Senotherapeutics: An emerging approach to the treatment of viral infectious diseases in the elderly.

In the context of the global COVID-19 pandemic, the phenomenon that the elderly have higher morbidity and mortality is of great concern. Existing evidence suggests that senescence and viral infection interact with each other. Viral infection can lead to the aggravation of senescence through multiple pathways, while virus-induced senescence combined with existing senescence in the elderly aggravates the severity of viral infections and promotes excessive age-related inflammation and multiple organ damage or dysfunction, ultimately resulting in higher mortality. The underlying mechanisms may involve mitochondrial dysfunction, abnormal activation of the cGAS-STING pathway and NLRP3 inflammasome, the role of pre-activated macrophages and over-recruited immune cells, and accumulation of immune cells with trained immunity. Thus, senescence-targeted drugs were shown to have positive effects on the treatment of viral infectious diseases in the elderly, which has received great attention and extensive research. Therefore, this review focused on the relationship between senescence and viral infection, as well as the significance of senotherapeutics for the treatment of viral infectious diseases.

IFITM3 is a host restriction factor that inhibits porcine transmissible gastroenteritis virus infection.

Interferon-induced transmembrane proteins (IFITMs) play an important role in the innate immune response triggered by viral infection. Transmissible gastroenteritis virus (TGEV) causes severe diarrhea, vomiting and dehydration in piglets, resulting in huge economic losses to the swine industry. In this study, we showed that IFITM3 inhibits the replication of TGEV and interferes with the binding of TGEV to PK15 cells. Moreover, the inhibitory effect of IFITM3 on TGEV circumvents the upregulation of inflammatory cytokines. Subsequently, we found that the M22A mutant loses part of the antiviral effect of IFITM3 on TGEV; in contrast, the K24A mutant enhances the antiviral effect of IFITM3. Notably, our data shows a synergistic effect between IFITM3 and CQ, which further amplifies the antiviral effect against TGEV.

Development and validation of chest CT-based imaging biomarkers for early stage COVID-19 screening

Coronavirus Disease 2019 (COVID-19) is currently a global pandemic, and early screening is one of the key factors for COVID-19 control and treatment. Here, we developed and validated chest CT-based imaging biomarkers for COVID-19 patient screening from two independent hospitals with 419 patients. We identified the vasculature-like signals from CT images and found that, compared to healthy and community acquired pneumonia (CAP) patients, COVID-19 patients display a significantly higher abundance of these signals. Furthermore, unsupervised feature learning led to the discovery of clinical-relevant imaging biomarkers from the vasculature-like signals for accurate and sensitive COVID-19 screening that have been double-blindly validated in an independent hospital (sensitivity: 0.941, specificity: 0.920, AUC: 0.971, accuracy 0.931, F1 score: 0.929). Our findings could open a new avenue to assist screening of COVID-19 patients.

Elevated D-dimer and Adverse In-hospital Outcomes in COVID-19 Patients and Synergism with Hyperglycemia.

Aim: One of the most common laboratory findings in COVID-19 patients has been observed to be hypercoagulability with elevated D-dimer levels. An activation of thrombosis may be generated by hyperglycemia. We aimed to explore the association between D-dimer and in-hospital outcomes, and evaluate the synergistic effect between elevated D-dimer and hyperglycemia on COVID-19 prognosis. Methods: A retrospective cohort study was undertaken with 2467 COVID-19 inpatients. D-dimer and fasting blood glucose (FBG) on admission and adverse in-hospital outcomes (events of death and aggravated severity) were collected. Cox proportional risk model was performed to assess the association of D-dimer and adverse in-hospital outcomes, and the combined effects of D-dimer and FBG. Results: Among these COVID-19 patients, 1100 (44.6%) patients had high D-dimer (≥0.50 mg/L). Patients with high D-dimer were older, with higher FBG (≥7.00 mmol/L), and had significantly higher adjusted risk of adverse in-hospital outcomes when comparing with those who with D-dimer<0.50 mg/L (hazard ratio, 2.73; 95% confidence interval, 1.46-5.11). Moreover, patients with high FBG and D-dimer levels had an increasing risk (hazard ratio, 5.72; 95% confidence interval: 2.65-12.34) than those with normal FBG and D-dimer. Conclusion: Risk of adverse in-hospital outcomes is higher among patients with high D-dimer levels. Additionally, this study found for the first time that elevated D-dimer and hyperglycemia had a synergistic effect on COVID-19 prognosis, and this risk was independent of diabetes history.

BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by Omicron infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages BA.2.12.1, BA.4 and BA.5 exhibit higher transmissibility than the BA.2 lineage1. The receptor binding and immune-evasion capability of these recently emerged variants require immediate investigation. Here, coupled with structural comparisons of the spike proteins, we show that BA.2.12.1, BA.4 and BA.5 (BA.4 and BA.5 are hereafter referred collectively to as BA.4/BA.5) exhibit similar binding affinities to BA.2 for the angiotensin-converting enzyme 2 (ACE2) receptor. Of note, BA.2.12.1 and BA.4/BA.5 display increased evasion of neutralizing antibodies compared with BA.2 against plasma from triple-vaccinated individuals or from individuals who developed a BA.1 infection after vaccination. To delineate the underlying antibody-evasion mechanism, we determined the escape mutation profiles2, epitope distribution3 and Omicron-neutralization efficiency of 1,640 neutralizing antibodies directed against the receptor-binding domain of the viral spike protein, including 614 antibodies isolated from people who had recovered from BA.1 infection. BA.1 infection after vaccination predominantly recalls humoral immune memory directed against ancestral (hereafter referred to as wild-type (WT)) SARS-CoV-2 spike protein. The resulting elicited antibodies could neutralize both WT SARS-CoV-2 and BA.1 and are enriched on epitopes on spike that do not bind ACE2. However, most of these cross-reactive neutralizing antibodies are evaded by spike mutants L452Q, L452R and F486V. BA.1 infection can also induce new clones of BA.1-specific antibodies that potently neutralize BA.1. Nevertheless, these neutralizing antibodies are largely evaded by BA.2 and BA.4/BA.5 owing to D405N and F486V mutations, and react weakly to pre-Omicron variants, exhibiting narrow neutralization breadths. The therapeutic neutralizing antibodies bebtelovimab4 and cilgavimab5 can effectively neutralize BA.2.12.1 and BA.4/BA.5, whereas the S371F, D405N and R408S mutations undermine most broadly sarbecovirus-neutralizing antibodies. Together, our results indicate that Omicron may evolve mutations to evade the humoral immunity elicited by BA.1 infection, suggesting that BA.1-derived vaccine boosters may not achieve broad-spectrum protection against new Omicron variants.

Prediction and analysis of COVID-19 daily new cases and cumulative cases: times series forecasting and machine learning models.

BACKGROUND: COVID-19 poses a severe threat to global human health, especially the USA, Brazil, and India cases continue to increase dynamically, which has a far-reaching impact on people's health, social activities, and the local economic situation. METHODS: The study proposed the ARIMA, SARIMA and Prophet models to predict daily new cases and cumulative confirmed cases in the USA, Brazil and India over the next 30 days based on the COVID-19 new confirmed cases and cumulative confirmed cases data set(May 1, 2020, and November 30, 2021) published by the official WHO, Three models were implemented in the R 4.1.1 software with forecast and prophet package. The performance of different models was evaluated by using root mean square error (RMSE), mean absolute error (MAE) and mean absolute percentage error (MAPE). RESULTS: Through the fitting and prediction of daily new case data, we reveal that the Prophet model has more advantages in the prediction of the COVID-19 of the USA, which could compose data components and capture periodic characteristics when the data changes significantly, while SARIMA is more likely to appear over-fitting in the USA. And the SARIMA model captured a seven-day period hidden in daily COVID-19 new cases from 3 countries. While in the prediction of new cumulative cases, the ARIMA model has a better ability to fit and predict the data with a positive growth trend in different countries(Brazil and India). CONCLUSIONS: This study can shed light on understanding the outbreak trends and give an insight into the epidemiological control of these regions. Further, the prediction of the Prophet model showed sufficient accuracy in the daily COVID-19 new cases of the USA. The ARIMA model is suitable for predicting Brazil and India, which can help take precautions and policy formulation for this epidemic in other countries.

Structural Comparison and Drug Screening of Spike Proteins of Ten SARS-CoV-2 Variants.

