Potentially inappropriate prescriptions of antithrombotic therapies in older outpatients: a French multicenter cross-sectional study.

PURPOSE: To assess the prevalence of inappropriate prescriptions of antithrombotic therapies (AT) in older outpatients and examine the associated factors. METHODS: A multicenter cross-sectional study was performed in 75 community pharmacies of 11 French districts. The study included 1178 patients aged ≥ 75 years filling a prescription from a general practitioner (GP) at a community pharmacy (mean [SD] age 83 [± 5.5] years, 59% female, median prescribed drugs 7 [range 5-10]).75 pharmacy students prospectively collected data from structured interviews with patients and from prescriptions into an electronic case report. Updated 2014 STOPP/START criteria regarding AT were applied to each prescription. Factors associated with ≥ 1 AT-STOPP criteria and ≥ 1 AT-START criteria were studied (multivariate analysis). RESULTS: 22.6% patients featured ≥ 1 in AT-STOPP criteria and 12.4% ≥ 1 in AT-START criteria. The most frequent AT-STOPP and AT-START criteria were AT prescription despite a concurrent significant bleeding risk and lack of AT prescription for patients with chronic atrial fibrillation, respectively. Two factors were associated with ≥ 1 AT-STOPP criteria: polymedication (≥ 5 drugs; p < 0.001) and previous hospitalization for a serious adverse drug event (ADE; p = 0.007). The only factor associated with ≥ 1 AT-START criteria was lack of information in the prescription regarding the duration of treatment. CONCLUSION: Suboptimal prescribing of AT is common in GP's prescriptions for older autonomous outpatients. The currently process of prescribing AT to older autonomous patients must be improved. Special attention should be given to those with polymedication and those with a history of severe ADEs.

The Shh receptor Boc promotes progression of early medulloblastoma to advanced tumors.

During cerebellar development, Sonic hedgehog (Shh) signaling drives the proliferation of granule cell precursors (GCPs). Aberrant activation of Shh signaling causes overproliferation of GCPs, leading to medulloblastoma. Although the Shh-binding protein Boc associates with the Shh receptor Ptch1 to mediate Shh signaling, whether Boc plays a role in medulloblastoma is unknown. Here, we show that BOC is upregulated in medulloblastomas and induces GCP proliferation. Conversely, Boc inactivation reduces proliferation and progression of early medulloblastomas to advanced tumors. Mechanistically, we find that Boc, through elevated Shh signaling, promotes high levels of DNA damage, an effect mediated by CyclinD1. High DNA damage in the presence of Boc increases the incidence of Ptch1 loss of heterozygosity, an important event in the progression from early to advanced medulloblastoma. Together, our results indicate that DNA damage promoted by Boc leads to the demise of its own coreceptor, Ptch1, and consequently medulloblastoma progression.

Boc and Gas1 each form distinct Shh receptor complexes with Ptch1 and are required for Shh-mediated cell proliferation.

Hedgehog (Hh) proteins regulate important developmental processes, including cell proliferation and differentiation. Although Patched acts as the main Hh receptor in Drosophila, Hh signaling absolutely requires the additional Hh-binding proteins Ihog and Boi. Here we show that, unexpectedly, cerebellar granule neuron progenitors (CGNPs) lacking Boc and Cdon, the vertebrate orthologs of Ihog and Boi, still proliferate in response to Hh. This is because in their absence, Gas1, an Hh-binding protein not present in Drosophila, mediates Hh signaling. Consistently, only CGNPs lacking all three molecules-Boc, Cdon, and Gas1-have a complete loss of Hh-dependent proliferation. In a complementary manner, we find that a mutated Hh ligand that binds Patched1 but not Boc, Cdon, or Gas1 cannot activate Hh signaling. Together, this demonstrates an absolute requirement for Boc, Cdon, and Gas1 in Hh signaling and reveals a distinct requirement for ligand-binding components that distinguishes the vertebrate and invertebrate Hh receptor systems.

The Patched dependence receptor triggers apoptosis through a DRAL-caspase-9 complex.

Sonic hedgehog (Shh) and its main receptor, Patched (Ptc), are implicated in both neural development and tumorigenesis. Besides its classic morphogenic activity, Shh is also a survival factor. Along this line, Ptc has been shown to function as a dependence receptor; it induces apoptosis in the absence of Shh, whereas its pro-apoptotic activity is blocked in the presence of Shh. Here we show that, in the absence of its ligand, Ptc interacts with the adaptor protein DRAL (downregulated in rhabdomyosarcoma LIM-domain protein; also known as FHL2). DRAL is required for the pro-apoptotic activity of Ptc both in immortalized cells and during neural tube development in chick embryos. We demonstrate that, in the absence of Shh, Ptc recruits a protein complex that includes DRAL, one of the caspase recruitment (CARD)-domain containing proteins TUCAN (family member, 8) or NALP1 (NLR family, pyrin domain containing 1) and apical caspase-9. Ptc triggers caspase-9 activation and enhances cell death through a caspase-9-dependent mechanism. Thus, we propose that in the absence of its ligand Shh the dependence receptor Ptc serves as the anchor for a caspase-activating complex that includes DRAL, and caspase-9.

