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Current Funded Research

Dong Sung An
Barbara Bates-Jensen
Mary-Lynn Brecht
Lynn Doering
Jo-Ann Eastwood
Nalo Hamilton
Felicia Hodge
Boyoung Hwang
Paul Macey
Sally Maliski
Adeline Nyamathi
Carol Pavlish
Linda Phillips
Huibrie Pieters
Nancy Pike
Michael Prelip
Wendie Robbins
Linda Sarna
Sophie Sokolow
Dorothy Wiley
Ann Williams
Marlyn Woo
Mary Woo

 

 

 

Dr. Dong Sung An

Title: GENETIC PROTECTION OF HEMATOPOIETIC STEM CELLS FOR STABLE HIV CONTROL
Agency: NIH National Institute of Allergy and Infectious Diseases, Project Number                                                                                                                                                                                                                                                                                                                                                                         1R01AI100652-01A1 
          DESCRIPTION (provided by applicant): Hematopoietic stem/progenitor cell (HSPC) based gene therapy holds great promise to provide long-term control of HIV with a single treatment. Like HAART, it is essential to combine multiple drugs to effectively suppress HIV and prevent drug resistant HIV escape mutants. The overall hypothesis of this proposal is that stable introduction of highly potent combinations of anti-HIV genes capable of inhibiting multiple early and late steps of HIV viral lifecycle into HSPC will provide lifelong protection from HIV infection The safety and efficacy of anti-HIV HSPC gene therapy strategies, including inhibition of HIV, lowering of viral load and selective growth advantage of protected cells and prevention of resistance will be evaluated in the recently developed human bone marrow, liver and thymus (BLT) transplanted mouse model. Specific aims are 1) To develop novel multi-pronged anti-HIV gene therapeutic lentiviral vectors and characterize therapeutic reagents to inhibit HIV infection in HSPC and their progeny in vitro 2) To determine the long-term anti-gene expression and stable control of HIV through genetically engineered human HSPC transplant in the BLT mouse model. The approach is innovative because it focuses on novel HIV-1 target HSPC protection and the development of novel potent, broad-range early stage and late stage anti-HIV combinations, maximizing the potential to HIV replication not only in HSPC but also all potential target cells. The proposed research is significant because the results may ultimately lead to an innovative, more effective, more convenient, less toxic, safe and more cost effective way of controlling HIV infection than is currently available. The long-term goal is to advance HSPC based gene therapy research and make rapid progress towards providing a new therapy that leads to stable control of HIV by a single treatment. PUBLIC HEALTH RELEVANCE: Our proposed research will positively impact public health with the development of an anti-HIV gene therapy by blocking the multiple early and late stages of the HIV infection. Ultimately, HIV infection will be controlled with a single treatment by protecting the hematopoietic stem cells and their progeny. This research will provide significant knowledge towards the long-term goal of the NIH "HIV cure."

Title:  GENE AND CELL THERAPY CORE
Agency: NIH National Institute of Allergy and Infectious Diseases, Project Number 5P30AI028697-23
          DESCRIPTION (provided by applicant): The advent of highly active antiretroviral therapy has resulted in a decline in the incidence of opportunistic infections and prolonged survival in HIV-1 infected individuals. Obstacles towards virus erradication include the continued presence of an infected quiescent pool, drug resistance, toxicities, and lack of treatment adherence. The goal of genetic therapies is the replacement of the HIV-1-infected cell reservoir with cells that have been genetically engineered to resist HIV-1 replication. Unlike conventional drugs, it is possible to create a "single administration" reagent. However, successful gene therapy strategies require efficient gene delivery into hematopoietic stem cells and the presence and expression of the anti HIV genes in differentiated progenies that persist for years if not for the life of the individual. Thus, these current limitations must be investigated. A better understanding of the limitations of gene therapy techniques can lead to strategies to overcome such limitations as well as design potential clinical scenarios in which to test them. As possible alternatives or complements to antiretroviral therapy, stem cell gene therapy strategies are of interest to the scientific community, to the health policy community in particular and to the public at large. The overall goal of the Gene and Cellular Therapy Core (Core G) is to provide scientific and technical support for basic laboratory and clinical trial projects that require the use of purified CD34+ hematopoietic stem cells for HIV/AIDS gene therapy, hematopoiesis and pathogenesis of HIV.

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Dr. Barbara Bates-Jensen

Title: BIOPHYSICAL MEASURE TO PREDICT PRESSURE ULCERS IN NURSING HOME RESIDENTS
Agency: NIH National Institute of Nursing Research, Project Number 5R01NR010736-03
          DESCRIPTION (provided by applicant): This study will test the validity of a non-visual assessment strategy for stage I pressure ulcers (PUs) among nursing home (NH) residents with light or dark skin tones using a multi-site, longitudinal cohort design. PUs are common, often preventable, and costly; detection of early-stage PUs is important because intervention may prevent decline to more severe PUs. The standard method of detection, visual skin assessment for non- blanchable erythema, is somewhat reliable for individuals with light skin tones but detects changes after skin damage has already occurred. In addition, visual skin assessment fails to detect skin color changes in persons with darkly pigmented skin. Documented health disparities between African Americans and Caucasians for incidence of stage I PUs and prevention intervention may be related to deficiencies in detection. In our prior studies, we showed that a hand-held device that assesses sub-epidermal moisture (SEM), a measure of edema from inflammatory changes in the tissues, identified stage I PUs. Further, SEM was higher (e.g., increased edema and inflammation) when there was no visible skin damage at the time but a stage I PU was visible on the skin one week later; SEM values predicted 26 percent of the subsequent stage I PUs. Findings were similar in a small sub-sample of NH residents with dark skin tones. We propose to test the validity of this innovative approach to detecting PUs, particularly focusing on residents with dark skin tones; to test threshold SEM values for detecting stage I PUs and detecting progression of stage I PUs to stage II+ PUs. We will recruit 389 NH residents, 62 of whom will have dark skin tones, who are at risk for PU based on the Minimum Data Set Assessment from 24 NHs. Visual skin assessments and blinded SEM measures will be completed by research staff at least weekly for consented residents for 4 months. Skin tone of NH residents will be assessed using color tiles rather than by proxy measures of ethnicity as in previous research. In addition, participant demographics, MDS assessment data on functional level, and comorbid medical conditions will be obtained from medical record review. Risk assessments using the Braden Scale for Predicting Pressure Sores will be collected at baseline. Generalized ordered logistic modeling, appropriately modeling the repeated observations and time-dependent measures, will be used to evaluate the effectiveness of SEM measures to identify future skin damage. Measurement of SEM represents a potentially important tool for decreasing the disparity of prevention interventions between persons with different skin tones. PUBLIC HEALTH RELEVANCE: Statement to Public Health This project is the next step in the evaluation of a new assessment technique for bedsores, a common problem for nursing home residents. If this measurement can identify skin damage at an earlier stage to allow prompt intervention, evidence will be powerful for evaluating its use through a clinical trial. In addition, replacing methods of assessing skin damage that rely on skin color changes has the potential of reducing the severity of skin damage in persons with darkly pigmented skin, leading to reduction in observed health disparities and equalizing the chance of detecting damage at a point when prevention practices can be most effective.

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Dr. Lynn Brecht

Title: METHAMPHETAMINE ABUSE: LONG-TERM TRAJECTORIES, CORRELATES, TREATMENT EFFECTS
Agency: NIH National Institute on Drug Abuse, Project Number 5R01DA025113-03
          DESCRIPTION (provided by applicant): A decade and a half of rapidly increasing use of and geographic penetration of methamphetamine (MA) across the U.S. and the consequences of its use have generated concern and increasing efforts to improve interdiction, prevention, and treatment strategies, with a priority on research to inform these strategies. Limited information is available regarding the life course of MA abuse, particularly as MA users age. Further research is needed to provide empirical support for developing strategies to address issues specific to older users. The proposed project is a follow-up of 596 previously studied MA users, half recruited from drug treatment participation, half from the same communities but with no prior treatment for MA use at recruitment. The project will collect data using the Natural History Interview to add an average of 8 years of detailed histories on substance use, treatment, and criminal careers of these MA users; these new data combined with previously collected data will produce life course trajectories averaging at least 28 years in duration, covering teen and adult periods. Additional data will come from administrative records from several state agencies. The sample is 35% female/65% male, 33% Hispanic/38% non-Hispanic White/17% African- American/12% other ethnicity. Subjects will range in age from about 28 to 74 (average 42) at beginning of the follow-up study. Analyses will describe the current status and extended MA use histories, examining patterns of MA and other drug use, including escalation, deceleration, and possible cessation and recovery; examine drug treatment utilization patterns and relationship to MA use patterns; and determine health morbidity and mortality and assess differences between surviving and deceased users. The study will also assess the long-term outcomes (14 or more years) of a previously identified drug treatment episode (for the subsample recruited from treatment). In addition, the study will estimate cumulative social costs of MA abuse for the sample in terms of criminal activity, incarceration, drug treatment services, health and mental health services, and welfare system participation; and it will examine differences in costs related to distinctive patterns of MA use and user characteristics. Analysis methods will include growth models and growth mixture models to assess MA use trajectories and their relationships to services utilization, other events, and selected user characteristics. PUBLIC HEALTH RELEVANCE: Findings from this follow-up study will provide additional detail on the life course of methamphetamine (MA) use and an empirical basis for improving strategies for treatment outreach, engagement, service delivery, and continuing care. The accumulated knowledge will have implications for policy regarding the shift in clinical thinking to the long-term management of MA dependence as a chronic disease, the social and health burden of dependence, and importantly, the potential benefits of successful cessation of MA use.

