From UML specification into FPGA implementation

In the paper a method of using the Unified Modeling Language for specification of digital systems, especially logic controllers, is presented. The proposed method is based mainly on the UML state machine diagrams and uses Hierarchical Concurrent Finite State Machines (HCFSMs) as a temporary model. The paper shows a way to transform the UML diagrams, expressed in XML language, to the form that is acceptable by reconfigurable FPGAs (Field Programmable Gate Arrays). The UML specification is used to generate an effective program in Hardware Description Languages (HDLs), especially Verilog

Diabetogenic effect of statins: a comprehensive review on the clinical relevance, underlying pathomechanisms and rationale for tailored statin therapy

Statins are potent hypolipidemic drugs effectively reducing low-density lipoprotein (LDL) cholesterol serum concentration, but also exerting a wide range of pleiotropic effects. In numerous clinical trials statins were proven to substantially decrease cardiovascular morbidity and mortality both in primary and secondary prevention. However, a growing body of evidence suggests that statins, although safe and generally well-tolerated, are associated with an increased occurrence of new-onset diabetes mellitus (DM). The aim of this review is to explore the relationship between statin therapy and new-onset DM, including its clinical relevance and underlying pathomechanisms, and to discuss the concept of tailored statin therapy. According to our recently published comprehensive network meta-analysis including 113,394 patients, the high-dose statin regimens were connected with an elevated risk of new-onset DM as compared with moderate-dose statin regimens and a gradient for the risk of new-onset DM across different types and doses of statins was demonstrated. There are multiple possible mechanisms explaining the diabetogenic effect of statins (e.g., decreased insulin secretion, induction of b-cell apoptosis, increased insulin resistance or compromised glucose transport into the cells). Statins are among the most widely used drugs worldwide and physicians should be aware of the fact that there is a risk of new-onset DM across different types and doses of statins. Selection of adequate statin that suits patient’s needs remains the challenge of hypolipidemic therapy. The identification of individuals who would benefit more from smaller doses and/or use of less diabetogenic compounds could help to optimize the treatment and reduce the number of patients developing DM. The non-pharmacological approach such as adequate physical activity, weight reduction and low fat diet should not be neglected either. These actions create a chance to decrease baseline LDL-cholesterol concentration and reduce the number of both cardiovascular and DM risk factors. All in all, statins with their exceptional cardiovascular benefits will undoubtedly defend their position of a cornerstone of cardiovascular prevention because profits derived from statin therapy far exceed the potential harms connected with statin-induced impairments of glucose metabolism

Prevalence of electrocardiographic left ventricular hypertrophy among patients with coronary artery disease and diabetes mellitus

Introduction. Electrocardiography (ECG) is a widely used non-invasive diagnostic method for assessment of patients with cardiovascular diseases. Numerous different electrocardiographic criteria exist for detection of left ventricular hypertrophy (LVH). LVH is an important risk factor in patients with coronary artery disease (CAD) or diabetes mellitus and its presence is associated with increased cardiovascular morbidity and mortality. The aim of this study was to evaluate the prevalence of the most frequently used electrocardiographic left ventricular hypertrophy (ECG-LVH) criteria among patients with CAD and diabetes. Methods. A cross-sectional, multicenter study was conducted in outpatient clinics across Poland. Family physicians performed physical examinations and collected relevant information about: onset of CAD and diabetes, presence and onset of hypertension, dyslipidemia, heart failure, diabetic complications, history of acute coronary syndrome and pharmacotherapy. In order to detect LVH, we used seven ECG criteria: 1) the Sokolow-Lyon voltage, 2) the Gubner voltage, 3) the criterion of the R wave amplitude on the leads V5–V6 and 4) aVL, 5) the gender specific Cornell voltage and 6) product, and 7) the Romhilt-Estes point score. Centralized manual assessment of the obtained ECG tracings were performed. Results. We enrolled 1001 patients (48.5% women, 51.5% men, mean age 65 ± 11 years) into the study. At least one ECG-LVH criterion was met in 20.0% (n = 200) of the study participants. The ECG-LVH diagnosis was the most common when using the Romhilt-Estes point score (n = 138; 13.8%). The corresponding prevalence rates for the Cornell voltage, the Cornell product, the R wave amplitude on the lead aVL, the Sokolow-Lyon voltage, the Gubner voltage and the R wave amplitude on the leads V5-V6 criteria were 5.5% (n = 55), 5.2% (n = 52), 3.2% (n = 32), 2.2% (n = 22), 1.9% (n = 19) and 1.3% (n = 13) respectively. Subsequently, the prevalence of the three most frequently used in clinical practice electrocardiographic criteria for LVH (the Sokolow-Lyon voltage, the Cornell voltage and the Romhilt-Estes point score) was analyzed. At least one of them was fulfilled in 185 ECGs. All three criteria at the same time were met only in 5 ECGs (2.7% of 185). Two and only one out of three criteria were fulfilled in 20 (10.8%) and 160 (86.5%) ECGs respectively. Conclusions. The co-occurrence of all assessed ECG-LVH criteria, including the three most frequently applied in clinical practice, is very low in diabetic CAD patients. The Romhilt-Estes point score identifies the highest number of ECG-LVH cases in this setting. However, it seems reasonable to use routinely several ECG criteria for detection of LVH. Further studies are needed to compare diagnostic values of ECG-LVH criteria with imaging methods and to assess prognostic values of various ECG-LVH criteria

