Clinical pharmacology facing the real-world setting: Pharmacovigilance, pharmacoepidemiology and the economic evaluation of drugs

Adverse drug reaction; Effectiveness; PharmacoeconomicsReacció adversa als fàrmacs; Eficàcia; FarmacoeconomiaReacción adversa a medicamentos; Eficacia; FarmacoeconomíaTraditionally, clinical pharmacology has focused its activities on drug-organism interaction, from an individual or collective perspective. Drug efficacy assessment by performing randomized clinical trials and analysis of drug use in clinical practice by carrying out drug utilization studies have also been other areas of interest. From now on, Clinical pharmacology should move from the analysis of the drug-individual interaction to the analysis of the drug-individual-society interaction. It should also analyze the clinical and economic consequences of the use of drugs in the conditions of normal clinical practice, beyond clinical trials. The current exponential technological development that facilitates the analysis of real-life data offers us a golden opportunity to move to all these other areas of interest. This review describes the role that clinical pharmacology has played at the beginning and during the evolution of pharmacovigilance, pharmacoepidemiology and economic drug evaluations in Spain. In addition, the challenges that clinical pharmacology is going to face in the following years in these three areas are going to be outlined too

Separation of Isomeric Forms of Urolithin Glucuronides Using Supercritical Fluid Chromatography

Producción CientíficaUrolithins are gut microbiota metabolites produced in humans after consuming foods containing ellagitannins and ellagic acid. Three urolithin metabotypes have been reported for different individuals depending on the final urolithins produced. After absorption, they are conjugated with glucuronic acid (phase II metabolism), and these are the main circulating metabolites in plasma and reach different tissues. Different regioisomeric isomers of urolithin glucuronides have been described. Still, their identification and quantification in humans have not been properly reported due to resolution limitations in their analysis by reversed-phase high-performance liquid chromatography. In the present study, we report a novel method for separating these isomers using supercritical fluid chromatography. With this method, urolithin A 3- and 8-glucuronide, isourolithin A 3- and 9- glucuronide, and urolithin B 3-glucuronide (8-hydroxy urolithin 3-glucuronide; 3-hydroxy urolithin 8-glucuronide; 3-hydroxyurolithin 9-glucuronide; 9-hydroxyurolithin 3-glucuronide; and urolithin 3-glucuronide) were separated in less than 15 min. The proposed method was applied to successfully analyze these metabolites in urine samples from different volunteers belonging to different metabotypes.Taif University (TURSP- HC2021/3

Subjective response to antipsychotic treatment and compliance in schizophrenia. A naturalistic study comparing olanzapine, risperidone and haloperidol (EFESO Study)

BACKGROUND: In order to compare the effectiveness of different antipsychotic drugs in the treatment of schizophrenia it is very important to evaluate subjective response and compliance in patient cohorts treated according to routine clinical practice. METHOD: Outpatients with schizophrenia entered this prospective, naturalistic study when they received a new prescription for an antipsychotic drug. Treatment assignment was based on purely clinical criteria, as the study did not include any experimental intervention. Patients treated with olanzapine, risperidone or haloperidol were included in the analysis. Subjective response was measured using the 10-item version of the Drug Attitude Inventory (DAI-10), and treatment compliance was measured using a physician-rated 4 point categorical scale. RESULTS: A total of 2128 patients initiated treatment (as monotherapy) with olanzapine, 417 with risperidone, and 112 with haloperidol. Olanzapine-treated patients had significantly higher DAI-10 scores and significantly better treatment compliance compared to both risperidone- and haloperidol-treated patients. Risperidone-treated patients had a significantly higher DAI-10 score compared to haloperidol-treated patients. CONCLUSION: Subjective response and compliance were superior in olanzapine-treated patients, compared to patients treated with risperidone and haloperidol, in routine clinical practice. Differences in subjective response were explained largely, but not completely, by differences in incidence of EPS

