Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase&nbsp;1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation&nbsp;disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age&nbsp; 6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score&nbsp; 652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc&nbsp;= 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N&nbsp;= 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in&nbsp;Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in&nbsp;Asia&nbsp;and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Judicial policymaking in the supranational context - the European Union and its experiences

Even though we are living in societies based on the principle of separation of powers, the current internal and international status quo develops mechanisms that depart from the traditional way of perceiving this idea. By giving primacy to constitutional review instruments, executives and legislatives are no longer the only policy makers actors; the involvement of judges in policy issues dilutes the politicians’ powers in this resort and brings legal expertize into play; moreover, as nowadays states commit themselves on the international arena, ‘judicialization’ of politic’ is also happening as a result of the creation of supranational Courts. The purpose of this thesis is to analyze what are the actual mechanisms through which such behavior is developed, which are the affected areas of interest and what kind of issues does the practice per se develop. In this matter, the result is a complex one due to the process’s dynamics and the fact that it is constructed on a particular decisional path that is composed of judicial decision-making and its subsequent political effects

Mammalian Cell Culture Process for Monoclonal Antibody Production: Nonlinear Modelling and Parameter Estimation

Monoclonal antibodies (mAbs) are at present one of the fastest growing products of pharmaceutical industry, with widespread applications in biochemistry, biology, and medicine. The operation of mAbs production processes is predominantly based on empirical knowledge, the improvements being achieved by using trial-and-error experiments and precedent practices. The nonlinearity of these processes and the absence of suitable instrumentation require an enhanced modelling effort and modern kinetic parameter estimation strategies. The present work is dedicated to nonlinear dynamic modelling and parameter estimation for a mammalian cell culture process used for mAb production. By using a dynamical model of such kind of processes, an optimization-based technique for estimation of kinetic parameters in the model of mammalian cell culture process is developed. The estimation is achieved as a result of minimizing an error function by a particle swarm optimization (PSO) algorithm. The proposed estimation approach is analyzed in this work by using a particular model of mammalian cell culture, as a case study, but is generic for this class of bioprocesses. The presented case study shows that the proposed parameter estimation technique provides a more accurate simulation of the experimentally observed process behaviour than reported in previous studies

Microbial production of enzymes: Nonlinear state and kinetic reaction rates estimation

International audienceThe nonlinearity of the biotechnological processes and the absence of cheap and reliable instrumentation require an enhanced modelling effort and estimation strategies for the state and the kinetic parameters. This work approaches nonlinear estimation strategies for microbial production of enzymes, exemplified by using a process of lipase production from olive oil by Candida rugosa. First, by using a dynamical mathematical model of this process, an asymptotic observer which reconstructs the unavailable state variables is proposed. The design of this kind of observers is based on mass and energy balances without the knowledge of kinetics being necessary; only minimal information concerning the measured concentrations is used. Second, a nonlinear high-gain observer is designed for the estimation of imprecisely known kinetics of the bioprocess. An important advantage of this high-gain estimator is that the tuning is reduced to the calibration of a single parameter. Numerical simulations in various scenarios are provided in order to test the behaviour and performances of the proposed nonlinear estimation strategies

Autograft Options for ACL Reconstruction. Which is Best?

Anterior cruciate ligament (ACL) tears are commonly seen in orthopedic practice, and usually restoration is recommended to re-establish normal knee function. Autografts and allografts are viable options. Among autografts the main sources are the patellar tendon, the hamstrings and the quadriceps tendon, each having advantages and drawbacks. Many factors should be taken into consideration when deciding on a graft source for ACL restoration; however, clinical data may aid the surgeon in choosing the right graft for every specific patient in an individualized manner. This short review is intended to highlight the main characteristics and clinical data for each type of autograft

Meniscal Tear Management Associated with ACL Reconstruction

Meniscal lesions often occur in association with anterior cruciate ligament (ACL) tears at the moment of the injury or, secondarily, as a consequence of knee instability. Both ACL and meniscus lesions are associated with a higher risk of osteoarthritis. Adequate treatment of these lesions reduces the rate of degenerative changes in the affected knee. Meniscal tears should be addressed concomitantly with ACL reconstruction and the treatment must be oriented towards preserving the meniscal tissue anytime this is possible. Several options for approaching a meniscus tear are available. The meniscal suture should always be considered, and, if possible, meniscectomy should be the last choice. “Masterly neglect” is a valuable option in selected cases

Meniscal Tear Management Associated with ACL Reconstruction

Meniscal lesions often occur in association with anterior cruciate ligament (ACL) tears at the moment of the injury or, secondarily, as a consequence of knee instability. Both ACL and meniscus lesions are associated with a higher risk of osteoarthritis. Adequate treatment of these lesions reduces the rate of degenerative changes in the affected knee. Meniscal tears should be addressed concomitantly with ACL reconstruction and the treatment must be oriented towards preserving the meniscal tissue anytime this is possible. Several options for approaching a meniscus tear are available. The meniscal suture should always be considered, and, if possible, meniscectomy should be the last choice. &ldquo;Masterly neglect&rdquo; is a valuable option in selected cases