Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2006. / Includes bibliographical references (leaves 62-68). / Sensory cells and afferent auditory neurons in the cochlea receive efferent feedback via olivocochlear (OC) neurons originating in the brainstem's olivary complex. The OC system comprises 1) medial (M)OC neurons that decrease electromotility in outer hair cells, and 2) lateral (L)OC neurons that elicit slow excitation or inhibition of auditory nerve dendrites that contact inner hair cells. We investigated the organization and function of the LOC system by immunohistochemical and physiological studies in mice with unilateral stereotaxic destruction of LOC cell bodies. Double immunostaining in control cochleas and brainstems revealed two cytochemical subgroups of LOC neurons: a majority cholinergic population and a minority dopaminergic population. The observation of two LOC subgroups is consistent with reports that LOC activation can either excite or inhibit auditory nerve activity. In lesioned mice, we observed two physiological abnormalities. First, ipsilateral ears were more vulnerable to noise-induced auditory nerve dysfunction, consistent with speculation that dopaminergic transmission controls glutamate excitotoxicity of auditory nerve dendrites after acoustic overexposure. / (cont.) Second, ipsilateral auditory nerve responses were increased while contralateral responses were decreased, and the normal tight correlation of neural excitability between the two ears was disrupted. A neural circuit is proposed to explain bilateral effects from unilateral LOC innervation. We suggest that a key LOC function is to bilaterally balance ascending inputs to olivary complex neurons, which are responsible for computing sound location based on the interaural level differences coded in the response rates of auditory nerve fibers. / by Keith N. Darrow. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2006. / Includes bibliographical references (leaves 29-30). / Some have argued that the genetic differences between continentally defined groups are relatively small and unlikely to have biomedical significance. In this study, the extent of variation between continentally defined groups was evaluated. Small numbers of randomly selected single nucleotide polymorphisms from the International HapMap Project were used to train classifiers for prediction of ancestral continent of origin. Predictive accuracy was then tested on independent data sets. A high degree of genetic similarity implies that groups will be difficult to distinguish, especially when only a limited amount of genetic information is used. It is shown that the genetic differences between continentally defined groups are sufficiently large that one can accurately predict ancestral continent of origin using only a minute, randomly selected fraction of the genetic variation present in the human genome. Genotype data from only 50 random single nucleotide polymorphisms can be used to predict ancestral continent of origin in the primary test data set with an average accuracy of 95%. / (cont.) Single nucleotide polymorphisms were also characterized as being in introns, coding exons, regulatory regions and regions coding for untranslated mRNA and classifiers constructed using only single nucleotide polymorphisms from a specific category. Predictive accuracy was similar across all of the classifiers created in this manner. Single nucleotide polymorphisms useful for prediction of ancestral continent of origin are common and distributed relatively evenly throughout the genome. These findings demonstrate the extent of variation between continentally defined groups and argue strongly against the contention that genetic differences between groups are too small to have biomedical significance. / by Dominic J. Allocco. / S.M.

Thesis (Ph.D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, 2000. / Includes bibliographical references (p. 133-137). / This research characterizes the respiratory system dynamics at the initiation and termination of utterances and determines correlations of physiological measures with acoustic cues for these prosodic boundaries. The analysis includes boundaries within a breath as well as boundaries that are aligned with the initiation and termination of exhalation. Simultaneous recordings of the acoustic signal, airflow, esophageal pressure and lung volume were collected during read isolated utterances and short paragraphs. These measures were used to derive estimates of recoil forces of the chest wall, net muscular forces, and the area of the airway constriction. Data are presented from four subjects (two men, two women), all native speakers of American English. Perceptual ratings for initial and final prominent syllables and the locations of pauses within the utterance were also collected. For speech boundaries th.i.t are aligned with breath boundaries, utterance initiation occurs during a rapid transition in muscular effort. Sound begins as soon as conditions permit and these conditions consistently occur during net inspiratory muscular force. Alveolar pressure reaches an initial peak (PpI) that is, in most cases, correlated to the relaxation characteristic of the chest wall. The timing of Pp1 generally coincides with a prominent syllable if that syllable is the first or second syllable in the utterance and precedes later prominences. Pressure at phonation onset is, on average, near 0.3PpI for utterances initiated with a voiced sonorant and is near 0. 8Pp1 for utterances initiated with a voiceless fricative. Phonation termination results from an approximately 3-fold increase in glottal area and a J-3 cm H20 fall in pressure. Irregular fundamental frequency (FO) at the end of voicing, in many cases, does not fit the classical definition of glottalization. Instead, voicing terminates with increasing glottal area, and FO becomes irregular during the increase. In some cases, regular FO resumes as glottal area continues to increase. Distinct respiratory gestures are made at pauses within a breath. The pressure is reduced by 2-3 cm H20, on average, during a period of relatively little volume change. The findings in this research show that the role of the respiratory system in speech production goes beyond a more traditional view of this role as one of simply providing a relatively constant driving pressure during speech. / by Janet Slifka. / Ph.D.

