Effect of X-ray tube parameters, iodine concentration, and patient size on image quality in pulmonary computed tomography angiography: a chest-phantom-study

OBJECTIVES: The aim of this phantom study was to evaluate the contrast-to-noise ratio (CNR) in pulmonary computed tomography (CT)-angiography for 300 and 400 mg iodine/mL contrast media using variable x-ray tube parameters and patient sizes. We also analyzed the possible strategies of dose reduction in patients with different sizes. MATERIALS AND METHODS: The segmental pulmonary arteries were simulated by plastic tubes filled with 1:30 diluted solutions of 300 and 400 mg iodine/mL contrast media in a chest phantom mimicking thick, intermediate, and thin patients. Volume scanning was done with a CT scanner at 80, 100, 120, and 140 kVp. Tube current-time products (mAs) varied between 50 and 120% of the optimal value given by the built-in automatic dose optimization protocol. Attenuation values and CNR for both contrast media were evaluated and compared with the volume CT dose index (CTDI(vol)). Figure of merit, calculated as CNR/CTDIvol, was used to quantify image quality improvement per exposure risk to the patient. RESULTS: Attenuation of iodinated contrast media increased both with decreasing tube voltage and patient size. A CTDIvol reduction by 44% was achieved in the thin phantom with the use of 80 instead of 140 kVp without deterioration of CNR. Figure of merit correlated with kVp in the thin phantom (r = -0.897 to -0.999; P < 0.05) but not in the intermediate and thick phantoms (P = 0.09-0.71), reflecting a decreasing benefit of tube voltage reduction on image quality as the thickness of the phantom increased. Compared with the 300 mg iodine/mL concentration, the same CNR for 400 mg iodine/mL contrast medium was achieved at a lower CTDIvol by 18 to 40%, depending on phantom size and applied tube voltage. CONCLUSIONS: Low kVp protocols for pulmonary embolism are potentially advantageous especially in thin and, to a lesser extent, in intermediate patients. Thin patients profit from low voltage protocols preserving a good CNR at a lower exposure. The use of 80 kVp in obese patients may be problematic because of the limitation of the tube current available, reduced CNR, and high skin dose. The high CNR of the 400 mg iodine/mL contrast medium together with lower tube energy and/or current can be used for exposure reduction.

Dual energy versus single energy MDCT: measurement of radiation dose using adult abdominal imaging protocols

RATIONALE AND OBJECTIVES: The aim of this study was to measure the radiation dose of dual-energy and single-energy multidetector computed tomographic (CT) imaging using adult liver, renal, and aortic imaging protocols. MATERIALS AND METHODS: Dual-energy CT (DECT) imaging was performed on a conventional 64-detector CT scanner using a software upgrade (Volume Dual Energy) at tube voltages of 140 and 80 kVp (with tube currents of 385 and 675 mA, respectively), with a 0.8-second gantry revolution time in axial mode. Parameters for single-energy CT (SECT) imaging were a tube voltage of 140 kVp, a tube current of 385 mA, a 0.5-second gantry revolution time, helical mode, and pitch of 1.375:1. The volume CT dose index (CTDI(vol)) value displayed on the console for each scan was recorded. Organ doses were measured using metal oxide semiconductor field-effect transistor technology. Effective dose was calculated as the sum of 20 organ doses multiplied by a weighting factor found in International Commission on Radiological Protection Publication 60. Radiation dose saving with virtual noncontrast imaging reconstruction was also determined. RESULTS: The CTDI(vol) values were 49.4 mGy for DECT imaging and 16.2 mGy for SECT imaging. Effective dose ranged from 22.5 to 36.4 mSv for DECT imaging and from 9.4 to 13.8 mSv for SECT imaging. Virtual noncontrast imaging reconstruction reduced the total effective dose of multiphase DECT imaging by 19% to 28%. CONCLUSION: Using the current Volume Dual Energy software, radiation doses with DECT imaging were higher than those with SECT imaging. Substantial radiation dose savings are possible with DECT imaging if virtual noncontrast imaging reconstruction replaces precontrast imaging.

New anthropometry-based age- and sex-specific reference values for urinary 24-hour creatinine excretion based on the adult Swiss population.

BACKGROUND Urinary creatinine excretion is used as a marker of completeness of timed urine collections, which are a keystone of several metabolic evaluations in clinical investigations and epidemiological surveys. The current reference values for 24-hour urinary creatinine excretion rely on observations performed in the 1960s and 1970s in relatively small and mostly selected groups, and may thus poorly fit to the present-day general European population. The aim of this study was to establish and validate anthropometry-based age- and sex-specific reference values of the 24-hour urinary creatinine excretion on adult populations with preserved renal function. METHODS We used data from two independent Swiss cross-sectional population-based studies with standardised 24-hour urinary collection and measured anthropometric variables. Only data from adults of European descent, with estimated glomerular filtration rate (eGFR) ≥60 ml/min/1.73 m(2) and reported completeness of the urinary collection were retained. A linear regression model was developed to predict centiles of the 24-hour urinary creatinine excretion in 1,137 participants from the Swiss Survey on Salt and validated in 994 participants from the Swiss Kidney Project on Genes in Hypertension. RESULTS The mean urinary creatinine excretion was 193 ± 41 μmol/kg/24 hours in men and 151 ± 38 μmol/kg/24 hours in women in the Swiss Survey on Salt. The values were inversely correlated with age and body mass index (BMI). Based on current reference values (177 to 221 μmol/kg/24 hours in men and 133 to 177 μmol/kg/24 hours in women), 56% of the urinary collections in the whole population and 67% in people >60 years old would have been considered as inaccurate. A linear regression model with sex, BMI and age as predictor variables was found to provide the best prediction of the observed values and showed a good fit when applied to the validation population. CONCLUSIONS We propose a validated prediction equation for 24-hour urinary creatinine excretion in the general European population, based on readily available variables such as age, sex and BMI, and a few derived normograms to ease its clinical application. This should help healthcare providers to interpret the completeness of a 24-hour urine collection in daily clinical practice and in epidemiological population studies.

