Financial systems and the role of banks in monetary policy transmission in the euro area

This paper offers a comprehensive comparison of the structure of banking and financial markets in the euro area. Based on this, several hypotheses about the role of banks in monetary policy transmission are developed. Many of the predictions that have been proposed for the U.S. are deemed unlikely to apply in Europe. Testing these hypotheses we find that monetary policy does alter bank loan supply, with the effects most dependent on the liquidity of individual banks. Unlike in the US, the size of a bank does generally not explain its lending reaction. We also show that the standard publicly available database, BankScope, obscures the heterogeneity across banks. Indeed, for several types of questions BankScope data suggest very different answers than more complete data that reside at national central banks. -- Dieses Papier bietet einen umfassenden Vergleich zwischen den Strukturen der Banksysteme und Finanzmärkte im Eurogebiet. Basierend hierauf werden einige Hypothesen über die Rolle von Banken in der geldpolitischen Transmission aufgestellt. Viele der für die USA diesbezüglich vermuteten Gegebenheiten gelten wahrscheinlich nicht für Europa. Die ökonometrische Analyse ergibt, dass die Geldpolitik das Bankkreditangebot beeinflußt, wobei die Stärke dieses Effekts über Banken in Abhängigkeit ihres Liquiditätsgrads variiert. Im Gegensatz zu den USA ist im Allgemeinen die Größe einer Bank kein direkter Einflussfaktor für ihre Reaktion mit der Kreditvergabe auf geldpolitische Maßnahmen. Wir zeigen darüber hinaus, dass die in vergleichbaren Studien üblicherweise verwendete, öffentlich verfügbare Datenbasis BankScope ein verzerrtes Bild der zwischen Banken bestehenden Heterogenität wieder gibt. Bei einigen Fragestellungen führt daher die BankScope Datenbasis verglichen mit den vollständigeren Datensätzen der nationalen Zentralbanken zu unterschiedlichen Ergebnissen.monetary policy transmission,financial structure,bank lending

Financial systems and the role of banks in monetary policy transmission in the euro area

This paper offers a comprehensive comparison of the structure of banking and financial markets in the euro area. Based on this, several hypotheses about the role of banks in monetary policy transmission are developed. Many of the predictions that have been proposed for the U.S. are deemed unlikely to apply in Europe. Testing these hypotheses we find that monetary policy does alter bank loan supply, with the effects most dependent on the liquidity of individual banks. Unlike in the US, the size of a bank does generally not explain its lending reaction. We also show that the standard publicly available database, BankScope, obscures the heterogeneity across banks. Indeed, for several types of questions BankScope data suggest very different answers than more complete data that reside at national central banks JEL Classification: C23, E44, E52, G21bank lending, financial structure, Monetary policy transmission

Dynamically simulating the interaction of midazolam and the CYP3A4 inhibitor itraconazole using individual coupled whole-body physiologically-based pharmacokinetic (WB-PBPK) models

BACKGROUND: Drug-drug interactions resulting from the inhibition of an enzymatic process can have serious implications for clinical drug therapy. Quantification of the drugs internal exposure increase upon administration with an inhibitor requires understanding to avoid the drug reaching toxic thresholds. In this study, we aim to predict the effect of the CYP3A4 inhibitors, itraconazole (ITZ) and its primary metabolite, hydroxyitraconazole (OH-ITZ) on the pharmacokinetics of the anesthetic, midazolam (MDZ) and its metabolites, 1' hydroxymidazolam (1OH-MDZ) and 1' hydroxymidazolam glucuronide (1OH-MDZ-Glu) using mechanistic whole body physiologically-based pharmacokinetic simulation models. The model is build on MDZ, 1OH-MDZ and 1OH-MDZ-Glu plasma concentration time data experimentally determined in 19 CYP3A5 genotyped adult male individuals, who received MDZ intravenously in a basal state. The model is then used to predict MDZ, 1OH-MDZ and 1OH-MDZ-Glu concentrations in an CYP3A-inhibited state following ITZ administration. RESULTS: For the basal state model, three linked WB-PBPK models (MDZ, 1OH-MDZ, 1OH-MDZ-Glu) for each individual were elimination optimized that resulted in MDZ and metabolite plasma concentration time curves that matched individual observed clinical data. In vivo K(m )and V(max )optimized values for MDZ hydroxylation were similar to literature based in vitro measures. With the addition of the ITZ/OH-ITZ model to each individual coupled MDZ + metabolite model, the plasma concentration time curves were predicted to greatly increase the exposure of MDZ as well as to both increase exposure and significantly alter the plasma concentration time curves of the MDZ metabolites in comparison to the basal state curves. As compared to the observed clinical data, the inhibited state curves were generally well described although the simulated concentrations tended to exceed the experimental data between approximately 6 to 12 hours following MDZ administration. This deviations appeared to be greater in the CYP3A5 *1/*1 and CYP3A5 *1/*3 group than in the CYP3A5 *3/*3 group and was potentially the result of assuming that ITZ/OH-ITZ inhibits both CYP3A4 and CYP3A5, whereas in vitro inhibition is due to CYP3A4. CONCLUSION: This study represents the first attempt to dynamically simulate metabolic enzymatic drug-drug interactions via coupled WB-PBPK models. The workflow described herein, basal state optimization followed by inhibition prediction, is novel and will provide a basis for the development of other inhibitor models that can be used to guide, interpret, and potentially replace clinical drug-drug interaction trials

