Vaccination, human mobility, and COVID-19 health outcomes: Empirical comparison before and during the outbreak of SARS-Cov-2 B.1.1.529 (Omicron) variant.

The B.1.1.529 (Omicron) variant surge has raised concerns about the effectiveness of vaccines and the impact of imprudent reopening. Leveraging over two years of county-level COVID-19 data in the US, this study aims to investigate relationships among vaccination, human mobility, and COVID-19 health outcomes (assessed via case rate and case-fatality rate), controlling for socioeconomic, demographic, racial/ethnic, and partisan factors. A set of cross-sectional models was first fitted to empirically compare disparities in COVID-19 health outcomes before and during the Omicron surge. Then, time-varying mediation analyses were employed to delineate how the effects of vaccine and mobility on COVID-19 health outcomes vary over time. Results showed that vaccine effectiveness against case rate lost significance during the Omicron surge, while its effectiveness against case-fatality rate remained significant throughout the pandemic. We also documented salient structural inequalities in COVID-19-related outcomes, with disadvantaged populations consistently bearing a larger brunt of case and death tolls, regardless of high vaccination rates. Last, findings revealed that mobility presented a significantly positive relationship with case rates during each wave of variant outbreak. Mobility substantially mediated the direct effect from vaccination to case rate, leading to a 10.276 % (95 % CI: 6.257, 14.294) decrease in vaccine effectiveness on average. Altogether, our study implies that sole reliance on vaccination to halt COVID-19 needs to be re-examined. Well-resourced and coordinated efforts to enhance vaccine effectiveness, mitigate health disparity and selectively loosen non-pharmaceutical interventions are essential to bringing the pandemic to an end.

Human mesenchymal stem cell therapy in severe COVID-19 patients: 2-year follow-up results of a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Long-term effects of human mesenchymal stem cell (MSC) treatment on COVID-19 patients have not been fully characterized. The aim of this study was to evaluate the safety and efficacy of a MSC treatment administered to severe COVID-19 patients enrolled in our previous randomized, double-blind, placebo-controlled clinical trial (NCT04288102). METHODS: A total of 100 patients experiencing severe COVID-19 received either MSC treatment (n = 65, 4 × 107 cells per infusion) or a placebo (n = 35) combined with standard of care on days 0, 3, and 6. Patients were subsequently evaluated 18 and 24 months after treatment to evaluate the long-term safety and efficacy of the MSC treatment. Outcomes measured included: 6-min walking distance (6-MWD), lung imaging, quality of life according to the Short Form 36 questionnaire (SF-36), COVID-19-related symptoms, titers of SARS-CoV-2 neutralizing antibodies, tumor markers, and MSC-related adverse events (AEs). FINDINGS: Two years after treatment, a marginally smaller proportion of patients had a 6-MWD below the lower limit of the normal range in the MSC group than in the placebo group (OR = 0.19, 95% CI: 0.04-0.80, Fisher's exact test, p = 0.015). At month 18, the general health score from the SF-36 was higher in the MSC group than in the placebo group (50.00 vs. 35.00, 95% CI: 0.00-20.00, Wilcoxon rank sum test, p = 0.018). Total severity score of lung imaging and the titer of neutralizing antibodies were similar between the two groups at months 18 and 24. There was no difference in AEs or tumor markers at the 2-year follow-up between the two groups. INTERPRETATION: Long-term safety was observed for the COVID-19 patients who received MSC treatment. However, efficacy of MSC treatment was not significantly sustained through the end of the 2-year follow-up period. FUNDING: The National Key Research and Development Program of China (2022YFA1105604, 2020YFC0860900, 2022YFC2304401), the specific research fund of The Innovation Platform for Academicians of Hainan Province (YSPTZX202216) and the Fund of National Clinical Center for Infectious Diseases, PLA General Hospital (NCRC-ID202105,413FZT6).

Novel Graph Topology Learning for Spatio-Temporal Analysis of COVID-19 Spread.

