Johns Hopkins University

NIH Research Projects · FY 2026 · 2023-01

Fragile X Syndrome (FXS) is the most common monogenic cause of Autism spectrum disorder (ASD), a group of complex neurodevelopmental disorders characterized by core diagnostic impairments in social interactions and communication, restricted repetitive behaviors and interests, and an association with intellectual disability. FXS results from deficiency in expression of the FMR1 gene encoding Fragile X Mental Retardation Protein (FMRP). An early overgrowth of neurons and excessive immature synaptic contacts have been observed in brains of children with FXS, as well as in the Fmr1 KO mouse model. At a molecular level, aberrant excessive protein synthesis, with altered production of key synaptic proteins, is implicated in the atypical neural and synaptic overgrowth. While FMRP loss can lead to excessive protein synthesis, mechanisms altering the gene-target selectivity of protein synthesis to produce the distinct phenotypes of FMRP-deficiency are incompletely understood. MicroRNAs (miRNAS) are small RNAs which can selectively target gene transcripts for repression in the RNA- induced silencing complex (RISC). FXS has been linked to misregulation of miRNAs and miRNA-mediated gene repression for over 15 years, but broad knowledge of alterations in targeted transcripts has been lacking. We propose to carry out genome-wide quantitative comparisons of RISC-mediated gene targeting in the wildtype and FMRP-deficient setting using both mice and human neurons. Directed by preliminary data, we will investigate the candidate let-7 miRNA family to test the hypothesis that dysregulation of let-7 miRNA biogenesis in the Fmr1 KO mouse contributes to altered repression of pro-growth mRNAs and downstream behavioral and neuroanatomical phenotypes. A multipronged approach for mechanistic investigation and prioritizing gene targets and pathways from genome-wide assessments will be followed by intervention to assess the functional consequences for FXS-associated phenotypes with the goal of enhancing our understanding of FMRP function and providing new molecular targets for intervention in phenotypes resulting from deficiency of FMRP.

NIH Research Projects · FY 2026 · 2023-01

PROJECT SUMMARY The objective of this study is to develop a new long-acting injectable (LAI) delivery system that provides tunable and sustained release of protein therapeutics, demonstrate its effectiveness in sustained local delivery of insulin-like growth factor-1 (IGF-1) and agrin targeted to nerve and muscle tissue, and assess its functional efficacy for treatment of peripheral nerve injury (PNI) in rat and NHP models. Current options for treating patients with PNI offer limited functional recovery due to the deleterious effects of prolonged denervation in the target muscle and progressive muscle atrophy. IGF-1 has shown potent trophic and anti-apoptotic effects on neural cell types and muscle cells; though requires frequent and high doses to achieve therapeutic outcomes due to its short half-life in vivo. However, clinical translation of such an approach is difficult due to the risks associated with high systemic dose of IGF-1. We have recently developed a kinetically controlled assembly method for preparation of biodegradable nanoparticles (NPs) that are capable of high loading, high bioactivity retention, and when given locally in affected muscle tissue and nerve tissue, provide sustained release of IGF-1, and demonstrated significantly improved functional recovery following local delivery in a rat PNI model. In addition, motor nerve-derived glycoprotein agrin is indispensable for neuromuscular junction formation and maintenance. Thus, we hypothesize that maintaining a sufficient concentration of agrin in target muscle for 3 months until reinnervation can further increase the level of functional recovery. In this design-driven study, we aim to optimize the delivery capacity of NPs and generate an off-the-shelf LAI delivery platform for both IGF-1 and agrin over 10 to 12 weeks and demonstrate the competitive advantage of this approach for functional regeneration using translational PNI models that recapitulate the clinically observed deleterious effects and anatomical features of PNI. We will pursue the following four aims: (1) to establish a new nanoparticle (NP)-based delivery system that achieves tunable and sustained release profile for IGF-1 and agrin; and understand the mechanism of high loading capacity, sustained release kinetics, and bioactivity retention; (2) to engineer NP-embedded hyaluronic acid (HA) hydrogel microparticles (MPs) as an off-the-shelf LAI system to extend IGF-1 and agrin release duration with preserved bioactivity and NP retention; and measure IGF-1 and agrin release kinetics and biodistribution following in vivo delivery in rats; (3) to assess efficacy of the optimized LAI system for IGF-1/agrin delivery in a chronic PNI rat model; and (4) to confirm efficacy, biocompatibility and safety of the optimized LAI delivery system in a new definitive preclinical NHP PNI model. Successful completion of this study will offer an LAI system specifically designed to transform the clinical treatment of PNI and demonstrate its translational potential regarding scalable manufacturing and functional efficacy in clinically relevant PNI models. It will also provide a versatile LAI platform for local and sustained delivery of a wide range of protein therapeutics.

NIH Research Projects · FY 2026 · 2022-12

PROJECT SUMMARY Preterm birth (PTB), or birth before 37 weeks of gestation, was the second leading cause of infant death in the US in 2017. Each year, more than $26 billion is spent on treatment and care of babies born prematurely, not accounting for the lifelong impact of developmental and cognitive impairments. Earlier this year, the FDA issued a recommendation that the synthetic progestin 17-hydroxyprogesterone caproate (OHPC, Makena®), the only approved product for PTB prevention, be withdrawn from the market due to lack of clinical benefit in a required post-market study. New and innovative therapeutic options for preventing PTB are desperately needed, but the etiology of PTB is complex and the potential for tissue sampling and clinical trials during pregnancy is limited. We recently developed an adapted mouse model of inflammation-induced PTB and a unique nanomedicine-based approach for more efficient vaginal delivery of therapeutics to the reproductive tract. Together, these new tools led to the first demonstration of therapeutic prevention of early intrauterine inflammation-induced PTB that led to full term delivery of litters with high percentages of pup viability and neurotypical motor development. The therapeutics delivered via the nanoformulation were histone deacetylase inhibitors (HDACi) dosed with or without the need for additional exogenous progesterone (P4). HDACi prevent deacetylation of histones, leading to more transcriptionally active chromatin, and thus, changes in gene expression. We also observed that the P4/HDACi combination inhibited human myometrial cell contractility and led to an increase in the ratio of P4 receptor (PR) isoform B (PR-B) compared to P4 receptor isoform A (PR-A), which is thought to maintain uterine quiescence and cervical competence. This supports the idea that HDACi- induced hyperacetylation creates a more favorable chromatin structure for ligand-bound PR to change the gene expression profile in a manner that prevents PTB. The overarching goals of this proposal are to determine the role of PR-B in the prevention of inflammation-induced PTB, to map epigenetic changes that are specific to therapeutic treatment, and to evaluate whether the epigenetic changes are sufficient to reset the uterine environment for normal fetal development. If these preclinical studies are successful, we will generate fundamental mechanistic knowledge of epigenetic regulation in PTB, as well as identify new cellular pathways that may be important targets for PTB prevention.

