Origin and Reversion of Omicron Core Mutations in the Evolution of SARS-CoV-2 Genomes.

Genetic analyses showed nearly 30 amino acid mutations occurred in the spike protein of the Omicron variant of SARS-CoV-2. However, how these mutations occurred and changed during the generation and development of Omicron remains unclear. In this study, 6.7 million (all publicly available data from 2020/04/01 to 2022/04/01) SARS-CoV-2 genomes were analyzed to track the origin and evolution of Omicron variants and to reveal the genetic pathways of the generation of core mutations in Omicron. The haplotype network visualized the pre-Omicron, intact-Omicron, and post-Omicron variants and revealed their evolutionary direction. The correlation analysis showed the correlation feature of the core mutations in Omicron. Moreover, we found some core mutations, such as 142D, 417N, 440K, and 764K, reversed to ancestral residues (142G, 417K, 440N, and 764N) in the post-Omicron variant, suggesting the reverse mutations provided sources for the emergence of new variants. In summary, our analysis probed the origin and further evolution of Omicron sub-variants, which may add to our understanding of new variants and facilitate the control of the pandemic.

Real-World Effectiveness of Sotrovimab for the Early Treatment of COVID-19 During SARS-CoV-2 Delta and Omicron Waves in the USA.

INTRODUCTION: Sotrovimab, a recombinant human monoclonal antibody (mAb) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had US Food and Drug Administration Emergency Use Authorization for the treatment of high-risk outpatients with mild-to-moderate coronavirus disease 2019 (COVID-19) from 26 May 2021 to 5 April 2022. Real-world clinical effectiveness of sotrovimab in reducing the risk of 30-day all-cause hospitalization and/or mortality was evaluated for the period when the prevalence of circulating SARS-CoV-2 variants changed between Delta and Omicron in the USA. METHODS: A retrospective analysis was conducted of de-identified patients diagnosed with COVID-19 between 1 September 2021 to 30 April 2022 in the FAIR Health National Private Insurance Claims database. Patients meeting high-risk criteria were divided into two cohorts: sotrovimab and not treated with a mAb ("no mAb"). All-cause hospitalizations and facility-reported mortality ≤ 30 days of diagnosis ("30-day hospitalization or mortality") were identified. Multivariable and propensity score-matched Poisson and logistic regressions were conducted to estimate the adjusted relative risk (RR) and odds of 30-day hospitalization or mortality in each cohort. RESULTS: Compared with the no mAb cohort (n = 1,514,868), the sotrovimab cohort (n = 15,633) was older and had a higher proportion of patients with high-risk conditions. In the no mAb cohort, 84,307 (5.57%) patients were hospitalized and 8167 (0.54%) deaths were identified, while in the sotrovimab cohort, 418 (2.67%) patients were hospitalized and 13 (0.08%) deaths were identified. After adjusting for potential confounders, the sotrovimab cohort had a 55% lower risk of 30-day hospitalization or mortality (RR 0.45, 95% CI 0.41-0.49) and an 85% lower risk of 30-day mortality (RR 0.15, 95% CI 0.08-0.29). Monthly, from September 2021 to April 2022, the RR reduction for 30-day hospitalization or mortality in the sotrovimab cohort was maintained, ranging from 46% to 71% compared with the no mAb cohort; the RR estimate in April 2022 was uncertain, with wide confidence intervals due to the small sample size. CONCLUSION: Sotrovimab was associated with reduced risk of 30-day all-cause hospitalization and mortality versus no mAb treatment. Clinical effectiveness persisted during Delta and early Omicron variant waves and among all high-risk subgroups assessed.

CRISPR/Cas Genome Editing Technologies for Plant Improvement against Biotic and Abiotic Stresses: Advances, Limitations, and Future Perspectives.

Crossbreeding, mutation breeding, and traditional transgenic breeding take much time to improve desirable characters/traits. CRISPR/Cas-mediated genome editing (GE) is a game-changing tool that can create variation in desired traits, such as biotic and abiotic resistance, increase quality and yield in less time with easy applications, high efficiency, and low cost in producing the targeted edits for rapid improvement of crop plants. Plant pathogens and the severe environment cause considerable crop losses worldwide. GE approaches have emerged and opened new doors for breeding multiple-resistance crop varieties. Here, we have summarized recent advances in CRISPR/Cas-mediated GE for resistance against biotic and abiotic stresses in a crop molecular breeding program that includes the modification and improvement of genes response to biotic stresses induced by fungus, virus, and bacterial pathogens. We also discussed in depth the application of CRISPR/Cas for abiotic stresses (herbicide, drought, heat, and cold) in plants. In addition, we discussed the limitations and future challenges faced by breeders using GE tools for crop improvement and suggested directions for future improvements in GE for agricultural applications, providing novel ideas to create super cultivars with broad resistance to biotic and abiotic stress.

