Palo Alto Veterans Institute For Research

ADVANCING VETERAN AND PUBLIC HEALTH THROUGH INNOVATIVE RESEARCH.

TARGETED STRATEGIES TO ACCELERATE EVIDENCE-BASED PSYCHOTHERAPY (EBP) IMPLEMENTATION IN MILITARY. PRINCIPAL INVESTIGATORS: CRAIG S. ROSEN, PH.D. AND CARMEN P. MCLEAN, PH.D. THIS FOUR-YEAR STUDY, FUNDED BY THE DEPARTMENT OF DEFENSE, IS AIMED AT INCREASING USE OF EVIDENCE-BASED PSYCHOTHERAPIES (THERAPIES PROVEN EFFECTIVE IN RESEARCH) IN CLINICS ON MILITARY BASES. DESPITE EFFORTS TO TRAIN MILITARY PROVIDERS IN EFFECTIVE PSYCHOTHERAPIES FOR POSTTRAUMATIC STRESS DISORDER (PTSD), ONLY A MINORITY OF SERVICE MEMBERS RECEIVE THESE TREATMENTS. THIS TRIAL TESTS WHETHER A TAILORED PROCESS IMPROVEMENT APPROACH (USING A TOOLKIT FOR MATCHING SPECIFIC CHANGE STRATEGIES TO LOCAL BARRIERS) IS MORE EFFECTIVE THAN PROVIDER TRAINING ALONE IN EXPANDING THE PROPORTION OF PATIENTS WHO RECEIVE AN EBP. THE PROJECT, LED BY INVESTIGATORS AT THE NATIONAL CENTER FOR PTSD AND PALO ALTO VETERANS INSTITUTE FOR RESEARCH (PAVIR), INCLUDES COLLABORATORS FROM FIVE UNIVERSITIES AND EIGHT MILITARY TREATMENT FACILITIES. OBJECTIVES: TO TEST IN A STEPPED-WEDGE RANDOMIZED TRIAL WHETHER THE TARGETED ASSESSMENT AND CONTEXT-TAILORED IMPLEMENTATION OF CHANGE STRATEGIES (TACTICS) INCREASES USE OF EVIDENCE-BASED PSYCHOTHERAPY MORE THAN DOES PROVIDER TRAINING ALONE. SECONDARY OUTCOMES INCLUDE EFFECTS OF TACTICS ON AVERAGE IMPROVEMENT IN PTSD SYMPTOMS, AND SATISFACTION WITH THE TACTICS PROCESS. ACCOMPLISHMENTS: ALL STAFF HAVE BEEN HIRED, EIGHT MILITARY CLINICS REPRESENTING ALL SERVICE BRANCHES WERE RECRUITED AND ALL REGULATORY APPROVALS OBTAINED. PROVIDER TRAINING AND THE SUBSEQUENT PROCESS IMPROVEMENT INTERVENTION (TACTICS) HAS BEEN IMPLEMENTED AT ALL STUDY SITES. PROVIDER SURVEY DATA COLLECTION IS COMPLETED. CENTRALIZED EXTRACTION OF STUDY DATA IN COLLABORATION WITH THE DEFENSE HEALTH AGENCY IS ONGOING.POTENTIAL IMPACT: IF EFFECTIVE, TACTICS MAY REPRESENT A SCALABLE APPROACH TO ACCELERATING THE USE OF BEHAVIORAL HEALTH BEST PRACTICES IN MILITARY SETTINGS.

