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BackgroundABBV-599 is a novel combination of elsubrutinib (ELS;a selective BTK inhibitor) and upadacitinib (UPA;a JAK inhibitor) that targets non-overlapping signaling pathways associated with systemic lupus erythematosus (SLE).ObjectivesTo report results from SLEek, a phase 2, randomized, placebo (PBO)-controlled, parallel-group, multicenter study evaluating efficacy and safety of ABBV-599 and UPA monotherapy in adults with moderately to severely active SLE (NCT03978520).MethodsPatients (pts) were randomized 1:1:1:1:1 to once daily (QD) ABBV-599 high dose (HD;ELS 60 mg + UPA 30 mg), ABBV-599 low dose (LD;ELS 60 mg + UPA 15 mg), ELS 60 mg, UPA 30 mg, or PBO. The primary endpoint was the proportion of patients at W24 achieving SLE Responder Index-4 (SRI-4) and steroid dose ≤ 10 mg QD;additional efficacy and safety endpoints through W48 are also reported. The pre-specified 2-sided alpha level was 0.1.Results341 patients were enrolled. After a planned interim analysis when 50% of pts reached W24, the ABBV-599LD and ELS 60 mg arms were discontinued for lack of efficacy (no safety concerns). Of 205 continuing pts (ABBV-599HD n = 68, UPA 30 mg n = 62, PBO n = 75), baseline characteristics were well balanced. The primary endpoint (proportion achieving SRI-4 and steroid dose ≤ 10 mg QD at W24 vs PBO) was met by ABBV-599HD and UPA 30 mg. Key secondary endpoints were also achieved at W48 in both groups (Table 1). Overall flares and time to first flare were substantially reduced in the ABBV-599HD and UPA 30 mg groups through W48 (Figure 1). Anti-double stranded DNA antibodies were significantly decreased with both treatments. TEAEs considered related to study drug were 42.6% ABBV-599HD, 32.3% UPA 30 mg, and 33.3% PBO. There were no malignancies or VTE. There were 3 non-fatal CV events (1 MI on PBO and 2 ruptured cerebral aneurysms [1 each on ABBV-599HD and UPA 30 mg]);all were assessed as unrelated to study drug by investigators. No new safety signals were observed beyond previously known data for UPA or ELS.ConclusionABBV-599HD (ELS 60 mg + UPA 30 mg) and UPA 30 mg demonstrated significant improvements in SLE disease activity and flares with acceptable safety through 48 weeks.Table 1.Key Endpoints at Week 48PBO (n = 75)ABBV-599HD (n = 68)UPA 30 mg (n = 62)SRI-4 and steroid dose ≤ 10 mg QD, n (%) [95% CI]a24 (32.0) [21.4, 42.6]33 (48.5) [36.7, 60.4]*27 (43.5) [31.2, 55.9]SRI-4, n (%) [95% CI]a24 (32.0) [21.4, 42.6]35 (51.5) [39.6, 63.3]*28 (45.2) [32.8, 57.5]+BICLA, n (%) [95% CI]a19 (25.3) [15.5, 35.2]33 (48.5) [36.7, 60.4]***33 (53.2) [40.8, 65.6]***LLDAS, n (%) [95% CI]a18 (24.0) [14.3, 33.7]27 (39.7) [28.1, 51.3]*31 (50.0) [37.6, 62.4]***Joint-Count 50 in patients with ≥ 6 affected joints at baseline, n/n (%) [95% CI]a26/59 (44.1) [31.4, 56.7]37/58 (63.8) [51.4, 76.2]*34/59 (57.6) [45.0, 70.2] +CLASI-50 in patients with baseline CLASI ≥ 10, n/n (%) [95% CI]a5/14 (35.7) [10.6, 60.8]6/12 (50.0) [21.7, 78.3]5/8 (62.5) [29.0, 96.0]*Change from baseline in steroid dose, mg, LS mean (SE)b−1.5 (0.5)−1.5 (0.5)−1.2 (0.5)SFI, events/patient-years (95% CI)c Overall flares2.8 (2.4, 3.3)1.5 (1.2, 1.9)***2.0 (1.6, 2.4)** Mild/moderate flares2.5 (2.1, 2.9)1.3 (1.0, 1.6)***1.9 (1.5, 2.3)* Severe flares0.3 (0.2, 0.5)0.2 (0.1, 0.3)0.2 (0.1, 0.3) +Time to first flare by SFI, days, median (Q1, Q3)c141 (57, NE)312 (114, NE)*311 (99, NE)**BILAG-based flare rate, estimated incidence ratec0.570.19*0.26Data are presented for the full analysis set.aMissing data imputed using NRI incorporating multiple imputation to handle missing data due to COVID 19.bMissing data imputed using MMRM.cObserved data w/o imputation.