This article presents a new graph-learning technique to accurately infer the graph structure of COVID-19 data, helping to reveal the correlation of pandemic dynamics among different countries and identify influential countries for pandemic response analysis. The new technique estimates the graph Laplacian of the COVID-19 data by first deriving analytically its precise eigenvectors, also known as graph Fourier transform (GFT) basis. Given the eigenvectors, the eigenvalues of the graph Laplacian are readily estimated using convex optimization. With the graph Laplacian, we analyze the confirmed cases of different COVID-19 variants among European countries based on centrality measures and identify a different set of the most influential and representative countries from the current techniques. The accuracy of the new method is validated by repurposing part of COVID-19 data to be the test data and gauging the capability of the method to recover missing test data, showing 33.3% better in root mean squared error (RMSE) and 11.11% better in correlation of determination than existing techniques. The set of identified influential countries by the method is anticipated to be meaningful and contribute to the study of COVID-19 spread.

Effect of Methylprednisolone on Mortality and Clinical Courses in Patients with Severe COVID-19: A Propensity Score Matching Analysis

Background Whether methylprednisolone therapy can reduce the mortality rate of patients with severe coronavirus disease 2019 (COVID-19) remains controversial, and its effects on the length of hospital stay and virus shedding time are also unknown. This retrospective study investigates the previous issues to provide more evidence for methylprednisolone treatment in severe COVID-19. Methods This retrospective study included 563 of 4827 patients with confirmed COVID-19 admitted to Wuhan Huoshenshan Hospital or Wuhan Guanggu Hospital between February 3, 2020 and March 30, 2020 who met the screening criteria. The participants' epidemiological and demographic data, comorbidities, laboratory test results, treatments, outcomes, and vital clinical time points were extracted from electronic medical records. The primary outcome was in-hospital death, and the secondary outcomes were 2 clinical courses: length from admission to viral clearance and discharge. Univariate and multivariate logistic or linear regression analyses were used to assess the role of methylprednisolone in different outcomes. Propensity score matching was performed to control for confounding factors. Results Of the 563 patients who met the screening criteria and were included in the subsequent analysis, 138 were included in the methylprednisolone group and 425 in the nonmethylprednisolone group. The in-hospital death rate between the methylprednisolone and nonmethylprednisolone groups showed a significant difference (23.91% vs. 1.65%, P < 0.001), which was maintained after propensity score matching (13.98% vs. 5.38%, P = 0.048). However, univariate logistic analysis in the matched groups showed that methylprednisolone treatment (odds ratio [OR], 5.242;95% confidence interval [CI], 0.802 to 34.246;P = 0.084) was not a risk factor for in-hospital death in severe patients. Further multivariate logistic regression analysis found comorbidities (OR, 3.327;95% CI, 1.702 to 6.501;P < 0.001), lower lymphocyte count (OR, 0.076;95% CI, 0.012 to 0.461;P = 0.005), higher lactate dehydrogenase (LDH) levels (OR, 1.008;95% CI, 1.003 to 1.013;P = 0.002), and anticoagulation therapy (OR, 11.187;95% CI, 2.459 to 50.900;P = 0.002) were associated with in-hospital mortality. Multivariate linear regression analysis in the matched groups showed that methylprednisolone treatment was not a risk factor for a prolonged duration from admission to viral clearance (β Value 0.081;95% CI, −1.012 to 3.657;P = 0.265) or discharge (β Value 0.114;95% CI, −0.723 to 6.408;P = 0.117). d-dimer (β Value, 0.144;95% CI, 0.012 to 0.817;P = 0.044), LDH (β Value 0.260;95% CI, 0.010 to 0.034;P < 0.001), and antiviral therapy (β Value 0.220;95% CI, 1.373 to 6.263;P = 0.002) were associated with a longer length from admission to viral clearance. The lymphocyte count (β Value −0.206;95% CI, −6.248 to −1.197;P = 0.004), LDH (β Value 0.231;95% CI, 0.012 to 0.048;P = 0.001), antiviral therapy (β Value 0.143;95% CI, 0.058 to 7.497;P = 0.047), and antibacterial therapy (β Value 0.152;95% CI, 0.133 to 8.154;P = 0.043) were associated with a longer hospitalization duration from admission to discharge. Further stratified analysis revealed that the low daily dose group (≤60 mg/d) and the low total dose group (≤200 mg) had shorter duration from admission to viral clearance (Z=−2.362, P = 0.018;Z=−2.010, P = 0.044) and a shorter hospital stay (Z=−2.735, P = 0.006;Z=−3.858, P < 0.001). Conclusions In patients with severe COVID-19, methylprednisolone is safe and does not prolong the duration from admission to viral clearance or discharge. Low-dose, short-term methylprednisolone treatment may be more beneficial in shortening the disease course.

