The Impact of Vaccination Time on the Antibody Response to an Inactivated Vaccine against SARS-CoV-2 (IMPROVE-2): A Randomized Controlled Trial.

There is still controversy about whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination at different times of day will induce a stronger immune response. Therefore, a randomized controlled trial (ChiCTR2100045109) is conducted to investigate the impact of vaccination time on the antibody response to the inactivated vaccine against SARS-CoV-2 from April 15 to 28, 2021. Participants are randomly assigned in a 1:1 ratio to receive inactivated SARS-CoV-2 vaccine in the morning or afternoon. The primary endpoint is the change of neutralizing antibody between baseline and 28 days after the second dose. In total, 503 participants are randomized, and 469 participants (238 in the morning group and 231 in the afternoon group) complete the follow-up. There is no significant difference in the change of neutralizing antibody between baseline and 28 days after the second dose between the morning and afternoon groups (22.2 [13.2, 45.0] AU mL-1  vs 22.0 [14.4, 40.7] AU mL-1 , P = 0.873). In prespecified age and sex subgroup analyses, there is also no significant difference in the morning and afternoon group (all P > 0.05). This study demonstrates that the vaccination time does not affect the antibody response of two doses of inactivated SARS-CoV-2 vaccine.

Potential impact of COVID-19 pandemic on endometriosis

The impact of coronavirus disease 2019 (COVID-19) on endometriosis (EM) is currently unclear. Here, we aimed to describe the potential influence of COVID-19 on the pathogenesis, clinical symptoms, and treatment of EM. The cytokine storm caused by COVID-19 may induce the occurrence and progression of EM, and immunosuppression of COVID-19 may help the ectopic endometrium escape from immune clearance. Consequently, the forced social isolation and the cancelation of non-emergency medical treatment during the COVID-19 pandemic aggravate anxiety and psychological pressure, which can aggravate the symptoms related to EM and delay routine medical services.

Persisting chemosensory impairments in 366 healthcare workers following COVID-19: an 11-month follow-up.

Olfactory and gustatory dysfunctions (OD, GD) are prevalent symptoms following COVID-19 and persist in 6%-44% of individuals post-infection. As only few reports have described their prognosis after 6 months, our main objective was to assess the prevalence of OD and GD 11-month post-COVID-19. We also aimed to determine intraclass correlation coefficients (ICC) of chemosensory self-ratings for the follow-up of chemosensory sensitivity. We designed an observational study and distributed an online questionnaire assessing chemosensory function to healthcare workers with a RT-PCR-confirmed SARS-CoV-2 infection 5- and 11-month post-COVID-19. Specifically, we assessed olfaction, gustation, and trigeminal sensitivity (10-point visual analog scale) and function (4-point Likert scale). We further measured clinically relevant OD using the Chemosensory Perception Test, a psychophysical test designed to provide a reliable remote olfactory evaluation. We included a total of 366 participants (mean [SD] age of 44.8 (11.7) years old). They completed the last online questionnaire 10.6 months (0.7) after the onset of COVID-19 symptoms. Of all participants, 307 (83.9%) and 301 (82.2%) individuals retrospectively reported lower olfactory or gustatory sensitivity during the acute phase of COVID-19. At the time of evaluation, 184 (50.3%) and 163 (44.5%) indicated reduced chemosensory sensitivity, 32.2% reported impairment of olfactory function while 24.9% exhibited clinically relevant OD. Olfactory sensitivity had a high test-retest reliability (ICC: 0.818; 95% CI: 0.760-0.860). This study suggests that chemosensory dysfunctions persist in a third of COVID-19 patients 11 months after COVID-19. OD appears to be a common symptom of post-COVID-19 important to consider when treating patients.

Robust induction of B cell and T cell responses by a third dose of inactivated SARS-CoV-2 vaccine.

