ABSTRACT
Background/Objectives: Corticosteroids are widely used for the treatment of coronavirus disease (COVID)-19 caused by SARS-CoV- 2 as they attenuate the immune response with their antiinflammatory properties. Genetic polymorphisms of glucocorticoid receptor, metabolizing enzymes or transporters may affect treatment response to dexamethasone. The aim of this study was to evaluate the association of polymorphisms in glucocorticoid pathway with disease severity and duration of dexamethasone treatment in COVID-19 patients. Method(s): Our study included 107 hospitalized COVID-19 patients treated with dexamethasone. We isolated DNA from peripheral blood and genotyped all samples for polymorphisms in NR3C1 (rs6198, rs33388), CYP3A4 (rs35599367), CYP3A5 (rs776746), GSTP1 (rs1695, rs1138272), GSTM1/GSTT1 deletions and ABCB1 (1045642, rs1128503, rs2032582 Fisher's and Mann- Whitney tests were used in statistical analysis. Result(s): The median (min-max) age of the included patients was 62 (26-85) years, 69.2 % were male and 30.8 % female and they had moderate (1.9 %), severe (83 %) or critical (15.1 %) disease. NR3C1 rs6198 polymorphism was associated with more severe disease in additive genetic model (P = 0.022). NR3C1 rs6198, ABCB1 rs1045642 and ABCB1 rs1128503 polymorphisms were associated with a shorter duration of dexamethasone treatment in additive (P = 0.048, P = 0.047 and P = 0.024, respectively) and dominant genetic models (P = 0.015, P = 0.048 and P = 0.020, respectively), while carriers of the polymorphic CYP3A4 rs35599367 allele required longer treatment with dexamethasone (P = 0.033). Other polymorphisms were not associated with disease severity or dexamethasone treatment duration. Conclusion(s): Genetic variability of glucocorticoid pathway genes was associated with the duration of dexamethasone treatment of COVID-19 patients.
ABSTRACT
Objective To analyze the epidemiological and genomic characteristics of COVID-19 cases imported by land in Ruili, and to provide reference for border epidemic prevention and control in Yunnan Province. Methods We collected information about SARS-CoV-2 infected individuals from overseas land in Ruili, Yunnan from July to November, 2021. The epidemiological characteristics were statistically analyzed. The second-generation sequencing platform of Illumina was used to conduct high-through-put sequencing on the selected 40 positive samples and to analyze their genotyping and variation characteristics. Results During the study period,Ruili City reported 796 COVID-19 cases from abroad.The median age of COVID-19 cases was 28.5 years (Interquantile range 10, range 1-85). The gender ratio between men and women was 4.61 : 1, Most of these infected individuals engaged in business services, accounting for 49.75% (396/796) , 95.60% of COVID-19 cases were mild and moderate cases. The sequencing results of 34 cases can be divided into three clades according to Nextstrain typing method, including 24 cases belong to 21A(Delta) clade, 9 cases belong to 21I(Delta) clade and 1 case belongs to 20I (Alpha V1) clade. Conclusions The virus genotypes of the cases in this study were mainly divided into three branches and there were some differences among them, most of which were Delta mutants.We should continue to implement border control measures and continue to monitor the virus mutation of imported cases, so as to evaluate the threat of the mutant strain to the current situation of epidemic prevention and control in Yunnan Province.Copyright © 2023, Publication Centre of Anhui Medical University. All rights reserved.
