Title: Brain-Selective Therapy to Alleviate Hot Flushes of Prostate Cancer Patients (Subcontract)
Principal Investigator: Istvan Merchenthaler, MD, PhD, DSc
Agency: University of North Texas Health Science Library (NIH passthrough)
Grant Number: 1R01CA2155550 (Prokai)
Funding Period: 4/1/17 – 3/31/20
Total Costs: $529,701
Synthetic estrogens are used in the clinic to alleviate debilitating neurological symptoms associated with androgen deprivation therapy (ADT), an effective treatment improving survival in prostate cancer patients when administered timely in the course of carcinoma. However, this remedy to relieve the symptoms, most commonly manifested as hot flushes, causes feminizations (most prominently gynecomastia) that significantly diminishes patients' compliance because of physical and psychological discomfort. Because only estrogens can provide adequate remedy of hot flushes based on current clinical practices, there is an unmet medical need for an effective, side effect-free and, consequently, compliance-gaining intervention to alleviate these vasomotor symptoms distressing prostate cancer patients on ADT.
The scientific premise of this grant application is based on it central hypotheses that treatment with 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED), an innovative brain-selective bioprecursor prodrug of 17b-estradiol, will ease ADT-associated hot flushes without feminizing side-effects. In the first specific aim, we will perform preclinical pharmacokinetics, distribution and bioavailability studies in orchidectomized male rats to support our particular hypotheses that DHED treatment confines the formation of17b-estradiol from the prodrug into the brain. In the second specific aim, we will assess DHED treatments through measuring effects elicited by the estrogen delivered selectively in the brain and, consequently, avoiding exposure of peripheral tissues to the hormone through multiple methodologies. One of our specific hypotheses is that oral treatment with DHED will abate orchidectomy- induced tail skin temperature elevation in a pharmacological model, and will restore diurnal changes lost after orchidectomy in a physiological paradigm, in two well-established and complementary rat models of hot flushes.
Since our hypothesis is that hot flushes are due to an imbalance of neurotransmitters/neuromodulators innervating thermosensitive neurons in the preoptic area of the hypothalamus, we will monitor norepinephrine, serotonin, and neurokinin B involved in thermoregulatory responses with in vivo microdialysis to provide additional, mechanism-focused approach for assessment. As the synthesis and release of these neurotransmitters and their cognate receptors are regulated by estrogen, we hypothesize that the major action of estrogen is to re-establish the physiological balance among these neurotransmitters to stabilize neuronal activity on the thermoregulatory center; i.e., to prevent heat dissipation (hot flush).
Finally, we will seek supporting evidence for the brain-specific action of DHED-derived 17b-estradiol by evaluating estrogen- induced gene expression in the brain, and its lack in the breast, pituitary, prostate and prostate cancer cells. The overall goal of our aims is to support subsequent translational research focusing on DHED’s therapeutic use toremedy hot flushes and potentially other neurological symptoms in prostate cancerpPatients undergoing ADT to manage their malignancy.
Title: A BRAIN Initiative Resource: The Neuroscience Multi-omic Data Archive
Principal Investigator: Owen White, PhD
Grant Number: 1R24MH114788
Funding Period: 09/15/17 – 07/31/22
Total Costs: $6,330,952
The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative promotes the development and application of technologies to describe the temporal and spatial dynamics of cell types and neural circuits in the brain. The Principal Investigator, senior personnel and staff of this project have diverse expertise required to marshall data across the BRAIN Initiative consortium, including experience in data collection from multiple institutions, large-scale quality control and analysis processing capability, familiarity with NIH policy and public archive deposition strategies. To promote smooth interactions across a large research consortium, we will develop the Neuroscience Multi-Omic Archive (NeMO Archive), a data repository that is specifically focused on the storage and dissemination of omic data from the BRAIN Initiative and related brain research projects. We will utilize a federated model for data storage such that the physical location of data can be distributed between the NeMO local file system, public repositories, and a cloud-based storage system (e.g. Amazon S3). We will leverage this capability and distribute BRAIN Initiative data between our local filesystem and the cloud. The Nemo Archive will be a data resource consistent with the principles advanced by research community members who are launching resources in next generation NIH data ecosystem. These practices include FAIR Principles, documentation of APIs, data-indexing systems, workflow sharing, use of shareable software pipelines and storage on cloud-based systems. The information incorporating into the NeMO archive will, in part, enable understanding of 1) genomic regions associated with brain abnormalities and disease; 2) transcription factor binding sites and other regulatory elements; 3) transcription activity; 4) levels of cytosine modification; and 5) histone modification profiles and chromatin accessibility. It will enable users to answer diverse questions of relevance to brain research, such as identifying diagnostic candidates, predicting prognosis, selecting treatments, and testing hypotheses. It will also provide the basic knowledge to guide the development and execution of predictive and machine learning algorithms in the future.
