Single-Cell Transcriptomics Reveals Evidence of Endothelial Dysfunction in the Brains of COVID-19 Patients with Implications for Glioblastoma Progression.

BACKGROUND: Endothelial dysfunction is implicated in various inflammatory diseases such as ischemic stroke, heart attack, organ failure, and COVID-19. Recent studies have shown that endothelial dysfunction in the brain is attributed to excessive inflammatory responses caused by the SARS-CoV-2 infection, leading to increased permeability of the blood-brain barrier and consequently neurological damage. Here, we aim to examine the single-cell transcriptomic landscape of endothelial dysfunction in COVID-19 and its implications for glioblastoma (GBM) progression. METHODS: Single-cell transcriptome data GSE131928 and GSE159812 were obtained from the gene expression omnibus (GEO) to analyze the expression profiles of key players in innate immunity and inflammation between brain endothelial dysfunction caused by COVID-19 and GBM progression. RESULTS: Single-cell transcriptomic analysis of the brain of COVID-19 patients revealed that endothelial cells had undergone significant transcriptomic changes, with several genes involved in immune responses and inflammation upregulated. Moreover, transcription factors were observed to modulate this inflammation, including interferon-regulated genes. CONCLUSIONS: The results indicate a significant overlap between COVID-19 and GBM in the context of endothelial dysfunction, suggesting that there may be an endothelial dysfunction link connecting severe SARS-CoV-2 infection in the brain to GBM progression.

Effectiveness of mRNA and viral-vector vaccines in epidemic period led by different SARS-CoV-2 variants: A systematic review and meta-analysis.

We assessed the effectiveness of mRNA and viral-vector vaccines in epidemic period led by different SARS-CoV-2 variants. Systematic search of PubMed, EMBASE, and CNKI (China National Knowledge Infrastructure) databases without language restriction for studies published before September 19, 2022. The review was registered with PROSPERO (CRD42022335430) and reported according to PRISMA guidelines. Forty studies met the inclusion criteria for this study, with 62 954 861 participants. The overall vaccine effectiveness (VE) to prevent COVID-19 infection was 0.76 (95% confidence interval [CI] 0.73-0.78), symptomatic infection was 0.87 (95% CI 0.83-0.91), hospital admissions was 0.82 (95% CI 0.75-0.87), and mortality was 0.76 (95% CI 0.48-0.89). Subgroup analysis were performed to characterize the effectiveness of different vaccines. When SARS-CoV-2 variants are taking account, the VE decreased along with the variation of the virus by clinical outcomes and vaccine types. The findings of this systematic review provide the best available evidence that BNT162b2, mRNA-1273, ChAdOx1, and Ad26. COV2.S seems to be approximately effective from predelta to omicron, but only modestly effective in participants aged 65 or older. When SARS-CoV-2 variants are taking account, VE decreased along with the variation of the virus for all mRNA and viral-vector vaccines.

Meplazumab in hospitalized adults with severe COVID-19 (DEFLECT): a multicenter, seamless phase 2/3, randomized, third-party double-blind clinical trial.

Meplazumab, a humanized CD147 antibody, has shown favourable safety and efficacy in our previous clinical studies. In DEFLECT (NCT04586153), 167 patients with severe COVID-19 were enroled and randomized to receive three dosages of meplazumab and a placebo. Meplazumab at 0.12 mg/kg, compared to the placebo group, showed clinical benefits in significantly reducing mortality by 83.6% (2.4% vs. 14.6%, p = 0.0150), increasing the proportion of patients alive and discharged without supplemental oxygen (82.9% vs. 70.7%, p = 0.0337) and increasing the proportion of patients who achieved sustained clinical improvement (41.5% vs. 31.7%). The response rate in the 0.2 mg/kg group was relatively increased by 16.0% compared with the placebo group (53.7% vs. 46.3%). Meplazumab also reduced the viral loads and multiple cytokine levels. Compare with the placebo group, the 0.3 mg/kg significantly increased the virus negative rate by 40.6% (p = 0.0363) and reduced IL-8 level (p = 0.0460); the 0.2 mg/kg increased the negative conversion rate by 36.9%, and reduced IL-4 (p = 0.0365) and IL-8 levels (p = 0.0484). In this study, the adverse events occurred at a comparable rate across the four groups, with no unexpected safety findings observed. In conclusion, meplazumab promoted COVID-19 convalescence and reduced mortality, viral load, and cytokine levels in severe COVID-19 population with good safety profile.

CD147 contributes to SARS-CoV-2-induced pulmonary fibrosis.

