Impact of physicochemical properties on biological effects of lipid nanoparticles: Are they completely safe.

Lipid nanoparticles (LNPs) are promising materials and human-use approved excipients, with manifold applications in biomedicine. Researchers have tended to focus on improving the pharmacological efficiency and organ targeting of LNPs, while paid relatively less attention to the negative aspects created by their specific physicochemical properties. Here, we discuss the impacts of LNPs' physicochemical properties (size, surface hydrophobicity, surface charge, surface modification and lipid composition) on the adsorption-transportation-distribution-clearance processes and bio-nano interactions. In addition, since there is a lack of review emphasizing on toxicological profiles of LNPs, this review outlined immunogenicity, inflammation, hemolytic toxicity, cytotoxicity and genotoxicity induced by LNPs and the underlying mechanisms, with the aim to understand the properties that underlie the biological effects of these materials. This provides a basic strategy that increased efficacy of medical application with minimized side-effects can be achieved by modulating the physicochemical properties of LNPs. Therefore, addressing the effects of physicochemical properties on toxicity induced by LNPs is critical for understanding their environmental and health risks and will help clear the way for LNPs-based drugs to eventually fulfill their promise as a highly effective therapeutic agents for diverse diseases in clinic.

Evolutionary and functional history of the Escherichia coli K1 capsule.

Escherichia coli is a leading cause of invasive bacterial infections in humans. Capsule polysaccharide has an important role in bacterial pathogenesis, and the K1 capsule has been firmly established as one of the most potent capsule types in E. coli through its association with severe infections. However, little is known about its distribution, evolution and functions across the E. coli phylogeny, which is fundamental to elucidating its role in the expansion of successful lineages. Using systematic surveys of invasive E. coli isolates, we show that the K1-cps locus is present in a quarter of bloodstream infection isolates and has emerged in at least four different extraintestinal pathogenic E. coli (ExPEC) phylogroups independently in the last 500 years. Phenotypic assessment demonstrates that K1 capsule synthesis enhances E. coli survival in human serum independent of genetic background, and that therapeutic targeting of the K1 capsule re-sensitizes E. coli from distinct genetic backgrounds to human serum. Our study highlights that assessing the evolutionary and functional properties of bacterial virulence factors at population levels is important to better monitor and predict the emergence of virulent clones, and to also inform therapies and preventive medicine to effectively control bacterial infections whilst significantly lowering antibiotic usage.

Experimental Findings and Clinical-Pathologic Correlation of Radiofrequency Catheter Ablation at the Left Ventricle Para-Hisian Region.

BACKGROUND: Catheter ablation target at the site with large His activation in the left ventricle poses a high risk of atrioventricular (AV) block. We aimed to identify far-field (FF) and near-field (NF) His activation at left upper septum (LUS). METHODS: Three-D mapping of the aortic root and left ventricle was performed in 12 dogs. Two sites located at either the base or apex of the triangle interposed between the hinges of the the noncornary coronary cusp (NCC) - right coronary cusp (RCC) were chosen for a single radiofrequency (RF) application. Bipolar and unipolar pacing with different outputs at both sites was attempted to discern NF and FF His activation. RESULTS: The sites chosen for NF and FF ablation were located at the base and apex of the triangle, which were 8.03 ± 1.18 mm (group 1) and 3.42 ± 0.61 mm (group 2) away from the RCC-NCC junction. Lower A/V ratios were found in group 1. Pacing could not differentiate NF from FF His activation. In group 1, ablation resulted in III degree AV block in all 6 dogs, whereas neither PR prolongation nor AV block occurred in group 2. Pathologic examination of group 1 showed complete/partial necrosis of the His bundle (HB) and left bundle branch in all 6 dogs. In group 2, no necrosis of the HB was seen in the 6/6 dogs. CONCLUSION: Anatomical localization in the triangle of RCC-NCC junction can help differentiate NF from FF His activation.

Minimally Interrupted Non-Vitamin K Antagonist Oral Anticoagulants vs. Bridging Therapy and Uninterrupted Vitamin K Antagonists During Atrial Fibrillation Ablation: A Retrospective Single-Center Study.

Objectives: Although the latest international guidelines recommend the use of uninterrupted non-vitamin K antagonist oral anticoagulants (NOAC) during atrial fibrillation (AF) ablation, it does not reflect current clinical practice, as most centers still use a minimally interrupted NOAC strategy. The purpose of this study was to evaluate the safety and effectiveness of minimally interrupted NOAC compared with bridging therapy and uninterrupted vitamin K antagonist (VKA) for nonvalvular AF ablation. Patients and Methods: A total of 4520 patients who underwent AF ablation between January 2010 and December 2018 were included in the analysis. According to their periprocedural anticoagulation strategies, patients were divided into three groups: Bridging heparin group (n = 1848); Uninterrupted VKA group (n = 796) and Minimally interrupted NOAC group (Total n = 1876; dabigatran: n = 865; rivaroxaban, n = 1011). A combined complication endpoint (CCE) as composed of any bleeding complications and thromboembolic events was analyzed. Results: Rates of thromboembolisms were similar among the three groups (0.22% for Bridging heparin group, 0.25% for Uninterrupted VKA group, and 0.11% for Minimally interrupted NOAC group, p = 0.626). There was a significant difference among the three groups for the incidence of overall bleeding events (8.50% for Bridging heparin group, 4.52% for Uninterrupted VKA group, and 2.67% for Minimally interrupted NOAC group, p < 0.001). A significant difference of CCE rates was shown in the Minimally interrupted NOAC group as compared with the Uninterrupted VKA group (2.77 vs. 4.77%, p = 0.008) and the Bridging heparin group (2.77 vs. 8.71%, p < 0.001). There was no significant difference in CCE rates among the different NOACs (dabigatran 2.89% vs. rivaroxaban 2.67%, p = 0.773). Conclusions: In patients undergoing AF ablation, minimally interrupted NOACs during the periprocedural period appears safer and equally effective when compared to the bridging heparin and uninterrupted VKA therapy.

Association between elevated blood glucose level and non-valvular atrial fibrillation: a report from the Guangzhou heart study.

BACKGROUND: To estimate the prevalence of elevated blood glucose level (EBG, including type 2 diabetes mellitus and impaired fasting glucose), and its association with non-valvular atrial fibrillation (NVAF) in Guangzhou, China. METHODS: The population-based follow-up Guangzhou Heart Study collected baseline data from July 2015 to August 2017 among 12,013 permanent residents aged > 35 from 4 Guangzhou districts. Two streets (Dadong and Baiyun) in the Yuexiu District, and one street (Xiaoguwei) and two towns (Xinzao and Nancun) in the Panyu District were chosen as representative of urban and rural areas, respectively. Each participant completed a comprehensive questionnaire, and underwent physical examination, blood sample collection for laboratory testing, electrocardiography, and other evaluations. Multivariable logistic regression analyses were used to estimate the independent association between hyperglycemia and NVAF prevalence. RESULTS: The prevalence of EBG in overall study population was 29.9%. Compared with residents without EBG, the odds ratio (OR) for AF among residents with EBG was significantly higher (1.94, 95% confidence interval [CI]: 1.40-2.70, P <  0.001), even after multivariate adjustment for metabolic abnormalities (OR = 1.60, 95% CI: 1.14-2.25, P = 0.007), and driven by women (OR = 1.80, 95% CI: 1.12-2.91, P = 0.016). CONCLUSIONS: In Guangzhou, China, prevalence of EBG is high among residents aged > 35 years and associated with a multivariate adjusted increase in prevalence of NVAF overall and in women.