# data[].attributes.title
Living Microrobot for Active Therapeutic Delivery to Treat Severe Pulmonary Infections

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National Institute of Allergy and Infectious Diseases (NIAID)

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Multidrug-resistant (MDR) lower respiratory tract infections represent the single leading cause of infectious disease-associated mortality in the United States. Particularly worrisome trends are being observed in the case of ventilator-associated pneumonia (VAP), which affects vulnerable patient populations in intensive care units (ICUs). Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA) are the most common causative agents in global epidemiology of VAP, and they are becoming increasingly prevalent as antibiotics continue to be used indiscriminately and with waning effectiveness. It is imperative that more effective treatment modalities be advanced to adequately manage serious pulmonary infections in the clinical setting. Here we describe a highly innovative delivery and therapeutic concept, living microrobot therapeutics, for critically ill patients with severe P. aeruginosa and MRSA lung infections. The microrobot platform is consisting of Chlamydomonas reinhardtii microalgae modified with neutrophil membrane-coated and drug-loaded polymeric nanoparticles (denoted ‘algae-NP-robots’), and has unique multifold mechanisms of action. The microalgae help to improve tissue penetration and retention of the drug payload within the lungs, while the neutrophil membrane- coated nanoparticles help to shield the drug payload from biological environments, reduce immune clearance, and enable specific binding with target pathogens. Besides carrying drug payload, the neutrophil membrane- coated nanoparticles can further serve as ‘nanosponges’ that act to neutralize excessive pro-inflammatory cytokines, thus reducing the danger of cytokine storm. By combining the unique properties of these two systems, the algae-NP-robots have proven to be a capable platform for active drug delivery and excel at treating bacterial pulmonary infections. In this proposal, we describe our extensive prior published and preliminary results that strongly support the novel therapeutic concept of algae-NP-robots for the treatment of severe Gram-negative and Gram-positive pulmonary bacterial infections in ICU patients. In Aim 1, we will focus on further optimizing the algae-NP-robot formulation to maximize its therapeutic potential. In Aim 2, we seek to better understand the mechanisms by which drug-loaded algae-NP-robots can effectively clear bacterial infection using P. aeruginosa lung infection model, in which efficacy has already been demonstrated. In Aim 3, we will extend the algae-NP- robot platform for the treatment of Gram-positive pathogen (MRSA) lung infection in order to demonstrate the generalizability of the platform. Each of the Aims can be completed independently, although the information gleaned from one can be used to improve the overall approach, which can then benefit the others.

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What interventions to reduce hospital nurse burnout are most effective?

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National Institute of Nursing Research (NINR)

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What Interventions to Reduce Hospital Nurse Burnout Are Most Effective? Nurse burnout is a threat to healthcare safety, and to nurse and patient outcomes. Burnout among nurses has been a long-standing concern only accelerated by the COVID-19 pandemic. Burnout is a syndrome caused by chronic workplace stress and characterized by feelings of emotional exhaustion, cynicism towards one’s work, and decreased professional efficacy. Pre-pandemic, about 30% of nurses were burned out. Today, nearly half of 4.7 million nurses are experiencing burnout. This unsustainable high level of burnout has dire consequences for nurses and patients alike. Nurse burnout is associated with higher odds of patient mortality, failure to rescue, and prolonged length of stay, as well as nurse job dissatisfaction and turnover. We propose to integrate two approaches to addressing burnout: investigation of organizational characteristics as determinants of burnout, notably conducted by the proposed research team in recent decades, and health system administrators’ current implementation of interventions to reduce nurse burnout. Our preliminary studies reveal that organizational and individual interventions are being implemented nationwide and that nurses prefer organizational ones. It is unknown how preferred and implemented interventions relate to hospitals’ performance on nurse burnout, individual nurse burnout, and reducing burnout over time. Crucially, whether these interventions’ effectiveness depends on the work environment is unknown. Integration of these two approaches will yield a representation of reality across a large, geographically diverse hospital sample to inform whether certain intervention combinations are most effective and in what organizational contexts. The proposed aims address the Notice of Special Interest NOT-NR-23-012, “Addressing Organizational Factors to Prevent or Mitigate Nurse Burnout,” which invites “research studies to develop and evaluate novel organizational interventions to prevent and mitigate nurse burnout,” by identifying the currently preferred and implemented interventions, their work environment contexts, and their relation to nurse burnout, dissatisfaction, and intent to leave and hospital performance on nurse burnout. We propose to conduct a cross-sectional and longitudinal observational study utilizing 2024 and 2026 hospital nurse survey data from 31,942 nurses in 1,278 hospitals (in 2024) in 10 U.S. states to determine how preferred and implemented interventions relate to hospitals’ performance on nurse burnout, individual nurse burnout, and reducing burnout over time. The potential impact of the proposed study would be high because it would provide actionable results to optimize burnout intervention choices and contexts to mitigate pervasive nurse burnout.

