Adjunctive Cenobamate for Focal-Onset Seizures in Adults: A Systematic Review and Meta-Analysis

Background: Cenobamate is a novel tetrazole-derived carbamate compound with a dual mechanism of action. This drug can enhance the inactivated state of voltage-gated sodium channels, preferentially inhibiting the persistent component of the sodium channel current, and acts as a positive allosteric modulator of GABAA receptors, binding at a non-benzodiazepine site. Objective: We assessed the efficacy and safety of adjunctive cenobamate for the treatment of focal-onset seizures in adult patients with epilepsy using meta-analytical techniques. Methods: We systematically searched (May, week 4, 2020) MEDLINE (accessed by PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL), and the US National Institutes of Health Clinical Trials Registry (http://www.clinicaltrials.gov). There were no date limitations or language restrictions. Randomized, placebo-controlled, single or double-blinded, add-on trials of cenobamate in adult patients with uncontrolled focal-onset seizures were identified. Main outcomes included the proportion of patients with ≥ 50 and 100% reduction in seizure frequency during the maintenance treatment period compared with baseline and the incidence of treatment withdrawal and adverse events (AEs). Risk ratio (RR) with 95% confidence interval (CI) was estimated for each outcome. Results: Two trials were included, overall enrolling 659 patients (442 for the add-on cenobamate group and 217 for the add-on placebo group). Seizure frequency reduction by at least 50% occurred during the maintenance phase in 50.1% of the patients randomized to cenobamate and 23.5% of the placebo-treated participants (RR 2.18, 95% CI 1.67–2.85; p < 0.001). The pooled estimated RR to achieve seizure freedom for the cenobamate group in comparison with placebo was 3.71 (95% CI 1.93–7.14; p < 0.001). Withdrawal from randomized treatment occurred in 16.7 and 11.1% of participants receiving cenobamate and placebo, respectively (RR 1.34, 95% CI 0.85–2.09; p = 0.205). Treatment was discontinued due to AEs in 12.2 and 4.1% of the patients in the active and control arms (RR 2.27, 95% CI 1.08–4.79; p = 0.031). AEs were reported in 76.9 and 66.8% of the patients during treatment with cenobamate and placebo (RR 1.14, 95% CI 1.02–1.26; p = 0.021). The cenobamate-associated AEs included somnolence, dizziness, fatigue, balance disorder, and diplopia. Conclusions: Adjunctive cenobamate in adult patients with uncontrolled focal-onset seizures is associated with a greater reduction in seizure frequency and a higher rate of AEs than placebo

Efficacy and Safety of Cannabidiol in Epilepsy: A Systematic Review and Meta-Analysis

Background: Approximately one-third of patients with epilepsy presents seizures despite adequate treatment. Hence, there is the need to search for new therapeutic options. Cannabidiol (CBD) is a major chemical component of the resin of Cannabis sativa plant, most commonly known as marijuana. The anti-seizure properties of CBD do not relate to the direct action on cannabinoid receptors, but are mediated by a multitude of mechanisms that include the agonist and antagonist effects on ionic channels, neurotransmitter transporters, and multiple 7-transmembrane receptors. In contrast to tetra-hydrocannabinol, CBD lacks psychoactive properties, does not produce euphoric or intrusive side effects, and is largely devoid of abuse liability. Objective: The aim of the study was to estimate the efficacy and safety of CBD as adjunctive treatment in patients with epilepsy using meta-analytical techniques. Methods: Randomized, placebo-controlled, single- or double-blinded add-on trials of oral CBD in patients with uncontrolled epilepsy were identified. Main outcomes included the percentage change and the proportion of patients with ≥ 50% reduction in monthly seizure frequency during the treatment period and the incidence of treatment withdrawal and adverse events (AEs). Results: Four trials involving 550 patients with Lennox–Gastaut syndrome (LGS) and Dravet syndrome (DS) were included. The pooled average difference in change in seizure frequency during the treatment period resulted 19.5 [95% confidence interval (CI) 8.1–31.0; p = 0.001] percentage points between the CBD 10 mg and placebo groups and 19.9 (95% CI 11.8–28.1; p < 0.001) percentage points between the CBD 20 mg and placebo arms, in favor of CBD. The reduction in all-types seizure frequency by at least 50% occurred in 37.2% of the patients in the CBD 20 mg group and 21.2% of the placebo-treated participants [risk ratio (RR) 1.76, 95% CI 1.07–2.88; p = 0.025]. Across the trials, drug withdrawal for any reason occurred in 11.1% and 2.6% of participants receiving CBD and placebo, respectively (RR 3.54, 95% CI 1.55–8.12; p = 0.003) [Chi squared = 2.53, degrees of freedom (df) = 3, p = 0.506; I2 = 0.0%]. The RRs to discontinue treatment were 1.45 (95% CI 0.28–7.41; p = 0.657) and 4.20 (95% CI 1.82–9.68; p = 0.001) for CBD at the doses of 10 and 20 mg/kg/day, respectively, in comparison to placebo. Treatment was discontinued due to AEs in 8.9% and 1.8% of patients in the active and control arms, respectively (RR 5.59, 95% CI 1.87–16.73; p = 0.002). The corresponding RRs for CBD at the doses of 10 and 20 mg/kg/day were 1.66 (95% CI 0.22–12.86; p = 0.626) and 6.89 (95% CI 2.28–20.80; p = 0.001). AEs occurred in 87.9% and 72.2% of patients treated with CBD and placebo (RR 1.22, 95% CI 1.11–1.33; p < 0.001). AEs significantly associated with CBD were somnolence, decreased appetite, diarrhea, and increased serum aminotransferases. Conclusions: Adjunctive CBD in patients with LGS or DS experiencing seizures uncontrolled by concomitant anti-epileptic treatment regimens is associated with a greater reduction in seizure frequency and a higher rate of AEs than placebo

