Design, Synthesis and Development of Transporter Targeting Agents for Image-guided Therapy and Drug Delivery

The purpose of this study was to design, synthesize and develop novel transporter targeting agents for image-guided therapy and drug delivery. Two novel agents, N4-guanine (N4amG) and glycopeptide (GP) were synthesized for tumor cell proliferation assessment and cancer theranostic platform, respectively. N4amG and GP were synthesized and radiolabeled with 99mTc and 68Ga. The chemical and radiochemical purities as well as radiochemical stabilities of radiolabeled N4amG and GP were tested. In vitro stability assessment showed both 99mTc-N4amG and 99mTc-GP were stable up to 6 hours, whereas 68Ga-GP was stable up to 2 hours. Cell culture studies confirmed radiolabeled N4amG and GP could penetrate the cell membrane through nucleoside transporters and amino acid transporters, respectively. Up to 40% of intracellular 99mTc-N4amG and 99mTc-GP was found within cell nucleus following 2 hours of incubation. Flow cytometry analysis revealed 99mTc-N4amG was a cell cycle S phase-specific agent. There was a significant difference of the uptake of 99mTc-GP between pre- and post- paclitaxel-treated cells, which suggests that 99mTc-GP may be useful in chemotherapy treatment monitoring. Moreover, radiolabeled N4amG and GP were tested in vivo using tumor-bearing animal models. 99mTc-N4amG showed an increase in tumor-to-muscle count density ratios up to 5 at 4 hour imaging. Both 99mTc-labeled agents showed decreased tumor uptake after paclitaxel treatment. Immunohistochemistry analysis demonstrated that the uptake of 99mTc-N4amG was correlated with Ki-67 expression. Both 99mTc-N4amG and 99mTc-GP could differentiate between tumor and inflammation in animal studies. Furthermore, 68Ga-GP was compared to 18F-FDG in rabbit PET imaging studies. 68Ga-GP had lower tumor standardized uptake values (SUV), but similar uptake dynamics, and different biodistribution compared with 18F-FDG. Finally, to demonstrate that GP can be a potential drug carrier for cancer theranostics, several drugs, including doxorubicin, were selected to be conjugated to GP. Imaging studies demonstrated that tumor uptake of GP-drug conjugates was increased as a function of time. GP-doxorubicin (GP-DOX) showed a slow-release pattern in in vitro cytotoxicity assay and exhibited anti-cancer efficacy with reduced toxicity in in vivo tumor growth delay study. In conclusion, both N4amG and GP are transporter-based targeting agents. Radiolabeled N4amG can be used for tumor cell proliferation assessment. GP is a potential agent for image-guided therapy and drug delivery.

Understanding and Characterizing Shared Decision-Making and Behavioral Intent in Medical Uncertainty

Applying Theoretical Constructs to Address Medical Uncertainty Situations involving medical reasoning usually include some level of medical uncertainty. Despite the identification of shared decision-making (SDM) as an effective technique, it has been observed that the likelihood of physicians and patients engaging in shared decision making is lower in those situations where it is most needed; specifically in circumstances of medical uncertainty. Having identified shared decision making as an effective, yet often a neglected approach to resolving a lack of information exchange in situations involving medical uncertainty, the next step is to determine the way(s) in which SDM can be integrated and the supplemental processes that may facilitate its integration. SDM involves unique types of communication and relationships between patients and physicians. Therefore, it is necessary to further understand and incorporate human behavioral elements - in particular, behavioral intent - in order to successfully identify and realize the potential benefits of SDM. This paper discusses the background and potential interaction between the theories of shared decision-making, medical uncertainty, and behavioral intent. Identifying Shared Decision-Making Elements in Medical Encounters Dealing with Uncertainty A recent summary of the state of medical knowledge in the U.S. reported that nearly half (47%) of all treatments were of unknown effectiveness, and an additional 7% involved an uncertain tradeoff between benefits and harms. Shared decision-making (SDM) was identified as an effective technique for managing uncertainty when two or more parties were involved. In order to understand which of the elements of SDM are used most frequently and effectively, it is necessary to identify these key elements, and understand how these elements related to each other and the SDM process. The elements identified through the course of the present research were selected from basic principles of the SDM model and the “Data, Information, Knowledge, Wisdom” (DIKW) Hierarchy. The goal of this ethnographic research was to identify which common elements of shared decision-making patients are most often observed applying in the medical encounter. The results of the present study facilitated the understanding of which elements patients were more likely to exhibit during a primary care medical encounter, as well as determining variables of interest leading to more successful shared decision-making practices between patients and their physicians. Understanding Behavioral Intent to Participate in Shared Decision-Making in Medically Uncertain Situations Objective: This article describes the process undertaken to identify and validate behavioral and normative beliefs and behavioral intent of men between the ages of 45-70 with regard to participating in shared decision-making in medically uncertain situations. This article also discusses the preliminary results of the aforementioned processes and explores potential future uses of this information which may facilitate greater understanding, efficiency and effectiveness of doctor-patient consultations.Design: Qualitative Study using deductive content analysisSetting: Individual semi-structure patient interviews were conducted until data saturation was reached. Researchers read the transcripts and developed a list of codes.Subjects: 25 subjects drawn from the Philadelphia community.Measurements: Qualitative indicators were developed to measure respondents’ experiences and beliefs related to behavioral intent to participate in shared decision-making during medical uncertainty. Subjects were also asked to complete the Krantz Health Opinion Survey as a method of triangulation.Results: Several factors were repeatedly described by respondents as being essential to participate in shared decision-making in medical uncertainty. These factors included past experience with medical uncertainty, an individual’s personality, and the relationship between the patient and his physician.Conclusions: The findings of this study led to the development of a category framework that helped understand an individual’s needs and motivational factors in their intent to participate in shared decision-making. The three main categories include 1) an individual’s representation of medically uncertainty, 2) how the individual copes with medical uncertainty, and 3) the individual’s behavioral intent to seek information and participate in shared decision-making during times of medically uncertain situations.