SARS-CoV-2 inactivated vaccines have shown remarkable efficacy in clinical trials, especially in reducing severe illness and casualty. However, the waning of humoral immunity over time has raised concern over the durability of immune memory following vaccination. Thus, we conducted a nonrandomized trial among the healthcare workers (HCWs) to investigate the long-term sustainability of SARS-CoV-2-specific B cells and T cells stimulated by inactivated vaccines and the potential need for a third booster dose. Although neutralizing antibodies elicited by the standard two-dose vaccination schedule dropped from a peak of 29.3 arbitrary units (AU)/mL to 8.8 AU/mL 5 months after the second vaccination, spike-specific memory B and T cells were still detectable, forming the basis for a quick recall response. As expected, the faded humoral immune response was vigorously elevated to 63.6 AU/mL by 7.2 folds 1 week after the third dose along with abundant spike-specific circulating follicular helper T cells in parallel. Meanwhile, spike-specific CD4+ and CD8+ T cells were also robustly elevated by 5.9 and 2.7 folds respectively. Robust expansion of memory pools by the third dose potentiated greater durability of protective immune responses. Another key finding in this trial was that HCWs with low serological response to two doses were not truly "non-responders" but fully equipped with immune memory that could be quickly recalled by a third dose even 5 months after the second vaccination. Collectively, these data provide insights into the generation of long-term immunological memory by the inactivated vaccine, which could be rapidly recalled and further boosted by a third dose.

The optimal vaccination strategy to control COVID-19: a modeling study in Wuhan City, China.

BACKGROUND: Reaching optimal vaccination rates is an essential public health strategy to control the coronavirus disease 2019 (COVID-19) pandemic. This study aimed to simulate the optimal vaccination strategy to control the disease by developing an age-specific model based on the current transmission patterns of COVID-19 in Wuhan City, China. METHODS: We collected two indicators of COVID-19, including illness onset data and age of confirmed case in Wuhan City, from December 2, 2019, to March 16, 2020. The reported cases were divided into four age groups: group 1, ≤ 14 years old; group 2, 15 to 44 years old; group 3, 44 to 64 years old; and group 4, ≥ 65 years old. An age-specific susceptible-exposed-symptomatic-asymptomatic-recovered/removed model was developed to estimate the transmissibility and simulate the optimal vaccination strategy. The effective reproduction number (Reff) was used to estimate the transmission interaction in different age groups. RESULTS: A total of 47 722 new cases were reported in Wuhan City from December 2, 2019, to March 16, 2020. Before the travel ban of Wuhan City, the highest transmissibility was observed among age group 2 (Reff = 4.28), followed by group 2 to 3 (Reff = 2.61), and group 2 to 4 (Reff = 1.69). China should vaccinate at least 85% of the total population to interrupt transmission. The priority for controlling transmission should be to vaccinate 5% to 8% of individuals in age group 2 per day (ultimately vaccinated 90% of age group 2), followed by 10% of age group 3 per day (ultimately vaccinated 90% age group 3). However, the optimal vaccination strategy for reducing the disease severity identified individuals ≥ 65 years old as a priority group, followed by those 45-64 years old. CONCLUSIONS: Approximately 85% of the total population (nearly 1.2 billion people) should be vaccinated to build an immune barrier in China to safely consider removing border restrictions. Based on these results, we concluded that 90% of adults aged 15-64 years should first be vaccinated to prevent transmission in China.

Chemosensory Dysfunctions Induced by COVID-19 Can Persist up to 7 Months: A Study of Over 700 Healthcare Workers.

