Network pharmacology and molecular docking analysis reveals the mechanism of asiaticoside on COVID-19.

Background: Asiaticoside (AS) is a saponin extracted from the traditional Chinese herbal medicine Centella Asiatica, which has the effects of reducing inflammatory infiltration and anti-oxidation in pneumonia and combating pulmonary fibrosis. We hypothesize that AS might have therapeutic potential for the treatment of the coronavirus disease 2019 (COVID-19). With the help of network pharmacology and molecular docking techniques, this study discussed the underlying molecular mechanism of AS in the treatment of COVID-19. Methods: The molecular structure of AS was obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) system. The targets of AS were achieved using PharmMapper, SwissTargetPrediction, and the Comparative Toxicogenomics Database (CTD). The targets corresponding to COVID-19 were obtained using GeneCards, Online Mendelian Inheritance in Man (OMIM), and CTD database. Then, a target protein-protein interaction (PPI) network was formed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. A network of AS, COVID-19, and their co-targets was built using Cytoscape. Afterwards, the co-targets were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Moreover, the predictions of crucial targets were further investigated by performing molecular docking with AS. Results: A total of 45 core targets of AS were found to be engaged in the pathogenesis of COVID-19. The KEGG enrichment analysis indicated that AS might be protective against COVID-19 through inflammation- and immune-related signaling pathways, including interleukin-17 (IL-17) signaling, T helper 17 (Th17) cell differentiation pathway, Coronavirus disease-COVID-19, MAPK, the PI3K-Akt signaling pathway, and so on. The results of molecular docking showed that AS had a high affinity with those core targets. Conclusions: The beneficial effect of AS on COVID-19 might be through regulating multiple immune or inflammation-related targets and signaling pathways.

Assessing vaccination priorities for different ages and age-specific vaccination strategies of COVID-19 using an SEIR modelling approach.

In the past year, the global epidemic situation is still not optimistic, showing a trend of continuous expansion. With the research and application of vaccines, there is an urgent need to develop some optimal vaccination strategies. How to make a reasonable vaccination strategy to determine the priority of vaccination under the limited vaccine resources to control the epidemic and reduce human casualties? We build a dynamic model with vaccination which is extended the classical SEIR model. By fitting the epidemic data of three countries-China, Brazil, Indonesia, we have evaluated age-specific vaccination strategy for the number of infections and deaths. Furthermore, we have evaluated the impact of age-specific vaccination strategies on the number of the basic reproduction number. At last, we also have evaluated the different age structure of the vaccination priority. It shows that giving priority to vaccination of young people can control the number of infections, while giving priority to vaccination of the elderly can greatly reduce the number of deaths in most cases. Furthermore, we have found that young people should be mainly vaccinated to reduce the number of infections. When the emphasis is on reducing the number of deaths, it is important to focus vaccination on the elderly. Simulations suggest that appropriate age-specific vaccination strategies can effectively control the epidemic, both in terms of the number of infections and deaths.

Incremental prognostic value of biventricular longitudinal strain and high-sensitivity troponin I in COVID-19 patients.