NIH Research Projects · FY 2026 · 2022-12

PROJECT SUMMARY/ABSTRACT: New studies in Uganda and Rwanda have reported increasing prevalence of mutations in pfkelch13 (K13) associated with delayed parasite clearance following clinical or in vitro treatment with artemisinins, suggesting that fears that resistance of Plasmodium falciparum to artemisinins will emerge in Africa, where >90% of malaria cases and deaths occur, have been realized. However, the extent of resistance to components of artemisinin-based combination therapies (ACTs) is not well understood. Our ongoing research activities and well-established infrastructure in Uganda put us in a unique position to rapidly address urgent needs for improved surveillance and characterization of resistance to artemisinins and partner drugs in Uganda. Benefitting from a network of 80 surveillance sites across the country and modern laboratories in Kampala and Tororo, we will use molecular, parasitological and epidemiological approaches a) to evaluate the origins, prevalence and distribution of known markers of artemisinin and ACT partner drug resistance and to characterize the genetic background(s) that facilitate the establishment and spread of resistance phenotypes, b) assess associations between genotypes and drug susceptibility/fitness phenotypes, and c) assess ecological and epidemiological factors that facilitate the evolution of resistance. With resistance to important drugs still geographically focal, our goal is to identify key drivers of its emergence and spread, and then to promptly inform public health leaders on the best means of blunting the spread of resistance across Africa.

NIH Research Projects · FY 2026 · 2022-12

Mitochondrial ADP/ATP carriers (Aac) mediate the 1:1 exchange of ADP into and ATP out of the mitochondrial matrix, an activity that is required for oxidative phosphorylation. Previously, we made the exciting discovery that the major yeast ADP/ATP carrier, Aac2, associates with the respiratory supercomplex (RSC; higher order assemblies of individual respiratory complexes) but only in the context of mitochondrial membranes that contain the unique phospholipid cardiolipin. Subsequently, we established that there is substantial overlap between the interactomes of yeast Aac2 and two human Aac isoforms. When combined, our results demonstrate that cardiolipin is of general importance to the extended and clinically relevant Aac family which participate in numerous evolutionarily conserved and cardiolipin-dependent protein-protein interactions that are therefore presumed to be functionally important. These collective findings strongly support our central hypothesis that the cardiolipin-dependent Aac interactome represents the mitochondrion’s “Achilles’ heel” in the multiple disease states that result from altered cardiolipin metabolism. In our ongoing efforts to drill into the cardiolipin- dependency of Aac2 we determined that cardiolipin promotes both the tertiary and quaternary assembly of Aac2, and excitingly, it does so via distinct mechanisms. We hypothesize that these two separable structural roles of cardiolipin with respect to Aac2 assembly reflect specific Aac2-cardiolipin interactions occurring within the folded carrier or on its periphery. From within, we speculate that three conserved cardiolipin-binding sites support the carriers folded structure and potentially enable its transport-related conformational dynamics. Armed with a series of rationally designed cardiolipin-binding Aac2 mutants, we will test our hypothesis using a suite of structural, biochemical, biophysical, and functional analyses. On the periphery, we hypothesize that the defining role of cardiolipin for the association of Aac2 with respiratory supercomplexes, composed in yeast of a complex III dimer and 1-2 copies of complex IV, involves individually weak interactions between Aac2-cardiolipin, Aac2- cardiolipin-RSC, and Aac2-RSC that when combined stabilize these multi-protein complexes. In Aim 2, mutations will be engineered into both Aac2 and specific complex III and IV subunits to disrupt this conserved interaction and then test our hypothesis that the cardiolipin-dependent association between Aac2 and the respiratory supercomplex is functionally and reciprocally beneficial. In testing a novel sixth model as to the functional relevance of RSCs, in this case those RSCs physically associated with Aac, results from this aim may help provide a contextual framework for the other proposed RSC-related models which are currently debated. Overall, results from this proposal will significantly impact our understanding of the consequences of alterations in the Aac interactome that may occur due to mutations in Aac and/or perturbations in cardiolipin metabolism. In turn, a greater understanding of basic mechanisms contributing to cardiovascular disease, the number one cause of death in the United States, will be obtained.

NIH Research Projects · FY 2025 · 2022-12

PROJECT SUMMARY Food banks and food pantries are critical community-based institutions for addressing food insecurity, which is associated with obesity, cardiovascular disease, type 2 diabetes, and cancer. The effectiveness and efficiency of food assistance programs are constrained by many factors, including: recruitment and training of of staff/volunteers; meeting client needs for acceptable, healthy choices; and providing real-time information for planning and emergency operations. In 2020, the COVID-19 pandemic exacerbated all of these problems and continues to do so. The effective management of food pantries, before, during, and after the pandemic, is a top priority as resources are limited, communications are often decentralized, and the in-house ability to adapt practices to an online setting is nearly non-existent. As well, pantry volunteers, commonly older adults, are both the main support staff at food pantries and the most at risk for severe COVID-19 health effects. Based on substantial preliminary data and more than two decades of experience working to improve Baltimore’s food system, this NHLBI Clinical Trial Pilot Study will develop and pilot a working mobile Support Application for Food PAntrieS (SAFPAS) application (app) to address these challenges. No such app that offers capabilities for staff/volunteer recruitment, training, and scheduling; nutrition education and messaging with clients; a safe form of client choice; and/or bidirectional communications for emergency preparedness and response currently exists. Our formative research with Baltimore food pantry and Maryland Food Bank personnel found high enthusiasm for an app that combines these features, as did our recent national survey of food pantry directors. This study will develop and pilot the app, and evaluate its feasibility and impact on food pantry staff emergency preparedness, stocking, and client uptake of healthful foods and beverages in Baltimore, with the following aims: 1) to develop and optimize a technically stable, functional app to improve food pantry services in Baltimore; 2) to pilot the SAFPAS app with Baltimore-based food pantries and clients, the Maryland Food Bank, and Baltimore’s Emergency Operations Center team, and assess its feasibility; and 3) to evaluate the impact of SAFPAS on the healthiness of foods received by food pantry clients in a sample of 360 low-income urban clients (at baseline), drawn from 20 pantries measured pre- and post-intervention in a randomized controlled pilot trial. Findings will allow us to: 1) produce a functional and acceptable app; 2) provide preliminary data for power calculations for a future full-scale trial; 3) generate and refine impact and process evaluation instruments and set standards for implementation; and 4) establish protocols and demonstrate our ability to recruit and retain food pantries and food pantry clients. We will assess potential scalability of the app by conducting formative and feasibility assessments with food pantry staff and clients in Detroit. The findings from this R34 study will support a full-scale clinical trial that will test a multi-city deployment of the SAFPAS app and assess its impact on food pantry client health outcomes, diet, and food security.

