Johns Hopkins University

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY Adoptive cellular therapy (ACT) treatments, in which cancer patients are infused with autologous tumor- specific cytotoxic (CD8+) T cells expanded and activated ex vivo, have become gradually more appealing for cancer patients. Although ACT has shown great clinical success with melanoma, universal adoption has been limited, as ACT relies on extremely complex cell-based methods with a significant price tag. Recently, increased emphasis has been placed on enhancing acellular platforms, such as artificial antigen presenting cells (aAPCs), that show promise in activating tumor-specific CD8+ T cells in a quicker, more tunable manner. While a majority of aAPC systems have been applied in ex vivo settings, the development of biocompatible materials for aAPC platforms have expanded the potential of these systems to be used in vivo, lessening the lengthy culture times and costs associated with therapy. The goal of the proposed project is to develop a novel biomaterial aAPC for direct, antigen-specific activation of CD8+ T cells in vivo for cancer immunotherapy. The particulate platform is made from a novel blend of biodegradable and biocompatible polymers, Poly(lactic-co-glycolic) acid (PLGA) and Poly(beta amino ester) (PBAE), that promotes inclusion of the three signals required for optimal T cell activation and expansion. We will investigate the effects of biomaterial properties and signal incorporation on in vitro T cell activation, as well as gain insight into in vivo antigen-specific T cell activation in a tumor-burdened host. We will develop immunologically compatible, particulate PLGA/PBAE aAPCs for in vivo injection and T cell activation. First, we will investigate physicochemical properties of these aAPCs, including biomaterial composition, size, and surface protein density. We will optimize these properties in the context of enhanced CD8+ T cell activation and biological function. Second, we will focus on incorporating cytokines, additional signals that are important in T cell activation, in a local and sustained manner. We will investigate various cytokines, such as IL-2, IL-15, and IL-21, that may play a role in generating effector and memory T cells. Taken together, we will identify leading tri-signal aAPCs that are optimized for both murine and human T cell activation in vitro. Finally, we will apply our leading aAPCs in vivo, to analyze their CD8+ T cell activation, expansion, and anti- tumor capacities. If successful, this proposal will generate a novel biomimetic approach for harnessing optimal antigen-specific CD8+ T cell responses, with the potential of expanding patient access to cancer immunotherapies and reducing health disparities.

NIH Research Projects · FY 2024 · 2023-09

Glioblastoma multiforme (GBM) is a common and highly aggressive form of brain cancer in adults with a dismal prognosis and limited therapeutic options. A critical component of GBM malignancy derives from the distinct population of glioma stem cells (GSCs) that function to promote and maintain malignancy through their capacity for self-renewal, cellular adaptation and multipotency. These stem-like cells engage in a synergistic relationship with the surrounding microenvironment to promote tumor progression and are key drivers of intratumoral heterogeneity, immune-suppression, and therapy resistance. Targeting GSCs and mechanisms that drive the stem-like phenotype presents a promising avenue for targeted therapeutics. The broad goal of this proposal is to understand the cell-intrinsic mechanisms driving maintenance of a unique, immunosuppressive GSC subset, identify cellular vulnerabilities associated with immunosuppressive GBM cells, and develop preclinical therapeutics to target these cells. We will achieve this goal by utilizing our validated GSC cell models, state-of-the art single-cell sequencing technology, and cutting-edge spatially resolved omics platforms applied to clinical GBM specimens, and advanced molecular in vitro techniques to define immunosuppressive tumor cell populations and determine the transcriptomic and metabolic changes associated with these cell populations that are amenable to therapeutic targeting. Our preliminary findings demonstrate that TGF-beta type II receptor (TGFBR2) signaling induces a TGFBR2high subset of GSCs that co-opt certain immunosuppressive mechanisms associated with and utilized by regulatory T cells (Tregs) to exert immunosuppressive behavior. In the F99 phase, we will investigate the potential for boosting the anti-tumor immune response by targeting this specific subset of TGFBR2-induced immunosuppressive GSCs endowed with Treg-like capabilities. To do so, we will utilize inducible shRNA constructs and a clinically translatable small-molecule drug to inhibit TGFBR2 in orthotopic tumor allografts in immune-competent mice and analyze the effects on tumor growth, immune cell infiltration and function, and cooperativity with check point inhibitor therapy. In the K00 phase, we will conduct spatially resolved transcriptomics and metabolomics on patient GBM tissue specimens to identify potential metabolic vulnerabilities in immunosuppressive GBM cells. Metabolic inhibitors will be utilized to exploit candidate vulnerabilities in an attempt to attenuate the transcriptomic and functional immune-suppressive characteristics of these cells. Subsequently, validated metabolic vulnerabilities will be targeted in vivo to assess the effects on tumor growth and the anti-tumor immune response. Our proposed methods of pharmacological TGFBR2 inhibition and metabolic exploitation will inform the development of novel strategies to reprogram the GBM microenvironment and enhance anti-tumor immune responses when combined with current emerging immunotherapeutics (e.g. checkpoint inhibitors, CAR-T cell technology, vaccines).

NIH Research Projects · FY 2025 · 2023-08

PROJECT SUMMARY/ABSTRACT This R33 application proposes a mechanistic clinical trial testing the effects of psilocybin on affective mechanisms of chronic pain in patients with comorbid chronic low back pain and depression (CLBP+D). CLBP is the top cause of disability worldwide, and is highly comorbid with depression. Patients with CLBP+D face a fragmented and limited set of treatment options that insufficiently address their pain and depression symptoms. As such, CLBP treatment guidelines call for a shift away from a sole outcome focus on pain intensity and toward treatments that enhance affective function. Positive and negative affect, pain catastrophizing, and positive affective pain inhibition are well-characterized, modifiable, biologically-mediated mechanisms of chronic pain that we propose to target in this study of patients with CLBP+D. Psilocybin, a classic (5-HT2A receptor-mediated) psychedelic, is a promising non-opioid candidate for the treatment of CLBP+D that reliably and durably improves affective function in healthy individuals, patients with major depressive disorder, and patients with a life-threatening cancer diagnosis. We aim to test whether psilocybin will benefit patients with CLBP+D by durably improving positive affect, negative affect, and pain catastrophizing, and augmenting the ability of positive affect to inhibit pain. The proposed study addresses an important unmet need, as it will be the first, to our knowledge, to test the ability of psilocybin to target pain-related affective function in patients with chronic pain. We propose a double-blind, randomized, controlled trial comparing the administration of high- dose psilocybin (25mg absolute dose; n=20) to an active control (methylphenidate 40mg absolute dose; n=20) among patients with CLBP+D. Psilocybin or methylphenidate will be administered once in the laboratory under close supervision and supportive monitoring. Primary outcomes will be positive and negative affect (Aim 1), pain catastrophizing (Aim 2), and positive affective pain inhibition (Aim 3). Ecological momentary assessment will be used to evaluate the hypotheses that aggregated momentary reports of positive and negative affect and pain catastrophizing will improve from baseline to 1-week post-session to a greater extent in patients in the psilocybin versus the methylphenidate condition. Quantitative sensory testing will be used to evaluate the hypothesis that positive affective pain inhibition will increase from baseline to 1-week post-session to a greater extent in patients in the psilocybin versus the methylphenidate condition. The durability of outcomes will be tested at 1-month post-administration in secondary analyses. By testing the effects of psilocybin on affective function in CLBP+D, we will develop critical data that will provide mechanistic insight into the utility of psilocybin as a pain management medicine. These data will build off our extensive preliminary findings in support of psilocybin’s efficacy for major depressive disorder, and pave the way for future pivotal efficacy trials for psilocybin as a primary treatment for patients with CLBP+D.

