The unreversible reduced but persistent activated NK and CD8+ T cells in severe/critical COVID-19 during omicron pandemic in China.

As a hallmark of COVID-19 progression, lymphopenia alongside its subtle immune disturbance has been widely reported, but yet to be thoroughly elucidated. Aiming at exploring clinical immune biomarkers with accessibility in the current and acute omicron epidemic abrupted in China post-control era, we design a real-world prospective observation cohort in Peking Union Medical College Hospital to describe immunological, haematological profiles inducing lymphocyte subsets related to SARS-CoV-2 infection. In this COVID-19 cohort, we enrolled 17 mild/moderate (M/M), 24 severe (S) and 25 critical (C) patients. The dynamics of lymphocytes of COVID-19 demonstrated that the sharp decline of NK, CD8+, and CD4+ T cell counts was the main contributor to lymphopenia in the S/C group, compared to the M/M group. Expressions of activation marker CD38 and proliferation marker Ki-67 both in CD8+ T and NK cells were significantly higher in all COVID-19 patients than that in healthy donors, independent of disease severity. The subsequent analysis showed in contrast to the M/M group, NK and CD8+ T cell counts remained low-level after therapy in the S/C group. CD38 and Ki-67 expressions in NK and CD8+ T cells still stay at a high level, despite active treatment. Targeting relatively elderly patients with SARS-CoV-2 infection, severe COVID-19 features the unreversible reduction of NK and CD8+ T cells with persistent activation and proliferation, which assist clinicians in early recognizing and saving severe or critical COVID-19 patients. Given that immunophenotype, the new immunotherapy improving NK and CD8+ T lymphocyte antiviral efficiency should be considered.

Human migration-based graph convolutional network for PM2.5 forecasting in post-COVID-19 pandemic age.

Due to the coronavirus disease 2019 pandemic, local authorities always implanted non-pharmaceutical interventions, such as maintaining social distance to reduce human migration. Besides, previous studies have proved that human migration highly influenced air pollution concentration in an area. Therefore, this study aims to explore whether human migration can work as a significant factor in the post-pandemic age to help PM2.5 concentration forecasting. In this work, we first analyze the variations of PM2.5 in 11 cities of Hubei from 2015 to 2020 and further compare PM2.5 trends with the migration trends of Hubei province in 2020. Experimental results indicate that the human migration indirectly affected the urban PM2.5 concentration. Then, we established a graph data structure based on the migration network describing the migration flow size between any two areas in the Hubei province and proposed a migration attentive graph convolutional network (MAGCN) for forecasting PM2.5. Combined with the migration data. The proposed model can attentively aggregate the information of neighbor nodes through migration weights. Experimental results indicate that the proposed MAGCN can forecast PM2.5 concentration accurately.

COVID-19 is associated with bystander polyclonal autoreactive B cell activation as reflected by a broad autoantibody production, but none is linked to disease severity.

Coronavirus disease 2019 (COVID-19) is associated with autoimmune features and autoantibody production in a small subset of the population. Pre-existing neutralizing antitype I interferons (IFNs) autoantibodies are related to the severity of COVID-19. Plasma levels of IgG and IgM against 12 viral antigens and 103 self-antigens were evaluated using an antibody protein array in patients with severe/critical or mild/moderate COVID-19 disease and uninfected controls. Patients exhibited increased IgGs against Severe acute respiratory syndrome coronavirus-2 proteins compared to controls, but no difference was observed in the two patient groups. 78% autoreactive IgGs and 93% autoreactive IgMs were increased in patients versus controls. There was no difference in the plasma levels of anti-type I IFN autoantibodies or neutralizing anti-type I IFN activity of plasma samples from the two patient groups. Increased anti-type I IFN IgGs were correlated with higher lymphocyte accounts, suggesting a role of nonpathogenic autoantibodies. Notably, among the 115 antibodies tested, only plasma levels of IgGs against human coronavirus (HCOV)-229E and HCOV-NL63 spike proteins were associated with mild disease outcome. COVID-19 was associated with a bystander polyclonal autoreactive B cell activation, but none of the autoantibody levels were linked to disease severity. Long-term humoral immunity against HCOV-22E and HCOV-NL63 spike protein was associated with mild disease outcome. Understanding the mechanism of life-threatening COVID-19 is critical to reducing mortality and morbidity.

