Brown University

NIH Research Projects · FY 2025 · 2023-05

The β-herpesvirus human cytomegalovirus (HCMV) infects around 50% of the world population. Although it remains asymptomatic in healthy individuals, it is never completely cleared from the host and can cause recurrent infections, especially at times of immunosuppression. HCMV poses the biggest threat to pregnant women, neonates, and immunocompromised individuals, whose symptoms tend to be more severe. The mouse homolog of HCMV, murine cytomegalovirus (MCMV), is a well-characterized animal model of viral infection. Like HCMV, MCMV has a tropism for the salivary glands (SMG) and persists in this organ for several months after primary infection. We have demonstrated that NK cells, which are critical in the spleen and blood, are hyporesponsive in the SMG, conceivably explaining the MCMV persistence in this organ. Interestingly, our preliminary data show that salivary gland NK cells regain normal effector functions against MCMV when relocated to different tissues, indicating that the salivary gland environment regulates NK cell function. MCMV exploits the SMG as the key site of viral persistence, which, similar to tumors, creates an immune environment with mechanisms to preclude excessive inflammation and/or tissue damage. Because the immune response to cancer and infection exhibit commonalities, we reasoned that the balance between pathogen clearance and immunopathology is likely to be regulated in part by checkpoint inhibitors within the salivary glands, especially during the persistence phase. Our data demonstrate that targeting KLRG1 improves the effector immune response to MCMV and survival at certain doses, but can lead to immunopathology depending on the dose. Our data also suggest that NK cells may inhibit CD8+ T cell recruitment, proliferation and effector functions in the salivary glands via the PD-1 pathway. This is supported by CITE-seq/TotalSeq on sorted T cells, showing expansion of unique CD8+ T cell clusters. Based on this preliminary data, we hypothesize that NK cells contribute to CMV control while preventing immunopathology by limiting the expansion of CD8+ T cells in the salivary glands. The overall goal of this proposal is to reveal the underlying mechanisms leading to MCMV persistence. In Specific Aim 1, we will investigate how the equilibrium between pathogen clearance and immunopathology is regulated. In Specific Aim 2, we will investigate how MCMV persistence is regulated in the salivary glands. In Specific Aim 3, we will investigate how NK cells inhibit T cell accumulation possibly limiting immunopathology in the salivary glands. We have generated a large number of tools to investigate the questions asked in this proposal. We are now in an excellent position to conduct the proposed studies. The results from these studies are likely to have relevance to infections caused by other viruses and aid in the design of strategies and therapeutics directed at manipulating effector cells during viral infection.

NIH Research Projects · FY 2025 · 2023-05

The International Society for Environmental Epidemiology (ISEE) is the preeminent scientific society focused on relationships between environmental agents and human health. The annual conference provides a critical forum for the exchange of ideas and development of potential solutions to pressing environmental health issues of regional, national, and global significance. It is regularly attended by prominent epidemiologists from academic, industrial, and governmental institutions from around the world. As one of the most important international forums for the presentation of human health research related to air and water pollution, the built environment, and ecosystems supporting food production, it provides a unique opportunity for environmental epidemiologists, regulators, and public health professionals to present their work, cultivate new collaborations, and develop solutions to emerging environmental health issues. Finally, it serves an important training, education, and networking opportunity for junior investigators. Over the next three years, the ISEE annual conference is excited to continue focusing on the effects of environmental exposures on human health, while drawing attention to and addressing ongoing and emerging environmental health issues. Upcoming meetings include: 1) the 35th meeting in Kaohsiung, Taiwan (September 16-21, 2013); 2) the 36th in Santiago, Chile (September 1-5, 2024); and 3) the 37th in Atlanta, Georgia, USA (August 17-24, 2025). The three-and-a-half-day annual meeting offers interdisciplinary examination of new research and methods that are of profound significance to the field of environmental epidemiology. The conference facilitates the exchange of ideas and information between epidemiological investigators and public health practitioners from around the world. The upcoming annual conferences will increase the presence of ISEE in Asia and South America, where environmental exposures are rife, but routinely understudied. Scholarships will be provided to distinguished experts, young investigators, students, and promising scientists from the US and abroad. In turn, this will enhance the global development of environmental health work forces and foster collaborations and exchange information both nationally and internationally.

NIH Research Projects · FY 2026 · 2023-05

PROJECT SUMMARY Explore the Chemistry and Chemical Biology of Reactive Sulfur Species Reactive sulfur species (RSS) include hydrogen sulfide (H2S), persulfides (RSSH), polysulfides (H2Sn or RSSnR, n≥2), and cysteine-modified adducts like S-nitrosothiols (SNO). These species play regulatory roles in redox biology. They are both indicators and effectors of disease states, simultaneously offering diagnostic and therapeutic opportunities. However, the exact mechanisms of action of many RSS are still unclear. A number of fundamental questions concerning the chemistry of these species must be addressed before we can expect a biological understanding and clinical applications. Our lab has discovered some interesting chemistry and reactions of RSS. We have also developed a variety of chemical tools that can be used to further their biological studies. In this R35 application we plan to continue our efforts on exploring the chemistry and chemical biology of reactive sulfur species. We propose four distinct research directions for the next five years: 1) to explore novel H2S/RSS donors and dual donors, and to study the applications of these compounds; 2) to study the reactions of persulfides and polysulfides, and to investigate mechanisms of protein S- modifications caused by persulfide donors; 3) to explore novel H2S scavenging systems and their applications; 4) to develop the next generation of xanthene-based fluorescent dyes and RSS sensors. The completion of this project will allow us to better understand the properties and biological significance of these sulfur species. It will also provide novel research tools that can be used in both basic and translational biomedical research on RSS.

