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.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2007. / Includes bibliographical references (leaves 55-57). / Recently, hospitals, regulatory agencies, and insurers have renewed their focus on improving patient care and safety. Outcomes based measures are being utilized and hospitals are being asked to report on whether patients are being treated according to a standard of care or a best practice guideline. As peri-operative physicians, anesthesiologists are able to evaluate and, to a great degree, affect the pre-operative, intra-operative, and post-operative course of a patient. However, several barriers exist. Although best practice guidelines exist, current models to risk stratify patients need improvement. Individual anesthesiologists currently have no uniform way to measure patient outcomes, either in an institutional or provider specific manner, and many treat patients based on anecdotal experience rather than on evidence based medicine. We addressed these issues through development of an electronic feedback system. The demonstration system targeted the problem of postoperative nausea and vomiting (PONV) in the ambulatory surgery patient population. Because performance of existing PONV risk prediction models was poor and could not be used for educational purposes, we created a new PONV risk prediction model and compared it against existing models. The new, improved risk prediction model was incorporated into an electronic system that gathered patient outcomes data related to best care practice and then fed back the information to care providers. After implementation of the electronic feedback system, we evaluated its efficacy in improving compliance with best care practices. / by Pankaj Sarin. / S.M.

Thesis (S.M.)--Harvard-MIT Program in Health Sciences and Technology, 2012. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 41). / The purpose of this research is to investigate potential strategic variables that executives at small to mid-sized biopharmaceutical companies should consider during the period of a drug launch. Bringing a product to market is a critical event for any biopharmaceutical company. It marks a major turning point within the biopharmaceutical's lifecycle and the company that can successfully launch a product will be viewed as a different asset class. Therefore, it is critical to understand potential drivers of the value and to encourage executives to raise probing questions when they are considering the next round of financing or whether to provide guidance. This study analyzed forty-six non-generic, therapeutic drugs launched in the US during January 2000- December 2009 by small to mid-sized biopharmaceutical companies with market capitalizations less than $20 billion at the time of launch. Predictor variables that were initially considered in the analysis are the following: management providing a sales guidance (binary), partnership (binary), market size of the partner(s) at the time of launch, specialty/primary care indication (binary), difference between year two actual sales number and that of pre-launch estimate, difference between year two actual sales number and that of post-launch estimate, financing activity prior to launch (binary), financing activity after launch (binary), average prelaunch file-to-offer discount, average post-launch file-to-offer discount, number of drugs launched by the same company (control variable) and NBI performance (control variable). Multiple linear regression analyses were then performed to determine which of these parameters were predictive of changes in stock price and changes in market capitalization. Those companies that did not provide guidance at the time of launch and raised additional capital within two years after launch performed better than those that did otherwise. Neither a partnership nor the market size of the partner contributed to either of the outcome measures. Whether or not the product is a specialty product also did not make any significant contribution to the models. The results from this study suggest several possible strategic and actionable items that can guide management to ask the right questions during the period around a drug launch. / by Sung Min You. / S.M.

Thesis (Ph.D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, 2002. / Vita. / Includes bibliographical references (leaves 72-76). / Prolonged exposure to microgravity in space flight missions (days) impairs the mechanisms responsible for defense of cardiac output (CO) and arterial blood pressure (Pa) against orthostatic stress during re-entry and in the post-flight period. To date, available countermeasures have not been able to eliminate the observed orthostatic hypotension. The mechanisms responsible for the observed orthostatic intolerance are not yet completely understood. Pa is maintained by control pathways, which influence either total peripheral resistance (Ra) or CO. Central control of Ra is achieved by a complex closed-loop negative feedback system composed of the arterial and the cardiopulmonary baroreflexes. The aims of the doctoral research presented in this thesis were: 1) design and employ a novel conscious animal model for the examination of arterial and cardiopulmonary baroreceptors in the dynamic closed-loop short-term control of Ra. 2) develop and apply a system identification method for the analysis of fluctuations in Pa, right atrial pressure (Pra), and Ra to quantitatively characterize the physiologic mechanisms responsible for the couplings between these variables. For this purpose, eight conscious sheep were used, where both types of baroreceptors were simultaneously exposed to random independent beat pressure variations over a small range around their operating points, while Ra was measured. Subsequently, system identification was applied to determine the quantitative dynamic contributions of Pa and Pra to short-term closed-loop regulation of Ra. To validate the dynamic properties of the transfer function estimates from the developed system identification method, step response estimates from Pa to Ra and from Pra to Ra were compared to directly measured step response observations. / by A. Nikolai Aljuri. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2011. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 66-73). / The United States is the world leader in development and manufacture of medical devices. Even with this leadership position, there is evidence that the US is often not the first country to have new medical technology approved for patient use. In many cases, the European Union is the first geographic region to approve a new medical technology for sale, with US approval coming later. This delay in approval of new devices between the EU and US is referred to as the "device lag." However, the extent or history of this lag over time and for different device types has not been examined. This thesis evaluated if a device approval lag has developed between US and EU at any time over the past 20 years and whether a device lag continues to exist today. US and EU regulatory approval data for 135 medical devices in three innovative medical device segments were collected and analyzed to evaluate the extent and history of the approval lag between the European Union and the United States. The collected approval data revealed a consistent approval lag between the US and EU in each of the three medical device segments explored in this study. Throughout the entire 20+ years of study, the United States had an average approval lag to the European Union in each of the three device segments, and an average lag for all devices of 21 months or almost 2 years (Ho: p. = 0, p = 8.2E-12). Furthermore, the device lag in these three segments has grown in recent years. These data are striking because they show, perhaps for the first time, that an approval lag has existed for medical devices between the US and EU for the past 20 years - since the beginning of the pan-European device regulatory system in the mid-1990s. The device lag is a useful metric for comparing the attractiveness of two markets for medical technology and may signal important changes in the medical technology industry. Furthermore, the existence of a persistent device approval lag in the United States may have significant implications for patients and their caregivers. / by Todd V. Dhavale. / S.M.