Association between chronic irritability and depressive symptoms in children and adolescents.

Association between chronic irritability and depressive symptoms in children and adolescents. Busto-Garrido, M.; Gutierrez-Castillo, D; Navas- Gonzalez, JR; Gutierrez-Bedmar, M; Gutierrez-Casares, JR; Martin-Lunar, MT; Rodríguez-Rosado, A; Pena-Andreu, JM. European Psychiatry 415(2017) 5221.Chronic irritability is the most frequently reported symptom in child and adolescent depression. The association of both has been linked with high rates of chronicity, comorbility and impairment. Objectives To study the association between chronic irritability and depressive symptoms in children and adolescents. Methods We have studied 857 participants recruited from the only Child and Adolescent Mental Health Clinic in a catchment area of 122968 people under 18 (2004-2010). A sample of 677 participants (57 controls and 620 patients) was included to carry out a cross-sectional study. Chronic irritability was measured by a Visual Analog Scale (VAS irritability) -scored from 0 to 10-, and depressive symptoms by the Children's Depression Inventory (CDI). The participants were categorized into controls and patients, and according to their chronic irritability (≤4 [I],5 [II] and ≥6 [III]). The mean of CDI score was calculated for each of the groups, adjusted by sex and age, and analyzed by ANCOVA. Results The following means were obtained from the controls: 13,71 (group I), 9,82 (group II) and 17,45 (group III). Regarding to the patients: 13,92 (group I), 11,54 (group II) and 15,64 (group III). A quadratic association (p <0,0015) was found between VAS irritability score and CDI score. Conclussions There is not a lineal association between chronic irritability and depressive symptoms in children and adolescent. High rates of depressive symptoms were associated both with high and low rates of irritability. Several questions remain unexplained about the status of irritability in psychiatry as Stringaris group has been pointed out. Disclosure statement I have no potential conflict of interest to discloseUniversidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Use of archival versus newly collected tumor samples for assessing PD-L1 expression and overall survival : an updated analysis of KEYNOTE-010 trial

Background: In KEYNOTE-010, pembrolizumab versus docetaxel improved overall survival (OS) in patients with programmed death-1 protein (PD)-L1-positive advanced non-small-cell lung cancer (NSCLC). A prespecified exploratory analysis compared outcomes in patients based on PD-L1 expression in archival versus newly collected tumor samples using recently updated survival data. Patients and methods: PD-L1 was assessed centrally by immunohistochemistry (22C3 antibody) in archival or newly collected tumor samples. Patients received pembrolizumab 2 or 10 mg/kg Q3W or docetaxel 75 mg/m2 Q3W for 24 months or until progression/intolerable toxicity/other reason. Response was assessed by RECIST v1.1 every 9 weeks, survival every 2 months. Primary end points were OS and progression-free survival (PFS) in tumor proportion score (TPS) 50% and 1%; pembrolizumab doses were pooled in this analysis. Results: At date cut-off of 24 March 2017, median follow-up was 31 months (range 23-41) representing 18 additional months of follow-up from the primary analysis. Pembrolizumab versus docetaxel continued to improve OS in patients with previously treated, PD-L1-expressing advanced NSCLC; hazard ratio (HR) was 0.66 [95% confidence interval (CI): 0.57, 0.77]. Of 1033 patients analyzed, 455(44%) were enrolled based on archival samples and 578 (56%) on newly collected tumor samples. Approximately 40% of archival samples and 45% of newly collected tumor samples were PD-L1 TPS 50%. For TPS 50%, the OS HRs were 0.64 (95% CI: 0.45, 0.91) and 0.40 (95% CI: 0.28, 0.56) for archival and newly collected samples, respectively. In patients with TPS 1%, OS HRs were 0.74 (95% CI: 0.59, 0.93) and 0.59 (95% CI: 0.48, 0.73) for archival and newly collected samples, respectively. In TPS 50%, PFS HRs were similar across archival [0.63 (95% CI: 0.45, 0.89)] and newly collected samples [0.53 (95% CI: 0.38, 0.72)]. In patients with TPS 1%, PFS HRs were similar across archival [0.82 (95% CI: 0.66, 1.02)] and newly collected samples [0.83 (95% CI: 0.68, 1.02)]. Conclusion: Pembrolizumab continued to improve OS over docetaxel in intention to treat population and in subsets of patients with newly collected and archival samples

Influência da aplicação de flúor sobre a rugosidade superficial do ionômero de vidro Vitremer e adesão microbiana a este material