NIH Research Projects · FY 2026 · 2023-04

PROJECT SUMMARY More than 2 million people have opioid use disorder (OUD) in the U.S. and opioids accounted for 70% of the nearly 100,000 drug-overdose deaths in 2020. Increasing OUD prevalence and opioid-involved overdose deaths underscore the urgent need for improved access to effective OUD treatments. Methadone, buprenorphine, and naltrexone are effective in treating OUD, yet these medications for OUD (MOUD) are underutilized, particularly among low-income Medicaid beneficiaries who represent a sizable portion of the U.S. population living with OUD. Prescription (Rx) caps represent a cost-containment strategy employed by some state Medicaid programs that limit the number of brand name drugs or total number of prescriptions that may be filled each month. Rx cap policies potentially exacerbate the opioid epidemic by impeding access to MOUD among financially constrained Medicaid beneficiaries, many of whom have comorbid chronic health conditions (e.g., mental illness, chronic pain, HIV), and who are forced to make tradeoffs between which medically necessary medications to fill. Though a few older studies have used Medicaid data to evaluate the impact of Rx caps on the health of the general population, until now, this has not been studied among people with OUD – an NIH priority population. The objective of this application is to examine whether and how Medicaid Rx caps affect the care and health of people with OUD and other chronic health conditions. Our long-term research goal is to develop an evidence base that can be used to revise medication utilization management policies in ways that balance budget priorities with improved patient and population health outcomes. Our central hypothesis is that Rx caps contribute to reduced uptake of and continuity with MOUD treatment, resulting in increased overdoses and mortality. The rationale for this hypothesis is that people with OUD frequently have co-occurring conditions and are likely to require several simultaneous prescriptions to manage their health, placing them at risk for exceeding the caps. Our skilled team of health services researchers, pharmacists, clinicians, and epidemiologists has extensive experience using Medicaid claims data and qualitative methods to study the impact of health policies on marginalized populations. We propose to analyze national Medicaid data to evaluate the impact of Rx cap policies on initiation and continuity of MOUD use among individuals diagnosed with OUD; and determine the impact of Rx cap policies on health services utilization, overdoses, and all-cause mortality among this population. We will then contextualize our quantitative findings via interviews with patients with OUD and providers who practice in states impacted by cap policies to elucidate their experiences with caps and identify best practices for navigating these policies. Completion of this research will help to close critical knowledge gaps by generating novel mixed-method findings on Rx drug coverage for OUD treatment and yield best-practice recommendations for navigating cap policies. As states continue to consider strategies to address the worsening opioid and overdose crises, due attention should be given to Medicaid benefit restrictions that can undermine individual and public health goals.

NIH Research Projects · FY 2026 · 2023-04

PROJECT SUMMARY The ultimate goal of this research program is to determine the neural mechanisms of sequence monitoring across species. This knowledge can contribute to understanding new treatments for disorders where sequential behaviors are disrupted, such as obsessive-compulsive disorder (OCD). Daily, we monitor sequences of visual information such as the series of bus or train stops when looking for the correct exit. Sequence monitoring is the active process of tracking the order of subsequent “states” or steps. Monitoring is distinct from other well-studied sequence processes, such as explicit memorization, or potentially more automatic behaviors such as a series of motor outputs (e.g., playing the piano) or statistical sequence learning. However, the monitoring aspects of sequence processing remain largely unknown. The goal of this proposal is to determine the neural mechanisms of nonmotor and nonspatial sequence monitoring across species. Reflecting its importance, a large network of cortical and subcortical areas is implicated in sequence processing, including frontal cortices, premotor cortex, medial temporal lobe, basal ganglia, hippocampus, and cerebellum. When focusing on high-level monitoring of nonmotor and nonspatial sequences by human and nonhuman primates, our Preliminary Data and other evidence indicates that lateral and medial prefrontal cortices (LPFC and MPFC, respectively), play a unique role. However, the specific contributions of each have not been determined. Two key features of sequences (e.g., ABCD) that may be encoded in neural activity are their ordinality or item-in-position associations (C in position 3) and temporal context or item-item associations (B is after A). Behavioral studies indicate that both kinds of information are used to monitor sequences. Previous studies, including our own, have found ordinality encoding in LPFC and MPFC. However, prior work has not established whether temporal encoding may additionally exist in these regions and any coding differences between these areas. We hypothesize MPFC primarily codes ordinality, and LPFC uses signals from MPFC to code ordinality and temporal context. We will directly test these hypotheses by triangulating behavioral, whole brain, and cellular data in studies across species. We will apply the unique capabilities of our lab to study cognitive capabilities across brain areas in behaving monkeys using fMRI (Aim 1), the functional homology and correspondence to more abstract sequential tasks in humans using fMRI (Aim 2), and use these signals to guide electrophysiology in monkeys (Aim 3). Parallel fMRI studies across species will allow us to leverage each for distinct strengths in hypothesis testing: detailed neurophysiology in monkeys, and detailed cognitive studies in humans.

NIH Research Projects · FY 2026 · 2023-04

This integrated research and training plan will prepare Dr. Thompson, a research assistant professor and licensed clinical neuropsychologist, to become an independent PI. Dr. Thompson’s long-term goal is to become an expert in the validation and application of novel AD screening methods within healthcare settings serving older adults. Her short-term goals for this K23 are to: (1) gain expertise in primary care-based recruitment, implementation science, pragmatic measurement, and statistical methods for the rigorous development and validation of novel cognitive protocols, (2) to test the hypothesis that combined use of remote (self-administered), app-based testing and table-based screening in primary care clinics will be feasible, acceptable, and associated with AD biomarkers. The early detection of cognitive impairment is one of the most important challenges in AD research. Cost-efficient and effective screening strategies for primary care will greatly enhance early diagnosis and treatment. Cognitive assessment is non-invasive, scalable, and covered by most insurance. Cognitive screening is a required part of the Medicare Annual Wellness Visit typically done by PCPs. However, current cognitive screening tools are insensitive to subtle cognitive changes. Digital cognitive tools overcome many limitations of current paper-and-pencil based approaches. In this project, Dr. Thompson will partner with local primary care practices to enroll 100 older adults without prior dementia diagnosis. Participants will complete phone screening and consent and do 5 days of brief NIH MobileToolbox (MTB) assessments on a smartphone within one month of their annual PCP follow-up visit. Participants without a compatible device or home internet receive a study-provided device. At their PCP follow-up visit, participants will complete brief tablet-based and traditional paper-and-pencil-based screening measures. We will obtain feedback from participants and PCPs on the use of the novel digital screening tools. Participants will complete a brief visit to the Butler Memory and Aging Program to do a blood draw for AD plasma biomarker analysis. Under the guidance of a strong mentorship team of NIH-funded researchers, Dr. Thompson will achieve four specific training goals: 1. Acquire experience and specialized training in primary care outreach and patient recruitment. 2. Extend her knowledge in implementation science, pragmatic measurement, and clinical research trial design. 3. Build advanced knowledge and skills in quantitative and qualitative data analysis, including biostatistics, psychometric evaluation, longitudinal data analysis, and clinical outcomes assessment. 4. Apply/actualize her skills from goals 1-3 to build expertise in the rigorous development and multimodal validation of novel cognitive measures, and develop a scalable primary care-based cognitive screening protocol.