Safety and Efficacy of Paxlovid Against Omicron Variants of Coronavirus Disease 2019 in Elderly Patients.

INTRODUCTION: Elderly patients are the most affected and vulnerable to COVID-19 and effective therapeutic interventions are urgently required. We clarified the safety and efficacy of Paxlovid in the treatment of elderly patients with coronavirus disease 2019 (COVID-19). METHODS: Patients aged over 60 years and with mild to moderate COVID-19 were admitted to the Zhongshan Hospital MinHang MeiLong Branch, Fudan University and received either Paxlovid treatment or only conventional therapy, between April 1 and May 31, 2022. Viral shedding time, duration of hospital stay, disease progression, and adverse events were analyzed, and multivariate Cox regression analysis was performed to detect the independent high-risk factors for COVID-19 progression in the patients. RESULTS: A total of 163 (82 and 81 in the treatment and control groups, respectively) patients had a median age of 82 (71-89) years, and 89.0% had at least one concomitant disease. The duration of hospitalization reduced from 15 to 13 days, and viral shedding time reduced from 20 to 16.5 days after Paxlovid treatment. The differences of these two variables between the groups were significant (p < 0.01). Moreover, no serious adverse events or obvious changes in laboratory test results were observed in patients treated with Paxlovid. One patient (1.2%) treated with Paxlovid experienced rebound 56 days after negative measurement. Multivariate analysis showed that Paxlovid therapy, age, hemoglobin, and nucleic acid Ct values at admission were independent risk factors for hospitalization within 14 days, and the differences were significant (p < 0.01). CONCLUSION: The use of Paxlovid in elderly patients may promote recovery from COVID-19 and reduce the viral load without adverse events. CLINICAL TRIAL REGISTRATION: www. CLINICALTRIALS: gov , ID: ChiCTR2200066990.

Effective Responses to Public Emergencies at the Urban Community Level: A Perspective of COVID-19 Prevention and Control

Community is directly responsible for implementing the policy measures against public emergencies such as extreme weather, earthquake, flash flood and pandemic diseases. Summarizing the experience at the urban community level can help promote the global emergency management. This paper, from the perspective of COVID-19 prevention and control, selects three communities with different features to explore an effective response system for public emergency management at the urban community level. It demonstrates that based on a centralized leadership, the multi-level governance (MLG) network combined with information technology has mobilized their participation in combating COVID-19 and ensured the effective and timely response to the public emergencies, which blocked the spread of epidemic to the greatest extent, proving worthy of being promoted as one of the Chinese approaches and Chinese wisdom. [ FROM AUTHOR]

The Analysis of Causality and Risk Spillover between Crude Oil and China's Agricultural Futures.

This paper aims to apply the time-varying Granger causality test (TVGC) and the DY Spillover Index (Diebold and Yilmaz, 2012) to measure the Granger causality and dynamic risk spillover effects of the international crude oil futures market on China's agricultural commodity futures market from the perspectives of return and volatility spillovers. Empirical evidence relating to the TVGC test suggests the existence of unidirectional Granger causality between crude oil futures and agricultural product futures. This relationship shows a strong time-varying property, in particular for sudden or extreme events such as financial crises and natural disasters. On the other hand, the volatility spillover in crude oil and agricultural product futures markets responds asymmetrically and bidirectionally according to the result of the DY Spillover index, and the periodicity of total volatility spillover correlates closely with the occurrence of global economic events, which indicates that the spillover effect between crude oil and agricultural commodity futures markets will be exacerbated in turbulent financial and economic times. Such findings are expected to help in formulating policy recommendations, portfolio design, and risk-management decisions.

A Novel Single-Stranded RNA-Based Adjuvant Improves the Immunogenicity of the SARS-CoV-2 Recombinant Protein Vaccine.

