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1.
2022 International Conference on Image Processing and Media Computing, ICIPMC 2022 ; : 73-79, 2022.
Article in English | Scopus | ID: covidwho-2078213

ABSTRACT

Coronavirus disease 2019 (COVID-19) epidemics have spread worldwide in recent years by its extreme contagiousness. The diagnosis of COVID-19 is crucial in the prevention, control, and treatment procedure. Deep learning-based image classification models have been proved to be valid for the pneumonia classification using chest X-ray images, helping physicians to diagnose and treat the disease more effectively. However, the vulnerability of deep neural networks was confirmed by researchers through the injection of tiny perturbations which is imperceptible to humans. These adversarial samples become a major threat to the medical safety system, especially in the disease detection field. In this regard, we made some experiments to attack chest X-ray images to investigate the efficiency of two types of attack methods with the sign and no-sign operators. Fast Gradient Sign Method (FGSM), Basic Iterative Method (BIM), and Projected Gradient Descent (PGD) were selected and transformed into no-sign attack methods to analyze their effectiveness on white-box and black-box testing. We theoretically and experimentally confirmed the alternative no-sign attack methods were more efficient. © 2022 IEEE.

2.
International Review of Financial Analysis ; 84, 2022.
Article in English | Web of Science | ID: covidwho-2069188

ABSTRACT

This paper mainly investigates whether the category-specific EPU indices have predictability for stock market returns. Empirical results show that the content of category-specific EPU can significantly predict the stock market return, no matter the individual category-specific EPU index or the principal component of category -specific EPU indices. In addition, the information of category-specific EPU indices can also have higher eco-nomic gains than traditional macroeconomic variables, even considering the trading cost and different investor risk aversion coefficients. During different forecasting windows, multi-period forecast horizons and the COVID-19 pandemic, we find the information contained in category-specific EPU indices can have better performances than that of the macroeconomic variables. Our paper tries to provide new evidence for stock market returns based on category-specific EPU indices.

3.
2022 ASABE Annual International Meeting ; 2022.
Article in English | Scopus | ID: covidwho-2040428

ABSTRACT

Since COVID-19 became a global pandemic, improving air quality has been increasingly important to mitigate the transmission of pathogenic aerosols. Air filters such as MERV filters have been widely used in heating, ventilation, and air conditioning (HVAC) systems to clean inlet air. In recent years, ultraviolet (UV) light has been used for decontamination and disinfection in various applications, including indoor air cleaning, e.g., upper-room ultraviolet germicidal irradiation (UVGI). There are a variety of air purification devices available in the market, with some incorporating UV technology. However, many of them are not formally tested and certified for their effectiveness in mitigating airborne pathogens and particulate matter. The research's objectives are to (1) evaluate, design, and upgrade an existing air filtration device (~2,200 CFM) with the addition of UV-C lamps;(2) test the effectiveness of the upgraded device in mitigating airborne pathogens (bacteria) and particulate matter (PM) in real scenario (poultry farm). The testing results of air quality are expressed in particular matter (PM) levels and colony-forming units (CFUs). The preliminary data showed that both MERV-8 & MERV 13 and UV-C lamps can inactivate up to 100% of airborne bacteria, and the device can remove over 95% of total PM after treatment in a ~150-layer room. © 2022 ASABE. All Rights Reserved.

4.
46th IEEE Annual Computers, Software, and Applications Conference, COMPSAC 2022 ; : 145-150, 2022.
Article in English | Scopus | ID: covidwho-2018645

ABSTRACT

In last two years, universities around the world have been using hyflex teaching due to COVID-19. This allows students to attend physical/online lectures in a flexible manner. A hyflex class comprises classroom students as well as online students. In this paper, we present a model for hyflex classrooms that highlights 4Cs: Content, Collaboration, Community and Communication. Based on the 4C model, a hyflex classroom has been designed and implemented through various teaching/learning tools or elements. These include the effective use of presentation slides, annotations, chatbox, open education resources, multiple choice exercises, group exercises etc. The effectiveness of these tools/elements were evaluated by means of an initial student survey. These results provide valuable insights into hyflex teaching/learning. © 2022 IEEE.