AL-FEC for streaming services in LTE E-MBMS

3rd Generation Partnership Project specified Application Layer - Forward Error Correction (AL-FEC) to be used for Enhanced Multimedia Broadcast Multicast Services (E-MBMS) in Long Term Evolution (LTE) networks. Specifically, Raptor coding is applied to both streaming and file delivery services. This article focuses on streaming services and investigates the optimum configuration of the AL-FEC mechanism depending on the signal-to-interference plus noise power ratio conditions. These configurations are compared with a scenario without an application layer protection to obtain the potential gain that can be achieved by means of AL-FEC. This article also studies the multiplexing of services within the AL-FEC time interleaving. These analyses were performed using a proprietary system level simulator and assuming both pedestrian and vehicular users. Different quality criterions were used to ensure the completeness of the study. Results show the significant benefit of using AL-FEC in E-MBMS in terms of coverage and service quality.This study was supported by the Spanish Ministry of Science under the project TEC2011-27723-C02-02.Calabuig Gaspar, J.; Monserrat Del Río, JF.; Gozálvez Serrano, D.; Gómez Barquero, D. (2013). AL-FEC for streaming services in LTE E-MBMS. EURASIP Journal on Wireless Communications and Networking. 2013(73):1-12. https://doi.org/10.1186/1687-1499-2013-73S1122013733GPP TS 25.346 V6.4.0, Introduction of the Multimedia Broadcast Multicast Service (MBMS) in the Radio Access Network (RAN); Stage 2, 2005.Deng H, Tao X, Lu J: Qos-aware resource allocation for mixed multicast and unicast traffic in OFDMA networks. EURASIP Journal on Wireless Communications and Networking 2012, 2012(195):1-10. 10.1186/1687-1499-2012-1953GPP TS 26.346 V9.5.0, Multimedia Broadcast/Multicast Service (MBMS); Protocols and codecs, 2011.Shokrollahi A: Raptor codes. 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METIS research advances towards the 5G mobile and wireless system definition

[EN] The Mobile and wireless communications Enablers for the Twenty-twenty Information Society (METIS) project is laying the foundations of Fifth Generation (5G) mobile and wireless communication system putting together the point of view of vendors, operators, vertical players, and academia. METIS envisions a 5G system concept that efficiently integrates new applications developed in the METIS horizontal topics and evolved versions of existing services and systems. This article provides a first view on the METIS system concept, highlights the main features including architecture, and addresses the challenges while discussing perspectives for the further research work.Part of this work has been performed in the framework of the FP7 project ICT-317669 METIS, which is partly funded by the European Commission. The authors would like to acknowledge the contributions of their colleagues in METIS with special thanks to Petar Popovski, Peter Fertl, David Gozalvez-Serrano, Andreas Hoglund, Zexian Li, and Krystian Pawlak. Also thanks to Josef Eichinger and Malte Schellmann for the fruitful discussions during the revision of this article.Monserrat Del Río, JF.; Mange, G.; Braun, V.; Tullberg, H.; Zimmermann, G.; Bulakci, O. (2015). METIS research advances towards the 5G mobile and wireless system definition. 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Implementing opportunistic spectrum access in LTE-Advanced

Long term evolution advanced (LTE-A) has emerged as a promising mobile broadband access technology aiming to cope with the increasing traffic demand in wireless networks. However, the enhanced spectral efficiency offered by LTE-A may become futile without a better management of scarce and overcrowded electromagnetic spectrum. In this sense, cognitive radio (CR) has been proposed as a potential solution to the problem of spectrum scarcity. Among all the mechanisms provided by CR, opportunistic spectrum access (OSA) aims at a dynamic and seamless use of certain licensed bands provided the licensee is not harmfully affected. This operation requires spectral awareness in order to avoid interferences with licensed systems. In spite of implementing some spectrum sensing mechanisms, LTE-A technology lacks other tools that are needed in order to improve the knowledge of the radio environment. This work studies the adoption of a Geo-located data base (Geo-DB) that cooperatively retrieves and maintains information regarding the location of unutilized portions of spectrum potentially available for OSA. Moreover, the potential benefit of this LTE-compliant OSA solution is evaluated using a calibrated simulation tool, by which numerical results allow us to optimally configure the system and show that the proposed opportunistic system is able to significantly improve its performance.The authors would like to thank the funding received from the Ministerio de Ciencia e Innovacion within the Project number TEC2011-27723-C02-02 and from the Ministerio de Industria, Turismo y Comercio TSI-020100-2011-266 funds. This article had been written in the framework of the CELTIC project CP08-001 COMMUNE. Study by X. Gelabert is funded by the BP-DGR 2010 scholarship (ref. 00192). 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Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Phylogenetic and genetic linkage between novel atypical dual-specificity phosphatases from non-metazoan organisms

