Impact of overlapping newer generation drug-eluting stents on clinical and angiographic outcomes: pooled analysis of five trials from the international Global RESOLUTE Program

BACKGROUND Overlapping first generation sirolimus- and paclitaxel-eluting stents are associated with persistent inflammation, fibrin deposition and delayed endothelialisation in preclinical models, and adverse angiographic and clinical outcomes--including death and myocardial infarction (MI)--in clinical studies. OBJECTIVES To establish as to whether there are any safety concerns with newer generation drug-eluting stents (DES). DESIGN Propensity score adjustment of baseline anatomical and clinical characteristics were used to compare clinical outcomes (Kaplan-Meier estimates) between patients implanted with overlapping DES (Resolute zotarolimus-eluting stent (R-ZES) or R-ZES/other DES) against no overlapping DES. Additionally, angiographic outcomes for overlapping R-ZES and everolimus-eluting stents were evaluated in the randomised RESOLUTE All-Comers Trial. SETTING Patient level data from five controlled studies of the RESOLUTE Global Clinical Program evaluating the R-ZES were pooled. Enrollment criteria were generally unrestrictive. PATIENTS 5130 patients. MAIN OUTCOME MEASURES 2-year clinical outcomes and 13-month angiographic outcomes. RESULTS 644 of 5130 patients (12.6%) in the RESOLUTE Global Clinical Program underwent overlapping DES implantation. Implantation of overlapping DES was associated with an increased frequency of MI and more complex/calcified lesion types at baseline. Adjusted in-hospital, 30-day and 2-year clinical outcomes indicated comparable cardiac death (2-year overlap vs non-overlap: 3.0% vs 2.1%, p=0.36), major adverse cardiac events (13.3% vs 10.7%, p=0.19), target-vessel MI (3.9% vs 3.4%, p=0.40), clinically driven target vessel revascularisation (7.7% vs 6.5%, p=0.32), and definite/probable stent thrombosis (1.4% vs 0.9%, p=0.28). 13-month adjusted angiographic outcomes were comparable between overlapping and non-overlapping DES. CONCLUSIONS Overlapping newer generation DES are safe and effective, with comparable angiographic and clinical outcomes--including repeat revascularisation--to non-overlapping DES.

Impact of body mass index on long-term clinical outcomes after second-generation drug eluting stent implantation: Insights from the international global RESOLUTE program

BACKGROUND An increased body mass index (BMI) is associated with a high risk of cardiovascular disease and reduction in life expectancy. However, several studies reported improved clinical outcomes in obese patients treated for cardiovascular diseases. The aim of the present study is to investigate the impact of BMI on long-term clinical outcomes after implantation of zotarolimus eluting stents. METHODS Individual patient data were pooled from the RESOLUTE Clinical Program comprising five trials worldwide. The study population was sorted according to BMI tertiles and clinical outcomes were evaluated at 2-year follow-up. RESULTS Data from a total of 5,127 patients receiving the R-ZES were included in the present study. BMI tertiles were as follow: I tertile (≤ 25.95 kg/m(2) -Low or normal weight) 1,727 patients; II tertile (>25.95 ≤ 29.74 kg/m(2) -overweight) 1,695 patients, and III tertile (>29.74 kg/m(2) -obese) 1,705 patients. At 2-years follow-up no difference was found for patients with high BMI (III tertile) compared with patients with normal or low BMI (I tertile) in terms of target lesion failure (I-III tertile, HR [95% CI] = 0.89 [0.69, 1.14], P = 0.341; major adverse cardiac events (I-III tertile, HR [95% CI] = 0.90 [0.72, 1.14], P = 0.389; cardiac death (I-III tertile, HR [95% CI] = 1.20 [0.73, 1.99], P = 0.476); myocardial infarction (I-III tertile, HR [95% CI] = 0.86 [0.55, 1.35], P = 0.509; clinically-driven target lesion revascularization (I-III tertile, HR [95% CI] = 0.75 [0.53, 1.08], P = 0.123; definite or probable stent thrombosis (I-III tertile, HR [95% CI] = 0.98 [0.49, 1.99], P = 0.964. CONCLUSIONS In the present study, the patients' body mass index was found to have no impact on long-term clinical outcomes after coronary artery interventions.

