Mayo Clinic

PRECISION MEDICINE INITIATIVE COHORT PROGRAM BIOBANK

MAYO COMPREHENSIVE CANCER CENTER GRANT

STATISTICS AND DATA CENTER FOR THE ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY

ARTFL LEFFTDS LONGITUDINAL FRONTOTEMPORAL LOBAR DEGENERATION (ALLFTD)

MAYO CLINIC CENTER FOR CLINICAL AND TRANSLATIONAL SCIENCE (CCATS)

CREST-2 CLINICAL COORDINATING CENTER

MAYO CLINIC CENTER FOR CLINICAL AND TRANSLATIONAL RESEARCH

MAYO CLINIC CENTER FOR CLINICAL AND TRANSLATIONAL SCIENCE (CCATS)

NORTH CENTRAL CANCER TREATMENT GROUP

ALZHEIMER DISEASE PATIENT REGISTRY

MAYO CLINIC BREAST CANCER SPORE

CENTRALLY-LINKED LONGITUDINAL PERIPHERAL BIOMARKERS OF AD IN MULTI-ETHNIC POPULATIONS - SUMMARY ABSTRACT (30 LINES): EXISTING CEREBROSPINAL FLUID (CSF) AND NEUROIMAGING MEASURES OF AMYLOID SS, TAU AND NEURODEGENERATION (A,T,N) SERVE AS USEFUL DIAGNOSTIC BIOMARKERS FOR ALZHEIMER’S DISEASE (AD), HOWEVER THERE REMAINS AN URGENT, UNMET NEED FOR BLOOD BASED BIOMARKERS IN AD. FIRST, MULTI-OMIC STUDIES DISCOVERED MANY PERTURBED BIOLOGICAL PATHWAYS IN AD, HOWEVER, SYSTEMATIC STUDIES FOR BIOMARKERS THAT CAPTURE THESE DIVERSE BIOLOGICAL FACETS OF AD ARE LIMITED. SECOND, AD IS A HETEROGENEOUS DISORDER BUT BIOMARKERS THAT CAN DISTINGUISH THE BIOLOGICAL SUBTYPES OF AD ARE LACKING. THIRD, CORE AD NEUROPATHOLOGY OFTEN CO-EXISTS WITH OTHER NEUROPATHOLOGIES SUCH AS VASCULAR DISEASE (V). THESE CO-MORBIDITIES AND CO-PATHOLOGIES NEED TO BE CONSIDERED IN BIOMARKER DISCOVERY. FOURTH, EXISTING BIOMARKER STUDIES ARE HEAVILY FOCUSED ON NON-HISPANIC WHITES (NHW). SIMILAR STUDIES IN UNDERREPRESENTED POPULATIONS (URP) ARE NEEDED. THIS U19, BRINGING TOGETHER >40 EXPERTS ACROSS 13 INSTITUTIONS, AIMS TO BRIDGE THESE KNOWLEDGE GAPS FOR DISCOVERY AND VALIDATION OF CENTRALLY-LINKED LONGITUDINAL PERIPHERAL BIOMARKERS OF AD (CLEAR-AD) IN MULTI-ETHNIC POPULATIONS. CLEAR-AD U19 IS BASED ON THE PREMISE THAT AD IS A COMPLEX DISORDER IN WHICH MANY BIOLOGICAL PATHWAYS ARE DISRUPTED DUE TO MULTI-OMIC PERTURBATIONS, WHICH CAN BE DETECTED IN BRAIN AND REFLECTED IN BLOOD, I.E. CENTRALLY-LINKED PERIPHERAL MOLECULAR SIGNATURES (CLPMS). THE SPECIFIC AIMS OF CLEAR-AD U19 ARE: 1) TO DISCOVER CLPMS OF THE COMPLEX AND HETEROGENEOUS AD PATHOPHYSIOLOGY AND ITS CO-PATHOLOGIES. 2) TO IDENTIFY LONGITUDINAL CLPMS THAT DETECT AND PREDICT DYNAMIC NEUROIMAGING, FLUID BIOMARKER, AND CLINICAL CHANGES ACROSS AD SPECTRUM. 3) TO CHARACTERIZE DIFFERENCES AND SIMILARITIES IN CLPMS PROFILES ACROSS NHW, AFRICAN AMERICAN (AA) AND LATINO AMERICAN (LA) PARTICIPANTS TO UNCOVER BIOMARKER PATTERNS IN MULTI-ETHNIC GROUPS. 4) TO MAKE THESE VAST RESOURCES AVAILABLE TO THE SCIENTIFIC COMMUNITY TO AMPLIFY AND ACCELERATE ITS IMPACT. IN THIS U19 MANAGED BY THE ADMINISTRATIVE CORE, WE WILL LEVERAGE NIH-FUNDED ADNI, MCSA AND ADRC COHORTS OF >3,700 MULTI-ETHNIC PARTICIPANTS TO GENERATE >20,000 MULTI-OMICS MEASURES (OMICS CORE) THAT WILL BE PROCESSED AND INTEGRATED WITH >48,000 HARMONIZED AD COGNITIVE, NEUROIMAGING AND FLUID ENDOPHENOTYPES (ANALYTIC CORE). USING THESE DATA, WE WILL IDENTIFY BRAIN REGION AND CELL-TYPE SPECIFIC CLPMS, WHICH REFLECT BIOLOGICAL SUBTYPES OF AD AND DISEASE STAGE (PROJECT 1). WE WILL DISCOVER LONGITUDINAL CHANGES IN CLPMS THAT PREDICT COGNITIVE AND A/T/N/V PROGRESSION (PROJECT 2). WE WILL DEFINE LONGITUDINAL COGNITIVE AND A/T/N/V CHANGES AND CLPMS IN URP THAT ARE EITHER CONSERVED WITH NHW OR POPULATION-SPECIFIC (PROJECT 3). THIS U19 WILL A) IDENTIFY THE NEXT GENERATION OF AD BIOMARKERS WITH MECHANISTIC INSIGHTS; B) ESTABLISH A PRECISION MEDICINE APPROACH FOR RIGOROUS MULTI-OMICS BIOMARKER DISCOVERY AND VALIDATION IN AD; C) DISCOVER MOLECULES THAT CAN SERVE AS BIOMARKERS AND THERAPEUTIC TARGETS; D) ENHANCE BIOMARKER RESEARCH IN TRIAL-READY MULTI-ETHNIC POPULATIONS; AND E) GENERATE AND SHARE A VAST AND HARMONIZED RESOURCE OF ENDOPHENOTYPE AND MULTI-OMICS DATA IN NIH-FUNDED COHORTS.

BIOINFORMATICS APPROACH TO INFLUENZA A/H1N1 VACCINE IMMUNE PROFILING

BIOLOGY AND PATHOBIOLOGY OF APOE IN AGING AND ALZHEIMER'S DISEASE - PROJECT SUMMARY (APOE U19: OVERALL) THE OVERARCHING GOAL OF THIS U19 PROJECT IS TO COMPREHENSIVELY UNDERSTAND THE BIOLOGY AND PATHOBIOLOGY OF APOLIPOPROTEIN E (APOE) IN AGING AND ALZHEIMER’S DISEASE (AD) TO INFORM THERAPEUTIC STRATEGIES. THE E4 ALLELE OF THE APOE GENE (APOE4) IS THE STRONGEST GENETIC RISK FACTOR FOR AD IMPACTING 50-70% OF ALL AD PATIENTS, WHILE THE E2 ALLELE IS PROTECTIVE COMPARED TO THE COMMON E3 ALLELE. APOE4 IS ALSO A STRONG RISK FACTOR FOR AGE-RELATED COGNITIVE DECLINE AND VASCULAR COGNITIVE IMPAIRMENT. TO INTEGRATE EXISTING KNOWLEDGE AND ADDRESS CRITICAL GAPS, WE PROPOSE A UNIFIED APOE CASCADE HYPOTHESIS THAT THE STRUCTURAL DIFFERENCES AND RELATED BIOCHEMICAL PROPERTIES AMONG THE THREE APOE ISOFORMS INITIATE THEIR DIFFERENTIAL EFFECTS ON A CASCADE OF EVENTS AT THE CELLULAR AND SYSTEMS LEVELS ULTIMATELY IMPACTING AGING-RELATED PATHOGENIC CONDITIONS INCLUDING AD. TOWARDS THIS, WE HAVE ASSEMBLED A MULTI-DISCIPLINARY TEAM TO SYNERGIZE EXPERTISE AND RESOURCES ACROSS MULTIPLE INSTITUTIONS. BY INTEGRATING FIVE INTERACTIVE PROJECTS AND SEVEN ROBUST CORES, WE WILL CREATE A NEXUS FOR APOE-RELATED AGING RESEARCH, SHARING THE KNOWLEDGE, EXPERTISE AND RESOURCES WITH THE BROADER SCIENTIFIC COMMUNITY. PROJECT 1 WILL WORK CLOSELY WITH CORE B TO ADDRESS THE STRUCTURAL AND BIOCHEMICAL PROPERTIES OF THE THREE APOE ISOFORMS TO GENERATE INSIGHTS FOR FUNCTIONAL OUTCOMES. PROJECTS 2, 3 AND 4 WILL INTERACTIVELY STUDY HOW APOE ISOFORMS EXPRESSED IN ASTROCYTES, MICROGLIA, OR VASCULAR MURAL CELLS IMPACT LIPID METABOLISM, GLIAL AND VASCULAR FUNCTIONS, AD-RELATED PATHOLOGIES, AND CELLULAR AND MOLECULAR PATHWAYS USING CONDITIONAL MOUSE MODELS AND SYSTEMS- BASED APPROACHES. THESE STUDIES WILL GENERATE CELL TYPE-SPECIFIC APOE/LIPOPROTEIN PARTICLES THAT WILL BE COLLECTED THROUGH IN VIVO MICRODIALYSIS FOR STRUCTURAL AND BIOCHEMICAL STUDIES. PROJECT 5 WILL CARRY OUT GENOMIC AND GENETIC ANALYSES TO IDENTIFY MODIFIERS OF APOE-RELATED AGE AT ONSET OF AD. STUDIES IN PROJECTS 2-5 WILL BE INTERACTIVELY SUPPLEMENTED BY NEUROPATHOLOGICAL STUDIES USING POSTMORTEM BRAINS FROM HEALTHY AGING STUDIES OR WITH AD PATHOLOGIES (CORE C), BIOMARKER STUDIES USING BOTH HUMAN AND MOUSE BIOSPECIMENS (CORE D), AND FUNCTIONAL STUDIES USING HUMAN IPSC-DERIVED CELLULAR AND ORGANOID MODELS (CORE E). THIS U19 PROPOSAL IS SUPPORTED BY A COMPREHENSIVE MULTI-OMICS CORE (CORE F) FOR CENTRALIZED PROTEOMICS, LIPIDOMICS, AND METABOLOMICS STUDIES ON VARIOUS ANIMAL AND IPSC MODELS, AS WELL AS HUMAN POSTMORTEM BRAINS AND FLUID BIOSPECIMENS. THE BIOINFORMATICS, BIOSTATISTICS, AND DATA MANAGEMENT CORE (CORE G) WILL PROVIDE CRITICAL SUPPORTS FOR ANALYZING LARGE DATASETS INCLUDING THOSE FROM SINGLE-CELL RNA-SEQ AND BIOSTATISTICS SUPPORTS TO ENSURE SCIENTIFIC RIGOR. CORE G WILL ALSO WORK CLOSELY WITH THE ADMINISTRATIVE CORE (CORE A) TO MAINTAIN AN APOE WEB PORTAL DESIGNATED AS EPAAD WHERE KNOWLEDGE, RESOURCES, AND DATA WILL BE SHARED WITH THE SCIENTIFIC COMMUNITY. CORE A WILL ALSO ORGANIZE ANNUAL APOE SYMPOSIUM TO PROMOTE COLLABORATION AND ENGAGE THE APOE COMMUNITY. AS SUCH, THIS U19 WILL DRIVE A TEAM-BASED EFFORT TO GENERATE ESSENTIAL KNOWLEDGE TO GUIDE DISEASE- MODIFYING THERAPIES FOR AD AND OTHER AGING-RELATED CONDITIONS.