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Organizational Changes to Reduce Nurse Burnout

# data[].attributes.funder_divisions[]
National Institute of Nursing Research (NINR)

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This study evaluates multi-level interventions—ranging from state-level policy action to healthcare organizational strategy and frontline care delivery innovations—to effectively prevent nurse burnout and mitigate the severity of burnout among the roughly half of hospital-based nurses already burned-out. Study objectives will be accomplished by leveraging unique data from thousands of nurses in approximately 535 hospitals in multiple states (CA, FL, NJ, PA) across 4 time-points spanning 20 years. We will generate repeated samples of these hospitals at multiple time-points (already collected: 2006, 2016, 2024, to be collected 2026). Using a repeated cross-sectional design with changing organizational and policy influences overtime, we are uniquely positioned to evaluate potentially causal relationships of modifiable organizational factors and state-level policy interventions on nurse burnout. Each time-period of data includes repeated measures of nurse outcomes (e.g., burnout, job dissatisfaction, intent to leave employment), and hospital factors and models of care (e.g., staffing levels, work environment, Magnet). These cross-sections of data will be linked with contemporaneous American Hospital Association data for considering structural features of hospitals (e.g. teaching status). In combination, we will have 4 cross-sections of data from 535 hospitals (with fluctuating nurse populations), with changing organizational, policy, and other intervening influences (e.g. CA staffing policy relative to non-policy states, 2008 Great Recession, 2020 Covid-19 pandemic). Our quantitative analytic approach uses hierarchical models with time-varying covariates to capture the multilevel structure of the data, as well as difference-in-difference models with propensity score weighting for rigorous causal inferences of changes in organizational factors on changes in outcomes. Using data collected in 2026, we will empirically identify typologies of hospitals with respect to their proportions of nurses with high burnout and average tenure and conduct in-depth interviews with key nurse leaders (hospital nurse executives, nurse managers) in hospitals representative of each of the typologies to elucidate the facilitators and barriers to reducing hospital nurse burnout and turnover. This multi-modal study has novel potential for sustained impact since it will (1) evaluate the impact of modifiable organizational and policy changes on hospital nursing and models of care on nurse burnout; (2) leverage 20 years of repeated cross-sections of data to evaluate potentially causal mechanisms between modifiable hospital factors and external policy interventions on nurse burnout; (3) evaluate currently employed nurses and those who recently left employment to understand whether the reasons nurses say they would leave hospital employment are the same as the reasons they actually leave; (4) integrate quantitative findings with qualitative frontline hospital leadership perspectives to move from evidence to action. The cumulative evidence will inform targeted recommendations for policy and hospital interventions for reducing the unprecedented high rates of nurse burnout and low retention.