The research and development (R&D) of novel adjuvants is an effective measure for improving the immunogenicity of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) recombinant protein vaccine. Toward this end, we designed a novel single-stranded RNA-based adjuvant, L2, from the SARS-CoV-2 prototype genome. L2 could initiate retinoic acid-inducible gene-I signaling pathways to effectively activate the innate immunity. ZF2001, an aluminum hydroxide (Al) adjuvanted SARS-CoV-2 recombinant receptor binding domain (RBD) subunit vaccine with emergency use authorization in China, was used for comparison. L2, with adjuvant compatibility with RBD, elevated the antibody response to a level more than that achieved with Al, CpG 7909, or poly(I:C) as adjuvants in mice. L2 plus Al with composite adjuvant compatibility with RBD markedly improved the immunogenicity of ZF2001; in particular, neutralizing antibody titers increased by about 44-fold for Omicron, and the combination also induced higher levels of antibodies than CpG 7909/poly(I:C) plus Al in mice. Moreover, L2 and L2 plus Al effectively improved the Th1 immune response, rather than the Th2 immune response. Taken together, L2, used as an adjuvant, enhanced the immune response of the SARS-CoV-2 recombinant RBD protein vaccine in mice. These findings should provide a basis for the R&D of novel RNA-based adjuvants.

COVID-19 mRNA vaccine BNT162b2 induces autoantibodies against type I interferons in a healthy woman.

Coronavirus disease (COVID-19) caused by SARS-CoV-2 virus is associated with a wide range of clinical manifestations, including autoimmune features and autoantibody production in a small subset of patients. Pre-exiting neutralizing autoantibodies against type I interferons (IFNs) are associated with COVID-19 disease severity. In this case report, plasma levels of IgG against type I interferons (IFNs) were increased specifically among the 103 autoantibodies tested following the second shot of COVID-19 vaccine BNT162b2 compared to pre-vaccination and further increased following the third shot of BNT162b2 in a healthy woman. Unlike COVID-19 mediated autoimmune responses, vaccination in this healthy woman did not induce autoantibodies against autoantigens associated with autoimmune diseases. Importantly, IFN-α-2a-induced STAT1 responses in human PBMCs in vitro were suppressed by adding plasma samples from the study subject post- but not pre-vaccination. After the second dose of vaccine, the study subject exhibited severe dermatitis for about six months and responded to treatments with Betamethasone Dipropionate Ointment and antihistamines for about one month. Immune responses to type I IFN can be double-edged swords in enhancing vaccine efficacy and immune responses to infectious diseases, as well as accelerating chronic disease pathogenesis (e.g., chronic viral infections and autoimmune diseases). This case highlights the BNT162b2-induced neutralizing anti-type I IFN autoantibody production, which may affect immune functions in a small subset of general population and patients with some chronic diseases.

Copula-based CUSUM charts for monitoring infectious disease using Markovian Poisson processes

The manuscript addresses the copula-based CUSUM charting scheme to monitor infectious disease. To facilitate the disease surveillance, the Poisson distribution is often used to model the number of diseases counts while the Markov process is used to model the serial correlation within sequential observations. In literature, the first-order autoregressive (AR(1)) process and the first-order integer autoregressive (INAR(1)) process have been used to model continuous observations and Poisson-distributed counts respectively when there exists the Markovian structure between two adjacent observations. However, both of them only describe the conditional linear correlation between adjacent observations. In this paper, the copula model is employed to fit board ranges of correlation structures in the Markovian Poisson processes especially when the conditional correlation between two adjacent Poisson observations is nonlinear. Further, a CUSUM chart based on the log-likelihood ratio is developed to monitor the Poisson processes. The proposed chart performs better in detecting Poisson counts when comparing with existing control charts, and the proposed CUSUM chart performs even better under moderate and strong dependence. A real case study of the counts COVID-19 cases in China is adopted to investigated the effectiveness of our proposed chart. Therefore, it supplies a new method for monitoring the potential changes of the disease infection.

Caveolin-1 Alleviates Acetaminophen-Induced Hepatotoxicity in Alcoholic Fatty Liver Disease by Regulating the Ang II/EGFR/ERK Axis.

