Content validity of visual analog scales to assess symptom severity of acute angioedema attacks in adults with hereditary angioedema : an interview study

Background: Hereditary angioedema (HAE) is a rare, debilitating, potentially life-threatening condition characterized by recurrent acute attacks of edema of the skin, face/upper airway, and gastrointestinal and urogenital tracts. During a laryngeal attack, people with HAE may be at risk of suffocation, while other attacks are often associated with intense pain, disfigurement, disability, and/or vomiting. The intensity of some symptoms is known only to the person experiencing them. Thus, interview studies are needed to explore such experience and patient-reported outcome measures (PROMs) are required for systematic assessment of symptoms in the clinical setting and in clinical trials of treatments for acute HAE attacks.

Objective: The aim of this interview study was to assess the content validity and suitability of four visual analog scale (VAS) instruments for use in clinical studies. The VAS instruments were designed to assess symptoms at abdominal, oro-facial-pharyngeal-laryngeal, peripheral, and urogenital attack locations. This is the first known study to report qualitative data about the patient's experience of the rare disorder, HAE.

Methods: Semi-structured exploratory and cognitive debriefing interviews were conducted with 27 adults with a confirmed clinical/laboratory diagnosis of HAE (baseline plasma level of functional plasma protein C1 esterase inhibitor [C1INH] <50% of normal without evidence for acquired angioedema). There were 17 participants from the US and 10 from Italy, with mean age 42.5 (SD 14.5) years, range 18–72 years, mean HAE duration 21.3 (SD 14.1) years, range 1–45 years, 67% female, and 44% VAS-naïve. Experience of acute angioedema attacks was first explored, noting spontaneous mentions by participants of HAE symptomatology. Cognitive debriefing of the VAS instruments was undertaken to assess the suitability, comprehensibility, and relevance of the VAS items. Asymptomatic participants completed the VAS instruments relevant to their angioedema experience, reporting as if they were experiencing an acute angioedema attack at the time. Interviews were conducted in the clinic setting in the US and Italy over an 8-month period.

Results: Participants mentioned spontaneously almost all aspects of acute angioedema attacks covered by the four VAS instruments, thus providing strong support for inclusion of nearly all VAS items, with no important symptoms missing. Predominant symptoms found to be associated with acute angioedema attacks were edema and pain, and there was evidence of varying degrees of disruption to everyday activities supporting the inclusion of an overall severity item reflecting the disabling effects of HAE symptoms. VAS item wording was understood by participants.

Conclusion: This interview study explored and reported the patient experience of HAE attacks. It demonstrated the content validity of the four anatomical location HAE VAS instruments and their suitability for use in clinical trials of recombinant human C1INH (rhC1INH) treatment for ascertaining trial participants' assessments of the severity of acute angioedema symptoms.

Mixed-signal analog-digital circuits design on the pre-diffused digital array using trapezoidal association of transistors

The mixed-signal and analog design on a pre-diffused array is a challenging task, given that the digital array is a linear matrix arrangement of minimum-length transistors. To surmount this drawback a specific discipline for designing analog circuits over such array is required. An important novel technique proposed is the use of TAT (Trapezoidal Associations of Transistors) composite transistors on the semi-custom Sea-Of-Transistors (SOT) array. The analysis and advantages of TAT arrangement are extensively analyzed and demonstrated, with simulation and measurement comparisons to equivalent single transistors. Basic analog cells were also designed as well in full-custom and TAT versions in 1.0mm and 0.5mm digital CMOS technologies. Most of the circuits were prototyped in full-custom and TAT-based on pre-diffused SOT arrays. An innovative demonstration of the TAT technique is shown with the design and implementation of a mixed-signal analog system, i. e., a fully differential 2nd order Sigma-Delta Analog-to-Digital (A/D) modulator, fabricated in both full-custom and SOT array methodologies in 0.5mm CMOS technology from MOSIS foundry. Three test-chips were designed and fabricated in 0.5mm. Two of them are IC chips containing the full-custom and SOT array versions of a 2nd-Order Sigma-Delta A/D modulator. The third IC contains a transistors-structure (TAT and single) and analog cells placed side-by-side, block components (Comparator and Folded-cascode OTA) of the Sigma-Delta modulator.

