As the digitisation of healthcare progresses, there are still problems in terms of usability. With the goal of exploring solutions to these, an email inspired design for an electronic health record system was implemented using modern web technologies. The implementation was then evaluated in a series of usability tests conducted with five orthopaedic surgeons. Participants were asked to perform small tasks on a mocked data set, and the sessions were concluded with debriefing interviews. The focus was on the areas that are new in this design. The results suggest that the general design works, and no critical flaws were identified at this stage. Most of the issues that were found are likely to be solved with more training and experience, but there is still room for improvement. Participants had positive reactions overall, and plenty of feedback was collected regarding areas of improvement and feature suggestions. Due to the limitations of the test, the findings mostly relate to the intuitiveness of the design. To draw stronger conclusions regarding the viability of the design in a real environment, further testing with more data, realistic test tasks and more prerequisite training is necessary. / Digitiseringen inom sjukvården ökar, men det finns fortfarande problem när det kommer till användbarheten av de digitala system som finns på marknaden. Med målet att utforska lösningar på dessa problem implementerades i detta arbete en e-post-inspirerad gränssnittsdesign för ett digitalt journalsystem med hjälp av moderna webb-teknologier. Implementationen utvärderades genom användartester där fem ortopediska kirurger deltog. Deltagarna ombads använda gränssnittet för att utföra små testuppgifter med påhittad patientdata, och sessionerna avslutades med intervjufrågor. Fokuset var på de delar som är nya i den här designen jämfört med redan existerande system. Resultatet visar att det generella upplägget fungerar, och inga kritiska brister upptäcktes i detta stadie. De flesta av problemen som uppdagades kan troligen lösas genom att användarna ges möjlighet till mer träning och får mer erfarenhet, men det finns fortfarande förbättringutrymme. Deltagarna hade positiva reaktioner i allmänhet, och många förslag kring förbättringsområden och önskemål kring utökad funktionalitet samlades upp. På grund av användartestets begränsningar belyser resultaten i detta test mest vilka delar av gränssnittet som är intuitiva eller ej, medan det som är mer intressant för den här typen av dagligen använda system egentligen är huruvida de är effektiva att använda i det dagliga arbetet. För att kunna dra säkrare slutsatser kring om den här designen skulle fungera i riktiga arbetssituationer behövs mer testning med större mängder patientdata, mer realistiska testuppgifter och mer tid för deltagarna att lära sig systemet i förväg.

During this thesis project, an eye-tracking application for medical use was developed for Stardots AB. Stardots AB is a company that develops a digital health platform for Parkinson´s disease and some other neurological conditions based on deep tech mathematical modelling and cloud services. This master thesis application was based on a previous eye-tracking application that was developed by Stardots. The new application contains improvements, new optimizations methodologies, and is build within state-of-the-art frameworks. Additionally, the previous application could handle only the EyeTribe camera; this application works with both EyeTribe and Tobii cameras.

Thesis: Ph. D. in Medical Engineering, Harvard-MIT Program in Health Sciences and Technology, 2018. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 217-226). / The objective of this work was to develop materials for continuous low-dose delivery of cisplatin directly into the abdomen, also known as intraperitoneal (IP) chemotherapy. IP chemotherapy can help treat peritoneal metastasis in many advanced gynecologic and gastrointestinal cancers and has shown particular promise in treating advanced ovarian cancer. It is however tremendously underutilized because it requires a lot of resources and the current technology and maximum tolerated dose regimen cause complications and severe toxicity to patients. We previously showed that continuous low-dose IP cisplatin delivery via an implanted diffusion-based reservoir device can be as effective as and less toxic than intermittent maximum tolerated dose IP injections. To translate this work to a clinically relevant implantable system, we developed composite materials that can deliver cisplatin at a continuous low dose that is tunable. The materials were mechanically well suited for placement in the abdomen and were evaluated for in vitro bioactivity, in vivo tolerability and in vivo ability to deliver platinum to key abdominal organs with promising results. Dosing studies with different material dimensions helped identify a dose to pilot treatment of ovarian cancer in human xenograft-bearing mice. The implications of more accessible and affordable IP chemotherapy are especially important in countries with limited resources. Design reviews and a clinician survey in India reveal eagerness for early adoption of new technologies and dosing regimens to treat peritoneal metastasis and show promise for utilization of our implant in the developing world. The work described in this thesis carries implications for the treatment of advanced ovarian cancer and peritoneal metastasis of other tumors affecting millions of patients worldwide and may help with the management of nonmalignant conditions with abdominal involvement. / by Aikaterini Mantzavinou. / Ph. D. in Medical Engineering

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 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.

Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, February 2015. / Cataloged from PDF version of thesis. "February 2015." / Includes bibliographical references. / In humans, SFOAEs can non-invasively assess MOC strength and, may predict the MOC reduction of damage from traumatic sounds. However, the functionally important MOC effect is inhibition of auditory-nerve (AN) responses. Understanding the relationship between MOC effects on SFOAEs and AN CAPs is important for understanding SFOAE generation and for development of clinical tools that use these measures. This thesis presents several novel data sets that address MOC effects on SFOAEs, CAPs and the relationship between them in guinea pigs. Classic theory indicates that SFOAEs come from cochlear irregularities that coherently reflect energy at the peak of the traveling wave (TW), and that reflected energy arrives in the ear canal as a single wave at certain delay. Contrary to theory, in humans and chinchillas there have been reports of SFOAEs having multiple components with different delays, and that lowfrequency SFOAE delays are too short. The first thesis aim used time-frequency analysis to show that guinea pigs have frequency regions over which SFOAEs appear to have multiple components. However, we argue that the multiple components can be a simple result of variations in the patters of irregularities near the TW peak and are not necessarily indicative of multiple SFAOE sources. From comparison of our SFOAE delays with previously reported neural delays, we hypothesize that short SFOAE delays at low frequencies arise from a cochlear motion with a group delay shorter than the TW group delay. Aim 2 investigated how SFOAEs are affected by brainstem electrical stimulation of MOC fibers and found that MOC activation sometimes inhibited and sometimes enhanced SFOAEs. MOC stimulation always decreased CAP sensitivity which rules out SFOAE enhancement from increased cochlear amplification. We propose that shock-evoked MOC activity increases cochlear irregularity which results in increased SFOAE amplitudes. Aim 3 investigated the relationship between MOC effects on SFOAEs and tone-pip-evoked AN CAPs at same frequency and sound level. The ratio of the MOC effect on the SFOAE to the MOC effect on the CAP showed a highly-significant decrease (p<0.001) as the strength of MOC stimulation was increased. Although this observation was unexpected, several hypothesis to explain it are presented. / by Maria Andrey Berezina. / Ph. D.

Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, 2015. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 86-97). / Human pluripotent stem (hPS) cells have the ability to reproduce indefinitely and differentiate into any cell type of the body, making them a potential source of cells for medical therapy and an ideal system to study fate decisions in early development. However, hPS cells exhibit a high degree of heterogeneity, which may be an obstacle to their clinical translation. Heterogeneity is at least partially induced as an artifact of removing the cells from the embryo and culturing them on a plastic dish. hPS cells grow in spatially patterned colony structures, which necessitates in situ quantitative single-cell image analysis. This dissertation offers a tool for analyzing the spatial population context of hPS cells that integrates automated fluorescent microscopy with an analysis pipeline. It enables high-throughput detection of colonies at low resolution, with single-cellular and sub-cellular analysis at high resolutions, generating seamless in situ maps of single-cellular data organized by colony. We demonstrate the tool's utility by analyzing inter- and intra-colony heterogeneity of hPS cell cycle regulation and pluripotency marker expression. We measured the heterogeneity within individual colonies by analyzing cell cycle as a function of distance. Cells loosely associated with the outside of the colony are more likely to be in G1, reflecting a less pluripotent state, while cells within the first pluripotent layer are more likely to be in G2, possibly reflecting a G2/M block. Our analysis tool can group colony regions into density classes, and cells belonging to those classes have distinct distributions of pluripotency markers and respond differently to DNA damage induction. Our platform also enabled noninvasive texture analysis of live hPS colonies, which was applied to monitoring subtle changes in differentiation state. Lastly, we demonstrate that our pipeline can robustly handle high-content, high-resolution single molecular mRNA FISH data by using novel image processing techniques. Overall, the imaging informatics pipeline presented offers a novel approach to the analysis of hPS cells, which includes not only single cell features but also spatial configuration across multiple length scales. / by Bryan Robert Gorman. / Ph. D.

Thesis: Ph. D. in Medical Engineering and Medical Physics, Harvard-MIT Program in Health Sciences and Technology, 2018. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 163-173). / The objective of this work was to translate the diagnostic capabilities of magnetic resonance imaging (MRI) to the patient bedside, specifically for the purpose of quantifying fluid overload. MRI is used extensively in clinical medicine, but it is still not used for routine diagnostics due to high cost, limited availability, and long scan times. Many of these impracticalities come from the hardware requirements associated with generating images. Images, however, are not necessary to harness some of magnetic resonance's (MR's) diagnostic potential. This thesis demonstrates that that a single-voxel MR sensor can obtain the same results as a traditional MRI in both phantoms and humans. A clinical study with hemodialysis patients and age-matched healthy controls was performed at MGH. The T2 relaxation times of study participants' legs were quantified at multiple time points with both a 1.5T clinical MRI scanner and a custom 0.27T single-voxel MR sensor. The results showed that the first sign of fluid overload is an increase in the relative fraction of extracellular fluid in the muscle. The relaxation time of the extracellular fluid in the muscle eventually increases after more fluid accumulates. Importantly, these MR findings occur before signs of lower-extremity edema are detectable on physical exam. Two healthy control subjects became dehydrated over the course of the study and the relative fraction of their extracellular fluid decreased. This incidental finding suggests MR can measure the full spectrum of hydration states. Furthermore, a single MRI measurement at a single time point can distinguish fluid overloaded patients from healthy controls. The amplitude associated with extracellular fluid most closely correlates to fluid loss, and these amplitude decreases are detectable with both the MRI and MR sensor. The results of this work point towards a promising future of using cheaper, faster MR sensors for bedside diagnostics. / by Lina Avancini Colucci. / Ph. D. in Medical Engineering and Medical Physics

