ABSTRACT
We aimed to determine the pattern of delay and its effect on the short-term outcomes of total gastrectomy before and during the coronavirus disease 2019 (COVID-19) pandemic. Overlaid line graphs were used to visualize the dynamic changes in the severity of the pandemic, number of gastric cancer patients, and waiting time for a total gastrectomy. We observed a slightly longer waiting time during the pandemic (median: 28.00 days, interquartile range: 22.00–34.75) than before the pandemic (median: 25.00 days, interquartile range: 18.00–34.00;p = 0.0071). Moreover, we study the effect of delayed surgery (waiting time > 30 days) on short-term outcomes using postoperative complications, extreme value of laboratory results, and postoperative stay. In patients who had longer waiting times, we did not observe worse short-term complication rates (grade II–IV: 15% vs. 19%, p = 0.27;grade III–IV: 7.3% vs. 9.2%, p = 0.51, the short waiting group vs. the prolonged waiting group) or a higher risk of a longer POD (univariable: OR 1.09, 95% CI 0.80–1.49, p = 0.59;multivariable: OR 1.10, 95% CI 0.78–1.55, p = 0.59). Patients in the short waiting group, rather than in the delayed surgery group, had an increased risk of bleeding in analyses of laboratory results (plasma prothrombin activity, hemoglobin, and hematocrit). A slightly prolonged preoperative waiting time during COVID-19 pandemic might not influence the short-term outcomes of patients who underwent total gastrectomy.
ABSTRACT
The effect of immune checkpoint blockade on COVID-19 immunity is unclear. In this study, we determine whether immune checkpoint blockade expanded age-associated B cells (ABCs) are similar to those present in other conditions, and whether they enhance or detract from the COVID-19 vaccine responses. First, we use single cell RNA sequencing (scRNAseq) to show that ABCs arising from distinct aetiologies have common transcriptional profiles and may be further subdivided according to expression of genes associated with different immune functions, including the autoimmune regulator (AIRE). Next, we perform detailed longitudinal profiling of the COVID-19 vaccination response in patients. Finally, we show that high pre-vaccination ABC frequency correlates with decreased levels of antigen-specific memory B cells, and reduced magnitude and longevity of neutralising capacity against authentic SARS-CoV-2 virus. Expansion of ABCs is a biomarker for individuals with cancer requiring additional or more frequent booster immunisation against COVID-19.
Subject(s)
COVID-19 , NeoplasmsABSTRACT
Recent studies have identified an association between perturbed type I interferon (IFN) responses and the severity of coronavirus disease 2019 (COVID-19). IFNα intervention may normalize the dysregulated innate immunity of COVID-19. However, details regarding its utilization and therapeutic evidence have yet to be systematically evaluated. The aim of this comprehensive review was to summarize the current utilization of IFNα for COVID-19 treatment and to explore the evidence on safety and efficacy. A comprehensive review of clinical studies in the literature prior to December 1st, 2021, was performed to identify the current utilization of IFNα, which included details on the route of administration, the number of patients who received the treatment, the severity at the initiation of treatment, age range, the time from the onset of symptoms to treatment, dose, frequency, and duration as well as safety and efficacy. Encouragingly, no evidence was found against the safety of IFNα treatment for COVID-19. Early intervention, either within five days from the onset of symptoms or at hospital admission, confers better clinical outcomes, whereas late intervention may result in prolonged hospitalization.