NIH Research Projects · FY 2025 · 2022-12

Project Summary Pancreatic ductal adenocarcinoma cancer (PDAC) is highly resistant to frontline surgical resection and chemotherapy treatments. Many treatment-resistant cancer types have benefited from immunotherapies that activate cytotoxic anti-tumor T cells against the somatic mutations, or neoantigens, expressed in cancer cells. One major challenge to the development of neoantigen-targeted immunotherapy for PDAC has been the low number and weakly immunogenic profile of identified neoantigens. Efficient activation of neoantigen-specific T cells is dependent on the recognition of 8- to 11-mer neoepitopes displayed on human leukocyte antigen (HLA) class I molecules. This recognition is the culmination of the biophysical and stereochemical contacts between the peptide, HLA, and T cell receptor (TCR) molecules. One mechanism to improve neoepitope immunogenicity is by modifying the peptide amino acid residues to enhance HLA binding or TCR recognition, thereby enhancing cognate T cell activation, while conserving reactivity to the parental epitope. These modified epitopes are termed heteroclitic epitopes. However, the stereochemical features of heteroclitic epitopes that enhance HLA binding or TCR recognition are understudied. Additionally, heteroclitic epitopes have been explored in the context of a limited number of HLA subtypes, restricting their development and application across patients. We hypothesize that rational design of heteroclitic neoepitope vaccines through structural modelling will improve T cell responses against PDAC neoantigens. To address this hypothesis, we will define the structural binding and spatial display dynamics of both shared and private PDAC heteroclitic neoepitopes in diverse HLAs. Among shared neoantigens expressed in PDAC, activating mutations in KRAS at codon 12 are present in up to 80% of PDAC tumors. In Specific Aim 1, we will interrogate the structural mechanics and immunogenic profile of heteroclitic KRAS G12D/V/C epitopes in a panel of 18, globally representative HLA subtypes. In Specific Aim 2, we will develop a computational pipeline to identify, prioritize and optimize patient- specific heteroclitic neoantigen vaccine candidates based on structural epitope features. We will use HLA binding measurements and T cell reactivity assays to validate immunogenic features of our computationally modelled heteroclitic epitopes. Together, these aims will define the structural features of immunogenic neoantigens in diverse HLAs, generate heteroclitic epitope vaccine candidates for shared and private PDAC antigens, and improve the therapeutic potential of cancer vaccines for hard-to-treat cancers such as PDAC.

NIH Research Projects · FY 2025 · 2022-12

PROJECT SUMMARY/ABSTRACT This proposal outlines a comprehensive five-year mentored career development plan with the goal of preparing the candidate, Sandeep Wontakal, M.D., Ph.D., for an independent academic research career as a physician- scientist. The training plan is designed to acquire and refine skills in three critical aspects essential for a successful career as a physician-scientist: 1) establishing the basis for an independent research program 2) expanding clinical expertise and 3) enhancing mentorship/leadership skills. His strong background in functional genomics from his graduate work and his experience as a board-certified molecular pathologist with expertise in genomic testing of rare disorders, provides a solid foundation upon which the training plan builds. Dr. Wontakal’s long-term research and clinical interest is to decode the information transmitted in the non-coding genome and how mutations in these regions can lead to neurodevelopmental disorders. The scientific aspects of the proposal will be mentored by Dr. Oliver Hobert, Professor and HHMI Investigator, who is a leading neuroscientist with a long track record of mentoring successful trainees. Dr. Wontakal will develop further clinical acumen in identifying pathogenic non-coding mutations under the guidance of the preeminent human geneticist, Dr. David Goldstein, Director of the Institute for Genomic Medicine at Columbia University. An advisory panel of renowned physician- scientists and an expert in RNA neurobiology will also oversee the candidate’s progress and provide guidance. This work will be performed at Columbia University under the auspices of the Department of Biological Sciences, one of the birthplaces of genetics, and the Department of Pathology & Cell Biology, which has a long history of training physician-scientists. The vibrant scientific and clinical environment at Columbia with its world-renowned neuroscience community, will serve as an ideal environment to successfully execute the proposed training plan. Taking advantage of the powerful genetic and cell biological tools available in C. elegans, Dr. Wontakal will study how the long non-coding RNA (lncRNA), lep-5, functions in regulating the timing of neurodevelopment. Lep-5 expression is temporally regulated and preliminary results show lep-5 is required for proper sexual maturation of the male nervous system. Dr. Wontakal has generated several novel strains to determine how the precise spatiotemporal expression of lep-5 is established through studying the following three aims: 1) determine the cis regulatory elements controlling lep-5 expression 2) determine how the transcription factor lin-14 represses lep- 5 expression 3) determine the transcriptional activator(s) of lep-5 expression. This project will enable Dr. Wontakal to gain expertise in genetic analysis, microscopy-based analysis, neurodevelopment, and non-coding RNAs. Importantly, the proposed project has the potential to serve as the foundation for starting his own independent research group. Clinically oriented training in neurogenetics, bioinformatics, and statistical genetics coupled with formal mentorship and leadership training will place Dr. Wontakal on a path to become a leader in genomic medicine.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY This is an application for an R21/R33 award titled “Smartphone-based community screening of anterior eye diseases in rural India.” The investigators from Johns Hopkins University and Aravind Eye Hospital have diverse expertise in ophthalmology, biomedical engineering, machine learning, epidemiology, biostatistics, and use of mobile health technology in low-resource settings. 90% of the world’s 275 million blind and visually impaired people live in low- and middle-income countries (LMICs). Cataract, refractive error, corneal opacities, and other anterior eye diseases account for the majority of global blindness. In rural LMIC settings, lack of access to highly trained eye care providers such as ophthalmologists is a key barrier to timely diagnosis and treatment for anterior eye diseases. Periodic “eye camp” screenings performed by highly trained ophthalmologists have been the mainstay of rural eye disease screening for many decades but have several limitations including lack of access to trained ophthalmologists, failure to reach the most remote communities, lack of consistent calendar coverage beyond eye camp dates, and high costs due to equipment, personnel, and community publicity. We propose development, validation, and implementation of a novel smartphone based device for community health worker (CHW)-led screening, diagnosis, and referral for eye diseases in rural LMIC settings. We will develop this smartphone platform using iterative prototyping and user-centered design approaches. After demonstrating feasibility, we will evaluate the diagnostic validity of CHW-led screenings using the smartphone platform compared to traditional in-person eye camp exams by an ophthalmologist. After collecting sufficient data and images using the platform, we will design, validate, and implement machine learning algorithms to permit real- time diagnosis and referral decisions by CHWs without dependence on ophthalmologists. This project will perform detailed data collection regarding referral patterns, loss to follow-up, cost-effectiveness, and differential outcomes among vulnerable groups in order to enable more targeted health interventions. This project is intended to overcome key longstanding geographic, financial, operational, and human resource constraints to eye screening while ensuring diagnostic validity, quality control, and interoperability with existing health system infrastructure. Our scalable approach has potential to transform global eye care delivery in low-resource settings. This collaboration will also result in permanent improvements in mobile health and research capacity at Aravind Eye Hospital.