Thesis (Ph. D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, 2000. / Includes bibliographical references (leaves 167-175). / by Christopher Joseph Long. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Program in Health Sciences and Technology, 2013. / Cataloged from PDF version of thesis. / Includes bibliographical references. / Introduction: It is postulated that music has been part of society for at least 50,000 years, since the time that humans lived in one location of the world before dispersing across the globe (44). Over the eras it evolved in its manifestation, from classical performances enjoyed only by the elite, to soulful songs sung in the fields, to myriad forms of expression to be used by anyone. Today, its prominence has even evolved into being used as a tool for cognitive therapy, such as for aphasia patients (41), or to heal those who no longer have the ability to move their bodies (40). Given its incredible, seemingly endless potential, it is fruitful to explore new innovations in its usage - with treatment for chronic diseases such as depression, anxiety, and other mental disorders being ideal candidates. These diseases are high in their cost on resources, both human and monetary, and have weighty long-term impacts on patients' lives as well as their families', with depression being the leading cause of disability worldwide according to the World Health Organization (43). Music is positioned as a potent remedy, as its attributes are almost the mirror negative of the effects from chronic disease: it is low cost, pleasurably pervasive, and socially connecting Thus, the intention behind the design of study 1 in this thesis was to create a pilot, self -driven, wellness-enhancing music treatment that could be used as the basis for a future treatment for depression. It was meant to be a relatively brief longitudinal study examining adherence and feasibility for a personal music augmented mindfulness practice in a small group of healthy subjects. From the insights gleaned during this study, it was determined that the choice of strongly emotional, personal music could be potentially powerful in another disease context. In study 2, the design contracted from a longitudinal one to an acute, nuanced observation of enhanced music analgesia during experimental heat pain with healthy subjects. The clinical tool of interest was a proven analgesia boosting conditioning paradigm, which was combined in this study with personal music. Together, the two studies provide a revealing glimpse of humankind's ability to harness the best attributes it can for self-care from a medium it itself created. / by Christine L. Hsieh. / Ph.D.

Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, 2016. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 151-158). / One of the hallmarks of long-duration spaceflight is physiological deconditioning seen in the absence of gravity. Negative changes in bone, muscle, and other physiological systems occur rapidly in space, and have the potential to severely limit the human space exploration program. The deficits in bone are mostly seen in the weight-bearing areas of the skeleton, highlighting the influence of gravity. Current countermeasures employed on the International Space Station are vastly improved over previous countermeasures equipment, however, with long duration exploration missions, there is a need to optimize countermeasures to adequately combat these physiological changes. One countermeasure concept that may aid in helping prevent deconditioning is the Gravity Loading Countermeasure Skinsuit, which uses elastic materials to provide bodyweight loading similar to that seen in the presence of gravity via compression along the cephalocaudal (head to toe) axis of the body. Preliminary work performed in our lab produced prototype garments that were characterized for comfort and wearability, but had design deficiencies that prevented them from providing full bodyweight loading to the subjects. In order to create an effective countermeasure garment we first developed a model of suit-body interactions through computational simulations to inform suit design. We then built and characterized prototype suits, and evaluated the potential of the suit for efficacy in ameliorating musculoskeletal deconditioning in earth-based analogs of unloading. Modeling efforts showed that the GLCS could provide bodyweight-like loading to the subjects in simulated microgravity, and in some cases provided higher loads to the muscles and joints than those seen during unsuited movements in Earth gravity. Prototype suits were constructed that provided 76-84% bodyweight loading to the subjects. During exercise testing on a vertical treadmill, the subjects were able to run and walk normally, and the suit was shown to increase physiological workload, as well as joint and muscle loading, during running in simulated microgravity. / by Dustin Paul Kendrick. / Ph. D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2009. