A program analysis framework for tccp based on abstract interpretation

[EN] The timed concurrent constraint language (tccp) is a timed extension of the concurrent constraint paradigm. tccp was defined to model reactive systems, where infinite behaviors arise naturally. In previous works, a semantic framework and abstract diagnosis method for the language have been defined. On the basis of that semantic framework, this paper proposes an abstract semantics that, together with a widening operator, is suitable for the definition of different analyses for tccp programs. The abstract semantics is correct and can be represented as a finite graph where each node represents a hypothetical (abstract) computational step of the program. The widening operator allows us to guarantee the convergence of the abstract fixpoint computation.This author has been supported by the Andalusian Excellence Project P11-TIC-7659. This work has been partially supported by the EU (FEDER) and the Spanish MINECO under grants TIN 2015-69175-C4-1-R and TIN 2013-45732-C4-1-P and by Generalitat Valenciana PROMETEOII/2015/013Comini, M.; Gallardo, M.; Titolo, L.; Villanueva, A. (2017). A program analysis framework for tccp based on abstract interpretation. Formal Aspects of Computing. 29(3):531-557. https://doi.org/10.1007/s00165-016-0409-8S531557293Alpuente M, Gallardo MM, Pimentel E, Villanueva A (2006) A semantic framework for the abstract model checking of tccp programs. Theor Comput Scie 346(1): 58–95Bagnara R, Hill PM., Ricci E, Zaffanella E (2005) Precise widening operators for convex polyhedra. Sci Comput Program 58(1–2):28–56Cousot P, Cousot R (1977) Abstract interpretation: a unified lattice model for static analysis of programs by construction or approximation of fixpoints. In: Proceedings of the 4th ACM SIGACT-SIGPLAN symposium on principles of programming languages, Los Angeles, California, January 17–19. ACM Press, New York, pp 238–252Clarke EM, Grumberg O, Jha S, Lu Y, Veith H (2000) Counterexample-guided abstraction refinement. In: CAV, Lecture Notes in Computer Science, vol 1855. Springer, pp 154–169Comini M, Gallardo MM, Titolo L, Villanueva A (2015) Abstract Analysis of Universal Properties for tccp. In: Falaschi M (ed) Logic-based Program Synthesis and Transformation, 25th International Symposium, LOPSTR 2015. Revised Selected Papers, Lecture Notes in Computer Science, vol 9527. Springer, pp 163–178Comini M, Titolo L, Villanueva A (2011) Abstract diagnosis for timed concurrent constraint programs. Theory Pract Logic Programm 11(4-5):487–502Comini M, Titolo L, Villanueva A (2013) A condensed goal-independent bottom-up fixpoint modeling the behavior of tccp. Technical report, DSIC, Universitat Politècnica de València. http://riunet.upv.es/handle/10251/34328de Boer FS, Gabbrielli M, Meo MC (2000) A timed concurrent constraint language. Inf Comput 161(1): 45–83Falaschi M, Gabbrielli M, Marriott K, Palamidessi C (1993) Compositional analysis for concurrent constraint programming. In: Proceedings of the eighth annual IEEE symposium on logic in computer science, Los Alamitos, CA, USA, IEEE Computer Society Press, pp 210–221Falaschi M, Olarte C, Palamidessi C (2015) Abstract interpretation of temporal concurrent constraint programs. Theory and Pract Logic Program (TPLP) 15(3): 312–357Falaschi M, Villanueva A (2006) Automatic verification of timed concurrent constraint programs. Theory Pract Logic Program 6(3): 265–300Gallardo MM, Merino P, Pimentel E (2002) Refinement of LTL formulas for abstract model checking. In: Static analysis, 9th international symposium, SAS 2002, Madrid, Spain, September 17–20, 2002, Proceedings, pp 395–410Saraswat VA (1993) Concurrent constraint programming. The MIT Press, CambridgeSaraswat VA, Rinard M, Panangaden P (1991) The semantic foundations of concurrent constraint programming. In: Proceedings of the 18th ACM SIGPLAN-SIGACT symposium on principles of programming languages. ACM, New York, pp 333–352Zaffanella E, Giacobazzi R, Levi G (1997) Abstracting synchronization in concurrent constraint programming. J Funct Logic Program (6

A systematic review of the evidence for single stage and two stage revision of infected knee replacement