+P <.1;*P <.05;**P <.01, ***P <.001 vs PBO.ABBV-599HD, elsubrutinib 60 mg QD and UPA 30 mg QD;CLASI-50, ≥ 50% reduction in CLASI activity score;Joint-Count 50, ≥ 50% improvement in tender or swollen lupus joints;LLDAS, Lupus Low Disease Activity State;NE, not estimated;PBO, placebo;SFI, SELENA SLEDAI Flare Index;UPA, upadacitinib.AcknowledgementsAbbVie and the authors thank the patients who particip ted in the study and all study investigators for their contributions. Medical writing assistance, funded by AbbVie, was provided by Callie A S Corsa, PhD, of JB Ashtin.Disclosure of InterestsJoan T Merrill Consultant of: AbbVie, Alexion, Alumis, Amgen, Astra Zeneca, Aurinia, Bristol Myers Squibb, EMD Serono, Genentech, Gilead, GlaxoSmithKline, Lilly, Merck, Pfizer, Provention, Remegen, Sanofi, UCB, and Zenas, Grant/research support from: Astra Zeneca, Bristol Myers Squibb, and GlaxoSmithKline, Yoshiya Tanaka Speakers bureau: AbbVie, Astra Zeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Gilead, Lilly, Mitsubishi-Tanabe, and Pfizer, Grant/research support from: AbbVie, Asahi-Kasei, Boehringer Ingelheim, Chugai, Daiichi-Sankyo, Eisai, and Takeda., David d'cruz Consultant of: GlaxoSmithKline, Lilly, and UCB., Karina Vila Consultant of: AbbVie, Daniel Siri Grant/research support from: AbbVie, Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, Gilead, Hoffman Laroche, Jansen, Lilly, and Sanofi, Xiaofeng Zeng: None declared, Kristin D'Silva Shareholder of: AbbVie, Employee of: AbbVie, Ling Cheng Shareholder of: AbbVie, Employee of: AbbVie, Thierry Sornasse Shareholder of: AbbVie, Employee of: AbbVie, Thao Doan Shareholder of: AbbVie, Employee of: AbbVie, Denise Kruzikas Shareholder of: AbbVie, Employee of: AbbVie, Alan Friedman Shareholder of: AbbVie, Employee of: AbbVie.
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Following the recent adjustments to coronavirus disease 2019 (COVID-19) prevention and control policies, an increasing number of medical staffs, especially those in primary care facilities are confront-ed with rapid growth of COVID-19 patients. Peking Union Medical College Hospital (PUMCH) has therefore compiled this recommendation for COVID-19 primary care practices based on a patient-centered perspective and following recommendations from domestic and international guidelines as well as the latest Chinese government policies. Further, PUMCH.s conception and compilation of this recommendation strictly adhere to evidence-based, concise and clinically applicable principles of practice. For the critical clinical questions with insufficient medical evidence, the recommendation offers insights on the basis of experience from PUMCH multi-disciplinary expert team and first-line medics.practices. Emphasizing on screening community residents with higher risk of severe illness, implementing early interventions including pharmaceutical treatment, enhan-cing nutritional support and improving sleep quality, we aim to construct a "Household-Community-Hospital" tertiary defense, with the hope of promoting health and reducing severe cases.Copyright © 2023, Peking Union Medical College Hospital. All rights reserved.
