Univ Of North Carolina Chapel Hill

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY/ABSTRACT The clinical burden of malaria infections in sub-Saharan Africa has been of tantamount public health importance for decades, but research and control efforts have previously focused on Plasmodium falciparum, the most common and severe of the malaria parasites in the subcontinent. Expanded molecular surveillance has revealed an unappreciated burden of non-falciparum species infections, which in some areas of Africa is increasing. In order to reach malaria elimination, research and control efforts must include a concerted effort to understand non-falciparum species. Plasmodium ovale has been found to be especially prevalent in sub-Saharan Africa, and its ability to cause liver-borne relapse infections lends it special public health significance. However, difficulties in the genetic and clinical study of this parasite have prevented robust examination of its population structure or relapse burden, and the discovery that P. ovale is actually composed of two distinct species further complicates the study of these topics. This proposal leverages the applicant's unique access to malaria clinical isolates collected across Africa and a prospective cohort of Tanzanian participants who were followed longitudinally for P. ovale recurrence, as well as the trainee's scientific and didactic background in molecular microbial genomics and infectious disease epidemiology, in order to examine the genomics and relapse behaviors of both species of this poorly characterized malaria parasite. The specific aims of this proposal are 1) to characterize the population genomics of Plasmodium ovale in sub-Saharan Africa and 2) to describe the epidemiology of P. ovale carriage and relapse in Tanzania. The proposed research and associated training plan will enable the trainee to achieve his specific scientific, clinical, and professional goals. Through the proposed dissertation research, he will cultivate translational research skills in the fields of genomics and epidemiology in order to genetically characterize a population of pathogens and apply the findings to human population health. With his medical training and longitudinal clinical clerkship, he will improve his clinical acumen in the care of infectious diseases for patients from marginalized communities. By continuing to invest in professional and teaching skills, he will develop leadership and educational competency for use in his future career as a physician-scientist in academia.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY Autism spectrum disorder (ASD) is a common neurodevelopmental condition that affects social behavior and cognitive flexibility. Sleep disruption is a common comorbidity in ASD, observed in more than 80% of affected individuals. It has been debated whether sleep disruption in ASD is a consequence of altered brain function, or whether sleep disruption is actually a core component of ASD and driver of altered brain function and behavior. Sleep disruption is often seen in advance of ASD diagnosis, and the severity of sleep disruption can be predicative of the severity of other ASD associated phenotypes, strongly suggesting that sleep disruption is an early symptom in ASD and a potential driver of the condition. Multiple studies, including new work from our lab, have shown in animal models (rodents and fruit flies) that a period of early life sleep disruption is causal in long- lasting and sex-specific changes in social and cognitive behaviors in adults. Thus, developmental sleep disruption is emerging as an important contributor to ASD susceptibility. Alterations in synapse number, structure, and function have been documented repeatedly in ASD models and patient samples, leading many to describe ASD as a “synaptophathy”: a dysfunction of synapse function. Consistent with this assertion, gene sequencing efforts have identified hundreds of risk genes associated with ASD, many of which encode proteins with known synaptic functions, such as the excitatory synaptic scaffold protein SHANK3. Another important cluster of ASD risk genes encode for proteins with nuclear functions such as CHD8. Sleep has been shown to be critical for synapse formation, maturation and elimination in the developing brain. Therefore, we hypothesize that synapse maturation is a critical vulnerability to the consequences of developmental sleep disruption. We have recently published that early life sleep disruption (ELSD) can cause long-lasting and sex-specific changes in behavior in the genetically vulnerable Shank3(+/C) heterozygous mice, whereas wild type littermates were found to be resilient (Lord et al., 2022, Molecular Autism). To determine if developmental sleep disruption is broadly relevant in ASD we must test whether ELSD similarly interacts with distinct genetic vulnerabilities. CHD8 is a high-confidence ASD risk gene that encodes a nuclear chromatin remodeling enzyme. CHD8 is believed to play an important role in brain development during embryogenesis, but whether CHD8 mutation also confers vulnerability to postnatal sleep disruption has not been tested. We will determine whether ELSD drives lasting changes in behavior in genetically vulnerable Chd8(+/V986*) ASD model mice, similarly to what we have recently demonstrated with heterozygous Shank3 ASD model mice. We will also examine whether postnatal synapse maturation is a convergent node of vulnerability to developmental sleep disruption. Our goals in this R21 proposal is to establish developmental sleep disruption as an important risk factor contributing to ASD susceptibility by interacting with diverse underlying genetic etiologies, and to develop methodologies to pursue the developing synapse as a convergent node of vulnerability to the effects of sleep disruption in ASD.

NIH Research Projects · FY 2025 · 2024-08

We know little about the mechanisms underlying a critical subset of heterogeneous obesity: Severe Obesity (SevO; BMI≥40kg/m2; ~>100 lbs overweight), which is a risk factor for a host of chronic cardiometabolic and other diseases, with disproportionate impact across populations. Given these differences, deepening the genomic translational pipeline, and identifying regulatory mechanisms of SevO across populations is imperative. Yet, because SevO is an exclusion criterion in many clinical research studies and certain groups are profoundly underrepresented in genomic, transcriptomic, and metabolomic research, we know little about its underlying mechanistic pathways or the clinical significance of SevO susceptibility in subpopulations. As a result, studies attempting to fine map GWAS loci, estimate expression quantitative trait loci (eQTL) and metabolomics quantitative trait loci (metaboQTL) have been uninformed by ancestry. Effects of ancestral heterogeneity within and across populations and differential disease risk by ancestry have also been historically under-investigated. These fundamental gaps in data and in ancestry-informed analyses necessitate integrative studies of multi-omics to propel mechanistic understanding and establish clinical significance of SevO susceptibility. Thus, we propose to leverage transcriptomics, metabolomics, and SevO GWAS data from extant epidemiologic and clinical studies in the US, Central, and South America, to discover, identify causal relationships, and reveal molecular mechanisms of SevO. We propose to examine: (Aim 1) whole blood RNAseq data from >15,000 individuals (892 SevO cases, 3,342 controls) and (Aim 2) metabolomic data from >46,000 individuals (1,588 SevO cases, 9,827 controls) to identify transcriptomic and metabolomic signals underlying SevO using ancestry-informed models to derive the first ever, ancestry-informed population-specific eQTL and metaboQTL maps for critical subpopulations. We have developed a rigorous plan of discovery, internal replication, external validation, and generalization across populations and cell types to ensure a high level of scientific rigor. In Aim 3, we propose to identify mechanisms and infer causal pathways underlying SevO by integrating these measures with SevO GWAS data from ~240,000 individuals to perform ancestry-informed colocalization, pathway, and causal inference modeling, and establish broad clinical significance using GWAS-, transcript-, and metabolite-informed polygenic risk scores of SevO in large, electronic health record-linked biobanks. These studies, unprecedented in size, will increase knowledge of the metabolic pathways and gene expression profiles of SevO, filling critical gaps. Using our deep expertise in cutting-edge methods in ancestry-informative analyses, we propose novel methodological approaches including integration of local ancestry eQTL and metaboQTL mapping studies and multi-omics informed polygenic risk scores for use in clinical biobank data. We will broaden the representativeness of the genomics literature, fundamentally alter understanding of mechanisms underlying SevO and shed light on potential targets for prevention, diagnostics, and treatments.

