Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, February 2009. / Includes bibliographical references (p. 132-143). / Multi-drug resistant tuberculosis (MDR-TB) patients in resource-poor settings experience large delays in starting appropriate drug regimens and are often not monitored appropriately due to an overburdened health care system, communication delays, and missing or error-prone data. Medical information systems can be used to alleviate these problems by increasing the timeliness and quality of laboratory information available. The research reported in this thesis developed, implemented, and evaluated two such systems in the urban, resource-poor setting of Lima, Peru in institutions with and without internet. The first part addresses the electronic collection of tuberculosis (TB) laboratory information from multiple institutions without internet. A handheld computer-based system was developed and implemented. A cluster randomized controlled trial and before-and-after comparison showed that this system had a significant effect in reducing processing times from 23 to 8 days, the proportion of cultures with delays >90 days from 9.2% to 0.1%, the number of errors by 57.1%, and the work-hours necessary to process results by 60%. A cost and timeline framework was developed to allow other organizations in resource-poor settings to implement this technology. The second part addresses a web-based system, e-Chasqui, developed to provide electronic communication and reporting of TB laboratory information to health care personnel within institutions with internet. A cluster randomized controlled trial showed that access to e-Chasqui resulted in significantly less time to receipt of test results, a 56% reduction in tests taking over 60 days to arrive and a 98% reduction of results that never arrived, as well as a significantly faster time to culture conversion among patients in intervention versus control centers. / (cont.) These two parts describe verified medical informatics tools and an implementation methodology for settings both with and without internet connectivity. / by Joaquin Andres Blaya. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2010. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 131-147). / Prostate cancer persists as a major public health issue in the United States and remains the second leading cause of cancer death in men. Early detection and disease monitoring in prostate cancer can significantly improve a patient's prognosis. The advent of prostate-specific antigen (PSA) screening has allowed physicians to monitor the levels of a specific protein, or biomarker, as a correlate of disease progression. This thesis focuses on optical detection of prostate tumors through the development of biomarker-targeted molecular imaging probes. In the first part of this work, engineered human prostate cancer cell lines were developed and characterized to determine the dynamics of post-translational processing for PSA proteolytic activity and to establish potential small animal models for validating protease-activatable imaging probes. Target-activatable gold nanoparticle imaging probes that can be self-assembled in a one-step reaction were then developed to detect biomarker proteases in vivo. The activated probes demonstrated a 5 to 8-fold fluorescence signal amplification, extended circulation time, and high image contrast in a mouse tumor model. Lastly, differential phage display selection was performed on human prostate cancer cells with low and high metastatic potentials to (1) identify cell-surface biomarkers specific to highly aggressive tumors, and (2) develop molecular imaging probes for detecting prostate cancer metastases. / (cont.) One peptide, LN4P-1, demonstrated preferential binding to highly metastatic PC3M-LN4 cells and identified a highly expressed protein on their cell surface. Fluorescently labeled LN4P-1 was able to detect PC3MLN4 tumors in vivo. In summary, this thesis outlines the development of molecular imaging probes for targeting tumors both at the primary site, through evaluation of biomarker protease activity, and at the metastatic site, through affinity-based analysis of biomarker expression. / by Chunyao Jenny Mu. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2006. / Includes bibliographical references. / Understanding intensity coding and auditory learning are basic concerns of research on the auditory central pathway. There is no unifying model of intensity coding but several mechanisms have been proposed to play a role. The first aim of this thesis was to determine the mechanisms of intensity coding in the central auditory pathway from the cochlear nucleus to the auditory cortex. The Fos labeling method was used to assess neuronal activation in the central auditory system. This technique allows one to study large regions of the brain in awake animals. Increasing sound pressure level led to: (1) spreading of labeling towards neurons with higher best frequencies; (2) spread of labeling orthogonal to the tonotopic axis; (3) and increased density of labeling within the tonotopic band. In addition to encoding the physical features of a stimulus, it is fundamental for survival that we learn about the meaning of sounds and put them in a behavioral context. The second aim of this thesis was to study how learning, in particular auditory fear conditioning, changes the pattern of neuronal activation of neurons, as measured with Fos labeling, in the central nervous system. Conditioning led to an increase in Fos labeling in central auditory nuclei. / (cont.) This increase in labeling was similar to the effects of increasing sound intensity. The present results support the idea that auditory fear memories are stored in the auditory pathway. / by Teresa P.G. Santos. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2011. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 145-159). / Epilepsy is a neurological disorder characterized predominantly by an enduring predisposition to generate epileptic seizures. The apprehension about injury, or even death, resulting from a seizure often overshadows the lives of those unable to achieve complete seizure control. Moreover, the risk of sudden death in people with epilepsy is 24 times higher compared to the general population and the pathophysiology of sudden unexpected death in epilepsy (SUDEP) remains unclear. This thesis describes the development of a wearable electrodermal activity (EDA) and accelerometry (ACM) biosensor, and demonstrates its clinical utility in the assessment of epileptic seizures. The first section presents the development of a wrist-worn sensor that can provide comfortable and continuous measurements of EDA, a sensitive index of sympathetic activity, and ACM over extensive periods of time. The wearable biosensor achieved high correlations with a Food and Drug Administration (FDA) approved system for the measurement of EDA during various classic arousal experiments. This device offers the unprecedented ability to perform comfortable, long-term, and in situ assessment of EDA and ACM. The second section describes the autonomic alterations that accompany epileptic seizures uncovered using the wearable EDA biosensor and time-frequency mapping of heart rate variability. We observed that the post-ictal period was characterized by a surge in sympathetic sudomotor and cardiac activity coinciding with vagal withdrawal and impaired reactivation. The impact of autonomic dysregulation was more pronounced after generalized tonic-clonic seizures compared to complex partial seizures. Importantly, we found that the intensity of both sympathetic activation and parasympathetic suppression increased approximately linearly with duration of post-ictal EEG suppression, a possible marker for the risk of SUDEP. These results highlight a critical window of post-ictal autonomic dysregulation that may be relevant in the pathogenesis of SUDEP and hint at the possibility for assessment of SUDEP risk by autonomic biomarkers. Lastly, this thesis presents a novel algorithm for generalized tonic-clonic seizure detection with the use of EDA and ACM. The algorithm was tested on 4213 hours (176 days) of recordings from 80 patients containing a wide range of ordinary daily activities and detected 15/16 (94%) tonic-clonic seizures with a low rate of false alarms (<; 1 per 24 h). It is anticipated that the proposed wearable biosensor and seizure detection algorithm will provide an ambulatory seizure alarm and improve the quality of life of patients with uncontrolled tonic-clonic seizures. / by Ming-Zher Poh. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2009. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 103-114). / Human Immunodeficiency Virus (HIV) is the cause of Acquired Immune Deficiency Syndrome (AIDS) and has killed over 25 million people since the disease was first recognized in 1981. As of 2007, 33 million people globally are infected with HIV and this number is growing. HIV infects and depletes CD4+ helper T cells, affecting the ability of the immune system to defend the host against common infections. While anti-retroviral therapy has decreased morbidity and mortality, these drugs are not curative. In addition, they are beyond the financial reach of many HIV infected patients. Thus, the development of strategies to control HIV spread is a high priority. The most relevant animal model for studying HIV is the Simian Immunodeficiency Virus (SIV) - infected rhesus monkey. While HIV research has focused on studying peripheral blood specimens, mucosal sites have recently been identified as a focal point for HIV replication and tissue destruction. They are usually the sites of primary infection in the setting of sexual transmission and they are also important sites of immune depletion. If methods for controlling the replication of the virus early after infection in mucosal sites are available, it may be possible to eliminate the virus prior to systemic spread. While strategies for generating strong neutralizing antibody responses have not yet been developed, emerging data suggest that CD8+ cytotoxic T cells can contribute substantially to early virus control. It is important to study CD8+ T cells in the setting of SIV infection in rhesus monkeys, particularly in mucosal sites, using functional as well as transcriptional assays. / (cont.) One of the challenges in studying mucosal cellular immunity is the limited number of cells available in biopsies, making traditional assay systems such as flow cytometry very difficult to employ. Here, technologies for isolating rare cell populations and extracting RNA from these cells for gene expression analysis were developed. These technologies were then applied to peripheral blood specimens, looking at gene expression differences between virus-specific CD8+ T cells in Mamu-A*01+ and Mamu-A*02+ monkeys. The ultimate goal of these studies is to gain a better understanding of SIV immunopathogenesis (as a model for HIV immunopathogenesis) and to find a way to control or eliminate the virus. / by Amy Shi. / S.M.

