs) are severely lacking. This results in misdiagnosis and death, as well as inappropriate antibiotic use that contribute to overall rising antibiotic resistance rates globally. We aim to develop, validate, and rigorously evaluate the implementation of an innovative, inexpensive multi- modal digital stethoscope capable of simultaneous automated lung sound and respiratory rate analysis, and mobile phone interoperability with an electronic health (eHealth) DHIS2 platform for real-time LRI and antibiotic surveillance in LMICs. We hypothesize that a multi-modal digital stethoscope will meet pre-specified performance benchmarks and its implementation within an eHealth platform will address key LRI diagnosis implementation outcomes. To accomplish our overall project goal we will build upon nearly a decade of our multi-disciplinary digital stethoscope research and development across seven LMICs, our previous successful LMIC pulse oximeter device development using a human centered design (HCD) strategy, and evidence from our recent randomized controlled trial of antibiotic treatment in Malawi that suggested the vast majority of non-severe LRIs did not require antibiotics at all. During the two-year R21 period we will apply the human centered design approach to develop a multi-modal digital stethoscope and eHealth system (Aim 1). The device will be validated in a sound laboratory and field tested in various clinical settings with a range of practitioners in Cape Town, South Africa. We will then implement the multimodal digital stethoscope and DHIS2 system at a variety of facilities (Khayelitsha Hospital, and two primary care clinics) that serve a large township in Cape Town, South Africa and conduct an individual randomized controlled trial to evaluate `correct LRI diagnosis' as the primary outcome (Aim 2), as well as secondary implementation outcomes. Successful completion of the research described in this application could lead to broader scale-up of an affordable, sustainable interoperable LRI and antibiotic use eHealth system with advanced diagnostic technology contextually appropriate for LMICs, where most pediatric deaths from LRIs occur.

NIH Research Projects · FY 2025 · 2025-09

Abstract The goal of this proposal is to support Dr. Preethi Korangath, as a Laboratory Research Specialist at Dr. Robert Ivkov’s laboratory in Johns Hopkins University. With her expertise in mouse models, molecular biology and imaging she will facilitate successful completion of R0-1 projects in unit director’s lab. Dr. Korangath’s successful career is evident through her publications in high impact journals and conference presentations. This Research Specialist Award will provide protected salary support for Dr. Korangath to pursue new directions and developing new technologies that enable early detection and treatment of cancer. Despite advances in cancer treatment and understanding, metastasis remains the main challenge in extending cancer patients' lives. Early detection of metastatic disease is crucial for effective treatment. Developing new imaging modalities to detect micrometastases using magnetic particle imaging (MPI) offers a non-invasive, radiation-free approach with high sensitivity and specificity. This could revolutionize cancer diagnostics and treatment, improving patient outcomes. However, further understanding of MPI's clinical applications is necessary. Dr. Korangath equipped with expertise in various mouse models and imaging techniques aims to leverage MPI for early metastasis detection and study the role of host cells in cancer progression.

NIH Research Projects · FY 2025 · 2025-09

Mycobacterium tuberculosis (Mtb) is known to subvert host immune responses to establish infection and cause tuberculosis (TB) disease. Thus, boosting host immune responses via host-directed therapy (HDT), as adjunctive treatment to traditional antitubercular regimens, is an attractive strategy. Apoptosis is an evolutionarily conserved pathway for genetically programmed cell death, and the successful execution of macrophage apoptosis following infection with Mtb serves as an important innate immune defense. However, Mtb has evolved virulence strategies to subvert macrophage apoptosis and induce necrosis, thereby promoting its survival and dissemination of infection. Mitochondria mediate intrinsic apoptosis and can participate in the amplification of extrinsic apoptosis signaling, as well as contribute to alternate cell death modalities. Previously, we observed alterations to canonical apoptosis activation in Mtb-infected macrophages, manifested by mitochondrial translocation of anti-apoptotic XIAP in parallel with incomplete mitochondrial apoptotic pore formation. Our data are consistent with those of other groups suggesting that Mtb interferes with the central process of intrinsic apoptosis signaling, namely mitochondrial outer membrane permeabilization (MOMP). In support of an apoptosis-inducing HDT approach for TB, we and others found that promotion of the intrinsic apoptosis pathway through pharmacological inhibition of the anti-apoptotic factors MCL-1 and BCL-2 reduces intracellular Mtb growth in macrophages and in vitro granulomas. We have shown that adjunctive treatment with an activator of caspase-3 enhances the bactericidal and sterilizing activities of the first-line anti-TB regimen in a murine TB model. Recently, we found that adjunctive treatment with a clinical-stage inhibitor of BCL-2/BCL-XL enhances the bactericidal activity of the first-line antitubercular regimen and decreases the size and necrosis of lung lesions in a murine model of human TB-like pathology. In addition, enhancement of both extrinsic and intrinsic apoptosis through inhibition of inhibitor of apoptosis (IAP) family proteins augments the clearance of Mtb in the lungs of chronically infected mice. In the current proposal, we will identify apoptosis-inducing HDT agents of clinical relevance that can be exploited to enhance macrophage-based clearance of Mtb. We will employ a combination of targeted genetic and pharmacological approaches and integrate state-of-the-art knowledge on MOMP regulation to comprehensively characterize mechanisms of action involved in their antitubercular HDT activity. Selected apoptosis-inducing HDT agents will be tested for their adjunctive ability to shorten the duration of curative TB treatment in a clinically- relevant animal model. Our team combines significant expertise in TB pathogenesis, the mechanistic investigation of apoptosis and alternative cell death modalities, single-cell microscopy and in vivo imaging, and HDT development for TB. Our findings are expected to yield novel HDTs that can be tested in clinical trials for their potential to shorten the duration of curative treatment and improve long-term lung function in patients with drug-susceptible and drug-resistant TB.