A Potential Novel Pathway of Pathological Vascularization of the Retina

withheld at the request of the investigator. Genetic Modifiers of Cardiotoxicity: PILOT Principal Investigator: Christopher Newton-Cheh, MD, MPH, Massachusetts General Hospital Co-Investigator(s): Paul Arpino, PharmD, Massachusetts General Hospital Peter Noseworthy, MD, Massachusetts General Hospital Drug-induced QT prolongation and resultant potentially fatal arrhythmia is a costly impediment to drug development and an important issue of public safety. Current efforts to reduce the burden of arrhythmic cardiotoxicity are focused on identifying characteristics of the vulnerable drug that is predisposed to bind to the HERG potassium channel in the heart. However, identification of the vulnerable patient could have important public health implications. Electrocardiographic QT interval duration, a reflection of myocardial repolarization time, has a strong, graded relationship to sudden cardiac death, and has a substantial genetic underpinning (h2=0.35-0.45). Repolarization, and thus the QT interval, is regulated by redundant mechanisms. A single defect in one of these redundant pathways may remain subclinical until a second hit (e.g. drug exposure) unmasks the defect and results in altered repolarization and prolongation of the QT interval. We have recently shown that 14 common variants in ten genes influence inter-individual variability in QT duration (Newton-Cheh et al, Nature Genetics 2009). We hypothesize that in aggregate common genetic variants with strong effects on resting QT may predispose a subgroup of individuals to exaggerated prolongation of the QT in response to QT-prolonging medication. In the Harvard clinical research center, we propose to measure the change in QT interval following administration of oral moxifloxacin (a drug known to cause transient and mild QT prolongation) in individuals with and without QT-prolonging genotypes. These findings will serve as important preliminary data for an R01 to establish the relevance of common QT variants to cardiotoxic response in humans. Boston Housing First: Evaluation of an Intervention to Decrease Homelessness and Improve Health Principal Investigator: James J. O'Connell, MD, Massachusetts General Hospital Co-Investigator(s): Earl Frances Cook, ScD, Harvard School of Public Health Jill Roncarati, MPH, MPAS, Harvard School of Public Health “Housing First” has swept the nation as a call to reduce chronic homelessness. In Boston, more than 200 homeless persons who receive care from the Boston Health Care for the Homeless Program (BHCHP) Street Team have moved into housing since 2000, most within the last 3-4 years. Although there has been an assumption that housing will lead to decreases in morbidity and mortality, there are currently no data that support this hypothesis. We propose forming a multi-disciplinary, cross-institutional collaboration between community-based practitioners at BHCHP and researchers from the Harvard School of Public Health to investigate whether housing the chronically homeless improves health outcomes and quality of life, decreases mortality, reduces health cost, and changes health utilization patterns. To do this, we aim to utilize data that are currently available on the housed group of 200 persons through the BHCHP electronic medical record (EMR), Medicaid data, and National Death Index (NDI) data as well as to collect supplemental housing data, health outcome data, and health cost and health utilization patterns. Using incidence rates or risk ratios and Cox proportional hazard models, we will compare these measures for clients during the 1-2 years prior to housing with the same outcomes at one, two, and three years of being housed. The study will provide critical new analysis as to whether Housing First is meeting its goals, thereby informing local and national stakeholders in how to move forward in preventing people from returning to homelessness and reducing health disparities among this vulnerable population. Oral Biome Patterns as a Biomarker of Necrotizing Enterocolitis in Preterm Newborns Principal Investigator: Richard Parad, MD, MPH, Brigham and Women's Hospital Co-Investigator(s): Camilia Martin, MD, Beth Israel Deaconess Medical Center Floyd Dewhirst, DDS, PhD, The Forsyth Institute The pathophysiology of Necrotizing Enterocolitis (NEC) in premature newborns is poorly understood, but may be associated with colonization by an abnormal gut flora pattern. Preemies fed breast milk early have a significantly lower risk of developing NEC. Protection could be due to establishment of maternal flora over pathogenic ICU organisms. We neither know what organisms to look for, nor have the capability of culturing these organisms. The Forsythe Institute’s Human Oral Microbiome Project has developed a human oral microarray that can detect nucleic acid fingerprints of approximately 300 of the 600 organisms found in the mouth, throat and lungs. The BWH NICU has a sample bank with tracheal aspirates from over 1200 intubated newborns born at <29 weeks gestational age. These samples contain traces of bacteria that likely reflect the oral and potentially enteral flora. Through a linked outcomes database, we propose to select infants with NEC and matched controls and compare tracheal aspirate flora patterns. In our hands, RNA and DNA can