Dual-specificity phosphatases (DSPs) constitute a large protein tyrosine phosphatase (PTP) family, with examples in distant evolutive phyla. PFA-DSPs (Plant and Fungi Atypical DSPs) are a group of atypical DSPs present in plants, fungi, kinetoplastids, and slime molds, the members of which share structural similarity with atypical- and lipid phosphatase DSPs from mammals. The analysis of the PFA-DSPs from the plant Arabidopsis thaliana (AtPFA-DSPs) showed differential tissue mRNA expression, substrate specificity, and catalytic activity for these proteins, suggesting different functional roles among plant PFA-DSPs. Bioinformatic analysis revealed the existence of novel PFA-DSP-related proteins in fungi (Oca1, Oca2, Oca4 and Oca6 in Saccharomyces cerevisiae) and protozoa, which were segregated from plant PFA-DSPs. The closest yeast homolog for these proteins was the PFA-DSP from S. cerevisiae ScPFA-DSP1/Siw14/Oca3. Oca1, Oca2, Siw14/Oca3, Oca4, and Oca6 were involved in the yeast response to caffeine and rapamycin stresses. Siw14/Oca3 was an active phosphatase in vitro, whereas no phosphatase activity could be detected for Oca1. Remarkably, overexpression of Siw14/Oca3 suppressed the caffeine sensitivity of oca1, oca2, oca4, and oca6 deleted strains, indicating a genetic linkage and suggesting a functional relationship for these proteins. Functional studies on mutations targeting putative catalytic residues from the A. thaliana AtPFA-DSP1/At1g05000 protein indicated the absence of canonical amino acids acting as the general acid/base in the phosphor-ester hydrolysis, which suggests a specific mechanism of reaction for PFA-DSPs and related enzymes. Our studies demonstrate the existence of novel phosphatase protein families in fungi and protozoa, with active and inactive enzymes linked in common signaling pathways. This illustrates the catalytic and functional complexity of the expanding family of atypical dual-specificity phosphatases in non-metazoans, including parasite organisms responsible for infectious human diseases. © Springer-Verlag 2011

Validez de un modelo reducido de items del DSM-IV según respuesta de padres y profesores en el diagnóstico del trastorno por déficit de atención con hiperactividad combinado.

Main Objective: To look for a reduced model of symptoms of the attention deficit hyperactivity disorder combined type (ADHD-C), that shows suitable levels of criterion validity for the diagnostic of the disease. Methods: Epidemiological study. Sample of 1095 children between 6 and 16 years. First stage: psicometric study using ADHD RS-IV answered by parents (P) and teachers (T). ADHD is suspected when both questionnaires are over 90th percentile. Second stage: Clinical interview DISC-IV (DSM-IV) only in those selected cases to confirm ADHD-C. Logistic regression is implemented to find the most parsimonious model to predict ADHD-C. Results: The model that predicts clinical ADHD-C consists of 8 of the 36 items of the ADHD RS-IV answered by P and T. If we consider the Odds Ratio obtained by regression, the items present a ranking of: 15 T> 1 P> 16 T> 12 P> 17 P> 10 P> 14 P> 4 T. The model has criterion validity for symptomatic ADHD-C (sensitivity: 97.9%. Specificity: 93.8%. Likelihood ratio: 16.02). Conclusions: It is possible to reduce the list of symptoms of ADHD-C with good criterion validity, removing redundant items and keeping those that provide greater discrimination between ADHD-C and the general population.Objetivo: Buscar un modelo reducido de síntomas del Trastorno por Déficit de Atención con Hiperactividad Combinado (TDAH-C), que presente adecuada validez de criterio para el diagnóstico del trastorno.Metodología: Contexto de estudio epidemiológico. Muestra de 1095 casos entre 6 y 16 años [4.38 % TDAH-C].  Selección de casos con  primera fase psicométrica de sospecha TDAH-C que requiere que ADHD RS-IV, implementado por padres (PA) y profesores (PR), supere el PC 90. Segunda fase: Los casos seleccionados se evalúan mediante entrevista clínica modelo DISC-IV (DSM-IV) para confirmar TDAH-C. Se implementa regresión logística para buscar modelo parsimonioso de ítems que permita predecir TDAH-C.Resultados: El modelo de ítems que permite predecir TDAH-C  contiene 8 de  36 ítems del  ADHD RS-IV contestados por PA y PR. Considerando odss ratio del modelo de regresión logística, los ítems del ADHD RS-IV presentan un ranking de 15PR > 1PA > 16PR > 12PA > 17PA > 10PA > 14PA > 4PR. El modelo presenta validez de criterio para TDAH-C clínico (sensibilidad: 97.9 %. Especifidad: 93.8%. Razón de verosimilitud: 16.02).Conclusiones: Es posible  reducir la lista de síntomas de TDAH-C con buena validez de criterio, manteniendo los que proporcionan mayor discriminación entre  TDAH-C y población general