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

PROJECT SUMMARY/ABSTRACT The proposed project for a K23 Career Development Award will enable Dr. Camilia Kamoun to become an independent physician-scientist expert in patient-centered research on psychosocial health in early female puberty. Early female puberty is increasingly common, yet there is a lack of patient-centered tools to assess its psychosocial impact and guide treatment decisions. The proposed research aims to develop a patient-oriented outcomes (PROs) measure for early puberty, addressing a critical gap in evidence-based, patient-centered care. This research would positively impact public health given high rates of early puberty. Dr. Kamoun’s long- term goal is to become an expert in researching psychosocial health in pediatric patients with endocrine conditions, integrating bioethical inquiry to advance just, patient-centered care. Her strong research background, as well as bioethics training, make her an ideal candidate. The research has the following specific aims: 1) To characterize parental health concerns related to early female puberty, as well as parental experiences of its social and mental health impacts; 2) To understand parental prioritization of patient-reported health outcomes for early female puberty and explore their association with parental and child traits; and 3) To assess early female puberty-related PROs using adapted existing relevant PROMIS® measures. These aims will be accomplished through integrated mixed methods. They will lead to the development of a patient- oriented outcomes measure to use in a clinical trial to assess the effect of pubertal suppression treatment on psychosocial health in early female puberty, which will constitute the next steps in the research. In the last two years of the K23, Dr. Kamoun will develop an R01 or equivalent proposal to secure funding for this follow-up research. An interdisciplinary team of mentors and collaborators will guide Dr. Kamoun in accomplishing the following training goals: 1) To acquire advanced theoretical and practical knowledge of research methodologies used in patient-centered research; 2) To gain skills and knowledge in patient-oriented health outcomes research; 3) To acquire knowledge in peripubertal psychoneuroendocrinology and developmental psychology; 4) To deepen her bioethics expertise with a focus on pediatric, research, women’s health ethics, and the relationship between risks, values and ethical care. This training will include survey science coursework through the Odum Institute for Research in Social Science at UNC-CH and advanced bioethics training through the Children's Mercy Bioethics Center's Certificate Program in Pediatric Bioethics. Dr. Kamoun’s mentorship team will meet regularly with her to monitor progress, as well as to provide guidance in writing manuscripts and R01 and equivalent grant proposals. This K23 Career Development Award will provide Dr. Kamoun with the necessary training, mentorship, and research foundation to launch an innovative patient- centered research program that aligns with the Eunice Kennedy Shriver National Institute of Child Health and Human Development’s mission to improve child and adolescent health and the transition to adulthood.

NIGMS - National Institute of General Medical Sciences

Summary Animals, from humans to flies, thrive with social interactions and suffer significant adverse mental and physical health consequences when isolated. In mammals, social isolation increases aggression, contributes to neuropsychiatric and neurodegenerative conditions, and disrupts sleep, memory, and attention. Yet, responses to isolation vary among individuals, populations, and species. How environmental and genetic constraints shape these individual responses remains poorly defined. Emerging data show that experience-dependent changes in gene regulation, neuromodulation, and behavioral modifications are linked. How variation among these mechanisms leads to variation in social experience-dependent behavior remains unclear. This proposal addresses this question by defining the molecular and neural circuit basis of individual susceptibility to the adverse mental and physical effects of social isolation. In previous studies, we showed that social experience alters transcriptional cascades in the brain to reprogram circadian genes to contribute to the modulation of behaviors in response to social experience. In preliminary studies, we identified individuals from specific population with variation in their behavioral and brain gene expression responses to social experience and determined candidate genes with synaptic and neuromodulatory functions driving the variation. The project aims to interrogate behavioral variation among individuals across populations in depth and identify molecular and circuit mechanisms driving this variation. Data from genomic, transcriptional, and neuronal patterns will be integrated to reveal patterns associated with behavioral variation. Causal links will be established between candidate gene expression, regulatory elements, and variation in behavioral responses to social isolation. The genes and mechanisms revealed from these studies will inform how natural genetic variation influences neuronal pathways to modulate plasticity of the responses to social experience.

NIMH - National Institute of Mental Health

Dysregulation of basal ganglia and cortical development in the forebrain is central to epilepsy, mental deficiency, autism and schizophrenia. During forebrain development, the medial ganglionic eminence (MGE) generates GABAergic projection neurons in the basal ganglia and GABAergic interneurons in the cortex and hippocampus. We aim to identify transcriptional and epigenetic mechanisms that control cell fate specification and neuronal differentiation of these forebrain GABAergic neurons - information that will lead to insights into how abnormalities in specific gene networks cause human neuropsychiatric disorders.

NIMH - National Institute of Mental Health

Summary One of the major problems in human genetics is understanding the genetic causes underlying complex phenotypes, including neuropsychiatric traits such as autism spectrum disorders, bipolar and schizophrenia. Despite tremendous work over the past few decades, it has been frustratingly difficult to get a good understanding of the underlying biological mechanisms in most cases. Nonetheless, large psychiatric genetic studies are beginning to deliver fundamental knowledge about genetic architecture, disease pathways and specific genetic loci for follow-up. Most psychiatric genetic studies to date have focused on individuals of European origin, leading to profound difference in genetic discoveries with limited transferability of results across populations, but also limiting our knowledge about disease pathophysiology in general. Recently, several large projects in neuropsychiatric genetics have focused on collecting and assembling genetic and deep phenotype data in admixed and populations of different geographic origins. Such projects include the Latin American Genomics Consortium (LAGC), the Genomics of Autism in Latino Ancestries (GALA), the Ancestral Population Network (APN), and PsycheMERGE. Most approaches for causal variant discovery fail to account for key complexities that arise in studies of varying geographic origin, including heterogeneity across populations in terms of effect sizes and linkage disequilibrium (LD) structure, and correlations across geographic origins. Furthermore, with meta-analyses with external LD from reference panels being commonly used in genome-wide association studies, certain types of inconsistencies are inevitable. Therefore, existing methods tend to have suboptimal power and can even produce invalid results, i.e., they prioritize non-causal variants. We propose to develop robust fine-mapping tools that model heterogeneity across populations and are robust to inconsistencies in the data. We also propose to leverage a possibly large number of genetically related traits available in electronic health record systems, including diagnoses, lab results and biomarkers with the goal to refine phenotypes and improve power of genetic association studies for psychiatric phenotypes. We further propose to apply these methods to the largest available collections of datasets from various geographic origins for autism, bipolar, schizophrenia and other neuropsychiatric traits, including data from several psychiatric genetics consortia and electronic health record systems. We believe that the proposed research is very timely and leverages modern datasets with the potential to substantially improve our understanding of the biological mechanisms underlying risk to neuropsychiatric diseases, including schizophrenia, autism and related disorders.