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Objective To investigate the effect of SARS-CoV-2 membrane protein on the processing of the 3' untranslated region (UTR) of the mRNA precursor (pre-mRNA) in host cells. Methods Based on the cell model of human lung epithelial cells A549, over-expression of the SARS-CoV-2 membrane protein was performed. The RNA-Seq high-throughput sequencing technique and bioinformatics methods was employed to analyze the systematic characterization of alternative polyadenylation (APA) events in host cells. Genes with significant APA events were uploaded to the Metascape database for functional enrichment analysis. In addition, alternative 3'UTR length of genes with APA events was verified by RT-qPCR. Then the target protein expression level was detected by Western blot. Results A total of 813 genes that were significant dynamic APA events in host cells that over-expressed SARS-CoV-2 membrane protein. These genes were enriched in cell biologicial processes such as the mitotic cell cycle and regulation of cellular response to stress. We further screened AKT1, which encodes a critical regulator involved in the above biological process, showing a 3'UTR lengthening in IGV software. RT-qPCR verified the trend of 3'UTR length changes of AKT1. Western blot showed the increased level of phosphorylated AKT1 protein in over-expressed group of M protein. Conclusion SARS-CoV-2 membrane protein potentially affects the 3' processing of host pre-mRNAs. AKT1, which is involved in a variety of viral biological processes, with 3'UTR lengthening, and its protein function was activated intracellularly. © 2022 Institute of Biophysics,Chinese Academy of Sciences. All rights reserved.
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A raw or processed meat product can be a breeding ground for spoilage bacteria (Enterobacteriaceae, Lactobacillus spp., Pseudomonas spp., etc.). Failure of decontamination results in food quality loss and foodborne illnesses caused by pathogens such as Salmonella, Escherichia coli, Staphylococcus aureus, and Listeria monocytogenes. Often, meat processors decontaminate the carcass using cheap chemicals or artificial antimicrobial agents not listed on the ingredient list, which is discouraged by health-conscious consumers. Foods with clean labels became more popular during the COVID-19 pandemic, which led consumers to choose healthier ingredients. Novel methods of controlling or improving meat safety are constantly being discovered. This review focuses on novel means of electrochemically activate water that is being investigated as a sanitizing agent for carcasses and processing area decontamination during production or at the end. Water can be activated by using non-thermal techniques such as ozonation, electrolysis, and cold plasma technologies. Recent studies showed that these activated liquids are powerful tools for reducing microbial activity in raw and processed meat. For instance, plasma-activated water can be used to enhance microbiological safety and avoid the negative effects of direct gaseous plasma on the organoleptic aspects of food products. In addition, electrolyzed water technology offers hurdle enhancement by combining with non-thermal strategies that have great potential. Ozonation is another way of activating water which provides a very convenient way to control microbiological safety and finds several recent applications as aqueous ozone for meat decontamination. These solutions are highly reactive and convenient for non-conventional applications in the meat industry related to food safety because of their antimicrobial or antiviral impact. The present review highlights the efficacy of activated-water decontamination of raw and processed meat via non-thermal solutions. Copyright © 2023 Roobab, Madni, Ranjha, Khan, Selim, Almuhayawi, Samy, Zeng and Aadil.
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Purpose: This paper aims to establish a systematic cognition to alleviate the supply–demand contradiction in rural financial markets from an integrated perspective of knowledge management and proposes the concept of rural financial knowledge ecosystem (RFKE) to encourage multifaceted solutions. Design/methodology/approach: The authors qualitatively describe the process that the knowledge management dilemmas cause the supply–demand contradiction in the rural finance and further summarize a systematic methodology from three dimensions: the knowledge subject, the knowledge environment and the knowledge ecology. Findings: The authors list four types of knowledge management dilemmas leading to the supply–demand contradiction in the rural finance, i.e. the weak knowledge sharing, the poor knowledge flow, the slow knowledge updating and the imperfect knowledge environment. Meanwhile, the RFKE model consisting of the ecological subject, the ecological environment and the ecological regulation is also presented. Research limitations/implications: The role of knowledge management in improving the allocation of financial resources to various rural financial market participants (government, rural financial institutions, farmers, agricultural enterprises, etc.). Originality/value: The authors creatively give the RFKE model, which complements and enriches the theory of knowledge management. Meanwhile, relevant management practices are urgently needed under the macro circumstance of the COVID-19 pandemic and the rural revitalization in China. © 2022, Emerald Publishing Limited.
