University Of Washington

NIH Research Projects · FY 2025 · 2021-05

PROJECT SUMMARY/ABSTRACT Every 3 minutes in the United States, a person dies after suffering a severe acute vascular brain injury (SABI): an ischemic stroke, intracerebral hemorrhage or cardiac arrest. SABI accounts for more than one in 10 deaths globally and is a leading cause of serious long-term disability. Though advances in acute management of SABI have improved the chance of good outcome for some, this condition continues to have a tremendous impact for many due to high mortality, long-term disability, high symptom burden, complex care transitions, and changing goals of care over time. Yet, as most studies focus on measures of functional outcome or mortality, evidence- based information about more global multidimensional symptoms over time, and especially in the last weeks of life, is lacking. In addition, family members of patients with SABI are at risk for long-term psychological distress and reduced quality of life due to the burdens of surrogate decision-making, caregiving, and complicated grief. In contrast to many other serious illnesses, such as cancer or dementia, where death often follows a progressive decline in function, palliative care provision and serious illness conversations after SABI are uniquely challenging due to the suddenness of onset and substantial prognostic uncertainty that includes the potential for recovery. Palliative care specialists are rarely involved in the care of these patients. Preliminary studies have identified substantial missed opportunities to identify and address symptoms such as pain or psychological distress, or to prepare families for the high likelihood of death. In addition, hospital survivors are rarely discharged home and face fragmented care across nursing facilities, rehabilitation centers and hospitals. Currently, there is a critical gap in our understanding of the symptom burden among SABI patients and their families, as well as our understanding of how palliative care is integrated into SABI management. To better understand how to re- imagine care delivery models, we will conduct a multi-center prospective, longitudinal, mixed-methods cohort study of 540 patients with SABI and their families to examine key modifiable healthcare system determinants that may be targets for future intervention. The aims of this proposal are: 1) To define the trajectory and determinants of multidimensional symptom burden and quality of dying among patients with SABI to facilitate intervention development; 2) To identify key healthcare system factors and patient-related determinants associated with psychological distress among family members of patients with SABI; and 3) To better understand patient and family caregiver needs, identify gaps in care, and explore their perspectives on potential nursing and palliative care interventions to address unmet needs across the SABI continuum with in-depth interviews. Results of this work will allow us to target deficiencies in our health system through the design of specific, tailorable nursing and palliative care interventions. The depth and breadth of our findings will lead to contextually appropriate interventions for this population that will reduce suffering and improve quality of life and the quality of end-of-life care for all individuals affected by severe acute brain injury.

NIH Research Projects · FY 2025 · 2021-05

ABSTRACT Mental disorders are the leading cause of disability worldwide, yet treatment gaps exceed 90% in many low- and middle-income countries (LMICs). Significant progress is being made in access to mental healthcare through task-shifting to lower-level healthcare providers. However, while task-sharing may increase access to care, limited attention has been paid to assessing and optimizing quality of care across the mental health (MH) care cascade. An urgent need exists for evidence-based strategies to optimize the MH care cascade globally. Implementation strategies focused on one step in a care cascade can contribute to unintended system bottlenecks and quality of care issues. By contrast, the “Systems Analysis and Improvement Approach (SAIA)” is a multicomponent implementation strategy focused on optimizing quality across an entire care cascade. SAIA blends external/internal facilitation, enhanced local clinical consultation, and the creation of facility-level learning collaboratives with systems-engineering tools in a 5-step approach developed for task-shared providers. The 5 steps of SAIA include: (1) cascade analysis to visualize treatment cascade drop-offs and prioritize areas for system improvements; (2) process mapping to identify modifiable facility-level bottlenecks; (3) identification and implementation of modifications to improve system performance; (4) assessment of modification effects on the cascade; and (5) repeated analysis and improvement cycles. A previous trial established that the SAIA implementation strategy improved maternal ARV initiation and early infant diagnosis for the prevention of mother- to-child transmission HIV care cascade (R01HD075057; PI: Sherr). The SAIA implementation strategy has shown effectiveness for HIV cascade improvement, although no evidence exists on the effectiveness of SAIA applied to other complex treatment cascades – such as outpatient schizophrenia treatment. The present study aims to fill this knowledge gap by testing the following specific aims: Primary Aim 1: test the effectiveness of the SAIA-MH implementation strategy for schizophrenia cascade optimization using a cluster RCT and assess determinants of implementation success; Secondary Aim 1: test causal pathway models to analyze mechanisms of action for effects of the SAIA-MH implementation strategy; Aim 2: estimate the cost and cost-effectiveness of scaling-up SAIA-MH in Mozambique. In response to PAR-19-274, this project tests a multicomponent implementation strategy affecting “organizational structure, climate, culture, and processes”, with the goal to optimize the “implementation of diagnostic interventions, effective treatments, and clinical procedures into existing care”. This project also analyzes “mechanisms of action that explain the impact of a multi-component strategy to inform how these strategies can optimally be delivered across various settings”. If effective, the SAIA-MH implementation strategy has a large potential to be rapidly scaled-up to decrease gaps in task-shared MH treatments globally.

NIH Research Projects · FY 2025 · 2021-05

SUMMARY Inflammasomes are cytosolic innate immune complexes that form in response to a variety of pathogen- associated or stress-induced stimuli. Activated inflammasomes recruit Caspase-1, which initiates downstream inflammatory signaling. Genetic deletion of inflammasome components in mice has demonstrated the critical importance of inflammasomes during infection by viral, bacterial and eukaryotic pathogens. In addition, the inappropriate activation of inflammasomes has been linked to numerous auto-inflammatory and auto-immune diseases in humans. Host-pathogen coevolution is a major factor underlying the genetic and molecular determinants of cross- species transmission and infectious disease. The antagonistic nature of host-pathogen interactions can drive recurrent cycles of adaptation and counter-adaptation. These evolutionary ‘arms races’ drive rapid molecular innovation. Thus, the unique history of pathogen encounters of each lineage has driven species-specific adaptations. It should therefore not be surprising that laboratory mice are poor models of many human-specific or human-adapted pathogens. In this proposal I outline my vision to leverage the species-specific nature of host-pathogen interactions to develop improved models of human immunity and pathogenesis. Using a combination of evolution-guided and mechanism-focused approaches, I have made the following discoveries: 1) the Dengue virus (DENV) protease NS2B3 activates the human (but not mouse) NLRP1 inflammasome. DENV is the first known pathogen that activates human NLRP1. This finding supports a formerly unrecognized role for NLRP1 in host immunity and pathogenesis to DENV infection. 2) the enteric bacterial pathogen Shigella antagonizes the human (but not mouse) NAIP/NLRC4 inflammasome. Based on this finding, I have found that NLRC4-deficient mice are highly susceptible to enteric infection and. exhibit hallmarks of intestinal inflammation. Thus, I have established the first mouse model of Shigellosis. This proposal seeks to boldly expand on these observations using innovative approaches to generate new or significantly refine models of human infectious disease. I propose to 1) establish a new model of DENV immunity and pathogenesis, and 2) advance the development of the Shigellosis mouse model. Both DENV and Shigella are important human pathogens, which combined cause >200 million infections per year. Improved DENV infection models is a clear but unmet need, and until my Shigellosis mouse model, mice were thought to be refractory to Shigella enteric infection. Thus, the successful completion of the stated goals will significantly impact human infectious disease research.