Title: Entrenching Training and Capacity in Research Ethics in Nigeria (ENTRENCH) Program
Principal Investigator: Clement Adebamowo, BM, ChB, ScD, FWACS, FACS
Grant Number: 1R25TW010514
Funding Period: 06/01/2017 – 05/31/2022
Total Costs: $240,981
The creation of a health Research Ethics regulatory environment is an important step in entrenching sustainable ethical oversight in any country. in that regard, since 2004, we have been involved in the establishment of a National Health Research Ethics Committee (NHREC); established or strengthened 35 institutional health Research Ethics committees, implemented over 20,000 online courses, conducted 82 onsite courses for Research Ethicists, biomedical Researchers and members of Ethics committees and admitted 43 Master’s degree in Bioethics students into our Training programs. We have therefore made substantial contributions to the development of Research Ethics in Nigeria. Nevertheless, there are more opportunities to further strengthen this system by increasing knowledge and compliance with Research Ethics Guidelines, standard operating procedures, and best practices ethical oversight of Research; training more research ethicists at every level so that there are enough for a large country like Nigeria with a population of 180 million people and a growing number and complexity of research projects. The Entrenching Training and Capacity in Research Ethics in Nigeria (ENTRENCH) Program therefore plans to continue Training Masters degrees students at the University of Ibadan; conduct curriculum revisions and initiate new degree programs at Olabisi Onabanjo University, University of Nigeria, and University of Ilorin in Nigeria; provide blended advanced diploma in research ethics training and enhance the engagement of Nigerian bioethicists with the public and the global bioethics discourse.
Title: Population Health Work Force Support for Disadvantaged Areas
Principal Investigator: Diane Marie St. George, PhD
Funding Period: 03/15/2016 – 06/30/2018
Total Costs: $232,280
This work provides services to the Maryland Department of Health and Mental Hygiene, Health Services Cost Review Commission (HSCRC) in developing and implementing the Population Health Work Force Support for Disadvantaged Areas Program (“PWSDA”) established by the HSCRC.
Dr. Diane Marie St. George from the Department of Epidemiology and Public Health (EPH) at University of Maryland School of Medicine (UMSOM) will work closely with the commission to achieve the following:
Phase I. Establish policies and procedures for the program consistent with the HSCRC purpose and finalize request for proposals.
Phase II. Establish a proposal review committee of independent individuals (with no conflict of interest with the proposing hospitals or their partners)
Phase III. Establish a process for periodic reporting of key metrics
The Recommendation approved by the Commission on December 9, 2015 provides up to $10 million in hospital rates on a competitive basis by July 1, 2016 for hospitals committing to train and hire workers from geographic areas of high economic disparities and unemployment to fill new care coordination, population health, health information exchange, alignment, consumer engagement, and related positions. Hospitals should provide matching funds of at least 50% of the amount included in rates to increase the resources that could be deployed. Thus, if $10 million is provided in rates, the hospital match would be at least $5 million.
Title: Incorporating Bayesian Reasoning Into Physician Testing and Treatment Decisions
Principal Investigator: Daniel Morgan, MD, MS
Grant Number: 1DP2LM012890
Funding Period: 09/30/2017 – 09/29/2022
Total Costs: $2,317,500
A significant, but under-recognized problem in clinical medicine is the accuracy of test interpretation and decision-making regarding treatment. Fewer than 20% of physicians understand the frequency of false positives in testing. When given an example of testing for a rare disease with a 95% specific test, most physicians answered that 95% of positive tests were true positive (vs. ~2% in reality). Similar results were found in real life examples of mammograms with practicing gynecologists, in which the majority incorrectly reported a positive test was >80% likely to be a true positive (the correct answer was only 7%). Our group and others have found, when asked about the benefits of common treatments for hypertension, myocardial infarction and stroke prevention, physicians overestimate the benefits of treatments, with less than 25% accurately identifying the absolute benefit of treatment (and many estimating an effect 2-10 times larger than reality). These misunderstandings lead to overdiagnosis, overtreatment and overuse, which may account for up to one third of medical care services. The benefits of medical care could be achieved with less patient harm and more satisfaction if test interpretation and decision-making were improved. Diagnostic probabilities underlie nearly all physician testing and treatment decisions. Bayesian reasoning is thought to be the most rational way to assess this. One application of Bayesian reasoning is in diagnosis. Given an initial assessment of the likelihood of a disease and clinical test results, Bayesian reasoning is the mathematically valid method to quantify the probability that the disease is truly present. Psychological techniques for online training in Bayesian reasoning or displaying the results of such reasoning in visual aids has improved performance on physician testing but we know of no interventions that have applied training or visual aids to improve clinician ability to interpret tests or understand treatment effects for actual patients. To reach our overall goal of reducing harms of medical care while maintaining benefits, we propose 3 objectives:1) explore physician factors associated with accurate Bayesian reasoning, 2) develop educational training and visual aids to improve physician understanding of tests and treatment, and 3) pilot these tools in a stepped wedge cluster trial. The PI is well suited for this innovative research based on a non-traditional background in psychology, epidemiology, quality improvement and clinical medicine and has assembled experts in evidence based medicine, visual presentation, qualitative and quantitative research methods. This project has the potential to transform clinical medicine, making it more evidence based with more patient involvement while improving patient outcomes and healthcare costs.
