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A Pseudovirus Nanoparticle-Based Mpox Vaccine for Oral Immunization

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NIAID - National Institute of Allergy and Infectious Diseases

ABSTRACT The two recent large mpox outbreaks, along with the WHO’s declarations of two global mpox emergencies, underscore the emergence of this infectious disease as a significant public health threat. While current vaccinia virus (VACV)-based smallpox vaccines provide moderate protection via subcutaneous injections, a vaccine specifically targeting MPXV antigens with improved efficacy and safety remains lacking and is urgently needed. To address this need, we will leverage our norovirus (NoV) shell nanoparticle (SNP) platform technology to develop pseudovirus nanoparticles (PVNPs), each displaying one of the major MPXV protective antigens, as an oral vaccine. Each PVNP will consist of an icosahedral inner shell that mimics the interior layer of the NoV capsid, with multiple MPXV antigens displayed on the surface, resembling NoV protrusions. This PVNP vaccine will be administered orally using U-Omp19 as an adjuvant to enhance mucosal immunity and prevent MPXV infection and transmission. U-Omp19 is a protease inhibitor that protects vaccine antigens from degradation in the gastrointestinal tract while promoting PVNP specific mucosal immune responses. Following evaluation, PVNPs demonstrating highest protective efficacy will be selected as components of a bi- or trivalent mpox vaccine for oral immunization. We hypothesize that a PVNP-based oral mpox vaccine incorporating two to three protective MPXV antigens from both infectious virion forms will induce robust protection against mpox infection and disease compared to current VACV-based vaccines. Importantly, this vaccine is expected to provide enhanced safety and lower manufacturing costs relative to live VACV-based vaccines. As proof of concept, we have already generated two PVNPs displaying the VACV L1 and MPXV J1 antigens, respectively. We demonstrated that the PVNP with the L1 antigen provided 100% protection against mortality in mice challenged with a lethal dose of VACV. In this project, two lines of experiments will be conducted to validate our hypothesis. First, we will generate a panel of six PVNPs, each displaying a major protective MPXV antigen using a mammalian cell expression system. Each PVNP will be evaluated for protective efficacy against VACV following oral administration. Two to three PVNPs demonstrating the highest protective efficacy (>90%) will be selected and combined to formulate the final bi-/trivalent mpox vaccine. Second, the final vaccine will be evaluated for protective efficacy in a mouse model of VACV challenge, using survival rates, body weight changes, and viral loads as primary indicators of protective immunity. The commercial JynneosTM vaccine will be included as a comparator. A subset of immunized mice will be assessed one year post-vaccination to evaluate durability of protection. Additionally, the PVNP-based bi/trivalent mpox vaccine will be analyzed for mucosal, systemic, and cellular immune responses against individual MPXV antigens to elucidate mechanisms of protection. Given our strong preliminary data and the excellent track record of our research team, we are well positioned to successfully achieve the goals outlined in this application.

Up to $243K

2028-07-31

health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

A Radical Pathway Toward C-F Bond Functionalization: Direct Fluorine-Atom Transfer

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NIGMS - National Institute of General Medical Sciences

Project Summary/Abstract The incorporation of carbon–fluorine (C–F) bonds into active pharmaceutical ingredients (APIs) can dramatically enhance their pharmacokinetic properties. The beneficial influence of C–F bonds on the success of small-molecule therapeutics has led to the incorporation of fluorine in approximately 20% of all pharmaceuticals. In line with this demand for C–F bonds, significant synthetic efforts focusing on fluorination strategies have led to the wide availability of organofluorine compounds as synthetic building blocks. However, C–F bonds often represent stagnant, persistent end products due to their exceptional strength and inertness. A general strategy for C–F bond functionalization would transform these linkages into useful synthetic linchpins for further product elaboration. For example, widely available trifluoromethyl groups (–CF3) could be utilized to construct valuable, difficult-to-access gem-difluoro motifs (–CF2R), which are of interest in medicinal chemistry as bioisosteres. Existing methods for C–F bond functionalization almost exclusively rely on two-electron, polar pathways of bond deconstruction that often require harsh conditions, which limits the functional group compatibility of these methods. Single-electron strategies toward C–F bond functionalization would be highly desirable, as radical cross-coupling is a powerful platform for the construction of complex molecular architectures. Thus, this proposal seeks to develop single-electron pathways toward C–F bond functionalization. The objective of this proposal will be met via the design of fluorophilic radical reagents based upon phosphorous, silicon, boron, and aluminum. Electrochemical redox will activate these radical reagents to promote fluorine-atom abstraction from C–F bonds. The resultant C-centered radicals will be harnessed for useful C–C and C–X bond formations. The proposed research is expected to constitute a significant advance in C–F functionalization methodology, as it will allow for 1) the introduction of organofluorine electrophiles into the pool of radical precursors, 2) the streamlined synthesis of medicinally relevant –CF2R motifs, and 3) the late-stage modification of fluorine-containing motifs in APIs. The Baran Lab at The Scripps Research Institute is the ideal environment for the execution of the proposed research. The Baran Group are experts in radical methodology and will provide broad training in organic chemistry, including methodology development, electrosynthesis, and retrosynthetic analysis. Furthermore, the training environment in the Baran Lab at Scripps will facilitate communication with end users of the developed synthetic techniques, including industrial chemists. This training will enable further identification of synthetic challenges that, if solved, would meaningfully improve human health by enhancing the efficiency of small- molecule therapeutic synthesis. These factors distinguish Scripps as the ideal institution to pursue the proposed ambitious research goals, as well as to develop the skills necessary for a future career in academic research.

Up to $76K

2029-08-02

health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

A Randomized Clinical Trial of a Peer Education Intervention to Promote Social Diffusion of Overdose Prevention and Drug Use Cessation in High Burden Communities

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NCIPC - National Center for Injury Prevention and Control

Abstract: The US opioid epidemic has significantly impacted public health, with high levels of opiate dependence and a surge in overdoses. The increasing prevalence of fentanyl and xylazine in the drug supply underscores the importance of novel approaches. Additionally, times of withdrawal have been found to increase overdose risk behaviors, highlighting a need to target this period. Particularly in the context of xylazine, as naloxone does not reverse the effect of xylazine-induced respiratory depression, enrollment and retention in medications for opioid use disorder (MOUD) is vital to reduce drug overdoses. In our prior work, we have shown that PWUO can be trained as peer educators (PEs) for overdose prevention, but we have not integrated withdrawal management or a social network approach to MOUD engagement. This five year proposal seeks to develop, implement, and rigorously evaluate a novel PE intervention designed to prevent overdoses and promote MOUD and drug use cessation among a population of PWUO disproportionally impacted by overdose (Funding Option B). The intervention has three novel components: (a) social network diffusion of overdose prevention and MOUD promotion, (b) strategies to address high-risk withdrawal periods, and (c) Certified Peer Recovery Specialist (CPRS)/ Contingency Management (CM) for MOUD engagement. Using an RCT study design, 300 index PWUO will be recruited along with 300 of their network members who use opioids. The indexes will be randomly assigned to the (1) standard of care (SOC) or (2) an experimental peer education condition (PEC). The proposed design allows for the examination of the effectiveness of the intervention on indexes and diffusion of behavior change to network members. The RE-AIM framework will guide the collection of qualitative interview data to identify barriers and facilitators to intervention implementation. Assessments will occur every 3 months for one year. 1. Development and Pilot Testing: Design and pilot test intervention components that diffuse overdose prevention behaviors and MOUD within social networks, promote overdose prevention during withdrawal, and enhance MOUD engagement through CPRS/CM. 2. Implementation of RCT: Evaluate the intervention in a 1:1 RCT, testing an intervention that includes (a) social network diffusion of overdose prevention and MOUD promotion, (b) strategies to address high-risk withdrawal periods, and (c) CPRS/CM for MOUD engagement (N=600; 300 index participants, 300 network members). 3. Evaluation of Outcomes: Assess changes in nonfatal overdose, drug use cessation, MOUD engagement, and overdose prevention behaviors among index participants, as well as the diffusion of these behaviors to their social network members.