Several studies have revealed either self-reported chemosensory alterations in large groups or objective quantified chemosensory impairments in smaller populations of patients diagnosed with COVID-19. However, due to the great variability in published results regarding COVID-19-induced chemosensory impairments and their follow-up, prognosis for chemosensory functions in patients with such complaints remains unclear. Our objective is to describe the various chemosensory alterations associated with COVID-19 and their prevalence and evolution after infection. A cross-sectional study of 704 healthcare workers with a RT-PCR-confirmed SARS-CoV-2 infection between 2020 February 28 and 2020 June 14 was conducted 3-7 months after onset of symptoms. Data were collected with an online questionnaire. Outcomes included differences in reported chemosensory self-assessment of olfactory, gustatory, and trigeminal functions across time points and Chemosensory Perception Test scores from an easy-to-use at-home self-administered chemosensory test. Among the 704 participants, 593 (84.2%) were women, the mean (SD) age was 42 (12) years, and the questionnaire was answered on average 4.8 (0.8) months after COVID-19. During COVID-19, a decrease in olfactory, gustatory, and trigeminal sensitivities was reported by 81.3%, 81.5%, and 48.0%, respectively. Three to 7 months later, reduced sensitivity was still reported by 52.0%, 41.9%, and 23.3%, respectively. Chemosensory Perception Test scores indicate that 19.5% of participants had objective olfactory impairment. These data suggest a significant proportion of COVID-19 cases have persistent chemosensory impairments at 3-7 months after their infection, but the majority of those who had completely lost their olfactory, gustatory, and trigeminal sensitivities have improved.

Active components in Ephedra sinica stapf disrupt the interaction between ACE2 and SARS-CoV-2 RBD: Potent COVID-19 therapeutic agents.

ETHNOPHARMACOLOGICAL RELEVANCE: Ephedra sinica Stapf is a widely used folk medicine in Asia to treat lung diseases, such as cold, cough and asthma. Many efforts have revealed that some traditional Chinese medicine (TCM) prescriptions containing Ephedra sinica could effectively alleviate the symptoms and prevent the fatal deterioration of COVID-19. AIM OF THE STUDY: The present study aims to discover active compounds in Ephedra sinica disrupting the interaction between angiotensin-converting enzyme 2 (ACE2) and the SARS-CoV-2 spike protein receptor-binding domain (SARS-CoV-2 RBD) to inhibit SARS-CoV-2 virus infection. MATERIALS AND METHODS: The ethanol extracts of Ephedra sinica were prepared. Activity guided isolation of constituents was carried out by measuring the inhibitory activity on ACE2-RBD interaction. The structures of active compounds were identified by HPLC-Q-TOF-MS/MS and NMR. To testify the contribution of main components for the inhibitory activity, different samples were prepared by components knock-out strategy. The mechanism of compounds inhibiting protein-protein interaction (PPI) was explored by competition inhibition assays, surface plasmon resonance (SPR) assays and molecular docking. SARS-CoV-2 S protein-pseudoviruses were used to observe the viropexis effect in cells. RESULTS: Ephedra sinica extracts (ESE) could effectively inhibit the interaction between ACE2 and SARS-CoV-2 RBD (IC50 = 95.01 µg/mL). Three active compounds, 4,6-dihydroxyquinoline-2-carboxylic acid, 4-hydroxyquinoline-2-carboxylic acid and 4-hydroxy-6-methoxyquinoline-2-carboxylic acid were identified to inhibit ACE2-RBD interaction (IC50 = 0.58 µM, 0.07 µM and 0.15 µM respectively). And knock-out the three components could eliminate the inhibitory activity of ESE. Molecular docking calculations indicated that the hydrogen bond was the major intermolecular force. Finally, our results also showed that these compounds could inhibit the infectivity of SARS-CoV-2 S protein-pseudoviruses to 293T-ACE2 (IC50 = 0.44-1.09 µM) and Calu-3 cells. CONCLUSION: These findings suggested that quinoline-2-carboxylic acids in Ephedra sinica could be considered as potential therapeutic agents for COVID-19. Further, this study provided some justification for the ethnomedicinal use of Ephedra sinica for COVID-19.

JCS: An Explainable COVID-19 Diagnosis System by Joint Classification and Segmentation.

