The DEXA-CORT trial: study protocol of a randomised placebo-controlled trial of hydrocortisone in patients with brain tumour on the prevention of neuropsychiatric adverse effects caused by perioperative dexamethasone

Introduction The synthetic glucocorticoid dexamethasone can induce serious neuropsychiatric adverse effects. Dexamethasone activates the glucocorticoid receptor (GR) but, unlike endogenous cortisol, not the mineralocorticoid receptor (MR). Moreover, dexamethasone suppresses cortisol production, thereby eliminating its MR binding. Consequently, GR overactivation combined with MR underactivation may contribute to the neuropsychiatric adverse effects of dexamethasone. The DEXA-CORT trial aims to reactivate the MR using cortisol to reduce neuropsychiatric adverse effects of dexamethasone treatment. Methods and analysis The DEXA-CORT study is a multicentre, randomised, double-blind, placebo-controlled trial in adult patients who undergo elective brain tumour resection treated perioperatively with high doses of dexamethasone to minimise cerebral oedema. 180 patients are randomised between treatment with either two times per day 10 mg hydrocortisone or placebo during dexamethasone treatment. The primary study outcome is the difference in proportion of patients scoring >= 3 points on at least one of the Brief Psychiatric Rating Scale (BPRS) questions 5 days postoperatively or earlier at discharge. Secondary outcomes are neuropsychiatric symptoms, quality of sleep, health-related quality of life and neurocognitive functioning at several time points postoperatively. Furthermore, neuropsychiatric history, serious adverse events, prescribed (psychiatric) medication and referrals or evaluations of psychiatrist/psychologist and laboratory measurements are assessed. Ethics and dissemination The study protocol has been approved by the Medical Research Ethics Committee of the Leiden University Medical Center, and by the Dutch competent authority, and by the Institutional Review Boards of the participating sites. It is an investigator-initiated study with financial support by The Netherlands Organisation for Health Research and Development (ZonMw) and the Dutch Brain Foundation. Results of the study will be submitted for publication in a peer-reviewed journal.Diabetes mellitus: pathophysiological changes and therap

Anti-SARS-CoV-2 inactivated vaccine in patients with ANCA-associated vasculitis: Immunogenicity, safety, antibody decay and the booster dose

Objective: To evaluate inactivated CoronaVac prime vaccination, antibody decay, booster dose, and safety in ANCA-Associated Vasculitis (AAV) patients. Methods: Fifty-three AAV patients and 106 Controls (CG) received CoronaVac on days: D0 (first dose), D28(second dose), and D210 (booster dose, 32 AAV: 32 CG). The primary outcome was immunogenicity after the second vaccine dose (day 69) assessed by Seroconversion Rates (SC) of anti-SARS-CoV-2 S1/S2 IgG and Neutralizing Antibodies (NAb). Secondary outcomes were safety, immunogenicity (D28/D240), 6-months antibody decay (D210) and the booster dose response (D240). Results: At D69 SC (65.1% vs. 96.8%, p = 0.0001), GMT (21.3 UA/mL vs. 67.7 UA/mL, p < 0.001) and NAb- positivity (53.7% vs. 80.6%, p = 0.001) were moderate but lower in naïve-AAV patients than CG. Patients without SC used more often IS (93.3% vs. 53.3%, p = 0.015), mycophenolate mofetil (20% vs. 0%, p = 0.037) and prednisone (60.0% vs. 28.6%, p = 0.057) than seroconverted. NAb negativity in AAV patients was associated with prednisone treatment (57.9% vs. 18.2%, p = 0.015) and IS (84.2% vs. 55.0%, p = 0.046). Logistic regression analysis models showed that only prednisone was associated with lower seroconversion (OR = 0.2, 0,95% CI 0.05‒0.86, p = 0.030) and with lower NAb positivity (OR = 0.2, 0,95% CI 0.05‒0.88, p = 0.034). After six months (D69‒D210) a decrease in IgG positivity occurred in 32 AAV patients (15.7%, p = 0.074) and 32 CG (18.7%, p = 0.041). For the NAb positivity, the 6-month decrease was not significant (p = 0.114) whereas a major reduction occurred for CG (p < 0.001). A booster dose (D240) resulted in an increment in IgG-positivity (21.9%, p = 0.023) and NAb-positivity (34.4%, p = 0.006) in AAV patients. No moderate/severe adverse events attributable to the vaccine were observed. Conclusion: This study provides novel data on the excellent safety and moderate immunogenicity of CoronaVac in AAV patients. A six-month mild antibody waning was observed with a good response to the booster dose, although levels remained lower than CG (CoronavRheum-NCT04754698)

Effects of advertisements and questionnaire interruptions on the player experience