Up to $700K

2030-09-29

health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

A Randomized Control Trial of a Scalable Parenting Program to support Candidate Brain Pathways, Autonomic Regulation, and Socio-Emotional Development in Preterm Infants

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NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development

Project Summary/Abstract In the US, more than one out of every ten babies are born prematurely (before < 37 weeks of gestation) each year, accounting for 10-11% of live births.1 Globally, an estimated 15 million babies are born preterm each year, which is likely underestimated, given difficulties with tracking in low- and middle-income countries.2 Medical breakthroughs before the turn of the century dramatically increased survival of babies born at earliest stages.3 The field now faces increased prevalence rates of mental health disorders among adult survivors of preterm birth,6,7 which comes at great cost to individuals, families, and society. Annually, the US spends over $26 billion dollars in direct and indirect costs related to preterm birth.8,9 This reality underscores the need for investment in services that can better promote long-term mental health of this growing population. Early parenting interventions are among the most promising and cost-effective solutions to support long term mental health and well-being. Few programs deliver services starting in early infancy shortly after hospital discharge– or use scalable approaches that can engage multiple parents. Efforts that better engage fathers are especially needed. Fathers are severely underserved for their own needs and are underrecognized as critical supporters for mother and infant well-being. Developmental studies indicate that brain dysmaturation in frontal-limbic pathways is a secondary consequence of preterm birth and may contribute to long term sequalae. Programs that show positive effects on both behavioral and neurodevelopmental levels may be essential for supporting lasting change in infants, which motivates hypotheses in our study. Our objective is to test the effectiveness of a web-based, scalable parenting program, Play and Learning Strategies (ePALS), for parents and prematurely born infants, to improve parental responsiveness, promote early childhood mental health, and examine mechanisms of effectiveness through changes in neurodevelopmental pathways. Parents of infants born preterm (between 3-9 months of age, corrected for prematurity) will be randomly assigned to our target intervention, ePALS versus an active control program of the same duration and format. We will use an innovative, multimodal approach to examine behavioral pathways (socio-emotional and emotion regulation) and associated neurodevelopmental substrates, using EEG electroencephalography/event related potentials (EEG/ERPs), structural and functional magnetic resonance imaging (sMRI, rsfMRI), diffusion tensor imaging (DTI), and autonomic nervous system (ANS) recordings. Aim 1 will test whether participation in infant ePALS improves parental responsiveness in the first years of their infants’ life. Aim 2 will test the effects of ePALS on reducing risk for poor emotion regulation based on 2A) behavioral outcomes (parent report and standardized assessments), 2B) neurophysiological processes (EEG, ERP, ANS) and 2C) and frontal-limbic brain pathways (structural, functional, MRI, DTI). Aim 3 will examine mediators and moderators, to understand mechanism of change driving intervention related improvements in parenting and child outcomes.

Up to $598K

2031-05-31

health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

A Randomized Controlled Trial of a Web-Based Moral Elevation Intervention for Veterans with PTSD

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NIH

Poor treatment engagement and retention with evidence-based practices (EBPs) are significant problems for Veterans with posttraumatic stress disorder (PTSD). [Additionally, Veterans with PTSD also face significant issues with impaired social functioning and diminished quality of life; however, research suggests EBPs may not full address these other important treatment targets despite their ability to reduce PTSD symptoms.] These limitations showcase how difficult it is to successfully treat PTSD and highlight the need for novel, [stand-alone approaches as alternatives to current treatments that can further facilitate trauma recovery. Accessible and easily disseminated treatments are needed to target ongoing concerns for Veterans including PTSD symptoms, lower QOL, and poor social functioning.] One approach that is well- suited to target these issues is a positive psychology-based intervention that focuses on eliciting moral elevation and its benefits. Moral elevation is a positive, emotional state of feeling inspired or moved by witnessing others’ virtuous actions, which leads to greater social engagement and self-improvement motives. Moral Elevation Online Intervention for Veterans Experiencing Distress (MOVED) was previously developed as a web-based, self-guided intervention (8 sessions; 4 weeks) and piloted with a sample of Veterans experiencing significant PTSD symptoms and moral injury-related distress. Results from the VA funded pilot trial suggested MOVED was highly feasible and acceptable by Veterans, it demonstrated high levels of treatment engagement, and Veterans reported positive treatment outcomes including large decreases in PTSD symptoms and medium increases in quality of life. Given the promising findings from the MOVED pilot trial, the goal of this proposed study is to proceed with the next phase of treatment development for MOVED by conducting a powered efficacy trial with a sample of Veterans [diagnosed with PTSD for at least one year.] Following recent adaptations to MOVED that were informed by Veteran feedback from the pilot trial and with input from key stakeholders (researchers, clinicians, and Veterans with PTSD), a refined version of MOVED will be examined with a randomized controlled trial (RCT). This RCT will test the efficacy of MOVED compared to a supportive care control treatment in decreasing PTSD symptom severity, increasing social functioning, and increasing quality of life. The targeted sample will include 250 Veterans who have a [PTSD diagnosis for at least one year.] Eligible participants will be randomized to the MOVED condition or a supportive care control condition. Both interventions will be self- guided, web-based, and will include 8 sessions lasting 4 weeks. The supportive care control treatment will be a present-centered, nondirective intervention that aims to control for the nonspecific therapeutic effects of supportive care, whereas MOVED will focus on eliciting experiences of moral elevation, guided reflection of those experiences, and facilitating the pursuit of weekly behavioral goals related to experiences of elevation. All participants in both conditions will complete clinician-administered interviews and self-report measures to assess outcomes at baseline, posttreatment, 3-month, and 6-month follow-up. Additionally, potential mechanisms of action on treatment outcomes will be assessed at each session including experiences of moral elevation and treatment adherence. Results from this study will indicate whether MOVED is a viable treatment that can reduce PTSD symptoms, boost quality of life, and enhance social functioning; [thus, expanding the number of treatment options available for PTSD care.]

2029-09-30

health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

A Randomized Controlled Trial of Brief Behavioral Activation for Older Adult Cancer Survivors

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NCI - National Cancer Institute