NIH Research Projects · FY 2025 · 2024-08

ABSTRACT This proposal builds into our ongoing research in genetics and disease risk in admixed Hispanic populations. Hispanics/Latinos are the larger racial/ethnic minority in the U.S. They have a high burden of cardiometabolic and inflammatory related diseases. Genetically, Hispanics are an heterogenous population comprised of multiple ancestral groups (primarily Native American, West African, European) from recent admixture. Few studies have leveraged genetic ancestry to address differences in disease susceptibility. This study will leverage the comprehensive data from the large population-based Hispanic Community Health Study/Study of Latinos for discovery of ancestry-enriched susceptibility loci. We propose to integrate genomics and multi- omics data to map genomic segments and variants inherited from the ancestral population with the higher disease variant frequency (Aim 1), use new approaches for fine-mapping genomic regions (Aim 2), and validate our findings for clinical relevance in Hispanics/Latinos from the All of Us study (Aim 3). We expect to gain insights into the identified ancestry-related genomic regions and variants and their relationship to disease states. This proposal uniquely complements large ongoing genome wide association approaches. Our results may provide insights into differences in disease risk in admixed populations. Ultimately this research could inform personalized medicine and improve public health.

NIH Research Projects · FY 2024 · 2024-08

PROJECT SUMMARY Value-based purchasing (VBP) reforms in the United States (e.g. pay-for-performance) seek to improve care efficiency by reducing wasteful health care practices, which may harm patients and account for ~30% of the $4.1 trillion spent annually on US healthcare. Surgical care, which comprises over 50% of Medicare spending, is a logical target for these reforms given it’s episodic and cost-intensive nature. However, surgical episodes are targeted by just one-third of VBP arrangements, none of which have achieved net cost savings. As such, there is a critical need to identify novel models of surgical care that provide insights/solutions to the failings of existing surgical VBP efforts. Symptomatic urinary stone disease—aka renal colic—is a common (1 in 10 US adults) and costly ($10 billion annually) surgical condition characterized by high levels of variation in perioperative outcomes and costs, making it a condition ideally suited to evaluate drivers of perioperative care variation. Current surgical VBP arrangement shortcomings may in part be due to misguided policies that reward strategies seeking to minimize post-operative care variation rather than streamlining the sequence of episode-specific clinical events preceding surgery. For example, there is growing literature demonstrating an association between improved pre-operative functional status and post-operative health outcomes. Similarly, addressing patients’ social needs ahead of surgery appears to improve 30-day post-operative outcomes. Consequently, developing and deploying value-based interventions in the pre-operative period that target clinical and non-clinical risk factors may be particularly effective at reducing variation in perioperative care, and by proxy surgical disparities. This proposal will employ an explanatory sequential mixed-methods design using a combination of claims data and patient/provider interviews to 1) identify social risk factors associated with variation in both pre- and post- operative expenditures/outcomes related to an episode of renal colic (Aim 1), 2) assess patient/provider perspectives on facilitators/barriers to timely and effective surgical care provided for an episode of renal colic (Aim 2), and 3) design and pilot a clinical decision support tool that personalizes follow-up for patients discharged from the emergency department with renal colic and who will subsequently undergo surgery (Aim 3). Ultimately, these efforts will 1) inform how social risk impacts surgical outcomes, 2) align surgical VBP efforts with the patient-provider experience, and 3) serve as the basis for a future R01-funded trial assessing the impact of a risk-adjusted clinical decision support tool on perioperative outcomes/expenditures following a renal colic diagnosis.

NIH Research Projects · FY 2025 · 2024-08

Project Summary (Abstract): The racial disparity in uterine leiomyomata (fibroids) is profound among Black/African American women (BW) – with an earlier age of onset by 10-15 years, a significantly higher incidence, and greater rates of hysterectomy, a major surgical procedure, compared to White women (WW). The impact of fibroids is significant for reproductive age women, especially BW who experience more symptomatology such as excessive bleeding, pain, and reproductive problems. Therefore, research on the risk factors for fibroids is important. Earlier onset of fibroids among BW may explain their larger fibroid size and increased symptomatology. Our main hypotheses are that exposure to adverse childhood events (ACEs) contributes to incident fibroids and greater growth and that psychosocial resources may buffer the risk. We will use data from the National Institute of Environmental Health Sciences Study of Lifestyle & Fibroids (SELF) that enrolled 1308 BW ages 23-34 years without a clinical diagnosis of fibroids and collected extensive data at baseline and across 3 follow-up visits on early childhood social and environmental factors, reproductive and sexual histories, and demographic, economic, behavioral, and psychosocial factors. We will evaluate the hypotheses by pursuing three specific aims: 1) Describe the prevalence ACEs occurring before age 12 by type, cumulative risk, and latent class profiles, and examine the association between each ACE measure and childhood and adult contextual factors; 2) Describe each ACE measure in relationship to the trajectory of C-reactive protein (CRP); and 3) Examine the association between each ACE measure and the incidence and growth of uterine fibroids, and then evaluate the modifying effect of psychosocial resources. This proposed ancillary research study will elucidate the association between ACEs and incident fibroids with less bias than previous research due to improved ascertainment of both the exposure (i.e., 7 ACEs) and outcome (i.e., repeated and standardized ultrasound exams in fibroid-free participants at study entry). Fibroids pose a major public health concern with an estimated total associated cost (medical, work-related, etc.) of up to $34.4 billion annually. Determining risk factors for fibroids, such as the early life stress of ACEs, will provide key information to improve the quality of life for Black women, who are more likely to experience missed days from work and disruption in physical activities and social relationships due to fibroids. It will also provide a strong research foundation that sheds light on potential intervention targets to reduce morbidity and surgical disparities, set the stage for identifying biological mechanisms for prevention, and elucidate the context of early life stressors on fibroid risk.