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The panic caused by COVID-19 and the stagnation of business activities induced the continuous breeding of China's financial risks. This paper considers the COVID-19 and economic indexes as nodes to establish the Bayesian topology of financial risk. The liquidity, sovereign, and stock market risks are mainly considered to evaluate the financial risk. Based on the risk characteristics, the central interval trapezoidal possibility functions are designed, then the grey clustering model is used to classify the financial risk into four different levels. The possibility distribution of financial risk levels under different COVID-19 index levels is inferenced through the Bayesian network. Finally, each node's monthly time series data from October 2019 to May 2021 is used to learn by NETICA software, and the conditional probability of each node and the possibility of financial risk are deduced. It is concluded that liquidity risk and sovereign risk are more sensitive to COVID-19, while the stock market risk is not very sensitive to it.
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Objective To investigate the effect of SARS-CoV-2 membrane protein on the processing of the 3' untranslated region (UTR) of the mRNA precursor (pre-mRNA) in host cells. Methods Based on the cell model of human lung epithelial cells A549, over-expression of the SARS-CoV-2 membrane protein was performed. The RNA-Seq high-throughput sequencing technique and bioinformatics methods was employed to analyze the systematic characterization of alternative polyadenylation (APA) events in host cells. Genes with significant APA events were uploaded to the Metascape database for functional enrichment analysis. In addition, alternative 3'UTR length of genes with APA events was verified by RT-qPCR. Then the target protein expression level was detected by Western blot. Results A total of 813 genes that were significant dynamic APA events in host cells that overexpressed SARS-CoV-2 membrane protein. These genes were enriched in cell biologicial processes such as the mitotic cell cycle and regulation of cellular response to stress. We further screened AKT1, which encodes a critical regulator involved in the above biological process, showing a 3'UTR lengthening in IGV software. RT-qPCR verified the trend of 3'UTR length changes of AKT1. Western blot showed the increased level of phosphorylated AKT1 protein in over-expressed group of M protein. Conclusion SARS-CoV-2 membrane protein potentially affects the 3' processing of host pre-mRNAs. AKT1, which is involved in a variety of viral biological processes, with 3'UTR lengthening, and its protein function was activated intracellularly.
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In this paper, we measure the risk interdependence of 12 major cryptocurrencies before and during the COVID-19 pandemic, based on a GARCH-Copula-VaR approach and a dynamic network analysis. We find that cryptocurrencies generally show high levels of volatility, speculation, homogeneity and tail risk contagion. Furthermore, the COVID-19 pandemic has a continuous impact on the cryptocurrency market. When financial institutions are increasingly investing in crypto assets, the hidden risks in the cryptocurrency market remain high. Therefore, this paper calls for attention on the cryptocurrency market from both investors and regulators.
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Objectives: Ganoderic acid Me [GA-Me], a major bioactive triterpene extracted from Ganoderma lucidum, is often used to treat immune system diseases caused by viral infections. Although triterpenes have been widely employed in traditional medicine, the comprehensive mechanisms by which GA-Me acts against viral infections have not been reported. Sendai virus [SeV]-infected host cells have been widely employed as an RNA viral model to elucidate the mechanisms of viral infection. Method(s): In this study, SeV-and mock-infected [Control] cells were treated with or without 54.3 muM GA-Me. RNA-Seq was performed to identify differentially expressed mRNAs, followed by qRT-PCR validation for selected genes. GO and KEGG analyses were applied to investigate potential mechanisms and critical pathways associated with these genes. Result(s): GA-Me altered the levels of certain genes' mRNA, these genes revealed are associated pathways related to immune processes, including antigen processing and presentation in SeV-infected cells. Multiple signaling pathways, such as the mTOR pathway, chemokine signaling pathway, and the p53 pathways, significantly correlate with GA-Me activity against the SeV infection process. qRT-PCR results were consistent with the trend of RNA-Seq findings. Moreover, PPI network analysis identified 20 crucial target proteins, including MTOR, CDKN2A, MDM2, RPL4, RPS6, CREBBP, UBC, UBB, and NEDD8. GA-Me significantly changed transcriptome-wide mRNA profiles of RNA polymerase II/III, protein posttranslational and immune signaling pathways. Conclusion(s): These results should be further assessed to determine the innate immune response against SeV infection, which might help in elucidating the functions of these genes affected by GA-Me treatment in virus-infected cells, including cells infected with SARS-CoV-2. Copyright © 2022 Bentham Science Publishers.
