Consistent Effects of Early Remdesivir on Symptoms and Disease Progression Across At-Risk Outpatient Subgroups: Treatment Effect Heterogeneity in PINETREE Study.

INTRODUCTION: In the PINETREE study, early remdesivir treatment reduced risk of coronavirus disease 2019 (COVID-19)-related hospitalizations or all-cause death versus placebo by 87% by day 28 in high-risk, non-hospitalized patients. Here we report results of assessment of heterogeneity of treatment effect (HTE) of early outpatient remdesivir, focusing on time from symptom onset and number of baseline risk factors (RFs). METHODS: PINETREE was a double-blind, placebo-controlled trial of non-hospitalized patients with COVID-19 who were randomized within 7 days of symptom onset and had ≥ 1 RF for disease progression (age ≥ 60 years, obesity [body mass index ≥ 30], or certain coexisting medical conditions). Patients received remdesivir intravenously (200 mg on day 1 and 100 mg on days 2 and 3) or placebo. RESULTS: In this subgroup analysis, HTE of remdesivir by time from symptom onset at treatment initiation and number of baseline RFs was not detected. Treatment with remdesivir reduced COVID-19-related hospitalizations independent of stratification by time from symptom onset to randomization. Of patients enrolled ≤ 5 days from symptom onset, 1/201 (0.5%) receiving remdesivir and 9/194 (4.6%) receiving placebo were hospitalized (hazard ratio [HR] 0.10; 95% confidence interval [CI] 0.01-0.82). Of those enrolled at > 5 days from symptom onset, 1/78 (1.3%) receiving remdesivir and 6/89 (6.7%) receiving placebo were hospitalized (HR 0.19; 95% CI 0.02-1.61). Remdesivir was also effective in reducing COVID-19-related hospitalizations when stratified by number of baseline RFs for severe disease. Of patients with ≤ 2 RFs, 0/159 (0.0%) receiving remdesivir and 4/164 (2.4%) receiving placebo were hospitalized; of those with ≥ 3 RFs, 2/120 (1.7%) receiving remdesivir and 11/119 (9.2%) receiving placebo were hospitalized (HR 0.16; 95% CI 0.04-0.73). CONCLUSIONS: In the outpatient setting, benefit of remdesivir initiated within 7 days of symptoms appeared to be consistent across patients with RFs. Therefore, it may be reasonable to broadly treat patients with remdesivir regardless of comorbidities. TRIAL REGISTRATION: ClinicalTrials.gov number NCT04501952.

Modular Metal-Quinone Networks with Tunable Architecture and Functionality.

Nanostructured materials with tunable structures and functionality are of interest in diverse areas. Herein, metal ions are coordinated with quinones through metal-acetylacetone coordination bonds to generate a class of structurally tunable, universally adhesive, hydrophilic, and pH-degradable materials. A library of metal-quinone networks (MQNs) is produced from five model quinone ligands paired with nine metal ions, leading to the assembly of particles, tubes, capsules, and films. Importantly, MQNs show bidirectional pH-responsive disassembly in acidic and alkaline solutions, where the quinone ligands mediate the disassembly kinetics, enabling temporal and spatial control over the release of multiple components using multilayered MQNs. Leveraging this tunable release and the inherent medicinal properties of quinones, MQN prodrugs with a high drug loading (>89 wt %) are engineered using doxorubicin for anti-cancer therapy and shikonin for the inhibition of the main protease in the SARS-CoV-2 virus.

Vast ecosystem disturbance in a warming climate may jeopardize our climate goal of reducing CO2: a case study for megafires in the Australian 'black summer'.

A warming climate is one of the most important driving forces of intensified wildfires globally. The unprecedented wildfires broke out in the Australian 'Black Summer' (November 2019-February 2020), which released massive heat, gases, and particles into the atmosphere. The total carbon dioxide (CO2) emissions from wildfires were estimated at ∼963 million tons by using a top-down approach based on direct satellite measurements of CO2 and fire radiative power. The fire emissions have led to an approximately 50-80 folds increase in total CO2 emission in Australia compared with the similar seasons of 2014-2019. The excess CO2 from wildfires has offset almost half of the global anthropogenic CO2 emission reductions due to the Corona Virus Disease 2019 in 2020. When the wildfires were intense in December 2019, they caused a 1.48 watts per square meter additional positive radiative forcing above the monthly average in Australia and the vicinity. Our findings demonstrate that vast ecosystem disturbance in a warming climate can strongly influence the global carbon cycle and hamper our climate goal of reducing CO2.