MAYO CLINIC SPORE IN OVARIAN CANCER

CANCER AND LEUKEMIA GROUP B STATISTICAL CENTER

TARGETING CELLULAR SENESCENCE TO EXTEND HEALTHSPAN

A SYSTEM APPROACH TO TARGETING INNATE IMMUNITY IN AD

MAYO ALZHEIMER'S DISEASE RESEARCH CENTER

MAYO CLINIC SPORE IN PANCREATIC CANCER

THE LYMPHOMA EPIDEMIOLOGY OF OUTCOMES (LEO) COHORT STUDY

MAYO ALZHEIMER'S DISEASE RESEARCH CENTER

MAYO CLINIC MULTIPLE MYELOMA SPORE

MAYO CENTER FOR CELL SIGNALING IN GASTROENTEROLOGY

PATHOBIOLOGY OF THE ENTERIC SYSTEM

PHYSIOLOGY OF BONE METABOLISM IN AN AGING POPULATION

LIVING ORGAN DONATION REIMBURSEMENT PROGRAM (LODRP)

PATHOBIOLOGY OF NEURODEGENERATION IN C9ORF72 REPEAT EXPANSION

COMMUNITY CLINICAL ONCOLOGY PROGRAM

LONGITUDINAL EVALUATION OF FAMILIAL FRONTOTEMPORAL DEMENTIA SUBJECTS (LEFFTDS)

LONGITUDINAL IMAGING BIOMARKERS OF DISEASE PROGRESSION IN DLB

PROSTATE CANCER SUSCEPTIBILITY: THE ICPCG STUDY

PATIENT-CENTRIC ELECTRONIC ENVIRONMENT FOR IMPROVING ACUTE CARE PERFORMANCE

MAYO CLINIC HEPATOBILIARY SPORE

EMR PHENOTYPE AND COMMUNITY ENGAGED GENOMIC ASSOCIATIONS

PHARMACOGENETICS OF PHASE II DRUG METABOLIZING ENZYMES

INVESTIGATING REGIONAL AND CELLULAR VULNERABILITIES TO TAU PATHOLOGY IN YOUNG-ONSET ALZHEIMER'S DISEASE - PROJECT SUMMARY/ABSTRACT DEVELOPMENT OF COGNITIVE PROBLEMS AT ANY AGE IS DEVASTATING, BUT DEVELOPMENT OF COGNITIVE PROBLEMS IN WORKING-AGE PEOPLE WITH DEPENDENTS REPRESENTS A MAJOR PUBLIC HEALTH CONCERN. YOUNG-ONSET ALZHEIMER'S DISEASE (YOAD) IS DEFINED AS INDIVIDUALS WHO PRESENT BEFORE AGE 65 AND LACK MUTATIONS KNOWN TO CAUSE ALZHEIMER'S DISEASE (AD) PATHOLOGY. NEUROPATHOLOGY AND NEUROIMAGING STUDIES DEMONSTRATE GREATER TAU ACCUMULATION IN YOAD WHO OFTEN PRESENT WITH ATYPICAL, NON-AMNESTIC SYNDROMES. OUR PRELIMINARY DATA DEMONSTRATES THAT TAU ACCUMULATION OCCURS THROUGH PROGRESSIVE MATURITY LEVELS IN TANGLE-BEARING NEURONS, WHICH DISPROPORTIONATELY AFFECTS CORTICAL MORE THAN LIMBIC STRUCTURES IN YOAD. MOREOVER, WE SHOW YOUNGER AGE ONSET IS ASSOCIATED WITH GREATER TANGLE ACCUMULATION AND NEURONAL LOSS IN NUCLEUS BASALIS OF MEYNERT (CHOLINERGIC HUB) AND LOCUS COERULEUS (NORADRENERGIC HUB) – TWO NEUROMODULATORY HUBS IMPLICATED IN EARLY STAGE OF DISEASE. AS STEREOTYPIC AMYLOID-SS PLAQUE PATTERNS ARE ROBUSTLY OBSERVED REGARDLESS OF AGE, AND COMORBID NEUROPATHOLOGIES ARE LESS FREQUENT IN YOAD, THIS COHORT IS IDEALLY SUITED FOR A TARGETED INVESTIGATION OF SELECTIVE VULNERABILITIES TO TANGLE PATHOLOGY IN AD. REGIONAL VULNERABILITIES TO ADVANCED TANGLE MATURITY LEVELS IN CORTICOLIMBIC STRUCTURES AND NEUROMODULATORY HUBS ARE HYPOTHESIZED TO UNDERLIE THE SYNDROMIC HETEROGENEITY OBSERVED IN YOAD. THE OVERALL GOAL OF THIS GRANT IS TO UNCOVER SIGNATURES OF REGIONAL AND CELLULAR VULNERABILITIES UNDERLYING SYNDROMIC HETEROGENEITY IN YOAD BY INVESTIGATING WHAT MODIFIES PATTERNS OF TANGLE ACCUMULATION AND MICROGLIAL ACTIVATION. OUR PRELIMINARY DATA FROM SINGLE-CELL RNA SEQUENCING UNDERSCORES THE IMPORTANCE OF CONSIDERING DISEASE HETEROGENEITY AND THE UTILITY OF QUANTITATIVE NEUROPATHOLOGY FOR VALIDATING GENE EXPRESSION CHANGES. THIS PROPOSAL SEEKS TO SHIFT CURRENT RESEARCH IN AD BY FOCUSING ON YOUNGER-AGED INDIVIDUALS AND DEMONSTRATING HOW REGIONAL VARIABILITY CAN INFORM CELLULAR BIOLOGY EVEN IN THE CONTEXT OF END-STAGE DISEASE. TO ACCOMPLISH OUR GOALS AND FACILITATE STRATIFICATION BY ATYPICAL AND TYPICAL (AMNESTIC) CLINICAL SYNDROMES, THE MPI TEAM HAS COMBINED EXPERTISE AND RESOURCES TO AMASS ONE OF THE LARGEST DOCUMENTED YOAD COHORTS TOTALING 558 BRAINS WITH AVAILABLE TISSUE FOR STUDY. THE GOAL OF THE GRANT IS TO TEST THE FOLLOWING HYPOTHESES: 1) MODIFIERS OF THE NEUROPATHOLOGIC PATTERNS OF TAU PATHOLOGY IN YOAD BRAINS DIFFER BETWEEN CASES STRATIFIED BY ATYPICAL VS. TYPICAL (AMNESTIC) CLINICAL SYNDROMES, 2) THE MOST VULNERABLE NEURONAL POPULATIONS TO AD-TAU SHARE A SIMILAR MOLECULAR SIGNATURE ACROSS CORTICOLIMBIC REGIONS REFLECTIVE OF SYNDROMIC HETEROGENEITY IN YOAD, AND 3) CORTICOLIMBIC MICROGLIAL ACTIVATION PATTERNS DIFFER IN THE BRAINS OF YOAD CASES STRATIFIED BY ATYPICAL VS. TYPICAL (AMNESTIC) CLINICAL SYNDROME. COMPLETION OF THIS PROJECT WILL IDENTIFY SPECIFIC CELL POPULATIONS VULNERABLE TO REGIONAL AD-TAU PATHOLOGY AND IDENTIFY MODIFIERS OF MICROGLIAL ACTIVATION PATTERNS CORRESPONDING TO AGGRESSIVE TAU ACCUMULATION IN YOAD.

