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Item1492 Reconsidered: Religious and Social Change in Fifteenth Century Ávila(Johns Hopkins University, 2014-05-27) Salomons, Carolyn; Sieber, Harry; Kagan, Richard L.; Marshall, John; Spiegel, Gabrielle; Pereda, FelipeThis dissertation is an assessment of the impact of the expulsion of the Jews from Spain in 1492 on the city of Ávila, in northwestern Castile. The expulsion was the culmination of a series of policies set forth by Isabel I of Castile and Ferdinand II of Aragon regarding Jewish-Christian relations. The monarchs invoked these policies in order to bolster the faith and religious praxis of Catholics in the kingdoms, especially those Catholics newly converted from Judaism. My work shows how the implementation of these strategies began to fracture the heretofore relatively convivial relations between the confessional groups residing in Ávila. A key component of the Crown’s policies was the creation of a Jewish quarter in the city, where previously, Jews had lived wherever they chose. This transformation of a previously shared civic place to one demarcated clearly by religious affiliation, i.e. the creation of both Jewish and Christian space, had a visceral impact on how Christians related to their former neighbors, and hostilities between the two communities increased in the closing decades of the fifteenth century. Yet at the same time, Jewish appeals to the Crown for assistance in the face of harassment and persecution were almost always answered positively, with the Crown intervening several times on behalf of their Jewish subjects. This seemingly incongruous attitude reveals a key component in the relationship between the Crown and Jews: the “royal alliance.” My work also details how invoking that alliance came at the expense of the horizontal alliances between Abulense Jews and Christians, and only fostered antagonism between the confessional groups. Ultimately, this antagonism was resolved by the expulsion of the Jews in 1492. But rather than plunge the community into a decline, the expulsion had no immediate detrimental effect on the city; rather, post-1492 Ávila experienced economic and social growth. Item19F MRI Tracking of Inflammation for Earlier Prediction of Colitis-Associated Cancer(Johns Hopkins University, 2014-05-01) Shin, Soo Hyun; Walczak, Piotr; Bulte, Jeff W. M.; Janowski, MiroslawColitis-associated cancer (CAC) develops through complication of inflammatory bowel diseases (IBD) such as ulcerative colitis (UC) and Crohn’s disease (CD). Currently, CACs can only be diagnosed by colonoscopy and biopsy, which are invasive and prone to sampling errors. In this study, the feasibility of using 19F MRI for earlier diagnosis of CAC development was investigated by serial imaging of inflammatory sites in the colon. In vivo MR imaging of CAC-induced mice showed patchy distributions of 19F signals on colon wall, and co-localization of 19F signal patches with dysplastic and inflammatory lesions were confirmed by ex vivo imaging. Histological scores of inflammation and dysplasia showed significant correlation with the intensity of 19F signals. Overall, 19F MRI was used for the first time to observe the early stage of carcinomatous change of inflammatory sites in the colon, which is expected to enable earlier diagnosis of CAC. Thewell established relationship between inflammation and cancer suggests that 19F MRI can also be used in early diagnosis of wide range of cancer types. Item2.5D Chiplet Architecture for Embedded Processing of High Velocity Streaming Data(Johns Hopkins University, 2018-01-16) Figliolia, Tomas; Andreou, Andreas G; Etienne-Cummings, Ralph; Pouliquen, Philippe OThis dissertation presents an energy efficient 2.5D chiplet-based architecture for real-time probabilistic processing of high-velocity sensor data, from an autonomous real-time ubiquitous surveillance imaging system. This work addresses problems at all levels of description. At the lowest physical level, new standard cell libraries have been developed for ultra-low voltage CMOS synthesis, as well as custom SRAM memory blocks, and mixed-signal physical true random number generators based on the perturbation of Sigma-Delta structures using random telegraph noise (RTN) in single transistor devices. At the chip level architecture, an innovative compact buffer-less switched circuit mesh network on chip (NoC) capable of reaching very high throughput (1.6Tbps), finite packet delay delivery, free from packet dropping, and free from dead-locks and live-locks, was designed for this chiplet-based solution. Additionally, a second NoC connecting processors in the network, was implemented based on token-rings, allowing access to external DDR memory. Furthermore, a new clock tree distribution network, and a wide bandwidth DRAM physical interface have been designed to address the data flow requirements within and across chiplets. At the algorithm and representation levels, the Online Change Point Detection (CPD) algorithm has been implemented for on-line learning of background-foreground segmentation. Instead of using traditional binary representation of numbers, this architecture relies on unconventional processing of signals using a