COVID-19 patients can develop clinical and histopathological features associated with fibrosis, but the pathogenesis of fibrosis remains poorly understood. CD147 has been identified as a universal receptor for SARS-CoV-2 and its variants, which could initiate COVID-19-related cytokine storm. Here, we systemically analyzed lung pathogenesis in SARS-CoV-2- and its delta variant-infected humanized CD147 transgenic mice. Histopathology and Transmission Electron Microscopy revealed inflammation, fibroblast expansion and pronounced fibrotic remodeling in SARS-CoV-2-infected lungs. Consistently, RNA-sequencing identified a set of fibrosis signature genes. Furthermore, we identified CD147 as a crucial regulator for fibroblast activation induced by SARS-CoV-2. We found conditional knockout of CD147 in fibroblast suppressed activation of fibroblasts, decreasing susceptibility to bleomycin-induced pulmonary fibrosis. Meplazumab, a CD147 antibody, was able to inhibit the accumulation of activated fibroblasts and the production of ECM proteins, thus alleviating the progression of pulmonary fibrosis caused by SARS-CoV-2. In conclusion, we demonstrated that CD147 contributed to SARS-CoV-2-triggered progressive pulmonary fibrosis and identified CD147 as a potential therapeutic target for treating patients with post-COVID-19 pulmonary fibrosis.

Predictors of poor serologic response to COVID-19 vaccine in patients with cancer: a systematic review and meta-analysis.

BACKGROUNDS: Patients with cancer presented a lower probability to obtain seroconversion after a complete course of COVID-19 vaccination. However, little was known on the factors that predict poor seroconversion in this frail population. METHODS: We searched the PubMed, EMBASE, and China National Knowledge Infrastructure databases for all articles within a range of published years from 2019 to 2022 on the predictors of response to COVID-19 vaccine in patients with cancer (last search was updated on 2st March 2022). The odds ratio corresponding to the 95% confidence interval was used to assess the outcome. The statistical heterogeneity among studies was assessed with the Q-test and I² statistics. The review was registered with PROSPERO (CRD42022315687) and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Twenty cohort studies met the inclusion criteria for this study, with 5,499 patients with cancer. We found that advanced age, male patients, and metastatic disease increased negative seropositivity to COVID-19 vaccine. Immunoglobulin heavy chain variable mutation status, high concentration of Ig G, Ig M, and Ig A were correlated with seropositivity. Relating to cancer treatment strategy, anti-CD20 therapy within recent 12 months and chemotherapy were negatively correlated with seroconversion. Meta-analysis found no significant difference associated with targeted treatment, immunotherapy, and endocrine treatment. CONCLUSIONS: Our meta-analysis assessed the factors that predict poor seroconversion in order to plan better prevention strategies in this frail population. The results proposed that enhanced vaccination strategies would be beneficial for the special patients such as advanced male, or patients receiving active chemotherapy, and carefully prevention should be emphasised even after a complete course of vaccination.

Risk factors for depression and anxiety in pregnant women during the COVID-19 pandemic: Evidence from meta-analysis.

BACKGROUND: The prevalence of anxiety and depression in pregnant women has significantly increased after the spread of COVID-19 throughout the world. We carried out this meta-analysis to reveal the information about risk factors for depression and anxiety in pregnant women during the COVID-19 pandemic. METHODS: We searched the PubMed, Embase and CNKI (China National Knowledge Infrastructure) databases for all articles. The odds ratio (OR) corresponding to the 95% confidence interval (95% CI) was used to assess the risk factors for mental health. The statistical heterogeneity among studies was assessed with the Q-test and I2 statistics. RESULTS: We collected 17 studies including 15,050 pregnant women during the COVID-19 pandemic. Our results found that factors including decrease in the perception of general support and difficulties in household finances have damage effects on anxiety, and factors including undereducated, unemployed during pregnancy, with a chronic physical illness before pregnancy, decrease in the perception of general support, difficulties in household finances, disobey the isolation rules, and smoking during pregnancy have increased risk of depression. CONCLUSION: Our meta-analysis revealed some risk factors for mental health in pregnant women during COVID-19 pandemic. Mental health interventions in pregnant women may involve targeted methods individually.

Differential effects of macrophage subtypes on SARS-CoV-2 infection in a human pluripotent stem cell-derived model.