PAUL CALABRESI PROGRAM IN CLINICAL-TRANSLATIONAL RESEARCH AT MAYO CLINIC

SHARP AREA 4: SECONDARY USE OF EHR DATA

SYNERGISTIC INTERACTION OF AMYLOID-BETA AND ALPHA-SYNUCLEIN IN LEWY BODY DEMENTIA

MAYO SPORE IN BRAIN CANCER

INSTITUTIONAL CAREER DEVELOPMENT CORE

BIOLOGY AND THERAPEUTICS OF CARDIOVASCULAR PEPTIDES

HEREDITARY CAUSES OF NEPHROLITHAISIS AND KIDNEY FAILURE

SOUTHEAST MINNESOTA COUNTY HEALTHCARE INFORMATION TECHNOLOGY COLLABORATION

BETA1-SELECTIVE BLOCKADE FOR PREVENTION OF POSTMENOPAUSAL BONE LOSS: A RANDOMIZED CONTROLLED TRIAL - OSTEOPOROSIS IS A DISEASE OF AGING THAT LEADS TO ~2 MILLION FRACTURES AND ~$17 BILLION IN HEALTHCARE COSTS ANNUALLY. ALTHOUGH SEVERAL DRUGS ARE FDA-APPROVED FOR THE TREATMENT OF OSTEOPOROSIS, THE POTENTIAL FOR SERIOUS SIDE EFFECTS (E.G., OSTEONECROSIS OF THE JAW, ATYPICAL FEMUR FRACTURES) HAS LED MOST PHYSICIANS TO USE THESE DRUGS ONLY FOR THE TREATMENT, BUT NOT THE PREVENTION, OF OSTEOPOROSIS. THIS HAS LED TO THE CURRENT SITUATION WHERE MOST POSTMENOPAUSAL WOMEN MUST WAIT UNTIL THEY DEVELOP FRANK OSTEOPOROSIS (I.E., FRACTURES, OR SUFFICIENTLY HIGH FRACTURE RISK) TO BEGIN DRUG THERAPY. AS SUCH, THERE IS A COMPELLING NEED FOR NOVEL, RELATIVELY LOW-RISK AND LOW-COST PHARMACOLOGICAL APPROACHES TO PREVENT OSTEOPOROSIS. THE CURRENT PROPOSAL AIMS TO TRANSLATE EVIDENCE FROM RODENT STUDIES SHOWING THAT THE SYMPATHETIC NERVOUS SYSTEM (SNS) IS AN IMPORTANT REGULATOR OF BONE METABOLISM TO A SIMPLE, COST-EFFECTIVE, AND SAFE APPROACH FOR OSTEOPOROSIS PREVENTION. IN KEY PRELIMINARY DATA, WE OBTAINED MULTIPLE LINES OF EVIDENCE TO ESTABLISH CLEARLY THE ROLE OF THE SNS IN REGULATING HUMAN BONE METABOLISM. A CRITICAL COMPONENT OF THESE DATA WAS A “PROOF-OF- CONCEPT” INTERVENTIONAL STUDY DEMONSTRATING THAT SS1-SELECTIVE BLOCKERS (ATENOLOL, NEBIVOLOL), BUT NOT A NON- SELECTIVE SS-AR BLOCKER (PROPRANOLOL), HAVE FAVORABLE EFFECTS ON BONE TURNOVER AND BONE MINERAL DENSITY (BMD) IN POSTMENOPAUSAL WOMEN. BASED ON THESE DATA, WE WILL PERFORM A RANDOMIZED, DOUBLE-BLIND, PLACEBO- CONTROLLED 2 YEAR CLINICAL TRIAL ADDRESSING THE FOLLOWING SPECIFIC AIMS: (1) TEST THE HYPOTHESIS THAT TREATMENT WITH A WIDELY USED, INEXPENSIVE, AND RELATIVELY SS1-SELECTIVE BLOCKER (ATENOLOL) WILL PREVENT BONE LOSS AT THE LUMBAR SPINE AND FEMUR NECK AS ASSESSED BY DUAL-ENERGY X-RAY ABSORPTIOMETRY IN 420 POSTMENOPAUSAL WOMEN WITHOUT PRE-EXISTING OSTEOPOROSIS (AIM 1A); AND EVALUATE THE TOLERABILITY AND SAFETY OF ATENOLOL WHEN USED FOR THE PREVENTION OF BONE LOSS (AIM 1B). (2) EVALUATE THE EFFECTS OF ATENOLOL ON TRABECULAR AND CORTICAL BONE MICROARCHITECTURE USING HIGH RESOLUTION-PERIPHERAL QUANTITATIVE COMPUTED TOMOGRAPHY (AIM 2A), ON BONE TURNOVER MARKERS (AIM 2B), AND TEST WHETHER BASELINE MEASURES OF BONE TURNOVER OR OF SYMPATHETIC ACTIVITY (RESTING HEART RATE, PLASMA CATECHOLAMINE LEVELS) ARE PREDICTIVE OF THE BMD RESPONSE TO ATENOLOL OVER 2 YEARS (AIM 2C). (3) IN A SUBSET OF PATIENTS, EXPLORE THE UNDERLYING MOLECULAR AND CELLULAR MECHANISMS FOR THE EFFECTS OF SS1-SELECTIVE BLOCKADE ON BONE IN HUMANS USING ANALYSES OF OSTEOBLAST POPULATIONS ISOLATED FROM BONE BIOPSIES AS WELL AS TISSUE-LEVEL BONE FORMATION RATES ON QUADRUPLE-LABELLED BONE BIOPSIES (AIM 3). THE PROPOSED STUDIES WILL RIGOROUSLY TEST WHETHER ATENOLOL IS EFFICACIOUS AND SAFE FOR THE PREVENTION OF OSTEOPOROSIS IN POSTMENOPAUSAL WOMEN AND ALSO FURTHER DEFINE THE MECHANISMS OF SNS EFFECTS ON BONE IN HUMANS. IF OUR PROPOSED CLINICAL TRIAL DEMONSTRATES PROTECTION FROM BONE LOSS IN POSTMENOPAUSAL WOMEN BY ATENOLOL, THIS WOULD FILL A CRUCIAL CLINICAL NEED, AS THESE WOMEN CURRENTLY HAVE VIRTUALLY NO PHARMACOLOGICAL OPTIONS FOR OSTEOPOROSIS PREVENTION.

SCALABLE EXPANDED ACCESS WITH ANALYSIS OF NEUROFILAMENT AND OTHER BIOMARKERS FOR IBUDILAST IN ALS (SEA-NOBI-ALS) - PROJECT SUMMARY/ABSTRACT CURRENT TREATMENT OPTIONS FOR AMYOTROPHIC LATERAL SCLEROSIS (ALS) ARE INADEQUATE, AND MANY PATIENTS LIVING WITH ALS SEEK ACCESS TO EXPERIMENTAL THERAPIES WITH THE HOPE THAT THEY WILL BE EFFECTIVE. SINCE MOST PATIENTS ARE EXCLUDED FROM PARTICIPATION IN INTERVENTIONAL TRIALS BASED ON RESTRICTIVE INCLUSION AND EXCLUSION CRITERIA, EXPANDED ACCESS PROGRAMS (EAPS) CAN BRIDGE AN IMPORTANT GAP. AS SUCH, THROUGH AN EAP, WE ARE NOW PROPOSING TO OFFER A PROMISING DRUG – IBUDILAST – THAT IS PRESENTLY IN A PHASE 2/3 TRIAL FOR ALS. IBUDILAST HAS A WELL-ESTABLISHED FAVORABLE SAFETY RECORD AND HAS BEEN APPROVED FOR ASTHMA AND POST-STROKE SYMPTOMS IN JAPAN. MOST RELEVANT TO OUR APPLICATION IS THE FACT THAT IT IS ABLE TO PENETRATE THE CENTRAL NERVOUS SYSTEM AND HAS BENEFICIAL PHARMACOLOGICAL EFFECTS FOR ALS, SUCH AS PHOSPHODIESTERASE INHIBITION, INCREASED AUTOPHAGY, AND AMELIORATION OF TDP-43 PATHOLOGY. THIS EAP WILL OFFER IBUDILAST AS AN EXPERIMENTAL TREATMENT TO 200 ALS PATIENTS FOR 6 MONTHS. OUR PROJECT WILL DEVELOP A NETWORK OF ALS PHYSICIANS, TO BE MANAGED BY MAYO CLINIC AND WIDETRIAL, WHICH FEATURES SELF-ACTIVATION AND STREAMLINED WORKFLOWS WITH E-CONSENT AND ENROLLMENT, HOME-HEALTH VISIT ORDERING, DRUG SUPPLY ORDERING, AND OVERSIGHT OF SAFETY EVENTS AND OUTCOMES DATA CAPTURE. EVALUATIONS WILL BE DONE EITHER IN A PHYSICIAN’S OFFICE OR VIRTUALLY IN THE PATIENT’S HOME TO MINIMIZE THE BURDEN OF PARTICIPATION. SAFETY MONITORING WILL BE CONDUCTED BY THE TREATING PHYSICIAN AND THROUGH BLOOD DRAWN IN THE PATIENT’S HOME, PROCESSED IN A CENTRAL LABORATORY. WE WILL DETERMINE THE EFFECT OF IBUDILAST ON ALS PROGRESSION USING THE GOLD STANDARD PRIMARY CLINICAL TRIAL OUTCOME MEASURE – THE ALS FUNCTIONAL RATING SCALE REVISED (ALSFRS-R) – WITH THE EMERGING BIOMARKER NEUROFILAMENT LIGHT (NFL) AS CO-PRIMARY OUTCOME. GIVEN THE URGENT NEED FOR RELIABLE BIOMARKERS, WE WILL ALSO TEST OTHER CANDIDATES (E.G., TDP-43 MARKERS). FURTHERMORE, TO AID IN DIFFERENTIATING BETWEEN IBUDILAST RESPONDERS AND NON-RESPONDERS, WE WILL USE CUTTING-EDGE MULTI-OMIC SEQUENCING METHODS. OUR USAGE OF LONG-READ WHOLE- GENOME SEQUENCING ENABLES US TO SPAN THE FULL RANGE OF GENOMIC VARIATION, AND BY GENERATING COMPLEMENTARY TRANSCRIPTOMIC DATA, WE CAN CAPTURE RNA SIGNATURES AND DISEASE-RELEVANT CELL POPULATIONS. THUS, WE STRONGLY BELIEVE THAT OUR DATASETS WILL PROVIDE A VALUABLE RESOURCE AND CAN POSSIBLY ASSIST IN PATIENT STRATIFICATION. IN SUMMARY, OUR EAP WILL OFFER A PROMISING DRUG, BRING TOGETHER NOVEL WEB-BASED INFRASTRUCTURES, IMPLEMENT NOVEL BIOMARKERS, AND OBTAIN MULTI-OMIC PROFILES OF RESPONDERS, THEREBY ALLOWING TAILORED PERSONALIZED THERAPIES AND SETTING THE STAGE FOR FUTURE ALS CLINICAL TRIALS.