NIH Research Projects · FY 2024 · 2024-08

Abstract Significance: Lesbian, gay, bisexual, transgender and other sexual and gender minority (LGBTQ+) populations make up a substantial proportion of the United States (US) population—over 23 million individuals. LGBTQ+ populations throughout the US face identity-related stigma, ranging from interpersonal to structural, that leads to a variety of physical, mental, and economic health disparities. At the same time, the rising costs of cancer care puts over half of cancer survivors at risk of financial hardship and the subsequent outcomes—poor quality of life and reduces access to care. Emerging research suggests that LGBTQ+ cancer survivors and caregivers may experience worse financial hardship in comparison to non-LGBTQ+ counterparts, driven by existing economic inequities and multi-level anti-LGBTQ+ stigma. However, inequity in financial burden has not been estimated using national datasets, nor, has an intersectional lens been taken to dig into the diversity of the LGBTQ+ population. Innovation: Employing multiple national datasets with sexual orientation and gender identity data (SOGI) data (Aims 1 and 2) as well as an explanatory sequential mixed-methods design with in- depth qualitative interviews (Aim 3) provides a novel opportunity to provide national findings among LGBTQ+ cancer survivors paired with in-depth experiences of LGBTQ+ cancer caregivers. Integration of cancer-related financial hardship frameworks and the theory of intersectionality is not only responsive to national calls to center health equity (NOT-HS-21-014) it allows, for the first time, comprehensive and robust estimates to be generated for LGBTQ+ cancer survivors of diverse identities. Aims: Aim 1 will use multivariable logit regression to estimate inequities in material, behavioral, and psychological financial hardship between LGB (e.g., lesbian, gay, bisexual) and non-LGB cancer survivors in the National Health Interview Survey. Aim 2 will employ intersectional analyses to estimate inequity in behavioral financial hardship across identities and ages between LGBTQ+ and non-LGBTQ+ cancer survivors in the All of Us Research Program dataset. Aim 3 will use an explanatory sequential mixed-methods design including in-depth qualitative interview building on an existing federally funded parent grant study. Aim 3 analyses will describe the lived experience of financial burden among LGBTQ+ cancer caregivers as well as provide multi-level LGBTQ+ specific recommendations. Study Impact: This study employs multiple data sources that each provide unique and important context to LGBTQ+ inequities in financial hardship. Affordability is crucial to access to care, thus understanding the between and within LGBTQ+ community variation in financial hardship promotes equity in health services delivery. Overall, the purpose of this study is to estimate inequity, identify modifiable factors, and elicit LGBTQ+ recommendations to improve the provision of cancer health services to LGBTQ+ populations.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY Fear of recurrence (FoR) is a pervasive, distressing concern among breast cancer survivors (BCS) that persists for years after cancer treatment. Long-term survivors identify help with managing FoR as their most pressing unmet need. Effective and scalable FoR interventions are needed to address the salient emotional, cognitive, and behavioral components of FoR. Cognitive behavior therapy (CBT) is well suited to address these components, but patients face many obstacles to psychosocial care due to a lack of available providers, cost, and time constraints. eHealth interventions can overcome these obstacles. We developed, refined, and evaluated FoRtitude 1.0, a 4 week targeted eHealth intervention designed to teach BCS CBT strategies to manage FoR through didactic content and interactive tools. We randomized 196 BCS with moderate or severe FoR to CBT or an attention control (health management content, HMC) and observed a significant reduction in FoR from pre-post intervention among all BCS. While we hypothesized CBT would be superior to HMC, our qualitative data indicate CBT and HMC are mechanistically distinct in reducing FoR. We also found BCS randomized to telephone-based motivational interviewing (telecoaching-MI) had higher eHealth adherence and retention compared to no telecoaching. The FoRtitude 2.0 trial addresses limitations from our last trial by enhancing intervention content through delivering CBT and HMC, adding culturally responsive content, doubling intervention duration (8 week), long- term follow-up, and more rigorously designed control conditions. We added secondary endpoints to assess healthcare utilization and a physiological marker of chronic stress: allostatic load. This phase III, randomized controlled trial (RCT) is designed to evaluate the efficacy of FoRtitude 2.0 augmented by telecoaching-MI to reduce FoR among BCS compared to two controls: an attention control and a usual care control. We will recruit a national, diverse sample of 800 BCS from NCI Community Oncology Research Program (NCORP) Community and Minority/Underserved Sites. We will stratify accrual by race to enroll 300 Black BCS and 500 non-Black BCS (Hispanic and non-Hispanic). Among female BCS with moderate or severe FoR enrolled from NCORP Sites, we propose the following Aims: Aim I. Evaluate the efficacy of FoRtitude 2.0 to reduce FoR at 3 months (1 month post-intervention) compared to attention control and usual care. Aim II. Evaluate the efficacy of FoRtitude 2.0 to improve psychological and behavioral consequences of FoR, including anxiety, depression, HRQL, and health care utilization. Exploratory Aim: Evaluate the efficacy of FoRtitude 2.0 to reduce allostatic load from baseline to 3 months compared to attention control and usual care. Findings will contribute to establishing an evidence-based scalable eHealth intervention targeting FoR that can be widely disseminated at low cost, leading to future research on the dissemination and implementation of FoRtitude among survivors of all cancer types and improving the quality of cancer survivorship.

NIH Research Projects · FY 2024 · 2024-08

ABSTRACT The Centers for Disease Control and Prevention (CDC) recommends initiating human papillomavirus (HPV) vaccination at ages 11-12 to confer protection against anogenital and oropharyngeal cancers, though it can be started as young as age 9. Two doses by age 13 is considered “up-to-date” (UTD), i.e. protected before the onset of sexual activity. Nationally, UTD coverage was only 62% in 2021. In North Carolina (NC), a largely rural state, UTD HPV vaccination coverage is only 47% in rural adolescents. Novel approaches are needed to alleviate barriers to HPV vaccination coverage in rural areas, where adolescents may have less access to health care or a pediatrician who routinely recommends HPV vaccination. Recommending HPV vaccination at age 9 could increase UTD coverage in rural adolescents by allowing earlier completion of the series and more time to achieve UTD coverage, promoting maximal and timely HPV prevention. Achieving parity in rural HPV vaccination rates can greatly reduce urban-rural cancer disparities, including cervical cancer. The goals of the proposed K01 project are to 1) define optimal systems for recommending HPV vaccination at age 9 years in rural NC clinics; 2) assess acceptability and appropriateness of age-9 vaccination among rural caregivers; and 3) conduct a hybrid effectiveness-implementation study of age-9 HPV vaccination in rural clinics. Specific Aim 1 will collaborate with health care personnel in rural clinics to measure appropriateness and acceptability of age-9 HPV vaccination, identify opportunities for clinic-based interventions to promote it, and incorporate these insights into a preliminary intervention plan. In Specific Aim 2, we will gauge rural caregivers’ acceptability of age-9 HPV vaccination for their children, and modify the intervention plan as needed to maximize acceptability. Finally, Specific Aim 3 will pilot the intervention in four rural clinics, using electronic medical records to measure UTD HPV vaccination coverage in a cohort of 9- year-old patients over two years. My technical skills in study design and data analysis will be complemented by extensive training in clinical research and implementation science to successfully complete this project, relying on mentorship from experts in pediatric and adolescent health care, implementation science, rural health, development and evaluation of clinical interventions, and research with health care personnel. By establishing collaborative relationships with clinic research networks, understanding the key factors associated with rural health disparities, and becoming adept at developing, implementing, and measuring evidence-based interventions, my research career promises to increase vaccination behaviors in areas that are most vulnerable to infections and their consequences. In addition, I will become a well-rounded and nimble vaccine researcher, studying myriad health areas that could benefit from the introduction of novel vaccines or improved delivery of existing vaccines. This training will prepare me to lead R01-funded studies, including large scale clinical trials to reduce health care disparities in underserved areas.