5.
Journal of Clinical Oncology ; 40(16), 2022.
Article in English | EMBASE | ID: covidwho-2009514

ABSTRACT

Background: Despite the use of multiple lines of targeted therapy has revolutionized treatment for HER2-positive breast cancer, these methods still have limited efficacy for triple-positive breast cancer (TPBC), which calls for persistent exploration for optimized treatment strategy. This MUKDEN-01 prospective trial aimed to evaluate the efficacy of oral, chemo-sparing neoadjuvant therapy with pyrotinib, letrozole and dalpiciclib, which also meet the need for treatment convenience under COVID-19 pandemic, for patients with TPBC. Methods: The MUKDEN 01 was an investigator-initiated, multicentre, single arm, prospective phase II trial, which was performed at twelve hospitals in China( NCT04486911). Treatment-naïve patients with stage II-III tumors that according to the AJCC 8th edition criteria were eligible. Patients were treated with each cycle of 4 weeks with oral administration of pyrotinib 320 mg, and letrozole 2.5mg once daily for 4 weeks, and dalpiciclib 125 mg once daily for three weeks, followed by one week off, for five cycles. The primary endpoint was pathological complete response (pCR) in the breast and axilla (ypT0/is ypN0). Secondary endpoints included pCR in the breast (ypT0/is). residual cancer burden (RCB) score, Ki67 index change at surgery compared with baseline, and safety. Safety was analyzed in all patients, who received treatment. The study is still ongoing, and the enrollment has been completed. Results: Between June 20, 2020 and Sep. 6, 2021, 68 patients were screened for eligibility and 61 patients were recruited into this first stage of study. After surgery, 18 (29.5%, 95% CI 18.5-42.6) out of 61 patients achieving tpCR(ypT0/is ypN0), 21 (34.4%, 95% CI 22.7-47.7) patients achieved bpCR(ypT0/is). The patients with excellent pathologic response (RCB 0-1) to the combined therapy accounted for 54.1% (33/61, 95% CI 40.9-66.9). Mean Ki67 expression was reduced from 38.7% (95%CI: 31.3-46.0) at baseline to 19.3% (95% CI:13.6- 25.0;p=0.0001) in the surgical samples. The most frequent grade 3 AE were neutropenia (35 [57%]), leukopenia (13 [21%]), diarrhea (9 [15%]) and oral mucositis (4 [7%]). There were five grade 4 neutropenia (8%) and one grade 4 increased AST (2%), but without other SAE and death throughout the study. Conclusions: Neoadjuvant therapy with pyrotinib, letrozole and dalpiciclib yielded a pCR rate comparable to standard chemotherapy plus dual HER2 blockade in TPBC patients. The combined therapy was also well-tolerated and provided a chemo-sparing neoadjuvant approach for TPBC patients. To our knowledge, this is the first study to evaluate the therapeutic efficacy of a chemo-free neoadjuvant treatment with HER2 TKI pyrotinib and letrozole plus CDK4/6 inhibitor dalpiciclib for TPBC patients. Further validation in a large-scale randomized controlled trial is warranted.

