Parametric timed model checking for guaranteeing timed opacity

Information leakage can have dramatic consequences on systems security. Among harmful information leaks, the timing information leakage is the ability for an attacker to deduce internal information depending on the system execution time. We address the following problem: given a timed system, synthesize the execution times for which one cannot deduce whether the system performed some secret behavior. We solve this problem in the setting of timed automata (TAs). We first provide a general solution, and then extend the problem to parametric TAs, by synthesizing internal timings making the TA secure. We study decidability, devise algorithms, and show that our method can also apply to program analysis.Comment: This is the author (and extended) version of the manuscript of the same name published in the proceedings of ATVA 2019. This work is partially supported by the ANR national research program PACS (ANR-14-CE28-0002), the ANR-NRF research program (ProMiS) and by ERATO HASUO Metamathematics for Systems Design Project (No. JPMJER1603), JS

Comparative effectiveness and safety of non-vitamin K antagonists for atrial fibrillation in clinical practice: GLORIA-AF Registry

Background and purpose: Prospectively collected data comparing the safety and effectiveness of individual non-vitamin K antagonists (NOACs) are lacking. Our objective was to directly compare the effectiveness and safety of NOACs in patients with newly diagnosed atrial fibrillation (AF). Methods: In GLORIA-AF, a large, prospective, global registry program, consecutive patients with newly diagnosed AF were followed for 3 years. The comparative analyses for (1) dabigatran vs rivaroxaban or apixaban and (2) rivaroxaban vs apixaban were performed on propensity score (PS)-matched patient sets. Proportional hazards regression was used to estimate hazard ratios (HRs) for outcomes of interest. Results: The GLORIA-AF Phase III registry enrolled 21,300 patients between January 2014 and December 2016. Of these, 3839 were prescribed dabigatran, 4015 rivaroxaban and 4505 apixaban, with median ages of 71.0, 71.0, and 73.0 years, respectively. In the PS-matched set, the adjusted HRs and 95% confidence intervals (CIs) for dabigatran vs rivaroxaban were, for stroke: 1.27 (0.79–2.03), major bleeding 0.59 (0.40–0.88), myocardial infarction 0.68 (0.40–1.16), and all-cause death 0.86 (0.67–1.10). For the comparison of dabigatran vs apixaban, in the PS-matched set, the adjusted HRs were, for stroke 1.16 (0.76–1.78), myocardial infarction 0.84 (0.48–1.46), major bleeding 0.98 (0.63–1.52) and all-cause death 1.01 (0.79–1.29). For the comparison of rivaroxaban vs apixaban, in the PS-matched set, the adjusted HRs were, for stroke 0.78 (0.52–1.19), myocardial infarction 0.96 (0.63–1.45), major bleeding 1.54 (1.14–2.08), and all-cause death 0.97 (0.80–1.19). Conclusions: Patients treated with dabigatran had a 41% lower risk of major bleeding compared with rivaroxaban, but similar risks of stroke, MI, and death. Relative to apixaban, patients treated with dabigatran had similar risks of stroke, major bleeding, MI, and death. Rivaroxaban relative to apixaban had increased risk for major bleeding, but similar risks for stroke, MI, and death. Registration: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01468701, NCT01671007. Date of registration: September 2013

Anticoagulant selection in relation to the SAMe-TT2R2 score in patients with atrial fibrillation. the GLORIA-AF registry

Aim: The SAMe-TT2R2 score helps identify patients with atrial fibrillation (AF) likely to have poor anticoagulation control during anticoagulation with vitamin K antagonists (VKA) and those with scores >2 might be better managed with a target-specific oral anticoagulant (NOAC). We hypothesized that in clinical practice, VKAs may be prescribed less frequently to patients with AF and SAMe-TT2R2 scores >2 than to patients with lower scores. Methods and results: We analyzed the Phase III dataset of the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF), a large, global, prospective global registry of patients with newly diagnosed AF and ≥1 stroke risk factor. We compared baseline clinical characteristics and antithrombotic prescriptions to determine the probability of the VKA prescription among anticoagulated patients with the baseline SAMe-TT2R2 score >2 and ≤ 2. Among 17,465 anticoagulated patients with AF, 4,828 (27.6%) patients were prescribed VKA and 12,637 (72.4%) patients an NOAC: 11,884 (68.0%) patients had SAMe-TT2R2 scores 0-2 and 5,581 (32.0%) patients had scores >2. The proportion of patients prescribed VKA was 28.0% among patients with SAMe-TT2R2 scores >2 and 27.5% in those with scores ≤2. Conclusions: The lack of a clear association between the SAMe-TT2R2 score and anticoagulant selection may be attributed to the relative efficacy and safety profiles between NOACs and VKAs as well as to the absence of trial evidence that an SAMe-TT2R2-guided strategy for the selection of the type of anticoagulation in NVAF patients has an impact on clinical outcomes of efficacy and safety. The latter hypothesis is currently being tested in a randomized controlled trial. Clinical trial registration: URL: https://www.clinicaltrials.gov//Unique identifier: NCT01937377, NCT01468701, and NCT01671007

