Optimized Substrate Positioning Enables Switches in the C-H Cleavage Site and Reaction Outcome in the Hydroxylation-Epoxidation Sequence Catalyzed by Hyoscyamine 6ß-Hydroxylase.

Hyoscyamine 6ß-hydroxylase (H6H) is an iron(II)- and 2-oxoglutarate-dependent (Fe/2OG) oxygenase that produces the prolifically administered antinausea drug, scopolamine. After its namesake hydroxylation reaction, H6H then couples the newly installed C6 oxygen to C7 to produce the drug's epoxide functionality. Oxoiron(IV) (ferryl) intermediates initiate both reactions by cleaving C-H bonds, but it remains unclear how the enzyme switches the target site and promotes (C6)O-C7 coupling in preference to C7 hydroxylation in the second step. In one possible epoxidation mechanism, the C6 oxygen would─analogously to mechanisms proposed for the Fe/2OG halogenases and, in our more recent study, N-acetylnorloline synthase (LolO)─coordinate as alkoxide to the C7-H-cleaving ferryl intermediate to enable alkoxyl coupling to the ensuing C7 radical. Here, we provide structural and kinetic evidence that H6H does not employ substrate coordination or repositioning for the epoxidation step but instead exploits the distinct spatial dependencies of competitive C-H cleavage (C6 vs C7) and C-O-coupling (oxygen rebound vs cyclization) steps to promote the two-step sequence. Structural comparisons of ferryl-mimicking vanadyl complexes of wild-type H6H and a variant that preferentially 7-hydroxylates instead of epoxidizing 6ß-hydroxyhyoscyamine suggest that a modest (∼10°) shift in the Fe-O-H(C7) approach angle is sufficient to change the outcome. The 7-hydroxylation:epoxidation partition ratios of both proteins increase more than 5-fold in 2H2O, reflecting an epoxidation-specific requirement for cleavage of the alcohol O-H bond, which, unlike in the LolO oxacyclization, is not accomplished by iron coordination in advance of C-H cleavage.

Post-Operative Order Set Decreases Opioid Prescriptions and Increases Efficiency.

BACKGROUND: Opioid addiction remains a public health crisis. We aimed to create an electronic medical record (EMR) based protocol to decrease post-operative prescribing of opioid medications and streamline the ordering process while maintaining adequate pain control. METHODS: An order set was created to minimize opioid prescriptions. The post-operative prescribing practices for minor urologic procedures (MUOs) over 6-week periods at three time points were compared: one period before and two periods after implementation of the order set. RESULTS: 72 MUOs were performed in the pre-implementation, 52 in post-implementation, and 60 in the long-term period. Opioid medications were prescribed for 66 patients (91.7%) pre-implementation, 23 patients (44.2%) post-implementation, and 45 patients (75.0%) at the long-term time point (P < .0001 and P = .015 respectively). The mean morphine milligram equivalent (MME) prescribed was 81.52 units before implementation, 38.74 units after, and 24.21 units at the long-term time point (P = .0002 and P < .0001 respectively). DISCUSSION: The integration of a post-operative prescribing order set into our EMR substantially decreased opioid prescribing after MUO while streamlining the ordering process to improve efficiency.

Digital health literacy and well-being among university students: Mediating roles of fear of COVID-19, information satisfaction, and internet information search.

Background: Digital health literacy (DHL) enables healthy decisions, improves protective behaviors and adherence to COVID-19 measures, especially during the era of the "infodemic", and enhances psychological well-being. Objective: We aimed to explore the mediating roles of fear of COVID-19, information satisfaction, and the importance of online information searching on the association between DHL and well-being. Methods: A cross-sectional web-based survey was conducted among 1631 Taiwanese university students, aged 18 years and above, from June 2021 to March 2022. The collected data include sociodemographic characteristics (sex, age, social status, and financial satisfaction), the importance of online information searching, information satisfaction, fear of COVID-19, DHL, and well-being. A linear regression model was utilized to investigate factors associated with well-being, followed by a pathway analysis to assess the direct and indirect relationship between DHL and well-being. Results: The scores of DHL and overall well-being were 3.1 ± 0.4 and 74.4 ± 19.7, respectively. Social status (B = 2.40, 95% confidence interval (CI) 1.73-3.07, p < 0.001), DHL (B 0.29, 95% CI 0.10-0.49, p < 0.001), importance of online information searching (B = 0.78, 95% CI 0.38-1.17, p < 0.001), and information satisfaction (B = 3.59, 95% CI 2.22-4.94, p < 0.001) were positively associated with well-being, whereas higher fear of COVID-19 scores (B = -0.38, 95% CI -0.55-(-0.21), p < 0.001) and female (B = -2.99, 95% CI -5.02-0.6, p = 0.004) were associated with lower well-being, when compared with lower fear scores and male, respectively. Fear of COVID-19 (B = 0.03, 95% CI 0.016-0.04, p < 0.001), importance of online information searching (B = 0.03, 95% CI 0.01-0.05, p = 0.005), and information satisfaction (B = 0.05, 95% CI 0.023-0.067, p < 0.001) were significantly mediated the relationship between DHL and well-being. Conclusion: Higher DHL scores show direct and indirect associations with higher well-being scores. Fear, importance of online information searching, and information satisfaction significantly contributed to the association.

Targeting Olokizumab-Interleukin 6 interaction interface to discover novel IL-6 inhibitors.