be extracted from these samples for microarray analysis. We thus propose a case-control study to address the question of whether tracheal (and thus presumably oral and enteric) flora differ between NEC and control cohorts, and if so whether specific organisms are prevalent. Identifying such biomarkers could both prove valuable in unraveling the pathophysiology of NEC and in identifying at risk patients for new preventive therapy strategies. A Robot-Guided Positron-Probe System for Tumor Resection with Enhanced Accuracy at the Surgical Margins Principal Investigator: Mi-Ae Park, PhD, Brigham and Women's Hospital Alexandra Golby, MD, Brigham and Women's Hospital Co-Investigator(s): Nobuhiko Hata, PhD, Brigham and Women's Hospital Robert Howe, PhD, Harvard School of Engineering and Applied Sciences Stephen Moore, PhD, Brigham and Women's Hospital Maximal surgical excision of brain tumors confers a prognostic advantage. Intra-operative delineation of tumor tissue from critical brain tissue is difficult, because tumors resemble normal brain, and may infiltrate. Positron emission tomography (PET) with tumor-avid radiopharmaceuticals is useful for detecting tumors and for helping to define their locations for surgery, however, because of its poor spatial resolution, intra-operative PET is not being studied extensively. A plastic-scintillator-based positron probe can detect positrons originating within ~2 mm of the probe’s tip. Since brain tumors are known to take up radiotracers in greater amounts than brain tissue, the use of a handheld probe capable of quantifying tracer concentration could allow surgeons to improve the intra-operative delineation of tumor margins. We propose to develop a reliable and robust robot-driven intra-operative system to assist surgeons in cleaning surgical margins of residual tumor tissue following bulk tumor resection. Our approach of integrating a robot and a positron probe within one intelligent system will (1) allow the probe to be held with no motion (shaking) immediately adjacent to the tissue, for a time interval computed to achieve reliable discrimination between tumor and non-tumor tissue, and (2) reduce radiation dose to the surgeon by increasing the distance between the patient and the surgeon guiding the probe. We currently have the positron detector probe with digital readout; in this cross-institution and multidisciplinary team project, we will integrate the probe with a surgeon-controlled robot positioning system, before seeking external funding to evaluate the system’s performance in animal/or human surgical procedures. Screening for Notch Inhibitors in Flies and Humans Principal Investigator: Norbert Perrimon, PhD, Harvard Medical School Co-Investigator(s): Jon Aster, PhD, Brigham and Women's Hospital There is increasing interest in targeting the Notch pathway for purposes that pertain to human health and in particular cancer. One of the clearest examples of an oncogenic role for Notch1 is found in human T-cell acute lymphoblastic leukemia/lymphoma (T-ALL), in which gain-offunction mutations causing ligand-independent activation of Notch1 are found in over 50% of patients with aggressive cancer. Failed Phase I clinical trial of a Merck gamma-secretase inhibitor (GSI), MK-0752, opened for patients with refractory/relapsed T-ALL, highlighted two major hurdles that must be surmounted for Notch therapeutics to move forward: 1) There is a need to identify inhibitors with a better therapeutic index, or drug combinations that obviate the toxicity caused by conventional GSIs while maintaining or enhancing “on-tumor” effects”; and 2) There is a need to identify drugs that synergize with Notch pathway inhibitors to enhance “ontumor” effects. To identify and characterize new Notch inhibitors, the Perrimon lab has developed a highly specific in vivo assay for Notch activity in the Drosophila gut that offers the opportunity to rapidly and cheaply screen small molecules and drug combinations. We propose to use the fly assay to perform a large-scale screen for small molecules that affect Notch signaling. Because the Aster lab has the capacity to test inhibitors and drug combinations in cell-based and murine leukemia assays, our collaboration has the potential to rapidly translate fly “hits” to pre-clinical trials in mice, or in the case of FDA-approved drugs, directly to human trials. Toward a Neurobiological Understanding of Anhedonia in Major Depression: A Novel Raclopride-based Molecular Imaging Technique Principal Investigator: Diego A. Pizzagalli, PhD, Faculty of Arts and Sciences, Harvard University Co-Investigator(s): Nathaniel Alpert, PhD, Massachusetts General Hospital Dan V. Iosifescu, MD, Massachusetts General Hospital Depression is a major public health problem, both in terms of personal suffering and socioeconomic burden. Unfortunately, the causes and pathophysiology of major depressive disorder remain largely unknown. Moreover, progress in understanding the neurobiology of depression is hindered by the lack of objective measures of core depressive symptoms. Anhedonia, the loss of pleasure or lack of reactivity to pleasurable stimuli, has emerged as a promising endophenotype of depression due to its potential as a vulnerability marker for the disorder. The goals of the proposed work are: (1) to test the hypothesis that decreased phasic