Volumetric analysis of lung nodules in computed tomography (CT): comparison of two different segmentation algorithm softwares and two different reconstruction filters on automated volume calculation.

BACKGROUND A precise detection of volume change allows for better estimating the biological behavior of the lung nodules. Postprocessing tools with automated detection, segmentation, and volumetric analysis of lung nodules may expedite radiological processes and give additional confidence to the radiologists. PURPOSE To compare two different postprocessing software algorithms (LMS Lung, Median Technologies; LungCARE®, Siemens) in CT volumetric measurement and to analyze the effect of soft (B30) and hard reconstruction filter (B70) on automated volume measurement. MATERIAL AND METHODS Between January 2010 and April 2010, 45 patients with a total of 113 pulmonary nodules were included. The CT exam was performed on a 64-row multidetector CT scanner (Somatom Sensation, Siemens, Erlangen, Germany) with the following parameters: collimation, 24x1.2 mm; pitch, 1.15; voltage, 120 kVp; reference tube current-time, 100 mAs. Automated volumetric measurement of each lung nodule was performed with the two different postprocessing algorithms based on two reconstruction filters (B30 and B70). The average relative volume measurement difference (VME%) and the limits of agreement between two methods were used for comparison. RESULTS At soft reconstruction filters the LMS system produced mean nodule volumes that were 34.1% (P < 0.0001) larger than those by LungCARE® system. The VME% was 42.2% with a limit of agreement between -53.9% and 138.4%.The volume measurement with soft filters (B30) was significantly larger than with hard filters (B70); 11.2% for LMS and 1.6% for LungCARE®, respectively (both with P < 0.05). LMS measured greater volumes with both filters, 13.6% for soft and 3.8% for hard filters, respectively (P < 0.01 and P > 0.05). CONCLUSION There is a substantial inter-software (LMS/LungCARE®) as well as intra-software variability (B30/B70) in lung nodule volume measurement; therefore, it is mandatory to use the same equipment with the same reconstruction filter for the follow-up of lung nodule volume.

Metamorphosis of human lumbar vertebrae induced by VEPTR growth modulation and stress shielding

INTRODUCTION Distraction-based spinal growth modulation by growing rods or vertical expandable prosthetic titanium ribs (VEPTRs) is the mainstay of instrumented operative strategies to correct early onset spinal deformities. In order to objectify the benefits, it has become common sense to measure the gain in spine height by assessing T1-S1 distance on anteroposterior (AP) radiographs. However, by ignoring growth changes on vertebral levels and by limiting measurement to one plane, valuable data is missed regarding the three-dimensional (3D) effects of growth modulation. This information might be interesting when it comes to final fusion or, even more so, when the protective growing implants are removed and the spine re-exposed to physiologic forces at the end of growth. METHODS The goal of this retrospective radiographic study was to assess the growth modulating impact of year-long, distraction-based VEPTR treatment on the morphology of single vertebral bodies. We digitally measured lumbar vertebral body height (VBH) and upper endplate depth (VBD) at the time of the index procedure and at follow-up in nine patients with rib-to-ileum constructs (G1) spanning an anatomically normal lumbar spine. Nine patients with congenital thoracic scoliosis and VEPTR rib-to-rib constructs, but uninstrumented lumbar spines, served as controls (G2). All had undergone more than eight half-yearly VEPTR expansions. A Wilcoxon signed-rank test was used for statistical comparison of initial and follow-up VBH, VBD and height/depth (H/D) ratio (significance level 0.05). RESULTS The average age was 7.1 years (G1) and 5.2 year (G2, p > 0.05) at initial surgery; the average overall follow-up time was 5.5 years (p = 1). In both groups, VBH increased significantly without a significant intergroup difference. Group 1 did not show significant growth in depth, whereas VBD increased significantly in the control group. As a consequence, the H/D ratio increased significantly in group 1 whereas it remained unchanged in group 2. The growth rate for height in mm/year was 1.4 (group 1) and 1.1 (group 2, p = 0.45), and for depth, it was -0.3 and 1.1 (p < 0.05), respectively. CONCLUSIONS VEPTR growth modulating treatment alters the geometry of vertebral bodies by increasing the H/D ratio. We hypothesize that the implant-related deprivation from axial loads (stress-shielding) impairs anteroposterior growth. The biomechanical consequence of such slender vertebrae when exposed to unprotected loads in case of definitive VEPTR removal at the end of growth is uncertain.