NIH Research Projects · FY 2025 · 2021-05

PROJECT SUMMARY Elevated blood pressure (BP) is one of the most important, potentially modifiable risk factors for cardiovascular disease (CVD) events and death. Hemodialysis (HD) patients are at particularly high risk for these adverse outcomes. Yet the management of BP in this population remains uncertain due to conflicting associations depending on setting of BP measurement. We and others have reported a paradoxical, U-shaped association of pre-dialysis systolic BP (SBP) with CVD events and death, where the nadir of the U-shape is 140-160 mmHg. However, in these same patients, the association between out-of-dialysis unit SBP and risk of mortality and CVD is linear. We hypothesize that targeting out-of-dialysis unit (e.g. home) SBP rather than pre-dialysis SBP (the current practice) will lead to different treatment actions and better outcomes. This would be a paradigm shift since targeting home BP is not recommended by guidelines nor is practiced by most clinicians. To test feasibility of home BP measurement and treatment in HD patients, we completed a 4-month pilot clinical trial (NCT03459807) of 50 HD patients at 2 centers randomized to treatment of home SBP vs. pre- dialysis SBP target of <140 mmHg. This pilot trial confirmed that our strategy to measure and treat home SBP in HD patients was feasible (with excellent recruitment/retention and adherence to home BP measurement; and successful adoption of a standardized treatment algorithm). We also identified several patient-level facilitators of adherence to home BP measurement including: weekly home BP measurement schedule; text message reminders; and use of technology for automated BP transmission. From these data, we hypothesize that ongoing barriers to adoption of home BP into practice include: (1) lack of data on the effect of treatment of home BP on important intermediate outcomes; (2) lack of data from other centers in the U.S. to show generalizability (as most of the U.S. literature is from a single center); (3) lack of longitudinal data on the effect of targeting pre-dialysis BP on home BP (and vice versa, in part to show that home BP cannot be predicted from dialysis unit BP); (4) lack of knowledge of physician-level barriers to adopt treatment of home BP in HD patients; and (5) lack of long-term adherence data using modern technology to support clinical adoption. To address these gaps, we now propose a larger (N=200) two-center cross-over randomized clinical trial with longer follow-up (12 month) targeting a home SBP goal vs. a pre-dialysis SBP goal of <140 mmHg in HD patients. The data generated from this study will lay the foundation for several next steps, including a larger, multi-center trial to test treatment using different home BP targets to reduce rates of CVD and mortality in HD patients as well as an implementation science trial to integrate home BP measurement into clinical care.

NIH Research Projects · FY 2025 · 2021-05

Abstract Research: Amyloid-beta (Ab) and tau represent the key pathological protein markers of Alzheimer’s Disease (AD). Compared with Aβ, tau co-localizes more with sites of neurodegeneration and is more closely associated with cognitive impairment. However, despite its pivotal clinical importance, mechanistic understanding of the role of tauopathy in AD, including the associated pathophysiological effects leading to cognitive impairment, has been elusive. Particularly, little is known about its relationship with the cerebrovascular dysfunction which is a critical component in AD pathogenesis and neurodegeneration. This is especially true in prodromal AD patients. Leveraging a state-of-the-art multimodal MRI/PET imaging approach, our proposal aims to address this gap and disentangle the neuronal and vascular effects associated with tauopathy in prodromal AD. We propose to investigate the regional association between tau deposition (measured using tau-PET) and two complementary MRI markers of vascular system function: cerebral blood flow (CBF), and cerebrovascular reactivity (CVR). To disentangle the vascular from the neuronal effects, we will also measure the regional glucose metabolism using FDG-PET. We will then repeat the CBF and CVR measurements after 18-24 months to determine the relationship between tau deposition and the temporal changes in CBF and CVR. The significance of this work is that it will provide much richer and more specific information about underlying vascular pathology in prodromal AD than is currently available and may emphasize for further developments of vasoprotective treatments. Our future work will focus on identifying vascular mechanisms linking tauopathy to cognitive impairment and predicting the pathological and cognitive trajectories of individual AD patients. Candidate: My long-term goal is to become an independent investigator focused on neuroimaging research to create knowledge and tools for developing effective therapies tailored to the individual characteristics of each AD patient. I have a strong technical background in a wide range of MRI-based neuroimaging methods. Through this award, I will gain complementary conceptual (pathophysiology and clinical aspects of AD) and technical (PET imaging, statistical modeling) skills, which will enable me to formulate and test well-informed hypotheses for AD mechanisms. My short-term goals are to 1) acquire in-depth knowledge about the pathology and biomolecular basis of AD, 2) acquire clinical perspectives of AD, 3) develop proficiency in PET imaging and PET-based AD biomarkers, and 4) enhance my skills in statistical longitudinal modeling. Environment: The unparalleled clinical and technical resources available at the University of Washington Alzheimer’s Disease Research Center provide the ideal environment for me to attain these goals. My exceptional mentoring team is comprised of senior faculty who are experts in AD neuroimaging and have successfully mentored multiple trainees through NIH K awards.

NIH Research Projects · FY 2026 · 2021-05

Project Summary / Abstract The University of Washington will operate a Regional Medical Library (RML) for the Network of the National Library of Medicine (NNLM) Region 5 (AK, CA, HI, NV, OR, WA and U.S. Territories and Freely Associated States in the Pacific). Health professionals, librarians, and communities are facing complex public health challenges. To address these barriers, the RML will continue the work begun in 2021 (5UG4LM013725 Region 5: Reaching More People in More Ways) to advance data driven health and health literacy by offering NNLM services, funding and training through national and regional partnerships.

