Pharmacokinetic/pharmacodynamic model of a methionine starvation based anti-cancer drug.

A new therapeutic approach against cancer is developed by the firm Erytech. This approach is based on starved cancer cells of an amino acid essential to their growth (the L-methionine). The depletion of plasma methionine level can be induced by an enzyme, the methionine-γ-lyase.

Combining mathematical modeling and deep learning to make rapid and explainable predictions of the patient-specific response to anticoagulant therapy under venous flow.

Anticoagulant drugs are commonly prescribed to prevent hypercoagulable states in patients with venous thromboembolism. The choice of the most efficient anticoagulant and the appropriate dosage regimen remain a complex problem because of the intersubject variability in the coagulation kinetics and the effect of blood flow. The rapid assessment of the patient-specific response to anticoagulant regimens would assist clinical decision-making and ensure efficient management of coagulopathy.

Needs for re-intervention on restored teeth in adults: a practice-based study.

Objectives: Evaluate the need for re-intervention on dental coronal restorations in adults seen in a network of general dental practitioners (ReCOL).  MATERIALS AND METHODS: This observational, cross-sectional, multicenter study involved 40 practitioners and 400 patients. Coronal restoration failures (needing re-intervention for unsatisfactory outcomes) were assessed with a simplified rating scale of seven criteria from the FDI World Dental Federation.

Determination of the optimal dose of ephedrine in the treatment of arterial hypotension due to general anesthesia in neonates and infants below 6 months old: the ephedrine study protocol for a randomized, open-label, controlled, dose escalation trial.

Background: Arterial hypotension induced by general anesthesia is commonly identified as a risk factor of morbidity, especially neurological, after cardiac or noncardiac surgery in adults and children. Intraoperative hypotension is observed with sevoflurane anesthesia in children, in particular in neonates, infants younger than 6 months, and preterm babies. Ephedrine is commonly used to treat intraoperative hypotension.

Effect of periodontal treatment on the glomerular filtration rate, reduction of inflammatory markers and mortality in patients with chronic kidney disease: A systematic review.

Aim: To assess the effect of periodontal treatment (PT) on glomerular filtration rate (GFR), systemic inflammation, or mortality in patients with chronic kidney disease (CKD).

Methods: A literature search was performed on PubMed and Web of Science databases on articles published until December 2019. The PRISMA guidelines were used throughout the manuscript.

Twice- or Once-Daily Dosing of Direct Oral Anticoagulants, a systematic review and meta-analysis.

Aim: The direct oral anticoagulants (DOAC) have similar half-lives, but the dosing regimen varies between once daily (QD) or twice daily (BID). For some prescribers, the QD regimen improves compliance. Others prefer BID regimens to promote better stability of plasma concentrations, particularly in the event of missed doses.

Adherence to cysteamine in nephropathic cystinosis: A unique electronic monitoring experience for a better understanding. A prospective cohort study: CrYSTobs.

Introduction: In nephropathic cystinosis (NC), adherence to cysteamine remains challenging; poor adherence is worsening the disease progression with a decline of kidney function and increase of extrarenal morbidities. Our objective was to describe adherence to cysteamine in NC patients, using electronic monitoring systems.

Methods: Patients with confirmed NC, aged > 4 years and receiving oral cysteamine (short acting or delayed release formulation as standard of care) from 3 French reference centers, were included.

A mathematical model to quantify the effects of platelet count, shear rate, and injury size on the initiation of blood coagulation under venous flow conditions.

Platelets upregulate the generation of thrombin and reinforce the fibrin clot which increases the incidence risk of venous thromboembolism (VTE). However, the role of platelets in the pathogenesis of venous cardiovascular diseases remains hard to quantify. An experimentally validated model of thrombin generation dynamics is formulated.

Dynamical modeling of pro- and anti-inflammatory cytokines in the early stage of septic shock.

A dynamical model of the pathophysiological behaviors of IL18 and IL10 cytokines with their receptors is tested against data for the case of early sepsis. The proposed approach considers the surroundings (organs and bone marrow) and the different subsystems (cells and cyctokines). The interactions between blood cells, cytokines and the surroundings are described via mass balances.

Effect of Non-Steroidal Anti-Inflammatory Drugs on Sport Performance Indices in Healthy People: a Meta-Analysis of Randomized Controlled Trials.

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are medications that are frequently used by athletes. There may also be some abuse of these substances, although it is unclear whether NSAIDs in fact enhance performance. We performed a systematic review and meta-analysis to evaluate the effect of NSAIDs on sport performance indices.

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Rare diseases usually concern small and disseminated population. Implementing clinical research with the right design, outcomes measures and the recruitment of patients are challenges. Collaborations, training and multidisciplinary approach are often required.

A methodological framework for drug development in rare diseases. The CRESim program: Epilogue and perspectives.

Based on the 'European Child-Rare-Euro-Simulation' (CRESim) project, this article proposes a generalizable strategy utilizing datasets analysis in combination with modeling and simulation, in order to optimize the clinical drug development applied in the field of rare diseases. The global process includes: (i) the simulation of a realistic virtual population of patients (modeled from a real dataset of patients), (ii) the modeling of disease pathophysiological components and of pharmacokinetic-pharmacodynamic relations of the drug(s) of interest, (iii) the modeling of several randomized controlled clinical trials (RCTs) designs and (iv) the analysis of the results (multi-dimensional approach for RCTs durations and precision of the estimation of the treatment effect). However, whereas modeling and numerical simulation may provide supplementary tools for drug development, they cannot be considered as a substitute for RCTs performed in 'real' patients.

