STING agonist-loaded mesoporous manganese-silica nanoparticles for vaccine applications.

Cyclic dinucleotides (CDNs), as one type of Stimulator of Interferon Genes (STING) pathway agonist, have shown promising results for eliciting immune responses against cancer and viral infection. However, the suboptimal drug-like properties of conventional CDNs, including their short in vivo half-life and poor cellular permeability, compromise their therapeutic efficacy. In this study, we have developed a manganese-silica nanoplatform (MnOx@HMSN) that enhances the adjuvant effects of CDN by achieving synergy with Mn2+ for vaccination against cancer and SARS-CoV-2. MnOx@HMSN with large mesopores were efficiently co-loaded with CDN and peptide/protein antigens. MnOx@HMSN(CDA) amplified the activation of the STING pathway and enhanced the production of type-I interferons and other proinflammatory cytokines from dendritic cells. MnOx@HMSN(CDA) carrying cancer neoantigens elicited robust antitumor T-cell immunity with therapeutic efficacy in two different murine tumor models. Furthermore, MnOx@HMSN(CDA) loaded with SARS-CoV-2 antigen achieved strong and durable (up to one year) humoral immune responses with neutralizing capability. These results demonstrate that MnOx@HMSN(CDA) is a versatile nanoplatform for vaccine applications.

GlPS1 overexpression accumulates coumarin secondary metabolites in transgenic Arabidopsis.

The dried root of Glehnia littoralis is a traditional Chinese herbal medicine mainly used to treat lung diseases and plays an important role in fighting coronavirus disease 2019 pneumonia in China. This study focused on the key enzyme gene GlPS1 for furanocoumarin synthesis in G. littoralis. In the 35S:GlPS1 transgenic Arabidopsis study, the Arabidopsis thaliana-overexpressing GlPS1 gene was more salt-tolerant than Arabidopsis in the blank group. Metabolomics analysis showed 30 differential metabolites in Arabidopsis, which overexpressed the GlPS1 gene. Twelve coumarin compounds were significantly upregulated, and six of these coumarin compounds were not detected in the blank group. Among these differential coumarin metabolites, isopimpinellin and aesculetin have been annotated by the Kyoto Encyclopedia of Genes and Genomes and isopimpinellin was not detected in the blank group. Through structural comparison, imperatorin was formed by dehydration and condensation of zanthotoxol and a molecule of isoprenol, and the difference between them was only one isoprene. Results showed that the GlPS1 gene positively regulated the synthesis of coumarin metabolites in A. thaliana and at the same time improved the salt tolerance of A. thaliana. Supplementary Information: The online version contains supplementary material available at 10.1007/s11240-022-02427-w.

SARS-CoV-2 Main Protease Inhibitors: Structure-Based Enhancement to Anti-Viral Pre-Clinical GC376 Encourages Further Development

SARS-CoV-2 Main protease (Mpro) is pivotal in viral replication and transcription. Mpro mediates proteolysis of translated products of replicase genes ORF1a and ORF1ab. Surveying pre-clinical trial Mpro inhibitors suggests potential enhanced efficacy for some moieties. Concordant with promising in vitro and in silico data, the protease inhibitor GC376 was chosen as a lead. Modification of GC376 analogues yielded a series of promising Mpro inhibitors. Design optimization identified compound G59i as lead candidate, displaying a binding energy of −10.54kcal/mol for the complex. Robust interactivity was noted between G59i and Mpro. With commendable ADMET characteristics and enhanced potency, further G59i analysis may be advantageous;moreover, identified key Mpro residues could contribute to the design of neotenic inhibitors. [ FROM AUTHOR]

Detection rate of SARS-CoV-2 RNA in relation to isolation time and environmental surface type

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) causes environmental contamination via respiratory droplets and persists on contaminants and environmental surfaces for anywhere from a few hours to 6 days. Therefore, it is particularly important to understand the transmission and containment of SARS-CoV-2 on the surface of objects within isolated environments. In this study, 356 environmental surface samples were collected and 79 tested positive, with the highest contamination rate (56.96%) in the wood category (bedside tables, wood floors, and walls). This study revealed differences in the detection rates of environmental surfaces in hospitalized and discharged rooms of patients with confirmed COVID-19 in 2 isolated settings (A: p = 0.001;B: p = 0.505) and suggested that environmental contamination may be an important route of virus transmission, providing a reference to guide the enhancement of ventilation, the use of hotel isolation model, the advocacy of cotton masks, and the effective suppression of virus transmission.