QT interval extracted from 30-minute short resting Holter ECG recordings predicts mortality in heart failure

Background: Prolonged repolarization duration is a significant total mortality (TM) predictor in post-myocardial infarction patients. Aim: We examined the clinical significance of QT interval that was extracted from a Short Resting Holter ECG (SRH ECG – 30-min duration) as a TM predictor in heart failure (HF) patients. Methods: One hundred forty-five HF patients (male = 84%, mean age = 64 ± 12 years, mean LVEF = 33 ± 10%) underwent an SRH ECG recording for 30 min. These high-resolution ECG signals were analyzed and the QT interval was calculated and corrected according to the Fridericia formula. After 42.1 months, 26 patients died. Results: Univariate analysis for Deceased and Living groups: QTc:455 ± 33 ms vs 441 ± 32 ms (p = 0.04), LVEF:32 ± 10% vs 34 ± 9% (p < 0.5), Mean Heart Rate: 73 ± 11 bpm vs 69 ± 12 bpm (p = 0.2), SDNN/HRV: 45 ± 42 ms vs 41 ± 29 ms (p = 0.4), QRS: 123 ± 26 ms vs 119 ± 29 ms (p = 0.5). Multivariate Cox regression analysis with model adjusted for QTc, Mean Heart Rate, LVEF, QRS, revealed that QTc-Fridericia interval was an independent TM predictor (H.R.:1.017, 95% C.I.: 1.003–1.030, p = 0.01). The cut-off point of 490 ms (90th percentile) in the same model presented HR: 2.9 for TM (95%C.I.: 1.066–7.882, p = 0.03). Kaplan Meier curves depicted a clear difference in survival between the two patients' groups (QTc Group≥490 ms vs QTc Group <490 ms). The curve diverge was important (log-rank, p = 0.02). Conclusion: A fast risk stratification approach with SRH ECG recording is an efficient method for flash evaluation of mortality risk in HF patients. © 2022 Elsevier Inc

Ticagrelor versus clopidogrel in patients with STEMI treated with thrombolysis: The MIRTOS trial

Aims: We aimed to demonstrate whether coronary microvascular function is improved after ticagrelor administration compared to clopidogrel administration in STEMI subjects undergoing thrombolysis. Methods and results: MIRTOS is a multicentre study of ticagrelor versus clopidogrel in STEMI subjects treated with fibrinolysis. We enrolled 335 patients <75 years old with STEMI eligible for thrombolysis, of whom 167 were randomised to receive clopidogrel and 168 to receive ticagrelor together with thrombolysis. Primary outcome was the difference in post-PCI corrected TIMI frame count (CTFC). All clinical events were recorded in a three-month follow-up period. From the 335 patients who were randomised, 259 underwent PCI (129 clopidogrel and 130 ticagrelor) and 154 angiographies were analysable for the study primary endpoint. No significant difference was found between the clopidogrel (n=85) and ticagrelor (n=69) groups for CTFC (24.33±17.35 vs 28.33±17.59, p=0.10). No significant differences were observed in MACE and major bleeding events between randomisation groups (OR 2.0, 95% CI: 0.18-22.2, p=0.99). Conclusions: Thrombolysis with ticagrelor in patients <75 years old was not able to demonstrate superiority compared to clopidogrel in terms of microvascular injury, while there was no difference between the two groups in MACE and major bleeding events. Trial Registration. ClinicalTrials.gov Identifier: NCT02429271. EudraCT Number 2014-004082-25. © Europa Digital & Publishing 2021. All rights reserved

