Accurate Assessment and Tracking the Process of Liver-Specific Injury by the Residual Tissue Activity of Carboxylesterase 1 and Dipeptidyl Peptidase 4

Accurately assessing and tracking the progression of liver-specific injury remains a major challenge in the field of biomarker research. Here, we took a retrospective validation approach built on the mutuality between serum and tissue biomarkers to characterize the liver-specific damage of bile duct cells caused by a-naphthyl isothiocyanate (ANIT). We found that carboxylesterase 1 (CES1), as an intrahepatic marker, and dipeptidyl peptidase 4 (DPP-IV), as an extrahepatic marker, can reflect the different pathophysiolo-gies of liver injury. Levels of CES1 and DPP-IV can be used to identify liver damage itself and the inflam-matory state, respectively. While the levels of the conventional serological biomarkers alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were all con-comitantly elevated in serum and tissues after ANIT-induced injury, the levels of bile acids decreased in bile, increased in serum, and ascended in intrahepatic tissue. Although the level of c-glutamyl transpeptidase (c-GT) changed in an opposite direction, the duration was much shorter than that of CES1 and was quickly restored to normal levels. Therefore, among the abovementioned biomarkers, only CES1 made it possible to specifically determine whether the liver cells were destroyed or damaged with-out interference from inflammation. CES1 also enabled accurate assessment of the anti-cholestasis effects of ursodeoxycholic acid (UDCA;single component) and Qing Fei Pai Du Decoction (QFPDD;multi-component). We found that both QFPDD and UDCA attenuated ANIT-induced liver damage. UDCA was more potent in promoting bile excretion but showed relatively weaker anti-injury and anti-inflammatory effects than QFPDD, whereas QFPDD was more effective in blocking liver inflammation and repairing liver damage. Our data highlights the potential of the combined use of CES1 (as an intra-hepatic marker of liver damage) and DPP-IV (as an extrahepatic marker of inflammation) for the accurate evaluation and tracking of liver-specific injury-an application that allows for the differentiation of liver damage and inflammatory liver injury.(c) 2021 THE AUTHORS. Published by Elsevier LTD on behalf of Chinese Academy of Engineering and Higher Education Press Limited Company. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

SARS-CoV-2 breakthrough infections after COVID-19 vaccination in patients with Inflammatory Bowel Disease: A systematic review and meta-analysis

Background: Patients with inflammatory bowel disease (IBD) have reduced seroconversion rates to COVID-19 vaccination. It is unclear whether an impaired immune response in vaccinated IBD patients impacts the susceptibility to SARS-CoV-2 infection and occurrence of (severe) COVID-19. We evaluated SARS-CoV-2 breakthrough infection rates and the disease course of COVID-19 in vaccinated IBD patients. Method(s): A systematic literature search was performed for studies which reported SARS-CoV-2 breakthrough infection rates and/or the disease course of COVID-19 in patients with IBD after COVID-19 vaccination. Primary outcome was the rates of breakthrough infection per time period. In meta-analyses, the pooled relative risk was calculated with a random effects model for vaccinated patients compared to vaccinated controls, to partially vaccinated and unvaccinated patients with IBD. Result(s): A total of 16 studies were included in analysis. The study period ranged from January 2020 to October 2021, and a follow-up time ranges from 3 weeks to 6 months. The breakthrough infection rates range from 0 to 37.4% in IBD patients within the study follow-up time. Strikingly, only studies with vaccination prior to December 2021 showed a breakthrough infection rate above 2%. (Figure 1). The disease course of a breakthrough infection is generally mild, with mild constitutional and respiratory symptoms in 85% of infected IBD patients. Hospitalization and mortality rates are low (0-8.7% and 0-4.3% respectively). Meta-analyses showed a significantly lower pooled relative risk of breakthrough infection for vaccinated as compared to unvaccinated IBD patients (RR 0.07, 95% CI 0.03;0.18). No difference was observed in risk of breakthrough infections between IBD patients and non-IBD controls (RR 1.01, 95% CI 0.92;1.10), and no difference between vaccinated and partially vaccinated IBD patients (RR 0.67, 95% CI 0.38;1.18). The impact of immunosuppressive therapy on breakthrough infection rates differs between studies. One study reported higher breakthrough infection rates for patients treated with infliximab in comparison to vedolizumab (P<.05). Other studies showed no impact on the breakthrough infection rates for immunosuppressive treatment vs no treatment, anti-TNF-alpha/corticosteroids vs without anti- TNF-alpha/corticosteroids and other biologics vs anti-TNF-alpha. Conclusion(s): Vaccination is effective to prevent COVID-19 infections in patients with IBD. Breakthrough infections do occur, but the disease course is generally mild. Available data seem to suggest a declining trend of breakthrough infections during calendar time. Data on the impact of IBD medication on the rate of breakthrough infections and disease course require further elucidation. (Figure Presented).