Thesis (Ph.D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, 2000. / Includes bibliographical references. / Understanding how the human brain works, in both health and disease, requires data with both high spatial and temporal resolution. This thesis develops and applies a spatiotemporal neuroimaging method. I describe a linear estimation inverse approach, which is a method for the combination of functional magnetic resonance imaging (fMRI) with electroencephalography (EEG) and magnetoencephalography (MEG). fMRI provides millimeter spatial resolution, while EEG and MEG provide millisecond temporal resolution. The thesis is divided into two broad sections: Monte Carlo modeling studies and experimental studies. Improvements to both the bioelectromagnetic forward and inverse solutions are demonstrated. Through modeling studies, I characterize the accuracy of the method with and without functional and anatomic constraints, the effects of various model mis-specifications, and as a function of EEG/MEG sensor configuration. I describe a noise sensitivity normalization to the traditional linear estimation operator that improves the point spread function (a measure of spatial resolution), increases the spatial homogeneity of the point spread, and allows interpretation of the localization in terms of a statistical measure (F-statistic). Using experimentally generated current dipoles implanted an epilepsy patient, I examine the accuracy of both a realistic and spherical EEG head model. This experimental data demonstrates the improved accuracy of the realistic head model, and gives us confidence in using this realistic head model for EEG source localization. The optimized and validated forward and inverse methods are then applied to a variety of empirical measurements. First, the combined multi modality imaging approach is used to simultaneous EEG/fMRI measurements of a visual stimulus, demonstrating the feasibility of measuring and localizing simultaneously acquired electric potential and hemodynamic measurements. Second, combined MEG/fMRI measurements are used to analyze the spatiotemporal characteristics of a cortical network that is responsive to visual motion coherency. Finally, in epilepsy patients, I compare the non-invasive MEG localization of interictal spikes with verification from invasive recordings and surgical results. These studies, in both normal volunteers and patients, clearly demonstrate the utility, accuracy, and power of the combined use of fMRI, EEG and MEG. The tools demonstrated here provide "real time movies" of the human brain at work during a given task or behavior. This information is required to develop computational models of how the human brain/mind works. / by ARthur K. Lui. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2008. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 84-85). / Valuing medical device companies and technologies is a complex process. Several different approaches and models are often used in combination to determine a transaction valuation. This research uses the Enterprise Value to Forward Sales model as a tool for valuing mergers and acquisitions in the device industry. This model was selected for its transportability across industry segments, ease of calculation, broad acceptance, and lack of detailed forecasting assumptions. This research seeks to: 1) explore the importance of 20 commonly cited factors in determining a medical device company EV/Sales multiple, 2) develop a model for forecasting the EV/Sales multiple of medical device transactions, and 3) assess the explanatory power of these factors in determining the enterprise value (measured in dollars) of pre-revenue transactions. For purposes of this analysis valuation was approached from a sector neutral or portfolio diversification perspective. Multivariate regression analysis was performed on a database of 352 M&A transactions announced between January 1, 1996 and December 31, 2007 to assess the importance of various factors and develop a model for forecasting EV/Sales multiples. Consistent with our expectations, supernormal growth, industry growth, market size, sector beta, position in market, venture funding, and IPO status were all significant factors in determining the multiple. Based on these factors, we developed a model that was 95% accurate in forecasting the EV/Sales multiple of medical device transactions that occurred between January and May of 2008. / (cont.) Based on the success of this model, we then explored the utility of these factors in determining the gross enterprise value of pre-revenue M&A transactions. As expected, this approach was not successful. Varying discount rates, timing assumptions, difficult to determine value synergies, and emotion are confounding factors which make it difficult to reliably forecast absolute dollar transaction valuations. / by Jason S. Robins. / S.M.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2011. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 30). / The purpose of this paper is to examine the interactions between licensing status, equity issuance cycles, and drug development success at the small pharmaceutical companies that originate these development projects. Specifically, this paper is aimed at identifying how financing alternatives available to small pharmaceutical companies influence development success and firm behavior. The hypotheses developed and tested in this paper are as follows: H 1: Pharmaceutical development projects that are licensed are more likely to advance to the next stage in the clinical development process. H2: A licensed pharmaceutical development projects' likelihood of advancing to the next stage of the clinical development process will depend on the amount of equity issuance during the period in which the project was licensed. H3: Pharmaceutical development projects that are licensed during periods of low