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: S.M., Massachusetts Institute of Technology, Dept. of Humanities, Program in Writing and Humanistic Studies, September 2012. / Includes bibliographical references (leaves 36-41). / by Amitabh Avasthi. / 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.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2005. / Includes bibliographical references (p. 142-146). / This study focuses on the acoustic patterns of stop consonants and adjacent vowels as they develop in young children (ages 2;6-3;3) over a six month period. Speech is generated using a series of articulatory, laryngeal, and respiratory gestures that children must learn to reproduce. As a child's speech develops, the gestures become more precise and coordinated, and the resulting acoustic patterns are refined. To explore their development, over forty different acoustic measurements were made on each of 1049 recorded utterances from ten children, including durational, amplitude, spectral, formant, and harmonic measurements. These acoustic data are interpreted in terms of the supraglottal, laryngeal, and respiratory actions that give rise to them. Data show that some details of the child's gestures are still far from achieving the adult pattern. Children have acquired appropriate positioning of their primary articulator for producing a stop consonant, but are still learning to adjust the tongue body during the consonant production. At constriction release, children have a high incidence of multiple bursts and a short burst duration, interpreted as a reflection of increased articulator compliance, smaller articulator size, and high subglottal pressure. Children are also still acquiring correct adjustment of vocal fold stiffness and glottal spreading as well as intraoral pressure, as evidenced by long voice onset times and highly variable fundamental frequencies. Additionally, amplitude changes over the course of the utterance and high amplitude variability reveal that children have not yet gained full control over subglottal pressure. / (cont.) Overall, results indicate that children are less consistent than adults in controlling and coordinating various gestures and with finding the ideal respiration and vocal tract postures, including the stiffness of their articulators. Certain aspects of child speech are found to become more similar to adult values over the six month period of the study. / by Annika Karin Karlsson Imbrie. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2007. / Includes bibliographical references (p. 223-237). / The ear represents a remarkable achievement in sensory physiology. It is very fast (timescales on the order of 1-100 kHz), has a large bandwidth (-10 octaves in the human), highly sensitive (threshold is ultimately determined by thermal noise), operates over an enormous dynamic range (factor of a trillion in terms of energy input), capable of sharp stimulus selectivity (e.g. frequency and intensity discrimination) and exhibits robust nonlinear behavior. As a sensor designed to detect acoustic sound pressure, surprisingly, the ear also emits sound as well. These otoacoustic emissions (OAEs) have been developed extensively for clinical applications (healthy ears emits while impaired ones do not), though their full potential has yet to be realized. Much of the effort gone into understanding OAEs has been developed within the context of mammals, where specific anatomical and physiological features (e.g. traveling waves and somatic motility) are thought to play an integral role in generation. This thesis approaches OAEs comparatively, systematically characterizing emissions in humans and an array of non-mammals (chickens, geckos and frogs) who lack these mammalian features and exhibit a diverse range of morphologies. / (cont.) First, our results show that for a fixed set of stimulus conditions (employing moderate intensities), emissions are relatively largest in the gecko and frog (the two species with the fewest number of sensory cells) and smallest in the human and chicken for frequencies below -2 kHz. At higher frequencies (3-5 kHz), emissions descend toward the noise floor for the non-mammals but remain relatively constant in human. Second, OAE phase behavior indicates that emissions are generated by multiple mechanisms in the human and chicken (and possibly gecko in certain stimulus conditions), but not the frog. OAEs in all species exhibit significant delays (-1 ms or longer), those being largest in humans. Tuning can explain these delays in all species except the frog, where some additional source of delay is present. Lastly, non-monotonic growth (relative to stimulus intensity) was found in all species, suggesting the presence of multiple level-dependent sources. We interpret the observed similarities and differences in emission properties across species within the context of anatomical/physiological comparisons. / by Christopher Bergevin. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2008. / Includes bibliographical references (p. 134-139). / In multicellular organisms, cells do not exist in isolation but communicate with other cells via extracellular signaling molecules, many of which diffuse into the microenvironment. More than most cell types, embryonic stem cells (ESCs) are critically sensitive to their microenvironment, which plays an important role in determining whether an ESC will self-renew or differentiate. Although conventional methods exist for controlling the soluble microenvironment, they are able to exert only limited control over diffusible signaling. Especially in conventional static culture, the content of the cell culture media changes constantly over time as cells interact with and modify their surroundings. This thesis explores the use of microfluidic perfusion as a tool for modulating diffusible cell-cell signaling in mESC culture, thus enabling more control over the soluble microenvironment over time. Non-recirculating microfluidic perfusion culture can effect a more defined microenvironment by continuously controlling the supply and removal of soluble factors, with minimal use of expensive reagents. We describe development of the first successful protocol for culturing mouse ESCs in microfluidic perfusion over several days. To optimize flow-rate conditions such that proliferation is achieved while avoiding nutrient deprivation and high shear stress regimes, we developed novel logarithmic flow-rate devices for characterizing mESC behavior across a wide range of flow rates simultaneously. We observed both flow-rate and location-dependent proliferation and investigated the role of glucose depletion in generating these effects. Finally, we demonstrate that perfusion culture can significantly affect diffusible cell-cell signaling in the soluble microenvironment, and thus the cell's biological state. / (cont.) We first show that typical flow rates are able to remove secreted factors by collecting leukemia inhibitory factor (LIF) from the output of microfluidic ESC cultures perfused with LIF-free media. We then show that two well-established serum-free media: N2B27 (neuronal differentiation media) and N2B27 +LIF+BMP4 (selfrenewal media) are not sufficient for successful perfusion culture of mESCs at typical densities, although they are able to support cultures in static conditions. These results suggest the presence of autocrine/paracrine loops that support ESC propagation in serum-free media when cultured under static conditions. / by lily Y. Kim. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2008. / Includes bibliographical references (p. 211-215). / Regions of phonation exhibiting nonmodal characteristics are likely to contain information about speaker identity, language, dialect, and vocal-fold health. As a basis for testing such dependencies, we develop a representation of patterns in the relative timing and height of nonmodal glottal pulses. To extract the timing and height of candidate pulses, we investigate a variety of inverse-filtering schemes including maximum-entropy deconvolution that minimizes predictability of a signal and minimum-entropy deconvolution that maximizes pulse-likeness. Hybrid formulations of these methods are also considered. we then derive a theoretical framework for understanding frequency- and time-domain properties of a pulse sequence, a process that sheds light on the transformation of nonmodal pulse trains into useful parameters. In the frequency domain, we introduce the first comprehensive mathematical derivation of the effect of deterministic and stochastic source perturbation on the short-time spectrum. We also propose a pitch representation of nonmodality that provides an alternative viewpoint on the frequency content that does not rely on Fourier bases. In developing time-domain properties, we use projected low-dimensional histograms of feature vectors derived from pulse timing and height parameters. For these features, we have found clusters of distinct pulse patterns, reflecting a wide variety of glottal-pulse phenomena including near-modal phonation, shimmer and jitter, diplophonia and triplophonia, and aperiodicity. Using temporal relationships between successive feature vectors, an algorithm by which to separate these different classes of glottal-pulse characteristics has also been developed. / (cont.) We have used our glottal-pulse-pattern representation to automatically test for one signal dependency: speaker dependence of glottal-pulse sequences. This choice is motivated by differences observed between talkers in our separated feature space. Using an automatic speaker verification experiment, we investigate tradeoffs in speaker dependency for short-time pulse patterns, reflecting local irregularity, as well as long-time patterns related to higher-level cyclic variations. Results, using speakers with a broad array of modal and nonmodal behaviors, indicate a high accuracy in speaker recognition performance, complementary to the use of conventional mel-cepstral features. These results suggest that there is rich structure to the source excitation that provides information about a particular speaker's identity. / by Nicolas Malyska. / Ph.D.

Thesis (Ph.D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, February 1999. / "January 1999." / Includes bibliographical references (leaves 219-239). / by Steven Treppo. / Ph.D.