Ultra-low-dose dual-source CT coronary angiography with high pitch: diagnostic yield of a volumetric planning scan and effects on dose reduction and imaging strategy

OBJECTIVE To evaluate the role of an ultra-low-dose dual-source CT coronary angiography (CTCA) scan with high pitch for delimiting the range of the subsequent standard CTCA scan. METHODS 30 patients with an indication for CTCA were prospectively examined using a two-scan dual-source CTCA protocol (2.0 × 64.0 × 0.6 mm; pitch, 3.4; rotation time of 280 ms; 100 kV): Scan 1 was acquired with one-fifth of the tube current suggested by the automatic exposure control software [CareDose 4D™ (Siemens Healthcare, Erlangen, Germany) using 100 kV and 370 mAs as a reference] with the scan length from the tracheal bifurcation to the diaphragmatic border. Scan 2 was acquired with standard tube current extending with reduced scan length based on Scan 1. Nine central coronary artery segments were analysed qualitatively on both scans. RESULTS Scan 2 (105.1 ± 10.1 mm) was significantly shorter than Scan 1 (127.0 ± 8.7 mm). Image quality scores were significantly better for Scan 2. However, in 5 of 6 (83%) patients with stenotic coronary artery disease, a stenosis was already detected in Scan 1 and in 13 of 24 (54%) patients with non-stenotic coronary arteries, a stenosis was already excluded by Scan 1. Using Scan 2 as reference, the positive- and negative-predictive value of Scan 1 was 83% (5 of 6 patients) and 100% (13 of 13 patients), respectively. CONCLUSION An ultra-low-dose CTCA planning scan enables a reliable scan length reduction of the following standard CTCA scan and allows for correct diagnosis in a substantial proportion of patients. ADVANCES IN KNOWLEDGE Further dose reductions are possible owing to a change in the individual patient's imaging strategy as a prior ultra-low-dose CTCA scan may already rule out the presence of a stenosis or may lead to a direct transferal to an invasive catheter procedure.

A current literature review of the social and economic ramifications of pharmacogenomic research

Objective. To explore issues in current literature concerning possible social and economic ramifications of pharmacogenomic research. Design. Review of the literature. Data sources: Academic Search Premier, Blackwell Synergy, PUBMED and Social Sciences Citation Index. Review methods. Articles dealing with the social and economic ramifications of pharmacogenomic research were selected. The articles discussed at least one of 5 areas (race, privacy/confidentiality, ethics, insurance, and research and development). Some restrictions were placed on the articles chosen to narrow down the number of articles to a relevant, manageable amount. Results. Approximately 219 articles were selected for review; 159 were fully reviewed and found to be relevant to the issues; and 33 were cited. Conclusion. Insurance and research and development decisions are led by the free-market system with limited intervention from government. Race/ethnicity, privacy/confidentiality, and ethics continue to be debated with no clear answer. However, some compromise is regulated by government based upon current laws involving these issues. ^

Economic evaluation of latent tuberculosis infection screening among health care workers in Houston

Since interferon-gamma release assays (IGRAs) were introduced in the 2000's, tuberculin skin testing (TST) and IGRAs have been used in various latent tuberculosis infection (LTBI) screening settings. IGRAs are laboratory-based tests and are considered not to be affected by previous Bacille de Calmette et Guérin (BCG) vaccination; however, they are more costly when compared directly with TST, which does not require specimen processing in a laboratory. This study aimed to examine TST and two types of IGRAs, QuantiFERON-TB Gold in Tube (QFT-GIT) and T-SPOT. TB (TSPOT), from an economic viewpoint. Firstly, a systematic literature review was conducted to identify cost related analyses of LTBI screening. Secondly, specific cost information detailing each test's items and labor was collected from an LTBI screening program of health care workers in Houston, and the cost of each test was computed. Thirdly, using the computed cost estimate of each test, cost-effectiveness analyses were conducted to compare TST and IGRAs.^ A literature search showed that a limited number of studies have been conducted, but the IGRA's economic advantages were common among studies. Cost analyses showed that IGRAs were much more costly than TST. The results were consistent with previous studies. In cost-effectiveness analyses, where test cost and consequential TB-related cost were considered, IGRAs showed variable advantages over TST depending on the targeted population. When only non BCG-vaccinated people were considered, TST was the least costly option among the three tests. On the other hand, when only BCG-vaccinated people were considered, IGRAs were less costly options. These results were mostly consistent even with varying assumption parameters.^ IGRAs can be more costly than TST, but their economic disadvantages are alleviated when the target population was BCG-vaccinated. Based on current knowledge, IGRAs may be recommended in a population where the BCG history is mixed. Additional studies are needed to better understand IGRA's reliability among low-incidence and low-risk populations in which background TB prevalence is low.^

High Efficiency Envelope Amplifier based on a Ripple Cancellation Buck Converter. Design, Optimization and Integration in an EER RFPA