NIH Research Projects · FY 2026 · 2021-05

Abstract Tuberculosis (TB) is the leading cause of death in people living with HIV infection (PLHIV). Despite the discovery of Mycobacterium tuberculosis (Mtb) over 100 years ago and the availability of effective drugs for over 60 years, there remain formidable hurdles for controlling TB including the lack of a highly efficacious vaccine, long drug treatment regimens, prevention of infection, and killing dormant bacilli within macrophages. To address these problems, novel research and public health strategies need to be developed and coupled with enhanced training and local capacity building in high TB endemic countries. Kenya is one of 30 TB high burden countries which together constitute over 80% of global TB cases. The University of Nairobi (UoN), the Kenya Medical Research Institute (KEMRI) and the University of Washington (UW) propose a new TB-HIV Training Program (TBHTP) to address these needs. The TBHTP includes close partnerships in Kenya with the Ministry of Health National Tuberculosis Leprosy and Lung Disease Program (MoH NTLP), and the Kenya Pediatric Research Consortium (KEPRECON) – the research organization affiliated with the Kenya Pediatric Association (KPA). The primary goal of our program is to collaboratively develop training opportunities to address local needs in training and research capacity building. This partnership builds on a 35- year history of collaboration and training in HIV research between UW, KEMRI, and UoN. Although this partnership has been highly successful, TB has not been a high priority or focused goal of previous efforts. To build the capacity of KEMRI and the University of Nairobi (UoN) to conduct TB and TB-HIV co-infection research, we propose to implement a long-term training degree-earning track, a medium-term training non- degree track, and a short-term training track. During the 5-year period, we will train 5 UW MPH, 5 UoN Fellowship in Epidemiology, and 5 UoN PhD students working at KEMRI, UoN, or the MoH. We will also train 10 medium term non-degree scientists who have interest and potential in TB research will attend UW and take coursework in epidemiology and biostatistics or work in a laboratory for one to three months before returning to Kenya and engaging in a mentored research project. Finally, we will conduct short term workshops and provide on-line courses to build a critical mass of trained researchers who will create a supportive environment for research in TB. Together, these training opportunities will enhance local capacity and train the next generation of leaders who will discover novel research and public health strategies to combat the TB epidemic in Kenya.

NIH Research Projects · FY 2025 · 2021-05

ABSTRACT Significant morbidity and health care costs are associated with Chlamydia trachomatis (CT) and Mycoplasma genitalium (MG) infections. Each is associated with male and female reproductive tract syndromes, yet each presents unique challenges for control. CT is the most commonly reported nationally notifiable condition in the US and is a known cause of pelvic inflammatory disease (PID) and infertility. Despite longstanding control programs, CT rates are at an all-time high and the utility and cost-effectiveness of CT prevention efforts are debated. As most CT infections are asymptomatic, our current understanding of the epidemiology and the effectiveness of CT control programs has depended entirely on case detection through screening, which is only targeted to select populations (women <25 years and other high risk persons). Much less is known about CT in women ≥25 who are infrequently screened, and screening is not recommended for men who have sex with women (MSW). These major gaps in our understanding have limited our ability to effectively target CT prevention programs to men and women at highest risk of infection. MG is a more recently emerged pathogen, responsible for 20-30% of male urethritis. There is no national MG surveillance and, despite general agreement that MG causes male urethritis, there is no consensus about whether it causes sequelae in women. Limited population based estimates of urogenital MG prevalence exist, yet prevalent infections are often a poor predictor of lifetime experience of PID and infertility and permit only partial understanding of population-level epidemiology. Antimicrobial resistance (AMR) in MG is rapidly expanding - MG is one of three bacteria on the CDC's 2019 Watch List of AMR threats - but AMR prevalence estimates are derived from high-risk STD clinic populations and there are no nationally representative data. A better understanding of the population-level epidemiology of CT and MG is critical to improving control efforts for each. To achieve this, we will conduct a seroepidemiologic study in the National Health and Nutrition Examinations Survey (NHANES) 2017-2018 cycle, using a novel serologic assay for CT that differentiates IgG isotypes to distinguish recent from distant infection, and a more sensitive and specific seroassay for MG. We will also identify AMR in urine specimens from MG-positive persons in NHANES 2017-2018. Finally, we will develop an individual-based CT and MG transmission dynamics model. Using these outputs, we will (1) estimate the lifetime prevalence of CT in US men and characterize factors associated with recent versus past infection among men and women; (2) estimate the seroprevalence and correlates of MG infection in US men and women, determine the association between prior MG infection and self-reported PID and infertility, and estimate prevalence and correlates of macrolide and quinolone resistance in MG; (3) evaluate the impact of CT and MG screening scenarios on reproductive health and treatment outcomes in mathematical models. These data will provide critical information to either support or change current CT screening guidelines, and to inform nascent national testing and treatment recommendations for MG.

NIH Research Projects · FY 2025 · 2021-05

PROJECT SUMMARY/ ABSTRACT Autophagy is a self-degradation pathway that has tissue-specific functions in erythropoiesis. During erythroid differentiation, autophagy facilitates the degradation of macromolecules and the programmed clearance of mitochondria. The long-term objective of this proposal is to determine how autophagy contributes to normal and impaired erythropoiesis. Patients with Myelodysplastic syndromes (MDS) often have impaired erythropoiesis and mitochondrial dysfunction. A subset of MDS, MDS with ring sideroblasts (RS), contain the aberrant accumulation of iron-laden mitochondria in erythroblasts suggesting that autophagy may be dysregulated in hematopoietic disorders and impair erythroid differentiation. While essential autophagy genes are known to contribute to autophagy in erythropoiesis, little is known about the tissue-specific regulation of autophagy during human erythroid differentiation. We have identified the selective expression of the autophagy protease ATG4A in the erythroid lineage. We have evaluated the contribution of ATG4A in an ex vivo model of human erythroid differentiation. Early in differentiation, ATG4A promotes the expansion and colony formation of erythroid progenitors. Late in differentiation, ATG4A promotes terminal maturation, enucleation, and mitochondrial clearance. Since ATG4 proteases are regulated by reactive oxygen species, the function of ATG4A in erythropoiesis may be sensitive to oxidative stress. Based on our preliminary results, we hypothesize that ATG4A mediates autophagy during early and late erythropoiesis and is dysregulated by oxidative stress. In aim 1, we will identify the role of ATG4A-dependent autophagy in early erythropoiesis. In aim 2, we will determine the mechanism of ATG4A-dependent mitochondrial clearance. In aim 3, we will examine the regulation of mitochondrial clearance in human models of MDS-RS. The experiments outlined in this proposal will be conducted under the mentorship of Dr. Sergei Doulatov, an expert in the development and use of human iPSC models to study erythroid disorders, and co-mentorship of Dr. Janis Abkowitz, Chair of the Division of Hematology at the University of Washington and international expert in MDS and erythroid biology. This career development award will support my training to become an independent investigator studying the contribution of autophagy to normal and dysfunctional erythropoiesis.