6.
Journal of General Internal Medicine ; 37:S594, 2022.
Article in English | EMBASE | ID: covidwho-1995728

ABSTRACT

STATEMENT OF PROBLEM/QUESTION: The transition between hospital discharge and primary care follow-up is a vulnerable period for patients that can result in adverse health outcomes and preventable hospital readmissions. The COVID-19 pandemic has exacerbated this transitional period, as many patients have forgone their routine healthcare visits, lost touch with their primary care providers (PCPs), and lacked a point of contact for their health needs after leaving the hospital. DESCRIPTION OF PROGRAM/INTERVENTION: We launched a postdischarge Transitions in Care Management (TCM) clinic to serve patients discharged from NYU Langone Hospital Brooklyn, an urban safety net academic hospital that serves a racially diverse and socioeconomically vulnerable population in Southwest Brooklyn. From October 2020 to October 2021, TCM visits were offered to patients prior to discharge from the general medicine service at NYU Langone Brooklyn who did not have a primary care provider or who could not get an appointment with their PCP within 10 days of discharge. Patients were given the option of in-person visits or virtual visits. TCM visits were scheduled with residents within 2 weeks of patient discharge. Questions at the TCM visit focused on scheduled speciality appointments, any discrepancy in medications prescribed at discharge, or if the patient was connected to additional community resources. MEASURES OF SUCCESS: The primary outcome was the 30-day readmission rate for patients referred to TCM compared to all patients discharged from the general medicine unit. FINDINGS TO DATE: From October 2020 through October 2021, there were a total of 357 TCM visits out of a total 806 referrals placed (44% completion rate). There was a reduction in 30-day hospital readmission rate for patients who completed a TCM visit compared with those who were not referred (5% vs 15.9%;p < 0.001). There was also a reduction in readmission rate for those who were referred but did not complete their TCM visit compared to those who were not referred (8.4% vs. 15.9%;p < 0.001). Of the completed visits, 172 were in-person, 138 were virtual, and 47 were over the telephone. Patients were also more likely to show up to their virtual visits than their in-person visits (30% no-show rate for in-person vs. 12% no-show rate for virtual). KEY LESSONS FOR DISSEMINATION: Thirty-day hospital readmission rate was lower for patients seen as part of the resident-run TCM clinic at a safety net academic medical center. Interestingly, patients referred but who did not complete TCM visits still had a decreased readmission rate compared to those who were not referred, suggesting that there may be an inherent difference in these two patient groups. Future studies will examine the differences between these groups, and analyze the factors that influence TCM referral and visit completion. Future studies will also analyze how the medium of visit (virtual vs. in-person) and specific interventions during the TCM visits (medication reconciliation, specialty appointments, community resources) influenced patients' transition in care.

7.
Annals of Blood ; 7, 2022.
Article in English | Scopus | ID: covidwho-1964904

ABSTRACT

The severe acute respiratory syndrome (SARS) coronavirus disease known as coronavirus disease 2019 (COVID-19), which is caused by SARS-CoV-2 has caused a global pandemic since late 2019. As of 7 February 2020, more than 106 million people have been infected, and approximately 2,317 thousand people have died due to SARS-CoV-2 across 200 countries. Unfortunately, to date, many aspects of pathogenesis, infection, clinical manifestations and treatment methods remain unclear, no specific antiviral drugs or vaccines have been reported for patients with COVID-19 infection. Most patients with severe infections require supportive organ function therapies in the intensive care unit (ICU). Passive antibody therapies such as convalescent plasma (CP) therapy have been proved to be effective in the treatment of many infectious diseases such as SARS and Middle East respiratory syndrome (MERS), which are also assumed as a promising strategy in the treatment of critically ill COVID-19 patients. With the increasing investigation, the objective understanding of COVID-19 prevention, treatment and comorbid disease is beneficial for the application of the strategy applied in the clinical trials. Herein, we briefly discuss the current therapeutic approaches for patients with COVID-19, especially focuses on the application of therapeutic plasma exchange (TPE) for selected critically ill patients, aiming to provide some guidance for the treatment of severe COVID-19. © Annals of Blood. All rights reserved.

8.
INTERNATIONAL JOURNAL OF MENTAL HEALTH PROMOTION ; 24(4):603-618, 2022.
Article in English | Web of Science | ID: covidwho-1912681

ABSTRACT

The study aimed to investigate the influence of academic stressors on mental health and the mediating effect of social support and self-identity among college students and further studied the difference between the graduating students and non-graduating students during the COVID-19 Pandemic. Recruiting 900 college students as subjects, used the college students??? academic stressors questionnaire, social support questionnaire, self-identity scale and depression anxiety stress scales (DASS-21). The results showed that: (1) The college students??? academic stressor positively predicted mental health;(2) Social support and self-identity mediated the relationship;(3) The model also held when academic stressors was replaced by work stressor, but there were differences between the graduating and nongraduating students;(4) The direct effect work stressor on mental health in the graduating group was not significant;(5) The non-graduating students??? work stressor could not predict mental health through social support.