Durante los últimos años la tendencia en el sector de las telecomunicaciones ha sido un aumento y diversificación en la transmisión de voz, video y fundamentalmente de datos. Para conseguir alcanzar las tasas de transmisión requeridas, los nuevos estándares de comunicaciones requieren un mayor ancho de banda y tienen un mayor factor de pico, lo cual influye en el bajo rendimiento del amplificador de radiofrecuencia (RFPA). Otro factor que ha influido en el bajo rendimiento es el diseño del amplificador de radiofrecuencia. Tradicionalmente se han utilizado amplificadores lineales por su buen funcionamiento. Sin embargo, debido al elevado factor de pico de las señales transmitidas, el rendimiento de este tipo de amplificadores es bajo. El bajo rendimiento del sistema conlleva desventajas adicionales como el aumento del coste y del tamaño del sistema de refrigeración, como en el caso de una estación base, o como la reducción del tiempo de uso y un mayor calentamiento del equipo para sistemas portátiles alimentados con baterías. Debido a estos factores, se han desarrollado durante las últimas décadas varias soluciones para aumentar el rendimiento del RFPA como la técnica de Outphasing, combinadores de potencia o la técnica de Doherty. Estas soluciones mejoran las prestaciones del RFPA y en algún caso han sido ampliamente utilizados comercialmente como la técnica de Doherty, que alcanza rendimientos hasta del 50% para el sistema completo para anchos de banda de hasta 20MHz. Pese a las mejoras obtenidas con estas soluciones, los mayores rendimientos del sistema se obtienen para soluciones basadas en la modulación de la tensión de alimentación del amplificador de potencia como “Envelope Tracking” o “EER”. La técnica de seguimiento de envolvente o “Envelope Tracking” está basada en la modulación de la tensión de alimentación de un amplificador lineal de potencia para obtener una mejora en el rendimiento en el sistema comparado a una solución con una tensión de alimentación constante. Para la implementación de esta técnica se necesita una etapa adicional, el amplificador de envolvente, que añade complejidad al amplificador de radiofrecuencia. En un amplificador diseñado con esta técnica, se aumentan las pérdidas debido a la etapa adicional que supone el amplificador de envolvente pero a su vez disminuyen las pérdidas en el amplificador de potencia. Si el diseño se optimiza adecuadamente, puede conseguirse un aumento global en el rendimiento del sistema superior al conseguido con las técnicas mencionadas anteriormente. Esta técnica presenta ventajas en el diseño del amplificador de envolvente, ya que el ancho de banda requerido puede ser menor que el ancho de banda de la señal de envolvente si se optimiza adecuadamente el diseño. Adicionalmente, debido a que la sincronización entre la señal de envolvente y de fase no tiene que ser perfecta, el proceso de integración conlleva ciertas ventajas respecto a otras técnicas como EER. La técnica de eliminación y restauración de envolvente, llamada EER o técnica de Kahn está basada en modulación simultánea de la envolvente y la fase de la señal usando un amplificador de potencia conmutado, no lineal y que permite obtener un elevado rendimiento. Esta solución fue propuesta en el año 1952, pero no ha sido implementada con éxito durante muchos años debido a los exigentes requerimientos en cuanto a la sincronización entre fase y envolvente, a las técnicas de control y de corrección de los errores y no linealidades de cada una de las etapas así como de los equipos para poder implementar estas técnicas, que tienen unos requerimientos exigentes en capacidad de cálculo y procesamiento. Dentro del diseño de un RFPA, el amplificador de envolvente tiene una gran importancia debido a su influencia en el rendimiento y ancho de banda del sistema completo. Adicionalmente, la linealidad y la calidad de la señal de transmitida deben ser elevados para poder cumplir con los diferentes estándares de telecomunicaciones. Esta tesis se centra en el amplificador de envolvente y el objetivo principal es el desarrollo de soluciones que permitan el aumento del rendimiento total del sistema a la vez que satisfagan los requerimientos de ancho de banda, calidad de la señal transmitida y de linealidad. Debido al elevado rendimiento que potencialmente puede alcanzarse con la técnica de EER, esta técnica ha sido objeto de análisis y en el estado del arte pueden encontrarse numerosas referencias que analizan el diseño y proponen diversas implementaciones. En una clasificación de alto nivel, podemos agrupar las soluciones propuestas del amplificador de envolvente según estén compuestas de una o múltiples etapas. Las soluciones para el amplificador de envolvente en una configuración multietapa se basan en la combinación de un convertidor conmutado, de elevado rendimiento con un regulador lineal, de alto ancho de banda, en una combinación serie o paralelo. Estas soluciones, debido a la combinación de las características de ambas etapas, proporcionan un buen compromiso entre rendimiento y buen funcionamiento del amplificador de RF. Por otro lado, la complejidad del sistema aumenta debido al mayor número de componentes y de señales de control necesarias y el aumento de rendimiento que se consigue con estas soluciones es limitado. Una configuración en una etapa tiene las ventajas de una mayor simplicidad, pero debido al elevado ancho de banda necesario, la frecuencia de conmutación debe aumentarse en gran medida. Esto implicará un bajo rendimiento y un peor funcionamiento del amplificador de envolvente. En el estado del arte pueden encontrarse diversas soluciones para un amplificador de envolvente en una etapa, como aumentar la frecuencia de conmutación y realizar la implementación en un circuito integrado, que tendrá mejor funcionamiento a altas frecuencias o utilizar técnicas topológicas y/o filtros de orden elevado, que permiten una reducción de la frecuencia de conmutación. En esta tesis se propone de manera original el uso de la técnica de cancelación de rizado, aplicado al convertidor reductor síncrono, para reducir la frecuencia de