Acetaminophen (APAP) is a widely used antipyretic analgesic which can lead to acute liver failure after overdoses. Chronic alcoholic fatty liver disease (AFLD) appears to enhance the risk and severity of APAP-induced liver injury, and the level of angiotensin II (Ang II) increased sharply at the same time. However, the underlying mechanisms remain unclear. Caveolin-1 (CAV1) has been proven to have a protective effect on AFLD. This study aimed to examine whether CAV1 can protect the APAP-induced hepatotoxicity of AFLD by affecting Ang II or its related targets. In vivo, the AFLD model was established according to the chronic-plus-binge ethanol model. Liver injury and hepatic lipid accumulation level were determined. The levels of Angiotensin converting enzyme 2 (ACE2), Ang II, CAV1, and other relevant proteins were evaluated by western blotting. In vitro, L02 cells were treated with alcohol and oleic acid mixture and APAP. CAV1 and ACE2 expression was downregulated in APAP-treated AFLD mice compared to APAP-treated mice. The overexpression of CAV1 in mice and L02 cells alleviated APAP-induced hepatotoxicity in AFLD and downregulated Ang II, p-EGFR/EGFR and P-ERK/ERK expression. Immunofluorescence experiments revealed interactions between CAV1, Ang II, and EGFR. The application of losartan (an Ang II receptor antagonist) and PD98059 (an ERK1/2 inhibitor) alleviated APAP-induced hepatotoxicity in AFLD. In conclusion, our findings verified that CAV1 alleviates APAP-aggravated hepatotoxicity in AFLD by downregulating the Ang II /EGFR/ERK axis, which could be a novel therapeutic target for its prevention or treatment.

The time-frequency connectedness among metal, energy and carbon markets pre and during COVID-19 outbreak.

The study investigates static and dynamic returns spillover effects between metal (gold, silver, copper and aluminum), energy (oil, natural gas and coal) and carbon markets in different frequency domains using the Diebold Yilmaz (2012) and the Baruník and Krehlík (2018) method. The results show that total connectedness in the post-COVID world is significantly higher compared to pre-COVID-19 outbreak period. The total spillover is contributed mainly by short-term spillover effects. Moreover, metal markets especially copper and silver have higher explanatory power. Spillover within markets is stronger than across these markets. In addition, the carbon market is more heavily interactive with other markets, and the metal market especially copper has relatively high explanatory power for the carbon price fluctuations in post-COVID-19outbreak periods. According to the net spillover, copper and gold has a hedge function in the short- and long-term, respectively. Furthermore, the relationship among these markets is time-varying, affected by market uncertainty such as the outbreak or major events.

Infant Mortality and Inflation in China: Based on the Mixed Frequency VAR Analyses.

Reducing neonatal mortality is an important goal in the Sustainable Development Goals (SDGs), and with the outbreak of the new crown epidemic and severe global inflation, it is extremely important to explore the relationship between inflation and infant mortality. This paper investigates the causal relationship between inflation and infant mortality using a mixed frequency vector autoregressive model (MF-VAR) without any filtering procedure, along with impulse response analysis and forecast misspecification variance decomposition, and compares it with a low frequency vector autoregressive model (LF-VAR). We find that there is a causal relationship between inflation and infant mortality, specifically, that is inflation increases infant mortality. Moreover, the contribution of CPI to IMR is greater in the forecast error variance decomposition in the MF-VAR model compared to the LF-VAR model, indicating that CPI has stronger explanatory power for IMR in mixed-frequency data. The results of the study have important implications for China and other developing countries in reducing infant mortality and achieving the Sustainable Development Goals (SDGs). Policymakers should focus on inflation as a macroeconomic variable that reduces the potential negative impact of inflation on infant mortality. The results of the analysis further emphasize the importance of price stability in the context of global inflation caused by the outbreak of the coronavirus pandemic outbreak.

Predicting progression to severe COVID-19 using the PAINT score.

OBJECTIVES: One of the major challenges in treating patients with coronavirus disease 2019 (COVID-19) is predicting the severity of disease. We aimed to develop a new score for predicting progression from mild/moderate to severe COVID-19. METHODS: A total of 239 hospitalized patients with COVID-19 from two medical centers in China between February 6 and April 6, 2020 were retrospectively included. The prognostic abilities of variables, including clinical data and laboratory findings from the electronic medical records of each hospital, were analysed using the Cox proportional hazards model and Kaplan-Meier methods. A prognostic score was developed to predict progression from mild/moderate to severe COVID-19. RESULTS: Among the 239 patients, 216 (90.38%) patients had mild/moderate disease, and 23 (9.62%) progressed to severe disease. After adjusting for multiple confounding factors, pulmonary disease, age > 75, IgM, CD16+/CD56+ NK cells and aspartate aminotransferase were independent predictors of progression to severe COVID-19. Based on these five factors, a new predictive score (the 'PAINT score') was established and showed a high predictive value (C-index = 0.91, 0.902 ± 0.021, p < 0.001). The PAINT score was validated using a nomogram, bootstrap analysis, calibration curves, decision curves and clinical impact curves, all of which confirmed its high predictive value. CONCLUSIONS: The PAINT score for progression from mild/moderate to severe COVID-19 may be helpful in identifying patients at high risk of progression.