NIH Research Projects · FY 2025 · 2023-08

PROJECT SUMMARY The vast majority of adults with Acute Respiratory Failure (ARF) in the U.S. now survive hospitalization as a result of clinical advances. Many ARF survivors experience new and persistent physical, cognitive, and mental health impairments and >50% of survivors remain dependent on caregiver assistance 1 year after discharge. Family/caregivers (“care partners”) of ARF patients also experience mental health symptoms and financial stress, and have difficulty reconciling their expectations with ARF survivors’ recovery. A 2015 systematic review found persistent symptoms of depression in 23% - 29% of family caregivers of ICU survivors 1 year after discharge. This is comparable to rates of depression in caregivers for people with dementia and significantly higher than the prevalence of depression in the U.S. adult population. A 2020 systematic review of 11 RCTs testing interventions to mitigate family emotional distress following critical illness reported that all trials had failed, suggesting a need for innovative approaches. We posit that expectations within ARF survivor- care partner dyads influence behaviors and outcomes and are a malleable and innovative target for dyadic coping interventions (DCI). However, before DCI can be developed, essential research is required to understand how expectations about recovery are formed following ARF and how they impact the mental health and coping behaviors of ARF survivor-care partner dyads. We hypothesize that when ARF survivor-care partner dyads lack confidence in their shared ability to manage new care needs (i.e. low self-efficacy) expectations for recovery within a dyad influence both mental health and dyadic coping. The overarching objectives of this application are to learn how expectations about ARF survivorship are related to dyadic mental health symptoms and dyadic coping (Aims 1 & 2) and to understand how expectations about ARF recovery are formed and shaped over time within survivor-care partner dyads (Aim 3). To achieve the above objectives, we propose a mixed methods research program. First, we will conduct a longitudinal cohort study of 235 dyads of adult ARF survivors and care partners from 4 hospitals (Aims 1 & 2). Thereafter in Aim 3, we will conduct semi- structured interviews with ≥36 Aim 1 dyads divided across a maximum variation sample of dyads whose expectations for recovery: a) improved, b) worsened, c) differed substantially between dyad members. We will also explore how dyads approach dyadic coping and health management to identify gaps that are potentially modifiable with intervention. The proposed work will provide essential information for developing dyadic coping interventions specifically tailored to the challenges of ARF survivorship.

NIH Research Projects · FY 2025 · 2023-08

Men with biochemical recurrence after prostatectomy receiving salvage radiation (RT) may benefit from added anti-androgen therapy (AAT) by decreasing their likelihood of progressing to distant metastasis and death. However, in RTOG 9601, not all men benefitted. No predictive biomarker currently exists to identify who is more likely or less likely to benefit from aggressive salvage therapy (RT+AAT). To address this unmet need for precision treatment decision-making, we will evaluate the telomere biomarker as a predictive biomarker for treatment response in this setting. Our conceptually innovative hypothesis is that the telomere biomarker – the combination of cancer cell-to-cell variability in telomere length coupled with stromal cell telomere length – captures information about tumor behavior beyond currently used indicators and thus, identifies men who are more likely or less likely to benefit from aggressive salvage therapy. We discovered that the telomere biomarker is an independent prognostic marker for lethal disease in surgically-treated men, identifying 3 prognostic categories: good, intermediate, and poor. The telomere biomarker has not been tested as predictive of treatment response in any setting. We will address the aims in 2 complementary settings, trial and clinical practice, totaling 839 men and 165 metastatic events. In the trial setting, we will use RTOG 9601, in which men were randomized to RT+/-AAT. In the clinical practice setting, we use cohorts who received RT+/-AAT at Johns Hopkins or Boston Medical Center and have tissue microarrays; in the analysis, we will weight by a propensity score to minimize bias due to patient and tumor factors. We will evaluate these aims stratified by the telomere biomarker: 1. In the standardized setting, test if rate of progression to metastasis and death from prostate cancer differs between RT+AAT and RT only. 2. In the clinical practice setting, test if rate of progression to metastasis and death from prostate cancer differs between RT+AAT and RT only. We will stain for telomeres and cell-type specific immunofluorescence markers and perform image capture and quantitative image analysis, and derive each man’s telomere biomarker. We will stratify by biomarker category and use Cox models to estimate associations between RT+AAT and progression, and determine if the biomarker adds to predictive capability for response to RT+AAT beyond currently used post-biochemical recurrence prognostic indicators. In men with the biomarker category associated with intermediate prognosis, we hypothesize that the progression rate is lower in men who received RT+AAT compared to men who received RT only. In men with biomarker categories associated with good or poor prognosis, we hypothesize that the progression rate in men who received RT+AAT is similar to the rate in men who received RT only. In RTOG 9601, RT+AAT was more efficacious than RT only in some subgroups. For optimized decision-making, we will determine if the biomarker is predictive in subgroups. If our hypothesis is confirmed, next steps would be prospective validation and commercial partnership to generate a kit-based system for automated platforms.

NIH Research Projects · FY 2025 · 2023-08

Plasmodium parasites are responsible for hundreds of millions of malaria cases annually. During the asexual stages of development in red blood cells, malaria parasites acquire certain nutrients from human serum while retaining the ability to synthesize others. We are studying an essential enzyme cofactor called lipoate and its metabolism in Plasmodium falciparum. Our studies demonstrate that erythrocytic stage parasites are auxotrophic for lipoate, even though they contain a metabolic pathway to synthesize this cofactor. Proteins in the apicoplast organelle rely on lipoate synthesis while proteins in the parasite mitochondrion rely on scavenging and cannot obtain lipoate synthesized in the apicoplast. The proposed studies are focused on two aspects of lipoate scavenging and employ a combination of biochemical, cell biology and genetic approaches. Our first aim is to define the essentail roles of lipoate-dependent proteins and identify the factors required to support these activities in the parasite mitochondrion. Our second aim will probe the mechanism of lipoate uptake and attachment to mitochondrial proteins in order to understand how, when and why this process is gated by redox potential. These studies will forge a detailed link between the lipoate attachment enzymes and their protein substrates. By virtue of relying on a host nutrient, these proteins represent a vulnerable aspect of parasite biology which could be targeted at several levels.