Dysfunctional immune responses contribute critically to the progression of Coronavirus Disease-2019 (COVID-19), with macrophages as one of the main cell types involved. It is urgent to understand the interactions among permissive cells, macrophages, and the SARS-CoV-2 virus, thereby offering important insights into effective therapeutic strategies. Here, we establish a lung and macrophage co-culture system derived from human pluripotent stem cells (hPSCs), modeling the host-pathogen interaction in SARS-CoV-2 infection. We find that both classically polarized macrophages (M1) and alternatively polarized macrophages (M2) have inhibitory effects on SARS-CoV-2 infection. However, M1 and non-activated (M0) macrophages, but not M2 macrophages, significantly up-regulate inflammatory factors upon viral infection. Moreover, M1 macrophages suppress the growth and enhance apoptosis of lung cells. Inhibition of viral entry using an ACE2 blocking antibody substantially enhances the activity of M2 macrophages. Our studies indicate differential immune response patterns in distinct macrophage phenotypes, which could lead to a range of COVID-19 disease severity.

Maternal infection with COVID-19 and increased risk of adverse pregnancy outcomes: a meta-analysis.

Background: The Coronavirus disease 2019 (COVID-19) pandemic has become worldwide, posing particularly severe challenges. Pregnancy brings changes that might make individuals more vulnerable to this viral infection. To date, the impact of COVID-19 infection on pregnancy outcomes remains controversial.Method: We performed a meta-analysis to address the impact of COVID-19 infection on pregnancy outcomes. We searched the PubMed and China National Knowledge infrastructure (CNKI) databases for related articles. The odds ratio (OR) corresponding to the 95% confidence interval (95% CI) was used to define the impact of INFECTION and severity of COVID-19 on pregnancy outcomes. The statistical heterogeneity among studies was batched with the Q-test and I2 statistics.Results: We collected 38 studies including 127,805 pregnancy women. Our meta-analysis revealed that pregnant women with COVID-19 have been linked to an increased risk of premature birth (OR = 1.66, 95% CI = 1.41-1.96), stillbirth (OR = 1.98, 95% CI = 1.22-3.21), pre-eclampsia (OR = 1.46, 95% CI = 1.18-1.80), and PROM (OR = 1.39, 95% CI = 1.07-1.81).Conclusions: Our meta-analysis showed that infection with COVID-19 increases the risk of preterm birth, stillbirth, pre-eclampsia, and PROM. Screening and early care for pregnant women to intervene with COVID-19 is important, given the increased risk of adverse pregnancy outcomes.

Impact of near-surface turbulence on PM2.5 concentration in Chengdu during the COVID-19 pandemic.

The role of meteorological conditions has long been recognized in modulating regional air quality. The impact of near-surface turbulence, nevertheless, remains poorly understood. To curb the spread of COVID-19, a variety of lockdown measures were implemented, providing us an unprecedented opportunity to examine the joint impact of emission control and meteorology on regional air quality. Here we examined the variations of planetary boundary layer (PBL) height, PM2.5 concentrations, turbulence kinetic energy (TKE), vertical wind shear, and their associations in Chengdu, Sichuan province in Southwest China between January 13 and February 24, 2020, by synergistically using micro pulse lidar, ground-level meteorological and PM2.5 measurements, as well as ultrasonic anemometer observations. During the study period, Sichuan basin was primarily regulated by the straight west wind, with an averaged wind speed of 2-3 m/s at 850 hPa, indicative of a relatively stable atmospheric dispersion condition. TKE was positively correlated with PBL height but negatively correlated with PM2.5. The PM2.5 concentration varied dramatically during pre- and post-lockdown periods but remained near constant at a relatively low level during the lockdown period. Meanwhile, the negative correlation between TKE and PM2.5 was much stronger during the lockdown and post-lockdown periods, when aerosol emissions were significantly reduced. Moreover, the correlation between TKE and PM2.5 exhibited large diurnal variability, with the strongest correlation observed during the daytime when solar radiation and turbulent mixing generally reached their peaks. Overall, the observational results in Chengdu underscore the non-negligible impact of turbulence on regional PM2.5 concentrations, which could help better understand the variation of regional air pollution events.

CD147 antibody specifically and effectively inhibits infection and cytokine storm of SARS-CoV-2 and its variants delta, alpha, beta, and gamma.