Low cost BIST techniques for linear and non-linear analog circuits

With the ever increasing demands for high complexity consumer electronic products, market pressures demand faster product development and lower cost. SoCbased design can provide the required design flexibility and speed by allowing the use of IP cores. However, testing costs in the SoC environment can reach a substantial percent of the total production cost. Analog testing costs may dominate the total test cost, as testing of analog circuits usually require functional verification of the circuit and special testing procedures. For RF analog circuits commonly used in wireless applications, testing is further complicated because of the high frequencies involved. In summary, reducing analog test cost is of major importance in the electronic industry today. BIST techniques for analog circuits, though potentially able to solve the analog test cost problem, have some limitations. Some techniques are circuit dependent, requiring reconfiguration of the circuit being tested, and are generally not usable in RF circuits. In the SoC environment, as processing and memory resources are available, they could be used in the test. However, the overhead for adding additional AD and DA converters may be too costly for most systems, and analog routing of signals may not be feasible and may introduce signal distortion. In this work a simple and low cost digitizer is used instead of an ADC in order to enable analog testing strategies to be implemented in a SoC environment. Thanks to the low analog area overhead of the converter, multiple analog test points can be observed and specific analog test strategies can be enabled. As the digitizer is always connected to the analog test point, it is not necessary to include muxes and switches that would degrade the signal path. For RF analog circuits, this is specially useful, as the circuit impedance is fixed and the influence of the digitizer can be accounted for in the design phase. Thanks to the simplicity of the converter, it is able to reach higher frequencies, and enables the implementation of low cost RF test strategies. The digitizer has been applied successfully in the testing of both low frequency and RF analog circuits. Also, as testing is based on frequency-domain characteristics, nonlinear characteristics like intermodulation products can also be evaluated. Specifically, practical results were obtained for prototyped base band filters and a 100MHz mixer. The application of the converter for noise figure evaluation was also addressed, and experimental results for low frequency amplifiers using conventional opamps were obtained. The proposed method is able to enhance the testability of current mixed-signal designs, being suitable for the SoC environment used in many industrial products nowadays.

Teste da rede de interconexões de field programmable analog arrays

Os dispositivos analógicos programáveis (FPAAs, do inglês, Field Programmable Analog Arrays), apesar de ainda não terem a mesma popularidade de seus pares digitais (FPGAs, do inglês, Field Programmable Gate Arrays), possuem uma gama de aplicações bastante ampla, que vai desde o condicionamento de sinais em sistemas de instrumentação, até o processamento de sinais de radiofreqüência (RF) em telecomunicações. Porém, ao mesmo tempo em que os FPAAs trouxeram um impressionante ganho na agilidade de concepção de circuitos analógicos, também trouxeram um conjunto de novos problemas relativos ao teste deste tipo de dispositivo. Os FPAAs podem ser divididos em duas partes fundamentais: seus blocos programáveis básicos (CABs, do inglês, Configurable Analog Blocks) e sua rede de interconexões. A rede de interconexões, por sua vez, pode ser dividida em duas partes: interconexões internas (locais e globais entre CABs) e interconexões externas (envolvendo células de I/O). Todas estas partes apresentam características estruturais e funcionais distintas, de forma que devem ser testadas separadamente, pois necessitam que se considerem modelos de falhas, configurações e estímulos de teste específicos para assegurar uma boa taxa de detecção de defeitos. Como trabalhos anteriores já estudaram o teste dos CABs, o foco desta dissertação está direcionado ao desenvolvimento de metodologias que se propõem a testar a rede de interconexões de FPAAs. Apesar das várias diferenças entre as redes de interconexões de FPGAs e FPAAs, muitas também são as semelhanças entre elas, sendo, portanto, indiscutível que o ponto de partida deste trabalho tenha que ser o estudo das muitas técnicas propostas para o teste de interconexões em FPGAs, para posterior adaptação ao caso dos FPAAs. Além disto, embora o seu foco não recaia sobre o teste de CABs, pretende-se utilizá-los como recursos internos do dispositivo passíveis de gerar sinais e analisar respostas de teste, propondo uma abordagem de auto-teste integrado de interconexões que reduza o custo relativo ao equipamento externo de teste. Eventualmente, estes mesmos recursos poderão também ser utilizados para diagnóstico das partes defeituosas. Neste trabalho, utiliza-se como veículo de experimentação um dispositivo específico (Anadigm AN10E40), mas pretende-se que as metodologias de teste propostas sejam abrangentes e possam ser facilmente adaptadas a outros FPAAs comerciais que apresentem redes de interconexão semelhantes.

