Angiotensin (1−7) peptide replacement therapy with plasma transfusion in COVID-19

AimTo determine whether convalescent angiotensin (1?7) peptide replacement therapy with plasma (peptide plasma) transfusion can be beneficial in the treatment of critically ill patients with severe coronavirus 2 (SARS-CoV-2) infection.Study designCase series of 9 critically ill patients with laboratory-confirmed COVID-19 who met the following criteria: severe pneumonia with rapid progression and continuously high viral load despite antiviral treatment.Peptide plasma: Plasma with angiotensin (1?7) content 8–10 times higher than healthy plasma donors was obtained from suitable donors. Peptide plasma transfusion was applied to 9 patients whose clinical status and/or laboratory profile deteriorated and who needed intensive care for 2 days.ResultsIn our COVID-19 cases, favipiravir, low molecular weight heparin treatment, which is included in the treatment protocol of the ministry of health, was started. Nine patients with oxygen saturation of 93% and below despite nasal oxygen support, whose clinical and/or laboratory deteriorated, were identified. The youngest of the cases was 36 years old, and the oldest patient was 85 years old. 6 of the 9 cases had male gender. 3 cases had been smoking for more than 10 years. 4 cases had at least one chronic disease.In all of our cases, SARS CoV2 lung involvement was bilateral and peptide plasma therapy was administered in cases when oxygen saturation was 93% and below despite nasal oxygen support of 5 liters/minute and above, and intensive care was required. Although it was not reflected in the laboratory parameters in the early period, 8 patients whose saturations improved with treatment were discharged without the need for intensive care. However, a similar response was not obtained in one case. Oxygen requirement increased gradually and, he died in intensive care process. An increase of the platelet count was observed in all cases following the peptide plasma treatment.ConclusionIn this preliminary case series of 9 critically ill patients with COVID-19, administration of plasma containing angiotensin (1?7) was followed by improvement in their clinical status. The limited sample size and study design preclude a definitive statement about the potential effectiveness of this treatment, and these observations require evaluation in clinical trials.     

Extracellular vesicles: Their emerging roles in the pathogenesis of respiratory diseases

Alveoli are the basic structure of the lungs, consisting of various types of parenchymal and bone marrow-derived cells including alveolar macrophages. These various types of cells have several important functions; thus, communication between these cells plays an important role in homeostasis as well as in the pathophysiology of diseases in the lungs. For a better understanding of the pathophysiology of lung diseases, researchers have isolated each type of lung cell to investigate the changes in their gene expressions, including their humoral factor or adhesion molecules, to reveal the intercellular communication among these cells. In particular, investigations during the past decade have focused on extracellular vesicles, which are lipid bilayer delimited vesicles released from a cell that can move among various cells and transfer substances, including microRNAs, mRNAs and proteins, thus, functioning as intercellular messengers. Extracellular vesicles can be classified into three general groups: apoptotic bodies, exosomes, and microparticles. Extracellular vesicles, especially exosomes and microparticles, are attracting increasing attention from pulmonologists as tools for understanding pathogenesis and disease diagnosis. Here, we review studies, including our own, on exosomes and microparticles and their roles in both lung homeostasis and the pathogenesis of lung diseases such as idiopathic pulmonary fibrosis, chronic obstructive lung diseases, and acute respiratory distress syndrome. This review also addresses the roles of extracellular vesicles in COVID-19, the current global public health crisis.     

