Notes

Confusions as well as reactions associated with managerial general public health nursing staff throughout the COVID-19 widespread within Asia.
The king cobra (Ophiophagus hannah) is an iconic elapid snake species distributed throughout tropical forests from southwestern India to the Philippines, and southern China to the Indonesian archipelago (Stuart et al., 2012). As the generic epithet suggests, king cobras are thought to specialize on snake prey. Documenting feeding habits of snakes in nature can be difficult due to their low detectability and long intervals between feeding bouts (Maritz et al., 2018). Radiotelemetry allows researchers to reliably locate individuals, making it possible to document predation by direct observation in the field. This article is protected by copyright. All rights reserved.CYP3A4 induction is an important cause of drug-drug interactions, making early identification of drug candidates with CYP3A4 induction liability in drug development a prerequisite. Here, we present 3D spheroid cultures of primary human hepatocytes (PHH) as a novel CYP3A4 induction screening model. Screening of 25 drugs (12 known CYP3A4 inducers in vivo and 13 negative controls) at physiologically relevant concentrations revealed a 100% sensitivity and 100% specificity of the system. Three of the in vivo CYP3A4 inducers displayed much higher CYP3A4 induction capacity in 3D spheroid cultures as compared to in 2D monolayer cultures. Among those, we identified AZD1208, a PIM kinase inhibitor terminated in phase I of development due to unexpected CYP3A4 autoinduction, as a CYP3A4 inducer only active in 3D spheroids but not in 2D monolayer cultures. Gene knockdown experiments revealed that AZD1208 requires PXR to induce CYP3A4. Rifampicin requires solely PXR to induce CYP3A4 and CYP2B6, while phenobarbital-mediated induction of these CYPs did not show absolute dependency on either PXR or CAR suggesting its ability to switch nuclear receptor activation. Mechanistic studies into AZD1208 uncovered an involvement of the MAPK/ERK pathway in CYP3A4 induction that is sensitive to the culture format used, as revealed by its inhibition of ERK1/2 Tyr204 phosphorylation and sensitivity to EGF pressure. In line, we also identified lapatinib, a dual EGFR/HER2 inhibitor, as another CYP3A4 inducer only active in 3D spheroid culture. Our findings offer insights into the pathways involved in CYP3A4 induction and suggest PHH spheroids for preclinical CYP3A4 induction screening. This article is protected by copyright. All rights reserved.Regulators wish to understand whether real-world evidence (RWE) can be used for secondary indications of biologics. Using the secondary indication of adalimumab for ulcerative colitis (UC) as an example, we aimed to replicate the ULTRA-2 RCT finding on the effectiveness of adalimumab in patients with UC using real world data analyses. Adalimumab, a TNF-alpha receptor inhibitor initially approved for Crohn's disease, was approved for moderate to severe UC in 2012. The ULTRA-2 trial had shown improved remission against placebo in patients with UC. Using claims data (2006-2012), we conducted a cohort study of patients with UC who initiated adalimumab and compared them to 1) non-users and 2) new users of infliximab using propensity score matching. The co-primary endpoints were corticosteroid (CS) discontinuation within 8 weeks and 1 year of treatment. We computed hazard ratios (HR) and 95% confidence intervals (CIs). We identified 398 matched pairs of adalimumab users vs non-users and 326 pairs of adalimumab vs infliximab users. Adalimumab users were 28% more likely to achieve CS-discontinuation compared to non-users over 1 year (HR=1.28, 95% CI 0.94 to 1.73). However, unlike in ULTRA-2, this effect was not observed in the first 8 weeks (HR 0.79, 95% CI 0.65-0.97). Compared against infliximab, adalimumab initiators showed no incremental benefit over 1 year (HR=1.08; 0.80 to 1.04), but showed a 22% reduction (HR=0.78; 0.64-0.95) during the first 8 weeks of treatment. In summary, our results highlight opportunities and some limitations of database analysis to identify treatment effects for secondary indications. This article is protected by copyright. All rights reserved.Individual studies have suggested that the association between occupational exposure to solar ultraviolet radiation (UVR) and the development of keratinocyte cancers (KC) may only be valid in populations of European ancestry living in certain geographic regions. Comparative global data are scarce and so this review aimed to summarize current evidence on the association between occupational exposure to solar UVR and the development of KC, with a specific focus on geographic location and skin colour. Ovid Medline, PubMed, EMBASE, and Web of Science were searched for potentially relevant records. Extracted data was summarised by study, country, and region. We included one prospective cohort study and 18 case-control studies (N=15,233) from 12 countries in regions where the majority of the population is white-skinned (Americas, Europe, and Oceania). Eighteen of the 19 studies reported effect estimates suggesting an increased risk of basal cell carcinoma (BCC) and/or squamous cell carcinoma (SCC) among outdoor workers. Only 11 studies found a significantly increased risk and many had imprecise estimates. There was a significantly increased risk of BCC and SCC in individual studies in North America, Latin America and the Caribbean, Western Europe, and Southern Europe but not across regions or countries. Overall, 95% of studies reported higher risks among outdoor workers, although the increases in risk were statistically significant in just over half of studies. Well-designed and sufficiently powered occupational case-control and cohort studies with adequate adjustment for confounding factors and other risk factors are required to provide more accurate risk estimates for occupational KC. This article is protected by copyright. All rights reserved.Revealing the mode of pollination in extant basal angiosperms might shed light on the evolution of early angiosperms (Hu et al. 