Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2004. / Includes bibliographical references (p. 38-39). / The task of gathering detailed patient information from narrative clinical text presents a significant barrier to clinical research. A prototype information extraction system was developed to extract pre-specified findings from narrative echocardiogram reports. The system which uses a Unified Medical Language System compatible architecture is very simple and takes advantage of canonical language use patterns to identify sentence templates with which concepts and their values can be identified. The data extracted from this system will be used to enrich an existing database used by clinical researchers in a large university healthcare system to identify potential research candidates fulfilling clinical inclusion criteria. The system was developed and evaluated using ten pre-determined clinical concepts. Concept-value pairs extracted by the system related to these ten conditions were compared with findings extracted manually by the author. The system was able to recall 78% of the relevant findings (CI, 76% to 80%), with a precision of 99% (CI, 98%-99%). Because data acquired from the system will ultimately be used in document and patient retrieval, preliminary analysis was done to evaluate document retrieval effectiveness. Median recall across the ten conditions was 36% (range, 0% to 93%). The system retrieved no documents for two of the ten conditions; median precision for the remaining eight conditions was 100% (range, 92% to 100%). / by Jeanhee Chung. / S.M.

Thesis (Ph.D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, 1999. / Includes bibliographical references. / Age-related vertebral fractures are a common public health problem for the elderly with an estimated 27 percent of U.S. women aged 65 years and over thought to have at least one vertebral fracture. It is important, therefore, to characterize the "at risk" patient and to find methods of reducing that risk. Fracture risk has been defined as the ratio of applied loads to the force required to fracture a bone. Although studies have examined the force required to fracture, few studies have tried to assess the applied loads associated with fractures. Epidemiological studies have found that as many as 30 to 50 percent of vertebral fractures are associated with falls. This work examines the forces on the spine during a backward fall. Models of a passive fall, without tension in the torso musculature, were constructed in order to examine the peak axial forces on the spine as a result of a passive fall. Muscle tension elements were added to examine the effect of pre-compression of the spine by the musculature. Three experimental and observational studies were performed to examine the input parameters of these models. This included an experimental measurement of the stiffness and damping of the spine segments, measurement and modeling of the fall dynamics in a backward fall, and measurement of the geometry of the torso musculature. The peak axial forces on the spine were found to range from 1100 Newtons to 3500 Newtons depending on a number of factors including the fall impact dynamics (fall velocity and torso angle), the body weight of the individual, the properties of the soft tissue of the pelvis and spine, and the amount of muscle tension in the torso musculature. These forces can be compared to a mean compressive failure force around 2000 N in elderly thoracolumbar vertebrae. This puts a portion of the elderly population at risk for a fracture simply from an upright passive fall of average velocity. The highest forces were found in upright, fast falls in which the individual had a high upper body weight and very tense torso musculature and little damping in the spine. / by Sara E. Wilson. / Ph.D.