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Testing the role of microbial infections in the development of auto-antibodies to type I interferons

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National Institute of Allergy and Infectious Diseases (NIAID)

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Type I interferons (IFN) are crucial to anti-viral immunity. Neutralizing autoantibodies (AAb) to IFN are found in the general population, increase in prevalence with age, and are linked to worse, often fatal, outcomes in some of the most lethal acute respiratory viral diseases known to date, including fulminant influenza and COVID-19 pneumonia. Despite this, the mechanisms behind the formation of IFN AAb remain unknown. Human data suggest that impairments in thymic tolerance—due to dysfunction of autoimmune regulator (AIRE) and medullary thymic epithelial cells (mTEC)—may be required for the development of IFN AAb. AIRE is a transcription factor expressed by mTEC that is essential for establishing T cell tolerance in the thymus. In mTEC, AIRE promotes the expression and presentation of antigens from extrathymic tissues to developing T cells (thymocytes). This allows for the elimination of auto-reactive thymocyte clones, thereby preventing autoimmunity. Interestingly, AIRE+ mTEC have been shown to express IFN at steady-state conditions in the thymus suggesting that, in this context, AIRE+ mTEC act as antigen-presenting cells to thymocytes to mediate T cell tolerance to IFN. Supporting this idea, individuals with Autoimmune Polyglandular Syndrome 1 (APS1), who lack AIRE and experience T cell tolerance loss, consistently develop IFN AAb. These AAb are isotype- switched and somatically hypermutated, supporting the notion that a failure of T cell tolerance, rather than solely B cell tolerance, is necessary for their generation. However, additional findings suggest that loss of thymic T cell tolerance alone is insufficient for IFN AAb to develop. First, APS1 patients do not typically present IFN AAb at birth or infancy; instead, they develop these AAb later in life after exposure to pathogens is likely to have occurred. Second, IFN AAb have not been observed in specific pathogen-free, Aire-deficient mice. Combined, these observations suggest that pathogen exposure, in addition to AIRE and mTEC dysfunction, may be required for IFN AAb to develop. This proposal aims to understand how infections, combined with AIRE deficiency, contribute to the loss of thymic tolerance to IFN. My central hypothesis is that in individuals with predisposing AIRE deficiency, infections that induce IFN expression act as a double hit, promoting the development of neutralizing IFN AAb. Until now, methods to detect neutralizing IFN AAb in mice have been lacking, which has hindered the field's ability to test this hypothesis. I have developed a novel, sensitive, reproducible, and high-throughput assay for detecting murine neutralizing IFN AAb. This new tool will serve as the basis for this proposal and will facilitate exploration of how microbial infections and thymic defects contribute to the development of IFN AAb in an animal model. The findings from this work will deepen our understanding of how tolerance to IFN is mediated and may inform strategies to prevent IFN AAb development in affected individuals.

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Investigating the Role of Epstein-Barr Virus in Long COVID Pathogenesis

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National Institute of Allergy and Infectious Diseases (NIAID)

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SARS-CoV-2 infection can result in the development of a constellation of persistent sequelae following acute disease, which is known as Long COVID. Individuals diagnosed with Long COVID frequently report unremitting fatigue, post-exertional malaise, and a variety of cognitive and autonomic dysfunctions; however, the basic biological mechanisms responsible for these debilitating symptoms are unclear. Previously, this research group profiled 177 individuals in an exploratory, cross-sectional study encompassing multi-dimensional immune phenotyping in conjunction with machine learning. Key immunological features distinguishing Long COVID were identified and described in the Mount Sinai Yale –Long COVID (MY-LC) study. A striking finding was an elevation in antibodies to lytic antigens of Epstein-Barr Virus (EBV) in Long COVID participants, which may be indicative of more recent reactivation of EBV in these patients. In addition, levels of these antibodies correlated with IL-4, IL-6 cytokine double-producing CD4+ T- cells, which suggests that EBV reactivation is not merely incidental but reflects, mediates or aggravates immune perturbations in these patients. The overarching goal of this proposal is to provide a thorough insight into whether EBV reactivation contributes to LC disease pathogenesis and symptomatology, building on current literature. The research plan proposed will utilize the Iwasaki lab’s expertise in in vitro and in vivo modeling to assess whether SARS-CoV-2 infection can reactivate EBV and contribute to lasting sequelae, as described in Aim 1. Aim 2 will leverage large patient cohorts previously recruited through the MY-LC study and robust sample and data availability to test whether patients with Long COVID characterized by recent EBV reactivation experience unique immune alterations. Aim 2 will also test whether these responses correlate to unique symptoms. The findings uncovered by these studies have the potential to deepen understanding of one cause of Long COVID, and to inform future treatment of a growing, currently largely-untreated patient population. Mentorship from an interdisciplinary group of collaborators, who are experts in the proposed techniques, will facilitate this applicant’s training as an independent immunologist.

