‘At the moment it is just a couple of eccentrics doing it’: concordance in day‐to‐day practice

Objectives To assess the feasibility and acceptability of concordance in pharmacy practice through examination of communication between customers and pharmacists in two community pharmacies in consultations for over‐the‐counter medicines. Method A qualitative pilot study involving data drawn from six sources: audiotaped training session with all the pharmacists involved, observational field work in the pharmacies, audiotaped consultations with pharmacists and customers, debriefing interviews with pharmacists after the consultation, and semi‐structured interviews with customers a few days after their consultation. Setting Two community pharmacies that concentrate their services on medicine advice and dispensing, one in a deprived inner‐city area, the other in a more affluent suburban area of London. Key findings The pharmacists developed a personal understanding of concordance which informed their practice. Customers reported a high level of satisfaction with services they received from the respective pharmacists. Their accounts of the consultations verified the pharmacists' patient‐centredness in their day‐to‐day practice. Conclusion The implementation of a concordance model was possible through the development of a personalised, patient‐centred model which drew on the model of concordance but was adapted in accordance with both structural constraints as well as the personal style of the pharmacists involved.     

Establishment of an optimized CTC detection model consisting of EpCAM,MUC1 and WT1 in epithelial ovarian cancer and its correlation with clinical characteristics

Objective: Emerging studies have demonstrated the promising clinical value of circulating tumor cells(CTCs)for diagnosis, disease assessment, treatment monitoring and prognosis in epithelial ovarian cancer. However, the clinical application of CTC remains restricted due to diverse detection techniques with variable sensitivity and specificity and a lack of common standards.Methods: We enrolled 160 patients with epithelial ovarian cancer as the experimental group, and 90 patients including 50 pat...     

Frontostriatal functional connectivity underlies self-enhancement during social evaluation

Self-enhancement, the tendency to view oneself positively, is a pervasive social motive widely investigated in the psychological sciences. Relatively little is known about the neurocognitive mechanisms underlying this motive, specifically in social-evaluative situations. To investigate whether positive emotion regulation circuitry, circuitry involved in modulating positive affect, relates to the self-enhancement motive in social contexts, we conducted an functional magnetic resonance imaging (fMRI) study in a healthy young adult sample. We hypothesized that self-enhancement indices (state and trait self-esteem) would relate to greater functional connectivity between right ventrolateral prefrontal cortex (RVLPFC), a region implicated in emotion regulation, and the ventral striatum (VS), a region associated with reward-related affect, during a social feedback task. Following social evaluation, participants experienced stable or decreased state self-esteem. Results showed that stable state self-esteem from pre- to post-scan and higher trait self-esteem related to greater RVLPFC–VS connectivity during positive evaluation. Stable-state self-esteem also related to greater RVLPFC–VS connectivity during negative evaluation. Moreover, RVLPFC activation during all types of feedback processing and left VS activation during negative feedback processing was greater for participants with stable-state self-esteem. These findings implicate neurocognitive mechanisms underlying emotion regulation in the self-enhancement motive and highlight a pathway through which self-enhancement may restore feelings of self-worth during threatening situations.     

Cardiovascular changes in response to selective monoamine oxidase inhibition in the rat

Chronic (21 days) treatment with the selective monoamine oxidase (MAO)-A inhibitor clorgyline, but not with the MAO-B inhibitor deprenyl in pithed rats leads to increased blood pressure responses to sympathetic stimulation and intravenous tyramine, and to elevated unstimulated heart rates. No significant changes are observed in plasma catecholamine responses to sympathetic stimulation, nor in β-adrenoreceptor numbers in heart ventricles. These findings suggest that the hypotensive effects of MAO inhibitors result from central nervous system rather than peripheral nervous system alterations.     