Project Summary/Abstract: By 2040, 73% of cancer survivors will be ≥65 years old, with up to 35% of them developing clinically significant depression. Depression is problematic for many reasons, including its potential to interfere with the ability to engage in preventive and follow-up healthcare. National Comprehensive Cancer Network guidelines strongly recommend the management of depression among cancer survivors. However, older adults are the least likely age group to utilize mental health services, and Hispanic older adults are even less likely, despite being at higher risk for depression. Older adult cancer survivors (OACs; ≥65, post-cancer treatment) also have unique challenges relative to their peers without cancer (e.g., fatigue, cognitive changes, mobility issues, pain, social distancing and isolation). These issues often create additional barriers to benefitting from existing evidence-based depression treatment, which is ineffective for many OACs. Brief Behavioral Activation (BBA) is an evidence-based psychotherapy for healthy adults that has a strong theoretical rationale for use with OACs and the potential to overcome the limitations of conventional psychotherapies in this age group. It is adaptable for a range of functional statuses, and thus may be especially helpful for OACs given their typically faster rate of functional decline. Moreover, in OACs, BBA has the potential to promote cancer survivorship self-efficacy and improve health behaviors. We developed a BBA manual for OACs (BBA-OACs) with cancer-specific psychoeducation and modified worksheets with a focus on cancer survivorship, self-efficacy, and American Cancer Society (ACS)-recommended preventive health behaviors (i.e., healthy weight, exercise, healthy eating, avoiding alcohol and tobacco). In a fully remote (i.e., recruitment, intervention, and assessment) pilot RCT of telehealth BBA-OACs (N=81) we demonstrated its excellent feasibility, acceptability, and initial superiority to an active control, Supportive Psychotherapy, for improving OACs’ depression, anxiety, and coping. While this demonstrates the promise of BBA-OACs for reducing depression in this medically vulnerable group, we need to ensure its efficacy in a fully powered trial with a diverse sample that will have the ability to identify mediators and moderators of change. For this NIH Stage II RCT of telehealth BBA-OACs (N=502) with 4-month follow-up, we will partner with Cancer Support Community to recruit a diverse nationwide sample of English- and Spanish-speaking OACs with three aims: 1) Determine the efficacy of BBA-OACs for improving depressive symptoms; 2) Determine the efficacy of BBA- OACs for improving anxiety, loneliness, coping, and cancer-related health behaviors; 3) Determine the extent to which behavioral activation, general self-efficacy, and cancer-survivorship self-efficacy mediate the relationship between BBA-OACs and depressive symptoms. By expanding viable, evidence-based telehealth treatment options for depression, these results will ultimately improve the quality of life and cancer survivorship trajectories of OACs.

Up to $732K

2031-05-31

health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

A Randomized Controlled Trial of Computer-Assisted Bilingual Vocabulary Intervention in Emergent Bilinguals with Developmental Language Disorder

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NIDCD - National Institute on Deafness and Other Communication Disorders

Project Summary/Abstract Over 45 million people in the U.S. speak Spanish at home, yet only ~5% of speech-language pathologists provide Spanish-language services. This critical shortage leaves many emergent bilingual children with developmental language disorder (DLD) without access to bilingual interventions, contributing to long-term disparities in communication outcomes. Bilingual intervention supports robust language growth in both Spanish and English with no loss of English gains, but is often unavailable due to the dearth of bilingual clinicians, leaving key aspects of these children's language development unaddressed. To address this gap, we propose a technology-driven solution: the Computer-Assisted Bilingual Vocabulary Intervention (CABVI), an approach that enables monolingual clinicians to deliver standardized, linguistically rich bilingual instruction using Spanish and English strategically to support learning and cross-linguistic transfer. CABVI uses interactive, responsive content to shift the clinician's role from sole language provider to facilitator, empowering SLPs to support dual-language development in emergent bilinguals with DLD. Our long-term goal is to reduce gaps in care for emergent bilinguals DLDs by leveraging such scalable, technology-based strategies to expand access to bilingual intervention. The immediate objective of this R01 is to rigorously evaluate CABVI's efficacy and ecological validity in a randomized controlled trial. Aim 1 will determine whether emergent bilinguals with DLD children receiving bilingual CABVI show greater vocabulary gains in Spanish and English than peers receiving monolingual interventions (either traditional English-only therapy or monolingual CABVI). Aim 2 will compare vocabulary growth in emergent bilinguals with DLD children versus their typically developing bilingual peers after CABVI to understand how developmental language disorder influences response to bilingual intervention. Aim 3 will assess the platform's real-world feasibility by examining monolingual SLPs' fidelity to the intervention protocol, as well as their satisfaction and confidence using CABVI. Preliminary findings underscore CABVI's promise: a pilot school implementation demonstrated that monolingual providers can feasibly deliver CABVI with high fidelity over several months, and children receiving bilingual CABVI achieved significant vocabulary gains in both Spanish and English while maintaining progress in English comparable to monolingual intervention outcomes. By validating this scalable, linguistically tailored intervention, the project will improve access to this population for appropriate therapy, enhance their bilingual communication outcomes, and inform future scalable clinical models that leverage technology to bridge clinician-language gaps - directly aligning with NIDCD priorities to develop evidence-based interventions and improve access to evidence-based care for all Americans.

Up to $530K

2031-04-30

health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

A Randomized Controlled Trial On Improving Prostate Cancer Screening Among Black Men in Oklahoma Using A Community-Based mHealth Approach (Prostate Cancer Genius App)

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NCI - National Cancer Institute

PROJECT ABSTRACT. Prostate cancer (PCa) is the most commonly diagnosed cancer among Black men in Oklahoma and the U.S., with mortality rates 2 to 4 times higher than other racial groups. Despite evidence that prostate-specific antigen (PSA) screening reduces mortality and healthcare costs, screening rates remain low, particularly in Oklahoma (27% screened in the past two years). Barriers such as limited provider engagement, knowledge gaps, and healthcare access challenges contribute to lower screening rates, underscoring the need for innovative, scalable interventions to improve early detection. To address this, we developed the Prostate Cancer Genius App (PCGA), a smartphone-based intervention that provides PCa education and navigation for a user-friendly, CLIA-certified at-home PSA test. In a pilot RCT of 94 Black men aged 55–69, PCGA users demonstrated significantly greater PCa knowledge (p<0.05) and higher app usability (p<0.05) compared to the Prevention Taskforce App (PTFA), a general screening tool developed by the U.S. Preventive Services Task Force. PCGA users also showed higher PSA test activation (51.2% vs. 43.9%) and completion (83.3% vs. 50%), suggesting improved engagement and clearer navigation. This fully powered RCT will evaluate PCGA’s efficacy compared to PTFA and usual care (UC) among 684 Black men aged 55–69 in Oklahoma who are not up to date with PSA screening. Participants will be randomized 1:1:1 into PCGA (n=228), PTFA (n=228), or UC (n=228) and engage with their assigned intervention for 30 days, with follow-up for 6 months. The study will evaluate PSA screening completion (primary outcome) and screening readiness (i.e., knowledge, intentions, motivation, self-efficacy), diagnostic follow-up, treatment initiation, and satisfaction with care. Additionally, we will assess social needs as a moderator of screening and follow-up outcomes. Aligned with NOT-CA-24-033, this study will provide valuable insights into scalable, home-based PSA screening interventions that integrate telehealth-based shared decision-making. Findings will inform strategies to improve screening rates and follow-up care using tailored digital health tools. This research will also explore the role of clinic-based vs. home-based screening pathways to determine the most effective model for increasing PSA screening uptake. By rigorously assessing intervention engagement, screening readiness, and follow-up outcomes, this study aims to provide critical evidence for a sustainable and accessible approach to PCa early detection.