NIH Research Projects · FY 2024 · 2024-08

Project Summary/Abstract The ability to localize sound sources and detect temporal features of sound is fundamental to hearing. Encoding this information within the first few auditory processing stations requires reliable and precise synaptic transmission in response to rapid and large fluctuations of upwards to the kilohertz range in action potential (AP) firing rates. However, the number of synaptic vesicles (SVs) available for AP-evoked release is limited. Many auditory brainstems synapses must sustain fast and repetitive SV release to encode sound information. Therefore, sound encoding places great demands on the temporal dynamics of SV release and replenishment. A key step regulating AP evoked SV release is priming, the process that creates fusion competent SVs in close proximity to voltage-gated CaV2 channels (CaV). The rate of priming and SV replenishment is highly dependent on the magnitude of presynaptic Ca2+ through CaV2 channels. Human mutations in the molecules regulating priming result in dysregulation of SV release which is the cause of many auditory and neurological disorders. In mammals, the pathway between the globular bushy cells (GBCs) and the medial nucleus of the trapezoid body neurons (MNTB) is critical for encoding sound localization and temporal features of sound in music and communication found in animal vocalizations to human speech. The GBC axon forms the calyx of Held, a glutamatergic presynaptic terminal, that is the sole input that drives AP spiking in the MNTB. The calyx uses fast SV release kinetics to relay the patterns of afferent AP spikes in the cochlear nucleus to the MNTB. This, in turn, results in rapid and precise inhibition of key mono- and binaural cell groups. It is emerging that aberrant MNTB signaling underlies sound localization and speech perception defects in the aging population and can contribute to central auditory defects found in neurological disorders. Therefore, our goal is to delineate the molecular mechanisms regulating the temporal dynamics of SV release and replenishment required for proper auditory information processing. Given the importance of priming in synaptic transmission, as well as the pathological consequences of aberrant SV release, our findings will provide fundamental insights into how information is encoded by the nervous system and are expected to facilitate the development of treatments for a wide range of neurological and neuropsychiatric disorders.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY Substance use is one of the most commonly occurring health risk behaviors and has been unambiguously linked to numerous negative outcomes (e.g., Stellern et al., 2023, Planell-Ripoll et al., 2019). These far- reaching public health issues have impelled substantial growth in the theoretical conceptualizations of causal processes of substance use, especially in theories of dynamic processes that unfold over time (e.g., Shiffman, 2009). However, the rapid growth in these theories has occurred before the empirical properties of statistical methodologies used to test the theories have been fully vetted. Multilevel Modeling (MLM) and Dynamic Structural Equation Modeling (DSEM) are widely used to examine dynamic theories of substance use, yet the performance of these models under conditions common to theories of substance use is unknown. This directly undermines the ability of substantive researchers to make informed choices about models. The integration of theory and methods is essential to building reliable and valid theories of substance use. MLM is a modeling framework commonly used to assess risk and protective processes of substance use. It has several strengths including the ability to model unequal time intervals, the use of maximum likelihood estimation, and the widespread availability of MLM in statistical programs. However, MLM is not well-suited to model reciprocal relationships (Falkenström et al., 2022), which are hypothesized in many theories of substance use. Reciprocal effects can be appropriately modeled in DSEM, and DSEM has other strengths such as the ability to address measurement error and to introduce random effects across a variety of estimates (Asparouhov et al., 2018). Yet, DSEM is not without limitations when applied to substance use theory. For example, there is currently no way to systematically build and evaluate DSEM models, which has serious implications for inference (Hamaker et al., 2018). Further, an assumption of DSEM that is often not met is that measurements are equally spaced. Undoubtedly, there are conditions in which MLM and DSEM can adequately and appropriately model dynamic processes of substance use. However, until these conditions are comprehensively evaluated, we risk building a literature marked by biased results that lack internal validity. The purpose of this proposed program of research and training is to improve researchers' ability to test novel theories of substance use, such as the edge on, edge off theory. I aim to (1) generate data consistent with the characteristics of theories from the substance use literature, (2) identify conditions under which MLM and DSEM perform optimally and conditions under which they result in biased parameter estimates, and (3) disseminate guidance for using these methodologies to substance use researchers and meaningfully contribute to the substance use literature by examining the novel edge-on, edge-off theory. My proposed project will fully integrate advanced substance use training and research with quantitative methodologies so that researchers can reliably and validly test dynamic risk and protective processes of substance use.

NIH Research Projects · FY 2024 · 2024-08

PROJECT SUMMARY Ample evidence suggests that Black parents are the most salient figures in the lives of Black adolescents, with the greatest potential to protect and prepare them from the adverse effects of racism through unique, culturally specific parenting strategies.33, 45 Racism is increasingly becoming a public health concern which poses a risk for an increase in depression symptoms among Black Americans during adolescence and with recent studies indicating that Black fathers are salient and active participants in the parenting process.5, 25, 39 However, our understanding of patterns of parenting strategies among Black fathers is methodological limitations in longitudinal explorations and person-centered approaches to advance our understanding of the long-term effects of exposure to racism on depression symptomatology. The overall goal of this NRSA proposal is to provide a methodologically rigorous examination of the heterogeneity of Black fathers’ parenting strategies and its protective capabilities on the long-term consequences of racism experiences on depression symptomatology among Black adolescents by 1) investigating the longitudinal stability of paternal strategies subgroups, 2) examining the concurrent and longitudinal associations with depression symptoms, and 3) exploring the mediational and protection effects paternal strategies in the face of racism experiences among Black adolescents. This goal aligns with NICHD’s priority of understanding the impact of adverse experiences during childhood and adolescence on development and identifying periods where intervention could have optimal effects. These aims will be addressed through secondary data analysis including self-identified Black adolescents (i.e., ages 10 -19): (1) Fathers And Mothers In the Lives of Youth (FAMILY) and (2) Representations of Fatherhood: Roles, Awareness, and Meaning (ReFRAME). The specific aims are to 1) Identify heterogeneous profiles of cultural parenting strategies among Black fathers, 2) Test for the longitudinal stability of heterogeneous profiles of cultural parenting strategies among Black Fathers, 3) To examine the direct and indirect effects of Black fathers’ parenting strategies on the effects of Black adolescents’ racism exposure and depression symptoms, and Exploratory Aim) To examine the attenuating effects of latent clusters of Black fathers’ parenting strategies on the effects of racism exposure on depression symptoms. Anticipated findings can inform child development research across adolescence, a critical developmental period, and one of five key goals outlined in the current strategic plan of the NICHD. Moreover, the research and training outlined in this NRSA F32 postdoctoral fellowship application will equip me with the skills and support needed to pursue a successful career as an independent research scientist by providing me with knowledge of relevant theoretical models of parenting strategies among Black fathers and familial experiences of Black families, competencies in longitudinal and person-centered approaches, and further develop my scientific writing, grant-writing, and presentation skills.