Health outcomes, quality improvement and cost-effectiveness of the Community Diabetes Education (CoDE) program: Results of a randomized controlled trial

The objectives of this dissertation were to evaluate health outcomes, quality improvement measures, and the long-term cost-effectiveness and impact on diabetes-related microvascular and macrovascular complications of a community health worker-led culturally tailored diabetes education and management intervention provided to uninsured Mexican Americans in an urban faith-based clinic. A prospective, randomized controlled repeated measures design was employed to compare the intervention effects between: (1) an intervention group (n=90) that participated in the Community Diabetes Education (CoDE) program along with usual medical care; and (2) a wait-listed comparison group (n=90) that received only usual medical care. Changes in hemoglobin A1c (HbA1c) and secondary outcomes (lipid status, blood pressure and body mass index) were assessed using linear mixed-models and an intention-to-treat approach. The CoDE group experienced greater reduction in HbA1c (-1.6%, p<.001) than the control group (-.9%, p<.001) over the 12 month study period. After adjusting for group-by-time interaction, antidiabetic medication use at baseline, changes made to the antidiabetic regime over the study period, duration of diabetes and baseline HbA1c, a statistically significant intervention effect on HbA1c (-.7%, p=.02) was observed for CoDE participants. Process and outcome quality measures were evaluated using multiple mixed-effects logistic regression models. Assessment of quality indicators revealed that the CoDE intervention group was significantly more likely to have received a dilated retinal examination than the control group, and 53% achieved a HbA1c below 7% compared with 38% of control group subjects. Long-term cost-effectiveness and impact on diabetes-related health outcomes were estimated through simulation modeling using the rigorously validated Archimedes Model. Over a 20 year time horizon, CoDE participants were forecasted to have less proliferative diabetic retinopathy, fewer foot ulcers, and reduced numbers of foot amputations than control group subjects who received usual medical care. An incremental cost-effectiveness ratio of $355 per quality-adjusted life-year gained was estimated for CoDE intervention participants over the same time period. The results from the three areas of program evaluation: impact on short-term health outcomes, quantification of improvement in quality of diabetes care, and projection of long-term cost-effectiveness and impact on diabetes-related health outcomes provide evidence that a community health worker can be a valuable resource to reduce diabetes disparities for uninsured Mexican Americans. This evidence supports formal integration of community health workers as members of the diabetes care team.^

Code and readme of a MATLAB-based graphical user interface program for computing functionals of the geopotential

We present a novel graphical user interface program GrafLab (GRAvity Field LABoratory) for spherical harmonic synthesis (SHS) created in MATLAB®. This program allows to comfortably compute 38 various functionals of the geopotential up to ultra-high degrees and orders of spherical harmonic expansion. For the most difficult part of the SHS, namely the evaluation of the fully normalized associated Legendre functions (fnALFs), we used three different approaches according to required maximum degree: (i) the standard forward column method (up to maximum degree 1800, in some cases up to degree 2190); (ii) the modified forward column method combined with Horner's scheme (up to maximum degree 2700); (iii) the extended-range arithmetic (up to an arbitrary maximum degree). For the maximum degree 2190, the SHS with fnALFs evaluated using the extended-range arithmetic approach takes only approximately 2-3 times longer than its standard arithmetic counterpart, i.e. the standard forward column method. In the GrafLab, the functionals of the geopotential can be evaluated on a regular grid or point-wise, while the input coordinates can either be read from a data file or entered manually. For the computation on a regular grid we decided to apply the lumped coefficients approach due to significant time-efficiency of this method. Furthermore, if a full variance-covariance matrix of spherical harmonic coefficients is available, it is possible to compute the commission errors of the functionals. When computing on a regular grid, the output functionals or their commission errors may be depicted on a map using automatically selected cartographic projection.

Abstraction-carrying code: a model for mobile code safety

Proof-Carrying Code (PCC) is a general approach to mobile code safety in which programs are augmented with a certificate (or proof). The intended benefit is that the program consumer can locally validate the certificate w.r.t. the "untrustcd" program by means of a certificate checker a process which should be much simpler, efficient, and automatic than generating the original proof. The practical uptake of PCC greatly depends on the existence of a variety of enabling technologies which allow both proving programs correct and replacing a costly verification process by an efficient checking proceduri on th( consumer side. In this work we propose Abstraction- Carrying Code (ACC), a novel approach which uses abstract interpretation as enabling technology. We argue that the large body of applications of abstract interpretation to program verification is amenable to the overall PCC scheme. In particular, we rely on an expressive class of safely policies which can be defined over different abstract domains. We use an abstraction (or abstract model) of the program computed by standard static analyzers as a certificate. The validity of the abstraction on ihe consumer side is checked in a single pass by a very efficient and specialized abstract-interpreter. We believe that ACC brings the expressiveness, flexibility and automation which is inherent in abstract interpretation techniques to the area of mobile code safety.

