Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2005. / Includes bibliographical references (v. 2, leaves 192-205). / Thrombosis is an initiating response to vascular injury. Physiologically, this process aids in the repair and remodeling of the vessel wall. However, if left unchecked, luminal occlusion may rapidly occur. The coronary vascular bed is a life-sustaining environment in which pathological thrombosis can lead to devastating outcomes such as acute coronary syndromes or post-interventional thrombosis. In order to study these coronary thrombotic reactions, it is essential to consider the physical environment in which they occur. We have developed an in vitro method for creating pulsatile flows to mimic the coronary hernodynamic setting on a beat-to-beat basis. Furthermore, he have developed techniques and protocols to parametrically vary both the biological and physical aspects of thrombosis and in doing so, have investigated the effects of real-world temporal and spatial flow perturbations on local site platelet adhesion. Not only do such variations create quantitative differences in local reactions, but qualitative differences as well as various receptors must interact to create stable adhesions in a given hemodynamic environments. These findings have implications on the propensity for certain individuals to form clot under certain conditions, as well as the environment-dependent efficacy of various clinically relevant anti-thrombotic strategies. / by Kumaran Kolandaivelu. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2006. / Includes bibliographical references (p. 136-148). / Arterial remodeling is a major pathophysiological mechanism underlying clinical cardiovascular disorders such as hypertension, atherosclerosis and restenosis. We examined heparan sulfate proteoglycan homeostasis as a mechanism of regulation of arterial vascular remodeling in response to altered mechanical environments such as hypertension and injury. We first studied the effect of in-vitro mechanical strain on the ability of endothelial cells to inhibit vascular smooth muscle cell proliferation. Under these conditions we found mechanical strain increased endothelial inhibition of smooth muscle cell proliferation through increased production of heparan sulfate proteoglycans. Using inhibitors to p38 MAPK and ERK, we showed that activation of both of these pathways was essential for load-induced heparan sulfate production, TGF-,f1 activation, smad-2 activation and increased FGF-2 uptake. Further, we exposed cells to strain in the presence of a neutralizing antibody to TGF-P 1 and demonstrated that autocrine TGF-1l signaling was essential for load-induced HSPG production and sustained p38 MAPK and ERK activation. / (cont.) We also examined the endothelium of spontaneously hypertensive rats using immunohistochemical staining for heparan sulfate proteoglycan core proteins, TGF-31 and phosphorylated signaling intermediates and found results that correlated well with our in-vitro experiments. Taken together these results imply a novel paradigm of vascular remodeling to mechanical stimuli in which net arterial remodeling is controlled by the dynamic interplay between pro-growth signals from vascular smooth muscle cells and anti-growth signals from endothelial cells. In a second portion of this work, we examined the role of heparanase in vascular remodeling. Using siRNA gene silencing and overexpression techniques, we showed that alterations in heparanase expression lead to a profound modulation in endothelial inhibition of vascular smooth muscle cell proliferation. In vivo, we quantified heparanase expression in animal models of hypertension, vascular disease and injury. Immunohistochemical analysis of the aortae of hypertensive rats revealed an increase in endothelial production of heparanase that strongly correlated with increased aortic structural remodeling. / (cont.) Studies of vascular injury with stenting in the Zucker rat model of diabetes showed a relationship between neointimal heparanase expression and lesion thickness. Our results define a new role for heparanase as a key molecular controller of vascular remodeling in diverse disease states. / by Aaron B. Blair. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2010. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 69-71). / The history of private philanthropy in the US has been dominated by family foundations with arms-length philanthropy practices that largely existed in separation from commercial enterprise and business operations. This paper looks at emerging organizational and funding models being used in a wide range of disease areas in which philanthropy has shifted towards a more "venture-oriented" model sometimes referred to as disease foundation venture philanthropy (DFVP) as practiced by disease focused foundations (DFFs). More specifically, this research seeks to understand how these models map onto the range of translational challenges confronted by those engaged in bringing ideas from the bench to the bedside and it explores our current understanding of DFVP best practices. It concludes by raising questions and addressing issues designed to assist those who seek to setup successful collaborations between DFFs and industry partners. / S.M.