9.
Zhonghua Liu Xing Bing Xue Za Zhi ; 43(6): 835-840, 2022 Jun 10.
Article in Chinese | MEDLINE | ID: covidwho-1903513

ABSTRACT

Objective: To analyze the epidemiological characteristics of COVID-19 caused by 2019-nCoV Delta variant (B.1.617.2) in Gansu province, and provide evidence for the prevention and control of COVID-19. Methods: The information of COVID-19 cases, including demographic characteristics, epidemiological history, onset date, diagnosis date, exposure place, detection way and infection source, in Gansu from 17 October to 25 November, 2021 were collected. Software Excel 2016,SPSS 22 and ArcGIS 10.7 were used for data process and analysis. Results: As of November 25, 2021, a total of 146 COVID-19 cases had been reported in Gansu and the epidemic affected 10 counties (districts) in 5 cities. The epidemic of COVID-19 in Gansu had three stages: imported case stage,imported-local case stage and local case stage. The age of cases ranged from 1 to 87 years,and the cases in age group 18-59 years accounted for 59.59% (87/146). The male to female ratio of the cases was 1∶1.12 (69∶77). The cases were mainly people engaged in business services (17.12%, 25/146),retirees (15.75%, 23/146),students (13.70%, 20/146),the jobless and unemployed (12.33%, 18/146). In 3 epidemic stages, the cases aged 18-59 years accounted for 44.44%,54.41% and 70.00% respectively,showing an upward trend,and there were differences among different populations (trend χ2=23.24, P<0.001). Also, the incubation period of the cases tended to decrease, and severe cases accounted for 33.33% (6/18), 19.12% (13/68) and 3.33% (2/60) respectively, showing a downward trend. Community screening (25.34%, 37/146) and close contact screening were the main ways to detect cases,the cases detected by close contact screening in 3 epidemic stages accounted for 50.00% (9/18), 66.18% (45/68) and 86.67% (52/60) respectively. The epidemic had obvious case clustering in confined places,and the main exposure modes were living together (24.66%), working/studying together (11.64%), taking same transportation (9.59%) and dining together (9.59%). Conclusions: The COVID-19 epidemic in Gansu was caused by 2019-nCoV Delta variant from imported cases. The virus was mainly transmitted through travel, sharing transportation, dining together and home contact. The characteristics of COVID-19 epidemic in Gansu changed with time, the case's clinical symptoms were not obvious and the incubation period became shorter. The infections mainly occurred in group aged 18 years and above.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/epidemiology , China/epidemiology , Cities , Cluster Analysis , Female , Humans , Male
10.
Industrial Management and Data Systems ; 2022.
Article in English | Scopus | ID: covidwho-1878902

ABSTRACT

Purpose: The purpose of this paper is to explore the factors affecting the intention of social networking sites (SNS) users to comply with government policy during the COVID-19 pandemic. Design/methodology/approach: Based on the theory of appraisal and coping, the research model is tested using survey data collected from 326 SNS users. Structural equation modeling is used to test the research model. Findings: The results show that social support has a positive effect on outbreak self-efficacy but has no significant effect on perceived avoidability. Government information transparency positively affects outbreak self-efficacy and perceived avoidability. Outbreak self-efficacy and perceived avoidability have a strong positive impact on policy compliance intention through problem-focused coping. Practical implications: The results suggest that both government and policymakers could deliver reliable pandemic information to the citizens via social media. Originality/value: This study brings novel insights into citizen coping behavior, showing that policy compliance intention is driven by the ability to cope with problems. Moreover, this study enhances the theoretical understanding of the role of social support, outbreak self-efficacy and problem-focused coping. © 2022, Emerald Publishing Limited.

11.
Journal of the American College of Cardiology ; 79(9):1842-1842, 2022.
Article in English | Web of Science | ID: covidwho-1848894
12.
Chinese Journal of Biochemistry and Molecular Biology ; 37(1):1-10, 2021.
Article in Chinese | Scopus | ID: covidwho-1791680

