RF1NS145626

UNDERSTANDING THE CAUSES OF SECOND EPISODE CRYPTOCOCCAL MENINGITIS TO IMPROVE DIAGNOSIS AND TREATMENT - ABSTRACT CRYPTOCOCCUS IS THE MOST COMMON CAUSE OF HIV-RELATED MENINGITIS WITH MORTALITY >25%. SYMPTOMS RECUR IN 5–10% OF SURVIVORS, TYPICALLY DUE TO EITHER PARADOXICAL IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME (IRIS) WITH STERILE CULTURES OR CULTURE-POSITIVE RELAPSE OF INFECTION. CEREBROSPINAL FLUID (CSF) CRYPTOCOCCAL ANTIGEN (CRAG) TESTING IS HIGHLY EFFECTIVE TO DIAGNOSE PRIMARY CRYPTOCOCCAL MENINGITIS BUT CANNOT DISTINGUISH RELAPSE FROM IRIS WHERE CULTURE IS THE GOLD STANDARD. CULTURE’S SLOW TURNAROUND (7–10 DAYS) HINDERS TIMELY CLINICAL ACTION. THUS, CLINICIANS MUST CHOOSE EMPIRIC CORTICOSTEROIDS (IRIS) OR AMPHOTERICIN (RELAPSE). INCORRECT TREATMENT MEANS EXPOSING PATIENTS TO UNNECESSARY TOXICITIES WITHOUT ADDRESSING THE UNDERLYING ILLNESS, HIGHLIGHTING A CLEAR CLINICAL NEED FOR A RAPID, ACCURATE TEST TO DIFFERENTIATE RELAPSE FROM IRIS TO IMPROVE OUTCOMES AND MINIMIZE DRUG-RELATED HARM. THE BIOFIRE MENINGITIS/ENCEPHALITIS PCR PANEL CORRECTLY IDENTIFIED 18 OF 19 PATIENTS WITH RELAPSE OR IRIS. YET, UTILITY IN CRYPTOCOCCOSIS IS LIMITED BY HIGH COST, PROPRIETARY EQUIPMENT, AND POOR SENSITIVITY (29%) AT LOW FUNGAL BURDENS. OUR CRYPTOCOCCUS NEOFORMANS QUANTITATIVE PCR ASSAY SHOWED EXCELLENT CORRELATION WITH BASELINE CSF QUANTITATIVE CULTURE AND FUNGAL CLEARANCE RATES IN FIRST-EPISODE MENINGITIS. WHETHER THE ASSAY CAN DIFFERENTIATE IRIS FROM RELAPSE OR DETECT EARLY TREATMENT FAILURE HAS NOT BEEN STUDIED. SIMILARLY, THE ROLES OF INADEQUATE IMMUNE RESPONSE (INCLUDING DUE TO POOR ANTIRETROVIRAL THERAPY ADHERENCE), RISING FLUCONAZOLE MINIMUM INHIBITORY CONCENTRATIONS (MICS), AND INSUFFICIENT FLUCONAZOLE LEVELS IN RELAPSE REMAIN UNDEREXPLORED. OUR OVERALL OBJECTIVE IS TO REDUCE SECOND EPISODE CRYPTOCOCCAL MENINGITIS MORTALITY AND MORBIDITY BY UNDERSTANDING THE CAUSE(S) AND THROUGH COST-EFFECTIVE, RAPID AND ACCURATE DIAGNOSTIC TESTS. OUR AIMS ARE: 1) TO VALIDATE THE DIAGNOSTIC PERFORMANCE OF A REAL-TIME CSF-BASED CRYPTOCOCCUS QPCR ASSAY FOR DIAGNOSING CULTURE-POSITIVE RELAPSE IN PARTICIPANTS PRESENTING WITH RECURRENT CRYPTOCOCCAL MENINGITIS; 2) TO DETERMINE THE CAUSES OF CULTURE-POSITIVE RELAPSE BY TESTING DRUG LEVELS FOR ANTIRETROVIRAL AND ANTIFUNGAL THERAPIES, TESTING IN VITRO MICS TO FLUCONAZOLE, CHARACTERIZING THE HOST IMMUNE RESPONSE AND DISTINGUISHING NEW INFECTION FROM RECURRENCE BY GENOMIC SEQUENCING OF CRYPTOCOCCUS YEAST; AND 3) TO PROSPECTIVELY EVALUATE THE DIAGNOSTIC ACCURACY OF CRYPTOCOCCUS QPCR TO DETECT REAL-TIME MYCOLOGIC TREATMENT FAILURE WITH INCREASING QUANTITATIVE CSF CULTURES. THIS PROPOSAL AIMS TO TRANSFORM THE DIAGNOSIS OF RELAPSE FROM SLOW AND OFTEN INACCURATE TO RAPID, PRECISE, AND COST-EFFECTIVE. IT ALSO PROVIDES A TOOL TO QUICKLY IDENTIFY MYCOLOGICAL TREATMENT FAILURE FOR CLINICAL CARE AND TRIALS. ADDITIONALLY, THE PROPOSED WORK SEEKS TO UNCOVER RELAPSE CAUSES TO INFORM FUTURE PREVENTION STRATEGIES, SUCH AS HIGHER FLUCONAZOLE DOSES DURING SECONDARY PROPHYLAXIS.

Regents Of The University Of Minnesota

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.310 - Trans-NIH Research Support

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Minneapolis, Minnesota 554551507 United States

Single Zip Code

Global Brain and Nervous System Disorders Research Across the Lifespan (R01 Clinical Trials Optional) (PAR-22-097)

Amendment Since initial award the total obligations have increased 131% from $1,311,237 to $3,032,667.