NIH Research Projects · FY 2025 · 2023-08

This five-year pragmatic trial is embedded in an existing program providing SNAP cross-enrollment outreach and enrollment assistance program among approximately 1 million Michigan Medicaid beneficiaries. This project will be conducted in partnership with Michigan Department of Health and Human Services and Benefits Data Trust and with guidance from an Advisory Committee. The proposed study will leverage the program’s random selection of households for treatment to estimate the effect of SNAP outreach and enrollment assistance among low-income adults with functional limitations. Households are randomly selected for either an information-only arm or an information plus assistance arm while a 3rd equivalent group waits for treatment, forming a control comparison arm by default. Medicaid data from adults aged 18 and older will be used to identify people with functional limitations, including those who: (a) receive disability benefits (e.g. SSDI, or, if younger than age 65, SSI); (b) are Medicaid eligible due to disability or blindness; (c) are eligible for home and community-based services or (d) are home help recipients needing assistance with Activities of Daily Living. Outcomes will be measured using Medicaid claims and SNAP utilization data. Aim 1 characterizes Medicaid beneficiaries at baseline with disproportionately lower SNAP utilization (participation and benefit amounts) for people with and without functional limitations and examine interactions with age, and presence of ambulatory care-sensitive conditions. Aim 2 evaluates the impact of a cross-benefit enrollment intervention on health care utilization, including inpatient hospital and emergency department utilization (emergency department visits; hospitalization and length of stay; end-of-the-month utilization; and utilization for ambulatory care-sensitive conditions) and on nursing home utilization (admission and length of stay) among community-dwelling adults with functional limitations. Aim 3 evaluates the impact of a cross-benefit enrollment intervention on SNAP utilization (participation and benefit amounts) and tests SNAP utilization as a mediator of intervention effectiveness health care utilization among community-dwelling adults with functional limitations. Aim 4 tests for effect modification of the intervention impact based on age, and presence of ambulatory care-sensitive conditions, among community-dwelling adults with functional limitations. Through these aims, this study evaluates a promising new intervention that may improve food affordability for low-income adults with functional limitations, who experience disproportionately high rates of food insecurity.

NIH Research Projects · FY 2024 · 2023-08

Project Summary In vertebrate animals, the vestibular system (primarily known as the “balance system” of the brain) interprets head-movement and orientation signals to provide organisms with a sense of self-motion. The vital contribution of vestibular system to reflexive control of posture, gaze, and gait is well characterized; however, far less is known about the neural substrates underlying higher-order vestibular functions, such as the perception of self- motion and the awareness of one's orientation in space. These functions rely on the cortical integration of vestibular input with somatosensory and visual input. In non-human primates, the parieto-insular vestibular cortex (PIVC) is uniquely suited to perform this multisensory integration. Unlike other vestibular-sensitive cortical areas, PIVC has direct access to vestibular, somatosensory, and visual input from the thalamus; indeed, it is hypothesized that other vestibular cortical areas receive their vestibular input from PIVC, thus making it a nexus for higher-order vestibular function. Despite its hypothesized importance, extremely little is known about the neural mechanisms by which PIVC integrates vestibular and extra-vestibular input, and whether this integration is context dependent. For example, it is unclear whether PIVC neurons differentiate between vestibular input generated during passive vs. active movements; such differentiation is seen in the vestibular nuclei and thalamus and is thought to be essential for producing a sense of motor agency. To investigate these issues, I propose to conduct high-density neurophysiological recordings in behaving primates during both passive stimulation and actively generated head and whole-body movement. In Aim 1, I will investigate how PIVC integrates passively applied vestibular and somatosensory input (Aim 1.1) and then vestibular and visual input (Aim 1.2). In Aim 2, I will investigate whether PIVC differentially processes vestibular input during passive and active movement. Specifically, I will examine how PIVC processes vestibular input generated during natural self-motion (i.e., self- motion relying on sensorimotor input in the form of a head-turning task, Aim 2.1). I will then examine how PIVC processes vestibular input generated during a learned, cognitively demanding motor task (Aim 2.2). In both aims, I will determine how individual neurons in PIVC encode vestibular and extra-vestibular input, as well as how this information is represented at the population level. The proposed experiments will resolve two questions which are fundamental to understanding PIVC function: 1) How does PIVC integrate multisensory input to construct a percept of self-motion? and 2) Is the processing of self-motion by PIVC neurons consistent with that required to provide a sense of motor agency? Furthermore, the proposed experiments will determine how sensorimotor and cognitive percepts of self-motion are represented in PIVC. This research will provide new insights into cortical vestibular function and how it supports the higher-order processes that allow primates (both human and non- human) to successfully perceive and navigate their environments.

NIH Research Projects · FY 2024 · 2023-08

PROJECT SUMMARY Type 1 diabetes (T1D) is a life-threatening autoimmune disease affecting over 1 million patients in the United States that occurs when the immune system attacks and destroys insulin- producing beta islet cells in the pancreas. Treatment of T1D requires a lifetime of constant maintenance to avoid life-threatening complications. There is an urgent need for a therapy that can engineer the immune system to prevent disease progression at early stages, prevent damage to islet cells, and have a long-lasting and transformative effect on patients. One method of achieving T1D-specific tolerance is to genetically engineer antigen-presenting cells (APCs) to present disease-relevant antigen(s). Antigen presentation in the presence of tolerogenic signals can lead to the maturation of disease-specific protective regulatory T cells (Tregs). In particular, liver-resident APCs express low levels of activating co-stimulatory molecules, and surrounding cells secrete immunosuppressive signals, making the liver a tolerogenic environment. We hypothesize that non-viral transfection of APCs in the liver with genes encoding T1D-specific autoantigens will promote safe and specific protective tolerance as a tolerogenic vaccine for the prevention and treatment of autoimmune T1D. We will develop biodegradable nanoparticles to safely and effectively program immune cells in vivo, including APCs. We will first create and well-characterize the new nanobiotechnology and validate it in in vitro models (Aim 1). We will then evaluate the nanobiotechnology in vivo in mouse models of T1D (Aim 2). Finally, we will evaluate these NPs with human immune cells in vitro and in vivo, bringing this technology closer to translation (Aim 3). This nanoparticle-based biotechnology is designed to enable a safe and effective method of immune cell engineering to treat T1D.