Mental health problems of preschool children during the COVID-19 home quarantine: A cross-sectional study in Shanghai, China.

Objective: As the coronavirus disease 2019 (COVID-19) pandemic spread across Shanghai, China, in late February 2022 and protective measures to mitigate its impact were enacted, this study aimed to estimate how home quarantine affected the mental health of preschool children in Shanghai, China and explore the association between lifestyle factors and mental health during this special period. Methods: A cross-sectional online survey of 2,110 preschool students from Shanghai, China, was conducted during May 20-25,2022. Preschooler' mental health (Strengths and Difficulties Questionnaire, SDQ) and daily activities were reported by parents. Results: The sample involved 2,110 children with a mean age of 4.65 years [standard deviation (SD): 0.91, range: 3-6 years]. Boys and children whose mother's education level were college and high school had higher rate of mental health problems. Boys had significantly higher rates of peer problems and prosocial behaviors than girls. The 3-year-old group had significantly higher rates of prosocial behaviors than other groups. As compared to the Shanghai norm and the SDQ results of preschool children in Shanghai in 2019 (SH2019), there were a significant decrease in emotional symptoms score, as well as a significant increase in conduct problems score. Additionally, peer problems score significantly increased compared to SH2019. Decreased time spent on daily sleep was associated with the increased risk for preschoolers' mental health problems. Conclusion: There was an increase in the frequency of emotional and behavioral problems, especially regarding conduct problems and peer problems, in preschool children during the COVID-19 home quarantine in Shanghai, China. Boys, younger preschool children and children whose mother's education level were college and high school may be especially vulnerable to emotional and behavioral problems. It was also found that decreased time spent on sleep may aggravate preschool children's mental health problems. It may be beneficial to differentiate and focus on conducting psychoeducation and implementing psycho-behavioral interventions to solve these issues.

Immunosenescence is a therapeutic target for frailty in older adults: a narrative review.

Background and Objective: Aging refers to a progressive decrease in functional performance, leading to increased mortality risk. At present, life expectancy is increasing worldwide and is expected to exceed 80 years by 2040. However, this increase in life expectancy also indicates a rise in the incidence and prevalence of diseases, such as cardiovascular, neurological, musculoskeletal, and oncological diseases, which are associated with aging. The exact underlying mechanisms of aging remain unknown, and whether it is a programmed process or the consequence of an accumulation of stress events remains unclear. Thus, more scientific research is needed to improve the management of complex and frail patients. Methods: Several databases were searched with the following key words: immunosenescence, inflamm-aging, frailty, sarcopenia and skeletal muscle, etc. Key Content and Findings: Skeletal muscle is the core phenotype of frailty and sarcopenia. Immune aging and skeletal muscle decline interplay with each other and form a vicious circle. Maintaining muscle health is beneficial for immune function and delays the onset of frailty. Particularly, in the context of the ongoing corona virus disease (COVID)-19 pandemic, studies have shown that the elderly are more prone to the consequences of the SARS-CoV-2 virus. It has been reported that the rates of hospitalization in the 65-74, 75-84, and ≥85 years old group were 5×, 8×, and 10× greater than the 18-29 years old group, with corresponding COVID-19-related deaths being 60×, 140×, and 330× that of the younger reference group, respectively. Considering the above, this review aims to discuss the relationship between immunosenescence, skeletal muscle, and frailty, and to explore immunosenescence as a potential therapeutic target to prevent frailty and extend healthspan, with some emphasis on the effects of the COVID-19 pandemic on the elderly. Conclusions: Immunosenescence is a promising potential therapeutic target for frailty and is worthy of further investigation.

An integrated rough-fuzzy WINGS-ISM method with an application in ASSCM.