Subject(s)
COVID-19 Drug Treatment , Humans , Interferon-alpha/therapeutic use , SARS-CoV-2 , Treatment OutcomeABSTRACT
Clinical and Immune response characteristics of COVID-19 between severe and non-severe patients have not been fully clarified. In this study, clinical features, antibody responses targeting SARS-CoV-2 spike protein (S) and its different domains, Ig isotypes and IgG subtypes, ACE2 competitive antibodies, binding titers with FcγIIa and FcγIIb receptors, and 14 cytokines were investigated in 119 serum samples from 37 PCR-confirmed COVID-19 patients. Severe group including 9 patients represented lower lymphocyte count, higher neutrophil count, higher level of LDH, total bile acid (TBA) ( P <1×10 -4 ), r-glutaminase ( P =0.011), adenosine deaminase ( P <1×10 -4 ), procalcitonin (P=0.004), C-reactive protein ( P <1×10 -4 ) and D-dimer (P=0.049) compared to non-severe group (28 patients). Significantly, higher-level antibody targeting S (IgA, IgM, and IgG), different S domains specificity (RBD, RBM, NTD, and CTD), FcγIIa and FcγIIb binding capability were observed in severe group than that of non-severe group, of which IgG1 and IgG3 were the main IgG subclasses. RBD-IgG were strongly correlated with S-IgG both in severe group and non-severe group. Additionally, CTD-IgG were strongly correlated with S-IgG in non-severe group. Positive RBD-ACE2 binding inhibition was strongly associated with high titers of antibody (S-IgG1, S-IgG3, NTD-IgG) especially RBD-IgG and CTD-IgG in severe group, while in non-severe group, S-IgG3, RBD-IgG and NTD-IgG titer correlated with ACE2 blocking rate. S-IgG1 was negatively associated with illness days in severe group (r=- 0.434, P=0.002), while S-IgG3 in severe group (r=0.363, P=0.011) and S-IgG1 (r=0.417, P=3×10-4) in non-severe group was positively associated with days after symptom onset. Moreover, GRO-α, IL-6, IL-8, IP-10, MCP-1, MCP-3, MIG, and BAFF were also significantly elevated in severe group. Overall, the results indicated different signatures in clinical and immune responses between the COVID-19 severe group and non-severe group, which will be markedly contributed to future therapeutic and preventive measures development.
Subject(s)
COVID-19ABSTRACT
Background In fulfilling the COVID-19 containment, primary health care (PHC) facilities in China played an important role. We sought to investigate the exact tasks performed at the PHC facilities and the processes of COVID-19 prevention and control.Methods Semi-structured face-to-face interviews for primary care physicians (PCPs) and a simple survey for residents were conducted in the field survey. Based-on purposive stratified sampling, 32 PCPs were selected from 22 PHC facilities in Wuhan as a high-risk city, in Shanghai as medium-risk city and in Zunyi as low-risk city. In the field survey, semi-structured face-to-face interviews were conducted with PCPs to summarize the tasks of COVID-19 prevention and control at the PHC facilities. A simple survey was used to investigate the local residents’ awareness about COVID-19 prevention and control.Results In pre-outbreak period, the PHC facilities mainly engaged in storing medical supplies; in out-break period, they were responsible for screening, transferring, quarantine and treatment; in regular prevention and control period, attention was given to the employees and items of cold-chain & fresh food markets, etc. In Wuhan, PHC facilities focused on graded diagnoses and treatments of patients; in Shanghai, they were mainly engaged in at-home/centralized quarantine; in Zunyi, they focused on the screening of high-risk individuals. In urban areas, COVID-19 were more likely to be transmitted; in urban-rural areas, it was difficult to perform screening on the migrant populations; in rural areas, the risk was much lower. The community residents had satisfactory compliance with the preventive measures.Conclusion We identified differences in the prevention and control tasks performed at the PHC facilities in China. During the different phases of the pandemic, the tasks were adjusted depending on the gradually comprehensive understanding of COVID-19. Among the cities at different risk levels, screening, quarantine, transferring or treatment was chosen to be a priority accordingly. Located in different intra-city geographic locations at different risk levels, the PHC facilities conducted their own tasks accordingly. Additionally, compliance on the part of the local community residents could not be overemphasized in COVID-19 prevention and control.
Subject(s)
COVID-19ABSTRACT
The SARS-CoV-2 protein Nsp2 has been implicated in a wide range of viral processes, but its exact functions, and the structural basis of those functions, remain unknown. Here, we report an atomic model for full-length Nsp2 obtained by combining cryo-electron microscopy with deep learning-based structure prediction from AlphaFold2. The resulting structure reveals a highly-conserved zinc ion-binding site, suggesting a role for Nsp2 in RNA binding. Mapping emerging mutations from variants of SARS-CoV-2 on the resulting structure shows potential host-Nsp2 interaction regions. Using structural analysis together with affinity tagged purification mass spectrometry experiments, we identify Nsp2 mutants that are unable to interact with the actin-nucleation-promoting WASH protein complex or with GIGYF2, an inhibitor of translation initiation and modulator of ribosome-associated quality control. Our work suggests a potential role of Nsp2 in linking viral transcription within the viral replication-transcription complexes (RTC) to the translation initiation of the viral message. Collectively, the structure reported here, combined with mutant interaction mapping, provides a foundation for functional studies of this evolutionary conserved coronavirus protein and may assist future drug design.