Recently, the coronavirus disease 2019 (COVID-19) has caused a pandemic disease in over 200 countries, influencing billions of humans. To control the infection, identifying and separating the infected people is the most crucial step. The main diagnostic tool is the Reverse Transcription Polymerase Chain Reaction (RT-PCR) test. Still, the sensitivity of the RT-PCR test is not high enough to effectively prevent the pandemic. The chest CT scan test provides a valuable complementary tool to the RT-PCR test, and it can identify the patients in the early-stage with high sensitivity. However, the chest CT scan test is usually time-consuming, requiring about 21.5 minutes per case. This paper develops a novel Joint Classification and Segmentation (JCS) system to perform real-time and explainable COVID- 19 chest CT diagnosis. To train our JCS system, we construct a large scale COVID- 19 Classification and Segmentation (COVID-CS) dataset, with 144,167 chest CT images of 400 COVID- 19 patients and 350 uninfected cases. 3,855 chest CT images of 200 patients are annotated with fine-grained pixel-level labels of opacifications, which are increased attenuation of the lung parenchyma. We also have annotated lesion counts, opacification areas, and locations and thus benefit various diagnosis aspects. Extensive experiments demonstrate that the proposed JCS diagnosis system is very efficient for COVID-19 classification and segmentation. It obtains an average sensitivity of 95.0% and a specificity of 93.0% on the classification test set, and 78.5% Dice score on the segmentation test set of our COVID-CS dataset. The COVID-CS dataset and code are available at https://github.com/yuhuan-wu/JCS.

CSF3 Is a Potential Drug Target for the Treatment of COVID-19.

Coronavirus Disease 2019 (COVID-19) is an acute respiratory infectious disease that appeared at the end of 2019. As of July 2020, the cumulative number of infections and deaths have exceeded 15 million and 630,000, respectively. And new cases are increasing. There are still many difficulties surrounding research on the mechanism and development of therapeutic vaccines. It is urgent to explore the pathogenic mechanism of viruses to help prevent and treat COVID-19. In our study, we downloaded two datasets related to COVID-19 (GSE150819 and GSE147507). By analyzing the high-throughput expression matrix of uninfected human bronchial organoids and infected human bronchial organoids in the GSE150819, 456 differentially expressed genes (DEGs) were identified, which were mainly enriched in the cytokine-cytokine receptor interaction pathway and so on. We also constructed the protein-protein interaction (PPI) network of DEGs to identify the hub genes. Then we analyzed GSE147507, which contained lung adenocarcinoma cell lines (A549 and Calu3) and the primary bronchial epithelial cell line (NHBE), obtaining 799, 460, and 46 DEGs, respectively. The results showed that in human bronchial organoids, A549, Calu3, and NHBE samples infected with SARS-CoV-2, only one upregulated gene CSF3 was identified. Interestingly, CSF3 is one of the hub genes we previously screened in GSE150819, suggesting that CSF3 may be a potential drug target. Further, we screened potential drugs targeting CSF3 by MOE; the top 50 drugs were screened by flexible docking and rigid docking, with 37 intersections. Two antiviral drugs (Elbasvir and Ritonavir) were included; Elbasvir and Ritonavir formed van der Waals (VDW) interactions with surrounding residues to bind with CSF3, and Elbasvir and Ritonavir significantly inhibited CSF3 protein expression.

Hematopoietic Cell Transplantation with Cryopreserved Grafts for Severe Aplastic Anemia.

With the COVID-19 pandemic and the ensuing barriers to the collection and transport of donor cells, it is often necessary to collect and cryopreserve grafts before initiation of transplantation conditioning. The effect on transplantation outcomes in nonmalignant disease is unknown. This analysis examined the effect of cryopreservation of related and unrelated donor grafts for transplantation for severe aplastic anemia in the United States during 2013 to 2019. Included are 52 recipients of cryopreserved grafts who were matched for age, donor type, and graft type to 194 recipients who received noncryopreserved grafts. Marginal Cox regression models were built to study the effect of cryopreservation and other risk factors associated with outcomes. We recorded higher 1-year rates of graft failure (hazard ratio [HR], 2.26; 95% confidence interval, 1.17 to 4.35; P = .01) and of 1-year overall mortality (HR, 3.13; 95% CI, 1.60 to 6.11; P = .0008) after transplantation of cryopreserved compared with noncryopreserved grafts, with adjustment for sex, performance score, comorbidity, cytomegalovirus serostatus, and ABO blood group match. The incidence of acute and chronic graft-versus-host disease did not differ between the 2 groups. Adjusted probabilities of 1-year survival were 73% (95% CI, 60% to 84%) in the cryopreserved graft group and 91% (95% CI, 86% to 94%) in the noncryopreserved graft group. These data support the use of noncryopreserved grafts whenever possible in patients with severe aplastic anemia.