The 3D-Printing-Accelerated Design for a Biodegradable Respirator from Tree Leaves (TRespirator).

The unpredictable coronavirus pandemic (COVID-19) has led to a sudden and massive demand for face masks, leading to severe plastic pollution. Here, we propose a method for manufacturing biodegradable masks using high-precision 3D printing technology, called "TRespirator", mainly made of banana leaves and dental floss silk fibers. By adding plastic recycling waste appropriately, TRespirator can achieve similar protection and mechanical properties as N95 masks. In addition, microorganisms attracted during the degradation of plant fibers will accelerate the degradation of microplastics. This respirator provides a new idea for solving the global problem of plastic pollution of masks.

Presumed Recurrent MEWDS following Covid-19 Vaccination.

PURPOSE: To present an unusual case of recurrent multiple evanescent white dot syndrome (MEWDS) following the coronavirus 2019 (Covid-19) vaccination. METHODS: Review of the clinical, laboratory, photographic, and angiographic records of a patient with MEWDS. RESULTS: A 49-year-old female who had MEWDS nine years ago presented to our clinic with blurred vision in her left eye. These symptoms occurred 2 days following Covid-19 vaccination. Fundus examinations and diagnostic testing were consistent with recurrent MEWDS. CONCLUSION: While rare, MEWDS can reoccur following Covid-19 vaccination.

Alzheimer's disease in elderly COVID-19 patients: potential mechanisms and preventive measures.

Advanced age correlates with higher morbidity and mortality among patients affected with the novel coronavirus disease 2019 (COVID-19). Because systemic inflammation and neurological symptoms are also common in severe COVID-19 cases, there is concern that COVID-19 may lead to neurodegenerative conditions such as Alzheimer's disease (AD). In this review, we summarize possible mechanisms by which infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, may cause AD in elderly COVID-19 patients and describe preventive measures to mitigate risk. Potential mechanisms include NLRP3 inflammasome activation and IL-1ß release, renin-angiotensin system hyperactivation, innate immune activation, oxidative stress, direct viral infection, and direct cytolytic ß-cell damage. Anti-inflammatory therapies, including TNF-α inhibitors and nonsteroidal anti-inflammatory drugs, antioxidants such as the vitamin E family, nutritional intervention, physical activity, blood glucose control, and vaccination are proposed as preventive measures to minimize AD risk in COVID-19 patients. Since several risk factors for AD may converge during severe SARS-CoV-2 infection, neurologists should be alert for potential symptoms of AD and actively implement preventive measures in patients presenting with neuropsychiatric symptoms and in high-risk patients such as the elderly.

Research Progress on the Antiviral Activity of Glycyrrhizin and its Derivatives in Liquorice.

Liquorice is a traditional medicine. Triterpenoids such as glycyrrhizin and glycyrrhetinic acid are the main active constituents of liquorice. Studies have revealed that these compounds exert inhibitory effects on several viruses, including SARS-CoV-2. The main mechanisms of action of these compounds include inhibition of virus replication, direct inactivation of viruses, inhibition of inflammation mediated by HMGB1/TLR4, inhibition of ß-chemokines, reduction in the binding of HMGB1 to DNA to weaken the activity of viruses, and inhibition of reactive oxygen species formation. We herein review the research progress on the antiviral effects of glycyrrhizin and its derivatives. In addition, we emphasise the significance of exploring unknown antiviral mechanisms, structural modifications, and drug combinations in future studies.

Decreased Low-Density Lipoprotein Cholesterol Level Indicates Poor Prognosis of Severe and Critical COVID-19 Patients: A Retrospective, Single-Center Study.