NIH Research Projects · FY 2026 · 2023-03

Project Summary The preteen years are a critical period in which to study the development of suicidal thoughts and behavior (STB). During this period, youth experience changes in emotion regulation and develop cognitive capacities that include an emerging understanding of the permanence of death, which, in turn, affect the expression of STB. However, as noted in the 2021 NIMHSponsored Research Round Table Series: Risk, Resilience, and Trajectories in Preteen Suicide, research on preteen STB has been hindered by the field’s failure to focus on an accurate, and thorough, assessment of STB in this age group. This application seeks to develop and test a comprehensive approach to the assessment of preteen STB that includes child and parent/guardian self-report, clinician interviews, an implicit association test, a death understanding interview, and observational measures. In order to address this question, this application will examine both concurrent and predictive validity of the assessment approach in a sample of preteens receiving intensive psychiatric services (inpatient or partial hospitalization) who have a range of internalizing and externalizing symptoms, as well as a range of STB. We will recruit 360 children and caregivers at Bradley Hospital/Brown Medical School and the Johns Hopkins School of Medicine. In addition to refining the assessment of preteen STB, we will also: 1) conduct a thorough clinical assessment of related symptomatology to better inform clinical practice, and 2) examine mechanisms hypothesized to underlie preteen STB, using an RDoC-informed approach. We will also examine which cooccurring symptoms and mechanisms significantly improve predictive validity for adverse clinical STB outcomes above that of the STB assessment alone. This assessment approach is innovative in that it is the first study to develop a multi-modal, multi-informant assessment approach for preteen STB across a range of backgrounds, experiences, and sociodemographic characteristics including use of real-time observational strategies, as well as an implicit association test. This is significant because we are studying the most high-risk population of preteens with STB and we will be able to delineate mechanisms related to preteen STB, including health disparities, ensuring our findings will be generalizable beyond our sites. This work addresses: NIMH Strategic Objective 2.1.B “Characterize the emergence and progression of mental illnesses”, 2.2.A “Determining early risk and protective factors and related mechanisms”, and 2.2.B“Developing reliable and robust biomarkers and assessment tools to predict illness onset, and course, across diverse populations”.

NIH Research Projects · FY 2026 · 2023-03

The diets of US children are suboptimal and effective primary prevention interventions are urgently needed to shape dietary behaviors early in life, especially among Latinx families, who experience higher prevalence of obesity and cardiovascular disease. The community energy balance framework suggests the need to intervene at multiple levels, while addressing cultural and contextual factors, to effectively impact diet quality for disease prevention including: 1) Child level, including appetitive traits (satiety responsiveness (sensitivity to internal satiety signals), food responsiveness (sensitivity to external food cues), and food fussiness; 2) Parent level including the food parenting practices they use to feed children; 3) Home level including the availability and accessibility of food, and; 4) Broader context including social determinants, food security/access to healthy foods. While there have been several interventions aimed at improving the diet quality of young children, few have targeted more than one of these levels and almost none are tailored to a child’s appetitive traits, culturally appropriate, and convenient for busy, working Latinx families. Further, most have only focused on what parents should not be doing, rather than supporting what they should be doing. This proposal will build on our recently completed R34 pilot feasibility trial (R34HL140229-01A1) to test the efficacy of a novel home-based intervention with 257 Latinx families of preschool children. The proposed 6-month intervention will include: 1) Three home visits by a community health worker (CHW) trained in brief motivational interviewing that include in-home cooking demonstrations to prepare a meal involving the child; using a family meal-time video to provide feedback on food parenting; 2) Screening for social-determinants of health and connecting families to federal/state/local resources; 3)Text-messages (2x/wk); 4) Tailored materials/messages; and 5) Three CHW phone calls to reinforce food parenting, food resource management and healthy eating. Specific Aims are to: Improve quality of the dietary intakes of 2–5-year-old children (Aim 1); Improve food parenting practices (Aim 2); and Improve the home availability of healthy foods (Aim 3). Exploratory aims will assess: the relationship between outcome measures and intervention dose; the relationship between outcome measures and potential mediators and moderators and the intervention’s effect on child BMI. This study fills an important research gap by targeting the home food environment with positive food parenting while acknowledging a child’s appetitive traits. It also meets the NIH call for needed research to reduce health disparities among Latinx populations and has the potential for high public health impact.

NIH Research Projects · FY 2026 · 2023-03

Project summary Understanding brain function critically depends on knowing the identities of neural cell types. The olfactory (piriform, PCx) cortex is the main recipient of afferent inputs from the olfactory bulb and plays key roles in odor perception and memory. However, we lack a detailed molecular description of piriform cell types and the molecular machinery that defines their functional properties. Furthermore, and in contrast to sensory and motor areas in the neocortex, the genetic programs underlying PCx cell lineage specification during development remain largely unknown. A comparative analysis of cell types in the PCx and neocortex will reveal piriform- specific cell types and molecular features. Here, we propose to determine the gene expression and chromatin accessibility states of PCx neurons in the adult mouse, and to characterize the dynamic interaction of domains of regulatory chromatin and transcription factor activity that drive cell lineage specification during development. Our central hypothesis is that cell type identity in PCx is specified during development by the activity of piriform-specific gene regulatory network (GRN) activity. We further posit that GRN activity in piriform is distinct from neocortex due to the scarcity of epigenetic mechanisms for transcriptional repression. Aim 1: to identify molecularly distinct cell types in the adult olfactory cortex of mice. We will simultaneously measure gene expression and chromatin accessibility states of single cells in the mouse PCx. We predict that the molecular diversity of piriform neurons matches the diversity of their functional properties. Aim 2: to determine epigenetic mechanisms of piriform cell lineage specification during development. We will measure changes in gene expression and chromatin accessibility in developing piriform neurons and computationally reconstruct their differentiation trajectories. We predict that cell lineage specification in PCx is driven by piriform-specific dynamic interactions between domains of regulatory chromatin and associated transcription factor activity. Aim 3: to reverse engineer a gene regulatory network model for piriform cell type specification. We will infer data-driven, mechanistic GRN models for piriform and neocortex (somatosensory cortex S1) development. We will compare GRNs for PCx and neocortex using dynamical systems theory to test our model that the scarcity of repressive interactions between transcription factors drives the specification of piriform cell types. Our work will provide mechanistic insight into the epigenetic control of TF activity during neuronal differentiation and test the role of TF cross-repression in cell type specification. By integrating experimental data across PCx and neocortex, we will reveal piriform-specific cell types and the molecular features that specify the functional properties of the olfactory cortex.

NIH Research Projects · FY 2024 · 2023-02

RNA abasic sites are recently identified modifications in RNA that are generated by methylpurine glycosylase to regulate gene expression. They are abundant in RNA and they stabilize RNA yet we do not know much about how they form, their precursors, and their functions. DNA abasic sites were identified in the 1960s and those discoveries led to the elucidation of the base excision repair pathway in DNA damage. But RNA abasic sites were largely unknown, except those generated by the plant poison, ricin, in ribosomal RNA. While studying proteins that bind to the nucleic acid structure, R-loop, we identified RNA modification enzymes and methylpurine glycosylase as well as apurinic/apyrimidinic endonuclease I that were known to process DNA abasic sites. We have now shown that methylpurine glycosylase cleaves the glycosidic bond in RNA to form abasic sites and these reactions occur on RNA in RNA/DNA hybrids of R-loops. By mass spectrometry, we found that RNA abasic sites are rather abundant, there are tens to hundreds of thousands of them in each cell. We also found in an enhancer RNA of APOE, N6- methyladenosines are cleaved by methylpurine glycosylase to form RNA abasic sites on R- loops. The abasic sites then stabilize R-loops and pause RNA Polymerase II transcription. We show that this mechanism keeps the noncoding RNA poised to activate APOE expression in response to cellular demands. Given that we have early evidence for the role of RNA abasic sites in the regulation of noncoding RNA, it is necessary to better understand them. We propose to 1) examine the genome-wide effect of nucleic-acid-mediated pausing on noncoding RNA, 2) identify other glycosylases that form RNA abasic sites, and 3) determine what other modified RNA bases are precursors of RNA abasic sites. Together, these results will characterize RNA abasic sites by finding how they form and what they do.