Graft Cryopreservation Does Not Impact Overall Survival after Allogeneic Hematopoietic Cell Transplantation Using Post-Transplantation Cyclophosphamide for Graft-versus-Host Disease Prophylaxis.

The COVID-19 pandemic has created significant barriers to timely donor evaluation, cell collection, and graft transport for allogeneic hematopoietic stem cell transplantation (allo-HCT). To ensure availability of donor cells on the scheduled date of infusion, many sites now collect cryopreserved grafts before the start of pretransplantation conditioning. Post-transplantation cyclophosphamide (ptCY) is an increasingly used approach for graft-versus-host disease (GVHD) prophylaxis, but the impact of graft cryopreservation on the outcomes of allo-HCT using ptCY is not known. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we compared the outcomes of HCT using cryopreserved versus fresh grafts in patients undergoing HCT for hematologic malignancy with ptCY. We analyzed 274 patients with hematologic malignancy undergoing allo-HCT between 2013 and 2018 with cryopreserved grafts and ptCY. Eighteen patients received bone marrow grafts and 256 received peripheral blood stem cell grafts. These patients were matched for age, graft type, disease risk index (DRI), and propensity score with 1080 patients who underwent allo-HCT with fresh grafts. The propensity score, which is an assessment of the likelihood of receiving a fresh graft versus a cryopreserved graft, was calculated using logistic regression to account for the following: disease histology, Karnofsky Performance Score (KPS), HCT Comorbidity Index, conditioning regimen intensity, donor type, and recipient race. The primary endpoint was overall survival (OS). Secondary endpoints included acute and chronic graft-versus-host disease (GVHD), non-relapse mortality (NRM), relapse/progression and disease-free survival (DFS). Because of multiple comparisons, only P values <.01 were considered statistically significant. The 2 cohorts (cryopreserved and fresh) were similar in terms of patient age, KPS, diagnosis, DRI, HCT-CI, donor/graft source, and conditioning intensity. One-year probabilities of OS were 71.1% (95% confidence interval [CI], 68.3% to 73.8%) with fresh grafts and 70.3% (95% CI, 64.6% to 75.7%) with cryopreserved grafts (P = .81). Corresponding probabilities of OS at 2 years were 60.6% (95% CI, 57.3% to 63.8%) and 58.7% (95% CI, 51.9% to 65.4%) (P = .62). In matched-pair regression analysis, graft cryopreservation was not associated with a significantly higher risk of mortality (hazard ratio [HR] for cryopreserved versus fresh, 1.05; 95% CI, .86 to 1.29; P = .60). Similarly, rates of neutrophil recovery (HR, .91; 95% CI, .80 to 1.02; P = .12), platelet recovery (HR, .88; 95% CI, .78 to 1.00; P = .05), grade III-IV acute GVHD (HR, .78; 95% CI, .50 to 1.22; P = .27), NRM (HR, 1.16; 95% CI, .86 to 1.55; P = .32) and relapse/progression (HR, 1.21; 95% CI, .97 to 1.50; P = .09) were similar with cryopreserved grafts versus fresh grafts. There were somewhat lower rates of chronic GVHD (HR, 78; 95% CI, .61 to .99; P = .04) and DFS (HR for treatment failure, 1.19; 95% CI, 1.01 to 1.29; P = .04) with graft cryopreservation that were of marginal statistical significance after adjusting for multiple comparisons. Overall, our data indicate that graft cryopreservation does not significantly delay hematopoietic recovery, increase the risk of acute GVHD or NRM, or decrease OS after allo-HCT using ptCY.