Coronavirus disease 2019 (COVID-19) has become a global public health crisis. Reduced low-density lipoprotein cholesterol (LDL-C) levels were observed in COVID-19 patients. The present study aimed to explore the relationship between LDL-C levels and the prognosis of severe and critical COVID-19 patients. A total of 211 severe and critical COVID-19 patients were enrolled and divided into four groups according to the LDL-C levels, including 53 patients in Group A (LDL-C ≥ 2.71 mmol/L), 53 patients in Group B (2.28 ≤ LDL-C < 2.71 mmol/L), 53 patients in Group C (1.83 ≤ LDL-C < 2.28 mmol/L) and 52 patients in Group D (LDL-C < 1.83 mmol/L). LDL-C levels were lower in critically ill patients than in severe patients. The main symptoms before admission, characteristics on admission and comorbidities of enrolled patients did not differ among the four groups. Compared with patients with high LDL-C levels, patients with low LDL-C levels were more likely to have immune and inflammation dysfunction, renal dysfunction, liver dysfunction and cardiac dysfunction on admission. The proportions of patients with shock and acute cardiac injury, of those admitted to intensive care unit (ICU) and of those treated with mechanical ventilation were inversely related to LDL-C level. The mortality of COVID-19 patients increased with LDL-C reduction. Serum LDL-C levels of COVID-19 patients was negatively correlated with CRP level, but positively correlated with lymphocyte count, as shown by Pearson correlation analysis. Proportional hazard models showed that low LDL-C levels were associated with increased risk of hospitalization death, cardiac injury and admission to the ICU. Taken together, these results suggest that decreased LDL-C levels indicate poor prognosis of severe and critical COVID-19 patients.

The Association between Obesity and Severity in Patients with Coronavirus Disease 2019: a Retrospective, Single-center Study, Wuhan.

Aim: In other respiratory infectious diseases, obesity may be associated with a poor outcome. For coronavirus disease 2019 (COVID-19), the association between obesity and severity or prognosis requires further analysis. Methods: This was a retrospective, single-center study. Hospitalized patients were recruited in Renmin Hospital of Wuhan University from January 2, 2020 to February 20, 2020. The data of body mass index (BMI) was obtained from follow-up of surviving patients. According to BMI, normal weight was defined as 18.5-23.9 kg/m2, overweight as 24.0-27.9 kg/m2 and obesity as > 28.0 kg/m2. Results: A total of 463 patients were enrolled, of which 242 (52.3%) patients were in the normal weight group; 179 (38.7%) were in the overweight group; and 42 (9.1%) were in the obesity group. Compared to the normal group, obese patients were more likely to have a higher heart rate; lower finger oxygen saturation; higher levels of white blood cells, neutrophil counts, basophil counts, intravenous glucose, triacylglycerol, uric acid, alanine aminotransferase, creatine kinase-MB, CD19+ cell counts and percentage; and lower levels of monocyte percentage, high density lipoprotein and CD3+ cell percentage. In addition, the proportions of hypertension (21.5% vs. 42.6%) and severe+critical illness (47.8 vs. 81.0 %) were significantly higher in the obesity group than those in normal group. However, no significant differences were observed between the normal and obesity groups in critical illness, organ damage and defined endpoint (mechanical ventilation or intensive care unit). Multiple logistic regression showed that obesity increased the risk of developing severe+critical illness (Odd ratio 3.586, 95% CI 1.550-8.298, P=0.003) in patients with COVID-19, and did not affect the risk of critical illness, organ damage and endpoints. Overweight did not affect the risk of severity, organ damage or endpoint in patients with COVID-19. Conclusion: Obesity may be a risk factor for developing severity in patients with COVID-19.

Recent progress of antiviral therapy for coronavirus disease 2019.

The coronavirus disease 2019 (COVID-19) pandemic has become a global public health crisis, for which antiviral treatments are considered mainstream therapeutic approaches. With the development of this pandemic, the number of clinical studies on antiviral therapy, including remdesivir, chloroquine and hydroxychloroquine, lopinavir/ritonavir, ribavirin, arbidol, interferon, favipiravir, oseltamivir, nitazoxanide, nelfinavir, and camostat mesylate, has been increasing. However, the efficacy of these antiviral drugs for COVID-19 remains controversial. In this review, we summarize the recent progress and findings on antiviral therapies, aiming to provide clinical support for the management of COVID-19. In addition, we analyze the causes of controversy in antiviral drug research and discuss the quality of current studies on antiviral treatments. High-quality randomized clinical trials are required to demonstrate the efficacy and safety of antiviral drugs for the treatment of COVID-19.

Clinical Features of COVID-19 Patients with Different Outcomes in Wuhan: A Retrospective Observational Study.