Impact of ticagrelor administration strategy on its pharmacokinetics and pharmacodynamics in patients with unstable angina pectoris: a protocol of a randomized study

Introduction. Dual antiplatelet therapy with aspirin and a P2Y12 receptor inhibitor constitutes an essential part of the management of patients with acute coronary syndromes (ACS). Based on the favorable results of the PLATO trial, ticagrelor is currently recommended as the first line P2Y12 receptor inhibitor in a broad spectrum of ACS patients. According to the recently published data, several conditions, including concurrent analgesia with morphine and clinical presentation as an ACS, may alter ticagrelor absorption and its antiplatelet effect. Therefore, the goal of the present study was to investigate pharmacokinetics and pharmacodynamics of new ticagrelor administration strategies aimed to overcome limitations of the standard ticagrelor loading regimen. Methods/design. The study is designed as a phase IV, single center, randomized, investigator-initiated, parallel-group, open-label, interventional study comparing the influence of various ticagrelor administration strategies on its pharmacokinetics and pharmacodynamics. Patients with unstable angina pectoris will be randomized in a 1:1:1 ratio into one of three arms, each receiving a 180 mg ticagrelor loading dose (LD). Ticagrelor administration strategies comprise: 1) pulverized ticagrelor administered sublingually, 2) pulverized ticagrelor in 10 mL suspension in tap water administered orally and 3) integral ticagrelor tablets administered orally. An internal pilot study including 30 (10 in each of the arms) is planned in order to determine the final sample size. The primary endpoint of the trial is time (tmax) required for ticagrelor and its active metabolite AR-C124900XX to reach maximum plasma concentration within time frame of six hours after administration of ticagrelor LD. The secondary endpoints include ticagrelor and AR-C124900XX maximum plasma concentration, area under the plasma concentration-time curve for ticagrelor and AR-C124900XX (AUC 0–6h) and platelet reactivity assessed with Multiple Electrode Aggregometry using the Multiplate™ Analyzer prior to and within time frame of six hours following ticagrelor LD. Discussion. This study is expected to provide essential evidence-based data on the impact of ticagrelor administration strategy on its pharmacokinetics and pharmacodynamics in patients with unstable angina pectoris. Hopefully, based on its results, further clinical outcome-powered trials on new ticagrelor administration strategies will be designed and conducted.

Off-target effects of glycoprotein IIb/IIIa receptor inhibitors

Soon after identification of the platelet membrane glycoprotein (GP) IIb/IIIa, it has become a target of antiplatelet therapy. There are 3 intravenous GP IIb/IIIa receptor inhibitors, namely— eptifibatide, tirofiban and abciximab, used in the contemporary clinical practice, particularly in patients with acute coronary syndrome undergoing percutaneous coronary intervention (PCI). The aim of the current review is to summarize available knowledge concerning off-target effects of GP IIb/IIIa receptor inhibitors. All 3 drugs have similar antithrombotic properties, but differ with respect to pharmacodynamics, pharmacokinetics and off-target effects. Eptifibatide and tirofiban are highly specific GP IIb/IIIa receptor inhibitors, while abciximab is unselectiveand cross-reacts with integrin avb3 — a vitronectin receptor and leukocyte-associatedi ntegrin Mac-1. As a result of these interactions, abciximab seems to reduce the development of clinical restenosis, decrease infarct size, inhibit adhesion of monocytes to medical steel and modulate the inflammatory response. Intracoronary administration of abciximab provides higher drug concentration in the target area, increasing dose-dependent interactions with other integrins. Off-target effects of small molecule GP IIb/IIIa receptor inhibitors (i.e. eptifibatide and tirofiban) are predominantly connected with their suppressive influence on the inflammatory response. All in all, although GP IIb/IIIa receptor inhibitors are not recommended as a routine therapy during PCI, their antiplatelet properties and potential off-target effects may bebeneficial in certain subsets of patients

