Thesis (Ph.D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, 1998. / Includes bibliographical references. / by James L. McGrath. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2003. / Includes bibliographical references (leaves 126-136). / Hair cells are the exquisitely-sensitive mechanosensory transducers of the inner ear. While the electrophysiology of hair cells has been extensively studied, little is known about the vital background processes that maintain the steady-state intracellular ionic environment. This study explored Na-coupled ion transport processes in isolated goldfish hair cells both in the steady state and in response to perturbations. Intracellular Na⁺ concentration ([Na⁺]i) and pH (pHi) were measured using the fluorescent probes SBFI and BCECF, respectively. The total steady-state Na⁺ entry, determined by measuring the initial rate of increase in [Na⁺]i during inhibition of Na⁺,K⁺-ATPase, was 9 mM/min, a rate higher than in many other epithelial cells involved in rapid ion transport. To uncover the entry pathways for such a high Na⁺ influx, pharmacological agents and manipulations of extracellular composition were used to dissect apart the contributions of various transporters or channels. A combination of Na⁺ entry via transduction channels, the Na⁺/H⁺ exchanger, and the Na⁺/Ca²⁺ exchanger accounted for 3/4 of the total steady-state Na⁺ entry. Consistent with a significant component via the Na⁺/Ca²⁺ exchanger, nifedipine, a blocker of L-type calcium channels, also reduced the Na⁺ entry rate. Since the Na⁺/H⁺ exchanger in goldfish hair cells, in contrast to many other cell types, displayed significant activity in the steady state, interactions between regulation of [Na⁺]i and pHi were examined during recovery from intracellular acid loads. The rate of Na+ entry or acid extrusion via the Na⁺/H⁺ exchanger increased by a factor of 6 during recovery from an acid load. In most cells, [Na⁺]i doubled after the acid load and subsequently recovered, even though the / (cont.) was not exogenously inhibited. These results indicate that intracellular acidification inhibits the Na⁺, K⁺-ATPase, and therefore poses a potential conflict for maintenance of intracellular Na⁺ homeostasis. Although hair cells were traditionally described as passive resistors, this thesis demonstrates that goldfish hair cells have a significant metabolic load, even in the steady state, arising from the activities of specific Na⁺-coupled transporters and channels. Under certain pathophysiological circumstances, such as ischemia or acoustic trauma, increased Na⁺ influx via these pathways may overwhelm the ion-homeostatic capabilities of hair cells. / by Diane Elizabeth Ronan. / Ph.D.

Thesis (Ph.D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, February 1999. / Includes bibliographical references (p. 188-195). / by Pankaj Oberoi. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2008. / Includes bibliographical references (p. 65-66). / Many factors contribute to a company's decision to launch a product in a new market. The company must be able to identify a clinical need that the product will address and the market must be willing to pay for the new technology. This thesis explores the clinical and market need for an improved shock monitoring technology. Shock occurs when there is not enough blood flow to adequately perfuse the body's organs. In the United States, about 500,000 patients go into sudden shock every year and half of these patients die. For millions of additional patients, shock is the final stage of a terminal disease. Despite advances in many other areas of medicine, shock continues to be a serious, life threatening condition. It is my hypothesis that the limitations of the current monitoring technologies contribute to the high mortality rate associated with shock. In my research, I examined the currently available monitoring technologies and their use for the diagnosis and resuscitation of shock patients. I conducted an extensive review of the scientific literature to identify the limitations of the current monitoring technologies and to understand the challenges of diagnosing and treating shock. To supplement my research, I interviewed clinicians who treat shock patients and scientists who are trying to develop new shock monitoring technologies. The clinicians confirmed that there is a critical need for improved shock monitoring technologies. However, for a new shock monitor to be successful, it will need to address the limitations of the current technologies. A well-designed clinical trial will be necessary to demonstrate that the new technology is sensitive and specific, clinically relevant, and easy to use. / by Amanda S. Jenkins. / S.M.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2010. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 41-44). / Collective intelligence techniques have been used to predict stock prices, customer purchasing habits, movies and books preferences for years, yet they remain unused in the medical profession. With the increasing adoption of electronic medical records, patients' medical data has grown exponentially and thus constitutes an untapped field where similar techniques could be applied. If data were collectively farmed and intelligently filtered, patient information could be added to traditional clinical decision support tools to arrive at personalized recommendations based on empiric evidence. The aim of this work is to use the collective, de facto, clinical experience to augment clinical guidelines thereby providing physicians with personalized clinical decision support. The pharmacological treatment of hypertension was chosen as the clinical domain in which to explore the feasibility of this approach. Twelve-thousand-three-hundred-forty-seven hypertensive patients were seen at the Internal Medical Associates (IMA) clinic at Massachusetts General Hospital (MGH) between July 2004 and September 2009. Their relevant clinical and demographic variables, drug regimens and blood pressure measurements were collected from the clinic's electronic medical record system and a dataset was generated. Back-end application software that draws upon case-based reasoning (CBR) was constructed and used to compute similarity between an index patient and existing hypertension patients. / (cont.) This program returned information regarding blood pressure control status and successful drug regimens used by similar patients. The use of EMR transactional data to provide a collective experience decision support (CEDSS) at the point-of-care using a computerized CBR approach is both technically possible and promising. Further studies are needed to evaluate the effectiveness of this method. / by Guido Alejandro Davidzon. / S.M.

Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, 2016. / This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. / Cataloged from student-submitted PDF version of thesis. / Includes bibliographical references (pages 124-130). / In natural environments, sounds are often not static. Usually, moving objects require the most attention, e.g. for identifying the presence and direction of a moving vehicle, or detecting and tracking the trajectory of a predator or prey. Faster time-varying location cues can occur in acoustic environments containing many spatially distributed sound sources, like at a cocktail party. In this case, we can identify the locations of the sources by "glimpsing" at short-duration localization cues when the sound energy from one source dominates the mixture. Even faster time-varying spatial cues result from reverberation in an echoic environment and we perceive them as spatially diffuse. We qualitatively perceive motion, a cocktail party, and reverberation differently, and these three percepts are determined by how quickly the spatial cues are moving. How these percepts come about in the auditory system is unknown. Here, we studied how neurons encode time-varying location cues and how the neural code relates to perception. Our focus was on time-varying interaural time differences (ITD), one of the main cues for localizing sounds in the horizontal plane. We recorded from single neurons in the inferior colliculus (IC) in the auditory midbrain of unanesthetized rabbits. The IC is the site of an obligatory synapse in the auditory pathway and one of the first stages of processing following the initial extraction of spatial cues in the brainstem. We hypothesized that the IC exhibits limitations in its ability to encode time-varying ITD that give rise to these different percepts. First, we show that IC neurons are more "sluggish" on average at synchronizing to the time-varying ITD than to amplitude modulations presented at a static ITD. Binaural sluggishness has been proposed based on human psychophysics but never validated neuro physiologically in the IC. Second, we show that most neurons are unable to synchronize to the time-varying ITD at speeds where humans no longer perceive fluctuations. Instead, neurons exhibit a change in average firing rate that corresponds to binaural decorrelation of the noise for very fast time-varying ITD, and this may explain the percept of a spatially diffuse sound at these speeds. We further recorded neural responses to slow-moving ITDs in opposite directions within the range of perceived motion. Using a generalized linear model to parse the neuron's response into ITD-following and direction selectivity components, we show that the responses of IC neurons are dominated by their ability to follow the ITD more than direction selectivity. In parallel experiments, we asked human participants to either identify the motion direction or detect the slow-moving ITD in the same stimuli and determined the threshold durations for direction identification and for detection for each participant. Direction identification threshold durations were larger than detection threshold durations. We then implemented neural classifiers that either identified the motion direction or detected the slow-moving ITD based on single-neuron responses to the stimuli, and we found that the classifier exhibited duration thresholds that matched human thresholds on both tasks. Together, these results suggest that temporal limitations of neural responses in the IC may give rise to the limiting speeds of time-varying localization cues where we perceive motion, "glimpse" the position of a source amidst a mixture, and perceive a spatially diffuse background in a reverberant environment. / by Nathaniel J. Zuk. / Ph. D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2007. / Includes bibliographical references (leaves 138-142). / Phonetic variation is pervasive in everyday speech. Studying these variations is essential for building acoustic models and lexical representations that effectively capture the variability of speech. This thesis examines one of the commonly-occurring phonetic variations in English: the stop-like modification of the dental fricative /ð/. This variant exhibits a drastic change from the canonical /ð/; the manner of production is changed from one that is fricative to one that is stop-like. Furthermore, the place of articulation of stop-like /0/ has been a point of uncertainty, leading to the confusion between stop-like /ð/1 and /d/. This thesis aims to uncover the segmental context of stop-like /ð/, possible causes of the modification, whether the dental place of articulation is preserved despite modification, and if there are salient acoustic cues that distinguish between stop-like /ð/ and /d/. Word-initial /ð/ in the read speech of the TIMIT Database, the task-oriented spontaneous speech of the AEMT Corpus, and the non-task-oriented spontaneous speech of the Buckeye Corpus are examined acoustically. It is found that stop-like /ð/ occurs most often when it is preceded by silence or when preceded by a stop consonant. The occurrence is less frequent when /ð/ is preceded by a fricative or an affricate consonant. This modification rarely occurs when /ð/ is preceded by a vowel or liquid consonant. The findings suggest that possible factors that may contribute to the stop-like modification of /ð/include physiological mechanisms of speech production, prosody, and/or other aspects of speaking style and manner. Acoustic analysis indicates that stop-like /ð/ is significantly different from /d/ in burst amplitude, burst spectrum shape, burst peak frequency, and second formant at following- vowel onset. / (cont.) Moreover, the acoustic differences indicate that the dental place of articulation is preserved for stop-like /ð/. Automatic classification experiments involving these acoustic measures suggest that they are robust in distinguishing stop-like /ð/ from /d/. Applications of these findings may lie in areas of automatic speech recognition, speech transcription, and development of acoustic measures for speech disorder diagnosis. / by Sherry Y. Zhao. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2006. / Includes bibliographical references. / In 1992, Accelerated Approval, or Subpart H approval, was added to the NDA regulations so promising products that provide a meaningful therapeutic benefit for serious or life-threatening diseases could be introduced to the market sooner, particularly for diseases or conditions where there was a great unmet medical need. Accelerated Approval is based on either a surrogate endpoint that is reasonably likely to predict clinical benefit or a clinical endpoint other than survival or irreversible morbidity. After approval, the sponsor is required to perform post-marketing studies to demonstrate clinical benefit. Since the FDA expanded the use of the Accelerated Approval regulatory path to include oncology drugs in 1995, thirty drugs (both small molecule as well as biologics) have been granted accelerated approval in oncology. However, from various reports in the literature and the FDA site, it appears that only a small fraction of these approvals (four to six) have been converted into regular approvals, based on the demonstration of clinical benefit in the post-marketing studies that support the benefit seen in the pivotal studies. / (cont.) In my research, I examined the basis of approval for six drugs that were converted to full approval and compared this group to the seven drugs that received accelerated approval before 2000 but as yet have not converted to full approval. The six drugs that were converted to full approval, with the exception of dexrazoxane, completed their post-marketing requirements in 2.3 years after initial approval. The sponsors, who were all well-capitalized pharmaceutical companies, also pursued additional indications for these drugs. In the group of drugs that were designated as "not converted" by several sources, two of the drugs have been granted full approval within the past year. And in March 2006, the FDA withdrew its accelerated approval for one drug based on the results of a negative clinical trial. Six years after having received accelerated approval, two drugs in this group are still undergoing clinical trials. Due to the lack of information about the ongoing trials, it is difficult to assess the underlying reasons for the delay in attaining full approval. But the sponsors of these two drugs are small biotechnology companies, while all of the sponsors of the drugs that have been converted to full approval are major pharmaceutical companies. / (cont.) A majority of the drugs that converted to full approval were granted a broader label based on the post-marketing studies, which demonstrated clinical benefit in a wider patient population than originally tested. While the accelerated approval process holds many advantages in that companies can introduce their drug to the market sooner, the requirements for accelerated approval often result in the drugs having to meet 'a higher standard' in that they have to demonstrate "meaningful clinical benefit" over existing agents, which may in fact be a requirement for superiority, as was seen in the case of one agent, Doxil. The post-marketing studies can be expensive and difficult to complete, but companies with ample resources and sufficient incentives, such as additional potential indications, seem able to clear this hurdle easily. / by Jean Jinsun Kim. / S.M.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2005. / Includes bibliographical references (leaves 19-20). / Merging of clinical systems and medical databases, or aggregation of information from disparate databases, frequently requires a process where vocabularies are compared and similar concepts are mapped. Using a normalization phase followed by a novel alignment stage inspired by DNA sequence alignment methods, automated lexical mapping can map terms from various databases to standard vocabularies such as UMLS (Unified Medical Language System) and SNOMED (the Systematized Nomenclature of Medicine). This automated lexical mapping was evaluated using a real-world database of consultation letters from Children's Hospital Boston. The first phase involved extracting the reason for referral from the consultation letters. The reasons for referral were then mapped to SNOMED. The alignment algorithm was able to map 72% of equivalent concepts through lexical mapping alone. Lexical mapping can facilitate the integration of data from diverse sources and decrease the time and cost required for manual mapping and integration of clinical systems and medical databases. / by Jennifer Y. Sun. / S.M.

Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, 2017. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 145-162). / Alzheimer's disease (AD) is a neurodegenerative disease for which there are no preventative or therapeutic interventions. It is currently understood to be linked to the accumulation of pathologic proteins in the brain. In the past several decades, a strong body of evidence has accumulated that is suggestive of a vascular-related pathway in AD. A deeper understanding of this phenomenon is critical in advancing our understanding of the AD biological process as well and may lead to the discovery of novel therapeutic targets. A common age-related change in the brain is the development of white matter signal abnormalities (WMSA) as seen on magnetic resonance imaging (MRI). These lesions are related to cognitive function and are thought to be due to compromised integrity of the brain's vascular system. Despite evidence that WMSA are known to influence the clinical progression of AD, we do not currently view AD as a vascular disease nor do we use WMSA as a clinical indicator of AD. This is because we still do not know whether or not WMSA are a distinct phenomenon in AD, their relationship to traditional AD biomarkers, and how they independently contribute to clinical status. In this work, we examine if and how WMSA are related to AD conversion, whether they differ in their spatial distribution between typical aging and AD, and how they are linked to classic pathologic markers of AD. This work also includes technical development for WMSA quantification and baseline studies of WMSA in cognitively healthy aging. The main findings of this work suggest that WMSA are distinctly different in AD than in typical aging and have a unique role in AD progression. This not only motivates the utility of WMSA in our clinical treatment of AD, but also provides insight into the biological underpinnings of the disease process that may lead to novel therapeutic targets. / by Emily Rose Lindemer. / Ph. D.