NIH Research Projects · FY 2025 · 2023-08

Over the past decade, roles for the endoplasmic reticulum (ER) in the biogenesis of select nuclear-encoded mitochondrial precursors and the degradation of mutant, mis-localized, or non-productively imported proteins from the mitochondrial outer membrane (OM) have begun to emerge. Our interest in this unanticipated, novel ER-associated mitochondrial biology was serendipitous. In our ongoing efforts to characterize the lipid substrate trafficking requirements for phosphatidylserine (PS) decarboxylase 1 (Psd1 in yeast, PISD in humans), an evolutionarily conserved, integral inner mitochondrial membrane protein that produces phosphatidylethanolamine (PE), it became a priority for us to independently ascertain if a small fraction of wild type (WT) Psd1 is glycosylated and thus targeted to the endomembrane system, as recently claimed. Our generated results support the unavoidable conclusion that in yeast, the vast majority, if not all, of functional Psd1 is mitochondrially localized. However, we did uncover an intimate relationship between Psd1 and the ER: unlike the WT protein, non-functional forms of Psd1 are dually localized to the ER, where they are glycosylated, ubiquitinated, and rapidly degraded. Given the role of the ER as a staging ground for the efficient removal of non-functional Psd1, we then asked two questions ― 1) Is Psd1 biogenesis supported by a recently discovered Djp1-mediated Endoplasmic Reticulum Surface Retrieval pathway (ER-SURF)? and 2) Does the accumulation of ER-associated non-functional Psd1 depend on Msp1, an outer mitochondrial membrane resident AAA-ATPase known to remove mis-targeted proteins and non-productively imported mitochondrial precursors from the outer membrane? The resulting answers establish the premise for our proposed aims and identify Psd1 as an ideal model substrate to define novel mechanisms of ER-SURF and protein degradation that will undoubtedly apply to other mitochondrial proteins. The goal of Aim 1 is to define the early, pre- mitochondrial steps of Psd1 biogenesis that are mediated by specific interactions that occur at the ER. Other than a critical role for the Hsp40 cochaperone, Djp1, virtually nothing is known about ER-SURF. Results from Aim 1 will provide mechanistic insight about mitochondrial targeting through this novel pathway and whether it can be coerced in specific contexts to support non-mitochondrial biology. Over the past seven years, it has become increasingly appreciated that the accumulation of mitochondrial precursors outside of this organelle activates a range of cellular stress responses. In this context, our discovery that non-functional mutant Psd1 temporarily associates with ER membranes prior to being degraded is particularly exciting. The goal of Aim 2 is to determine the molecular mechanisms of non-functional Psd1 resolution. Results from Aim 2 will transform our understanding of how cells cope with mitochondrial precursors that fail to reach their correct destination, an emerging focus in the field.

NIH Research Projects · FY 2025 · 2023-08

PROJECT SUMMARY Sickle cell disease (SCD) is a multi-system, life-threatening, inherited blood disorder that disproportionally affects low-income vulnerable minorities in the United States. Of the approximately 100,000 individuals living with this condition in the country, people of African descend account for 90% of patients. A hallmark of the disease is the development of vascular-endothelial dysfunction that promotes a chronic prothrombotic state increasing the risk of venous thromboembolism (VTE). Hospitalized pediatric patients with SCD have substantively higher rates of incident and recurrent VTE compared to the hospitalized general pediatric population. However, despite the known association between hypercoagulability and SCD, VTE has remained an underrecognized and understudied complication, particularly in the pediatric SCD population. Specifically, biomarkers and mechanisms for the development of VTE in pediatric SCD have received little attention in research despite such work being urgently needed in order to identify modifiable factors for future investigation in interventional trials. This proposal aims to address this critical gap in knowledge by systematically analyzing VTE data derived from a multicenter mixed prospective-retrospective cohort with parallel biobanking of pediatric patients with SCD with- and without VTE. The Specific Aims are to: 1) Identify clinical risk factors for incident (1a) and recurrent (1b) VTE in pediatric SCD; 2) identify plasma markers of coagulation activation, inflammation, endothelial damage, and unbiased proteomic profiles prognostic of the development of incident (2a) and recurrent (2b) VTE in pediatric SCD; and 3) to develop a novel biomarker-informed clinical prognostic model for VTE in pediatric SCD. The applicant’s long-term goal is to become an independent clinical and translational investigator with expertise in the development of biomarker-informed VTE clinical prognostic models in pediatric SCD. She has designed an individual career development plan with the overarching goal of gaining expertise in biomarker discovery and validation for pediatric VTE, and in the application of biomarkers and clinical risk factors for the development of VTE prognostic models and the design of risk-stratified VTE prevention trials. The specific aims of her career development plan are: 1) to obtain mentored, advanced didactic and experiential education and training in conducting multicenter observational and interventional studies in pediatric VTE and SCD populations; 2) to gain mentored didactic and hands-on expertise on proteomics methods and biomarker discovery, validation and implementation in pediatric hematologic diseases; and 3) to obtain mentored, advanced education and training on the development and application of prognostic models for pediatric hematologic diseases.

NIH Research Projects · FY 2025 · 2023-08

PROJECT SUMMARY/ABSTRACT Candidate: Dr. Roy Adams applies for this K25 Mentored Quantitative Research Career Development Award with the goal of building a productive independent research career as a methodologist focused on developing electronic health record (EHR)-based models and tools to improve our understanding of Alzheimer’s disease and related dementias (ADRDs). Dr. Adams brings with him excellent training in computational methods for observational health data but lacks expertise in ADRDs and the methods used to study them. “Big data” is powerful but understanding the context surrounding the data is essential for knowing the limits of the data and avoiding bias. The K25 training will support Dr. Adams in becoming an independent ADRD researcher by allowing him to: (1) develop an understanding of dementia biology and care, (2) gain expertise in the methods used to model psychiatric measurements, (3) gain exposure to the study of ADRDs from observational data, and (4) form a network of collaborators in clinical ADRD research. These training aims will be accomplished through in-person clinical exposure, didactic courses, directed readings and journal groups, and participation in professional research networks. Research and Environment: Phenotyping is an essential step of most EHR-based studies of ADRDs. Due to common sources of error – such as fragmented care and selection bias – phenotyping ADRDs in EHR data remains a challenge. Recent advances in machine learning present a potential way to account for these sources of bias in high-dimensional EHR data by combining multiple proxies for the phenotype of interest, while explicitly modeling the error and bias in each proxy. However, these methods remain limited and methodological development is needed before they can be applied to ADRD data without risking substantial bias. The proposed research focuses on developing these methods to extract two types of EHR-based phenotypes of ADRD: a binary phenotype indicating whether a patient has dementia and a continuous phenotype measuring the severity of that dementia. Dr. Adams will apply these methods to a large database of Johns Hopkins EHRs and validate them using a combination of data from a memory center, data from a parallel ongoing longitudinal study of ADRDs, and assessments of patient severity based on chart review. This work will take advantage of a unique combination of resources available through the Johns Hopkins Alzheimer’s Disease Research Center, the Richman Family Precision Medicine Center of Excellence in Alzheimer’s Disease, and the Johns Hopkins inHealth Precision Medicine initiative. Further, this research will provide Dr. Adams with valuable experience working with ADRD patient data, set the foundation for future methodological work, and generate methods that can be directly applied to several planned and ongoing ADRD precision medicine studies at Johns Hopkins.