The IL-6/IL-6R or IL-6/GP130 protein-protein interactions play a significant role in controlling the development of chronic inflammatory diseases, such as rheumatoid arthritis, Castleman disease, psoriasis, and, most recently, COVID-19. Modulating or antagonizing protein-protein interactions of IL6 binding to its receptors by oral drugs promises similar efficacy to biological therapy in patients, namely monoclonal antibodies. In this study, we used a crystal structure of the Fab part of olokizumab in a complex with IL-6 (PDB ID: 4CNI) to uncover starting points for small molecule IL-6 antagonist discovery. Firstly, a structure­based pharmacophore model of the protein active site cavity was generated to identify possible candidates, followed by virtual screening with a significant database Drugbank. After the docking protocol validation, a virtual screening by molecular docking was carried out and a total of 11 top hits were reported. Detailed analysis of the best scoring molecules was performed with ADME/T analysis and molecular dynamics simulation. Furthermore, the Molecular Mechanics-Generalized Born Surface Area (MM/GBSA) technique has been utilized to evaluate the free binding energy. Based on the finding, one newly obtained compound in this study, namely DB15187, may serve as a lead compound for the discovery of IL-6 inhibitors.Communicated by Ramaswamy H. Sarma.

Association of Digital Health Literacy with Future Anxiety as Mediated by Information Satisfaction and Fear of COVID-19: A Pathway Analysis among Taiwanese Students.

Digital Health Literacy (DHL) helps online users with navigating the infodemic and co-existing conspiracy beliefs to avoid mental distress and maintain well-being. We aimed to investigate the association between DHL and future anxiety (FA); and examine the potential mediation roles of information satisfaction and fear of COVID-19 (F-CoV). A web-based cross-sectional survey was carried out among 1631 Taiwanese university students aged 18 years and above from June 2021 to March 2022. Data collected were socio-demographic characteristics (sex, age, social status, university location), information satisfaction, F-CoV, DHL and FA (using Future Dark scale). The linear regression model was used to explore factors associated with FA. The pathway analysis was further used to evaluate the direct and indirect relationship between DHL and FA. A higher score of DHL (B = -0.21; 95% CI, -0.37, -0.06; p = 0.006), and information satisfaction (B = -0.16; 95% CI, -0.24, -0.08; p < 0.001) were associated with a lower FA score, whereas a higher F-CoV score was associated with a higher FA score (B = 0.43; 95% CI, 0.36, 0.50; p < 0.001). DHL showed the direct impact (B = -0.1; 95% CI, -0.17, -0.04; p = 0.002) and indirect impact on FA as mediated by information satisfaction (B = -0.04; 95% CI, -0.06, -0.01; p = 0.002) and F-CoV (B = -0.06, 95% CI, -0.08, -0.04; p < 0.001). Strategic approaches to promote DHL, information satisfaction, lower F-CoV are suggested to reduce FA among students.

Insight into global research on health literacy and heart diseases: A bibliometric analysis.

Background: Health literacy (HL) has shown its important role on reducing the burden of heart diseases. However, no study has provided a comprehensive worldwide view of the data regarding HL and heart diseases. The study aimed to provide insight into: (1) the intellectual structure, (2) research trends, and (3) research gaps on HL and heart diseases; and (4) to explore HL scales commonly utilized in heart studies. Materials and methods: Studies related to HL and heart diseases were retrieved from Web of Science, Scopus, and PubMed. All publications published between 2000 and 2021 were included after conducting keyword searches on "heart diseases" in general or on specific types of heart diseases (e.g., "heart failure") and "health literacy". Bibliometric analyses were carried out using the Bibliometrix R package and VOSviewer 1.6.14. Findings: A total of 388 original research articles and reviews on HL and heart diseases were included in our study. The studies were primarily conducted in the United States and developed countries. A total of 337 studies (86.9%) focused on heart failure (200 studies, 51.5%) and ischemic heart diseases (137 studies, 35.3%). Sixty-two studies (16.0%) focused on other heart diseases (e.g., valvular diseases and rheumatic heart diseases). The number of interventional studies was limited (52 studies, 13.4%) and fluctuated from 2000 to 2021. The most common questionnaires measuring health literacy among patients with heart diseases were the Test of Functional Health Literacy in Adults (TOFHLA), Short Test of Functional Health Literacy in Adults (STOFHLA), and Brief Health Literacy Screen (BHLS). Use of the eHealth Literacy Scale (eHEALS) has become the latest trend among patients with heart diseases. Conclusion: Health literacy and heart diseases were most often studied in the United States and developed countries. Several HL tools were used; eHEALS has been lately used in this field. These findings suggest the need to conduct more empirical studies on HL and heart diseases in different settings (e.g., developing or poor countries) and with different types of heart diseases (e.g., valvular and rheumatic disorders). Additionally, it is necessary to develop heart disease-specified HL scales for research and practice.

Latent profile analysis of students' reading development and the relation of cognitive variables to reading profiles.

Previous studies have showed that early problems with word decoding can lead to poor performance in text reading and comprehension and suggest that poor readers often struggle with reading deficits throughout their school years. Therefore, early detection of those children who are at risk for slow reading development and/or who belong to the lowest reading profiles is essential in order to organize proper support. The present study explores the heterogeneity and prevalence of latent reading profiles among 769 Finnish- and German-reading students during their first and second school years in three countries (Finland, Germany, and Italy) using latent profile analysis. The results identified three latent profiles among Finnish readers, one of which (sentence-level reading) was identified as developing slowly. Among German-reading students, four latent profiles were discovered, two of which were identified as developing slowly. The results of ordinal logistic regression modeling show that rapid automatic naming (RAN) was significantly related to poorer reading profiles among Finnish- and German-reading students, and that the poorer results in letter-sound connection testing among the German-reading group was also significantly related to poorer reading profiles. Although the educational systems have some differences between Germany and German-speaking areas of Italy, no significant country effect was detected. In addition, a child's age and spoken language did not significantly affect the student's reading profile.