bio-inspired (spike-based) unary representation of numbers, where these numbers are represented in a stochastic stream of Bernoulli random variables. By using this representation, probabilistic algorithms can be executed in a native architecture with precision on demand, where if more accuracy is required, more computational time and power can be allocated. The SoC chiplet architecture has been extensively simulated and validated using state of the art CAD methodology, and has been submitted to fabrication in a dedicated 55nm GF CMOS technology wafer run. Experimental results from fabricated test chips in the same technology are also presented. Item20th and 21st Century Hispanic Settlement Sites: Three Essays on Place, Schooling, and Student Outcomes(Johns Hopkins University, 2020-06-29) Chunduru, Dhathri; Morgan, Stephen L; Day-Vines, Norma; Burdick-Will, Julia; Hao, Lingxin; Durham, RachelThe explosive growth of the U.S. Hispanic population since 1990 to newer and more non-traditional areas is the result of political, economic, and environmental instability across the world as well as a declining quality of life in large urban U.S. cities. Understanding the effects of this population growth and dispersion to less traditional areas across the U.S. on schools and students is critical for the future of educational institutions. Using six large-scale datasets comprising population-level and survey data, the three papers of this project attempt to advance our understanding of how Hispanic settlement sites in the late 20th and early 21st centuries are distinct from one another and the ways in which these distinctions shape the schooling experiences of Hispanic students. Beginning with an exploration of place, the first paper lays the foundation for how Hispanic sites of settlement could be categorized to account for the various causes of migration and dispersion in the 1990s versus the 2000s. The second paper explores how sites of settlement may shape the achievement of Hispanic students. Finally, the third paper probes the effects of a specific school-level mechanism – within-school stratification – on student outcomes. It also considers the extent to which this effect varies by place to emphasize how institutions might reinforce racial and social hierarchies based on the social and legal contexts, co-ethnic status, and racial and ethnic diversity of an area. The findings of this project indicate that there are distinctions in both the population compositions and institutional characteristics of 21st and 20th century sites, which offers support for the need to distinguish between these areas. Furthermore, there are diverging stories of achievement and post-secondary educational attainment, such that student achievement in newer sites is higher than in established sites, while post-secondary attainment and success of students is far lower. Finally, I find that within-school stratification as a racialized system broadly reflects the stratification of place and is negatively associated with college enrollment. The contributors to post-secondary attainment, particularly for Hispanic students, many of whom might be immigrants, is a far more complex process that may extend beyond the functions of secondary schooling. Item30-day Hospital Readmission Prediction Models: Design, Performance and Generalizability(Johns Hopkins University, 2016-03-18) Cropp, Brett Franklin; Kharrazi, Hadi H. K.Following the introduction of the Hospital Readmissions Reduction Program (HRRP) in 2012, there has been a push in research and quality improvement efforts to reduce 30-day hospital readmissions. While the needle has moved slightly downward for the high-risk conditions targeted, the majority of hospitals have received some penalty in 2015, totaling over $400 million. Having prediction models for avoidable readmissions would help providers in allocating resources and designing interventions for high-risk individuals. This systematic review searched for peer-reviewed efforts to predict 30-day readmissions published since 1990. In total, 428 articles were assessed for inclusion / exclusion criteria, resulting in 38 articles surviving all criteria. These articles were coded for several factors influencing study design including research setting, data sources, cohort size and characteristics. Further, methodologies were assessed for models implemented, input variable types, validation procedures, and model output and performance. Most studies used electronic medical or administrative records, while a few studies integrated additional data sources such as patient registries and direct patient follow-up. Cohorts varied, with congestive heart failure being the most frequently studied and, surprisingly, only one study developing a combined model for all three conditions originally included in the HRRP. The vast majority of studies used multivariate logistic regression to predict 30-day readmission outcomes, with varied performance. A few efforts were made to include novel statistical methods for readmission prediction, but their ability to improve performance was inconclusive. Unexpectedly, only one study integrated a prediction model into a clinical workflow. The low number of integration efforts could