Johns Hopkins University

NIH Research Projects · FY 2025 · 2023-09

PROJECTSUMMARY/ABSTRACT Lyme disease is an inflammatory disease, transmitted by ticks that are infected with the bacterium Borrelia bugdorferi. Despite treatment with antibiotics, 10-20% of patients develop post-treatment Lyme disease (PTLD) that often includes neurocognitive symptoms. The mechanisms underlying this are not well understood. Prior published and preliminary data from our research group suggests that cognitive performance is impaired in PTLD and that white matter (WM) changes on functional MRI (fMRI) are part of this process. WM changes are also, however, associated with better patient-reported outcomes. Thus, WM changes during Lyme disease may be part of a healing process following injury that comes at a cost to cognition, but more information is needed. In this study, we will draw upon a unique longitudinal cohort of patients with early Lyme disease and erythema migrans who will be studied longitudinally for 12 months. Their data will be compared to that of healthy controls without a history of Lyme disease. Our overall objective is to study the underlying mechanism of neurologic symptoms in PTLD. We will test the overarching hypothesis that WM changes reflect an adaptive response, and these changes predict better outcomes after treatment of early Lyme disease. To accomplish this goal, we will track WM activity immediately after initial antibiotic therapy and longitudinally 6 and 12 months later. Functional MRI (fMRI) will be used to measure WM activity that will be compared to outcomes, which will be measured using clinical scales and cognitive testing (AIM 1). We will also address the underlying neurobiological basis of WM changes by determining whether the myelin sheath or the underlying axon, both of which comprise WM, are affected in PTLD. To do so, we will use multimodal neuroimaging measures including diffusion tensor imaging (DTI), QSM and 𝜒-separation to understand axon and myelin integrity and health. A blood plasma marker, neurofilament light chain (NfL), will be used to quantify axonal injury. These variables will be correlated with cognitive performance, clinical scales, and blood inflammation markers, which, if successful, would provide simple prognostic indicators. (AIM 2) Finally, we will examine inflammatory markers including the chemokine ligand 19 (CCL19), which has been associated with increased risk of developing PTLD, and Interleukin-6 (IL-6), which plays a role in mediating inflammation and demyelination. These have not been shown to correspond with central nervous system markers in Lyme disease thus far, but they may correspond with MRI WM values, which has never been tested. (AIM 3). Collectively, our studies represent a rigorous approach by including multimodal neuroimaging combined with blood biomarker measurement towards elucidating determinants that are associated with the cognitive and clinical outcomes of PTLD. The long-term goal is to generate insights that may lay the foundation for new diagnostic, prognostic, and therapeutic approaches to the cognitive manifestations of PTLD.

NIH Research Projects · FY 2024 · 2023-09

Project Summary Alcohol is a common potential source of DNA damage in humans. Indeed, its metabolic byproducts, acetaldehyde and reactive oxygen species (ROS), mutate hematopoietic stem cells (HSCs). Importantly, DNA damage is central to the aging process by contributing to stem cell exhaustion, cellular senescence, inflammation, and deregulated nutrient sensing. Together, these findings have led us to hypothesize that alcohol-induced DNA damage accelerates aging in HSCs. Moreover, aged HSCs have myeloid-biased differentiation, reduced long- term repopulating potential and decreased DNA repair function, which may lend themselves to being more vulnerable to alcohol-induced DNA damage. Prior research has used very high doses of alcohol to study their DNA-damaging effects on HSCs, which is difficult to generalize to the broader aging population who may enjoy only moderate alcohol drinking. Also, the effects of moderate alcohol consumption on overall health in the general population remain controversial. The overarching goal of this proposal is to shed light on the key aspects of HSC aging using cell-based and animal models. We aim to identify DNA repair genes essential for repairing alcohol- induced DNA damage in HSCs by a pooled CRISPR screen. We also aim to determine whether aged HSCs are more vulnerable to moderate alcohol drinking using a mouse bone marrow transplant model and a single-cell RNA-sequencing approach. Our proposed studies will reveal genes that repair DNA lesions caused by alcohol and its toxic metabolic by-products. It will also inform us how aged HSCs respond differently to alcohol-induced DNA damage than younger HSCs. Identification of key differences in DNA damage response and DNA repair in aged HSCs will enable us to uncover ways to prevent aging due to alcohol and potentially due to other endogenous and exogenous DNA damaging agents as well.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY Universal firearm injury and violence prevention counseling of patients has been recommended by multiple national organizations for over a decade, yet clinicians rarely deliver this counseling. Implementation barriers must be addressed to effectively deliver firearm related injury prevention programs. The research team has demonstrated success in the implementation and sustainability of alcohol screening, brief intervention and referral to treatment protocols in two federally funded multi-site trials. The team also has expertise in clinically- based strategies for firearm injury prevention and educational program development. We will apply our implementation science and subject matter expertise to implement a universal firearm injury prevention initiative in a phased approach: first at a single, urban level 1 trauma center and second at a cohort of 4 trauma centers serving urban, suburban, and rural communities following a stepped-wedge approach. All sites have a successful history of prior collaboration through the Johns Hopkins Clinical Research Network. Our goal is to demonstrate best practices for trauma center-based firearm injury prevention strategies that promote safe storage practices and reduce firearm related injury and death. This proposal, submitted in response to PAR- 23-066, will refine a feasible, comprehensive training strategy for improving the implementation of a universal firearm injury prevention program, ACTFAST (Adopting Comprehensive Training for FireArm Safety in Trauma centers), and then study its implementation and effectiveness. In Phase 1 we will: (Primary Aim 1) demonstrate feasibility of a program for adoption, implementation, and maintenance of a universal firearm injury prevention intervention within one level 1 trauma center; and (Secondary Aim 1) evaluate trauma center clinicians’ firearm injury prevention knowledge and confidence in delivering a firearm injury prevention intervention. In Phase 2, we aim to: (Primary Aim 2) increase the adoption, implementation, and maintenance of a universal firearm injury prevention intervention within four participating trauma centers in Johns Hopkins Medicine and the Clinical Research Network, an alliance of academic and community hospitals in the mid-Atlantic states; (Primary Aim 3) assess firearm injury prevention knowledge, attitudes, and safe storage practices among trauma patients treated within participating trauma centers; and (Secondary Aim 2) evaluate trauma center clinicians’ firearm injury prevention knowledge and confidence in delivering a firearm injury prevention intervention. Using the RE-AIM methodology, we will evaluate our comprehensive strategy across the domains of adoption, implementation, and maintenance at the institutional level. We will measure clinician firearm safety knowledge and confidence in delivering firearm prevention counseling after participation in the clinician training program as measured by pre and post training surveys. In addition, we will collect and analyze patient data before and after ACTFAST implementation for changes in knowledge, attitudes and, most importantly, practices at baseline and at 2 weeks and 3 months after hospital discharge.