Coronavirus disease 2019 (COVID-19) has caused considerable morbidity and mortality worldwide since December 2019. This retrospective study determined the characteristics and prognostic factors of COVID-19 patients, focusing on inpatients who died or were discharged between 30 December 2019 and 29 February 2020 at Renmin Hospital of Wuhan University. Patients' medical histories, comorbidities, symptoms, signs, laboratory findings, computed tomography (CT) findings, and clinical management were recorded. All 293 patients were divided into the nonsurviving (n = 116) and surviving (n = 177) groups. The median age was older in the nonsurviving group than in the surviving group; most patients were older than 65 years in the nonsurviving group. The incidence rates of lymphopenia, neutrophilia, and leukocytosis were significantly higher in the nonsurviving group than in the surviving group. More patients in the nonsurviving group had increased levels of nonspecific infection markers, abnormal liver and kidney function, cardiac injury, and blood coagulation abnormalities on admission. Immune and inflammatory responses were more severely disturbed in the nonsurviving group than in the surviving group. The incidence rates of complications during hospitalization were higher in the nonsurviving group than in the surviving group. Cox regression results also showed that older age, symptoms of dyspnea, comorbidities, and complications were all predictors of death. Close monitoring and timely treatment are needed for high-risk COVID-19 patients.

Clinical Features of COVID-19 in Patients With Essential Hypertension and the Impacts of Renin-angiotensin-aldosterone System Inhibitors on the Prognosis of COVID-19 Patients.

Hypertension is one of the most common comorbidities in patients with coronavirus disease 2019 (COVID-19). This study aimed to clarify the impact of hypertension on COVID-19 and investigate whether the prior use of renin-angiotensin-aldosterone system (RAAS) inhibitors affects the prognosis of COVID-19. A total of 996 patients with COVID-19 were enrolled, including 282 patients with hypertension and 714 patients without hypertension. Propensity score-matched analysis (1:1 matching) was used to adjust the imbalanced baseline variables between the 2 groups. Patients with hypertension were further divided into the RAAS inhibitor group (n=41) and non-RAAS inhibitor group (n=241) according to their medication history. The results showed that COVID-19 patients with hypertension had more severe secondary infections, cardiac and renal dysfunction, and depletion of CD8+ cells on admission. Patients with hypertension were more likely to have comorbidities and complications and were more likely to be classified as critically ill than those without hypertension. Cox regression analysis revealed that hypertension (hazard ratio, 95% CI, unmatched cohort [1.80, 1.20-2.70]; matched cohort [2.24, 1.36-3.70]) was independently associated with all-cause mortality in patients with COVID-19. In addition, hypertensive patients with a history of RAAS inhibitor treatment had lower levels of C-reactive protein and higher levels of CD4+ cells. The mortality of patients in the RAAS inhibitor group (9.8% versus 26.1%) was significantly lower than that of patients in the non-RAAS inhibitor group. In conclusion, hypertension may be an independent risk factor for all-cause mortality in patients with COVID-19. Patients who previously used RAAS inhibitors may have a better prognosis.

Time-dependent changes in the clinical characteristics and prognosis of hospitalized COVID-19 patients in Wuhan, China: A retrospective study.

Cases of coronavirus disease 2019 (COVID-19) have been breaking out around the world recently. However, the dynamic changes in the clinical symptoms and prognosis of COVID-19 patients remain unknown. According to the onset time of initial clinical symptoms, 843 COVID-19 patients admitted between Jan 22 and Feb 14, 2020 were divided into three groups: group A (Jan 21 to Jan 25, n = 324), group B (Jan 26 to Jan 31, n = 358) and group C (Feb 1 to Feb 10, n = 161). Data on the demographics, symptoms, first laboratory results, treatments and outcomes (within 12 days of hospitalization) were collected. The results showed that the median duration from symptom onset to admission shortened over time (13, 10 and 5 days, respectively, p < 0.05). Fewer patients had fever symptoms and bilateral pneumonia in group C than in the group A and B. Laboratory results showed that white blood cell, neutrophil, and platelet counts, lactic acid and D-dimer levels were lower, while lymphocyte, CD3, and CD8 counts were higher in group C. In addition, group C had more mild-moderate cases and fewer severe cases than the other two groups. More importantly, the incidence of complications (18.5%, 14.2% and 11.2%, respectively, p < 0.05) and all-cause mortality (11.7%, 8.4%, and 5.6%, respectively, p < 0.05) decreased over time. The clinical characteristics and prognosis of COVID-19 patients changed over time. Improved prognosis was found at a later stage.

The Clinical Characteristics and Prognosis Factors of Mild-Moderate Patients With COVID-19 in a Mobile Cabin Hospital: A Retrospective, Single-Center Study.

