Parallel symbolic state-space exploration is difficult, but what is the alternative?

State-space exploration is an essential step in many modeling and analysis problems. Its goal is to find the states reachable from the initial state of a discrete-state model described. The state space can used to answer important questions, e.g., "Is there a dead state?" and "Can N become negative?", or as a starting point for sophisticated investigations expressed in temporal logic. Unfortunately, the state space is often so large that ordinary explicit data structures and sequential algorithms cannot cope, prompting the exploration of (1) parallel approaches using multiple processors, from simple workstation networks to shared-memory supercomputers, to satisfy large memory and runtime requirements and (2) symbolic approaches using decision diagrams to encode the large structured sets and relations manipulated during state-space generation. Both approaches have merits and limitations. Parallel explicit state-space generation is challenging, but almost linear speedup can be achieved; however, the analysis is ultimately limited by the memory and processors available. Symbolic methods are a heuristic that can efficiently encode many, but not all, functions over a structured and exponentially large domain; here the pitfalls are subtler: their performance varies widely depending on the class of decision diagram chosen, the state variable order, and obscure algorithmic parameters. As symbolic approaches are often much more efficient than explicit ones for many practical models, we argue for the need to parallelize symbolic state-space generation algorithms, so that we can realize the advantage of both approaches. This is a challenging endeavor, as the most efficient symbolic algorithm, Saturation, is inherently sequential. We conclude by discussing challenges, efforts, and promising directions toward this goal

Exposure to Endocrine Disruptors and Nuclear Receptors Gene Expression in Infertile and Fertile Men from Italian Areas with Different Environmental Features

Internal levels of selected endocrine disruptors (EDs) (i.e., perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), di-2-ethylhexyl-phthalate (DEHP), mono-(2-ethylhexyl)-phthalate (MEHP), and bisphenol A (BPA)) were analyzed in blood/serum of infertile and fertile men from metropolitan, urban and rural Italian areas. PFOS and PFOA levels were also evaluated in seminal plasma. In peripheral blood mononuclear cells (PBMCs) of same subjects, gene expression levels of a panel of nuclear receptors (NRs), namely estrogen receptor α (ERα) estrogen receptor β (ERβ), androgen receptor (AR), aryl hydrocarbon receptor (AhR), peroxisome proliferator-activated receptor γ (PPARγ) and pregnane X receptor (PXR) were also assessed. Infertile men from the metropolitan area had significantly higher levels of BPA and gene expression of all NRs, except PPARγ, compared to subjects from other areas. Subjects from urban areas had significantly higher levels of MEHP, whereas subjects from rural area had higher levels of PFOA in both blood and seminal plasma. Interestingly, ERα, ERβ, AR, PXR and AhR expression is directly correlated with BPA and inversely correlated with PFOA serum levels. Our study indicates the relevance of the living environment when investigating the exposure to specific EDs. Moreover, the NRs panel in PBMCs demonstrated to be a potential biomarker of effect to assess the EDs impact on reproductive health

On-the-fly Uniformization of Time-Inhomogeneous Infinite Markov Population Models

This paper presents an on-the-fly uniformization technique for the analysis of time-inhomogeneous Markov population models. This technique is applicable to models with infinite state spaces and unbounded rates, which are, for instance, encountered in the realm of biochemical reaction networks. To deal with the infinite state space, we dynamically maintain a finite subset of the states where most of the probability mass is located. This approach yields an underapproximation of the original, infinite system. We present experimental results to show the applicability of our technique

Component-wise incremental LTL model checking

Efficient symbolic and explicit-state model checking approaches have been developed for the verification of linear time temporal logic (LTL) properties. Several attempts have been made to combine the advantages of the various algorithms. Model checking LTL properties usually poses two challenges: one must compute the synchronous product of the state space and the automaton model of the desired property, then look for counterexamples that is reduced to finding strongly connected components (SCCs) in the state space of the product. In case of concurrent systems, where the phenomenon of state space explosion often prevents the successful verification, the so-called saturation algorithm has proved its efficiency in state space exploration. This paper proposes a new approach that leverages the saturation algorithm both as an iteration strategy constructing the product directly, as well as in a new fixed-point computation algorithm to find strongly connected components on-the-fly by incrementally processing the components of the model. Complementing the search for SCCs, explicit techniques and component-wise abstractions are used to prove the absence of counterexamples. The resulting on-the-fly, incremental LTL model checking algorithm proved to scale well with the size of models, as the evaluation on models of the Model Checking Contest suggests