A Computational Systems Biology Software Platform for Multiscale Modeling and Simulation: Integrating Whole-Body Physiology, Disease Biology, and Molecular Reaction Networks

Today, in silico studies and trial simulations already complement experimental approaches in pharmaceutical R&D and have become indispensable tools for decision making and communication with regulatory agencies. While biology is multiscale by nature, project work, and software tools usually focus on isolated aspects of drug action, such as pharmacokinetics at the organism scale or pharmacodynamic interaction on the molecular level. We present a modeling and simulation software platform consisting of PK-Sim® and MoBi® capable of building and simulating models that integrate across biological scales. A prototypical multiscale model for the progression of a pancreatic tumor and its response to pharmacotherapy is constructed and virtual patients are treated with a prodrug activated by hepatic metabolization. Tumor growth is driven by signal transduction leading to cell cycle transition and proliferation. Free tumor concentrations of the active metabolite inhibit Raf kinase in the signaling cascade and thereby cell cycle progression. In a virtual clinical study, the individual therapeutic outcome of the chemotherapeutic intervention is simulated for a large population with heterogeneous genomic background. Thereby, the platform allows efficient model building and integration of biological knowledge and prior data from all biological scales. Experimental in vitro model systems can be linked with observations in animal experiments and clinical trials. The interplay between patients, diseases, and drugs and topics with high clinical relevance such as the role of pharmacogenomics, drug–drug, or drug–metabolite interactions can be addressed using this mechanistic, insight driven multiscale modeling approach

Financial Systems and the Role of Banks in Monetary Policy Transmission in the Euro Area

This paper offers a comprehensive comparison of the structure of banking and financial markets in the euro area. Based on this, several hypotheses about the role of banks in monetary policy transmission are developed. Many of the predictions that have been proposed for the U.S. are deemed unlikely to apply in Europe. Testing these hypotheses we find that monetary policy does alter bank loan supply, with the effects most dependent on the liquidity of individual banks. Unlike in the US, the size of a bank does generally not explain its lending reaction. We also show that the standard publicly available database, BankScope, obscures the heterogeneity across banks. Indeed, for several types of questions BankScope data suggest very different answers than more complete data that reside at national central banks.monetary policy transmission, financial structure, bank lending

