Occult Hepatitis B Virus Infection in Hemodialysis Patients in Japan

Hepatitis B surface antigen is widely used in hepatitis B virus surveillance; patients who test negative for the antigen are judged to be uninfected. However, occult hepatitis B virus infection has been confirmed with hepatitis B virus DNA at low levels in the liver and peripheral blood in patients positive for hepatitis B core antibody or hepatitis B surface antibody, even if they test negative for hepatitis B surface antigen. To investigate the prevalence of occult hepatitis B virus in hemodialysis patients, we performed cross‐sectional analysis of 161 hemodialysis patients in two related institutions for hepatitis B surface antigen, hepatitis B core antibody, and hepatitis B surface antibody. Hepatitis B surface antigen, hepatitis B core antibody, or hepatitis B surface antibody was present in 45 patients (28.0%). Hepatitis B virus DNA was present in six patients (3.7%), all of whom also tested positive for hepatitis B core antibody. Hepatitis B surface antibody positivity was unrelated in only one of the six patients. Four of the six patients were positive for hepatitis B surface antigen; however, two (1.3%) of these with occult hepatitis B virus infection were found to be hepatitis B surface antigen negative. Occult hepatitis B virus infection may be missed in hepatitis B virus surveillance using hepatitis B surface antigen alone; therefore, routine hepatitis B core antibody screening is necessary. Patients who test positive for hepatitis B core antibody should undergo further hepatitis B virus DNA testing to enable accurate hepatitis B virus screening.     

Synthesis of Dual‐Sensitive Core Cross‐Linked Mixed Micelles through Thiol–Ene Addition and Subsequent Drug Release Behavior

Herein the synthesis of core cross‐linked (CCL) mixed micelles through a UV‐promoted thiol–ene addition onto lipid core unsaturations and the subsequent release of an encapsulated drug depending on the external conditions (pH/temperature) are reported. The thiol–ene addition proceeds even in the absence of a photoinitiator to reach a complete conversion in a few minutes in bulk. The cross‐linking reaction is applied in aqueous media onto lipid‐b‐poly(acrylic acid) (lipid‐b‐PAA) only and then a mixture of pH‐sensitive lipid‐b‐PAA and thermo‐sensitive lipid‐block‐poly(2‐isopropyl‐2‐oxazoline) copolymers. Structurally CCL micelles, preserved in any conditions, with a stimuli‐sensitive corona whose swelling depends on the external pH or/and temperature, are successfully prepared. The release of vitamin K1 (VK1) is then investigated from all the previous systems and demonstrates a strong dependency to the external conditions. Indeed, the dual‐sensitive CCL micelles release VK1 only when two triggers (pH 10 and T = 38 °C) are simultaneously activated.

     

High-resolution crystal structure of a hepatitis B virus replication inhibitor bound to the viral core protein

The hepatitis B virus (HBV) core protein is essential for HBV replication and an important target for antiviral drug discovery. We report the first, to our knowledge, high-resolution crystal structure of an antiviral compound bound to the HBV core protein. The compound NVR-010–001-E2 can induce assembly of the HBV core wild-type and Y132A mutant proteins and thermostabilize the proteins with a T_m increase of more than 10 °C. NVR-010–001-E2 binds at the dimer–dimer interface of the core proteins, forms a new interaction surface promoting protein–protein interaction, induces protein assembly, and increases stability. The impact of naturally occurring core protein mutations on antiviral activity correlates with NVR-010–001-E2 binding interactions determined by crystallography. The crystal structure provides understanding of a drug efficacy mechanism related to the induction and stabilization of protein–protein interactions and enables structure-guided design to improve antiviral potency and drug-like properties.Hepatitis B virus (HBV) infection is a major global health concern. It is estimated that 240 million people live with chronic hepatitis B (CHB) with a high risk of developing severe liver disease or liver cancer. Globally, 780,000 deaths per year are associated with HBV infection (1). Current approved treatment options (IFN alpha products or nucleoside analogs) are indicated for treatment of only a subset of CHB patients and are curative in only a very small proportion of patients, resulting in an urgent need for new types of therapies that can increase HBV cure rates.The HBV core protein is a viral protein with no known related protein present in human cells. The core protein performs multiple essential roles at different stages of the virus life cycle; it interacts with other host and viral proteins and has to be able to form a capsid stable enough to protect viral RNA and DNA and be able to release viral DNA at the right time in the virus life cycle. HBV core protein is therefore an excellent target for the development of new, virus-selective, safe and effective antiviral agents to improve treatment options for this disease (2, 3). The HBV core protein consists of 183–185 amino acids that form an N-terminal (amino acids 1–149) capsid assembly domain and a C-terminal nucleic acid binding domain (amino acids 150–185). The viral capsid in infectious HBV particles is formed from 120 copies of assembled core protein dimers enclosing the viral DNA (4, 5). Small molecules that target the HBV core protein assembly domain can disrupt functional HBV capsid assembly and can be potent inhibitors of HBV replication (6–11). Most of these compounds have the ability to induce aggregation of the HBV core N-terminal assembly domain in vitro. Representative HBV core inhibitors from the heteroaryldihydropyrimidine (HAP) series of compounds, BAY 41–4109 and GLS4, have also shown antiviral activity in vivo, in mouse models of HBV replication (12–14). However, drug-like properties of current leads have not been optimized, and new classes of HBV core protein targeting compounds need to be developed to maximize antiviral efficacy as well as pharmacokinetic and safety profiles. Lead optimization has been hampered by the lack of high-resolution crystal structures. Crystal structures of assembled wild-type HBV capsid have only been obtained at resolutions above 3 Å, and structures including bound small-molecule inhibitors have been determined at 4.2- and 5.05-Å resolution. Considering these resolution limits together with the technical and time challenges in achieving these structures, the previously published methods are insufficient to support structure-guided lead optimization (5, 15, 16).Here we present the structure of NVR-010–001-E2, a potent inhibitor of HBV replication from the HAP series of antiviral agents, bound to its target site on the HBV core protein at 1.95-Å resolution. The impact of mutations in the binding site on antiviral activity of NVR-010–001-E2 is consistent with the compound–protein interactions observed in the crystal structure and provides a starting point for the evaluation of possible pathways to drug resistance development. The data presented here provide a structural explanation for the ability of a small molecule to induce protein assembly and exemplify an efficient method to facilitate structure-guided optimization of HBV core inhibitors.     