Turning point: A new global COVID-19 wave or a signal of the beginning of the end of the global COVID-19 pandemic?

A new variant named Omicron (B.1.1.529), first identified in South Africa, has become of considerable interest to the World Health Organization. This variant differs from the other known major variants, as it carries a large number of unusual mutations, particularly in the spinous process protein and receptor binding domains. Some specific mutation sites make it vaccine resistant, highly infectious, and highly pathogenic. The world fears that the Omicron variant could be even more harmful than the previous major variant, given that it has emerged amid fierce competition to trigger a new global pandemic peak as infections in South Africa rise. However, some epidemiological evidence has emerged that the Omicron variant may produce milder patient symptoms. We speculate if the virulence of the Omicron variant will diminish as transmissibility increases, thereby signaling the beginning of the end for the global COVID-19 pandemic. Based on this view, we make recommendations for COVID-19 mitigation in the present and future. However, it will take a few weeks to determine the true threat posed by the Omicron variant and we need to be fully prepared for future outbreaks, regardless of their severity.

treekoR: identifying cellular-to-phenotype associations by elucidating hierarchical relationships in high-dimensional cytometry data.

High-throughput single-cell technologies hold the promise of discovering novel cellular relationships with disease. However, analytical workflows constructed for these technologies to associate cell proportions with disease often employ unsupervised clustering techniques that overlook the valuable hierarchical structures that have been used to define cell types. We present treekoR, a framework that empirically recapitulates these structures, facilitating multiple quantifications and comparisons of cell type proportions. Our results from twelve case studies reinforce the importance of quantifying proportions relative to parent populations in the analyses of cytometry data - as failing to do so can lead to missing important biological insights.

Mycoplasma pneumoniae among Chinese Outpatient Children with Mild Respiratory Tract Infections during the Coronavirus Disease 2019 Pandemic.

Mycoplasma pneumoniae is a common pathogen causing respiratory disease in children. We sought to investigate the epidemiology of M. pneumoniae among outpatient children with mild respiratory tract infections (RTIs) during the coronavirus disease 2019 (COVID-19) pandemic. Eligible patients were prospectively enrolled from January 2020 to June 2021. Throat swabs were tested for M. pneumoniae RNA. M. pneumoniae IgM was tested by a colloidal gold assay. Macrolide resistance and the effect of the COVID-19 countermeasures on M. pneumoniae prevalence were assessed. Symptom scores, treatments, and outcomes were evaluated. Eight hundred sixty-two eligible children at 15 centers in China were enrolled. M. pneumoniae was detected in 78 (9.0%) patients. Seasonally, M. pneumoniae peaked in the first spring and dropped dramatically to extremely low levels over time until the next summer. Decreases in COVID-19 prevalence were significantly associated with decreases in M. pneumoniae prevalence (r = 0.76, P = 0.001). The macrolide resistance rate was 7.7%. The overall sensitivity and specificity of the colloidal gold assay used in determining M. pneumoniae infection were 32.1% and 77.9%, respectively. No more benefits for improving the severity of symptoms and outcomes were observed in M. pneumoniae-infected patients treated with a macrolide than in those not treated with a macrolide during follow-up. The prevalences of M. pneumoniae and macrolide resistance in outpatient children with mild RTIs were at low levels in the early stage of the COVID-19 pandemic but may have rebounded recently. The colloidal gold assay for M. pneumoniae IgM may be not appropriate for diagnosis of M. pneumoniae infection. Macrolides should be used with caution among outpatients with mild RTIs. IMPORTANCE This is the first and largest prospective, multicenter, active, population-based surveillance study of the epidemiology of Mycoplasma pneumoniae among outpatient children with mild respiratory tract infections (RTIs) during the COVID-19 pandemic. Nationwide measures like strict face mask wearing and restrictions on population movement implemented to prevent the spread of COVID-19 might also effectively prevent the spread of M. pneumoniae. The prevalence of M. pneumoniae and the proportion of drug-resistant M. pneumoniae isolates in outpatient children with mild RTIs were at low levels in the early stage of the COVID-19 pandemic but may have rebounded recently. The colloidal gold assay for M. pneumoniae IgM may be not appropriate for screening and diagnosis of M. pneumoniae infection. Macrolides should be used with caution among outpatients with mild RTIs.