A simulation study of the standard design, the rolling six design, the CRM, and the modified CRM in Phase I clinical trials

The Phase I clinical trial is considered the "first in human" study in medical research to examine the toxicity of a new agent. It determines the maximum tolerable dose (MTD) of a new agent, i.e., the highest dose in which toxicity is still acceptable. Several phase I clinical trial designs have been proposed in the past 30 years. The well known standard method, so called the 3+3 design, is widely accepted by clinicians since it is the easiest to implement and it does not need a statistical calculation. Continual reassessment method (CRM), a design uses Bayesian method, has been rising in popularity in the last two decades. Several variants of the CRM design have also been suggested in numerous statistical literatures. Rolling six is a new method introduced in pediatric oncology in 2008, which claims to shorten the trial duration as compared to the 3+3 design. The goal of the present research was to simulate clinical trials and compare these phase I clinical trial designs. Patient population was created by discrete event simulation (DES) method. The characteristics of the patients were generated by several distributions with the parameters derived from a historical phase I clinical trial data review. Patients were then selected and enrolled in clinical trials, each of which uses the 3+3 design, the rolling six, or the CRM design. Five scenarios of dose-toxicity relationship were used to compare the performance of the phase I clinical trial designs. One thousand trials were simulated per phase I clinical trial design per dose-toxicity scenario. The results showed the rolling six design was not superior to the 3+3 design in terms of trial duration. The time to trial completion was comparable between the rolling six and the 3+3 design. However, they both shorten the duration as compared to the two CRM designs. Both CRMs were superior to the 3+3 design and the rolling six in accuracy of MTD estimation. The 3+3 design and rolling six tended to assign more patients to undesired lower dose levels. The toxicities were slightly greater in the CRMs.^

Adaptive clinical trial design for targeted therapy development

The development of targeted therapy involve many challenges. Our study will address some of the key issues involved in biomarker identification and clinical trial design. In our study, we propose two biomarker selection methods, and then apply them in two different clinical trial designs for targeted therapy development. In particular, we propose a Bayesian two-step lasso procedure for biomarker selection in the proportional hazards model in Chapter 2. In the first step of this strategy, we use the Bayesian group lasso to identify the important marker groups, wherein each group contains the main effect of a single marker and its interactions with treatments. In the second step, we zoom in to select each individual marker and the interactions between markers and treatments in order to identify prognostic or predictive markers using the Bayesian adaptive lasso. In Chapter 3, we propose a Bayesian two-stage adaptive design for targeted therapy development while implementing the variable selection method given in Chapter 2. In Chapter 4, we proposed an alternate frequentist adaptive randomization strategy for situations where a large number of biomarkers need to be incorporated in the study design. We also propose a new adaptive randomization rule, which takes into account the variations associated with the point estimates of survival times. In all of our designs, we seek to identify the key markers that are either prognostic or predictive with respect to treatment. We are going to use extensive simulation to evaluate the operating characteristics of our methods.^