NIH Research Projects · FY 2025 · 2023-09

The increasing complexities of clinical trials, along with a particular emphasis on precision medicine trials, have led to a recent decline in enrollments. This proposal identifies strategies to address the challenges of enhancing clinical trial enrollments in the hematologic malignancies (HM) program at the Sidney Kimmel Comprehensive Cancer Center (SKCCC). The two-pronged approach tackles system barriers and patient barriers. A clinical trial toolkit will be developed to address systems barriers with the goal of minimizing inefficiencies within our research operations program, increasing enrollment, and ultimately creating a clinical trial portfolio that best serves our patients. Components of the toolkit include metrics to ensure feasibility of trials, establish a prioritization queue for resourcing potential studies, trackers for effort and finances, and performance standards. With many patients preferring to receive their care closer to home, while also having access to the same novel approaches offered at academic medical centers, the proposal seeks to extend our clinical research studies to satellite sites. To achieve that end, Dr. Wagner-Johnston addresses strategies to create the necessary research culture to enhance enrollment. Focus will be placed on establishing leadership and providing a collaborative learning culture at the satellite sites. Rational portfolio building at the satellite sites will rely on the same metrics developed as part of the toolkit. Engagement from both physicians and prospective trial participants is essential and this proposal outlines practical approaches to attend to these concerns. Involvement in routine research meetings and recognition of physicians’ effort in consenting to trials will incentivize trial participation. Outreach efforts including monthly email newsletters to referring physicians, updates to our HM website, as well as a better tool to identify potential trials for patients are planned. The outlined research strategy seeks to improve the operational aspects beginning with pre-trial activation through study closure. Attention to increased efficiencies will be essential in bringing needed research to satellite sites. Best practices identified from this project will be readily transferrable to the entire cancer center enterprise at SKCCC and shared with other academic medical centers. As a nationally recognized lymphoma expert with a strong commitment to the NCTN and extensive knowledge in clinical research operations, Dr. Wagner-Johnston is poised to lead these efforts and successfully enhance accruals.

NIH Research Projects · FY 2025 · 2023-09

Treatment for almost all patients with metastatic cancer has become a balance between managing often severe, treatment-induced toxicity and preventing cancer progression. Progression leads to increasingly toxic combination regimens until the patient succumbs either to treatment toxicity or to disease progression. Radiopharmaceutical therapy (RPT) is an emerging treatment modality that delivers radiation to targeted cells. Alpha-particle-emitter RPT (αRPT) is a new and fundamentally different therapeutic modality that can break this cycle. It is the only modality that can deliver highly potent, α-particles to disseminated cancer metastases. Fundamentally, it is a radiation delivery modality. The radiation type delivered is far less susceptible to the resistance mechanisms or unanticipated side-effects observed with biologic (or pathway inhibition) therapy and chemotherapy. Despite these key differences, αRPT is being administered in a prolonged multi-cycle scheme that severely compromises the potential efficacy of this treatment modality. In large part, this is because rigorous, validated dosimetry methods for α-emitters do not exist. Such methods would make it possible to project potential normal organ toxicity for individual patients so that treatment need not be prolonged for the sake of toxicity evaluation. Our primary objectives are: 1) to develop and test dosimetry methodologies that will enable precision medicine/treatment-planning-based αRPT for cancer therapy and 2) to gain the understanding needed to optimize combination therapies involving αRPT. The hypotheses underpinning this program project grant are as follows: 1. αRPT is a systemic cancer therapy modality that is particularly applicable to targeting metastatic cancer; it is far less susceptible to conventional resistance mechanisms. It is also amenable to dosimetry-driven treatment planning. 2. As currently implemented αRPT is not achieving its potential. Dosimetry-driven treatment planning for RPT has been demonstrated to substantially improve long-term survival. 3. No one cancer treatment modality is curative, and patients differ in their potential therapeutic response and toxicity. Promising agents are inevitably combined with other therapeutics. Although mechanistic studies are used to point towards rational combinations, clinical trials continue to be largely empirical in terms of the sequencing and amount of each administered drug. A dosimetry and radiobiology-driven approach will substantially reduce the scope of human experimentation. Considering these hypotheses, our overall objective is to develop methodologies and investigate how best to transition RPT implementation from that of a “radioactive chemotherapy paradigm” to one more closely aligned with treatment planning for radiation delivery. These foundational hypotheses motivate the work proposed in this program project. Put very simply: dosimetry has been proven to improve outcome for RPT agents but dosimetry for alpha-emitters is hard. Five years support of this program project will make αRPT dosimetry easy enough to implement widely and thereby improve survival for currently incurable cancers.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY/ABSTRACT More than 40% of the 250 million people living with asthma in the United States are obese. Obese individuals with asthma are more likely to develop “obesity-associated asthma,” a phenotype that is exacerbation-prone and resistant to treatment. While weight loss is an effective treatment, this is difficult to attain and sustain, and consequently there are few effective and specific treatment options for this prevalent asthma phenotype. Obesity-induced metabolic inflammation, insulin resistance, and pre-diabetes may explain some of the excess morbidity of obesity-associated asthma. Metformin, the first-line treatment for type 2 diabetes, comprehensively treats these conditions. Preclinical data suggest that metformin improves airways hyperresponsiveness and allergic airway inflammation among animal models of obese asthma, and observational data have shown an inverse relationship between metformin use and risk of asthma exacerbation, suggesting that metformin may be beneficial among patients with asthma and elevated body mass index. The objective of this application is to conduct a pilot, six-month, randomized, placebo-controlled, parallel-arm, two-center trial of metformin among overweight and obese individuals with physician-diagnosed asthma recruited from Baylor College of Medicine and Johns Hopkins University. The pilot RCT will determine (1) feasibility of a study design that utilizes remote methods for research participation and (2) preliminary estimates of the effect of metformin on core patient- centered and physiologic outcomes. Completion of these aims will inform the decision to proceed with a pivotal multi-center efficacy RCT testing metformin among overweight and obese participants with asthma and inform specifics of its design and enrollment strategies. This project will provide findings that address an urgent research priority relevant to the millions of Americans with obesity-associated asthma.

NIH Research Projects · FY 2025 · 2023-09

In the US, nearly half of all pregnancies are unintended. Unintended pregnancies are associated with risks to maternal and child health including late prenatal care, premature delivery, developmental delay, and family instability. Governmental agencies and professional maternal and child health organizations support access to contraceptive use and family planning services as essential for women’s health. However, some communities face barriers to sexual and reproductive health (SRH) access. The Latino/a community in the US is growing and many Latinos have limited preventive health care access. With the growing number of US-born Latino children, the pediatric setting is an unexplored venue for interventions that address SRH access for Latina parents. SRH interventions must also be person-centered and culturally relevant. In this K23 application, Dr Caballero, a research-trained pediatrician, proposes a rigorous training and research plan that will facilitate her long-term career goal: to strengthen child and family health by developing and implementing person-centered interventions to improve SRH for Latinas. She proposes to: 1) develop expertise in qualitative methods and analysis to inform implementation-focused outcomes; 2) develop skills in human factors engineering principles and implementation science; and 3) learn and apply family planning demography principles to intervention design and analysis. She also proposes innovative mentored research to develop and pilot a contraceptive screening and care coordination intervention (Family Connect) in a pediatric primary care setting. Family Connect will be stakeholder-informed and rooted in human factors engineering approaches to health care redesign. This study will provide preliminary data to support a future larger trial of Family Connect. Dr. Caballero’s research will occur in a supportive, collaborative environment at Johns Hopkins School of Medicine, under the guidance of an experienced and dedicated multidisciplinary mentoring team. This team is committed to supporting Dr. Caballero in achieving her research and training goals and her long-term goal of becoming a highly productive independent clinician-investigator and leader in innovative health disparities research to advance SRH access for Latinas.