NIH Research Projects · FY 2024 · 2022-09

PROJECT ABSTRACT Firearm violence is associated with access to firearms at both the individual and ecological levels. Preventing firearm access by those at significant risk of violence is a logical strategy to reduce firearm homicide, firearm suicide, and nonfatal firearm violence. Extreme Risk Protection Order (ERPO) laws provide a civil court option for temporarily removing firearms from, and preventing purchase by, high-risk individuals. To date there are no empirically developed guidelines on how law enforcement agencies are to implement ERPO, including firearm removal from newly prohibited individuals. This project will develop ERPO implementation guidelines through the use of community-based participatory research with a focus on communities that experience high rates of firearm violence. The research will unfold through a process that will be responsive to feedback about ERPO from impacted communities about the need for ERPO implementation processes that recognize the fractured relationships between their communities and law enforcement, and are trained on how to constructively interact with people experiencing mental illness or a suicidal crisis. We will develop an implementation strategy for implementing ERPO in a just and equitable manner. Our aims are as follows: 1. Identify counties in Florida and Maryland where ERPO use is high and describe how ERPO is being used in those counties. 2. Document, understand, and examine the perspectives of impacted communities, prior respondents to ERPO, and implementers about ERPO and its implementation. 3. Develop an Implementation Strategy for Impacted Communities centering on just and equitable implementation of ERPO. 4. Pilot the ERPO Implementation Strategy for Impacted Communities and measure the acceptability, feasibility, and sustainability of the Strategy among implementing stakeholders. 5. Revise and disseminate the implementation guide to interested stakeholders around the United States. This project is responsive to the CDC’s RFA-CE-22-004 under Funding Option B. We will address Objective One: Research to improve understanding of firearm injury and inform the development of innovative and promising prevention strategies. An accomplished group of gun violence prevention researchers—including national leaders in the field and those on the front lines of providing information and technical assistance to policymakers and actors in the ERPO process—has come together for this innovative and timely research. This project’s use of community-based participatory research and a framework of just and equitable ERPO implementation will be invaluable to jurisdictions as they seek to implement this firearm violence reduction tool.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY/ABSTRACT As cannabis legalization has expanded, many novel products have emerged. Oral cannabis products (or “edibles”) are among the most popular. Similar to traditional forms of cannabis, edibles that contain delta-9- tentrahydrocannabinol (THC) as the primary constituent have abuse liability and can produce unwanted negative effects (e.g., cognitive/psychomotor impairment, panicked reactions). Cannabis users often report that edibles produce highly unpredictable effects, making these products prone to eliciting adverse events. Edibles are responsible for most emergency room visits related to cannabis over-intoxication. Inconsistency in cannabis edible effects likely stems, in part, from the large variety of formulations within this diverse product category. Preclinical research has shown that THC absorption is markedly increased when ingested in lipid or “nanoemulsion” formulations relative to non-lipid or non-nanoemulsion formulations; nanoemulsion is a process used to make cannabinoids more hydrophilic and purportedly, more bioavailable. Thus, these formulation characteristics may directly impact the magnitude of THC absorption and THC-related acute effects in humans. However, controlled clinical research on cannabis edibles is limited and few studies have evaluated if the formulation of these products influences pharmacokinetic (PK) or pharmacodynamic (PD) outcomes. The proposed, double-blind, placebo-controlled human laboratory study will compare the PK and PD effects of 3 popular types of cannabis edibles: THC-infused chocolates, gummies, and drinks. We hypothesize that THC absorption and resultant PD effects will be significantly greater for the chocolate (high lipid concentration) and drink (nanoemulsion formulation) relative to the gummy (low lipid concentration and no nanoemulsion). Healthy adults will attend 9 outpatient laboratory sessions. For each session, they will consume 1 of 3 cannabis edible formulations (chocolate, gummy, or nanoemulsion drink) at either 0mg THC (placebo), 10mg THC, or 25mg THC (i.e., 2 and 5 Standard THC Units, STUs); sessions will be preceded by 8 hrs of monitored overnight fasting. Sessions will be completed in a randomized order and separated by at least 1 week. PD assessments will include a battery of cognitive/psychomotor performance tasks and a subjective drug effect questionnaire, all shown to be sensitive to cannabis at the proposed STUs. Blood plasma will be collected to quantify concentrations of THC and its primary metabolites (11-OH-THC, THCCOOH). This project will determine whether the formulation of cannabis edibles influences PK/PD effects when THC doses are held constant, which is of growing importance given initiatives to utilize STUs for research and regulatory purposes. Data generated from this project can potentially inform educational efforts to reduce the incidence of adverse events caused by cannabis edibles and provide insight into whether cannabis edible formulation should be a consideration, in conjunction with STUs, for research, regulatory, and clinical decisions.