Reduced certificates for abstraction-carrying code

Abstraction-Carrying Code (ACC) has recently been proposed as a framework for mobile code safety in which the code supplier provides a program together with an abstraction whose validity entails compliance with a predefined safety policy. The abstraction plays thus the role of safety certifícate and its generation is carried out automatically by a fixed-point analyzer. The advantage of providing a (fixedpoint) abstraction to the code consumer is that its validity is checked in a single pass of an abstract interpretation-based checker. A main challenge is to reduce the size of certificates as much as possible while at the same time not increasing checking time. We introduce the notion of reduced certifícate which characterizes the subset of the abstraction which a checker needs in order to validate (and re-construct) the full certifícate in a single pass. Based on this notion, we instrument a generic analysis algorithm with the necessary extensions in order to identify the information relevant to the checker. We also provide a correct checking algorithm together with sufficient conditions for ensuring its completeness. The experimental results within the CiaoPP system show that our proposal is able to greatly reduce the size of certificates in practice.

Abstraction-carrying code

Proof-Carrying Code (PCC) is a general approach to mobile code safety in which programs are augmented with a certifícate (or proof). The practical uptake of PCC greatly depends on the existence of a variety of enabling technologies which allow both to prove programs correct and to replace a costly verification process by an efñcient checking procedure on the consumer side. In this work we propose Abstraction-Carrying Code (ACC), a novel approach which uses abstract interpretation as enabling technology. We argüe that the large body of applications of abstract interpretation to program verification is amenable to the overall PCC scheme. In particular, we rely on an expressive class of safety policies which can be defined over different abstract domains. We use an abstraction (or abstract model) of the program computed by standard static analyzers as a certifícate. The validity of the abstraction on the consumer side is checked in a single-pass by a very efficient and specialized abstract-interpreter. We believe that ACC brings the expressiveness, flexibility and automation which is inherent in abstract interpretation techniques to the área of mobile code safety. We have implemented and benchmarked ACC within the Ciao system preprocessor. The experimental results show that the checking phase is indeed faster than the proof generation phase, and that the sizes of certificates are reasonable.

On abstraction-carrying code and certificate-size reduction

Abstraction-Carrying Code (ACC) is a framework for mobile code safety in which the code supplier provides a program together with an abstraction (or abstract model of the program) whose validity entails compliance with a predefined safety policy. The abstraction plays thus the role of safety certificate and its generation is carried out automatically by a fixed-point analyzer. The advantage of providing a (fixed-point) abstraction to the code consumer is that its validity is checked in a single pass (i.e., one iteration) of an abstract interpretation-based checker. A main challenge to make ACC useful in practice is to reduce the size of certificates as much as possible, while at the same time not increasing checking time. Intuitively, we only include in the certificate the information which the checker is unable to reproduce without iterating. We introduce the notion of reduced certifícate which characterizes the subset of the abstraction which a checker needs in order to validate (and re-construct) the full certificate in a single pass. Based on this notion, we show how to instrument a generic analysis algorithm with the necessary extensions in order to identify the information relevant to the checker.

Abstraction carrying code and resource-awareness

Proof-Carrying Code (PCC) is a general approach to mobile code safety in which the code supplier augments the program with a certifícate (or proof). The intended benefit is that the program consumer can locally validate the certifícate w.r.t. the "untrusted" program by means of a certifícate checker—a process which should be much simpler, eíñcient, and automatic than generating the original proof. Abstraction Carrying Code (ACC) is an enabling technology for PCC in which an abstract model of the program plays the role of certifícate. The generation of the certifícate, Le., the abstraction, is automatically carried out by an abstract interpretation-based analysis engine, which is parametric w.r.t. different abstract domains. While the analyzer on the producer side typically has to compute a semantic fixpoint in a complex, iterative process, on the receiver it is only necessary to check that the certifícate is indeed a fixpoint of the abstract semantics equations representing the program. This is done in a single pass in a much more efficient process. ACC addresses the fundamental issues in PCC and opens the door to the applicability of the large body of frameworks and domains based on abstract interpretation as enabling technology for PCC. We present an overview of ACC and we describe in a tutorial fashion an application to the problem of resource-aware security in mobile code. Essentially the information computed by a cost analyzer is used to genérate cost certificates which attest a safe and efficient use of a mobile code. A receiving side can then reject code which brings cost certificates (which it cannot validate or) which have too large cost requirements in terms of computing resources (in time and/or space) and accept mobile code which meets the established requirements.