conmutación comparado con diseño equivalente del convertidor reductor convencional. Adicionalmente se han desarrollado dos variantes topológicas basadas en esta solución para aumentar la robustez y las prestaciones de la misma. Otro punto de interés en el diseño de un RFPA es la dificultad de poder estimar la influencia de los parámetros de diseño del amplificador de envolvente en el amplificador final integrado. En esta tesis se ha abordado este problema y se ha desarrollado una herramienta de diseño que permite obtener las principales figuras de mérito del amplificador integrado para la técnica de EER a partir del diseño del amplificador de envolvente. Mediante el uso de esta herramienta pueden validarse el efecto del ancho de banda, el rizado de tensión de salida o las no linealidades del diseño del amplificador de envolvente para varias modulaciones digitales. Las principales contribuciones originales de esta tesis son las siguientes: La aplicación de la técnica de cancelación de rizado a un convertidor reductor síncrono para un amplificador de envolvente de alto rendimiento para un RFPA linealizado mediante la técnica de EER. Una reducción del 66% en la frecuencia de conmutación, comparado con el reductor convencional equivalente. Esta reducción se ha validado experimentalmente obteniéndose una mejora en el rendimiento de entre el 12.4% y el 16% para las especificaciones de este trabajo. La topología y el diseño del convertidor reductor con dos redes de cancelación de rizado en cascada para mejorar el funcionamiento y robustez de la solución con una red de cancelación. La combinación de un convertidor redactor multifase con la técnica de cancelación de rizado para obtener una topología que proporciona una reducción del cociente entre frecuencia de conmutación y ancho de banda de la señal. El proceso de optimización del control del amplificador de envolvente en lazo cerrado para mejorar el funcionamiento respecto a la solución en lazo abierto del convertidor reductor con red de cancelación de rizado. Una herramienta de simulación para optimizar el proceso de diseño del amplificador de envolvente mediante la estimación de las figuras de mérito del RFPA, implementado mediante EER, basada en el diseño del amplificador de envolvente. La integración y caracterización del amplificador de envolvente basado en un convertidor reductor con red de cancelación de rizado en el transmisor de radiofrecuencia completo consiguiendo un elevado rendimiento, entre 57% y 70.6% para potencias de salida de 14.4W y 40.7W respectivamente. Esta tesis se divide en seis capítulos. El primer capítulo aborda la introducción enfocada en la aplicación, los amplificadores de potencia de radiofrecuencia, así como los principales problemas, retos y soluciones existentes. En el capítulo dos se desarrolla el estado del arte de amplificadores de potencia de RF, describiéndose las principales técnicas de diseño, las causas de no linealidad y las técnicas de optimización. El capítulo tres está centrado en las soluciones propuestas para el amplificador de envolvente. El modo de control se ha abordado en este capítulo y se ha presentado una optimización del diseño en lazo cerrado para el convertidor reductor convencional y para el convertidor reductor con red de cancelación de rizado. El capítulo cuatro se centra en el proceso de diseño del amplificador de envolvente. Se ha desarrollado una herramienta de diseño para evaluar la influencia del amplificador de envolvente en las figuras de mérito del RFPA. En el capítulo cinco se presenta el proceso de integración realizado y las pruebas realizadas para las diversas modulaciones, así como la completa caracterización y análisis del amplificador de RF. El capítulo seis describe las principales conclusiones de la tesis y las líneas futuras. ABSTRACT The trend in the telecommunications sector during the last years follow a high increase in the transmission rate of voice, video and mainly in data. To achieve the required levels of data rates, the new modulation standards demand higher bandwidths and have a higher peak to average power ratio (PAPR). These specifications have a direct impact in the low efficiency of the RFPA. An additional factor for the low efficiency of the RFPA is in the power amplifier design. Traditionally, linear classes have been used for the implementation of the power amplifier as they comply with the technical requirements. However, they have a low efficiency, especially in the operating range of signals with a high PAPR. The low efficiency of the transmitter has additional disadvantages as an increase in the cost and size as the cooling system needs to be increased for a base station and a temperature increase and a lower use time for portable devices. Several solutions have been proposed in the state of the art to improve the efficiency of the transmitter as Outphasing, power combiners or Doherty technique. However, the highest potential of efficiency improvement can be obtained using a modulated power supply for the power amplifier, as in the Envelope Tracking and EER techniques. The Envelope Tracking technique is based on the modulation of the power supply of a linear power amplifier to improve the overall efficiency compared to a fixed voltage supply. In the implementation of this technique an additional stage is needed, the envelope amplifier, that will increase the complexity of the RFPA. However, the efficiency of the linear power amplifier will increase and, if designed properly, the RFPA efficiency will be improved. The advantages of this technique are that the envelope amplifier design does not require such a high bandwidth as the envelope signal and that in the integration process a perfect synchronization between envelope and phase is not required. The Envelope Elimination and Restoration (EER) technique, known also as Kahn’s technique, is based on the simultaneous modulation of envelope and phase using a high efficiency switched power amplifier. This solution has the highest potential in terms of the efficiency improvement but also has the most challenging specifications. This solution, proposed