Thesis (Sc. D.)--Harvard-MIT Division of Health Sciences and Technology, 2007. / Includes bibliographical references (p. 169-182). / The ability to form auditory objects is important in the natural environment where sounds arriving at our ears are a resultant of all spectro-temporal components that may have arisen from different auditory events. It has been shown that auditory spatial cues are effective for grouping acoustical energy across time or across frequency. However, little is known about the effect of spatial cues on scene analysis when more than one auditory object is being presented. In this thesis dissertation, a novel two-object paradigm was used to investigate how spatial cues influence the identification and the localization of object in the auditory foreground. Specifically, the effect of both spatial and non-spatial cues on auditory grouping and object identification was ascertained. Using an acoustic pointer and the same stimuli for the object identification task, the apparent spatial location of these objects was measured to test the hypothesis that only the spatial attributes of the components grouped to form an object influences the localization of the same object. A conceptual model was generated to highlight the role of spatial cues in object formation, and the dissociation between the auditory computation of "what" and "where" was further investigated. In current technology, object segregation presents a fundamental challenge for the hearing impaired, hearing aid design and speech recognition algorithms. It is hopeful that the findings in this dissertation will inspire new biologically-based algorithms for auditory scene analysis and in turn, influence designs in assistive hearing devices and other technological development that is dependent on multi-source segregation. / by Adrian Kuo Ching Lee. / Sc.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2010. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 57-59). / Generics in the pharmaceutical industry have been instrumental in reducing overall healthcare cost and allowing for greater dispersal of life saving drugs to the general population. The Hatch-Waxman Act of 1984 played a critical role in changing the landscape of the pharmaceutical industry and providing legislation for an abbreviated regulatory pathway for generic drugs. The conversation has shifted to the need to implement similar regulatory paths for generics of biologics. First generation biologic patents have or are geared to expire within the next five years, providing a great opportunity for generic companies in this space to enter. Biologic generics, termed biosimilars or follow-on biologics, are more difficult to evaluate due to the complex nature of the molecule and the variables involved in the development and manufacturing process. This research seeks to understand the current debate in the biosimilar conversation, and examine whether there is a clear regulatory path to market for biosimilars using epoetin as a case example across the three main markets; US, Europe and Japan. / byZeenat Patrawala. / S.M.

Thesis (Ph. D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, 1997. / "August, 1997." / Includes bibliographical references. / by Nada Boustany. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2009. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 82-88). / This thesis asks one basic question: how do "vertical" disease- or intervention-focused global health programs impact the underlying health systems of the nations they serve? Vertical programs-health aid focused on a particular disease, such as HIV, or type of intervention, such as immunization-receive the lion's share of global health aid dollars, and yet we know uncomfortably little about their long-run impact on broader health systems. Many speculate that vertical aid undermines health worker effectiveness, distorts national policies, and disrupts the supply chain for drugs and medical products. Unfortunately, a lack of hard data makes quantitative analysis extremely difficult. Using the tools of system dynamics, this thesis consolidates the collective wisdom of previously published investigations and anecdotal observations to reveal the field's prevailing "mental model" of the dynamic in question. The result is a set of diagrams that describe the known impacts of vertical programs on health systems, and also reveal dynamic effects not yet explicitly identified in the literature. These effects fall into four sub-systems of impact: care delivery specialization and fragmentation, care delivery development and mediocritization, health policy development and mismatch, and market development and distortion. These models are then used to better understand the effects of recent contextual developments-the HIV/AIDS epidemic and the emergence of large Global Health Initiatives. / (cont.) Through expert interviews, this thesis identifies the most pressing system stresses in this contemporary context: the commitment to chronic care delivery which HIV/AIDS intervention creates, and the critical need for harmonization between donors which this commitment reveals. Using case examples from Kenya, these dynamics are shown to be active today, and to have instigated mitigation strategies by practitioners in the field. Finally, the systems identified above bring into focus key leverage points, including donor coordination, health worker augmentation, and engagement of local markets, which can "tip" the impact of vertical programs from harming health systems to strengthening them. In doing so, this thesis provides guidance to policymakers and program implementers who seek to use their resources to strengthen systems and eventually obviate health aid entirely. / by Brian J. Newkirk. / S.M.