be a result of the difficulty in generating highly accurate models. As the HRRP expands to more conditions, and 30-day readmission gains traction as a quality metric, it is imperative that hospitals are fully informed when deciding which readmission prediction models to implement and when to use them. Several studies suggested model generalizability as a limitation and there were also several key pieces of information missing from some studies. To help assess model generalizability and ensure consistent reporting, this review proposes a modified checklist for 30-day readmission prediction efforts. Item3D Attention M-net for Short-axis Left Ventricular Myocardium Segmentation in Mice MR cardiac Images(Johns Hopkins University, 2021-05-11) Huang, Luojie; Ardekani, Siamak; Sulam, Jeremias; Weiss, Robert GeorgeSmall rodent cardiac magnetic resonance imaging (MRI) plays an important role in preclinical models of cardiac disease, which is routinely used to probe the effect of individual genes or groups of genes on the etiology of a large number of cardiovascular diseases. Accurate myocardial boundaries delineation is crucial to most morphological and functional analysis in rodent cardiac MRI. However, due to the small volume of the mouse heart and its high heart rate, rodent cardiac MRIs are usually acquired with sub-optimal resolution and low signal-to-noise ratio(SNR). The rodent cardiac MRIs can also suffer from signal loss due to the intra-voxel dephasing. These factors make automatic myocardial segmentation more challenging. Manual contouring could be applied to label myocardial boundaries but it is usually laborious and time-consuming and not systematically objective. An automatic myocardium segmentation algorithm specifically designed for these data can enhance accuracy and reproducibility of cardiac structure and function analysis. In this study, we present a deep learning approach based on 3D attention M-net to perform automatic segmentation of the left ventricular myocardium. In this architecture, we use dual spatial-channel attention gates between encoder and decoder along with a multi-scale feature fusion path after decoder. Attention gates enable networks to focus on relevant spatial information and channel features to improve segmentation performance. A distance-derived loss term, besides general dice score loss and binary cross entropy loss, was also introduced to our hybrid loss functions to refine our segmentation contour. The proposed model outperforms previous generic models for segmentation, with similar number of parameters, in major segmentation metrics including the dice score (0.9072), Jaccard index (0.8307) and Hausdorff distance (3.1754 pixels), which are comparable to the results achieved by state-of-the-art models on human cardiac datasets. Item3D Digital Methods for Quantitative CT-based Trabecular Vertebral Bone Texture and Microarchitecture Analysis for Fracture Risk(Johns Hopkins University, 2020-05-12) Xu, Xin; Zbijewski, Wojciech; Moseley, Kendall F.; Sisniega, AlejandroThis work describes a new approach to building 3D digital bone tissue phantoms with microarchitecture features that capture the variability and complexity of human vertebral trabecular bone. Item3D Expansion of Induced Pluripotent Stem Cells(Johns Hopkins University, 2020-02-17) Morrow, Marina A; Cui, Honggang; Kokkoli, EfieHuman induced pluripotent stem cells (iPSCs) have numerous applications in drug discovery, drug safety assays, in vitro disease modeling, and cell-based regenerative therapy since iPSCs are capable of becoming specialized cells. Therefore, there is a great need in industry to generate a cost-effective, scalable, and robust process to increase the number of iPSCs while maintaining their undifferentiated state. The current standard of growing iPSCs in 2D culture is space, labor, and cost intensive; 3D suspension culture is a viable alternative to grow iPSCs, with benefits such as homogenous culture conditions, automation, monitoring, and feedback-based control. The two principal ways of growing iPSCs in suspension are as aggregates or on microcarriers (MCs). For aggregates, medium, seeding density, agitation and passaging method were evaluated: in a 125 mL shaker vessel, 1-3e5 cells/mL at 70 RPM was found to be best for STEMCELL Technologies 3D media. Three methods of aggregate passaging –strain, settle and centrifuge– were assessed with the goal of reducing cell loss while maintaining characteristic morphology. Strain method lost ~15-20% of cells while settle lost <10% of cells with each passage; centrifuge method was discontinued since keeping free cells in culture had a negative impact on morphology. For the iPSCs tested, it was found that it may be necessary to coat MCs with a matrix for improved cell attachment, however, preparation of these MCs sometimes resulted in shattering or improper hydration, leading them to float. Furthermore, challenges were encountered when counting the cells on MCs. The aggregate expansion system described has the potential to grow iPSCs to clinically relevant quantities. ItemThe 3D Knee: Visualizing Real Data from 3D Magnetic Resonance Neurography(Johns Hopkins University, 2015-03-24) Thompson Schumacher, Mesa Bree; Rini, David