Modified 3+3 design for phase I clinical trials

Phase I clinical trial is mainly designed to determine the maximum tolerated dose (MTD) of a new drug. Optimization of phase I trial design is crucial to minimize the number of enrolled patients exposed to unsafe dose levels and to provide reliable information to the later phases of clinical trials. Although it has been criticized about its inefficient MTD estimation, nowadays the traditional 3+3 method remains dominant in practice due to its simplicity and conservative estimation. There are many new designs that have been proven to generate more credible MTD estimation, such as the Continual Reassessment Method (CRM). Despite its accepted better performance, the CRM design is still not widely used in real trials. There are several factors that contribute to the difficulties of CRM adaption in practice. First, CRM is not widely accepted by the regulatory agencies such as FDA in terms of safety. It is considered to be less conservative and tend to expose more patients above the MTD level than the traditional design. Second, CRM is relatively complex and not intuitive for the clinicians to fully understand. Third, the CRM method take much more time and need statistical experts and computer programs throughout the trial. The current situation is that the clinicians still tend to follow the trial process that they are comfortable with. This situation is not likely to change in the near future. Based on this situation, we have the motivation to improve the accuracy of MTD selection while follow the procedure of the traditional design to maintain simplicity. We found that in 3+3 method, the dose transition and the MTD determination are relatively independent. Thus we proposed to separate the two stages. The dose transition rule remained the same as 3+3 method. After getting the toxicity information from the dose transition stage, we combined the isotonic transformation to ensure the monotonic increasing order before selecting the optimal MTD. To compare the operating characteristics of the proposed isotonic method and the other designs, we carried out 10,000 simulation trials under different dose setting scenarios to compare the design characteristics of the isotonic modified method with standard 3+3 method, CRM, biased coin design (BC) and k-in-a-row design (KIAW). The isotonic modified method improved MTD estimation of the standard 3+3 in 39 out of 40 scenarios. The improvement is much greater when the target is 0.3 other than 0.25. The modified design is also competitive when comparing with other selected methods. A CRM method performed better in general but was not as stable as the isotonic method throughout the different dose settings. The results demonstrated that our proposed isotonic modified method is not only easily conducted using the same procedure as 3+3 but also outperforms the conventional 3+3 design. It can also be applied to determine MTD for any given TTL. These features make the isotonic modified method of practical value in phase I clinical trials.^

Design, synthesis and cellular and molecular pharmacology of 2$\sp\prime$-bromo-4$\sp\prime$-epidaunorubicin (WP401): A novel non-cross-resistant anthracycline antibiotic with the intrinsic ability to circumvent P -glycoprotein-mediated drug resistance

We designed and synthesized a novel daunorubicin (DNR) analogue that effectively circumvents P-glycoprotein (P-gp)-mediated drug resistance. The fully protected carbohydrate intermediate 1,2-dibromoacosamine was prepared from acosamine and effectively coupled to daunomycinone in high yield. Deprotection under alkaline conditions yielded 2$\sp\prime$-bromo-4$\sp\prime$-epidaunorubicin (WP401). The in vitro cytotoxicity and cellular and molecular pharmacology of WP401 were compared with those of DNR in a panel of wild-type cell lines (KB-3-1, P388S, and HL60S) and their multidrug-resistant (MDR) counterparts (KB-V1, P388/DOX, and HL60/DOX). Fluorescent spectrophotometry, flow cytometry, and confocal laser scanning microscopy were used to measure intracellular accumulation, retention, and subcellular distribution of these agents. All MDR cell lines exhibited reduced DNR uptake that was restored, upon incubation with either verapamil (VER) or cyclosporin A (CSA), to the level found in sensitive cell lines. In contrast, the uptake of WP401 was essentially the same in the absence or presence of VER or CSA in all tested cell lines. The in vitro cytotoxicity of WP401 was similar to that of DNR in the sensitive cell lines but significantly higher in resistant cell lines (resistance index (RI) of 2-6 for WP401 vs 75-85 for DNR). To ascertain whether drug-mediated cytotoxicity and retention were accompanied by DNA strand breaks, DNA single- and double-strand breaks were assessed by alkaline elution. High levels of such breaks were obtained using 0.1-2 $\mu$g/mL of WP401 in both sensitive and resistant cells. In contrast, DNR caused strand breaks only in sensitive cells and not much in resistant cells. We also compared drug-induced DNA fragmentation similar to that induced by DNR. However, in P-gp-positive cells, WP401 induced 2- to 5-fold more DNA fragmentation than DNR. This increased DNA strand breakage by WP401 was correlated with its increased uptake and cytotoxicity in these cell lines. Overall these results indicate that WP401 is more cytotoxic than DNR in MDR cells and that this phenomenon might be related to the reduced basicity of the amino group and increased lipophilicity of WP401. ^