4-Fluoro-2-methoxyphenol, an apocynin analog with enhanced inhibitory effect on leukocyte oxidant production and phagocytosis

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Analog neural nonderivative optimizers

Continuous-time neural networks for solving convex nonlinear unconstrained;programming problems without using gradient information of the objective function are proposed and analyzed. Thus, the proposed networks are nonderivative optimizers. First, networks for optimizing objective functions of one variable are discussed. Then, an existing one-dimensional optimizer is analyzed, and a new line search optimizer is proposed. It is shown that the proposed optimizer network is robust in the sense that it has disturbance rejection property. The network can be implemented easily in hardware using standard circuit elements. The one-dimensional net is used as a building block in multidimensional networks for optimizing objective functions of several variables. The multidimensional nets implement a continuous version of the coordinate descent method.

Hardware implementation of an analog neural nonderivative optimizer

Analog neural systems that can automatically find the minimum value of the outputs of unknown analog systems, described by convex functions, are studied. When information about derivative or gradient are not used, these systems are called analog nonderivative optimizers. An electronic circuit for the analog neural nonderivative optimizer proposed by Teixeira and Zak, and its simulation with software PSPICE, is presented. With the simulation results and hardware implementation of the system, the validity of the proposed optimizer can be verified. These results are original, from the best of the authors knowledge.

A current-mode based Field-Programmable Analog Array for signal processing applications

This paper presents a new approach to develop Field Programmable Analog Arrays (FPAAs),(1) which avoids excessive number of programming elements in the signal path, thus enhancing the performance. The paper also introduces a novel FPAA architecture, devoid of the conventional switching and connection modules. The proposed FPAA is based on simple current mode sub-circuits. An uncompounded methodology has been employed for the programming of the Configurable Analog Cell (CAC). Current mode approach has enabled the operation of the FPAA presented here, over almost three decades of frequency range. We have demonstrated the feasibility of the FPAA by implementing some signal processing functions.

Low voltage analog synthesizer of orthogonal signals: A current-mode approach

An analog synthesizer of orthogonal signals for digital CMOS technology and 3V supply voltage is presented. The adaptive architecture accomplishes the synthesis of mutually orthogonal signal, such as trigonometric and polynomial basis. Experimental results using 0.35 mu m AMS CMOS process are presented for generation of the cosine and Legendre basis.

An algorithmic of analog-to-digital converter using current-mode and digital CMOS process

In this paper a new algorithmic of Analog-to-Digital Converter is presented. This new topology use the current-mode technique that allows a large dynamic range and can be implemented in digital CMOS process. The ADC proposed is very small and can handle high sampling rates. Simulation results using a 1.2um CMOS process show that an 8-b ADC can support a sampling rate of 50MHz.

Low voltage analog synthesizer of orthogonal signals using current mode techniques

An analog synthesizer of orthogonal signals for digital CMOS technology and 3V supply voltage is presented. The adaptive architecture accomplishes the synthesis of mutually orthogonal signal, such as trigonometric and polynomial basis. Simulation results using 0.35 mu m AMS CMOS process are presented for generation of the cosine and Legendre basis.

Frequency synthesizer using a hybrid analog/digital loop filter: A low complexity approach

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

q-Analog of the gap equation for cuprates

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)