Prognostic Value of a Negative Peak Supine Bicycle Stress Echocardiography With or Without Concomitant Ischemic Stress Electrocardiographic Changes: a Cohort Study.

BACKGROUND: a negative peak supine bicycle exercise stress echocardiography (ESE) was shown to have a long-term favourable prognostic value. Data on the long-term prognosis of ischaemic electrocardiographic (ISECG) changes in the setting of a negative peak supine bicycle ESE are lacking. DESIGN: we evaluated the prognostic value of negative peak supine bicycle ESE with or without concomitant ISECG changes in a referral population evaluated for chest pain after an inconclusive first-line work-up including clinical evaluation and exercise ECG stress. METHODS: from 2003 to 2010, patients who underwent a peak supine bicycle ESE and were deemed to be negative were evaluated. Two groups based on concomitant stress ECG tracing were analysed - those with normal stress ECG and those with ISECG changes. The primary endpoint was cumulative incidence of cardiovascular death, hospitalizations for acute coronary syndrome and coronary revascularizations. RESULTS: a total of 371 patients (mean age 59.1 ± 12.1 years, 49.9% women) were studied. Of those, 141 (38.0%) had concomitant ISECG changes. Mean follow-up was 3.46 ± 1.76 years. The primary endpoint occurred in 3.0% of patients, (2.2% in those with normal stress ECG, and in 4.3% with ISECG changes, p = 0.251); with unadjusted hazard ratio for primary endpoint of 2.04 (95%CI 0.62-6.69, p = 0.239) in patients with ISECG changes compared to those with normal stress ECG. CONCLUSIONS: in an outpatient population without known CAD evaluated for chest pain after inconclusive first-line work-up, a negative peak supine bicycle ESE confers an excellent prognosis regardless of the nature of concomitant stress ECG abnormalities

Prognostic value of a negative peak supine bicycle stress echocardiography with or without concomitant ischaemic stress electrocardiographic changes: a cohort study

Background: a negative peak supine bicycle exercise stress echocardiography (ESE) was shown to have a long-term favourable prognostic value. Data on the long-term prognosis of ischaemic electrocardiographic (ISECG) changes in the setting of a negative peak supine bicycle ESE are lacking. Design: we evaluated the prognostic value of negative peak supine bicycle ESE with or without concomitant ISECG changes in a referral population evaluated for chest pain after an inconclusive first-line work-up including clinical evaluation and exercise ECG stress. Methods: from 2003 to 2010, patients who underwent a peak supine bicycle ESE and were deemed to be negative were evaluated. Two groups based on concomitant stress ECG tracing were analysed-those with normal stress ECG and those with ISECG changes. The primary endpoint was cumulative incidence of cardiovascular death, hospitalizations for acute coronary syndrome and coronary revascularizations. Results: a total of 371 patients (mean age 59.1±12.1 years, 49.9% women) were studied. Of those, 141 (38.0%) had concomitant ISECG changes. Mean follow-up was 3.46±1.76 years. The primary endpoint occurred in 3.0% of patients, (2.2% in those with normal stress ECG, and in 4.3% with ISECG changes, p=0.251); with unadjusted hazard ratio for primary endpoint of 2.04 (95%CI 0.62-6.69, p=0.239) in patients with ISECG changes compared to those with normal stress ECG. Conclusions: in an outpatient population without known CAD evaluated for chest pain after inconclusive first-line work-up, a negative peak supine bicycle ESE confers an excellent prognosis regardless of the nature of concomitant stress ECG abnormalities

From Molecular Spectra to Biological Activities: a Comparative Spectra Analysis (CoSA) study on Epidermal Growth Factor Receptor Protein Tyrosine Kinase Inhibitors

Abstract not availabl

Assessment of the potential hazard represented by natural raw materials containing mineral fibres—The case of the feldspar from Orani, Sardinia (Italy)

This work describes the nature of the potentially hazardous fibrous amphibole found in the Orani's feldspar mine (Sardinia, Italy). To identify its nature, a protocol of analysis including morphometric, chemical and crystallographic characterizations was applied. Thanks to this approach, it was possible to classify the observed fibres as tremolite after comparing chemical data, SEM/TEM observations, FTIR/ Raman spectra and X-ray diffraction data with those reported for a standard sample. The unit cell parameters of the investigated tremolite phase are a = 9.82(1) Å, b = 18.08(3) Å, c = 5.27(1) Å, and the angle β corresponds to 104.4(1)°. The mean concentration of asbestos tremolite in the Orani's feldspar is 0.28 wt%. Most of the fibres (0.26 wt%) are respirable ‘regulated’ fibres, representing a potential hazard. Because the total amount of tremolite in the sample is 0.6 wt%, a large fraction of it has a crystal habit other than fibrous-asbestiform or acicular. The obtained results allowed us to suggest possible solutions for a safe exploitation and mineral processing of the Orani's mine. The procedure proposed herein may be a general tool suitable to identify the mineralogical nature of fibrous minerals in raw materials and assess if they may represent a potential health/environmental hazard