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Improving Specialty Care Through Virtual Care Models

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VETERANS ADMIN PALO ALTO HEALTH CARE SYS

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1 Background: Specialty care deserts—the absence of specialists in geographic regions—have led to an access  2 crisis for the VA. In addition to increasing wait times and causing delays in care, these access needs drive many  3 Veterans to seek care outside VA, resulting in fragmented care, increased risks for hospitalization and hospital  4 readmission, and higher costs. In response, VA has launched the Clinical Resource Hub (CRH) program, which  5 seeks to deliver virtual care from “hub” to “spoke” sites in VA. VISN 21 has begun implementing this model in  6 cardiology at several spoke sites, but little is known about how care utilization and quality within the program.  7 Significance/Impact: This work seeks to better understand the effects of a virtual model of specialty care, in  8 this case cardiology care, on Veterans’ care access and quality. In addition, it aligns closely with several VA and  9 HSR&D priorities, chiefly access to care, virtual care/telehealth, and advancing the goals of the MISSION Act. 10 Innovation: The CRH program and the virtual care model at its core have yet to be studied in depth, and there 11 is no research in progress regarding specialty CRH despite strong interest at the national VA level in 12 understanding how specialty CRH is used and associated outcomes. Given that virtual cardiology care was very 13 limited prior to the COVID-19 pandemic, cardiology CRH is particularly novel. Hence, this project would add to 14 the limited body of research examining virtual cardiology care in the VA. In addition, the proposed work seeks to 15 evaluate this virtual care model at a time of unprecedented choice for Veterans between in-person and virtual 16 care, and limited data on how best to integrate these modalities. 17 Specific Aims: The proposed CDA will offer mentorship and training for me to pursue the following aims: 18 Aim 1. Evaluate quality of cardiology care associated with CRH implementation with administrative data. 19 I will use adjusted difference-in-difference event studies to compare cardiology quality metric achievement for 20 patients who received cardiology care via CRH versus those who received conventional VA-based cardiology care. 21 Aim 2. Assess Veteran perceptions of quality of cardiology care delivered via CRH. 22 I will interview Veterans participating in the CRH program and their caregivers regarding their experiences and 23 perceptions of quality of CRH cardiology care and elicit suggestions for key metrics to focus on for improvement. 24 Aim 3. Construct intervention to track and improve access to high-quality, equitable care through CRH. 25 Building on finding from Aims 1 and 2, I will interview clinicians and employ a facilitated deliberative process with 26 an expert advisory group to construct and pilot an intervention to improve quality. 27 Methodology: In Aim 1, I will use a difference-in-difference event study design to assess the impact of the program 28 on a battery of validated and/or guideline-based quality of cardiology care metrics. In Aim 2, guided by the Fortney 29 model of care access and quality, I will conduct semi-structured interviews of Veterans and caregivers receiving 30 care through the VISN 21 CRH program to understand their experiences with the CRH program and what outcomes 31 they recommend to include in a quality improvement intervention. In Aim 3, I will interview clinicians (Aim 3.1) and 32 conduct a facilitated deliberation process (Aim 3.2) to inform the construction of an intervention (proactive panel 33 management using a clinical dashboard tool) to track and improve quality of care and pilot the intervention. 34 Next Steps/Implementation: To continue moving this research into practice to improve health outcomes for 35 Veterans, I will extend the analysis of cardiology quality of care to compare cardiology care in the community to 36 CRH care. In addition, I will assess the effect of the intervention constructed in Aim 3 on patient outcomes and 37 clinician satisfaction via a hybrid implementation-effectiveness trial. I will continue to work with operational partners 38 to ensure cardiology CRH is improving access to high-quality cardiology care for Veterans. This project supports 39 my goal of becoming an independent VA health services researcher and leader in optimizing cardiovascular 40 disease care access, value, and equity for Veterans through virtual care innovations and implementation.