NIH Research Projects · FY 2024 · 2024-08

ABSTRACT Cocaine use disorder (CUD) is a persistent public health concern in the United States, exacerbated by the coronavirus-19 pandemic. Moreover, the only treatment for CUD is behavioral therapy, as there are currently no FDA-approved pharmaceutical therapeutics for CUD. This poses a concern, as individuals experiencing CUD are at substantial risk for relapse across abstinence. A deeper understanding of the cellular and molecular underpinnings of CUD is essential for developing therapeutics and relapse prevention for sustainable abstinence. Although extensive research to date has focused primarily on neuronal mechanisms of cocaine action in the brain, available evidence indicates that neuroglia may significantly contribute to mechanisms of dependence and relapse. The Reissner Lab focuses heavily on understanding the role of astrocytes and microglia in the maintenance of cocaine use disorder and relapse-like behaviors. Published research from the Reissner lab illustrates substantial morphological decreases in the nucleus accumbens core astrocytes following long-access (LgA, 6 h/day, 10 days) cocaine self-administration and a 45-day abstinence period. Preliminary data for this proposal show a significant effect of cocaine and abstinence on the colocalization of astrocyte membranes within microglia, suggesting that microglia may be mediating the effect of cocaine on astrocytes and raising the possibility that microglia phagocytosis is a long-lasting consequence of cocaine use. Thus, this proposal aims to investigate how structural and functional microglial responses in the nucleus accumbens contribute to cocaine dependence and relapse behaviors. In Aim 1, I will explore morphological responses of accumbens microglial, in addition to evidence of engulfment of astrocyte membranes, across abstinence in males and females. In Aim 2, I will test the hypothesis that pharmacological inhibition of microglial phagocytosis will protect against the effects of cocaine on astrocyte structure, microglial engulfment of astrocytes, and cocaine-seeking behavior. A neutrophil inhibitory factor (NIF) peptide which inhibits the protein interaction between complement protein C3 and the microglial C3 receptors will be directly microinjected into the nucleus accumbens, inhibiting phagocytosis. Additionally, this aim will explore the source of phagocytosis signaling by examining “eat me”/“don’t eat me” signals such as C3 colocalization with astrocytes and synapses. The experiments proposed in Aim 3 will characterize the genetic profiles of microglial cells following long-access cocaine self-administration. Through the use of magnetic bead sorting and RT- qPCR, I will be able to identify expression changes of microglia-specific genes. Overall, the findings of this study will provide a foundation for understanding how microglial morphological and functional responses contribute to cocaine dependence in both male and female rats. Further, insights into the role microglia play in cocaine effects and cocaine seeking may inform prospective avenues for therapeutic intervention.

NIH Research Projects · FY 2025 · 2024-08

Project Summary Osteoarthritis (OA) is a prevalent joint disease that affects over 250 million individuals globally. Despite extensive research, there are no known cures or therapies to prevent the disease's progression. Understanding the complex molecular mechanisms responsible for its development and progression is crucial. Genome-wide association studies (GWAS) have identified over 100 loci associated with OA disease risk; however, identifying the putative causal variants and the affected genes has been challenging due to the non-coding nature of most OA risk variants and the linkage disequilibrium between nearby variants. Alternative mRNA splicing can alter transcript and protein function, and its dysregulation has been implicated in a wide variety of human diseases. Previous studies have found differentially spliced transcripts in OA tissue, suggesting it may play a role in OA pathogenesis; however, the genetic causes and OA-related impacts of alternative splicing in human chondrocytes have not yet been explored. The overall objective is to identify genetic variants that alter OA risk by influencing RNA splicing in either resting or stimulated chondrocytes. The project will identify differential splicing events in chondrocytes responding to cartilage matrix damage (Aim 1), identify genetic variants that influence splicing patterns (i.e., splicing QTLs) in both resting and activated chondrocytes (Aim 2), and integrate these results with OA GWAS data to identify putative disease-relevant variants and genes, followed by experimental validation. (Aim 3). The findings from this research will pave the way for developing new treatments and drug targets for OA.

NIH Research Projects · FY 2025 · 2024-08

Project Summary/Abstract Metabolic reprogramming is a hallmark of cancer, prompting molecular mechanisms to promote tumor survival, growth, and resistance to treatment. Therapeutic targeting of tumor metabolism therefore is believed to be a promising avenue of cancer treatment. To further the development of metabolism-targeted cancer therapy, more information is needed concerning the heterogeneity of tumor metabolism and how tumor type, stage, and other tumor/patient characteristics determine the metabotype of tumors. Although publicly available resources exist for genomics and proteomics data, such as The Cancer Genome Atlas (TCGA) and the Human Proteome Atlas (HPA), no such database exists for the cancer metabolome. Resources like TCGA and HPA have become cornerstones of cancer research, making the lack of a cancer metabolome resource a glaring omission, particularly since metabolomics is considered to be the omics closest to phenotype. We propose to create the Human Cancer Metabolome Atlas (HCMA) by collecting metabolomics data on numerous patient- derived tumors and making an open-access resource to the cancer community to better understand the role of metabolism in cancers. In Aim 1,we will analyze a large-scale collection (>2000) patient-derived xenografts (PDXs) using mass spectrometry-based metabolomics. We will obtain these PDXs from NCI’s patient derived model repository (PDMR), Charles River Laboratory, and Crown Bioscience. Each PDX model has already been characterized by RNA-sequencing, whole exome sequencing, and comes with a wealth of patient information/metadata. In Aim 2, we will evaluate how metabotypes of PDXs vary based on gene expression patterns, presence of metastatic disease, and survival outcomes. Using a combination of univariate, multivariate, and pathway analyses, we will uncover key roles of cancer metabolism in these processes and which aspects of cancer metabolism contribute to heterogeneity across patients. Finally, in Aim 3 we will create a public resource for the HCMA using the National Metabolomics Data Repository (NMDR, also known as Metabolomics Workbench). Raw and processed metabolomics data will be uploaded to this resource along with associated patient metadata and existing genetic data to facilitate data mining and discovery efforts to be performed by outside investigators. Existing data analysis modules of the NMDR including univariate analysis, multivariate analysis, pathway analysis, and metabolite class analysis will be integrated with the HCMA to make the metabolomics data accessible and easily analyzable by other investigators. This resource will continually be built upon in future proposals to expand the HCMA and provide a powerful resource for new discoveries in cancer biology and therapeutics.

NIH Research Projects · FY 2026 · 2024-08

Project Summary Chromatin-modifying enzymes that are associated with enhancer function are frequently mutated in human craniofacial disorders. Kabuki syndrome (KS) is a craniofacial development disorder characterized by mutations in KMT2D, a histone H3 lysine 4 (H3K4) methyltransferase. Neural crest cells (NCCs) are the stem cells from which anterior facial bone and cartilage originate. Our preliminary studies show that mouse NCC deletion of KMT2D results in a lack of cranial base chondrocyte hypertrophic differentiation. As KS patients present with skeletal defects that may result from abnormal chondrocyte differentiation, understanding the mechanism of KMT2D function in this differentiation process is crucial to a better understanding of both craniofacial and skeletal development disorders. This proposal will assess KMT2D’s molecular mechanism in Aim 1 by interrogation of KMT2C/D-deficient NCCs in culture for changes in KMT2D genome binding, chromatin accessibility, differential gene expression, and localization of histone-methylation at enhancer regions utilizing genomic methodologies during chondrocyte differentiation. As previous publications have indicated methylase-independent roles for KMT2D, this proposal will utilize KMT2D rescue constructs to identify critical domains and non-enzymatic roles of KMT2D in cranial chondrocyte differentiation using genomics and genetic approaches. Aim 2 will explore the cellular mechanism of chondrocyte-specific loss of KMT2C/D on cranial base formation using histology, immunofluorescence, and other imaging approaches. Long bone growth plates will also be examined in chondrocyte-specific KMT2D mutant mice for morphological and molecular changes of chondrogenic differentiation markers to assay broader KMT2D-dependent chondrocyte mechanisms. Collectively, this proposal will ascertain the novel functional roles that KMT2C and KMT2D play in regulating chondrocyte differentiation and the results of this study will implicate epigenetic modifiers in the progression and therapeutics of skeletal disease.