Environmental deterioration, the COVID-19 pandemic and the Russian-Ukrainian conflict had brought chronic and dramatic impacts on agricultural supply chain around the world, resulting in high inflation rates and unavoidable costs. In order to reduce the adverse impacts and achieve sustainability in agricultural supply chain, it's necessary to scientifically explore composite indicators interlinked with agricultural sustainable supply chain management (ASSCM). The current study developed an integrated rough-fuzzy WINGS-ISM method to reveal the hierarchal and causal structure of indicators. It is found that environmental legislation, regulation, licensing, and government subsidies are the main drivers of ASSCM. Specifically, the government can guide the sustainable development of ASSCM by regulating the business environment. The financial support needs to be enlarged to optimize the structure in science and technology of ASSCM. Moreover, corporates and organizations are highly motivated by the increasing awareness of social responsibility and sustainability consciousness to improve the economic performance and achieve the ASSCM goals. A comparative analysis is proposed to illustrate the practicality and reliability of the results obtained from the proposed method, which can be utilized as a reference in ASSCM.

The Relationship Between Enterprise Financial Risk and R&D Investment Under the Influence of the COVID-19

The COVID-19 pandemic has dealt a considerable blow to the development of Chinese enterprises. Therefore, exploring how to reduce the enterprise financial risk under the impact of the COVID-19 has become a current research hotspot. We select the data of 3,098 A-share companies in the quarters of 2019 and 2020, use the Z-score model to reasonably evaluate enterprise financial risk, and analyze the impact of Research and Development (R&D) investment on enterprise financial risk under the COVID-19.The results show that: ① The COVID-19 pandemic has increased the number of high-risk enterprises. ② R&D investment can effectively reduce the enterprise financial risk, and enterprises that attach importance to scientific research are relatively less affected by the COVID-19. ③ Compared with non-state-owned enterprises, R&D investment under state-owned enterprises can better help enterprises reduce financial risk. ④ When the enterprise financial risk is lower, the role of R&D investment in reducing financial risk is more significant. With the increase of financial risk, the effect of R&D investment on it is weakened. The research results are beneficial to help enterprises to correctly assess their financial risks during the COVID-19, so that enterprises can reasonably invest in research and development, and ultimately ensure the sustainable development of enterprises under the COVID-19.

The Impact of Digital Economy on the Economic Growth and the Development Strategies in the post-COVID-19 Era: Evidence From Countries Along the "Belt and Road".

The digital economy is considered as an effective measure to mitigate the negative economic impact of the Corona Virus Disease 2019 (COVID-19) epidemic. However, few studies evaluated the role of digital economy on the economic growth of countries along the "Belt and Road" and the impact of COVID-19 on their digital industries. This study constructed a comprehensive evaluation index system and applied a panel data regression model to empirically analyze the impact of digital economy on the economic growth of countries along the "Belt and Road" before COVID-19. Then, a Global Trade Analysis Project (GTAP) model was used to examine the impact of COVID-19 on their digital industries and trade pattern. Our results show that although there is an obvious regional imbalance in the digital economy development in countries along the "Belt and Road", the digital economy has a significantly positive effect on their economic growth. The main impact mechanism is through promoting industrial structure upgrading, the total employment and restructuring of employment. Furthermore, COVID-19 has generally boosted the demand for the digital industries, and the impact from the demand side is much larger than that from the supply side. Specifically, the digital industries in Armenia, Israel, Latvia and Estonia have shown great growth potential during the epidemic. On the contrast, COVID-19 has brought adverse impacts to the digital industries in Ukraine, Egypt, Turkey, and the Philippines. The development strategies are proposed to bridge the "digital divide" of countries along the "Belt and Road," and to strengthen the driving effect of the digital economy on industrial upgrading, employment and trade in the post-COVID-19 era.

Investment, payout, and cash management under risk and ambiguity

This study extends the theoretical model of dynamic investment, dividend payout, costly external financing, and liquidation for financially constrained firms by incorporating ambiguity. We demonstrate that ambiguity aversion induces a trade-off between the “bird-in-hand” effect and an amplified precautionary motive in determining firms’ cash management, which consequently affects firms’ investment, dividend payout, costly external financing, and liquidation decisions. Unlike the models considering risk only, we identify a non-monotonic relationship between the endogenous payout boundary and ambiguity aversion. Our model generates several new implications, including providing an explanation for the high cash holdings and speed-up of asset sales during the recent COVID-19 crisis.

