Efficient Generation of Correctness Certificates for the Abstract Domain of Polyhedra

Polyhedra form an established abstract domain for inferring runtime properties of programs using abstract interpretation. Computations on them need to be certified for the whole static analysis results to be trusted. In this work, we look at how far we can get down the road of a posteriori verification to lower the overhead of certification of the abstract domain of polyhedra. We demonstrate methods for making the cost of inclusion certificate generation negligible. From a performance point of view, our single-representation, constraints-based implementation compares with state-of-the-art implementations

Outcomes of patients with COVID-19 on kidney replacement therapy: a comparison among modalities in England.

BACKGROUND: Chronic kidney disease is a recognized risk factor of poor outcomes from coronavirus disease 2019 (COVID-19). METHODS: This retrospective cohort study used the UK Renal Registry database of people on kidney replacement therapy (KRT) at the end of 2019 in England and who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) between 1 March 2020 and 31 August 2020 to analyse the incidence and outcomes of COVID-19 among different KRT modalities. Comparisons with 2015-2019 mortality data were used to estimate excess deaths. RESULTS: A total of 2783 individuals on KRT tested positive for SARS-CoV-2. Patients from more-deprived areas {most deprived versus least deprived hazard ratio [HR] 1.20 [95% confidence interval (CI) 1.04-1.39]} and those with diabetes compared with those without [HR 1.51 (95% CI 1.39-1.64)] were more likely to test positive. Approximately 25% of in-centre haemodialysis and transplanted patients died within 28 days of testing positive compared with 36% of those on home therapies. Mortality was higher in those ≥80 years of age compared with those 60-79 years [odds ratio (OR) 1.71 (95% CI 1.34-2.19)] and much lower in those listed for transplantation compared with those not listed [OR 0.56 (95% CI 0.40-0.80)]. Overall, excess mortality in 2020 for people on KRT was 36% higher than the 2015-2019 average. Excess deaths peaked in April 2020 at the height of the pandemic and were characterized by wide ethnic and regional disparities. CONCLUSIONS: The impact of COVID-19 on the English KRT population highlights their extreme vulnerability and emphasizes the need to protect and prioritize this group for vaccination. COVID-19 has widened underlying inequalities in people with kidney disease, making interventions that address health inequalities a priority

Global Guidance for Local Generalization in Model Checking

SMT-based model checkers, especially IC3-style ones, are currently the most effective techniques for verification of infinite state systems. They infer global inductive invariants via local reasoning about a single step of the transition relation of a system, while employing SMT-based procedures, such as interpolation, to mitigate the limitations of local reasoning and allow for better generalization. Unfortunately, these mitigations intertwine model checking with heuristics of the underlying SMT-solver, negatively affecting stability of model checking. In this paper, we propose to tackle the limitations of locality in a systematic manner. We introduce explicit global guidance into the local reasoning performed by IC3-style algorithms. To this end, we extend the SMT-IC3 paradigm with three novel rules, designed to mitigate fundamental sources of failure that stem from locality. We instantiate these rules for the theory of Linear Integer Arithmetic and implement them on top of SPACER solver in Z3. Our empirical results show that GSPACER, SPACER extended with global guidance, is significantly more effective than both SPACER and sole global reasoning, and, furthermore, is insensitive to interpolation.Comment: Published in CAV 202

Global Guidance for Local Generalization in Model Checking

SMT-based model checkers, especially IC3-style ones, are currently the most effective techniques for verification of infinite state systems. They infer global inductive invariants via local reasoning about a single step of the transition relation of a system, while employing SMT-based procedures, such as interpolation, to mitigate the limitations of local reasoning and allow for better generalization. Unfortunately, these mitigations intertwine model checking with heuristics of the underlying SMT-solver, negatively affecting stability of model checking. In this paper, we propose to tackle the limitations of locality in a systematic manner. We introduce explicit global guidance into the local reasoning performed by IC3-style algorithms. To this end, we extend the SMT-IC3 paradigm with three novel rules, designed to mitigate fundamental sources of failure that stem from locality. We instantiate these rules for the theory of Linear Integer Arithmetic and implement them on top of Spacer solver in Z3. Our empirical results show that GSpacer, Spacer extended with global guidance, is significantly more effective than both Spacer and sole global reasoning, and, furthermore, is insensitive to interpolation

Detection of mammaglobin mRNA in peripheral blood is associated with high grade breast cancer: Interim results of a prospective cohort study

