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.

Thesis: Ph. D. in Biomedical Engineering, Harvard-MIT Program in Health Sciences and Technology, 2017. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 113-120). / Cancer is one of leading cause of deaths, and responsible for 8.2 million deaths worldwide. Especially, 70% of deaths from cancer occur in low or mid income countries. In order to deliver affordable and accessible cancer care to low income developing countries, it is critical to develop rapid, low cost, and highly accurate tools for cancer detection and treatment. Recently, liquid biopsy and circulating cancer biomarkers such as circulating tumor cells (CTC), extracellular vesicles (EV), and cell free DNA (cfDNA) have gained great attentions for early diagnosis, prognosis, and treatment monitoring of cancer patients because they can be accessed in less invasive approaches through body fluids while providing quantitative information about original tumors at low cost. To facilitate detection of circulating cancer biomarkers, we developed electromagnetic biosensing systems for rapid and quantitative molecular analysis. First, we report portable nuclear magnetic resonance (NMR) system that detects cancer cells or proteins labelled with magnetic nanoparticles (MNPs). The developed NMR system could detect as low as 20 cancer cells in 5 uL samples. Second, we describe micro-Hall magnetometer that molecularly profiles single cancer cell with magnetic multiplexing. The micro-Hall magnetometer, which consisted of an array of 7 um x 7 um Hall sensors, showed its capability to differentiate magnetic particles with distinct magnetic moments. We applied this technology to molecular profiling of single ovarian cancer cell. Last, we introduce wirelessly powered electrochemical system that detect cancer specific EV and DNA. Using immuno-magnetic sandwich assay, we could enrich almost 100% of EVs from clinical specimens without ultracentrifugation and profile cancer specific transmembrane proteins from as low as 105 EVs. Also, we demonstrated PCR-free detection of single stranded DNA with in-vitro protein synthesis assay. These electromagnetic biosensors will be powerful tools to deliver more accessible and affordable cancer care to resource limited areas in developing countries. / by Changwook Min. / Ph. D. in Biomedical Engineering

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2011. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 96-98). / Understanding the true incidence and prevalence of a disease has tremendous value for the biopharmaceutical industry, particularly for orphan diseases that affect a minority of the population (in the US, the definition of orphan disease is a disorder that must affect less than 200,000 people, or 1 in 1,500). However, incidence and prevalence data for orphan diseases in scientific literature is poorly studied, inconsistent, numbers range widely and articles often contain poorly supported citations. Additionally, once a treatment is available and disease awareness increases, there may be an increase in reported disease prevalence, as patients proactively seek treatment from their healthcare providers. The goal of this research is to investigate the incidence of X-linked Hypohidrotic Ectodermal Dysplasia (XLHED) and provide a framework for investigators to study the incidence and prevalence of other rare diseases. Specific research objectives include: 1) Develop a clinical phenotype to identify XLHED patients in medical records and/or claims data 2) Analyze patient registry data to identify characteristics that are unique to XLHED and distinguish XLHED from other ectodermal dysplasias 3) Develop a robust search algorithm to accurately identify XLHED patients in claims databases By performing a thorough literature review, and an analysis of the National Foundation for Ectodermal Dysplasias (NFED) patient registry, I was able to meet the first two research objectives. After analyzing the medical record and claims data at two major academic medical centers, we were only able to identify 25 total patients, 19 of whom had associated claims data, to include in our patient cohort. Since this number was too small of a base from which to develop an identification algorithm as originally planned, I instead analyzed descriptive statistics of their claims data in order to better understand how these patients flow through the healthcare system, and what identification criteria might be valuable for an investigator studying a larger patient population in the future. Further studies using different combinations of claims and/or narrative data to more accurately identify HED patients and therefore increase the sample size of future analyses are recommended to continue this epidemiological research and provide new insights into the diagnosis and treatment patterns of XLHED. / by Julie Hermann. / S.M.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, February 2006. / "December 2005." / Includes bibliographical references. / The prevalence of severe to profound bilateral congenital hearing loss is estimated at 1 in 1000 births, at least half of which can be attributed to a genetic cause. To date, mutations in at least 67 genes have been associated with hearing loss. Discovery of these genes has revealed fundamental processes within the ear, and enabled diagnosis and implementation of genetic counseling in affected patients. As a part of the continuing effort to study genes important for hearing and deafness, a novel cochlear transcript with predominantly fetal expression containing a single tetramerization domain (PFET1, HUGO-approved symbol KCTD]2) was identified from the Morton fetal cochlear cDNA library. KCTD12/Kctd]2 is an evolutionarily conserved intronless gene encoding a 6 kb transcript in human and three transcripts of approximately 4, 4.5 and 6 kb in mouse. The protein, pfetin, is predicted to contain a voltage-gated potassium channel tetramerization (T1) domain. This thesis reports characterization of this novel human gene and its encoded protein pfetin in relation to its role in auditory function. Experimental data from tissue and cellular expression profiling, and genetic and functional analyses suggests KCTD12 and its orthologs playing a crucial role in the developmental of the auditory sense organ. / by Sharon Fan Kuo. / Ph.D.

Thesis (S.M.)--Harvard-MIT Program in Health Sciences and Technology, 2012. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 60-64). / Hepatitis C (HCV) is the most common bloodborne infection in the United States. Although the incidence of HCV is declining, the burden of the disease is rising, driven by the increasing rates of end-stage liver disease and other consequences of advanced HCV infection. According to a 2009 report, the number of patients with advanced liver disease will quadruple over the next 20 years; in that time, total medical costs for patients with HCV infection are expected nearly to triple, from $30 billion to more than $85 billion. Given the limitations of current treatments and diagnostic technologies, HCV often goes undiagnosed and/or untreated. With new therapies in the pipeline that offer the promise of increased efficacy and improved side effect profiles, there likely will be a demand for improved diagnostics to more quickly and accurately identify patients in need of treatment. Daktari Diagnostics, Inc., based in Cambridge, Massachusetts, is developing a point-of-care, microfluidic diagnostic system that could be used both to diagnose HCV patients and to monitor treatment response. This thesis hypothesizes that Daktari's HCV diagnostic system can generate revenue in the United States, given the dynamics of the market. To explore this hypothesis, a background on the current diagnostic and treatment standards in HCV is presented, followed by an analysis of diagnostics and treatments currently in development. The thesis then defines the current paradigm of HCV testing and treatment and explores one potential future paradigm. Finally, a model of the HCV diagnostic market from 2012- 2019 is generated. This model demonstrates that, under conservative assumptions, the Daktari diagnostic system could generate a minimum of $25MM in revenue in the United States over its first five years on the market, from 2015-2019. / by Charlotte Rocker. / S.M.

Thesis (Ph. D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, 2002. / Includes bibliographical references. / by Scott DeWitt Packard. / Ph.D.