A 20-year study of persistence of lower urinary tract symptoms and urinary incontinence in young women treated in childhood

OBJECTIVE: To determine whether urinary incontinence (UI) and lower urinary tract symptoms (LUTS) persist over years, patients treated for UI and LUTS in childhood were re-evaluated in adulthood. MATERIALS AND METHODS: Forty-seven women (cases) treated in childhood for daytime UI/LUTS (group A) and nocturnal enuresis (group B) self-completed (average age: 24.89 ± 3.5 years) the International Consultation on Incontinence Questionnaire for Female with LUTS (ICIQ-FLUTS). ICIQ-FLUTS was self-administered to 111 healthy women (average age: 23 ± 5.1 years) from a nursing school as a control group. Data obtained from ICIQ-FLUTS and quality of life (QoL) score (0-10) were compared (Fisher's exact test) between patients and controls, and between group A (n = 28) and group B (n = 19). RESULTS: Prevalence of LUTS was higher in patients than in controls. The difference between patients and controls was statistically significant (p = 0.0001) for UI (34% vs. 7%) and feeling of incomplete bladder emptying (49% vs. 28%). QoL score was >5 in 59% of patients and 1% of controls (p = 0.0001). No significant differences were found between groups A and B. CONCLUSIONS: UI and LUTS are confirmed in young women who suffered for the same condition in childhood. Longitudinal studies are needed to assess if these symptoms persist or are newly onset

REGIME DIFERENCIADO DE CONTRATAÇÕES NA GESTÃO UNIVERSITÁRIA: UM ESTUDO SOBRE A AMPLIAÇÃO DE COMPETÊNCIA

O Regime Diferenciado de Contratações públicas, uma nova modalidade de licitação criada pela lei 12.462/11, tem o escopo de fiscalizar as contratações necessárias para a realização da Copa do Mundo de 2014 e dos Jogos Olímpicos de 2016 e os eventos em que há uma relação mútua, em um país em que há uma lei específica para a regular a contratação pública, que é a lei 8.666/93. Este estudo tem o objetivo de analisar o conceito, os princípios, os objetivos e os mecanismos básicos da contratação pública e as alterações trazidas pelo regime diferenciado de contratações e os novos métodos do processo licitatório da administração pública brasileira mediante o estudo dessas duas leis. Foi utilizado um pluralismo metodológico, utilizando os métodos dedutivos, histórico e comparativo e a técnica de pesquisa da documentação indireta. Decorrente disso, foi realizado um estudo aprofundado da necessidade de atualização da lei 8.666/93 e uma discussão sobre a ampla abrangência da lei 12.462/11, uma lei criada para ter uma vigência temporária sendo considerada como uma lei geral