Title: Epicenters for the Prevention of Healthcare Associated Infections (HAI) – Cycle II
Principal Investigator: Anthony Harris, MD, MPH
Grant Number: 1U54CK000450
Funding Period: 8/10/2016 – 07/31/2018
Total Costs: $2,181,088
Healthcare-associated infections (HAIs) increase patient morbidity and mortality. The transmission of bacteria and viruses is an area that needs further study. Our group has over 160 publications in the area of healthcare-associated infections, with over 40 publications in the application focus of transmission of infectious pathogens and identification of novel strategies to improve the effectiveness of personal protective equipment. We have translated numerous T0 results into T2 studies to prevent transmission of infectious pathogens. We have experience developing and implementing multi-site studies across the spectrum of healthcare. We have had over 16 grants funded by CDC, NIH, VA and AHRQ to study optimal methods to prevent the transmission of bacterial pathogens. We have successfully performed nine multi-center studies across over 50 institutions in 32 states. We also had a project with the Maryland state health department that we led involving 40 facilities including 30 acute care facilities and 10 long-term care facilities. Thus, we believe we are well-qualified to be chosen to be a member of the CDC Prevention Epicenters for the Prevention of Healthcare Associated Infections. Our aims directly address the funding announcement; they are: Aim 1: Perform a multi-site intensive-care unit (ICU) cohort study to determine which patient risk factors, including comorbid conditions and severity of illness markers, and which healthcare worker-patient interactions lead to greater transmission of carbapenem-resistant Enterobacteriaceae (CRE) and methicillin-resistant Staphylococcus aureus (MRSA). Aim 2: Using an existing cohort of residents from community-based nursing homes in two states, estimate the overall transmission risk for resistant Gram-negative bacteria, as well as which patient risk factors and healthcare activities lead to greater transmission. Aim 3: Perform a randomized non-inferiority trial to determine if using an alcohol-based hand rub to "clean" gloved hands when an indication for hand hygiene arises during a single patient encounter is as effective as the current recommendation of changing gloves. Aim 4: Evaluate the effectiveness of practices to decontaminate personal protective equipment (PPE) after use for antibiotic-resistant bacteria and viruses similar to Ebola and Influenza in a laboratory setting.
Title: University of Maryland Claude D. Pepper Older Americans Independence Center
Principal Investigator: Jay Magaziner, PhD, MSHyg
Grant Number: 5P30AG028747
Funding Period: 07/01/2016 – 06/30/2021
Total Costs: $5,091,455
The overarching UM-OAIC goal is to build on the sciences and therapeutic applications of exercise and rehabilitation by: 1) advancing our understanding of the mechanisms by which exercise and activity-based rehabilitation interventions directed at specific impairments affect multiple body systems underlying functional performance; and 2) developing and testing interventions to restore function and minimize disability following acute disabling events and gradual declines related to serious chronic diseases. The functional impairments and disabilities that occur in Older people emanate from acute events, such as stroke, heart attack, and hip fracture, or reflect the progression of chronic diseases. Older people aging with chronic diseases have a reduced aerobic capacity and develop sarcopenia, fatigue, and neuromotor and cognitive impairments that reduce their physiological reserve, impair their ability to function independently, and increase their level of medical care and risk for institutionalization and death. This pathway of how disease leads to disability has been discussed extensively. The UM-OAIC mission embodies this process and focuses on the restoration of function in order to improve function in those with impairments, and prevent or delay further progression in those who are already disabled. This has been aptly referred to as enablement. (9,10) The UM-OAIC will continue to focus its research on enablement by identifying the impairments associated with disabling conditions, investigating the mechanisms and pathophysiology of the impairments, developing exercise and activity-based interventions that target these mechanisms and deficits, testing them in clinical laboratories/centers, and then adapting them for implementation and further testing in community settings. The aims of the UM-OAIC are to: 1) Conduct research that examines the mechanisms underlying the functional impairments associated with stroke, hip fracture, and prevalent chronic diseases in Older people. 2) Design novel, exercise and activity-based rehabilitation interventions that produce clinically relevant outcomes and study the mechanisms underlying them. 3) Translate interventions developed in UM-OAIC clinical laboratories and in other clinical centers for implementation and rigorous evaluation in community settings. 4) Support pilot and exploratory studies (PESs), development projects (DPs) and externally funded projects (EP) that examine the mechanisms underlying disability and the processes of recovery, and that design and test interventions for the restoration and maintenance of function in clinical laboratories and settings outside the medical Center. 5) Foster the career development of junior faculty/scholars from multiple disciplines into independent, academic scientists with expertise in the study of Older persons with disabling diseases through mentor-based, bench-to-bedside translational research training that includes didactic and experiential/practical- applied training in conducting independent, aging research.