ABSTRACT
Background. Neutralizing antibody therapy such as casirivimab/imdevimab is known to significantly reduce the viral load of SARS-CoV-2, but there is limited study on the clinical prognosis of neutralizing antibody therapy, especially in Asia, and the dynamics of cytokines is unknown worldwide. Several cytokines have been investigated as biomarkers to predict oxygen demand, among which CCL17 and INF3 have received approved and covered by the national health insurance in Japan. Methods. Between July 2021 - December 2021, patient's demographic, laboratory, radiological findings, prognosis, and cytokine kinetics (IFN-gamma3, CCL17) at National Center for Global Health and Medicine, Tokyo, Japan, were analyzed using medical charts and serum samples. Univariate analysis was performed using Fisher's exact probability test and Mann-Whitney U test to evaluate the clinical characteristics of the group with oxygen demand compared with those of the group without oxygen demand. Results. Thirty-four patients were analyzed. The median age of the cohort was 57.5 years (IQR 52.8-67.3), and 25 (73.5%) were male. Eight patients (23.5%) had been fully vaccinated and three patients (8.8%) had been vaccinated once. The severity of disease before casirivimab/imdevimab was asymptomatic in two (5.9%), mild in 12 (35.3%), moderate in 20 (58.8%) cases. Of the 17 cases in which mutant strains were identified, 16 were delta strains. The IFN-gamma3 level (pg/mL) before casirivimab/imdevimab was significantly higher (7.6 vs. 17.2, p = 0.005), while the CCL17 level (pg/mL) was significantly lower (148.8 vs. 64.2, p = 0.036) in the group with oxygen demand during the therapeutic course compared to those in the group without oxygen demand. After casirivimab/imdevimab was administered, the IFN-gamma3 level decreased to a median of 0.0 (IQR 0.0-0.3), while the CCL17 level increased to median of 220.3 (IQR 135.8-304.8), with no statistically significant differences between both groups (Figure 1). None of the patients became seriously ill. Figure 1A and 1B show the changing of the cytokine dynamics in COVID-19 patients who were treated with casirivimab/imdevimab on IFN-gamma3 level and CCL17 level, respectively. Conclusion. There was a statistically significant difference between IFN-gamma3 and CCL17 levels before casirivimab/imdevimab in both groups. Our results suggest that casirivimab/immudevimab may improve the clinical prognosis for COVID-19 patients with delta strains.
ABSTRACT
Objective: The mechanism of action, metabolic kinetics, efficacy, safety and drug-drug interaction of molnupiravir were reviewed to provide a basis for clinical use. Method(s): Literature related to molnupiravir was systematically searched in Chinese Clinical Trial Registry, clinicaltrials.gov, Pubmed, Chinese Journal Full-text Database (CNKI) and Wanfang database, and the relevant information was reviewed. Results & Conclusion(s): Molnupiravir was the world's first small-molecule oral drug for COVID-19, which had been approved or authorized for emergency use in more than 40 countries all over the world. Molnupiravir was a ribonucleoside analogue that could be caused mutations in RNA products by viral RNA polymerase, and thus halt viral replication. Clinical trial results showed that molnupiravir could be reduced hospitalization and mortality rates in patients with mild and moderate COVID-19, and might be effective against SARS-CoV-2 mutant strains.Molnupiravir had good safety and tolerability, to provide reference for the treatment of COVID-19 in the future. Copyright © 2022, Chinese Journal of New Drugs Co. Ltd. All right reserved.
ABSTRACT
Coronavirus disease 2019 (COVID-19) has been a global pandemic for over 2 years. During the Omicron (B.1.1.529) variant-predominant period in South Korea, confirmed cases among children and adolescents surged. This review found that, although younger children may be less susceptible to COVID-19 than adolescents, more research is needed on the role of children and adolescents in the disease’s spread. Detailed epidemiological information about the transmissibility of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain in children and adolescents is currently scarce, and more research is needed on the role of children and adolescents in disease’s spread. There may be a difference in the proportion of cases with severe disease requiring hospitalization depending on the dominant mutant strain;however, COVID-19 generally presents with a mild-to-moderate course in children aged 5–11 years old.
ABSTRACT
Coronaviruses exist widely in nature, can cause cross-species transmission, and pose serious threats to human and animal health. Over the past 20 years, coronaviruses have led to three major epidemics that have caused global panic, including severe acute respiratory syndrome, Middle East respiratory syndrome, and coronavirus disease-19. At present, coronavirus disease-19 not only spreads rapidly, but also mutates easily to escape host immune response, becoming more pathogenic. At present, there are no effective specific therapeutic drugs or vaccines. Drugs targeting severe acute respiratory syndrome coronavirus 2 and the host cell defense system that have been developed based on the structure and replication cycle of coronaviruses have a certain broad-spectrum antiviral effect;however, their efficacy still needs to be demonstrated in further clinical trials. Traditional Chinese medicine has an indispensable role in the ongoing response to coronavirus disease-19. Anti-virus treatment with traditional Chinese medicine has advantages such as broad-spectrum application, low toxicity and side effects, low susceptibility to drug resistance, and overall comprehensive regulation. Therefore, researches on effective components and mechanisms of action of the anti-viral effects of traditional Chinese medicine have increasingly gained attention. The present paper examines coronaviruses, specifically summarizing the genomes, replication mechanisms, and mutant strains. Afterward, the therapeutic effects and mechanisms of action of modern broad-spectrum anti-coronavirus drugs and traditional Chinese medicine are summarized. By considering the virus and the targets in the host comprehensively, in addition to the beneficial multi-target and multi-path antiviral effects of traditional Chinese medicines, this paper could guide the development of treatment strategies for broad-spectrum anti-coronavirus traditional Chinese medicines, and could facilitate the modernization and globalization of traditional Chinese medicine.