dopaminergic transmission within mesolimbic regions plays a key role in the pathophysiology of major depressive disorder and the emergence of anhedonia; and (2) to investigate phasic dopaminergic release in major depressive disorder using positron emission tomography (PET) techniques during a reinforcement learning task. These aims will be accomplished by bringing together a highly interdisciplinary research team involving three different departments (Psychology, Psychiatry, and Radiology), two different schools (Harvard Faculty of Arts and Sciences and Harvard Medical School), and expertise in clinical neuroscience, psychiatry, molecular imaging, and mathematical modeling. By combining molecular imaging, careful clinical characterization, and objective behavioral measure of core aspects of depression, the proposed study is expected to provide novel insights into pathways associated with increased vulnerability to this life-threatening and debilitating disease. If successful, the proposed research might provide novel targets for treatment strategies and disorder prevention, and critical pilot funding for larger, federally funded grant applications. Development of a Point-of-Care Lab-on-a-chip Urine Antigen Detection Test for Active Tuberculosis Principal Investigator: Nira Pollock, MD, PhD, Beth Israel Deaconess Medical Center Co-Investigator(s): Antonio Campos-Neto, MD, PhD, The Forsyth Institute Alexis Sauer-Budge, PhD, Fraunhofer USA Improved methods to diagnose active tuberculosis(TB), and in particular sputum smearnegative or extra-pulmonary disease, are sorely needed. Worldwide, diagnosis of active TB relies primarily on sputum microscopy. However, sputum smears under field conditions detect only 40-60% of culture-proven cases of pulmonary TB, and sensitivity falls to as low as 20% in patients with HIV. We propose to develop a highly accurate, point-of-care urine antigen detection assay for diagnosis of active TB. Testing urine should in theory only detect M. tuberculosis(MTB) antigens generated by a large burden of actively dividing organisms and thus be specific for active (vs latent) TB. Moreover, this type of assay could provide a critical tool to monitor the effectiveness of treatment. Drs. Campos-Neto and Pollock, using mass spectrometry, have identified four MTB proteins present in the urine of patients with pulmonary TB. Preliminary data from ELISA and rapid immunochromatographic (RICH) test analysis shows that these antigens can indeed be detected in the urine of patients with active TB. However, conventional ELISAs cannot be done at point-of-care, and the detection limit of the RICH format (approximately 250 pg/ml) may be prohibitively high. In collaboration with Dr. Sauer-Budge, we propose to develop a completely automated and miniaturized, low-cost, labon-a-chip ELISA test (integrated disposable chip and instrument) for detection of our novel urinary TB antigens which 1) maintains or increases the sensitivity of conventional ELISA and 2) allows performance of ELISAs at point-of-care. This work has the potential to transform global TB control, particularly in resource-poor areas. Using Pregnancy Outcomes to Predict and Prevent Cardiovascular Disease in Women Principal Investigator: Janet Rich-Edwards, ScD, Brigham and Women's Hospital Co-Investigator(s): Ananth Karumanchi, MD, Beth Israel Deaconess Medical Center We propose a project that could kindle a paradigm shift in the prevention and detection of cardiovascular disease (CVD) in women. Surveys from Europe indicate that delivering a preterm or low birthweight infant doubles the risk that the mother will die from CVD in maturity. Determination of the mechanisms behind this striking observation is urgent, as 20% of US women will have a pregnancy complicated by hypertensive disorders, diabetes, or ending in preterm or low birthweight delivery. As African Americans have twice the risk of complicated pregnancies, the unexplored implications for their future health are even greater. To investigate these questions, a group of twenty basic and clinical researchers from Brigham and Women’s, Beth Israel, and Children’s Hospitals are collaborating to propose a large longitudinal cohort that would follow women longitudinally from pregnancy to detect emerging signs of CVD. To support proposal development, we need preliminary data from a U.S. population. The Nurses’ Health Study II has collected data on pregnancy outcomes, lifestyle factors, and CVD risk factors and events for over 68,000 women, including several thousand African American women. This Catalyst proposal is to fund a new postdoctoral position for a fellow to analyse these data with Drs. Janet Rich-Edwards (BWH) and Ananth Karumanchi (BI). The findings would be important in their own right. The work would directly support the foundation of a longitudinal cohort to investigate how clinical characteristics of pregnancy can inform women’s health care, generating novel methods to alter disease trajectories to prevent CVD in women. Development of an Animal Model for Testing Cholera Vaccine Safety Principal Investigator: Jennifer Ritchie, PhD, Brigham and Women's Hospital Co-Investigator(s): Jonathan Kagan, PhD, Children's Hospital Boston Tomas Kirchhausen, PhD, Harvard Medical School John Mekalanos, PhD, Harvard Medical School Matthew Waldor, PhD, MD, Brigham and Women's