NIMH - National Institute of Mental Health

Although the rate of suicide death across the U.S. has risen dramatically over the past two decades, prevention of mortality remains challenging. This proposal will continue discovery efforts leveraging unique genetic data, comprehensive health records, and deep genealogical records. The variation in responses to environmental and social risks due to underlying genetic vulnerabilities creates an opportunity for discovery of subtypes of individuals at particularly high risk for mortality to lead to future clinical translation. Thus far, genetic discoveries associated with suicidality remain largely removed from translational utility, and are additionally primarily focused on the outcome of suicide attempt. Among individuals with evident suicidality, fewer than 10% go on to die by suicide, and roughly half of suicide deaths occur with no prior evidence of suicide attempts, suggesting that suicide attempt may be a poor proxy for determining risks leading to mortality. Data resources in the Utah Suicide Mortality Risk Study (USMRS) offer much needed opportunities to bridge this knowledge gap, including >12,000 suicide deaths linked to statewide electronic health records; ~9,000 with genotyping, and 1,053 selected for high extended familial risk with whole genome sequencing. All data linkage, subsequent de-identification, and analyses are possible via the Utah Population Database (UPDB); this comprehensive statewide resource also includes unique knowledge of familial risk through genealogical records that go back to the 1700s. In the previous award period, we used the WGS resource, prioritizing genomic regions using 43 very extended families at high risk of suicide death. We pursued non- synonymous variants in the NRXN1 gene which is important for synaptic function, demonstrating the utility of the familial approach. We more broadly characterized suicide deaths with significant extended familiality, finding significant reduction in age at death and significant increase in polygenic risk specific to suicide. We expanded our sequencing sample from N=281 to N=1,053, prioritizing suicide deaths in extended high-risk families. In addition to familial prioritization, we prioritized brain-related expression quantitative trait loci in the deaths with WGS, finding significance associated with RFPL3S (a gene important for arousal), in addition to implicating other gene pathways. We characterized non-transmitted genomic deletions using a conservative strategy of internal replication and rigorous bench validation. Our large sample of genotyped suicides provides information regarding background common genetic risks of hundreds of diagnoses and traits via polygenic scores. Additional ongoing work has also strongly implicated underlying transdiagnostic risks above and beyond psychiatric risks, driving new research directions. We propose to target discovery of mechanistic genomic change within homogeneous subtypes. Extended families provide one method of reducing heterogeneity. We also propose complementary strategies of risk discovery within extreme subtypes of physiological stress response and of brain-related function.

NIDA - National Institute on Drug Abuse

PROJECT SUMMARY Early initiation of cannabis use (<16 years of age) increases risk for cannabis use disorder (CUD), mental illness, cognitive impairment, later unemployment, and poor social relationships. Prevention of early initiation is critical for improving social and health outcomes. Precision prevention programs have reduced youth substance use, but no approaches have specifically targeted cannabis use. Furthermore, no studies have comprehensively considered risk factors for early cannabis initiation (genetic, social, behavioral, environmental, and cognitive) to enhance the prediction of early use and inform precision prevention approaches. Comprehensive multivariable prediction models for early cannabis initiation that include genetics and social/environmental factors are needed. Cannabis use is polygenic, influenced by multiple genetic variants with weak-to-moderate effects, and polygenicity makes it difficult to translate genetics for clinical application. One method for clinically applying genetics is through the development of polygenic risk scores (PRS) that are composite scores representative of overall genetic risk. Prior PRS have typically lacked portability to non-European populations; however, a state- of-the-art method has been developed to build PRS with significantly improved risk prediction (34% improvement) across ancestries. There is a need to apply this method to develop cross-ancestry PRS for cannabis use for inclusion of overall genetic risk in comprehensive prediction models. Furthermore, given the complex interplay between genetics and social/environmental factors, research is needed to understand gene by environment (GxE) interactions in which social/environmental factors synergistically impact the risk conferred by genetics. Research into GxE interactions is statistically and computationally challenging, and traditional single-variant and more recent polygenic approaches focus on lower order 2-way interactions. Our logic forest (LF) algorithm efficiently searches all possible interactions up to 8 variables without a priori specification. This study will apply these state-of-the-art computational methods to the Adolescent Brain Cognitive Development (ABCD) Study, which examines childhood risk factors and initiation of substance use from ages 9-10 years to early adulthood in a population demographically reflective of the U.S. Nearly all youth had not used cannabis at recruitment, enabling the prospective measurement of initiation and the development of prediction models integrating genetics with pre-substance use measurements of cognitive, social, and environmental factors. This research will 1) develop cross-ancestry PRS for inclusion in prediction models that comprehensively consider genetic, sociodemographic, behavioral, cognitive, and environmental factors, and 2) apply LF to gene-sets within known biological pathways across the whole genome to identify pathway-specific GxE interactions. Comprehensive models coupled with a more complete understanding of GxE factors influencing early cannabis initiation can identify 1) high risk youth populations for targeted prevention, 2) targetable factors present among high-risk clusters for tailored interventions, and 3) biological pathways for therapeutic development.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