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 80-84). / Many early-stage biotech companies face a significant funding gap when trying to develop a new drug from preclinical development to a proof of concept clinical trial. This funding gap is sometimes referred to as the "valley of death", a reflection of the vast number of companies that are unable to raise the needed capital to progress into the clinic. The suggestion behind the "valley of death" phrase is that companies that should be able to attract investment do not get funded, because (1) the technical risks inherent in taking a new drug through clinical trials are high, (2) a significant amount of capital is needed to finance clinical development, and (3) the time horizon of investment is on the order of 6-8 years. Ultimately, the valley of death reflects the perceived imbalance of risk and reward for an investment at this stage as well as the resulting difficulty for a biotech company in raising capital during this time. For companies focused on a neglected disease, this risk/reward profile is even more skewed, with significantly greater market risks and fewer exit opportunities for an investor. As a result, the "valley of death" phenomenon for a global health company developing a therapeutic for a neglected disease is even more pronounced As a result, private sector funding for translational research of neglected disease therapeutics has beeri severely lacking. In an effort to spur more private sector investment into the development of neglected disease therapeutics, several market design mechanisms have been developed including Advanced Market Commitments (AMCs) and Priority Review Vouchers (PRVs). These market design mechanisms are new and unproven. / (cont.) To date venture capital has not yet flowed in a meaningful way into startup companies focusing on neglected diseases. This is partially attributable to uncertainties surrounding the credibility and value of the incentives, but it also raises the question of whether these incentives will be sufficient to attract venture investment to a small biotech company focused on neglected diseases. The objective of this thesis is to explore the potential impact of these market design mechanisms on the financial prospects of early stage, pre-revenue biotech companies focused on neglected diseases, including an evaluation of whether the incentives will be sufficient to attract venture investment to the company. To accomplish this, a simulation model was created to compare the relative impacts of these incentive schemes on a small biotech company focused exclusively on a neglected disease therapeutic. The simulation data presented herein reflect the inherent tensions between the social benefit of a neglected disease therapeutic and the need for investors to pursue a financial return commensurate with the risk of the investment. I conclude that, while market design mechanisms like PRVs and AMCs are an intriguing first step, a dual market strategy is likely still necessary for a neglected disease company to attract private investment. / by Brian L. K. Miller. / S.M.

Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, 2014. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 158-169). / Vestibular schwannomas (VSs), the most common tumors of the cerebellopontine angle, arise from Schwann cells of the vestibular nerve. VSs can lead to sensorineural hearing loss (SNHL), disequilibrium, facial nerve paralysis, and brainstem compression. Treatment options available today are associated with significant morbidity, leading to an unmet need for well-tolerated pharmacotherapies to curb VS growth and associated SNHL. To identify pharmacologic targets, this thesis investigated inflammatory pathways in VS. Proinflammatory transcription factor nuclear factor kappa B (NF-KB) and enzyme cyclooxygenase 2 (COX- 2) were aberrantly active in VS. NF-KB inhibition, achieved through siRNA, an experimental agent BAYl 1-7082 or a clinically relevant drug curcumin, was cytotoxic against primary VS cells and HEI-193 VS cell line. COX-2 inhibition, achieved through salicylates, was cytostatic against primary VS cells. Our in vitro findings are in line with our retrospective findings that VS patients taking aspirin demonstrate halted tumor growth. Anti-inflammatory drugs such as aspirin could be efficacious against VS. Additionally, as the etiology of SNHL due to VS is unknown, this thesis explored the potential of VS secreted factors to modulate SNHL. Applying human VS secretions to organotypic cochlear explant cultures, we demonstrate that VS secreted factors can lead to hair cell and neurite degeneration. Exogenous application of tumor necrosis factor alpha (TNF[alpha]), an ototoxic cytokine whose VS secreted levels correlate with degree of SNHL, led to neurite loss in cochlear explants and TNF[alpha] neutralization in VS secretions partially rescued cochlear degeneration due to VS secretions. Interestingly, otoprotective fibroblast growth factor 2 (FGF2) levels in VS secretions inversely correlate with degree of SNHL, suggesting that different ototoxic and otoprotective VS-secreted molecules modulate VS's effect on hearing. TNF[alpha] and FGF2 could serve as biomarkers or pharmacologic targets against VS associated SNHL. Exploring angiogenic pathways, cross-talk between vascular endothelial growth factor (VEGF-A) and hepatocyte growth factor (HGF) was found in Schwann cells, VS cells and in cochlear cells. VEGF-A neutralization in VS secretions could not rescue cochlear degeneration but VEGF-A or HGF receptor knockdown was cytostatic in VS cells. Overall, several pathobiological pathways were investigated to provide promising therapeutic targets against neoplastic VS growth and associated SNHL. / by Sonam Dilwali. / Ph. D.

