2016 Pilot Awardees

2016 Pilot Awardees

Using a Symptom Heuristics iPad App to Improve Symptom Self-Management in Adolescents and Young Adults with Cancer: A Pilot Study

Co-PI: John Charlson, MD, Medical College of Wisconsin
Co-PI: Jeanne Erickson, PhD, University of Wisconsin-Milwaukee
Co-Investigator: Kristin Bingen, PhD, Medical College of Wisconsin

Adolescents and young adults (AYAs) with cancer, defined as patients between 15 and 39 years old, are an understudied group at risk for poor outcomes. Survival rates for some cancers are lower in AYAs than in older and younger patients, and cancer treatment interrupts AYAs as they transition through school, begin a career, and start a family. AYAs experience multiple cancer- and treatment-related symptoms, such as fatigue, nausea, and sleep-wake disturbances that affect quality of life. A new approach to improve self-management of symptoms, the Computerized Symptom Capture Tool (C-SCAT), gives AYAs the opportunity to use reflective thinking to generate an image of their symptom experience on a tablet computer using graphics and text. The resulting images show how AYAs prioritize their symptoms and think about relationships between their symptoms. This study will examine whether this new approach using C-SCAT can improve AYAs’ abilities to self-manage their symptoms, including improving their communication with providers about symptom management. The study will enroll 30 AYAs who are receiving chemotherapy at Froedtert Hospital/Medical College of Wisconsin Cancer Center. AYAs will use the C-SCAT before two clinical visits and discuss the resulting images of their symptoms with their providers at those visits. Using interviews and questionnaires, we will evaluate whether use of the C-SCAT helps AYAs to: a) feel more confident about their ability to self-manage their symptoms, b) feel more prepared to make sense of and take action on their symptoms, and c) discuss their symptoms more effectively with their health care providers. We will also ask physicians and other providers who deliver care to these AYAs whether they believe the C-SCAT is a useful resource for discussing and understanding AYAs’ symptom experiences.

Awarded: $50,000

Functional MRI of the Brain in Adults with Sickle Cell Disease

PI: Joshua Field, MD, MS, BloodCenter of Wisconsin
Co-Investigators: Robert Hurley, MD, PhD, Medical College of Wisconsin; Shi-Jiang Li, PhD, Medical College of Wisconsin; Amanda Brandow, MD, MS, Medical College of Wisconsin; Raymond Hoffmann, PhD, Medical College of Wisconsin; Nancy Wandersee, PhD, BloodCenter of Wisconsin

One-third of adults of with sickle cell disease (SCD) suffer from a daily chronic pain syndrome. Although key aspects of SCD pathogenesis (inflammation, injury, and frequent pain) may contribute to peripheral and central sensitization to pain, little is known about the mechanism of chronic pain in SCD. Therapy for chronic pain, therefore, remains largely limited to opioids. To investigate the mechanism of chronic pain in adults with SCD, we performed functional MRI (fMRI) in 7 patients and 7 controls. Our goal was to compare the connectivity between patients and controls, with special attention paid to pain regions. Preliminary data shows that adults with SCD, compared to controls, have abnormal connectivity between an area of the brain involved in pain, the periaqueductal gray (PAG), and others involved in emotion, memory and executive function. Based on these data, our working model is that excess peripheral and spinal cord input to the brain causes a re-organization of brain’s connectivity, which may be maladaptive and contribute to the severe, chronic pain syndrome seen in adults with SCD. The current proposal expands on these preliminary findings with a larger and more robust study of fMRI in adults with SCD. We hypothesize that the severity of chronic pain in adults with SCD will be associated with altered connectivity between regions of the brain associated with pain both at rest and during a noxious stimulus. Aim 1 will determine the association between chronic pain phenotype and functional connectivity on fMRI in adults with SCD at rest. Aim 2 will determine functional connectivity after a painful stimulus to examine how adults with SCD process afferent input. If we find that severity of chronic pain is associated with increased functional connectivity, future studies will examine whether therapeutic approaches targeted to central pain and/or SCD will reverse the fMRI changes.