Blockade of the renin-angiotensin-aldosterone system in patients with arrhythmogenic right ventricular dysplasia: A double-blind, multicenter, prospective, randomized, genotype-driven study (BRAVE study).

Arrhythmogenic right ventricular dysplasia (ARVD) is a rare cardiomyopathy characterized by the progressive replacement of cardiomyocytes by fatty and fibrous tissue in the right ventricle (RV). These infiltrations lead to cardiac electrical instability and ventricular arrhythmia. Current treatment for ARVD is empirical and essentially based on treatment of arrhythmia.

A double-blind placebo-controlled randomised trial of omega-3 supplementation in children with moderate ADHD symptoms.

Objective: Clinical trials and inconclusive meta-analyses have investigated the effects of omega-3 supplements in children with Attention-Deficit Hyperactivity Disorder (ADHD). We performed a randomised placebo-controlled trial to evaluate the efficacy of omega-3 fatty acids.

Methods: Children aged 6-15 years with established diagnosis of ADHD were randomised 1:1 to receive either supplements containing docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) or a placebo for 3 months.

Ephrin-B3 supports glioblastoma growth by inhibiting apoptosis induced by the dependence receptor EphA4.

EphA4, an Ephrins tyrosine kinase receptor, behaves as a dependence receptor (DR) by triggering cell apoptosis in the absence of its ligand Ephrin-B3. DRs act as conditional tumor suppressors, engaging cell death based on ligand availability; this mechanism is bypassed by overexpression of DRs ligands in some aggressive cancers. The pair EphA4/Ephrin-B3 favors survival of neuronal progenitors of the brain subventricular zone, an area where glioblastoma multiform (GBM) are thought to originate.

Mathematical model of T-cell lymphoblastic lymphoma: disease, treatment, cure or relapse of a virtual cohort of patients.

T lymphoblastic lymphoma (T-LBL) is a rare type of lymphoma with a good prognosis with a remission rate of 85%. Patients can be completely cured or can relapse during or after a 2-year treatment. Relapses usually occur early after the remission of the acute phase.

Conditions of microvessel occlusion for blood coagulation in flow.

Vessel occlusion is a perturbation of blood flow inside a blood vessel because of the fibrin clot formation. As a result, blood circulation in the vessel can be slowed down or even stopped. This can provoke the risk of cardiovascular events.

One-step partial or complete caries removal and bonding with antibacterial or traditional self-etch adhesives: study protocol for a randomized controlled trial.

Background: Current concepts in conservative dentistry advocate minimally invasive dentistry and pulp vitality preservation. Moreover, complete removal of carious dentin in deep carious lesions often leads to pulp exposure and root canal treatment, despite the absence of irreversible pulp inflammation. For years, partial caries removal has been performed on primary teeth, but little evidence supports its effectiveness for permanent teeth.

Dynamic changes of depolarizing GABA in a computational model of epileptogenic brain: Insight for Dravet syndrome.

Abnormal reemergence of depolarizing GABAA current during postnatal brain maturation may play a major role in paediatric epilepsies, Dravet syndrome (DS) being among the most severe. To study the impact of depolarizing GABA onto distinct patterns of EEG activity, we extended a neural mass model as follows: one sub-population of pyramidal cells was added as well as two sub-populations of interacting interneurons, perisomatic-projecting interneurons (basket-like) with fast synaptic kinetics GABAA (fast, I1) and dendritic-projecting interneurons with slow synaptic kinetics GABAA (slow, I2). Basket-like cells were interconnected to reproduce mutual inhibition mechanisms (I1➔I1).

High Risk versus Proportional Benefit: Modelling Equitable Strategies in Cardiovascular Prevention.

Objective: To examine the performances of an alternative strategy to decide initiating BP-lowering drugs called Proportional Benefit (PB). It selects candidates addressing the inequity induced by the high-risk approach since it distributes the gains proportionally to the burden of disease by genders and ages.

Study Design And Setting: Mild hypertensives from a Realistic Virtual Population by genders and 10-year age classes (range 35-64 years) received simulated treatment over 10 years according to the PB strategy or the 2007 ESH/ESC guidelines (ESH/ESC).

An in silico approach helped to identify the best experimental design, population, and outcome for future randomized clinical trials.

Objectives: The main objective of our work was to compare different randomized clinical trial (RCT) experimental designs in terms of power, accuracy of the estimation of treatment effect, and number of patients receiving active treatment using in silico simulations.

Study Design And Setting: A virtual population of patients was simulated and randomized in potential clinical trials. Treatment effect was modeled using a dose-effect relation for quantitative or qualitative outcomes.

Model of mucociliary clearance in cystic fibrosis lungs.

Mucus clearance is a primary innate defense mechanism in the human airways. Cystic fibrosis (CF) is a genetic disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. CF is characterized by dehydration of airway surface liquid and impaired mucociliary clearance.

Methodological choices for the clinical development of medical devices.

Clinical evidence available for the assessment of medical devices (MDs) is frequently insufficient. New MDs should be subjected to high quality clinical studies to demonstrate their benefit to patients. The randomized controlled trial (RCT) is the study design reaching the highest level of evidence in order to demonstrate the efficacy of a new MD.

Determinants of torsades de pointes in older patients with drug-associated long QT syndrome: a case-control study.

Objective: Many elderly patients are routinely exposed to drugs that may prolong the cardiac QT interval and cause Torsades de pointes (TdP). However, predictors of TdP in patients with drug-associated long QT syndrome (LQTS) are not fully understood, especially in the geriatric population. The objective of this study was to identify risk factors of TdP in elderly patients with drug-associated LQTS.