NIH Research Projects · FY 2025 · 2021-05

ABSTRACT The field of sight restoration has made dramatic progress over the last decade. Two types of retinal implants have been commercially approved, and several other designs are in development worldwide. In addition, two groups are actively implanting and developing cortical electronic implants. The first optogenetic clinical trial has begun, with many others likely in the next two years. Within a decade, many blind individuals are likely to be offered a wide range of options for sight restoration that depend on widely different technologies. Interactions between implant electronics and the underlying neurophysiology of the retina or cortex mean that the vision provided by most of these technologies will differ substantially from normal sight. The question of this proposal is – What role can cortical plasticity play in helping patients make use of this artificial visual input? Over the past 15 years our research group has been generating computational models, developed using a combination of physiological and psychophysical data, which can predict the percepts that patients might experience for a variety of sight recovery technologies. We propose to use these models to simulate, within visually normal participants, four critical neurophysiological distortions inherent in sight restoration technologies: Aim 1. Abnormal neuronal population responses during retinal stimulation: Simultaneous stimulation of on and off cells. Aim 2. Spatial distortions: Stimulation of retinal ganglion cell axons. Aim 3. Abnormal cortical neuronal population responses: Distortions induced by the V1 neural architecture. Aim 4. Temporal blurring due to slow optogenetic kinetics. Our goal is to use normally sighted participants, viewing distorted visual input, as ‘virtual patients’ to learn which spatiotemporal distortions can be compensated for by plasticity, and which must be compensated for in device design. This will provide device manufacturers with a more nuanced understanding of the abilities and limits of visual perceptual adaptability. Finally, this work will provide novel insights regarding the fundamental mechanisms of cortical plasticity by asking whether, in adulthood, it is possible to reconfigure the fundamental building blocks of visual perception?

NIH Research Projects · FY 2025 · 2021-05

Abstract: Motivated behaviors such as feeding and reward-seeking are critical for an organism's survival. These processes require distributed neuronal networks and supporting cell types in multiple brain regions to be tightly regulated and tuned in order to orchestrate behavioral output. The lateral hypothalamic area (LHA) has long been identified as a critical neuroanatomical substrate for motivated behavior. Despite decades of research, the molecular identity of defined LHA cell types remains poorly understood. Additionally, while LHA neurons have been previously shown to encode appetitive and consummatory behaviors via distinct cellular ensembles, it remains unknown how distinct LHA output neurons contribute to these processes. Here we propose to continue to study the neural circuits of the LHA, and to identify how distinct cell types contribute to feeding and reinforcement. Using an interdisciplinary approach to leverage cutting edge tools such as single cell transcriptional profiling, two photon calcium imaging, and viral we aim to undercover key circuit elements, and novel circuit specific gene expression patterns that can be leveraged for future therapeutic interventions for addiction and other neuropsychiatric disorders.

NIH Research Projects · FY 2025 · 2021-05

Development on Skyline started in 2008 to fill a critical need for a software tool to enable targeted proteomics experiments. The development of Skyline grew into an entire ecosystem of tools and has since expanded beyond targeted proteomics. The Skyline software ecosystem is one of the most widely used software platforms in all of mass spectrometry. The current software and its thriving community create exciting new opportunities for quantitative mass spectrometry. As of June 2020, Skyline has been installed >110,000 times, has over 14,000 registered users on its website (http://skyline.ms) and is booted up >9,000 times per week (exceeding 17,500 bootups in a single vveek). The Skyline project has grown beyond the bounds of a single tool. There are now 16 Skyline external tools that rely on a formalized framework in Skyline, with more in development. Some of these tools have been installed >10,000 times. We have also created the Panorama Knowledgebase (http://panoramavveb.org) and Panorama Public, a platform where Skyline users can organize, share, and disseminate processed quantitative proteomics data. Furthermore, our lab is now the primary contributor to Chorus (http://chorusproject.org), a unique mass spectrometry file sharing resource. In this grant, we propose creating a resource that will enable the continued development and maintenance of these community tools and their dissemination within the community. These tools support >14,000 registered users in their basic science, pre-clinical, and translational research. Specifically, our proposal has four aims. 1) Expand our test infrastructure to improve the robustness, stress test the software, confirm compatibility across computer systems, and track performance over time. 2) Improve support for both proteomics and nonproteomics workflows. 3) Improve the collection, sharing, annotation and dissemination of mass spectrometry data and Skyline documents. 4) Provide continued support and training for the Skyline ecosystem.

NIH Research Projects · FY 2025 · 2021-04

PROJECT SUMMARY/ABSTRACT In 2017, 2.5 million children died in the first month of life. An estimated 2 million of these deaths could have been prevented by provision of essential newborn care at home and rapid identification of illness and care-seeking by the caregiver. Community health volunteers (CHVs) are a large cadre of lay health workers whose role is to promote access to preventative care and treatment in resource-limited settings. In Kenya, CHVs conduct monthly home visits to pregnant and postpartum women to provide education and screen for complications. Several counties in Kenya have adopted a digital community health toolkit (dCHT) that supports CHV workflow by tracking clients, managing tasks, and guiding home visits. Standardized CHV home visits expand mothers’ access to information and support, however the concentrated risk of neonatal illness in the first weeks of life and its potential to rapidly deteriorate mean that even monthly home visits leave mothers and neonates in need of on-demand support. Our team developed an interactive SMS text messaging intervention, Mobile WACh Neo (NEO), that connects mothers with healthcare workers remotely in the high-risk period immediately following birth to improve maternal and neonatal health. NEO sends automated, theory-based, actionable daily messages that systematically guide mothers to evaluate neonatal danger signs, and facilitates real-time dialogue with a healthcare worker to triage medical concerns and augment maternal social support. The overarching goal of this proposal is to integrate NEO interactive SMS into the existing digital infrastructure supporting CHV workflow in Western Kenya (dCHT) to enable remote communication by mothers with CHVs between home visits. We propose the following specific aims. Aim 1: Employ a human- centered design approach to develop a NEO interactive SMS module in the dCHT, named CHV-NEO. Aim 2: Evaluate CHV-NEO’s impact on neonatal mortality, clinic visit attendance, and caregiver provision of essential newborn care (cord care, thermal care and initiation of breastfeeding), in a pragmatic cluster-randomized trial. Aim 3: Determine the effect of CHV-NEO on CHV and supervisor workflow, and evaluate determinants of CHV- NEO’s acceptability, adoption and fidelity of use. We hypothesize that this innovative strategy will be successfully implemented within existing CHV infrastructure and will improve provision of at-home preventative care, increase timely referral of neonatal illness to facilities, and reduce neonatal mortality. CHV-NEO has potential to address a critical gap in efforts to improve neonatal health in resource-limited settings. Completion of these aims will generate a ready-to-scale intervention and rigorous data on both its effectiveness and the enablers of its successful implementation.