Awarded: $50,000

Innovative Diagnosis, Evaluation, and Assessment of Hemostasis

Co-PI: Veronica Flood, MD, Medical College of Wisconsin
Co-PI: Rachel Bercovitz, MD, MS, BloodCenter of Wisconsin
Co-Investigators: Shawn Jobe, MD, PhD, BloodCenter of Wisconsin; Deborah Newman, PhD, BloodCenter of Wisconsin

The Comprehensive Center for Bleeding Disorders at BloodCenter of Wisconsin currently manages approximately 1,000 patients with a clinical history of bleeding for whom standard clinical hemostasis assays have failed to identify a causal defect. Without a definitive diagnosis, prevention and treatment of bleeding complications is often empiric. These non-targeted interventions include use of transfusions, anti-fibrinolytics, or expensive factor replacements, potentially exposing patients to risks of these therapies without conferring a benefit. Researchers from BloodCenter of Wisconsin and Medical College of Wisconsin have developed novel assays to test platelet function in each of the various stages necessary to form a stable clot at a site of bleeding. These tests include 1) evaluating platelet binding to collagen and von Willebrand factor, which is the first step in forming a platelet plug in a damaged blood vessel, 2) evaluating platelet activation and aggregation, which are the second and third steps, in response to various stimuli, and 3) visualizing clot formation in real time, which is the culmination of these steps. These assays overcome limitations of current clinical testing, which include constraints in commercially available substrates and agonists, large sample volume requirements, and static evaluation of platelet function. Our proposed study will use these assays to characterize hemostasis in patients with known disorders as well as in those for whom standard assays have failed to provide a diagnosis. We hypothesize that these assays will be more sensitive and specific in identifying the hemostatic defect responsible for bleeding symptoms in previously undiagnosed patients. We anticipate our findings will broaden current diagnostic capabilities, which will enable clinician’s to provide timely and targeted therapies to prevent and treat bleeding in these complex patients.

Awarded: $50,000

Diastolic Ventricular Function: A Pediatric Heart Network (NHLBI) Ancillary Study to Establish Normal Values in Children

Co-PI: Peter Frommelt, MD, Medical College of Wisconsin
Co-PI: Shaji Menon, MBBS, MD, University of Utah

Echocardiography is the primary imaging modality for the evaluation of children with congenital and acquired heart diseases. Recent studies in children have shown that echocardiography allows accurate evaluation of diastolic function. However, there is lack of normal echo-derived diastolic function values in children adjusted for age, gender, and race. The National Heart, Lung, and Blood Institute-funded Pediatric Heart Network (PHN) recognized the importance of normal echocardiographic measurements of heart structures in children and funded the Pediatric Echocardiography Normative Z-score project. This PHN project recently completed enrollment of 3600 normal children to calculate normative values for common heart structures adjusted for body size, age, gender, and race from multiple centers over a large geographic area. All study echocardiograms are stored at the Pediatric Echocardiography Core Laboratory at the Medical College of Wisconsin, providing the largest repository of normal studies available. The original PHN project did not extract measures of diastolic function; however, the imaging needed to make diastolic measures is available from the stored echocardiograms. This study will use the existing unutilized rich human dataset in a cost-effective manner to bridge a significant clinical knowledge gap by providing normal diastolic function data from a uniformly defined group of normal children from multiple centers. Partnering with the University of Utah Study Design and Biostatistics Center for data entry and statistical analysis, the Pediatric Echocardiography Core Laboratory at the Medical College of Wisconsin will leverage the imaging already stored at the core lab from the Pediatric Echocardiography Normative Z-score project to generate new and accurate normative values for diastolic function in children. This will provide normal reference values for echo measurements obtained from multiple centers and geographic locations and adjusted for body size, age, gender, and race.