MAYO TRANSLATIONAL PKD CENTER (MTPC)

MAYO CLINIC CENTER FOR CLINICAL AND TRANSLATIONAL RESEARCH

THE ROLE OF HYPOXIA IN VENOUS NEOINTIMAL HYPERPLASIA IN HEMODIALYSIS GRAFTS

MOLECULAR DIAGNOSIS, PROGNOSIS, AND THERAPEUTIC TARGETS IN LYMPHOMA

A MULTIDISCIPLINARY TRANSLATIONAL APPROACH TO INVESTIGATE THE MECHANISMS, PREDICTORS, AND PREVENTION OF PERSISTENT POST-TRAUMATIC HEADACHE

FECAL INCONTINENCE TREATMENT STUDY (FIT STUDY)

THE MACRO- AND MICRO- ANATOMY AND PATHOLOGY OF THE AGING KIDNEY

INTEGRATIVE TRANSLATIONAL DISCOVERY OF VASCULAR RISK FACTORS IN AGING AND DEMENTIA

CELLULAR SENESCENCE AND AGING

TRANSFORMING CLINICAL PRACTICES INITIATIVE - PTN

REGIONAL FATTY ACID METABOLISM IN HUMANS

EXPANDING INSIGHTS INTO FTD DISEASE MECHANISMS

ROCHESTER EPIDEMIOLOGY PROJECT

OPTIMIZING THE DIAGNOSTIC APPROACH TO CEPHALOSPORIN ALLERGY TESTING (DACAT TRIAL) - PROJECT SUMMARY IN THE UNITED STATES, BETA-LACTAM ANTIBIOTICS ARE THE LEADING CAUSE OF ALLERGIC REACTIONS. CEPHALOSPORIN ANTIBIOTICS, IN PARTICULAR, ARE THE MOST COMMON CAUSE OF DRUG-INDUCED ANAPHYLAXIS AND PERIOPERATIVE ALLERGY. FOR PENICILLIN ALLERGY, THE MECHANISM OF ALLERGY AND THE ANTIGENIC DETERMINANTS ARE KNOWN; VALIDATED PENICILLIN SKIN TESTING FOLLOWED BY DRUG CHALLENGE HAS A 100% NEGATIVE PREDICTIVE VALUE TO EXCLUDE AN IMMUNOGLOBULIN (IG)E-MEDIATED REACTION. FOR CEPHALOSPORIN ALLERGY, THE ANTIGENIC DETERMINANTS AND MECHANISM ARE NOT KNOWN, AND SKIN TESTING IS NOT VALIDATED. THE DIAGNOSTIC TEST CHARACTERISTICS OF SKIN TESTING WITH NATIVE CEPHALOSPORINS REMAIN UNCLEAR WITH NO SENSITIVITY NOR SPECIFICITY REPORTED. ALTHOUGH BETA-LACTAM CROSS-REACTIVITY HAS BEEN HYPOTHESIZED TO BE FROM THE SIMILARITY OF THE R1 SIDE CHAINS, RATHER THAN THE BETA-LACTAM RING, CROSS-REACTIVITY ESTIMATES AMONG BETA-LACTAMS VARY. FURTHERMORE, IT IS NOT KNOWN WHETHER THE VARIANCE IN CROSS-REACTIVITY IS DUE TO TRUE ALLERGY VERSUS SENSITIZATION BASED ON POSITIVE SKIN TESTING, GIVEN THAT DRUG CHALLENGES WERE NOT PERFORMED ON SKIN-TEST-POSITIVE PATIENTS. WHILE AN IGE MECHANISM IS ASSUMED FOR CEPHALOSPORIN ALLERGY AND SUPPORTED BY SKIN TESTING THAT HAS BEEN POSITIVE, THE BIOLOGY HAS YET TO BE CHARACTERIZED, AND SOME CEPHALOSPORIN ANAPHYLAXIS CAN OCCUR ON THE FIRST EXPOSURE, WHICH IS INCONSISTENT WITH AN IGE MECHANISM. GIVEN THE COMPLEXITY OF CEPHALOSPORIN STRUCTURES AND POTENTIAL EPITOPES, THERE MAY BE SEVERAL DISTINCT BIOLOGIC PATHWAYS INVOLVED IN CEPHALOSPORIN ALLERGY. FUTURE DIAGNOSTICS IN CEPHALOSPORIN ALLERGY ARE RELIANT ON DETERMINATION OF THESE BIOLOGICAL PATHWAYS AND FINDING KEY HAPTENS. CURRENT NATIONAL PRACTICE GUIDELINES RELATED TO CEPHALOSPORIN ALLERGY ASSESSMENT ARE CONSIDERED CONDITIONAL AND BASED ON LOW-QUALITY EVIDENCE. OUR OVERALL GOAL IS TO IDENTIFY THE OPTIMAL DIAGNOSTIC APPROACH TO CEPHALOSPORIN ALLERGY AND DETERMINE BETA-LACTAM CROSS-REACTIVITY, WHILE DISCOVERING THE MECHANISM AND ANTIGENIC DETERMINANTS OF CEPHALOSPORIN ALLERGY TO ADVANCE FUTURE DIAGNOSTICS. WE WILL DO THIS THROUGH A CLINICAL TRIAL THAT WILL GENERATE EMPIRICAL EVIDENCE THROUGH NOVEL TRIAL PROCEDURES, DOUBLE-BLIND SKIN TESTING, AND DOUBLE- BLIND PLACEBO-CONTROLLED DRUG CHALLENGES. OUR SPECIFIC AIMS ARE: 1) TO DETERMINE THE OPTIMAL APPROACH TO CEPHALOSPORIN ALLERGY EVALUATION; 2) TO ASSESS BETA-LACTAM CROSS-REACTIVITY IN CEPHALOSPORIN-ALLERGIC INDIVIDUALS; AND 3) TO INVESTIGATE THE ANTIGENIC DETERMINANTS AND MECHANISM OF CEPHALOSPORIN ALLERGY. WE WILL ACHIEVE THESE AIMS THROUGH COLLABORATION WITH AN ESTABLISHED NETWORK OF DRUG ALLERGY SPECIALISTS. OUR STUDY IS THE FIRST CLINICAL TRIAL IN DRUG ALLERGY THAT INVESTIGATES DIAGNOSTIC STRATEGIES AND MECHANISMS FOR A COMMON AND IMPORTANT ANTIBIOTIC CLASS. THIS PROJECT ALIGNS WITH NIH/NIAID GOALS TO ADVANCE DRUG ALLERGY RESEARCH AND PAR-21-083 TO SUPPORT HIGH-RISK CLINICAL TRIALS WITH MECHANISTIC STUDIES.

ADPKD: DISEASE SPECTRUM & GENOTYPE-PHENOTYPE CORRELATIONS

PANCREATIC CANCER GENETIC EPIDEMIOLOGY CONSORTIUM (PACGENE)

TARGETING CYCLIC AMP AND PROTEIN KINASE A SIGNALING TO TREAT ADPKD: AN EFFICACIOUS STRATEGY WITH FURTHER POTENTIAL

MAYO CLINIC METABOLOMICS RESOURCE CORE

EPIDEMIOLOGY OF AGE-RELATED BONE LOSS AND FRACTURES

MAYO CLINIC PHYSICAL ACTIVITY RESEARCH CENTER: METABOLOMICS AND PROTEOMICS ANALYSIS SITE

ENHANCED, EHR-FACILITATED CANCER SYMPTOM CONTROL (E2C2) PRAGMATIC CLINICAL TRIAL

PREVENTION OF ALZHEIMER'S DISEASE IN WOMEN: RISKS AND BENEFITS OF HORMONE THERAPY

NEONATAL MODULATION OF AIRWAY CONTRACTILITY

GENETICS AND MOLECULAR BIOLOGY PARKINSONISM

FOLATE RECEPTOR ALPHA VACCINES FOR PREVENTING PROGRESSION OF TNBC FOLLOWING FIRST-LINE CONVENTIONAL THERAPY

THE EFFECT OF TCF7L2 ON GLUCOSE METABOLISM

IRREVERSIBLE KIDNEY INJURY IN RENOVASCULAR HYPERTENSION

MAYO CLINIC PROSPECTIVE RESOURCE FOR BIOMARKER VALIDATION AND EARLY DETECTION OF PANCREATIC CANCER

HEART DISEASE IN RHEUMATOID ARTHRITIS

MECHANOBIOLOGY OF LUNG FIBROSIS

NCI, NATIONAL CLINICAL TRIALS NETWORK LEAD ACADEMIC PARTICIPATING SITE (LAPS) UG1

IDENTIFYING MECHANISMS OF DEMENTIA: ROLE FOR MRI IN THE ERA OF MOLECULAR IMAGING

DISSECTING THE PATHOGENESIS AND OUTCOMES OF PSC USING MULTI-OMICS BY STUDYING THE EXPOSOME AND GENOME

CHARACTERIZING THE FUNTION OF FIBBROCYSTIN AND FIBBROCYSTIN-L

SEX-SPECIFIC EFFECTS OF ENDOCRINE DISRUPTION ON AGING AND ALZHEIMER'S DISEASE

CENTER OF INNOVATION FOR BRAIN TUMOR THERAPEUTICS - PROJECT DESCRIPTION/ABSTRACT – OVERALL THE DEVELOPMENT OF EFFECTIVE THERAPIES FOR GLIOBLASTOMA (GBM) HAS BEEN INCREDIBLY VEXING WITH NO NEW DRUG APPROVALS IN OVER A DECADE. THERAPEUTIC RESISTANCE IN ANY ONE PATIENT WITH GBM CAN BE RELATED TO MULTIPLE FACTORS INCLUDING EXTENSIVE TUMOR CELL INFILTRATION INTO ADJACENT BRAIN, MOLECULAR HETEROGENEITY OF TUMOR CELL POPULATIONS, AND HETEROGENEITY OF DRUG DISTRIBUTION. IN ORDER TO UNDERSTAND AND OVERCOME THESE CHALLENGES, WE HAVE BUILT A HIGHLY PRODUCTIVE, MULTI-DISCIPLINARY SCIENTIFIC TEAM OVER THE PAST DECADE WITH EXPERTISE SPANNING SYSTEMS BIOLOGY, PHARMACOLOGY, TUMOR BIOLOGY, AND ANIMAL MODELS OF GBM. IN THE PROPOSED U19 CENTER APPLICATION, WE WILL INTEGRATE THIS ESTABLISHED CROSS-DISCIPLINARY TRANSLATIONAL SCIENCE TEAM WITH PHYSICIAN SCIENTISTS IN RADIATION AND MEDICAL ONCOLOGY, NEUROSURGERY AND NEURORADIOLOGY WITH A COLLECTIVE FOCUS OF TRANSLATING NOVEL THERAPEUTIC STRATEGIES INTO HIGHLY EFFECTIVE THERAPIES FOR PATIENTS WITH GBM. IMPAIRED DDR ENABLES THE GENOMIC INSTABILITY REQUIRED FOR TUMORIGENESIS, AND DIFFERENCES IN DDR FUNCTIONALITY BETWEEN TUMOR AND NORMAL TISSUE PROVIDES THE FUNDAMENTAL RATIONALE FOR USING RADIATION THERAPY OR GENOTOXIC DRUGS AS ANTI-CANCER THERAPIES. ADDITIONAL TARGETED PHARMACOLOGIC DISRUPTION OF DDR IN TUMORS CAN MARKEDLY ENHANCE THE EFFICACY OF THESE CYTOTOXIC THERAPIES AND WIDEN THE THERAPEUTIC WINDOW. IN THIS CONTEXT, WE HAVE COLLABORATED EXTENSIVELY WITH MULTIPLE PHARMACEUTICAL COMPANIES TO EVALUATE VARIOUS SMALL MOLECULE DDR INHIBITORS AND HAVE DEVELOPED SIGNIFICANT PRELIMINARY DATA DEMONSTRATING PROFOUND COMBINATORIAL EFFICACY FOR THESE DRUGS WHEN COMBINED WITH RADIATION OR ALKYLATING CHEMOTHERAPY ROUTINELY USED FOR GBM. THUS, THE INITIAL FOCUS FOR OUR CENTER IS TO OPTIMIZE THE CLINICAL DEPLOYMENT OF DDR INHIBITORS IN COMBINATION WITH CYTOTOXIC THERAPIES FOR GBM. A PHARMACOLOGY CORE WILL SUPPORT BOTH PHARMACOKINETIC (PK) AND PHARMACODYNAMIC (PD) EVALUATIONS IN ANIMAL MODELS AND HUMAN SAMPLES, AND OUR THERAPY EVALUATION CORE WILL SUPPORT BOTH PRE-CLINICAL AND CLINICAL TESTING OF NOVEL THERAPEUTIC STRATEGIES. THE PROJECT AND CORE TEAMS WILL WORK IN CLOSE COLLABORATION TO ACCOMPLISH THE GOALS OF THE CENTER, AND THIS COLLABORATIVE EFFORT WITHIN THE CENTER AND ACROSS THE BROADER GLIOMA THERAPEUTICS NETWORK (GTN) WILL BE COORDINATED BY THE ADMINISTRATIVE CORE.