Phylogeny of European Anodontini (Bivalvia: Unionidae) with a redescription of Anodonta exulcerata

Freshwater bivalves are highly threatened and globally declining due to multiple anthropogenic impacts, making them important conservation targets. Because conservation policies and actions generally occur at the species level, accurate species identification and delimitation is critical. A recent phylogenetic study of Italian mussel populations revalidated an Anodonta species bringing the number of known European Anodontini from three to four species. The current study contributes to the clarification of the taxonomy and systematics of European Anodontini, using a combination of molecular, morphological and anatomical data, and constructs phylogenies based on complete mitogenomes. A redescription of A. exulcerata and a comparative analysis of morphological and anatomical characters with respect to the other two species of Anodonta present in the area are provided. No reliable diagnostic character has emerged from comparative analysis of the morphometric characters of 109 specimens from 16 sites across the Italian peninsula. In fact, the discriminant analysis resulted in a greater probability of correct assignment to the site of origin than to the species. This confirms the difficulties of an uncritical application of visual characters for the delimitation of species, especially for Anodontinae.This research was developed under ConBiomics: the missing approach for the conservation of freshwater bivalves project Nº NORTE-01-0145-FEDER-030286, cofinanced by COMPETE 2020, Portugal 2020 and the European Union through the ERDF - European Regional Development Fund and by FCT - Fundação para a Ciência e a Tecnologia, through national funds (UID/Multi/04423/2019). FCT also supported Manuel Lopes-Lima (SFRH/BD/115728/2016).info:eu-repo/semantics/publishedVersio

Do neurologists agree in diagnosing drug resistance in adults with focal epilepsy?

OBJECTIVE: To evaluate interrater agreement in categorizing treatment outcomes and drug responsiveness status according to the International League Against Epilepsy (ILAE) definition of drug-resistant epilepsy. METHODS: A total of 1053 adults with focal epilepsy considered by the investigators to meet ILAE criteria for drug resistance were enrolled consecutively at 43 centers and followed up prospectively for 18-34 months. Treatment outcomes for all antiepileptic drugs (AEDs) used up to enrollment (retrospective assessment), and on an AED newly introduced at enrollment, were categorized by individual investigators and by 2 rotating members of a 16-member expert panel (EP) that reviewed the patient records independently. Interrater agreement was tested by Cohen's kappa (k) statistics and rated according to Landis and Koch's criteria. RESULTS: Agreement between EP members in categorizing outcomes on the newly introduced AED was almost perfect (90.1%, k = 0.84, 95% confidence interval [CI] 0.80-0.87), whereas agreement between the EP and individual investigators was moderate (70.4%, k = 0.57, 95% CI 0.53-0.61). Similarly, categorization of outcomes on previously used AEDs was almost perfect between EP members (91.7%, k = 0.83, 95% CI 0.81-0.84) and moderate between the EP and investigators (68.2%, k = 0.50, 95% CI 0.48-0.52). Disagreement was related predominantly to outcomes considered to be treatment failures by the investigators but categorized as undetermined by the EP. Overall, 19% of patients classified as having drug-resistant epilepsy by the investigators were considered by the EP to have "undefined responsiveness." SIGNIFICANCE: Interrater agreement in categorizing treatment outcomes according to ILAE criteria ranges from moderate to almost perfect. Nearly 1 in 5 patients considered by enrolling neurologists to be "drug-resistant" were classified by the EP as having "undefined responsiveness.

Restoration, Transformation and Adaptation: Authoritarianism after 2011 in Egypt, Saudi Arabia and Iran

Following the push for reform during the popular uprising in 2011, authoritarianism is once again dominating domestic politics and power relations in the MENA region. Drawing on data collected during field trips to Cairo, Tehran, Beirut and Kuwait city, the authors of this MENARA report analyse three distinct ways in which political leaders in Egypt, Saudi Arabia and Iran have stood their grounds since 2011 by. The report shows that the region’s autocratic leaders have adopted highly distinct strategies to cope with the challenges they have been confronted with internally – including strategies of “restoration”, of “transformation” and of “adaptation”. The report ends by suggesting that European leaders, in spite of their limited leverage and resources, have a longterm strategic interest in fostering alternative forms of political regimes in the MENA region