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Dr. Lynn Doering

Title: HOME ECG MONITORING TO DETECT ALLOGRAFT REJECTION FOLLOWING HEART TRANSPLANTATION 
Agency: NIH National Institute of Nursing Research, Project Number 1R01NR012003-01A1 
          DESCRIPTION (provided by applicant): The long-term goal of this research is to apply novel technology for detection of donor organ (allograft) 3 rejection to improve patient outcomes following heart transplantation. The specific goal of this study is to 4 determine whether daily monitoring of the transplant recipient's electrocardiogram (ECG) using a simple home 5 device with transmission to an ECG Core Laboratory would provide an early biomarker for acute rejection. 6 Despite routine immunosuppressant drug therapy, acute rejection is common, especially within the first 6 7 months following transplant surgery. To detect rejection, frequent endomyocardial biopsies of heart tissue are 8 performed. An endomyocardial biopsy is a costly and invasive procedure performed in a hospital cardiac 9 catheterization laboratory that has associated risks. Recent evidence suggests that acute allograft rejection 10 causes delays in ventricular repolarization resulting in a longer QT interval on the ECG. The specific aims of 11 the study are to: 1) determine whether an increase in the QT interval during the first 6 months following heart 12 transplant is a sensitive and specific biomarker for acute rejection; and 2) determine the timing of QT interval 13 increases relative to biopsy-diagnosed stages of mild/moderate/severe rejection. Secondary aims are to: 3) 14 determine whether an increase in the QT interval predicts 1-year mortality; and 4) explore additional ECG 15 measurements that might predict rejection or death. 16 A prospective, double-blind, descriptive and correlational research design is planned. Investigators who 17 analyze ECG data will be blinded from biopsy results; healthcare providers will be blinded from QT 18 measurements. A sample of 325 adult heart transplant recipients will be recruited from 3 transplant centers: 19 Columbia University-New York Presbyterian Medical Center; University of California, Los Angeles and Cedars- 20 Sinai Medical Center, Los Angeles. Each subject will record a 30-second ECG daily using the HeartOneTM 21 device; the device will automatically transmit the ECG to an ECG Core Laboratory at the University of 22 California, San Francisco. For Primary Aim #1, a log regression analysis will be performed with the 23 independent variable being presence /absence of the ECG criteria ( QTC e25 milliseconds X 3 days) and the 24 dependent variable being presence /absence of acute allograft rejection. Odds ratios and confidence intervals 25 will be reported, as well as established evaluative criteria for new diagnostic instruments (sensitivity, specificity, 26 positive /negative predictive value, predictive accuracy). For Primary Aim #2, descriptive statistics will be used 27 to report the average time period between the development of the ECG criterion and biopsy evidence of 28 rejection. The potential benefit of finding a simple ECG biomarker of allograph rejection that could be 29 measured at home is that it might yield earlier detection of rejection, allow more timely therapy and reduce 30 mortality from acute allograft rejection. PUBLIC HEALTH RELEVANCE: The goal of this research is to identify changes in a heart transplant patient's electrocardiogram (ECG) that indicate donor organ rejection, a major cause of death in the first year. Patients will record their ECG daily using a simple home device combined with novel mobile phone technology that will automatically send their ECG to the researchers. The public health benefit of detecting a simple ECG marker of heart transplant rejection is that it might yield earlier detection, allow more timely initiation of medical therapy and reduce mortality from acute rejection.

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Dr. Jo-Ann Eastwood

Title: CARDIAC RISK REDUCTION INTERVENTION FOR AT RISK YOUNG BLACK WOMEN 
Agency: American Heart Association, Clinical Research Grant  
          DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is the number one killer of women in the U.S. Morbidity and mortality rates are increasing in young women aged 25-45 years and are significantly higher in black women than white women. The higher prevalence of risk factors among young black women (YBW) may put them at a substantially higher risk for an earlier onset of CVD, or premature death due to heart disease or stroke. Thus, it is imperative that effective interventions be developed to reduce CVD risk factors in YBW. Interventions based on gender are limited and have been based commonly on studies where YBW were underrepresented or nonexistent. There is little evidence regarding targeted behavior change interventions and thus it is essential that we determine the best approach to CVD risk reduction specifically for this group. In this randomized control trial we propose to compare the effectiveness of a self-management risk reduction program combined with wireless coaching (SMP & WC) to usual care (UC) in order to determine effect sizes for the intervention. A survey will be administered to determine participants' views about the intervention and feedback about problematic areas and recommendations for change. Primary Specific Aim: To examine the short term effectiveness and describe effect sizes of the SMP+WC compared to UC on CVD risk behaviors (physical activity levels, and eating patterns) and biological outcomes (blood pressure, lipid profile, hsCRP, body mass index, waist circumference) in YBW living in Los Angeles County. Secondary Aim: To test the acceptability and feasibility (i.e. adherence to the intervention protocol; completion of the study by intervention and control patients) of the protocol. Impact: This study is important because it targets YBW, an extremely high risk group for whom CVD risk reduction interventions have not been developed. We will pilot test a highly effective program for self-management of CVD risk reduction from a white sample of predominately women, in a sample of urban, black women. Its novelty is twofold: 1) it will apply wireless technology to transfer patient data from the community to a nurse who will provide immediate assessment and feedback; and 2) it applies a delivery system (wireless technology) that is attractive, familiar and salient to its target population. The study findings will yield critical information regarding behavior change for YBW at risk for CVD and will provide extensive data for a large implementation study.

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Dr. Nalo Hamilton

Title: Evaluating biological differences between breast cancer in African-American and Caucasian women to improve outcomes
Agency: Robert Wood Johnson Foundation
          DESCRIPTION (provided by applicant): The Robert Wood Johnson Foundation Nurse Faculty Scholars program was designed to increase the stature and academic standing of nursing faculty and draw more nurses to teaching careers by creating a cadre of national leaders in academic nursing through career development awards to outstanding junior nursing faculty. The purpose of this project is to assess the role of insulin-like growth factor-II (IGF-2) in the development of estrogen-independent breast cancer in African American (AA) and Caucasian (CA) women. This descriptive comparative study will evaluate the correlation between IGF-2 expression and ER localization in normal and malignant tissue of AA and CA breast cancer patients. These results will be compared with data obtained from in vitro studies using ethnic cell lines. The project will test the clinical utility of IGF-2 as a biomarker in predicting clinical outcome between AA and CA women with breast cancer.

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Dr. Felicia Hodge

Title: VULNERABLE POPULATIONS/HEALTH DISPARITIES RESEARCH
Agency: NIH National Institute of Nursing Research, Project Number 2T32NR007077-16
          DESCRIPTION (provided by applicant): This application is designed to continue our long trajectory of recruiting and training nurse scholars in pre- doctoral and postdoctoral education emphasizing methods and measures for ameliorating health disparities experienced by vulnerable populations (VPs). This training program began at the UCLA School of Nursing (SoN) in1994. Since then 23 pre-doctoral and 11 postdoctoral students were trained and supported in their VP- related research. Our program, VP/HD, is supported by the SoN's long history of working with VPs, expertise in research methods and measures, the SoN's research centers that includes research targeting the elderly, homeless, vulnerable and Indigenous populations, and a history of interdisciplinary faculty and community investigators. An improved curriculum targets methods and measures specific to vulnerable group research, as well as a summer Internship/immersion program that provides expanded experience in health disparities in rural and urban sites (such as among the homeless and Indian reservations). The strengths of this application are the long-term experience of the training program and the (1) Transition to new Program Director, (2) Significant numbers of new/continuing key faculty supporting trainee research, (3) Recruitment of trainees who reflect the ethnic make-up of the region, (4) A well-funded faculty research grant support program and research centers targeting VPs, (5) A well-designed curriculum on VP research methods and measures, and (6) a VP focused summer Internship/immersion program to provide pre-doctoral students with expanded hands-on experience in VP settings and healthcare needs.

Title: HOME VISITATION PROGRAM
Agency: DHHS/ADMINISTRATION FOR CHILDREN AND FAMILIESSub-Contract Number  
          DESCRIPTION (provided by applicant):  The project assists in the development and evaluation of a home visitation program in American Indian communities in two counties for children 0-5 years of age.  The intervention targets American Indian families during the perinatal and early childhood periods of life. This is a five year program consisting of planning and training of the Riverside San Bernardino Counties Indian Health, Inc. (RSBCIHI) program staff. (1) Program technical and evaluative support includes modifying the training for cultural appropriateness and test measurement of mandated benchmark constructs. Bench mark measures to be reported to demonstrate improvement are: (a) Maternal, Newborn, and Child Health, (b) Child Injuries, Child Abuse, Neglect or Maltreatment, and Emergency Department Visits, c) School Readiness and Achievement, d) Domestic Violence, 5) Family Economic Self-Sufficiency, and e) Coordination and Referrals for Other Community Resources and Supports.  Other activities include: (2) To develop an ongoing Continuous Quality Improvement programs, in identify critical areas for improvement and preparing a Quality Improve Plan, and (3) To develop and host a Geographic Information System for resource management enhancement.  We developed a geographic information system locating tribal, county, state, and private resources accessible by home visitors. The GIS resource management system is an enhancement of the home visiting program that will facilitate appropriate referrals and improve coordination with non-RSBCIHI services, and is hosted at the Charles Drew Medical Geographic Information Systems Laboratory., and (4) Finalize the evaluation plan for the RSBCIHI Outreach Home Visiting Program.

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Dr. Boyoung Hwang

Title: STRESS AND HEALTH IN FAMILY CAREGIVERS OF PERSONS WITH HEART FAILURE
Agency: NIH National Institute of Nursing Research, Project Number 1K23NR013475-01A1
          DESCRIPTION (provided by applicant): The objective of this application for a K23 award is to provide additional training and mentored research experience for Dr. Boyoung Hwang to establish herself as an independent investigator in clinical research that is focused on the improvement of the health and well-being of caregivers of HF patients, and subsequently, of the HF patients themselves. The career development plan consists of obtaining training in design and implementation of randomized clinical trials, advanced biostatistical methods, cognitive behavioral interventions, and salivary biomarkers of stress. To achieve her training goals, Dr. Hwang has developed a focused research study and assembled an outstanding mentoring team comprised of a primary mentor, Dr. Lynn Doering, Professor of School of Nursing at UCLA, who is an expert in biobehavioral research in cardiovascular disease and cognitive behavioral therapy, and two co-mentors: Dr. Mary-Lynn Brecht, Biostatistician at UCLA, who has expertise in study design and complex biostatistical analysis; and Dr. Douglas A. Granger, Professor of Nursing, Public Health, and Medicine at the Johns Hopkins University, who is an expert in salivary biomarker research. Heart failure (HF) is a prevalent and debilitating disease. While support from family caregivers is crucial for better outcomes for HF patients, caring for a chronically ill family member can be challenging and stressful. It has been reported that HF caregivers are distressed and socially isolated due to their care responsibilities, perceive their health to be compromised, and suffer from poor quality of life. However, the literature lacks a comprehensive description of the health status of HF caregivers; no intervention study aimed at alleviating stress in HF caregivers has been reported to date. To fill these gaps, Dr. Hwang will conduct a pilot randomized clinical trial with 50 dyads of HF patients and their caregivers. The study will provide a comprehensive description of health problems and symptoms that caregivers experience (Aim 1) and evaluate the potential of a cognitive behavioral (CB) intervention designed to reduce stress and improve knowledge about HF care and perceived social support among caregivers. Using salivary cortisol measures, the study will examine how psychological benefits from the intervention lead to improvement in caregiver health. Specifically, the study will provide preliminary effect sizes of an 8-week CB caregiver intervention on psychological stress responses (i.e., perceived stress, caregiver stress, and depression), physiological stress responses (i.e., salivary cortisol), stress-related symptoms, health-related quality of life, and health care usage of caregivers. Clinical outcomes of HF patients will also be measured to determine the effects of this caregiver intervention on care recipients (Aim 2). Finally, the potential mediating effects of knowledge about HF care and perceived social support on changes in psychological stress responses and caregiver health will be examined (Aim 3). The study will provide critical pilot data to support an R01 application for a large randomized clinical trial. PUBLIC HEALTH RELEVANCE: Caregivers are vulnerable to health problems because of the stress and demands of their role as a caregiver. With the growing incidence of HF and the anticipated growth in the aging population, the number of HF caregivers is expected to rise. Therefore, the project will pilot test a cognitive behavioral intervention designed to reduce stres and improve knowledge about HF care and perceived social support among HF caregivers, which will ultimately contribute to promoting health and quality of life among HF caregivers and their loved ones with HF.