NIH Research Projects · FY 2025 · 2023-02

Project Summary/Abstract This program will address shortages in science of individuals from underrepresented (UR) groups, including those from UR racial, gender, gender identity, ability groups and educationally disadvantaged background, by strengthening Brown’s capacity to train more diverse Ph.D. cohorts. Using our IMSD Program as the primary vehicle for change we will: a) Increase the numbers of UR students completing a Ph.D.degree and pursuing careers in the biological, biomedical, & public health sciences and interdisciplinary fields to levels proportional to their representation in the U.S. population. This will be achieved by strengthening and expanding our successful BioMed IMSD program to other Ph.D. programs where biological training occurs. This updated program, IMSD@Brown, will implement and establish practices that promote, improve and sustain STEM student Ph.D. training and post-training success. It will drive increases in student compositional diversity, institutional culture & climate, student retention & degree attainment. IMSD@Brown will operate as the central integration hub that aligns graduate level diversity and inclusion training practices across all programs and will institutionalize best practices by leveraging them to the benefit of the larger Ph.D. student population across all STEM programs. The program’s practices include: 1) developing inter-institutional relationships that serve UR students and our goals for excellence; 2) equipping graduate programs with IMSD resources and tools that complement locally provided disciplinary-specific training and coursework. These include training support for didactic, research, mentoring, and advising support, training through IMSD skills-based modules, and IMSD community-building programming to foster a sense of belonging for all students; and 3) Investing in processes that make permanent a culture that values and promotes diversity and inclusion. IMSD Program faculty will be drawn from 21 STEM Ph.D. programs – all of which engage in biologically & biomedically related work- to support 15 UR Ph.D. students appointed yearly for 12 months as IMSD trainees. We will meet our, and the goal of NIH, by a) building relationships which support UR students and enable their graduate and post-training career success, and b) improve program outcomes by collaborating with faculty, partner institutions and the extended alumnae network which our trainees can ‘tap’ into and c) lay the groundwork for broader change across Brown by embedding best practices in all Ph.D. training programs.

NIH Research Projects · FY 2026 · 2023-01

ABSTRACT Genetic research in autism spectrum disorder (ASD) has led to the discovery of a growing list of highly penetrant mutations in chromatin modifiers and transcription factors. This recent progress provides an important opportunity to define the molecular mechanisms in ASD, as well as to identify targets for new treatment strategies. However, given the large number of seemingly independent ASD risk factors, a major challenge for ASD research is to establish convergent mechanisms that group apparently distinct genetic etiologies. We identified a novel point of convergence between the histone-methyltransferase ASH1L, a major ASD genetic risk factor, and a cluster of ASD high-risk genes (e.g. FOXP1, RIMS1, NRX1a). We also find that ASH1L counteracts the activity of Polycomb repressor complex in neural development. Hence, our data uncover a transcriptional and epigenetic node linked to cell and circuit dysfunction underlying ASD phenotypes. However, the transcriptional programs modulated by ASH1L that lead to neuronal dysfunction are understudied. Our central hypothesis is that ASH1L counteracts Polycomb activity to orchestrate neuronal development by modulating transcriptional programs that control synaptic function and neuronal morphogenesis. We will define how ASH1L regulates neuronal development and function. We will use a multilevel, synergistic and translational approach that leverages human and mouse systems to determine how ASH1L modulates neuronal programs relevant to ASD pathogenesis. We are positioned to undertake this work, based on our robust preliminary data and combined expertise in cellular/molecular neuroscience, bioinformatic, chromatin biology and electrophysiology. 1) Determine how mutations in ASH1L disrupt neuronal arborization and function in human stem cell experimental systems, 2) Define functional and circuit phenotypes associated with ASH1L in rodent systems. 3) Define bulk and cell type specific epigenetic and transcriptional signatures associated with ASH1L mutations that cause disease in mouse and human neurons. Finally, we will define rescue strategies for the cellular, molecular, and electrophysiological phenotypes observed in both mouse and human experimental systems.

NIH Research Projects · FY 2026 · 2022-12

PROJECT SUMMARY Sepsis is a devastating condition resulting from the immune system’s reaction to infection. 1.7 million Americans are hospitalized annually with sepsis, resulting in over 270,000 deaths. Sepsis is more common among older patients, leading to spending among Medicare beneficiaries totaling $41B in 2018. Treatment costs and episode spending also vary widely across hospitals, driven largely by differences in post-acute care. In an attempt to improve care, sepsis was included as one of the 31 inpatient episodes targeted under Medicare’s Bundled Payment for Care Improvement Advanced (BPCI-A) program. BPCI-A is a voluntary program that creates incentives for hospitals to improve patient outcomes and reduce spending across a 90- day post-discharge episode. BPCI-A has the potential to encourage hospitals to more effectively manage patients during the admission to avoid subsequent complications and to discharge patients to lower acuity post-acute settings. At the same time, BPCI-A is not designed primarily to improve quality, and changes in patient outcomes – positive or negative – will be closely tied to hospital efforts to reduce spending. Patients with Alzheimer’s disease and related dementias (ADRD) are both more likely to develop sepsis and to have worse outcomes. Patients with ADRD have very high episode spending and are particularly vulnerable to adverse outcomes following discharge, making their treatment for sepsis under BPCI-A critically important to understand. Outside of ADRD, how patient risk and sepsis care pathways influence patient outcomes for sepsis in the context of BPCI-A are not well understood. In this context, we propose the following aims: Aim 1. Evaluate the effects of BPCI-A on outcomes for patients with sepsis. We will link hospital participation in BPCI- A with national Medicare data to test the effects of the program on mortality, readmission, post-acute care, days alive and at home, burdensome transitions, and discharge to hospice. Aim 2. Evaluate the effects of BPCI-A on outcomes for sepsis patients with ADRD. Using validated Medicare claims algorithms to identify patients with ADRD, we will test the impact of BPCI-A on outcomes for patients with ADRD. Aim 3. Understand the relationship between clinical risk, treatment, and post-acute care treatment patterns and outcomes under BPCI-A. Using unique data from the Michigan Sepsis Initiative linked to Medicare claims data, we will identify the clinical treatment patterns, patient risk factors, and hospital characteristics that predict patient outcomes. We will examine whether hospitals participating in BPCI-A deploy a different set of strategies to manage patients with sepsis. Our proposal is significant because it combines national data with detailed clinical insights to understand the interplay between national policy and nuanced clinical care for patients with sepsis. Our proposal is innovative in its combination of administration and registry data sources coupled with sophisticated quantitative methods to answer a novel question.