NOVOS HORIZONTES DA GESTÃO DOS HOSPITAIS UNIVERSITÁRIOS BRASILEIROS: A MUDANÇA DE PARADIGMAS PROMOVIDA PELA EBSERH

A administração pública brasileira estava diminuindo a carga de eficiência em relação aos demais países do mundo, em razão da histórica imutabilidade de sua organização institucionalizada e burocrática. No início do século XXI, observou-se um processo de reformulação da administração pública que implicou na ruptura de paradigmas historicamente concebidos e que se mostravam anacrônicos em comparação com aquele apresentado por outras nações. Esta mudança é claramente verificada em relação à gestão pública dos hospitais universitários que migraram – em muitos Estados da Federação – das universidades federais para a Empresa Brasileira de Serviços Hospitalares – a EBSERH – cuja criação foi autorizada pela lei federal n.º 12.550 de 15 de dezembro de 2011 e nasceu imbuída da finalidade de aumentar a carga de eficiência dos serviços públicos de saúde no Brasil. Esta empresa pública representa um novo modelo de prestação de serviços de saúde em comparação com aquele oferecido ao longo de todo o século XX pelo Poder Público e encontra resistência em muitas universidades em relação à sua implantação, mas se apresenta como um caminho viável para a reestruturação de todo o funcionalismo público brasileiro

Antiepileptic drugs’ tolerability and safety – a systematic review and meta-analysis of adverse effects in dogs

<p>Various anti-epileptic drugs (AEDs) are used for the management of idiopathic epilepsy (IE) in dogs. Their safety profile is an important consideration for regulatory bodies, owners and prescribing clinicians. However, information on their adverse effects still remains limited with most of it derived from non-blinded non-randomized uncontrolled trials and case reports.</p><p><span>This poster won third place, which was presented at the Veterinary Evidence Today conference, Edinburgh November 1-3, 2016. </span></p><br /> <img src="https://www.veterinaryevidence.org/rcvskmod/icons/oa-icon.jpg" alt="Open Access" /

po 077 identification of dhx30 as an inhibitor of the translation of pro apoptotic mrnas after p53 activation by nutlin

Introduction The transcription factor p53 can be efficiently activated by the small molecule Nutlin-3 without inducing genotoxic stress. Treatment of different cell lines with this small molecule can result in different phenotypes, ranging from cell cycle arrest to apoptosis. HCT116 (colon cancer-derived cells) and SJSA1 (osteosarcoma-derived cells) were used to model the opposite behaviour respectively, by analysing the transcriptional and translational responses after Nutlin-3 treatment. Material and methods Total and polysomal-bound mRNAs were collected and sequenced after 12 hour of 10 uM Nutlin-3 treatment. A bioinformatics analysis of the polysome-enriched mRNAs using Weeder allowed the identification of a 3'UTR motif ('CG-rich') which is enriched in the translationally upregulated genes of SJSA1. The effect of the motif on translation was evaluated after cloning its consensus sequence in the 3'UTR of the b-globin gene, which was put downstream the luciferase reporter. The activity of the construct was evaluated after 12 or 24 hours of Nutlin-3. The same consensus was used for a pull-down experiment followed by mass spectrometry to identify proteins interacting with it. Results and discussions RNA-seq data indicate that HCT116 and SJSA1, although sharing almost completely the transcriptional program lead by p53, show almost no overlap at a translation level. SJSA1 present different pro-apoptotic translationally-upregulated genes after Nutlin-3, which have one or more instances of a CG-rich motif in the 3'UTR. The impact of the motif is to enhance the activity of the luciferase reported when cloned in two copies flanking the 3'UTR of the b-globin gene, but only in SJSA1. A pull-down experiment using an RNA bait with the consensus motif was used to identify interactors, among which DHX30 was deeply studied. DHX30 silencing in HCT116 causes: 1) enhanced the activity of the reporter construct after Nutlin; 2) polysomal association of selected mRNAs containing the motif; 3) induction of apoptosis as assessed by Annexin-V staining. In addition, silencing of DHX30 in U2OS cells decreased their survival after Nutlin-3 treatment. Conclusion We show how a p53-dependent transcriptional program can be shaped at a translational level thanks to the action of a CG-rich motif which is enriched in the 3'UTR of some pro-apoptotic mRNAs and that can be bound by DHX30. This protein acts as a translational repressor of mRNAs containing the motif. The exact mechanism and the generalisation of the model are currently being investigated