in 1952, has not been successfully implemented until the last two decades due to the high demanding requirements for each of the stages as well as for the highly demanding processing and computation capabilities needed. At the system level, a very precise synchronization is required between the envelope and phase paths to avoid a linearity decrease of the system. Several techniques are used to compensate the non-linear effects in amplitude and phase and to improve the rejection of the out of band noise as predistortion, feedback and feed-forward. In order to obtain a high bandwidth and efficient RFPA using either ET or EER, the envelope amplifier stage will have a critical importance. The requirements for this stage are very demanding in terms of bandwidth, linearity and quality of the transmitted signal. Additionally the efficiency should be as high as possible, as the envelope amplifier has a direct impact in the efficiency of the overall system. This thesis is focused on the envelope amplifier stage and the main objective will be the development of high efficiency envelope amplifier solutions that comply with the requirements of the RFPA application. The design and optimization of an envelope amplifier for a RFPA application is a highly referenced research topic, and many solutions that address the envelope amplifier and the RFPA design and optimization can be found in the state of the art. From a high level classification, multiple and single stage envelope amplifiers can be identified. Envelope amplifiers for EER based on multiple stage architecture combine a linear assisted stage and a switched-mode stage, either in a series or parallel configuration, to achieve a very high performance RFPA. However, the complexity of the system increases and the efficiency improvement is limited. A single-stage envelope amplifier has the advantage of a lower complexity but in order to achieve the required bandwidth the switching frequency has to be highly increased, and therefore the performance and the efficiency are degraded. Several techniques are used to overcome this limitation, as the design of integrated circuits that are capable of switching at very high rates or the use of topological solutions, high order filters or a combination of both to reduce the switching frequency requirements. In this thesis it is originally proposed the use of the ripple cancellation technique, applied to a synchronous buck converter, to reduce the switching frequency requirements compared to a conventional buck converter for an envelope amplifier application. Three original proposals for the envelope amplifier stage, based on the ripple cancellation technique, are presented and one of the solutions has been experimentally validated and integrated in the complete amplifier, showing a high total efficiency increase compared to other solutions of the state of the art. Additionally, the proposed envelope amplifier has been integrated in the complete RFPA achieving a high total efficiency. The design process optimization has also been analyzed in this thesis. Due to the different figures of merit between the envelope amplifier and the complete RFPA it is very difficult to obtain an optimized design for the envelope amplifier. To reduce the design uncertainties, a design tool has been developed to provide an estimation of the RFPA figures of merit based on the design of the envelope amplifier. The main contributions of this thesis are: The application of the ripple cancellation technique to a synchronous buck converter for an envelope amplifier application to achieve a high efficiency and high bandwidth EER RFPA. A 66% reduction of the switching frequency, validated experimentally, compared to the equivalent conventional buck converter. This reduction has been reflected in an improvement in the efficiency between 12.4% and 16%, validated for the specifications of this work. The synchronous buck converter with two cascaded ripple cancellation networks (RCNs) topology and design to improve the robustness and the performance of the envelope amplifier. The combination of a phase-shifted multi-phase buck converter with the ripple cancellation technique to improve the envelope amplifier switching frequency to signal bandwidth ratio. The optimization of the control loop of an envelope amplifier to improve the performance of the open loop design for the conventional and ripple cancellation buck converter. A simulation tool to optimize the envelope amplifier design process. Using the envelope amplifier design as the input data, the main figures of merit of the complete RFPA for an EER application are obtained for several digital modulations. The successful integration of the envelope amplifier based on a RCN buck converter in the complete RFPA obtaining a high efficiency integrated amplifier. The efficiency obtained is between 57% and 70.6% for an output power of 14.4W and 40.7W respectively. The main figures of merit for the different modulations have been characterized and analyzed. This thesis is organized in six chapters. In Chapter 1 is provided an introduction of the RFPA application, where the main problems, challenges and solutions are described. In Chapter 2 the technical background for radiofrequency power amplifiers (RF) is presented. The main techniques to implement an RFPA are described and analyzed. The state of the art techniques to improve performance of the RFPA are identified as well as the main sources of no-linearities for the RFPA. Chapter 3 is focused on the envelope amplifier stage. The three different solutions proposed originally in this thesis for the envelope amplifier are presented and analyzed. The control stage design is analyzed and an optimization is proposed both for the conventional and the RCN buck converter. Chapter 4 is focused in the design and optimization process of the envelope amplifier and a design tool to evaluate the envelope amplifier design impact in the RFPA is presented. Chapter 5 shows the integration process of the complete amplifier. Chapter 6 addresses the main conclusions of the thesis and the future work.