COMPUTATIONAL AND BIOLOGICAL APPROACH TO FLOW DIVERSION

LONGITUDINAL MULTI-MODALITY IMAGING IN PROGRESSIVE APRAXIA OF SPEECH

OPEN HEALTH NATURAL LANGUAGE PROCESSING COLLABORATORY

PNEUMOCYSTIS CARINII: MACROPHAGE AND EPITHELIAL ACTIVATION

EXCEPTIONAL AGING: IDENTIFYING MODIFIERS OF ALZHEIMER'S DISEASE TRAJECTORIES

MUSCULOSKELETAL RESEARCH TRAINING PROGRAM

MITOCHONDRIAL COMPLEX I AS A TARGET FOR NEUROPROTECTION IN AD

CLINICAL IMPLEMENTATION OF CLOPIDOGREL PHARMACOGENETICS: THE TAILOR-PCI TRIAL - CCC - LEAD APPLICATION

TRADE-OFFS IN HUMAN OBSERVER PERFORMANCE, IMAGE QUALITY METRICS, AND PATIENT DOSE

PRIME SHOCK AND KILL FOR HIV ERRADICATION

STRUCTURE AND FUNCTION OF ACETYLCHOLINE RECEPTORS

RESPIRATORY CONTROL IN OLD AGE

STUDIES IN PIG-TO-PRIMATE CARDIAC XENOTRANSPLANTATION

DISEASE PATHWAYS IN THE POPULATION DETERMINED BY AMYLOID, TAU, AND NEURODEGENERATION IMAGING BIOMARKERS

PATHOGENESIS AND DIAGNOSIS OF MULTIPLE SYSTEM ATROPHY

DIABETES AND METABOLISM

MECHANISMS FOR CHEMOPREVENTION OF CANCER

RISK FACTORS FOR VENOUS THROMBOEMBOLISM IN THE COMMINITY

GENETIC STUDIES OF SARCOMERE-BASED CARDIAC DISEASES

PATHOBIOLOGY OF HEPATIC EPITHELIA

MAYO CLINIC INTERDISCIPLINARY WOMEN'S HEALTH RESEARCH PROGRAM

FFA METABOLISM IN DIFFERENT TYPES OF HUMAN OBESITY

SPORE IN PROSTATE CANCER

NAIONAL CANCER INSTITUTE, NAITONAL CLINICAL TRIALS NETWORK U10 LEAD ACADEMIC SITE

MULTIDISCIPLINARY TRAINING IN DIGESTIVE DISEASES

MULTIPLE SYSTEM ATROPHY - NOVEL TARGETS IN EARLY DIAGNOSIS, PATHOPHYSIOLOGY, AND THERAPEUTIC APPROACH

FOLATE RECEPTOR ALPHA VACCINES FOR PREVENTING PROGRESSION OF TNBC FOLLOWING FIRST-LINE CONVENTIONAL THERAPY

DISCOVERING CARDIOMYOPATHY MODIFIERS IN TOR SIGNALING VIA ZEBRAFISH GENETICS

MECHANOTRANSDUCTION IN INTESTINAL SMOOTH MUSCLE CELLS

ROLE OF PROTEIN KINASE C IN COLON CARCINOGENESIS

UNDERSTANDING THE ROLE OF TDP-43 IN ALZHEIMERS DISEASE AND FTLD

CARDIOVASOLOGY

CALCIUM DYNAMICS IN INTERSTITIAL CELLS OF CAJAL

THE IMMUNOGENETICS OF MEASLES IMMUNITY

SPIRIT OF EAGLES COMMUNITEES NETWORK PROGRAM

TRAINING GRANT IN CLINICAL PHARMACOLOGY

RISK AND PENETRANCE OF MUTATIONS FROM BREAST CANCER TESTING PANELS.

CONTROLLED TRIAL OF RENIN ANGIOTENSIN BLOCKADE IN ADPKD

KLF10 REGULATES COLITIS THROUGH MEDIATING TGFB INDUCTION OF FOXP3 IN TREG CELLS.

VALIDATING THE NEW CRITERIA FOR PRECLINICAL ALZHEIMER'S DISEASE

IMPROVING STONE DISEASE TREATMENT BY ACCURATE PHENOTYPING AND RISK STRATIFICATION

METASTATIC SPINE TUMORS: MINIMALLY INVASIVE FRACTURE RISK ANALYSIS AND TREATMENT

IDENTIFYING GENES AND PATHWAYS THAT IMPACT TAU TOXICITY IN FTD

SEX-SPECIFIC RISK FOR VASCULAR DYSFUNCTION AND COGNITIVE DECLINE

MARKVCID VALIDATION IN THE GENERAL COMMUNITY - PROJECT SUMMARY / ABSTRACT CEREBRAL SMALL VESSEL DISEASE (SVD) IS A COMMON PATHOLOGY CONTRIBUTING TO COGNITIVE IMPAIRMENT AND LOWERS THE THRESHOLD FOR THE EXPRESSION OF DEMENTIA IN THE PRESENCE OF ALZHEIMER’S DISEASE, AND ALZHEIMER’S RELATED DEMENTIAS (AD/ADRD) IN THE POPULATION. MARKVCID CONSORTIUM WAS ESTABLISHED BY THE NIH WITH THE GOAL OF IDENTIFYING AND VALIDATING SVD BIOMARKERS THAT HELP CAPTURE VASCULAR CONTRIBUTIONS TO COGNITIVE IMPAIRMENT AND DEMENTIA (VCID). AS THE MARKVCID CONSORTIUM MOVES TOWARDS COMPREHENSIVE MULTI-SITE CLINICAL VALIDATION OF HIGH-QUALITY BIOMARKERS IDENTIFIED SO FAR, OUR ASSEMBLED TEAM BRINGS TOGETHER THE EXPERTISE AND RESOURCES NEEDED TO BE A SUCCESSFUL VALIDATION SITE AS PART OF THIS FUNDING OPPORTUNITY ANNOUNCEMENT (RFA- NS-21-005). WE WILL FOCUS ON RECRUITING A DIVERSE GROUP OF 200 PARTICIPANTS (120 CAUCASIANS, 40 AFRICAN AMERICANS, 40 HISPANICS) AT MAYO CLINIC ROCHESTER (MCR), UNIVERSITY OF MISSISSIPPI MEDICAL CENTER (UMMC), AND MAYO CLINIC FLORIDA (MCF). WE WILL RECRUIT A DIVERSE GROUP OF PARTICIPANTS AT RISK OF VCID USING AN INNOVATIVE TWO-STEP SCREENING APPROACH. A KEY STRENGTH OF OUR APPLICATION IS THE RECRUITMENT OF PARTICIPANTS AT MCR FROM MAYO CLINIC STUDY OF AGING (MCSA) WHERE LEGACY RESOURCES (CLINICAL, IMAGING, ELECTRONIC HEALTH RECORDS) FROM THE LONGITUDINAL STUDY OF OVER 3000 ACTIVE PARTICIPANTS WILL BE LEVERAGED TO ENRICH THE COHORT OF PARTICIPANTS AS WELL AS ALLOW US TO EVALUATE THE RELEVANCE AND IMPORTANCE OF THE PROPOSED MARKVCID BIOMARKERS IN THE SETTING OF RICH DATA AND AD BIOMARKERS ON THESE PARTICIPANTS. IN THIS GRANT, WE WILL FOCUS ON COLLECTING DATA FOR THE EVALUATION AND COMPARISON OF TWO PLASMA AND FOUR MRI-BASED MARKVCID BIOMARKERS. AFTER THE COLLECTION OF DATA IN AIM 1, AIM 2 WILL FOCUS ON EVALUATING AND COMPARING THESE MARKVCID BIOMARKERS AS A FUNCTION OF AGE, SEX, SYSTEMIC VASCULAR HEALTH, RACE, AND COGNITIVE TRAJECTORIES. THESE ANALYSES WILL ALLOW US TO BETTER UNDERSTAND THE UTILITY OF EACH OF THE SVD MARKERS FOR CLINICAL PURPOSES. IN AIM 3, WE WILL UTILIZE EXISTING MCSA IMAGING DATA (FLAIR AND DTI MRI) WITH SERIAL MRI AND CLINICAL FOLLOW-UP TO COMPUTE MARKVCID IMAGING BIOMARKERS AND EVALUATE THEIR CLINICAL USEFULNESS WITH AMYLOID AND TAU PET IN PREDICTING LONGITUDINAL STRUCTURAL MRI AND COGNITIVE DECLINE. THIS INDEPENDENT VALIDATION OF IMAGING BIOMARKERS IN MCSA WILL BE IMPORTANT FOR PROVIDING MECHANISTIC INSIGHTS INTO THE MARKVCID BIOMARKERS AND EVALUATING THEIR CLINICAL UTILITY IN A POPULATION-BASED SAMPLE.