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The clinical efficacy and safety of a drug is determined by its molecular properties and targets in humans. However, proteome-wide evaluation of all compounds in humans, or even animal models, is challenging. In this study, we present an unsupervised pretraining deep learning framework, named ImageMol, pretrained on 10 million unlabelled drug-like, bioactive molecules, to predict molecular targets of candidate compounds. The ImageMol framework is designed to pretrain chemical representations from unlabelled molecular images on the basis of local and global structural characteristics of molecules from pixels. We demonstrate high performance of ImageMol in evaluation of molecular properties (that is, the drug's metabolism, brain penetration and toxicity) and molecular target profiles (that is, beta-secretase enzyme and kinases) across 51 benchmark datasets. ImageMol shows high accuracy in identifying anti-SARS-CoV-2 molecules across 13 high-throughput experimental datasets from the National Center for Advancing Translational Sciences. Via ImageMol, we identified candidate clinical 3C-like protease inhibitors for potential treatment of COVID-19. Predicting the properties of a molecule from its structure with high accuracy is a crucial problem in digital drug design. Instead of sequence features, Zeng and colleagues use an image representation of a large collection of bioactive molecules to pretrain a model that can be fine-tuned on specific property prediction tasks.
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Objectives: Hypertensive disorders occur in approximately 12% to 22% of pregnancies and cause substantial perinatal morbidity and mortality of both mother and fetus. Hypertensive disease is directly responsible for approximately 20% of maternal deaths and can be classified as chronic hypertension, gestational hypertension, preeclampsia-eclampsia, and chronic hypertension with superimposed preeclampsia. At present, the pathogenesis of preeclampsia is still unclear, we wrote this article to make a uptodate review of this disease. Mechanism: A comprehensive search of several databases was conducted from inception up to March 2022. The searched databases were Web of Science, MEDLINE, Ovid, and Cochrane Database of Systematic Reviews. The search strategy included the combinations of the following medical terms: Hypertensive disorders;preeclampsia;mechanism;pathogenesis hypothesis. Findings in Brief: At present, the pathogenesis of preeclampsia is still unclear, the theory of Genetic, Inflammatory Response, Immune Imbalance in Maternal-Fetal Interface, Oxidative Stress, Vascular Endothelial Cell Damage are supposed involved in the progress of preeclampsia. Conclusions: Although there are various theories mentioned above, none of the hypothesis can fully explain preeclampsia. More research is needed on the mechanism of preeclampsia.
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Background: Upadacitinib (UPA) was shown to be safe and effective through 2 years in patients (pts) with active ankylosing spondylitis (AS) naïve to biologic disease-modifying antirheumatic drugs (bDMARDs) in the pivotal phase 2/3 SELECT-AXIS 1 trial.1,2 Objectives: To assess the efficacy and safety of UPA in pts with active AS with an inadequate response (IR) to bDMARDs. Methods: SELECT-AXIS 2 (NCT04169373) was conducted under a master protocol and includes two separate studies (one for AS bDMARD-IR and one for non-radiographic axial spondyloarthritis [nr-axSpA]). The AS bDMARD-IR study is a randomized, double-blind, placebo (PBO)-controlled, phase 3 trial that enrolled adults ≥18 years with AS who met modifed New York criteria, had BAS-DAI and pt's assessment of total back pain scores ≥4 (numeric rating scale 0-10) at study entry, and had an IR to one or two bDMARDs (TNF inhibitor or IL-17 inhibitor). Pts were randomized 1:1 to receive oral UPA 15 mg once daily (QD) or PBO during the 14-week (wk) double-blind treatment period. The primary endpoint was ASAS40 response at wk 14. Multiplicity-controlled secondary endpoints evaluated at wk 14 were improvements from baseline in disease activity (ASDAS [CRP], ASDAS ID [<1.3], ASDAS LDA [<2.1], BASDAI50, ASAS20, and ASAS PR), pain (total and nocturnal back pain), function (BASFI), objective measure of infammation (SPARCC MRI score of the spine), spinal mobility (BASMI), enthesitis (MASES), and quality of life (ASQoL and ASAS HI). Non-responder imputation incorporating multiple imputation (NRI-MI) was used to handle intercurrent events and missing data for binary endpoints. Cochran-Mantel-Haenszel (CMH) test and mixed-effect model for repeated measures (MMRM) were used for analyzing binary and continuous endpoints, respectively. Treatment-emergent adverse events (TEAEs) assessed through wk 14 are reported for pts who had ≥1 dose of study drug. Results: All 420 randomized pts with active AS received assigned treatment (UPA 15 mg, n=211;PBO, n=209);409 (97%) received study drug through wk 14. Baseline demographic and disease characteristics were generally similar between treatment groups and refective of an active AS bDMARD-IR population (74% male;mean age 42.4 years;mean disease duration 7. 