Disruption of the m1 receptor gene ablates muscarinic receptor-dependent M current regulation and seizure activity in mice

Muscarinic acetylcholine receptors are members of the G protein-coupled receptor superfamily expressed in neurons, cardiomyocytes, smooth muscle, and a variety of epithelia. Five subtypes of muscarinic acetylcholine receptors have been discovered by molecular cloning, but their pharmacological similarities and frequent colocalization make it difficult to assign functional roles for individual subtypes in specific neuronal responses. We have used gene targeting by homologous recombination in embryonic stem cells to produce mice lacking the m1 receptor. These mice show no obvious behavioral or histological defects, and the m2, m3, and m4 receptors continue to be expressed in brain with no evidence of compensatory induction. However, the robust suppression of the M-current potassium channel activity evoked by muscarinic agonists in sympathetic ganglion neurons is completely lost in m1 mutant mice. In addition, both homozygous and heterozygous mutant mice are highly resistant to the seizures produced by systemic administration of the muscarinic agonist pilocarpine. Thus, the m1 receptor subtype mediates M current modulation in sympathetic neurons and induction of seizure activity in the pilocarpine model of epilepsy.

Pharmacokinetic considerations relating to tacrolimus dosing in the elderly

Relaxation of the upper age limits for solid organ transplantation coupled with improvements in post-transplant survival have resulted in greater numbers of elderly patients receiving immunosuppressant drugs such as tacrolimus. Tacrolimus is a potent agent with a narrow therapeutic window and large inter- and intraindividual pharmacokinetic variability. Numerous physiological changes occur with aging that could potentially affect the pharmacokinetics of tacrolimus and, hence, patient dosage requirements. Tacrolimus is primarily metabolised by cytochrome P450 (CYP) 3A enzymes in the gut wall and liver. It is also a substrate for P-glycoprotein, which counter-transports diffused tacrolimus out of intestinal cells and back into the gut lumen. Age-associated alterations in CYP3A and P-glycoprotein expression and/or activity, along with liver mass and body composition changes, would be expected to affect the pharmacokinetics of tacrolimus in the elderly. However, interindividual variation in these processes may mask any changes caused by aging. More investigation is needed into the impact aging has on CYP and P-glycoprotein activity and expression. No single-dose, intense blood-sampling study has specifically compared the pharmacokinetics of tacrolimus across different patient age groups. However, five population pharmacokinetic studies, one in kidney, one in bone marrow and three in liver transplant recipients, have investigated age as a co-variate. None found a significant influence for age on tacrolimus bioavailability, volume of distribution or clearance. The number of elderly patients included in each study, however, was not documented and may have been only small. It is likely that inter- and intraindividual pharmacokinetic variability associated with tacrolimus increase in elderly populations. In addition to pharmacokinetic differences, donor organ viability, multiple co-morbidity, polypharmacy and immunological changes need to be considered when using tacrolimus in the elderly. Aging is associated with decreased immunoresponsiveness, a slower body repair process and increased drug adverse effects. Elderly liver and kidney transplant recipients are more likely to develop new-onset diabetes mellitus than younger patients. Elderly transplant recipients exhibit higher mortality from infectious and cardiovascular causes than younger patients but may be less likely to develop acute rejection. Elderly kidney recipients have a higher potential for chronic allograft nephropathy, and a single rejection episode can be more devastating. There is a paucity of information on optimal tacrolimus dosage and target trough concentration in the elderly. The therapeutic window for tacrolimus concentrations may be narrower. Further integrated pharmacokinetic-pharmaco-dynamic studies of tacrolimus are required. It would appear reasonable, based on current knowledge, to commence tacrolimus at similar doses as those used in younger patients. Maintenance dose requirements over the longer term may be lower in the elderly, but the increased variability in kinetics and the variety of factors that impact on dosage suggest that patient care needs to be based around more frequent monitoring in this age group.

Fuzzy logic-based implicit authentication for mobile access control

In order to address the increasing compromise of user privacy on mobile devices, a Fuzzy Logic based implicit authentication scheme is proposed in this paper. The proposed scheme computes an aggregate score based on selected features and a threshold in real-time based on current and historic data depicting user routine. The tuned fuzzy system is then applied to the aggregated score and the threshold to determine the trust level of the current user. The proposed fuzzy-integrated implicit authentication scheme is designed to: operate adaptively and completely in the background, require minimal training period, enable high system accuracy while provide timely detection of abnormal activity. In this paper, we explore Fuzzy Logic based authentication in depth. Gaussian and triangle-based membership functions are investigated and compared using real data over several weeks from different Android phone users. The presented results show that our proposed Fuzzy Logic approach is a highly effective, and viable scheme for lightweight real-time implicit authentication on mobile devices.