NIH Research Projects · FY 2025 · 2022-09

Recent years have created numerous shocks to the U.S. health care system and to care delivery for patients. These sudden and dramatic changes to the US health care system, include a rapid escalation in use of telehealth services, an abrupt decline in in-person services, and a large volume of deferred services. It is unclear how these care patterns will evolve in subsequent years. The persistence of delayed care, and differences among complex patient populations, is not understood. Physician organizations (POs) face differing burdens in rapidly adopting telemedicine, and the PO barriers to telemedicine adoption may be reflected in the outcomes of patients treated by these POs. Likewise, the reduction in in-person care has placed financial stress on many POs, leading to concerns that many POs may go out of business or consolidate. The impacts of care reductions, the adoption of telemedicine as a new care delivery modality, and access to POs are likely to have larger effects among vulnerable patient populations, including lower-income, rural, and minority populations, and patients with multiple chronic conditions or Alzheimer’s/dementia. Understanding patient and provider responses to these changes and the care patients receive, particularly those who are medically and socially complex, is essential to inform immediate-term and longer-term policymaking intended to help the health system and health care professionals respond to these changes to the delivery system. We propose to conduct a set of analyses to 1) Estimate how health services have changed during recent years, the factors associated with changes in health service use, if health delayed care remains unmet, and how these patterns differ for medically and socially complex patient populations; 2) Asses PO barriers to adopting telemedicine and assess if PO adoption of telemedicine lessens adverse health outcomes, particularly among complex patient populations; and 3) Examine if PO closure or consolidation in recent years leads to gaps in patient care continuity or access barriers among complex patient populations. To do so, we will leverage the existing data assets and expertise of the RAND U19 Center of Excellence that the research team has built over the past 5 years. We will use 100% Medicare fee-for-service claims data. Findings from this study will help inform an array of immediate-term and longer-term legislative actions, policies, and regulatory changes being considered, including changes to payment policies, use of technology, financial assistance to providers to ensure their survival, and improving the ability of health systems to respond to withstand significant shocks.

NIH Research Projects · FY 2025 · 2022-09

Project Summary RNA-binding proteins are essential components of numerous large complexes that carry out fundamental processes including transcription, splicing, and DNA repair. Many RNA-binding proteins possess regions predicted to be disordered based on low-complexity sequence characteristics that are critical to normal RNA- processing functions, but also drive aberrant protein assembly in various neurodegenerative disease and cancers. The molecular interactions and functional roles of these disordered domains remain incompletely characterized, especially in the context of disease. Fused in Sarcoma (FUS) is one of twenty-nine human RNA-binding proteins that contains both an essential disordered low-complexity domain (LC) with unusually low charged residue composition and a high frequency of aromatic amino acids as well as several RGG motif regions. Despite disorder, these domains are thought to facilitate interactions in normal RNA metabolism by forming dynamic associations, thereby enabling tunable, reversible spatial clustering. Yet, excessive self- association between FUS disordered domains is believed to result in the formation of pathological neuronal inclusions in sub-types of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), irreversible neurodegenerative diseases that lack effective treatments. Moreover, fusion of the FUS disordered domains to several DNA-binding domains through chromosomal translocations results in uncontrolled gene expression leading to a family of aggressive cancers. Though FUS has emerged as the primary model system for understanding biological phase separation, the contacts holding together FUS assemblies and their structures in physiology and disease are currently unknown because they are invisible to traditional techniques in structural biology. However, we have demonstrated that we can visualize dynamic assemblies of FUS with residue-level resolution. This project will apply advanced nuclear magnetic resonance spectroscopy, molecular simulation, and cell models of FUS function to 1) visualize the molecular contacts that mediate LLPS and in- cell interactions, 2) probe the molecular and cellular impact of LC and RGG mutations of FUS found in familial ALS, and 3) determine the functionally relevant atomic details of FUS complexes with RNA and the C-terminal domain (CTD) of RNA polymerase II associated with RNA processing and transcription. These studies of FUS assembly will provide necessary structure/function information on future pharmacological targets for inhibiting pathological protein associations in types of ALS, FTD, leukemia, and sarcoma. Furthermore, because FUS is only one of many essential RNA-binding proteins containing aggregation-prone low complexity domains, the results of the project will serve as a foundation for understanding an entire class of proteins and for correcting their dysfunctions in disease.

NIH Research Projects · FY 2025 · 2022-09

Project Summary Macrophage migration inhibitory factor (MIF) is critical to the pathophysiology of inflammation through its interaction with the chemokine receptor CD74, while also opposing the immunosuppressive effects of glucocorticoids and catalyzing enzymatic reactions of unknown biological significance. The mechanism by which MIF accommodates these and other biochemical functions within its compact structure is unclear, but we recently identified a network of amino acids that link the enzymatic active site of MIF with peripheral regions of the protein, including the proposed CD74 binding site. These residues, and likely others, allosterically regulate several biochemical functions of MIF, including enzyme catalysis, receptor activation, and protein-protein interaction. Preliminary data showed that multi-timescale dynamics of the MIF structure (and resulting changes to intersubunit hydrogen bonding) contribute to its function, leading us to hypothesize that intrinsic structural flexibility is a major driving force of the allosteric mechanism that enhances spatial-temporal control of MIF. The design of MIF selective inhibitors with therapeutic value for inflammatory diseases would be aided by a more detailed understanding of the biophysical underpinnings of MIF allostery. This proposal will explore how changes to the MIF structure via mutations and pro-inflammatory solution conditions affect its allosteric crosstalk, catalytic activity, and activation of CD74. We will complete three specific aims, beginning with atomic level characterization of the MIF allosteric network using state-of-the-art solution nuclear magnetic resonance (NMR) spectroscopy and molecular simulations. The impact of oxidative solution conditions on the MIF structure and allosteric network will then be assessed with solution NMR and quantitative proteomics. We will mimic inflammatory environments to determine how the MIF structure is modified, and if those modifications result in downstream functional differences. Lastly, we will apply our integrated NMR-MD approach to study the first MIF mutant ever associated with human disease, a Y99C variant found in children with juvenile arthritis. This mutation occurs directly at the allosteric site we identified in earlier publications. Each aim will assess the resulting biological outcomes with measurements of active site chemical properties, catalytic function (in vitro) and CD74 activation (in vivo) function. The project will dissect allosteric pathways through the analysis of differential motions probed by NMR spin relaxation, molecular simulations, and network analysis, mapping the specific amino acids and interactions responsible for transmitting structural or dynamic changes between the allosteric, enzymatic, and CD74 receptor sites. The outcomes of the work can broadly inform the promiscuous mechanisms of cytokines, the role of allostery in the extended MIF superfamily, and focus NMR-guided computational screens of molecular libraries against the MIF allosteric pathway, relevant to asthma, respiratory distress, and cancer therapies.