A.; Fritz, JanEstablished 2D MRI techniques are of limited clinical usefulness for visualizing of small peripheral cutaneous nerves of the knee due to limitations in spatial resolution and partial volume averaging effects. This leads clinicians to rely on their knowledge of anatomy, clinical evaluation, and diagnostic nerve blocks for diagnosis and treatment. Peripheral nerves have become increasingly visible with the development of new high-resolution 3T 3D MR techniques, with nerves peripheral nerves visible down to a diameter of less than 1 mm. (Fritz, personal interview, 2015) With increasing possibility for clinical integration comes greater need for teaching models correlated with Real Data, and increasing possibilities for accurate and efficient 3D visualization solutions for a variety of educational and clinical applications. Improvements in isotropic MR imaging data aquisition offer biomedical artists the opportunity to extrapolate 3D mesh from real patient data into 3D models of smaller and more complex anatomic features. 3D model creation also has the benefit of parenting many derivitive visualization solutions, including 3D derivative still images, 3D animations, and interactive 3D applications all from the same data, registered in 3D space, and useful in the creation of large multimedia projects for educational or clinical use. 3D surface mesh exports were taken from 3 Tesla high spatial resolution 3D MR data sets of the knee in OsiriX. Meshes were optimized in Meshlab, then a master 3D model of component parts created in ZBrush digital sculpting software. The model was textured and painted in Cinema 4D and Adobe Photoshop, and still images, 3D animated media, and 3D files were exported composed of the bones, ligaments, cartilage, muscles, vessels and most importantly nerves of the knee. These parallel 3D assets were used in the design and creation of an Interactive 3D application built in the Unity 3D game development engine. The real time 3D environment provides a platform for effective ontological learning. The application allows medical students, radiology residents, and radiology fellows to explore the 3D knee in an interactive manner, then switch seamlessly to linear defined learning applications created from still and animated content and radiological data, all correlated with the application’s master model. The workflow developed in this project for taking Real Data from MRI to interactive visualization can provide a useful path for the creation of future educational and clinical applications from radiological data. It is our hope that this project encourages future partnerships between biomedical illustrators and radiologists in developing better and more accurate visualization, which may education, and improve patient clinical outcome. Item3D printing of biomedical devices with soft and biocompatible elastomers(Johns Hopkins University, 2020-05-08) Tao, Runhan; Kang, Sung Hoon; Gracias, David; Romer, Lewis HartleyAdditive manufacturing (AM) which is commonly known as 3D printing is evolving quickly during the last decades. It has been utilized in various areas including biomedical applications, such as tissue engineering, therapeutic delivery, surgical planning and implant designs. The possibility to fabricate complex geometries allows us to solve many problems that cannot be done using traditional methods. In this thesis, we explored possible applications of 3D printing in biomedical engineering. The first application was using 3D printing to address challenges in treatments for congenital heart diseases (CHD). 1.35 million infants are born with CHD each year in the world, reconstruction of right ventricle–to–pulmonary artery (RVPA) continuity is an integral part of various surgical procedures commonly performed in neonates and young infants to treat CHD. However, these conduits need multiple open-chest replacement surgeries because the size of the conduits cannot grow as infants grow. We addressed the lack of growth potential of RV-PA conduits using novel 3D-printed conduits that can change their shape in response to the physiological changes during pediatric growth. We utilized thermoplastic polycarbonate-based polyurethane as a filament material in a fused filament fabrication printing process. We characterized the material to determine the suitable printing parameters, then developed a customized bench-top fluidic set up to study the in-vitro functionalities of the 3D-printed conduits. The conduits can increase the effective diameters as the RV pressure increases during growth to accommodate increased blood flow rate. The second application was utilizing the same material to address the technique difficulties in vascular and microvascular anastomosis. Traditional suture method requires surgeons to have a long-time training before they can perform vascular anastomosis, and the surgeries usually last for hours, the sewing material may cause further damage to blood vessels after the surgery. To address these issues, we developed a 3D-printed device that can connect blood vessels together and allow a broader access of vascular and microvascular anastomosis by making the process simpler, faster, and safer. We believe that using 3D printing