<p>Abstract</p> <p>Background</p> <p>We sought to examine the detection rate of cancer cells in peripheral blood (PBL) and in bone marrow (BM) using an established 7-gene marker panel and evaluated whether there were any definable associations of any individual gene with traditional predictors of prognosis.</p> <p>Methods</p> <p>Patients with T1-T3 primary breast cancer were enrolled into a prospective, multi-institutional cohort study. In this interim analysis 215 PBL and 177 BM samples were analyzed by multimarker, real-time RT-PCR analysis designed to detect circulating and disseminated breast cancer cells.</p> <p>Results</p> <p>At a threshold of three standard deviations from the mean expression level of normal controls, 63% (136/215) of PBL and 11% (19/177) of BM samples were positive for at least one cancer-associated marker. Marker positivity in PBL demonstrated a statistically significant association with grade II-III (vs. grade I; p = 0.0083). Overexpression of the mammaglobin (<it>mam</it>) gene alone had a statistically significant association with high tumor grade (p = 0.0315), and showed a trend towards ER-negative tumors and a high risk category. There was no association between marker positivity in PBL and the pathologic (H&E) and/or molecular (RT-PCR) status of the axillary lymph nodes (ALN).</p> <p>Conclusion</p> <p>This study suggests that molecular detection of circulating cancer cells in PBL detected by RT-PCR is associated with high tumor grade and specifically that overexpression of the <it>mam </it>gene in PBL may be a poor prognostic indicator. There was no statistically significant association between overexpression of cancer-associated genes in PBL and ALN status, supporting the concept of two potentially separate metastatic pathways.</p

Real-time RT–PCR detection of disseminated tumour cells in bone marrow has superior prognostic significance in comparison with circulating tumour cells in patients with breast cancer

This study assessed the ability of real-time reverse transcription–polymerase chain reaction (RT–PCR) analysis to detect disseminated epithelial cells (DEC) in peripheral blood (PB) and bone marrow (BM) of patients with breast cancer (BC). Detection of DEC in BM is an obvious choice in BC, but blood sampling is more convenient. The aim of this study was to evaluate whether the detection of DEC in either PB or BM predicts overall survival (OS). Peripheral blood and BM samples were collected from 148 patients with primary (stage M0, n=116/78%) and metastatic (stage M+, n=32/21%) BC before the initiation of any local or systemic treatment. Peripheral blood of healthy volunteers and BM of patients with a nonmalignant breast lesion or a haematological malignancy served as the control group. Disseminated epithelial cells was detected by measuring relative gene expression (RGE) for cytokeratin-19 (CK-19) and mammaglobin (MAM), using a quantitative RT–PCR detection method. The mean follow-up time was 786 days (+/− 487). Kaplan–Meier analysis was used for predicting OS. By taking the 95 percentile of the RGE of CK-19 (BM: 26.3 and PB: 58.7) of the control group as cutoff, elevated CK-19 expression was detected in 42 (28%) BM samples and in 22 (15%) PB samples. Mammaglobin expression was elevated in 20% (both PB and BM) of the patients with BC. There was a 68% (CK-19) and 75% (MAM) concordance between PB and BM samples when classifying the results as either positive or negative. Patients with an elevated CK-19 or MAM expression in the BM had a worse prognosis than patients without elevated expression levels (OS: log-rank test, P=0.0045 (CK-19) and P=0.025 (MAM)). For PB survival analysis, no statistical significant difference was observed between patients with or without elevated CK-19 or MAM expression (OS: log-rank test, P=0.551 (CK-19) and P=0.329 (MAM)). Separate analyses of the M0 and M+ patients revealed a marked difference in OS according to the BM CK-19 or MAM status in the M+ patient group, but in the M0 group, only MAM expression was a prognostic marker for OS. Disseminated epithelial cells, measured as elevated CK-19 or MAM mRNA expression, could be detected in both PB and BM of patients with BC. Only the presence of DEC in BM was highly predictive for OS. The occurrence of DEC in the BM is probably less time-dependent and may act as a filter for circulating BC cells. The use of either larger volumes of PB or performing an enrichment step for circulating tumour in blood cells might improve these results

Recent translational research: circulating tumor cells in breast cancer patients

In breast cancer patients, hematogenous tumor cell dissemination can be detected, even at the single cell level, by applying immunocytochemical and molecular assays. Various methods for the detection of circulating tumor cells in the peripheral blood have been described. Results from recently reported studies suggest that circulating tumor cell levels may serve as a prognostic marker and for the early assessment of therapeutic response in patients with metastatic breast cancer. However, in early-stage breast cancer, the impact of circulating tumor cells is less well established than the presence of disseminated tumor cells in bone marrow; several clinical studies have demonstrated that cells of the latter type are an independent prognostic factor at primary diagnosis. In this article we briefly summarize recent studies examining the presence of circulating tumor cells in the blood and discuss further clinical applications