SAT0461 SHORT-TERM MONITORING OF DENOSUMAB EFFECT IN BREAST CANCER PATIENTS RECEIVING AROMATASE INHIBITORS USING REMS TECHNOLOGY ON LUMBAR SPINE

Background:Aromatase inhibitor (AI) therapy in women with estrogen receptor-positive (ER+) breast cancer (BC) causes accelerated bone loss and increased risk of osteoporosis and fractures as side effects. Denosumab (i.e. 60 mg twice a year) is a viable therapy against bone resorption, but the short-term monitoring of bone mineral density (BMD) change with time is still an unmet clinical need, since the current techniques (including dual-energy X-ray absorptiometry, DXA) require 1-2 years between two consecutive measurements [1]. Radiofrequency Echographic Multi Spectrometry (REMS), with high performance in terms of precision and repeatability [2], might be used in this setting of patients for short-term monitoring of bone health-related parameters.Objectives:The objective is the short-term monitoring of the effect of AIs with/without denosumab on bone health in BC patients using REMS and DXA scans at lumbar spine.Methods:Post-menopausal ER+ BC patients treated with adjuvant AIs were recruited. Two subgroups were identified, whether receiving also 60 mg of denosumab therapy every 6 months or not (named Group A and Group B, respectively). All patients underwent baseline DXA and REMS lumbar spine scans at time T0, previous to the first AI therapy, and after 12 months (time T1). REMS scan only was repeated also at 18 months (T2), since a 6-month interval between two consecutive scans is not recommended for DXA. The bone mineral density (BMD) was measured with both techniques.Results:Overall, 254 ER+ BC patients were enrolled (127 per group). The effect of denosumab on BMD is reported in Table. The BMD values obtained by DXA and REMS were not significantly different at T0 and T1, whereas the difference between Group A and B at T1 was statistically significant (p<0.001) both for REMS and DXA. At T2, REMS confirmed the increasing trend of BMD for Group A and the decreasing one for Group B, and the difference between groups was statistically significant (p<0.001). For each time point and each group, there were not statistically significant differences between DXA and REMS.Conclusion:Several studies have shown the effect of denosumab on BMD over a period not less than 2 years from the start of treatment. This study showed the feasibility of short-term follow-up using REMS lumbar spine scans at 6-month time steps.References:[1]Diez-Perez A et al, Aging Clin Exp Res 2019;31(10):1375–89[2]Di Paola M et al, Osteoporos Int 2018;30:391–402Table 1.BMD values, expressed as g/cm2, measured by DXA and REMS for Group A (patients receiving AIs only) and Group B (patients receiving AIs and denosumab) at baseline (T0), 12 months (T1) and 18 months (T2) from the start of therapy. Results are presented as median values with 25thand 75thpercentiles. P-values are obtained with a Mann-Whitney test.DXAREMSScan timeGroup AGroup BpGroup AGroup BpT00.840 (0.719-0.959)0.867 (0.723-0.958)0.990.833 (0.708-0.949)0.855 (0.714-0.973)0.77T10.823 (0.702-0.944)0.889 (0.749-0.990)0.0030.819 (0.691-0.927)0.887 (0.740-1.018)<0.001T2---0.801 (0.679-0.909)0.899 (0.754-1.020)<0.001Note:The authorsD. Ciardo, M. Ciccarese, F. Conversano, M. Di Paola, R. Forcignanò, A. Grimaldi, F.A. Lombardi, M. Muratore and P. Pisaniare listed in alphabetical orderDisclosure of Interests:None declare

Decreasing Proportion of Recent Infections among Newly Diagnosed HIV-1 Cases in Switzerland, 2008 to 2013 Based on Line-Immunoassay-Based Algorithms.