Antibody therapy reverses biological signatures of COVID-19 progression.

Understanding who is at risk of progression to severe coronavirus disease 2019 (COVID-19) is key to clinical decision making and effective treatment. We study correlates of disease severity in the COMET-ICE clinical trial that randomized 1:1 to placebo or to sotrovimab, a monoclonal antibody for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (ClinicalTrials.gov04545060). Laboratory parameters identify study participants at greater risk of severe disease, including a high neutrophil-to-lymphocyte ratio (NLR), a negative SARS-CoV-2 serologic test, and whole-blood transcriptome profiles. Sotrovimab treatment is associated with normalization of NLR and the transcriptomic profile and with a decrease of viral RNA in nasopharyngeal samples. Transcriptomics provides the most sensitive detection of participants who would go on to be hospitalized or die. To facilitate timely measurement, we identify a 10-gene signature with similar predictive accuracy. We identify markers of risk for disease progression and demonstrate that normalization of these parameters occurs with antibody treatment of established infection.

Mapping Genetic Events of SARS-CoV-2 Variants.

Genetic mutation and recombination are driving the evolution of SARS-CoV-2, leaving many genetic imprints which could be utilized to track the evolutionary pathway of SARS-CoV-2 and explore the relationships among variants. Here, we constructed a complete genetic map, showing the explicit evolutionary relationship among all SARS-CoV-2 variants including 58 groups and 46 recombination types identified from 3,392,553 sequences, which enables us to keep well informed of the evolution of SARS-CoV-2 and quickly determine the parents of novel variants. We found that the 5' and 3' of the spike and nucleoprotein genes have high frequencies to form the recombination junctions and that the RBD region in S gene is always exchanged as a whole. Although these recombinants did not show advantages in community transmission, it is necessary to keep a wary eye on the novel genetic events, in particular, the mutants with mutations on spike and recombinants with exchanged moieties on spike gene.

Application of a time-delay SIR model with vaccination in COVID-19 prediction and its optimal control strategy (preprint)

In the classical infectious disease compartment model, the parameters are fixed. In reality, the probability of virus transmission in the process of disease transmission depends on the concentration of virus in the environment, and the concentration depends on the proportion of patients in the environment. Therefore, the probability of virus transmission changes with time. Then how to fit the parameters and get the trend of the parameters changing with time is the key to predict the disease course with the model. In this paper, based on the US COVID-19 epidemic statistics during calibration period, the parameters such as incidence rate and recovery rate are fitted by using the linear regression algorithm of machine science, and the laws of these parameters changing with time are obtained. Then a SIR model with time delay and vaccination is proposed, and the optimal control strategy of epidemic situation is analyzed by using the optimal control theory and Pontryagin maximum principle, which proves  the effectiveness of the control strategy in restraining the spread of COVID-19. The numerical simulation results show that the time-varying law of the number of active cases obtained by our model basically conforms to the real changing law of the US COVID-19 epidemic statistics during calibration period. In addition, we have predicted the changes of the number of active cases in the COVID-19 epidemic in the United States over time in the future beyond the calibration cycle, and the predicted results are more in line with the actual epidemic data.

Novel nucleocapsid protein-targeting phenanthridine inhibitors of SARS-CoV-2.

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unprecedented in human history. As a major structural protein, nucleocapsid protein (NPro) is critical to the replication of SARS-CoV-2. In this work, 17 NPro-targeting phenanthridine derivatives were rationally designed and synthesized, based on the crystal structure of NPro. Most of these compounds can interact with SARS-CoV-2 NPro tightly and inhibit the replication of SARS-CoV-2 in vitro. Compounds 12 and 16 exhibited the most potent anti-viral activities with 50% effective concentration values of 3.69 and 2.18 µM, respectively. Furthermore, site-directed mutagenesis of NPro and Surface Plasmon Resonance (SPR) assays revealed that 12 and 16 target N-terminal domain (NTD) of NPro by binding to Tyr109. This work found two potent anti-SARS-CoV-2 bioactive compounds and also indicated that SARS-CoV-2 NPro-NTD can be a target for new anti-virus agents.