NIH Research Projects · FY 2025 · 2022-09

APPLICATION SUMMARY This is a K08 Mentored Clinician Scientist Research Career Development Award application for Bryce Chiang, MD PhD. Upon completion of ophthalmology residency, Dr. Chiang will be hired as an Assistant Professor of Ophthalmology at the Byers Eye Institute at Stanford. The purpose of this application is to provide Dr. Chiang with the needed training, mentorship, and support to become an investigator with expertise in ocular drug delivery, specifically to the optic nerve head. A clinical glaucoma fellowship will be completed during the 25% clinical time through the timeline of the K08 award. Dr. Chiang has assembled a mentorship team consisting of Dr. Jeffrey Goldberg, an expert on optic nerve neuro-protection and neuro- regeneration; and Dr. Mark Prausntiz, an expert in ocular drug delivery. In addition, he has identified key collaborators including Dr. Uday Kompella, an expert in ocular drug delivery; Dr. Joyce Liao, an expert in optic nerve diseases and animal models; Dr. Jonathan Lin, an ocular pathologist; Dr. Vinit Mahajan, a vitreoretinal surgeon. Optic neuropathy is a class of devastating vision threatening diseases that affect the optic nerve. There are no methods to selectively deliver therapeutics to the optic nerve head, and targeted delivery could improve outcomes due to physiologic spatiotemporal cues and/or selective targeting of injured tissue. The proposed technique is to access the optic nerve head by a SupraChoroidal-to-Optic-NErve (SCONE) injection. The central hypothesis is that the SCONE injection technique can be used to selectively target optic nerve head, and that therapies delivered with this method will be more efficacious compared with intravitreal or intraorbital optic nerve injections. The hypothesis of Aim 1 is that SCONE injection can be further optimized, and the technique will not impact the optic nerve head tissue functionally or structurally. The hypothesis of Aim 2 is that SCONE injection will be more localized to optic nerve head than intravitreal or intraorbital optic nerve injections. The hypothesis of Aim 3 is that Ciliary NeuroTrophic Factor (CNTF) delivered to the optic nerve head–either as free protein, or in a sustained release polymer, or transducing local cells with AAV–will bring greater neuroprotection and regeneration than intravitreal or intraorbital injections after optic nerve injury. The research may lead to improved delivery techniques to the optic nerve head, and will form the basis of an R01 application before the end of the K award.

NIH Research Projects · FY 2026 · 2022-09

Project Summary / Abstract AUD affects ~28–29 million U.S. adults and drives ~$249–300B in annual costs. Despite this burden, clinicians and researchers lack a discreet, continuous way to quantify alcohol intake in real time. We propose to develop a discreet microneedle-based wearable that continuously measures alcohol in interstitial fluid to provide accurate, real-time blood-correlated data. The device enables early relapse detection, adherence tracking, and objective endpoints for addiction treatment and clinical research, addressing gaps in current episodic and user-dependent alcohol testing methods. In our sprinter plan, we to complete the first critical de‑risking steps which include confirmation of need requirements, early risk/usability planning, alpha bench performance, safety screening, verification scaffolding, DFM/supplier mapping, and regulatory groundwork—without animal/human testing or IP activities, culminating in an evidence‑based Go/No‑Go.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY About 70% of all ocular infections are caused by bacteria. Each year in the US alone, there are millions of cases of bacterial keratitis and conjunctivitis. Fluoroquinolones are effective for both treatment and prevention of these infections, and moxifloxacin is often the drug of choice due to higher intraocular bioavailability compared to other fluoroquinolones. The newest fluoroquinolone, besifloxacin, has also shown to have some advantages in treating resistant organisms, including methicillin-resistant Staphyloccocus species and Pseudomonas species associated with contact lens-related keratitis. Regardless, antibiotic eye drops are prescribed to be used at least three times per day, and up to once every hour for severe infections. As the required number of doses per day increases, patient compliance, and thus, treatment efficacy, decreases. Issues with adherence can lead to sight-threatening complications and potentially contribute to bacterial resistance. Antibiotic eye drop formulations that are more effective with less frequent dosing are needed to improve patient outcomes and quality of life and slow the development of bacterial resistance. While eye drops dominate the ophthalmic market, achieving effective intraocular drug delivery via eye drops is quite challenging. Tear production, reflexive blinking, and nasolacrimal drainage limit residence time, while formulation and drug properties can further limit the potential for the rapid intraocular drug absorption needed. We have developed a mucosal drug delivery technology that increases drug delivery and absorption across mucosal barriers, termed the mucus-penetrating particle (MPP) technology. Here, we describe an innovative approach for formulating water-soluble fluoroquinolone antibiotic salts into ion-paired drug-core nanosuspensions. Our preliminary data demonstrates that a moxifloxacin-pamoic acid MPP nanosuspension (MOX-PAM NS) provides improved prevention and treatment in a rat model of bacterial keratitis. Importantly, once daily dosing with MOX-PAM NS was as good or better than three times daily dosing with the commercial formulation, Vigamox. The goal is to develop eye drop formulations of both moxifloxacin and besifloxacin to provide broad spectrum treatment options for gram-positive, gram-negative, and resistant bacterial infections. In Aim 1, we will make further formulation changes in the eye drops to increase intraocular drug absorption and screen for antimicrobial activity against commercial and clinical bacterial isolates. In Aim 2, we will characterize the topical drug penetration and efficacy in treating bacterial keratitis in rats. In Aim 3, we will perform full pharmacokinetic studies, treatment efficacy studies, and topical safety studies in rabbits, which have ocular size and structure more similar to humans. We anticipate that a reduction in dosing frequency while maintaining efficacy against a wide range of common bacterial pathogens will have a positive impact on patient care and quality of life.

NIH Research Projects · FY 2024 · 2022-09

PROJECT SUMMARY/ABSTRACT The provision of low-value medical services contributes to high healthcare costs in the US. Studies showing regional variation in the intensity of healthcare provision within the US that are not explained by differences in medical complexity and not associated with differences in outcomes demonstrate that low-value healthcare is not homogenously distributed throughout the country. However, variation in healthcare intensity at the hospital level has not been well-studied. Well-calibrated and validated hospital-level measures of diagnostic intensity are lacking. Effective methods to identify outlier hospitals with respect to diagnostic intensity will allow a better understanding of the drivers of low-value care and diagnostic overuse. Additionally, this will allow for better characterization of the relationship between diagnostic intensity and quality of care, specifically missed diagnoses. It will also allow identification of hospitals with lower levels of diagnostic testing and yet low rates of missed diagnoses so their care processes can be studied and replicated. The candidate is a hospitalist physician and junior investigator at Johns Hopkins University. He has recently published a manuscript describing the development of a hospital-level diagnostic intensity index which utilizes non-specific diagnosis codes paired with specific diagnostic tests as a proxy for diagnostic yield. He has assembled a mentoring/advising team with expertise in evaluating the strength of evidence, measuring low- value care, and identifying diagnostic errors. The candidate’s long-term goal is to become an independent investigator with expertise in understanding the drivers of low-value health, the relationship between diagnostic intensity and quality, and ultimately developing interventions to help low-performing hospital systems minimize overuse without compromising quality. This work will characterize hospital-level diagnostic intensity such that outlier hospitals can be identified and the relationship between diagnostic intensity and missed diagnoses at the hospital level can be elucidated. The project includes three aims: 1) Perform a systematic review of the literature characterizing hospital-level diagnostic intensity, 2) Apply the hospital-level diagnostic intensity index to Medicare claims data and develop and test an augmented diagnostic intensity index, 3) Utilize this index to characterize the relationship between diagnostic intensity and missed diagnoses. Aims 2 and 3 will use Medicare 100% limited dataset claims. In addition to executing these aims, the candidate will take courses, learn from directed readings by his mentors and advisor, attend seminars and national conferences, and meet with his mentoring team regularly. He will learn the skills necessary to conduct systematic reviews, gain expertise in analyzing large claims datasets, and develop a better understanding of how to measure quality. This mentored research and career development will help him achieve his goal of becoming an independent investigator.