BACKGROUND: HIV surveillance requires monitoring of new HIV diagnoses and differentiation of incident and older infections. In 2008, Switzerland implemented a system for monitoring incident HIV infections based on the results of a line immunoassay (Inno-Lia) mandatorily conducted for HIV confirmation and type differentiation (HIV-1, HIV-2) of all newly diagnosed patients. Based on this system, we assessed the proportion of incident HIV infection among newly diagnosed cases in Switzerland during 2008-2013. METHODS AND RESULTS: Inno-Lia antibody reaction patterns recorded in anonymous HIV notifications to the federal health authority were classified by 10 published algorithms into incident (up to 12 months) or older infections. Utilizing these data, annual incident infection estimates were obtained in two ways, (i) based on the diagnostic performance of the algorithms and utilizing the relationship 'incident = true incident + false incident', (ii) based on the window-periods of the algorithms and utilizing the relationship 'Prevalence = Incidence x Duration'. From 2008-2013, 3'851 HIV notifications were received. Adult HIV-1 infections amounted to 3'809 cases, and 3'636 of them (95.5%) contained Inno-Lia data. Incident infection totals calculated were similar for the performance- and window-based methods, amounting on average to 1'755 (95% confidence interval, 1588-1923) and 1'790 cases (95% CI, 1679-1900), respectively. More than half of these were among men who had sex with men. Both methods showed a continuous decline of annual incident infections 2008-2013, totaling -59.5% and -50.2%, respectively. The decline of incident infections continued even in 2012, when a 15% increase in HIV notifications had been observed. This increase was entirely due to older infections. Overall declines 2008-2013 were of similar extent among the major transmission groups. CONCLUSIONS: Inno-Lia based incident HIV-1 infection surveillance proved useful and reliable. It represents a free, additional public health benefit of the use of this relatively costly test for HIV confirmation and type differentiation

VERO (R) radiotherapy for low burden cancer: 789 patients with 957 lesions

Purpose: The aim of this retrospective study is to evaluate patient profile, feasibility, and acute toxicity of RadioTherapy (RT) delivered by VERO\uae in the first 20 months of clinical activity. Methods: Inclusion criteria: 1) adult patients; 2) limited volume cancer (M0 or oligometastatic); 3) small extracranial lesions; 4) treatment between April 2012 and December 2013 and 5) written informed consent. Two techniques were employed: intensity modulated radiotherapy (IMRT) and stereotactic body radiotherapy (SBRT). Toxicity was evaluated using Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer (RTOG/EORTC) criteria. Results: Between April 2012 and December 2013, 789 consecutive patients (957 lesions) were treated. In 84% of them one lesion was treated and in 16% more than one lesion were treated synchronously/metachronously; first radiotherapy course in 85%, re-irradiation in 13%, and boost in 2% of cases. The treated region included pelvis 46%, thorax 38%, upper abdomen 15%, and neck 1%. Radiotherapy schedules included &lt;5 and &gt;5 fractions in 75% and 25% respectively. All patients completed the planned treatment and an acceptable acute toxicity was observed. Conclusions: RT delivered by VERO\uae was administrated predominantly to thoracic and pelvic lesions (lung and urologic tumours) using hypofractionation. It is a feasible approach for limited burden cancer offering short and well accepted treatment with favourable acute toxicity profile. Further investigation including dose escalation and other available VERO\uae functionalities such as real-time dynamic tumour tracking is warranted in order to fully evaluate this innovative radiotherapy system

Voxel-based analysis unveils regional dose differences associated with radiation-induced morbidity in head and neck cancer patients

The risk of radiation-induced toxicity in patients treated for head and neck (HN) cancer with radiation therapy (RT) is traditionally estimated by condensing the 3D dose distribution into a monodimensional cumulative dose-volume histogram which disregards information on dose localization. We hypothesized that a voxel-based approach would identify correlations between radiation-induced morbidity and local dose release, thus providing a new insight into spatial signature of radiation sensitivity in composite regions like the HN district. This methodology was applied to a cohort of HN cancer patients treated with RT at risk of radiation-induced acute dysphagia (RIAD). We implemented an inter-patient elastic image registration framework that proved robust enough to match even the most elusive HN structures and to provide accurate dose warping. A voxel-based statistical analysis was then performed to test regional dosimetric differences between patients with and without RIAD. We identified a significantly higher dose delivered to RIAD patients in two voxel clusters in correspondence of the cricopharyngeus muscle and cervical esophagus. Our study goes beyond the well-established organ-based philosophy exploring the relationship between radiation-induced morbidity and local dose differences in the HN region. This approach is generally applicable to different HN toxicity endpoints and is not specific to RIAD