AAV-CRISPR Gene Editing Is Negated by Pre-existing Immunity to Cas9

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Understanding the Influence of Nanocarrier-Mediated Brain Delivery on Therapeutic Performance Through Pharmacokinetic-Pharmacodynamic Modeling

This study aimed at evaluating how encapsulation in a regular nanocarrier (NC) (providing extended circulation time) or in a brain-targeting NC (providing prolonged circulation time and increased brain uptake) may influence the therapeutic index compared with the unformulated drug and to explore the key parameters affecting therapeutic performance using a model-based approach. Pharmacokinetic (PK) models were built with chosen PK parameters. For a scenario where central effect depends on area under the unbound brain concentration curve and peripheral toxicity relates to peak unbound plasma concentration, dose-effect and drug-side effect curves were constructed, and the therapeutic index was evaluated. Regular NC improved the therapeutic index compared with the unformulated drug due to reduced peripheral toxicity, while brain-targeting NC enhanced the therapeutic index by lowering peripheral toxicity and increasing central effect. Decreasing drug release rate or systemic clearance of NC with drug still encapsulated could increase the therapeutic index. Also, a drug with shorter half-life would therapeutically benefit more from a NC encapsulation. This work provides insights into how a NC for brain delivery should be optimized to maximize the therapeutic performance and is helpful to predict if and to what extent a drug with certain PK properties would obtain therapeutic benefit from nanoencapsulation.     

Renal Denervation for Treatment of Cardiac Arrhythmias: State of the Art and Future Directions

Renal Denervation for Treatment of Cardiac Arrhythmias . It has now been more than a quarter of a century since modulation of the sympathetic nervous system was proposed for the treatment of cardiac arrhythmias of different origins. But it has also been some time since some of the early surgical attempts have been abandoned. With the development of ablation techniques, however, new approaches and targets have been recently introduced that have revolutionized our way of thinking about sympathetic modulation. Renal nerve ablation technology is now being successfully used for the treatment of resistant hypertension, but the indication spectrum might broaden and new therapeutic options might arise in the near future. This review focuses on the possible impact of renal sympathetic system modulation on cardiac arrhythmias, the current evidence supporting this approach, and the ongoing trials of this method in electrophysiological laboratories. We will discuss the potential roles that sympathetic modulation may play in the future.     

High-definition optical magnification with digital chromoendoscopy detects gastric mucosal changes in dyspeptic-patients

BACKGROUND Accurate detection of gastric infection by Helicobacter pylori(H.pylori) and premalignant lesions are important for effective provision of treatment,preventing the development of gastric neoplasia.Optical enhancement systems with optical magnification improved the identification of mucosal superficial and vascular patterns in patients with dyspepsia.AIM To evaluate an optical enhancement system with high-definition magnification,for diagnosis of normal gastric mucosa,H.pylori-associated gastritis,and gastric atrophy.METHODS A cross-sectional,nonrandomized study from November 2015 to April 2016 performed in a single-tertiary academic center from Ecuador.Seventy-two consecutive patients with functional dyspepsia according to the Rome III criteria,were tested for H.pylori using a stool antigen test and were assigned to an Hp+group or an Hp-control group.Esophagogastroduodenoscopy with highdefinition optical magnification and digital chromoendoscopy was performed,and patients were classified into 4 groups,in accordance to the microvasculararchitecture pattern of the mucosa.Interobserver and intraobserver agreement among operators were calculated.RESULTS Of the 72 participants,35 were Hp+ and 37 were Hp-.Among 10 patients with normal mucosal histology in biopsy samples,90% had a Type I pattern of microvascular architecture by endoscopy.Among participants with type IIa and type IIb patterns,significantly more were Hp+ than Hp-(32 vs 8),and most(31 out of 40) had histological diagnoses of chronic active gastritis.Two of the three participants with a histological diagnosis of atrophy had a type III microvascular pattern.The type I pattern predicted normal mucosa,type IIa–IIb predicted H.pylori infection,and type III predicted atrophy with sensitivities of 90.0%,91.4%,and 66.7%,respectively.The intraobserver and interobserver agreements had kappa values of 0.91 and 0.89,respectively.CONCLUSION High-definition optical magnification with digital chromoendoscopy is useful for diagnosis of normal gastric mucosa and H.pylori-associated gastritis with high accuracy,but further studies are needed to determine whether endoscopic diagnosis of gastric atrophy is feasible.     

DRG支付方式改革下医院财务管理应对策略

通过探讨DRG支付方式改革下医院财务管理的应对策略,可以有效地降低医疗支付方式改革对医院财务管理的负面影响,促使医院财务管理在"危"与"机"的转换中抢抓机遇,促进医院财务管理提质增效。     

Immune checkpoint inhibitor-induced inflammatory arthritis: identification and management

ABSTRACT

Introduction

Immune checkpoint inhibitors (ICIs) have proved to be groundbreaking in the field of oncology. However, immune system overactivation from ICIs has introduced a novel medical entity known as immune-related adverse events (irAEs), that can affect any organ or tissue. ICI-induced inflammatory arthritis (ICI-IIA) is the most common musculoskeletal irAE and can lead to significant morbidity and limitation in anti-cancer therapy.