technology, we can provide new aspects in designing patient specific biomedical devices and develop experience of both patients and surgeons. Item3D PRINTING OF MULTI-FUNCTIONAL HYDROGELS(Johns Hopkins University, 2019-08-09) Liu, Wangqu; Gracias, David Hugo; Kang, Sung Hoon3D printing technology has been widely applied to rapid design and fabrication in recent years. Hydrogels fabricated by 3D printing are spotlighted owing to the emerging demands for complicated soft structures and biocompatible devices. The large variety of hydrogels provides the potential to produce multifunctional structures with hydrogels of different formulations and properties. Herein, we reported two works of 3D printing of multifunctional hydrogels by direct ink writing, a 3D printing technology based on the rheological properties of the hydrogel precursor ink. The first work developed a highly stretchable in situ grown metal-organic framework (MOF), overcomes the longstanding challenge of processing MOF materials into the flexible matrix by 3D printing without compromising on the MOF functionality performance. The prepared MOF hydrogel by facile in situ growth of MOF in 3D printed pAAM/alginate double networks hydrogel matrix exhibits high loading of MOF distributed in the whole hydrogel matrix, can be stretched to over 450 % of its original length and shows the best dye adsorption performance among the existing 3D printed MOF-polymer composites. We anticipate that this method would introduce new opportunities fabrication of complex flexible MOF-polymer composite devices for diverse applications such as wearable, implantable biosensors, flexible electronics. The second work introduces 3D printed segmented dual-gel tubes composed of an active thermally responsive swelling gel (poly N-isopropylacrylamide; pNIPAM) and a passive thermally non-responsive gel (polyacrylamide; pAAM). The dual-gel structures are able to achieve reversible shape deformation including uniaxial elongation, radial expansion, bending, and gripping by thermal actuation. The shape changes are programmable, predictable guided by CAD design and finite element simulations. The dual-gel 4D printing opens new avenues such as stimulus-responsive soft robotics and biomimetic 3D cell scaffold for biomedical engineering, with a high level of customization and tunability in three dimensions. Item3D Printing PTFE with Direct Ink Writing(Johns Hopkins University, 2018-07-19) Jiang, Zhuoran; Gracias, David; Singh, AnirudhaPolytetrafluoroethylene (PTFE) is a unique fluoropolymer comprising of only fluorine and carbon atoms with various desirable properties such as non-stick, chemical inertness, thermal stability and electrical insulation. Molding and sintering techniques following by pressurized preforming are commonly used to cast PTFE for desirable shapes and forms with considerable amount of waste under high cost. However, rapid prototyping and customizable tooling of PTFE is yet developed. Herein, we reported a novel and facile way for PTFE 3D printing by Direct Ink Writing (DIW). PTFE dispersion based composite, with varying amount of Gellan gum additives, was developed as 3D printable ink to generate millimeter features following by multi-steps thermal process. In order to fabricate molding PTFE properties similar structures, the design of experiments (DOE) method based on Taguchi’s orthogonal arrays were applied. The printed structures were prepared by varying three controlled factors including the Gellan gum weight percentage, the maximum temperature, and the cooling rate with three selected levels. An optimal parameter setting is obtained through a desirability function analysis of variance (ANOVA) that balances the desired Young’s modulus and yield strength targets. The Young’s modulus and yield strength are found to be controllable by varying the amount of Gellan gum. Based on its mechanical, hydrophobic and chemical inert properties, tubular structures with various designs were fabricated to demonstrate its potential in medical implants. Item3D PRINTING SMART CAPSULE FOR ORAL DELIVERY OF INSULIN USING MICROINJECTORS(Johns Hopkins University, 2023-05-08) Zhong, Zijian; Gracias, DavidOver several decades, large molecules such as proteins, antibodies, and peptides have been utilized as therapeutic agents for advanced treatment options. While these macromolecular drugs have demonstrated effectiveness in treating various diseases, there are challenges associated with their oral administration. These challenges primarily involve rapid degradation and poor absorption in the gastrointestinal tract. Enclosed with this letter is a detailed proposal for oral-taking capsules delivering micro-scale devices acting on the gastrointestinal (GI) tract with biodegradable material, high stability, high versatility, low cost, and a smart environmental response release mechanism. The GI tract is the most common target of drug delivery. Larger volumes and lengths in the GI tract have the potential to reduce dosing frequency and improve compliance, such as extended-release formulations and gastrointestinal retention tablets for prolonged release. Compared with conventional drug delivery targets, long-acting drug delivery targets in the GI tract