NIH Research Projects · FY 2025 · 2023-09

ABSTRACT The Fogarty International Center is at the forefront of advancing National Institutes of Health (NIH) support for international research to promote health and reduce disease burden both in the US and globally. A large part of this mission is linked to the successful creation and maintenance of international partnerships between institutions and research groups in low- and middle-income countries (LMICs) and the United States (US). Successful collaboration among research partners - defined as the proactive and sustained prioritization of mutually beneficial inputs, processes, outcomes, and impact - is an ethical and practical imperative needed to achieve meaningful scientific aims and outputs within these partnerships. Despite the importance of establishing formal collaborative practices and several recommendations and guidelines available to do so, tools for systematically acknowledging existing partnership asymmetries and methods to overcome them are not well-described. The goal of this proposal is to develop and pilot a pragmatic collaboration tool using experienced HIV- focused research partnerships between Uganda, an LMIC, and the US as a case series given the dominance of the HIV epidemic on global health research paradigms over the past 40 years and the continued focus as a priority for many research partnerships in Uganda and the US. This will be accomplished through an explanatory quantitative to qualitative evaluation of these partnerships that generates a holistic understanding of best practices and barriers to collaborative research practices (Aim 1). These results will inform the creation of an ethics-informed collaboration tool that consists of structured survey and focus group materials to systematically evaluate an international research partnership and create a summative report that highlights exemplar practices, identifies feasible areas for improvement, generates attainable program-level goals, and creates an action plan (Aim 2). The tool will then be prospectively piloted and assessed for efficacy, feasibility, and acceptability within a research partnership (Aim 3). Collectively, this proposal seeks to elucidate a tool to recognize and, importantly, rectify barriers and instigate change at a program level within international research partnerships. This K01 will provide Dr. Chelsea Modlin with the training she requires in advanced qualitative and ethnographic methods including reflexivity, empiric and applied methods in international research ethics, and developing global health program assessment tools. This award will also support preliminary research findings needed to pursue R01 funding to scale up the collaboration tool to other geographic areas and fields of global health research. This tool has the potential to assist with ensuring that the ongoing research practices, outputs, and legacies of international research collaborations benefit both research partners and ultimately, the global communities they serve.

NIH Research Projects · FY 2025 · 2023-09

Project Summary Globally, colorectal cancer (CRC) is the second leading cause of cancer-related deaths in men and women and is projected to increase by 70% in the next 20 years. One of the earliest initiating events of CRC is mutation of adenomatous polyposis coli (APC), a tumor suppressor gene. This mutation initiates the gradual progression from normal proliferating colon epithelial cells (CECs) to dysplastic lesions, to the eventual formation of tumors, known as adenomas. Somatic APC mutations occur in >80% of sporadic CRCs. Growing evidence demonstrates that factors within the local microenvironment can significantly influence cancer risk and onset. One key characteristic of the colon adenomatous environment is an imbalanced microbiome. Disruption in the makeup of these microbiota, known as dysbiosis, is related to many diseases, including colitis, inflammatory bowel disease, and CRC. While dysbiosis contributes to promoting adenoma progression and CRC, whether APC mutation triggers changes in the local microenvironment to facilitate tumor progression and microbiome dysbiosis remains largely unknown. Using an inducible murine model of CEC Apc truncation, our lab found that Apc inactivation and subsequent colon tumorigenesis results in microbiome dysbiosis and outgrowth of pathogenic species, further, associated with increased bacterial mucosal adherence. This proposal aims to define the timing and mechanisms by which the early microbiome changes following Apc inactivation. We hypothesize that Apc loss alters the microenvironment to cause early loss of commensal species and provides a habitat for pathogenic outgrowth and pro-carcinogenesis. We will test our hypothesis through the following aims. Aim 1: Defining the effects of Apc inactivation on the composition, spatial/temporal dynamics, and tumorigenic potential of the host microbiome. Using 16S rRNA amplicon sequencing and microbiology, I will identify early microbiome changes following Apc loss during gradual colon tumorigenesis and will determine if this differs by colon region. I will use germ-free models to evaluate if the changing microbiome is sufficient to induce colon tumorigenesis. Aim 2: Identifying the mechanism(s) by which Apc inactivation contributes to microbiome dysbiosis and the expansion of pathogenic species. I will utilize transcriptomics and metabolomics to examine changes in metabolic pathways and gene regulation in association with changes in microbiome composition and timing of Apc inactivation. This research will provide novel insights into the events occurring upon Apc mutation and the crosstalk between mutated CECs and the local microbiome.

NIH Research Projects · FY 2024 · 2023-09

Project Summary Vascular access is the most common medical procedure in the world, with over a billion insertions performed annually. In the United States, over 350-million peripheral intravenous (IV) catheters are sold yearly, in addition to millions of central and arterial lines. However, peripheral IV placement often requires several attempts at insertion, which is painful and time consuming. Furthermore, there is a high rate of early failure that can lead to further complications, including extravasation, thrombophlebitis, and compartment syndrome, as well as delays in delivery of therapeutic medications. Ultrasound guided vascular access is widespread and has advanced difficult IV access success rates, but there is clearly room for improvement as the success rate for ultrasound guided peripheral IV placement is stagnant at 80%. Improving the success rate for vascular access will have a huge impact on patient care and patient safety. To address the clinical need described above and overcome the current technical challenges, we have pioneered a novel concept of ‘active acoustic communication’ between needle and imaging systems for guidance. We are further evolving the concept into a clinical prototype that is intuitive and easy to use, low cost, disposable, works with any ultrasound vendor, offers easy needle tip tracking, and differentiates between tissue types. A ‘5T (tool tip tracking + tissue typing)-IV’ guidance platform will offer an integrated interface layer for clinicians, providing (1) high-spatiotemporal resolution (sub-millimeter and sub-second) tool tip tracking over a wide field-of-view, (2) encoded contrast with a flashing active echo pulse to visualize the needle tip, and (3) highly accurate tissue typing at the needle tip with (4) an unaltered clinical workflow. In this project, we will first develop a vendor-independent clinical prototype hardware and software package with comprehensive performance characterizations in tissue-mimicking phantoms, and this will guide further iteration of the form- factor and software user interface included in the clinical prototype to be tested in animals. The efficacy and user experience will be extensively evaluated in preclinical phantom models by performing human factor studies with 65 end users. Quantifiable metrics (e.g., success rate, time duration and number of trials) will be compared between conventional US and the 5T-IV guidance methods will be expanded to swine animal models for both jugular and femoral cannulation with different experience level (residents vs. attending anesthesiologists).

