Synergistic effect of elevated glucose levels with SARS-CoV-2 spike protein induced NOX-dependent ROS production in endothelial cells.

BACKGROUND: Diabetic patients infected with coronavirus disease 2019 (COVID-19) often have a higher probability of organ failure and mortality. The potential cellular mechanisms through which blood glucose exacerbates tissue damage due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is still unclear. METHODS AND RESULTS: We cultured endothelial cells within differing glucose mediums with an increasing concentration gradient of SARS-CoV-2 Spike protein (S protein). S protein can cause the reduction of ACE2 and TMPRSS2, and activation of NOX2 and NOX4. A high glucose medium was shown to aggravate the decrease of ACE2 and activation of NOX2 and NOX4 in cultured cells, but had no effect on TMPRSS2. S protein mediated activation of the ACE2-NOX axis induced oxidative stress and apoptosis within endothelial cells, leading to cellular dysfunction via the reduction of NO and tight junction proteins which may collectively be exacerbated by elevated glucose. In addition, the glucose variability model demonstrated activation of the ACE2-NOX axis in a similar manner observed in the high glucose model in vitro. CONCLUSIONS: Our present study provides evidence for a mechanism through which hyperglycemia aggravates endothelial cell injury resulting from S protein mediated activation of the ACE2-NOX axis. Our research thus highlights the importance of strict monitoring and control of blood glucose levels within the context of COVID-19 treatment to potentially improve clinical outcomes.

A new generation Mpro inhibitor with potent activity against SARS-CoV-2 Omicron variants.

Emerging SARS-CoV-2 variants, particularly the Omicron variant and its sublineages, continually threaten the global public health. Small molecule antivirals are an effective treatment strategy to fight against the virus. However, the first-generation antivirals either show limited clinical efficacy and/or have some defects in pharmacokinetic (PK) properties. Moreover, with increased use of these drugs across the globe, they face great pressure of drug resistance. We herein present the discovery and characterization of a new generation antiviral drug candidate (SY110), which is a potent and selective inhibitor of SARS-CoV-2 main protease (Mpro). This compound displayed potent in vitro antiviral activity against not only the predominant SARS-CoV-2 Omicron sublineage BA.5, but also other highly pathogenic human coronaviruses including SARS-CoV-1 and MERS-CoV. In the Omicron-infected K18-hACE2 mouse model, oral treatment with SY110 significantly lowered the viral burdens in lung and alleviated the virus-induced pathology. Importantly, SY110 possesses favorable PK properties with high oral drug exposure and oral bioavailability, and also an outstanding safety profile. Furthermore, SY110 exhibited sensitivity to several drug-resistance Mpro mutations. Collectively, this investigation provides a promising new drug candidate against Omicron and other variants of SARS-CoV-2.

Can Green Economy stocks hedge natural gas market risk? Evidence during Russia-Ukraine conflict and other crisis periods

One of the ultimate goals of the Green Economy is to move away from dependence on fossil energy, thereby achieving a sustainable development of a resource-saving and environment-friendly society. Thus, whether Green Economy stocks can hedge the risks of fossil energy markets, especially for natural gas market during recent crisis periods, is of great importance for both policy makers and portfolio managers. This paper identifies the time-varying connectedness and hedging effects of twelve NASDAQ OMX Green Economy sector stocks on NYMEX natural gas futures during three major turmoil events, i.e., European debt crisis, COVID-19 pandemic, and recent Russia-Ukraine conflict. The empirical results show that various Green Economy sector stocks can provide gratifying hedge effectiveness on the market risk of natural gas futures, and some of them can even perform similarly to gold and USD. Moreover, NASDAQ OMX Green Economy sector stocks offer better hedge effectiveness during recent Russia-Ukraine conflict than those of them in the periods of European debt crisis and COVID-19 pandemic. Finally, the Sharpe ratio results further show the important but time-varying roles of Green Economy sector stocks in hedging risks of natural gas market.