Hospital Cholera, an acutely dehydrating secretory diarrheal disease caused by Vibrio cholerae, is endemic in many developing countries and remains a substantial, often under-reported, health burden worldwide. Many individuals in endemic regions do not have access to life-saving treatments for cholera; consequently, there is an urgent need for a safe, effective, and low-cost cholera vaccine. Oral live-attenuated V. cholerae vaccines have great potential to fulfill this need, since natural infection with V. cholerae is thought to bestow long-lasting protection against cholera. Current live-attenuated vaccine candidates consist of genetically modified V. cholerae strains that no longer produce cholera toxin, the causative agent of secretory diarrhea. However, administration of such ctx vaccines to human volunteers is associated with ‘reactogenicity’, defined as self-limiting, non-choleric ‘fecal’ diarrhea and stomach cramps. The causes of reactogenicity remain obscure, in part due to the lack of an animal model suitable for analysis of this problem. We have recently found that oro-gastric administration of V. cholerae to infant rabbits resulted in a cholera-like illness. Furthermore, administration of V. cholerae ctx mutants to infant rabbits results in transient fecal diarrhea resembling human reactogenic diarrhea. The two main aims of the proposed work are 1) to establish that infant rabbits are a good model of reactogenicity, using vaccine strains previously tested in human volunteers and 2) to determine the molecular basis of reactogenicity with the goal of designing safer vaccine candidates. This work will be an inter-disciplinary collaboration between microbiologists, cell biologists, and immunologists located at several Harvard-affiliated institutions. Evaluation of Cardiac Disease Phenotypes In Vitro Using a Human Cardiomyocyte Cell Culture System Derived From Inducible Pluripotent Stem Cells Principal Investigator: Anthony Rosenzweig, MD, Beth Israel Deaconess Medical Center Co-Investigator(s): Chad Cowan, PhD, Massachusetts General Hospital Laurence Daheron, PhD, Massachusetts General Hospital Michael Rosenberg, MD, Beth Israel Deaconess Medical Center Most adult human cardiovascular diseases are the result of complex genetic traits, whose manifestation is dependent on the intricate relationship between the individual’s genome and the environment. Study of these traits in humans is difficult because even when affected patient material is available, study cannot often be propagated in vitro. To overcome this limitation, we describe in this protocol a plan to use inducible pluripotent stem (iPS) cell technology, refined in the Harvard Stem Cell Institute, to explore human cardiomyocyte biology of the complex genetic disease atrial fibrillation (AF) in vitro. AF is the most common arrhythmia, and despite being well-studied, has limited treatment options available, at least in part due to a lack of experimental models. In this study, we plan to obtain skin samples from patients with AF, as well as matched controls, isolate the fibroblasts, and reprogram the cells into iPS cells, which will provide an unlimited source of cells for future experimentation. Beginning with control samples for protocol optimization, we will differentiate the iPS cells into atrial cardiomyocytes and examine variability as well as gene expression for markers of differentiation. Then, in a case-control design, we will examine cellular electrophysiological properties and calcium handling properties in AF vs. control samples. We will also examine gene expression differences between the groups, and identify targets for future validation and treatment. This study is the first step towards our larger goal of establishing a human in vitro model of cardiac disease for biological exploration and patient-specific drug testing. A Pilot Trial of Sonoelastography for Planning Tumor-targeted Prostate Biopsy Principal Investigator: Anthony Samir, MD, Massachusetts General Hospital Co-Investigator(s): Douglas Dahl, MD, Massachusetts General Hospital Adam Feldman, MD, Massachusetts General Hospital Scott McDougal, MD, Massachusetts General Hospital Peter Mueller, MD, Massachusetts General Hospital Shahin Tabatabei, MD, Massachusetts General Hospital Chin-Lee Wu, MD, Massachusetts General Hospital Prostate cancer is the most common malignancy in men in the United States. Current screening for prostate cancer consists of serum PSA measurement followed by transrectal ultrasoundguided prostate biopsy. Transrectal ultrasound is used to target the entire prostate gland, not the cancer itself, by performing between 6 and 12 non-targeted random biopsies of the prostate gland. The biopsies are non-targeted, as prostate cancer does not have a specific appearance on conventional ultrasound imaging. Unfortunately, non-targeted biopsy of the prostate fails to detect prostate cancer in up to 35% of cases. Consequently, many prostate cancers are diagnosed on repeat biopsy after a delay of months. Since the treatment and prognosis of prostate cancer is highly dependent on the extent to which the tumor is locally invasive, it is likely that this delay in diagnosis ultimately affects prognosis. Sonoelastography is a new diagnostic ultrasound technology that permits assessment of the stiffness of structures deep inside the prostate. Prostate