2008). Because an extant basal-most angiosperm, Amborella trichopoda, is pollinated by a diversity of arthropods, the extinct early angiosperms might have been pollination generalists (Gottsberger 2016). Other extant basal angiosperms, including Schisandraceae, are pollinated by specialized insects that use flowers as mating and larval development sites (i.e., brood-site pollination mutualism; Pellmyr and Thien 1986, Luo et al. 2017). However, the pollination biology of many lineages of extant basal angiosperms is still unknown. This article is protected by copyright. All rights reserved.Atopic dermatitis (AD) has a significant impact on patients' quality of life, and due to pruritus it particularly affects sleep. Actigraphy is a well-recognized objective tool that is used in sleep medicine. Its relevance for assessing sleep in patients with AD has been shown by several studies. This study aimed to evaluate the sleep of patients with AD and to compare it with that of healthy volunteers using wrist actigraphy and a smartphone application. This article is protected by copyright. All rights reserved.Concerns have been raised regarding the safety of angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in patients with coronavirus disease of 2019 (COVID-19), based on the hypothesis that such medications may raise expression of ACE2, the receptor for severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). We conducted a literature review of studies (n = 12) in experimental animals and human subjects (n = 12) and evaluated the evidence regarding the impact of administration of ACEIs and ARBs on ACE2 expression. We prioritized studies that assessed ACE2 protein expression data, measured directly or inferred from ACE2 activity assays. The findings in animals are inconsistent with respect to an increase in ACE2 expression in response to treatment with ACEIs or ARBs. Control/sham animals show little to no effect in the plurality of studies. Those studies that report increases in ACE2 expression tend to involve acute injury models and/or higher doses of ACEIs or ARBs than are typically administered to patients. Data from human studies overwhelmingly imply that administration of ACEIs/ARBs does not increase ACE2 expression. Available evidence, in particular, data from human studies, does not support the hypothesis that ACEI/ARB use increases ACE2 expression and the risk of complications from COVID-19. We conclude that patients being treated with ACEIs and ARBs should continue their use for approved indications. © 2020 The Authors Clinical Pharmacology & Therapeutics © 2020 American Society for Clinical Pharmacology and Therapeutics.As chloroquine (CHQ) is part of the Dutch Centre for Infectious Disease Control COVID-19 experimental treatment guideline, pediatric dosing guidelines are needed. Recent pediatric data suggest that existing WHO dosing guidelines for children with malaria are suboptimal. The aim of our study was to establish best-evidence to inform pediatric CHQ doses for children infected with COVID-19. YK-4-279 mouse A previously developed physiologically-based pharmacokinetic (PBPK) model for CHQ was used to simulate exposure in adults and children and verified against published pharmacokinetic data. The COVID-19 recommended adult dosage regimen of 44mg/kg total was tested in adults and children to evaluate the extent of variation in exposure. Based on differences in AUC0-70h the optimal CHQ dose was determined in children of different ages compared to adults. Revised doses were re-introduced into the model to verify that overall CHQ exposure in each age band was within 5% of the predicted adult value. Simulations showed differences in drug exposure in children of different ages and adults when the same body-weight based dose is given. As such, we propose the following total cumulative doses 35 mg/kg (CHQ base) for children 0-1 month, 47 mg/kg for 1-6 months, 55 mg/kg for 6 months-12 years and 44 mg/kg for adolescents and adults, not to exceed 3300 mg in any patient. Our study supports age-adjusted CHQ dosing in children with COVID-19 in order to avoid suboptimal or toxic doses. The knowledge-driven, model-informed dose selection paradigm can serve as a science-based alternative to recommend pediatric dosing when pediatric clinical trial data is absent. This article is protected by copyright. All rights reserved.Superpotent topical corticosteroids (TCS) were demonstrated to be more effective and safer than high doses of oral corticosteroids to treat extensive bullous pemphigoid (BP).1 They are proposed as first-line treatment for BP in the Cochrane review2 and in European guidelines.3 In France, TCS are the recommended first-line treatment for BP, whatever the severity of the disease.4 The objectives of this study were to determine whether TCS alone were actually used as first-line therapy and could be successfully continued during the first year of treatment in routine practice, and to estimate the related healthcare costs. This article is protected by copyright. All rights reserved.INTRODUCTION The present study aimed first to investigate the change in prevalence of major levator ani muscle (LAM) defects, also called avulsions, from six weeks to one year postpartum, and second to assess maternal and obstetric risk factors for having persistent major LAM defects/avulsions at one year postpartum. MATERIAL AND METHODS This is a secondary analysis of data from a prospective cohort study including 300 nulliparous women at 17-19 weeks of gestation. Major LAM defects were diagnosed at six weeks and one year postpartum using transperineal ultrasonography. We defined persistent major LAM defects as a defect diagnosed both at six weeks and one year postpartum. Maternal and obstetric data were obtained from the hospital's electronic birth records. Pelvic floor muscle function was measured vaginally by manometer at 22 weeks of gestation. Main outcome measurement was change in prevalence of major LAM defects. Maternal and obstetric risk factors for having persistent major LAM defect were also assessed.
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