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) has evolved many variants with stronger infectivity and immune evasion than the original strain, including Alpha, Beta, Gamma, Delta, Epsilon, Kappa, Iota, Lambda, and 21H strains. Amino acid mutations are enriched in the spike protein of SARS-CoV-2, which plays a crucial role in cell infection. However, the impact of these mutations on protein structure and function is unclear. Understanding the pathophysiology and pandemic features of these SARS-CoV-2 variants requires knowledge of the spike protein structures. Here, we obtained the spike protein structures of 10 main globally endemic SARS-CoV-2 strains using AlphaFold2. The clustering analysis based on structural similarity revealed the unique features of the mainly pandemic SARS-CoV-2 Delta variants, indicating that structural clusters can reflect the current characteristics of the epidemic more accurately than those based on the protein sequence. The analysis of the binding affinities of ACE2-RBD, antibody-NTD, and antibody-RBD complexes in the different variants revealed that the recognition of antibodies against S1 NTD and RBD was decreased in the variants, especially the Delta variant compared with the original strain, which may induce the immune evasion of SARS-CoV-2 variants. Furthermore, by virtual screening the ZINC database against a high-accuracy predicted structure of Delta spike protein and experimental validation, we identified multiple compounds that target S1 NTD and RBD, which might contribute towards the development of clinical anti-SARS-CoV-2 medicines. Our findings provided a basic foundation for future in vitro and in vivo investigations that might speed up the development of potential therapies for the SARS-CoV-2 variants.

Chinese Medicine Formula Huashibaidu Granule Early Treatment for Mild COVID-19 Patients: An Unblinded, Cluster-Randomized Clinical Trial.

Background: Previous research suggested that Chinese Medicine (CM) Formula Huashibaidu granule might shorten the disease course in coronavirus disease 2019 (COVID-19) patients. This research aimed to investigate the early treatment effect of Huashibaidu granule in well-managed patients with mild COVID-19. Methods: An unblinded cluster-randomized clinical trial was conducted at the Dongxihu FangCang hospital. Two cabins were randomly allocated to a CM or control group, with 204 mild COVID-19 participants in each cabin. All participants received conventional treatment over a 7 day period, while the ones in CM group were additionally given Huashibaidu granule 10 g twice daily. Participants were followed up to their clinical endpoint. The primary outcome was worsening symptoms before the clinical endpoint. The secondary outcomes were cure and discharge before the clinical endpoint and alleviation of composite symptoms after the 7 days of treatment. Results: All 408 participants were followed up to their clinical endpoint and included in statistical analysis. Baseline characteristics were comparable between the two groups (P > 0.05). The number of worsening patients in the CM group was 5 (2.5%), and that in the control group was 16 (7.8%) with a significant difference between groups (P = 0.014). Eight foreseeable mild adverse events occurred without statistical difference between groups (P = 0.151). Conclusion: Seven days of early treatment with Huashibaidu granule reduced the likelihood of worsening symptoms in patients with mild COVID-19. Our study supports Huashibaidu granule as an active option for early treatment of mild COVID-19 in similar well-managed medical environments. Clinical Trial Registration:www.chictr.org.cn/showproj.aspx?proj=49408, identifier: ChiCTR2000029763.

Coordinated Management of COVID-19 Response: Lessons From Whole-of-Society and Whole-of-Health Strategies in Wuhan, China.

Background: The outbreak of novel coronavirus disease 2019 (COVID-19) has been challenging globally following the scarcity of medical resources after a surge in demand. As the pandemic continues, the question remains on how to accomplish more with the existing resources and improve the efficiency of existing health care delivery systems worldwide. In this study, we reviewed the experience from Wuhan - the first city to experience a COVID-19 outbreak - that has presently shown evidence for efficient and effective local control of the epidemic. Material and Methods: We performed a retrospective qualitative study based on the document analysis of COVID-19-related materials and interviews with first-line people in Wuhan. Results: We extracted two themes (the evolution of Wuhan's prevention and control strategies on COVID-19 and corresponding effectiveness) and four sub-themes (routine prevention and control period, exploration period of targeted prevention and control strategies, mature period of prevention and control strategies, and recovery period). How Wuhan combatted COVID-19 through multi-tiered and multi-sectoral collaboration, overcoming its fragmented, hospital-centered, and treatment-dominated healthcare system, was illustrated and summarized. Conclusion: Four lessons for COVID-19 prevention and control were summarized: (a) Engage the communities and primary care not only in supporting but also in screening and controlling, and retain community and primary care as among the first line of COVID-19 defense; (b) Extend and stratify the existing health care delivery system; (c) Integrate person-centered integrated care into the whole coordination; and (d) Delink the revenue relationship between doctors and patients and safeguard the free-will of physicians when treating patients.

High Performance of SARS-Cov-2N Protein Antigen Chemiluminescence Immunoassay as Frontline Testing for Acute Phase COVID-19 Diagnosis: A Retrospective Cohort Study.