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Dr. Paul Macey

Title:  OBSTRUCTIVE SLEEP APNEA, GENDER BIOLOGY AND AUTONOMIC REGULATION
Agency: NIH National Institute of Nursing Research, Project Number 1R01NR013693-01A1 

DESCRIPTION (provided by applicant): Obstructive sleep apnea (OSA) occurs in close to 20% of men and 10% of women in the adult population, and is an independent risk factor for cardiovascular disease and death. Despite the lower prevalence in women, female OSA patients show more severe cardiovascular and neuropsychological consequences than men with the disorder. The causes of the health problems associated with OSA are unclear, and there are few clinical guidelines for treating symptoms other breathing support with positive airway pressure (PAP); that support assists ventilation, but does little to restore sympathetic dysfunction, one factor that likely contributes to hypertension and other cardiovascular sequelae in the syndrome. Since sympathetic outflow is regulated by the brain, a possible contribution to the cardiovascular sequelae is impaired regulation due to neural injury from the intermittent hypoxia and other characteristics of OSA. We showed such injury in OSA together with deficient cardiovascular control in many brain regions, including the insular cortex, an area that integrates higher brain processing and sensory input to modulate brainstem and hypothalamic autonomic outflow. Our R21 data show that female OSA patients have an even greater extent of insular cortex injury and dysfunction than male OSA patients. We therefore hypothesize that in OSA patients, the insular cortex has impaired function due to injury, resulting in less effective cardiovascular regulation, and these effects are especially severe in female OSA patients. We will evaluate brain structure with diffusion tensor imaging, brain function with functional magneti resonance imaging (fMRI), and cardiovascular function with heart rate measurements during three autonomic challenges, an inspiratory apnea, Valsalva maneuver, and static hand grip. We will localize the insular cortex subdivisions involved in sympathetic modulation from high-resolution MRI scans. We will study 144 people across four age-matched groups: newly-diagnosed OSA females and males matched for disease severity, and healthy control females and males. Females will be assessed for menopausal and hormonal status, with the aim of balancing the numbers of pre- and post-menopausal women, and including hormonal factors in statistical models. In males and females, the findings will show whether disrupted neural regulation of sympathetic activity occurs in OSA, whether that dysfunction is paralleled by brain injury, and whether cardiovascular responsiveness is also impaired. We will also perform an exploratory assessment of the effects of 3 months of PAP treatment on autonomic function in 15 male and 15 female patients, and gather evidence as to whether autonomic central function can recover, at least in the short term. A lack of recovery would suggest additional treatments to PAP should be investigated. Findings of worse effects of OSA in women would highlight the need to broaden OSA treatment, which currently solely focuses on resolving breathing disruptions for moderate and severe OSA, and is typically ignored in mild OSA in women, despite evidence that mild OSA in females is accompanied by severe cardiovascular characteristics. PUBLIC HEALTH RELEVANCE: We will investigate a possible cause of the cardiovascular and neuropsychological symptoms that women with Obstructive Sleep Apnea (OSA) show to a greater degree than men. We will test whether brain function in the insula, a region controlling blood pressure and mood, is abnormal in female OSA patients by using magnetic resonance imaging, and look at brain damage as a possible cause of this dysfunction, as well as looking at the cardiovascular consequences, and in a subset of patients the influence of treatment. This study will help show whether impaired brain function in the insula due to injury is associated with poor cardiovascular control, whether women are more physically affected by OSA than men, and whether treatment for the sleep disorder may improve brain and cardiovascular function

 
 

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Dr. Sally Maliski

Title: UNDESERVED MEN'S UNDERSTANDING OF ANDROGEN DEPRIVATION THERAPY RELATED RISKS
Agency: NIH National Institute of Nursing Research, Project Number 1R21NR012786-01

DESCRIPTION (provided by applicant): Androgen deprivation therapy (ADT) is increasingly being used to treat prostate cancer in the neoadjuvant and adjuvant contexts with radiation therapy (RT), for recurrence following primary treatment with surgery or radiation, or when the prostate cancer is at an advanced stage such that local treatments, surgery or radiation, are no longer indicated. This is significant because prostate cancer is the most commonly diagnosed noncutaneous cancer in American men. Of particular concern are underserved men. Latinos are the fastest growing minority in the United States (US) and have lower rates of health insurance coverage. African American (AA men) have almost twice the incidence as men of other ethnicities, and have advanced, aggressive disease. For purposes of this study, we will define underserved as low-income and uninsured or publically insured. Low-income will be household income 300% of the Federal Poverty Level (FPL) or less. Despite the proven survival benefit of ADT relative to prostate cancer, studies have shown that men on ADT are at increased risk for vasomotor symptoms, depression, fatigue, diminished healthrelated quality of life (HRQOL), decreased bone mineral density (BMD), sexual dysfunction, metabolic syndrome, increased fat mass, along with decreased lean muscle mass, increased serum lipids, and decreased arterial compliance all of which places them at higher risk for cardiovascular disease (CVD), osteoporosis, and type II diabetes. Both Latinos and AA more often have components of metabolic syndrome, obesity, dyslipidemia, low cardiovascular fitness, and diabetes placing them at higher risk for CVD. However, little is known about how these men understand ADT and its associated risks relative to their own health and well-being. Therefore, we aim to: 1. From previously collected data explore men's explanations of ADT, its purpose, effects, and risks among underserved men on ADT in order to develop interview guides focused on issues related to 2 Elicit in-depth narratives from underserved men on ADT focused on their understanding and experience of ADT and 3. Develop a descriptive framework of men's understanding of and response to ADT and its associated risks to guide development of interventions to decrease morbidity and mortality related to ADT-associated risks. We will use a two-stage qualitative approach to meet these aims. First we will conduct a new, in-depth analysis of existing qualitative data focused on men who were receiving ADT at the time of their interviews. From this analysis we will develop focused interview guides to more completely explore men's understanding and management of ADT-related with a new cohort of underserved men. This is necessary formative work to lay the foundation for the development and testing of interventions to minimize ADT-associated risks among highly vulnerable underserved men. These interventions have the potential to While androgen deprivation therapy (ADT) has survival benefit for men with recurrent of advanced prostate cancer, it has multiple associated risks related to cardiovascular disease, bone fraction, metabolic syndrome, and sexual dysfunction. Underserved men are at particular risk. Our goal is to understand how underserved men treated for prostate cancer with ADT understand their treatment and the risks associated with it. To do this, we will conduct the study in two phases. In the first phase we will use transcripts of interviews conducted with underserved men in two studies; one on the meaning of prostate cancer treatment-related incontinence and impotence among low-income African American and Latino men and the second on the impact for prostate cancer treatment-related symptoms on low income Latino couples. We will select the transcripts of the men who were on ADT and re-analyze them for understanding of ADT and its risks and for their management of related symptoms. We will use this to develop an interview guide to do in-depth interviews focused on ADT understanding and risks. We will use the analysis of this data to help develop interventions to minimize ADT-related risks.

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Dr. Adeline Nyamathi

Title:  HEALTH PROMOTION COACHING/VACCINE FOR HOMELESS PAROLEES
Agency: NIH National Institute on Drug Abuse, Project Number 5R01DA027213-03
          DESCRIPTION (provided by applicant): Homeless parolees are at high risk for Hepatitis B virus (HBV), Hepatitis C virus (HCV) and HIV infection due to high rates of injection drug use and unprotected sexual activity. Although HBV is a vaccine-preventable illness, 12% to 25% of formerly incarcerated individuals are infected with HBV. Homeless parolees pose a particular challenge for successful reentry as they have underlying mental health issues combined with substance use and abuse and must contend with unstable housing situations, disorganized lives, unemployment, and limited access to health care and social services. Generally about 50% of all parolees scheduled to enroll in community-based drug treatment fail to enroll and less than 10% of enrollees actually complete treatment. Not surprisingly, about two-thirds of all individuals on parole are rearrested and return to custody within three years of release from prison. Our recent data also revealed homeless persons least likely to complete a HAV/HBV vaccine series were young (< 40), and were men who had been discharged from prison. Therefore, it is critical to engage paroled adults in comprehensive intervention programs that not only protect them from HBV, but also reduce risky behavior, promote access to health care, social and employment services, and enable positive coping and communication skills. With advice from our community partners who have successfully treated parolees and our experience with hepatitis vaccination work, we propose to conduct a prospective, three-group study that randomly assigns 700 ready-for- discharge parolees, scheduled to enter a community residential drug treatment program, to enter one of three groups: 1) a PCPC (Parolee Comprehensive Care + Phone Coaching Program), which includes nurse case management and specialized hepatitis education sessions and referrals, the HAV/HBV vaccination series (to all eligible) and coach- facilitated mentoring (mostly by cell-phone); 2) a Parolee Brief Hepatitis Education + HBV vaccination + Phone Coaching (PBCP) Program, which includes brief hepatitis/HIV education, the HAV/HBV vaccination and coach-facilitated mentoring; or 3) a Usual Care (UC) control program, which includes brief general health information, and the HAV/HBV vaccine. For the randomized parolees, the primary aims will be to examine: reincarceration (any vs none), number of days to first reincarceration, completion of HAV/HBV vaccination (among those HBV-negative), and completion of six months of the Amity community-based residential drug treatment program. Secondary aims are to examine program- related differences in potential mediating variables, such as reduction in drug and alcohol use and sexual risk behaviors, visit to health care or social service providers, and improved knowledge of Hepatitis/HIV and communication skills, between 6 and 12 months or over the one-year study period, depending on the measure, and to assess the relative costs of the three programs. This study will advance our knowledge about drug treatment and HBV vaccine completion and recidivism among homeless parolees. Findings from this study can inform targeted interventions and lay the groundwork for health policy decisions that may impact hepatitis and HIV risk reduction and recidivism in this group who are a reservoir for these viruses in the general population, and are returning to prison at unprecedented numbers. PUBLIC HEALTH RELEVANCE: In this study, researchers from UCLA will partner with Amity Foundation and will work together in designing a program to engage soon-to-be discharged prisoners targeted to enter community-based residential drug treatment to receive a comprehensive program that not only protects them from hepatitis A and B infection by means of the hepatitis vaccination, but also reduces risky behaviors, helps them access health care, and social services, and help them to use more positive coping and communication skills. Using nurse case management strategies found successful with homeless adults, incorporating phone coaching, where a buddy who has successfully completed the drug treatment program supports the newly released parolee, we will evaluate the effectiveness of a Parolee Comprehensive Phone Coaching program compared to a less intense program or a usual care program. Findings from this study can inform targeted interventions and lay the groundwork for health policy decisions that may impact hepatitis and HIV risk reduction and rearrest and/or return to custody in this group who can spread hepatitis infection in the general population, and, are returning to prison at unprecedented numbers.