本科护理带教老师注册护士核心能力评价方法比较

[目的]探讨本科护理带教老师注册护士核心能力自我评价与护士长评价、护生评价的差异。[方法]采用方便抽样和整群抽样方法,选择126名本科护理带教老师、79名带教老师现任护士长和126名正在被带教的本科护生为研究对象,应用注册护士核心能力问卷对带教老师注册护士核心能力的自我评价、护士长评价和护生评价进行调查。[结果]本科护理带教老师注册护士核心能力及工作满意度得分低于护士长评价及护生评价(P0.05)。在注册护士核心能力各个维度中,领导力、法律/伦理实践、人际关系得分在3种评价中得分最高。[结论]本科护理带教老师自我要求较高,自我认可度低,学校和医院应采取内部和外部两方面措施,使带教老师能够提高信心正确认识护理工作及自身能力。     

湖北省二级医院护士核心能力现状的调查分析

目的了解湖北省二级医院护士的核心能力水平,为护理管理者制订相应的培训计划提供依据。方法随机选取湖北省7所二级医院680名护士作为调查对象,采用修订版注册护士核心能力量表(CIRN)进行问卷调查。结果护士的核心能力总分为(148.66±33.36),总均分为(2.75±0.61);各维度均分最高为法律及伦理实践能力(2.90±0.64),得分最低为批判性思维及科研能力(2.56±0.65);护士的核心能力水平受到护龄、职称及职务影响。结论湖北省二级医院护士的核心能力总体处于中等偏下水平,护理管理者应为护士创造更多继续教育的机会,并加强对护士的岗位培训,尤其是对低年资、低职称护士的针对性培训。     

磁敏感加权成像技术在帕金森病患者的脑基底节和红核铁含量的变化分析中的应用研究

目的应用磁敏感加权成像技术(SWI)测量分析帕金森病患者脑基底节和红核中铁含量变化,并探讨该技术在帕金森患者临床研究中的应用价值。方法对60例帕金森病患者及55例健康对照者进行磁敏感加权成像检查,在滤波后的校正相位图上测量基底节、红核的相位值,随后分析二者相位值在帕金森病患者中的异常情况以及与疾病的病情、病程的相关性。结果帕金森病患者的基底节与红核中的相位值分别是0.064±0.025,0.071±0.018,明显低于健康对照组,差异有统计学意义(P0.05);Hoehn-Yahr分级为Ⅲ~Ⅳ的帕金森病患者比分级为Ⅰ~Ⅱ级的帕金森病患者同样存在显著高的相位值(P0.05),说明基底节与红核的相位值与帕金森病的病情密切相关,而基底节与红核的相位值与帕金森病的病程无关。结论磁敏感加权成像技术作为一个新型的影像技术,可以有效地检测帕金森病患者脑内铁沉积情况,有助于临床判断帕金森病患者的病情变化。