Effect of Methylprednisolone on Mortality and Clinical Courses in Patients with Severe COVID-19: A Propensity Score Matching Analysis.

Background: Whether methylprednisolone therapy can reduce the mortality rate of patients with severe coronavirus disease 2019 (COVID-19) remains controversial, and its effects on the length of hospital stay and virus shedding time are also unknown. This retrospective study investigates the previous issues to provide more evidence for methylprednisolone treatment in severe COVID-19. Methods: This retrospective study included 563 of 4827 patients with confirmed COVID-19 admitted to Wuhan Huoshenshan Hospital or Wuhan Guanggu Hospital between February 3, 2020 and March 30, 2020 who met the screening criteria. The participants' epidemiological and demographic data, comorbidities, laboratory test results, treatments, outcomes, and vital clinical time points were extracted from electronic medical records. The primary outcome was in-hospital death, and the secondary outcomes were 2 clinical courses: length from admission to viral clearance and discharge. Univariate and multivariate logistic or linear regression analyses were used to assess the role of methylprednisolone in different outcomes. Propensity score matching was performed to control for confounding factors. Results: Of the 563 patients who met the screening criteria and were included in the subsequent analysis, 138 were included in the methylprednisolone group and 425 in the nonmethylprednisolone group. The in-hospital death rate between the methylprednisolone and nonmethylprednisolone groups showed a significant difference (23.91% vs. 1.65%, P < 0.001), which was maintained after propensity score matching (13.98% vs. 5.38%, P = 0.048). However, univariate logistic analysis in the matched groups showed that methylprednisolone treatment (odds ratio [OR], 5.242; 95% confidence interval [CI], 0.802 to 34.246; P = 0.084) was not a risk factor for in-hospital death in severe patients. Further multivariate logistic regression analysis found comorbidities (OR, 3.327; 95% CI, 1.702 to 6.501; P < 0.001), lower lymphocyte count (OR, 0.076; 95% CI, 0.012 to 0.461; P = 0.005), higher lactate dehydrogenase (LDH) levels (OR, 1.008; 95% CI, 1.003 to 1.013; P = 0.002), and anticoagulation therapy (OR, 11.187; 95% CI, 2.459 to 50.900; P = 0.002) were associated with in-hospital mortality. Multivariate linear regression analysis in the matched groups showed that methylprednisolone treatment was not a risk factor for a prolonged duration from admission to viral clearance (ß Value 0.081; 95% CI, -1.012 to 3.657; P = 0.265) or discharge (ß Value 0.114; 95% CI, -0.723 to 6.408; P = 0.117). d-dimer (ß Value, 0.144; 95% CI, 0.012 to 0.817; P = 0.044), LDH (ß Value 0.260; 95% CI, 0.010 to 0.034; P < 0.001), and antiviral therapy (ß Value 0.220; 95% CI, 1.373 to 6.263; P = 0.002) were associated with a longer length from admission to viral clearance. The lymphocyte count (ß Value -0.206; 95% CI, -6.248 to -1.197; P = 0.004), LDH (ß Value 0.231; 95% CI, 0.012 to 0.048; P = 0.001), antiviral therapy (ß Value 0.143; 95% CI, 0.058 to 7.497; P = 0.047), and antibacterial therapy (ß Value 0.152; 95% CI, 0.133 to 8.154; P = 0.043) were associated with a longer hospitalization duration from admission to discharge. Further stratified analysis revealed that the low daily dose group (≤60 mg/d) and the low total dose group (≤200 mg) had shorter duration from admission to viral clearance (Z=-2.362, P = 0.018; Z=-2.010, P = 0.044) and a shorter hospital stay (Z=-2.735, P = 0.006; Z=-3.858, P < 0.001). Conclusions: In patients with severe COVID-19, methylprednisolone is safe and does not prolong the duration from admission to viral clearance or discharge. Low-dose, short-term methylprednisolone treatment may be more beneficial in shortening the disease course.