Title:  HBV PREVENTION FOR HOMELESS AT RISK FOR HBV/HCV/HIV
Agency: NIH National Institute on Drug Abuse, Project Number 5R01DA016147-08
          DESCRIPTION (provided by applicant): Homeless adults are at high risk for Hepatitis B virus (HBV), Hepatitis C virus (HCV) and HIV infection due to high rates of injection drug use and unprotected sexual activity. Our NIDA-funded RO1 award has enabled us to implement a successful intervention improve morbidity and mortality of underserved men on ADT thereby decreasing some of the health care and human costs that can be associated with ADT. PUBLIC HEALTH RELEVANCE: designed to evaluate the effectiveness of a HBV vaccination intervention with homeless adults. Our findings revealed that a greater percent of homeless adults randomized to the Nurse Case Managed Plus Incentive and Tracking group completed the HAV/HBV vaccine series compared to a Standard program without tracking. Homeless persons least likely to complete the vaccine series were young (<40), and were men having sex with men (MSM); a significant number of these young adults also reported methamphetamine (MA) and cocaine/crack use. Stimulants (SAs), including MA and cocaine/crack are commonly used by homeless MSM, who contend with disorganized lives, unemployment, and little access to health and social services; thus, HBV vaccination is particularly challenging in this population. HAV/HBV vaccination and effective behavioral treatment are two of the most important strategies for reducing HBV infection among this at-risk group of SA users. Based upon advice from our community partners who have successfully treated SA-using gay and bisexual men (GBM), we will incorporate contingency management into our vaccination completion program, which had lower completion rates among young adults and MSMs. Thus, in this competitive renewal, we propose a randomized, experimental, twogroup design to evaluate the effectiveness of a Nurse Case Managed Program, which includes specialized education and Contingency Management and Tracking (NCCMT), with a Standard Program, including brief education, Contingency Management and Tracking (SCMT) with 500 homeless, young (18-39), SA-using GBM, on completion of theTwinrixHAV/HBV vaccine and, secondarily, on reduction of risk for hepatitis and HIV. This study is innovative in that it will allow us to look at the effect of an enhanced case management and contingency management program versus a standard contingency management program. The proposed study combines optimal strategies to approach, engage and intervene with a hidden and high- risk population to assess the feasibility and efficacy of interventions that may prove beneficial in preventing HBV and HAV infections. We will also assess the relative cost of these programs in terms of completion of the HAV/HBV vaccination series. As use of SAs threatens to intensify homeless persons' risk of exposure to HAV and HBV, particularly among young users who may not yet be HBV-infected, research targeted to engage this group in treatment, until they are suitably protected from HBV, is critical. PUBLIC HEALTH RELEVANCE: In this study, researchers from UCLA and Friends Community Center will work together in designing a program to assist young homeless stimulant-using gay and bisexual homeless men to complete the hepatitis vaccine and in reducing drug and sexual activity. Using nurse case management strategies, found successful with homeless adults as well as contingency management strategies, found successful with gay and bisexual homeless adults by our community partners, we will evaluate the effectiveness of a program that combines both strategies. As Stimulant use threatens to increase homeless persons' risk of exposure to hepatitis A and B viruses, particularly among young users who may not yet be HBV-infected, this research is targeted to engage this group in treatment, until they are suitably protected from HBV, and hopefully reduce risk for HCV and HIV as well.

Title: ASHA IMPROVING HEALTH AND NUTRITION OF INDIAN WOMEN WITH AIDS AND THEIR CHILDREN  
Agency: NIH National Institute of Mental Health, 1RO1MH098728-01A1  
          DESCRIPTION (provided by applicant): Rural women living with AIDS (WLA) in India continue to face profound challenges in accessing and following treatment regimens, caring for family members, and maintaining positive mental health. Furthermore, they are generally underweight and malnourished, with adherence to antiretroviral therapy (ART) at levels lower than 50%. While the Indian Government's National Rural Health Mission utilizes a successful model to address the health needs of the rural population by training village women as Ashas (Accredited Social Work Activists) to enhance health of pregnant women and their infants, the focus on rural WLA needs to be significantly strengthened. U.S. and Indian collaborators recently completed an R34 pilot study which has demonstrated successful improvement in ART adherence, CD4 levels, and physical and mental health among rural Indian WLA. In total, 34 rural intervention WLA were supported by grant-trained, HIV-focused Ashas who provided assistance to WLA in decreasing barriers to ART adherence and provided protein supplementation compared to equal numbers of usual care WLA who received minimal protein supplementation. While very successful, our Asha pilot study monitored only WLA, despite the fact that many rural children are also at risk for delayed physical growth and psychomotor development. More importantly, we were not able to separate the nutritional component from the care and support component of the Asha, did not incorporate nutritional biomarkers, and were limited by only a six-month follow-up. In light of the mandate to advance both the science of nutrition and sustainability in real settings, our experienced team proposes to build on and extend our successful pilot work to meet this need, by assessing the incremental advantages of nutritional support to Asha care and support alone, and the impact of these programs on an index child (oldest between 3-8 years). In addition, we will take advantage of rural India's excellent mobile phone coverage and computer technology for both wireless data collection and data transfer. The proposed longitudinal study will use a 2x2 factorial design, specifically, 1) Asha support alone for WLA , vs. 2) Asha support for WLA + nutrition (food-based) training, vs. 3) Asha support for WLA + food supplementation, vs. 4) Asha support for WLA + nutrition training + food supplementation, to test the effects of nutrition training and/or food supplementation on primary outcomes of anthropometric parameters and immune status (CD4 levels) of the WLA at 6-, 12- and 18-month follow-up; and secondarily on ART adherence, psychological health, nutritional adequacy and lipid status of the WLA over time. Based upon reviewers' comments, among index children, we streamlined our assessments to include anthropometric parameters and psychomotor development; and among those HIV positive, immune status.    PUBLIC HEALTH RELEVANCE: Rural women living with AIDS experience profound challenges in accessing and following treatment for AIDS, while caring for children and maintaining a positive mental health outcome; yet, there has been very little research conducted regarding their nutritional needs and that of their growing children, some of whom may also have HIV/AIDS. This proposed collaboration between U.S. and Indian researchers builds on our previous work with rural women living with AIDS and our successful Asha program; using a 2x2 factorial design, we plan to assess the effects of nutrition training and/or food supplements on primary outcomes for rural women living with AIDS in improving body composition and immune status (CD4 levels) as assessed at 6-, 12- and 18-month follow- up; and secondarily, adherence to ART, psychological health, nutritional adequacy and lipid profile over time. For the oldest child (aged 3-8), our grant will focus on improving their growth and development. This program, if found efficacious, could easily be scaled up and sustained by local governmental and non-governmental organizations in rural and urban settings across India and elsewhere.       

Title: VULNERABLE POPULATIONS/HEALTH DISPARITIES RESEARCH
Agency: NIH National Institute of Nursing Research, Project Number 2T32NR007077-16 
          DESCRIPTION (provided by applicant): This application is designed to continue our long trajectory of recruiting and training nurse scholars in pre- doctoral and postdoctoral education emphasizing methods and measures for ameliorating health disparities experienced by vulnerable populations (VPs). This training program began at the UCLA School of Nursing (SoN) in1994. Since then 23 pre-doctoral and 11 postdoctoral students were trained and supported in their VP- related research. Our program, VP/HD, is supported by the SoN's long history of working with VPs, expertise in research methods and measures, the SoN's research centers that includes research targeting the elderly, homeless, vulnerable and Indigenous populations, and a history of interdisciplinary faculty and community investigators. An improved curriculum targets methods and measures specific to vulnerable group research, as well as a summer Internship/immersion program that provides expanded experience in health disparities in rural and urban sites (such as among the homeless and Indian reservations). The strengths of this application are the long-term experience of the training program and the (1) Transition to new Program Director, (2) Significant numbers of new/continuing key faculty supporting trainee research, (3) Recruitment of trainees who reflect the ethnic make-up of the region, (4) A well-funded faculty research grant support program and research centers targeting VPs, (5) A well-designed curriculum on VP research methods and measures, and (6) a VP focused summer Internship/immersion program to provide pre-doctoral students with expanded hands-on experience in VP settings and healthcare needs.

