Efficacy of repetitive transcranial magnetic stimulation (rTMS) for reducing consumption in patients with alcohol use disorders (ALCOSTIM): study protocol for a randomized controlled trial.

BACKGROUND: The number of people with an alcohol use disorder (AUD) was recently estimated to be 63.5 million worldwide. The global burden of disease and injury attributable to alcohol is considerable: about 3 million deaths, namely one in 20, were caused by alcohol in 2015. At the same time, AUD remains seriously undertreated. In this context, alternative or adjunctive therapies such as brain stimulation could play an important role. The early results of studies using repetitive transcranial magnetic stimulation (rTMS) suggest that stimulations delivered to the dorsolateral prefrontal cortex significantly reduce cravings and improve decision-making processes in various addictive disorders. We therefore hypothesize that rTMS could lead to a decrease in alcohol consumption in patients with AUD. METHODS/DESIGN: We report the protocol of a randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the efficacy of rTMS on alcohol reduction in individuals diagnosed with AUD. The study will be conducted in 2 centers in France. Altogether, 144 subjects older than 18 years and diagnosed with AUD will be randomized to receive 5 consecutive twice-daily sessions of either active or sham rTMS (10 Hz over the right DLPFC, 2000 pulses per day). The main outcomes of the study will be changes in alcohol consumption within the 4 weeks after the rTMS sessions. Secondary outcome measures will include changes in alcohol consumption within the 24 weeks, alcohol cravings, clinical and biological improvements, effects on mood and quality of life, and cognitive and safety assessments, and, for smokers, an assessment of the effects of rTMS on tobacco consumption. DISCUSSION: Several studies have observed a beneficial effect of rTMS on substance use disorders by reducing craving, impulsivity, and risk-taking behavior and suggest that rTMS may be a promising treatment in addiction. However, to date, no studies have included sufficiently large samples and sufficient follow-up to confirm this hypothesis. The results from this large randomized controlled trial will give a better overview of the therapeutic potential of rTMS in AUD. TRIAL REGISTRATION: ClinicalTrials.gov NCT04773691. Registered on 26 February 2021 https://clinicaltrials.gov/ct2/show/NCT04773691?term=trojak&draw=2&rank=5 .

A Review of Cyber-Ranges and Test-Beds: Current and Future Trends.

Cyber situational awareness has been proven to be of value in forming a comprehensive understanding of threats and vulnerabilities within organisations, as the degree of exposure is governed by the prevailing levels of cyber-hygiene and established processes. A more accurate assessment of the security provision informs on the most vulnerable environments that necessitate more diligent management. The rapid proliferation in the automation of cyber-attacks is reducing the gap between information and operational technologies and the need to review the current levels of robustness against new sophisticated cyber-attacks, trends, technologies and mitigation countermeasures has become pressing. A deeper characterisation is also the basis with which to predict future vulnerabilities in turn guiding the most appropriate deployment technologies. Thus, refreshing established practices and the scope of the training to support the decision making of users and operators. The foundation of the training provision is the use of Cyber-Ranges (CRs) and Test-Beds (TBs), platforms/tools that help inculcate a deeper understanding of the evolution of an attack and the methodology to deploy the most impactful countermeasures to arrest breaches. In this paper, an evaluation of documented CR and TB platforms is evaluated. CRs and TBs are segmented by type, technology, threat scenarios, applications and the scope of attainable training. To enrich the analysis of documented CR and TB research and cap the study, a taxonomy is developed to provide a broader comprehension of the future of CRs and TBs. The taxonomy elaborates on the CRs/TBs dimensions, as well as, highlighting a diminishing differentiation between application areas.

Anti-persister activity of squalamine against Acinetobacter baumannii.

Squalamine is a natural polycationic aminosterol extracted from the shark Squalus acanthias. Squalamine displays remarkable efficacy against antimicrobial-resistant Gram-negative and Gram-positive bacteria. Its membranolytic activity and low cytotoxicity make squalamine one of the most promising agents to fight nosocomial pathogens such as Acinetobacter baumannii. In the context of chronic diseases and therapeutic failures associated with this pathogen, the presence of dormant cells, i.e. persisters and viable but non-culturable cells (VBNCs), highly tolerant to antimicrobial compounds is problematic. The aim of this study was to investigate the antibacterial activity of squalamine against this bacterial population of A. baumannii. Bacterial dormancy was induced by cold shock and nutrient starvation in the presence of high doses of either colistin, ciprofloxacin or squalamine. Persisters and VBNCs induced by these treatments were then challenged with 100 mg/L squalamine. The efficacy of each treatment was determined by evaluating culturability on agar medium, membrane integrity (LIVE/DEAD®BacLightTM staining) and respiratory activity (BacLightTM RedoxSensorTM CTC staining) of bacteria. A. baumannii ATCC 17978 generated persisters as well as VBNCs in the presence of high doses of ciprofloxacin but not colistin or squalamine. Squalamine at 100 mg/L (below its haemolytic concentration) was able to kill dormant cells. Squalamine did not induce persister cell or VBNC formation in A. baumannii ATCC 17978. Interestingly, squalamine was significantly active against this type of dormant population generated by ciprofloxacin, making it a very promising anti-persister agent.

A Novel Three Domains Glycoside Hydrolase Family 3 from Sclerotinia sclerotiorum Exhibits ß-Glucosidase and Exoglucanase Activities: Molecular, Biochemical, and Transglycosylation Potential Analysis.

The filamentous fungus Sclerotinia sclerotiorum produces a complete set of cellulolytic enzymes. We report here the purification and the biochemical characterization of a new ß-glucosidase from S. sclerotiorum which belongs to the family 3 of glycoside hydrolases and that was named as SsBgl3. After two size-exclusion chromatography steps, purified protein bands of 80 and 90 kDa from SDS-PAGE were subjected to a mass spectrometry analysis. The results displayed four peptides from the upper band belonging to a polypeptide of 777 amino acids having a calculated molecular weight of 83.7 kDa. Biochemical analysis has been carried out to determine some properties. We showed that this SsBgl3 protein displayed both ß-glucosidase and exoglucanase activities with optimal activity at 55 °C and at pH 5. The transglycosylation activity was investigated using gluco-oligosaccharides TLC analysis. The molecular modeling and comparison with different crystal structures of ß-glucosidases showed that SsBgl3 putative protein present three domains. They correspond to an (α/ß)8 domain TIM barrel, a five-stranded α/ß sandwich domain (both of which are important for active-site organization), and a C-terminal fibronectin type III domain. Enzyme engineering will be soon investigated to identify the key residues for the catalytic reactions.