Moving forward through the in silico modeling of multiple sclerosis: Treatment layer implementation and validation

Multiple sclerosis is an autoimmune inflammatory disease that affects the central nervous system through chronic demyelination and loss of oligodendrocytes. Since the relapsing-remitting form is the most prevalent, relapse-reducing therapies are a primary choice for specialists. Universal Immune System Simulator is an agent-based model that simulates the human immune system dynamics under physiological conditions and during several diseases, including multiple sclerosis. In this work, we extended the UISS-MS disease layer by adding two new treatments, i.e., cladribine and ocrelizumab, to show that UISS-MS can be potentially used to predict the effects of any existing or newly designed treatment against multiple sclerosis. To retrospectively validate UISS-MS with ocrelizumab and cladribine, we extracted the clinical and MRI data from patients included in two clinical trials, thus creating specific cohorts of digital patients for predicting and validating the effects of the considered drugs. The obtained results mirror those of the clinical trials, demonstrating that UISS-MS can correctly simulate the mechanisms of action and outcomes of the treatments. The successful retrospective validation concurred to confirm that UISS-MS can be considered a digital twin solution to be used as a support system to inform clinical decisions and predict disease course and therapeutic response at a single patient level

Translational PK–PD modelling of molecular target modulation for the AMPA receptor positive allosteric modulator Org 26576

Introduction The α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor potentiator Org 26576 represents an interesting pharmacological tool to evaluate the utility of glutamatergic enhancement towards the treatment of psychiatric disorders. In this study, a rat–human translational pharmacokinetic–pharmacodynamic (PK–PD) model of AMPA receptor modulation was used to predict human target engagement and inform dose selection in efficacy clinical trials. Methods Modelling and simulation was applied to rat plasma and cerebrospinal fluid (CSF) pharmacokinetic and pharmacodynamic measurements to identify a target concentration (EC80) for AMPA receptor modulation. Human plasma pharmacokinetics was determined from 33 healthy volunteers and eight major depressive disorder patients. From four out of these eight patients, CSF PK was also determined. Simulations of human CSF levels were performed for several doses of Org 26576. Results Org 26576 (0.1–10 mg/kg, i.v.) potentiated rat hippocampal AMPA receptor responses in an exposure-dependant manner. The rat plasma and CSF PK data were fitted by one-compartment model each. The rat CSF PK–PD model yielded an EC80 value of 593 ng/ml (90% confidence interval 406.8, 1,264.1). The human plasma and CSF PK data were simultaneously well described by a two-compartment model. Simulations showed that in humans at 100 mg QD, CSF levels of Org 26576 would exceed the EC80 target concentration for about 2 h and that 400 mg BID would engage AMPA receptors for 24 h. Conclusion The modelling approach provided useful insight on the likely human dose–molecular target engagement relationship for Org 26576. Based on the current analysis, 100 and 400 mg BID would be suitable to provide ‘phasic’ and ‘continuous’ AMPA receptor engagement, respectively

Verifying and Validating Quantitative Systems Pharmacology and In Silico Models in Drug Development: Current Needs, Gaps, and Challenges

The added value of in silico models (including quantitative systems pharmacology models) for drug development is now unanimously recognized. It is, therefore, important that the standards used are commonly acknowledged by all the parties involved. On April 25 and 26, 2019, a multistakeholder workshop on the validation challenges for in silico models in drug development was organized in Belgium. As an outcome, a White Paper is foreseen in 2020 on standards for in silico model verification and validation.status: publishe

Scientific and regulatory evaluation of mechanistic in silico

Abstract The value of in silico methods in drug development and evaluation has been demonstrated repeatedly and convincingly. While their benefits are now unanimously recognized, international standards for their evaluation, accepted by all stakeholders involved, are still to be established. In this white paper, we propose a risk‐informed evaluation framework for mechanistic model credibility evaluation. To properly frame the proposed verification and validation activities, concepts such as context of use, regulatory impact and risk‐based analysis are discussed. To ensure common understanding between all stakeholders, an overview is provided of relevant in silico terminology used throughout this paper. To illustrate the feasibility of the proposed approach, we have applied it to three real case examples in the context of drug development, using a credibility matrix currently being tested as a quick‐start tool by regulators. Altogether, this white paper provides a practical approach to model evaluation, applicable in both scientific and regulatory evaluation contexts