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Dr. Carol Pavlish

Title: CO:ADVOCATE: A PROGRAM TO PREVENT ETHICAL CONFLICTS AND MORAL DISTRESS IN ICU
Agency: American Association of Critical Care Nurses
          DESCRIPTION: Ethical conflicts are among the most challenging situations faced by patients with life-threatening conditions, their families, healthcare providers, and the healthcare system. Ethical conflicts are particularly relevant during care of critically ill patients near the end of life. These conflicts can occur between patients, families, and healthcare teams or within healthcare teams, or within families. Regardless of origin, ethical conflicts threaten patient safety and quality care. For clinicians, ethical conflicts can lead to recurring and increasing moral distress which the American Association of Critical-Care Nurses (AACN) identifies as a critically important topic for critical care nurses. Moral distress may result in disengagement, medical errors, absenteeism, and burnout. Healthcare systems also suffer increased organization costs with ethical conflicts. In a recent consensus statement, the American College of Critical-Care Medicine (ACCM) asserted that effective team communication plays a crucial role in preventing and managing ethical conflicts during end-of-life care.32 However, both the ACCM and the AACN acknowledge a lack of proven strategies that decrease the risk for ethical conflicts, moral distress, and burnout. This research proposal builds on the investigators' previous work that evidenced nurses' awareness of moral concerns and impending ethical conflicts regarding treatment decision making; however this awareness was often accompanied by reluctance to initiate discussion about their concerns. The purpose of the proposed study is to to evaluate the effectiveness of an ethics educational program called CO:ADVOCATE in ICU settings in three institutions: University of California Los Angeles Medical Center, Mayo Clinic, and Massachusetts General. Our working hypothesis is that educational programs aimed at improving interdisciplinary teamwork will facilitate timely interdisciplinary goals-of-care conversations, increase family satisfaction, improve ethical climate, and decrease clinicians' moral distress. CO:ADVOCATE has the potential for creating safer and more effective systems of care for seriously ill patients and their families.

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Dr. Linda Phillips

Title: UCLA/CDU PARTNERSHIP FOR ENHANCING DIVERSITY OF NURSES WITH RESEARCH CAREERS
Agency: NIH National Institute of General Medical Sciences, Project Number 1R25GM102777-01 
          DESCRIPTION (provided by applicant): Health disparities for individuals from under-represented minority groups (URMGs) continue to plague the US population. The roots of this problem are many and complex, but of great relevance is the dearth of individuals from URMGs in the health professions workforce, with serious disparities in the ethnic/racial composition of the workforce being particularly pronounced in nursing. The 2008 NSSRN survey showed 32.1% of Black/African American nurses and 39.4% of Latino nurses had baccalaureate degrees; for all racial/ethnic groups combined, only 11.4% had graduate degrees including PhDs. This state exists at a time when the US population is becoming older and more ethnically diverse. Given this dire state of affairs, we are proposing to enhance an existing relationship between the Schools of Nursing at the University of California, Los Angeles (UCLA) and Charles R. Drew University of Medicine and Science (CDU), an Historically Black Graduate Institution and Hispanic Serving Institution, for the purpose developing and implementing an integrated plan of individual and institutional activities to prepare masters students from URMGs to make a seamless transition to doctoral education. The long term goal of this project is to increase the ethnic/racial diversity of those prepared to pursue research careers in nursing focusing on research about aging adults (45+ years) by (1) increasing involvement of master's students and faculty at CDU SON in the scientific enterprise through structured development activities; (2) enriching the research course offerings and scientific environment at CDU SON to prepare master's students to seamlessly transition to doctoral education; and (3) facilitating student advancement to the UCLA SON via systems that facilitate student enrollment and scientific exchange between faculty at UCLA and CDU. PUBLIC HEALTH RELEVANCE: Health disparities persist despite efforts to curb them. Encouraging more diverse, underrepresented minority individuals to pursue doctoral education in the health care field, such as nursing, is one documented way to reduce health disparities. This application proposes collaboration between University of California Los Angeles and Charles Drew University to provide the supportive and educational activities required to prepare a more diverse nursing workforce at the doctoral level, who will ask the relevant research questions and develop the science that will ultimately reduce health disparities.

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Dr. Huibrie Pieters

Title: Decision Making on Aramatase Inhibitors in Breast Cancer Survivors 65 and Older
Agency: NCI (National Cancer Institute)  Project Number 1R21CA167218-01A1
DESCRIPTION (provided by applicant): Age is a strong and independent risk factor for dying from breast cancer (BC) in and of itself. This becomes highly significant when considering that BC is the most commonly diagnosed cancer in women and the second most deadly. Hormone positive BC is especially common among older women. While adjuvant hormonal treatment is proven to dramatically reduce the risk of cancer recurrence and mortality for hormone- sensitive BC, evidence shows that about half of all women 65 years discontinue this life-saving treatment. What contributes to discontinuation is poorly understood. Aromatase inhibitors (AIs) are associated with adverse side effects such as an arthralgia syndrome, hot flashes, loss of bone density, and cardiovascular events which may influence whether women persist with the treatment. Although the numbers of older women with BC is growing and this population has disproportionately high mortality rates compared with younger women, little or no research has explored the processes by which women 65 years decide to continue or discontinue AI treatment. Our multidisciplinary study will elicit in-depth narratives to explore what influences te trajectory of continuing or discontinuing an AI in the context of the lives of women 65 years and above. We will gain understanding of how women 65 years interpret, and act upon information that they have received about AIs. In addition, based on the pragmatic evidence in the women's own words, we will develop a novel descriptive framework of the decisional processes about using AIs within the context of the women's lives. The choice of research method is constructivist grounded theory, providing a methodology to access and understand meanings and decisional processes from a personal perspective. Approximately 50 personal interviews with 40 women, 65 years who were treated for primary, invasive loco-regional BC and are either taking an AI or have discontinued the treatment will supply the data. A focused interview guide has been developed from preliminary findings including the PI's research with women 70 years who recently completed treatment for early stage BC. The interview guide will extend previous research to include questions about preferred ways to receive information about AIs and what the women did to self-manage the modifiable factors of side effects. Furthermore, from the perspective of cancer survivorship science, the interview guide contains questions about the role of family and support people. A novel framework will result from this study to provide the foundation to design and test an age- appropriate and cost-effective supportive intervention to improve informed decision making and increase continuation with AIs. We also foresee that the findings may be transferable to women 65 years in other contexts of geriatric oncology and other areas of oncology such as the use of an AI to reduce the relative risk of a first time invasive BC in healthy postmenopausal women.  PUBLIC HEALTH RELEVANCE: Despite progress in early detection and treatment, breast cancer is the second most deadly cancer and women 65 years are even more likely than younger women to die from breast cancer itself. Aromatase inhibitors, a proven effective treatment to prevent deadly complications of a first-time breast cancer, are discontinued by an estimated 50% of all women who stand to benefit from this treatment. Using the women's own words, our research will assess what comprises the decisions of women 65 years to continue or discontinue this potentially life-saving treatment towards the goal of developing an intervention for improved decision-making.

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Dr. Nancy Pike

Title: MEMORY AND BRAIN STRUCTURE IN ADOLESCENTS WITH SINGLE VENTRICLE HEART DISEASE
Agency: NIH National Institute of Nursing Research  Project Number: 1R01NR013930-01A1
DESCRIPTION: Cognitive impairment, especially short-term memory, [is] prevalent in adolescents with single ventricle congenital heart disease (CHD), [which] can deleteriously impact one's ability for self-care. To date, no research team has reported a link between memory loss and brain structural changes in this high risk, vulnerable population. Therefore, the specific aims for this study are to: 1) Compare brain [structural integrity] of regions which control memory (hippocampus, mammillary bodies [controlling for global cerebral volume and with other relevant cofactors]) between CHD adolescents and age- and gender-matched healthy controls, and 2) Examine the relationship between clinical/questionnaire measures of memory and [volumes of] brain structure[s that control memory function] [ controlling for global cerebral volume] in adolescents with single ventricle CHD and healthy controls. Using a comparative [research] design, 20 single ventricle CHD subjects and 40 age- and gender-matched healthy controls will undergo [high-resolution T1-weighted] structural brain [magnetic resonance imaging] and have memory testing using the Montreal Assessment of Cognition (MoCA) and the Wide Range Assessment of Memory and Learning (WRAML2). Inclusion criteria [for CHD] will be subjects between the ages of 14 to [18] years, single ventricl heart disease, and have undergone Fontan surgical completion, [and for controls will be age (+1 year) and gender-matched to CHD subjects and without any condition that may affect the brain.] [Magnetic resonance imaging] analysis will consist of volumetric measures of [bilateral] hippocampus and mammillary bodies of each subject. Statistical tests will consist of Spearman's Rho and [MANCOVA with age, gender, and global cerebral volume] as covariates with significance set at p < 0.05. In summary, the overall purpose of the study is to identify the association between memory and structural brain injury in adolescents with CHD after staged surgical palliation. [The proposed study] has the potential to dramatically impact clinical practic, as information from this study can guide clinicians toward improved patient education/self-management strategies and assist researchers in the identification and testing of innovative interventions to improve memory and self-care in this growing [patient] population of single ventricle CHD survivors. PUBLIC HEALTH RELEVANCE: Cognitive deficits, particularly memory loss, are common in adolescents with single ventricle congenital heart disease and can impact their ability for self-care; [however, it] is uncertain if these memory deficits are associated with brain injury. This study will be the first to examine the relationship between memory loss and structural brain injury in adolescents with single ventricle congenital heart disease. The [proposed] study has the potential to dramatically impact clinical practice, as information from this study can guide clinicians toward improved patient education/self-care strategies and test innovative interventions to improve memory in this growing [patient] population.