ABSTRACT
The proceedings contain 593 papers. The topics discussed include: association of transthyretin VAL122ILE variant with incident heart failure and mortality among Black Americans: insights from the regards study;vitamin d modulates histone modifications governing the natriuretic peptide receptor-a gene;cell to cell communication through entanglement and superconductivity improving left ventricular function in an uncoupled state;association of serum lipid levels with COVID-19 infection, severity and mortality;impaired glucose tolerance in guanylyl cyclase/natriuretic peptide receptor-a gene-knockout and gene-duplication mutant mice;meta-analysis of randomized vs observational studies of the effects of invasive therapy in patients with non-ST-elevation myocardial infarction and chronic kidney disease;a retrospective analysis of mortality in adult patients with acute coronary syndrome and cardiogenic shock requiring temporary mechanical circulatory support;and mitochondrial myopathy mimicking Guillain-Barre syndrome in a 21-year-old graduate student.
ABSTRACT
Introduction: About 1.5% global populations (80-90 million) arecarriers and approximately 4.4 out of every 10,000 live births areaffected throughout the world of which 60,000 symptomatic individuals born annually. India has burden of estimated 100,000 patients with a b thalassemia with average prevalence of b thalassemia carriers of 3-4%(Sensus of India2011). Transfusion dependent infectionsagain surmount the ongoing major health issues in these patients,mainly including HCV/HBV and HIV infection.Hepatitis B and Cinfections are prevalent in India and carrier rate is about 1-5% and1%, respectively. Post transfusion hepatitis B/C and HIV is a majorchallenge in India (about 10%) due to low viremia, undetectable mutant strains and long window period (Chowdary.et.al). Ourstudy was designed to determine the prevalence of HBV/HCV/HIV inmultiply transfused thalassemia patients by standard laboratory tests.The factors affecting were studied and analyzed.Aims &Objectives: To determine the prevalence of Hepatitis C,Hepatitis B &Human immunodeficiency virus (HIV) in transfusiondependent b-thalassemia major (TM) patients and to determine thefactors i.e. chronicity;frequency of transfusions;multi institutes/donor provided transfusions with frequent lost to fallow upsecondary to covid lock-down affecting them. And to correlate Liverfunction tests and Ferritin levels among these positive children tothose who are not.Materials &Methods: This is a retrospective cross-sectional studyconducted from January 1st 2020 till September 30, 2021. A total 134patients were enrolled from thalassemia unit of tertiary care hospitalof western Maharashtra ageing from 1 to 13 years. Statistical analysiswas done by using SPSS 17.0 software using T test and chi squaretest.Result: Among them, infected cases with HCV, HBV and HIV were27.61%, 0.75% and 2.24% respectively. Moreover, of the patientswere found to be co-infected with both HBV and HCV. The percentage of infections in the patients with frequent transfusion interval(B 30 days) was significantly higher (p <0 > 30 days) so was thepatients who received transfusions long time. Ferritin, SGPT andSGOT were significantly raised in infected patients. The rate ofinfection for HIV, HBV HCV was significantly high in patients whowere diagnosed early for thalassemia, who lost follow up &transfused from multiple institutes due to COVID lockdown due to lack oftransportation facilities.Conclusions: To ensure the frequently transfused patients, a goodquality of life from the preventable HBV/HCV/HIV related complications. Efficient screening methods for proper donor selectionshould be adopted and awareness should be built to ascertain a safetransfusion.
ABSTRACT
Background and Aims: The North Lantau Hospital Hong Kong Infection Control Centre (HKICC) was established in February 2021 as a designated hospital to combat the coronavirus disease 2019 (COVID-19) in Hong Kong, during which an increase in emergent mutant strains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) raised concerns pertinent to increased transmissibility and disease severity. We aim to describe the treatment outcomes of SARS-CoV-2 infection in HKICC, and to evaluate the impact of mutant strains in imported cases. Methods: Consecutive patients with COVID-19 admitted to HKICC from February to April 2021 were identified with their clinical features and treatment outcomes evaluated. Clinical features of mutant strains and wild-type strains were compared. Results: of 513 COVID-19 patients treated in HKICC (mean age 38 years, 45.2% male), 238 (46.4 %) were imported. The incidence of hypoxemia was 3.1% (16/513). All patients were discharged successfully with a median length of stay of 10 days (IQR 6-13). All mutant strains were imported with an incidence of 47.9% (114/238), N501Y mutation was most frequently found (111/114, 97.4%). Among imported cases, strains with N501Y mutation alone were associated with more cough (16.5% vs 6.5%, p=0.022), but had similar incidence of hypoxemia and length of stay, compared with wild-type strains. Conclusion: HKICC successfully contributed to combating COVID-19 pandemic in Hong Kong. Imported cases with N501Y mutation alone presented with more cough, but had similar incidence of hypoxemia and length of stay, compared with wild-type strains. Further studies to evaluate the impact of other mutant strains are warranted.