Épidémiologie de l’artériopathie des membres inférieurs

International audienceIt is estimated that more than 200 million individuals are affected by lower extremity artery disease (LEAD) worldwide. This prevalence has increased between 2000 and 2010 by 25%, especially in low/middle income countries. In France, about one million people are affected by this condition. Almost two-thirds of patients with LEAD are asymptomatic. This explains the interest of the measurement of the ankle-brachial index (ABI), an objective and harmless diagnostic tool. An ABI≤0.90 is considered as diagnostic for LEAD. The detection of symptomatic LEAD requires standardized questionnaires identifying intermittent claudication. Epidemiological studies on chronic limb-threatening ischemia (CLTI) - the most severe presentation of the disease - are scarce: the prevalence is estimated around 0.5-2.0% after the age of 40, mostly affecting elderly people. Similar to other atherosclerotic diseases, the risk factors are multiple (genetic factors, traditional risk factors, metabolic and inflammatory factors, socioeconomic factors), with different weighs of association as compared to coronary artery diseases. Due to their high prevalence and strength of association, cigarette smoking and hypertension are the most frequent purveyors of this disease in population. Diabetes mellitus is a strong risk factor, and its increasing prevalence contributes to the global epidemics of LEAD. In claudicants, the 5-year amputation risk is estimated at 5%, increasing to 25% at one year in case of CLTI. However, the main risk is related to general cardiovascular events. It is estimated that patients with LEAD present concomitantly coronary and cerebrovascular disease in respectively 50% and 20% of cases. The non-cardiovascular mortality, especially related to cancer, is also higher than in general population. Overall, the control of traditional risk factors has a beneficial effect both for the limb and general prognosis.On estime à plus de 200 millions le nombre d’individus touchés par l’artériopathie des membres (AOMI) dans le monde. Cette prévalence aurait augmenté d’environ 25 % entre 2000 et 2010, et notamment dans les pays à revenu faible/intermédiaire. En France, on estime que près d’un million de français présenterait cette maladie. Près de deux-tiers de la population atteinte d’AOMI présente sa forme asymptomatique. Ainsi, la majorité des études épidémiologiques ont recours à la mesure de l’index de pression systolique (IPS). Un IPS ≤ 0,90 signe la présence d’une AOMI. La détection des formes symptomatiques de l’AOMI nécessite le recours à des questionnaires standardisés, permettant de diagnostiquer la claudication intermittente. Les études concernant l’ischémie critique – la forme la plus sévère de la maladie – sont encore rares : on estime dans les pays occidentaux une prévalence de l’ordre de 0,5–2,0 % dans la population de plus de 40 ans. Comme toute maladie athéromateuse, les facteurs de risque sont de 4 ordres (facteurs génétiques, les facteurs de risque traditionnels, les facteurs métaboliques et inflammatoires, et les facteurs psycho-socioéconomiques) avec néanmoins des poids différents par rapport à la maladie coronaire. Du fait de leur grande prévalence et leur association avec la survenue de l’AOMI, le tabagisme et l’hypertension artérielle sont les deux premiers pourvoyeurs de cette maladie en population. Le diabète est un puissant facteur de risque, et son essor dans la population contribue à l’augmentation de la prévalence de l’AOMI. Chez le claudicant, le risque d’amputation est de 5 % à 5 ans, passant à 25 % à un an en cas d’ischémie critique. Mais le risque principal est celui des évènements cardiovasculaires tels que l’infarctus et l’accident vasculaire cérébral. On estime que 50 % de ces patients ont une atteinte coronaire concomitante, et 20 % ont une atteinte cérébrovasculaire. La mortalité non cardiovasculaire, essentiellement liée au cancer, est également plus importante que la population générale. Globalement, le contrôle des facteurs de risque traditionnels a un effet favorable tant sur la diminution du risque de survenue de la maladie que son évolution et ses complications

Impact of anatomical location of lower limb venous thrombus on the risk of subsequent cancer

International audienceAfter a proximal deep-vein thrombosis (P-DVT), the risk of diagnosis of a previously unsuspected cancer is high. Isolated distal DVT (iD-DVT; i.e. infra-popliteal DVT without pulmonary embolism [PE]) and isolated superficial-vein thrombosis (iSVT; i.e. without concomitant DVT and PE) are at least as frequent as P-DVT but their association with subsequent cancer is uncertain. We exploited data from the OPTIMEV prospective, observational, multicentre study to i) compare the risk of subsequent cancer three years after a first objectively confirmed iSVT, iD-DVT and iP-DVT in patients without a prior history of cancer or of venous thromboembolism, ii) assess predictors of subsequent cancer in cases of iD-DVT. The overall cumulative rates of cancer among the 304 patients with iSVT, 536 patients with iD-DVT, and 327 patients with iP-DVT were similar (3.4% 95% confidence interval [1.8-6.2], 3.9% [2.5-5.9] and 3.9% [2.3-6.8], respectively), regardless of whether the index venous thromboembolic event was unprovoked or associated with a major transient risk factor. Neither anatomical (muscular vs deep-calf DVT) nor ultrasound scan characteristics (number of thrombosed veins, clot diameter under compression) seemed strongly associated with the risk of cancer in cases of iD-DVT. In patients managed in routine practice, all the different clinical expressions of lower limb venous thromboembolism are associated with a similar risk of subsequent cancer. From a clinical practice point of view, this suggests that cancer screening, without discussing the necessity, or not, of such screening, should not differ between a deep-proximal, deep-distal or superficial location of thrombosis