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2006. / Includes bibliographical references (p. 91-98). / Large health cohort studies are among the most effective ways in studying the causes, treatments and outcomes of diseases by systematically collecting a wide range of data over long periods. The wealth of data in such studies may yield important results in addition to the already numerous findings, especially when subjected to newer analytical methods. Bayesian Networks (BN) provide a relatively new method of representing uncertain relationships among variables, using the tools of probability and graph theory, and have been widely used in analyzing dependencies and the interplay between variables. We used BN to perform an exploratory analysis on a rich collection of data from one large health cohort study, the Nurses' Health Study (NHS), with the focus on breast cancer. We explored the data from the NHS using BN to look for breast cancer risk factors, including a group of Single Nucleotide Polymorphisms (SNP). We found no association between the SNPs and breast cancer, but found a dependency between clomid and breast cancer. We evaluated clomid as a potential riskfactor after matching on age and number of children. Our results showed for clomid an increased risk of estrogen receptor positive breast cancer (odds ratio 1.52, 95% CI 1.11-2.09) and a decreased risk of estrogen receptor negative breast cancer (odds ratio 0.46, 95% CI 0.22-0.97). / (cont.) We developed breast cancer risk models using BN. We trained models on 75% of the data, and evaluated them on the remaining. Because of the clinical importance of predicting risks for Estrogen Receptor positive and Progesterone Receptor positive breast cancer, we focused on this specific type of breast cancer to predict two-year, four-year, and six-year risks. The concordance statistics of the prediction results on test sets are 0.70 (95% CI: 0.67-0.74), 0.68 (95% CI: 0.64-0.72), and 0.66 (95% CI: 0.62-0.69) for two, four, and six year models, respectively. We also evaluated the calibration performance of the models, and applied a filter to the output to improve the linear relationship between predicted and observed risks using Agglomerative Information Bottleneck clustering without sacrificing much discrimination performance. / by Delin Shen. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2007. / Vita. / Includes bibliographical references. / The development of high resolution, high speed imaging techniques allows the study of dynamical processes in biological systems. Optical fluorescence microscopy is an essential tool for investigations in many disciplines in biology and medicine with molecular specificity. The resolution of optical far-field microscopy has been limited by the wave nature of light. In this thesis, a microscopy technique, standing wave total internal reflection fluorescence (SW-TIRF), has been developed with resolution beyond the classical diffraction limit. The SW-TIRF approach modifies the point-spread function to effectively decrease the excitation wavelength by utilizing an evanescent standing wave, carrying high spatial frequency information near the interface between the specimen and a high refractive index substrate. Evanescent standing wave illumination is used to generate a sinusoidal, high-spatial frequency, fringe pattern on the specimen providing lateral resolution enhancement. Furthermore, the less than 100 nm penetration depth of the evanescent field from the substrate ensures a thin excitation region resulting in low background fluorescence. The first experimental realization of SW-TIRF in an objective-launched geometry demonstrates the potential for super-resolution imaging at high speed in wide-field microscopy. / (cont.) The super-resolution has been realized with the effective point-spread function providing better than a fifth of the emission wavelength or approximately 100 nm, which is better than twice that of conventional microscopy. In addition, imaging biological specimens with SW-TIRF demonstrated the performance revealing the fine actin cytoskeleton structures of fibroblasts. On the other hand, the surface plasmons induced by evanescent fields at a specific angle can generate an enhanced electric field which can effectively excite fluorophores near a metal coated surface. We observed a unique doughnut-shaped point-spread function of surface plasmon coupled emission and explained it with theoretical modeling using vector field theory. The combination of surface plasmon resonance fluorescence imaging and SW-TIRF resulted in a novel high-resolution microscopy, the standing wave surface plasmon resonance fluorescence (SW-SPRF) microscopy. These findings may allow super-resolution imaging with even higher sensitivity and signal-to-noise ratio at high imaging speed. / by Euiheon Chung. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2004. / Includes bibliographical references (p. 65). / This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. / Drug development in the United States is a lengthy and expensive endeavor. It is estimated that average development times range from eleven to fifteen years and exceed costs of one billion dollars. The development pathway includes basic scientific discovery, pre-clinical testing in animals, clinical development in humans, and an application process. The Food and Drug Administration is responsible for the oversight and approval of drugs going through this process. Numerous financial and economic studies have been conducted that show the benefits to accelerating the drug development process. In 1992, the United States Congress enacted the Prescription Drug User Fee Act I, which mandated faster response times from the FDA in return for user fee payments to the FDA by the drug developing companies. Data on approval times for new drugs indicate that this process was indeed shortened. In contrast, the average drug development process prior to the filing of an application has been increasing in cost and time. The first purpose of this research is to quantify the benefits of accelerated new drug application review time under the Prescription Drug User Fee Acts I and II. The second purpose of the research is to investigate what industry and the FDA can do together to reduce the development process time between the IND and NDA without compromising patient safety and welfare, specifically the Phase II, Phase III, and NDA components. The research indicates that PDUFA has improved approval times in a statistically significant way. Furthermore, the financial and social benefits as measured using net present value have far exceeded the PDUFA costs. Quantitative and qualitative surveys of fifty individuals in large pharmaceutical and biotech companies / (cont.) resulted in the identification of several significant opportunities and useful suggestions for reducing development times in Phase II, Phase III, and the NDA. Specifically, company interviewees indicated that they were willing to pay additional monies for increased interaction and communication with the FDA from Phase II through the NDA in hopes of reducing information asymmetry and increasing information transparency. Other recommendations included a mandatory audit and review of a sample of NDAs post approval to identify best practices, implementation of metrics and performance tracking during clinical phases, and implementation of consistent project management and communication standards across therapeutic divisions. / by Adrian Hedley Benjamin Gottschalk. / S.M.

Thesis (Ph.D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, 1998. / Includes bibliographical references (leaves 214-229). / by Stephen Allen Boppart. / Ph.D.

Thesis (M. Eng.)--Harvard-MIT Division of Health Sciences and Technology, 2005. / Includes bibliographical references (leaves 48-49). / Hepatocytes are widely used in the pharmaceutical and medical fields for drug metabolism studies, bioartificial liver devices, and repopulation of damaged livers as an alternative to transplantation. However, these cells are scarce and difficult to maintain in culture for prolonged periods of time. Banks of cryopreserved liver cells would significantly alleviate issues of hepatocyte availability, and efforts are being made to improve the viability and functionality of frozen hepatocytes. Previously, most work on improving post-thaw viability has hinged on limiting the physical damage of freezing by adding cryoprotective agents and optimizing cooling rates. Membrane-permeable cryoprotectants, such as dimethyl sulfoxide, though widely used, can be extremely toxic to the cell. More natural, non-membrane-permeable cryoprotectants, inspired by freeze-tolerant animals have also been used. A non-metabolizable glucose analog, 3-0-methyl- glucose (30MG), has shown promise with hepatocytes and was used in this study. Kinetics of the rGLUT2 cellular transporter used for 30MG uptake were quantified; Km and Vmax were determined to be 27.6 mM and 1.38 mM/s, respectively, by Lineweaver-Burk analysis and 70.0 mM and 1.82 mM/s, respectively, by Eadie-Hofstee analysis. This study also aimed to investigate the role of mitochondria in cell death induced by freezing. In particular, mitochondrial membrane potential (MMP) was investigated as a predictor of a cell's likelihood to avoid apoptosis from freeze-induced stress. Cells were sorted into high and low MMP subpopulations, frozen, thawed, and cultured for 24 hours. / (cont.) Cell cultures were analyzed for attachment yield, viability of attached cells and overall viability, which were 87%, 68% and 59%, respectively for the high MMP subpopulation, and 68%, 53% and 35%, respectively for the low MMP subpopulation. Morphological differences such as extent of membrane blebbing were observed as well, verifying that cells with a high MMP are more likely to survive the cryopreservation process. These results demonstrated that MMP is a determinant of both frozen hepatocyte adherence efficiency and viability; a high MMP yields a significant advantage in both. Our understanding of the role of MMP in freeze-thaw death and of the characteristics of the rGLUT2 transporter will lead to the development of more successful cryopreservation protocols. / by Margaux E. Daly. / M.Eng.