Background: Novel mobile cabin hospitals have been built to provide more makeshift beds for patients with COVID-19 in Wuhan. However, the characteristics of these patients needed be further described. Methods: This was a retrospective, single-center study. A total of 869 patients with confirmed COVID-19 were admitted to Wuchang Mobile Cabin Hospital in Wuhan, between February 6th, 2020 and February 20th, 2020. The final date of follow-up was March 6th, 2020. Clinical characteristics and outcome data were collected and analyzed. Results: Of 869 patients, the median age was 51 years (IQR, 40-58 years), and 377 patients (377/869; 43.4%) were men. A total of 616 patients (616/869; 70.9%) were discharged, 95 patients (95/869; 10.9%) were transferred to the designated hospital due to worsening condition (endpoint), and 158 patients (158/869; 18.2%) were still in the hospital. The incidence of the main symptoms, including fever, cough, fatigue, muscle aches, and anorexia, decreased with time. However, there were no differences in outcome among the patients with different onset times. Generally, both patients aged 45 years or older and patients with comorbidities were more likely to reach the endpoint (transfer to designated high-level hospitals due to condition worsen). In the other model, patients with the lung CT feature (e.g., ground-glass opacity, reticular/linear, air bronchogram, or consolidation shadow) were more likely to reach the endpoint. Conclusion: Older age, comorbidity, special chest CT features (e.g., ground-glass opacity, reticular/linear, air bronchogram, or consolidation shadow) are associated with poor prognosis for mild-moderate patients. The initial symptoms of mild-moderate patients may become insidious, which deserves our attention.

Potential mechanisms of hemorrhagic stroke in elderly COVID-19 patients.

The novel severe acute respiratory syndrome coronavirus 2 is the causative agent of coronavirus disease 2019, a new human infectious disease. While fever, cough, and respiratory distress are typical first symptoms, a fraction of those affected present instead with neurological symptoms suggestive of central nervous system compromise. This review summarizes the potential contribution of coronavirus disease 2019 to hemorrhagic stroke in the elderly and proposes possible mechanisms. Reports show that the most affected patients have underlying chronic diseases such as hypertension and diabetes, which are two key risk factors for hemorrhagic stroke. Angiotensin-converting enzyme 2 is the main host cell surface receptor interacting with the severe acute respiratory syndrome coronavirus 2 spike glycoprotein to allow viral entry and infection. We speculate that ensuing downregulation of angiotensin-converting enzyme 2 expression may compound the risk conferred by pre-existing comorbidities and critically influence the pathogenesis of hemorrhagic stroke by elevating blood pressure and impairing cerebrovascular endothelial function. Additionally, both age- and/or disease-related immune dysfunction and enhanced catecholamine release secondary to anxiety and stress may also aggravate central nervous system symptoms of severe acute respiratory syndrome coronavirus 2 infection. Thus, assessment of systemic inflammatory biomarkers and tight control of hemodynamic parameters upon admission are crucial to minimize mortality and morbidity in coronavirus disease 2019 patients with central nervous system symptoms suggestive of incipient stroke.

Comparison of clinical characteristics and outcomes of patients with coronavirus disease 2019 at different ages.

BACKGROUND: Information about the clinical characteristics and mortality of patients with coronavirus disease 2019 at different ages is limited. RESULTS: The older group had more patients with dyspnea and fewer patients with fever and muscle pain. Older patients had more underlying diseases, secondary infection, myocardial injury, renal dysfunction, coagulation dysfunction, and immune dysfunction on admission. More older patients received immunoglobulin therapy and mechanical ventilation. The proportions of patients with multiple organ injuries, critically ill patients and death increased significantly with age. The older groups had higher cumulative death risk than the younger group. Hypertension, cerebrovascular disease, comorbidities, acute cardiac injury, shock and complications are independent predictors of death. CONCLUSIONS: The symptoms of the elderly patients were more atypical, with more comorbidities, secondary infection, organ injuries, immune dysfunction and a higher risk of critical illness. Older age was an important risk factor for mortality. METHODS: 1000 patients diagnosed with coronavirus disease 2019 from January 1, 2020 to February 14, 2020 were enrolled. According to age, patients were divided into group 1 (<60 years old), group 2 (60-74 years old) and group 3 (≥75 years old). The clinical symptoms, first laboratory results, CT findings, organ injuries, disease severity and mortality were analyzed.