Awarded: $50,000

Cortical Structure and Function as Possible Mediators of Performance on an Attention Task: A Pilot Study

Co-PI: Wendy Huddleston, PT, PhD, University of Wisconsin-Milwaukee
Co-PI: Edgar DeYoe, PhD, Medical College of Wisconsin
Co-Investigator: Adam Greenberg, PhD, University of Wisconsin-Milwaukee

Many stroke survivors have difficulty functioning due to individual-specific attention deficits, such as being unable to attend to items located on one side of the body, called unilateral neglect. We are interested in how brain structure and function contributes to attention-mediated behavior. We aim to elucidate the connections among behavior, function, and structure in healthy adults as a preliminary step to our long-term goal of studying attention deficits in stroke survivors. We hypothesize that individual differences in performance of an attention-mediated, goal-directed, motor task will be reflected in the variability of the superior longitudinal fasciculus (SLF) II, the functional connectivity of the fronto-parietal resting state network, and the ‘quality’ of visuospatial activation maps in regions of posterior parietal cortex (PPC); and that these factors will be positively correlated with one another. Understanding the relative contributions of anatomical structure and brain function to attention processes will ultimately facilitate improved therapies to treat people with impaired attention. We will use the unique capabilities of the 7T magnetic resonance imaging scanner to obtain brain maps of attentional priority in human parietal cortex, along with functional and structural connectivity, specifically the SLF II, at an unprecedented level of spatial resolution in healthy adult participants. The positive impact of our innovative proposed methodology will allow us to evaluate structure and function in relation to behavior in the same participants, providing a sound foundation for understanding the basis of attentional maps from a structural and behavioral perspective, and creating a normative data base to identify aberrant structure and function in stroke survivors.

Awarded: $50,000

Mobile Tele-ophthalmology for Community Eye Screening (mTOCS)

PI: Judy Kim, MD, Medical College of Wisconsin
Co-Investigators: Sheikh Iqbal Ahamed, PhD, Marquette University; Al Castro, MS, United Community Center

Health disparities, such as diabetes related eye diseases, are evident in the United States with Latinos among high risk population. This may be partially due to disparities in preventive health care. We need to address such disparities since over 90% of vision loss due to diabetic retinopathy can be prevented through early detection and timely treatment. Currently, less than 50% of diabetics receive annual eye exam, and the rate is even lower among Latinos. Our previous study called “Teleophthalmology to Improve Eye Health among Latinos (TIEHL)” found that teleophthalmology is an acceptable modality to screen eye diseases and it can be done at a community center rather than at a medical clinic. However, we found greater health disparities and more serious diseases when we went out into the community during recruitment efforts. Therefore, we believe that a paradigm shift is needed to increase early disease detection in this population. We hypothesize that the traditional model of patients making an appointment to see a doctor at a medical clinic is not the best approach for all and the next step in improving screening for Latino community would be through mobile screening by a bilingual staff reaching out during planned activities of the community. This is now more feasible than ever with recent development of cameras that are compact and portable. To serve this community with barriers to health screening, to decrease health disparity, and to preserve vision, we propose to test the implementation, feasibility and efficacy of the performing mobile eye screenings at community events and to develop a teleophthalmology interface through the cloud. The outcome measure will include the number of screenings performed, subjects screened, eye diseases detected, referrals made, and development of HIPAA compliant interface that makes this novel delivery of health care feasible and applicable to many communities.

Awarded: $50,000

CTSI Pilot: Working Memory Training for Veterans with Elevated Trauma-related Symptoms

Co-PI: Sadie Larsen, PhD, Clement J. Zablocki VA Medical Center/Medical College of Wisconsin
Co-PI: Hanjoo Lee, PhD, University of Wisconsin-Milwaukee
Co-Investigators: Christine Larson, PhD, University of Wisconsin-Milwaukee; Caron Dean-Berhoft, PhD, Medical College of Wisconsin