NOVEL STRATEGIES TO COMBAT POST-TRAUMATIC OSTEOARTHRITIS (PTOA): GAIT RETRAINING TO REDUCE JOINT LOADING, INFLAMMATION, AND PTOA RISK AKA NOVEL STRATEGIES TO COMBAT POST-TRAUMATIC OSTEOARTHRITIS. PRINCIPAL INVESTIGATORS: CONSTANCE CHU, M.D. AND WILLIAM ROBINSON, M.D., PH.D.DRS. CONSTANCE CHU AND WILLIAM ROBINSON ARE CLINICIAN-SCIENTISTS WHOSE PROJECTS AT PAVIR REPRESENT TWO OF FIVE SYNERGISTIC PROJECTS INTEGRATING COMPLEX INTERACTIONS BETWEEN MECHANICAL, BIOLOGICAL, AND STRUCTURAL FACTORS TO PROVIDE INSIGHTS INTO THE PATHOGENESIS OF POST-TRAUMATIC OSTEOARTHRITIS (PTOA). THIS INTEGRATED PROGRAM EVALUATES AND OPTIMIZES NOVEL DIAGNOSTIC AND THERAPEUTIC STRATEGIES POISED FOR TRANSLATION INTO CLINICAL PRACTICE AND CONTRIBUTE NEW BIOMARKER, IMAGING AND THERAPEUTIC TARGETS FOR EARLY DETECTION AND STAGING OF JOIN DEGENERATION LEADING TO PTOA. PROJECT 1 DEFINES THE ROLE OF FIBRINOLYSIS IN THE DEVELOPMENT OF PTOA. THIS PROJECT EXAMINES THE HYPOTHESIS THAT DEREGULATION OF THE FIBRINOLYSIS SYSTEM DRIVES THE PATHOGENESIS OF PTOA BY PROMOTING INFLAMMATION AND CARTILAGE DEGRADATION. OBJECTIVES 1: PERFORM ELISA AND LUMINEX ASSAYS ON THE ANTERIOR CRUCIATE TEAR AND DEGENERATIVE MENISCAL TEAR CLINICAL COHORTS. 2: SURGICALLY INDUCE OA IN MICE AND ADMINISTER TRANEXAMIC ACID TREATMENT. 3: DESIGN AND PERFORM TRANEXAMIC ACID TREATMENT ON MICE SUBJECTED TO MOUSE OA. ACCOMPLISHMENTS: 1: THE RESEARCHERS IDENTIFIED DYSREGULATED TYPE II INFLAMMATORY MEDIATORS IN HUMAN PATIENTS WITH ACL AND DEGENERATIVE MENISCAL TEARS. 2: THE RESEARCH SHOWS THAT TRANEXAMIC ACID PREVENTS DEVELOPMENT OF OA. 3: THE RESEARCH SHOWS SOME BENEFIT OF TRANEXAMIC ACID TREATMENT WHEN TREATMENT IS STARTED 4 WEEKS AFTER JOINT INJURY, AND INCREASED BENEFIT WHEN STARTED 2 WEEKS AFTER SURGICAL JOINT INJURY.STATISTICAL TESTS ARE PERFORMED ON ALL EXPERIMENTAL DATA AND INCLUDE SIGNIFICANCE ANALYSIS OF MICROARRAYS (SAM) ANALYSIS OF MULTIPLEX CYTOKINE DATASETS (WHICH P < 0.05) AS WELL AS MANN WHITNEY TEST FOR MOUSE DATASETS (P<0.05 FOR KEY COMPARISONS).PROJECT 2 IS AN EARLY PHASE II DOUBLE-BLIND RANDOMIZED CONTROLLED TRIAL TO TEST THE HYPOTHESIS THAT TRANEXAMIC ACID AFTER JOINT INJURY WILL REDUCE MARKERS OF INFLAMMATION AND CARTILAGE DEGRADATION. IT WILL PROVIDE SCIENTIFIC GUIDANCE ON ANTERIOR CRUCIATE LIGAMENT TEAR (ACLT) SURGERY, CLINICAL OUTCOMES, AND ANALYSIS OF THE DATASETS. OBJECTIVES 1: DISCOVER THE DIFFERENCES IN SYNOVIAL FLUID LEVELS OF INFLAMMATORY & CARTILAGE BIOMARKERS. 2: TEST THE CELLS-BASED THERAPY IN ACL REGENERATION. 3: DISCOVER THE CHANGES IN BIOMARKERS IN CORRELATION WITH CARTILAGE HEALTH AFTER GAIT RE-TRAINING.ACCOMPLISHMENTS: 20 PATIENTS WITH ACUTE ACL WERE ENROLLED AND THEIR SAMPLES WERE COLLECTED AT THREE TIME POINTS. SAMPLES WILL BE ASSAYED FOR INFLAMMATORY FACTORS AND CYTOKINES. ANIMAL EXPERIMENTS WITH ACLT SURGERY HAVE BEEN CONDUCTED FOR THE FIRST 10 RATS. WE ARE IN THE PROCESS OF DOING THE NEXT 10 RATS TO DATE.WE WILL ENROLL AND COLLECT 50 PATIENTS' SAMPLES TO BE IN A LARGER COHORT AND ASSAY THE CYTOKINES IN WHOLE SET. THIS WAY, THE RESEARCH WILL GET ENOUGH STATISTICAL POWER TO CONCLUDE. STATICAL ANALYSIS BY A STATISTICIAN WILL BE PERFORMED ONCE OUR RECRUITMENT GOAL BASED ON A PRIORI POWER ANALYSIS IS REACHED. CURRENTLY, THE RESEARCHERS ARE RAMPING UP RECRUITMENT AND STRIVING TO COMPLETE DATA COLLECTION AND PROCESSING.