BACKGROUND: Whether the combination of ventricular strain with high-sensitivity troponin I (hs-TNI) has an incremental prognostic value in coronavirus disease 2019 (COVID-19) patients has not been evaluated. The study aimed to evaluate the prognostic value of biventricular longitudinal strain and its combination with hs-TNI in COVID-19 patients. METHODS: A total of 160 COVID-19 patients who underwent both echocardiography and hs-TNI testing were enrolled in our study. COVID-19 patients were divided into two groups (critical and non-critical) according to severity-of-illness. The clinical characteristics, cardiac structure and function were compared between the two groups. The prognostic value of biventricular longitudinal strain and its combination with hs-TNI were evaluated by logistic regression analyses and receiver operating characteristic curves. Left ventricular longitudinal strain (LV LS) and right ventricular free wall longitudinal strain (RVFWLS) were determined by 2D speckle-tracking echocardiography. RESULTS: The LV LS and RVFWLS both were significantly lower in critical patients than non-critical patients (LV LS: -16.6±2.4 vs -17.9±3.0, P = .003; RVFWLS :-18.8±3.6 vs -23.9±4.4, P<.001). During a median follow-up of 60 days, 23 (14.4%) patients died. The multivariant analysis revealed that LV LS and RVFWLS [Odd ratio (95% confidence interval): 1.533 (1.131-2.079), P = .006; 1.267 (1.036-1.551), P = .021, respectively] were the independent predictors of higher mortality. Further, receiver-operating characteristic analysis revealed that the accuracy for predicting death was greater for the combination of hs-TNI levels with LV LS than separate LV LS (AUC: .91 vs .77, P = .001), and the combination of hs-TNI levels with RVFWLS than RVFWLS alone (AUC: .89 vs .83, P = .041). CONCLUSIONS: Our study highlights that the combination of ventricular longitudinal strain with hs-TNI can provide higher accuracy for predicting mortality in COVID-19 patients, which may enhance risk stratification in COVID-19 patients.

Early vs. Late Onset Cardiac Injury and Mortality in Hospitalized COVID-19 Patients in Wuhan.

Background: Increasing evidence points to cardiac injury (CI) as a common coronavirus disease 2019 (COVID-19) related complication. The characteristics of early CI (occurred within 72 h of admission) and late CI (occurred after 72 h of admission) and its association with mortality in COVID-19 patients is unknown. Methods: This retrospective study analyzed patients confirmed with COVID-19 in Union Hospital (Wuhan, China) from Jan 29th to Mar 15th, 2020. Clinical outcomes (discharge, or death) were monitored to April 15, 2020, the latest date of follow-up. Demographic, clinical, laboratory, as well as treatment and prognosis were collected and analyzed in patients with early, late CI and without CI. Results: A total of 196 COVID-19 patients were included for analysis. The median age was 65 years [interquartile range (IQR) 56-73 years], and 112 (57.1%) were male. Of the 196 COVID-19 patients, 49 (25.0%) patients had early and 20 (10.2%) patients had late CI, 56.6% developed Acute-Respiratory-Distress-Syndrome (ARDS) and 43 (21.9%) patients died. Patients with any CI were more likely to have developed ARDS (87.0 vs. 40.2%) and had a higher in-hospital mortality than those without (52.2 vs. 5.5%, P < 0.001). Among CI subtypes, a significantly higher risk of in-hospital death was found in patients with early CI with recurrence [19/49 patients, adjusted odds ratio (OR) = 7.184, 95% CI 1.472-35.071] and patients with late CI (adjusted OR = 5.019, 95% CI 1.125-22.388) compared to patients with early CI but no recurrence. Conclusions: CI can occur early on or late after, the initial 72 h of admission and is associated with ARDS and an increased risk of in-hospital mortality. Both late CI and recurrent CI after the initial episode were associated with worse outcomes than patients with early CI alone. This study highlights the importance of early examination and periodical monitoring of cardiac biomarkers, especially for patients with early CI or at risk of clinical deterioration.

Lung Ultrasound Score as a Predictor of Mortality in Patients With COVID-19.