SARS-CoV-2 mutations contribute to increased viral transmissibility and immune escape, compromising the effectiveness of existing vaccines and neutralizing antibodies. An in-depth investigation on COVID-19 pathogenesis is urgently needed to develop a strategy against SARS-CoV-2 variants. Here, we identified CD147 as a universal receptor for SARS-CoV-2 and its variants. Meanwhile, Meplazeumab, a humanized anti-CD147 antibody, could block cellular entry of SARS-CoV-2 and its variants-alpha, beta, gamma, and delta, with inhibition rates of 68.7, 75.7, 52.1, 52.1, and 62.3% at 60 µg/ml, respectively. Furthermore, humanized CD147 transgenic mice were susceptible to SARS-CoV-2 and its two variants, alpha and beta. When infected, these mice developed exudative alveolar pneumonia, featured by immune responses involving alveoli-infiltrated macrophages, neutrophils, and lymphocytes and activation of IL-17 signaling pathway. Mechanistically, we proposed that severe COVID-19-related cytokine storm is induced by a "spike protein-CD147-CyPA signaling axis": Infection of SARS-CoV-2 through CD147 initiated the JAK-STAT pathway, which further induced expression of cyclophilin A (CyPA); CyPA reciprocally bound to CD147 and triggered MAPK pathway. Consequently, the MAPK pathway regulated the expression of cytokines and chemokines, which promoted the development of cytokine storm. Importantly, Meplazumab could effectively inhibit viral entry and inflammation caused by SARS-CoV-2 and its variants. Therefore, our findings provided a new perspective for severe COVID-19-related pathogenesis. Furthermore, the validated universal receptor for SARS-CoV-2 and its variants can be targeted for COVID-19 treatment.

The effect of metformin on mortality and severity in COVID-19 patients with diabetes mellitus.

AIM: COVID-19 has spread globally with heavy impact on most countries and our therapeutic strategies in COVID-19 patients with diabetes are still limited. Recently, some new information was added to this field. We performed this updated meta-analysis to reveal the underlying effect of metformin on COVID-19 patients with diabetes. METHODS: We searched the PubMed, Embase and CNKI (China National Knowledge Infrastructure) databases for all articles. The odds ratio (OR) corresponding to the 95% confidence interval (95% CI) was used to assess the effect of metformin on COVID-19 patients with diabetes. The statistical heterogeneity among studies was assessed with the Q-test and I2 statistics. RESULTS: We collected 17 studies including 20,719 COVID-19 patients with diabetes. Our results found that metformin was associated with significantly decreased mortality and severity in COVID-19 patients with diabetes (OR = 0.64, 95% CI = 0.51-0.79 for mortality, and OR = 0.81, 95% CI = 0.66-0.99 for severity). CONCLUSIONS: Our meta-analysis indicated that following metformin treatment might benefit the patients with T2DM, both the mortality and severity. However, patients with severe COVID-19 should be monitored closely for the development of lactic acidosis, acidosis, and decreased kidney function.

Safety and efficacy of meplazumab in healthy volunteers and COVID-19 patients: a randomized phase 1 and an exploratory phase 2 trial.

Recent evidence suggests that CD147 serves as a novel receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Blocking CD147 via anti-CD147 antibody could suppress the in vitro SARS-CoV-2 replication. Meplazumab is a humanized anti-CD147 IgG2 monoclonal antibody, which may effectively prevent SARS-CoV-2 infection in coronavirus disease 2019 (COVID-19) patients. Here, we conducted a randomized, double-blinded, placebo-controlled phase 1 trial to evaluate the safety, tolerability, and pharmacokinetics of meplazumab in healthy subjects, and an open-labeled, concurrent controlled add-on exploratory phase 2 study to determine the efficacy in COVID-19 patients. In phase 1 study, 59 subjects were enrolled and assigned to eight cohorts, and no serious treatment-emergent adverse event (TEAE) or TEAE grade ≥3 was observed. The serum and peripheral blood Cmax and area under the curve showed non-linear pharmacokinetic characteristics. No obvious relation between the incidence or titer of positive anti-drug antibody and dosage was observed in each cohort. The biodistribution study indicated that meplazumab reached lung tissue and maintained >14 days stable with the lung tissue/cardiac blood-pool ratio ranging from 0.41 to 0.32. In the exploratory phase 2 study, 17 COVID-19 patients were enrolled, and 11 hospitalized patients were involved as concurrent control. The meplazumab treatment significantly improved the discharged (P = 0.005) and case severity (P = 0.021), and reduced the time to virus negative (P = 0.045) in comparison to the control group. These results show a sound safety and tolerance of meplazumab in healthy volunteers and suggest that meplazumab could accelerate the recovery of patients from COVID-19 pneumonia with a favorable safety profile.

CD147-spike protein is a novel route for SARS-CoV-2 infection to host cells.