Objectives: COVID-19 emerged and rapidly spread throughout the world. Testing strategies focussing on patients with COVID-19 require assays that are high-throughput, low-risk of infection, and with small sample volumes. Antigen surveillance can be used to identify exposure to pathogens and measure acute infections. Methods: A total of 914 serum samples, collected from 309 currently infected COVID-19 patients, 48 recovered ones, and 410 non-COVID-19 patients, were used to measure N protein antigen levels by a chemilumineseent immunoassay. Diagnostic performances were analyzed in different periods after onset. Results: There was a high level of N protein antigen in COVID-19 patients (0.56 COI), comparing to the recovered patients (0.12 COI) and controls (0.19 COI). In receiver-operating characteristic curve analysis, the area under the curve of serum N protein antigen was 0.911 in the first week after onset. In this period, Sensitivity and specificity of serologic N protein antigen testing was 76.27 and 98.78%. Diagnosis performance of specific antibodies became better from the third week after onset. Subgroup analysis suggested that severe patients had higher levels of antigens than mild patients. Conclusions: High level of serum antigen suggested early infection and serious illness. Serum N protein antigen testing by chemiluminescence immunoassay is considered as a viable assay used to improve diagnostic sensitivity for current patients.

Characterization of Chloroplast Genomes From Two Salvia Medicinal Plants and Gene Transfer Among Their Mitochondrial and Chloroplast Genomes.

Salvia species have been widely used as medicinal plants and have played an important role in the treatment and recovery of individuals with COVID-19. In this study, we reported two newly identified whole chloroplast genome sequences of Salvia medicinal plants (Salvia yangii and Salvia miltiorrhiza f. alba) and compared them with those of seven other reported Salvia chloroplast genomes. These were proven to be highly similar in terms of overall size, genome structure, gene content, and gene order. We identified 10 mutation hot spots (trnK-rps16, atpH-atpI, psaA-ycf3, ndhC-trnV, ndhF, rpl32-trnL, ndhG-ndhI, rps15-ycf1, ycf1a, and ycf1b) as candidate DNA barcodes for Salvia. Additionally, we observed the transfer of nine large-sized chloroplast genome fragments, with a total size of 49,895 bp (accounting for 32.97% of the chloroplast genome), into the mitochondrial genome as they shared >97% sequence similarity. Phylogenetic analyses of the whole chloroplast genome provided a high resolution of Salvia. This study will pave the way for the identification and breeding of Salvia medicinal plants and further phylogenetic evolutionary research on them as well.

The Utility of Specific Antibodies Against SARS-CoV-2 in Laboratory Diagnosis.

The Coronavirus Disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has now become a global pandemic due to its high transmissibility. The unavoidable shortcomings of traditional diagnostic assay, including nucleic acid testing, diverse serological assays characterized by high-throughput and less workload, are playing a more and more crucial role to supplement the nucleic acid test. In this review, we summarize the dynamic change of the specific IgM, IgG, and IgA antibodies against SARS-CoV-2 as well as neutralizing antibodies and discuss the clinical utility and limitations of the different serological assays. SARS-CoV-2, a newly discovered virus, shows some unique pathogenetic and epidemiological characteristics that have not been completely understood so far. Currently, studies about the antibody responses against SARS-CoV-2 and the clinical utility of serological testing are increasing. It's well suggested that the combination of serological tests and nucleic acid tests can cohesively improve the testing efficiency for identifying COVID-19 suspected patients.

Tracheostomy in 80 COVID-19 Patients: A Multicenter, Retrospective, Observational Study.