Background: Lung injury is a common condition among hospitalized patients with coronavirus disease 2019 (COVID-19). However, whether lung ultrasound (LUS) score predicts all-cause mortality in patients with COVID-19 is unknown. The aim of the present study was to explore the predictive value of lung ultrasound score for mortality in patients with COVID-19. Methods: Patients with COVID-19 who underwent lung ultrasound were prospectively enrolled from three hospitals in Wuhan, China between February 2020 and March 2020. Demographic, clinical, and laboratory data were collected from digital patient records. Lung ultrasound scores were analyzed offline by two observers. Primary outcome was in-hospital mortality. Results: Of the 402 patients, 318 (79.1%) had abnormal lung ultrasound. Compared with survivors (n = 360), non-survivors (n = 42) presented with more B2 lines, pleural line abnormalities, pulmonary consolidation, and pleural effusion (all p < 0.05). Moreover, non-survivors had higher global and anterolateral lung ultrasound score than survivors. In the receiver operating characteristic analysis, areas under the curve were 0.936 and 0.913 for global and anterolateral lung ultrasound score, respectively. A cutoff value of 15 for global lung ultrasound score had a sensitivity of 92.9% and specificity of 85.3%, and 9 for anterolateral score had a sensitivity of 88.1% and specificity of 83.3% for prediction of death. Kaplan-Meier analysis showed that both global and anterolateral scores were strong predictors of death (both p < 0.001). Multivariate Cox regression analysis showed that global lung ultrasound score was an independent predictor (hazard ratio, 1.08; 95% confidence interval, 1.01-1.16; p = 0.03) of death together with age, male sex, C-reactive protein, and creatine kinase-myocardial band. Conclusion: Lung ultrasound score as a semiquantitative tool can be easily measured by bedside lung ultrasound. It is a powerful predictor of in-hospital mortality and may play a crucial role in risk stratification of patients with COVID-19.

First-Phase Ejection Fraction, a Measure of Preclinical Heart Failure, Is Strongly Associated With Increased Mortality in Patients With COVID-19.

Presence of heart failure is associated with a poor prognosis in patients with coronavirus disease 2019 (COVID-19). The aim of the present study was to examine whether first-phase ejection fraction (EF1), the ejection fraction measured in early systole up to the time of peak aortic velocity, a sensitive measure of preclinical heart failure, is associated with survival in patients hospitalized with COVID-19. A retrospective outcome study was performed in patients hospitalized with COVID-19 who underwent echocardiography (n=380) at the West Branch of the Union Hospital, Wuhan, China and in patients admitted to King's Health Partners in South London, United Kingdom. Association of EF1 with survival was performed using Cox proportional hazards regression. EF1 was compared in patients with COVID-19 and in historical controls with similar comorbidities (n=266) who had undergone echocardiography before the COVID-19 pandemic. In patients with COVID-19, EF1 was a strong predictor of survival in each patient group (Wuhan and London). In the combined group, EF1 was a stronger predictor of survival than other clinical, laboratory, and echocardiographic characteristics including age, comorbidities, and biochemical markers. A cutoff value of 25% for EF1 gave a hazard ratio of 5.23 ([95% CI, 2.85-9.60]; P<0.001) unadjusted and 4.83 ([95% CI, 2.35-9.95], P<0.001) when adjusted for demographics, comorbidities, hs-cTnI (high-sensitive cardiac troponin), and CRP (C-reactive protein). EF1 was similar in patients with and without COVID-19 (23.2±7.3 versus 22.0±7.6%, P=0.092, adjusted for prevalence of risk factors and comorbidities). Impaired EF1 is strongly associated with mortality in COVID-19 and probably reflects preexisting, preclinical heart failure.

Echocardiographic Characteristics and Outcome in Patients With COVID-19 Infection and Underlying Cardiovascular Disease.