Investment, payout, and cash management under risk and ambiguity

We extend a theoretical model of dynamic investment, dividend payout, costly external financing, and liquidation for financially constrained firms by incorporating ambiguity. Ambiguity aversion induces a trade-off between a “bird-in-the-hand” effect and an amplified precautionary motive in determining firms’ cash management, which consequently affects firms’ investment, dividend payout, costly external financing, and liquidation decisions. Unlike models considering risk only, we demonstrate a non-monotonic relationship between the endogenous payout boundary and ambiguity aversion. Moreover, we demonstrate that the relation between asset sales and ambiguity exhibits differently, depending on whether costly refinancing is available. Our model generates several new implications, including providing an explanation for the high cash holdings and speed-up of asset sales observed in the recent COVID-19 crisis.

Antibacterial surfaces: Strategies and applications

Antibacterial surfaces are surfaces that can resist bacteria, relying on the nature of the material itself. It is significant for safe food and water, human health, and industrial equipment. Biofilm is the main form of bacterial contamination on the material surface. Preventing the formation of biofilm is an efficient way to develop antibacterial surfaces. The strategy for constructing the antibacterial surface is divided into bacteria repelling and bacteria killing based on the formation of the biofilm. Material surface wettability, adhesion, and steric hindrance determine bacteria repelling performance. Bacteria should be killed by surface chemistry or physical structures when they are attached to a material surface irreversibly. Killing approaches are usually in the light of the cell membrane of bacteria. This review summarizes the fabrication methods and applications of antibacterial surfaces from the view of the treatment of the material surfaces. We also present several crucial points for developing long-term stability, no drug resistance, broad-spectrum, and even programable antibacterial surfaces.

Self-organization's responses to the COVID-19 pandemic in China

Self-organization was a key informal channel used to fight COVID-19 in Wuhan when the local government and other formal organizations failed to respond in the very early stages of the pandemic. The present study aims to investigate the effectiveness of self-organization during an emergency from both a demand-driven and a social mission identity perspective. Using 14 cases, this study examines the lifecycles of self-organization in alignment with the consistent changes in social demands. Volunteers' social mission identity and a flexible organizational structure have been identified as two major attributes of the outstanding performance of self-organization. Moreover, self-organization demonstrates a striking feature of noncontiguous service provision with the assistance of social media. This study extends the literature on the changing roles of governments and civil society to the emergency context.

Social learning along international migrant networks

We document the transmission of social distancing practices from the United States to Mexico along migrant networks during the early 2020 Covid-19 pandemic. Using data on pre-existing migrant connections between Mexican and U.S. locations and mobile-phone tracking data revealing social distancing behavior, we find larger declines in mobility in Mexican regions whose emigrants live in U.S. locations with stronger social distancing practices. We document the absence of confounding pre-trends and use a variety of controls to rule out the potential influence of disease transmission, migrant sorting between similar locations, and remittances. Given this evidence, we conclude that our findings represent the effect of information transmission between Mexican migrants living in the U.S. and residents of their home locations in Mexico. Our results demonstrate the importance of personal connections when policymakers seek to change fundamental social behaviors.

Recombinase polymerase amplification integrated with microfluidics for nucleic acid testing at point of care.

Nucleic acid testing (NAT) implemented on a portable, miniaturized, and integrated device with rapid and sensitive results readout is highly demanded for pathogen detection or genetic screening at resource-limited settings, especially after the outbreak of coronavirus disease 2019 (COVID-19). The integration of recombinase polymerase amplification (RPA) with emerging microfluidics, classified by paper-based microfluidics and chip-based microfluidics, shows great potential to perform laboratory independent NAT assays at point of care with minimal labor, time and energy consumption. This review summarizes the state-of-the-art of RPA integrated with paper-based microfluidics and chip-based microfluidics, and discusses their pros and cons. Finally, existing challenges and possible ways for optimization of microfluidics-based RPA are proposed.

Single-cell immunology of SARS-CoV-2 infection.