ABSTRACT

COVID-19 is a severe acute respiratory syndrome caused by a novel coronavirus, SARS-CoV- 2.COVID-19 is now a pandemic, and is not yet fully under control.As the surface spike protein (S) mediates the recognition between the virus and cell membrane and the process of cell entry, it plays an important role in the course of disease transmission.The study on the S protein not only elucidates the structure and function of virus-related proteins and explains their cellular entry mechanism, but also provides valuable information for the prevention, diagnosis and treatment of COVII)-19.Concentrated on the S protein of SARS-CoV-2, this review covers four aspects: (1 ) The structure of the S protein and its binding with angiotensin converting enzyme II (ACE2) , the specific receptor of SARS-CoV-2, is introduced in detail.Compared with SARS-CoV, the receptor binding domain (RBD) of the SARS-CoV- 2 S protein has a higher affinity with ACE2, while the affinity of the entire S protein is on the contrary.(2) Currently, the cell entry mechanism of SARS-CoV-2 meditated by the S protein is proposed to include endosomal and non-endosomal pathways.With the recognition and binding between the S protein and ACE2 or after cell entry, transmembrane protease serine 2(TMPRSS2) , lysosomal cathepsin or the furin enzyme can cleave S protein at S1/S2 cleavage site, facilitating the fusion between the virus and target membrane.(3) For the progress in SARS-CoV-2 S protein antibodies, a collection of significant antibodies are introduced and compared in the fields of the target, source and type.(4) Mechanisms of therapeutic treatments for SARS-CoV-2 varied.Though the antibody and medicine treatments related to the SARS-CoV-2 S protein are of high specificity and great efficacy, the mechanism, safety, applicability and stability of some agents are still unclear and need further assessment.Therefore, to curb the pandemic, researchers in all fields need more cooperation in the development of SARS-CoV-2 antibodies and medicines to face the great challenge. © Palaeogeography (Chinese Edition).All right reserved.

13.
2nd IEEE International Conference on Power, Electronics and Computer Applications, ICPECA 2022 ; : 357-359, 2022.
Article in English | Scopus | ID: covidwho-1788730

ABSTRACT

As COVID-19 spreads across the globe, more cases are being confirmed around the world, making it imperative that we take a better approach to fighting the outbreak. To stop the spread of the disease and better screen for cases, we need a more sensitive and efficient test that can classify images of lung abnormalities in patients. In this paper, residual network is used to classify the collected chest radiographs. Feature extraction and classification were carried out on the original chest X-ray images, which were divided into the following three categories: normal lung, bacterial pneumonia and virus pneumonia. This can quickly rule out normal and routine infections, screen out large numbers of cases, and reduce the burden on health care workers who need to further examine cases. At the same time, our results are also very good, with an accuracy of 94%, which has practical classification significance. © 2022 IEEE.

14.
PubMed; 2020.
Preprint in English | PubMed | ID: ppcovidwho-333035

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a rapidly emerging virus causing the ongoing Covid-19 pandemic with no known effective prophylaxis. We investigated whether hydroxychloroquine could prevent SARS CoV-2 in healthcare workers at high-risk of exposure. METHODS: We conducted a randomized, double-blind, placebo-controlled clinical trial of healthcare workers with ongoing exposure to persons with Covid-19, including those working in emergency departments, intensive care units, Covid-19 hospital wards, and first responders. Participants across the United States and in the Canadian province of Manitoba were randomized to hydroxychloroquine 400mg once weekly or twice weekly for 12 weeks. The primary endpoint was confirmed or probable Covid-19-compatible illness. We measured hydroxychloroquine whole blood concentrations. RESULTS: We enrolled 1483 healthcare workers, of which 79% reported performing aerosol-generating procedures. The incidence of Covid-19 (laboratory-confirmed or symptomatic compatible illness) was 0.27 events per person-year with once-weekly and 0.28 events per person-year with twice-weekly hydroxychloroquine compared with 0.38 events per person-year with placebo. For once weekly hydroxychloroquine prophylaxis, the hazard ratio was 0.72 (95%CI 0.44 to 1.16;P=0.18) and for twice weekly was 0.74 (95%CI 0.46 to 1.19;P=0.22) as compared with placebo. Median hydroxychloroquine concentrations in whole blood were 98 ng/mL (IQR, 82-120) with once-weekly and 200 ng/mL (IQR, 159-258) with twice-weekly dosing. Hydroxychloroquine concentrations did not differ between participants who developed Covid-19 (154 ng/mL) versus participants without Covid-19 (133 ng/mL;P=0.08). CONCLUSIONS: Pre-exposure prophylaxis with hydroxychloroquine once or twice weekly did not significantly reduce laboratory-confirmed Covid-19 or Covid-19-compatible illness among healthcare workers.