Flexible Scheduling Model of Bus Services between Venues of the Beijing Winter Olympic Games

Traditional buses travel on fixed routes and areas, which cannot satisfy the flexible demands of athletes in the context of COVID-19 and the closed-loop traffic management policy during the 2022 Beijing Winter Olympic Games (BWOG). This study predicts the travel demands based on the characteristics of athletes' daily travel demands and then presents a flexible bus service scheduling model for cross-region scheduling among Beijing, Yanqing, and Zhangjiakou to provide high-level service. The flexible bus service is point-to-point and avoids unnecessary contact, which reduces the risk of spreading COVID-19 and ensures athletes' safety. In this study, the flexible bus scheduling model is established to optimize scheduling schemes, whose object is to minimize the cost of the system based on some realistic constraints. These constraints consider not only the preferred time windows of athletes' demand but also the vehicle's capacity, depot, minimum load factor, total demands, etc. In addition, a genetic-simulated annealing hybrid algorithm (GSAHA) is designed to solve the model based on the characteristics of the genetic algorithm (GA) and simulated annealing. To assess the feasibility and efficiency of the model and algorithm, a case study is conducted in the Beijing-Yanqing area. Furthermore, the travel time of the flexible bus is compared to that of the traditional bus, according to the results of the case study. Moreover, the sensitivity of the model and algorithm are analyzed. The experimental results show that the proposed model and algorithm can dispatch buses with superior flexibility and high-level services during the BWOG. [ FROM AUTHOR]

Connectedness among El Niño-Southern Oscillation, carbon emission allowance, crude oil and renewable energy stock markets: Time- and frequency-domain evidence based on TVP-VAR model

Understanding the interactions among climate change, carbon emission allowance trading, crude oil and renewable energy stock markets, especially the role of climate change in this system is of great significance for policy makers, energy producers/consumers and relevant investors. The present paper aims to quantify the time-varying connectedness effects among the four factors by using the TVP-VAR based extensions of both time- and frequency-domain connectedness index measurements proposed by Antonakakis et al. (2020) and Ellington and Barunik (2021) [8,48]. The empirical results suggest that, firstly, the average total connectedness among climate change, carbon emission allowance trading, crude oil and renewable energy stock markets is not so strong for the heterogenous fundamentals underlying them. Nevertheless, the time-varying total connectedness fluctuates fiercely through May 2005 to September 2021, varying from about 8% to 30% and rocket to very high levels during the global subprime mortgage crisis and the COVID-19 pandemic. Furthermore, the total connectedness mainly centers on the short-term frequency, i.e., 1–3 months. Secondly, climate change is generally the leading information contributor among the four factors, although not particularly strong, and its leading role also performs mainly on the short-term frequency (1–3 months). Thirdly, renewable energy stock market and crude oil market show tight interactions between them and they are the two major bridges of information exchanges across various time frequencies (horizons) in this system. Finally, we confirm the evidence that the primary net connectedness contributor and receiver switch frequently across different time frequencies, implying that it is extremely essential for policy makers, energy producers/consumers and investors to make time-horizon-specific regulatory, production/purchasing or investment decisions when facing the uncertain effects of climate change on the interactions among carbon emission allowance, crude oil and renewable energy stock markets.

Evolutionary Pattern Comparisons of the SARS-CoV-2 Delta Variant in Countries/Regions with High and Low Vaccine Coverage.

It has been argued that vaccine-breakthrough infections of SARS-CoV-2 would likely accelerate the emergence of novel variants with immune evasion. This study explored the evolutionary patterns of the Delta variant in countries/regions with relatively high and low vaccine coverage based on large-scale sequences. Our results showed that (i) the sequences were grouped into two clusters (L and R); the R cluster was dominant, its proportion increased over time and was higher in the high-vaccine-coverage areas; (ii) genetic diversities in the countries/regions with low vaccine coverage were higher than those in the ones with high vaccine coverage; (iii) unique mutations and co-mutations were detected in different countries/regions; in particular, common co-mutations were exhibited in highly occurring frequencies in the areas with high vaccine coverage and presented in increasing frequencies over time in the areas with low vaccine coverage; (iv) five sites on the S protein were under strong positive selection in different countries/regions, with three in non-C to U sites (I95T, G142D and T950N), and the occurring frequencies of I95T in high vaccine coverage areas were higher, while G142D and T950N were potentially immune-pressure-selected sites; and (v) mutation at the N6-methyladenosine site 4 on ORF7a (C27527T, P45L) was detected and might be caused by immune pressure. Our study suggested that certain variation differences existed between countries/regions with high and low vaccine coverage, but they were not likely caused by host immune pressure. We inferred that no extra immune pressures on SARS-CoV-2 were generated with high vaccine coverage, and we suggest promoting and strengthening the uptake of the COVID-19 vaccine worldwide, especially in less developed areas.