NIH Research Projects · FY 2024 · 2023-09

Project Summary Xylazine is an emerging serious threat to people who inject drugs (PWID). Xylazine and fentanyl drug mixtures elevate risk overdose and because xylazine is not an opioid, naloxone does not reverse its effects. Despite the increasing presence of xylazine in overdose deaths across the US, there is limited epidemiologic research focused on characterizing the prevalence and risk factors of its use in settings where mortality data indicates a known elevated risk. Although there has been a marked uptick of severe wounds and necrosis among those using drugs that contain xylazine, the specific drug use practices or other characteristics related to the development of wounds are not known. The goal of this research is to generate urgently needed evidence to understand the prevalence, risk factors, knowledge, and harm reduction practices associated with xylazine use and the development of wounds among PWID, in order to effectively inform practice and raise awareness among the affected communities, health care and harm reduction service providers and the public regarding the health risks associated with xylazine. We propose a mixed methods approach using respondent-driven sampling to identify and survey approximately n=300 PWID in Baltimore and n=40 qualitative interviews with those who use xylazine, health care and harm reduction providers. We will estimate the prevalence and correlates of both intentional and suspected xylazine use and examine xylazine-specific overdose knowledge, beliefs and practices. We will determine the prevalence of wounds associated with xylazine use and the association between HIV infection, drug use practices and wounds. We will also characterize barriers to accessing wound care using qualitative methods. This research on a sudden emerging illicit drug will generate time-sensitive knowledge that will directly contribute to preventing the harmful consequences associated with xylazine emergence. We will translate our findings and conduct broad dissemination, working with local stakeholders, partner organizations, and governmental agencies to inform overdose and treatment programs.

NIH Research Projects · FY 2025 · 2023-09

Even before COVID-19, pneumonia with respiratory failure was a very common cause of hospitalization. Unfortunately, many patients who survive pneumonia have persistent health problems for months or years afterwards. The objective of this Effective Primary Care Practices that Enhance Recovery Trajectories after Pneumonia (EXPERT) study is to use appreciative inquiry to help primary care clinicians take better care of pneumonia patients in the 6 months after hospital–by taking a strengths-based approach for transformational change to design and test a new systems-level intervention. We will use a multi-methods approach wherein quantitative analysis of primary care actions and qualitative interviews with expert primary care clinicians and patients are used to refine an innovative intervention in a participatory prototyping pilot trial. The pilot trial targets mechanistic process outcomes linked to increased hospital-free days for pneumonia survivors. Our team from primary care, hospitalist medicine, critical care, palliative care, sepsis, informatics, clinical epidemiology, medical sociology, and clinical trials, will: Aim 1: Quantitatively analyze granular EHR data to identify and refine candidate components for a primary care intervention to improve post-pneumonia care. We will leverage large, feature-rich datasets from our team’s 3 diverse health systems to identify specific orders, referrals, and billing services by primary care clinicians that are substantially more frequent in the 6 months after pneumonia than before and temporally associated with reduced subsequent hospitalization. Aim 2: Qualitatively analyze the experiential insights of primary care clinicians and pneumonia survivors to identify and refine candidate components and identify enablers and barriers for the post-pneumonia intervention. We will conduct semi-structured interviews and focus groups with PCCs and pneumonia survivors across 4 states to evaluate key actions and implementation factors for successful post-pneumonia recovery. Aim 3. Refine and pilot a novel multicomponent primary care intervention to improve delivery of post-pneumonia care that will lead to improved health outcomes for pneumonia survivors. We will use a novel stakeholder-engaged strategy of participatory prototyping to iteratively optimize the intervention and evaluate its effects on target mechanistic outcomes in an eight-site cluster randomized pilot trial design. EXPERT’s research addresses a fundamental knowledge gap in post-pneumonia care, a public health priority. We propose to use appreciative inquiry to help primary care do what primary care does well, and to optimize an intervention that makes it easier for them to do so.

NIH Research Projects · FY 2025 · 2023-09

Project Summary Vascular access is the most common medical procedure in the world, with over a billion insertions performed annually. In the United States, over 350-million peripheral intravenous (IV) catheters are sold yearly, in addition to millions of central and arterial lines. However, peripheral IV placement often requires several attempts at insertion, which is painful and time consuming. Furthermore, there is a high rate of early failure that can lead to further complications, including extravasation, thrombophlebitis, and compartment syndrome, as well as delays in delivery of therapeutic medications. Ultrasound guided vascular access is widespread and has advanced difficult IV access success rates, but there is clearly room for improvement as the success rate for ultrasound guided peripheral IV placement is stagnant at 80%. Improving the success rate for vascular access will have a huge impact on patient care and patient safety. To address the clinical need described above and overcome the current technical challenges, we have pioneered a novel concept of ‘active acoustic communication’ between needle and imaging systems for guidance. We are further evolving the concept into a clinical prototype that is intuitive and easy to use, low cost, disposable, works with any ultrasound vendor, offers easy needle tip tracking, and differentiates between tissue types. A ‘5T (tool tip tracking + tissue typing)-IV’ guidance platform will offer an integrated interface layer for clinicians, providing (1) high-spatiotemporal resolution (sub-millimeter and sub-second) tool tip tracking over a wide field-of-view, (2) encoded contrast with a flashing active echo pulse to visualize the needle tip, and (3) highly accurate tissue typing at the needle tip with (4) an unaltered clinical workflow. In this project, we will first develop a vendor-independent clinical prototype hardware and software package with comprehensive performance characterizations in tissue-mimicking phantoms, and this will guide further iteration of the form- factor and software user interface included in the clinical prototype to be tested in animals. The efficacy and user experience will be extensively evaluated in preclinical phantom models by performing human factor studies with 65 end users. Quantifiable metrics (e.g., success rate, time duration and number of trials) will be compared between conventional US and the 5T-IV guidance methods will be expanded to swine animal models for both jugular and femoral cannulation with different experience level (residents vs. attending anesthesiologists).