Includes bibliographical references (leaves 87-89). / Thesis (M. Eng.)--Harvard-MIT Division of Health Sciences and Technology, 2007. / (cont.) The EWS models were then tested in a forward, casual manner on a random cohort of 500 ICU patients to mimic the patients' stay in the unit. The model with the highest performance achieved a sensitivity of 0.85 and a positive predictive value (PPV) of 0.70. Of the 35 episodes of hypotension despite fluid resuscitation present in the random patient dataset, the model provided early warnings for 29 episodes with a mean early warning time of 582 ± 355 minutes. / Early goal-directed therapy (EGDT) in severe sepsis and septic shock has shown to provide substantial benefits in patient outcomes. However, these preventive therapeutic interventions are contingent upon an early detection or suspicion of the underlying septic etiology. Detection of sepsis in the early stages can be difficult, as the initial pathogenesis can occur while the patient is still displaying normal vital signs. This study focuses on developing an early warning system (EWS) to provide clinicians with a forewarning of an impending hypotensive crisis-thus allowing for EGDT intervention. Research was completed in three main stages: (1) generating an annotated septic shock dataset, (2) constructing multivariate logistic regression EWS models using the annotated dataset, and (3) testing the EWS models in a forward, causal manner on a random cohort of patients to simulate performance in a real-life ICU setting. The annotated septic shock dataset was created using the Multi-parameter Intelligent Monitoring for Intensive Care II (MIMIC II) database. Automated pre-annotations were generated using search criteria designed to identify two patient types: (1) sepsis patients who do not progress to septic shock, and (2) sepsis patient who progress to septic shock. Currently, manual review by expert clinicians to verify the pre-annotations has not been completed. Six separate EWS models were constructed using the annotated septic shock dataset. The multivariate logistic regression EWS models were trained to differentiate between 107 high-risk sepsis patients of whom 39 experienced a hypotensive crisis and 68 who remained stable. The models were tested using 7-fold cross validation; the mean area under the receiver operating characteristic (ROC) curve for the best model was 0.940 ± 0.038. / by Dewang Shavdia. / M.Eng.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2009. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 165-180). / Vocal hyperfunction refers to "conditions of abuse and/or misuse of the vocal mechanism due to excessive and/or 'imbalanced' muscular forces" (Hillman, Holmberg, Perkell, Walsh, & Vaughan, 1989), characterized by excessive laryngeal and paralaryngeal tension (Aronson, 1980; M. D. Morrison, Rammage, Belisle, Pullan, & Nichol, 1983; N. Roy, Ford, & Bless, 1996). There is no widely accepted diagnostic measure of the presence and degree of vocal hyperfunction, and currently, assessment during diagnosis is often primarily based on subjective impressions given the patient's history and presentation of symptoms such as auditory-perceptual and visual or tactile discrimination of muscle tension (e.g., laryngeal palpation). Clinical care is hindered by the lack of a "gold standard" objective measure for the assessment of vocal hyperfunction. The first study in this thesis evaluated a novel experimental design for the study of vocal hyperfunction, making use of the established clinical procedure of injection laryngoplasty. This work found that the use of injection laryngoplasty as a platform for the study of some types of vocal hyperfunction is limited, but may offer a convenient opportunity to study selected associated parameters. Particular promising objective measures were investigated in the remaining four studies: kinematics of the vocal folds, root-mean-squared (RMS) measures of surface electromyography (sEMG), and spectral characteristics of sEMG. Kinematic features of vocal fold abduction and adduction were shown to discriminate between individuals with muscle tension dysphonia and controls. / (cont.) RMS measures of sEMG were investigated through correlation with current clinical neck palpation techniques in voice therapy patients and via a cross-sectional study of individuals with vocal fold nodules. Correlations between RMS neck sEMG and palpation ratings were low, and although some individuals with nodules displayed RMS neck sEMG patterns that were inconsistent with those seen in controls, overall the RMS measures were unable to discriminate between disordered and control groups. Mean coherence between two neck sEMG locations in individuals with vocal nodules was significantly lower in the 15 - 35 Hz band relative to controls, possibly agreeing with past subjective accounts of "imbalanced" muscle activity. / by Cara Elizabeth Stepp. / Ph.D.

Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, 2015. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 269-287). / Telehealth technologies are being employed to increase access, quality of care, and cost containment. However, there are no widely accepted measures of telehealth performance and little information about long-term changes in access. The Veterans Health Administration (VHA) is advantageous for telehealth research because of the widespread implementation, organic development of multiple distinctively structured programs, and national electronic medical records. Using teledermatology, one of the earliest and most widely adopted uses, a set of recommended performance metrics are established and a select few are evaluated across the different programs. Store and forward (SF) teledermatology, taking a picture and sending it to a dermatologist for asynchronous evaluation, is the prominent method of care. In SF programs there is variation in the level of follow-up care available locally. Some locations have "surrogate dermatology providers" that are trained to do basic treatments and procedures. Based on four site visits and twenty-five interviews with stakeholders, recommendations for performance measurements were created. VHA is already in the process of executing three of the measures nationally: image quality, time to consult response, and patient satisfaction. Additionally, VHA has the data available to measure time to treatment, post-teledermatology utilization of care, travel distance, and wait-times. Finally, VHA should improve data to create future metrics regarding: cost, particularly payment for outside dermatologists; provider satisfaction; and quality of care through chart review or adverse event reporting. Using administrative databases, the metrics for which data were available were retrospectively evaluated. At a national level for 2013, entry into the care process through teledermatology is associated with faster time to treatment than entry from an in-person referral for both melanoma (teledermatology median: 62 days; in-person consult median: 70 days; p=0.002) and non-melanoma skin cancer (teledermatology median: 79 days; in-person consult median: 88 days; p<0.001). There was little consistency in the post-teledermatology care utilized across programs. Testing three programs with different resources used for local follow-up care, travel distance saved over 2013 was calculated. The program with surrogate dermatology providers had the most travel saved per patient. Implementation of teledermatology had no statistically significant impact on in-person wait times for dermatology clinics. / by Ashley Mateus. / Ph. D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, September 2011. / "August, 2011." Vita. Cataloged from PDF version of thesis. / Includes bibliographical references. / One of the primary functions of the human auditory system is to separate the complex mixture of sound arriving at the ears into neural representations of individual sound sources. This function is thought to be crucial for survival and communication in noisy settings, and allows listeners to selectively and dynamically attend to a sound source of interest while suppressing irrelevant information. How the brain works to perceptually organize the acoustic environment remains unclear despite the multitude of recent studies utilizing microelectrode recordings in experimental animals or non-invasive human neuroimaging. In particular, the role that brain areas outside the auditory cortex might play is, comparatively, vastly understudied. The experiments described in this thesis combined classic behavioral paradigms with electrical recordings made directly from the cortical surface of neurosurgical patients undergoing clinically-indicated invasive monitoring for localization of epileptogenic foci. By sampling from widespread brain areas with high temporal resolution while participants simultaneously engaged in streaming and jittered multi-tone masking paradigms, the present experiments sought to overcome limitations inherent in previous work, namely sampling extent, resolution in time and space, and direct knowledge of the perceptual experience of the listener. In experiment 1, participants listened to sequences of tones alternating in frequency (i.e., ABA-) and indicated whether they perceived the tones as grouped ("1 stream") or segregated ("2 streams"). As has been reported in neurologically-normal listeners since the 1950s, patients heard the sequences as grouped when the frequency separation between the A and B tones was small and segregated when it was large. Evoked potentials from widespread brain areas showed amplitude correlations with frequency separation but surprisingly did not differ based solely on perceptual organization in the absence of changes in the stimuli. In experiment 2, participants listened to sequences of jittered multi-tone masking stimuli on which a regularly-repeating target stream of tones was sometimes superimposed and indicated when they heard the target stream. Target detectability, as indexed behaviorally, increased throughout the course of each sequence. Evoked potentials and high-gamma activity differed strongly based on the listener's subjective perception of the target tones. These results extend and constrain theories of how the brain subserves auditory perceptual organization and suggests several new avenues of research for understanding the neural mechanisms underlying this critical function. / by Andrew R. Dykstra. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2007. / Includes bibliographical references (p. 133-141). / Inquiry into intracellular and cytoskeletal mechanics requires an intracellular mechanical sensor to verify models of sub-cellular structure dynamics. To this end, the green fluorescent protein (GFP) is considered as a mechanical sensor candidate with many desirable characteristics. Implicit solvent molecular dynamics CHARMM simulations demonstrated details inaccessible by AFM and OT methods, such as the linkage dependency of fluorophore environment changes and the energy exchanges between protein components during protein unfolding. Theoretical considerations and in vitro experiments explored the parameters important to GFP conjugation by N-hydroxysuccinimide (NHS) ester chemistry, and the complexities associated with a polymer approach to a controlled distribution of force across fluorescent proteins in a polyacrylamide (PAM) gel. / by Taro M. Muso. / S.M.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2009. / Cataloged from PDF version of thesis. / Includes bibliographical references. / Early enthusiasm over angiogenic therapy, a method to induce vascular regeneration to treat ischemic tissue with growth factors, has been tempered by a series of unsuccessful clinical trials with limited late efficacy and a wide range of mixed results. This thesis was designed to examine critically whether the lack of late efficacy of local delivery of angiogenic factors could be explained by a comprehensive understanding of local pharmacokinetics (PK) and pharmacodynamics (PD) in the myocardial tissue. Our central hypothesis is that early success at inducing vessel growth powerfully self-regulates angiogenic therapies by dynamically altering local tissue pharmacokinetic properties and hinders long-term efficacy. We used a multipronged approach to investigate this hypothesis. We characterized the baseline local myocardial PK through a series of ex-vivo isolated heart studies and mathematical analysis, examined the local coupling of PK and PD with an in-vivo ischemic heart model, created a computational model of myocardial PK and PD to predict distribution of growth factors and their biologic effects, discussed implications and future studies. Our findings suggest that microvascular washout impedes myocardial drug transport, early angiogenic response further exacerbates drug washout and is likely responsible for late vessel regression, modulating drug PK properties to mitigate drug clearance through washout can enhance late tissue response. These results imply that local PK-PD interdependence should be carefully examined to improve clinical efficacy of angiogenic therapy with local angiogenic growth factor delivery. / by Kha N. Le. / Ph.D.