Development of an IgG-Fc fusion COVID-19 subunit vaccine,AKS-452

AKS-452 is a biologically-engineered vaccine comprising an Fc fusion protein of the SARS-CoV-2 viral spike protein receptor binding domain antigen (Ag) and human IgG1 Fc (SP/RBD-Fc) in clinical development for the induction and augmentation of neutralizing IgG titers against SARS-CoV-2 viral infection to address the COVID-19 pandemic. The Fc moiety is designed to enhance immunogenicity by increasing uptake via Fc-receptors (FcγR) on Ag-presenting cells (APCs) and prolonging exposure due to neonatal Fc receptor (FcRn) recycling. AKS-452 induced approximately 20-fold greater neutralizing IgG titers in mice relative to those induced by SP/RBD without the Fc moiety and induced comparable long-term neutralizing titers with a single dose vs. two doses. To further enhance immunogenicity, AKS-452 was evaluated in formulations containing a panel of adjuvants in which the water-in-oil adjuvant, Montanide™ ISA 720, enhanced neutralizing IgG titers by approximately 7-fold after one and two doses in mice, including the neutralization of live SARS-CoV-2 virus infection of VERO-E6 cells. Furthermore, ISA 720-adjuvanted AKS-452 was immunogenic in rabbits and non-human primates (NHPs) and protected from infection and clinical symptoms with live SARS-CoV-2 virus in NHPs (USA-WA1/2020 viral strain) and the K18 human ACE2-trangenic (K18-huACE2-Tg) mouse (South African B.1.351 viral variant). These preclinical studies support the initiation of Phase I clinical studies with adjuvanted AKS-452 with the expectation that this room-temperature stable, Fc-fusion subunit vaccine can be rapidly and inexpensively manufactured to provide billions of doses per year especially in regions where the cold-chain is difficult to maintain.     

Association of ACE I/D and AGTR1 A1166C Gene Polymorphisms and Risk of Uterine Leiomyoma: A Case-Control Study

Objective: Uterine leiomyoma (UL) can be considered as the most common benign gynecological tumors of the smooth muscle cells in the myometrium. They are likely to be associated with infertility and recurrent abortion as well as obstructed labor and post-partum hemorrhage. Moreover, altered vascular-related genes can be linked to developing leiomyoma. Polymorphisms of the angiotensin-converting enzyme (ACE) gene are associated with some vascular diseases. The present study was carried out to investigate the association of ACE I/D and AGTR1 A1166C gene polymorphisms and the risk of uterine leiomyoma in a sample of Iranian population. Methods: The study was carried out on a total of 413 women divided into 202 patients with diagnosed uterine leiomyomas and a control group of 211. Genotyping was performed using the PCR or PCR-RFLP methods. Results: The ID and DD genotypes of ACE I/D polymorphism were associated with 2 and 2.9 fold higher risk of UL compared to II genotype (OR, 2 [95% CI, 1.3 to 3.2]; P = 0.004 and OR, 2.9 [95% CI, 1.6 to 5]; P = 0.0002). The frequencies of ACE D alleles were 53.7% in women with UL and 40.3% in controls, which were observed to be statistically different (P < 0.0001). The alleles and genotypes of AGTR1 A1166C polymorphism were not different between UL and control women (P=0.9). Conclusion: The ACE ID and DD genotypes were associated with a higher risk of UL. No relationship was found between AGTR1 A1166C polymorphism and UL.     

Statin use and medically attended acute respiratory illness among influenza vaccine recipients

BackgroundPrevious studies have suggested that statins decrease influenza vaccine effectiveness and increase risk of medically attended acute respiratory illness (MAARI).ObjectivesTo examine the association of incident statin use and MAARI in a cohort of influenza vaccine recipients.MethodsThis retrospective cohort study evaluated influenza vaccine recipients within the Tricare population. The primary outcome compared MAARI incidence during the follow-up period in a propensity score-matched cohort of incident statin users and statin non-users. Secondary analysis included propensity score-adjusted comparisons between incident statin users and statin non-users in the entire cohort and prespecified sub-cohorts with and without comorbidities. The propensity score was derived from 72 variables encompassing demographics, medical history, comorbidities, medication use, and healthcare utilization.ResultsMAARI incidence in statin users was similar to non-users in the propensity score-matched cohort (odds ratio [OR] 0.92; 95% confidence interval [CI] 0.84–1.01). In contrast, statin users with lower comorbidity had lower OR for MAARI compared to non-users (Charlson Score zero cohort: 0.85 [CI 0.74–0.98]; No Diabetes cohort: 0.88 [CI 0.80–0.96]).ConclusionIncident statin use was not associated with increased MAARI incidence and may be associated with lower incidence of MAARI in those with less comorbidity. This study thus offers reassurance regarding the effectiveness of the influenza vaccine in statin users.     

Getting to Why: Adverse Childhood Experiences' Impact on Adult Health

Exposure to adverse childhood experiences (ACEs) contributes to 7 of the 10 leading causes of death in the United States as well as health risk behaviors, including substance abuse, physical inactivity, and high-risk sex behaviors. ACEs are traumatic childhood events that effect biopsychosocial health across the lifespan. It is vital for health care providers to view individuals from a trauma-informed perspective to guide best practice, but few are aware of ACEs, particularly those who treat adults. A review of the science of ACEs research, feasibility of screening for ACEs, and effective responses to trauma-impacted patients is presented in this report.     