ANTIMICROBIAL RESISTANCE AND HORIZONTAL GENE TRANSFER IN THE HUMAN GUT MICROBIOME IN RESPONSE TO AN ANTIBIOTIC. PRINCIPAL INVESTIGATOR: DAVID A. RELMAN, M.D.ANTIMICROBIAL RESISTANCE (AMR) IS AN INCREASINGLY PREVALENT AND SERIOUS PROBLEM WORLDWIDE. THE HUMAN GUT IS A HOTSPOT FOR BOTH THE EVOLUTION AND SPREAD OF AMR; COMMENSALS SERVE AS A SOURCE OF AMR FOR PATHOGENS VIA HORIZONTAL GUT TRANSFER (HGT). WE ARE STUDYING RESPONSES TO ANTIBIOTIC EXPOSURE IN THE HUMAN GUT MICROBIOTA IN VIVO, AS WELL AS IN COMPLEX STOOL-DERIVED SUBJECT-SPECIFIC COMMUNITIES IN VITRO, AT HIGH TEMPORAL RESOLUTION AND USING INNOVATIVE APPROACHES. WE LINK AMR AND OTHER MOBILE GENETIC ELEMENT (MGE)-ASSOCIATED GENES TO THEIR HOST CORE GENOMES USING HIGH THROUGHOUT CHROMOSOME CONFORMATION CAPTURE (HI-C) AND MONITOR THESE GENES AND ELEMENTS IN BACTERIAL HOSTS BEFORE, DURING AND AFTER ANTIBIOTIC EXPOSURE. THE SHORT TERM-OBJECTIVES OF THE PROPOSED WORK ARE TO CHARACTERIZE AND ASSESS THE CONTRIBUTIONS OF DE NOVO MUTATIONS AND HGT TO THE SPREAD AND DEVELOPMENT OF AMR IN THE HUMAN GUT MICROBIOTA DURING ANTIBIOTIC EXPOSURE. THE LONG-TERM OBJECTIVES ARE TO IMPROVE ANTIBIOTIC STEWARDSHIP BY IDENTIFYING CRITICAL EVENTS OR TRANSITIONS IN THE EVOLUTION AND DISSEMINATION OF AMR IN VIVO, AND THE FACTORS AND CONDITIONS THAT MAKE THOSE EVENTS LESS LIKELY.OBJECTIVES - 1. DETERMINE THE DISTRIBUTION OF AMR GENES IN THE GUT MICROBIOTA OF 60 HEALTHY HUMANS PRIOR TO A CIPROFLOXACIN EXPOSURE . 2. CHARACTERIZE THE EFFECTS OF CIPROFLOXACIN ON THE ABUNDANCE AND MOBILIZATION OF AMR GENES IN THE HUMAN GUT MICROBIOTA IN VIVO FROM THE SAME 60 SUBJECTS DURING AND AFTER THE CIPROFLOXACIN EXPOSURE. 3. CHARACTERIZE THE EFFECTS OF CIPROFLOXACIN ON THE MOBILIZATION OF AMR GENES IN SYNTHETIC, HUMAN GUT-DERIVED MICROBIAL COMMUNITIES IN VITRO. WE ARE PROPAGATING PRE-EXPOSURE FECAL COMMUNITIES EX VIVO FROM ALL 60 SUBJECTS, AS WELL AS GENERATING COMPLEX, SYNTHETIC COMMUNITIES FROM PRE-EXPOSURE SAMPLES OF 5 SUBJECTS, AND THEN PASSAGING BOTH BULK AND SYNTHETIC COMMUNITIES ANAEROBICALLY UNDER MULTIPLE CIPROFLOXACIN REGIMES. WE ARE IDENTIFYING FACTORS AND CONDITIONS THAT AFFECT EMERGENCE OF AMR THROUGH HGT AND DE NOVO MUTATIONS IN VITRO.ACCOMPLISHMENTS: 1. STOOL SAMPLES FROM 60 SUBJECTS WERE EXTRACTED AND SEQUENCED. 