15.
ACS Applied Polymer Materials ; 2021.
Article in English | Scopus | ID: covidwho-1768763

ABSTRACT

The demand for air filtration products has increased significantly with the aggravation of air pollution and the pandemic of coronavirus disease (COVID-19). It is urgently needed to develop an air filtration membrane that exhibits lasting filtration performance and antibacterial activity. Herein, we report a large-scale blow spinning technique to produce polyvinylidene fluoride (PVDF) nanofiber membranes for highly efficient air mechanical filtration and its antibacterial modification by adding the silver nanoparticles (AgNPs). The PVDF nanofiber membrane with an area density of only 1.0 g/m2 exhibits the highest filtration efficiency of 98.63% for the particle with a size of 0.3 μm. After eliminating static electricity, there is almost no reduction in the filtration efficiency of particulate matter with a size larger than 1 μm and only 4.69% decrease in the particulate matter with a size of 0.5 μm. Hence, the PVDF nanofiber membrane with nanostructures for air filtration works mainly by the means of mechanical filtration. To inhibit the survival or growth of the intercepted bacteria on the membrane, the PVDF/AgNPs nanofiber membrane was fabricated by adding AgNPs to PVDF nanofibers, which exhibits the strongest antibacterial activity of more than 99% and an excellent filtration efficiency similar to that without adding AgNPs. The nanofiber membrane with antibacterial activity is expected to extend the service or storage time or be reused without loss of filtration performance. Additionally, large-scale production of nanofiber filtration membranes has been realized using a multi-needle blow spinning machine. © 2022 American Chemical Society.

16.
Progress in Biochemistry and Biophysics ; 49(2):349-358, 2022.
Article in Chinese | Web of Science | ID: covidwho-1754036

ABSTRACT

Exosome is one of the extracellular vesicles, which plays an important role in intercellular communication and material transportation. Its content includes proteins, lipids, RNAs and other substances from host cells, and has an important influence on the physiological state of recipient cells. Flaviviridae including hepatitis C virus and Coronaviridae including SARS-CoV-2 are pathogens causing a variety of human infectious diseases. Understanding the interaction between virus and host is of great significance for screening therapeutic cellular targets and developing exosome-based vaccines. Accumulating studies have shown that exosomal protein and RNA play inhibitory roles for viruses. Moreover, Flaviviridae and Coronaviridae could hijack exosomemediated cellular communication to harm the hosts and promote virus spread. In current review, we summarized the recent progress on the interaction between Flaviviridae/Coronaviridae and exosome, shedding the mechanistic insights into Flaviviridae/Coronaviridae induced exosome.

17.
20th IEEE International Symposium on Mixed and Augmented Reality (ISMAR) ; : 450-459, 2021.
Article in English | Web of Science | ID: covidwho-1735816

ABSTRACT

Although the COVID-19 pandemic has made the need for remote data collection more apparent than ever, progress has been slow in the virtual reality (VR) research community, and little is known about the quality of the data acquired from crowdsourced participants who own a head-mounted display (HMD), which we call crowdXR. To investigate this problem, we report on a VR spatial cognition experiment that was conducted both in-lab and out-of-lab. The in-lab study was administered as a traditional experiment with undergraduate students and dedicated VR equipment. The out-of-lab study was carried out remotely by recruiting HMD owners from VR-related research mailing lists, VR subreddits in Reddit, and crowdsourcing platforms. Demographic comparisons show that our out-of-lab sample was older, included more males, and had a higher sense of direction than our in-lab sample. The results of the involved spatial memory tasks indicate that the reliability of the data from out-of-lab participants was as good as or better than their in-lab counterparts. Additionally, the data for testing our research hypotheses were comparable between in- and out-of-lab studies. We conclude that crowdsourcing is a feasible and effective alternative to the use of university participant pools for collecting survey and performance data for VR research, despite potential design issues that may affect the generalizability of study results. We discuss the implications and future directions of running VR studies outside the laboratory and provide a set of practical recommendations.