New online stores and digital distribution methods have led to the development of alternative monetization models for video-games, such as free-to-play games with advertisements. Although there are many games using such models, until now the effect on the player experience from such interruptions has not been studied. In this controlled experiment, we requested that participants (N=236) play one of three different versions of a platformer game with: 1) no interruptions, 2) 30-second video advertisements, and 3) a multiple-choice questionnaire. We then evaluated the effects on the player experience. The study shows differences in their experiences, namely in: competence, immersion, annoyance, affects, and the reliability of the questionnaire answers. The contribution of this work is to identify which player experience variables are affected by interruptions, which can be valuable for selecting the business model and guiding the game design process

Efeito do produto iônico do biovidro 60S na diferenciação osteogênica de células-tronco mesenquimais do tecido adiposo de cães

O objetivo do presente trabalho foi avaliar o produto iônico do biovidro 60S (BV60S) na diferenciação osteogênica de células-tronco mesenquimais de origem adiposa (CTM-AD) de cães. As CTM-AD foram diferenciadas sem OSTe com o produto iônico (PI OST) por sete, 14 e 21 dias. Avaliou-se o MTT, a fosfatase alcalina (FA), o colágeno, mineralização e as expressões de osterix (OSX), sialoproteína óssea (BSP), osteonectina (ON) e osteocalcina (OC). O grupo PI OSTmostrou menor conversão de MTT aos sete dias e maior conversão aos 21 dias. A atividade de FA foi maior no grupo OST, aos 14 e 21 dias. A síntese de colágeno foi maior no grupo OST aos sete e 21 dias. Verificou-se maior área mineralizada no grupo PI OSTem todos os tempos. Não houve diferenças nas expressões de OSX e OC entre os grupos. Observou-se maior expressão de BSP no grupo PI OST, aos 14 e 21 dias. A expressão de ON foi maior no grupo OST aos 14 dias. Concluiu-se que o produto iônico do BV60S favorece a osteogênese in vitro de CTM-AD de cães

Endoplasmic reticulum stress occurs downstream of NR2B subunit of N-methyl-D-aspartate receptor in mature hippocampal cultures treated with amyloid-β oligomers

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder affecting both the hippocampus and the cerebral cortex. Reduced synaptic density that occurs early in the disease process seems to be partially due to the overactivation of N-methyl-D-aspartate receptors (NMDARs) leading to excitotoxicity. Recently, we demonstrated that amyloid-beta oligomers (AO), the species implicated in synaptic loss during the initial disease stages, induce endoplasmic reticulum (ER) stress in cultured cortical neurons. Here, we investigated whether AO trigger ER stress by an NMDAR-dependent mechanism leading to hippocampal dysfunction and analyzed the contribution of NR2A and NR2B subunits of NMDAR. Our data revealed that AO induce ER stress in mature hippocampal cultures, activating ER stress-associated sensors and increasing the levels of the ER chaperone GRP78. We also showed that AO treatment induces NADPH oxidase (NOX)-mediated superoxide production downstream of NR2B and impairs ER and cytosolic Ca2+ homeostasis. These events precede changes in cell viability and activation of the ER stress-mediated apoptotic pathway, occurring by a caspase-12-independent mechanism. Moreover, AO-mediated ER stress was characterized by increased nuclear levels of the transcription factor GADD153/CHOP. Significantly, ER stress took place after AO interaction with NR2B subunits. In addition, AO-induced ER stress and hippocampal dysfunction was prevented by pre-incubation with ifenprodil, an antagonist of NR2B subunits while the NR2A antagonist NVP-AAM077 only slightly attenuated AO-induced neurotoxicity. Taken together, our results highlight the role of NR2B subunit of NMDARs on ER stress-mediated hippocampal dysfunction caused by AO suggesting that it can be a potential therapeutic target during the early stages of AD

Matriz porosa do BV60S no tratamento de defeitos ósseos críticosem rádios de cães

O objetivo deste estudo foi avaliar o efeito da matriz porosa do biovidro de composição molar 60% SiO2 - 36% CaO - 4% P2O5 (BV60S) no tratamento de defeitos ósseos críticos de cães. Foram utilizados 20 cães, machos, sem raça definida, com dois anos e massa corporal média de 25kg. Foram constituídos três grupos experimentais: defeitos ósseos preenchidos com BV60S (BV), com osso autógeno (C+) e defeitos não preenchidos (C-). A regeneração óssea foi avaliada por meio de exames radiográficos, densitométricos e histomorfométricos ao longo de 90 dias. A matriz do BV60S mostrou rápida reabsorção com redução média de 12,62% a cada 15 dias. A regeneração foi completa no grupo C+ e incompleta nos grupos BV e C-, aos 90 dias. A área de neoformação óssea foi semelhante entre os grupos BV e C-, em todos os tempos estudados. Conclui-se que a matriz porosa do BV60S possui rápida reabsorção, não sendo eficiente no tratamento de defeitos ósseos críticos em rádios de cães