Pandemic racism and sexism in Australia: Responses and reflections among Asian women

Since the COVID-19 pandemic, studies have emerged to address either racism or women's issues. Studies that address the intersection of pandemic racism and sexism are lacking and the experiences of Asian women have been neglected. Drawing on interviews with 20 Asian women living in Victoria, Australia, this article aims to bridge the gap between studies of pandemic racism and the issues women faced during the pandemic. The article's intervention is threefold, we ask: first, how have Asian women in Australia experienced racism? Second, how have their experiences of racism intersected with sexism? Third, how do they make sense of their experiences and thoughts about the future? Our analysis argues three points: first, the lack of attention to Asian women's experiences of racism obscures the fact that Asian women can encounter racism more than their male counterparts. Second, the lack of attention to how sexism intersects with Asian women's experiences of racism causes them the inability to make sense of their experiences and prevents them from stopping mistreatment. Third, participants' reflections show that there is potential for women of colour in general to form coalitions based on sharing intersectionality and offer valuable insights for feminist and antiracist studies and initiatives. © The Author(s) 2023.

Immunosuppressants Exert Differential Effects against Pan-Coronavirus Infection and Distinct Combinatory Antiviral Activity with Molnupiravir and Nirmatrelvir

Introduction: There are seven types of coronaviruses that are known to infect humans, including three highly pathogenic members MERS-CoV, SARS-CoV-1 and SARS-CoV-2, and four seasonal coronaviruses, including NL63, 229E, OC43 and HKU1. Immunocompromised populations, such as organ transplant recipients receiving immunosuppressive medications and patients with inflammatory bowel disease treated with immunosuppressive or immunomodulatory therapies, are in general more susceptible to coronavirus infections. However, little is known how immunosuppressants directly affect coronavirus infection. Aims & Methods: This study aims to profile the effects of immunosuppressants and the combination of immunosuppressants with oral antiviral drug molnupiravir and nirmatrelvir on pan-coronavirus infection in cell culture models. Different coronaviruses (including wild type, delta and omicron variants of SARS-CoV-2, NL63, 229E and OC43) were used in cell culture models. The effects of immunosuppressants including dexamethasone, budesonide, prednisolone, sulfasalazine, aminosalicylates, 6-thioguanine, azathioprine, 6-mercaptopurine, methotrexate, tacrolimus, cyclosporine A, mycophenolic acid (MPA), rapamycin, everolimus, tofacitinib and figotinib on coronavirus infections, and the combination with molnupiravir and nirmatrelvir were studied in cell culture. Result(s): To profile the effect of immunosuppressants, we first tested all these regimens at 1 muM on wild type SARS-CoV-2, and then validated on different coronaviruses. We found dexamethasone and aminosalicylates can significantly stimulate the replication of these coronaviruses. For example, treatment with 1 muM dexamethasone significantly increased virus RNA level of wild type SARS-CoV-2 by 137+/-40%. 6-thioguanine, MPA, tofacitinib and figotinib treatment inhibited viral replication in a dosedependent manner in all tested coronaviruses. 6-thioguanine at 1 muM concentration had already potently inhibited the replication of wild type SARS-CoV-2 by 95+/-16%. The half maximum effective concentration (EC50) of tofacitinib against wild type SARS-CoV-2 replication was 0.60 muM and the half maximum cytotoxic concentration (CC50) was above 30 muM, which resulted in a selective index (SI) above 50. Combination treatment is often used to enhance antiviral efficacy, avoid drug resistance development in clinical applications. We evaluated the combined antiviral effects of 6-thioguanine, MPA and tofacitinib with molnupiravir and nirmatrelvir in wild type SARS-CoV-2 infection model. The combination of tofacitinib with molnupiravir had a moderate additive effect with the ZIP synergy score of 7, whereas the other two combinations had no such effect. However, the combination of MPA, 6-thioguanine, and tofacitinib with nirmatrelvir resulted in strong synergistic effect, and the ZIP synergy scores were 31, 22 and 12 respectively. Conclusion(s): These results demonstrated that different immunosuppressants had differential effects on coronavirus replication. 6-thioguanine, MPA, tofacitinib and figotinib were identified as potent inhibitors against pan-coronavirus infections. Although combination of MPA, 6-thioguanine, and tofacitinib with molnupiravir exerted moderate additive effect, combination with nirmatrelvir exerted strong synergistic antiviral activity. Thus, these findings provide as an important reference for clinicians to choose the optimal immunosuppressants for coronavirus infected immunocompromised patients or when they are under antiviral treatment of molnupiravir or nirmatrelvir.