Thesis (Ph.D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, 2000. / Includes bibliographical references (p. 286-290). / by Kelly Lynn Poort. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2010. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 61-64). / Genetic testing companies have come under fire lately for an array of reasons. Many direct-to-consumer outfits are being challenged by the federal regulatory authorities, by the physicians' community and by the public itself. The desire to derive utility from the existing mass of genetic research is only outpaced by the sheer amount of new information being added to our understanding daily. These genetic testing companies are simultaneously trying to apply the existing knowledge, build a base for further study and be credible, going concerns from a business perspective. It is a worthy but difficult objective. The direct-to-consumer genetic initiatives face resistance from physicians who are the traditional intermediaries between medical insight and application of this insight. The companies also face a strong adversary in a government that wants to protect its constituents from fraudulent marketing claims and misinformation. Recent, informal studies have also exposed flaws in the product offerings and delivery of information by these companies. Finally, these are all for-profit entities which are struggling to become profitable. The objective of this thesis is to identify an attractive consumer base and opportunity that would allow for successful deployment of genetic diagnostic capability. I postulate that the success of a direct-to-consumer company would depend on finding a customer that values the genetic insight deeply and is able to take action from such insight. Based on those two fundamental criteria-perceived value and actionable utility-I build a profile of place, person and disease to test my hypothesis. Driven by the findings of my research, I anchored my hypothesis around an Indian consumer who pays for health care out-of-pocket, is vulnerable to certain genetic diseases due to narrow, endogamous customs and has grown up in a culture of arranged marriages. If this individual's religious and moral code forbids early termination of pregnancy or if financial and logistical circumstances make abortion impossible, I posit the desire for this cohort to use pre-marital genetic testing will increase. My research showed that people born in India and people who had considered arranged marriage as a viable option (the two groups overlapped but not completely) did display a greater likelihood of using genetic tests at the pre-marital and pre-natal stage to make informed decisions about family planning. These groups also showed a greater inclination towards early termination of pregnancy as well as reconsidering partner choice based on the outcome of genetic testing. However, the data also showed that those groups that did not believe in abortion still did not preferentially want a pre-marital genetic test. / by Ridhi Tariyal. / S.M.

Thesis: S.M., Harvard-MIT Program in Health Sciences and Technology, 2015. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 75-76). / While much is known about the process of how airborne sound is conducted to the inner-ear via the outer ear and middle ear, so-called air conduction (AC), the mechanisms by which vibrations of the head and body, so-called bone conduction (BC), produce an auditory response are not well understood. It is clear that the inner ear is the sensory site of auditory stimulation by bone conduction, and that the resultant activation of the inner ear has many features in common with air-conduction stimulation; however, bone conduction is known to stimulate the inner ear through multiple pathways. The relative significance and frequency dependence of these different pathways have not been well defined. Our previous work on bone conduction in chinchillas suggested inner-ear mechanisms are the dominant sources in BC. This thesis builds upon the early work by investigating inner ear mechanisms with stapes fixation and ear canal occlusion. Results of stapes fixation show a decrease in scala vestibuli sound pressure Psv and little change in scala tympani sound pressure PST in bone conduction. Ear canal occlusion produces an increase in ear canal sound pressure PEC with a similar amount of increase in Psv, but almost no change in Pst. We attributed the differences in the change between Psv and PST in bone conduction after these manipulations to the existence of compressible cochlear structures or third window pathways, e.g. the cochlear aqueduct. While ear canal compression and middle ear inertia sources may contribute to the total bone conduction response (a 10 dB decrease in Psv after middle ear interruption and stapes fixation, and a 10 dB increase after ear canal occlusion), inner ear mechanisms are still the most significant sources in bone conduction because the changes in Psv and Pst in BC are much smaller than the changes in AC. / by David Chhan. / S.M.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2007. / This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. / Includes bibliographical references (p. 162-170). / To achieve any motor behavior, the central nervous system (CNS) must coordinate the many degrees of freedom in the musculoskeletal apparatus. It has been suggested that the CNS simplifies this formidable task of coordination by grouping multiple muscles together into units of activation, or muscle synergies. Previous studies have shown that electromyogram (EMG) signals collected from many muscles during natural behaviors can be reconstructed by linearly combining a few synergies, identified by the non-negative matrix factorization algorithm. But to what extent synergies are neural constraints, or merely structures reflecting experimental constraints, has remained an open question. I address this question with the hypothesis that, muscle synergies are robust neural patterns constraining motor outputs. The strategy adopted was that of analyzing EMGs collected before and after delivery of a perturbation to the motor system. In my first experiment, EMGs from bullfrog muscles were recorded during locomotor behaviors before and after deafferentation. Systematic comparison of intact and deafferented synergies suggests that most of the synergies remained unchanged after afferent removal. / (cont.) In my second experiment, the frog hindlimb was perturbed by either an inertial load or an elastic load. Using a novel algorithm capable of simultaneously extracting shared and specific synergies, I demonstrate that, most synergies were shared between the different conditions, but their activation patterns were reversibly altered by loading. Overall, my results suggest that muscle synergies are robust, centrally organized structures, and descending and afferent signals cooperate in modulating their activations so that the resulting motor commands can be efficiently adapted to the external environment. / by Vincent Chi-Kwan Cheung. / Ph.D.

Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, 2014. / Cataloged from PDF version of thesis. / Includes bibliographical references. / This work investigated the utility of reflectance (R), a measure of middle-ear mobility, in the differential diagnosis of pathologies responsible for conductive hearing loss (CHL). Current clinical practice cannot distinguish the multiple pathologies that produce conductive hearing loss in patients with an intact tympanic membrane and a well-aerated middle ear. The lack of a more effective non-surgical diagnostic procedure leads to unnecessary surgery and limits the accuracy of information available during pre-surgical consultations with the patient. A noninvasive measurement to determine the pathology responsible for a conductive hearing loss prior to surgery would be of great value. This work focuses on determining whether a non-invasive diagnostic method, R, is a possible solution to this problem. Reflectance is a measure of the amount of sound that is reflected back when a sound stimulus is played in the ear canal. Measurements of R were made in a large number of patients who had a variety of pathologies that cause CHL including ossicular fixations, disarticulations, and third window disorders in order to explore the clinical utility of R measurements in differentiating these pathologies. Measurements of ossicular motion using laser Doppler vibrometry were also made in the same patients in order to compare the diagnostic utility of this well studied method to that of R. Using this patient information, multiple diagnostic uses and possibilities were explored, which showed the pre-surgical diagnoses of various pathologies. In order to investigate the effects of these pathologies in a controlled and systematic way, R and other metrics of middle-ear performance were also measured in human temporal bone preparations with simulated pathologies similar to those in the patient populations. Reflectance was also measured up to a higher frequency than had previously been possible using an experimental acoustic reflectance measurement system. We then analyzed the extended frequency measurements in novel ways to determine the effects of pathology on the time-domain characteristics. The high-frequency measurements in temporal bones were then used to explore potentially diagnostically useful computational models of middle-ear mechanical function in normal and pathological ears. / by Gabrielle Ryan Merchant. / Ph. D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2006. / Includes bibliographical references. / The degree of irregularity apparent in the discharge patterns of electrically stimulated auditory-nerve fibers depends upon the stimulation rate. Whereas fibers fire regularly at low stimulation rates, the same fibers fire irregularly at high rates. The irregularity observed at high stimulation rates has been attributed to noise caused by the random open and closing of voltage-gated ion channels. This explanation however is incomplete: an additional mechanism must be operating to account for the different effects of noise at the two stimulation rates. We have identified such an additional rate-dependent mechanism. Specifically, we show in the Fitzhugh-Nagumo (FN) model that the stability to perturbations such as noise depends upon the stimulation rate. At sufficiently high rates a dynamical instability arises that accounts for the main statistical features of the irregular discharge pattern, even in the absence of ongoing physiological noise. In addition, we show that this instability accounts for both the statistical independence exhibited by different fibers in the stimulated population and their sensitivity to amplitude modulations applied to an ongoing stimulus. / (cont.) In cochlear implants, amplitude modulations are used to encode acoustic information such as speech. Psychophysically, sensitivity to small modulations correlates strongly with speech perception, suggesting a critical role for dynamical stability/instability in speech perception. We show that rate-dependent stability/instability occurs in the classical Hodgkin-Huxley model, as well as in biophysical models of the mammalian node of Ranvier. / by David E. O'Gorman. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2007. / This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. / Includes bibliographical references (p. 155-171). / We routinely produce movements under different mechanical contexts. All interactions with the physical environment, such as swinging a hammer or lifting a carton of milk, alter the forces experienced during movement. With repeated experience, sensorimotor maps are adapted to maintain a high level of movement performance regardless of the mechanical environment. This dissertation explored the contribution of the precentral cortex to this process of motor adaptation. In the first experiment, we recorded precentral neural activity in rhesus monkeys that were trained to perform visually-cued reaching movements while holding on to a robotic manipulandum capable of changing the forces experienced during the task. Preparation and control of the reaching movements were correlated with single cell activity throughout the precentral cortex, including the primary motor cortex and five different premotor areas. Precentral field potential activity was also modulated during the reaching behavior, particularly in the beta and high gamma frequency bands. When novel forces were introduced, single cell activity changed in a manner that specifically compensated for the applied forces and mirrored the time course of behavioral adaptation. / (cont.) Force-related changes were present in the field potential activity as well. Some of these changes were maintained following removal of the forces. Control data and simulations revealed that these residual changes were well described by a model of noisy adaptation in a redundant cortical network. In the second experiment, human subjects performed the same reaching paradigm after receiving transcranial magnetic stimulation to transiently inhibit cortical activity. Initial learning of the novel force environment was normal but recall of the field 24 hours later was impaired relative to controls. Taken together, the results suggest that distributed areas within the precentral cortex are involved in recalibrating sensorimotor maps to fit the present mechanical context and in initiating a memory trace of newly-experienced environments. / by Andrew Garmory Richardson. / Ph.D.

Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, February 2015. / Cataloged from PDF version of thesis. "February 2015." / Includes bibliographical references. / The successes of vaccines in modern medicine diminished the morbidity and mortality of many pathogenic infections. Yet, difficulties remain in improving the immunogenicity of modern subunit vaccines. In addition, isolation of antigen-specific memory B cells that would elucidate the long-term efficacy of vaccines beyond using antibody titers as surrogates has been challenging due to the lack of specific and sensitive detection reagent. We sought to improve the binding and activation of B cells by presenting antigens in a multivalent manner on the surface of liposomes. Motivated by structural requirements originally defined for haptens triggering T-cell-independent stimulation of B cells, we investigated how the mode of antigen presentation, antigen density, particle size, and lipid mobility influence B cell receptor (BCR) crosslinking by multivalent antigen-bearing liposomes, and found that BCR binding is not only a function of antigen density, but also the spacing of antigens on a nanoscale- even for highly multivalent particles. We demonstrated high sensitivity in detecting antigen-specific B cells in vitro, as well as in detecting antigenspecific memory B cells in immunized mice. We first present a novel method of nanoclustering biotinylated antigens conjugated on liposomes with streptavidin, and examine the effect of nanoclustering on BCR binding and B cell response. The mere addition of streptavidin to otherwise 'unclustered' antigens displayed on liposomes increased binding of these particles to antigen-specific B-cells twofold and upregulated activation markers six fold while demonstrating a dose-sparing effect. A three-fold increase in the expression of the activation marker CD86 over soluble tetrameric antigen indicated that surface presentation on liposomes enhances the recognition of nanoclustered antigen by B cells. We then examined how nanoscale organization of antigens influences B cell responses for application to subunit vaccines, using well-defined peptide antigen multimers. Our experiments revealed that B cells bind to and respond to antigens in a valency-dependent manner, with a end-to-end distance spacing of approximately 11.8 nm required between antigens. In vivo immunization experiments demonstrated that higher antigen valencies elicited increased antigen titers and antibody avidity, as well as a responsive memory B cell population that proliferated more rapidly during secondary challenge, indicating a promising strategy for designing subunit vaccines of high immunogenicity. In conclusion, we demonstrated that multivalent presentation of antigens on liposomes enhanced BCR crosslinking and subsequent B cell activation. In addition, we showed that by systematically optimizing the structural requirements of nanoscale antigen organization, we are able to elicit robust B cell responses to low-affinity antigens. / by Chyan Ying Ke. / Ph. D.