ABSTRACT
The SARS-CoV-2 protein Nsp2 has been implicated in a wide range of viral processes, but its exact functions, and the structural basis of those functions, remain unknown. Here, we report an atomic model for full-length Nsp2 obtained by combining cryo-electron microscopy with deep learning-based structure prediction from AlphaFold2. The resulting structure reveals a highly-conserved zinc ion-binding site, suggesting a role for Nsp2 in RNA binding. Mapping emerging mutations from variants of SARS-CoV-2 on the resulting structure shows potential host-Nsp2 interaction regions. Using structural analysis together with affinity tagged purification mass spectrometry experiments, we identify Nsp2 mutants that are unable to interact with the actin-nucleation-promoting WASH protein complex or with GIGYF2, an inhibitor of translation initiation and modulator of ribosome-associated quality control. Our work suggests a potential role of Nsp2 in linking viral transcription within the viral replication-transcription complexes (RTC) to the translation initiation of the viral message. Collectively, the structure reported here, combined with mutant interaction mapping, provides a foundation for functional studies of this evolutionary conserved coronavirus protein and may assist future drug design.
ABSTRACT
Background Early diagnostic indicators and the identification of possible progression to severe or critical COVID-19 in children are unknown. To investigate the immune characteristics of early SARS-CoV-2 infection in children and possible key prognostic factors for early identification of critical COVID-19, a retrospective study including 121 children with COVID-19 was conducted. Peripheral blood lymphocyte subset counts, T cell-derived cytokine concentrations, inflammatory factor concentrations, and routine blood counts were analyzed statistically at the initial presentation. Results The T lymphocyte subset and natural killer cell counts decreased with increasing disease severity. Group III (critical cases) had a higher Th/Tc ratio than groups I and II (common and severe cases); group I had a higher B cell count than groups II and III. IL-6, IL-10, IFN-γ, SAA, and procalcitonin levels increased with disease severity. Hemoglobin concentration, and RBC and eosinophil counts decreased with disease severity. Groups II and III had significantly lower lymphocyte counts than group I. T, Th, Tc, IL-6, IL-10, RBC, and hemoglobin had relatively high contribution and area under the curve values. Conclusions Decreased T, Th, Tc, RBC, hemoglobin and increased IL-6 and IL-10 in early SARS-CoV-2 infection in children are valuable indices for early diagnosis of disease severity. The significantly reduced Th and Tc cells and significantly increased IL-6, IL-10, ferritin, procalcitonin, and SAA at this stage in children with critical COVID-19 may be closely associated with the systemic cytokine storm caused by immune dysregulation.
Subject(s)
COVID-19 , Reflex, AbnormalABSTRACT
Without an effective prophylactic solution, infections from SARS-CoV-2 continue to rise worldwide with devastating health and economic costs. SARS-CoV-2 gains entry into host cells via an interaction between its Spike protein and the host cell receptor angiotensin converting enzyme 2 (ACE2). Disruption of this interaction confers potent neutralization of viral entry, providing an avenue for vaccine design and for therapeutic antibodies. Here, we develop single-domain antibodies (nanobodies) that potently disrupt the interaction between the SARS-CoV-2 Spike and ACE2. By screening a yeast surface-displayed library of synthetic nanobody sequences, we identified a panel of nanobodies that bind to multiple epitopes on Spike and block ACE2 interaction via two distinct mechanisms. Cryogenic electron microscopy (cryo-EM) revealed that one exceptionally stable nanobody, Nb6, binds Spike in a fully inactive conformation with its receptor binding domains (RBDs) locked into their inaccessible down-state, incapable of binding ACE2. Affinity maturation and structure-guided design of multivalency yielded a trivalent nanobody, mNb6-tri, with femtomolar affinity for SARS-CoV-2 Spike and picomolar neutralization of SARS-CoV-2 infection. mNb6-tri retains stability and function after aerosolization, lyophilization, and heat treatment. These properties may enable aerosol-mediated delivery of this potent neutralizer directly to the airway epithelia, promising to yield a widely deployable, patient-friendly prophylactic and/or early infection therapeutic agent to stem the worst pandemic in a century.