Thesis (Ph. D.)--Harvard University--Massachusetts Institute of Technology Division of Health Sciences and Technology, Program in Medical Engineering and Medical Physics, 1990. / Includes bibliographical references (leaves 185-203). / by Gregory Alexander Brown. / Ph.D.

Thesis (Ph. D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, 2001. / Includes bibliographical references (p. 223-240). / When bone is loaded beyond its failure point, it develops damage in the form of microcracks. Normally, microcracks are repaired by the remodeling process, limiting the number of in vivo microcracks. However, if the rate of microdamage accumulation increases or the rate of remodeling slows, microdamage can accumulate, reducing bone stiffness and strength and may lead to stress fractures or fragility fractures. A new technique for visualizing microdamage in vitro has been developed that uses chelating fluorochromes to label microcracks. Sequential staining is used to distinguish between microdamage that occurred before testing and damage created during testing. Microdamage parameters quantified include the total number of microcracks, total length of microcracks, damaged area, the number of trabeculae containing microcracks, the pattern of microcracking, the extent of microdamage across the thickness of the trabeculae, and the size of the damage-containing region in the specimen. The chelating fluorochrome marker technique was used to label and quantify microdamage in specimens of bovine trabecular bone damaged in uniaxial compression and compressive fatigue, and relationships between microdamage parameters and changes in mechanical properties (maximum compressive strain, modulus reduction) were quantified. / (cont.) The progressions of damage accumulation during a single compression cycle and during fatigue to failure were determined. Comparisons were made between specimens tested in different loading modes, including uniaxial compression, compressive fatigue, and compressive creep (Pierce, 1999). Microdamage accumulation increases with increasing specimen strain and with increasing stiffness loss. A model was developed to predict modulus reductions based on observed microdamage using cellular solid principles. The predictions were compared to experimentally measured changes in mechanical properties during uniaxial compressive loading and compressive fatigue. There was good agreement between model predictions and experimental results for specimens tested in uniaxial compression. The model predictions were less accurate when applied to specimens tested in compressive fatigue. / by Tara L. Arthur Moore. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, February 2010. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 171-180). / Dysarthria is a motor speech disorder characterized by weak or uncoordinated movements of the speech musculature. While unfamiliar listeners struggle to understand speakers with severe dysarthria, familiar listeners are often able to comprehend with high accuracy. This observation implies that although the speech produced by an individual with dysarthria may appear distorted and unintelligible to the untrained listener, there must be a set of consistent acoustic cues that the familiar communication partner is able to interpret. While dysarthric speech has been characterized both acoustically and perceptually, most accounts tend to compare dysarthric productions to those of healthy controls rather than identify the set of reliable and consistently controlled segmental cues. This work aimed to elucidate possible recognition strategies used by familiar listeners by optimizing a model of human speech recognition, Stevens' Lexical Access from Features (LAFF) framework, for ten individual speakers with dysarthria (SWDs). The LAFF model is rooted in distinctive feature theory, with acoustic landmarks indicating changes in the manner of articulation. The acoustic correlates manifested around landmarks provide the identity to articulator-free (manner) and articulator-bound (place) features. / (cont.) SWDs created weaker consonantal landmarks, likely due to an inability to form complete closures in the vocal tract and to fully release consonantal constrictions. Identification of speaker-optimized acoustic correlate sets improved discrimination of each speaker's productions, evidenced by increased sensitivity and specificity. While there was overlap between the types of correlates identified for healthy and dysarthric speakers, using the optimal sets of correlates identified for SWDs adversely impaired discrimination of healthy speech. These results suggest that the combinations of correlates suggested for SWDs were specific to the individual and different from the segmental cues used by healthy individuals. Application of the LAFF model to dysarthric speech has potential clinical utility as a diagnostic tool, highlighting the fine-grain components of speech production that require intervention and quantifying the degree of impairment. / by Thomas M. DiCicco, Jr. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2007. / Includes bibliographical references (leaves 56-61). / It has been widely reported that pharmaceutical drug discovery innovation began its major decline somewhere in the last decade of the 20th century. After reaching a historical high of 53 new molecular entities (NMEs) in 1996, the industry has since witnessed a steady decline of NME filings (down to 18 in 2006) with the Center for Drug Evaluation and Research (CDER)---despite rapidly escalating R&D spending among the world's major pharmaceutical firms (the "majors"). Industry leaders, researchers, and observers have all but acknowledged this drug discovery productivity crisis, much of it attributed to the industry's preference for and eventual exhaustion of simple, single molecular targets-the so-called "low-hanging fruit" whose discovery is characteristically attributed to serendipity. Collectively, pharmacological compounds were identified that targeted the products of -400-500 genes in the human body over the past five decades. These single-molecular targets-the majority of which are mechanistically overrepresented by the G-protein coupled receptors and key enzymes--are now believed to have been mostly discovered and commercialized into the ubiquitous blockbuster drugs on the market, ranging from statins to proton-pump inhibitors (PPIs). / (cont.) Historically and nearly coincident with this apparent dearth of new molecular targets was the advent of the 99% completed euchromatic sequence' of the human genome in 2004, as reported by the International Human Genome Sequencing Consortium (IHGSC). Launched in 1990, the Human Genome Project (HGP) thus made available thousands of the approximately 30,000-40,000 estimated human genes that could be potentially associated with disease. Given the therapeutic promise of the supposed -3,000 druggable genes2, the major pharmaceutical firms have allocated sizeable investment into genomics-based drug discovery. The realization of senior research executives that future drug innovation will likely be based on a multi-gene, systems biology-based model for understanding complex disease mechanisms of action has resulted in a shift away from reliance on serendipity toward a model informed by genomic elucidation of inter-pathway connectivity. In my research, I examined the level and type of genomics-related investments made by selected majors in the West (U.S., Europe) and Japan. Moreover, I have leveraged genomics as a "lens" to assess the nature and role of serendipity in drug discovery-which I have posited can be deconstructed into the two different facets of technological capability and organizational design. / (cont.) Thirdly, the impact of personal-, firm-, and country-level ethnic & national identity, cultural & historical legacy, and social factors on productivity are investigated. Through the use of personal interviews with senior pharmaceutical industry research executives, an online survey questionnaire completed by research managers and staff, and publicly available information, it was found that the Western and Japanese majors shared major similarities surrounding the original impetus to invest in genomics. While Western firms were found to reap significant benefits from superior scale and decisively 'permeated' genomics as the central platform technology throughout their drug discovery organizations, Japanese firms were found to exhibit greater efficiency in resource utilization in genomics-based discovery. Furthermore, the finding of 3 distinctive national culture characterizations for Western, Japanese, and Chinese firms revealed differential influences on their respective firms' drug discovery practices and productivity. Finally, the state of China's genomics and life sciences firms was evaluated. Prescriptive recommendations for the development of the nascent pharmaceutical industry in China, based on conclusions drawn above, are provided. / by Trent Yen-wei Lu. / S.M.

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.