Iterative computational design and crystallographic screening identifies potent inhibitors targeting the Nsp3 macrodomain of SARS-CoV-2

The nonstructural protein 3 (NSP3) of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) contains a conserved macrodomain enzyme (Mac1) that is critical for pathogenesis and lethality. While small-molecule inhibitors of Mac1 have great therapeutic potential, at the outset of the COVID-19 pandemic, there were no well-validated inhibitors for this protein nor, indeed, the macrodomain enzyme family, making this target a pharmacological orphan. Here, we report the structure-based discovery and development of several different chemical scaffolds exhibiting low- to sub-micromolar affinity for Mac1 through iterations of computer-aided design, structural characterization by ultra-high-resolution protein crystallography, and binding evaluation. Potent scaffolds were designed with in silico fragment linkage and by ultra-large library docking of over 450 million molecules. Both techniques leverage the computational exploration of tangible chemical space and are applicable to other pharmacological orphans. Overall, 160 ligands in 119 different scaffolds were discovered, and 153 Mac1-ligand complex crystal structures were determined, typically to 1 Å resolution or better. Our analyses discovered selective and cell-permeable molecules, unexpected ligand-mediated conformational changes within the active site, and key inhibitor motifs that will template future drug development against Mac1.

The macrodomain of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) nonstructural protein 3 (NSP3) (Mac1) presents an intriguing target for drug discovery (1–5). Upon viral infection, host cells initiate an innate interferon-mediated immune response leading to the expression of poly-(ADP-ribose)-polymerases (PARPs), which catalyze the antiviral posttranslational addition of ADP-ribose (ADPr) to a large range of target proteins (6). Mac1 enzymatically reverses this mono-ADP-ribosylation, counteracting immune signaling (7). Promisingly, inactivation of Mac1 by single-point mutations in the ADPr-binding site significantly reduced lethality and pathogenicity in mice after SARS-CoV infection (8). Small-molecule inhibitors of SARS-CoV-2 Mac1 should therefore offer novel therapeutics to mitigate COVID-19 (9, 10).A challenge for the development of such inhibitors has been the lack of small-molecule modulators of macrodomain activity, other than ADPr; indeed, only recently have quantitative assays been developed (10, 11). This is true not only for Mac1 from SARS-CoV-2, but also for the overall family of enzymes, which lack good chemical matter by which their activity can be probed, despite their importance in several areas of health and diseases. Accordingly, to map the recognition determinants of Mac1, we adopted a biophysical approach, screening for fragment ligands using protein crystallography, molecular docking, isothermal titration calorimetry (ITC), differential scanning fluorimetry (DSF), and a binding assay based on homogeneous time-resolved fluorescence (HTRF) (12). Mac1 proved to be unusually amenable to structure determination, enabling us to determine the structures of over 230 fragment complexes, typically to ultra-high resolution (often better than 1.1 Å), affording us a detailed map of enzyme hot spots with chemical matter of sufficient potency with which to optimize a quantitative assay (12, 13).Nevertheless, our best fragments remained of modest potency, with none more potent than 180 µM. Here, we describe the discovery and optimization of potent macrodomain ligands using two strategies (Fig. 1). In the first, we sought to link and merge pairs of fragments to create larger molecules that exploited multiple hot spots, so reaching higher affinities. This used a fragment-linking method (12), adapted to explore a virtual library of 22 billion readily synthesizable molecules (14). In the second approach, we exploited the hot spots revealed by the initial fragments to guide computational docking of ultra-large chemical libraries of lead-like molecules, potentially more potent than the fragments docked in our original study (12). Both approaches ultimately led to compounds with IC₅₀ values as low as 0.4 µM for the merged fragments and as low as 1.7 µM for the docking hits (Fig. 1). These represent the most potent inhibitors reported for any member of the broad family of macrodomains. Furthermore, the many X-ray crystal structures determined here provide an extensive resource for drug development campaigns against this promising antiviral target.Open in a separate windowFig. 1.Overview of the structure-based strategies used to discover ligands that bind to the NSP3 macrodomain of SARS-CoV-2 (Mac1).     

互动性月度教育简报在提高医生实践水平中的作用

1 介绍 美国的血液供应情况不容乐观,很多地区都存在血液储备不足的情况.随着人口老龄化问题日趋严重,对供血量的要求日益增加.同时为了减少输血传播疾病的风险,对献血者的要求也越来越严格,导致了有效献血者数量的减少.因此对于很多患者来说,输血的治疗费用比较昂贵.