BACKGROUND: Periprosthetic infection about the knee is a devastating complication that may affect between 1% and 5% of knee replacement. With over 79 000 knee replacements being implanted each year in the UK, periprosthetic infection (PJI) is set to become an important burden of disease and cost to the healthcare economy. One of the important controversies in treatment of PJI is whether a single stage revision operation is superior to a two-stage procedure. This study sought to systematically evaluate the published evidence to determine which technique had lowest reinfection rates. METHODS: A systematic review of the literature was undertaken using the MEDLINE and EMBASE databases with the aim to identify existing studies that present the outcomes of each surgical technique. Reinfection rate was the primary outcome measure. Studies of specific subsets of patients such as resistant organisms were excluded. RESULTS: 63 studies were identified that met the inclusion criteria. The majority of which (58) were reports of two-stage revision. Reinfection rated varied between 0% and 41% in two-stage studies, and 0% and 11% in single stage studies. No clinical trials were identified and the majority of studies were observational studies. CONCLUSIONS: Evidence for both one-stage and two-stage revision is largely of low quality. The evidence basis for two-stage revision is significantly larger, and further work into direct comparison between the two techniques should be undertaken as a priority

Narrowing the knowledge gaps for melanoma

Cutaneous melanoma originates from pigment producing melanocytes or their precursors and is considered the deadliest form of skin cancer. For the last 40 years, few treatment options were available for patients with late-stage melanoma. However, remarkable advances in the therapy field were made recently, leading to the approval of two new drugs, the mutant BRAF inhibitor vemurafenib and the immunostimulant ipilimumab. Although these drugs prolong patients' lives, neither drug cures the disease completely, emphasizing the need for improvements of current therapies. Our knowledge about the complex genetic and biological mechanisms leading to melanoma development has increased, but there are still gaps in our understanding of the early events of melanocyte transformation and disease progression. In this review, we present a summary of the main contributing factors leading to melanocyte transformation and discuss recent novel findings and technologies that will help answer some of the key biological melanoma questions and lay the groundwork for novel therapies

The efficacy of indwelling pleural catheter placement versus placement plus talc sclerosant in patients with malignant pleural effusions managed exclusively as outpatients (IPC-PLUS): study protocol for a randomised controlled trial

BACKGROUND: Malignant pleural effusions (MPEs) remain a common problem, with 40,000 new cases in the United Kingdom each year and up to 250,000 in the United States. Traditional management of MPE usually involves an inpatient stay with placement of a chest drain, followed by the instillation of a pleural sclerosing agent such as talc, which aims to minimise further fluid build-up. Despite a good success rate in studies, this approach can be expensive, time-consuming and inconvenient for patients. More recently, an alternative method has become available in the form of indwelling pleural catheters (IPCs), which can be inserted and managed in an outpatient setting. It is currently unknown whether combining talc pleurodesis with IPCs will provide improved pleural symphysis rates over those of IPCs alone. METHODS/DESIGN: IPC-PLUS is a patient-blind, multicentre randomised controlled trial (RCT) comparing the combination of talc with an IPC to the use of an IPC alone for inducing pleurodesis in MPEs. The primary outcome is successful pleurodesis at five weeks post-randomisation. This study will recruit 154 patients, with an interim analysis for efficacy after 100 patients, and aims to help to define the future gold standard for outpatient management of patients with symptomatic MPEs. DISCUSSION: IPC-PLUS is the first RCT to examine the practicality and utility of talc administered via an IPC. The study remains in active recruitment and has the potential to significantly alter how patients requiring pleurodesis for MPE are approached in the future. TRIAL REGISTRATION: This trial was registered with Current Controlled Trials (identifier: ISRCTN73255764) on 23 August 2012

Quantification of resting myocardial blood flow velocity in normal humans using real-time contrast echocardiography. A feasibility study

BACKGROUND: Real-time myocardial contrast echocardiography (MCE) is a novel method for assessing myocardial perfusion. The aim of this study was to evaluate the feasibility of a very low-power real-time MCE for quantification of regional resting myocardial blood flow (MBF) velocity in normal human myocardium. METHODS: Twenty study subjects with normal left ventricular (LV) wall motion and normal coronary arteries, underwent low-power real-time MCE based on color-coded pulse inversion Doppler. Standard apical LV views were acquired during constant IV. infusion of SonoVue(®). Following transient microbubble destruction, the contrast replenishment rate (β), reflecting MBF velocity, was derived by plotting signal intensity vs. time and fitting data to the exponential function; y (t) =A (1-e(-β(t-t0))) + C. RESULTS: Quantification was feasible in 82%, 49% and 63% of four-chamber, two-chamber and apical long-axis view segments, respectively. The LAD (left anterior descending artery) and RCA (right coronary artery) territories could potentially be evaluated in most, but contrast detection in the LCx (left circumflex artery) bed was poor. Depending on localisation and which frames to be analysed, mean values of [Image: see text] were 0.21–0.69 s(-1), with higher values in medial than lateral, and in basal compared to apical regions of scan plane (p = 0.03 and p < 0.01). Higher β-values were obtained from end-diastole than end-systole (p < 0.001), values from all-frames analysis lying between. CONCLUSION: Low-power real-time MCE did have the potential to give contrast enhancement for quantification of resting regional MBF velocity. However, the technique is difficult and subjected to several limitations. Significant variability in β suggests that this parameter is best suited for with-in patient changes, comparing values of stress studies to baseline