The Effect of Class Experiences via Online Education on Japanese University Students’ Learning Outcomes amid the COVID-19 Pandemic

Implementing quality assurance of university students’ learning outcomes is an important challenge. In response to the COVID-19 pandemic, wherein many universities are implementing online education as “a new form of education,” there is a pressing need to rethink class methods. This study clarifies the effect of class experience via online education on Japanese university students’ learning outcomes amid the COVID-19 pandemic. The results indicate that students acquire knowledge and skills through online education in the same way as conventional face-to-face education, but regardless of the specialized field, the knowledge and skills acquired differ according to the form of online education employed. Our finding that appropriate learning outcomes are assured even for online education in the same way as face-to-face education is likely to be of major significance. © 2022, Hiroshima University,Research Institute for Higher Education,. All rights reserved.

Optimal strategy for a dose-escalation vaccination against COVID-19 in refugee camps

An immunogenic and safe vaccine against COVID-19 for use in the healthy population will become available in the near future. In this paper, we aim to determine the optimal vaccine administration strategy in refugee camps considering maximum daily administration and limited total vaccine supply. For this purpose, extended SEAIRD compartmental models are established to describe the epidemic dynamics with both single-dose and double-dose vaccine administration. Taking the vaccination rates in different susceptible compartments as control variables, the optimal vaccine administration problems are then solved under the framework of nonlinear constrained optimal control problems. To the best of our knowledge, this is the first paper that addresses an optimal vaccine administration strategy considering practical constraints on limited medical care resources. Numerical simulations show that both the single-dose and double-dose strategies can successfully control COVID-19. By comparison, the double-dose vaccination strategy can achieve a better reduction in infection and death, while the single-dose vaccination strategy can postpone the infection peak more efficiently. Further studies of the influence of parameters indicate that increasing the number of medical care personnel and total vaccine supply can greatly contribute to the fight against COVID-19. The results of this study are instructive for potential forthcoming vaccine administration. Moreover, the work in this paper provides a general framework for developing epidemic control strategies in the presence of limited medical resources.

Permission and content management model based on ASP.NET technology and three-layer network architecture

In order to strengthen the management and control of personnel flow and the timeliness of information dissemination during the COVID-19 epidemic, it is necessary to improve the reliability of authority and content management. The extensive application of authority information management can closely connect the professional system with the production activities of enterprises. At present, the traditional authority management level is complex, and the management of complex data is chaotic. This paper is based on ASP.NET. This paper proposes a data authority management method. The main function of this method is to establish a standard three-tier structure of rights management level by using the open-source string template engine technology, tag analysis, SEO search engine optimization technology and information collection technology. This method provides a general process oriented and automatic management platform for users through the hierarchical management mechanism. This technology can meet people's rights and content requirements for creating, publishing and updating websites without understanding the technology itself. The experimental results show that the rapid management mechanism based on authority management can accurately handle and manage authority and data which can improve the accuracy and timeliness of personnel flow control under the impact of the COVID-19 epidemic. © 2020 - IOS Press and the authors. All rights reserved.