NIH Research Projects · FY 2024 · 2023-09

PROJECT SUMMARY AMPA-type glutamate receptors (AMPARs) are the major excitatory neurotransmitter receptors in the brain and changes in AMPAR number at synapses underlie learning and memory as well as human disease. A detailed understanding of how AMPARs are organized at synapses is critical to understand how synaptic strength is regulated and for the development of therapeutics to correct circuit imbalances in human disease. The long-term goal of this proposal is to use Cryo-EM to understand how the structural basis of AMPAR N-terminal domain interactions (NTDs) drive functional outcomes such as increased AMPAR accumulation and synaptic strength. The rationale for this approach is twofold 1) it will help resolve long-standing questions about the regulation of key neurotransmitter receptors; and 2) a detailed structural model of AMPARs participating in key regulatory complexes will guide future therapeutic approaches that seek to alter the strength of excitatory input onto neurons implicated in psychiatric illnesses like schizophrenia. The adhesion protein NPTX2 binds to AMPARs, clusters AMPARs at synapses, and is required for homeostatic scaling of interneuron-specific GluA4- containing AMPARs. Therefore, NPTX2-dependent GluA4 scaling is an ideal model for testing the hypothesis that direct extracellular interactions with AMPARs control synaptic strength. This approach is innovative because models of AMPAR plasticity have never been observed in structural detail. This research is significant because it will yield new insights into how AMPAR interactions drive plasticity and how this can be exploited for therapeutic benefit in the future. An example of such an approach would be a structure-guided therapeutic strategy for clustering GluA4 on the surface of Parvalbumin-expressing interneurons (PVINs), which exhibit lowered excitatory drive in models of schizophrenia. The long-term goal of this project will be achieved with the following two specific aims: 1) Determine the structure of the NPTX2/GluA4 complex via single particle Cryo-EM. and 2) Test whether NPTX2 drives GluA4 PVIN scaling through a direct interaction. For the first aim we will employ single-particle Cryo-EM to solve the structure of the activity-regulated synaptic adhesion molecule NPTX2 in complex with the interneuron- specific GluA4 AMPARs. For the second aim, we will employ transgenic mouse models, biochemistry, neuron culture, confocal light microscopy, and electrophysiology to test the hypothesis that direct binding of NPTX2 to the NTD of GluA4 drives homeostatic scaling in disease-associated PVINs. The applicant has proposed this work in part to further their long-term goal of establishing an independent research career connecting the structure of synaptic proteins to their synaptic function. The candidate will undertake extensive training in Cryo-EM and biophysics which will be facilitated by an expert mentoring team composed of an AMPAR Cryo-EM expert, an AMPAR plasticity expert, and an expert in NPTX2, all of whom will mentor the applicant through the transition to a tenure track academic position.

NIH Research Projects · FY 2024 · 2023-09

Hypothalamic tanycytes have limited postnatal neurogenic competence, but the extrinsic and intrinsic factors that promote this are not well understood. My predoctoral research identified a defined developmental window during which neurogenic competence is lost from hypothalamic tanycytes. I have also identified the neurogenic bHLH transcription factor Ascl1 as a candidate activator of neurogenic competence in tanycytes and identified Shh signaling as potentially promoting the survival of tanycyte-derived neurons. In the F99 phase of this award, I will investigate whether AAV-mediated overexpression of Ascl1 induces neurogenic competence and whether Shh signaling promotes the survival of tanycyte-derived neurons using cell-specific conditional genetic approaches. During the K00 phase, I will pursue postdoctoral training using zebrafish as a model to identify gene regulatory networks controlling injury-induced hypothalamic neural regeneration, identifying yet uncharacterized extrinsic and intrinsic mechanisms that regulate neurogenic competence in tanycyte-like radial glial cells. By comparing these findings to data obtained from mammalian tanycytes, I plan to identify both positive and negative regulators of neurogenic competence that could be manipulated to induce the tanycyte-derived generation of specific hypothalamic neuronal cell types for treatment of metabolic and other homeostatic disorders. These opportunities will advance my career as a neuroscientist and prepare me for a principal investigator role at an R1 institution studying tanycyte biology and hypothalamic regeneration.

NIH Research Projects · FY 2025 · 2023-09

We propose to leverage recent advances in machine learning and systems biology to enable high dimensional molecular assessment of the dynamic cell state transitions driving metastasis. We hypothesize that the interaction between a cancer cell's intrinsic reactivation of developmental programs with its spatiotemporal context determines its metastatic potential. We will exploit developmental changes in the mammary epithelium to define their cell state basis and map the aberrant reuse of these transcriptional programs in metastatic disease. Both normal mammary epithelium and breast tumors undergo dramatic changes in differentiation and tissue architecture, and loss of differentiation correlates with poor patient outcomes. We developed 3D culture assays that recapitulate epithelial morphogenesis and cancer growth, invasion, and metastatic colony formation. The key concepts arising are that: (1) a conserved process of dedifferentiation and loss of polarity accompanies both normal and neoplastic morphogenesis and (2) the cancer cells in luminal and basal breast cancer recapitulate basal epithelial and hybrid EMT programs. Recent advances in single cell sequencing, spatial transcriptomics, and machine learning enable transcriptome-wide resolution of these states in tissue, quantitative comparison of normal and cancerous cell states, and the identification of targetable cell state regulators. Aim 1: Map cell states in space and time during development, tumor formation, and metastasis. We will generate scRNA-seq data from normal glands, ductal carcinoma in situ, and invasive tumors collected at different ages and also longitudinally in 3D culture. We will use our CoGAPS algorithm to infer cell states and their temporal progression. We will then use our patternMarker2 statistic to identify cell state makers for MERSCOPE analysis in tissue. We will map these states in normal glands, primary tumors, and metastases isolated from genetically engineered mouse models (GEMM) and patient derived xenografts (PDX). Aim 2: Model the dynamics of differentiation state during development and cancer progression. To define the effect of cell state on metastatic progression, we will construct an ecosystem-style multinomial diversity model. We will initialize the model with literature-based parameter values to predict the interactions between cell type and cell state. We will then extend the model to use the weights assigned by CoGAPS to each cell, thereby linking gene regulatory programs to the cell state changes driving metastasis. Aim 3: Validate candidate regulators of metastatic cell state transitions in 3D culture and in vivo. To isolate the genes regulating metastasis, we will use our transfer learning algorithm, projectR, to score each cancer cell for its relative utilization of scRNA-seq-defined molecular programs. We will then use our projectionDriver statistic to identify differentially expressed (DE) genes at sites of cancer invasion, relative to the tumor interior. DE genes will be tested genetically in 3D culture assays modeling invasion and colony formation and then in orthotopic and tail vein metastasis assays in vivo.