Value of adenosine infusion for infarct size determination using real-time myocardial contrast echocardiography

BACKGROUND: Myocardial contrast echocardiography has been used for determination of infarct size (IS) in experimental models. However, with intermittent harmonic imaging, IS seems to be underestimated immediately after reperfusion due to areas with preserved, yet dysfunctional, microvasculature. The use of exogenous vasodilators showed to be useful to unmask these infarcted areas with depressed coronary flow reserve. This study was undertaken to assess the value of adenosine for IS determination in an open-chest canine model of coronary occlusion and reperfusion, using real-time myocardial contrast echocardiography (RTMCE). METHODS: Nine dogs underwent 180 minutes of coronary occlusion followed by reperfusion. PESDA (Perfluorocarbon-Exposed Sonicated Dextrose Albumin) was used as contrast agent. IS was determined by RTMCE before and during adenosine infusion at a rate of 140 mcg·Kg(-1)·min(-1). Post-mortem necrotic area was determined by triphenyl-tetrazolium chloride (TTC) staining. RESULTS: IS determined by RTMCE was 1.98 ± 1.30 cm(2 )and increased to 2.58 ± 1.53 cm(2 )during adenosine infusion (p = 0.004), with good correlation between measurements (r = 0.91; p < 0.01). The necrotic area determined by TTC was 2.29 ± 1.36 cm(2 )and showed no significant difference with IS determined by RTMCE before or during hyperemia. A slight better correlation between RTMCE and TTC measurements was observed during adenosine (r = 0.99; p < 0.001) then before it (r = 0.92; p = 0.0013). CONCLUSION: RTMCE can accurately determine IS in immediate period after acute myocardial infarction. Adenosine infusion results in a slight better detection of actual size of myocardial damage

Detection and characteristics of microvascular obstruction in reperfused acute myocardial infarction using an optimized protocol for contrast-enhanced cardiovascular magnetic resonance imaging

Several cardiovascular magnetic resonance imaging (CMR) techniques are used to detect microvascular obstruction (MVO) after acute myocardial infarction (AMI). To determine the prevalence of MVO and gain more insight into the dynamic changes in appearance of MVO, we studied 84 consecutive patients with a reperfused AMI on average 5 and 104 days after admission, using an optimised single breath-hold 3D inversion recovery gradient echo pulse sequence (IR-GRE) protocol. Early MVO (2 min post-contrast) was detected in 53 patients (63%) and late MVO (10 min post-contrast) in 45 patients (54%; p = 0.008). The extent of MVO decreased from early to late imaging (4.3 ± 3.2% vs. 1.8 ± 1.8%, p < 0.001) and showed a heterogeneous pattern. At baseline, patients without MVO (early and late) had a higher left ventricular ejection fraction (LVEF) than patients with persistent late MVO (56 ± 7% vs. 48 ± 7%, p < 0.001) and LVEF was intermediate in patients with early MVO but late MVO disappearance (54 ± 6%). During follow-up, LVEF improved in all three subgroups but remained intermediate in patients with late MVO disappearance. This optimised single breath-hold 3D IR-GRE technique for imaging MVO early and late after contrast administration is fast, accurate and allows detection of patients with intermediate remodelling at follow-up

The use of microbubbles to target drug delivery

Ultrasound-mediated microbubbles destruction has been proposed as an innovative method for noninvasive delivering of drugs and genes to different tissues. Microbubbles are used to carry a drug or gene until a specific area of interest is reached, and then ultrasound is used to burst the microbubbles, causing site-specific delivery of the bioactive materials. Furthermore, the ability of albumin-coated microbubbles to adhere to vascular regions with glycocalix damage or endothelial dysfunction is another possible mechanism to deliver drugs even in the absence of ultrasound. This review focuses on the characteristics of microbubbles that give them therapeutic properties and some important aspects of ultrasound parameters that are known to influence microbubble-mediated drug delivery. In addition, current studies involving this novel therapeutical application of microbubbles will be discussed

Therapy for metastatic melanoma: the past, present, and future

Metastatic melanoma is the most aggressive form of skin cancer with a median overall survival of less than one year. Advancements in our understanding of how melanoma evades the immune system as well as the recognition that melanoma is a molecularly heterogeneous disease have led to major improvements in the treatment of patients with metastatic melanoma. In 2011, the US Food and Drug Administration (FDA) approved two novel therapies for advanced melanoma: a BRAF inhibitor, vemurafenib, and an immune stimulatory agent, ipilimumab. The success of these agents has injected excitement and hope into patients and clinicians and, while these therapies have their limitations, they will likely provide excellent building blocks for the next generation of therapies. In this review we will discuss the advantages and limitations of the two new approved agents, current clinical trials designed to overcome these limitations, and future clinical trials that we feel hold the most promise