Amplificador de RF Doherty assimétrico de 2-vias

Os atuais esquemas de modulação e acesso ao meio, tais como o Wide- Band Code-Division Multiple Access (WCDMA) ou Orthogonal Frequency- Division Multiple Access (OFDMA), que são otimizados para a gestão eficiente do espetro electromagnético e elevada taxa de transmissão, originam sinais de elevado Peak-to-Average Power Ratio (PAPR) e requisitos de linearidade rigorosos. As arquiteturas de amplificação tradicionais, i.e. baseadas no operação em modo de corrente do dispositivo ativo, são incapazes de satisfazer estes requisitos em simultâneo. Assim, o amplificador de potência (do inglês, Power Ampli_er (PA)) incorre numa degradação significativa de rendimento energético em favor de maior linearidade, aumentando simultaneamente os custos de operação das estacões base para os operadores de telecomunicações móveis e o impacte ambiental. Este trabalho foca-se no estudo da arquitetura Doherty, a principal solução encontrada para melhorar o compromisso linearidade/rendimento para aplicações em estações-base de comunicações móveis. Para tal, são expostos os princípios básicos de amplificadores de rádio frequência assim como a análise teórica do tradicional PA Doherty (do inglês, Doherty Power Amplifier (DhPA)) de duas vias e suas variantes. O estudo _e complementado com o projeto e implementação de um PA excitador, em classe-AB, e de um DhPA de elevada potência, colocando-se em prática a teoria e técnicas de projeto estudadas ao longo deste trabalho, aliadas aos desafios da implementação com dispositivos reais de elevada potência.

The development of planar high-K/III-V p-channel MOSFETs for post-silicon CMOS

Conventional Si complementary-metal-oxide-semiconductor (CMOS) scaling is fast approaching its limits. The extension of the logic device roadmap for future enhancements in transistor performance requires non-Si materials and new device architectures. III-V materials, due to their superior electron transport properties, are well poised to replace Si as the channel material beyond the 10nm technology node to mitigate the performance loss of Si transistors from further reductions in supply voltage to minimise power dissipation in logic circuits. However several key challenges, including a high quality dielectric/III-V gate stack, a low-resistance source/drain (S/D) technology, heterointegration onto a Si platform and a viable III-V p-metal-oxide-semiconductor field-effect-transistor (MOSFET), need to be addressed before III-Vs can be employed in CMOS. This Thesis specifically addressed the development and demonstration of planar III-V p-MOSFETs, to complement the n-MOSFET, thereby enabling an all III-V CMOS technology to be realised. This work explored the application of InGaAs and InGaSb material systems as the channel, in conjunction with Al2O3/metal gate stacks, for p-MOSFET development based on the buried-channel flatband device architecture. The body of work undertaken comprised material development, process module development and integration into a robust fabrication flow for the demonstration of p-channel devices. The parameter space in the design of the device layer structure, based around the III-V channel/barrier material options of In_x≥0.53Ga_1-xAs/In_0.52Al_0.48As and In_x≥0.1Ga_1-xSb/AlSb, was systematically examined to improve hole channel transport. A mobility of 433 cm²/Vs, the highest room temperature hole mobility of any InGaAs quantum-well channel reported to date, was obtained for the In_0.85Ga_0.15As (2.1% strain) structure. S/D ohmic contacts were developed based on thermally annealed Au/Zn/Au metallisation and validated using transmission line model test structures. The effects of metallisation thickness, diffusion barriers and de-oxidation conditions were examined. Contacts to InGaSb-channel structures were found to be sensitive to de-oxidation conditions. A fabrication process, based on a lithographically-aligned double ohmic patterning approach, was realised for deep submicron gate-to-source/drain gap (L_side) scaling to minimise the access resistance, thereby mitigating the effects of parasitic S/D series resistance on transistor performance. The developed process yielded gaps as small as 20nm. For high-k integration on GaSb, ex-situ ammonium sulphide ((NH₄)₂S) treatments, in the range 1%-22%, for 10min at 295K were systematically explored for improving the electrical properties of the Al₂O₃/GaSb interface. Electrical and physical characterisation indicated the 1% treatment to be most effective with interface trap densities in the range of 4 - 10×10¹²cm^-2eV^-1 in the lower half of the bandgap. An extended study, comprising additional immersion times at each sulphide concentration, was further undertaken to determine the surface roughness and the etching nature of the treatments on GaSb. A number of p-MOSFETs based on III-V-channels with the most promising hole transport and integration of the developed process modules were successfully demonstrated in this work. Although the non-inverted InGaAs-channel devices showed good current modulation and switch-off characteristics, several aspects of performance were non-ideal; depletion-mode operation, modest drive current (I_d,sat=1.14mA/mm), double peaked transconductance (g_m=1.06mS/mm), high subthreshold swing (SS=301mV/dec) and high on-resistance (R_on=845kΩ.μm). Despite demonstrating substantial improvement in the on-state metrics of I_d,sat (11×), g_m (5.5×) and R_on (5.6×), inverted devices did not switch-off. Scaling gate-to-source/drain gap (L_side) from 1μm down to 70nm improved I_d,sat (72.4mA/mm) by a factor of 3.6 and gm (25.8mS/mm) by a factor of 4.1 in inverted InGaAs-channel devices. Well-controlled current modulation and good saturation behaviour was observed for InGaSb-channel devices. In the on-state In_0.3Ga_0.7Sb-channel (I_d,sat=49.4mA/mm, g_m=12.3mS/mm, R_on=31.7kΩ.μm) and In_0.4Ga_0.6Sb-channel (I_d,sat=38mA/mm, g_m=11.9mS/mm, R_on=73.5kΩ.μm) devices outperformed the InGaAs-channel devices. However the devices could not be switched off. These findings indicate that III-V p-MOSFETs based on InGaSb as opposed to InGaAs channels are more suited as the p-channel option for post-Si CMOS.