Reduced certificates for abstraction-carrying code

Abstraction-Carrying Code (ACC) has recently been proposed as a framework for mobile code safety in which the code supplier provides a program together with an abstraction (or abstract model of the program) whose validity entails compliance with a predefined safety policy. The abstraction plays thus the role of safety certifícate and its generation is carried out automatically by a fixed-point analyzer. The advantage of providing a (fixed-point) abstraction to the code consumer is that its validity is checked in a single pass (i.e., one iteration) of an abstract interpretation-based checker. A main challenge to make ACC useful in practice is to reduce the size of certificates as much as possible while at the same time not increasing checking time. The intuitive idea is to only include in the certifícate information that the checker is unable to reproduce without iterating. We introduce the notion of reduced certifícate which characterizes the subset of the abstraction which a checker needs in order to validate (and re-construct) the full certifícate in a single pass. Based on this notion, we instrument a generic analysis algorithm with the necessary extensions in order to identify information which can be reconstructed by the single-pass checker. Finally, we study what the effects of reduced certificates are on the correctness and completeness of the checking process. We provide a correct checking algorithm together with sufficient conditions for ensuring its completeness. Our ideas are illustrated through a running example, implemented in the context of constraint logic programs, which shows that our approach improves state-of-the-art techniques for reducing the size of certificates.

Certificate size reduction in abstraction-carrying code

Abstraction-Carrying Code (ACC) has recently been proposed as a framework for mobile code safety in which the code supplier provides a program together with an abstraction (or abstract model of the program) whose validity entails compliance with a predefined safety policy. The abstraction plays thus the role of safety certificate and its generation is carried out automatically by a fixpoint analyzer. The advantage of providing a (fixpoint) abstraction to the code consumer is that its validity is checked in a single pass (i.e., one iteration) of an abstract interpretation-based checker. A main challenge to make ACC useful in practice is to reduce the size of certificates as much as possible while at the same time not increasing checking time. The intuitive idea is to only include in the certificate information that the checker is unable to reproduce without iterating. We introduce the notion of reduced certificate which characterizes the subset of the abstraction which a checker needs in order to validate (and re-construct) the fall certificate in a single pass. Based on this notion, we instrument a generic analysis algorithm with the necessary extensions in order to identify the information relevant to the checker. Interestingly, the fact that the reduced certificate omits (parts of) the abstraction has implications in the design of the checker. We provide the sufficient conditions which allow us to ensure that 1) if the checker succeeds in validating the certificate, then the certificate is valid for the program (correctness) and 2) the checker will succeed for any reduced certificate which is valid (completeness). Our approach has been implemented and benchmarked within the CiaoPP system. The experimental results show t h a t our proposal is able to greatly reduce the size of certificates in practice. To appear in Theory and Practice of Logic Programming (TPLP).

Generación de Casos de Prueba en Programación Orientada a Objetos = Test Case Generation in Object-Oriented Programming