PTSD is characterized by recurrent intrusion of trauma-related memories and images that causes significant distress and impairment. The long-term objective of this line of research is to develop an effective cognitive intervention for intrusive cognitions in PTSD and anxiety problems. The current study aims to examine whether computerized emotional working memory training (eWMT) can help improve working memory (WM) and reduce trauma symptoms characterized by cognitive intrusions and re-experiencing. eWMT is designed to improve the individual’s ability to stay focused on the target and filter out irrelevant information from WM, which is expected to reduce cognitive intrusions and other related PTSD symptoms. To this end, individuals who display elevated trauma symptoms will be randomly assigned to one of the two Internet-based WM training conditions: (a) a potent WM training (eWMT), and (b) a control WM training with limited potency (cWMT). Before and after the training, participants will undergo an assessment of emotional symptoms and WM-related cognitive performance. One-month follow-up assessment data will also be obtained. Our primary outcome measures include (a) the PCL-5, a well-established scale of PTSD symptoms, (b) the Automated Complex Span Tasks, a well-validated suite of WM performance tasks covering operation, reading, and symmetry span, (c) an electroencephalographic measure directly indexing inability to filter information from WM, and (d) heart rate variability during a 3-minute trauma recollection task. We hypothesize that the eWMT group will outperform the cWMT group by showing more favorable outcomes: (a) reduced PTSD symptoms, (b) enhanced WM performance, (c) improved filtering of irrelevant information from WM (EEG), and (d) improved psychophysiological regulation of trauma-related intrusions. Pending successful outcomes, this study will provide important knowledge that will guide our future efforts to develop an effective, accessible, and cost-efficient intervention program for PTSD. These data will provide strong preliminary data for an NIH R01-level application.

Awarded: $50,000

EPR Spectroscopy as a Diagnostic Tool for Mitochondrial Disease

Co-PI: Michael W. Lawlor MD, PhD, Medical College of Wisconsin
Co-PI: Brian Bennett, PhD, Marquette University
Co-Investigators: David Dimmock, MD, Medical College of Wisconsin

Mitochondrial disease (MD) occurs when genetic changes impair energy production that normally occurs in mitochondria. The symptoms of MD are complex and varied among patients, due to both variation in the specific mutations involved and variation in the distribution of abnormal mitochondria throughout the body. While MD is thought to be a common and highly significant health problem, it is currently difficult to diagnose due to limitations in the tests available. This pilot proposal is focused on the evaluation of electron paramagnetic resonance spectroscopy (EPR) of human muscle biopsy tissue as a new diagnostic strategy for the evaluation of MD. EPR provides information about the redox states of mitochondrial electron transport chain (mETC) components, and can be used to determine the distribution of electrons among mETC components. EPR thus directly identifies and characterizes abnormal mETC function associated with MD, and provides additional and complementary information to what is currently available. We have recently established that EPR can provide useful information on a rat model of MD, and the objective of this proposal is to establish the usefulness of EPR of human muscle biopsy specimens. The central hypothesis of this proposal is that EPR will be useful for the identification and classification of MD in human tissue samples, but that control of specific elements of tissue handling is necessary for samples that will provide informative EPR data. Aim 1 will focus on determining the requirements for sample handling for informative EPR of human muscle tissue, and whether EPR markers can be identified for samples that are compromised through mishandling. Aim 2 will focus on whether EPR can identify abnormalities in biopsy tissue from known MD patients, and determine whether different genetic/functional subtypes of MD produce distinct EPR spectra. Success in these studies would dramatically improve the diagnosis of MD.

Awarded: $50,000

Association between Post-Concussive Activity and Clinical and Neurophysiologic Recovery

PI: Lindsay Nelson, PhD, Medical College of Wisconsin
Co-Investigators: Danny Thomas, MD, MPH, Medical College of Wisconsin; Michael Danduran, MS, Marquette University; Timothy Meier, PhD, Medical College of Wisconsin