ABSTRACT Gastrointestinal motility disorders in childhood include rare but life-threatening conditions of Hirschsprung's disease and pediatric intestinal pseudo-obstruction and common conditions termed disorders of gut-brain interaction, including irritable bowel syndrome, functional abdominal pain, constipation, and dyspepsia. These conditions create a substantial burden through chronic health issues and lower quality of life. Hirschsprung and pediatric intestinal pseudo-obstruction are well-understood to be due to abnormalities in the enteric nervous system (ENS), which controls motility, secretion, absorption, and blood flow. Mounting evidence suggests that unrecognized abnormalities in ENS and nervous system development may also predispose to disorders of gut- brain interaction. It follows that disruption of fetal development of the ENS could result in a range of motility disorders and identification of potential disruptors could lead to novel opportunities for prevention. The objective of this proposal is to determine whether antidepressant exposure in pregnancy increases the risk of various pediatric gastrointestinal motility disorders and disorders of gut-brain interaction. We hypothesize that modulation of serotonin, norepinephrine, and dopamine through antidepressant exposure during fetal development, essential for development of the ENS and for maintaining daily functioning of the GI tract, will have long-term effects on ENS function. Animal data has demonstrated this potential, but limited human data exist. To fill this substantial gap in knowledge, we will assess the association between antidepressant use in pregnancy and pediatric motility and disorders of gut-brain interaction using three large healthcare utilization databases in the US and the UK. Specifically, we will estimate the association between in utero exposure to antidepressants and life-threatening GI motility disorders (Aim 1), and common disorders of gut-brain interaction (Aim 2). In both aims, associations of each antidepressant class and individual medications will be explore, as well as gestational timing of exposure. Multiple sources of confounding by indication, familial susceptibility, and environment will be addressed using propensity score methods and through design techniques, including use of various comparator groups, sibling comparisons, and negative control exposures. Acknowledging the complex etiology of disorders of gut-brain interaction, Aims 2.1-2.3 will assess whether various early life stressors (neonatal factors, childhood mental health, and maternal mental health in childhood) are causal mediators or modifiers of the association between antidepressant exposure and disorders of gut- brain interaction. These sub-aims will provide critical insight into causal pathways and interventions. This work will produce generalizable and actionable results that will lead to improvements in preventing these debilitating pediatric GI conditions.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Serotonin is an important growth factor during gestation. Animal studies have shown that in early gestation, before the fetus’ own ability to synthesize serotonin develops, the mother’s serotonin system plays an important role in the fetus’ brain development in ways that impact future cognition and behavior. In mice, for example, we found that manipulation of the maternal serotonin system alters placental gene expression, fetal brain serotonin levels, and neuronal projections from the thalamus to the somatosensory cortex. When we initially tested these pathways in humans, we saw a similar initial relationship between maternal whole blood serotonin and offspring symptom severity; however, that study was retrospective, and restricted to a clinical population with autism spectrum disorder, and no study has examined the role of the placenta. Recognizing these limitations, it would be premature to develop a large new study without first testing whether and how the pathways identified in the animal models are conserved in humans. Thus, we propose an Exploratory/Developmental R21 project harnassing the strengths of an ongoing study of 375 mother-infants being followed from early pregnancy to offspring 30-36 months of life (R01MH119510). Because the parent study has already collected the maternal blood in early pregnancy, placenta and cordblood, infant neuroimaging at 2-4 weeks of age, and prospective offspring cognitive and behavioral assessments, there is no data collection in this proposal, and we will be able to test our questions immediately and cost-effectively. Our central hypothesis that lower maternal (but not paternal) whole blood serotonin levels in early (14-18 weeks) pregnancy will be associated with changes in placental transcriptome and diminished cord blood serotonin, reduced infant thalamocortical connectivity (using existing structural connectivity measures) at 2-4 weeks of life, and, ultimately, difficulties in neurocognitive and social functioning at 30-36 months of age. Preliminary analyses of the first twenty maternal blood samples we collected support feasibility and demonstrate a range of serotonin levels consistent with those in the population. This developmental proposal will dissect, for the first time, the effects of maternal and placental serotonergic systems on offspring brain and neurodevelopment. Anchoring this proposal to an established study further provides a rigorous and cost-effective infrastructure. Data from this study can fuel future studies to confirm and test generalizability of mechanisms in larger samples, and test promising interventions. Importantly, serotonin function is modifiable, e.g., through diet, micribiome and pharmacological changes, potentially opening up opportunities for maternal screening and prevention.

NIMH - National Institute of Mental Health

Project Summary/Abstract Our daily lives require constant decision-making in which we pursue potential rewards at the expense of potential costs. The integration of costs and benefits is an essential component of decision-making. Abnormal decision- making, including increased pursuit of high cost/ high reward options, is a transdiagnostic symptom of multiple psychiatric and neurological disorders including depression, post-traumatic stress disorder, addiction and many others. Stress exposure can induce these disorders and lead to long-term alterations in decision-making. Here, we will explore interactions between neural circuits and endocrine mechanisms that contribute to the pursuit of high cost/high reward options in mouse models of chronic stress exposure. Our previous work showed that the striosomal patches of the dorsomedial striatum are essential for integration of cost and benefit and that dysregulated activity in striosomal inputs contributes to persistent pursuit of high cost-high reward options in previously stressed rodents. Our previous work also showed that ghrelin receptor activity contributes to processing of reward and cost, and that the ghrelin receptor is present within the striatum. Here, we hypothesize that striosomal projection neuron hyperactivity is a key factor in stress-induced cost insensitivity, and activation of ghrelin receptor in the striosomes plays a causal role in this shift in decision- making. Using a naturalistic cost-benefit decision-making task that does not require food deprivation as motivation, we will examine decisions to pursue high costs paired with rewards and lower costs paired with rewards. We will record from striosomal projection neurons within and following different types of chronic stressor exposures to identify the “tipping point” at which abnormal striosomal activity and altered decision-making first emerge. We will use optogenetics to manipulate activity patterns in stress-exposed mice to “correct” stress- induced changes in decision-making and to “mimic” stress-induced striosomal firing patterns in unstressed mice to induce cost insensitivity. We will pharmacologically activate ghrelin receptors and determine whether this is sufficient to induce cost insensitivity and striosomal hyperactivity in unstressed mice. We will perform virus- mediated knockdown of the ghrelin receptor in striosomes and determine whether this is sufficient to prevent stress-induced changes in decision-making in stress-exposed mice. The goal of our proposed work is to identify a mechanistic basis for the shift in circuit activity and decision-making after repeated exposure to stressors, thereby advancing towards our long-term goals of predicting individuals who are at-risk for altered decision- making, and providing new peripheral and central targets for intervention to restore normal decision-making in the face of trauma and psychiatric illness.