Thesis (Ph. D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, 2001. / Includes bibliographical references. / This thesis presents a novel optical technique, light scattering spectroscopy (LSS), developed for quantitative characterization of tissue morphology as well as in vivo detection and diagnosis of the diseases associated with alteration of normal tissue structure such as precancerous and early cancerous transformations in various epithelia. LSS employs a wavelength dependent component of light scattered by epithelial cells to obtain information about subcellular structures, such as cell nuclei. Since nuclear atypia is one of the hallmarks of precancerous and cancerous changes in most human tissues, the technique has the potential to provide a broadly applicable means of detecting epithelial precancerous lesions and noninvasive cancers in various organs, which can be optically accessed either directly or by means of optical fibers. We have developed several types of LSS instrumentation including 1) endoscopically compatible LSS-based fiber-optic system; / (cont.) 2) LSS-based imaging instrumentation, which allows mapping quantitative parameters characterizing nuclear properties over wide, several cm2, areas of epithelial lining; and 3) scattering angle sensitive LSS instrumentation (a/LSS), which enables to study the internal structure of cells and their organelles, i.e. nuclei, on a submicron scale. Multipatient clinical studies conducted to test the diagnostic potential of LSS in five organs (esophagus, colon, bladder, cervix and oral cavity) have shown the generality and efficacy of the technique and indicated that LSS may become an important tool for early cancer detection as well as better biological understanding of the disease. / by Vadim Backman. / Ph.D.

Thesis (S.M.)--Harvard-MIT Program in Health Sciences and Technology, 2012. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 63-67). / Over the past ten years there has been increasing public concern regarding the rising costs of pharmaceuticals. Drug expenditure is the fastest growing sector of healthcare costs in the United States. The structure of the U.S. healthcare system allows pharmaceutical companies to freely price their drugs. Then payers decide whether and how to cover these drugs. Payers have at their disposal several utilization management tools, such as tiering and prior authorizations, to steer their members to less costly drugs. However, the ability of payers to implement these tools varies significantly depending on whether the drug is covered under the pharmaceutical benefit / Medicare Part D provisions of healthcare plans or the medical benefit / Medicare Part B provisions. Drugs covered under the pharmaceutical benefit / Part D are distributed via retail pharmacies and, in general, are oral pills. Drugs covered under the medical benefit / Part B are physician administered drugs and, in general, are injectables or intravenous drugs. As pharmaceutical companies increasingly price their drugs at higher and higher levels, payers must take a drug's pricing into account when determining how to cover these drugs. This thesis assesses the role pricing plays in how a drug is covered. Two different classes of drugs were chosen to examine this topic: fixed dose combination (FDC) cardiovascular drugs and intravenous oncologies. FDC cardiovascular drugs were chosen because they are covered under the pharmacy benefit / Part D and are considered to have questionable efficacious value over their individual drug components. Intravenous oncologies were chosen because they are covered under the medical benefit / Part B and represent a highly politicized therapy area. These two therapy areas are illustrative of strongly contrasting classes of drugs. Literature review and public sources were used to obtain prices for the select cardiovascular FDCs and oncologies. Medicare's Formulary Finder was used to obtain the coverage level for the cardiovascular FDCs. This preliminary information showed that the most expensive of the select FDCs, Caduet, has the worst coverage. The literature review suggested that Provenge and Avastin, the most expensive of the select oncologies, had difficulty obtaining coverage. To confirm these results, interviews were conducted with a variety of payers. These interviews focused on what factors went into the coverage decision-making process for cardiovascular FDCs and intravenous oncologies. Interviews were also conducted with an oncologic distributor to determine distributors' impact on price. We hypothesized that price was the driving reason for Caduet's, Provenge's, and Avastin's relatively poor coverage. However, our hypothesis was not entirely confirmed. Payers confirmed that price and contracting were the driving factors for Caduet's relatively poor coverage, but they indicated that the situation was not as simple for the intravenous oncologies. Although price does play a small role in the coverage decision-making process for intravenous oncologies, other factors such as public policies and the unmet need in the therapy area drive coverage decisions more than price. Additionally, payers indicated that they lack the ability to steer members to less costly intravenous oncologies due to the drug acquisition and reimbursement structure of the medical benefit. Consequently, payers are beginning to utilize new techniques such as specialty pharmacies to help control utilization of these products. Also, other organizations such as certain oncologic distributors are attempting to implement cost-effective guidelines for intravenous oncologies. Our results have significant implications for what pharmaceutical companies should be considering when pricing their drugs, and highlight the pricing and coverage issues in the current healthcare system's structure that payers and other organizations are facing. / by Drew Cronin-Fine. / S.M.