NIH Research Projects · FY 2025 · 2024-08

ABSTRACT The dynamic regulation of arousal is fundamental for the flexibility of inward emotional state and outward behavior. Research has revealed that the noradrenergic locus coeruleus (LC) is an important hub of arousal encoding. The activity of the LC has an important influence on stress and anxiety, highlighting the involvement of arousal on these processes. Importantly, dysregulation of the LC has been implicated in a wide range of stress-related disorders that have characteristic changes in mood, anxiety, and arousal. Accordingly, further investigation is needed in unraveling the regulatory inputs onto LC that are critical for flexible regulation of arousal that may be impacted in stress-related disorders. Attention has recently shifted towards understanding how interoception of bodily cues might influence affective and behavioral states like anxiety. The nucleus of the tractus solitarius (NTS) is a major hub of interoception of these bodily cues. Notably, the awareness and manipulation of cardiac dynamics like heart rate drive changes in anxiety-like behavior in both humans and preclinical animal models. Accordingly, there is a compelling link between interoception and affective processes like anxiety that is conserved across species. However, little is known about how interoception influences arousal as an adaptive regulator of affective and behavioral states. Here, we propose investigation of noradrenergic inputs onto the LC from A2 neurons in the nucleus of the tractus solitarius (NTS→LCNA neurons) as an important link in interoception and arousal encoding. The anatomical connection between the NTS and the LC has been previously described, and the identity of A2 NTS neurons in this projection is supported by preliminary findings shown in this proposal. Strikingly, to our knowledge, the functional nature of this projection has never been investigated. We believe that this connection may serve as an important regulator of arousal based on interoceptive feedback that may be sensitive to stress as a source of LC dysregulation underlying changes in arousal and anxiety. This link may play an important role in shaping affective and behavioral states influenced by the LC that become dysregulated in stress-related disorders. To properly treat prominent and debilitating changes in arousal and anxiety in patients with stress-related disorders, it is important to understand dysfunction in interoception and arousal as functional domains driving these phenotypes. The experimental aims laid out in this proposal will investigate the NTS as an important regulator of LC arousal encoding following interoceptive feedback of heart rate. This work will unveil interaction between noradrenergic nuclei that has yet to be described, advancing our understanding of catecholamine signaling systems in the brain and their important neuromodulatory role in shaping affective and behavioral states. Finally, the multi-disciplinary approach and utilization of novel technologies in molecular biology, systems neuroscience, and optical engineering detailed in this proposal will provide a balanced and comprehensive training plan for the applicant (Noah Miller) to grow as an independent scientist.

NIH Research Projects · FY 2024 · 2024-08

ABSTRACT The landscape of clinical research is in a constant state of evolution as a greater understanding of unmet patient needs and current clinical trial limitations are exposed, necessitating innovative solutions to address the challenges encountered by traditional clinical trial paradigms. One of the most pressing issues is the difficulty in recruiting and retaining diverse patient populations, leading to significant underrepresentation of minority groups, rural communities, elderly patients, and individuals with limited access to healthcare resources. This lack in diversity not only skews our understanding of treatment efficacy and safety but also compromises the generalizability of data generated from traditional trials. In response to these challenges, hybrid decentralized clinical trials (DCTs) have emerged as a promising alternative. Hybrid DCTs allow for tasks aligned with clinical practice to be performed by local health care providers (HCPs) with their established patient relationships and limit clinical trial site visits to those with complex procedures that require extensive knowledge of the investigational product. By leveraging the capabilities of both local HCPs and academic medical centers, implementing digital health tools, and minimizing the need for frequent in-person visits, hybrid DCTs prioritize patient comfort and convenience while breaking down geographic and socioeconomic barriers. Here we outline a comprehensive plan to establish the Hybrid Operations to Promote Equity (HOPE) at the University of North Carolina- Chapel Hill Lineberger Comprehensive Cancer Center (LCCC). This proposal will address the health disparities within North Carolina’s diverse patient population where nearly 30% of individuals identify as belonging to a minority race across vast rural and urban regions. By engaging local healthcare providers in bi- directional educational efforts and creating use-friendly tools, we aim to facilitate patient referrals and education on clinical trial opportunities, particularly in underserved communities. Additionally, our approach includes the development of specialized infrastructure and oversight procedures to streamline internal hybrid DCT development and optimize clinical and regulatory procedures. Success of these endeavors will create a HOPE network of healthcare providers across the state of NC with access to clinical trial opportunities for their patients with most/all assessments occurring locally and will develop HOPE infrastructure to pilot hybrid DCT efforts to expand awareness of and participation in clinical trials addressing disparities in cancer prevention, treatment, and control across NC.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY/ABSTRACT This competing application requests R49 funding to continue the work of the University of North Carolina (UNC) Injury Prevention Research Center (IPRC) as a CDC-supported Injury Control Research Center (ICRC). The Center’s mission is to advance the field of Injury and Violence Prevention (IVP) through interdisciplinary research studies, and by training the next generation of IVP researchers and practitioners. The Center is organized around three Cores. The Administrative Core, led by Center Director Marshall and Associate Director Moracco, ensures timely communication and synergy among the three Cores, and between the Cores and the Center’s Research Projects. The Administrative Core also oversees operational support functions. The Outreach Core, led by IPRC’s Managing Director for Outreach, Partnerships and Capacity Building (Taraskiewicz), and mentored by Center Associate Director Moracco, utilizes well-established practice-based partnerships to conduct programs that build capacity in the IVP workforce. The Outreach Core also ensures that the Center’s scientific and practice-based products are rapidly disseminated to diverse communities, using tools and messaging that translate readily into evidence-based practice and policy. The Training and Education Core, led by Associate Professor Shanahan, implements education and training programs that support and diversify the future IVP workforce. These include student-led research groups, student fellowships and internships, formal courses and webinars, and mentoring support. The Center’s Core Faculty, led by Associate Professor Naumann, are an interdisciplinary group of emerging, mid-career, and established IVP scholars. All aspects of the Center’s work are infused with a strong commitment to equity and inclusion. The four Research Projects proposed in this application build upon and extend existing areas of strength among the Center’s Core Faculty. The four Projects are led by one mid-career investigator (Reyes) and three early-stage investigators (Austin, Ising, and Naumann). All four Projects include an equity focus area. Three of the four Projects address the three NCIPC Director’s Strategic Priorities (Project 1: Adverse Childhood Experiences; Project 2: Suicide; Project 4: Drug Overdose) and each Project addresses at least one NCIPC Research Priority. Projects 1, 3, and 4 are Translation Science. UNC IPRC has strong Institutional Support from UNC and support from state IVP leadership and government. The Center is a trusted wellspring of injury and violence knowledge and expertise, both in-state and nationally. We bring 35 years of ICRC experience and scholarship to bear on emerging issues and trends in injury and violence. In summary, the Center is dedicated to producing high- quality IVP science, and ensuring that science is translated into lives saved and improved.