Analysis of overridden alerts in a drug-drug interaction detection system.

OBJECTIVE: The aim of this study was to evaluate the relevance of the signals generated by a computerized drug-drug interaction detection system and to design a classification of overridden drug-drug interaction alerts. STUDY DESIGN: Prospective study over two months. SETTING: Five hundred and ten-bed university paediatric hospital. MAIN OUTCOME MEASURES: In Robert Debré Hospital physicians generate drug orders online using a computerized physician order entry system that also detects drug-drug interactions in real time. We analysed the relevance of a sample of alerts overridden by physicians. RESULTS: We analysed a sample of 613 overridden alerts. We defined three categories of overridden alerts: informational errors (35); system errors (244) and accurate alerts (334). Two reasons account for 40% of false-positive alerts: an inability of the system to recognize real conflicts between drug treatments and guidelines stating that the two drugs can be used together, because the benefit outweighs the risk of side effects due to the drug-drug interaction. CONCLUSIONS: We created a classification of overridden alerts, in the context of computerized physician order entry system coupled with a drug-drug interaction detection system. There is clearly room for improvement in the development of drug-drug interaction software. This classification should make it possible to break this work down into smaller tasks, making it possible to decrease the sensitivity to background noise of drug-drug interaction detection systems.

Uncomplicated outcome after an accidental overdose of nevirapine in a newborn.

We report the first case of a massive accidental overdose of nevirapine in a 1-week newborn, due to confusion between nevirapine (Viramune) and nelfinavir (Viracept). The drug was eliminated spontaneously and quickly. We only observed mild neutropenia and hyperlactatemia, which regressed on its own without any clinical complication. Despite the good evolution of this massive overdose, physicians should be aware of confusion risks between some antiretroviral drugs.

Modeling and acquisition of drug-drug interaction knowledge.

OBJECTIVES: The effectiveness of computerized clinical decision support systems (CDSS) depends on the quality of the knowledge they refer to. In this article, we are interested in the acquisition, modeling and representation of the knowledge embedded in the "national reference framework of drug-drug interaction" published by the French Health Products Safety Agency. METHODS: A model of drug-drug interactions has been designed using bottom-up and top-down approaches. This model is the basis for the design of an XML format to represent and extract information on drug interactions from the reference framework. RESULTS: A specific tool has been developed to extract the information from a corpus of 1053 drug monographs using a methodology similar to the one used by the GEM-Cutter tool to extract information from clinical guidelines. Strategies to integrate the XML files produced into CDDSSs are discussed. DISCUSSION-CONCLUSION: Modeling and acquisition of drug-drug interaction knowledge from a corpus of drug monographs is a potential approach to foster the development of CDSS and improve their specificity.

[Non-guideline use of innovative and expensive drugs in pediatrics: assessing clinical practice]. / Utilisation hors recommandations des médicaments innovants et coûteux en pédiatrie.

OBJECTIVE: The objective of this study was to analyze in a pediatric hospital the use of expensive drugs as part of the new activity-based system (T2A) of funding for French public hospitals. We identified and analyzed the therapeutic use of these drugs in indications not included in the expert recommendations issued to accompany this change, with the goal of proposing specific pediatric recommendations. METHOD: Analysis of prescriptions from May through September 2005 showed that 259 patients received expensive drugs subject to special reimbursement. The computerized prescription system enabled us to monitor and validate prescriptions daily. Indications for these expensive drugs were ranked by relevance. RESULTS: The prescriptions analyzed covered 26 expensive drugs. Among the 344 "patient-drugs", 80% were expensive drugs for an accepted therapeutic use, 5% for a pertinent therapeutic use (under evaluation), and 15% for "off-label" uses (2% "not approved" and 13% for indications not considered by the recommendations). CONCLUSION: This study showed that some therapeutic uses not approved by the official recommendations are nevertheless justified. Gathering data from other pediatric hospitals is essential to determine the need for pediatric clinical trials.

Morphogens and cell survival during development.

The notion of "morphogens" is an important one in developmental biology. By definition, a morphogen is a molecule that emanates from a specific set of cells that is present in a concentration gradient and that specifies the fate of each cell along this gradient. The strongest candidate morphogens are members of the transforming growth factor-beta (TGF-beta), Hedgehog (Hh), and Wnt families. While these morphogens have been extensively described as differentiation inducers, some reports also suggest their possible involvement in cell death and cell survival. It is frequently speculated that the cell death induction that is found associated with experimental removal of morphogens is the manifestation of abnormal differentiation signals. However, several recent reports have raised controversy about this death by default, suggesting that cell death regulation is an active process for shaping tissues and organs. In this review, we will present morphogens, with a specific emphasis on Sonic Hedgehog, a mammalian member of the Hh family, not as a positive regulators of cell differentiation but as key regulators of cell survival.