The impacts of El Niño-southern oscillation on renewable energy stock markets: Evidence from quantile perspective

Little attention has been paid to the effects of climate oscillations on the performance of renewable energy stock markets, although many studies have examined the instability of these markets caused by various external shocks. This paper aims to investigate the heterogenous impacts of El Niño-Southern Oscillation (ENSO) on renewable energy stock markets under different market conditions using a quantile framework. Our results show that, firstly, ENSO has significant shocks on the EU renewable energy stock market in most market conditions, whereas it has no significant influence on the US market. Secondly, there is an obvious asymmetry in the responses of the EU renewable energy stock markets under bullish and bearish markets to ENSO, respectively. Thirdly, strong La Niña events appear to have larger impacts than those of strong El Niño on the EU renewable energy stock markets. Finally, the good performance of the EU renewable energy stock markets can be deteriorated by strong La Niña events during the COVID-19 crisis. These findings can not only help us to understand the heterogenous shocks of ENSO on different renewable energy markets, but also provide deeper insights on efficient managements of extreme climate risks to renewable energy stock markets.

The role of kidney injury biomarkers in COVID-19.

The coronavirus disease-2019 (COVID-19) outbreak has been declared a global pandemic. COVID-19-associated acute kidney injury (COVID-19 AKI) is related to a high mortality rate and serves as an independent risk factor for hospital death in patients with COVID-19. Early diagnosis would allow for earlier intervention and potentially improve patient outcomes. The goal of early identification of AKI has been the primary impetus for AKI biomarker research, and several kidney injury biomarkers have been demonstrated to be beneficial in predicting COVID-19 AKI as well as disease progression in COVID-19. Furthermore, such data provide valuable insights into the molecular mechanisms underlying this complex and unique disease and serve as a molecular phenotyping tool that could be utilized to direct clinical intervention. This review focuses on a number of kidney injury biomarkers, such as CysC, NAGAL, KIM-1, L-FABP, IL-18, suPAR, and [TIMP-2] • [IGFBP7], which have been widely studied in common clinical settings, such as sepsis, cardiac surgery, and contrast-induced AKI. We explore the role of kidney injury biomarkers in COVID-19 and discuss what remains to be learned.

Considerations for the Surgical Management of Thoracic Cancers During the COVID-19 Pandemic: Rational Strategies for Thoracic Surgeons.

Objective: The novel Coronavirus Disease 2019 (COVID-19) has resulted in a global health crisis since first case was identified in December 2019. As the pandemic continues to strain global public health systems, elective surgeries for thoracic cancer, such as early-stage lung cancer and esophageal cancer (EC), have been postponed due to a shortage of medical resources and the risk of nosocomial transmission. This review is aimed to discuss the influence of COVID-19 on thoracic surgical practice, prevention of nosocomial transmission during the pandemic, and propose modifications to the standard practices in the surgical management of different thoracic cancer. Methods: A literature search of PubMed, Medline, and Google Scholar was performed for articles focusing on COVID-19, early-stage lung cancer, and EC prior to 1 July 2021. The evidence from articles was combined with our data and experience. Results: We review the challenges in the management of different thoracic cancer from the perspectives of thoracic surgeons and propose rational strategies for the diagnosis and treatment of early-stage lung cancer and EC during the COVID-19 pandemic. Conclusions: During the COVID-19 pandemic, the optimization of hospital systems and medical resources is to fight against COVID-19. Indolent early lung cancers, such as pure ground-glass nodules/opacities (GGOs), can be postponed with a lower risk of progression, while selective surgeries of more biologically aggressive tumors should be prioritized. As for EC, we recommend immediate or prioritized surgeries for patients with stage Ib or more advanced stage and patients after neoadjuvant therapy. Routine COVID-19 screening should be performed preoperatively before thoracic surgeries. Prevention of nosocomial transmission by providing appropriate personal protective equipment (PPE), such as N-95 respirator masks with eye protection to healthcare workers, is necessary.