In face of the everlasting battle toward COVID-19 and the rapid evolution of SARS-CoV-2, no specific and effective drugs for treating this disease have been reported until today. Angiotensin-converting enzyme 2 (ACE2), a receptor of SARS-CoV-2, mediates the virus infection by binding to spike protein. Although ACE2 is expressed in the lung, kidney, and intestine, its expressing levels are rather low, especially in the lung. Considering the great infectivity of COVID-19, we speculate that SARS-CoV-2 may depend on other routes to facilitate its infection. Here, we first discover an interaction between host cell receptor CD147 and SARS-CoV-2 spike protein. The loss of CD147 or blocking CD147 in Vero E6 and BEAS-2B cell lines by anti-CD147 antibody, Meplazumab, inhibits SARS-CoV-2 amplification. Expression of human CD147 allows virus entry into non-susceptible BHK-21 cells, which can be neutralized by CD147 extracellular fragment. Viral loads are detectable in the lungs of human CD147 (hCD147) mice infected with SARS-CoV-2, but not in those of virus-infected wild type mice. Interestingly, virions are observed in lymphocytes of lung tissue from a COVID-19 patient. Human T cells with a property of ACE2 natural deficiency can be infected with SARS-CoV-2 pseudovirus in a dose-dependent manner, which is specifically inhibited by Meplazumab. Furthermore, CD147 mediates virus entering host cells by endocytosis. Together, our study reveals a novel virus entry route, CD147-spike protein, which provides an important target for developing specific and effective drug against COVID-19.

A cross-sectional survey of knowledge, attitude and practice associated with COVID-19 among undergraduate students in China.

BACKGROUND: The COVID-19 pandemic has become a great threat to public health, which has greatly impacted the study and life of undergraduate students in China. This study aims to perform a survey of their knowledge, attitude and practice (KAP) associated with COVID-19. METHODS: A cross-sectional survey was designed to gather information regarding the COVID-19 related KAP among undergraduates during the home isolation in the outbreak. Subjects were recruited from 10 universities in Shaanxi Province, China. Enrollees voluntarily submitted their answers to a pre-designed questionnaire online. RESULTS: A total of 872 subjects (female, 534; male, 338) were enrolled with ages from 17 to 25 years old. This cohort included 430 medical and 442 non-medical students, 580 freshmen and 292 higher school year students. There were 453 from public schools and 442 from private school, residing in 28 regions and provinces at the time of study. Results showed that appropriate knowledge was acquired by 82.34% subjects; the levels were significantly higher in undergraduates from public universities and medical majors than those from private schools and non-medical majors (p<0.05). 73.81% subjects reported positive attitudes; females showed significantly higher levels of positive attitudes than males (p<0.05). Proactive practice was found in 87.94% subjects. Using a common scoring method, the overall scores for Knowledge, Attitude and Practice were 4.12 ± 0.749 (range: 0 ~ 5), 8.54 ± 1.201 (range: 0 ~ 10), and 8.91 ± 1.431 (range: 0 ~ 10), respectively. There was a positive correlation between attitude and practice (r = 0.319, p < 0.05) in the whole study group. Total KAP score was 21.57 ± 2.291 (range: 0 ~ 25), which was significantly different between gender groups and major groups. CONCLUSIONS: Most undergraduates acquired necessary knowledge, positive attitude and proactive practice in response to COVID-19 outbreak; but their KAP scores significantly varied by gender, major and school types.

The combined therapy of a traditional Chinese medicine formula and Western medicine for a critically ill case infected with COVID-19.

OBJECTIVE: Presentation of a case illustrating the benefits of traditional Chinese medicine (TCM) for treatment of Coronavirus disease 2019 (COVID-19) in critically ill patients. CLINICAL FEATURES AND OUTCOME: A 58-year-old woman presented with cough, fever, dizziness, chest tightness, polypnea and poor appetite. She was admitted to Guizhou Provincial People's hospital, and diagnosed with critically ill type of COVID-19 in February 2020. According to the patient's symptoms and signs, the TCM syndrome differentiation was qi deficiency, dampness-stasis and toxin accumulation. Then she received the combined therapy of a modified Chinese herbal formula and Western medicine. During a twelve-day period of treatment, her respiratory distress and appetite quickly improved. Abnormal laboratory indicators were resumed in time and lung lesions in CT scan largely absorbed. No side effects associated with this Chinese herbal formula were found. Before discharge, two consecutive nasopharyngeal swabs were shown to be negative for severe acute respiratory coronavirus 2 (SARS-CoV-2). CONCLUSIONS: Our case report suggests that collaborative treatments with traditional Chinese medicine prove beneficial in the management of COVID-19 in critically ill patients. In order to give optimal care for this COVID-19 crisis for the whole world, Chinese medicine practitioners and Western medical doctors should work together in frontline.