Las pruebas de software (Testing) son en la actualidad la técnica más utilizada para la validación y la evaluación de la calidad de un programa. El testing está integrado en todas las metodologías prácticas de desarrollo de software y juega un papel crucial en el éxito de cualquier proyecto de software. Desde las unidades de código más pequeñas a los componentes más complejos, su integración en un sistema de software y su despliegue a producción, todas las piezas de un producto de software deben ser probadas a fondo antes de que el producto de software pueda ser liberado a un entorno de producción. La mayor limitación del testing de software es que continúa siendo un conjunto de tareas manuales, representando una buena parte del coste total de desarrollo. En este escenario, la automatización resulta fundamental para aliviar estos altos costes. La generación automática de casos de pruebas (TCG, del inglés test case generation) es el proceso de generar automáticamente casos de prueba que logren un alto recubrimiento del programa. Entre la gran variedad de enfoques hacia la TCG, esta tesis se centra en un enfoque estructural de caja blanca, y más concretamente en una de las técnicas más utilizadas actualmente, la ejecución simbólica. En ejecución simbólica, el programa bajo pruebas es ejecutado con expresiones simbólicas como argumentos de entrada en lugar de valores concretos. Esta tesis se basa en un marco general para la generación automática de casos de prueba dirigido a programas imperativos orientados a objetos (Java, por ejemplo) y basado en programación lógica con restricciones (CLP, del inglés constraint logic programming). En este marco general, el programa imperativo bajo pruebas es primeramente traducido a un programa CLP equivalente, y luego dicho programa CLP es ejecutado simbólicamente utilizando los mecanismos de evaluación estándar de CLP, extendidos con operaciones especiales para el tratamiento de estructuras de datos dinámicas. Mejorar la escalabilidad y la eficiencia de la ejecución simbólica constituye un reto muy importante. Es bien sabido que la ejecución simbólica resulta impracticable debido al gran número de caminos de ejecución que deben ser explorados y a tamaño de las restricciones que se deben manipular. Además, la generación de casos de prueba mediante ejecución simbólica tiende a producir un número innecesariamente grande de casos de prueba cuando es aplicada a programas de tamaño medio o grande. Las contribuciones de esta tesis pueden ser resumidas como sigue. (1) Se desarrolla un enfoque composicional basado en CLP para la generación de casos de prueba, el cual busca aliviar el problema de la explosión de caminos interprocedimiento analizando de forma separada cada componente (p.ej. método) del programa bajo pruebas, almacenando los resultados y reutilizándolos incrementalmente hasta obtener resultados para el programa completo. También se ha desarrollado un enfoque composicional basado en especialización de programas (evaluación parcial) para la herramienta de ejecución simbólica Symbolic PathFinder (SPF). (2) Se propone una metodología para usar información del consumo de recursos del programa bajo pruebas para guiar la ejecución simbólica hacia aquellas partes del programa que satisfacen una determinada política de recursos, evitando la exploración de aquellas partes del programa que violan dicha política. (3) Se propone una metodología genérica para guiar la ejecución simbólica hacia las partes más interesantes del programa, la cual utiliza abstracciones como generadores de trazas para guiar la ejecución de acuerdo a criterios de selección estructurales. (4) Se propone un nuevo resolutor de restricciones, el cual maneja eficientemente restricciones sobre el uso de la memoria dinámica global (heap) durante ejecución simbólica, el cual mejora considerablemente el rendimiento de la técnica estándar utilizada para este propósito, la \lazy initialization". (5) Todas las técnicas propuestas han sido implementadas en el sistema PET (el enfoque composicional ha sido también implementado en la herramienta SPF). Mediante evaluación experimental se ha confirmado que todas ellas mejoran considerablemente la escalabilidad y eficiencia de la ejecución simbólica y la generación de casos de prueba. ABSTRACT Testing is nowadays the most used technique to validate software and assess its quality. It is integrated into all practical software development methodologies and plays a crucial role towards the success of any software project. From the smallest units of code to the most complex components and their integration into a software system and later deployment; all pieces of a software product must be tested thoroughly before a software product can be released. The main limitation of software testing is that it remains a mostly manual task, representing a large fraction of the total development cost. In this scenario, test automation is paramount to alleviate such high costs. Test case generation (TCG) is the process of automatically generating test inputs that achieve high coverage of the system under test. Among a wide variety of approaches to TCG, this thesis focuses on structural (white-box) TCG, where one of the most successful enabling techniques is symbolic execution. In symbolic execution, the program under test is executed with its input arguments being symbolic expressions rather than concrete values. This thesis relies on a previously developed constraint-based TCG framework for imperative object-oriented programs (e.g., Java), in which the imperative program under test is first translated into an equivalent constraint logic program, and then such translated program is symbolically executed by relying on standard evaluation mechanisms of Constraint Logic Programming (CLP), extended with special treatment for dynamically allocated data structures. Improving the scalability and efficiency of symbolic execution constitutes a major challenge. It is well known that symbolic execution quickly becomes impractical due to the large number of paths that must be explored and the size of the constraints that must be handled. Moreover, symbolic execution-based TCG tends to produce an unnecessarily large number of test cases when applied to medium or large programs. The contributions of this dissertation can be summarized as follows. (1) A compositional approach to CLP-based TCG is developed which overcomes the inter-procedural path explosion by separately analyzing each component (method) in a program under test, stowing the results as method summaries and incrementally reusing them to obtain whole-program results. A similar compositional strategy that relies on program specialization is also developed for the state-of-the-art symbolic execution tool Symbolic PathFinder (SPF). (2) Resource-driven TCG is proposed as a methodology to use resource consumption information to drive symbolic execution towards those parts of the program under test that comply with a user-provided resource policy, avoiding the exploration of those parts of the program that violate such policy. (3) A generic methodology to guide symbolic execution towards the most interesting parts of a program is proposed, which uses abstractions as oracles to steer symbolic execution through those parts of the program under test that interest the programmer/tester most. (4) A new heap-constraint solver is proposed, which efficiently handles heap-related constraints and aliasing of references during symbolic execution and greatly outperforms the state-of-the-art standard technique known as lazy initialization. (5) All techniques above have been implemented in the PET system (and some of them in the SPF tool). Experimental evaluation has confirmed that they considerably help towards a more scalable and efficient symbolic execution and TCG.

A flowchart-to-source-code conversion program for GPSS/360 /

Originally presented as the author's thesis (M.S.), University of Illinois at Urbana-Champaign.