Clinical Characteristics and Risk Factors for Acute Kidney Injury in COVID-19

Objective: The objective of the study is to describe the clinical characteristics, risk factors, and prognosis for acute kidney injury (AKI) among patients with coronavirus disease (COVID-19). Methods: Retrospective study of 456 consecutive patients with confirmed COVID-19 infection at the whole hospital from January 1 to March 1, 2020 was enrolled. Demographic, clinical characteristics, the risk factors, and prognosis were collected and analyzed. Results: Of 456 patients with COVID-19, 38 patients developed AKI. Patients with AKI were older and predominantly male sex and were more likely to have comorbidities such as hypertension, cardiovascular, and cerebrovascular diseases. Among patients with AKI, the white blood cell count, neutrophil count, neutrophil-to-lymphocyte ratio, alanine aminotransferase, and C-reaction protein were increased, and lymphocyte and platelet count were decreased. Multivariate analysis showed that age, hypertension, and lymphocyte count were independent risk factors for AKI. The overall mortality rate of 456 patients was 9.9%, and the mortality rate of patients with AKI was 23.7%. In particular, increasing AKI severity was associated with increased risk. Conclusions: The risk of AKI was high in patients with COVID-19. Older age, hypertension, and lower lymphocyte count were independent risk factors for AKI. COVID-19-associated AKI was associated with higher risk of death in patients with COVID-19.

Corticosteroids Utilization in the Management of Critically Ill Coronavirus Disease-2019 Pneumonia

Background: There are controversies regarding corticosteroids using in coronavirus disease-2019 (COVID-19) pneumonia in the current pandemic. Objectives: This study investigates the efficacy and safety profiles of corticosteroids therapy in COVID-19 patients. Methods: Retrospective, multicenter study case series of consecutive patients with confirmed COVID-19 infection at the whole hospital from January 1 to March 1, 2020, were enrolled. Demographic, clinical, radiological, laboratory, and treatment data were collected and analyzed. The effect of corticosteroids therapy on death and organ-failure complications of pneumonia were analyzed by logistic regression. Results: A total of 470 COVID-19 patients at the whole hospital were enrolled. According to the time of corticosteroids initiation and severity of illness, there were 159 patients stratified into critical ill group and 64% (102 of 159) patients received corticosteroids treatments. Ninety-four percent (166 of 176) of corticosteroids were methylprednisolone. The median cumulative corticosteroids dosage was 300 mg equivalent of methylprednisolone over a median duration of 6 days. Multivariate regression analysis showed that corticosteroids use did not affect the mortality. However, corticosteroids therapy at moderate cumulative doses (total exposure 480 mg to 1200 mg) was associated with deceased occurrence of organ-failure complications in critically ill COVID-19. Conclusions: Corticosteroids have no effect to mortality in COVID-19 patients. The moderate cumulative doses of corticosteroids might decrease organ-failure complications in critically ill COVID-19. Further large-scale randomized controlled trials are warranted to confirm our findings, until then use of corticosteroids should be used with caution COVID-19 patients.

Differential Effects of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers on COVID-19