Up to $593K

2031-04-30

health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

A Randomized Trial of Male Partner Treatment with Oral Metronidazole and Topical Clindamycin or Topical Clindamycin Alone for Prevention of Recurrent Bacterial Vaginosis

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NIAID - National Institute of Allergy and Infectious Diseases

Bacterial vaginosis (BV), a common disorder of the vaginal microbiota which can result in vaginal odor and discharge, affects nearly 30% of women in the United States (US) and is associated with increased risk of sexually transmitted infection acquisition and adverse obstetric outcomes. Available treatments have limited efficacy; more than half of patients experience recurrence within 12 weeks of antibiotics. Although it has long been speculated that BV recurrence may relate to sexual transmission of bacteria from asymptomatically colonized male partners, there are no current recommendations to treat male partners of women with BV, mainly because seven previous male partner treatment (MPT) trials using oral antibiotics had failed. However, recently, a new randomized open label trial of MPT with oral metronidazole plus topical clindamycin conducted in Australia and published in March 2025, (the “StepUp” trial), showed a significant decrease in BV recurrence in the female partner (63% recurrence in the control arm vs. 35% in the MPT arm) over 12 weeks. While these results are exciting, additional research is urgently needed before broad recommendations for MPT can be made for US populations. There is uncertainty regarding whether the intervention would be equally efficacious in the US given important differences, including circumcision status, between US and the Australian study populations. Moreover, since the male partner must take on risk of MPT without direct benefit to themselves, a non-systemic antibiotic option would be preferred. One key unanswered question is whether topical clindamycin alone could be an effective MPT approach-which is plausible (though not certain) because the most notable difference in treatment regimen between StepUp and the previous failed trials was the addition of this topical antibiotic. We therefore propose a US-based, three-arm, parallel-group, open-label (investigator-masked), Phase III randomized controlled trial to enroll women of reproductive age with symptomatic BV and their monogamous male partners. The women will be treated with standard BV antibiotics while their male partners will be randomized to no treatment, topical clindamycin alone, or oral metronidazole plus topical clindamycin. Participants will be followed over 12 weeks to 1. Compare efficacy of MPT with topical clindamycin versus no MPT in reducing BV recurrence in the BV patient and 2. Compare efficacy of MPT with oral metronidazole plus topical clindamycin versus no MPT in reducing BV recurrence in the BV patient over 12 weeks after treatment. We will additionally collect longitudinal samples from women and their male partners which can be leveraged in the future to elucidate biologic mechanisms underlying BV recurrence and guide additional treatment approaches. The proposed MPT trial, if successful, could change clinical practice for thousands of BV patients in the US. Moreover, it will provide needed evidence on which to base national guidelines around MPT, and ultimately improve BV treatments to benefit reproductive and obstetric health in the US.

Up to $1.6M

2031-07-31

health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

A Randomized Trial of REFRAME: an Emotion Regulation Intervention to Improve Psychological Outcomes in Surrogate Decision-Makers of the Critically Ill

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NIA - National Institute on Aging

Project Summary/Abstract Each year, more than three million adults aged 35 and older are admitted to intensive care units (ICUs) in the United States. Most require a surrogate decision-maker (SDM) to make timely, emotionally charged treatment decisions. Often unprepared for this responsibility, SDMs frequently experience significant psychological distress that can impair their ability to make informed, value-congruent decisions. Long-term psychological consequences, such as post-traumatic stress disorder (PTSD) and decision regret, often follow these acute effects. Despite decades of research, few evidence-based and scalable interventions effectively address the SDMs’ emotional needs during ICU stays. This project will evaluate the efficacy and mechanisms of REFRAME, a brief, self-directed, tablet-based intervention grounded in cognitive reappraisal theory. REFRAME is designed to help SDMs recognize, reinterpret, and regulate their emotional responses in real time as they navigate high-stakes decisions. The intervention includes interactive psychoeducation and emotional assessments, guided strategy selection, emotionally relevant ICU scenarios, and structured planning to apply reappraisal techniques to real-world decision-making. In a two-arm, parallel-group randomized controlled trial, 387 SDMs of critically ill patients will be enrolled and randomized to either the REFRAME intervention or an attention-matched informational support (IS) control condition. Participants will complete standardized outcome measures at baseline (T0), 24-48 hours post- intervention (T1), 24-48 hours post-T1 (T2), and 90 days post-baseline (T3). Aim 1 will evaluate the effects of REFRAME on depressive symptoms (primary outcome at T2) and PTSD symptoms and decision regret (secondary outcomes at T3). Aim 2 will examine differences between groups in state emotion regulation (cognitive reappraisal and expressive suppression) at T1. Aim 3 will test whether changes in state emotion regulation mediate the effect of the intervention condition on psychological outcomes. By targeting a core, modifiable mechanism—emotion regulation—this trial aims to enhance psychological resilience, decision-making quality, and overall family-centered outcomes. The study findings will guide the development of scalable, mechanism-focused interventions to alleviate mental health burdens and improve care experiences in critical care and other surrogate decision-making contexts.

Up to $659K

2031-05-31

health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

A randomized trial to evaluate the optimal timing of antiretroviral therapy initiation in persons with early disseminated cryptococcal infection

open

NIAID - National Institute of Allergy and Infectious Diseases

Abstract Cryptococcus remains the leading cause of HIV-related meningitis. Cryptococcal antigenemia (CrAg) is detectable weeks before onset of meningitis, offering a critical window for intervention. Conflicting guidelines on the timing of antiretroviral therapy (ART) initiation among asymptomatic CrAg+ persons result in potentially harmful delays for those with advanced HIV disease. Additionally, 10 weeks of preemptive fluconazole therapy for CrAg+ persons has demonstrated a 28% survival benefit in trials, yet current WHO guidelines—based on expert opinion alone—recommend an extended 6-month fluconazole treatment course. These inefficiencies drive unnecessary costs, excessive antifungal exposure, and missed opportunities for streamlined care. Objective: To inform international guidelines by rigorously evaluating: 1. The safest and most effective timing for ART initiation to maximize survival; 2. The optimal duration of fluconazole therapy for asymptomatic CrAg+ persons with low titers (<1:80). Methods: We propose a highly innovative sequential randomized clinical trial (RCT) in Uganda involving 505 CrAg+ persons with low plasma titers (<1:80): Aim 1: Determine whether immediate ART initiation yields non-inferior 10-week hospitalization-free survival compared to the current standard-of-care 2-week delay. Hypothesis: If immediate ART is safe and effective, this could eliminate unnecessary delays in lifesaving HIV care and streamline HIV care pathways globally. Aim 2: Determine whether a short 10-week course of fluconazole achieves non-inferior 24-week meningitis- free survival compared to the WHO-recommended 24-week regimen. Hypothesis: If 10 weeks of fluconazole preemptive therapy is non-inferior, this will reduce unnecessary antifungal exposure, drug toxicity, and costs. Innovation: This trial challenges the outdated one-size-fits-all approach by introducing treatment stratification based on CrAg titer levels, a biomarker for cryptococcal burden. Our results will directly address current gaps in treatment for CrAg+ persons, aligning guidelines with evidence-based care to improve survival, potentially reduce unnecessary antifungal exposure, and optimize resource use. Impact: This trial has the potential to redefine global HIV and cryptococcal care by: 1. Resolving uncertainty around ART timing to prevent harmful delays and reduce mortality, 2. Establishing the optimal duration of fluconazole therapy for people with low CrAg titers, 3. Informing and harmonizing WHO, U.S., and national treatment guidelines for cryptococcal prevention. We will generate evidence to maximize survival, streamline ART initiation, and optimize antifungal treatment for people with advanced HIV disease globally. This evidence-based approach will empower policymakers to optimize care for millions of people with advanced HIV disease and reduce AIDS-related deaths.