NIMH - National Institute of Mental Health

ABSTRACT The global burden of mental illness is immense, costing the global economy over $6 trillion USD annually. Even so, neuropsychiatry is still in severe need of reliable biosignatures - to improve diagnosis and disease subtyping, and to better evaluate treatments. Resting-state functional MRI (rs-fMRI) opens up a vast landscape of discovery by approximating large-scale intrinsic brain networks. Even so, most individual rs-fMRI studies focus on single disorders with limited power, constrained by a complex analysis decision tree resulting in highly heterogeneous methods, with no global forum to verify or replicate discoveries. Here we launch an unprecedented Global fMRI Initiative in Psychiatry - with the goal of transforming functional neuroimaging in psychiatry by addressing long-standing roadblocks of reproducibility and standardization. We leverage the success of 15 years of work in the ENIGMA consortium to bring together over 1,000 laboratories from 45 countries to conduct the largest fMRI study in the literature. In doing so, we will harmonize international data sets across 8 psychiatric and neurodevelopmental disorders including: schizophrenia (SCZ), bipolar disorder (BD), post-traumatic stress disorder (PTSD), major depression disorder (MDD), obsessive compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and anorexia nervosa (AN). In Aim 1, our novel AI tools will create a global framework for transdiagnostic research by accelerating analysis and image quality control, quantifying methods-related variance and reliability. In Aim 2, we will isolate and rigorously validate biosignatures of mental illness on 15,719 cases and 20,225 controls. We then identify shared and distinct functional connectivity patterns across the 8 disorders, mirroring genetic findings from GWAS studies. This project includes a foreign subaward to MPI Dr. Clara Moreau’s team at Centre Hospitalier Universitaire Sainte-Justine, Montreal, Canada. The foreign effort is limited to analysis and creation of fMRI workflows; no data collection of any kind is supported by this award, and the project instead leverages already-collected data at no cost to U.S. taxpayers. This work cannot be conducted in the U.S.: Dr. Moreau chairs the ENIGMA fMRI Working Group and her team leads and architected HALFpipe, the primary analysis pipeline now in wide use across ENIGMA, an expertise that is not substitutable. The clear benefit to the U.S. is decisive: this is the largest, best-powered psychiatric neuroimaging study ever conducted, validating brain biomarkers across 8 disorders of urgent U.S. public-health importance and directly serving the U.S. biotech, pharmaceutical, and healthcare economy. As our Letters of Support show, a vast and growing community will benefit from this rigorous framework with efficient tools to replicate and validate their findings, galvanizing the field to address the replication crisis in neuroscience and psychiatry.

NIMH - National Institute of Mental Health

ABSTRACT The global burden of mental illness is immense, costing the global economy over $6 trillion USD annually. Even so, neuropsychiatry is still in severe need of reliable biosignatures - to improve diagnosis and disease subtyping, and to better evaluate treatments. Resting-state functional MRI (rs-fMRI) opens up a vast landscape of discovery by approximating large-scale intrinsic brain networks. Even so, most individual rs-fMRI studies focus on single disorders with limited power, constrained by a complex analysis decision tree resulting in highly heterogeneous methods, with no global forum to verify or replicate discoveries. Here we launch an unprecedented Global fMRI Initiative in Psychiatry - with the goal of transforming functional neuroimaging in psychiatry by addressing long-standing roadblocks of reproducibility and standardization. We leverage the success of 15 years of work in the ENIGMA consortium to bring together over 1,000 laboratories from 45 countries to conduct the largest fMRI study in the literature. In doing so, we will harmonize international data sets across 8 psychiatric and neurodevelopmental disorders including: schizophrenia (SCZ), bipolar disorder (BD), post-traumatic stress disorder (PTSD), major depression disorder (MDD), obsessive compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and anorexia nervosa (AN). In Aim 1, our novel AI tools will create a global framework for transdiagnostic research by accelerating analysis and image quality control, quantifying methods-related variance and reliability. In Aim 2, we will isolate and rigorously validate biosignatures of mental illness on 15,719 cases and 20,225 controls. We then identify shared and distinct functional connectivity patterns across the 8 disorders, mirroring genetic findings from GWAS studies. This project includes a foreign subaward to MPI Dr. Clara Moreau’s team at Centre Hospitalier Universitaire Sainte-Justine, Montreal, Canada. The foreign effort is limited to analysis and creation of fMRI workflows; no data collection of any kind is supported by this award, and the project instead leverages already-collected data at no cost to U.S. taxpayers. This work cannot be conducted in the U.S.: Dr. Moreau chairs the ENIGMA fMRI Working Group and her team leads and architected HALFpipe, the primary analysis pipeline now in wide use across ENIGMA, an expertise that is not substitutable. The clear benefit to the U.S. is decisive: this is the largest, best-powered psychiatric neuroimaging study ever conducted, validating brain biomarkers across 8 disorders of urgent U.S. public-health importance and directly serving the U.S. biotech, pharmaceutical, and healthcare economy. As our Letters of Support show, a vast and growing community will benefit from this rigorous framework with efficient tools to replicate and validate their findings, galvanizing the field to address the replication crisis in neuroscience and psychiatry.