OVERCOMING DRUG RESISTANCE IN MULTIPLE MYELOMA

COMBINATION TRASTUZUMAB AND VACCINE THERAPY TO PREVENT DISEASE RECURRENCE IN LOCALLY ADVANCED HER2+ BREAST CANCER

NON-PHARMACOLOGICAL OPTIONS IN POSTOPERATIVE HOSPITAL-BASED AND REHABILITATION PAIN MANAGEMENT (NOHARM) PRAGMATIC CLINICAL TRIAL

MEASURING ARTERIAL MATERIAL PROPERTIES USING WAVE-BASED APPROACHES WITH ULTRASOUND AND COMPUTATIONAL MODELS

LIPS-A: LUNG INJURY PREVENTION STUDY WITH ASPIRIN

NEUROTROPHINS IN THE LUNG

MOLECULAR APPROACHES TO PATHOGENESIS AND THERAPY IN HUM*

NEUROMUSCULAR INTERVENTION TARGETED TO MECHANISMS OF ACL LOAD IN FEMALE ATHLETES

MAYO CLINIC CENTER FOR CLINICAL AND TRANSLATIONAL SCIENCE (CCATS)

MOLECULAR AND STRUCTURAL IMAGING IN ATYPICAL ALZHEIMER'S DISEASE: A LONGITUDINAL STUDY

PATHOPHYSIOLOGY OF BILIARY CRYPTOSPORIDIOSIS

GENETIC EPIDEMIOLOGY OF CHRONIC LYMPHOCYTIC LEUKEMIA

NCCTG BIOSPECIMEN RESOURCE

VARIANT HEMOGLOBIN AND CARDIORESPIRATORY REGULATION IN HUMANS

RELIABLE SEIZURE PREDICTION USING PHYSIOLOGICAL SIGNALS AND MACHINE LEARNING

HARNESSING MOLECULAR NETWORKS OF RESILIENCE FOR THERAPEUTIC DISCOVERIES IN AD

TARGETING PANCREATIC CANCER USING PEPTIDE CHEMISTRY: FROM BENCH TO BEDSIDE

MECHANISMS OF IL-33 SECRETION IN ALLERGIC DISEASES

POST-BACCALAUREATE TRAINING IN BIOMEDICAL RESEARCH

A MOLECULAR ANATOMIC IMAGING ANALYSIS OF TAU IN PROGRESSIVE SUPRANUCLEAR PALSY

COMBINATION TRASTUZUMAB AND VACCINE THERAPY TO PREVENT DISEASE RECURRENCE IN LOCALLY ADVANCED HER2+ BREAST CANCER

TRANSLATIONAL GEROSCIENCE NETWORK

THE ELECTRICIDAL EFFECT, A NOVEL ANTI-BIOFILM STRATEGY

OBESITY RELATED PANCREATIC FAT WORSENS LOCAL INJURY VIA UNSATURATED FATTY ACIDS

HUMAN CARDIORENAL SYNDROME

THE EXOCRINE AND ENDOCRINE PANCREAS IN TYPE 2 DIABETES, PANCREATITIS AND CANCER

MECHANISMS OF ALLOSTERY AND MOLECULAR RECOGNITION IN THE SMALL MULTIDRUG RESISTAN

ENHANCING RESPIRATORY MOTOR FUNCTION AFTER SPINAL CORD INJURY

PHASE I CLINICAL TRIALS OF ANTICANCER AGENTS

IMMUNOGENETIC MECHANISMS OF VACCINE RESPONSE

NRSA TRAINING CORE

ROLE OF CIRCADIAN MISALIGNMENT IN BETA-CELL FAILURE IN TYPE 2 DIABETES

THE FAMILIAL COLORECTAL NEOPLASIA COLLABORATIVE GROUP

MAYO CLINIC UROLOGY O'BRIEN RESEARCH CENTER

HIGH-PERFORMANCE COMPACT 3T MRI: TECHNICAL OPTIMIZATION FOR ADVANCED BRAIN IMAGING

MECHANISMS OF ALLERGEN-INDUCED TYPE 2 IMMUNITY

MOLECULAR MECHANISMS OF PORTAL HYPERTENSION

NCI EXPERIMENTAL THERAPEUTICS-CLINICAL TRIALS NETWORK WITH PHASE 1 EMPHASIS

MEASUREMENT OF RENAL VISCOELASTIC PROPERTIES WITH ULTRASOUND

PHOTON-COUNTING SPECTRAL CT TO REDUCE DOSE AND DETECT EARLY VASCULAR DISEASE

HOW BETA-CATENIN EXPANDS FOXP3+RORGAMMAT+ PRO-INFLAMMATORY T-REGULATORY CELLS

UNINTENDED PROLONGED OPIOID USE

EVALUATION OF THE CARDIAC AND METABOLIC EFFECTS OF SEMAGLUTIDE IN HEART FAILURE WITH PRESERVED EJECTION FRACTION

EXOSOME-MEDIATED PROPAGATION OF PATHOGENIC TAU PROTEIN

ACHIEVING EQUITY THROUGH SOCIOCULTURALLY-INFORMED, DIGITALLY-ENABLED CANCER PAIN MANAGEMENT? (ASCENT) CLINICAL TRIAL - ABSTRACT CANCER PAIN DISPARITIES ARE PROFOUND AND UNIQUELY HARMFUL AMONG HISPANIC/LATINX AND RURAL DWELLING SURVIVORS AS THEY UNDERMINE THEIR ALREADY LIMITED ABILITY TO ACCESS, TOLERATE, AND/OR RECEIVE TREATMENT FOR THEIR CANCER. DISPARITIES ARE TIED TO POOR CARE, NEEDLESSLY PERSISTENT AND INTENSE PAIN, AS WELL AS THE OVER- AND UNDER-PRESCRIBING OF OPIOIDS. MULTI-MODAL PAIN CARE (MMPC), A ROBUSTLY VALIDATED, SAFER, AND MORE EFFECTIVE ALTERNATIVE TO A SOLELY MEDICATION-BASED APPROACH HAS PROVEN CHALLENGING TO IMPLEMENT BROADLY, AND VIRTUALLY IMPOSSIBLE IN RESOURCE LIMITED SETTINGS. THE FACTORS THAT IMPEDE DELIVERY OF MMPC; PROVIDER BIAS, PATIENTS’ RELUCTANCE TO REPORT PAIN, AND LACK OF PATIENT-CENTERED MMPC OPTIONS, ALSO MEDIATE DISPARITIES MAKING THEM KEY TARGETS FOR IMPROVEMENT. THE COLLABORATIVE CARE MODEL (CCM) PROVIDES A WELL-ES- TABLISHED AND VALIDATED FRAMEWORK THAT CAN NEUTRALIZE FACTORS THAT PERPETUATE DISPARITIES, GUIDE MMPC DELIVERY, AND IM- PROVE PAIN DETECTION AND TREATMENT. HOWEVER, AS CURRENTLY CONFIGURED THE CCM’S SINGLE SYMPTOM EMPHASIS NEEDS TO BE MODIFIED TO ADDRESS THE MULTI-LEVEL DRIVERS OF PAIN DISPARITIES. OUR TEAM HAS DEVELOPED AND TESTED CCM ITERATIONS THAT INTE- GRATE ELEMENTS OF TEAM-BASED CARE (TBC) TO IMPROVE THE CCM’S MONITORING OF SOCIOCULTURAL NEEDS, AS WELL AS TO ACCOMMO- DATE MMPC’S MULTI-DISCIPLINARY CARE REQUIREMENTS. IN ADDITION, WE HAVE LEVERAGED ELECTRONIC HEALTH RECORDS (EHRS) TO EN- ABLE CARE TEAMS TO LINK SYMPTOMATIC CANCER PATIENTS WITH MMPC PROVIDERS AND RESOURCES. OUR PRIOR RESEARCH DEPLOYING CCM-TBC HYBRID INTERVENTIONS WITH PATIENT-AND-CARE TEAM-CENTERED EHR-REENGINEERING HAS ALSO SIGNIFICANTLY IMPROVED PATIENT SYMPTOM REPORTING AND DEPLOYMENT OF MMPC. THESE EFFORTS, WHILE FRUITFUL, HAVE ALSO SHOWN US THAT A BROADER EHR RETROFITTING IS REQUIRED TO ADDRESS THE BREADTH OF PATIENTS’ NEEDS AND THE REQUIREMENTS OF REAL-WORLD CLINICAL WORK- FLOWS. THIS EXPERIENCE SUGGESTS THAT A FLEXIBLE, MODULAR CCM-TBC HYBRID SYSTEM, SUPPORTED BY EHR ENABLEMENT, CAN DE- LIVER HIGH FIDELITY MMPC IN A MANNER THAT IMPROVES CARE AND MITIGATES DISPARITIES AT MULTIPLE LEVELS AMONG HISPANIC AND RURAL CANCER SURVIVORS. WE PLAN TO EVALUATE THE EFFECTIVENESS OF THIS APPROACH IN A CLINICAL TRIAL ENTITLED “ACHIEVING EQUITY THROUGH SOCIOCULTURALLY-INFORMED, DIGITALLY-ENABLED CANCER PAIN MANAGEMENT (ASCENT ).” MORE SPECIFICALLY, WE WILL PART- NER WITH OUR COMMUNITY STAKEHOLDERS DURING AN INITIAL, 1-YEAR R61 DEVELOPMENT PHASE TO REFINE A CULTURALLY INFORMED VERSION OF OUR CCM-TBC HYBRID THAT ADDRESSES HISPANIC AND RURAL SURVIVORS’ LINGUISTIC, SOCIAL, AND IT NEEDS (AIM 1). AFTER CONFIRMING THE FUNCTIONALITY OF THE INTERVENTION’S COMPONENTS, WE PLAN TO TRANSITION TO A 4-YEAR R33 EXECUTION PHASE WITH A 2-ARM, PARALLEL GROUP RANDOMIZED CLINICAL TRIAL. THIS TRIAL (AIM 2) WILL BE CONDUCTED IN 4 SEMI-AUTONOMOUS HEALTH CARE SYS- TEMS AND IS DESIGNED TO ASSESS WHETHER OUR CULTURALLY INFORMED CCM-TBC HYBRID INTERVENTION IMPROVES PAIN OUTCOMES RELA- TIVE TO USUAL CARE AMONG 578 SURVIVORS, 60% RURAL AND 60% HISPANIC, ASSUMING 30% OVERLAP. PRIMARY (PAIN) AND SECONDARY (MOOD, SLEEP, PHYSICAL FUNCTION, WORK STATUS, AND HEALTHCARE UTILIZATION) OUTCOMES WILL BE ASSESSED AT 0, 3, AND 6 MONTHS. ALL DATA, EXCEPTING PATIENT REPORTED OUTCOME MEASURES, WILL BE EXTRACTED FROM THE EHR FOR MAIN EFFECTS, AS WELL AS EXPLORA-TORY MEDIATOR AND MACHINE LEARNING ANALYSES; THE LATTER TO IDENTIFY CHARACTERISTICS ASSOCIATED WITH POSITIVE RESPONSES. AIM 3 WILL EVALUATE IMPLEMENTATION STRATEGIES TO SUPPORT MULTISTAKEHOLDER ADOPTION AND USE OF INTERVENTION COMPONENTS.