can maintain more constant drug concentrations within the therapeutic period, thereby improving drug pharmacokinetics. This stable concentration enhances the efficacy of the drug, reduces toxic side effects, and improves tolerance, thereby increasing patient compliance. In addition, real-time monitoring of the gastrointestinal environment can reflect the health of intestinal diseases. Researchers have developed many micro-scale devices that function in drug delivery, imaging, monitoring, and even operating small surgery. For these devices with complex structures, the use of oral capsule delivery is a far more reasonable implantation modality than surgery. Therefore, It is necessary to develop a highly versatile oral capsule for targeted gastrointestinal delivery. In conclusion, the development of highly versatile oral capsules containing micro-scale devices presents an exciting opportunity for drug delivery in the treatment of various diseases. These capsules can provide targeted delivery to the gastrointestinal tract, maintain constant drug concentrations, and provide real-time monitoring of the gastrointestinal environment. With ongoing research in this field, we can expect to see the development of novel drug delivery systems that can provide effective and convenient treatments for patients. Item3D Reconstruction of Fossilized Skull of South American Miocene Monkey Homunculus patagonicus: An Augmented Reality for Field Application(Johns Hopkins University, 2020-03-23) Sanders, Kellyn; Fairman, Jennifer E.; Perry, Jonathan M.G.For most Miocene taxa, primate fossil evidence consists of broken cranial bones, teeth, and jaws. Studying these fossils is difficult due to the damage and distortion during geological stress. During fossilization the soft tissue preservation of these specimens is usually nonexistent. Homunculus patagonicus is an unusual primate from the Miocene epoch (~17 million years old) of extreme southern Argentina. The first associated cranium and mandible of this species will allow the most complete reconstruction of the adaptations of any early platyrrhine. To reconstruct the diet of such extinct mammals, the jaws, skull and muscles of mastication provide insight into how food properties influence skull morphology over evolutionary time (Perry, 2018). This project allows the use of comparative anatomy to learn how H. patagonicus lived, and its relationship to its environment through an examination of dietary adaptations. Using extant analogs, correlations can be made between muscle and bone dimensions providing informed inferences about feeding behaviors in fossils. Inferences can be validated because, “Diet and mastication are closely tied to hard anatomy” (Perry, 2008). Thus, access to data from living analogs makes reconstructions of mastication especially justifiable for early primates (Perry, 2008). This data can be then used to recreate the magnitude and orientation of the force produced by the adductor muscles. These variables can be used to better understand the properties of foods and how they relate to food processing anatomy and behavior (Perry et al. 2011). This project leverages digital visualization techniques to provide an interactive application using the digital fossil reconstruction of Homunculus patagonicus. The reconstruction of the skull and jaw adductor muscles are implemented through an interactive iOS application in addition to the original CT fossil data, extant distribution maps, and primate phylogeny. This application will not only provide researchers, students and the general public a learning resource but will also contribute to the fields of virtual paleontology, biocommunication and plastic surgery, especially facial reconstruction. Item3D Shell MEA to Record Electrical Activity of Brain Organoids(Johns Hopkins University, 2022-05-10) Xiang, Terry; Gracias, David H; Smirnova, LenaAs organoids have become one of the premier models for experimentation due to their ability to mimic in vivo organs through their existence as a three dimensional (3D) multicellular in vitro model created from tissue culture, researchers have studied various different organs using organoids mimicking those organs. In this study, brain organoids were studied for their 3D microenvironment retaining cytoarchitecture seen in the brain utilizing Multielectrode Arrays (MEAs). MEAs allow for both the recording and the stimulation of electrical activity from electrogenic–involving the production of changes in electric potential–cells. Conventional MEAs are two dimensional (2D) in nature. They were designed originally for 2D monolayer cell cultures, which means they do not fully grasp the potential of electrical recording of organoids, which are 3D in nature. In this study, we developed miniature chip-integrated MEA caps that have the capability to maximize electrode contact with brain organoids, therefore allowing for more effective electrical recording. The optically transparent shells were created from self-folding polymer leaflets with conductive polymer-coated metal electrodes sandwiched in between the polymer bilayer. The MEAs tunable nature allows for versatile recording of brain organoids from 400 μm to 600 μm for up to four weeks, which was