One year of SARS-CoV-2 evolution.

Since the outbreak of SARS-CoV-2, the etiologic agent of the COVID-19 pandemic, the viral genome has acquired numerous mutations with the potential to increase transmission. One year after its emergence, we now further analyze emergent SARS-CoV-2 genome sequences in an effort to understand the evolution of this virus.

Collection calendar: the diversity and local knowledge of wild edible plants used by Chenthang Sherpa people to treat seasonal food shortages in Tibet, China.

BACKGROUND: Wild edible plants (WEPs) are non-cultivated and non-domesticated plants used for food. WEPs provided food, nutrition, herbs and other plant products for people in underdeveloped areas, such as the Everest region, to maintain their daily lives. Chenthang Town is the only Sherpa ethnic township in Tibet, China. The core purpose of this research is to investigate, collect and record the WEPs and related local knowledge and functions within the Sherpa community. The ultimate goal is to answer the question of why Sherpa people choose these particular plants. MATERIALS AND METHODS: The field study was carried out in the six Sherpa communities of Chenthang Township from September 2019 to August 2020. The WEPs and related local knowledge were collected through semistructured interviews and direct observations. The field work was performed with the assistance of local guides. During the field survey, we collected plant specimens based on the principle of one plant with one vernacular name. In this study, we utilised a use report (UR) and cultural importance index (CI) to evaluate the comprehensive utilization value of WEPs in the daily diet of Sherpa people. RESULTS: We interviewed 78 people individually who provided us with 1199 use reports. In total, we collected 84 WEPs belonging to 65 genera in 41 families. These species were identified as 78 distinct ethno-species by local people, and the vernacular name of each ethno-species was recorded. Then, these use reports were classified into six use categories. All these plants were native wild plants. In these plants, Arisaema utile, Sorbus cuspidata and Elaeagnus umbellata have been introduced into home gardens by local people. Following the description of the Sherpa people, we articulated a collection calendar for WEPs. The Sherpa collect WEPs throughout nearly the entire year, January and February being the exceptions. CONCLUSION: The collection calendar of wild edible plants reflects the wisdom of the Sherpa in terms of survival. The Sherpa cleverly survive the food shortage periods by harnessing the phenology of different species. In general, WEPs can provide the Sherpa with seasonal carbohydrates, nutrition, healthcare supplements and other products and services necessary for survival, which is likely why the Sherpa choose these plants.

Co-mutation modules capture the evolution and transmission patterns of SARS-CoV-2.

The rapid spread and huge impact of the COVID-19 pandemic caused by the emerging SARS-CoV-2 have driven large efforts for sequencing and analyzing the viral genomes. Mutation analyses have revealed that the virus keeps mutating and shows a certain degree of genetic diversity, which could result in the alteration of its infectivity and pathogenicity. Therefore, appropriate delineation of SARS-CoV-2 genetic variants enables us to understand its evolution and transmission patterns. By focusing on the nucleotides that co-substituted, we first identified 42 co-mutation modules that consist of at least two co-substituted nucleotides during the SARS-CoV-2 evolution. Then based on these co-mutation modules, we classified the SARS-CoV-2 population into 43 groups and further identified the phylogenetic relationships among groups based on the number of inconsistent co-mutation modules, which were validated with phylogenetic trees. Intuitively, we tracked tempo-spatial patterns of the 43 groups, of which 11 groups were geographic-specific. Different epidemic periods showed specific co-circulating groups, where the dominant groups existed and had multiple sub-groups of parallel evolution. Our work enables us to capture the evolution and transmission patterns of SARS-CoV-2, which can contribute to guiding the prevention and control of the COVID-19 pandemic. An interactive website for grouping SARS-CoV-2 genomes and visualizing the spatio-temporal distribution of groups is available at https://www.jianglab.tech/cmm-grouping/.

Recommendation to Use Wearable-Based mHealth in Closed-Loop Management of Acute Cardiovascular Disease Patients During the COVID-19 Pandemic.

Because of the rapid and serious nature of acute cardiovascular disease (CVD) especially ST segment elevation myocardial infarction (STEMI), a leading cause of death worldwide, prompt diagnosis and treatment is of crucial importance to reduce both mortality and morbidity. During a pandemic such as coronavirus disease-2019 (COVID-19), it is critical to balance cardiovascular emergencies with infectious risk. In this work, we recommend using wearable device based mobile health (mHealth) as an early screening and real-time monitoring tool to address this balance and facilitate remote monitoring to tackle this unprecedented challenge. This recommendation may help to improve the efficiency and effectiveness of acute CVD patient management while reducing infection risk.