Gaining a better understanding of the immune cell subsets and molecular factors associated with protective or pathological immunity against severe acute respiratory syndrome coronavirus (SARS-CoV)-2 could aid the development of vaccines and therapeutics for coronavirus disease 2019 (COVID-19). Single-cell technologies, such as flow cytometry, mass cytometry, single-cell transcriptomics and single-cell multi-omic profiling, offer considerable promise in dissecting the heterogeneity of immune responses among individual cells and uncovering the molecular mechanisms of COVID-19 pathogenesis. Single-cell immune-profiling studies reported to date have identified innate and adaptive immune cell subsets that correlate with COVID-19 disease severity, as well as immunological factors and pathways of potential relevance to the development of vaccines and treatments for COVID-19. For facilitation of integrative studies and meta-analyses into the immunology of SARS-CoV-2 infection, we provide standardized, download-ready versions of 21 published single-cell sequencing datasets (over 3.2 million cells in total) as well as an interactive visualization portal for data exploration.

Site-Specific Glycosylation Patterns of the SARS-CoV-2 Spike Protein Derived From Recombinant Protein and Viral WA1 and D614G Strains.

The SARS-CoV-2 spike protein is heavily glycosylated, having 22 predicted N-glycosylation sites per monomer. It is also O-glycosylated, although the number of O-glycosites is less defined. Recent studies show that spike protein glycans play critical roles in viral entry and infection. The spike monomer has two subdomains, S1 and S2, and a receptor-binding domain (RBD) within the S1 domain. In this study, we have characterized the site-specific glycosylation patterns of the HEK293 recombinant spike RBD and S1 domains as well as the intact spike derived from the whole virus produced in Vero cells. The Vero cell-derived spike from the WA1 strain and a D614G variant was analyzed. All spike proteins, S1, and RBDs were analyzed using hydrophilic interaction chromatography (HILIC) and LC-MS/MS on an Orbitrap Eclipse Tribrid mass spectrometer. N-glycans identified in HEK293-derived S1 were structurally diverse. Those found in the HEK293-derived RBD were highly similar to those in HEK293 S1 where N-glycosites were shared. Comparison of the whole cell-derived WA1 and D614G spike proteins revealed that N-glycosites local to the mutation site appeared to be more readily detected, hinting that these sites are more exposed to glycosylation machinery. Moreover, recombinant HEK293-derived S1 was occupied almost completely with complex glycan, while both WA1 and D614G derived from the Vero E6 cell whole virus were predominantly high-mannose glycans. This stands in stark contrast to glycosylation patterns seen in both CHO- and HEK cell-derived recombinant S1, S2, and the whole spike previously reported. Concerning O-glycosylation, our analyses revealed that HEK293 recombinant proteins possessed a range of O-glycosites with compositions consistent with Core type 1 and 2 glycans. The O-glycosites shared between the S1 and RBD constructs, sites T323 and T523, were occupied by a similar range of Core 1 and 2 type O-glycans. Overall, this study reveals that the sample nature and cell substrate used for production of these proteins can have a dramatic impact on the glycosylation profile. SARS-CoV-2 spike glycans are associated with host ACE2 receptor interaction efficiency. Therefore, understanding such differences will serve to better understand these host-pathogen interactions and inform the choice of cell substrates to suite downstream investigations.

Social Learning along International Migrant Networks

We document the transmission of social distancing practices from the United States to Mexico along migrant networks during the early 2020 Covid-19 pandemic. Using data on pre-existing migrant connections between Mexican and U.S. locations and mobile-phone tracking data revealing social distancing behavior, we find larger declines in mobility in Mexican regions whose emigrants live in U.S. locations with stronger social distancing practices. We rule out confounding pre-trends and use a variety of controls and an instrumental variables strategy based on U.S. stay-at-home orders to rule out the potential influence of disease transmission and migrant sorting between similar locations. Given this evidence, we conclude that our findings represent the effect of information transmission between Mexican migrants living in the U.S. and residents of their home locations in Mexico. Our results demonstrate the importance of personal connections when policymakers seek to change fundamental social behaviors.