Up to $247K

2031-07-31

health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

A randomized trial to evaluate the optimal timing of antiretroviral therapy initiation in persons with early disseminated cryptococcal infection

open

NIAID - National Institute of Allergy and Infectious Diseases

Up to $446K

2031-07-31

health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

A randomized, double-blinded, controlled clinical trial to assess the impact of dietary flaxseed on heart health and allostatic load in young adults

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NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY Chronic stress and malnutrition are increasingly recognized as major, synergistic contributors to early cardiometabolic disease, particularly among young adults. College students represent a vulnerable population, facing high academic, social, and financial demands with limited access to preventive health care. Our recent data from over 100 students revealed striking rates of perceived stress, depression, anxiety, and emergency- range hypertension, alongside widespread nutrient deficiencies. Notably, key nutrients such as alpha-linolenic acid (ALA), magnesium, and fiber were inversely associated with stress scores. These nutrients are abundant in flaxseed, suggesting potential as a targeted nutrition intervention. Cardiovascular and psychological health are closely linked through the physiological process of allostatic load, the cumulative burden of chronic stress on the body. Allostatic load leads to dysregulation across multiple systems, including the hypothalamic- pituitary-adrenal axis, autonomic function, and metabolic regulation. This multisystem dysfunction contributes to both vascular disease and mood disorders, emphasizing the pressing need to target allostatic load. To address this, we will evaluate if daily consumption of flaxseed can reduce allostatic load in young adults. In a randomized, double-blind, placebo-controlled clinical trial, participants will consume flaxseed or control muffins for six weeks. We will assess systemic, cellular, and mitochondrial markers of allostatic load, including salivary/plasma/blood cortisol, melatonin, brain-derived neurotrophic factor, reactive oxygen species, and mitochondrial activity. Cardiovascular reactivity and neurovascular responses to acute stress will be measured using blood pressure monitoring and functional near-infrared spectroscopy (fNIRS) targeting the prefrontal cortex. To complement these physiological measures, we will collect behavioral and psychological data using validated questionnaires assessing mood, fatigue, sleep quality, and perceived stress. Wearable biosensor watches will provide continuous objective data on sleep architecture, heart rate variability, and physical activity. These behavioral outcomes will serve as key covariates and exploratory endpoints in our analysis. Our prior work indicates that flaxseed reduces inflammation and lowers blood pressure within four weeks, demonstrating feasibility and physiological impact. This will be the first study to test whether a nutrient-dense whole food can reduce allostatic load in young adults, a high-risk but understudied group. The project is innovative in its integration of dietary, physiological, neuroimaging, and wearable technology approaches to capture multisystem outcomes. Finally, this study offers robust, hands-on research training for undergraduate students in biospecimen handling, wearable device data collection, behavioral assessments, clinical trial coordination, and neuroimaging analysis. By targeting early, lifestyle-based prevention, this research aligns with NHLBI’s mission to reduce cardiovascular disease burden, investigate sleep and stress, promote health across the lifespan, and leverage emerging technologies to enhance well-being.

Up to $585K

2029-04-30

health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

A randomized, sham controlled clinical trial to assess the effectiveness of a positive end expiratory device for accelerating and maintaining pulmonary rehabilitation gains

open

NIH

Chronic Obstructive Pulmonary Disease (COPD) is a debilitating condition with a higher prevalence among Veterans compared to the general population. Pulmonary rehabilitation (PR) represents the most effective non- pharmaceutical treatment option for control of daily symptoms and promoting functional independence. Successful completion of PR is roundly thought to improve quality of life. While the benefits of PR are well documented, there is a critical need to improve PR outcomes, accelerate response to PR, and maintain gains made in programs. In this randomized controlled trial, we will test the impact of a portable, user-friendly positive expiratory pressure device (PEP Buddy) as an additional tool used in PR vs. sham. This study investigates outcomes in both the active PR setting and post discharge. In preliminary studies, PEP Buddy has been shown to improve symptoms and quality-of-life scores, improve walk distance, and enhance physiological response to exercise after a brief time in persons with COPD and excessive dynamic airways collapse. Based on promising preliminary data, we propose investigation of outcomes over the course of PR and post-discharge to define the utility of PEP Buddy as an integral tool for COPD patients. Further, we find it necessary to fully define the effect of PEP Buddy on respiratory mechanics during exercise and have developed an aim using modified graded cycle ergometry that will thoroughly define the differential exercise physiology when the PEP Buddy is being used vs not by employing a cross-over study. As stated above, the main benefits of PR fall into a multitude of domains including psychological, functional, and physiological which we will investigate separately in this trial. The trial will run for four years, in the first three years we will recruit at least 120 new enrollees to PR with COPD, block randomized into equally-sized, double-blinded cohorts of PEP Buddy vs. sham. Our center actively enrolled ~140 COPD participants in pulmonary rehabilitation in Fiscal Year 2021 among ~220 referrals, with increases in 2022 and 2023, respectively. Outcomes will be collected at enrollment, every three weeks up to discharge, and at the six- and 12-month time periods after enrollment (e.g., post-discharge outcomes). In AIM 1a, we will compare total and rate of improvements in validated psychological and quality-of-life questionnaires between groups at each time point. We hypothesize that those in the PEP Buddy arm will show greater improvements earlier in their PR course and maintain the gains made in PR after discharge. AIM 1b assesses the results of actigraphy monitoring, walk distance, sit-to-stand testing, and other metrics of functional status in PEP Buddy vs. sham. Similar to quality-of-life and psychological scores, we expect improvements to be seen early in the PR course and be greater over the course of PR and after discharge. Our rationale for these hypotheses is that PEP Buddy will provide a readily accessible tool to overcome the symptoms of dynamic hyperinflation, assist in breathing control, and allow PR participants to recover more quickly and thoroughly from exercise-induced symptoms when compared to those learning the standard techniques in PR. In AIM 2, we will select 30 participants from Aim 1a/b and perform a crossover study utilizing graded cycle ergometry and dynamic tidal volume measurements to define the differences in the physiologic response to exercise when using the PEP Buddy device and when not. This will define the mechanism by which PEP Buddy is effective in preventing dynamic hyperinflation and increasing work output in those with COPD. At the conclusion of this study, we will have identified a user-friendly device that can be readily implemented into any PR program that promotes self-efficacy, directly enhances the response to PR, and leads to maintained PR gains. As the availability of PR expands, we are hopeful that fully elucidating the benefits of tools such as PEP Buddy will directly benefit Veterans by promoting self-efficacy and independence, increasing confidence in controlling daily symptoms, and maximizing the response to the effort these men and women put into PR training.

2029-12-31

health research

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A rapid antibiotic susceptibility testing (AST) platform using multiplex static gradients

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NIAID - National Institute of Allergy and Infectious Diseases

Summary: This project aims to prototype an innovative microfluidic reporting system that identifies effective antibiotics within 30 minutes for acute bacterial infections, such as sepsis. Bacteria cause widespread diseases, including urinary tract infections (UTI), acute lung infections, and bloodstream infections. Prescriptions to treat acute bacterial infections are often empiric, using broad-spectrum antibiotics at high doses, because the urgency of treatment does not allow for lab test results that take hours or days. However, this practice risks ineffective treatments, disruption of the healthy micro biome, and, more drastically, the development of antibiotic resistance, which can deprive future effective antibiotic treatments when needed. Timely microbial susceptibility to narrow-spectrum antibiotics at the clinic site is impractical because standard antibiotic susceptibility testing (AST) takes 2~3 days and requires well- equipped facilities and skilled laborers. Recently, researchers have developed alternative AST tests with great potential using microfluidic devices. These methods, however, mainly rely on bacterial growth, which takes hours, are incapable of testing more than a single bacterial species or a few antibiotic conditions, or require better accuracy and throughput. The field needs a rapid, inexpensive, and accurate AST platform to define individualized treatment plans. We propose to prototype a fast and precise AST platform to provide insights into effective treatments of acute bacterial infections. Our solution recognizes that motile bacteria, the primary source of common bacterial infections, swim away from effective antibiotic gradients and quickly lose their motility when exposed to survival doses of effective drugs. In Aim I, we will design and microfabricate a novel microfluidic device to generate multiplex static gradients of multiple antibiotics simultaneously. The multiplex gradient device is cheap to fabricate, easy to operate, and capable of simultaneously evaluating the effectiveness of multiple antibiotics based on bacterial chemotaxis and growth analyses when needed. In Aim II, we will map and quantify bacterial swimming behaviors under bright-field microscopy to report on antibiotic effectiveness in real time. In Aim III, we will optimize the rapid AST platform to screen effective antibiotics against known and unknown bacterial samples. By integrating robust microfluidic chemotaxis in multiplexed antibiotic gradients with advanced image processing, the rapid AST platform will provide timely insights for physicians to prescribe individually optimized treatments for acute bacterial infections, dramatically decreasing the waiting time from days for standard AST results to 30 minutes for motile cell-induced infections and 60 more minutes for non-motile cell-induced conditions. This prototype project will fulfill the primary objective of an AREA program by involving nine undergraduate students with various backgrounds in biomedical research and lay the foundation for follow-up grant submissions to screen clinical samples.