NIH Research Projects · FY 2024 · 2023-09

Project Summary Aging is a progressive process in all cells that leads to tissue dysfunction and is a major cause of degenerative changes. Aging cells show characteristic patterns of epigenetic changes that are often cell-type and tissue- specific. The development of methylation-based clocks has harnessed this phenomenon and is successfully used to predict the biological age of cells, tissues, and organisms across species. However, the functional implications of these epigenetic changes are not well understood. Furthermore, bulk analyses of aging cells limit the identification of subtle, unique, cell-type specific changes. Therefore, investigating cellular aging mechanisms with single cell resolution is essential for teasing out these cell-type specific changes. Most blinding diseases are a result of age-related retinal degeneration, for which there are currently no treatments. It is essential to understand the molecular mechanisms that regulate retinal aging to identify targets and develop therapeutics to slow or prevent the onset of these degenerative diseases. I propose to use approaches that have previously been applied to studying retinal development and regeneration to conduct a comprehensive analysis of normal retinal aging with single cell resolution to identify gene regulatory networks that control cellular aging in the retina. I will determine how acute injury influences the rate of retinal aging, and test potential retina specific aging targets to slow the aging process. I will manipulate expression of transcription factors whose activity is altered by natural aging, injury, and/or rejuvenation, and determine whether this can regulate cellular age. Completion of this work will create accurate cell type-specific molecular aging clocks for all major retinal cell types, identify gene networks and targets that control cellular aging, and determine if modulation of these networks can be used to rejuvenate cells. The datasets created in this work will not only enhance the study of retinal aging, but cellular aging throughout the central nervous system in general.

NIH Research Projects · FY 2024 · 2023-09

PROJECT SUMMARY Proprioception is an indispensable sense of the body’s position and movement in space. Fine motor control depends on proprioceptors to monitor the mechanical consequences of motor actions. In particular, muscle spindles are a class of primary proprioceptors that detect muscle length and stretch at the intrafusal fibers. The signals generated by muscle spindles are complex with dynamical regulation of intrafusal fiber lengths via γ motor neuron (fusimotor) activity. The interaction between feedforward mechanical signals at the muscle spindle and descending motor commands at the parent muscle, especially in the context of naturalistic movements, remains poorly understood. Opposing views disagree on whether muscle spindles passively sense muscle length/stretch or actively process biomechanical signals based on motor commands to the muscle. Using the unique advantages of rodent jaw proprioceptors in the hindbrain mesencephalic trigeminal (MeV) nucleus, I will test the hypothesis that motor commands flexibly tune jaw muscle spindle coding in a context-dependent manner. With experimental access to many levels of the jaw sensorimotor circuit, I will determine how feedforward mechanical signals and descending motor commands interact at the primary proprioceptors. Aim 1 will find the relationship between motor unit activity in jaw muscles and corresponding muscle spindle activity during passive and active movements. Aim 2 will record muscle spindle activity with (a) external loads on the jaw and (b) optogenetic decoupling of motor drives from muscle-driven motion. Aim 3 will provide an overarching framework to model the jaw system as a feedback control loop. The proposed project investigates proprioceptive feedback in craniofacial structures, electrophysiological mechanisms for controlling jaw function, and quantitative models of the neural controller and muscles of the jaw. The immense training potential in this project lies in the application of novel in vivo electrophysiology tools, well-designed use of optogenetics, and quantitative modeling rooted in control theory. The proposed work has important implications in elucidating orofacial proprioception at the primary receptors and understanding temporomandibular disorders and orofacial pain involving maladaptive control of the jaw.

NIH Research Projects · FY 2025 · 2023-09

Tuberculosis (TB) remains a major global health crisis, causing 10 million new cases in 2023. Despite extensive efforts by the global community to identify TB cases, 30% of new cases went undiagnosed. Current strategies focus on active case finding, which is costly and hard to implement practically. One potential solution to these challenges is self-testing. Although self-testing for TB has not been widely adopted so far, partly due to a lack of suitable testing options and studies evaluating this method, recent advances in diagnostic technology make self-testing a feasible option. This development opens a new avenue for patient-centered TB care. I propose a type 3 hybrid implementation-effectiveness study to assess the feasibility of implementing self-testing for active TB. I will use a currently available diagnostic tool—oral swab specimens for molecular testing—which are easy to self-collect and sensitive but require shipping to a laboratory. I have identified barriers to TB self-testing implementation and will refine strategies to address these barriers through qualitative interviews and quantitative surveys (Aim 1). I will conduct a prospective study in high-burden community settings in Baltimore, U.S., where known TB contacts and/or working-age individuals are less likely to seek care, distributing oral swab kits in intervention facilities while maintaining TB training standards in comparison facilities (Aim 2). I will evaluate the implementation and effectiveness of each strategy guided by the Reach, Effectiveness, Adopt, Implementation, and Maintenance (RE-AIM) framework. My primary outcome will be an increase in the proportion of individuals receiving microbiological testing results, reflecting the acceptability and fidelity of TB self-testing. To achieve these aims, I will employ a highly pragmatic study design in which the research team minimizes contact with study households. This approach will allow me to evaluate whether TB self-testing implementation can impact case detection and improve health outcomes for individuals in a “real-world” setting. Completing this study will provide pragmatic, preliminary data on the potential implementation and effectiveness of TB self-testing in high-burden settings. If successful, it will justify a larger trial; if not, it will inform alternative strategies to overcome barriers to seeking TB care. In either case, the findings will motivate a larger R01 proposal at the end of the five-year grant period and advance the field of TB self-testing. While this proposal will assess self-testing using an available tool, a broader goal is to develop a self-testing strategy for TB disease that can be applied to future tools. This approach aims to advance patient-initiated or patient-centered TB care. Additionally, the study will help me gain skills in mixed methods research and implementation science, positioning me as a future leader in implementing patient-centered TB interventions globally. Modified