NIH Research Projects · FY 2025 · 2023-08

Mental health and substance misuse pose some of the greatest risks to the health and wellbeing of Tribal communities and result in intergenerational morbidity and mortality. These risks are the legacy of chronic underfunding of mental health and substance use care, resulting in massive care and treatment gaps. Simultaneously, many Tribal communities emphasize a holistic view of wellbeing centered around family and community and prefer upstream preventative and family-based interventions with potential to disrupt intergenerational cycles of trauma and adversity. Our team of experienced researchers has worked closely with participating communities to design and pilot the Family Spirit Strengths (FSS) intervention, to provide transdiagnostic skills- based preventive strategies to mothers and primary caregivers at elevated risk for mental health and substance use disorders. We propose a Hybrid Type I Effectiveness-Implementation design with the primary goal of testing FSS effectiveness at reducing symptoms of depression, anxiety, and substance use, among N = 188 primary caregivers across three different Tribal settings and contexts. Participants will be randomized to receive FSS or a beneficial control, which is an evidence-based nutritional support program called Family Spirit Nurture. Primary outcomes will be measured at 6 months post-enrollment. We will also seek to characterize heterogeneity in and mechanisms of FSS effects by exploring moderators and mediators, respectively, guided by both Western and Tribal theories of action. As part of our Hybrid approach, we will estimate FSS costs, cost-effectiveness, and budget impact. Finally, we will undertake a process with National stakeholders to understand barriers to and facilitators of FSS implementation across the country, including co-design of implementation strategies to support FSS at scale across different Tribal communities. This study is responsive to Program Announcement PAR-20-238 and focuses on key areas of interest including the testing of evidence- based practices in community settings (MH-22-170) and expanding perinatal mental health interventions (MH- 21-215, MH-21-270). Our overall objective is to rigorously test a secondary preventative intervention designed to be embedded in home visiting programs so that we can extend the reach of mental and behavioral health services in Tribal communities across the country.

NIH Research Projects · FY 2026 · 2023-08

To better understand genetic basis of complex human traits, two fundamentally different and complementary designs employed in genome-wide association studies (GWAS) are population-based and family-based designs. With the advent of biobanks and large-scale biomedical databases, recent years have seen an explosion in genetic studies of adult traits/diseases, and consequently, a rapid advancement in methodology for population-based designs that these biobanks depend on. In contrast, methods for family-based designs have received little to no attention although they play an important role in the investigation of genetic basis of low-prevalence/rare disorders and of child health outcomes. Analysis methods based on family-based designs can protect against population stratification and admixture, and can be more powerful than a population-based study of similar sample size. Another consequence of large-scale biobanks is the public availability of aggregate-level genotype-trait association results (or GWAS summary statistics) for a wide spectrum of complex human traits, including molecular traits that are intermediate between genotype and a disease-related trait. Methods that can leverage GWAS summary statistics to understand biology underlying diseases are in high demand since they are nearly as efficient and avoid logistical/ethical concerns related to sharing individual-level data. In this application, I propose a research program of developing novel statistical methods and open-access tools for genetic epidemiology studies, with a particular focus on family based designs. Some of these methods/tools will leverage only association summary statistics to innovatively integrate omics with disease data, thereby helping improve understanding of regulatory mechanisms underlying human health. We seek to address some of the open problems of human trait genetics, including methodological challenges in identifying non-additive genetic effects (e.g. gene-gene interaction, gene-environment interaction, parent-of-origin effect), effects of rare variants, and in prioritizing causal variants through integrative omics. We will bring obscure mathematical functions from statistical literature to real public health applications while illustrating them on existing databases. This research program will make three distinct contributions: support methodological advancement of family-based designs that overcome challenges related to sampling; efficient methods/tools that allow genomic researchers to conduct genetic epidemiology studies using publicly available summary data even in resource-poor environments; and help train graduate students recruited annually by the Johns Hopkins School of Public Health through research engagement and skill-building opportunities. In the last 5 years, I have built a research profile in family-based genetic studies alongside population-based ones, have developed cutting-edge methods based on summary-level data, have enabled data-driven policy-making via reproducible data science methods/tools, and have acquired mentoring skills. My multidisciplinary training and my prior experience put me in a unique position to successfully complete this program.

NIH Research Projects · FY 2025 · 2023-08

Humans are ubiquitously exposed to metals and per-and polyfluoroalkyl substances (PFAS), which are either established or suspected neurotoxicants in experimental and population settings. Exposure to these chemicals can be particularly harmful in utero, a critical period of fetal brain development. Four major literature gaps exist: 1) prospective studies of in utero exposure to these chemicals and child risk of neurodevelopmental disorders (NDs) are limited in the U.S, with most studies from predominantly European populations; 2) despite growing evidence that these chemicals may affect multiple NDs and systems, most studies are limited to a single ND outcome without consideration of comorbidities; 3) exposures rarely occur in isolation, yet combined exposure across different chemical classes remain unclear let alone chemical-nutrition interplay (nutrition may modify chemical toxicities); 4) most children’s environmental health studies focus on identifying risk factors with few that use or develop solution-oriented analytic methods that can directly inform public health actions. To fill these critical gaps, Dr. Choi proposes to investigate nutritional modifiers that may mitigate relationships between chemicals (i.e., metals and PFAS) and NDs and generating policy-relevant effect estimates via simulating intervention effects on chemicals and nutrition. To address this overarching goal, she will leverage rich existing resources (biospecimen data and clinical diagnoses of NDs and comorbidities across the lifespan) in the Boston Birth Cohort, a large prospective birth cohort. In R00, Dr. Choi will utilize the newly assayed PFAS data on which she has conducted quality control assessments during the K99 to complete Aims 1-2. For the adverse chemical-ND relations identified in during the K99 phase, she will evaluate nutritional modifiers (Aim 1) and simulate intervention effects by estimating the number of NDs that could have been prevented had there been pregnancy interventions on chemicals, nutrition, and both chemicals and nutrition (Aim 2). This R00 will position Dr. Choi as an innovative, independent researcher in environmental epidemiology, with a unique niche in NDs and comorbidities, chemical-nutrition interplay, research translation, and advanced methods. Our findings and activities will increase public awareness and serve as scientific evidence for future policies on the environment or nutrition to reduce the burdens of NDs.

NIH Research Projects · FY 2026 · 2023-08

Metastatic cancers often manifest in the skeleton. The lesions arise from disseminated tumor cells (DTCs) that often persist in a dormant state for months to decades after initial primary tumor treatment. Despite our knowledge that DTCs give rise to incurable bone metastatic cancer, there remains gaps in our understanding as to the cellular changes within the local and distant microenvironments underpinning entry and reawakening from the dormancy program. Insight into those mechanisms could yield new therapeutic approaches that would prevent the metastatic relapse and ultimately death of numerous cancer patients each year. To address this, we have developed novel syngeneic mouse models of cancer dormancy and reawakening across multiple cancer types including breast, prostate, and pancreatic cancer. These syngeneic models allow the investigation of how dormant DTCs within the bone alters the microenvironment around to facilitate or prevent metastatic outbreak in the bone. Moreover, these models allow the investigation of systemic changes (macroenvironment) resulting from dormant DTCs inhabiting the bone marrow. This investigation is of critical importance for prostate and breast cancer patients among others, because cancer cells often metastasize to the bone microenvironment, while patients succumb due to one or multiple metastases such as liver or lung metastases. Taken together we aim to investigate how dormant DTCs alter the microenvironment to prevent or facilitate reawakening of DTCs within the local or distant microenvironments.