Os cimentos ionoméricos representam importante opção de material restaurador em Odontologia e sua adesão à estrutura dental, diminuindo a infiltração marginal, somada à liberação de flúor, inibindo o metabolismo de microrganismos acidogênicos e favorecendo a remineralização dental, podem diminuir a ocorrência de cárie secundária. A aplicação tópica de géis acidulados ou neutros contendo flúor tem sido largamente utilizada em Odontologia. No entanto, este procedimento pode afetar a integridade dos materiais restauradores, aumentando sua rugosidade e a retenção de placa bacteriana. Dessa forma, o presente estudo avaliou o período de tempo no qual o cimento ionomérico Vitremer mantém sua capacidade inibitória sobre Streptococcus mutans ATCC 25175 e a adesão dos mesmos sobre a superfície do material, bem como a influência da aplicação tópica de flúor acidulado e neutro sobre esses parâmetros microbiológicos e as características superficiais daquele material. Verificou-se que a atividade antimicrobiana do cimento ionomérico Vitremer se mantém por aproximadamente quatro dias e não é recuperada com o uso de flúor gel acidulado ou neutro. Observou-se, também, que Streptococcus mutans ATCC 25175 adere ao material restaurador testado sendo que a aplicação tópica de flúor não influenciou esta adesão. As características superficiais desses materiais não se alteraram com a aplicação dos géis.Glass ionomer cements are important options in restorative and preventive dentistry due to their adhesion to the tooth surface and to fluoride release, which can decrease the risk of recurrent caries. The topical use of acidulated and neutral fluoride gels has been frequent in dentistry. However, this procedure can adversely affect the surface of restorative materials, increasing their roughness and the retention of dental plaque. Thus, this study evaluated the period in which Vitremer glass ionomer cement maintains its antimicrobial activity over Streptococcus mutans ATCC 25175, as well as the effects of topical application of acidulated and neutral fluoride gels on these microbiological parameters and on the superficial characteristics of the restorative material. It was verified that the antimicrobial activity of Vitremer is very transient, decreasing to an undetectable level after four days, and the topical application of fluoride gel did not restore this activity. It was observed that S. mutans ATCC 25175 adheres to this restorative material, and the topical fluorides did not affect this event. The surface of Vitremer was not altered by the application of fluoride gels

Clinical use of HIV integrase inhibitors : a systematic review and meta-analysis

Background: Optimal regimen choice of antiretroviral therapy is essential to achieve long-term clinical success. Integrase inhibitors have swiftly been adopted as part of current antiretroviral regimens. The purpose of this study was to review the evidence for integrase inhibitor use in clinical settings. Methods: MEDLINE and Web-of-Science were screened from April 2006 until November 2012, as were hand-searched scientific meeting proceedings. Multiple reviewers independently screened 1323 citations in duplicate to identify randomized controlled trials, nonrandomized controlled trials and cohort studies on integrase inhibitor use in clinical practice. Independent, duplicate data extraction and quality assessment were conducted. Results: 48 unique studies were included on the use of integrase inhibitors in antiretroviral therapy-naive patients and treatment-experienced patients with either virological failure or switching to integrase inhibitors while virologically suppressed. On the selected studies with comparable outcome measures and indication (n = 16), a meta-analysis was performed based on modified intention-to-treat (mITT), on-treatment (OT) and as-treated (AT) virological outcome data. In therapy-naive patients, favorable odds ratios (OR) for integrase inhibitor-based regimens were observed, (mITT OR 0.71, 95% CI 0.59-0.86). However, integrase inhibitors combined with protease inhibitors only did not result in a significant better virological outcome. Evidence further supported integrase inhibitor use following virological failure (mITT OR 0.27; 95% CI 0.11-0.66), but switching to integrase inhibitors from a high genetic barrier drug during successful treatment was not supported (mITT OR 1.43; 95% CI 0.89-2.31). Integrase inhibitor-based regimens result in similar immunological responses compared to other regimens. A low genetic barrier to drug-resistance development was observed for raltegravir and elvitegravir, but not for dolutegravir. Conclusion: In first-line therapy, integrase inhibitors are superior to other regimens. Integrase inhibitor use after virological failure is supported as well by the meta-analysis. Careful use is however warranted when replacing a high genetic barrier drug in treatment-experienced patients switching successful treatment

The biological potential hidden in inclusion bodies

Inclusion bodies (IBs) are protein nanoclusters obtained during recombinant protein production processes, and several studies have demonstrated their potential as biomaterials for therapeutic protein delivery. Nevertheless, IBs have been, so far, exclusively sifted by their biological activity in vitro to be considered in further protein-based treatments in vivo. Matrix metalloproteinase-9 (MMP-9) protein, which has an important role facilitating the migration of immune cells, was used as model protein. The MMP-9 IBs were compared with their soluble counterpart and with MMP-9 encapsulated in polymeric-based micelles (PM) through ionic and covalent binding. The soluble MMP-9 and the MMP-9-ionic PM showed the highest activity values in vitro. IBs showed the lowest activity values in vitro, but the specific activity evolution in 50% bovine serum at room temperature proved that they were the most stable format. The data obtained with the use of an air-pouch mouse model showed that MMP-9 IBs presented the highest in vivo activity compared to the soluble MMP-9, which was associated only to a low and a transitory peak of activity. These results demonstrated that the in vivo performance is the addition of many parameters that did not always correlate with the in vitro behavior of the protein of interest, becoming especially relevant at evaluating the potential of IBs as a protein-based nanomaterial for therapeutic purposesinfo:eu-repo/semantics/publishedVersio