A Linkage-specific Sialic Acid Labeling Strategy Reveals Different Site-specific Glycosylation Patterns in SARS-CoV-2 Spike Protein Produced in CHO and HEK Cell Substrates.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus utilizes the extensively glycosylated spike (S) protein protruding from the viral envelope to bind to angiotensin-converting enzyme-related carboxypeptidase (ACE2) as its primary receptor to mediate host-cell entry. Currently, the main recombinant S protein production hosts are Chinese hamster ovary (CHO) and human embryonic kidney (HEK) cells. In this study, a recombinant S protein truncated at the transmembrane domain and engineered to express a C-terminal trimerization motif was transiently produced in CHO and HEK cell suspensions. To further evaluate the sialic acid linkages presenting on S protein, a two-step amidation process, employing dimethylamine and ammonium hydroxide reactions in a solid support system, was developed to differentially modify the sialic acid linkages on the glycans and glycopeptides from the S protein. The process also adds a charge to Asp and Glu which aids in ionization. We used MALDI-TOF and LC-MS/MS with electron-transfer/higher-energy collision dissociation (EThcD) fragmentation to determine global and site-specific N-linked glycosylation patterns. We identified 21 and 19 out of the 22 predicted N-glycosites of the SARS-CoV-2 S proteins produced in CHO and HEK, respectively. It was found that the N-glycosite at 1,158 position (N1158) and at 122, 282 and 1,158 positions (N122, N282 and N1158) were absent on S from CHO and HEK cells, respectively. The structural mapping of glycans of recombinant human S proteins reveals that CHO-Spike exhibits more complex and higher sialylation (α2,3-linked) content while HEK-Spike exhibits more high-mannose and a small amount of α2,3- and α2,6-linked sialic acids. The N74 site represents the most abundant glycosite on both spike proteins. The relatively higher amount of high-mannose abundant sites (N17, N234, N343, N616, N709, N717, N801, and N1134) on HEK-Spike suggests that glycan-shielding may differ among the two constructs. HEK-Spike can also provide different host immune system interaction profiles based on known immune system active lectins. Collectively, these data underscore the importance of characterizing the site-specific glycosylation of recombinant human spike proteins from HEK and CHO cells in order to better understand the impact of the production host on this complex and important protein used in research, diagnostics and vaccines.

The safest time to fly: pandemic response in the era of Fox News.

We document a causal effect of the conservative Fox News Channel in the USA on physical distancing during COVID-19 pandemic. We measure county-level mobility covering all US states and District of Columbia produced by GPS pings to 15-17 million smartphones and zip-code-level mobility using Facebook location data. Using the historical position of Fox News Channel in the cable lineup as the source of exogenous variation, we show that increased exposure to Fox News led to a smaller reduction in distance traveled and a smaller increase in the probability of staying home after the national emergency declaration in the USA. Our results show that slanted media can have a harmful effect on containment efforts during a pandemic by affecting people's behavior.

The Status of Occupational Protection During COVID-19 Pandemic: Knowledge, Attitudes, and Practice of Healthcare Workers in Endoscopy Units, China.

Background: SARS-CoV-2 spreads rapidly around the world, and some patients present gastrointestinal symptoms. The existence of the virus in the gastrointestinal tract makes digestive endoscopy a high-risk operation, which associated with an increased risk of infection rate in healthcare workers. This study aimed at exploring current knowledge, practice and attitudes of healthcare workers in endoscopy units in China regarding the status of occupational protection during COVID-19 pandemic. Methods: A cross-sectional study of a national online survey involving 717 healthcare workers in endoscopy units from 94 medical structures in 24 provinces and municipalities around China was conducted online via a questionnaire platform called Wenjuanxing (wjx.cn). The data were analyzed using correlation approaches, Kruskal-Wallis test for independent samples, and linear regression models. Results: Most Chinese healthcare workers in endoscopy units had a good knowledge of COVID-19 (median: 10; range: 7-12), showed a strikingly positive attitude (median: 65; range: 39-65), and carried out good practice (median: 47; range: 14-50) in strengthening the protection, disinfection and management of COVID-19. In terms of attitudes, female staff was more concerned about protection against COVID-19 than male staff (KW = 8.146, P = 0.004). Nurses performed better in both attitude (KW = 2.600, P = 0.009) and practice (KW = 6.358, P < 0.001) than endoscopic physicians when carrying out personal protection, patient care and environmental disinfection against SARS-CoV-2 infection. More positive attitudes in protection were related to better protective behavior in endoscopic daily medical work (r = 0.312; P < 0.001). Conclusion: The findings of this study suggest that Chinese endoscopy healthcare workers have an excellent mastery of knowledge about COVID-19, which is transformed into positive beliefs and attitudes, contributing to good practice during daily endoscopic procedures. Medical staff may benefit from further education. With the gradual normalization amid the ongoing COVID-19 pandemic, protection and management in endoscopy units may be changed accordingly.