Up to $596K

2029-04-30

health research

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A rationally designed phage cocktail to treat MDR P. aeruginosa infections

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NIAID - National Institute of Allergy and Infectious Diseases

SUMMARY Infections caused by multidrug-resistant (MDR) Pseudomonas aeruginosa pose an urgent public health threat. MDR P. aeruginosa is a critical priority global pathogen for which new therapeutic approaches are desperately needed. At UPMC, over 100 patients each year develop serious infections with MDR P. aeruginosa; these infections are difficult to manage, frequently evolve resistance to last-line antibiotics, and are often deadly. There is an urgent need to develop new antimicrobial approaches for the treatment of MDR P. aeruginosa infections. Bacteriophage (phage) therapy is one such approach that has gained significant attention in recent years. We currently treat dozens of patients each year at both UPMC and across the country with phage therapy under compassionate use, which uses personalized phage cocktails to treat resistant bacterial infections in individual patients who have no other viable treatment options. Most of the patients we treat are suffering from MDR P. aeruginosa infections, and in the majority of patients treated thus far, phage therapy improved their clinical status. Despite this success, single patient anecdotes are not sufficient to rigorously test and develop phage therapy for widespread use. Here we propose to systematically assemble and evaluate a multi-phage cocktail targeting diverse MDR P. aeruginosa clinical isolates which can be paired with new β-lactam/β-lactamase inhibitor (BL/BLI) combinations currently used to treat MDR P. aeruginosa infections to improve antibacterial efficacy. Our central hypothesis is that a rationally selected cocktail of P. aeruginosa phages targeting contemporary MDR P. aeruginosa isolates will improve the activity of antibiotics commonly used to treat MDR P. aeruginosa infections. To test this hypothesis, we will leverage a large collection of contemporary MDR P. aeruginosa clinical isolates collected from 28 medical centers across the country as well as a panel of 10 lytic phages that have been previously approved for use in phage therapy to treat patients, and which were safe and well tolerated. In Aim 1, we will assemble a P. aeruginosa-targeting multi-phage cocktail that exhibits broad lytic activity against a national panel of 100 diverse MDR P. aeruginosa clinical isolates. In Aim 2, we will determine whether the combination of this P. aeruginosa-targeting phage cocktail and P. aeruginosa-targeting antibiotics results in superior and more sustained in vitro killing than either agent alone. Successful completion of these aims will establish a phage-antibiotic combination therapy that can advance in preclinical development and be used in an eventual clinical trial. The project will also directly inform the treatment of critically ill patients who cannot wait for a trial but could still benefit from receiving phage therapy under compassionate use.

Up to $437K

2028-01-31

health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

A Registry-Based Study of Patterns of Use of Targeted Therapies for Metastatic Cancers in Diverse Populations

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NCI - National Cancer Institute

Project Summary/Abstract One of the most important cancer care advances in recent history is the rapid dissemination of targeted and immunotherapies into the care of patients with metastatic cancer. The marked expansion of indications for use of these novel therapies has been fueled by growing enthusiasm among medical oncologists regarding their potential impact on survival for patients with very poor prognosis. Although the survival benefit of these therapies is modest for most patients, a small proportion experience long-term remission and potentially even cure of previously incurable cancer. Despite the exciting promise of these therapies, they are very expensive – sometimes exceeding $10,000 per month. Because of the high cost and high stakes of these therapies, it is critical to understand their patterns of use; yet very little is known about targeted therapy use across diverse populations. Moreover, the impact of clinician factors on variations in use is not known. In the absence of such knowledge it is difficult to develop effective interventions to support equitable delivery of these therapies. Guidelines for the use of targeted and immunotherapies in cancer care have continued to evolve rapidly since our parent study was funded. Most notably, there have been marked changes in the treatment paradigm of metastatic gastrointestinal (GI) cancers with rapid expansion in indications for use of immunotherapies and, to a lesser extent, targeted therapies. Comprised of multiple primary cancer types—colorectal, pancreatic, gastric and esophageal, hepatobiliary—GI malignancies are on the rise and are often diagnosed late in the disease course when they are already metastatic and incurable. Importantly, these patients were excluded from our parent study because at the time of our original submission targeted and immunotherapies were only rarely used for GI cancers outside of clinical trials. Now we propose to incorporate these patients and their treating oncology clinicians into our study and examine their treatment experiences. We have been working together with our SEER registry partners to ascertain receipt of targeted and immunotherapies directly from oncology clinicians for our parent study sample. However, this approach is both labor intensive and time consuming. Therefore, innovative methods to automate the collection of treatment data and allow scalability across cancer types and across SEER registries are urgently needed. We now propose a logical extension of our parent study to 1) expand the study cohort to include 1000 patients diagnosed with metastatic GI cancers and their treating oncology clinicians, and 2) incorporate innovative natural language processing (NLP) methodologies to automate the extraction of data about specific treatments and in-tumor molecular alterations from existing free text fields in the SEER registry data. Taken together with the contributions of our parent study, our findings will lay the groundwork for future population-based research of cancer care delivery and outcomes among diverse patients with metastatic cancers, inform interventions, and advance population science across SEER program regional registries.

Up to $335K

2028-04-30

health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

A Remote Behavioral Economics-Based Intervention for Cannabis Use Disorder: Bridging Gaps in Care

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NIDA - National Institute on Drug Abuse

Project Summary/Abstract In the current landscape of increasing access to adult-use cannabis via legalization and lower-than-ever cannabis-related risk perceptions, cannabis use and cannabis use disorder (CUD) are increasing in the United States. CUD, occurring in about 22% of people who use cannabis, is associated with serious consequences on health and wellbeing, including worsened mental health. Despite these outcomes, fewer than 10% of people living with CUD receive treatment or care for this chronic condition. To improve engagement and accessibility of CUD care, we urgently need to develop and study new care models with proactive outreach and provision of new, appealing interventions that meet the goals of the large population of patients with CUD who are not actively seeking traditional substance use disorder treatments. Virtually-delivered care (herein: synchronous videoconferencing between providers and patients across locations) can potentially improve accessibility and appeal of different intervention strategies while reducing stigma about engaging in treatment for substance use disorders. Our proposed strategy seeks to increase involvement in CUD care by delivering interventions in patient-preferred locations and reducing barriers to attending traditional treatments, including by supporting harm reduction and wellbeing outcomes. Behavioral economics-based interventions as applied to CUD bring novel approaches to substitute alternative, healthier behaviors for cannabis use. There is an untapped potential for virtually-delivered, behavioral economic approaches to engage the large majority of individuals who have CUD, who otherwise do not receive treatment, but could benefit from change. Building on our prior work engaging non-treatment-seeking adults in virtual substance use interventions, we piloted a novel behavioral economic intervention, infused with motivational interviewing principles (MI-BE). The MI-BE intervention engages adults with CUD into a virtual intervention focused on enhancing valued activities (with reinforcement for cannabis-free activity sampling) and reducing cannabis use. Using a Hybrid Type 1 efficacy-implementation design, we will evaluate the virtually-delivered behavioral economic-based intervention for CUD compared to an enhanced usual care (EUC) control condition. Patients with CUD will be recruited from a large health system and randomized to either MI-BE or an EUC and followed over 1 year. We will then evaluate the effect of MI-BE vs. EUC on cannabis and health outcomes (e.g., quality of life/functioning), and explore behavioral economic mechanisms of change (e.g., cannabis demand, cannabis-free reinforcement). With consideration for future translation, we will also collect and evaluate qualitative data from clinicians/administrators (N=10) and selected participants (N=20) on barriers and facilitators to future implementation in healthcare settings using a rapid analysis process. Impact: The findings from this study will have a significant public health impact and move the field forward as a novel, patient-centered, scalable approach to address the gap in care that is urgently needed in the context of rising CUD rates.