NIH Research Projects · FY 2025 · 2021-04

Abstract Cystic fibrosis (CF) is the most common life-limiting autosomal recessive disease in Caucasians. Impaired mucociliary clearance predisposes individuals with CF to chronic respiratory infections, resulting in progressive lung damage and premature death. We and others have shown that oral bacteria infect the lungs in individuals with CF at high concentrations. Caries and gingivitis are associated with an increased abundance of pathogenic and often proinflammatory intraoral bacteria that can be aspirated. Dental plaque flora can cause pneumonia, for example in mechanically-ventilated patients. Given the broader evidence of oral-respiratory links, it is surprising that the association between oral diseases and respiratory health in CF has never been evaluated, even though there is a plausible microbiological mechanism. The overall hypothesis of this proposal is that oral diseases, defined as caries and gingivitis, are potentially modifiable contributors to lung disease in CF. In this 5-year observational U01, we will enroll 210 adolescents and young adults with CF ages 12 to 30 years at 3 sites: Seattle Children’s Hospital, the University of North Carolina Chapel Hill, and the University of Alabama at Birmingham. The study will involve 3 study visits over 24 months. We will obtain quantitative and qualitative data on risk factors for oral diseases; perform a standardized assessment of caries and gingivitis; evaluate respiratory health outcomes; and collect sputum, saliva, and plaque for microbiome analyses. The Aims are to: (1) Describe the prevalence and incidence of oral diseases in adolescents and young adults with CF and identify corresponding risk factors with an emphasis on how to improve key oral health behaviors; (2) Evaluate cross-sectional and longitudinal associations between oral diseases and respiratory outcomes; and (3) Explore microbiome pathways that link oral and respiratory health. The proposed study will be the largest and first longitudinal CF oral health study to date, and the first to evaluate respiratory outcomes associated with oral diseases in CF. Our long-term objective is to develop behavioral randomized clinical trials for adolescents and young adults with CF to prevent oral diseases and protect respiratory health. We also seek to elucidate mechanisms that explain the systemic health consequences of oral diseases. More broadly, our approach provides a framework for improving the oral health of medically compromised populations through critical epidemiologic inquiry and evidence-based interventions.

NIH Research Projects · FY 2025 · 2021-04

ABSTRACT Recent pandemic spread of antimicrobial resistance is highly alarming. Fluoroquinolones (FQ) are broadly used by clinicians for treatment of urinary tract infections, but FQ resistance levels in Escherichia coli (the main uropathogen) are reaching 15-35%. FQ targets DNA gyrase (GyrAB) and topoisomerase IV (ParCE), complexes that ensure maintenance of nucleoid super-coiling and structure in states appropriate for replication and partitioning. The FQ resistance acquisition primarily emerges by structural alteration of the target proteins with multiple mutations in so-called quinolone-resistance determining regions (QRDR) - two mutations in GyrA (usually Ser83Leu and Asp87Asn) that are tightly coupled to the presence of at least one mutation in ParC (usually Ser80Ile). We hypothesize that some clinical E. coli strains are more prone than others to acquire and, also, to spread or transmit the FQ resistance. Surprisingly, the most common uropathogenic groups of E. coli appear to demonstrate certain restraints to becoming FQ resistant, probably due to some physiological barriers for the sequential structural alteration of GyrA and ParC. We discovered that, instead, that urinary FQ resistant isolates can emerge by acquisition of genes already carrying the full set of QRDR changes, demonstrating for the first time that high-level FQ resistance can be transmitted between clinical strains of unrelated clonal groups. This, for example, was the mechanism of recent emergence of new pandemic FQ resistant clonal group of E. coli – ST1193 that spread globally with last decade. Here we will study whether there is a clonal association between the ability of clinical E. coli strains to acquire and spread in nature the full set of QRDR mutations sequentially or, alternatively, by gene transfer and what could be potential physiological factors that either promote or restrain the FQ resistance emergence, transmission and spread among uropathogenic E. coli.

NIH Research Projects · FY 2025 · 2021-04

PROJECT ABSTRACT Social isolation is a major contributor to poorer health outcomes, quality of life, and even survival. Adults with communication disabilities are at a high risk for social isolation because communication impairments make it difficult for them to interact with others. Many communication disorders in adults are chronic, thus restoring typical communication abilities to enable people to resume usual participation in daily activities is not feasible. For that reason, people with communication disabilities depend on accommodations in the environment to help them remain active and engaged. Communication inherently involves interactions among people. Thus, the most critical environmental accommodation (or barrier) is the behavior of people – the communication partners - with whom the person interacts. The term ‘perceived social support’ is often used to refer to the help that people feel they have available to them in times of illness or disability. Our prior research has identified that perceived social support, as defined and measured in general healthcare domains, is not adequate for capturing social support for communication as shaped by physical, attitudinal, and behavioral barriers in the environment. Furthermore, family members who might usually provide such support may be hindered because of how they are impacted by the communication disability themselves (third-party disability) through increased care burden and loss of emotional connections. Qualitative research suggests that communication partners are highly influential in keeping people with communication disabilities active in work, home, and social activities. However, little is known about: 1) the extent and nature of perceived social support for communication and how this influences life participation for people with communication disabilities, 2) the extent to which families experience third-party disability and how this impacts social participation for people with communication disabilities, and 3) the extent to which these phenomena are similar across different communication disorders. Speech-language pathologists are called to provide patient-centered, biopsychosocial care addressing all contributors to communication disability. However, the significant gap in our understanding of the role of socio- environmental factors in life participation has left clinicians with sparse empirical foundations or clinical tools for addressing the socio-environmental needs of clients. The long-term goal of this research is to help people with communication disabilities and their families reduce social isolation and engage in fulfilling life participation by improving environmental accommodations / social support for patients and reciprocal support for families. The aims of this survey-methods study are to explore the hypothesis that perceived social support for communication is a unique construct that contributes to life participation separately from the general concept of perceived social support used in healthcare. This study will also explore how third-party disability contributes to reduced communicative participation. The populations included are those with speech or voice impairments due to Parkinson’s disease, laryngeal dystonia, laryngectomy, and oral-pharyngeal cancer.