National Institutes of Health

In 1999, at the direction of Congress, the National Institute on Aging (NIA), in conjunction with the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute of Mental Health (NIMH), and the National Institute of Nursing Research (NINR) embarked on the Alzheimer's Disease (AD) Prevention Initiative. An important part of the AD Prevention Initiative is to quicken the pace for translating basic science findings into clinical trials to evaluate treatment and prevention strategies. This Funding Opportunity Announcement (FOA) focuses on AD drug discovery while companion FOAs are targeted to AD drug development and AD pilot clinical trials. In this FOA, participating institutes invite qualified researchers to submit research grant applications directed toward the discovery, development, and preclinical testing in cellular, tissue, and animal models of novel compounds for the prevention and treatment of the cognitive impairment and behavioral symptoms associated with Alzheimer's disease (AD). Applications submitted to the NIH will be assigned and reviewed according to the usual NIH peer review procedures. Meritorious applications will be funded by the assigned NIH Institutes or co-funded by the assigned NIH Institute and the Institute for the Study of Aging (ISOA). NIA has set-aside $3.0 Million total costs in FY 2006 for applications sent in response to this PA. -This FOA will use the NIH Exploratory/Developmental Grant (R21) award mechanism. -The R21 is intended to encourage exploratory and developmental research projects by providing support for the early and conceptual stages of these projects. -All investigator-initiated exploratory/developmental grant applications described in this announcement will be assigned to participating ICs according to standard PHS referral guidelines and specific program interests. -Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. The total amount awarded and the number of awards will depend upon the mechanism numbers, quality, duration, and costs of the applications received. -Project Period and Award Levels: The applicant may request a project period of up to two years with a combined budget for direct costs of up to $275,000 for the two-year period. -Eligible organizations: For-profit organizations; Non-profit organizations; Public or private institutions, such as universities, colleges, hospitals, and laboratories; Eligible agencies of the Federal government; Units of State government; Units of local government; Domestic Institutions; and Foreign Institutions. -Eligible Project Directors/Principal Investigators (PD/PIs): Any individual with the skills, knowledge and resources necessary to carry out the proposed research, is invited to work with his/her institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support. -An R21 is not renewable. -Applicants may submit more than one application, provided they are scientifically distinct.

NHLBI - National Heart Lung and Blood Institute

Project Summary Sudden, life-threatening cardiac events can be terrifying experiences that can trigger the onset of posttraumatic stress disorder (PTSD). PTSD symptoms are common after cardiac events, with over 1 in 5 patients receiving implantable cardioverter defibrillators (ICDs) for prevention of life-threatening arrhythmias and sudden cardiac arrest exhibiting elevated PTSD symptoms. Cardiac disease-induced PTSD symptoms are associated not only with worse mental health but a worse clinical prognosis, including poorer quality of life (QoL), greater disability, and greater risk of event recurrence and/or all-cause mortality. Further, cardiac-focused anxiety sensitivity—a unique aspect of cardiac disease-induced PTSD—is linked to worse health, medical reassurance seeking, and greater healthcare utilization. However, evidence-based interventions for these cardiac-induced psychological presentations are lacking. This R34 proposal will draw from existing, evidence-based psychotherapies to develop a streamlined intervention that addresses cardiac trauma-related fear and cardiac-focused anxiety sensitivity— two key manifestations of PTSD after cardiac events that relate to adverse outcomes and are direct targets of gold standard, exposure-based interventions for PTSD and panic disorder. Trauma-focused exposure reduces trauma-related fear and interoceptive exposure reduces anxiety sensitivity, but neither intervention has been tested in patients with cardiac trauma. After initial intervention development (Stage Ia), a pilot randomized controlled trial (RCT) will be conducted (Stage Ib), in which patients with ICDs (N=70) from the UCLA Cardiac Arrhythmia Center will be randomized to 1) the trauma and anxiety sensitivity exposure-based treatment, called Cardiac Fears Treatment (CFT), or 2) standard supportive therapy (treatment as usual [TAU]). Participants will be assessed at pre-treatment, several periods throughout treatment, post-treatment, and a 6-month follow-up. In Aim 1, we will develop the CFT intervention using an iterative approach, guided by prior research and qualitative interviews with key stakeholders (e.g., cardiology experts), and pilot testing in a small (N=8) open trial of patients with ICDs will yield initial feasibility and acceptability data. Subsequent aims will analyze data from the pilot RCT, generating additional feasibility and acceptability data, along with preliminary efficacy information. In Aim 2, we will compare CFT to TAU on psychological responses (self-report and behavioral task measures of cardiac trauma-related fear and cardiac-focused anxiety sensitivity). Aim 3 will compare CFT to TAU on health- related outcomes (health-related QoL and healthcare utilization). Finally, in Aim 4, we will explore whether key psychological processes targeted in the intervention (cardiac trauma-related fear and cardiac-focused anxiety sensitivity) mediate change in health-related outcomes. By targeting key psychological processes associated with adverse outcomes after a cardiac trauma, this mechanism-focused study has the potential to improve the emotional and physical health of cardiac patients and will generate critical feasibility, acceptability, and preliminary efficacy data needed to inform a grant proposal to test a refined version of CFT in a larger RCT.

NIMH - National Institute of Mental Health

Artificial intelligence (AI) shows significant promise in optimizing HIV prevention and treatment efforts by identifying modifiable behavioral or environmental factors and enhancing intervention strategies to deliver more impactful interventions. This proposal focuses on identifying factors that predict virologic failure among persons living with HIV (PLWH) in the United States (US). We propose to design and integrate multimodal data from a mobile health system called Behavioral Engagement and Adherence Monitoring (BEAM), guided by human- centered design and AI ethical principles, to capture deeper contextual information surrounding HIV virologic failure in a two-year longitudinal cohort study of PLWH at a large US-based HIV clinic. Multimodal data will be collected to develop accurate, safe, efficient, and unbiased AI models that, in conjunction with knowledge graphs (KGs), will predict virologic failure among PLWH. Throughout this process, a Community Advisory Board (CAB) of PLWH will provide iterative feedback on all aspects of the study to ensure the models conform to AI ethical principles, minimizes bias, and are patient centered. We propose the following aims: Aim 1: With extensive input from the CAB, focus groups, and scientific literature, we will identify key predictors of HIV virologic failure, and their interconnections, and develop a knowledge graph to inform the design and implementation of BEAM (Behavioral Engagement and Adherence Monitoring). We will conduct four focus groups (n=8/group) of PLWH and integrate findings with scientific evidence to develop initial drafts of KGs. Aim 2: Implement BEAM in a 24-month longitudinal cohort of 200 patients at a large US-based HIV clinic to capture multimodal indicators of virologic failure risk allowing for real-world validation and adaptation of the knowledge graphs. We will collect participant data from wearables (i.e., Fitbits), medication event monitoring systems (MEMS), surveys, ecological momentary assessment (EMA) surveys, and a mobile app over a 12-month period, and clinical data from electronic health records (EHR) over a 24-month period. Aim 3: Using a human-centered and ethical approach, develop AI models to predict HIV virologic failure and iteratively refine knowledge graphs. AI models will be constructed through pre-processing the data, model training and evaluation, and integrating knowledge graphs. Aim 4: Leverage AI models and knowledge graphs to identify and co-develop, with the CAB, intervention use cases to deliver tailored behavioral supports to at-risk PLWH and evaluate them through theater testing. We will co-create with the CAB novel intervention strategies by leveraging AI-predicted risk factors and knowledge graph-derived insights and conduct theater testing with PLWH (n=8) and key stakeholders (n=8). The proposal is significant because rate of viral suppression among PLWH in the US is only at 65%, despite decades of efforts to engage PLWH in care. The public health impact of this proposal is strengthened by the application of the model to multiple lines of promising interventions to maximize their impact, to be tested more fully in future trials.