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2007. / Includes bibliographical references (p. 157-168). / Spectrally encoded confocal microscopy (SECM) is a technique that facilitates the incorporation of confocal microscopy into small, portable clinical instruments. This would allow in vivo evaluation of cellular and sub-cellular features in a non-destructive, minimally invasive manner. Prior studies have demonstrated the potential of the techniques as well as highlighted the need for faster acquisition rates and higher sensitivity. In this thesis, new laser sources, optical fiber arrangements and probe designs are explored to ultimately evaluate SECM's relevance as a clinical tool. Clinical imaging at cellular scales requires imaging rates on the order of tens of frames per second to reduce motion artifacts from unavoidable patient movements. Rapid SECM imaging was achieved through the development of a novel wavelength swept laser which simultaneously provided high output power (> 10mrW), narrow linewidth (10GHz), broad wavelength tuning (80 nm centered at 1310 nm) and fast repetition rates (up to 16,000 Hz), while being compact and environmentally stable. Imaging with a wavelength swept SECM system was characterized by coupling the laser to a tabletop imaging arm comprising a high density holographic grating, a galvanometer mounted mirror and a 0.9 NA water immersion microscope objective. / (cont.) Rapid SECM imaging is performed at a transverse resolution of 1.4 microns, axial resolution of 6 microns over a field of view of 440x440 microns and allows subcellular imaging ex vivo (excised specimens) and in vivo (human skin). A study on 40 excised head and neck specimens showed that SECM has the potential to perform tissue identification, but also revealed the presence of speckle noise due to the coherent nature of the illumination and collection schemes through a single mode optical fiber. A partially coherent system based on single mode fiber for illumination and multimode fiber for detection was simulated, implemented and tested to find adequate balance between attenuation of speckle noise and conservation of resolution. A coupling of 20 modes was found to reduce speckle by a factor 4.5 with a minimal sectioning penalty of 0.25, while allowing a signal increase of 8dB. This improvement in sensitivity allowed SECM table top system to be used for investigations in developmental biology where Dual clad fibers (DCF) were previously shown to allow partially coherent endoscopic imaging, using the single mode core for illumination and inner clad for multimodal collection. / (cont.) Commercially available DCF's which propagate thousands of modes are ill suited for confocal endoscopes as collecting such a number of modes would destroy the axial resolution. Based on results from the previous section and through modal analysis, a DCF was designed, drawn - via a collaboration with Boston University Photonics Center -, and tested for use with SECM. The prototype DCF yielded promising results (3 fold speckle attenuation, optical sectioning degradation of 0.85), and showed the need for implementation of better coupling mechanisms to take advantage of increased signal collection. Finally, a portable SECM system was built for in vivo evaluation of pediatric vocal fold. A preliminary study on porcine and cadaveric tissue showed that SECM can distinguish between epithelium, superior and intermediate layers of the lamina propria, which could help elucidate the development mechanism of the voice apparatus if performed in vivo. The handheld instrument comprises a custom grating scanner imaging the scanning pivot onto the back pupil of a high NA microscope objective. The imaging tube can easily be interchanged to accommodate geometrical constraints imposed by different age groups. / (cont.) The probe, currently under review by the biomedical engineering committee, revealed cellular and sub cellular details of human skin in vivo at depth and acquisition rates sufficient to capture blood cells flowing through capillaries. Through major improvements in acquisition speeds, sensitivity, and speckle appearance, this work established SECM as a potent clinical and biological imaging tool. Ultimate confirmation will be revealed through in vivo studies to come, but limitations are likely to be of engineering nature rather than from physical considerations. Future work should explore the possibility to combine SECM with other contrast mechanisms to provide imaging with increased specificity. / by Caroline Boudoux. / Ph.D.