Title: Progenitor Cell Biology Consortium Administrative Coordinating Center
Principal Investigator: Michael Terrin, MDCM, MPH
Grant Number: 5U01HL099997
Funding Period: 09/30/09-09/29/16
Total Costs: $3,517,404
The Progenitor Cell Biology Consortium Administrative Coordinating Center will make available to the public accessible video reports on the research accomplishments of the Consortium, to the general scientific community reports and data from the Consortium that will advance their research on stem and progenitor cell related health problems and to the members of the Consortium data and meta-data from each other’s work to advance their collaborative research. In addition to providing all involved with newly developed, valuable information, the exchange of this information is expected to result in new therapeutic approaches that could shift paradigms and enormously improve outcomes of some of the most frequently fatal diseases in the U.S.; coronary artery disease and emphysema are just two examples.
Title: Combining Testosterone Therapy and Exercise to Improve Function Post Hip Fracture
Principal Investigator: Denise Orwig, PhD
Agency: Washington University (NIH Passthrough)
Grant Number: 1R01AG051647 (Binder)
Funding Period: 09/15/2017 – 05/31/2022
Total Costs: $2,696,085
Hip fractures are common among older women and can have a devastating impact on their ability to remain independent. A clinically important functional decline and failure to recover following a hip fracture has been documented as much as a year after the fracture, even among individuals who were functioning at high levels before the event. Age-associated androgen deficiency in women contributes to deficits in muscle mass, strength and power that are common in this patient population before the fracture, and are exacerbated afterward. A pilot study of Testosterone (T) supplementation in elderly female hip fracture patients has demonstrated the feasibility of T treatment in this population, and showed gains in lean body mass (LBM) and muscle strength with active drug, compared to placebo. The benefits of exercise in restoring muscle strength and physical function after a hip fracture have been documented. However, it remains unclear whether T treatment can augment the effects of exercise on mobility and patient-reported function, or whether any observed benefits are sustained beyond the period of active treatment. Proposed is a 3-group, multi-center, randomized, placebo-controlled, double-blinded, parallel group clinical trial in frail elderly female hip fracture patients. 300 female hip fracture patients will be enrolled from 6 clinical sites, using objective screening criteria for T deficiency (serum total Testosterone level < 30 ng/dl) and physical frailty (Modified Physical Performance Test (PPT) Score < 28). The trial will compare the effects of supervised exercise training (EX) alone, EX combined with T therapy (EX+T) and no EX with placebo T treatment (CON), to ascertain the incremental impact of adding T to ET in older adult women following hip fracture. The 6-month intervention will be followed by a 6-month no-treatment sustainability phase. The primary outcome measure is the Six Minute Walk Distance (6MWD). Secondary outcome measures include: 1) dual energy x-ray absorptiometry (DXA) measurements of whole body and appendicular LBM and bone mineral density of the unfractured proximal femur; 2) maximal skeletal muscle strength (1-RM) for leg extension in both limbs; 3) objective physical performance measures; and 4) self-reported performance of activities of daily living and quality of life, including the Hip Rating Questionnaire (HRQ). We plan to carefully monitor Testosterone levels, adverse events, biochemical parameters, and factors related to adherence to the interventions. Information from this study has the potential to alter treatment of hip fracture in older women, a problem that contributes to significant morbidity and mortality, and has a large public health impact. The proposed study is highly aligned with NIA’s mission of identifying interventions that target common geriatric conditions, and improve treatment options for older adults with multiple morbidities or risk factors.