Pathological Q waves as an indicator of prior myocardial infarction in patients with coronary artery disease and diabetes mellitus: a comparison of the prevalence and diagnostic accuracy according to present and former criteria

Introduction. Electrocardiography (ECG) is a widely used diagnostic method for identification of patients with previous myocardial infarction (MI). The ECG manifestation of prior MI is the presence of the pathological Q waves. Patients with coronary artery disease (CAD) and diabetes are at high risk of MI. The aim of this study was to compare the prevalence and diagnostic accuracy of the pathological Q waves as an indicator of prior MI in patients with CAD and diabetes according to the present and former criteria. Methods. A cross-sectional, multi-centre study was conducted in outpatient clinics across Poland. Family physicians performed physical examinations, registered ECGs, and collected relevant information about onset of CAD and diabetes, presence and onset of hypertension, dyslipidaemia, heart failure, diabetic complications, history of MI, and pharmacotherapy. Centralised manual assessment of the obtained ECG tracings was performed. Two definitions of the pathological Q-waves were used — a present one according to the Universal Definition of MI and a former one based on the definition of MI developed by the World Health Organization. Results. We enrolled 796 patients (48.1% women, mean age 67.5 ± 10.2 years, and 51.9% men, mean age 64.3 ± 10.3 years) into the study. There were 158 patients (19.8%) — 102 men (24.7%) and 56 women (14.6%), who met the present definition of the pathological Q waves and 106 patients (13.3%) — 74 men (17.9%) and 32 women (8.4%), who met the former definition of the pathological Q waves. The prevalence of the pathological Q waves varied due to the certain group of leads. It was highest in the inferior leads — 104 and 75 according to the present and former definitions, respectively. Of note, the rate of the pathological Q waves increased up to 2.6 times in the lateral leads after the introduction of the less restrictive present definition. Sensitivity of prior MI detection by means of the present and former criteria was 26.8% and 19.8%, and specificity was 87.0% and 92.8%, respectively. The application of the present and former definitions detected prior MI with 65.6% and 71.6% positive predictive value, and with 56.3% and 55.6% negative predictive value, respectively. Conclusions. In the era of reperfusion therapy, ECG appears to be a poor diagnostic tool for detection of previous MI due to its low sensitivity. However, it may identify individuals without previous MI with rather high specificity. In diabetics with CAD, the present definition of the pathological Q waves increases sensitivity of prior MI detection by 7%, with a decrease in specificity by 6% as compared with the former definition

The AGTR1 gene A1166C polymorphism as a risk factor and outcome predictor of primary intracerebral and aneurysmal subarachnoid hemorrhages

Associations between the angiotensin II type 1 receptor (AGTR1) gene A1166C polymorphism and hypertension, aortic abdominal aneurysms (as a risk factor) as well as cardiovascular disorders (as a risk factor and an outcome predictor) have been demonstrated. We aimed to investigate the role of this polymorphism as risk factors and outcome predictors in primary intracerebral hemorrhage (PICH) and aneurysmal subarachnoid hemorrhage (aSAH). We have prospectively recruited 1078 Polish participants to the study: 261 PICH patients, 392 aSAH patients, and 425 unrelated control subjects. The A1166C AGTR1 gene polymorphism was studied using the tetra-primer ARMS-PCR method. Allele and genotype frequencies were compared with other ethnically different populations. The A1166C polymorphism was not associated with the risk of PICH or aSAH. Among the aSAH patients the AA genotype was associated with a good outcome, defined by a Glasgow Outcome Scale of 4 or 5 (p < 0.02). The distribution of A1166C genotypes in our cohort did not differ from other white or other populations of European descent. In conclusion, we found an association between the A1166C AGTR1 polymorphism and outcome of aSAH patients, but not with the risk of PICH or aSAH

The AGTR1 gene A1166C polymorphism as a risk factor and outcome predictor of primary intracerebral and aneurysmal subarachnoid hemorrhages