7 years;83% HLA-B27 positive;mean BASDAI 6.8). Signifcantly more pts achieved the primary endpoint of ASAS40 response at wk 14 with UPA vs PBO (45% vs 18%;P<0.0001;Figure 1);UPA showed onset of effect in ASAS40 as early as wk 4 (nominal P≤0.05). All multiplicity-controlled secondary endpoints met statistical signifcance for UPA vs PBO at wk 14 across multiple clinical domains of AS (P<0.0001;Figure 1). The rate of TEAEs was similar between treatment groups through wk 14 (UPA, 41%;PBO, 37%). TEAEs led to discontinuation in 3 (1.4%) pts treated with PBO and none with UPA. Serious infections occurred with UPA (2.4%) but not with PBO and included 4 events of COVID-19 and 1 event of uveitis. Additional events of uveitis were reported in 3 (1.4%) pts treated with PBO. Infammatory bowel disease (IBD) occurred in 1 (0.5%) pt on UPA and none on PBO. No malignancy, major adverse cardiovascular events, venous thromboembolic events, or death were reported with UPA;1 event of malignancy was observed with PBO. Conclusion: UPA 15 mg QD was signifcantly more effective than PBO over 14 wks of treatment in pts with active AS and IR to bDMARDs. No new safety risks were identifed with UPA compared with its known safety profile.3,4 These fndings are consistent with and complementary to those of SELECT-AXIS 1 (bDMARD-naïve AS population),1,2 and support the use of UPA in pts with active AS, including those who had a previous IR to bDMARD therapy.
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Background: BAT1806/BIIB800 is a proposed biosimilar to reference tocili-zumab (TCZ). A Phase III randomised, double-blind, active-controlled clinical trial was conducted as part of a biosimilar development programme. Objectives: To evaluate the efficacy, pharmacokinetics (PK), safety and immu-nogenicity of BAT1806/BIIB800 in comparison with EU-sourced TCZ in subjects with moderate to severe rheumatoid arthritis with inadequate response to meth-otrexate (MTX). Methods: The study was conducted at 55 centres in China and Europe, between June 2018 and January 2021. Eligible subjects were randomised in a 2:1:1 ratio to one of three treatment groups: (1) BAT1806/BIIB800 up to Week 48, (2) TCZ up to Week 48, or (3) TCZ up to Week 24, followed by BAT1806/BIIB800 from Week 24 to Week 48, administered intravenously every 4 weeks at a dose of 8mg/kg. The primary endpoint was the proportion of subjects achieving an ACR20 response at timepoints pre-specifed to meet the requirements of different Regulatory Agencies: Week 12, for EMA;Week 24, for FDA and NMPA. Equivalence margins applied to differences in ACR20 response rates in the BAT1806/BIIB800 and TCZ treatment groups were pre-specifed as follows: +/-14.5% for EMA (95% confdence interval (CI));-12.0%,15% for FDA (90% CI);+/-13.6% for NMPA (95% CI). Secondary endpoints included pharmacokinetics, safety and immunogenicity. The ICH E9(R1) estimands framework including intercurrent events (related or unrelated to the COVID19 pandemic) was implemented for the ACR20 evaluation. A logistic regression model including 'region' (China and Eastern Europe) and 'previous biologic or targeted synthetic DMARD use' (Yes/No) as captured in Interactive Web Response System as stratifcation factors was utilised to assess equivalence for the primary endpoint. The difference in response rates was estimated and corresponding confdence intervals were derived to assess equivalence for the primary endpoint. This presents results up to Week 24. Results: In total, 621 subjects were randomised to receive BAT1806/BIIB800 (N=312), TCZ (N=155), or TCZ followed by BAT1806/BIIB800 (N=154). The groups were comparable in terms of baseline demographics and disease characteristics, including age, gender, disease activity and disease duration. The estimated proportions of subjects achieving an ACR20 response in the BAT1806/BIIB800 vs. the TCZ groups, respectively, were 68.97% vs. 64.82% at Week 12 and 69.89% vs. 67.94% at Week 24. The estimated difference between ACR response rates was 4.15% (95% CI-3.63, 11.93) at week 12, and 1.94% (90% CI-4.04, 7.92;95% CI-5.18, 9.07) at Week 24. The CIs for the estimated differences between the treatment groups were within the pre-defned equivalence margins (Figure 1). The treatment groups were comparable in terms of serum trough levels, incidence of TEAEs and ADA/NAb positivity (Table 1). Conclusion: BAT1806/BIIB800 has demonstrated equivalent efficacy at Week 12 and Week 24 and a similar PK, safety and immunogenicity profile as reference tocilizumab up to Week 24.