equity issuance are more likely to advance to the next stage in the clinical development process than projects that were not licensed or were licensed but not in a low equity issuance period. H4: Pharmaceutical development projects that originate at firms that have multiple projects in development at the beginning of a particular clinical trial stage are less likely to advance from phase I to phase II, but more likely to advance in later stages. H5: Pharmaceutical development projects that originate at firms that have previously launched a project in the market are more likely to be launched in the market. The results of a logistic regression analysis suggest that drugs licensed in periods of lowest equity issuance exhibit a higher rate of advancement from phase II to phase III. The relationship between advancement and amount of equity issuance at the time of licensing suggests that the lower the equity issuance in the licensing period the more likely the drug will advance. These results point to the possible existence of a "lemons" phenomenon in the market for pharmaceutical development projects. However, a different interpretation of the results suggests that large pharmaceutical company licensees are superior evaluators of quality and are perhaps more selective and opportunistically license higher quality drugs when equity issuance is low and licensors have no other financing options. Both interpretations point to the issue of information asymmetry as a central theme to this work. / by Jonathan D. Alspaugh. / S.M.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2008. / Includes bibliographical references. / Cancer mortality still remains high despite significant investments in diagnostics, drug development, and treatment. The systemic route is convenient both for routine monitoring and for drug administration. Local cancer biomarker concentrations, however, are more indicative of the state of solid tumors and their response to therapy. Furthermore, local drug delivery can achieve efficacy where systemic treatments fail. This dissertation describes two reservoir-based devices to enable such local approaches. We are applying superparamagnetic crosslinked iron oxide nanoparticles (CLIO) for the quantitative measurements of soluble cancer biomarkers. These nanoparticles are functionalized to react specifically in the presence of their target analyte. An implanted device with a size-exclusion membrane was used to contain the CLIO and to expose them to the cancer milieu. The system was designed to be deployed deep within the body and indirectly detect cancer cells and their activity by their secreted products, which are produced at a very high copy number by each cell. A reservoir-based polymeric device has also been applied for local chemotherapy. A biodegradable polymer microchip was designed in our group to independently deliver more than one therapeutic agent. Only in vitro release of active compounds had been previously demonstrated. The work in this thesis achieves local drug therapy from the polymer microchip and demonstrates efficacy against an in vivo tumor model of brain cancer. The reservoir-based device approach has the potential to enable early detection of cancer recurrence, personalized drug treatments, and localized multi-drug therapy. / by Grace Young Kim. / Ph.D.

Thesis (M. Eng.)--Harvard-MIT Division of Health Sciences and Technology, 2009. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 59-61). / Diseases affecting the retina, such as Age-related Macular Degeneration (AMD) and Retinitis Pigmentosa (RP), result in the degeneration of the photoreceptor cells and can ultimately lead to blindness in patients. There is currently no cure for AMD or RP, and only a few methods exist for slowing the progression of these diseases. Although there has been much recent headway in cell replacement therapy to restore vision loss, a number of challenges still remain. More specifically, there is a need for the development of a device that can deliver a large number of cells to the posterior segment of the eye, while promoting cell survival, differentiation and integration into the retina following transplantation. This research focuses on designing a device to meet these demands and improve the vision of those afflicted with blinding diseases. The specific hypothesis behind the proposed research is that a MEMS-based strategy to engineer a device can provide precisely defined spatial and chemical cues to influence retinal progenitor cells (RPCs) attachment, promote differentiation, and provide physical guidance in a more normal anatomical organization for their integration as neurosensory retina after transplantation to the subretinal space. Therefore, the specific aims of this research are to design, fabricate, and evaluate in vitro a novel ultrathin 3-D device made of polycaprolactone (PCL) for retinal cell replacement synthesized by the stacking, aligning, and bonding of three uniquely designed layers. / (cont.)Photolithography, standard replica molding, and soft lithography techniques are used to fabricate the device elements. The 3-D device is designed with a defined cage structure to encapsulate a large number of cells. Another layer of the design allows for unidirectional cell migration out of one end into the subretinal space with the aid of contact guidance ridges. The third design layer allows for nutrient infiltration from the retinal pigment epithelium into the cell cages. The ultimate goal is to provide an environment compatible with the normal retinal tissue and conducive to the formation of functional synapses under the appropriate conditions, thereby restoring proper vision. With demonstration of efficacy and cell retention in vitro, the scaffold has the potential to reverse retinal degeneration due to disease or trauma and improve retinal function and integrity in vivo. / by Sonal Sodha. / M.Eng.