cancer has been shown to be stiffer than normal prostatic tissue. Several studies have shown that sonoelastography increases the sensitivity of prostate biopsy for prostate cancer. We propose to undertake a pilot study in patients with known prostate cancer who are to undergo prostatectomy, in which we assess (1) whether biopsies planned with sonoelastography are more likely to intersect foci of tumor than random non-targeted prostate biopsies and (2) whether biopsies planned with sonoelastography will yield more representative tissue samples than non-targeted biopsies, using prostatectomy pathology as the gold standard. Patient-Specific Particle Deposition Model to Predict Tobacco Smoke Injury in COPD Principal Investigator: Raul San Jose Estepar, PhD, Brigham and Women's Hospital Co-Investigator(s): Alejandro Diaz, MD, Brigham and Women's Hospital Matthew Hancock, PhD, Brigham and Women's Hospital Hiroto Hatabu, PhD, MD, Brigham and Women's Hospital James Ross, MSc, Brigham and Women's Hospital George Washko, MD, Brigham and Women's Hospital Overall Hypothesis: Tracheobronchial tree morphology influences regional distribution of particle deposition and by doing so may mitigate inhalational injury in the lung. Overall Project Proposal: Using tobacco smoke as the exposure model, the regional distribution of computed tomographic measures of both emphysema and airway disease will be examined and correlated with the 3-Dimensional morphology of the tracheobronchial tree in current and former smokers. A validated airflow/particle deposition model will be applied to each subject’s tracheobronchial tree to predict under simulated conditions of respiration the degree and distribution of particle deposition in the airways and distal parenchyma. The regional burden of airway and parenchymal disease will then be compared to the idealized particle deposition pattern obtained under simulated conditions. Our proposal is focused on personalizing this particle deposition model by generating 3-D airway tree reconstructions from high resolution CT scans. Such an effort may allow the prediction of inhalational injury patterns based upon an individual’s airway morphology. By performing such an investigation, we may find that native airway structure may in part dictate which smoker will develop emphysema, chronic bronchitis, or both. Team Strengths: Our multidisciplinary team provides expertise in particle deposition, mathematical modeling, image analysis, computer programming, and clinical pulmonary medicine. Our team also has access to very detailed physiologic and radiographic data on a large cohort of current and former tobacco smokers. This latter cohort is provided by the Lung Tissue Research Consortium (LTRC) and the data is currently stored in Dr. Washko’s lab in Brigham and Women’s Hospital. Development of an Innovative Test of Sustained Visual Function Principal Investigator: Debra Schaumberg, ScD, OD, MPH, Brigham and Women's Hospital Co-Investigator(s): Pedram Hamrah, MD, Massachusetts Eye and Ear Infirmary Deborah Jacobs, MD, Beth Israel Deaconess Medical Center Jeremy Wolfe, PhD, Brigham and Women's Hospital Dry eye disease is a major public health problem affecting over 10 million Americans. It is characterized by chronic ocular surface pain and fluctuating vision impairment. There is a critical need for effective therapies for this disease, yet only one such therapy has actually made it through the regulatory process. One of the major limiting factors to making headway in the development of more effective pharmaceuticals for the treatment of dry eye disease has been the absence of a clinically meaningful measure of its impact on patients’ vision. Standard measures of visual acuity have virtually no utility in dry eye disease, because they fail to capture the type of impairment seen in dry eye. The goal of this research project is to capitalize on the combined expertise of an interdisciplinary group of investigators to develop an innovative Sustained Visual Function Test (SVFT) that would accurately measure visual impairment in patients with dry eye disease. The SVFT will be based on a dynamic measurement of spatial vision, incorporating elements of spatial frequency and contrast, and sustainability of the response over time. The test will be designed to be relatively quick, easy to administer, and to successfully distinguish errors due to visual deterioration over time in dry eye subjects from errors due to lapses of attention or other reasons. Development of such a test will fill a critical need for the conduct of clinical trials in dry eye disease, and is of keen interest to researchers, clinicians, and the ophthalmic pharmaceutical industry. Mechanistic Impact of the Novel MTNR1B Type 2 Diabetes Gene on Changes in Circadian, Metabolic and Sleep Physiology Principal Investigator: Frank Scheer, PhD, Brigham and Women's Hospital Richa Saxena, PhD, The Broad Institute Co-Investigator(s): Orfeu Buxton, PhD, Brigham and Women's Hospital Anne-Marie Chang, PhD, Brigham and Women's Hospital Jeanne Duffy, MBA, PhD, Brigham and Women's Hospital Jose Florez, MD, PhD, Massachusetts General Hospital Steven Shea, PhD, Brigham and Women's Hospital Dick Swaab, MD, PhD, Netherlands Institute for Neuroscience A novel type 2 diabetes gene (MTNR1B) recently discovered by our group encodes the