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY. COPD is a leading cause of death and morbidity worldwide and is attributable to the aggregate burden of toxic gases and particles that individuals inhale during their lifetime. In the US, this exposure is primarily cigarette smoke; however, even after smoking cessation, patients with COPD continue to suffer respiratory morbidity. International 2022 COPD guidelines (GOLD) emphasize non-pharmacological interventions to improve health, but few evidence-based interventions exist. The indoor environment is of particular concern, as adults with COPD spend >90% of their time in the home. Particulate matter (PM) and nitrogen dioxide (NO2) are common pollutants in indoor environments and lead to worse respiratory morbidity. Our own study found that former smokers with COPD who have higher exposure to indoor pollutants have worse respiratory-specific quality of life, symptoms, and a higher risk of respiratory exacerbations. Our group recently completed a randomized controlled trial of 116 former smokers with COPD in Baltimore, MD (PI Hansel), demonstrating that the placement of two portable air cleaners with high efficiency particulate air and carbon filters can significantly reduce in-home PM and NO2 concentrations. In intention-to-treat analysis, there was a trend toward better respiratory-specific quality of life, as measured by the St. George's Respiratory Questionnaire (SGRQ) and statistically significant lower risk for moderate exacerbation, but not severe exacerbations, among those who received the active air cleaner compared to sham. Further, per-protocol analysis suggested a dose- response; among those who used the air cleaner at least 80% of the time, with a statistically significant improvement in SGRQ. Despite encouraging results, the study did not meet its primary endpoint and was not powered to determine whether air cleaner interventions can reduce moderate/severe exacerbations, including acute health care utilization. Furthermore, the trial did not include strategies to increase adherence; and results are limited to a small geographic area, limiting generalizability. The proposed study is a Phase III multi-center randomized sham-controlled environmental trial to test the effectiveness of an air cleaner intervention targeting indoor pollutants (PM and NO2) on quality of life and exacerbation risk reduction among former smokers with COPD (n~770) across multiple clinical practice locations. We will conduct cost-effectiveness analysis to ensure that study results address both clinical and economic efficacy to support policy decisions. We hypothesize that the placement of two portable air cleaners with high efficiency particulate air and carbon filters can lead to improved quality of life, reduced COPD exacerbation risk and reduced need for rescue medication use. Lastly, we hypothesize that the use of portable air cleaners is cost-effective. The trial will provide a novel approach to improve quality of life in these patients with significant morbidity; and for the prevention of COPD exacerbations, which drive the morbidity and mortality of this chronic disabling disease. In addition to addressing clinical efficacy, the study results will provide an economic evaluation to support policy decisions regarding reimbursement.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY. COPD is a leading cause of death and morbidity worldwide and is attributable to the aggregate burden of toxic gases and particles that individuals inhale during their lifetime. In the US, this exposure is primarily cigarette smoke; however, even after smoking cessation, patients with COPD continue to suffer respiratory morbidity. International 2022 COPD guidelines (GOLD) emphasize non-pharmacological interventions to improve health, but few evidence-based interventions exist. The indoor environment is of particular concern, as adults with COPD spend >90% of their time in the home. Particulate matter (PM) and nitrogen dioxide (NO2) are common pollutants in indoor environments and lead to worse respiratory morbidity. Our own study found that former smokers with COPD who have higher exposure to indoor pollutants have worse respiratory-specific quality of life, symptoms, and a higher risk of respiratory exacerbations. Our group recently completed a randomized controlled trial of 116 former smokers with COPD in Baltimore, MD (PI Hansel), demonstrating that the placement of two portable air cleaners with high efficiency particulate air and carbon filters can significantly reduce in-home PM and NO2 concentrations. In intention-to-treat analysis, there was a trend toward better respiratory-specific quality of life, as measured by the St. George's Respiratory Questionnaire (SGRQ) and statistically significant lower risk for moderate exacerbation, but not severe exacerbations, among those who received the active air cleaner compared to sham. Further, per-protocol analysis suggested a dose- response; among those who used the air cleaner at least 80% of the time, with a statistically significant improvement in SGRQ. Despite encouraging results, the study did not meet its primary endpoint and was not powered to determine whether air cleaner interventions can reduce moderate/severe exacerbations, including acute health care utilization. Furthermore, the trial did not include strategies to increase adherence; and results are limited to a small geographic area, limiting generalizability. The proposed study is a Phase III multi-center randomized sham-controlled environmental trial to test the effectiveness of an air cleaner intervention targeting indoor pollutants (PM and NO2) on quality of life and exacerbation risk reduction among former smokers with COPD (n~770) across multiple clinical practice locations. We will conduct cost-effectiveness analysis to ensure that study results address both clinical and economic efficacy to support policy decisions. We hypothesize that the placement of two portable air cleaners with high efficiency particulate air and carbon filters can lead to improved quality of life, reduced COPD exacerbation risk and reduced need for rescue medication use. Lastly, we hypothesize that the use of portable air cleaners is cost-effective. The trial will provide a novel approach to improve quality of life in these patients with significant morbidity; and for the prevention of COPD exacerbations, which drive the morbidity and mortality of this chronic disabling disease. In addition to addressing clinical efficacy, the study results will provide an economic evaluation to support policy decisions regarding reimbursement.

NIH Research Projects · FY 2025 · 2023-09

ABSTRACT EBV(+) lymphomas are an important cause of death in people living with HIV (PLWH). Different patterns of viral and cellular gene expression have been found to characterize different subtypes of EBV(+) lymphomas. CpG methylation of EBV DNA is an important epigenetic regulator of viral and cellular gene expression. At present, we have a very limited understanding of CpG methylation in EBV(+) lymphomas in PLWH, and how this may determine patterns of viral gene expression. Although we are very successful in treating some EBV(+) lymphoma in HIV patients, many cases are diagnosed very late after organ function has been compromised, or only on post-mortem exam. This is especially true in populations with limited access to health care in the US, as well as in low- and middle-income countries (LMIC) with high HIV prevalence. Assessment of cell-free DNA (cfDNA) in plasma is increasingly recognized as useful in early cancer detection. Plasma cell-free EBV DNA has been shown to be useful in screening for nasopharyngeal cancer. However, high levels of EBV DNA in some PLWH reduce the specificity of EBV DNA quantitation as a diagnostic maker of lymphoma. Evidence is emerging that EBV CpG methylation, or patterns of methylation, could accurately identify EBV(+) malignancies. The proposed studies should improve the collective understanding of epigenetic modification of EBV and viral and cellular gene expression, and enable discovery of novel EBV liquid biopsy diagnostics for early cancer detection in PLWH. In aim 1, we will characterize lymphoma transcriptomes by RNA-Seq and EBV methylomes by high throughput bisulfite sequencing (bs-Seq) to investigate the relationship between the cellular and viral transcriptome and EBV methylation. In aim 2, we will systematically investigate the plasma EBV DNA methylome in PLWH with EBV(+) lymphoma and PLWH controls so as to identify differentially methylated regions of the viral genome that are most informative for lymphoma. These results will guide design and evaluation of methylation-specific PCR primer sets that can enable rapid assessment of EBV methylation states. The results from the qMSP studies will be used to develop and train an automated qMSP classifier for the presence of EBV(+) lymphoma. In aim 3, we propose to establish a new plasma (and saliva) specimen collection from PLWH with EBV(+) lymphoma and matched controls. We will validate the plasma classifier developed in this independent cohort. We will also apply this qMSP classifier to saliva to explore the possibility that saliva cfDNA may be a useful surrogate for plasma cfDNA. At the conclusion of our studies, we anticipate having an improved understanding of the interplay between lymphoma gene expression, EBV gene expression and EBV CpG methylation. Our results will aid in the development of the first plasma EBV qMSP PCR assay for EBV(+) lymphoma in PLWH, and will enable exploration of saliva as an alternate source for cfDNA for future liquid biopsy applications in PLWH. We anticipate that our findings will pave the way for the development of point of care multiplex PCR assay systems appropriate for future investigations of low-cost screening assays in the US and in LMICs. 1