Background: The cardiac manifestations of coronavirus disease 2019 (COVID-19) patients with cardiovascular disease (CVD) remain unclear. We aimed to investigate the prognostic value of echocardiographic parameters in patients with COVID-19 infection and underlying CVD. Methods: One hundred fifty-seven consecutive hospitalized COVID-19 patients were enrolled. The left ventricular (LV) and right ventricular (RV) structure and function were assessed using bedside echocardiography. Results: Eighty-nine of the 157 patients (56.7%) had underlying CVD. Compared with patients without CVD, those with CVD had a higher mortality (22.5 vs. 4.4%, p = 0.002) and experienced more clinical events including acute respiratory distress syndrome, acute heart injury, or deep vein thrombosis. CVD patients presented with poorer LV diastolic and RV systolic function compared to those without CVD. RV dysfunction (30.3%) was the most frequent, followed by LV diastolic dysfunction (9.0%) and LV systolic dysfunction (5.6%) in CVD patients. CVD patients with high-sensitivity troponin I (hs-TNI) elevation or requiring mechanical ventilation therapy demonstrated worsening RV function compared with those with normal hs-TNI or non-intubated patients, whereas LV systolic or diastolic function was similar. Impaired RV function was associated with elevated hs-TNI level. RV function and elevated hs-TNI level were independent predictors of higher mortality in COVID-19 patients with CVD. Conclusions: Patients with COVID-19 infection and underlying CVD displayed impaired LV diastolic and RV function, whereas LV systolic function was normal in most patients. Importantly, RV function parameters are predictive of higher mortality.

Prognostic Value of Right Ventricular Ejection Fraction Assessed by 3D Echocardiography in COVID-19 Patients.

Background: RVEF (right ventricular ejection fraction) measured by three-dimensional echocardiography (3DE) has been used in evaluating right ventricular (RV) function and can provide useful prognostic information in other various cardiovascular diseases. However, the prognostic value of 3D-RVEF in coronavirus disease 2019 (COVID-19) remains unknown. We aimed to investigate whether 3D-RVEF can predict the mortality of COVID-19 patients. Methods: A cohort of 128 COVID-19-confirmed patients who had undergone echocardiography were studied. Thirty-one healthy volunteers were also enrolled as controls. COVID-19 patients were divided into three subgroups (general, severe, and critical) according to COVID-19 severity-of-illness. Conventional RV structure and function parameters, RV free wall longitudinal strain (FWLS) and 3D-RVEF were acquired. RVFWLS was measured by two-dimensional speckle tracking echocardiography. RVEF was acquired by 3DE. Results: Compared with controls, 2D-RVFWLS and 3D-RVEF were both significantly decreased in COVID-19 patients (-27.2 ± 4.4% vs. -22.9 ± 4.8%, P < 0.001; 53.7 ± 4.5% vs. 48.5 ± 5.8%, P < 0.001). Critical patients were more likely to have a higher incidence of acute cardiac injury and acute respiratory distress syndrome (ARDS), and worse prognosis than general and severe patients. The critical patients exhibited larger right-heart chambers, worse RV fractional area change (RVFAC), 2D-RVFWLS, and 3D-RVEF and higher proportion of pulmonary hypertension than general and severe patients. Eighteen patients died during a median follow-up of 91 days. The multivariate Cox regression analysis revealed the acute cardiac injury, ARDS, RVFAC, RVFWLS, and 3D-RVEF were independent predictors of death. 3D-RVEF (chi-square to improve 18.3; P < 0.001), RVFAC (chi-square to improve 4.5; P = 0.034) and 2D-RVFWLS (chi-square to improve 5.1; P = 0.024) all provided additional prognostic value of higher mortality over clinical risk factors. Moreover, the incremental predictive value of 3D-RVEF was significantly (P < 0.05) higher than RVFAC and RVFWLS. Conclusion: 3D-RVEF was the most robust independent predictor of mortality in COVID-19 patients and provided a higher predictive value over conventional RV function parameters and RVFWLS, which may be helpful to identify COVID-19 patients at a higher risk of death.

Biventricular Longitudinal Strain Predict Mortality in COVID-19 Patients.