National Institutes of Health

<p>Forty to sixty percent of individuals with opioid use disorder (OUD) have co-occurring chronic pain (CP), which impacts their ability to fully engage in treatment. Effective management of both conditions is hindered by siloed medical disciplines and health systems. HEAL Integrative Management of Chronic Pain and OUD for Whole Recovery (IMPOWR) was funded in FY21 to support 11 unique clinical trials to test novel interventions for the management of co-occurring chronic pain and OUD at the patient-level. The current NOFO will develop strategies to address barriers to the sustainable and effective delivery of integrated OUD/pain care at the health systems level. IMPOWR identified patient interventions that were effective and ready to implement. The current NOFO will address how health systems could be improved to facilitate the use of effective integrative interventions, including the involvement and roles of peer specialists, clinicians, health system leaders and other key decision makers.&nbsp;Also, this NOFO will characterize where such care can be optimally and efficiently delivered. Studies will identify collaborative care models, implementation strategies, and other innovative health system approaches to meaningfully integrate CP and OUD service provision in health settings. These studies will address complex factors that influence the ability to scale and sustain effective collaborative and integrated care for pain and OUD.&nbsp;</p><p><br></p><p>The National Institute on Drug Abuse (NIDA) in partnership with National Institute on Alcohol and Alcoholism (NIAAA), National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institute of Mental Health (NIMH), and National Center for Complementary and Integrative Health (NCCIH), and National Institute of Neurological Disorders and Stroke (NINDS) intends to publish a Notice of Funding Opportunity (NOFO) to solicit applications for research on the effective management of OUD and CP. Applications are not being solicited at this time. Notice is being provided to allow potential applicants sufficient time to develop meaningful collaborations and responsive projects. This NOFO will utilize the RM1 activity code. Investigators with expertise and insights into this area of chronic pain management and OUD/opioid misuse are encouraged to begin to consider applying for this new NOFO. In addition, collaborative investigations combining expertise in community-based participatory research approaches, implementation science, and other strategies to amplify scalability and sustainability will be encouraged and, these investigators should also begin considering applying for this NOFO.</p>

National Institutes of Health

Forty to sixty percent of individuals with opioid use disorder (OUD) have co-occurring chronic pain (CP), which impacts their ability to fully engage in treatment. Effective management of both conditions is hindered by siloed medical disciplines and health systems. HEAL Integrative Management of Chronic Pain and OUD for Whole Recovery (IMPOWR) was funded in FY21 to support 11 unique clinical trials to test novel interventions for the management of co-occurring chronic pain and OUD at the patient-level. The current NOFO will develop strategies to address barriers to the sustainable and effective delivery of integrated OUD/pain care at the health systems level. IMPOWR identified patient interventions that were effective and ready to implement. The current NOFO will address how health systems could be improved to facilitate the use of effective integrative interventions, including the involvement and roles of peer specialists, clinicians, health system leaders and other key decision makers. Also, this NOFO will characterize where such care can be optimally and efficiently delivered. Studies will identify collaborative care models, implementation strategies, and other innovative health system approaches to meaningfully integrate CP and OUD service provision in health settings. These studies will address complex factors that influence the ability to scale and sustain effective collaborative and integrated care for pain and OUD. The National Institute on Drug Abuse (NIDA) in partnership with National Institute on Alcohol and Alcoholism (NIAAA), National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institute of Mental Health (NIMH), and National Center for Complementary and Integrative Health (NCCIH), and National Institute of Neurological Disorders and Stroke (NINDS) intends to publish a Notice of Funding Opportunity (NOFO) to solicit applications for research on the effective management of OUD and CP. Applications are not being solicited at this time. Notice is being provided to allow potential applicants sufficient time to develop meaningful collaborations and responsive projects. This NOFO will utilize the RM1 activity code. Investigators with expertise and insights into this area of chronic pain management and OUD/opioid misuse are encouraged to begin to consider applying for this new NOFO. In addition, collaborative investigations combining expertise in community-based participatory research approaches, implementation science, and other strategies to amplify scalability and sustainability will be encouraged and, these investigators should also begin considering applying for this NOFO.