THE NOTCH SIGNALING PATHWAY IN LARGE VESSEL VASCULITIS

TRAINING IN TRANSLATIONAL RESEARCH-BENCH TO BEDSIDE

PATHOPHYSIOLOGY OF ANORECTAL DISORDERS

RECOVERY OF RESPIRATORY FUNCTION AFTER SPINAL CORD INJURY

MULTI-FACETED APPROACH MODELING ACL INJURY MECHANISMS

THE NEUROBIOLOGY OF TWO DISTINCT TYPES OF PROGRESSIVE APRAXIA OF SPEECH

GLUCAGON SUPPRESSION AND DIABETES-ASSOCIATED VARIATION IN TCF7L2

RESOLVING THE CANCER RELEVANCE OF PREDISPOSITION GENE MUTATIONS

MECHANISM OF MUSCLE WASTING IN AGING MAN

A PHASE I CLINICAL TRIAL IN OSTEOARTHRITIS GENE THERAPY

NETWORKS AMONG TRIBAL ORGANIZATIONS FOR CLEAN AIR POLICIIES (NATO CAP)

CARDIAC CHANNEL MUTATIONS IN SUDDEN INFANT DEATH SYNDROME (SIDS)

A GENOME-WIDE ASSOCIATION STUDY FOR BREAST CANCER IN BRCA1 MUTATION CARRIERS

RELATING MOLECULAR SUBGROUPS OF ENDOMETRIOSIS-ASSOCIATED OVARIAN CANCERS TO SURVIVAL AND RISK - PROJECT SUMMARY/ABSTRACT OVARIAN CANCER (OC) IS THE ELEVENTH MOST COMMON CANCER AND FIFTH DEADLIEST AMONG U.S. WOMEN. THE LOW INCIDENCE, HIGH FATALITY AND MOLECULARLY BROAD RANGE OF TUMOR HISTOTYPES MAKE OC CHALLENGING TO STUDY AND TO TREAT. CONSEQUENTLY, SURVIVAL RATES HAVE SCARCELY CHANGED OVER THE PAST 35 YEARS, LARGELY BECAUSE PRECISION THERAPY LAGS BEHIND MOST OTHER CANCERS. ENDOMETRIOID (ENOC) AND CLEAR CELL (CCOC) ACCOUNT FOR ~25% OF ALL INVASIVE OC. THEY ARE A HETEROGENEOUS AND UNDERSTUDIED GROUP OF TUMORS THAT ARE CLOSELY ASSOCIATED WITH ENDOMETRIOSIS, BUT SHOW FEW SIMILARITIES TO THE MORE COMMON HIGH GRADE SEROUS OC. ENOC OR CCOC HAVE VARIABLE OR POOR RESPONSE TO STANDARD PLATINUM-BASED CHEMOTHERAPY. CCOC, IN PARTICULAR, IS MORE LIKELY TO BE PLATINUM RESISTANT AT EARLY STAGE AND RESISTANT TO SECOND LINE CHEMOTHERAPY AT ADVANCED STAGE, RESULTING IN WORSE SURVIVAL THAN HGSOC. WE HYPOTHESIZE THAT MOLECULAR TUMOR SUBTYPES EXIST FOR ENOC AND CCOC THAT REFLECT DIFFERENCES IN BIOLOGICAL PROCESSES AND RISK FACTORS AND THAT MIGHT INFORM NEW TREATMENT STRATEGIES. OUR PRELIMINARY RESULTS USING GENOMICS ANALYSES OF 185 ENOC AND 115 CCOC SUPPORTS THIS HYPOTHESIS BY SHOWING THAT ASSOCIATIONS WITH SURVIVAL AND RISK FACTORS SUCH AS SMOKING AND BODY MASS INDEX DIFFER ACCORDING TO THE TUMOR’S MOLECULAR PROFILE, WITH SOME SUBGROUPS SHOWING RAPIDLY FATAL OUTCOME. IN THE CURRENT PROPOSAL, WE INTEND TO DELVE DEEPER INTO THE GENOMIC PROFILE OF ~1,100 ENOC AND CCOC TUMORS TO IDENTIFY KEY MOLECULAR FEATURES OF THE TUMOR SUBTYPES. OUR APPROACH USES A CONSORTIUM EFFORT THAT COMBINES EXISTING DATA FROM WELL-CONDUCTED EPIDEMIOLOGIC STUDIES OF RISK FACTORS WITH CORRESPONDING CLINICAL INFORMATION AMONG INVESTIGATORS WITH A STRONG HISTORY OF COLLABORATION. WE WILL FIRST CHARACTERIZE MOLECULAR SUBTYPES, SEPARATELY FOR ENOC AND CCOC, BY INTEGRATING SEQUENCING AND ARRAY DATA FROM GENE EXPRESSION, MUTATIONS AND METHYLATED REGIONS FROM A TRAINING SET (483 ENOC, 292 CCOC) USING STATISTICAL CLUSTERING. NEXT, WE WILL ASSESS REPLICATION OF THE MOLECULAR SUBTYPES IN AN INDEPENDENT TEST SET (207 ENOC, 125 CCOC). TO ASSESS SUBTYPE-SPECIFIC ASSOCIATIONS IN THE TOTAL SAMPLE (689 ENOC, 417 CCOC), WE WILL RELATE MOLECULAR SUBTYPES OF ENOC AND CCOC SEPARATELY TO RISK FACTORS AND TO SURVIVAL. IMPACT: LESS COMMON OC SUCH AS ENOC OR CCOC ARE OFTEN OVERSHADOWED BY INVESTIGATIONS OF MORE COMMON CANCERS, YET OUR DATA SHOW THAT ENOC AND CCOC CAN ALSO BE RAPIDLY FATAL IN CERTAIN PATIENT SUBSETS OR SHOW MORE FAVORABLE OUTCOME IN OTHERS, DIRECTLY IMPACTING PATIENTS’ LIVES. FINDING PATTERNS WITH OTHER CANCERS BY USING INTEGRATED ANALYSIS OF ENOC AND CCOC SUBTYPES HAS HIGH POTENTIAL TO INFORM NEW AVENUES FOR TARGETED THERAPY AND TO ENHANCE UNDERSTANDING OF ENOC AND CCOC CANCER BIOLOGY. FUTURE REPLICATION OF OUR FINDINGS USING AN INDEPENDENT 1,400 ENOC/CCOC TUMORS FROM OUR UNIQUE CONSORTIA RESOURCES CAN LEAD TO NEEDED GAINS IN BIOLOGICAL, EPIDEMIOLOGIC AND THERAPEUTIC INSIGHTS FOR THESE PATIENTS.

TREAT-MAYO

MICRORNA REGULATION OF T CELL SENESCENCE

CD8 T CELL MEDIATED DISRUPTION OF BLOOD BRAIN BARRIER TIGHT JUNCTIONS

THE INCLUSIVE CANCER CARE RESEARCH EQUITY (ICCARE) FOR BLACK MEN CONSORTIUM

TB CENTERS OF EXCELLENCE FOR TRAINING, EDUCATION AND MEDICAL CONSULTATION (TB COE) - IN RESPONSE TO CDC-RFA-PS23-2301, THE MAYO CLINIC CENTER FOR TUBERCULOSIS (MCCT) PROPOSES TO BECOME A TB CENTER OF EXCELLENCE FOR TRAINING, EDUCATION, AND MEDICAL CONSULTATION. MCCT IS A REGIONAL, NATIONAL, AND INTERNATIONAL REFERRAL CENTER FOR TUBERCULOSIS AS WELL AS A WORLD HEALTH ORGANIZATION COLLABORATING CENTER IN DIGITAL HEALTH AND PRECISION MEDICINE FOR TUBERCULOSIS. AS A CENTER OF EXCELLENCE, MCCT WILL SUPPORT THE MISSION OF THE CENTERS FOR DISEASE CONTROL AND PREVENTION (CDC) DIVISION OF TUBERCULOSIS ELIMINATION (DTBE) TO CONTROL AND ELIMINATE TB IN THE US BY DEVELOPING EDUCATION MATERIALS, CONDUCTING TRAINING, DELIVERING TECHNICAL ASSISTANCE TO INCREASE HUMAN RESOURCE DEVELOPMENT FOR TB PROGRAMS, AND PROVIDING MEDICAL CONSULTATION FOR COMPLEX TB CASES. THESE ACTIVITIES WILL RESULT IN INCREASED NUMBER OF EDUCATED AND TRAINED TB HEALTH CARE WORKERS; IMPROVED QUALITY OF TB AND LTBI CARE; AND IMPROVED HEALTH OUTCOMES AMONG VULNERABLE/HIGH RISK POPULATION.