Conceptual framework for the design, implementation and validation of psychomotor skills’ assessment systems in minimally invasive surgery

Las técnicas de cirugía de mínima invasión (CMI) se están consolidando hoy en día como alternativa a la cirugía tradicional, debido a sus numerosos beneficios para los pacientes. Este cambio de paradigma implica que los cirujanos deben aprender una serie de habilidades distintas de aquellas requeridas en cirugía abierta. El entrenamiento y evaluación de estas habilidades se ha convertido en una de las mayores preocupaciones en los programas de formación de cirujanos, debido en gran parte a la presión de una sociedad que exige cirujanos bien preparados y una reducción en el número de errores médicos. Por tanto, se está prestando especial atención a la definición de nuevos programas que permitan el entrenamiento y la evaluación de las habilidades psicomotoras en entornos seguros antes de que los nuevos cirujanos puedan operar sobre pacientes reales. Para tal fin, hospitales y centros de formación están gradualmente incorporando instalaciones de entrenamiento donde los residentes puedan practicar y aprender sin riesgos. Es cada vez más común que estos laboratorios dispongan de simuladores virtuales o simuladores físicos capaces de registrar los movimientos del instrumental de cada residente. Estos simuladores ofrecen una gran variedad de tareas de entrenamiento y evaluación, así como la posibilidad de obtener información objetiva de los ejercicios. Los diferentes estudios de validación llevados a cabo dan muestra de su utilidad; pese a todo, los niveles de evidencia presentados son en muchas ocasiones insuficientes. Lo que es más importante, no existe un consenso claro a la hora de definir qué métricas son más útiles para caracterizar la pericia quirúrgica. El objetivo de esta tesis doctoral es diseñar y validar un marco de trabajo conceptual para la definición y validación de entornos para la evaluación de habilidades en CMI, en base a un modelo en tres fases: pedagógica (tareas y métricas a emplear), tecnológica (tecnologías de adquisición de métricas) y analítica (interpretación de la competencia en base a las métricas). Para tal fin, se describe la implementación práctica de un entorno basado en (1) un sistema de seguimiento de instrumental fundamentado en el análisis del vídeo laparoscópico; y (2) la determinación de la pericia en base a métricas de movimiento del instrumental. Para la fase pedagógica se diseñó e implementó un conjunto de tareas para la evaluación de habilidades psicomotoras básicas, así como una serie de métricas de movimiento. La validación de construcción llevada a cabo sobre ellas mostró buenos resultados para tiempo, camino recorrido, profundidad, velocidad media, aceleración media, economía de área y economía de volumen. Adicionalmente, los resultados obtenidos en la validación de apariencia fueron en general positivos en todos los grupos considerados (noveles, residentes, expertos). Para la fase tecnológica, se introdujo el EVA Tracking System, una solución para el seguimiento del instrumental quirúrgico basado en el análisis del vídeo endoscópico. La precisión del sistema se evaluó a 16,33ppRMS para el seguimiento 2D de la herramienta en la imagen; y a 13mmRMS para el seguimiento espacial de la misma. La validación de construcción con una de las tareas de evaluación mostró buenos resultados para tiempo, camino recorrido, profundidad, velocidad media, aceleración media, economía de área y economía de volumen. La validación concurrente con el TrEndo® Tracking System por su parte presentó valores altos de correlación para 8 de las 9 métricas analizadas. Finalmente, para la fase analítica se comparó el comportamiento de tres clasificadores supervisados a la hora de determinar automáticamente la pericia quirúrgica en base a la información de movimiento del instrumental, basados en aproximaciones lineales (análisis lineal discriminante, LDA), no lineales (máquinas de soporte vectorial, SVM) y difusas (sistemas adaptativos de inferencia neurodifusa, ANFIS). Los resultados muestran que en media SVM presenta un comportamiento ligeramente superior: 78,2% frente a los 71% y 71,7% obtenidos por ANFIS y LDA respectivamente. Sin embargo las diferencias estadísticas medidas entre los tres no fueron demostradas significativas. En general, esta tesis doctoral corrobora las hipótesis de investigación postuladas relativas a la definición de sistemas de evaluación de habilidades para cirugía de mínima invasión, a la utilidad del análisis de vídeo como fuente de información y a la importancia de la información de movimiento de instrumental a la hora de caracterizar la pericia quirúrgica. Basándose en estos cimientos, se han de abrir nuevos campos de investigación que contribuyan a la definición de programas de formación estructurados y objetivos, que puedan garantizar la acreditación