Effect of methylprednisolone therapy on hospital stay and viral clearance in patients with moderate COVID-19

Background The benefits and harms of methylprednisolone treatment in patients with moderate coronavirus disease 2019 (COVID-19) remain controversial. In this study, we investigated the effect of methylprednisolone on mortality rate, viral clearance, and hospitalization stay in patients with moderate COVID-19. Methods This retrospective study included 4827 patients admitted to Wuhan Huoshenshan and Wuhan Guanggu hospitals from February to March 2020 diagnosed with COVID-19 pneumonia. The participants’ epidemiological and demographic data, comorbidities, laboratory test results, treatments, outcomes, and vital clinical time points were extracted from electronic medical records. The primary outcome was in-hospital death;secondary outcomes were time from admission to viral clearance and hospital stay. Univariate and multivariate logistic or linear regression analysis were used to assess the roles of methylprednisolone in different outcomes. The propensity score matching (PSM) method was used to control for confounding factors. Results A total of 1320 patients were included in this study, of whom 100 received methylprednisolone. Overall in-hospital mortality was 0.91% (12/1320);the 12 patients who died were all in the methylprednisolone group, though multivariate logistic regression analysis showed methylprednisolone treatment was not a risk factor for in-hospital death in moderate patients before or after adjustment for confounders by PSM. Methylprednisolone treatment was correlated with longer length from admission to viral clearance time and hospital stay before and after adjustment for confounders. Conclusions Methylprednisolone therapy was not associated with increased in-hospital mortality but with delayed viral clearance and extended hospital stay in moderate COVID-19 patients.

An engineered 5-helix bundle derived from SARS-CoV-2 S2 pre-binds sarbecoviral spike at both serological- and endosomal-pH to inhibit virus entry.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and related sarbecoviruses enter host cells by receptor-recognition and membrane-fusion. An indispensable step in fusion is the formation of 6-helix bundle by viral spike heptad repeats 1 and 2 (HR1 and HR2). Here, we report the construction of 5-helix bundle (5HB) proteins for virus infection inhibition. The optimal construct inhibits SARS-CoV-2 pseudovirus entry with sub-micromolar IC50. Unlike HR2-based peptides that cannot bind spike in the pre-fusion conformation, 5HB features with the capability of binding to pre-fusion spike. Furthermore, 5HB binds viral HR2 at both serological- and endosomal-pH, highlighting its entry-inhibition capacity when SARS-CoV-2 enters via either cell membrane fusion or endosomal route. Finally, we show that 5HB could neutralize S-mediated entry of the predominant SARS-CoV-2 variants and a wide spectrum of sarbecoviruses. These data provide proof-of-concept evidence that 5HB might be developed for the prevention and treatment of SARS-CoV-2 and other emerging sarbecovirus infections.

Human mesenchymal stem cells treatment for severe COVID-19: 1-year follow-up results of a randomized, double-blind, placebo-controlled trial.