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This study aims to discover how technology firms accomplish digital innovation through AI adoption. The current research also investigated digital resilience's role as a mediator and training protocol's role as a moderator between AI adoption and digital innovation links. The data collection and analysis were conducted using a quantitative method. To examine the research hypotheses, we chose technology firms that face problems regarding the enhancement of digital innovation. The findings confirmed that the digital innovation of technology firms is forecasted through AI adoption. The results proved that digital resilience plays a mediating role between AI adoption and digital innovation links. Technology firms play a key role in the advancement of digital technology. This research study adds to the existing knowledge by offering a digital innovation model with the combined influence of AI adoption, digital resilience, and training protocol. This study will be helpful for top management by showing when, why, and how AI adoption helps firms in their achievement of digital innovation. Moreover, digital resilience's role is also important in the current digitalized world;thus, we used digital resilience as mediator in this research.
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The deterioration of environmental quality has attracted the attention of the Chinese government and the public. The Chinese government has delegated part of the power of environmental regulation to local governments. To fulfill the KPI, local governments tend to loosen environmental regulations to attract more settlement of enterprises, thus leading to an increasingly fierce local environmental regulation competition. The improvement of people’s living standards makes it possible for the public to participate in environmental regulation. This article seeks to carry out the empirical study to interpret the relationship between local environmental regulation competition, public participation, and enterprise location selection through a random effects (RE) spatial Durbin model with 29 provincial panel data in China from 2004 to 2017. The results show that the provincial spatial spillover effect of enterprise location selection is significant. More intensified local environmental regulation competition can attract more investment but may harm sustainable economic development. Active public participation can effectively avoid the excessive investment caused by local environmental regulation competition and sustain economic development. Therefore, we should establish and improve the local environmental prevention and regulation system and establish an information disclosure mechanism to ensure public participation. The local government’s environmental regulation and public participation mechanism should be effectively coordinated. Copyright © 2022 Mu, Zhan, Ameer, Anser, Zeng and Amin.
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Pollutants emitted from motor vehicles have become an important source of air pollution. Based on the traffic flow data of the expressways in Fujian Province, a high-resolution pollutant emission inventory of the expressways from January to July in 2020 was established by the bottom-up calculation method. The results show that under the influence of the COVID-19, the monthly average traffic flow and pollutant emissions of the expressways in Fujian province decreased firstly and then increased. Pollutant emissions reached the lowest in April, and quickly recovered to the pre-COVID-19 emission level in May. The pollutant emissions of the CO, HC, NOx, PM2.5 and PM10 in the middle stage of the COVID-19 decreased by 90.68%, 89.06%, 92.58%, 89.58% and 89.63%, respectively, compared with those in the post stage of the COVID-19. In the entire study period, different cities have different sharing rates of the pollutant emissions from motor vehicles, with Quanzhou, Fuzhou and Zhangzhou having higher motor vehicle emission sharing rates on the expressways. In terms of the vehicle types, the small passenger buses and the light trucks are the main contributors for CO and HC, and the heavy trucks and the light trucks are the main contributors for NOx and PM. In terms of the fuel types, the gasoline vehicle is the main source of CO and HC, and the diesel vehicle is the main source of NOx and PM. In terms of the emission standards, vehicles with China 3 and China 4 have the largest contribution rate to various pollutants. However, the spatial distribution of various pollutants is consistent, with the higher level emissions in the eastern coastal expressways, while the lower level emissions in the western inland expressways. From the spatial distribution of NOx emission intensity of Expressways in Fujian Province, the emission intensity of each section in March and April was at a very low level. Taking the main emission of the motor vehicle: NOx as a case, the Shenyang-Haikou Expressway section has the highest NOx emission intensity. Moreover, the Xiamen and Quanzhou sections of Shenyang-Haikou Expressway have relatively high exposure levels of motor vehicle pollution, while other sections have relatively low exposure levels. © 2022, Science Press. All right reserved.