Thesis: S.M., Harvard-MIT Program in Health Sciences and Technology, 2015. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 137-171). / The goal of this work was to characterize the maturational trajectory of two core developmental language functions: phonological working memory (PWM) as indexed on nonword repetition (NWR) tasks, and finiteness-related grammatical processing, as indexed by grammaticality judgment. These fundamental language abilities make particularly alluring candidates for investigation due to their central role in language development and academic achievement as well as their theoretical basis. Moreover, PWM and finiteness-marking appear to have genetic bases (e.g., Bishop, Adams, & Norbury, 2006) are powerful markers of language impairment (Conti-Ramsden, Botting, & Faragher, 2001), highlighting the clinical significance of these abilities. PWM, the capacity to temporarily store and flexibly operate on units of auditory information in the service of a goal, is a developmental ability central to language acquisition. As assessed using NWR tasks, PWM has been shown to be instrumental for the development of both spoken and written language (e.g., Baddeley, Gathercole, & Papagano, 1998), and weaknesses in this system are not only associated with problems of language and literacy but are a common correlate of communication deficits in a number of developmental disorders. Despite their demonstrated clinical and theoretical significance, however, there is a surprising paucity of studies examining NWR in a wide, continuous age range including childhood and young adulthood. In the current work, we administered several assessments of NWR to a wide sample of typically-developing children and adults age 5-35 in order to discover the shape of the developmental trajectory of this skill and the age at which proficient levels of performance are achieved. Across several measures varying in the nature and length of the stimuli, the maturational trajectory of NWR was characterized by rapid growth for younger ages which sharply transitions to relatively stable levels. The transitional age between mature and immature performance was found to lie in the 8-11 year old age range, suggesting that NWR ability develops over the later elementary school years. Consistent with prior work, the effect of stimulus length was greater in younger participants, and the tasks involving stimuli which do not resemble real English words were found to be more challenging for all ages than those involving wordlike stimuli. The ability to appropriately mark tense on verbs is also crucial to language development. Children in the Optional Infinitive (01) stage of language acquisition interchangeably use finite (marked for tense and agreement) and non-finite (infinitival) verb forms in clauses requiring finiteness; likewise, both finite and non-finite forms are accepted as grammatically correct in clauses mandating the finite form. Although appropriate use of finiteness has previously been thought to be in place by the time children enter formal schooling (Rice & Wexler, 1996), our recent work (Kovelman et al., 2014) challenged this notion, as linguistically-proficient adults found sentences containing finiteness errors more difficult to process than sentences containing non-developmental agreement errors or grammatically correct sentences. As yet, no one has examined the continuous progression of 01-related processing from early childhood to adulthood using a receptive (or any) measure. In order to discover the shape of the maturational trajectory of finiteness processing and the age at which proficient performance is achieved, in the current work, we administered a grammaticality judgment task involving sentences with developmental errors of finiteness and control grammatical errors to a large sample of typically developing participants age 5-35. Similar to the case of NWR, the shape of the maturational trajectory of finiteness was marked by initially rapid growth transitioning to stable performance. Not only were sentences with errors of finiteness found to be more difficult than those with non-developmental errors, but this condition was characterized by slower developmental growth and an older transition to mature performance than other conditions. Adult-like levels of performance on sentences with finiteness errors were achieved around age 8, suggesting a more protracted developmental course for this ability than previously believed (c.f. Rice, Wexler, & Hershberger, 1998). Taken together, it is hoped that this work will increase our understanding of the developmental trajectories of finiteness-based grammatical processing and PWM. We hope this work will impact early identification of weaknesses in these systems such that appropriate interventions can be implemented. / by Irina Ostrovskaya. / S.M.