NIH Research Projects · FY 2025 · 2024-08

Project Summary/Abstract The COVID-19 pandemic has underscored the need for robust mental health services in the United States (US). In contrast, the mental health workforce is shrinking. Lack of resources has led to patients “boarding” for days in the Emergency Department (ED) while they await inpatient hospital beds. In attempt to address these issues, federal and state policymakers have recently enacted policies to improve the Nation’s mental health crisis care infrastructure. One such law changed the phone number for the National Suicide Prevention Lifeline (NSPL) to “988.” This simple number created an unprecedented demand for psychiatric crisis professionals who can respond to callers deemed to be at imminent risk of harm to themselves or others. The Substance Abuse and Mental Health Services Administration (SAMHSA) has put forth Mobile Crisis Units (MCUs) as a solution to this problem. MCUs are a psychiatric service that meets individuals in crisis wherever they are in the community to de-escalate, triage, and refer them to additional services. They represent a way to ensure NSPL callers can receive care in the least restrictive setting, thus preventing unnecessary hospitalization. According to the SAMSHA model, MCUs are two person teams composed of a mental health professional and a certified peer provider (i.e. a Certified Recovery Support Specialist [CRSS]). Many states must now significantly expand their mental health crisis workforce to effectively meet the needs of their citizens and follow SAMHSA’s recommendations. Illinois (IL) is an example of a state that has enacted policies designed to fill this gap. Two programs, the CRSS Success Program (CRSS-SP) and Program 590, were designed to increase the workforce of CRSSs able to work on MCUs and increase the number of MCUs in the state, respectively. These relatively new programs have yet to be evaluated on how effectively they are able to grow the state’s MCU workforce. Systems thinking is a framework that seeks to solve complex problems by understanding how parts of a system function to produce outcomes. Methods grounded in systems thinking, such as Group Model Building (GMB) and Simulation Modeling (SM), have a proven track record for effectively generating policies that solve healthcare workforce issues, but they have yet to be used in the context of the MCU workforce pipeline. The objectives of this study are therefore to 1) use GMB to create a map of Illinois’s MCU workforce pipeline system and evaluate if this method is effective in this context, 2) evaluate data from the CRSS-SP and Program 590 to determine which factors increase the likelihood that CRSSs and MHPs obtain and retain employment at MCUs, and 3) use SM to test policies that will help the state meet its MCU workforce needs. The recommendations generated by this study will be given to state government officials so they can be used to improve the lives of individuals in IL experiencing mental health crises.

NIH Research Projects · FY 2025 · 2024-08

Abstract Recurring and debilitating seizures affect ~90% of individuals with Angelman syndrome (AS), a neurodevelopmental disorder further characterized by intellectual disability, sleep disruption, and ataxia. These seizures are often refractory to commonly prescribed antiepileptic drugs, whose side effects can exacerbate other AS symptoms. As a result, AS-associated seizures are consistently ranked as one of the most challenging aspects of AS by caretakers and physicians. AS is caused by a loss of the maternally inherited UBE3A allele because the paternally inherited UBE3A allele is epigenetically silenced in neurons, resulting in a complete loss of UBE3A protein in all neurons. Previous preclinical therapeutic strategies and current clinical trials have shown some promise by re-expressing UBE3A in neurons, but these efforts face several delivery and toxicity challenges that may limit their clinical development. Therefore, it is necessary to identify other novel treatment strategies to mitigate seizures in AS. UBE3A is an E3 ubiquitin ligase that targets substrates for proteasomal degradation and consists of two main isoforms – short-UBE3A and long-UBE3A. Dysregulation of UBE3A isoform substrates underlies AS symptoms. Indeed, each isoform may have distinct cellular and phenotypic contributions to AS symptoms due to their unique N-termini, protein levels, and subcellular localizations. However, how each UBE3A isoform and their respective substrates contributes to AS epileptogenesis remains unclear. Such knowledge could suggest novel therapeutic avenues for treating refractory AS-associated epileptogenesis. Accordingly, in the current proposal I will use two seizure models to establish the contribution of each UBE3A isoform to AS seizure susceptibility (Aim 1), and I will use a proximity ligation assay to define isoform-specific UBE3A substrates in a cell type that drives seizure susceptibility in AS model mice (Aim 2). My work will thus identify the contribution of each UBE3A isoform and their respective substrates to epilepsy in AS, enabling future pharmacological targeting that may overcome the limitations of current therapeutic efforts.

NIH Research Projects · FY 2024 · 2024-08

Abstract The transition to young adulthood involves navigating educational investments, job opportunities, entry into marital unions, and decisions about whether and when to have children. Behaviors and outcomes in these spheres are almost certainly shaped by levels of cognition, but we know relatively little about these links, particularly in low resource settings. This project will provide novel insights into how domain-specific cognitive skills that have a foundation in neuroscience are related to education, labor market success, entry into marriage, and fertility for young adults in Indonesia. Data are drawn from the Study of the Tsunami Aftermath and Recovery (STAR), a 15-year population-representative panel study of households and individuals in Aceh and North Sumatra on the island of Sumatra in Indonesia, who were at risk of exposure to the 2004 Indian Ocean earthquake and tsunami. STAR is representative of the pre-disaster population. In addition, we will harness data from a specially-designed subcomponent of STAR, the Extended Assessment of Biomarkers and Cognition (EABC), which involves two rounds of longitudinal data of a 25% randomly-selected subsample of STAR respondents that includes a tablet-based approach to precisely measuring seven different cognitive skills using game-like tasks adapted for the setting from widely-used assessments. We focus on respondents who were between 8 and 22 years in the first round of the EABC (13 years after the disaster), and so they were in adolescence and early adulthood in the second round (20 years after the disaster). We leverage our cognitive data and the panel design of the EABC and STAR to provide evidence on the association between performance in the cognitive tasks and key markers of the transition to adulthood. We will also examine the role of parental and family background characteristics in the association between cognition and early adult outcomes by adjusting for background characteristics and estimating models that focus on comparisons between siblings. Finally, we leverage the fact that the tsunami was completely unanticipated, exploiting exogenous local variation in the intensity of exposure to the tsunami to examine the role of a large unanticipated natural disaster in moderating the relationship between cognitive performance and early adult outcomes.