melatonin receptor 1B, and a common MTNR1B variant (rs10830963) raises fasting glucose and increases risk for type 2 diabetes. Since the hormone melatonin has primary effects on sleep and the circadian system, the goal of this proposal is to determine the mechanistic role of the circadian, sleep and metabolic systems on the effect of the MTNR1B variant on glycemic parameters. We have shown that disruption of sleep and the circadian system leads to adverse metabolic changes and increases diabetes risk. We thus hypothesize that the effect of rs10830963 on diabetes could be mediated via effects on sleep or circadian systems. We propose to genotype MTNR1B variants in ~650 participants in two workplace/field studies, ~250 participants in laboratory studies of circadian and sleep physiology, and ~40 individuals with available post-mortem studies of detailed melatonin receptor 1B expression in the suprachiasmatic nucleus, the master circadian pacemaker. Specifically, we will test for association of MTNR1B variants with circadian (neuroanatomy and physiology), sleep and metabolic variables. If MTNR1B increases risk of diabetes by influencing circadian physiology, we expect the genetic variants to have much stronger effects on these proximal phenotypes than on glycemic measures. Results of this study will inform the experimental design of prospective laboratory studies in a population pre-selected by genotype, contribute to a mechanistic understanding of diabetes that could lead to novel therapeutics, and highlight the importance of sleep and circadian parameters in diabetes clinical risk prediction. Treating Children with Severe Burns Using Video Games Principal Investigator: Jeffrey Schneider, MD, Spaulding Rehabilitation Hospital Co-Investigator(s): Paolo Bonato, PhD, Spaulding Rehabilitation Hospital Robert Sheridan, MD, Massachusetts General Hospital Recent advances in topical and systemic antibiotics, early excision and grafting, and artificial skin substitutes have significantly improved survival rates after severe burns. With increased survival, clinicians face significant challenges in the design of rehabilitation interventions since severe burns lead to major functional impairments, including contractures and joint deformities, amputations and severe deconditioning. A complex multifactorial approach is implemented to design therapy interventions that control for stress exerted on the joints and speed and range of movement while maximizing the functional outcomes. The use of robotic and virtual reality technologies is very attractive in this context. Robotics provides a means to administer the “right amount” of therapy by progressively increasing resistance and range of motion as the subject progresses. Virtual reality gaming systems are able to engage subjects in the exercise routine in the form of video games. The “distraction” associated with virtual reality has been shown to be beneficial to patients undergoing rehabilitation following severe burns, but it has not been tied into an exercise routine. The objective of this project is to develop a platform that utilizes robotics and virtual reality to facilitate rehabilitation in children with severe burns. We intend to build and test a system to facilitate and monitor rehabilitation exercises and asses its usability in a small cohort of patients as a first step toward a systematic clinical evaluation of the potential impact of these technologies on burn rehabilitation. A Low-Cost, Incentive-based Therapeutic Adherence Platform for Infectious Diseases Using Point-of-care Diagnostics and Mobile Telephony Principal Investigator: Amit Srivastava, PhD, Children's Hospital Boston Co-Investigator(s): Rachel Glennerster, PhD, Massachusetts Institute of Technology Jose Gomez-Marquez, BS, Massachusetts Institute of Technology Christopher Hug, MD, PhD, Children's Hospital Boston Amy Smith, MS, Massachusetts Institute of Technology Jose Trevejo, MD, PhD, Beth Israel Deaconess Medical Center Effective cures exist for several infectious diseases but patient adherence or compliance with therapy remains a serious problem. Patients often do not take medicines for the prescribed time or abandon therapy altogether; this exacerbates the overall disease burden and promotes the development of drug-resistant pathogens. Non-adherence presents a unique challenge in resource-constrained settings that are often beyond the reach of traditional health infrastructure. Behavioral economic studies show definitively that drug adherence is achievable via the dual approach of fail-safe monitoring and pertinent incentives. We propose to develop a novel and versatile therapeutic adherence platform for resource-constrained settings using antituberculosis (TB) therapy as a model. TB remains a major public health concern more than 60 years after the first effective antibiotics were developed; a prime contributing factor globally is inconsistent patient adherence to the 6-9 month drug treatment regimen. Non-adherence contributes to morbidity, mortality and rise of multiply drug resistant (MDR) TB. Our platform allows for remote monitoring of patient compliance using encrypted, diagnostic paper microfluidic strips that detect metabolites of anti-TB drugs in the patient's urine. Adherence is reported to a central database via cell phone and is incentivized by a monetary rewards