Thesis (Ph. D. in Medical Engineering and Medical Physics)--Harvard-MIT Program in Health Sciences and Technology, 2013. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 93-96). / Vaccines have revolutionized medicine by increasing the life expectancy of children and substantially decreasing the morbidity of multiple infectious diseases worldwide. Over several decades, we have acquired significant gains in the understanding of the underlying mechanisms involved in developing protective immunity, yet vaccine development has progressed comparatively slowly. This thesis serves to explore two polymeric nanoparticle platforms to demonstrate the therapeutic potential of synthetic nanocarriers as vaccines with the aim of 1) providing greater spatiotemporal release of small molecule adjuvant to secondary lymphoid sites and 2) providing a tunable surface for loading B cell antigen epitopes in a specific conformation to drive epitope-specific antibody response. In recent decades, TLR mechanisms have been elucidated and novel agonists have been developed, yet our generation still has not seen paramount progress in the clinical translation of these agonists due to risks of systemic toxicity and off target effects. In the first section, we synthesized 223±18 nm poly(lactic-co-glycolic acid)- poly(ethylene glycol)/ poly(lactic acid)-R848 (PLGA-PEG/PLA-R848) nanoparticle vaccine that is designed to deliver a combination of antigen and control release of a small molecule adjuvant R848 (tl/2= 42 hours) to drive a potent antigen-specific immune response. Using ovalbumin as a model protein, this vaccine is able to enhance antigen presentation and co-stimulatory molecules on dendritic cells and subsequently enhanced proliferation of antigen-specific naive CD8+ cells in vitro. Upon vaccination, our delivery system is able to increase cell-mediated and humoral response in comparison to its soluble form, thereby illustrating the potential to bring novel small molecule adjuvants to the clinics. In the second section, we developed a nanoparticle vaccine platform that allows selective orientation of peptide epitopes to enhance B cell response in an application that has therapeutic potential for treatment for cardiovascular disease (CVD). Utilizing epitopes discovered through in silico modeling for human PCSK9, a plasma protein that plays an important role in LDL cholesterol (LDL-c) levels in the blood, our nanoparticle allows selective orientation through biotin-streptavidin conjugation. Upon vaccination with CPG, selected synthetic epitopes conjugated to polymeric nanoparticles trended to reduce serum LDL-c and serum PCSK9 in murine models. Additionally, antibodies in the serum showed promise to increase LDL-receptor levels in HepG2 cells transfected in with WT-hPCSK9 and GOF-hPCSK9 separately suggesting that this vaccine has the potential to reduce risks of CVD. These studies demonstrate that designing polymeric nanoparticles for applications to stimulate the immune system can help define new, cost-effective treatment options in applications for prophylaxis against infectious diseases that are unresponsive to traditional routes of vaccination or for immunotherapy against cardiovascular disease and cancer. / by Pamela A. Basto. / Ph.D.in Medical Engineering and Medical Physics

Thesis: Ph. D. in Biomedical Engineering, Harvard-MIT Program in Health Sciences and Technology, 2016. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 149-166). / Accurate, timely, and effective diagnosis is the first step in appropriately treating disease. Many diseases have confusing symptoms, nonspecific biomarkers, or require invasive biopsy; these factors and others contribute to the low rates of early diagnosis for noncommunicable diseases like cancer, clotting disorders, or fibrotic diseases. A promising approach is the introduction of pro-diagnostic agents that interact with pathologic processes to produce a readout. In this vein, our group has developed responsive nanomaterials that, upon cleavage by disease-associated proteases, release reporters into the urine. This thesis sought to improve these tools by enabling the noninvasive quantification of disease-associated protease activity, deskilling complex diagnostic procedures, and developing a pipeline for extending these tools to additional diseases. Drawing inspiration from existing diagnostics, we modified our protease nanosensors to release ligand-encoded reporters compatible with clinical ELISA and paper-based lateral flow assays. These detection techniques enable simple and inexpensive quantification of our synthetic disease reporters by ensuring compatibility with existing diagnostic resources and infrastructure. To demonstrate our platform's versatility, we adapted it to a highly sensitive single molecule array (SiMoA) assay and validated disease detection in mice using 1000-fold lower doses of nanosensors. We next used disease-specific protease expression data to develop an inhalable formulation of our protease nanosensors and investigated direct tissue delivery. Finally, we built a pipeline to improve protease substrate sensitivity and specificity. Using liver fibrosis as a model, we identified target proteases, designed a peptide-screening assay, and nominated peptide candidates that efficiently classify diseased tissue. The protease nanosensors developed here provide a noninvasive, quantitative, and otherwise unavailable glimpse of the complex proteolytic milieu of disease and health. These tools form a framework for developing new diagnostics that simply, rapidly, and inexpensively identify protease-driven diseases without complex equipment or specialized personnel. / by Andrew David Warren. / Ph. D. in Biomedical Engineering