Background: Biventricular longitudinal strain has been recently demonstrated to be predictive of poor outcomes in various cardiovascular settings. Therefore, this study sought to investigate the prognostic implications of biventricular longitudinal strain in patients with coronavirus disease 2019 (COVID-19). Methods: We enrolled 132 consecutive patients with COVID-19. Left ventricular global longitudinal strain from the apical four-chamber views (LV GLS4CH) and right ventricular free wall longitudinal strain (RV FWLS) were obtained using two-dimensional speckle-tracking echocardiography. Results: Compared with patients without cardiac injury, those with cardiac injury had higher levels of coagulopathy and inflammatory biomarkers, higher incidence of complications, more mechanical ventilation therapy, and higher mortality. Patients with cardiac injury displayed decreased LV GLS4CH and RV FWLS, elevated pulmonary artery systolic pressure, and higher proportion of pericardial effusion. Higher biomarkers levels of inflammation and cardiac injury, and the presence of pericardial effusion were correlated with decreases in LV GLS4CH and RV FWLS. During hospitalization, 19 patients died. Compared with survivors, LV GLS4CH and RV FWLS were impaired in non-survivors. At a 3-month follow-up after discharge, significant improvements were observed in LV GLS4CH and RV FWLS. Multivariate Cox analysis revealed that LV GLS4CH [hazard ratio: 1.41; 95% confidence interval [CI]: 1.08 to 1.84; P = 0.011] and RV FWLS (HR: 1.29; 95% CI: 1.09-1.52; P = 0.003) were independent predictors of higher mortality in patients with COVID-19. Conclusions: LV GLS4CH and RV FWLS are independent and strong predictors of higher mortality in COVID-19 patients and can track improvement during the convalescent phase of their illness. Therefore, biventricular longitudinal strain may be crucial for risk stratification and serial follow-up in patients with COVID-19.

Modeling and analysis of COVID-19 based on a time delay dynamic model.

The new type of coronavirus pneumonia is caused by the new type of coronavirus which appeared at the end of 2019. Because of its strong contagiousness, rapid spread and great harm, it has already given countries around the world serious effects. So far there is no clear specific drug. Scientifically grasping the development law of epidemics is extremely important for preventing and controlling epidemics. Since the latent of this epidemic are also highly contagious, traditional infectious disease models cannot accurately describe the regularity of this epidemic transmission. Based on the traditional infectious disease model, an infectious disease model with a time delay is proposed. The time difference is used to characterize the cycle of viral infection and treatment time. Using the epidemic data released in real time, firstly, through the numerical simulation parameter inversion, the minimum error is obtained; then we simulate the development trend of the epidemic according to the dynamics system; finally, we compare and analyze the effectiveness of isolation measures. This article has simulated COVID-19 and analyzed the development of the epidemic in Beijing and Wuhan. By comparing the severity of the epidemic in the two regions, early detection and isolation are still the top priority of epidemic prevention and control.

Prognostic value of bedside lung ultrasound score in patients with COVID-19.

BACKGROUND: Bedside lung ultrasound (LUS) has emerged as a useful and non-invasive tool to detect lung involvement and monitor changes in patients with coronavirus disease 2019 (COVID-19). However, the clinical significance of the LUS score in patients with COVID-19 remains unknown. We aimed to investigate the prognostic value of the LUS score in patients with COVID-19. METHOD: The LUS protocol consisted of 12 scanning zones and was performed in 280 consecutive patients with COVID-19. The LUS score based on B-lines, lung consolidation and pleural line abnormalities was evaluated. RESULTS: The median time from admission to LUS examinations was 7 days (interquartile range [IQR] 3-10). Patients in the highest LUS score group were more likely to have a lower lymphocyte percentage (LYM%); higher levels of D-dimer, C-reactive protein, hypersensitive troponin I and creatine kinase muscle-brain; more invasive mechanical ventilation therapy; higher incidence of ARDS; and higher mortality than patients in the lowest LUS score group. After a median follow-up of 14 days [IQR, 10-20 days], 37 patients developed ARDS, and 13 died. Patients with adverse outcomes presented a higher rate of bilateral involvement; more involved zones and B-lines, pleural line abnormalities and consolidation; and a higher LUS score than event-free survivors. The Cox models adding the LUS score as a continuous variable (hazard ratio [HR]: 1.05, 95% confidence intervals [CI] 1.02 ~ 1.08; P < 0.001; Akaike information criterion [AIC] = 272; C-index = 0.903) or as a categorical variable (HR 10.76, 95% CI 2.75 ~ 42.05; P = 0.001; AIC = 272; C-index = 0.902) were found to predict poor outcomes more accurately than the basic model (AIC = 286; C-index = 0.866). An LUS score cut-off > 12 predicted adverse outcomes with a specificity and sensitivity of 90.5% and 91.9%, respectively. CONCLUSIONS: The LUS score devised by our group performs well at predicting adverse outcomes in patients with COVID-19 and is important for risk stratification in COVID-19 patients.