National Institutes of Health

<p>40-75% percent of individuals with opioid use disorder (OUD) have co-occurring chronic pain (CP), which impacts their ability to fully engage in treatment. Effective management of both conditions is hindered by siloed medical disciplines and health systems. HEAL Integrative Management of Chronic Pain and OUD for Whole Recovery (IMPOWR) was funded in FY21 to test novel interventions for the management of co-occurring CP and OUD at the patient level. This initiative will test different implementation strategies and other approaches to address scalability and sustainability of evidence based practices for CP and OUD from a health system perspective. Studies will engage key decision leaders in health systems including but not limited to: peer specialists, clinicians, health system leaders, and payers. Studies will execute a single hybrid II/III implementation-effectiveness trial to focus on collaborative care models and implementation strategies to meaningfully integrate CP and OUD service provision in diverse health settings. These studies will address complex factors that influence the ability to scale and sustain effective and integrated care for CP and OUD. The BEACON Center will provide: (1) network coordination support, (2) capacity building at the intersection of CP, OUD, and implementation science, (3) annual surveys/qualitative activities to understand different barriers and attitudes impacting access and sustained use to integrated CP and OUD service delivery, (4) develop important resources for key stakeholder audiences that can inform/improve sustainability and scalability of evidence-based practices.</p><p>The National Institute on Drug Abuse (NIDA) in partnership with National Institute on Alcohol and Alcoholism (NIAAA), National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institute of Mental Health (NIMH), and National Center for Complementary and Integrative Health (NCCIH), and National Institute of Neurological Disorders and Stroke (NINDS) intends to publish a Notice of Funding Opportunity (NOFO) to solicit applications for research on the effective management of OUD and CP. Applications are not being solicited at this time. Notice is being provided to allow potential applicants sufficient time to develop meaningful collaborations and responsive projects. This NOFO will utilize the U2C activity code. Investigators with expertise and insights into this area of CP management and OUD/opioid misuse are encouraged to begin to consider applying for this new NOFO. In addition, collaborative investigations combining expertise in community-based participatory research approaches, implementation science, and other strategies to amplify scalability and sustainability will be encouraged and, these investigators should also begin considering applying for this NOFO. Grant authorities that allow NIDA to forecast this opportunity are as follows: 42 U.S.C. § 241 and § 284.</p>

National Institutes of Health

40-75% percent of individuals with opioid use disorder (OUD) have co-occurring chronic pain (CP), which impacts their ability to fully engage in treatment. Effective management of both conditions is hindered by siloed medical disciplines and health systems. HEAL Integrative Management of Chronic Pain and OUD for Whole Recovery (IMPOWR) was funded in FY21 to test novel interventions for the management of co-occurring CP and OUD at the patient level. This initiative will test different implementation strategies and other approaches to address scalability and sustainability of evidence based practices for CP and OUD from a health system perspective. Studies will engage key decision leaders in health systems including but not limited to: peer specialists, clinicians, health system leaders, and payers. Studies will execute a single hybrid II/III implementation-effectiveness trial to focus on collaborative care models and implementation strategies to meaningfully integrate CP and OUD service provision in diverse health settings. These studies will address complex factors that influence the ability to scale and sustain effective and integrated care for CP and OUD. The BEACON Center will provide: (1) network coordination support, (2) capacity building at the intersection of CP, OUD, and implementation science, (3) annual surveys/qualitative activities to understand different barriers and attitudes impacting access and sustained use to integrated CP and OUD service delivery, (4) develop important resources for key stakeholder audiences that can inform/improve sustainability and scalability of evidence-based practices.The National Institute on Drug Abuse (NIDA) in partnership with National Institute on Alcohol and Alcoholism (NIAAA), National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institute of Mental Health (NIMH), and National Center for Complementary and Integrative Health (NCCIH), and National Institute of Neurological Disorders and Stroke (NINDS) intends to publish a Notice of Funding Opportunity (NOFO) to solicit applications for research on the effective management of OUD and CP. Applications are not being solicited at this time. Notice is being provided to allow potential applicants sufficient time to develop meaningful collaborations and responsive projects. This NOFO will utilize the U2C activity code. Investigators with expertise and insights into this area of CP management and OUD/opioid misuse are encouraged to begin to consider applying for this new NOFO. In addition, collaborative investigations combining expertise in community-based participatory research approaches, implementation science, and other strategies to amplify scalability and sustainability will be encouraged and, these investigators should also begin considering applying for this NOFO. Grant authorities that allow NIDA to forecast this opportunity are as follows: 42 U.S.C. 241 and 284.

Heal The Hood Committee

The Marvin Thomas Memorial Fund requests Neighborhood Matching Funds to host five community events from November 2024 to October 2025, promoting engagement among underrepresented groups, non-native English speakers, and communities of color in King County, specifically Southeast Seattle residents who have some of the highest poverty rates and the largest percentage of low-income residents in Seattle. These free, inclusive events will strengthen community connections, raise awareness of health disparities, and celebrate local culture. Events include a basketball tournament, a community BBQ, a back-to-school supply giveaway, a cancer awareness event honoring local heroes, and a senior storytelling and basket giveaway. All events will be held in Seattle encouraging relationship building and physical, mental, and social well-being.

Health Canada

Grants for community-based mental health promotion, substance use prevention, and harm reduction programs across Canada.

NIDA - National Institute on Drug Abuse

PROJECT SUMMARY Alcohol, tobacco, and other drug use (ATOD), sexual health risks, and postpartum depression (PPD) are common and significant interrelated factors that are associated with poor health consequences for pregnant women and their infants, especially among rural, under-resourced communities. Thus, there is an urgent need to simultaneously address these health risks together during this vulnerable time. While pregnancy has been recognized as a window of opportunity in which to intervene, there are no empirically supported interventions tailored to specifically address these growing public health concerns together in rural women during pregnancy and postpartum. The objective of this R01 study is to fill this critical gap by building upon our promising R21/R01 findings by (1) partnering with a community advisory board to adapt and optimize the existing Health Check-up for Expectant Moms (HCEM) web-delivered Screening, Brief Intervention and Referral to Treatment or Prevention (SBIRT/P) program to include the interconnected risks of tobacco use and postpartum depression (PPD) among rural pregnant women (herein referred to as HCEM+), and (2) testing the efficacy of the HCEM+ in reducing ADOT, STI, and PPD risk more than a time and information matched control condition in rural pregnant women seeking prenatal care. This research addresses cross-cutting priorities in line with NIDA’s Strategic Plan to advance science on drug use: (1) prioritizing research to combat stigma and improve engagement in treatment, (2) developing and enhancing culturally responsive and tailored interventions, and (3) delivering care for substance use and co-occurring health conditions such as STIs and mental illness. We propose a two-group, randomized controlled trial in which a sample of 250 high-risk rural pregnant women attending prenatal care will be assigned to either (a) a web-delivered, two-session SBIRT/P plus two booster sessions consistent with motivational interviewing and informed by the Information-Motivation-Behavior (IMB) model, the HCEM+, or (b) a web-delivered control condition. Web-delivered follow-up assessments will occur at 8 and 24 weeks antenatally, and at 6 weeks postpartum, extending outcomes to the postpartum period. Specific Aim 1 is to test the hypothesis that HCEM+, compared to an attention, time and information matched control condition, will reduce unprotected sexual occasions and ADOT use among at-risk pregnant women during pregnancy at 2 and 6-months follow-up, and will increase treatment engagement. Specific Aim 2 is to test the hypothesis that HCEM+, compared to control, will reduce STIs and ADOT use at 6 weeks postpartum and will result in better birth outcomes and reduced rates of PPD. An economic evaluation of the costs of the HCEM+ will occur to guide future implementation and dissemination. Results of this program of research are expected to inform the development of a practical, cost-effective, high-reaching web-delivered SBIRT/P program tailored to reach high-risk rural and under-resourced women with extended impact to the postpartum period.