NIH Research Projects · FY 2024 · 2023-08

Abstract/Project Summary Osteonecrosis of the femoral head (ONFH) is characterized by disrupted circulation within the bony compartment, leading to death of bone and marrow cells. It is associated with progressive pain, bony collapse, and joint degeneration within months to several years. Over 10 million people are afflicted worldwide. Most patients are diagnosed in their mid-30s, during their peak working years. The pathogenesis and treatment of this disease are controversial. If diagnosed early, the goal is to preserve the native hip joint. Total hip replacement is reserved for painful end-stage disease. Core decompression (CD) is the most common treatment in the early stages of ONFH and creates a drill tract into the lesion. However, the clinical outcome of CD is variable. There is increasing interest in using bone marrow aspirate concentrate (BMAC) to augment CD. Yet, studies have been limited to small case series, different disease stages, multiple risk factors, variable surgical techniques, or otherwise have lacked rigor. A randomized controlled trial (RCT) is needed to obtain a more definitive answer regarding the efficacy of BMAC with CD for early-stage ONFH. The overall goal of our multicenter clinical trial (U01) is to test the following hypotheses: “Patients who have early-stage ONFH undergoing CD augmented with autogenous BMAC will have better clinical and radiological outcomes than CD alone.” This RCT will also define specific patient characteristics that determine the long-term outcomes of these procedures. The Co-PIs are world-renowned experts, who are academic and clinical leaders in osteonecrosis. A team of highly recognized clinicians, who have expertise in the treatment of osteonecrosis from 12 centers in the United States have been recruited. For standardization, we will utilize a centralized radiologist, a central bone biology laboratory, and a center for data management and biostatistical analysis. Our specific aims are: Specific Aim 1 (SA1). To determine if CD with autogenous BMAC results in better outcomes than CD alone for the treatment of early-stage (pre-collapse) ARCO Stage I and II ONFH. Specific Aim 2 (SA2). SA 2A. To determine the cellular phenotype of the patients’ bone marrow aspirates, as assessed by Mass Cytometry by Time of Flight (CyTOF). SA 2B. To build a multivariate model classifying patients who have satisfactory and unsatisfactory clinical and/or radiological outcomes based on the combined mass cytometry cell frequency and functional feature dataset. In summary, we have planned this multicenter trial with our NIAMS-sponsored project team (R34 AR073505) and assembled a team of experts in the diagnosis and treatment of ONFH. The trial will benefit from existing studies and infrastructure by our group. We will determine if ON patients benefit from autogenous BMAC to augment CD, and investigate the biological mechanisms underlying improvements in outcome.

NIH Research Projects · FY 2025 · 2023-08

PROJECT SUMMARY Extensive work has implicated human resistin (Hresistin) and its rodent correlate resistin-like molecule (RELM)- α in inflammatory mechanisms of pulmonary hypertension (PH). Elevated levels of Hresistin in the lungs of idiopathic PAH and Scleroderma PH patients1,2 correlate with the disease severity of PH and predict mortality.3 Rodent models of PH show RELMα is critical to PH remodeling of the lung vasculature and right heart.3-7 We reported Bruton’s Tyrosine Kinase (BTK) as a binding partner of RELMα/Hresistin,8 and mediator of chemokine activities of RELMα/Hresistin in myeloid cells.1,8 We also reported that, Hresistin/RELMα initiates the inflammatory response to injury at PH onset, through activating damage-associated molecular pattern (DAMP) pathway high-mobility group box-1 (HMGB1).1,4,9 However, it is unclear how Hresistin/RELMα’s diverse inflammatory effects are integrated or how they amplify and sustain inflammation to induce vascular remodeling over time. The NLRP3 inflammasome was recently suggested to be central to the vascular inflammation in PH.10 It mediates the innate response to injury and is associated with the transition to adaptive immunity. Here, we intend to demonstrate the novel concept that Hresistin/RELMα is a critical regulator of the priming and activation stages of the NLRP3 inflammasome. Our preliminary data suggests the hypothesis that Hresistin/RELM ritical α is c to both NLRP3 priming (via HMGB1)11 and NLRP3 activation (via BTK) and production of IL-1β and IL-18 (via critical BTK12 phosphorylation of four specific NLRP3 tyrosine residues) in both macrophages and B cells, leading to pulmonary vascular remodeling and PH. It suggests a major and novel role for Hresistin/RELMα in engaging the NLRP3 inflammasome in the innate immune response to injury and to a sustaining adaptive immune response in the long-term remodeling associated with PH. We address this hypothesis in two aims: Aim 1: To dissect and prove the detailed mechanism of how Hresistin regulates NLRP3 inflammasome in inflammatory cells; Aim 2: To investigate the contribution of Hresistin- regulated inflammasome to vascular remodeling and PH.

NIH Research Projects · FY 2024 · 2023-08

Project Summary / Abstract The ability of cells to recognize and respond to extrinsic and intrinsic perturbations is critical for their survival. Recent studies have shown that the status of translating ribosomes is constantly monitored by surveillance factors to determine signs of translational distress. For example, the exposure of cells to ultraviolet radiation and reactive oxygen species causes transcriptome-wide RNA damage and prolonged stalling of ribosomes within the coding sequence of damaged messenger RNAs triggers ribosomal collisions. Recently, our laboratory has shown that the mitogen-activated protein kinase kinase kinase ZAK, and the general control nonderepressible 2 (GCN2) kinase are activated on collided ribosomes to trigger activation of the Ribotoxic and Integrated Stress Response programs (RSR and ISR) respectively. The goal of my proposal is to understand how the cell mounts a measured ZAK- and GCN2-mediated response that depends on the pervasiveness of ribosome collisions to determine cell fate. In preliminary experiments, I performed quantitative time-resolved phosphoproteomics to determine the temporal order of activation of signaling cascades in cells responding to ribotoxic stress. The data thus generated is providing an unprecedented high-resolution atlas of signaling events occurring in response to ribosome collisions and will be further explored in two proposed aims. In Aim 1, I will determine how ZAK is activated in response to ribosomal collisions and regulates cell fate outcomes through activation of the p38 and JNK signaling cascades. I will also test how a negative-feedback loop for ZAK enables cells to mount a measured response to ribotoxic stress. These studies will employ biochemical, quantitative proteomics, and live cell imaging approaches. In Aim 2, I will determine how GCN2 regulates the ISR pathway, and JNK and mTOR activity in response to ribotoxic stress by genetically and chemically perturbing GCN2’s kinase activity. Finally, I will test how co-factors and regulators of GCN2 set the threshold for its activation in response to ribosomal collisions. Together, the successful completion of these complementary approaches will provide foundational mechanistic insights into how the RSR and ISR pathways are coordinated by ZAK and GCN2 to regulate cell fate decisions during ribotoxic stress. Towards this, the experiments proposed will enable me to develop new skills and technologies in quantitative proteomics and live-cell imaging approaches, which will allow me to substantially differentiate my own research program from that of my mentor Dr. Green. I am confident that the team of collaborators that I have assembled and the accompanying training plan, will be instrumental in the growth and development of my independent research program and prepare me for a tenure-track position.