Verteporfin inhibits growth of human glioma in vitro without light activation

Verteporfin (VP), a light-activated drug used in photodynamic therapy for the treatment of choroidal neovascular membranes, has also been shown to be an effective inhibitor of malignant cells. Recently, studies have demonstrated that, even without photo-activation, VP may still inhibit certain tumor cell lines, including ovarian cancer, hepatocarcinoma and retinoblastoma, through the inhibition of the YAP-TEAD complex. In this study, we examined the effects of VP without light activation on human glioma cell lines (LN229 and SNB19). Through western blot analysis, we identified that human glioma cells that were exposed to VP without light activation demonstrated a downregulation of YAP-TEAD-associated downstream signaling molecules, including c-myc, axl, CTGF, cyr61 and survivin and upregulation of the tumor growth inhibitor molecule p38 MAPK. In addition, we observed that expression of VEGFA and the pluripotent marker Oct-4 were also decreased. Verteporfin did not alter the Akt survival pathway or the mTor pathway but there was a modest increase in LC3-IIB, a marker of autophagosome biogenesis. This study suggests that verteporfin should be further explored as an adjuvant therapy for the treatment of glioblastoma

Patients with Acute Coronary Syndrome are at High Risk Prior to the Event and Lipid Management is Underachieved Pre- and Post-Hospitalization

Background: Current European Guidelines suggest the use of cardiovascular risk categories and also recommend using high-intensity statins for patients with acute coronary syndromes (ACS). Objective: We examined the risk of ACS patients prior to the event, as well as the overall use and intensity of statins. Methods: We enrolled 687 ACS patients (mean age 63 years, 78% males). Low-density lipoprotein cholesterol (LDL-C) levels upon admission were used to assess attainment of LDL-C targets. Patients were categorized as very high, high, moderate and low risk based on their prior to admission cardiovascular (CV) risk. We examined statin use and dosage intensity among patients discharged from the hospital. Patients were followed for a median period of 189 days. Results: The majority of the patients (n=371, 54%) were at very high CV risk prior to admission, while 101 patients were at high risk (15%), 147 (21%) moderate risk and 68 (10%) low risk. Interestingly, LDL-C target attainment decreased as the risk increased (p<0.001). The majority (96%) of patients received statins at discharge; however, most of them (60.4%) received low/moderate intensity statins and just 35.9% received the suggested by the Guidelines high-intensity dose of statins. At follow-up, the rate of patients at high-intensity dose of statins remained similar (34.8%); 6% received no statins at all at follow-up. Conclusion: According to our study, the majority of ACS patients are already at high risk prior to their admission. Further, LDL-C targets are underachieved prior to the event and high-intensity statins are underutilized in ACS patients at, and post-discharge

Epidemiological characteristics, management and early outcomes of acute coronary syndromes in Greece: The PHAETHON study

AbstractIntroductionIn view of recent therapeutic breakthroughs in acute coronary syndromes (ACS) and essential demographic and socioeconomic changes in Greece, we conducted the prospective, multi-center, nationwide PHAETHON study (An Epidemiological Cohort Study of Acute Coronary Syndromes in the Greek Population) that aimed to recruit a representative cohort of ACS patients and examine current management practices and patient prognosis.MethodsThe PHAETHON study was conducted from May 2012 to February 2014. We enrolled 800 consecutive ACS patients from 37 hospitals with a proportional representation of all types of hospitals and geographical areas. Patients were followed for a median period of 189 days. Outcome was assessed with a composite endpoint of death, myocardial infarction, stroke, urgent revascularization and urgent hospitalization for cardiovascular causes.ResultsThe mean age of patients was 62.7 years (78% males). The majority of patients (n=411, 51%) presented with ST-elevation myocardial infarction (STEMI), whereas 389 patients presented with NSTEMI (n=303, 38%) or UA (n=86, 11%). Overall, 58.8% of the patients had hypertension, 26.5% were diabetic, 52.5% had dyslipidemia, 71.1% had a smoking history (current or past), 25.8% had a family history of coronary artery disease (CAD) and 24.1% had a prior history of CAD. In STEMI patients, 44.5% of patients were treated with thrombolysis, 38.9% underwent a coronary angiogram (34.1% were treated with primary percutaneous coronary intervention) and 16.5% did not receive urgent treatment. The pain-to-door time was 169 minutes. During hospitalization, 301 (38%) patients presented one or more complications, and 13 died (1.6%). During follow-up, 99 (12.6%) patients experienced the composite endpoint, and 21 died (2.7%).ConclusionsThe PHAETHON study provided valuable insights into the epidemiology, management and outcome of ACS patients in Greece. Management of ACS resembles the management observed in other European countries. However, several issues still to be addressed by public authorities for the timely and proper management of ACS