Significant advances have been made to understand the natural course of clinical and neurophysiologic recovery after sport-related concussion (SRC). Although experts recommend that athletes assume some degree of cognitive and physical rest in the acute period post-SRC, almost no data are available regarding the effects of post-concussive activities on athletes’ recovery. Pre-clinical data indicate that physical activity too soon post-injury is harmful for neural recovery, yet activity performed later is beneficial. The aim of proposed study is to advance our understanding of the relationship between post-injury activities and measures of clinical and neural recovery in humans. The project will use a commercially-available device (Fitbit) and locally developed smart phone application to obtain detailed, real-time data about athletes’ postconcussive activities in the acute post-concussive period in order to establish the degree to which concussion affects athletes’ typical activity levels, understand the degree of variability among concussed athletes’ postinjury activity levels, and to correlate activity data with clinical and neuroimaging-based markers of recovery. Our multidisciplinary investigative team has the extensive clinical and research expertise needed to aggregate these varying types of data and has long contributed to cutting-edge SRC research with high translational value. The study will provide important data regarding the tolerability of these devices with participants and the foundational data necessary to secure extramural funding aimed at developing and validating evidence-based concussion management guidelines. The study will recruit athletes with SRC identified acutely (< 24 hours) post-injury and will follow them during their recovery. Leveraging the infrastructure, clinical data, and neuroimaging data being collected in our ongoing study of sport-related concussion, this pilot study will, for the first time, collect detailed data about concussed athletes’ activities during the acute recovery period (with comparison to well-matched non-injured controls from the same teams).

Awarded: $50,000

Sarcopenic Obesity in Critical Illness Study (SOS)

PI: Jayshil Patel, MD, Medical College of Wisconsin
Co-Investigators: Kaushik Shahir, MD, Medical College of Wisconsin; Dennis Sobush, MD, Froedtert/Marquette University

Obesity is defined using a body mass index of ≥30 kg/m2. Despite significant challenges to healthcare providers, obese patients are reported to have improved intensive care unit (ICU) outcomes. This survival advantage is termed the ‘obesity paradox’. Reliance solely on body mass index (BMI) to define obesity does not discern the various types of obesity, including sarcopenic obesity, which may have a poorer outcome. Sarcopenia is a progressive loss of muscle mass. Sarcopenic obesity is an obese patient who meets BMI criteria with muscle mass loss. The incidence or functional impacts of sarcopenic obesity in critically-ill patients are unknown. We aim to identify sarcopenia in critically-ill obese patients using a novel CT scan method and then determine the impact of sarcopenia on muscle function. Hypotheses: We hypothesize that CT imaging to determine muscle-to-fat ratio at the level of the psoas and para-spinal muscles will reliably identify sarcopenia in critically-ill obese patients. We will measure sarcopenia in critically-ill obese patients by reconstructing CT images and determining psoas and paraspinal muscle-to-fat ratio using Hounsfield units. We will correlate sarcopenia in critically-ill patients to objective measures of physical function in the same population. Methods: We will conduct a prospective pilot study of obese critically-ill patients to identify sarcopenia using reconstructed CT imaging to calculate psoas and para-spinal muscle-to-fat ratio. Physical function will be measured using validated Modified-Research-Council and EGRESS muscle strength tests. Between-rater agreement will be quantified with the concordance correlation coefficient (CCC), which is a measure of agreement for continuous variables. This pilot study will identify sarcopenic obesity in patients who are critically-ill. It will also determine if sarcopenia, as opposed to BMI alone, has an impact on physical functioning outcomes. Importantly, these data position us to acquire prognostic information and are essential for studies to explore interventions.

Awarded: $50,000

Role of Endoplasmic Reticulum in the Evolution of Bronchopulmonary Dysplasia with Pulmonary Hypertension

PI: Ru-Jeng Teng, MD, Medical College of Wisconsin
Co-Investigators: Qing Miao, PhD, Medical College of Wisconsin; Said Audi, PhD, Marquette University; Pippa Simpson, PhD, Medical College of Wisconsin

Bronchopulmonary dysplasia (BPD) is a common complication of premature birth under oxygen therapy. Roughly 300 BPD are diagnosed in Wisconsin each year while the cost for medical care is estimated to surpass 2-billion dollars in the USA. A third of BPD infants will develop a condition called pulmonary hypertension (PH) which means their blood cannot be delivered into the lungs adequately. Half of the BPD infants with PH will die within three years. The reason why PH develops in BPD is unknown and the lack of laboratory test that can be used to monitor the disease progression hampers the development of preventive measures. Endoplasmic reticulum (ER) is a special structure inside of cells that provides quality control of protein formation and energy production. Oxygen treatment in premature infants causes oxidative stress that disturbs ER function and contributes to the development of BPD. We recently reported that a protein (Nogo- B) and its receptor (NgBR) not only modulate ER response to oxidative stress but also control the growth of immature lungs in animals. In established pulmonary artery hypertension of adults, a totally different type of PH, it is reported that blood level of Nogo-B increases. Some drugs that can reduce ER stress have been reported to show some efficacy in preventing the development of adult type PH. We plan to use rat pups, the most useful animal model for BPD study, to determine the role of Nogo-B/NgBR and ER stress in the development of BPD and PH. Change of Nogo-B/NgBR will be compared to the change in corresponding lung histology in rat pups. Blood Nogo-B levels in premature infants will also be measured to evaluate the possibility as a laboratory test to predict the development of PH. Our long-term goal is to seek medications that may prevent or ameliorate the diseases progress.