藿朴夏苓汤治疗早期新型冠状病毒肺炎（COVID-19）湿邪郁肺证物质基础及功效的网络分析

目的筛选藿朴夏苓汤治疗早期新型冠状病毒肺炎(COVID-19)湿邪郁肺证的物质基础,预测其作用机制。方法查阅文献及临床报道分析藿朴夏苓汤与早期COVID-19湿邪郁肺证的方证关系。运用TCMSP数据库筛选藿朴夏苓汤中潜在活性成分,将活性成分与新型冠状病毒(SARS-CoV-2)3CL水解酶、血管紧张素转化酶Ⅱ(ACE2)进行分子对接,根据结合能筛选与两者均有较好结合作用的核心成分。借助Cytoscape软件构建关键成分靶点蛋白互作网络,筛选出核心靶点;通过STRING数据库进行核心靶点的GO分析,Cytoscape软件Clue GO插件进行Pathway、KEGG富集分析。结果方证关系分析藿朴夏苓汤用于治疗早期COVID-19湿邪郁肺证,筛选出藿朴夏苓汤中潜在作用成分12个,核心靶点67个。其中通草中的通脱木皂苷元Ⅰ,茯苓、猪苓中的过氧麦角甾醇,半夏中的黄芩苷与SARS-CoV-2 3CL水解酶、ACE2均具有较好的结合活性。GO、Pathway、KEGG富集分析结果显示藿朴夏苓汤中12个潜在作用成分参与调节刺激反应、信号转导、细胞死亡等生物过程以及白介素信号通路、癌症EGFR信号通路、酪氨酸激酶信号转导途径、编程性细胞死亡途径、MAPK信号通路等。结论藿朴夏苓汤以化湿解毒、宣肺透邪治疗早期COVID-19湿邪郁肺证患者,菲酮、黄芩苷、酸枣仁皂苷、啤酒甾醇、常春藤皂苷元、过氧麦角甾醇、柠檬二烯醇、麦角甾-7,22-二烯-3-酮、通脱木皂苷元Ⅰ、泽泻醇B-23-醋酸酯、泽泻醇B、新橙皮苷可能为其主要的物质基础,通过阻断SARS-CoV-2病毒蛋白合成,阻止病毒进入宿主细胞,通过调控白介素信号通路、MAPK信号通路、PI3K-Akt信号通路、T细胞受体信号通路、C型凝集素受体信号通路,抑制相关炎症因子的表达发挥作用。     

Consensus summary report for CEPI/BC March 12–13, 2020 meeting: Assessment of risk of disease enhancement with COVID-19 vaccines

A novel coronavirus (CoV), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in late 2019 in Wuhan, China and has since spread as a global pandemic. Safe and effective vaccines are thus urgently needed to reduce the significant morbidity and mortality of Coronavirus Disease 2019 (COVID-19) disease and ease the major economic impact. There has been an unprecedented rapid response by vaccine developers with now over one hundred vaccine candidates in development and at least six having reached clinical trials. However, a major challenge during rapid development is to avoid safety issues both by thoughtful vaccine design and by thorough evaluation in a timely manner. A syndrome of “disease enhancement” has been reported in the past for a few viral vaccines where those immunized suffered increased severity or death when they later encountered the virus or were found to have an increased frequency of infection. Animal models allowed scientists to determine the underlying mechanism for the former in the case of Respiratory syncytial virus (RSV) vaccine and have been utilized to design and screen new RSV vaccine candidates. Because some Middle East respiratory syndrome (MERS) and SARS-CoV-1 vaccines have shown evidence of disease enhancement in some animal models, this is a particular concern for SARS-CoV-2 vaccines. To address this challenge, the Coalition for Epidemic Preparedness Innovations (CEPI) and the Brighton Collaboration (BC) Safety Platform for Emergency vACcines (SPEAC) convened a scientific working meeting on March 12 and 13, 2020 of experts in the field of vaccine immunology and coronaviruses to consider what vaccine designs could reduce safety concerns and how animal models and immunological assessments in early clinical trials can help to assess the risk. This report summarizes the evidence presented and provides considerations for safety assessment of COVID-19 vaccine candidates in accelerated vaccine development.