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A worldwide effort to counter the COVID-19 pandemic has resulted in hundreds of candidate vaccines moving through various stages of research and development, including several vaccines in phase 1, 2 and 3 clinical trials. A relatively small number of these vaccines have been evaluated in SARS-CoV-2 disease models, and fewer in a severe disease model. Here, a SARS-CoV-2 DNA targeting the spike protein and delivered by jet injection, nCoV-S(JET), elicited neutralizing antibodies in hamsters and was protective in both wild-type and transiently immunosuppressed hamster models. This study highlights the DNA vaccine, nCoV-S(JET), we developed has a great potential to move to next stage of preclinical studies, and it also demonstrates that the transiently immunosuppressed Syrian hamsters, which recapitulate severe and prolonged COVID-19 disease, can be used for preclinical evaluation of the protective efficacy of spike-based COVID-19 vaccines.
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Drug development is time-consuming and expensive. Repurposing existing drugs for new therapies is an attractive solution that accelerates drug development at reduced experimental costs, specifically for Coronavirus Disease 2019 (COVID-19), an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, comprehensively obtaining and productively integrating available knowledge and big biomedical data to effectively advance deep learning models is still challenging for drug repurposing in other complex diseases. In this review, we introduce guidelines on how to utilize deep learning methodologies and tools for drug repurposing. We first summarized the commonly used bioinformatics and pharmacogenomics databases for drug repurposing. Next, we discuss recently developed sequence-based and graph-based representation approaches as well as state-of-the-art deep learning-based methods. Finally, we present applications of drug repurposing to fight the COVID-19 pandemic and outline its future challenges. This article is categorized under: Data Science > Artificial Intelligence/Machine Learning
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BACKGROUND: In response to the COVID-19 pandemic, the Alzheimer's Disease Research Center (ADRC) at the Icahn School of Medicine at Mount Sinai began conducting evaluations for the National Alzheimer's Coordinating Center Uniform Data Set (NACC UDS) by telephone in March 2020. The ADRC designed a survey to evaluate participant and research coordinator satisfaction with telephone evaluations. METHOD: Following UDS evaluations, participants rated their satisfaction on 5 items: voice quality on telephone, respect for privacy, degree of comfort using the telephone, and confidence that the information collected was accurate. Coordinators were asked to gauge their satisfaction on similar items. To calculate satisfaction scores, responses were assigned values: "Very" = 3, "Fairly" = 2, and "Not at all" = 1. Maximum satisfaction score was 15 for participants and 18 for coordinators. RESULT: Data was available for 130 participants evaluated by telephone between March 2020 and January 2021. Of these, 68.5% were female, 53.7% were white, with an average age of 76.4 and 16 years of education. 74% of participants had a Global Clinical Dementia Rating (CDR) score of 0;22% CDR 0.5;4% CDR 1. Participants with CDR >1 were evaluated by caregiver interviews without testing, and those with CDR=1 were offered testing at the discretion of their family and examiners. Average total satisfaction rating was 14.2/15 for participants and 16.8/18 for coordinators. 98% of participants felt their privacy was "very" respected (mean 2.98/3). When looking at global CDR scores, 89.6% of participants with CDR=0 and 88.2% with CDR ≥0.5 were "very" confident in the accuracy of the information collected. In contrast, coordinators were "very" confident in the accuracy of their evaluation 84.4% of the time when participants had a CDR=0 and 67.7% of the time when participants had a CDR ≥0.5. CONCLUSION: Overall satisfaction with telephone evaluations was high, but participant and coordinator confidence in the accuracy of assessments varied, with coordinator satisfaction lower for more cognitively impaired participants. Future work will analyze satisfaction with ongoing remote assessments and evaluate the impact of additional demographic and diagnostic variables. © 2021 the Alzheimer's Association.
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