Up to $702K

2031-03-31

health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

A Remote Intervention to Prevent Overdose among People who Use Stimulants and/or Opioids

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NIDA - National Institute on Drug Abuse

This Type 1 hybrid effectiveness-implementation randomized controlled trial, Remote Fentanyl Test Strip Distribution and Education to Prevent Drug Overdose, aims to address the United States opioid crisis driven by fentanyl and other synthetic opioids. Fentanyl test strips (FTS) are a cheap, low burden tool used to detect the presence of fentanyl in drugs, and they are associated with high acceptability, yet critical FTS knowledge and implementation gaps persist. Moreover, extant studies of FTS programs are either limited to one city or region and enroll from brick-and-mortar sites, with no remote randomized controlled trials (RCTs) to date. Our study would be the first national, fully remote RCT to assess the impact of FTS on overdose outcomes among people using illicit stimulants and/or opioids. This project adapts our Remote Opioid Overdose Education and Naloxone Distribution intervention to FTS using a human-centered design approach, leveraging partnerships with national and regional community partners to co-create a fully remote intervention. We will use a 2x2 design to cross remote FTS distribution with remote FTS education, thereby isolating the individual and combined effects of the two components. The R61 phase focuses on adapting and piloting the interventions with 100 participants, assessing feasibility, acceptability, and appropriateness. The R33 phase implements a fully powered trial to compare overdose outcomes (fatal and non-fatal) among 2,952 participants randomized to the four study arms, which include: FTS distribution and education, FTS education only, FTS distribution only, and a control group. All groups will receive a resource list for naloxone and FTS. The secondary outcome is FTS knowledge, while exploratory outcomes include behavioral strategies to reduce risk of overdose (including FTS-specific behaviors) and utilization of substance use services engagement and treatment. The study also incorporates ecological momentary assessment to offer insights into daily contextual factors influencing FTS use, as well as a cost-effectiveness analysis to determine the most cost-effective approach with most overdoses averted. The study’s 2x2 design allows for a thorough examination of the interactions between FTS distribution and education, identifying the most effective and cost-efficient approach for reducing overdose rates. Overall, findings will inform the scalability of remote overdose prevention interventions. This work represents a sustainable, fully remote model that can be implemented nationwide, setting the stage for transformative advancements in overdose prevention.

Up to $447K

2028-03-31

health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

A Risk Score for Thromboembolism in Heart Failure Without Atrial Fibrillation

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NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY/ABSTRACT Heart failure (HF) affects 6.7 million Americans and creates a hypercoagulable state that substantially increases the risk of left ventricular thrombus and related systemic embolic complications, including ischemic stroke and extracranial embolism. These thromboembolic events cause major disability and death, yet no validated risk stratification tool exists to identify the 4-5 million HF patients without atrial fibrillation (AF) who would benefit most from anticoagulation. Randomized trials demonstrate that universal anticoagulation in HF without AF reduces stroke but causes net harm due to increased major bleeding, highlighting the critical need for precision risk stratification analogous to the CHA2DS2-VASc score used in AF. This R21 project will develop and validate the first comprehensive risk prediction tool for thromboembolism in HF patients without AF by integrating clinical variables with cardiovascular magnetic resonance (CMR) biomarkers of the thrombogenic substrate. The broad objective is to enable targeted anticoagulation strategies that prevent stroke in high-risk HF patients while avoiding unnecessary bleeding in lower-risk individuals. The project will use secondary analysis of existing multicenter CMR datasets to develop and internally validate a risk score for incident ischemic stroke and extracranial embolism in HF patients with reduced ejection fraction and no AF, followed by external validation in an independent patient cohort. The risk score will integrate clinical predictors with CMR biomarkers corresponding to Virchow's triad: systolic dysfunction, myocardial scar, and left ventricular hypertrabeculation. The project will further demonstrate that left ventricular thrombus serves as the mechanistic mediator linking risk factors to thromboembolic events through formal causal mediation analysis, providing biological validation for the risk score and establishing left ventricular thrombus prevention as a therapeutic target. This work directly addresses Strategic Objective 5 in the NHLBI Strategic Vision by developing a novel diagnostic strategy to prevent cardiovascular disease. If validated, the risk score will provide essential data to enable targeted anticoagulation trials in high-risk subgroups and to create a reproducible framework for integrating advanced imaging biomarkers into cardiovascular risk assessment, potentially preventing thousands of annual strokes among Americans with HF without AF.

Up to $231K

2028-05-31

health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

A role for neurexins in serotonin-IPN circuitry and social behavior

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NIMH - National Institute of Mental Health

Project Summary/Abstract Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder affecting 1 in 36 children. A dyad of impairments in social interaction and flexibility of thoughts manifests early in these individuals’ lives. The heterogeneous clinical presentation of ASD arises in part due to disturbances in serotonin (5-HT) signaling. While a standard therapeutic regimen for ASD does not currently exist, 5-HT-based medications provide variable benefit for disorder relief, highlighting the need for better elucidation of specific serotonergic circuits and mechanisms contributing to ASD behaviors. Indeed, 5-HTergic signaling is derived from a widespread network of axonal projections that influence neural activity throughout the brain. Neurexins (Nrxns) are presynaptic cell-adhesion molecules and are involved in synapse formation and regulation through trans-synaptic protein interactions with postsynaptic adhesion molecules such as neuroligins. Importantly, Nrxns are a well-accepted risk factor for ASD and schizophrenia (SCZ), and both Nrxn and 5-HT mutant mouse models display deficits in social cognitive behaviors reminiscent of ASD. However, the role of Nrxns in 5-HT synaptic transmission remains unknown. The overarching goal of this proposal is to elucidate molecular mechanisms underlying 5-HT circuit formation and identify a specific 5-HT circuit responsible for social behavior by focusing on Nrxn genes. This proposal is supported by strong preliminary data demonstrating, i) social behavior deficit in 5-HT neuron-specific Nrxn triple knockout (5-HT NrxnTKO) and 5-HT Nrxn1 KO mice, and ii) altered 5-HT projections to the interpeduncular nucleus (IPN) by whole-brain imaging of serotonin transporter (SERT)-positive fibers in 5- HT Nrxn TKO mice. As recent studies have implicated the IPN as a critical node for social behavior, our data highlight the potential significance of the 5-HT→IPN circuit in regulating social behavior under normal conditions but also in the context of ASD. Thus, in this proposal, we will address our central hypothesis that Nrxns are essential for proper serotonergic innervation in the IPN, and their expression in 5-HT neurons is required for social behavior. To test this hypothesis, we will use a multidisciplinary approach that includes whole-brain imaging (Aim 1), in vitro fast scan cyclic voltammetry (Aim 1), and in vivo photometry (Aim 2) to investigate the molecular and circuit-level mechanisms underlying social behavior. The proposed studies will shed light on the fundamental role of Nrxn-mediated 5-HT synaptic function for the appropriate development of 5-HT circuits that influence social novelty behavior. In the long term, exploring the consequences of abnormal 5-HT signaling due to impaired Nrxn regulation may reveal novel therapeutic targets to treat social deficits in ASD.