[Effect of moxibustion on clinical symptoms, peripheral inflammatory indexes and T lymphocyte subsets in COVID-19 patients].

OBJECTIVE: To explore the therapeutic effect and the mechanism of the adjuvant treatment with moxibustion on coronavirus disease 2019 (COVID-19). METHODS: A total of 95 patients with COVID-19 were randomly divided into a moxibustion group (45 cases) and a basic treatment group (50 cases). The routine treatment of western medicine was applied in the patients of both groups. In the moxibustion group, on the base of the treatment of western medicine, moxibustion was applied to Dazhui (GV 14), Feishu (BL 13), Qihai (CV 6) and Zusanli (ST 36), once daily and consecutively for 14 days. At the end of treatment courses, clinical symptom scores for cough, asthmatic breathing, chest oppression and short breath, as well as their remission rates were compared between the two groups before and after treatment. Before and after treatment, the white blood cell (WBC) count, the levels of c-reactive protein (CRP) and interleukin-6 (IL-6) and the absolute number of T lymphocyte subsets, i.e. , and of the peripheral blood were compared in the patients between the two groups. The principal component analysis was adopted to analyze the common data extracted from the above 10 clinical indexes variables and comprehensively evaluate the differences in the therapeutic effect of two regimens. RESULTS: The clinical symptom scores were all decreased after treatment in both of the moxibustion group and the basic treatment group as compared with those before treatment (P<0.05). After treatment, the clinical symptom scores of cough, chest oppression and asthmatic breathing in the moxibustion group were lower significantly than those in the basic treatment group (P<0.05) and the remission rates of cough, chest oppression and asthmatic breathing were higher than the basic treatment group (P<0.05). After treatment, WBC count was increased as compared with that before treatment in either group (P<0.05) and the levels of CRP and IL-6 in the moxibustion group were reduced as compared with those before treatment (P<0.05). The reducing range of IL-6 level in the moxibustion group was larger than the basic treatment group (P<0.05). After treatment, the absolute number of , and T lymphocytes was increased as compared with that before treatment in the moxibustion group (P<0.05), and its increase range was larger than the basic treatment group (P<0.05). The difference value was 33.38 for the score of comprehensive evaluation before and after treatment in the moxbustion group, higher obviously than 8.91 in the basic treatment group. CONCLUSION: On the base of the routine treatment with western medicine, moxibustion therapy supplemented relieves the clinical symptoms, reduces the levels of inflammatory indexes, i.e. IL-6 and CRP as well as improves the absolute number of peripheral T lymphocyte subsets. The clinical therapeutic effect of such regimen with moxibustion supplemented is significantly better than the simple routine treatment of western medicine.

Red cell distribution width (RDW): a prognostic indicator of severe COVID-19.

BACKGROUND: The global mortality rate for coronavirus disease 2019 (COVID-19) is 3.68%, but the mortality rate for critically ill patients is as high as 50%. Therefore, the exploration of prognostic predictors for patients with COVID-19 is vital for prompt clinical intervention. Our study aims to explore the predictive value of hematological parameters in the prognosis of patients with severe COVID-19. METHODS: Ninety-eight patients who were diagnosed with COVID-19 at Jingzhou Central Hospital and Central Hospital of Wuhan, Hubei Province, were included in this study. RESULTS: The median age of the patients was 59 [28-80] years; the median age of patients with a good prognosis was 56 [28-79] years, and the median age of patients with a poor outcome was 67 [35-80] years. The patients in the poor outcome group were older than the patients in the good outcome group (P<0.05). The comparison of hematological parameters showed that lymphocyte count (Lym#), red blood cells (RBCs), hemoglobin (HGB), hematocrit (HCT), mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH) were significantly lower in the poor outcome group than in the good outcome group (P<0.05). Further, the red cell volume distribution width-CV (RDW-CV) and red cell volume distribution width-SD (RDW-SD) were significantly higher in the poor outcome group than in the good outcome group (P<0.0001). Receiver operating characteristic (ROC) curves showed RDW-SD, with an area under the ROC curve (AUC) of 0.870 [95% confidence interval (CI) 0.796-0.943], was the most significant single parameter for predicting the prognosis of severe patients. When the cut-off value was 42.15, the sensitivity and specificity of RDW-SD for predicting the prognosis of severe patients were 73.1% and 80.2%, respectively. Reticulocyte (RET) channel results showed the RET level was significantly higher in critical patients than in moderate patients and severe patients (P<0.05), which may be one cause of the elevated RDW in patients with a poor outcome. CONCLUSIONS: In this study, the hematological parameters of COVID-19 patients were statistically analyzed. RDW was found to be a prognostic predictor for patients with severe COVID-19, and the increase in RET may contribute to elevated RDW.