NIH Research Projects · FY 2025 · 2022-09

Project Summary Sixty percent of older adults who start osteoporosis drug therapy (ODT) with an oral bisphosphonate (BP) have long-term exposure (3 or more years with 80% or higher adherence). Although a minimum of 6 to 12 months of BP treatment is required to reduce fracture risk, BPs have extended half-lives and can provide benefits long after discontinuation. Clinical trials have identified little difference in fracture risk for women who stopped versus continued BP after 3 to 5 years. Further, prolonged BP use has been linked to adverse events like atypical femoral fracture (AFF). Thus, guidelines recommend a drug holiday (pause in therapy) for most patients after 3 to 5 years of BP use. Patients at high fracture risk are recommended to continue BP or switch to another ODT, like denosumab, teriparatide, abaloparatide, or raloxifene. Several critical gaps in knowledge exist about the risks and benefits of long-term BP use, drug holidays, ODT switching on clinical outcomes and adverse events, particularly in groups with limited representation in trials like men and nursing home (NH) residents. This proposal has three specific aims: (1) Among community-dwelling older adults with at least 3 years of BP use, examine the effects of BP drug holidays and ODT switching on fractures, fracture sequelae (e.g., death, entry into NH), and AFF. (2) Among NH residents with at least 3 years of ODT, compare the effects of discontinuing versus continuing ODT on fractures/sequelae and patient-centered outcomes (e.g., functioning, pain); and (3) Develop and validate clinical prediction algorithms for osteoporotic fracture and AFF to guide clinicians making decisions on whether to initiate a drug holiday. Our central hypothesis is that the effects of long-term ODT strategies will be dependent on treatment length, type, and patient characteristics. The rigorous studies we propose will use multinational linked administrative and clinical datasets. The study population will comprise older adults aged 66 years or older in the US and Ontario, Canada who have at least 3 years of long-term ODT. Data for this study will come from 1) Linked, universal healthcare and medication claims data for all people (community-dwelling and NH) aged ≥65 years in Ontario; 2) U.S. Medicare claims on community-dwelling older adults; and 3) Electronic health record (EHR) data for up to 10,000 NHs linked to Medicare claims. We will implement a validated data cleaning algorithm for osteoporosis medication claims and novel rolling window method to capture long-term ODT. Time-varying propensity score approaches and novel causal inference methods like target trial emulation will be employed. This project will generate critical, generalizable evidence to guide long-term ODT, prevent fractures, and minimize AFF among older adults. This research will directly address RFA-AG-22-018, the Appropriate Use of Drug Therapies for Osteoporotic Fracture Prevention Pathways to Prevention Workshop Panel Recommendations 1 and 4, and Strategic Goal C of the National Institute on Aging. Additionally, the project will create an international data partnership to leverage EHR and universal healthcare data to answer emerging research questions on ODT.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY Polypharmacy is common among nursing home (NH) residents and is most prevalent among residents with Alzheimer's Disease and Related Dementias (ADRD) due to their high burden of multiple chronic conditions that predispose them to medication use. Polypharmacy is dangerous for NH residents with ADRD because it substantially increases the risk of drug interactions. Fall-related injuries, including fractures, joint dislocations, and hemorrhages, are one of the most common and impactful adverse outcomes of drug interactions and result in morbidity, disability, and death. Many theoretical interactions between drugs have been identified and healthcare providers believe that drug interactions are common and harmful among older NH residents with ADRD, yet limited data exist about which interactions are most clinically significant. Given that drug interactions resulting from polypharmacy are likely a major, yet modifiable, cause of fall-related injuries among older NH residents with ADRD, identifying drug interactions and their effects is essential for avoiding fall-related injuries. Thus, the overall objective of this proposal is to identify, test, and validate clinically significant drug interactions in NH residents with ADRD through a series of rigorous epidemiological studies that employ novel drug interaction screening and causal inference methods. The central hypothesis is that multiple clinically significant drug interactions will increase the risk of fall-related injuries, and that this risk will be greatest among individuals with the most severe cognitive impairment and on higher medication doses. This hypothesis will be tested through three specific aims: Aim 1 (Screening), Conduct hypothesis-free high-throughput semi-automated screening to identify potential interactions involving drug pairs and triads that increase the risk of fall-related injuries among NH residents with ADRD; Aim 2 (Testing), After prioritizing interaction screening results with the guidance of a multidisciplinary expert stakeholder panel, perform a series of hypothesis-driven studies to quantify the effects of drug interactions on fall-related injuries, including dose, duration, and NH resident subgroup effects; and Aim 3 (Replication), Conduct a series of validation studies in independent data to determine whether the drug interactions identified during screening and testing are consistently associated with fall-related injuries among NH residents with ADRD. To accomplish the three proposed aims, a large novel database of NH electronic health record information be leveraged along with national MDS 3.0 clinical assessment records linked to Medicare health insurance and prescription drug claims. The proposed research is highly significant because it will provide clinically actionable empirical evidence to help guide the prescribing, deprescribing, and management of medications to minimize the risk of important drug interactions and fall-related injuries among NH residents with ADRD. This proposal is directly responsive to PAR-19-070 and advances the National Institute on Aging's Strategic Goal C to improve the safe use of medications.