Up to $461K

2028-07-31

health research

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A role for Nup358/RanBP2 in microtubule-based transport of HIV capsids

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NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY HIV infection is critically dependent on the transport of the viral genome from the cell periphery to the nucleus. This process is facilitated by the HIV capsid, which serves as a vehicle for the genome and interacts with the host cell’s intracellular transport machinery. However, the mechanisms by which the virus connects to microtubule motors for cytoplasmic transport remain unclear. This research seeks to address these knowledge gaps by investigating the role of the nucleoporin Nup358 (also known as RanBP2), as a potential adaptor for HIV capsid transport. Nup358 localizes to the cytoplasmic face of the nuclear pore complex (NPC), and has been shown to bind the HIV capsid through its cyclophilin-homology domain. Disruption of Nup358 activity inhibits HIV infection, an outcome that has always been interpreted within the context of blocking the nuclear import of HIV. Interestingly, a number of studies have demonstrated that a fraction of Nup358 is also present in the cytoplasm, and is capable of binding both kinesin and dynein motor complexes. Pilot experiments have revealed that Nup358 engages with capsids beyond its cyclophilin-homology domain, recruits kinesin, and facilitates capsid transport with kinesin along microtubules in vitro. These data suggest an additional role for Nup358, serving as a cargo adaptor protein between the capsid and microtubule motors. This hypothesis challenges the current view of Nup358 as solely an NPC component and positions it as a key mediator of early-stage HIV infection. To explore this hypothesis, the project is organized into two specific aims. Aim 1 focuses on elucidating the architecture and transport properties of capsid-Nup358-motor complexes involved in HIV transport. Using interaction assays and in vitro reconstitution, the study will explore how Nup358 stabilizes capsid-motor complexes, activates motor activity, and coordinates motor functions for efficient microtubule-based transport. Aim 2 seeks to validate the physiological roles of capsid-Nup358-motor complexes by disrupting these complexes in cells and testing the effect on infection and subcellular localization of capsids. This research will uncover how the cytoplasmic form of nucleoporin Nup358 facilitates HIV's active transport, and how it links the microtubule network to nuclear targeting, providing insights to guide antiviral development targeting early stages of the HIV life cycle.

Up to $148K

2028-05-31

health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

A Scalable and Effective Digital Behavioral Intervention for Mitigating Hypoglycemia among People with Diabetes: An Optimization Trial

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NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

Project Summary Level 2 hypoglycemia (i.e., low blood glucose) can affect one’s daily life; generate fear and psychological distress; and lead to brain dysfunction, heart complications, and even death. People living with type 1 diabetes (T1D) are particularly susceptible to developing Level 2 hypoglycemia due to the obligatory use of exogenous insulin to manage diabetes. Advanced diabetes technologies (ADTs), such as continuous glucose monitoring and closed- loop insulin pumps, have become the standard of care to improve diabetes control and reduce hypoglycemia. Yet roughly one in three adults living with diabetes continue to develop Level 2 hypoglycemia despite using ADTs, and no strategies have demonstrated effectiveness in alleviating hypoglycemia beyond these standard-of-care technologies. Training to improve hypoglycemia symptom detection and psychoeducation for addressing unhelpful hypoglycemia beliefs have shown promise in reducing Level 2 hypoglycemia. However, these approaches’ effectiveness requires confirmation in ADT users. A scalable intervention with low patient burden is especially needed to expand access to these strategies. We have developed and feasibility-tested two automated real-time patient glucose data–guided digital intervention components delivered via SMS messages: digital hypoglycemia symptom detection training and digital hypoglycemia psychoeducation. In the proposed project, we will conduct a clinical trial to determine the individual and combined contributions of these two components to reducing Level 2 hypoglycemia in T1D adults who continue to develop Level 2 hypoglycemia despite using ADTs. We will then select the intervention that best balances effectiveness with recipient burden as the optimized program for future implementation. We will recruit 208 participants across the U.S. to achieve this objective. Under a 2×2 factorial design, participants will be randomly assigned to one of four experimental conditions: (1) digital hypoglycemia symptom detection training; (2) digital hypoglycemia psychoeducation; (3) both; or (4) usual care only; all participants will be followed up for 1 year. We will determine the individual and combined effects of the digital hypoglycemia symptom detection training and hypoglycemia psychoeducation on reducing Level 2 hypoglycemia (Aim 1). Then, we will identify and select the intervention that best balances effectiveness with recipient burden as the final program (Aim 2). Finally, we will investigate the intervention mechanisms of action and explore potential factors moderating the intervention effectiveness (Aim 3) based on our trial and qualitative interview data. We hypothesize that each digital component (i.e., hypoglycemia symptom detection training and hypoglycemia psychoeducation) will have an effect in reducing Level 2 hypoglycemia in adult ADT users. By the end of this study, we will (1) inform the strategies necessary to address Level 2 hypoglycemia beyond the current standard of care and (2) provide an effective, scalable solution to alleviate this devastating and even life-threatening complication.

Up to $780K

2030-01-31

health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

A Scalable, Open-Source Generative LLM Tool for Automated Classification of Diagnostic Errors

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NLM - National Library of Medicine

1 Medical errors are the third leading cause of death in the United States yet estimates of their total 2 burden and epidemiology remain largely unknown, with few comprehensive assessments 3 available. To address this gap, we propose leveraging the Retract-and-Reorder (RAR) method, 4 an existing health information technology (IT) tool that detects near-miss, self-caught order errors, 5 to better understand the underlying causes of medical errors. The RAR method has been reliably 6 used to detect wrong-patient and certain types of medication prescribing order errors. We 7 expanded its application to diagnostic imaging, identifying additional error types such as wrong- 8 site, wrong-contrast, wrong-side, and wrong-modality, using logic-based natural language 9 processing (NLP). However, over 42% of detected errors remained unclassified, requiring labor- 10 intensive manual review for further categorization. In this proposal, we aim to develop a scalable 11 pipeline that automatically classifies order errors and addresses unknown error types using 12 generative large language models (LLMs). To accomplish this, we will first (AIM 1) develop and 13 validate a generative LLM-based classification model for categorizing RAR events into predefined 14 error types, focusing on imaging order errors. We will compare its performance against the current 15 logic-based NLP approach, hypothesizing that the LLM will achieve equal or better accuracy by 16 correctly classifying known error and identifying previously missed error types, thereby improving 17 overall classification. Then, we will (AIM 2) demonstrate the scalability of the LLM pipeline by 18 applying it to medication order errors and developing a dissemination plan. We hypothesize that 19 LLMs can be readily adapted to diverse large sets of order types across various domains without 20 requiring fine-tuning. This study will establish the feasibility of developing an advanced, 21 automated, and scalable open-source tool for classifying and characterizing RAR events across 22 different medical orders. By identifying and understanding various order error types across 23 domains, this research will support the development of measures and targeted interventions to 24 improve patient safety. Furthermore, our privacy-preserving approach, achieved by deploying an 25 open-source LLM along with comprehensive documentation and structured dissemination, will 26 enable adoption across institutions and diverse healthcare settings. Beyond imaging and 27 medication orders, this framework could support cross-institutional implementation, facilitating its 28 expansion into other order domains.

Up to $82K

2028-04-30

health research

Free to search & build · $99 one-time to unlock the application pack · No subscription