program. This new system is significantly less resource-intensive than the current standard: onsite, in-person monitoring of drug adherence, also known as Directly Observed Therapy Short Course (DOTS). Our multidisciplinary team, consisting of scientists, engineers, physicians and economists, envisages application of this adherence platform to other ailments with significant public health impact, such as insulin-dependent diabetes and smoking. A Pilot Study of the Effectiveness of Point-of-purchase Menu Labeling and Choice Architecture in Promoting Healthier Food and Beverage Choices Principal Investigator: Anne Thorndike, MD, MPH, Massachusetts General Hospital Co-Investigator(s): Susan Barraclough, MS, RD, LDN, Massachusetts General Hospital Doug Levy, PhD, Massachusetts General Hospital Jason Riis, PhD, Harvard Business School Lillian Sonnenberg, DSc, RD, Massachusetts General Hospital A major contributor to the obesity epidemic is a food environment that promotes excessive eating and energy-dense food and beverages. Mandatory menu labeling with nutritional information has been advocated by multiple public health groups, and despite strong opposition from the restaurant industry, legislation for menu labeling has been initiated in the U.S. Although recent laboratory studies in consumer psychology demonstrate that choice architecture (i.e., which foods are offered as the default) can affect food choice, the effectiveness of these interventions as well as menu labeling have not been tested in the real world. This Catalyst proposal is a pilot study of a 2-phase intervention to label all food and beverages and then to alter the choice architecture to increase healthy default items in the main cafeteria at Massachusetts General Hospital (MGH). The cafeteria, operated by the Department of Nutrition, serves over 6000 employees, visitors, and patients a day; 27% of daily revenues are purchased by employees using a card that tracks their purchases. This Catalyst will initiate a novel collaboration between a physician, 2 nutritionists, and a health economist from MGH with a consumer psychologist from Harvard Business School to conduct a real-world experiment of point-of-purchase food labeling and choice architecture. Cash register sales will be analyzed before and after the intervention phases. Data from the subset of employees using the cafeteria card will be analyzed to assess changes in individual purchasing behavior. Findings from this project will provide pilot data for conducting a multi-site randomized trial. New Preoperative Factors Predict Resectability of Malignant Pleural Mesothelioma Principal Investigator: Tamara Tilleman, MD, PhD, Brigham and Women's Hospital Co-Investigator(s): Hiroto Hatabu, MD, PhD, Brigham and Women's Hospital David Sugarbaker, MD, Brigham and Women's Hospital Beow Yong Yeap, ScD, Massachusetts General Hospital Malignant pleural mesothelioma (MPM) is a rare thoracic cancer that ultimately causes death by locoregional extension. Multimodality therapy that includes surgical extirpation of tumor by extrapleural pneumonectomy has yielded prolonged survival for a defined subset of patients. About 25% of patients, however, are deemed unresectable intraoperatively because of an inability to identify advanced local invasion of tumor preoperatively. Objective: To improve patient selection by identifying preoperative variables that are indicative of advanced local infiltration of MPM and thereby reduce the number of surgical candidates found to be unresectable at surgery. To validate these variables prospectively under an IRB-approved protocol. Aim 1: To identify variables in MPM patients that enable accurate prediction of resectability by cytoreductive surgery and develop a preoperative resectability index (PRI). We hypothesize that independent indicators of advanced locally invasive disease can be isolated. Aim 2: To determine the predictive accuracy of the factors identified in Aim 1 in a prospective clinical study. We hypothesize that the rate of resectability for patients brought to surgery will increase by using the PRI. Aim 3: To evaluate the survival effect in patients determined to be unresectable by PRI. We hypothesize that survival of unresectable patients will increase by deferring surgery as the primary treatment. Potential Impact: This study will improve patient selection, survival, and quality of life by deferring surgery in individuals deemed unresectable preoperatively. This novel approach to preoperative diagnosis has the potential to redefine the paradigm for determining eligibility for any locally invasive thoracic cancer. Magnetic Resonance Spectroscopy Biomarkers in Duchenne Muscular Dystrophy Principal Investigator: Martin Torriani, MD, MSc, Massachusetts General Hospital Co-Investigator(s): Elise Townsend, PT, PhD, Massachusetts General Hospital Brian Tseng, MD, PhD, Massachusetts General Hospital Duchenne muscular dystrophy (DMD) is an incurable childhood disease and the most common pediatric muscular dystrophy, affecting 1 in every 3,500 male births. Boys with DMD suffer progressive loss of muscle strength and function: they are unable to walk by 13 years of age and die in their late teens or twenties. Disease progression is staged using strength and functional tests, such as dynamometry and timed tasks. These methods are limited in