Methadone adverse reaction presenting with large increase in plasma methadone binding: a case series

<p>Abstract</p> <p>Introduction</p> <p>The use of methadone as an analgesic is on the increase, but it is widely recognized that the goal of predictable and reproducible dosing is confounded by considerable variability in methadone pharmacokinetics, and unpredictable side effects that include sedation, respiratory depression and cardiac arrhythmias. The mechanisms underlying these unpredictable effects are frequently unclear. Here, to the best of our knowledge we present the first report of an association between accidental methadone overexposure and increased plasma protein binding, a new potential mechanism for drug interactions with methadone.</p> <p>Case presentation</p> <p>We describe here the cases of two patients who experienced markedly different responses to the same dose of methadone during co-administration of letrozole. Both patients were post-menopausal Caucasian women who were among healthy volunteers participating in a clinical trial. Under the trial protocol both patients received 6 mg of intravenous methadone before and then after taking letrozole for seven days. One woman (aged 59) experienced symptoms consistent with opiate overexposure after the second dose of methadone that were reversed by naloxone, while the other (aged 49) did not. To understand the etiology of this event, we measured methadone pharmacokinetics in both patients. In our affected patient only, a fourfold to eightfold increase in methadone plasma concentrations after letrozole treatment was observed. Detailed pharmacokinetic analysis indicated no change in metabolism or renal elimination in our patient, but the percentage of unbound methadone in the plasma decreased 3.7-fold. As a result, the volume of distribution of methadone decreased approximately fourfold. The increased plasma binding in our affected patient was consistent with observed increases in plasma protein concentrations.</p> <p>Conclusions</p> <p>The marked increase in the total plasma methadone concentration observed in our patient, and the enhanced pharmacodynamic effect, appear primarily due to a reduced volume of distribution. The extent of plasma methadone binding may help to explain the unpredictability of its pharmacokinetics. Changes in volume of distribution due to plasma binding may represent important causes of clinically meaningful drug interactions.</p

Causal hierarchy within the thalamo-cortical network in spike and wave discharges

Background: Generalised spike wave (GSW) discharges are the electroencephalographic (EEG) hallmark of absence seizures, clinically characterised by a transitory interruption of ongoing activities and impaired consciousness, occurring during states of reduced awareness. Several theories have been proposed to explain the pathophysiology of GSW discharges and the role of thalamus and cortex as generators. In this work we extend the existing theories by hypothesizing a role for the precuneus, a brain region neglected in previous works on GSW generation but already known to be linked to consciousness and awareness. We analysed fMRI data using dynamic causal modelling (DCM) to investigate the effective connectivity between precuneus, thalamus and prefrontal cortex in patients with GSW discharges. Methodology and Principal Findings: We analysed fMRI data from seven patients affected by Idiopathic Generalized Epilepsy (IGE) with frequent GSW discharges and significant GSW-correlated haemodynamic signal changes in the thalamus, the prefrontal cortex and the precuneus. Using DCM we assessed their effective connectivity, i.e. which region drives another region. Three dynamic causal models were constructed: GSW was modelled as autonomous input to the thalamus (model A), ventromedial prefrontal cortex (model B), and precuneus (model C). Bayesian model comparison revealed Model C (GSW as autonomous input to precuneus), to be the best in 5 patients while model A prevailed in two cases. At the group level model C dominated and at the population-level the p value of model C was ∼1. Conclusion: Our results provide strong evidence that activity in the precuneus gates GSW discharges in the thalamo-(fronto) cortical network. This study is the first demonstration of a causal link between haemodynamic changes in the precuneus - an index of awareness - and the occurrence of pathological discharges in epilepsy. © 2009 Vaudano et al

Characterization of complex networks: A survey of measurements

Each complex network (or class of networks) presents specific topological features which characterize its connectivity and highly influence the dynamics of processes executed on the network. The analysis, discrimination, and synthesis of complex networks therefore rely on the use of measurements capable of expressing the most relevant topological features. This article presents a survey of such measurements. It includes general considerations about complex network characterization, a brief review of the principal models, and the presentation of the main existing measurements. Important related issues covered in this work comprise the representation of the evolution of complex networks in terms of trajectories in several measurement spaces, the analysis of the correlations between some of the most traditional measurements, perturbation analysis, as well as the use of multivariate statistics for feature selection and network classification. Depending on the network and the analysis task one has in mind, a specific set of features may be chosen. It is hoped that the present survey will help the proper application and interpretation of measurements.Comment: A working manuscript with 78 pages, 32 figures. Suggestions of measurements for inclusion are welcomed by the author