Repeated ketamine injections in synergy with antidepressants for treating refractory depression: A case showing 6-month improvement.

WHAT IS KNOWN AND OBJECTIVE: Some patients with refractory depression who fail to respond to rapid injection of standard-dose ketamine are injected with high doses, but the safety and efficacy of this practice are unclear. CASE DESCRIPTION: A 57-year-old woman with refractory depression whose symptoms did not improve after 20-seconds intravenous injection of 0.5 mg/kg ketamine went into remission following eight, 1-minute intravenous injections of 1 mg/kg ketamine delivered over a 4-week period. By 6-month follow-up, no significant adverse events had occurred and cognitive function had improved. WHAT IS NEW AND CONCLUSION: High-dose intravenous injections of ketamine may stably improve depressive symptoms and cognitive function in patients with refractory depression who do not respond to rapid intravenous injection of standard-dose ketamine. The high-dose treatment appears to be associated with only mild side effects.

Prognostic Value of Right Ventricular Longitudinal Strain in Patients With COVID-19.

Objectives: The aim of this study was to investigate whether right ventricular longitudinal strain (RVLS) was independently predictive of higher mortality in patients with coronavirus disease-2019 (COVID-19). Background: RVLS obtained from 2-dimensional speckle-tracking echocardiography has been recently demonstrated to be a more accurate and sensitive tool to estimate right ventricular (RV) function. The prognostic value of RVLS in patients with COVID-19 remains unknown. Methods: One hundred twenty consecutive patients with COVID-19 who underwent echocardiographic examinations were enrolled in our study. Conventional RV functional parameters, including RV fractional area change, tricuspid annular plane systolic excursion, and tricuspid tissue Doppler annular velocity, were obtained. RVLS was determined using 2-dimensional speckle-tracking echocardiography. RV function was categorized in tertiles of RVLS. Results: Compared with patients in the highest RVLS tertile, those in the lowest tertile were more likely to have higher heart rate; elevated levels of D-dimer and C-reactive protein; more high-flow oxygen and invasive mechanical ventilation therapy; higher incidence of acute heart injury, acute respiratory distress syndrome, and deep vein thrombosis; and higher mortality. After a median follow-up period of 51 days, 18 patients died. Compared with survivors, nonsurvivors displayed enlarged right heart chambers, diminished RV function, and elevated pulmonary artery systolic pressure. Male sex, acute respiratory distress syndrome, RVLS, RV fractional area change, and tricuspid annular plane systolic excursion were significant univariate predictors of higher risk for mortality (p < 0.05 for all). A Cox model using RVLS (hazard ratio: 1.33; 95% confidence interval [CI]: 1.15 to 1.53; p < 0.001; Akaike information criterion = 129; C-index = 0.89) was found to predict higher mortality more accurately than a model with RV fractional area change (Akaike information criterion = 142, C-index = 0.84) and tricuspid annular plane systolic excursion (Akaike information criterion = 144, C-index = 0.83). The best cutoff value of RVLS for prediction of outcome was -23% (AUC: 0.87; p < 0.001; sensitivity, 94.4%; specificity, 64.7%). Conclusions: RVLS is a powerful predictor of higher mortality in patients with COVID-19. These results support the application of RVLS to identify higher risk patients with COVID-19.