BACKGROUND: The long-term consequences of human umbilical cord-derived mesenchymal stem cell (UC-MSC) treatment for COVID-19 patients are yet to be reported. This study assessed the 1-year outcomes in patients with severe COVID-19, who were recruited in our previous UC-MSC clinical trial. METHODS: In this prospective, longitudinal, cohort study, 100 patients enrolled in our phase 2 trial were prospectively followed up at 3-month intervals for 1 year to evaluate the long-term safety and effectiveness of UC-MSC treatment. The primary endpoint was an altered proportion of whole-lung lesion volumes measured by high-resolution CT. Other imaging outcomes, 6 min walking distance (6-MWD), lung function, plasma biomarkers, and adverse events were also recorded and analyzed. This trial was registered with ClinicalTrials.gov (NCT04288102). FINDINGS: MSC administration improved in whole-lung lesion volume compared with the placebo with a difference of -10.8% (95% CI: -20.7%, -1.5%, p = 0.030) on day 10. MSC also reduced the proportion of solid component lesion volume compared with the placebo at each follow-up point. More interestingly, 17.9% (10/56) of patients in the MSC group had normal CT images at month 12, but none in the placebo group (p = 0.013). The incidence of symptoms was lower in the MSC group than in the placebo group at each follow-up time. Neutralizing antibodies were all positive, with a similar median inhibition rate (61.6% vs. 67.6%) in both groups at month 12. No difference in adverse events at the 1-year follow-up and tumor markers at month 12 were observed between the two groups. INTERPRETATION: UC-MSC administration achieves a long-term benefit in the recovery of lung lesions and symptoms in COVID-19 patients. FUNDING: The National Key R&D Program of China, the Innovation Groups of the National Natural Science Foundation of China, and the National Science and Technology Major Project.

SARS-CoV-2 Inactivation Simulation Using 14 MeV Neutron Irradiation.

The SARS-CoV-2 virus is deadly, contagious, can cause COVID-19 disease, and endangers public health and safety. The development of SARS-CoV-2 inactivation technology is crucial and imminent in current pandemic period. Neutron radiation is usually used to sterilize viruses because neutron radiation is 10 times more effective than gamma-rays in inactivating viruses. In this work we established a closed SARS-CoV-2 inactivation container model by the Monte Carlo method and simulated the inactivation performance by using several different neutrons sources. To study the effects of inactivation container factors, including the reflector thickness, the type of the reflector material, the SARS-CoV-2 layer area and the distance from the radiation source on the energy deposition of a single neutron particle in SARS-CoV-2 sample, we simulated the neutron energy deposition on a SARS-CoV-2 sample. The simulation results indicate that the saturated thicknesses of reflector materials for graphite, water and paraffin are approximately 30 cm, 15 cm, and 10 cm, respectively, and the energy deposition (radiation dose) becomes larger when the SARS-CoV-2 layer area is smaller and the SARS-CoV-2 layer is placed closer to the neutron source. The calculated single-neutron energy deposition on 10 × 10 cm2 SARS-CoV-2 layer is about 3.0059 × 10-4 MeV/g with graphite as the reflection layer, when the 14 MeV neutron source intensity is 1012 n/s and the SARS-CoV-2 layer is 5 cm away from the neutron source. If the lethal dose of SARS-CoV-2 is assumed as the IAEA recommended reference dose, 25 kGy, the SARS-CoV-2 could be decontaminated in about 87 min, and the sterilization time could be less than 52 s if the 14 MeV neutron intensity is increased to 1014 n/s.

Development and characterization of SARS-CoV-2 variant-neutralizing monoclonal antibodies

Vaccination and administration of monoclonal antibody cocktails are effective tools to control the progression of infectious diseases and to terminate pandemics such as COVID-19. However, the emergence of SARS-CoV-2 mutants with enhanced transmissibility and altered antigenicity requires broad-spectrum therapies. Here we developed a panel of SARS-CoV-2 specific mouse monoclonal antibodies (mAbs), and characterized them based on ELISA, Western immunoblot, isotyping, and virus neutralization. Six neutralizing mAbs that exhibited high-affinity binding to SARS-CoV-2 spike protein were identified, and their amino acid sequences were determined by mass spectrometry. Functional assays confirmed that three mAbs, F461G11, F461G15, and F461G16 neutralized four variants of concern (VOC): B.1.1.7 (alpha), B.1.351 (beta), P.1 (gamma) and B.1.617.2 (delta) These mAbs are promising candidates for COVID-19 therapy, and understanding their interactions with virus spike protein should support further vaccine and antibody development.