NIH Research Projects · FY 2024 · 2022-09

PROJECT SUMMARY Risk for substance use disorder (SUD) begins early in the life course. Although preventing and decreasing illicit and nonmedical drug use among youth is an urgent public health priority, there are currently few evidence- based prevention strategies feasible for delivery in the primary care setting. We propose a three-year plan to collect critical pilot data to pilot test and optimize a dyadic intervention that aims to increase family resilience, strengthen coping skills, help families plan for the future, and prevent youth SUD. Currently, over 12% of children in the US live in households with at least one parent who has SUD, including an estimated 3 million children between the ages of 12 and 17. Parental SUD is a known risk factor for the initiation and progression of substance use in adolescence and young adulthood. At the same time, parental recovery from SUD has been shown to be protective against youth substance use, particularly when there are supports in place to promote supportive parent-child relationships, problem solving skills, and effective family coping strategies. A key premise of our work is that an effective SUD prevention strategy for high-risk youth therefore needs to incorporate the family unit deliberately in the intervention process. The long-term objective of this proposed trajectory of work is to prevent substance use among a selective population of youth whose parents are in recovery from SUD. The ‘prototype’ for our intervention approach is Family Talk, an evidence-based parent-youth dyadic intervention that can be delivered within the existing infrastructure of the patient-centered medical home. We have made preliminary adaptations to the model in preparation for testing. To prepare for a subsequent efficacy study, we will conduct a two-arm pilot randomized controlled trial of the intervention with 40 parent- youth dyads to optimize the intervention model; evaluate feasibility; obtain empiric estimates of study parameters to inform the planning of a fully powered randomized controlled trial; and identify plausible intervention targets using semi-structured qualitative interviews. The product at the end of this R34 will be an optimized intervention model, ready for efficacy testing, adapted with parent and youth input. Our ultimate goal is to develop an effective approach to youth substance use prevention that can be delivered within the infrastructure of the patient-centered medical home. If successful, this trajectory of work has the potential to identify a novel, family-centered approach to SUD prevention for a high-risk population of youth whose parents are in recovery from SUD.

NIH Research Projects · FY 2025 · 2022-09

Project Abstract The purpose of this study is to conduct a comprehensive and state-of-the-art meta-analysis of Cognitive Behavioral Therapy, Relapse Prevention, and other Cognitive-Behavioral Intervention (CBIs) efficacy, moderated efficacy, and mediating processes. Building upon our prior work (R21 AA026006; PI: Magill, Co-Is: Kiluk & Ray; Consultants: Carroll & Tonigan), this R01 project will extract additional functional endpoints from the prior meta-analytic sample (i.e., K~100 primary studies), will conduct an updated search to yield all recent trials, and will incorporate advanced methodologies such as Network Meta-Analysis (NMA) and Individual Participant Data Meta-Analysis (IPD). In our prior work, consumption frequency and heavy frequency at one early and one late follow-up time point were the a priori indicators of interest. However, the dialogue on what constitutes an optimal endpoint in randomized clinical trials has grown in recent years (e.g., ACTIVE Initiative), arguing that a range of functional endpoints beyond abstinence or heavy consumption should be of greater emphasis in treatment development and clinical outcome research. Alternative endpoints such as related problems, coping behaviors, and mental and general health are certainly of interest to patients, families, and clinical providers. These indicators have additionally become key constructs in the what defines recovery. Preliminary analyses of the sample of trials reviewed in R21 AA026006 show that data for 4 to 50 possible endpoints are available per study, and that approximately 79% of the available data have yet to be collected, analyzed, or reported. In addition, using the methods of R21 AA023662 (PI: Magill), direct data requests for a selection of alcohol use disorder (AUD) studies will be conducted, and a number of relevant PIs have already agreed to meet such requests. In this case, a two-stage IPD will be used to conduct an aggregate path analysis of CBI process, considering putative mechanisms of CBI efficacy. Although R01-level meta-analytic projects have been conducted on a) alcohol pharmacotherapies, b) DUI interventions, c) brief interventions for adolescents/young adults, and d) combined AUD and trauma-related therapies, no such project has been undertaken on CBIs, and this is despite their longevity and centrality in direct patient care for alcohol and other drug use disorders. The proposed project, extracting all available endpoints from the published reports, conducting data requests for AUD trials specifically, and conducting NMA to account for variability in type of contrast condition will inform clinical and methodological recommendations on: 1) CBI implementation and delivery, 2) optimal endpoints for measuring CBI effect, and 3) defining and understanding recovery in the context of evidence-based treatment.

NIH Research Projects · FY 2026 · 2022-09

Project Summary We propose to develop statistical methods for the analysis of longitudinal positron emission tomography (PET) data for patients with Alzheimer’s disease (AD). Disease biomarkers identified from PET data are necessary for integrating these imaging modalities in observational studies and in clinical trials for drug development for AD. We propose statistical methods for the analysis of PET images including dimension reduction and biomarker extraction from voxel-wise intensity analysis that incorporate disease progression in two observational studies including data on early-onset and late-onset AD participants. Our methods allow for integration of MRI atrophy measures in the analyses to obtain multimodal predictors of disease severity and progression. The proposed methods will utilize the complex data and noise structure for developing powerful tools for biomarker identification that can be used for finding differences of disease progression between populations of interest. Particularly, our proposed biomarkers incorporate information on shape and texture of radiological images for prediction. The proposed methods can be incorporated to analyze data in future studies in most AD data collection centers as well as to apply in radiomics of imaging data in general.

NIH Research Projects · FY 2025 · 2022-08

Project Summary/Abstract Physical inactivity and poor diet quality, including low fruit and vegetable consumption and high sugar- sweetened beverages, have been linked with diabetes, overweight/obesity and numerous chronic health conditions. For Latina women in the U.S., the disproportionately low physical activity (PA) levels and unhealthy dietary habits contribute to the high and rising prevalence of diabetes and overweight/obesity, as well as heart disease, hypertension, and stroke. Reducing these disparities requires culturally appropriate interventions that promote multiple health behaviors of PA and healthy eating. The majority of lifestyle interventions that target these behaviors in Latinos have been implemented using face-to-face approaches, which may not be accessible to Latinas due to common barriers (e.g., lack of time, fear of immigration enforcement, and lack of transportation) and can require costly resources to implement. Internet-based interventions can overcome barriers of face-to-face approaches and have potential for wide reach. Latinos now report higher Internet usage than White and Black adults (95% Latinos use Internet) and are more likely than non-Latinos to use their mobile devices to access health information. While most Latinas report more than one modifiable risk factor contributing to cardiometabolic disease (physical inactivity, poor diet quality) no Internet-based interventions have yet been developed that are culturally tailored to address both diet and PA needs of Latinas. Our research team has already developed and tested a culturally and linguistically adapted, theory-driven, Internet- based intervention promoting PA in Latina women, Pasos Hacia la Salud, that has shown success by increasing and maintaining PA gains in this population over 12 months. Latina participants in our team’s PA studies have also expressed interest in learning more about dietary quality. Thus, we will expand our Internet- based PA intervention to include promotion of healthy eating in Latinas as a more comprehensive approach to reducing cardiometabolic disease in Latinas. We will then test the preliminary efficacy of the adapted web- based multiple behavior change intervention for Latinas in a 12-week pilot RCT. Participants (N=70) will be randomized to: 1) PA and dietary intervention arm, or 2) wait-list control arm. The goal of the proposed study is to help Latinas meet national PA and dietary guidelines for F&V and SSB consumption. This work leverages our existing infrastructure (web-based platform), didactic training, and the unique and complementary expertise of the mentorship team and collaborators in developing innovative technology-based and individually tailored PA and diet interventions in at-risk populations. The proposed project will provide the PI (Dr. Benitez) training on nutrition research and new methodologies in this area (Intervention Mapping process, evaluation of nutrition interventions, and multiple behavior clinical trials). This study proposes a novel, low-cost and high reach approach to reduce the burden of cardiometabolic disease in Latinas and will provide the PI with skills for developing and conducting culturally tailored multiple behavior (nutrition and physical activity) clinical trials.