NIH Research Projects · FY 2024 · 2022-09

PROJECT SUMMARY Degenerative vision disorders are caused by the loss of retinal cells. In zebrafish, retinal Müller glial (MG) act as stem cells, generating MG-derived progenitor cells (MGPCs) which replace lost retinal cells. Mammalian MG/MGPCs can also produce new retinal neurons, however, proliferative capacity is limited and disease- relevant cell types (e.g., photoreceptors) are rarely generated. Our goal is to understand why the regenerative potential of MG/MGPCs are limited in mammals in comparison to a regenerative species (i.e. zebrafish). In zebrafish, widespread retinal cell loss triggers “developmental” regeneration, producing all major retinal cell classes. Conversely, selective retinal cell loss results in a “fate-biased” process where MGPCs give rise to the lost cell type. How MG sense the extent of loss, however, is unknown. As the immune system plays critical roles during retinal regeneration, we examined the impact of microglia reactivity on MG activation in zebrafish. We observed that microglia are required for MG stem cell activation and that immunosuppression can inhibit or enhance regeneration kinetics depending on the treatment timing. We hypothesize that microglia reactivity levels scale to the extent, duration, and/or specificity of retinal cell loss in order to coordinate MG activation, MGPC proliferation rates and fat decisions to the type of injury incurred. To test our hypothesis, here we propose to combine an improved targeted cell ablation system enabling titratable, sustainable, and selective retinal cell loss with resources/methods for labeling of immune cell types, intravital timelapse imaging, lineage tracing, and single cell transcriptomics. Specifically we will define how the extent (Aim 1), the duration (Aim 2) and specificity (Aim 3) of cone photoreceptor or retinal ganglion cell loss impact immune cell reactivity and retinal regeneration. These experiments will serve to define roles specific immune cell subtypes play in shaping MGPC proliferation and cell fates during regeneration in zebrafish.

NIH Research Projects · FY 2025 · 2022-09

Nearly 92,000 Americans died of drug overdoses in 2020, primarily driven by a lethal drug supply dominated by synthetic opioids (i.e., fentanyl and fentanyl analogs) and increased stimulant-related deaths. We have documented the magnitude of this epidemic experienced by women who use drugs (WWUD) (N=385) in Baltimore City, who reported high rates of experiencing an overdose (28%), witnessing a fatal overdose (35%), and witnessing a non-fatal overdose (52%) in the past 6 months. We have also documented high rates of homelessness, hunger, mental health morbidities (i.e., PTSD, depression), and chaotic drug use patterns (i.e., polysubstance use,) that indirectly and directly drive women’s distinct risk of overdose and other morbidities (i.e., HIV, HCV). Yet WWUD experience numerous barriers to receiving necessary medical and behavioral services that can reduce their risk of overdose and other morbidities, with barriers amplified by the COVID-19 pandemic. We propose conducting the SHOUT (Sustained Health-Enhancing OUTreach) study, a type 1 hybrid effectiveness-implementation design to evaluate the impact and implementation of WWUD-centered, mobile risk reduction services on nonfatal overdose and clinical care engagement among WWUD (N=400) recruited from Baltimore City and County neighborhoods new to Mobile SPARC services. Mobile SPARC is an existing low-barrier, outreach program serving other neighborhood and offers risk reduction supplies, individual counseling, and necessary referrals. The study aims to: 1) adapt and expand Mobile SPARC’s services to identify predisposing (i.e., drug use patterns) and enabling (i.e., access to trusted health services) factors that facilitate or hinder utilization of risk reduction services, employing in-depth interviews with WWUD (N=40) and key informant interviews with Mobile SPARC staff (N=5); 2) evaluate the impact of expanding Mobile SPARC on nonfatal overdose and clinical service engagement (including drug treatment) over 18 months among WWUD (N=400) recruited from neighborhoods in which Mobile SPARC will be newly implemented; and 3) to characterize the implementation of Mobile SPARC using the Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) framework to inform future implementation and scale up. The SHOUT study will make a significant contribution to the literature in evaluating the impact of tailored, low-barrier mobile outreach on overdose among WWUD. The study’s relevance and sustainability will be enhanced through its partnership with SPARC, input from a community advisory board, and support of long-term collaborating organizations and health department stakeholders as well as the cost effectiveness analysis. This proposal is highly responsive to the RFA DA-22-046’s emphasis on replicable risk reduction service delivery model targeting women with elevated susceptibility of overdose.