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Dr. Michael Prelip

Title: IMPACT OF A CBPR SCHOOL PROGRAM ON OBESITY-RELATED OUTCOMES IN UNDERSERVED YOUTH
Agency: NIH National Institute of Nursing Research, Project Number 1R01NR012676-01
          DESCRIPTION (provided by applicant): Over the past 20 years, obesity rates in U.S. children and youth have skyrocketed. National studies show that disparities exist where racial/ethnic minorities and those from a low-income are at higher risk for being overweight or obese. Design, implementation and dissemination of effective school-based prevention programs are critical to addressing these disparities in the obesity epidemic, however few successful models exist. Interventions that are both informed by community partners using a CBPR approach and are comprehensive, and those that include the integration of individual (physical activity behaviors), social (PE teacher curriculum training activities) and environmental (improved school PE equipment) factors have greater success in achieving long-term effects on children's obesity-related behaviors and cognitive performance, especially among medically underserved areas/populations (MUA/P). Resulting from a partnership with the UCLA School of Nursing, the Los Angeles Unified School District (LAUSD) we propose to assess the impact of a middle-school based environmental and curriculum intervention on physical activity and fitness behaviors and standardized achievement test scores among MUA/P youth. This research also examines whether the effects of the intervention vary by gender and ethnicity. The proposed environment and curriculum, coordinated school health program will consist of three components: (1) the SPARK Middle School Physical Education and Nutrition (M-SPAN) Program, 2) professional development (PD) and curriculum training for PE teachers; and 3) provision of quality PE equipment. This study uses a cluster randomized controlled trial design at 24 MUA/P middle schools in the LAUSD with repeated measures (pre-program, mid-program, immediate post-program) and random assignment to the intervention. M-SPAN is an evidenced-based program and is recommended by the CDC to decrease childhood obesity. In order to enhance M-SPAN, SPARK has created PE equipment to match the activities in M-SPAN. The curriculum intervention entails the combination of SPARK Active Recreation and LAUSD PE Standards curricula and will be delivered once a month over 11 months of each of the two intervention years (total 22 months). The project design will be implemented in two waves. Wave I (with 6 sites from each study condition) will run from Years 1-3 and Wave II (with 6 sites from each study condition); will run from Years 2-4. The study aims will be evaluated with objective and subjective activity measures including SOPLAY (System for Observing Plan and Leisure Activity in Youth), physical fitness via the FitnessGram assessment, measured by body composition (decreased BMI and skinfold thickness), aerobic fitness (one mile run), and muscular strength/endurance (curl-up and pull-up) as well as standardized achievement test scores. A small subsample of youth from intervention schools (n=3,960) will also be assessed for physical activity via a modified Youth Risk Behavior Survey (YRBSS), pre-intervention, mid- intervention and immediate post-intervention. For Wave I years 1, 2, and 3 and for Wave II, years 2, 3 and 4. PUBLIC HEALTH RELEVANCE: Childhood overweight and obesity have detrimental consequences in terms of physical and mental health for all children but especially youth from MUA/P. The outcome knowledge from this study will likely demonstrate the value of utilizing a culturally-sensitive, multi-component, collaborative intervention to decrease childhood obesity. Findings from this comprehensive study could impact future programs that aim to improve minority adolescent health and academic status and over the long term may result in a significant decrease in childhood obesity, especially among MUA/P.

 

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Dr. Wendie Robbins

Title: EFFECT OF WALNUTS ON PROSTATE HEALTH
Agency: Walnut Commission
          DESCRIPTION: Having children is an important part of life, yet many couples struggle with this milestone due to infertility. Worldwide ~70 million couples suffer from infertility. In the USA infertility affects ~one in seven couples and has led to a steady increase in the number of couples seeking infertility services. In vitro fertilization and other assisted reproductive technologies now account for ~3 in every 100 live births. A more natural first step toward dealing with infertility would be to focus on factors we know are associated with good health, for example diet. As described below, walnuts provide a rich dietary source of nutrients needed for male reproductive health.

The male partner is responsible for about 30 - 50% of all cases of infertility. Although the underlying causes of most male infertility are not known, the clinical hallmark is poor semen quality (low sperm count, poor sperm motility, abnormally shaped sperm, fragmented sperm DNA). There are multiple reports of declining semen quality in specific geographic locations around the world, usually associated with industrialized nations. Some research suggests environmental pollutants and a trend toward a more Western diet (laden with saturated fats, refined sugars, low fruit and vegetable intake) are to blame.

It is logical to think that Western diets are not healthy for semen quality. Sperm need very flexible plasma membranes in order to swim and fuse with ova. Sperm require membranes that are highly enriched with beneficial polyunsaturated fatty acids. If polyunsaturated fatty acids are low in sperm, fertility is low. Decreasing the ratio of omega-3 to omega-6 polyunsaturated fatty acids in the diet has been shown to improve male fertility. Selenium is also critical to normal sperm development and function and if not adequate in the diet, sperm swim in circles and suffer damage to their membranes and DNA. A recent study has shown that increased folate in the diet reduces the number of sperm carrying too many or too few chromosomes. Sperm with an altered number of chromosomes can lead to disorders such as Down syndrome or spontaneous abortion. However, walnuts provide a rich dietary source of all the factors above needed for healthy semen quality. Walnuts contain beneficial lipids, selenium, folate, and antioxidants to protect sperm membranes and sperm DNA.  Walnuts have been shown repeatedly to improve lipid profiles in published dietary studies. Based on this, we propose a study to examine whether enriching the diet with walnuts might improve semen quality.
 
We will combine two respected research laboratories at UCLA to accomplish the research. One laboratory has a long history of conducting male reproductive health studies and the other a long history of conducting diet and nutrition research.

The plan is to enroll 120 men who habitually eat Western diets and then randomly assign half to eat their usual diet supplemented with walnuts (3 ounces per day) and the other half to eat their usual diet excluding nuts. At the beginning of the study we would collect full dietary histories, blood measures of omega-3 and omega-6 fatty acids, selenium, anti-oxidants and folate (the factors critical to sperm). We would also directly measure the semen quality including sperm count, motility, shape, chromosome number, and DNA fragmentation (the factors necessary to male fertility). After three months on the diets, we would collect the same measures again and look for changes in those measures. Throughout the study the research team would be available to monitor and assist study participants with the diets and other study procedures.

We have designed the study to be able to detect beneficial effects of walnuts on male reproductive health.  If couples planning pregnancies could enhance their fertility with a natural dietary source like walnuts, it would be preferable to taking supplements or rushing into in vitro technologies. Similar to the health information given on benefits of walnuts for cardiovascular health, information on benefits of walnuts for male reproductive health would be very beneficial to couples of reproductive age.

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Dr. Linda Sarna

Title: SMOKING CESSATION LEARNING FOR NURSES IN CHINA
Agency: Pfizer
Executive Summary:

  1. Health problem: The People's Republic of China (PRC) has the largest population of smokers in the world (350 million), but quitting is not common, few smokers receive help with cessation, and healthcare professionals and are not prepared to intervene. There have been limited efforts to educate the 1.65 million nurses about smoking cessation. The Chinese Registered Nurse-Helping Smokers Quit (CRN-HSQ) web-based program will be used to improve 1000 RNs' knowledge, skills and interventions with patients. Educated PRC RNs could have a significant impact on decreasing tobacco-related morbidity and mortality.
  2. Assessment of needs: Available evidence of needs will be supplemented by objective data. RNs' knowledge, skills, and delivery of smoking cessation interventions with patients will be evaluated using a Chinese translation of a web-based survey at baseline and at 3- and 6-months post-program. The Project team will meet with key nursing and health professional leaders in Beijing to discuss cultural appropriateness of the materials.
  3. Methods: The CRN-HSQ project, housed on the existing Tobacco Free Nurses website, includes downloadable materials and a 20 minute video-webcast, using Power Point slides adapted and translated into Chinese, based on the Rx for Change© validated curriculum.
  4. Outcome measures. Changes in RNs' knowledge, skills, and frequency of delivery of  cessation interventions at 3- and 6-month will be assessed using self-reports via web-based surveys with unique identifiers to link responses over time. Process measures to assess feasibility and acceptability of the educational program project will include the response rates, patterns of traffic on the project website, and specific questions on the 3 and 6 months surveys. Chinese nursing leaders will assess usefulness/ usability of the program and subjective outcomes related to content.
  5. Bias and conflict of interest:  We will have ongoing communication with our educational partner, ISNCC, and our colleagues in Beijing. No personnel supported or affiliated with the tobacco industry will be allowed to participate in this project.

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Dr. Sophie Sokolow

Title: Biochemical & functional analyses of the Na+/Ca2+ exchanger in AD pathology
Agency: Alzheimer's Association Grant
          DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common form of dementia. Since there is no disease-modifying drug, the prevalence of AD is predicted to quadruple by 2050. Interventions that can prevent or delay AD onset will have a major impact on the health of seniors and on the economic toll this illness imposes on the US. AD is characterized by synapse loss, senile plaques and neurofibrillary tangles in the hippocampus and neocortex. The degree of clinical impairment strongly correlates to the decrease of electrophysiologically active synapses. Although the molecular triggers of AD are unknown, extensive studies indicate that the amyloid-beta (Aβ) protein plays a principal role in AD pathogenesis. New evidence suggests that presynaptic buildup of soluble Aβ is the proximal cause of synapse dysfunction in AD. Nonetheless, the direct link between presynaptic Aβ and the loss of synaptic function has yet to be established. Altered glutamate reuptake, postsynaptic decrease in glutamate receptor surface expression (Li et al., 2009) and disruption of calcium (Ca2+) homeostasis (Green and LaFerla, 2008; Kuchibhotla et al., 2008) are pathways by which soluble Aβ species alter synaptic function in different experimental models. Indirect evidence in AD models implies that elevated intracellular Ca2+ levels and Aβ buildup may be functionally associated with altered synaptic plasticity and synapse loss (Stutzmann, 2007; Kuchibhotla et al., 2008; Lopez et al., 2008). This leads to the hypothesis that Ca2+ overload might contribute to AD pathogenesis. The majority of publications on Ca2+ signaling in AD concern intracellular Ca2+ elevation resulting from i) impaired entry from the extracellular compartment (Demuro et al., 2005; Bezprozvanny and Mattson, 2008) or ii) abnormal release from the endoplasmic reticulum stores (Stutzmann et al., 2003; Stutzmann et al., 2007). The role of extrusion mechanisms regulating intracellular Ca2+ levels and their effects on glutamate release has not been thoroughly examined. The sodium-calcium exchanger (NCX) is a plasma membrane protein that plays an important role in maintaining Ca2+ homeostasis and protecting neurons from Ca2+overload and eventual death (Carafoli, 1991; Blaustein and Lederer, 1999). In its forward mode, NCX extrudes one Ca2+ against three entering sodium (Na+) (Philipson and Nicoll, 1992; Blaustein and Lederer, 1999). Three NCX isoforms have been identified (NCX1-3) and each NCX variant is expressed in mammalian brains (Minelli et al., 2007). Few investigations have addressed the role played by NCX in AD pathology (Colvin et al., 1994; Wu et al., 1997; Kim et al., 1999). Our recent study showed that NCX1-3 isoforms are co-localized with Aβ and specifically regulated in AD synaptosomes (Sokolow et al., 2011 in press).
The purpose of this proposal is i) to understand how intrasynaptic Aβ buildup affects NCX synaptic activity, NCX1-3 expression and glutamate release, in AD nerve terminals. Our overall hypothesis is that in a mouse model of AD (J20 line), NCX activity and protein expression will decrease in an age-dependent manner and as Aβ buildups in nerve terminals. We further hypothesize that this decline in NCX activity will impair presynaptic Ca2+ homeostasis and glutamate release.