NIH Research Projects · FY 2025 · 2021-04

PROJECT SUMMARY/ABSTRACT The ability of patients with cochlear-implants (CI) to discriminate speech sounds is the fundamental measure of efficacy that clinicians use to create personalized clinical interventions. Given the universal importance of early identification and treatment for children born with hearing loss, the most appropriate clinical intervention for children with CIs should be initiated at the earliest possible age. Despite the routine implantation of prelingually-deaf infants as young as 9-months-old, there are currently no established clinical measures of CI efficacy for children younger than approximately 4-years-old. The long-term goal of the proposed research is to develop new measures of device efficacy in cochlear-implanted infants that can be used to drive clinical decisions at a much earlier age than is currently possible. The ability to perceive patterns of temporal or spectral intensity modulation in a noise, or “acoustic modulation perception”, is known to predict speech understanding in adult CI users. In previous work, the PI adapted tests of acoustic modulation perception for testing infants and young children. The next step, proposed in this application, will be to investigate how acoustic modulation perception develops, and relates to speech perception, in implanted infants. This will involve examining the development of two independent factors with markedly different trajectories: the ability to resolve the spectral place or timing of modulation, and sensitivity to intensity modulation across frequency or time. The central hypothesis is that both normal hearing and implanted infants will show an asymmetry in development of these factors. Frequency and temporal resolution is expected to mature by 6-months postnatal hearing-age whereas sensitivity to intensity modulation is expected to remain immature through 7-10 years old. The basis for this hypothesis is that frequency and temporal resolution reflect early-developing peripheral auditory mechanisms whereas sensitivity to intensity modulation reflects later-developing central auditory mechanisms. There are 3 specific aims to this proposal. The first is to characterize the developmental trajectory for frequency and temporal resolution in implanted and normal hearing infants during the first 6 months of post- natal hearing experience. The second is to compare the developmental trajectory of spectral and temporal modulation sensitivity in children implanted during infancy with that of normal hearing children through 10- years-of-age. The third is to determine if frequency and temporal resolution independently predict speech perception outcomes in implanted children. This work is a necessary step toward the goal of developing age- appropriate, nonlinguistic measures of acoustic modulation perception that reflect CI efficacy in implanted infants. If the long-term goal of the proposed research is realized, the positive impact will be to enable earlier, more effective, clinical interventions for young patients who use CIs.

NIH Research Projects · FY 2025 · 2021-04

PROJECT SUMMARY This application is being submitted in response to the (NOSI) identified as NOT-CA-22-056. Background. The specific aims of the parent grant (RF1AG071024) are to estimate the risk of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) and AD-related dementias (ADRD) associated with wildfire particulate matter (PM2.5) (Aim 1), to identify individual- and area-level susceptibility factors that exacerbate the association between wildfire PM2.5 and MCI and AD/ADRD (Aim 2), and to estimate the risk of MCI and AD/ADRD associated with living near a wildfire disaster and the extent to which specific sub-groups have better or worse outcomes (Aim 3). As part of the work conducted in Aims 1 and 2 of the parent R01, we are modeling daily exposure to wildfire- specific PM2.5 levels using a two-stage machine learning (ML) approach. We have curated and processed a large quantity of data from a range of sources including weather variables, satellite data, and Environmental Protection Agency (EPA) monitor data, in order to model wildfire specific PM2.5 levels. While we have expended considerable effort on the data curation, we have not focused on making the data Artificial Intelligence (AI)/ML ready and publicly available, both for our own researchers and for the broader research community. The data sources required for effective wildfire analysis are disparate, not very accessible, and unfriendly to AI/ML applications. Although the data is rich and publicly available through US agencies, acquiring it and preparing it for analysis presents a significant investment for any researcher. Overall Goals and Aims. With this administrative proposal, we plan to establish a new collaboration with AI/ML and data experts at Harvard University with the goals of improving the vast and wide range of data sources, developing reproducible pipelines, annotating, documenting, and processing the data, ensuring computational scalability, encouraging community engagement, and disseminating these important AI/ML ready datasets for the prediction of wildfire PM2.5 to a wider research community. Our specific aims are to improve the data for AI/ML readiness (Aim 1), make the data publicly available to AI/ML applications (Aim 2), and demonstrate the transformed data in an AI/ML application to predict wildfire PM2.5 exposure for California (Aim 3). Impact. The final datasets will be AI/ML ready, reproducible, and disseminated to a wide user base. We will build a collaborative environment allowing both internal and external researchers to use, contribute, and improve the data inputs. This work will serve as a foundation for our group in the prediction of wildfire PM2.5 exposures for the whole US and for the community and will strengthen the aims of the parent R01.

NIH Research Projects · FY 2025 · 2021-04

Abstract The goal of this project is a develop a non-contact, non-invasive clinical tool to characterize, image and monitor skin grafting procedures using quantitative, volumetric, sub-mm resolved maps of Young's modulus based on Optical Coherence Elastography (OCE). Factors related to or directly defined by skin's elastic properties (such as contractions and shearing forces) are among the most common complications of full thickness skin graft (FTSG) procedures. In addition, the recipient site functions best when its elastic properties are matched by transplanted donor tissue. With tens of millions of aesthetic procedures performed every year in the USA alone, surgical cosmesis is clearly critical, especially when procedures are performed on the face, neck or breast. Currently there are no clinical tools, or even methods, that can quantitatively map skin's Young's modulus and anisotropy in vivo. We propose to map these parameters in skin using a non-contact, fully non-invasive method, with sub-mm spatial resolution and nearly in real time. We hypothesize that quantifying skin elasticity in vivo will enable significant innovation within all areas of plastic surgery, burn surgery, oncologic surgery, and dermatology that modify a patient's tissue quality and elastic properties through medical, radiologic, or surgical intervention. To achieve our objective, we propose a new non-contact OCE method. Our approach is based on: (i) acoustic micro-tapping (AµT) using ultrasound propagating in air to launch mechanical waves in soft media with the highest efficiency and best resolution among all non-contact wave-excitation methods, (ii) state-of-the-art real- time 4-D PhS-OCT imaging to track wave propagation, and (iii) reconstruction of volumetric maps of Young's modulus and anisotropy using imaged wavefields in skin analyzed with a transversally isotropic model. SA1 will focus on refining previously developed analytic and numerical models of mechanical wave propagation in skin considering its layered anisotropic structure, and developing algorithms to reconstruct skin's moduli. Then, SA2 will develop a robotized AµT-OCE imaging system for in vivo skin measurements in a clinical environment. We will perform routine measurements of skin elastic moduli in vivo on healthy volunteers to understand normal variability in skin elastic properties in a representative population of normal human subjects to help define the level of expected improvements possible in matching skin elastic properties in FTSG procedures. SA3 will focus on in vivo monitoring changes in grafted skin elastic properties during grafting procedures in the clinic, including pre-operative mapping of skin's elastic properties in donor and recipient sites and mapping longitudinal changes in fundamental structural and elastic parameters of FTSGs and surrounding tissue over the reconstruction process. If successful, this project can be the starting point for multiple continuation projects testing whether new methods and clinical protocols can be developed using information from OCE to help select the best donor tissue for grafting and guide post-surgery procedures.