de cirujanos sobradamente preparados y promocionen la seguridad del paciente en el quirófano. Abstract Minimally invasive surgery (MIS) techniques have become a standard in many surgical sub-specialties, due to their many benefits for patients. However, this shift in paradigm implies that surgeons must acquire a complete different set of skills than those normally attributed to open surgery. Training and assessment of these skills has become a major concern in surgical learning programmes, especially considering the social demand for better-prepared professionals and for the decrease of medical errors. Therefore, much effort is being put in the definition of structured MIS learning programmes, where practice with real patients in the operating room (OR) can be delayed until the resident can attest for a minimum level of psychomotor competence. To this end, skills’ laboratory settings are being introduced in hospitals and training centres where residents may practice and be assessed on their psychomotor skills. Technological advances in the field of tracking technologies and virtual reality (VR) have enabled the creation of new learning systems such as VR simulators or enhanced box trainers. These systems offer a wide range of tasks, as well as the capability of registering objective data on the trainees’ performance. Validation studies give proof of their usefulness; however, levels of evidence reported are in many cases low. More importantly, there is still no clear consensus on topics such as the optimal metrics that must be used to assess competence, the validity of VR simulation, the portability of tracking technologies into real surgeries (for advanced assessment) or the degree to which the skills measured and obtained in laboratory environments transfer to the OR. The purpose of this PhD is to design and validate a conceptual framework for the definition and validation of MIS assessment environments based on a three-pillared model defining three main stages: pedagogical (tasks and metrics to employ), technological (metric acquisition technologies) and analytical (interpretation of competence based on metrics). To this end, a practical implementation of the framework is presented, focused on (1) a video-based tracking system and (2) the determination of surgical competence based on the laparoscopic instruments’ motionrelated data. The pedagogical stage’s results led to the design and implementation of a set of basic tasks for MIS psychomotor skills’ assessment, as well as the definition of motion analysis parameters (MAPs) to measure performance on said tasks. Validation yielded good construct results for parameters such as time, path length, depth, average speed, average acceleration, economy of area and economy of volume. Additionally, face validation results showed positive acceptance on behalf of the experts, residents and novices. For the technological stage the EVA Tracking System is introduced. EVA provides a solution for tracking laparoscopic instruments from the analysis of the monoscopic video image. Accuracy tests for the system are presented, which yielded an average RMSE of 16.33pp for 2D tracking of the instrument on the image and of 13mm for 3D spatial tracking. A validation experiment was conducted using one of the tasks and the most relevant MAPs. Construct validation showed significant differences for time, path length, depth, average speed, average acceleration, economy of area and economy of volume; especially between novices and residents/experts. More importantly, concurrent validation with the TrEndo® Tracking System presented high correlation values (>0.7) for 8 of the 9 MAPs proposed. Finally, the analytical stage allowed comparing the performance of three different supervised classification strategies in the determination of surgical competence based on motion-related information. The three classifiers were based on linear (linear discriminant analysis, LDA), non-linear (support vector machines, SVM) and fuzzy (adaptive neuro fuzzy inference systems, ANFIS) approaches. Results for SVM show slightly better performance than the other two classifiers: on average, accuracy for LDA, SVM and ANFIS was of 71.7%, 78.2% and 71% respectively. However, when confronted, no statistical significance was found between any of the three. Overall, this PhD corroborates the investigated research hypotheses regarding the definition of MIS assessment systems, the use of endoscopic video analysis as the main source of information and the relevance of motion analysis in the determination of surgical competence. New research fields in the training and assessment of MIS surgeons can be proposed based on these foundations, in order to contribute to the definition of structured and objective learning programmes that guarantee the accreditation of well-prepared professionals and the promotion of patient safety in the OR.