validated through glutamate stimulation. Our work suggests that 3D shell MEAs provide significantly effective results related to signal-to-noise and 3D spatiotemporal recordings for brain organoids. Item3D VISCOELASTIC ENVIRONMENT REGULATES RESPONSE OF MACROPHAGES(Johns Hopkins University, 2022-05-06) Fang, Zhiwei; Gu, LuoMacrophages are innate immune cells with multiple physiological roles in the body. They respond to both biochemical and biophysical cues from the viscoelastic tissue environment and are highly plastic in changing their phenotypes and corresponding behaviors. Although many studies are focusing on macrophages response to stimuli of soluble factors, how matrix properties regulate their response and function is largely unknown. Here, in this thesis we proposed a hydrogel system that mimics the viscoelasticity of native tissue and cultured bone marrow-derived macrophages (BMDM) in 3D environments to study their behaviors in response to matrix mechanics. We found that under proinflammatory factors (IFN-γ+LPS) stimulation, macrophages expressed different levels of inducible nitric oxide synthase (iNOS), which is a key enzyme in the macrophage inflammatory response. This indicates that 3D viscoelastic environments regulate the inflammatory response of macrophages and faster stress relaxation of matrix downregulates its activation. This finding has potential implications in future studies in macrophages-related immune diseases. Item3D VISUALIZATION OF GENETIC MUTATIONS IN PANCREATIC INTRAEPITHELIAL NEOPLASIA(Johns Hopkins University, 2022-03-30) Wang, Ting I; Fairman, Jennifer E; Hruban, Ralph H; Wirtz, DenisPancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer in the United States and is often diagnosed in advanced stages with poor prognosis. A new workflow called CODA that uses machine learning to reconstruct pancreas pathology, from precursor lesions to PDAC, has been established to study PDAC in humans in three-dimensions. Although the genetic mutations that drive PDAC are known, there exists little information regarding 3D spatial distribution of these mutations. Once defined in 3D, these mutations would need to be visualized in a clear and organized way. The application of genetic sequencing to 3D-constructed precursor lesions in the human pancreas afforded a novel opportunity to develop tools to visualize complex genetic changes in three dimensions. Each lesion was subdivided for deeper resolution of lesion heterogeneity. The visualization developed took a 3D scatter plot approach. Genetic mutations were represented by mapped objected spaced equally throughout the precursor lesions. Each genetic mutation was assigned a color. Object size was used to represent prevalence of each genetic mutation in 4 distinct 3D precursor lesions in each gene sequencing region. Four visualization outputs were created, including still images, turntable videos, an interactive platform, and a promotional image. The interactive platform includes a 3D interactive model that a user can rotate and scale, togglable genetic mutation representations, and a switch between “prevalence” and “no prevalence” modes. Modeling was done using 4D® and ZBrush®. Unity was used for lighting, materials, and creation of the 3D interactive platform. This thesis project experimented with ways in which data commonly visualized in a 2D manner could be visualized in a 3D space. The visualization represents a first step in understanding tumorigenesis in three dimensions and its contributing factors as related to tumor microenvironments in human. Item4D Image Reconstruction with Dual Respiratory and Cardiac Motion Correction for Cardiac PET(Johns Hopkins University, 2015-10-23) Feng, Tao; Tsui, Benjamin M. W.; Xu, Jingyan; Goutsias, John I.; Tran, Trac Duy4D image reconstruction with motion correction is the solution to improve image quality and resolution degraded by respiratory motion (RM) and cardiac motion (CM) in cardiac PET scans. The improved image quality can potentially improve clinical diagnosis, and can be traded for reduced injected radiation dose or reduced imaging time for improving patient comfort. There are three steps for 4D image reconstruction with motion correction: 1) 4D data generation (gating), 2) 4D respiratory and cardiac (R&C) motion estimation, and 3) 4D R&C motion correction. We have developed and evaluated multiple methods for each step including (step 1) data-driven gating, MRI-navigator-gating, (step 2) 4 different methods for dual R&C motion estimation after reconstruction (MEAR), CM estimation during reconstruction (MEDR), RM estimation before reconstruction (MEBR), and (step 3) dual R&C motion correction after (MCAR), during (MCDR), and before (MCBR) image reconstruction. Realistic Monte Carlo simulated 4D cardiac PET data using the 4D XCAT phantom and accurate models of the scanner design parameters and performance characteristics and clinical patient data were used to evaluate all different methods. Data-driven gating method was shown to provide robust gating results in high myocardium uptake situations while MRI-navigator based gating showed better results in low myocardium uptake situations. Separate R&C MEAR with modeling of RM on CM estimation was shown