NIH Research Projects · FY 2025 · 2022-08

Pre-exposure prophylaxis (PrEP), in which persons with ongoing HIV risk use antiretroviral medications to reduce their risk of acquiring HIV infection, is a promising prevention strategy. However, data show that PrEP’s effectiveness is greatly compromised by suboptimal adherence to treatment.1 Persons on PrEP face many challenges to optimal adherence and retention in care.2,3 Due to these challenges, the prescribing of PrEP should be accompanied by adherence interventions that are appealing to patients.1,4 We developed and examined the preliminary efficacy of an action-oriented, appealing, mobile game to improve adherence to PrEP entitled Viral Combat.5,6 Viral Combat was tested in a randomized trial with 69 participants newly initiating PrEP. At the 24-week follow-up, those in the intervention group were 3.75 times (p=0.02) as likely to engage in optimal PrEP dosing (i.e. 4 or more days/week as indicated using levels of tenofovir diphosphate from dried blood spots) compared to the control group.6 In this next phase of research, we will test Viral Combat through a multisite Hybrid Type 1 effectiveness- implementation randomized controlled trial (RCT) with 200 participants ages 15-34 years, receiving PrEP care at clinical sites in the South (n=100 Jackson, MS) and New England (n=100, Providence, RI; Boston, MA). The integrated Promoting Action on Research Implementation in Health Services (i-PARIHS) framework will examine the facilitators and barriers to the intervention’s implementation. Formative interviews with stakeholders will inform this intervention prior to the trial, and post-evaluation interview will summarize issues relevant to future dissemination.45

NIH Research Projects · FY 2025 · 2022-08

PROJECT SUMMARY Exposure to trauma is associated with a range of negative outcomes such as posttraumatic stress disorder (PTSD) and substance use disorder, particularly cannabis. The early posttrauma period (i.e., the days, weeks, and months following exposure) represents a critical period of risk for long term problem behaviors, especially among emerging adults (aged 18-25), which constitutes continued development accompanied by a peak in substance use and increased risk for trauma exposure. As regional laws, cultures, and beliefs about cannabis use (CU) continue to shift, there is concern that trauma exposure may exacerbate use (via self-regulation) and lead to greater cannabis-related problems, as many individuals report using cannabis to relieve distress, hyperarousal, and other posttrauma symptoms. Furthermore, while the majority of US states that have legalized cannabis for medical use include outcomes of stress and trauma, such as PTSD, as qualifying conditions for a state-issued medical marijuana license, little is known about how cannabis may impact the early post-trauma course. Given that the endocannabinoid system plays an essential role in regulating stress response and learned fear, CU in the acute post-trauma period may alter mechanisms contributing to alterations in fear neurocircuitry (e.g., alterations in consolidation/ reconsolidation, retrieval, extinction) and physiological reactivity. Limited (and contradicting) evidence, however, regarding safety and efficacy of cannabis preclude strong conclusions about its potential therapeutic role, with some prospective studies demonstrating detrimental or no long-term effects of CU on PTSD symptoms. The overall goal of our study is to examine the interplay between posttraumatic stress symptoms and cannabis use behavior during the period immediately following trauma exposure. We will recruit and prospectively follow N=200 trauma-exposed regular cannabis users admitted to the general hospital emergency department after medical evaluation for traumatic injury. Upon discharge, participants will complete ecological momentary assessment (EMA) paired with wearable biosensors (smartwatch) to record CU behavior, symptom development, and physiological output (i.e., heart rate) during early trauma recovery. Participants will return for completion of clinical interview and self-report, as well as laboratory procedures to characterize fear extinction and physiological reactivity. The main goals of this research are to: (a) assess alterations in fear response and physiological reactivity associated with CU, (b) characterize the impact of posttraumatic stress symptoms on cannabis use behaviors, and (c) determine whether early markers of altered physiology and posttraumatic stress symptoms are makers for trajectories of long-term adverse cannabis-related outcomes (i.e., use disorder, problems, chronic/heavy use).

NIH Research Projects · FY 2025 · 2022-08

PROJECT SUMMARY Older adults with Alzheimer's Disease (AD) and related dementia disorders are at increased risk of a motor vehicle crash due to impairment of the cognitive and sensory functions necessary for safe driving.1 Because there are few sources of long-term longitudinal data on dementia and motor vehicle crashes, and even fewer that include the prodromal stage of AD related dementia called mild cognitive impairment (MCI), very little is known about how the risk of a crash changes over the course of AD and how a crash may change the clinical course of disease. Here, we propose to use a novel data source of Medicare insurance claims linked to licensing, citation, and crash data for more than 1.5 million older drivers over a 13-year period to evaluate longitudinal changes in the risk of a crash and changes in the trajectory of health, health care utilization, and long-term care assistance following a crash, among older drivers with AD. The lack of information on the longitudinal risks and consequences of a crash among older adults with AD represents a critical gap in the literature for two reasons. First, research suggests that there is substantial individual variation in driving ability by stage of disease. While some individuals demonstrate a significant increase in unsafe driving behaviors early in the course of disease, before they are even diagnosed, others are able to drive safely with MCI through the mild to moderate stage of AD.2 As the number of older drivers with AD grows, providers and organizations that serve older adults are increasingly focused on developing interventions to promote “safe-mobility,” allowing older adults to drive for as long as is safely possible. However, to be effective, interventions need to account for longitudinal changes in the risk of a crash over time, and how these trajectories may vary across individual characteristics. Second, the effects of a crash can have long-lasting physical, psychological and social consequences. Current studies have identified short term effects of a crash,5 but no study has followed crash-involved-drivers with AD for long enough to understand how the impact of a crash manifests over time. Individuals with AD are already at higher risk of comorbidity, hospitalization, and early transition to long term care. Thus, given the rise in licensed drivers with AD, it is critical to understand how a crash may compound these risks. A major barrier to identifying periods of high crash risk and the contributing factors is the lack of longitudinal data on motor vehicle crashes. Instead, most studies have evaluated individuals retrospectively at a particular stage of the disease or followed older adults for relatively short periods of time and without knowledge of their cognitive status, making it difficult to identify longitudinal patterns of crash risk. Here, we propose to use 13 years of Medicare claims data linked to licensing, crash and citations for all drivers with a license in New Jersey between 2007 and 2019 to (1) characterize the longitudinal trajectories of crash risk over time (2) identify sentinel points in these trajectories where the risk of crash is highest and thus interventions would be most effective and (3) evaluate the impact of a crash on the health and health care outcomes for cognitively impaired older drivers.