BioMet®Tools: from modeling and simulation to product design and development

BioMet®Tools is a set of software applications developed for the biometrical characterization of voice in different fields as voice quality evaluation in laryngology, speech therapy and rehabilitation, education of the singing voice, forensic voice analysis in court, emotional detection in voice, secure access to facilities and services, etc. Initially it was conceived as plain research code to estimate the glottal source from voice and obtain the biomechanical parameters of the vocal folds from the spectral density of the estimate. This code grew to what is now the Glottex®Engine package (G®E). Further demands from users in medical and forensic fields instantiated the development of different Graphic User Interfaces (GUI’s) to encapsulate user interaction with the G®E. This required the personalized design of different GUI’s handling the same G®E. In this way development costs and time could be saved. The development model is described in detail leading to commercial production and distribution. Study cases from its application to the field of laryngology and speech therapy are given and discussed.

Design and control of multi-finger haptic devices for dexterous manipulation

En la interacción con el entorno que nos rodea durante nuestra vida diaria (utilizar un cepillo de dientes, abrir puertas, utilizar el teléfono móvil, etc.) y en situaciones profesionales (intervenciones médicas, procesos de producción, etc.), típicamente realizamos manipulaciones avanzadas que incluyen la utilización de los dedos de ambas manos. De esta forma el desarrollo de métodos de interacción háptica multi-dedo dan lugar a interfaces hombre-máquina más naturales y realistas. No obstante, la mayoría de interfaces hápticas disponibles en el mercado están basadas en interacciones con un solo punto de contacto; esto puede ser suficiente para la exploración o palpación del entorno pero no permite la realización de tareas más avanzadas como agarres. En esta tesis, se investiga el diseño mecánico, control y aplicaciones de dispositivos hápticos modulares con capacidad de reflexión de fuerzas en los dedos índice, corazón y pulgar del usuario. El diseño mecánico de la interfaz diseñada, ha sido optimizado con funciones multi-objetivo para conseguir una baja inercia, un amplio espacio de trabajo, alta manipulabilidad y reflexión de fuerzas superiores a 3 N en el espacio de trabajo. El ancho de banda y la rigidez del dispositivo se han evaluado mediante simulación y experimentación real. Una de las áreas más importantes en el diseño de estos dispositivos es el efector final, ya que es la parte que está en contacto con el usuario. Durante este trabajo se ha diseñado un dedal de bajo peso, adaptable a diferentes usuarios que, mediante la incorporación de sensores de contacto, permite estimar fuerzas normales y tangenciales durante la interacción con entornos reales y virtuales. Para el diseño de la arquitectura de control, se estudiaron los principales requisitos para estos dispositivos. Entre estos, cabe destacar la adquisición, procesado e intercambio a través de internet de numerosas señales de control e instrumentación; la computación de equaciones matemáticas incluyendo la cinemática directa e inversa, jacobiana, algoritmos de detección de agarres, etc. Todos estos componentes deben calcularse en tiempo real garantizando una frecuencia mínima de 1 KHz. Además, se describen sistemas para manipulación de precisión virtual y remota; así como el diseño de un método denominado "desacoplo cinemático iterativo" para computar la cinemática inversa de robots y la comparación con otros métodos actuales. Para entender la importancia de la interacción multimodal, se ha llevado a cabo un estudio para comprobar qué estímulos sensoriales se correlacionan con tiempos de respuesta más rápidos y de mayor precisión. Estos experimentos se desarrollaron en colaboración con neurocientíficos del instituto Technion Israel Institute of Technology. Comparando los tiempos de respuesta en la interacción unimodal (auditiva, visual y háptica) con combinaciones bimodales y trimodales de los mismos, se demuestra que el movimiento sincronizado de los dedos para generar respuestas de agarre se basa principalmente en la percepción háptica. La ventaja en el tiempo de procesamiento de los estímulos hápticos, sugiere que los entornos virtuales que incluyen esta componente sensorial generan mejores contingencias motoras y mejoran la credibilidad de los eventos. Se concluye que, los sistemas que incluyen percepción háptica dotan a los usuarios de más tiempo en las etapas cognitivas para rellenar información de forma creativa y formar una experiencia más rica. Una aplicación interesante de los dispositivos hápticos es el diseño de nuevos simuladores que permitan entrenar habilidades manuales en el sector médico. En colaboración con fisioterapeutas de Griffith University en Australia, se desarrolló un simulador que permite realizar ejercicios de rehabilitación de la mano. Las propiedades de rigidez no lineales de la articulación metacarpofalange del dedo índice se estimaron mediante la utilización del efector final diseñado. Estos parámetros, se han implementado en un escenario que simula el comportamiento de la mano humana y que permite la interacción háptica a través de esta interfaz. Las aplicaciones potenciales de este simulador están relacionadas con entrenamiento y educación de estudiantes de fisioterapia. En esta tesis, se han desarrollado nuevos métodos que permiten el control simultáneo de robots y manos robóticas en la interacción con entornos reales. El espacio de trabajo alcanzable por el dispositivo háptico, se extiende mediante el cambio de modo de