NIH Research Projects · FY 2025 · 2023-09

SUMMARY Tremendous advances have been made in the study of adipose biology but there are gaps in our understanding of adipose development and functions. The long-term goal of our research is to understand how adipose tissues regulate whole-body energy metabolism, insulin sensitivity and glucose homeostasis. To achieve these goals, we have developed cellular and animal models to study the effects of gene perturbations in relation to adipose tissues development. One such gene is Four-and-half-LIM domain 1 (FHL1), a protein highly expressed in skeletal and cardiac muscles, and has recently been implicated in human adipose tissue development. A case report on a 15-year old patient with a complete deletion of FHL1 with adjacent MAP7D3 gene exhibited a near total loss of adipose tissues accompanied by muscular hypertrophy, rigid spine and short stature. The specific role of FHL1 in adipose development and function is unknown. In preliminary experiments, we identified FHL1 as a major co-transcription factor of PPARg, suggesting a role in transcriptional regulation of adipose tissues. To mimic the loss of adipose tissues in the human patient, we created a mouse model where FHL1 is globally deficient. Whole body Fhl1 knockout mice were resistant to diet-induced obesity (DIO). Interestingly, a previous study has shown that mice lacking a related paralog, FHL2, are also resistant to DIO. We found that FHL1 deficiency in murine preadipocytes partially attenuated differentiation into adipocytes, and a single amino acid substitution from tryptophan to serine at position 122 within FHL1 specifically abrogated PPARg isoform 2 (PPARg2) expression, but not isoform 1 (PPARg1). In agreement, knockdown of FHL1 in human adipocytes preferentially reduced PPARg2 expression, but not PPARg1. It has been reported that PPARg2 is adipose- specific, necessary and sufficient in activation of adipogenesis in fibroblast. In addition to activation of PPARg, FHL1 cooperates with PPARg in activation of PPARg-dependent gene expression. Based on our preliminary data, we hypothesized that FHL1 regulates adipocyte differentiation, at least in part, through transcriptional regulation of PPARg. This proposal seeks to investigate the cellular, molecular and physiological mechanisms by which FHL1 regulates adipose tissue development and energy homeostasis. Specific Aim 1 will examine the roles of FHL1 and FHL2 in murine adipocyte differentiation. Specific Aim 2 will address the underlying molecular mechanisms linking FHL1 and transcriptional regulation of adipocyte differentiation. Specific Aim 3 will investigate the in vivo functions of FHL1 in adipose-specific knockout mice and in human transplant models. Together, the proposed experiments will provide mechanistic insights into adipose biology, pathophysiology of obesity, potentially lead to novel therapeutic strategies for obesity and related metabolic diseases.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY/ABSTRACT Weight loss maintenance remains the Achilles' heel of obesity management. Extended intervention contact reduces weight regain. However, continued counseling in practice is rare. Digital health interventions can address barriers to providing in-person maintenance counseling. Our long-term goal is to develop more effective weight loss maintenance strategies that are accessible, patient-centered, and tailored to meet individuals' needs. To accomplish this goal, the proposed trial will examine whether, after 16 weeks of initial weight loss, a stepped-care, digital health intervention improves the maintenance of a >5% weight loss. Phase I lifestyle phase, (UC); (STEP). SELF is a non-randomized, 16-week, weight-loss phase during which all participants wil receive the same group intervention designed to induce a > 5% weight l oss. In Phase II, a 52-week weight-loss maintenance 180 adults with obesity who have lost >5% will be randomized to one of three interventions: usual care daily self-monitoring of weight, diet, and physical activity with digital tools (SELF); or The UC group will receive monthly, emailed weight loss maintenance education. Participants in the group will have access to a digital health intervention that uses: l stepped care daily remote monitoring of weight, physical activity, and calorie intake; and automated, personalized text-messaging to adherence. 13 additionally (Step percentage weeks, transition encourage behaviora begin with access to the digital health program (Step 1). Participants who, after the first weeks, have not maintained their 5% weight loss or have regained 2 percentage points of their weight, will receive monthly visits with a counselor to promote behavioral adherence and address barriers 2). Participants who, at 26 weeks, have not maintained a > 5% weight loss or have regained 2 points with Step 2 will transition to twice-monthly counseling (Step 3). Participants who, at 39 still have not maintained a > 5% weight l oss or have regained 2 percentage points with Step 3 will to a partial meal replacement plan for the last 13 weeks (Step 4). l STEP will Our primary aim is to determine if SELF and STEP result in better maintenance of weight loss compared to UC. Our secondary aims are to examine differences in self-weighing frequency, eating behaviors, and physical activity, and examine if STEP, relative to SELF, produces greater improvements in weight, self-weighing frequency, eating behaviors, and physical activity. each We will also conduct an economic analysis to evaluate the incremental cost effectiveness of intervention per unit decrease in weight (kg).The expected outcome of the study is to demonstrate the efficacy of a digital health intervention for weight loss maintenance, providing a solution to many challenges that interfere with successful delivery of obesity treatment. We also expect to show the efficacy of a stepped care model for weight loss maintenance, providing a individuals' responses to treatment. strategy to address themarked heterogeneity in

NIH Research Projects · FY 2025 · 2023-09

Project summary Malignant gliomas, including the most common type glioblastoma (GBM), are histologically heterogeneous and invasive tumors known as the most devastating neoplasms with high morbidity and mortality. Despite multimodal treatment including surgery, radiotherapy, and chemotherapy, the disease inevitably recurs and proves fatal. Local application of carmustine implants (Gliadel® wafers) as an adjunct to surgery and radiation therapy has been clinically proven to extend the survival time for patients with malignant gliomas, strongly suggesting that local chemotherapy after tumor resection presents a feasible and effective strategy to treat brain tumor patients. However, the rapid depletion of carmustine and low tissue penetration greatly limit the clinical benefits of Gliadel® wafers, which only extend the median survival of treated patients by six months compared to those untreated. This proposal aims to develop a novel type of self-assembling nanofiber hydrogels that use the anticancer drug camptothecin (CPT) as the molecular building blocks and that can be locally administered to the resection cavities after tumor removal, with the ultimate goal to achieve more effective treatments for patients diagnosed with malignant gliomas. We hypothesize that the proposed nanofiber hydrogels will spread across large tissue areas and sustainably release therapeutic agents for long-term cytotoxicity against glioma cells, thus leading to significantly extended survival time in our rodent model. To test our hypothesis, we outlined the proposed research activities in the three specific Aims, seeking to address the three key challenges in local delivery of therapeutic drugs into resection cavities: 1) the nanofiber gelation properties. The gel form enables prolonged retention in the delivery sites and also minimizes capillary loss of free drugs that would otherwise occur; 2) the sustained release of free drugs over a long period of time. The release rate and period are critical for effective elimination of glioma cells without causing devastating side effects; 3) diffusion across large tissue areas. In Aim 1, we will identify the key molecular parameters in the design of self-assembling CPT DAs to create CPT nanofibers of varying surface chemistries that would promote the formation of hydrogels upon contact with body fluids. Aim 2 is focused on the evaluation and fine-tuning of the drug release rate and mechanism, their ability to overcome the MDR mechanisms, as well as diffusion distance within organotypic tissues. In Aim 3, we will use an animal model to evaluate the nanofibers’ ability to diffuse across large tissue areas, pharmacokinetics, in vivo efficacy and toxicity of two already developed nanofiber hydrogels and also those to be developed in Aim 1 and Aim 2. Our ultimate goal is to develop a nanofiber hydrogel platform technology that will extend the survival time of rodents bearing human brain cancer, and translate this platform to a pre-clinical approach.