showing change over time and are influenced by patient effort or examiner variability. Furthermore, they do not provide insight of muscle physiology as the disease progresses or improves with therapy. Magnetic resonance spectroscopy (MRS) is an established non-invasive method to examine muscle physiology. There is preliminary evidence that muscle MRS of DMD patients shows abnormal concentrations of high-energy phosphates and other metabolites, which may serve as biomarkers for strength and functional status. We will perform cross-sectional studies using 31Pand 1H-MRS to measure energy metabolites, pH, indices of cellular turnover and adiposity in DMD patients compared to ageand BMI-matched healthy subjects. In DMD patients, we will correlate MRS data with results from standardized strength and functional tests. Our goal is to validate MRS as a safe and objective method to stage DMD without the use of ionizing radiation. This study will provide novel physiologic data and serve as the basis for non-invasive monitoring of emerging therapies for DMD. This proposal brings together investigators from three distinct specialties with unique strengths in MRS, DMD, and pediatric physical therapy. Characterization of “KIMeter”: A Biosensor for Early Detection of Kidney Injury Principal Investigator: Vishal Vaidya, PhD, Brigham and Women's Hospital Co-Investigator(s): Anuradha Agarwal, PhD, Massachusetts Institute of Technology Michael Ferguson, MD, Children's Hospital Boston Lionel Kimerling, PhD, Massachusetts Institute of Technology Sushrut Waikar, MD, MPH, Brigham and Women's Hospital Acute kidney injury (AKI) is a common medical condition with significant morbidity and mortality. Early detection of AKI before significant loss of kidney function would permit more timely diagnosis, prediction of injury severity, and safety assessment during drug development. Recently, kidney injury molecule-1 (Kim-1 in rats; KIM-1 in humans) was qualified by the USFDA and EMEA as a highly sensitive and specific urinary biomarker to monitor drug-induced kidney injury in preclinical studies and on a case-by-case basis in clinical trials. The interventional therapy for AKI will ultimately depend on development of novel tools that allow rapid and continuous detection of biomarkers at the bedside. We propose to develop an optical resonance based biosensor (KIMeter: Kidney Injury Meter) that will facilitate sensitive, specific, rapid, economic, high throughput and ‘online’ detection of kidney injury. The first aim is to develop and evaluate the performance of KIMeter by conjugating anti Kim-1/KIM-1 monoclonal antibodies on silicon surface of the resonator. The change in the refractive index resulting from antigen-antibody binding will cause a corresponding change in the resonant frequency that will be detected by the photodiode. The second and third aims are to evaluate the use of KIMeter in preclinical safety assessment and as a bedside instrument in patient care by using urine samples from various forms of kidney injury in preclinical and clinical models of AKI in adult and pediatric population. Such a tool has the potential to transform safety assessment, environmental health screening and renal medicine towards effective and economic patient care. Molecular Basis of Immunity Against Severe Malaria Mediated by the RTS,S/AS02 Vaccine Principal Investigator: Clarissa Valim, MD, ScD, Children's Hospital Boston Co-Investigator(s): Daniel Neafsey, PhD, The Broad Institute Sarah Volkman, ScD, Harvard School of Public Health Dyann Wirth, PhD, Harvard School of Public Health Malaria causes 1-3 million deaths annually. The RTS,S candidate malaria vaccine contains sequences of the circumsporozoite protein (CSP) and has undergone Phase I/II trials with efficacy of 27-64%. Vaccine efficacy against severe disease was higher (~50%) than against infection and mild disease (~30%) in the Mozambique Phase IIb trial. Identifying parasite variants evading vaccine protection in severe cases could help elucidate the mechanism of protection against severe disease and improve vaccine immunogenicity. To protect an infected subject from contracting severe disease the vaccine may be selectively filtering pathogenic parasite variants with detectable signatures at the CSP locus. Alternatively the vaccine could be non-selectively limiting the multiplicity of parasite variants in an infection, thereby reducing the likelihood that a subject encounters parasites expressing antigens not previously encountered. We propose to study these hypotheses in a pilot study nested within the completed Mozambique trial in collaboration with investigators of the Malaria Genomic Diversity project, Harvard/Broad Malaria Initiative. In order to identify factors associated with vaccination failure we will compare vaccinees with infection versus those with severe disease with respect to: (1) parasite variants defined by signatures within the CSP locus, and (2) multiplicity of infection defined by diversity within the MSP locus. Differences between vaccinee groups will be contrasted to differences between non-vaccinee groups. At the conclusion of our study, we expect to propose a model to assess parasite evasion for studying malaria vaccines. Our results could support planning of confirmatory studies nested within the upcoming Phase III trials of the RTS,S/AS02.