control automático entre posición y velocidad. Además, estos métodos permiten reconocer el gesto del usuario durante las primeras etapas de aproximación al objeto para su agarre. Mediante experimentos de manipulación avanzada de objetos con un manipulador y diferentes manos robóticas, se muestra que el tiempo en realizar una tarea se reduce y que el sistema permite la realización de la tarea con precisión. Este trabajo, es el resultado de una colaboración con investigadores de Harvard BioRobotics Laboratory. ABSTRACT When we interact with the environment in our daily life (using a toothbrush, opening doors, using cell-phones, etc.), or in professional situations (medical interventions, manufacturing processes, etc.) we typically perform dexterous manipulations that involve multiple fingers and palm for both hands. Therefore, multi-Finger haptic methods can provide a realistic and natural human-machine interface to enhance immersion when interacting with simulated or remote environments. Most commercial devices allow haptic interaction with only one contact point, which may be sufficient for some exploration or palpation tasks but are not enough to perform advanced object manipulations such as grasping. In this thesis, I investigate the mechanical design, control and applications of a modular haptic device that can provide force feedback to the index, thumb and middle fingers of the user. The designed mechanical device is optimized with a multi-objective design function to achieve a low inertia, a large workspace, manipulability, and force-feedback of up to 3 N within the workspace; the bandwidth and rigidity for the device is assessed through simulation and real experimentation. One of the most important areas when designing haptic devices is the end-effector, since it is in contact with the user. In this thesis the design and evaluation of a thimble-like, lightweight, user-adaptable, and cost-effective device that incorporates four contact force sensors is described. This design allows estimation of the forces applied by a user during manipulation of virtual and real objects. The design of a real-time, modular control architecture for multi-finger haptic interaction is described. Requirements for control of multi-finger haptic devices are explored. Moreover, a large number of signals have to be acquired, processed, sent over the network and mathematical computations such as device direct and inverse kinematics, jacobian, grasp detection algorithms, etc. have to be calculated in Real Time to assure the required high fidelity for the haptic interaction. The Hardware control architecture has different modules and consists of an FPGA for the low-level controller and a RT controller for managing all the complex calculations (jacobian, kinematics, etc.); this provides a compact and scalable solution for the required high computation capabilities assuring a correct frequency rate for the control loop of 1 kHz. A set-up for dexterous virtual and real manipulation is described. Moreover, a new algorithm named the iterative kinematic decoupling method was implemented to solve the inverse kinematics of a robotic manipulator. In order to understand the importance of multi-modal interaction including haptics, a subject study was carried out to look for sensory stimuli that correlate with fast response time and enhanced accuracy. This experiment was carried out in collaboration with neuro-scientists from Technion Israel Institute of Technology. By comparing the grasping response times in unimodal (auditory, visual, and haptic) events with the response times in events with bimodal and trimodal combinations. It is concluded that in grasping tasks the synchronized motion of the fingers to generate the grasping response relies on haptic cues. This processing-speed advantage of haptic cues suggests that multimodalhaptic virtual environments are superior in generating motor contingencies, enhancing the plausibility of events. Applications that include haptics provide users with more time at the cognitive stages to fill in missing information creatively and form a richer experience. A major application of haptic devices is the design of new simulators to train manual skills for the medical sector. In collaboration with physical therapists from Griffith University in Australia, we developed a simulator to allow hand rehabilitation manipulations. First, the non-linear stiffness properties of the metacarpophalangeal joint of the index finger were estimated by using the designed end-effector; these parameters are implemented in a scenario that simulates the behavior of the human hand and that allows haptic interaction through the designed haptic device. The potential application of this work is related to educational and medical training purposes. In this thesis, new methods to simultaneously control the position and orientation of a robotic manipulator and the grasp of a robotic hand when interacting with large real environments are studied. The reachable workspace is extended by automatically switching between rate and position control modes. Moreover, the human hand gesture is recognized by reading the relative movements of the index, thumb and middle fingers of the user during the early stages of the approximation-to-the-object phase and then mapped to the robotic hand actuators. These methods are validated to perform dexterous manipulation of objects with a robotic manipulator, and different robotic hands. This work is the result of a research collaboration with researchers from the Harvard BioRobotics Laboratory. The developed experiments show that the overall task time is reduced and that the developed methods allow for full dexterity and correct completion of dexterous manipulations.