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Dr. Dorothy Wiley

 

Title: Comparison Of Flocked vs. Dacron Swab for Anal Cytology, Correspondence with High Resolution Anoscopy
Agency: NIH/National Cancer Institute  Project Number 1P30CA016042 (PI Gasson)
DESCRIPTION (provided by applicant) Competitive Grant Award for HIV-Associated Malignancy Research at an NCI-designated Cancer Center. This randomized comparison trial evaluates the role of 34 angiogenesis, cell cycle regulation, cytoskeletal regulators, DNA synthesis & repair, methylation, & transcription regulation human genes, two early HPV genes (E6 & E7) & the L1-capsid gene (biomarkers) in anal swab specimens & odds of high-grade anal intraepithelial neoplasia (HG-AIN). 

Title: Improving Screening Tools to Better Predict High-Grade Anal Dysplasia For MSM
Agency: NCI (National Cancer Institute) Project Number 1R01CA169508-01A1
          DESCRIPTION (provided by applicant): Invasive anal cancer (IAC) is a health crisis for gay, bisexual, transgender & other men who have sex with men (MSM), where risk for disease is now 20-40-fold higher than all U.S. males.9-12 Thirteen human papillomaviruses (high-risk HPVs) cause most invasive cervical cancers (ICC) in women & likely cause most IACs.13 High-risk HPV infections are sexually transmitted between partners. Persistent infections, together with their associated high-grade dysplasias, strongly predict ICCs.14-17 Recent data suggests we poorly understand HPV infections in men, especially among MSM who are at highest risk for IAC.18-25 Cervical cytology using Papanicolaou's staining (Pap test) significantly reduced ICC beginning in the mid-1950's; & cytology specimens are currently collected using cytobrush, a tool poorly adapted to anal sampling.26,27 Experts now recommend anal Pap test for MSM every 1-2 years, using Dacron swab passed blindly through the anal verge.28 Dacron-cytology specimens are marginally sufficient & require diagnostic follow-up for any detected abnormalities, a lower threshold than used for cervical cytology. Our pilot data show that sensitivity & specificity of anal cytology to predict HG-AIN is improved 1.5-fold using nylon-flocked swab, but only improved specificity 1.3-fold to 73%. Although most IACs test positive for HPV using PCR, the high prevalence of infection among MSM without cancer makes HPV PCR genotyping a poorly specific screening test, with low positive predictive value (PPV). High-threshold, nucleic acid HPV assays (molecular HPV tests) are calibrated to better predict high-grade cervical dysplasia in older females without atypias & to triage women to colposcopy with atypical squamous cells on cytology; they are not calibrated for IAC screening. Two molecular HPV tests that detect viral DNA & -mRNA may be relevant for IAC screening: HPV-Hybrid-capture II (HC-2) & -APTIMA. Both tests detect the 13 highest-risk HPVs; APTIMA detects HPV66, additionally. HC-2 detects HPV-DNA >1 pg/mL.29 HPV E6/E7 are often detected at higher levels where HPV is integrated into human DNA, a hallmark of cancer.30 Molecular HPV tests significantly reduce diagnostic follow-up referrals for women with equivocal cytology, limiting costly & invasive procedures, & while these tests improve detection of in situ & ICCs, they have not been explored as adjunctive tests for IAC screening. Also, sufficient attention has not been paid to improving the quality of anal Pap test specimens. This study seeks to evaluate two Pap test collection protocols & molecular HPV tests, as biomarker assays, using specimens collected at a single examination visit & randomized controlled study design. Optimizing the sequence of biomarker assays & cytology to predict HG- AIN will decrease morbidity & mortality, & lower use of costly & invasive diagnostic testing. We will evaluate the contribution that molecular HPV testing makes when simultaneously or sequentially positive tests, with or without (anal) cytology, are used to predict HG-AIN. Sensitivity, specificity, & PPV for anal cancer screening algorithms & their cost-effectiveness to prevent invasive anal cancer will be evaluated to inform practice.  PUBLIC HEALTH RELEVANCE: Invasive anal cancer (IAC) is a health crisis for gay, bisexual & other men who have sex with men & male-to- female transgender females who have sex with men (MSM), especially where men are infected with HIV. Improved Pap test specimen collection together with properly calibrated laboratory biomarker tests will improve the accuracy of IAC screening strategies. Improved IAC screening will better drive research to develop better precancer treatments, decreasing the number of cancer cases & improving costs, the number of years lived & the quality of life for affected individuals.

 

 

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Dr. Ann Williams

Title: ART Adherence Program in South East China
Agency: National Institute of Allergy and Infectious Diseases
          DESCRIPTION: This is a developmental project to design and test the feasibility and preliminary efficacy of a culturally appropriate intervention for supporting antiretroviral therapy (ART) adherence in South Central China, in a resource-constrained setting where the national CDC is presently scaling up ART-treatment. We will adapt a theoretically driven ART adherence intervention, which demonstrated efficacy in a randomized clinical trial conducted in the United States, to the Chinese cultural and social context. The adaptation will be informed by the results of our preliminary quantitative and qualitative work in this region of China and will be validated by patient, provider, and community review groups. We will conduct a randomized, controlled pilot study of the feasibility and acceptability of the intervention among 90 patients beginning ART through the China national ART program in Hunan Province and establish a preliminary effect size in anticipation of a full-scale clinical trial. We will also use Ultra Deep Sequencing technology to describe baseline prevalence and incidence of genotypic ART resistance and explore the relationship between adherence and ART resistance. Knowledge acquired from this study will contribute to successful treatment of HIV disease through increased understanding of factors associated with ART adherence and interventions to support or improve adherence and through increased understanding of the clinical significance of genotypic mutations, including low abundance species, and the value of genotypic testing as part of clinical care. These benefits will accrue to patients in both the developed and developing world. The opportunity to acquire this knowledge is unique and time-limited, because China is in the early stages of an ambitious and well-organized ART roll out.

Title: Xiangya-UCLA HIV/AIDS Nursing Research Initiative
Agency:Fogerty International Center, NIH  Project Number 1D43TW009579-01
          DESCRIPTION (provided by applicant): The long-term objective of the Xiangya-UCLA HIV/AIDS Nursing Research Initiative is to enhance capacity at Xiangya School of Nursing (Central South University, Hunan, China) and affiliated institutions to conduct research addressing questions in HIV/AIDS nursing with a focus on mental health and management of cognitive/affective symptoms of HIV and concomitant conditions. Specific aims include 1) development of research expertise in a cadre of Chinese nurses and psychologists who will conduct collaborative HIV/AIDS behavioral research; and 2) enhancement of the institutional capacity for nursing, mental health and behavioral HIV/AIDS research, including rigorous measurement of biological outcomes. The research training plan comprises 1) long-term (9 month) post doctoral training in HIV behavioral studies for 8 Chinese investigators at UCLA; 2) medium term training (6 months) in measurement of biological outcomes for 1 Chinese laboratory fellow at Yale and UCLA; 3) part-time, long term, in-country training in behavioral research methods for a cohort of 20 Chinese nurses and psychologists; and 4) mentored research projects. The proposed program responds to and extends ongoing HIV/AIDS collaborations which have demonstrated the need for additional post doctoral training in order to conduct rigorous studies of emerging questions related to mental health and behavioral aspects of HIV/AIDS in China including measurement of biological outcomes. The rationale for the program is that while Xiangya has strengthened its doctoral studies program for nurses and psychologists, local expertise is limited regarding the behavioral research methods that are key to high quality investigations of psychosocial and self-management issues of interest to nurse-researchers and psychologists. The program links nursing and psychology in recognition of common academic interests and the existing relationship between these two disciplines among the partner institutions. The program design builds in collaboration, long term mentorship and ongoing support of trainees as they design, implement, and evaluate mentored research of immediate relevance to China and by extension to similar countries faced with maturing HIV epidemics. It is anticipated that this program will substantially increase the number of young and mid career nurse-scientists, psychologists, and others conducting research related to the mental health and behavioral aspects of HIV/AIDS. Increased capacity will be measured by the number of research projects conducted by trainees; peer reviewed publications and professional presentations; successful applications for external funding; and number of courses taught and individuals mentored by trainees.   PUBLIC HEALTH RELEVANCE: This project will provide advanced training in HIV/AIDS research with a focus on mental health and management of cognitive/affective symptoms of HIV and concomitant conditions for nurses and psychologists at Xiangya School of Nursing in Hunan, China. The training will improve the ability of researchers at Xiangya to conduct studies of behavioral interventions for HIV/AIDS with benefits for patients in both the developed and developing world.

 

 

 

 

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Dr. Marlyn Woo

 

Title: SLEEP DISORDERED BREATHING AND PASSIVE LIMB MOVEMENT IN CHILDREN WITH PARAPLEGIA
Agency: NIH National Institute on Nursing Research, Project Number 1R21NR012810-01A1
          DESCRIPTION (provided by applicant): Children and young adults with spinal cord injury (SCI) commonly show sleep-disordered breathing (SDB), which is associated with increased morbidity and mortality, with an incidence conservatively reported at over 30%. Current treatments for SDB have high non-compliance due to associated discomfort or lack of efficacy. The most common intervention, continuous positive airway pressure, poses special problems with children and young adolescents, since the necessary masks distort developing facial bone structure over time, often forcing surgical reconstruction, and are difficult to fit as the child grows. Passive limb movement, the rhythmic movement of extremities without voluntary effort, increases ventilation during sleep in subjects with intact spinal cords; the impact of this intervention in complete thoracic SCI (paraplegic) patients lacking sensory information from the lower limbs is unknown. We hypothesize that passive limb movement (PLM) in these SCI patients with intact spinal cords above the thoracic cord region will decrease SDB [decrease the Apnea- Hypopnea Index (AHI)] for both obstructive and central apnea events, improve ventilation and oxygenation, and do so without arousing subjects during the night.. Using a one-group, quasi-experimental, pre- and post- test design, we will perform overnight polysomnography on 26 pediatric and young adults with complete thoracic spinal cord injury (ASIA A paraplegia, age 12-25 years), earlier screened to show SDB, who will be randomized to undergo passive limb (hand) movement either during the first or last half of the night during overnight polysomnography. The specific aims for this study are to: 1) Determine whether PLM therapy in pediatric and young adults with complete thoracic SCI (complete paraplegia) with SDB will improve SDB (as indicated by apnea-hyperpnoea index), ventilation (end-tidal carbon dioxide), and oxygen saturation; and 2) Compare number of arousals in pediatric and young adults with complete thoracic SCI during baseline sleep and during sleep when they are receiving PLM therapy. The objective of this study is to determine whether a novel treatment, passive limb movement, will improve ventilation in complete thoracic SCI adolescents and young adults with SDB, and do so with minimal disturbance to sleep. If passive limb movement improves ventilation and is tolerable to SCI patients, the intervention will provide an inexpensive, non-invasive therapy that could change clinical practice and significantly improve quality of life and outcomes in this high risk patient population. PUBLIC HEALTH RELEVANCE: Sleep-disordered breathing is common in children and adult spinal cord injury patients, and is associated with increased risk for high blood pressure, learning disorders, anxiety, and depression. Current treatments for sleep-disordered breathing are associated with high non-compliance, ineffectiveness, and discomfort. Upper limb cyclic movement (passive limb movement) may assist breathing in patients with spinal cord lesions below the cervical vertebrae (paraplegia). Passive limb movement is an innovative treatment option for sleep- disordered breathing which has the potential to effectively treat both children and adults with paraplegia.