NIH Research Projects · FY 2024 · 2022-09

Project Summary Polydrug use (PDU) is increasingly implicated as a crucial factor underlying the U.S. overdose crisis, responsible for the deaths of over 100,000 Americans in the past year alone. Overdose is still highly associated with opioid use, but also overwhelmingly occurs in the context of combinations of drugs - notably stimulants and synthetic opioids. In 2019, the Northeast had the highest proportion of overdose deaths involving synthetic opioids and the largest absolute increase in stimulant-involved overdose deaths, and the Maryland overdose rate was among the highest in the country. The overdose prevention infrastructure has not yet been optimized to address PDU and the heterogeneity of associated experiences. With a multi-level perspective informed by life course and social network theories, we propose a multi-phase mixed methods study to examine patterns, trajectories, and risk and protective factors for PDU and overdose among people with various patterns of stimulant and opioid use. We will use behavioral data from the AIDS Linked to the IntraVenous Experience (ALIVE) study to identify PDU patterns and trajectories, mixed methods data from the 2019 Statewide Ethnographic Assessment of Drug Use and Services (SEADS) project to identify descriptive PDU trajectories and contextualize periods of drug use transition and stability, and complementary qualitative life course data collection (n=100) to explore recent changes and life course events aligned with different types of PDU, which will in turn inform statistical models of risk and protective factors for PDU types and overdose. Results from this study will allow program planners to estimate range and scale of heterogeneity among PDU and begin to disentangle intervention needs of unique sub-groups of PDU. This project will result in specific recommendations for tailored overdose risk reduction approaches and supportive resources for the heterogeneous needs of PDU and key turning points of PDU trajectories. We will translate our findings and conduct broad dissemination, working with local stakeholders, partner organizations, and governmental agencies to inform overdose and treatment programs in real time and across all three project years.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY Early detection of cognitive and functional decline is a major goal of the NIA in its fight against Alzheimer's Disease and Related Dementias (ADRD). Physical, physiological, and cognitive changes associated with ADRD may emerge years prior to clinical manifestations, thus there is an urgent need for novel, cost-effective, noninvasive, and scalable tools to improve detection of ADRD risk. Older adults with cognitive impairment often exhibit changes in movement, sleep, and heart rhythms, suggesting possible shared vascular or neurodegenerative pathways. Emerging research from our group and others links digital signals from movement, sleep, and heart rhythms with brain and cognitive health; however, knowledge gaps remain in the associations among these signals and brain and cognitive health across the cognitive spectrum. In response to NOT-AG-20- 017, this application will directly address these gaps using existing and ongoing/new data collection from wearable technology (7-day accelerometry and 14-day ambulatory electrocardiogram (ECG)), cognitive assessments (neuropsychological battery, adjudicated cognitive diagnosis), and neuroimaging (florbetapir PET for beta amyloid (Aβ), 3T brain MRI for neurodegeneration and white matter disease) from ≥1000 older adults participating in the Atherosclerosis Risk in Communities (ARIC) Neurocognitive Study. We will use novel analytic approaches to integrate movement, sleep, and heart rhythm features and assess their individual and joint associations with brain and cognitive health. Our overarching goal is to identify clinically relevant digital biomarkers that combine movement, sleep, and heart rhythm signals as sensitive indicators of cognitive function, cognitive trajectories, ADRD pathology, and cognitive diagnosis. To this end, this research will inform the future use of wearable devices in large-scale studies, provide novel targets for screening and early detection of ADRD in disease stages during which intervention and treatment are more likely to be effective, and aid in identifying high-risk participants for prevention trials.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY Autosomal dominant optic atrophy (DOA) is the most commonly diagnosed inherited optic neuropathy. Mutations in the OPA1 gene, which encodes a mitochondrial dynamin like GTPase, account for 60-70% of all DOA cases. Although OPA1 is expressed throughout the body, secondary to dysfunctional mitochondria, patients with DOA associated OPA1 mutations exhibit loss of retinal ganglion cells (RGCs) specifically. Despite intensive study and the availability of mouse models of DOA, critical questions regarding how OPA1 mutations lead to specific loss of human RGCs in DOA patients remain unanswered and there are currently no treatments for this condition. A human RGC model would greatly facilitate the study of disease mechanisms as well as drug discovery efforts. Obtaining RGCs from DOA patient samples is not feasible, however, due to the rarity of DOA donor eyes, the sparsity of RGCs in the human retina, and poor RGC viability upon isolation. The proposed studies will address this unmet need by developing and characterizing in detail three human pluripotent stem cell (hPSC) models of DOA that track disease progress from stem cell differentiation to RGC degeneration. An important feature of our stem cell models is that they make use of techniques that produce large quantities of highly purified RGCs that display long term survival, features important for biochemical, functional, morphological, and transcriptomic analyses. We combined this protocol with CRISPR/Cas9 genome-editing to model OPA1 haploinsufficiency and developed an inducible CRISPR inference (CRISPRi) DOA model to control the timing of OPA1 loss of function. We propose to use these two complementary models together with RGCs derived from patient iPSCs to study the role of OPA1 in RGC differentiation and degeneration. In the future, these well-characterized stem cell models could be used for large-sale functional genomics studies and high throughput screening for neuroprotective and regenerative agents.

NIH Research Projects · FY 2025 · 2022-09

Project Summary (Abstract) This four-year Center grant proposal has as its long-range goal the active development and dissemination of approaches to achieve Diagnostic Excellence in the emergency department (ED) by leveraging safety science principles and strategies. The proposal seeks to mature and focus ED diagnostic safety, quality, equity, and value-oriented activities at an existing Center at Johns Hopkins Medicine (JHM). The Armstrong Institute Center for Diagnostic Excellence (DXC) will become part of a new AHRQ-sponsored network of Diagnostic Centers of Excellence (DCE) via RFA-HS-22-008, to which this application responds. Diagnostic errors are the largest cause of preventable harms in US medical care, likely affecting more than 12 million Americans each year and leading to permanent disability or death for at least 0.5 million. The ED is a known high-risk site for diagnostic errors where patients are at risk for misdiagnosis-related harms. To achieve the goal of Diagnostic Excellence, it will be necessary not only to develop strategies that improve diagnostic accuracy and reliability, but also to identify and overcome barriers to their effective use and dissemination. Safety science applies engineering and social science expertise to address hazards in the health care field. Currently, Safety I (e.g., “find and fix”) and Safety II (e.g., “resilience engineering”; “high reliability organizing”) are active and ever-evolving approaches to quality improvement. Safety I strategies emphasize informing harm prevention by identifying failed processes and adverse events, while Safety II strategies take complexity and human factors as critical to understanding the effects of socio-technical systems of care on patient safety and quality. Often improvement teams adopt one or the other strategy, but, in this proposal, we will blend the two approaches, capitalizing on the strengths of each through the process of double-loop learning. “Double-loop” learning originates from organizational science and emphasizes “meta” learning through deliberate examination of how structural and psychological norms interact with the normal operational “single-loop” mechanisms of feedback and learning. As a result, double-loop learning represents a unique mechanism to integrate Safety I and II strategies and thereby advance safety science in pursuit of Diagnostic Excellence. Projects supported by this proposal will pursue ED Diagnostic Excellence through a mix of research and quality improvement activities both within and beyond the walls of JHM. Our transdisciplinary research team will pursue Diagnostic Excellence via three Specific Aims: (1) target the top causes of ED serious misdiagnosis- related harms; (2) partner and share knowledge with the DCE network and others; and (3) develop a JHM framework for sustainability of the DXC’s mission. Each Aim will be accompanied by double-loop “meta” learning that informs our understanding of barriers and facilitators to Diagnostic Excellence. Accomplishing these Aims will directly reduce diagnostic errors/harms in the ED and yield generalizable scientific insights that streamline future development and dissemination of innovative approaches to achieve Diagnostic Excellence.