NIH Research Projects · FY 2024 · 2024-07

Consistent access to needed calories from healthy foods are fundamental to the health of pediatric populations, including those with serious illnesses, for example, cancer. One approach being studied to improve consistent access to food in the pediatric cancer context is to provide gift cards for an online grocery delivery platform. Prior research of compensatory cost coping with illness-related financial burden suggests that parents stretch food dollars by purchasing lower priced food with poor nutritional value. We also know that parents and siblings cope with illness-related financial burden by going without food to conserve household assets to meet the needs of the child who is ill, which can worsen parents and siblings’ nutritional intake and thus their health. To address inconsistent access to needed calories from healthy foods in households experiencing serious pediatric illness, we need holistic models of care that integrate food and nutrition with state of the science clinical care. Medically tailored meals (MTM; home-delivered meals tailored to medical needs of individuals with inconsistent access to needed calories from healthy foods + barriers to preparing healthy meals) that consider nutrition, treatment-related symptoms, and parental time demands offer a Food is Medicine approach to addressing inconsistent access to needed calories from healthy foods in pediatric populations with serious illnesses. In studies of adults with health conditions, MTM interventions were associated with better health outcomes and less health care spending. We extend the MTM concept to pediatric populations experiencing serious illness using pediatric cancer as proof of concept. Our purpose is to determine the feasibility of our methods and the MTM intervention for a future efficacy trial to improve access to needed calories from healthy food for households of children experiencing serious illnesses like cancer where nutritional status is fundamental to treatment tolerance and thus health outcomes. We will accomplish our aims by collaborating with a small business that makes tasty, healthy frozen meals. Our primary research question is: is an intervention that provides healthy, frozen meals tailored to tastes of children undergoing chemotherapy feasible and acceptable to the children and their primary parental caregiver? During year 1, we will conduct taste tastings with children undergoing chemotherapy to inform adaptation of meal flavorings to treatment-related taste alterations (Aim 1). In year 2, we will collect quantitative and qualitative data at multiple time points from children undergoing chemotherapy and their parents to inform rapid, data-driven refinements in our methods and intervention. Our results will inform the potential and protocol for a future full-scale trial and later cost effectiveness studies to advance our goal of advancing holistic models of care that integrate food and nutrition with state of the science clinical care. The project aligns well with the socio-ecological perspective of National Institutes of Nursing Research’s 2022-2026 strategic plan, and its models of care research lens.

NIH Research Projects · FY 2025 · 2024-07

PROJECT SUMMARY Medical and behavioral interventions are critical for preventing the spread of infectious diseases. But there are statistical challenges when estimating causal effects for such interventions. Most statistical methods assume the treatment of one individual does not affect outcomes of other individuals, i.e., that there is no interference or spillover effect. However, the effects of infectious disease interventions often include both direct effects on individuals receiving treatment and spillover effects in the community. An additional challenge for estimation of effects in infectious disease settings is external validity, as study samples often differ from the populations where interventions will be applied. Such differences can limit generalizability of study findings. Despite the importance in the field of infectious disease research, there has been no research at the intersection of interference and generalizability. The candidate's long-term career goal is to become an independent scientist and expert biostatistician working at the interface of causal inference, epidemiology, and infectious diseases. Therefore, the primary goal of this K01 award is to acquire training in infectious disease epidemiology, interference, and machine learning to develop and apply innovative statistical methods for infectious disease research. The candidate, Dr. Bonnie Shook-Sa, has assembled a strong team of mentors and collaborators who are leaders in each of these training areas. Training will support Dr. Shook-Sa's research aims which bring together the fields of interference and generalizability for the development of estimators of overall and spillover effects from infectious disease prevention studies that generalize to target populations that differ from study samples. Methods will first be developed in a standard interference setting, where individuals eligible for treatment are at risk of the outcome, e.g., for estimating the effect of child bed net use on incidence of malaria among children. Then, methods will be extended to the “bipartite interference” setting, where individuals eligible for treatment are distinct from those at risk of the outcome, e.g., for estimating the effect of universal HIV testing and treatment of persons with HIV on forward infection among persons without HIV. The proposed work will consider a variety of study designs, including cluster-randomized trials, probability-based sample designs, and convenience sample designs. Nonparametric estimators based on flexible machine learning methods will be proposed in each setting. The properties of proposed estimators will be derived, and estimators will be evaluated empirically through simulation studies. Proposed methods are motivated by and will be applied to data from the Uganda Malaria Indicator Survey, the HPTN 071: Population Effects of Antiretroviral Therapy to Reduce HIV Transmission (PopART) cluster-randomized trial, and the Hutterite Influenza Prevention Study.

NIH Research Projects · FY 2024 · 2024-07

Project Summary/Abstract Maternal mortality is a pressing global issue, especially impacting vulnerable populations. Intimate partner violence (IPV) is a widespread problem that significantly intersects with maternal health, leading to adverse outcomes and an increased risk of maternal mortality. Homicide, often committed by intimate partners, is the primary cause of death during pregnancy, with the highest risk among Black and adolescent populations. Despite its importance, addressing IPV in maternal mortality research remains an underdeveloped aspect of public health research. This R25 grant proposal seeks to bridge this gap by developing a comprehensive research education program to equip maternal health researchers with the essential skills to effectively measure and address IPV in their research. Our program will be developed following the ADDIE (Analyze, Design, Develop, Implement, and Evaluate) Model of Instructional Design and is organized into three distinct aims. In Aim 1, we will build upon our prior work to develop a webinar-based curriculum focused on four core areas essential for effective measurement of IPV in maternal health research: (1) understanding the scope and impact of IPV, (2) IPV measurement characteristics and tools, (3) analysis and interpretation of IPV data, and (4) cultural safety in maternal health and IPV research. We will also develop an online resource toolkit with webinar recordings, IPV measurement tools, sample protocols, and ethical guidelines. Aim 2 will involve implementation of the research education program in an online synchronous format, delivered through two webinars lasting 2 hours each. We will offer the education program four times during the 2-year grant period, with the first offering serving as a pilot. We aim to enroll 10-12 participants in the pilot and 20-25 in each subsequent offering. We will extend the reach of our curriculum through the dissemination of our online resource toolkit, ensuring wide access and sustainability beyond the funding period. Aim 3 will involve a comprehensive evaluation of feedback obtained from our Advisory Board, comprised of experts and stakeholders (formative evaluation); the implementation of proposed activities (process evaluation), and the overall effectiveness of the activities in achieving the aims of the training program (outcome evaluation). The outcome evaluation will be guided by Kirkpatrick’s Four Levels of Training Evaluation to assess participants’ satisfaction, learning, behavior, and results. By evaluating the program's impact and refining it accordingly, the team aims to strengthen the program's efficacy over time, ensuring that it remains relevant and effective in addressing IPV in maternal health research and supporting the needs of researchers in the field. Empowering maternal health researchers with these tools will enhance their capacity to generate translatable evidence- based solutions, thus strengthening the ability of health professionals to provide comprehensive care and, ultimately, contribute to the reduction of maternal mortality and IPV among vulnerable populations.