BONE CELL GROWTH REGULATION BY RUNX2/CBFA1

PHARMACOGENETICS OF PHASE II DRUG METABOLIZING ENZYMES

STRUCTURAL BIOLOGY OF LYSINE METHYLATION IN DNA DAMAGE AND CHECKPOINT SIGNALING

MOLECULAR DETECTION OF BIOFILMS ON HIP AND KNEE IMPLANTS

MOLECULAR MECHANISMS OF EXERCISE BENEFITS TO INSULIN RESISTANT PEOPLE

VALIDATION OF THE MAYO TEST DRIVE SCREENING BATTERY COMPOSITE AND STRICKER LEARNING SPAN FOR EARLY DETECTION AND MONITORING OF COGNITIVE DECLINE IN PRECLINICAL AND PRODROMAL ALZHEIMER’S DISEASE - PROJECT SUMMARY/ABSTRACT THE FIELD OF ALZHEIMER'S DISEASE (AD) IS ENTERING A NEW ERA WHERE INCREASING NUMBERS OF NOVEL TREATMENTS TARGETING THE BIOLOGICAL UNDERPINNINGS OF AD WILL BE AVAILABLE WITHIN THE FORESEEABLE FUTURE. IF WE FAIL TO IDENTIFY COGNITIVE IMPAIRMENT DUE TO AD EARLY, WE WILL MISS AN IMPORTANT TREATMENT WINDOW. THERE IS A CRITICAL NEED FOR EASILY ACCESSIBLE, SCALABLE, AND SENSITIVE COGNITIVE TOOLS THAT CAN AID EARLY DETECTION AND MONITORING OF COGNITIVE IMPAIRMENT AND THEREBY ALLOW EARLIER INTERVENTION TO MITIGATE FURTHER DECLINE. HIGH QUALITY, BRIEF COGNITIVE ASSESSMENT TOOLS THAT CAN BE DEPLOYED REMOTELY OR VIA SELF-ADMINISTRATION IN CLINIC SETTINGS REPRESENT ONE KEY COMPONENT OF THE FUTURE OF AD RESEARCH AND CLINICAL PRACTICE. THESE TOOLS WILL HELP ENRICH CLINICAL TRIALS AND AID TRIAGE DECISIONS TO INFORM SPECIALTY CLINIC REFERRALS AND INITIATION OF TREATMENT IN CLINICS, IDEALLY IN CONJUNCTION WITH PLASMA BIOMARKERS TO ADDRESS BOTH CLINICAL SYMPTOMS AND UNDERLYING BIOLOGY. ADDITIONAL VALIDATION OF NOVEL REMOTE COGNITIVE ASSESSMENT TOOLS IS NEEDED. MAYO TEST DEVELOPMENT THROUGH RAPID ITERATION, VALIDATION AND EXPANSION (MAYO TEST DRIVE, MTD) IS A COGNITIVE TESTING PLATFORM DEVELOPED FOR SELF- ADMINISTERED DIGITAL COGNITIVE ASSESSMENT. MTD ADDRESSES REMOTE ASSESSMENT NEEDS AND IS A MULTI-DEVICE (SMARTPHONE, TABLET, PC), FLEXIBLE AND EASILY ACCESSIBLE PLATFORM, WITH SUBTESTS THAT PROVIDE MORE IN-DEPTH ASSESSMENT OF TARGETED COGNITIVE DOMAINS RELATIVE TO TYPICAL SCREENING TESTS. THE MTD BRIEF COGNITIVE SCREENING BATTERY TAKES 15-20 MINUTES AND INCLUDES 2 SUBTESTS: (1) THE STRICKER LEARNING SPAN (SLS), A NOVEL COMPUTER ADAPTIVE WORD LIST MEMORY TEST (LEARNING AND DELAY TRIALS) AND (2) SYMBOLS TEST, AN OPEN-SOURCE MEASURE OF VISUAL MATCHING AND PROCESSING SPEED/EXECUTIVE FUNCTION; THESE ARE COMBINED INTO A SCREENING BATTERY COMPOSITE (MTD-SBC). THE OVERALL GOAL OF THIS R01 IS TO ESTABLISH THE VALIDITY OF THE MTD-SBC AND THE SLS FOR SEVERAL SPECIFIC CONTEXTS OF USE. SPECIFIC AIMS ARE TO (1) DETERMINE CROSS-SECTIONAL DIAGNOSTIC ACCURACY OF MTD FOR CLINICALLY DEFINED AND PET BIOMARKER-DEFINED GROUPS, (2) DEMONSTRATE SENSITIVITY OF MTD TO AMYLOID- RELATED COGNITIVE DECLINE OVER 30 MONTHS, (3) DETERMINE UTILITY OF MTD FOR DETECTING CLINICAL PROGRESSION OVER 45 MONTHS, AND (4) DETERMINE WHETHER MTD PERFORMANCE IS ASSOCIATED WITH PLASMA BIOMARKERS TO A SIMILAR DEGREE AS IN-PERSON NEUROPSYCHOLOGICAL MEASURES. MOST PARTICIPANTS WILL BE RECRUITED FROM THE MAYO CLINIC STUDY OF AGING, WITH ADDITIONAL RECRUITMENT FROM THE ALZHEIMER'S DISEASE RESEARCH CENTER (ROCHESTER, MN AND JACKSONVILLE, FL) AND THE MEMORY IMPAIRMENT AND NEURODEGENERATIVE DEMENTIA CENTER - MAYO CLINIC STUDY OF AGING AT THE UNIVERSITY OF MISSISSIPPI MEDICAL CENTER IN JACKSON, MS (N=2,300 ACROSS COHORTS, PREDOMINANTLY REMOTE ADMINISTRATION). BY INCREASING THE REPRESENTATION OF DIVERSE PARTICIPANTS AND THE RANGE OF SOCIAL AND STRUCTURAL DETERMINANTS OF HEALTH (SSDOH) WITH THE JACKSON, MS AND JACKSONVILLE, FL COHORTS, WE WILL BE ABLE TO COMPLETE EXPLORATORY ANALYSES FOR AIM 4 FOCUSED ON WHETHER SSDOH MODERATES THESE RESULTS. FUTURE RESEARCH WILL DETERMINE THE COMBINED UTILITY OF MTD AND PLASMA BIOMARKERS.

PROJECT HOPE: ACHIEVING HOME DISCHARGE FOR INSTITUTIONALLY-BOUND PATIENTS WITH PROMS, AI, AND THE EHR - UNNECESSARY DISCHARGES FROM A HOSPITAL TO A SKILLED NURSING FACILITY (SNF) ARE COSTLY AND MAY ACCELERATE PATIENTS’ FUNCTIONAL LOSSES AND REQUIREMENT FOR LONG-TERM INSTITUTIONALIZATION. PATIENTS WITH ALZHEIMER'S DISEASE AND ALZHEIMER'S DISEASE RELATED DEMENTIAS (AD/ADRD) AND OTHER TYPES OF COGNITIVE IMPAIRMENT ARE UNIQUELY DISADVANTAGED BY THIS STATUS QUO IN THAT THEY ARE TWICE AS LIKELY TO BE HOSPITALIZED, FOUR TIMES MORE LIKELY TO BE DISCHARGED TO SNFS WITH LESS THAN 50% RETURNING TO THEIR HOMES. THIS SITUATION CAN BE ADDRESSED AS IT IS THE PRODUCT OF A TYPICALLY RUSHED DISCHARGE PLANNING PROCESS WITH INADEQUATE TIME TO DISCOVER, MUCH LESS ADDRESS, A PATIENT’S BARRIERS TO HOME DISCHARGE. RECENT REPORTS SUGGEST THAT AS MANY AS A THIRD OF PATIENTS DISMISSED TO SNFS, INCLUDING THOSE WITH AD/ADRD, COULD RETURN DIRECTLY HOME IF THEIR POST-ACUTE CARE (PAC) NEEDS AND BARRIERS WERE ANTICIPATED AND ADDRESSED. SEVERAL KEY DEFICITS PREVENT BROAD REALIZATION OF A PATIENTS’ POTENTIAL TO DISCHARGE DIRECTLY HOME, OR THEIR HOME PAC POTENTIAL (HOPE). THESE INCLUDE A LIMITED ABILITY TO: 1) QUANTIFY FACTORS THAT DETERMINE PAC NEEDS, 2) IDENTIFY AND ADDRESS REMEDIABLE BARRIERS TO HOME DISCHARGE, AND 3) MOBILIZE STAKEHOLDERS FOR ADVANCEMENT OF INDIVIDUALIZED DISCHARGE PLANS. COLLECTIVELY, THESE DEFICITS PREVENT THE TIMELY INITIATION OF ACUTE CARE SERVICES THAT CAN REALIZE A PATIENT’S POTENTIAL FOR HOME DISCHARGE, WITH PAC AS NECESSARY. REHABILITATION-FOCUSED, HOSPITAL-HOME HEALTHCARE AGENCY (HHA) PARTNERSHIPS HAVE ESTABLISHED THAT INTERDISCIPLINARY CARE PLANS ENACTED EARLY IN A HOSPITAL STAY WITH PATIENT AND CAREGIVER INVOLVEMENT INCREASE THE LIKELIHOOD OF A PATIENT’S RETURN HOME. OUR TEAM DEVELOPED AN EPIC ELECTRONIC HEALTH RECORD (EHR)-BASED DISCHARGE PLANNING SYSTEM THAT TRIANGULATES EHR, PATIENT REPORTED OUTCOMES (PROS), AND SOCIAL DETERMINANTS OF HEALTH DATA TO IDENTIFY HOPE BARRIERS AND DIRECT NEEDS-MATCHED REHABILITATION SERVICE DELIVERY. A PILOT OF THE SYSTEM AMONG 358 PATIENTS INCREASED THE HOME DISCHARGE RATE BY OVER 25% AND REVEALED HIGH USER ACCEPTABILITY. HOWEVER, THE PILOT ALSO IDENTIFIED THE NEED TO IMPROVE ADDRESSING OF COGNITIVE IMPAIRMENTS, TARGETING OF HIGH-YIELD HOPE BARRIERS, AND ENGAGEMENT OF NON-CLINICAL STAKEHOLDERS. WE PROPOSE TO ADDRESS THESE LIMITATIONS BY PURSUING THREE SPECIFIC AIMS: 1) DEVELOP A LOW-BURDEN COMPUTERIZED ADAPTIVE TEST PRO TO ASSESS THE DOMAINS OF FUNCTIONAL COGNITION RELEVANT TO A SAFE HOME DISCHARGE; 2) DEVELOP A MACHINE LEARNING ALGORITHM TO PRIORITIZE ACTIONABLE HOPE BARRIERS AND ESTIMATE THE DEGREE OF CHANGE NEEDED FOR HOME DISCHARGE; AND 3) APPLY USER-CENTERED DESIGN PRINCIPLES TO REFINE THE EHR DISCHARGE PLANNING SYSTEM FOR OPTIMAL USABILITY AND ENHANCED EHR PORTAL PATIENT, CAREGIVER, AND HHA STAFF ACCESS. OUR GOAL IS TO BOTH INTEGRATE AND PILOT THESE DELIVERABLES IN A MATURE AND OPTIMALLY USABLE EHR DISCHARGE PLANNING SYSTEM, AND TO EVALUATE THE FEASIBILITY AND ACCEPTABILITY OF ITS IMPLEMENTATION. WE ANTICIPATE THAT THE SYSTEM WILL BE SCALABLE, AND AMENABLE TO INTER-INSTITUTION TRANSFER FOR TESTING IN A MULTI-SITE PRAGMATIC TRIAL.

MEDICAL SCIENTIST TRANING PROGRAM AT MAYO CLINIC