ABSTRACT
Background: Within seconds of antigen-encounter, B-cell receptor (BCR) signaling induces dramatic changes of cell membrane lipid composition, including >40-fold increases of local PIP3-concentrations within lipid rafts. While several structural elements, including pleckstrin homology (PH) domains have been identified as PIP3-binding proteins, the underlying mechanisms that amplify BCR-signaling to assemble large signaling complexes within lipid rafts within 15 to 30 seconds, remained elusive. To understand the mechanistic and biophysical requirements for PIP3 accumulation during normal B-cell activation and acute oncogenic transformation, we identified PIP3-interacting proteins by cell-surface proteomic analyses. Results: In addition to proteins known to bind PIP3 with their PH-domains, we identified the short 133 aa protein IFITM3 (interferon-inducible transmembrane protein 3) as a top-ranking PIP3 scaffold. This was unexpected because IFITM3 was previously identified as endosomal protein that blocks viral infection by stiffening endosomal membranes to firmly contain viral cargo. Previous studies revealed that polymorphisms that lead to the expression of truncated IFITM3 are associated with increased susceptibility to viral infections, including SARS-CoV2. Among known cell membrane lipids, PIP3 has the highest negative charge. Instead of a PH-domain, IFITM3 laterally sequestered PIP3 through electrostatic interactions with two basic lysine residues (K83 and K104) located at the membrane-solution interface. Together with three other basic lysine and arginine residues K83 and K104 form a conserved intracellular loop (CIL), which enable IFITM3 to efficiently capture two PIP3 molecules. Bivalent PIP3-binding of the IFITM3-CIL enables a crosslinking mechanism that results in dramatic amplification of B-cell activation signals and clustering of large signaling complexes within lipid rafts. In normal resting B-cells, Ifitm3 was minimally expressed and mainly localized in endosomes. However, B-cell activation and oncogenic kinases induced phosphorylation at IFITM3-Y20, resulting in translocation of IFITM3 from endosomes and massive accumulation at the cell surface. Ifitm3ˉ /ˉ naïve B-cells developed at normal numbers, however, activation by antigen encounter was compromised. In Ifitm3ˉ /ˉ B-cells, lipid rafts were depleted of PIP3, resulting in defective expression of >60 lipid raft-associated surface receptors and impaired PI3K-signaling. Ifitm3ˉ /ˉ B-cells were unable to undergo affinity maturation and di not contribute to germinal center formation upon immunization. Analyses of gene expression and clinical outcome data from patients in six clinical cohorts for pediatric and adult B-ALL, mantle cell lymphoma, CLL and DLBCL, we consistently identified IFITM3 as a top-ranking predictor of poor clinical outcome. Inducible activation of BCR-ABL1 and NRAS G12D rapidly induced development of B-ALL but failed to transform and initiate B-ALL from Ifitm3ˉ /ˉ B-cell precursors. Conversely, the phospho-mimetic IFITM3-Y20E mutation, mimicking phosphorylation of the IFITM3 N-terminus at Y20 induced constitutive membrane localization of IFITM3, spontaneous aggregation of large oncogenic signaling complexes and readily initiated transformation in a genetic model of pre-malignant B-cells. Conclusions: We conclude that phosphorylation of IFITM3 upon B-cell activation induces a dynamic switch from antiviral effector functions in endosomes to oncogenic signal-amplification at the cell-surface. IFITM3-dependent amplification of PI3K-signaling is critical to enable rapid expansion of activated B-cells. In addition, multiple oncogenes depend on IFITM3 to assemble PIP3-dependent signaling complexes and amplify PI3K-signaling for malignant transformation and initiation of B-lymphoid leukemia and lymphoma. [Formula presented] Disclosures: Weinstock: SecuraBio: Consultancy;ASELL: Consultancy;Bantam: Consultancy;Abcuro: Research Funding;Verastem: Research Funding;Daiichi Sankyo: Consultancy, Research Funding;AstraZeneca: Consultanc ;Travera: Other: Founder/Equity;Ajax: Other: Founder/Equity.