to be the best option for accurate estimation of dual R&C motion estimation. The MCDR method yields the best performance for different noise situations for both patient and simulation, while MCBR reduces computational time dramatically but the resultant 4D cardiac gated PET images has overall inferior image quality when compared to that from the MCAR and MCDR approaches in the ‘almost’ noise free case. Also, the MCBR method has better noise handling properties when compared with MCAR and provides better quantitative result in high noise cases. In general, our developed methods demonstrated the importance of motion correction on image qualities, our work also provide a general guideline for different applications that requires either highly quantitative data or qualitative images. Our works also provide practical means for applying 4D image reconstruction with reasonable computational cost. Item4D Printing of Bioinspired hydrogel structures(Johns Hopkins University, 2019-07-10) Pantula, Aishwarya; Gracias, David H; Singh, AnirudhaBiological structures in nature are made out of components which respond to external cues present in their environments. For example, sea creatures and plants swell and deswell to adapt and grow in their environment. Stimuli-responsive hydrogels are synthetic polymers that exhibit similar behavior and undergo large volumetric or phase transitions in response to external stimuli. The integration of these hydrogels with other material systems can create engineered self-sufficient structures that can function in complex environments like the human body. This study provides insights into the possible routes to program shape changing structures using stimuli-responsive hydrogels and 3D/4D printing for applications in soft robotics, microfluidics, and biomedical engineering. 4-D printable inks were developed using a thermoresponsive active hydrogel Poly(N-isopropylacrylamide) and a passive hydrogel Poly(acrylamide). By printing tubes with alternating walls of active and passive hydrogel arranged either vertically, horizontally or at angles, structures with different functionalities which were reversible with temperature. A gripper was printed based on a coral polyp which could extend and then grip a structure. All these structures can be extended towards applications in soft robotic endoscopy, in which endoscopes have to extend, bend and grip. Enzymatic degradation is another stimulus to trigger transitions in hydrogels. It takes different times to digest various kinds of food by enzymes in our body depending on its macromolecular composition. We developed 4D printable edible inks that degraded due to the hydrolysis of the glycosidic bonds of the polysaccharides in an apple by the enzyme amylase. By controlling their concentration in the hydrogel, the degradation of the structures could be tuned. Functional structures were printed using these inks which could actuate over time as the materials degrade. These actuating structures could be used as drug or nutrient delivery systems as a nontoxic and cheap alternative for people with dietary restrictions. In summary, this study outlined the development of smart hydrogels and their application in designing stimuli responsive structures for biomedical applications. ItemA 10 year retrospective study of the National Rehabilitation Centre Abu Dhabi: Trends, population characteristics, associations and predictors of treatment outcomes(Johns Hopkins University, 2017-04-04) Al Dhaheri, Fatima Al sayed; Latkin, Carl A.; Celentano, David D.; Engineer, Lilly D.; McGready, John; Wanigaratne, ShamilData extracted from case notes of all NRC patients from February 2002 to August 2011were analyzed to obtain a descriptive profile and changes in trends during this period. The data were extracted manually using a template and entered into a spreadsheet for analysis. During the period under consideration only male patients were admitted to the NRC. Data were available on 591 patients to be included in the study. The results showed that the average age of the patients was 32.4 years, 42% were married, 44% were single and 13% were divorced. A very high percentage, 60%, was unemployed and 32% were employed or were students. Fifty-one percent% had not completed their secondary education, 33% had completed secondary education and 16% had post-secondary education. The main substance of abuse was alcohol (41%), followed by heroin (16%), marijuana (11%), Benzodiazepines (6%), inhalants (2%), amphetamines (2%). Other substances (20%) included prescription drugs, including. Painkillers such as Tramadol, Methadone, and codeine, sedatives such as Xanax and Valium, and substances such as Kemadrine, Artane and Khat amounted to 20%. Fifteen-percent of all patients tested positive for Hepatitis C, 2% positive for Hepatitis B and there we no reports of HIV. The presence of co-morbid psychiatric illnesses ranged from 9% to 25% depending on the substance of abuse. The changes in trends in the main drugs of abuse as well as other analysis of patterns of use are reported. Comparisons of the findings with other studies in the region, implications of the findings, the limitations of the study, as well as areas for future research are discussed.