 

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Dr. Mary Woo

 

 

Dr. Mary Woo, presented the third NINR Director's Lecture on May 21, 2013. Dr. Woo discussed her research on brain-heart interactions in a lecture entitled "It's All in the Mind: Heart Failure and the Brain." Watch here:

Title: CENTRAL AUTONOMIC NERVOUS SYSTEM REGULATION IN HEART FAILURE
Agency: CENTRAL AUTONOMIC NERVOUS SYSTEM REGULATION IN HEART FAILURE, Project Number 1R01NR013625-01A1  
          DESCRIPTION (provided by applicant): The objective is to determine how damaged brain autonomic nervous system (ANS) regulatory areas (hypothalamus, insula cortex, and cerebellum) respond to an ANS challenge, and to assess the laterality of functional responses to that challenge in heart failure (HF) subjects. Abnormal autonomic nervous system activity in HF is associated with increased morbidity and mortality. It is unclear if the structural damage seen in central ANS control regions reflects functional ANS abnormalities. Our preliminary studies found that injury in ANS control regions was accompanied by lateralized, altered (blunted, inverted, or time-delayed) functional deficits to ANS challenges in HF, and these changes preferentially occurred on the right side. The lateralization of damage and impaired functional responses on the right-side can increase risk for cardiac dysrhythmias and increase ANS abnormalities. However, responses of these damaged brain regions to ANS challenges are unclear, and the extent to which the lateralized injury contributes to abnormal ANS reactivity in HF has yet to be described. Therefore, using a two-group comparative design, we will examine the structural integrity in brain ANS control areas using diffusion tensor imaging procedures and functional responses and laterality of those signal changes to an ANS challenge using functional magnetic resonance imaging (MRI) procedures in 40 HF and 40 age- and gender-matched healthy controls. The specific aims are to:1) evaluate functional responses to an ANS challenge eliciting sequential sympathetic and parasympathetic actions (Valsalva maneuver) in a set of ANS regulatory brain regions (hypothalamus, insular cortices, and cerebellum) using functional MRI procedures in HF and healthy controls; 2) evaluate the relationships between structural integrity (using diffusion tensor imaging procedures) and functional activity (via functional MRI) of brain regions which regulate ANS tone in HF subjects. These studies will aid in the identification, development, and evaluation of new therapeutic strategies to protect and retrain central nervous system regions to restore ANS function, and improve survival and quality of life in this high risk patient population. Potential future interventions for these structural and functional ANS abnormalities could include peripheral or centrally-acting pharmacologic agents (such as statins or angiotensin-renin blockers), or neuroprotective interventions, including retraining/reorganization of alternative brain structures to restore ANS brain functions. PUBLIC HEALTH RELEVANCE: Heart failure patients show severe autonomic control irregularities, which are linked to increased morbidity and mortality, and may result from injury t autonomic regulatory brain sites. Determination of relationships between structural injury in autonomic control areas and aberrant functional responses to an autonomic challenge has the potential to disclose the processes contributing to abnormal autonomic control in the condition. [Understanding of the relationships between structural brain injury and functional consequences will assist in the identification of appropriate interventions to limit further brain injury, or reover brain functions which have the potential to impact morbidity and mortality and quality of life in this high risk patient population.

 

 

Title: SLEEP AND BRAIN STRUCTURE IN HEART FAILURE
Agency: NIH National Institute on Nursing Research, Project Number 5R01NR009116-06
          DESCRIPTION (provided by applicant): Heart failure (HF) patients show multiple neuropsychological and cardiovascular abnormalities which indicate changes in brain function. Brain injury, defined as loss of tissue and changes in tissue properties and function, occurs in areas which regulate mood, memory, blood pressure, heart rate, and breathing. All of these symptoms have been linked to increased morbidity and mortality in HF. However, the processes which elicit this brain injury are uncertain. Sleep-disordered breathing (SDB) characterized by repetitive hypoxia/reperfusion of oxygen and intermittent ischemia is common in HF, and may contribute significantly to brain damage found in the syndrome. However, the relationship between SDB and the extent and location of brain injury in HF patients is not established. We hypothesize that processes accompanying ischemia and hypoxia, and subsequent reperfusion associated with sleep-disordered breathing (SDB) in HF initiate and exacerbate the brain injury. We will 1) demonstrate that the extent of gray matter damage (assessed by structural magnetic resonance imaging, including mean diffusivity and fractional anisotropy) in HF depends on the presence of SDB (assessed via overnight polysomnography); 2) show that nerve fibers (white matter - evaluated via structural MRI and fiber tracking techniques) interconnecting major autonomic control structures are injured in HF patients with SDB; and 3) Determine whether the extent of brain injury (gray matter damage and white matter integrity) relates to aspects of deoxygenation/oxygen reperfusion during SDB, and whether such disordered breathing is more injurious during particular sleep states, or with more-frequent oxygen reperfusion. Using 2-group comparative and correlational designs, 80 subjects (30 HF subjects with SDB, 30 HF subjects without SDB, 20 healthy controls without SDB) will undergo structural MRI and overnight polysomnography studies. Inclusion criteria for all subjects will be age 40 - 65 yrs; HF will be systolic dilated, and LVEF < 0.40. Exclusion criteria for all subjects include claustrophobia, presence of loose metal (for example, pacemakers, braces, implanted hearing aids, or embolic coils). Statistical tests will consist of T-tests and Pearson's correlations with significance set at p < 0.05. The objective is to determine whether SDB is associated with alterations in brain structure in HF, and whether oxygenation/reperfusion processes accompanying apnea could lead to brain injuries in the syndrome. Determining the ongoing detrimental processes which cause brain damage in HF is essential to develop innovative treatments to reduce or prevent brain injury which can exacerbate the autonomic, cognitive, and mood deficits in this high-risk patient population. PUBLIC HEALTH RELEVANCE: Heart failure patients show multiple neuropsychological and cardiovascular abnormalities which indicate changes in brain function, and have been linked to increased morbidity and mortality in the syndrome. We reported brain injury, appearing as tissue loss or changes, and altered function in areas which regulate mood, memory, blood pressure, heart rate, and breathing; however, the processes underlying these brain alterations are uncertain. Sleep-disordered breathing imposes repetitive exposure to hypoxia and ischemia, is common in heart failure, and may contribute significantly to the brain damage. However, the relationship between sleep-disordered breathing and the extent and location of brain injury in heart failure patients is not established. Determining an association between sleep-disordered breathing components (such as the extent of decline in oxygen saturation, total duration of oxygen desaturation as reflected in apnea time, the number of oxygen reperfusions as indicated by number of arousals from apnea, and the patterns of sleep states) and extent of brain injury (evaluated by brain magnetic resonance imaging of gray and white matter) would allow health care providers to identify patients at increased risk for brain damage as well as to select and implement interventions which could alleviate the autonomic and neuropsychological impairment.

Title: PASSIVE FOOT MOVEMENT AND SLEEP-DISORDERED BREATHING IN HEART FAILURE
Agency: NIH National Institute of Nursing Research, Project Number 1R21NR012292-01
          DESCRIPTION (provided by applicant): Sleep-disordered breathing (SDB) is common in heart failure (HF) patients and associated with increased morbidity and mortality. Current treatments for SDB have not been shown to improve survival and often have high non-compliance, lack of efficacy in SDB alleviation, and/or associated with pain. Passive foot movement, the rhythmic movement of feet without voluntary effort, is known to increase ventilation but has not been examined in HF patients. We hypothesize that passive foot movement will decrease SDB (decrease in Apnea-Hypopnea Index [AHI]) with little or no impact on sleep state (fewer arousals during sleep), better sleep (measured by the Pittsburgh Sleep Quality Index Questionnaire) and greater preference for passive foot movement compared to continuous/biphasic positive airway pressure (CPAP/BiPAP - traditional SDB treatment methods). Using a one-group, quasi-experimental, pre- and post-test design, we will examine 26 subjects with advanced HF (left ventricular ejection fraction < 0.40, dilated systolic dysfunction, not in acute HF, age 40-65 years) and SDB (AHI > 5 via overnight polysomnography in the previous 6 months) who will be randomized to undergo passive foot movement either during the first or last half of the night during overnight polysomnography. The specific aims for this study are to: 1) Examine the association between SDB (as indicated by AHI), blood oxygen desaturation, carbon dioxide blood levels and passive foot movement; 2) Examine the association between passive foot movement and changes in sleep stage during an overnight sleep study (polysomnography) in HF patients with SDB; 3) Determine the impact of passive foot movement on subjective reports of sleep quality in HF patients with a history of SDB. The objective is of this study is to determine the relationships between a novel treatment option, passive foot movement, and SDB in HF patients. If passive foot movement decreases SDB and is tolerable to persons with HF, this intervention could have change clinical practice and improve outcomes in this high risk patient population. PUBLIC HEALTH RELEVANCE: Sleep-disordered breathing is common in heart failure and is associated with increased morbidity and mortality. Current treatments for sleep-disordered breathing have not demonstrated improvement in heart failure outcomes and often are associated with high non-compliance, ineffectiveness, and/or increased risk for pain. Passive foot movement is the rhythmic movement of the feet without voluntary effort, which results in increased ventilation. It is an innovative treatment option for sleep-disordered breathing which has the potential to effectively treat heart failure patients with dramatically decreased risk of adverse effects. If effective, passive foot movement could have important impact on heart failure disease progression and survival.

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