NIH Research Projects · FY 2025 · 2021-04

Substance use and sexual health risk are increasingly prevalent, costly, and deadly -- fueling a synergistic epidemic in the United States (US) that disproportionately affects American Indian and Alaska Native (AIAN) communities. AIAN youth are at the heart of the AIAN health crisis. AIAN youth are disproportionately affected by many of these historical, structural, social, and behavioral factors that contribute to significant health disparities including high alcohol, tobacco, opiate and other drug (ATOD) use and sexual and reproductive health risks (SRH; ATOD-SHR). The overall mean age of tobacco use, alcohol use, and marijuana initiation for AIANs is much younger (11.5 years) than the general population, with AIAN youth having the highest prevalence of smoking and the earliest age of first use of ATOD. Alarmingly, more that 20% of Native high school students who used a prescription pain med without a prescription also used heroin in the past 30 days. Substance use is one of the most significant risk factors for unprotected sex and AIAN youth have the earliest age of first sexual intercourse. AIANs under 25 years of age have three times the rate of chlamydia, gonorrhea, and syphilis compared to White youth. Taken together, these ATOD-SHR disparities underscore the urgent need for interventions that simultaneously target ATOD and SHR among AI teens. While there is a paucity of research addressing the ATOD-SRH prevention needs of AIAN youth in general, there is even less information available on ATOD-SRH-related disparities for the nearly 1 out of 10 AIAN youth attending the 183 tribal day or boarding schools nationwide. To address this crisis and the dearth of evidence-based programs for this population, the proposed study, prepared in response to PAR-17-496, involves a 5-year RO1 to test the preliminary efficacy of the Chemawa Journey of Transformation–Native Youth Health Leadership Program (CHJ) which is an adapted and expanded version of the Discovering Our Story intervention, a 2010 SAMSHA- identified best practice AIAN strengths-based comprehensive substance use and health risk prevention and health leadership program for AIAN youth. The CJOT emphasizes a holistic, positive youth approach that incorporates storytelling with traditional archetypes and responsibilities as both a process and metaphor for guiding AIAN youth through behavioral change. The CJOT is a culturally-centered experiential 8-week (10 sessions) school-based positive youth health leadership development intervention to prevent ATOD use and SHR among AIAN youth (ages 13-16). The program involves a 2-month intervention (3 individual sessions + 10 sessions) + 5 booster sessions including digital storytelling training + 1 community event (digital and oral storytelling premiere) that targets behavior change relative storytelling and a youth-led storytelling event.

NIH Research Projects · FY 2025 · 2021-04

PROJECT SUMMARY BARD1 (BRCA1-Associated RING Domain protein-1) is an essential partner of the breast and ovarian cancer tumor-suppressor protein, BRCA1, and is included in a panel of genes used to evaluate patients with suspected hereditary cancer predisposition, especially breast and ovarian cancers. Despite this, little is known about the cellular role of BARD1. This project aims to address this serious gap in knowledge by defining at a molecular level how BARD1 contributes to DNA damage repair and to transcriptional repression. An ultimate goal is to enable predictions regarding potential loss-of-function phenotypes for mutations identified in patients. BRCA1 and its obligate partner BARD1 form a heterodimeric complex that is implicated in numerous cellular processes, most notably, transcriptional regulation and DNA repair via homologous recombination. The sole enzymatic activity directly associated with the BRCA1/BARD1 complex is as an E3 Ubiquitin ligase. The RING domains of BRCA1 and BARD1 specifically and uniquely target positions on the tail of nucleosomal histone H2A. The ability of BRCA1/BARD1 to place these Ub marks is essential to both its transcriptional repression of certain genes and its function in DNA damage repair by homologous recombination. While the RING of BRCA1 is required for all ligase activity, breast cancer patient mutations in the RING of BARD1 display loss-of-function specifically for ubiquitylation of H2A. A newly determined cryo-EM structure of the BRCA1/BARD1 RING domains sitting atop a nucleosome reveals that BARD1 dictates the orientation of the E3 ligase and, therefore, determines the site(s) of modification on H2A. In this project, we will build on this exciting new structural insight to address how regions outside BARD1’s RING contribute to its function as an essential partner of BRCA1.

NIH Research Projects · FY 2025 · 2021-04

Project Summary Understanding the role of TP53 mutation in genetic susceptibility to ovarian cancer Women with germline mutations in BRCA1 and BRCA2 (BRCA carriers) are at high risk of developing high-grade serous ovarian cancer (OC) but little is known about the biological mechanisms that underlie this susceptibility. BRCA-associated OC is believed to originate from TP53 mutant cells in the fallopian tube, where precursor lesions synchronous to OC and carrying the same TP53-driver mutation have been identified. However, early precursor lesions overexpressing TP53 but histologically normal (called p53 foci) have been reported in women without OC, questioning their significance to carcinogenesis. The goal of this grant is to elucidate the role of TP53 clonal expansions in BRCA-associated carcinogenesis by using ultra-sensitive sequencing to detect TP53 mutations at a resolution never possible before. Using ultra-sensitive TP53 sequencing, we discovered that most women, with and without OC, carry TP53 mutations in peritoneal fluid and Pap test DNA, but these mutations are more abundant in women with OC and in BRCA carriers. We also obtained pilot data that indicates that TP53 mutations are frequent in the fallopian tubes of women without cancer, increasing in abundance and pathogenicity with age. These results are consistent with recent findings of cancer driver mutations in normal tissues and the notion of cancer as an evolutionary process that takes place through life. Based on these findings, we hypothesize that TP53 clonal evolution takes place in the fallopian tubes of women in the general population but this process is enhanced in women with genetic susceptibility to ovarian cancer. As a result, women at high risk of OC will carry more pathogenic TP53 mutant clones, which we can detect with unprecedented sensitivity (>4,000 depth) using CRISPR-DS, a novel ultra-sensitive sequencing method developed by our group. In Aim 1, we will sequence TP53 in fallopian tubes collected at autopsy from 82 women at all decades of life from newborn to centenarian, pioneering the discovery of the natural history of TP53 mutations in this organ and providing a baseline control for Aim 2. In Aim 2, we will sequence TP53 in fallopian tubes of 235 women that underwent prophylactic removal of fallopian tubes and ovaries due to susceptibility to OC, including BRCA carriers and women with mutations in other OC risk genes or without identified germline mutations. We will perform a comprehensive characterization of mutation traits (type, location, functional impact, pathogenicity) and we will compare TP53 mutation frequency and traits with those of women in Aim 1, across groups in Aim 2 and with standard pathological findings of p53 foci. For the same women, in Aim 3, we will sequence peritoneal fluid, Pap test, and blood DNA collected at surgery to compare TP53 mutations in those samples with those identified in fallopian tube. These studies will provide a high-resolution picture of the landscape of TP53 mutation in the fallopian tube during normal aging and in women with OC susceptibility, improving our understanding of the pathogenesis of OC and opening new venues for OC prevention and early detection.