A Wearable Tele-Health System towards Monitoring COVID-19 and Chronic Diseases.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic since early 2020. The coronavirus disease 2019 (COVID-19) has already caused more than three million deaths worldwide and affected people's physical and mental health. COVID-19 patients with mild symptoms are generally required to self-isolate and monitor for symptoms at least for 14 days in the case the disease turns towards severe complications. In this work, we overviewed the impact of COVID-19 on the patients' general health with a focus on their cardiovascular, respiratory and mental health, and investigated several existing patient monitoring systems. We addressed the limitations of these systems and proposed a wearable telehealth solution for monitoring a set of physiological parameters that are critical for COVID-19 patients such as body temperature, heart rate, heart rate variability, blood oxygen saturation, respiratory rate, blood pressure, and cough. This physiological information can be further combined to potentially estimate the lung function using artificial intelligence (AI) and sensor fusion techniques. The prototype, which includes the hardware and a smartphone app, showed promising results with performance comparable to or better than similar commercial devices, thus potentially making the proposed system an ideal wearable solution for long-term monitoring of COVID-19 patients and other chronic diseases.

Aromatic Cadinane Sesquiterpenoids from the Fruiting Bodies of Phellinus pini Block SARS-CoV-2 Spike-ACE2 Interaction.

The ongoing COVID-19 global pandemic caused by SARS-CoV-2 inspires the development of effective inhibitors to block the SARS-CoV-2 spike-ACE2 interaction. A chemical investigation on the fruiting bodies of Phellinus pini led to the isolation of five aromatic cadinane sesquiterpenoids including four new ones, named piniterpenoids A-D (1-4), as well as three known lignans. Their structures were determined by extensive spectroscopic analysis including HRMS and 1D and 2D NMR. All of the aromatic cadinane sesquiterpenoids inhibited the SARS-CoV-2 spike-ACE2 interaction, with IC50 values ranging from 64.5 to 99.1 µM. A molecular docking study showed the disruption of the interaction of compound 1 via hydrogen interactions with Arg403, Asp405, and Arg408 of SARS-CoV-2 RBD and Arg393 and His34 residues of ACE2. These results suggested that aromatic cadinane sesquiterpenoids might be useful in developing agents for COVID-19.

The dynamic changes of cellular immunity among frontline medical workers who supported Wuhan for fighting against the COVID-19.

The outbreak of novel coronavirus disease 2019 (COVID-19) poses a great stress to frontline medical workers. Our previous study indicated that immune cells in the peripheral blood of frontline medical workers changed significantly. However, the dynamic changes of immune cells of frontline medical workers remain unclear. Here, we reported the dynamic changes of lymphocyte subsets in the peripheral blood of 51 frontline medical worker. The frontline medical workers struggling with COVID-19 from February 8 to March 31, 2020. Demographic and clinical data, including routine blood test data were extracted from the electronic health examination record and retrospectively analyzed. The lymphocyte (LYM) count and LYM ratio increased while the monocyte (MONO) ratio, neutrophil to lymphocyte ratio (NLR), monocyte to lymphocyte ratio (MLR) and neutrophil (NEUT) ratio in the peripheral blood of frontline medical workers decreased 10 days after struggling with COVID-19. Interestingly, the differences of LYM count, LYM ratio, MONO ratio, NLR, NEUT ratio were more significantly in nurse than doctor. The differences of LYM ratio, NLR and NEUT ratio were more significantly in female than male. However, the changes of LYM count, LYM ratio, MONO ratio, NLR, MLR, NEUT ratio returned to the baseline 10 months after struggling with COVID-19. Together, these data indicated that immune cells in the peripheral blood changed significantly 10 days after struggling with COVID-19, but returned to normal after 10 months. Those maybe caused by psychological stress and we recommend to pay more attention to mental health and immune response of frontline medical workers.