2. HI-C DNA LIBRARIES ARE BEING CONSISTENTLY GENERATED. NEW COMPUTATIONAL APPROACHES HAVE BEEN DEVELOPED THAT WORK DIRECTLY FROM METAGENOMIC DATA TO RECOVER EXTRA-CHROMOSAL MGES (ECMGES). A NEW TOOL FOR RECONSTRUCTING ECMGE GENOMES FROM METAGENOMIC DATA WAS CREATED. 3. FACS SORTING APPROACH FOR OBTAINING GUT ISOLATES HAS BEEN DRAMATICALLY IMPROVED. SYSTEMATIC STUDY OF NUTRIENT AVAILABILITY AND COMMUNITY COMPOSITION PROVIDES A PREDICTIVE FRAMEWORK THAT WILL AID IN RATIONAL DESIGN OF COMMUNITIES FOR STUDYING HGT OF AMR GENES AND HAS ESTABLISHED THE LAB'S ABILITY TO MODEL VARIOUS HUMAN FECAL SAMPLES WITH COMMUNITIES IN VITRO.

PAVIR IS PRIVILEGED TO WORK WITH A LARGE COMMUNITY OF UNIQUELY TALENTED MEDICAL RESEARCHERS ACROSS A BROAD SPECTRUM OF RESEARCH AREAS AS WE FULFILL OUR MISSION OF ADVANCING VETERANS AND PUBLIC HEALTH THROUGH INNOVATIVE RESEARCH. THE RANGE OF RESEARCH ACTIVITIES IS BROAD AND INCLUDES SPECIAL EMPHASIS ON MAJOR DISEASE CATEGORIES, ALL OF WHICH ARE PREVALENT IN THE VA'S PATIENT POPULATION. THESE INCLUDE CARDIOVASCULAR MEDICINE, MENTAL HEALTH, CHRONIC INFLAMMATORY DISEASE, STEM CELL/REGENERATIVE MEDICINE, PAIN, SLEEP DISORDERS, AND MANY OTHERS. IN ADDITION TO DISEASE SPECIFIC RESEARCH, PAVIR IS ENGAGED IN SUPPORTING RESEARCH AIMED AT ENHANCING HEALTH CARE. PAVIR'S RESEARCH PORTFOLIO INCLUDES COMPARATIVE STUDIES IN WHICH RESEARCH TEAMS ARE LEARNING WHICH TREATMENTS ARE SUPERIOR TO OTHERS, HOW TO AUGMENT OR IMPROVE STANDARD OF CARE, AS WELL AS HOW TO ENHANCE THE OPERATION OF HEALTH CARE. FURTHERMORE, PAVIR IS SUPPORTING EDUCATIONAL ACTIVITIES, ESPECIALLY IN AREAS OF ADVANCING CLINICAL CARE FOR VETERANS AND FOSTERING THE PROFESSIONAL DEVELOPMENT OF OUR EXPERT STAFF.