Awarded: $50,000

Effect of Concussion on Sensorimotor Function in Children

Co-PI: Jinsung Wang, PhD, University of Wisconsin-Milwaukee
Co-PI: Danny Thomas MD, MPH, Medical College of Wisconsin

According to the Centers for Disease Control and Prevention, sports- and recreation-related head injuries including concussions affect nearly 3 million people per year in the U.S. In addition, children between the ages of 5 and 18 years account each year for an estimated 65% of emergency department (ED) visits for sport-related concussions. What’s more, ED visits for concussions among children increased by 60% over the last 10 years. Although the negative impact of concussions on neurocognitive function is recognized, their impact on sensorimotor function, including motor learning abilities and motor memory functioning, has not been formally assessed especially in the acute concussion. Recently, oculomotor disruptions have been recognized as a contributing factor to prolonged recovery in patients. Additionally, given the critical importance of sensorimotor function on rapidly adapting to changes associated with sports, sensorimotor disruptions may influence performance and increase risk of reinjury. In this research project, we propose to develop a portable device that can be used in a clinical setting to collect movement data during visuomotor adaptation, which can reflect movement control and skill acquisition abilities in individuals, and to use that device to examine the pattern of visuomotor adaptation in concussed children. It is hypothesized that visuomotor adaptation tasks will effectively reveal motor control and/or learning deficits in concussed children as compared to age- and gender-matched controls. The contribution of this proposed research is significant because it is the first step toward understanding the negative impacts of concussions on children’s sensorimotor function using visuomotor adaptation tasks. Findings from the proposed research will help us to identify a more effective method to assess sensorimotor impairments in concussed children, and also to develop a cost-effective system that can be used by clinicians.

Awarded: $50,000

Cloning and characterization of PF4/heparin-specific antibodies in heparin-induced thrombocytopenia

Co-PI: Renren Wen, PhD, BloodCenter of Wisconsin
Co-PI: Padmanabhan, Anand MD, PhD, Medical College of Wisconsin
Co-Investigator: Richard Aster, MD, Medical College of Wisconsin

Heparin-induced thrombocytopenia (HIT) is an immune-mediated disorder that may cause fatal arterial or venous thrombosis/thromboembolism following heparin treatment during surgery. It is generally accepted that immune complexes consisting of platelet factor 4 (PF4), heparin, and PF4/heparin-specific antibodies are central to the pathogenesis of HIT. These antibody complexes activate platelets and monocytes, which lead to HIT development. One of the unique features of this disease is that antibodies against PF4/heparin complexes are detected at a much higher frequency than the incidence of HIT in heparin exposed patients. Previous studies trying to address this issue have been unsuccessful. A common problem with these studies is that the antibodies involved in the disease have been studied only at a polyclonal level. Recently, it is has been shown that HIT-inducing antibodies (pathogenic antibodies) bind to PF4 associated with glycosaminoglycan on platelet and activate platelets, and suggest that this distinguish pathogenic PF4/heparin antibodies from non-pathogenic antibodies. We thus hypothesize that PF4/heparin specific antibodies contain qualitatively distinct clones: platelet-activating and platelet-non-activating clones. We will clone PF4/heparin-specific antibodies and examine their platelet-activating ability. The cloned PF4-heparin antibodies associated with HIT can potentially be used in prediction, diagnosis and treatment of HIT.

Awarded: $50,000