Viewpoint The Domestic Computer Science Graduate Students Are There, We Just Need to Recruit Them

The sudden disruption brought to our world by COVID-19 has put science and research at the center of the public attention. Scientists have been asked why the pandemic developed, how it may be countered and possibly defeated, and how its spread could be prevented. Almost all branches of science have been involved: from health to social sciences, from economics to technological sciences. Computer science was no exception. Researchers know how to communicate with peers. They learn how to do it since they enter a Ph.D. program, and continue to learn and improve throughout their career. Research is an intrinsically open process that relies on communication among peers. The main ambition of scientists is to achieve novel results and disseminate them to the world, contributing to the advance of human knowledge and welfare. COVID-19 brought science back on stage in the spotlight, emerging from the shaded "death of expertise" corner. Science and technology proved to be decisive weapons to fight against the virus.

Effect of human umbilical cord-derived mesenchymal stem cells on lung damage in severe COVID-19 patients: a randomized, double-blind, placebo-controlled phase 2 trial.

Treatment of severe Coronavirus Disease 2019 (COVID-19) is challenging. We performed a phase 2 trial to assess the efficacy and safety of human umbilical cord-mesenchymal stem cells (UC-MSCs) to treat severe COVID-19 patients with lung damage, based on our phase 1 data. In this randomized, double-blind, and placebo-controlled trial, we recruited 101 severe COVID-19 patients with lung damage. They were randomly assigned at a 2:1 ratio to receive either UC-MSCs (4 × 107 cells per infusion) or placebo on day 0, 3, and 6. The primary endpoint was an altered proportion of whole lung lesion volumes from baseline to day 28. Other imaging outcomes, 6-minute walk test (6-MWT), maximum vital capacity, diffusing capacity, and adverse events were recorded and analyzed. In all, 100 COVID-19 patients were finally received either UC-MSCs (n = 65) or placebo (n = 35). UC-MSCs administration exerted numerical improvement in whole lung lesion volume from baseline to day 28 compared with the placebo (the median difference was -13.31%, 95% CI -29.14%, 2.13%, P = 0.080). UC-MSCs significantly reduced the proportions of solid component lesion volume compared with the placebo (median difference: -15.45%; 95% CI -30.82%, -0.39%; P = 0.043). The 6-MWT showed an increased distance in patients treated with UC-MSCs (difference: 27.00 m; 95% CI 0.00, 57.00; P = 0.057). The incidence of adverse events was similar in the two groups. These results suggest that UC-MSCs treatment is a safe and potentially effective therapeutic approach for COVID-19 patients with lung damage. A phase 3 trial is required to evaluate effects on reducing mortality and preventing long-term pulmonary disability. (Funded by The National Key R&D Program of China and others. ClinicalTrials.gov number, NCT04288102.

Human umbilical cord-derived mesenchymal stem cell therapy in patients with COVID-19: a phase 1 clinical trial.

No effective drug treatments are available for coronavirus disease 2019 (COVID-19). Host-directed therapies targeting the underlying aberrant immune responses leading to pulmonary tissue damage, death, or long-term functional disability in survivors require clinical evaluation. We performed a parallel assigned controlled, non-randomized, phase 1 clinical trial to evaluate the safety of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) infusions in the treatment of patients with moderate and severe COVID-19 pulmonary disease. The study enrolled 18 hospitalized patients with COVID-19 (n = 9 for each group). The treatment group received three cycles of intravenous infusion of UC-MSCs (3 × 107 cells per infusion) on days 0, 3, and 6. Both groups received standard COVID-treatment regimens. Adverse events, duration of clinical symptoms, laboratory parameters, length of hospitalization, serial chest computed tomography (CT) images, the PaO2/FiO2 ratio, dynamics of cytokines, and IgG and IgM anti-SARS-CoV-2 antibodies were analyzed. No serious UC-MSCs infusion-associated adverse events were observed. Two patients receiving UC-MSCs developed transient facial flushing and fever, and one patient developed transient hypoxia at 12 h post UC-MSCs transfusion. Mechanical ventilation was required in one patient in the treatment group compared with four in the control group. All patients recovered and were discharged. Our data show that intravenous UC-MSCs infusion in patients with moderate and severe COVID-19 is safe and well tolerated. Phase 2/3 randomized, controlled, double-blinded trials with long-term follow-up are needed to evaluate the therapeutic use of UC-MSCs to reduce deaths and improve long-term treatment outcomes in patients with serious COVID-19.