National Institutes of Health

-Purpose. The purpose of this Funding Opportunity Announcement (FOA) is to invite grant applications for biological, behavioral, social, addictive, and mental health research related to the health of lesbian, gay, bisexual, transgender, intersex, and other diverse populations. Proposed research should be appropriate for the missions of one or more of the participating Institutes. -Mechanism of Support. This FOA will utilize the NIH Research Project Grant (R01) award mechanism. Research applications that better fit under other award mechanisms, including the NIH Small Research Grant (R03) (see http://grants.nih.gov/grants/guide/pa-files/PA-06-180.html ), the NIH Academic Research Enhancement Award (R15) (see http://grants.nih.gov/grants/guide/pa-files/PA-06-042.html ), and the NIH Exploratory/Developmental Research Grant (R21) (see http://grants.nih.gov/grants/guide/pa-files/PA-06-181.html) are encouraged to be submitted under those other mechanisms. -Funds Available and Anticipated Number of Awards. Awards issued under this FOA are contingent upon the availability of funds and the submission of a sufficient number of meritorious applications.

State Treasurer's Office

Eligibility -Must be a health facility as defined in the Authority's Act (Section 15432(d) of the California Government Code) -Must be a non-profit 501(c)(3) corporation and qualify as a small or rural health facility or public health facility (e.g., district hospital) as defined in the Authority's Act (Section 15432(e) of the California Government Code)  -Small facilities must have annual gross revenues of $30 million or less (no revenue limit for rural facilities or district hospitals) -Must be licensed by the State of California, typically through the Department of Health Care Services, Public Health, or Social Services -Must have been in existence for at least three years, providing the same types of services -Must demonstrate evidence of discal soundness and the ability to meet the terms of the proposed loan -Facility must be certified, organized, maintained and operated for the diagnosis, care, prevention, and treatment of human illness, or physical, mental, or developmental disability, including convalescence and rehabilitation and including during care during and after pregnancy Use of Funds Funds may be used for: -Purchase, construction, renovation, or remodeling of real property -Purchase equipment and furnishings -Perform feasibility studies, site tests, and surveys associated with real property -Pay permit fees, architectural fees, and pre-construction costs -Refinancing existing debt Loan Terms -Minimum loan amount of $25,000 -Maximum loan amount of $1.5 million ($1 million for refinancing existing debt) -Interest rate of 3% (4% for refinancing existing debt) -Maximum loan maturity depends on use of funds.  Between 5 years for equipment and furnishings and 20 years for the purchase, construction and renovation of real property (15 years for refinancing existing debt) -Gross revenue pledge, as well as a lien on the equipment or property, is required -Maximum loan-to-value ratio of 95% -Borrowers must contribute a minimum of 5% (in the form of cash or documented project expenditures) toward project costs -Proforma debt service coverage of at least 1.0x Fees -$50 non-refundable application fee -Initial fee of 1.25% of the loan amount payable at closing -No ongoing program fees Required Documentation -Three most recent fiscal years of audited financial statements -Proof of adequate property and business insurance  

FIC - John E. Fogarty International Center for Advanced Study in the Health Sciences

Healthy Choices is a four-session behavior change communication intervention that was developmentally tailored for emerging adults to address self-management of health behaviors and HIV with evidence of positive effect on stigma and depression, built on Motivational Enhancement Therapy, integrating Motivational Interviewing with brief cognitive-behavioral strategies. Healthy Choices can be delivered in community settings by trained community health workers. When delivered with fidelity and in adequate dose, Healthy Choices results in reductions in alcohol use, HIV stigma, viral loads, and depression over follow-up compared to standard care. In the Dominican Republic, stigmas harm young people with HIV (YPWH). The Dominican Republic is a low- to middle- income country in the Latin America and Caribbean region, is 1 of 5 countries that accounts for over 95% of Caribbean HIV infections and has a culture that perpetuates stigmatizing attitudes and behaviors toward YPWH. To our knowledge, there are no Spanish-language interventions that concurrently address mental health, viral suppression, and stigma, tailored for young adults who are in a developmental period marked by exploration and a need for autonomy in health decision making. Considering the need for stigma reduction among YPWH to improve rates of viral suppression, reduce poor mental health, and encourage healthy coping by reducing problem alcohol use, we propose to adapt Healthy Choices for Spanish with local contexts plus co-create implementation strategies with community advising for future scale up. We will pilot test the adapted intervention and proposed intervention strategies, using a community-led implementation approach for feasibility, acceptability, and to assess for a signal of potential effectiveness on continuum of care outcomes including antiretroviral adherence and viral load. Considering the importance of context and the community-orientation of this study, we will apply the Exploration, Preparation, Implementation, Sustainment (EPIS) implementation science model, focusing on the Exploration and Preparation phases. We will engage community-based organizations (CBO) and a clinic in the Dominican Republic that work extensively with YPWH. Our investigator team has a long history of successful collaboration with impact on public health policy in the Latin American and Caribbean region. We propose three aims: (1) Elucidate barriers and implementation strategies for the Healthy Choices intervention; (2) Adapt and culturally translate the intervention for local contexts, and (3) Pilot test Healthy Choices with implementation strategies for feasibility and acceptability. If successful, we will have preliminary data for a full-scale hybrid type 1 effectiveness implementation randomized controlled trial of the intervention for underserved Spanish-speaking YPWH in the Dominican Republic with potential relevance to Spanish-speaking groups in the United States.