Associations between the angiotensin II type 1 receptor (AGTR1) gene A1166C polymorphism and hypertension, aortic abdominal aneurysms (as a risk factor) as well as cardiovascular disorders (as a risk factor and an outcome predictor) have been demonstrated. We aimed to investigate the role of this polymorphism as risk factors and outcome predictors in primary intracerebral hemorrhage (PICH) and aneurysmal subarachnoid hemorrhage (aSAH). We have prospectively recruited 1078 Polish participants to the study: 261 PICH patients, 392 aSAH patients, and 425 unrelated control subjects. The A1166C AGTR1 gene polymorphism was studied using the tetra-primer ARMS-PCR method. Allele and genotype frequencies were compared with other ethnically different populations. The A1166C polymorphism was not associated with the risk of PICH or aSAH. Among the aSAH patients the AA genotype was associated with a good outcome, defined by a Glasgow Outcome Scale of 4 or 5 (p&lt;0.02). The distribution of A1166C genotypes in our cohort did not differ from other white or other populations of European descent. In conclusion, we found an association between the A1166C AGTR1 polymorphism and outcome of aSAH patients, but not with the risk of PICH or aSAH

Does morphine administration affect ticagrelor conversion to its active metabolite in patients with acute myocardial infarction? A sub-analysis of the randomized, double-blind, placebo- -controlled IMPRESSION trial

Background. Therapy with aspirin and one of the platelet P2Y12 receptor inhibitors, preferably ticagrelor or prasugrel, is the mainstay of acute myocardial infarction (AMI) treatment. Morphine is the most commonly used analgesic in AMI patients. The IMPRESSION study was the first randomized trial to confirm that morphine use in this clinical setting leads to a delayed and attenuated exposure to ticagrelor and its active metabolite (AR-C124910XX). The mechanism underlying this drug-drug interaction remains hypothetical. Material and methods. A post hoc sub-analysis of the IMPRESSION study, a phase IV, single center, randomized, double-blind, placebo-controlled trial, was performed to examine whether morphine administration interferes with the proportion of AR-C124910XX produced from ticagrelor in AMI patients. Pharmacokinetic results of all subjects pretreated with placebo (n = 35) and morphine (n = 35) were analyzed. The ratio of total exposure to AR-C124910XX to total exposure to ticagrelor for 12 h was used to illustrate the rate of ticagrelor metabolism. Total exposure to investigated compounds was measured as the area under the plasma concentration-time curve (AUC). Results. The ratios of AUC(0–12) for AR-C124910XX to AUC(0–12) for ticagrelor were comparable between morphine and placebo pretreated patients (20.9 [13.9–34.6] v. 24.7 [18.1–29.6] %; p = 0.58). Importantly, visual inspection of the relationship between AUC(0–12) for AR-C124910XX and AUC(0–12) for ticagrelor revealed that regression lines for the morphine and placebo groups were located closely to each other, with a tendency for superimposing. Additionally, we observed similar values of slope coefficients for both study arms in the linear regression equations illustrating the relationship between AUC(0–12) for AR-C124910XX and AUC(0–12) for ticagrelor (0.19 [± 0.03] v. 0.21 [± 0.04]; p for the statistical significance of both slope coefficients &lt; 0.0001). Conclusions. In the IMPRESSION study, conversion of ticagrelor to AR-C124910XX in AMI patients was not affected by morphine administration

Mild therapeutic hypothermia for patients with acute coronary syndrome and cardiac arrest treated with percutaneous coronary intervention (UNICORN). The design and rationale for the prospective, observational, multicenter study

Introduction. Cardiac arrest constitutes the most frequent reason for sudden death in developed countries. Out-of-hospital cardiac arrest (OHCA) survivors are at high risk of death or neurologic deficits. The existing data regarding effectiveness and safety of mild therapeutic hypothermia (MTH) for treatment of OHCA survivors are inconsistent and ambiguous. Moreover, a uniform protocol of treatment by means of MTH is lacking. Methods. The UNICORN study is a phase IV, prospective, international, multi-centre, observational study designed to assess the effectiveness of MTH in patients after OHCA with shockable rhythm presenting with acute coronary syndrome (ACS). The trial is expected to include up to 500 patients. Depending on the availability of MTH in each study centre, besides the routine treatment of ACS in OHCA survivors, patients will either undergo MTH according to a uniform protocol or will not undergo MTH (250 patients per group). The primary end-point of the study is all cause mortality at 180 days after enrolment. Secondary end-points include: neurological outcome at discharge, stent thrombosis at 30 days, bleeding according to the BARC criteria, infectious complications at 180 days, and rhythm and conduction disorders at 180 days. Ethics and dissemination. The study received approval from the Local Ethics Committee to conduct the study (Komisja Bioetyczna Uniwersytetu Mikołaja Kopernika w Toruniu przy Collegium Medicum im. Ludwika Rydygiera w Bydgoszczy; study approval reference number KB 615/2015). The study results will be disseminated through conference presentations and publications in peer-reviewed journals. Trial registration. ClinicalTrials.gov identifier: NCT02611934 (18 November 2015).