Background: The outbreak of coronavirus disease 2019 (COVID-19) has led to a large and increasing number of patients requiring prolonged mechanical ventilation and tracheostomy. The indication and optimal timing of tracheostomy in COVID-19 patients are still unclear, and the outcomes about tracheostomy have not been extensively reported. We aimed to describe the clinical characteristics and outcomes of patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia who underwent elective tracheostomies. Methods: The multi-center, retrospective, observational study investigated all the COVID-19 patients who underwent elective tracheostomies in intensive care units (ICUs) of 23 hospitals in Hubei province, China, from January 8, 2020 to March 25, 2020. Demographic information, clinical characteristics, treatment, details of the tracheostomy procedure, successful weaning after tracheostomy, and living status were collected and analyzed. Data were compared between early tracheostomy patients (tracheostomy performed within 14 days of intubation) and late tracheostomy patients (tracheostomy performed after 14 days). Results: A total of 80 patients were included. The median duration from endotracheal intubation to tracheostomy was 17.5 [IQR 11.3-27.0] days. Most tracheotomies were performed by ICU physician [62 (77.5%)], and using percutaneous techniques [63 (78.8%)] at the ICU bedside [76 (95.0%)]. The most common complication was tracheostoma bleeding [14 (17.5%)], and major bleeding occurred in 4 (5.0%) patients. At 60 days after intubation, 31 (38.8%) patients experienced successful weaning from ventilator, 17 (21.2%) patients discharged from ICU, and 43 (53.8%) patients had died. Higher 60 day mortality [22 (73.3%) vs. 21 (42.0%)] were identified in patients who underwent early tracheostomy. Conclusions: In patients with SARS-CoV-2 pneumonia, tracheostomies were feasible to conduct by ICU physician at bedside with few major complications. Compared with tracheostomies conducted after 14 days of intubation, tracheostomies within 14 days were associated with an increased mortality rate.

Clinical characteristics of imported and second-generation coronavirus disease 2019 (COVID-19) cases in Shaanxi outside Wuhan, China: a multicentre retrospective study.

The mortality of coronavirus disease 2019 (COVID-19) differs between countries and regions. This study aimed to clarify the clinical characteristics of imported and second-generation cases in Shaanxi. This study included 134 COVID-19 cases in Shaanxi outside Wuhan. Clinical data were compared between severe and non-severe cases. We further profiled the dynamic laboratory findings of some patients. In total, 34.3% of the 134 patients were severe cases, 11.2% had complications. As of 7 March 2020, 91.8% patients were discharged and one patient (0.7%) died. Age, lymphocyte count, C-reactive protein, erythrocyte sedimentation rate, direct bilirubin, lactate dehydrogenase and hydroxybutyrate dehydrogenase showed difference between severe and no-severe cases (all P < 0.05). Baseline lymphocyte count was higher in survived patients than in non-survivor case, and it increased as the condition improved, but declined sharply when death occurred. The interleukin-6 (IL-6) level displayed a downtrend in survivors, but rose very high in the death case. Pulmonary fibrosis was found on later chest computed tomography images in 51.5% of the pneumonia cases. Imported and second-generation cases outside Wuhan had a better prognosis than initial cases in Wuhan. Lymphocyte count and IL-6 level could be used for evaluating prognosis. Pulmonary fibrosis as the sequelae of COVID-19 should be taken into account.

Clinical Characteristics and Outcomes of 421 Patients With Coronavirus Disease 2019 Treated in a Mobile Cabin Hospital

Background: In December 2019, a novel coronavirus-associated pneumonia, now known as coronavirus disease 2019 (COVID-19), was first detected in Wuhan, China. To prevent the rapid spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and treat patients with mild symptoms, sports stadiums and convention centers were reconstructed into mobile hospitals. Research Question: It is unknown whether a mobile cabin hospital can provide a safe treatment site for patients with mild COVID-19 symptoms. Study Design and Methods: This study retrospectively reviewed the medical records of 421 patients with COVID-19 admitted to a mobile cabin hospital in Wuhan from February 9, 2020, to March 5, 2020. Clinical data comprised patient age, sex, clinical presentation, chest imaging, nucleic acid testing, length of hospitalization, and outcomes. Results: Of the patients who were discharged from the cabin hospital, 362 (86.0%) were categorized as recovered;14.0% developed severe symptoms and were transferred to a designated hospital. The most common presenting symptoms were fever (60.6%) and cough (52.0%);5.2% exhibited no obvious symptoms. High fever (> 39.0°C) was more common in severe cases than in recovered cases (18.6% vs 6.6%). The distribution of lung lesions was peripheral in 85.0% of patients, multifocal in 69.4%, and bilateral in 68.2%. The most common pattern was ground-glass opacity (67.7%), followed by patchy shadowing (49.2%). The incidence of patchy shadowing was higher in patients with severe disease (66.1%) than in those who recovered (31.8%, P < .0001). The median length of hospitalization was 17 days (interquartile range, 14-19 days), and the median time taken for positive real-time reverse transcriptase polymerase chain reaction results to become negative in recovered patients was 8 days (interquartile range, 6-10 days). Interpretation: Mobile cabin hospitals provide a safe treatment site for patients with mild COVID-19 symptoms and offer an effective isolation area to prevent the spread of severe acute respiratory syndrome coronavirus 2.