NIH Research Projects · FY 2025 · 2021-03

PROJECT SUMMARY/ABSTRACT Globally, prematurity is the leading cause of neonatal mortality. Prematurity is also on the rise in the U.S., with 9.93% of infants born preterm in 2017. This resulted in 382,851preterm births, more than 25,800 of whom were born before 28 weeks' gestation. This group, also known as extremely low gestational age newborns (ELGANs), is at a significant risk for poor outcomes; mortality in ELGANs is 10-20%, and up to 50% of survivors will have moderate or severe neurocognitive deficits in childhood. Preterm birth is commonly initiated by maternal infection or inflammation, and is often associated with additional perinatal insults including oxidative injury due to fluctuating hypoxia, hyperoxia, as well as ischemia and hypotension. These insults contribute to significant long- term neurodevelopmental impairment, which has remained essentially unchanged over the past decades. New approaches to treating the injured premature brain that improve outcomes and reduce long-term morbidity in ELGANs therefore remains a significant unmet clinical need. Azithromycin (AZ) is a macrolide antibiotic commonly prescribed to treat community-based infections. It is easy to administer, safe to use in pregnant women, and crosses both the placenta and blood brain barrier. AZ accumulates in phagocytes, providing a form of targeted drug delivery as phagocytes migrate to the site of infection or inflammation. AZ has anti-inflammatory effects, particularly modulating macrophages and microglia to a less inflammatory or injurious phenotype. This results in significant neuroprotection in experimental rodent models of stroke, spinal cord injury, and hypoxic- ischemic brain injury in neonatal rats. AZ is an attractive neuroprotectant as it is FDA approved, inexpensive, and safe. If it were to be found effective, it could be used in both high and low resource settings to improve outcomes of premature brain injury. The overarching objective of this proposal is to determine whether AZ provides long-term neuroprotection in a ferret model of inflammation-sensitized brain injury in ELGANs. Unlike the rodent, the ferret has a gyrified brain that is very similar to the human brain in terms of both development and structure. It is also amenable to long-term behavioral testing and complex imaging, making it ideal for investigating the short- and long-term effects of premature brain injury. The first aim will evaluate how AZ alters inflammation and oxidative stress, including microglial phenotype, in organotypic brain slices taken from the P12 ferret (26-28 weeks' gestation-equivalent). The second aim will examine the pharmacokinetics and short-term neuroprotective effects of single versus multiple doses of AZ in a P12 ferret model of inflammation- sensitized hypoxic-ischemic/hyperoxic (HIH) premature brain injury developed in our laboratory. The third aim will then examine the long-term effects of AZ treatment in the ferret HIH model, including behavioral outcomes, MRI, immunohistochemistry, and microglial phenotyping. Successful completion of the aims could support a clinical trial in this at-risk population for which no specific neuroprotective therapies are currently available.

NIH Research Projects · FY 2025 · 2021-03

Abstract: Bumped-Kinase Inhibitor Drug Development for Toxoplasmosis Toxoplasma gondii infection is the most common known parasitic infection and causes systemic infections, particularly severe in immunocompromised humans, that damage the central nervous system. No clear beneficial therapy exists for pregnant women, who are experiencing new infections and possible fetal infection. Bumped-kinase inhibitors (BKIs) target Calcium-Dependent Protein Kinase 1, necessary for cell entry and growth of T. gondii. We have developed and shown proof-of-concept for treating Toxoplasma gondii CNS infections and pregnancy infections with BKIs. However, our late leads still have some issues such as optimal CNS penetration and metabolites associated with safety issues. In Aim 1 of the proposed work, we will develop BKIs that retain high systemic concentrations and distribution to both the central nervous system (CNS) AND the fetus with acceptable safety attributes for use in pregnancy. This work will be aided by the extensive knowledge of our leads, computational predictions, and iterative experimentation addressing the few remaining issues. We will elucidate the pharmacodynamics and pharmacokinetics (PK/PD) associated with efficacious T. gondii therapy, an area that hasn’t been explored before in toxoplasmosis therapy. Once optimal BKIs are obtained and the optimal PK/PD known, in Aim 2 we will test BKI late leads for effects in rodent and ovine models of congenital toxoplasmosis. The pregnant mice T. gondii congenital model will be useful for prioritizing compounds to further study in the pregnant sheep T. gondii congenital model. The pregnant sheep T. gondii congenital model is a superior model for human T. gondii congenital therapy than the mouse model because of similarities in sheep and humans (vs. mice) in length of gestation, numbers of fetuses per pregnancy, similarities in outcomes of congenital infection, and immune recognition of T. gondii. Our deliverables will be late lead BKIs, with demonstrated safety and efficacy in two animal models of congenital toxoplasmosis, to advance to GLP toxicity testing required for IND approval. Our likelihood for success is greatly improved by our collective knowledge from working on these compounds for cryptosporidiosis and the well-established scientific team together with advisors and consultants from our partners at PATH, AbbVie, and Bayer, who have decades of experience in pharmaceutical development.

NIH Research Projects · FY 2026 · 2021-03

PROJECT SUMMARY/ABSTRACT Colorectal cancer (CRC) is the third leading cause of cancer death in the United States. Appropriate screening can reduce CRC mortality. Colonoscopy, a procedure to detect CRC early, is recommended for patients with a positive fecal immunochemical test (FIT) result to detect CRC and can even prevent CRC through the removal of pre-cancerous polyps. Rural and low-income populations face significant barriers to colonoscopy completion after positive FIT, including difficult access to the procedure (lack of local providers/long travel times), socioeconomic barriers to completing the procedure (difficulty getting time off work, arranging childcare and transportation, high out of pocket procedure costs), lack of knowledge about the procedure and its role in CRC screening and early detection, and fear of the procedure and of CRC. Patient navigation is an evidence-based approach to increasing colonoscopy completion. Patient navigation provides one-on-one support to patients preparing for and completing colonoscopy and addresses barriers through education, motivational interviewing, care coordination and connection to community resources. The effectiveness of patient navigation for increasing colonoscopy completion among low-income rural populations with positive FIT has not been demonstrated. The overall objective of this study is to test the effectiveness of a patient navigation program for increasing colonoscopy completion among rural, low-income populations who have had a positive FIT result. The project will be implemented in partnership with the Rural Health Council and the Washington Association for Community Health, and will engage four rural Federally Qualified Health Centers (FQHCs). The intervention will be evaluated in a type 1 hybrid implementation-effectiveness study that includes a 600-patient randomized controlled trial and comprehensive quantitative and qualitative data collection to better understand implementation and sustainability of the program. This project is critical in advancing our knowledge of the effectiveness of patient navigation for increasing colonoscopy in this patient population as well as for understanding factors that can support long term implementation and sustainability of effective interventions.