New HIV diagnoses in patients with COVID-19: two case reports and a brief literature review.

BACKGROUND: COVID-19 is novel infectious disease with an evolving understanding of its epidemiology and clinical manifestations. Severe cases developed life-threatening complications, such as respiratory failure, shock, and multiple organs dysfunction. Immunocompromised patients often present atypical presentations of viral infected diseases. CASE PRESENTATION: We report newly diagnosed HIV infections in two patients with COVID-19 in China. In our two cases, both patients with elevated IL-6 received Tocilizumab treatment, but did not present obvious therapeutic effect. CONCLUSIONS: These cases highlight possible co-detection of known immunocompromised diseases such as HIV. The two cases we reported stressed the risk of misdiagnosis, especially during the pandemic of an infectious disease and the importance of extended testing even if in immune-compromised condition the immune state may be ignored.

Genome Composition and Divergence of the Novel Coronavirus (2019-nCoV) Originating in China.

An in-depth annotation of the newly discovered coronavirus (2019-nCoV) genome has revealed differences between 2019-nCoV and severe acute respiratory syndrome (SARS) or SARS-like coronaviruses. A systematic comparison identified 380 amino acid substitutions between these coronaviruses, which may have caused functional and pathogenic divergence of 2019-nCoV.

Preliminary study to identify severe from moderate cases of COVID-19 using combined hematology parameters.

BACKGROUND: The third fatal coronavirus is the novel coronavirus (SARS-CoV-2) that causes novel coronavirus pneumonia (COVID-19) which first broke out in December 2019. Patients will develop rapidly if there is no any intervention, so the risk identification of severe patients is critical. The aim of this study was to investigate the characteristics and rules of hematology changes in patients with COVID-19, and to explore the possibility differentiating moderate and severe patients using conventional hematology parameters or combined parameters. METHODS: The clinical data of 45 moderate and severe type patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in Jingzhou Central Hospital from January 23 to February 13, 2020 were collected. The epidemiological indexes, clinical symptoms, and laboratory test results of the patients were retrospectively analyzed. Those parameters with significant differences between moderate and severe cases were analyzed, and the combination parameters with the best diagnostic performance were selected using the linear discriminant analysis (LDA) method. RESULTS: Of the 45 patients with the novel 2019 corona virus (COVID-19) (35 moderate and 10 severe cases), 23 were male and 22 were female, with ages ranging from 16 to 62 years. The most common clinical symptoms were fever (89%) and dry cough (60%). As the disease progressed, white blood cell count (WBC), neutrophil count, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), red blood cell distribution width-coefficient of variation (RDW-CV), and red cell volume distribution width-standard deviation (RDW-SD) parameters in the severe group were significantly higher than those in the moderate group (P<0.05); meanwhile, lymphocyte count (Lym#), eosinophil count (Eos#), high fluorescent cell percentage (HFC%), red blood cell count (RBC), hemoglobin (HGB), and hematocrit (HCT) parameters in the severe group were significantly lower than those in the moderate group (P<0.05). For NLR parameter, it's area under the curve (AUC), cutoff, sensitivity and specificity were 0.890, 13.39, 83.3% and 82.4% respectively; meanwhile, for PLR parameter, it's AUC, cutoff, sensitivity and specificity were 0.842, 267.03, 83.3% and 74.0% respectively. The combined parameters of NLR and RDW-SD had the best diagnostic efficiency (AUC =0.938), and when the cutoff value was 1.046, the sensitivity and the specificity were 90.0% and 84.7% respectively, followed by the combined parameter NLR&RDW-CV (AUC =0.923). When the cut-off value was 0.62, the sensitivity and the specificity for distinguishing severe type from moderate cases of COVID-19 were 90.0% and 82.4% respectively. CONCLUSIONS: The combined NLR and RDW-SD parameter is the best hematology index. It may help clinicians to predict the severity of COVID-19 patients and can be used as a useful indicator to help prevent and control the epidemic.