Background: The effect of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs) on the coronavirus disease 2019 (COVID-19) remains controversial from clinic evidence. Objectives: The objectives of this study were to report the major characteristics and clinical outcomes of COVID-19 patients treated with ACEIs and ARBs and compare the different effects of the two drugs for outcomes of COVID-19 patients. Methods: This is a retrospective, two-center case series of 198 consecutive COVID-19 patients with a history of hypertension. Results: Among 198 patients, 58 (29.3%) and 16 (8.1%) were on ARB and ACEI, respectively. Patients who were on ARB or ACEI/ARB had a significantly lower rate of severe illness and acute respiratory distress syndrome (ARDS) when compared with patients treated with ACEI alone or not receiving RAAS blocker (P < 0.05). The Kaplan–Meier survival curve showed that patients with ARB in their antihypertensive regimen had a trend toward a higher survival rate when compared with individuals without ARB (adjusted hazard ratio, 0.27;95% confidence interval [CI], 0.07–1.02;P = 0.054). The occurrence rates of severe illness, ARDS, and death were similar in the two groups regardless of receiving ACEI. The Cox regression analyses showed a better survival in the ARB group than the ACEI group (adjusted hazard ratio, 0.03;95% CI, 0.00–0.58;P = 0.02). Conclusions: Our data may provide that some evidence of using ARB, but not ACEI, was associated with a reduced rate of severe illness and ARDS, indicating their potential protective impact in COVID-19. Further large sample sizes and multiethnic populations are warranted to confirm our findings.

Clinical Characteristics and Risk Factors of Liver Dysfunction in COVID-19 Patients

Background: COVID-19 outbreak has spread around the world. Liver dysfunction (LD) was related with high mortality in COVID-19. Methods: Retrospective, single-center study case series of 425 consecutive hospitalized COVID-19 patients were enrolled. Demographic, clinical, laboratory, and treatment data were collected. Results: A total of 425 patients were included in this study, 145 of whom had LD. The overall mortality rate was 8.9%, while 17.9% in the LD group and 4.3% in the nonliver dysfunction (NLD) group. Age, sex, and hypertension were the independent risk factors of LD. LD was an independent risk factor for incidence of severe illness, acute respiratory distress syndrome, and death. The survival rate of patients in LD group was lower than that in NLD group (P < 0.001). A similar trend was observed by the multivariate regression analysis (adjusted hazard ratio, 3.52;95% confidence interval [CI], 1.69–7.33;P = 0.001). Angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers had effect to reduce LD (odds ratio of 0.48 [95% CI, 0.232–0.989;P = 0.045]). Conclusions: LD is one of the main features of hospitalized patients of COVID-19, with a worse prognosis. Patients of COVID-19 with LD on admission should be more cautions.

Complex Contact Network of Patients at the Beginning of an Epidemic Outbreak: An Analysis Based on 1218 COVID-19 Cases in China.

The spread of viruses essentially occurs through the interaction and contact between people, which is closely related to the network of interpersonal relationships. Based on the epidemiological investigations of 1218 COVID-19 cases in eight areas of China, we use text analysis, social network analysis and visualization methods to construct a dynamic contact network of the epidemic. We analyze the corresponding demographic characteristics, network indicators, and structural characteristics of this network. We found that more than 65% of cases are likely to be infected by a strong relationship, and nearly 40% of cases have family members infected at the same time. The overall connectivity of the contact network is low, but there are still some clustered infections. In terms of the degree distribution, most cases' degrees are concentrated between 0 and 2, which is relatively low, and only a few ones have a higher degree value. The degree distribution also conforms to the power law distribution, indicating the network is a scale-free network. There are 17 cases with a degree greater than 10, and these cluster infections are usually caused by local transmission. The first implication of this research is we find that the COVID-19 spread is closely related to social structures by applying computational sociological methods for infectious disease studies; the second implication is to confirm that text analysis can quickly visualize the spread trajectory at the beginning of an epidemic.

COVID-19 and early-stage lung cancer both featuring ground-glass opacities: a propensity score-matched study.