18.
Global Strategy Journal ; 2022.
Article in English | Scopus | ID: covidwho-1712076

ABSTRACT

Research Summary: The spread of protectionist policies and the COVID-19 pandemic force policymakers and managers to fundamentally rethink the relationship between location and strategy. We examine this location-strategy interplay through a structure-agency perspective by investigating how the economic landscape shapes and, simultaneously, is shaped by firm strategies. Increasing spatial disparity and diversity of innovation and wealth in clusters and city-regions create both tremendous challenges and opportunities for multinational enterprises to strategically leverage knowledge over space. Locational choices and actions of multinationals, in turn, affect regional economic development paths and geographies of innovation. We argue for deep dialogue and collaboration between economic geography, international business and strategy to untie the knots in the intricate interplay between location and strategy and solve the grand challenges in our turbulent age. Managerial Summary: The wide spread of protectionism and the COVID-19 pandemic have disrupted global value chains unprecedently, forcing policymakers and firm managers to rethink the relationship between business strategies and locations. We suggest that this relationship can be understood in a bilateral way. The concentration of innovation and economic activities in city-regions and clusters creates big challenges but also tremendous opportunities for multinational enterprises. Multinationals need to direct knowledge across space but also have to deal with local resistance and opposition. The choices and actions of these firms are shaped by and, simultaneously, influence spatial patterns of economic activities. We argue for deep collaboration between economic geographers and international business scholars to solve the grand challenges for business, community and society in our turbulent time. © 2022 Strategic Management Society.

19.
Circulation ; 144:2, 2021.
Article in English | Web of Science | ID: covidwho-1711026
20.
Embase;
Preprint in English | EMBASE | ID: ppcovidwho-326884

ABSTRACT

Boceprevir is an HCV NSP3 inhibitor that has been explored as a repurposed drug for COVID-19. It inhibits the SARS-CoV-2 main protease (MPro) and contains an α-ketoamide warhead, a P1 β-cyclobutylalanyl moiety, a P2 dimethylcyclopropylproline, a P3 tert-butylglycine, and a P4 N-terminal tert-butylcarbamide. By introducing modifications at all four positions, we synthesized 20 boceprevir-based MProinhibitors including PF-07321332 and characterized their MProinhibition potency in test tubes (in vitro) and human host cells (in cellulo). Crystal structures of MProbound with 10 inhibitors and antiviral potency of 4 inhibitors were characterized as well. Replacing the P1 site with a β-(S-2-oxopyrrolidin-3-yl)-alanyl (opal) residue and the warhead with an aldehyde leads to high in vitro potency. The original moieties at P2, P3 and the P4 N-terminal cap positions in boceprevir are better than other tested chemical moieties for high in vitro potency. In crystal structures, all inhibitors form a covalent adduct with the MProactive site cysteine. The P1 opal residue, P2 dimethylcyclopropylproline and P4 N-terminal tert-butylcarbamide make strong hydrophobic interactions with MPro, explaining high in vitro potency of inhibitors that contain these moieties. A unique observation was made with an inhibitor that contains an P4 N-terminal isovaleramide. In its MProcomplex structure, the P4 N-terminal isovaleramide is tucked deep in a small pocket of MProthat originally recognizes a P4 alanine side chain in a substrate. Although all inhibitors show high in vitro potency, they have drastically different in cellulo potency in inhibiting ectopically expressed MProin human 293T cells. All inhibitors including PF-07321332 with a P4 N-terminal carbamide or amide have low in cellulo potency. This trend is reversed when the P4 N-terminal cap is changed to a carbamate. The installation of a P3 O-tert-butyl-threonine iMProves in cellulo potency. Three molecules that contain a P4 N-terminal carbamate were advanced to antiviral tests on three SARSCoV-2 variants. They all have high potency with EC50 values around 1 μM. A control compound with a nitrile warhead and a P4 N-terminal amide has undetectable antiviral potency. Based on all observations, we conclude that a P4 N-terminal carbamate in a boceprevir derivative is key for high antiviral potency against SARS-CoV-2.

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