NIH Research Projects · FY 2025 · 2022-09

Overdose deaths surpassed 100,000 in the United States in 2020. While opioid-related deaths largely attributable to fentanyl continue to rise, deaths involving stimulants, including cocaine, have increased by over 300% since 2013. A growing driver of the continued overdose crisis in the US is the role of concurrent use of multiple substances. Although there are pharmacological treatments to address opioid use disorder, few evidence-based options are available for addressing concurrent stimulant use among people using opioids. Understanding the dynamics of polysubstance use, particularly opioid and stimulant co-use, and the role of treatment with respect to the dynamics of co-use, is critical to inform ongoing overdose prevention. Yet, there are major gaps in our knowledge regarding the patterns and trajectories of opioid and stimulant co-use and their role in overdose. There is an urgent need to characterize the longitudinal nature of polysubstance use, treatment utilization, and overdose in community-based samples. The overarching objective of this proposal is to further our understanding of both long- and short-term patterns of opioid/stimulant use and examine the longitudinal relationship between co-use of opioids/stimulants and substance use treatment and non-fatal and fatal overdose over time, in order to inform treatment and overdose prevention services. We propose the following three specific aims: 1) To characterize long-term patterns of opioid and stimulant co-use and examine the relationship between trajectories of co-use, substance use treatment, overdose and mortality; 2) To examine real-time short-term patterns and transitions in and out of opioid and stimulant co-use and their association with substance use treatment and overdose; and 3) To assess opportunities and readiness for expanding and strengthening service capacity related to treatment and overdose among those with different patterns of opioid/stimulant use. To achieve these aims, we will leverage over 30 years of behavioral, laboratory and clinical data from among over 5,000 people who inject drugs within the AIDS Linked to the IntraVenous Experience (ALIVE) cohort to examine long-term trends of concurrent opioid/stimulant use. Supplemented with new recruitment of the Stimulant Opioid Non-Injection Cohort (SONIC), we will conduct new ecological momentary assessments in both samples to examine micro-patterns of use and employ state-of-the-art machine learning methods to identify patterns and their association with treatment and overdose over time in this community-based sample at high risk of overdose. Qualitative research with stakeholders and people with differing patterns of opioid/stimulant co-use will highlight gaps and challenges within the service system and identify specific implementation strategies to increase capacity to address heterogeneous concurrent opioid/stimulant use and related needs. The results of this study will provide evidence to inform intervention and policy to improve outcomes for people who use multiple substances with the goal of reducing overdose deaths in the US in the context of synthetic opioids.

NIH Research Projects · FY 2025 · 2022-09

Substance use disorder (SUD), overdose risk, and housing insecurity have reached crisis levels in the US. In 2019, over 8 million individuals met criteria for SUD, and nearly 37 million households were spending more than 30% of their income on housing. Beyond initiatives focused on people without housing such as housing first, there has been a paucity of research focusing on the intersection of SUD and housing insecurity. Even less is known about whether policy attempts designed to support housing security have the potential to improve engagement in substance use treatment and reduce fatal and non-fatal overdose. Innovative housing policies—including eviction moratoriums, emergency rental assistance, and legal representation to tenants facing eviction (right to counsel)—offer an unprecedented opportunity to fill this vital knowledge gap. Widespread variation across states in whether and how these policies were implemented allow them to be rigorously studied using causal methods with mechanisms and potential mechanisms explored using qualitative approaches. In Aims 1-2, we will conduct a 50-state study using a difference-in-differences approach to examine the effects of the three housing policies of interest on rates of substance use treatment and fatal and non-fatal drug overdose. Data sources for Aims 1-2 will include 50-state administrative databases capturing services delivered in the general medical sector (IQVIA LRx/Dx and HCUP) and specialty addiction treatment sector (TEDS), as well as CDC fatal drug overdose data. In Aim 3, we will conduct in-depth qualitative interviews with people with recent histories of drug use as well as providers and policy officials in urban and rural counties. Our study will yield actionable evidence to inform policy development and implementation at the intersection of housing and SUD designed to enhance engagement in addiction treatment and prevent drug overdose

NIH Research Projects · FY 2025 · 2022-09

High dietary quality is protective against cancer. Previous work to improve dietary quality by changing the food environment has emphasized increasing access to healthy foods in retail stores, but relatively little attention has focused on intervening in independently owned restaurants, which have the potential to contribute to cancer prevention in low-income urban neighborhoods. Our team has worked extensively with these types of restaurants to increase access to and promote healthier entrees, sides and beverages, leading to significant increases in total revenues, sales, and purchasing of promoted foods. Stemming from that work, this study has two interrelated objectives to sustainably improve access to and promotion of healthier foods in independently owned restaurants: 1) to use systems science approaches to refine, implement and test the effects of a novel intervention (FRESH: Focus on Restaurant Engagement to Strengthen Health) on dietary quality, and health of regular customers, among other outcomes; and 2) to use FRESH formative, baseline, implementation and outcome data to develop, parametrize, and calibrate a system dynamics model that will allow stakeholders to virtually test the effects of FRESH strategies on outcomes in their own communities. FRESH is a multilevel theory- and practice-based intervention for independently owned restaurants with 3 core components: food preparation, food access & procurement, and consumer nutrition environment. Aim 1) To use systems science approaches to refine existing materials from our successful restaurant interventions and adapt the intervention to two urban sites (Baltimore and the DC metro area) that are predominantly low-income. Aim 2) To implement FRESH in 24 independently owned restaurants across both sites during 16 months and collect process data. Aim 3) To assess the impact of FRESH using a multisite cluster randomized controlled trial on dietary quality (primary outcome); health indicators; psychosocial factors of regular customers (n=576), and evaluate its impacts on unit sales and weekly revenues. Primary Hypothesis: Regular customers of participating restaurants in FRESH intervention neighborhoods will demonstrate at least a 5-point increase in Healthy Eating Index score, as compared to restaurant customers in comparison neighborhoods. Data from Aims 1- 3 will be used to develop, parameterize, and calibrate a system dynamics model to simulate the effects of FRESH intervention strategies under different scenarios, leading to Aim 4) To disseminate a planning tool that enables stakeholders to simulate and virtually test FRESH intervention strategies in other urban contexts, visualizing potential effects on unit sales, revenues, customer health indicators, and cancer-prevention dietary behaviors, via a web-based user-friendly interactive dashboard. This study will yield results that are both novel and significant, including a simulation model to test restaurant-based cancer-prevention strategies, yielding substantial cost-savings from avoided trial-and-error implementation.

NIH Research Projects · FY 2025 · 2022-09

ABSTRACT The JHU-Tufts TIC is an established, functioning team of multisite trial PIs, experienced lead managers, administrators, and scientists at both Johns Hopkins University (JHU) and Tufts University. BIOS, a JHU trials research group, will operationally convene this group and provide staff to execute the required Statistical and Safety Resource Center program and its specific assigned tasks in the areas of statistics, safety, and DSMB management. Our joint expertise, developing and managing trials in these specified areas extends well beyond the last three years of work on the ongoing HEAL Pain ERN studies with our group having served as clinical coordinating centers and data coordinating centers for dozens of large multi-centered clinical trials at various NIH ICs. Together with our partners at Duke, Utah, and Vanderbilt, we will support the awardee teams for the new sickle cell trials in the same collaborative and comprehensive manner that has been demonstrated for the ongoing five trials currently awarded as part of the HEAL Pain ERN initiative.