BACKGROUND: Radiological manifestations of coronavirus disease 2019 (COVID-19) featured ground-glass opacities (GGOs), especially in the early stage, which might create confusion in differential diagnosis with early lung cancer. We aimed to specify the radiological characteristics of COVID-19 and early lung cancer and to unveil the discrepancy between them. METHODS: One hundred and fifty-seven COVID-19 patients and 374 early lung cancer patients from four hospitals in China were retrospectively enrolled. Epidemiological, clinical, radiological, and pathological characteristics were compared between the two groups using propensity score-matched (PSM) analysis. RESULTS: COVID-19 patients had more distinct symptoms, tended to be younger (P<0.0001), male (P<0.0001), and had a higher body mass index (P=0.014). After 1:1 PSM, 121 matched pairs were identified. Regarding radiological characteristics, patients with a single lesion accounted for 17% in COVID-19 and 89% in lung cancer (P<0.0001). Most lesions were peripherally found in both groups. Lesions in COVID-19 involved more lobes (median 3.5 vs. 1; P<0.0001) and segments (median 6 vs. 1; P<0.0001) and tended to have multiple types (67%) with patchy form (54%). Early lung cancer was more likely to have a single type (92%) with oval form (66%). Also, COVID-19 and early lung cancer either had some distinctive features on computed tomography (CT) images. CONCLUSIONS: Both COVID-19 and early lung cancers showed GGOs, with similar but independent features. The imaging characteristics should be fully understood and combined with epidemiological history, pathogen detection, laboratory tests, short-term CT reexamination, and pathological results to aid differential diagnosis.

[Clinical characteristics and risk factors of acute kidney injury in coronavirus disease 2019].

OBJECTIVE: To investigate the characteristics and the risk factors of coronavirus disease 2019 (COVID-19) associated acute kidney injury (AKI). METHODS: A retrospective cohort study was performed to examine the basic data, clinical characteristics and prognosis of patients with COVID-19 in Zhongnan Hospital of Wuhan University and Wuhan Fourth Hospital from January 1st to February 1st in 2020. According to the diagnostic criteria of Kidney Disease: Improving Global Outcomes (KDIGO), patients with AKI were included in AKI group and those without AKI were included in non-AKI group. The differences of each index between the two groups were compared. The prognostic value of AKI for COVID-19 was analyzed by Kaplan-Meier survival curve and Cox regression. RESULTS: A total of 394 COVID-19 patients were included, with a total mortality of 5.6%; 37 (9.4%) of them developed AKI. The mortality of patients with COVID-19 associated AKI was 18.9%. There were significant differences in age, gender, smoking history, hypertension history, malignancy history, cardiovascular disease history and cerebrovascular disease history between the two groups. In addition to the difference of serum creatinine (SCr) and blood urea nitrogen (BUN), white blood cell count (WBC), neutrophil count (NEU), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), D-dimer, procalcitonin (PCT) and C-reaction protein (CRP) in AKI group were significantly higher than those in non-AKI group [WBC (×109/L): 5.75 (4.13, 7.83) vs. 4.52 (3.35, 5.90), NEU (×109/L): 4.55 (2.81, 6.11) vs. 3.06 (2.03, 4.50), AST (U/L): 40.0 (24.5, 69.5) vs. 30.0 (23.0, 42.5), LDH (µmol×s-1×L-1): 5.21 (3.68, 7.57) vs. 4.24 (3.05, 5.53), D-dimer (µg/L): 456 (266, 2 172) vs. 290 (152, 610), PCT (µg/L): 0.33 (0.03, 1.52) vs. 0.01 (0.01, 0.11), CRP (mg/L): 53.80 (26.00, 100.90) vs. 23.60 (9.25, 51.10), all P < 0.05], while lymphocyte count (LYM) and platelet count (PLT) were decreased [LYM (×109/L): 0.68 (0.47, 1.05) vs. 0.91 (0.63, 1.25), PLT (×109/L): 142.0 (118.0, 190.0) vs. 171.0 (130.0, 2 190.0), both P < 0.05]. The mortality of AKI group was significantly higher than that of non-AKI group [18.9% (7/37) vs. 4.2% (15/357), P < 0.01]. Kaplan-Meier survival curve showed that the 30-day cumulative survival of AKI group was lower than that of non-AKI group (log-rank: P = 0.003). Cox analysis also showed that AKI increased the odds of patients with COVID-19 mortality by 3.2-fold [hazard ratio (HR) = 3.208, 95% confidence interval (95%CI) was 1.076-9.566, P = 0.037]. CONCLUSIONS: The risk of AKI is higher in patients with COVID-19. Early intervention to prevent AKI in patients with COVID-19 is of great significance to improve the prognosis of patients.