NIH Research Projects · FY 2025 · 2023-08

Recognizing that effective implementation of health programs requires attention to sex-based differences and the integration of sex-disaggregated analysis, the Applied Curriculum in Women’s Health and Social Systems (ACES) will develop an applied educational program to strengthen research and implementation skills related to sex-based and social analysis in health globally. ACES will pilot and implement this curriculum through an online Summer Institute at Johns Hopkins University and will sustain a community of practice of specialists by leveraging existing external and internal networks. Building on existing successful courses in women’s leadership, women’s health, and research methods, ACES will offer a series of short, intensive, online courses through an Accelerated Learning Institute at the Bloomberg School of Public Health. These courses will focus on applied approaches such as using data to improve health outcomes, designing interventions, budgeting with attention to social factors, conducting situational analyses that consider women’s health needs, monitoring and evaluation practices that reflect sex-based data, and communication and advocacy strategies to improve the health of women, girls, and other groups. The curriculum will be grounded in real-world challenges, informed by current scholarship, and taught by a faculty of leading experts in the field. It will serve current and future public health professionals from the U.S. and globally who seek practical skills to address sex-related and social determinants of health in program design and implementation. The training will enhance participants’ qualifications for roles in government, non-profit, and academic sectors focused on improving health outcomes through evidence-informed strategies.

NIH Research Projects · FY 2025 · 2023-08

SUMMARY The health and development of the infant is inherently linked to the health of the mother through the absorption and secretion of nutrients. Dietary minerals, including metals (Cu, Zn, Ca, Mn, Fe) are essential nutrients required for all aspects of physiological function. Yet the transport proteins critical for nutrient absorption and secretion are poorly defined and there is a paucity of functional data in human tissues or in vitro models derived from normal human cells to elucidate how and what adaptations in transporters occur to support pregnancy and lactation. This fundamental gap must be bridged to improve health outcomes for children and mothers. Our Transport Elucidation Center (TEC) on Minerals In Nutrition and Development (MINeD) will capitalize on our rich scientific, clinical, and mentoring expertise to serve as a hub for discovery, bench-to- bedside translation, and training in the area of human metal transport and nutrient uptake. The initial focus of the MINeD center will be in the developing gut and adapting maternal intestine and breast. During pregnancy and lactation, drastic remodeling of the mammary gland enables the synthesis and secretion of milk to sustain and nourish the infant. Importantly, transcriptional data from human milk-derived epithelial cells point to a key role for metal homeostasis. However, given the ethical challenges of acquiring human samples and establishing suitable in vitro models for transport flux studies, a functional understanding of metal transporters and their broader role in nutrient transport during lactogenesis is lacking. In Aim 1, we will address this gap in knowledge by defining the human ‘transportome’ in lactating mammary epithelium and how it relates to the mammary metallome to elucidate how nutrients are transported into milk. We will use human in vitro organoid models of mammary gland function to identify functional modules of transporters that are synchronously induced and discretely localized to accomplish transepithelial metal transport. Using gene-editing technology, we will systematically engineer deletions in the SLC family of solute carriers to de-orphanize understudied transporters and reveal potential new roles in milk production and secretion. In Aim 2, complementary studies using human adult and pediatric duodenal and jejunal enteroids will determine the role of metal transporters in intestinal adaptation and nutrient absorption to support child development, maternal pregnancy and lactation. We will ask how pregnancy- and lactogenic hormones change intestinal proliferation, transporter protein abundance at the plasma membrane, fat absorption, and metal content and distribution. Aim 3 of MINeD is to build the infrastructure and fundamental discovery pipeline to support future studies on human transporters. MINeD is well positioned to serve as a nexus for collaborations between basic and clinical research, to foster interactions in the scientific community by sharing knowledge and resources and hosting research-in-progress talks, workshops and seminars in the scientific areas of human transporter physiology, and to promote career development of diverse early career scientists by providing seed funding for innovative projects.

NIH Research Projects · FY 2025 · 2023-08

PROJECT SUMMARY/ABSTRACT This career development award will support Chad Hochberg, MD MHS, to become an independent investigator in critical care implementation science. In this award, Dr. Hochberg will build on his prior NHBLI-funded F32 studies investigating the changes in critical care practice that occurred early in the coronavirus disease 19 (COVID-19) pandemic. With this award, he seeks further training in 1) Informatics to monitor and support implementation, 2) Survey methodology, and 3) Developing, adapting, and evaluating implementation strategies for intensive care unit (ICU) implementation trials. To achieve these goals, he has outlined a 5-year career development plan that involves targeted didactics, hands-on research experience, and intensive mentoring. This research and training will be facilitated by the highly supportive training environment at the Johns Hopkins University, and guided by an experienced mentorship team with relevant expertise. Acute respiratory distress syndrome (ARDS) is a common and deadly form of respiratory failure in patients receiving mechanical ventilation. Prone positioning, a key evidence-based practice (EBP) for ARDS, involves positioning patients to lie on their stomachs, facilitating less injurious mechanical ventilation. Despite strong evidence that prone positioning reduces risk of death, it was historically underused. However, during the early COVID-19 pandemic, the use of prone positioning in patients with COVID-19 ARDS drastically increased compared to historic practice. Yet, preliminary data show falling proning rates, and other implementation experience suggests that without active intervention, appropriate use of this life-saving measure will decline. The strategies needed to support the sustainability of prone positioning in ICU practice are unknown. In this K23, Dr. Hochberg will use an established implementation framework, the dynamic sustainability framework, to structure an investigation into the strategies needed to support sustainability of prone positioning in ICU practice. In Aim 1, he will use granular patient-level data combined with staff surveys of ICU implementation climate from the five-hospital Johns Hopkins Health System, and evaluate the associations between the continued use of proning over time with specific patient characteristics and ICU implementation climate domains. In Aim 2, he will further explore the influence of ICU climate and culture on proning processes using a sequential explanatory mixed methods design. Finally, in Aim 3, he will conduct a pilot implementation trial to support further penetration and sustainability of prone positioning in routine ICU practice, and will assess the feasibility, acceptability, and appropriateness of this intervention using validated implementation surveys of ICU staff. This research and training will establish a strong foundation for a career focused on implementation science in critical care, and provide the preliminary data and experience for Dr. Hochberg to conduct a future R01-level multisite intervention to improve the implementation of prone positioning and other EBPs for ARDS.