MIA - a free and open source software for gray scale medical image analysis

Background Gray scale images make the bulk of data in bio-medical image analysis, and hence, the main focus of many image processing tasks lies in the processing of these monochrome images. With ever improving acquisition devices, spatial and temporal image resolution increases, and data sets become very large. Various image processing frameworks exists that make the development of new algorithms easy by using high level programming languages or visual programming. These frameworks are also accessable to researchers that have no background or little in software development because they take care of otherwise complex tasks. Specifically, the management of working memory is taken care of automatically, usually at the price of requiring more it. As a result, processing large data sets with these tools becomes increasingly difficult on work station class computers. One alternative to using these high level processing tools is the development of new algorithms in a languages like C++, that gives the developer full control over how memory is handled, but the resulting workflow for the prototyping of new algorithms is rather time intensive, and also not appropriate for a researcher with little or no knowledge in software development. Another alternative is in using command line tools that run image processing tasks, use the hard disk to store intermediate results, and provide automation by using shell scripts. Although not as convenient as, e.g. visual programming, this approach is still accessable to researchers without a background in computer science. However, only few tools exist that provide this kind of processing interface, they are usually quite task specific, and don’t provide an clear approach when one wants to shape a new command line tool from a prototype shell script. Results The proposed framework, MIA, provides a combination of command line tools, plug-ins, and libraries that make it possible to run image processing tasks interactively in a command shell and to prototype by using the according shell scripting language. Since the hard disk becomes the temporal storage memory management is usually a non-issue in the prototyping phase. By using string-based descriptions for filters, optimizers, and the likes, the transition from shell scripts to full fledged programs implemented in C++ is also made easy. In addition, its design based on atomic plug-ins and single tasks command line tools makes it easy to extend MIA, usually without the requirement to touch or recompile existing code. Conclusion In this article, we describe the general design of MIA, a general purpouse framework for gray scale image processing. We demonstrated the applicability of the software with example applications from three different research scenarios, namely motion compensation in myocardial perfusion imaging, the processing of high resolution image data that arises in virtual anthropology, and retrospective analysis of treatment outcome in orthognathic surgery. With MIA prototyping algorithms by using shell scripts that combine small, single-task command line tools is a viable alternative to the use of high level languages, an approach that is especially useful when large data sets need to be processed.

Fitting of a New Design of Full Scleral Contact Lens in Advanced Keratoconus with Previous Implantation of Intracorneal Ring Segments

This case report reports the visual rehabilitation obtained with the fitting of a new design of full scleral contact lens (ICD 16.5 contact lens, Paragon Vision Sciences, distributed by Lenticon, Madrid, Spain) in a cornea with advanced keratoconus and previous implantation of intracorneal ring segment with a very limited effect. This eye had a refraction of –3.00 × 55° cylinder, providing a visual acuity of 0.5 LogMAR. The topographic pattern was very irregular with the presence of a significant central protrusion and a significant central corneal thinning. Some previous unsuccessful fittings have been performed with corneal and corneal-scleral lenses. A comfortable wearing was achieved with a fully scleral contact lens of 4600 μm of sagittal height, optical power of –11.25 D, and providing an apical clearance of 196 μm. A visual acuity of 0.0 LogMAR combined with a relevant aberrometric improvement was achieved with this contact lens. The patient was completely satisfied with the fitting. The result was maintained during 1 year after the fitting. Full scleral lenses are then able to provide comfortable wear and a significant increase in visual acuity combined with a significant improvement in the visual quality in eyes with advanced keratoconus.

Outpatient prescription drugs : data collection and editing in the 1996 Medical Expenditure Panel Survey (HC-010A).

"June 2001."

Application of the quality functional deployment method in mobility aid securement system design. Final report.

Federal Transit Administration, Washington, D.C.

Report and summary of activities - The North Carolina Medical Care Commission [serial].

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