NIH Research Projects · FY 2024 · 2023-08

ABSTRACT Peanut allergy (PA) has emerged as a major clinical and public health problem worldwide, due to the dramatic increase in prevalence, its life-long persistence in most cases, and its associated life-threatening anaphylactic response. The causes and precise molecular mechanisms underlying the development of PA remain largely unknown. Available data underscore the early life period (i.e., in-utero and first few years of life) as the critical window in the development of PA, which is also the critical developmental window for the adaptive immune system. There is increasing evidence that T cells play a critical role in modulating tolerance to peanut and risk of PA. Specifically, CD4+ T cells recognize peanut antigens through the engagement of T cell receptors (TCRs). Each individual has a large and highly variable TCR repertoire which is a major determinant in the immune response to a given antigen. To date, few studies have longitudinally characterized TCR repertoire development and dynamics in relation to PA, especially in the context of early life risk or protective factors of PA such as nutrition and metabolomic alteration and their joint associations with PA development during childhood. This proposal, motivated by our intriguing previous work and promising preliminary data, will harness the cutting-edge Adaptive immunoSEQ® technology to deep sequence the TCR ß-chain (TCRß) complementarity determining region 3 (CDR3) at birth (reflecting in-utero development) and at age 1-2 years (reflecting postnatal development) in 300 children (150 peanut allergic and 150 non-allergic, non-sensitized children) from the prospective Boston Birth Cohort (BBC), a NIH-funded U.S. urban, low-resourced underrepresented multi-ethnic cohort. By leveraging the BBC’s existing biospecimen, genome-wide genotype data, metabolome, and extensive epidemiological and clinical databases, we aim to investigate: (1) Longitudinal associations of early life TCRß repertoire development with child risk of PA. We hypothesize that TCRß repertoire features (i.e., composition, diversity, and dynamics) at birth, at age 1-2 years, and their longitudinal changes are associated with childhood risk of PA. We will further identify peanut- specific CD4+ T cell subsets with enriched peanut-specific CDR3 (ps-CDR3) sequences or motifs; (2) The interplay of early life factors, metabolome, and TCRß repertoire on child risk of PA. We hypothesize that early life nutritional and metabolic factors may influence TCRß repertoire development, and, in turn, may jointly affect child risk of PA. This proposal is strengthened by its prospective birth cohort design; a strong multi-disciplinary collaborative team, novel integration of TCRß repertoires with early life exposure to nutrition and metabolome; and focus on underrepresented, under-studied, high risk, predominantly minority children. Successful completion of this project will identify novel biomarkers for early risk assessment of PA and new targets for intervention during the earliest developmental windows. In short, this study represents a unique opportunity to advance the field and open doors to promising new directions to unlock the mystery of PA.

NIH Research Projects · FY 2026 · 2023-08

PROJECT SUMMARY Tourette Syndrome and persistent tic disorders (collectively TS) are characterized by the childhood onset of tics that cause functional impairment and persist into adulthood in most cases. Alongside tics, patients with TS experience premonitory urges and comorbid mental health conditions (e.g., anxiety, ADHD, OCD, depression) that all diminish quality of life. Presently, only two evidence-based treatments exist for patients with TS: behavior therapy and pharmacotherapy. Behavior therapy is recommended as the first-line treatment for TS. However, 60% of adults with TS do not respond to behavior therapy and it does not confer any benefit for common comorbid mental health conditions. It is also inaccessible for many. Less than 20% of adults with TS receive behavior therapy because of limited accessibility to trained TS providers. Consequently, most adults with TS rely on FDA-approved medications for tic management, which infrequently produce tic remission and are often discontinued due to adverse health effects. Thus, it is critical to identify new safe, efficacious, and accessible treatments to improve therapeutic outcomes and quality of life for adults with TS. In response, our team has developed an online mindfulness-based group intervention for tics (MBIT). Our pilot clinical trial compared group MBIT to group psychoeducation, relaxation, and supportive therapy (PRST) in adults with TS. All interventions and assessments were delivered remotely using secure telehealth platforms and online electronic data capture systems. MBIT was found to be feasible, acceptable, and efficacious for reducing tic severity and impairment relative to PRST. Additionally, MBIT produced improvement in comorbid mental health conditions, and sustained benefit for up to 6-months. Building on this work, we will conduct a randomized clinical trial (RCT) that: (1) tests the efficacy of MBIT for reducing tic severity, (2) examines the mechanism by which MBIT reduces tic severity, (3) evaluates the secondary benefit of MBIT for comorbid mental health conditions and quality of life, and (4) explores the long-term benefit of MBIT. Here, 150 adults with TS with moderate or greater tic severity will participate. Adults will complete a baseline assessment to characterize tic severity, premonitory urge severity, the severity of comorbid mental health conditions, and quality of life. Next, participants will be randomized to 8 weekly sessions of group MBIT or group PRST in a 1:1 ratio. Participants will complete mid-treatment, post- treatment, 1-month and 3-month follow-up assessments. Participants receiving MBIT will also complete a 6- month follow-up to assess its sustained benefit. All ratings will be made by an independent evaluator (IE) masked to treatment condition. Findings will establish a new, accessible, evidence-based treatment for adults with TS that comprehensively reduces tic severity, improves co-occurring mental health conditions and quality of life, and produces lasting therapeutic benefit. This intervention and its remote group delivery approach provides a practical, scalable, and sustainable solution to improve therapeutic outcomes for adults with TS.

NIH Research Projects · FY 2025 · 2023-08

Contact PD/PI: Yakusheva, Olga PROJECT SUMMARY Specialty registered nurse (RN) certifications can be a popular choice for practicing RNs to to advance their knowledge and expertise and are one way hospitals invest in their nursing workforce. An estimated 40% of acute care RNs hold specialty certification and as many as 55% of hospitals offer tuition reimbursement and paid time off for completion potentially costing organizations several mission dollars annually. While RN specialty certification is a multi-million dollar industry, surprisingly little evidence exists about the value added by RN specialty certifications in terms of improved nurse performance and patient and organizational outcomes. Evidence that does exist is inconclusive and judged as low quality due to cross-sectional study designs, aggregation of data at the hospital- or unit-level, and poor quality of certifications data in most hospital human resource databases. Lack of robust evidence may lead to broad-scale under- (or over-) investment in specialty RN certification in the healthcare industry, potentially contributing to excessive costs and suboptimal patient outcomes. In collaboration with the 4th largest healthcare system in the United States (CommonSpirit Health, over 140 hospitals across 21 states), we will conduct nurse-patient linked analyses of the impact of RN specialty certification on nurse performance, patient outcomes, and costs. Our proposal draws on our team’s prior and current expertise in nurse-patient linked analyses of electronic health record data, individual nurse value-added performance measurement, and quasi-experimental regression methods for causal inference (i.e. difference-in-difference with time-varying treatment effects). In Aim 1, we will determine whether RN specialty certifications improve nurse performance using a one-nurse-to-many-patients linking approach we developed, allowing us to test the causal effect of obtaining a specialty certification on nurse performance and whether the effect of specialty certification on nurse performance depends on the type of certification (e.g. critical care, medical-surgical, wound/ostomy) and on nurse characteristics (education, experience). In Aim 2, using a one- patient-to-many-nurses linking approach we have developed, we will determine if patient outcomes and organizational financial outcome improve with a higher proportion of specialty-certified nurses; this Aim allow us to examine whether patients who receive a greater proportion of care from specialty certified nurses have improved outcomes and lower costs, and the financial impact (cost-benefit) of increasing the proportion of specialty certified nurses in different types of organizations (e.g. Magnet/non-Magnet, teaching/non-teaching). In Aim 3, we will explore the contexts and mechanisms that support or hinder the impact of specialty nurse certification on patients, costs, and organizational outcomes, through focus groups and interviews with nurses and nurse leaders. Taken together the aims of this mixed methods study will provide the most robust, causal, and generalizable evidence to inform investments in nurse human capital to optimize nurse performance, achieve targeted patient outcomes, and reduce costs of care. Project Summary/Abstract Page 7