Female-Male Differences in COVID Vaccine Adverse Events Have Precedence in Seasonal Flu Shots: A Potential Link to Sex-Associated Baseline Gene Expression Patterns (preprint)

Nearly 150 million doses of FDA-authorized COVID vaccines have been administered in the United States. Sex-based differences of adverse events remain poorly understood, mandating the need for real-world investigation from Electronic Health Records (EHRs) and broader epidemiological data sets. Based on an augmented curation of EHR clinical notes of 31,064 COVID-vaccinated individuals (19,321 females and 11,743 males) in the Mayo Clinic, we find that nausea and vomiting were documented significantly more frequently in females than males after both vaccine doses (nausea: RRDose 1 = 1.67, pDose 1 <0.001, RRDose 2 = 2.2, pDose 1 < 0.001; vomiting: RRDose 1 = 1.58, pDose 1 < 0.001, RRDose 2 = 1.88, pDose 1 = 3.4x10-2). Conversely, fever, fatigue, and lymphadenopathy were more common in males after the first dose vaccination (fever RR = 0.62; p = 8.65x10-3; fatigue RR = 0.86, p = 2.89x10-2; lymphadenopathy RR = 0.61, p = 3.45x10-3). Analysis of the Vaccine Adverse Events Reporting System (VAERS) database further confirms that nausea comprises a larger fraction of total reports among females than males (RR: 1.58; p<0.001), while fever comprises a larger fraction of total reports among males than females (RR: 0.84; p<0.001). Importantly, increased reporting of nausea and fever among females and males, respectively, is also observed for prior influenza vaccines in the VAERS database, establishing that these differences are not unique to the recently developed COVID-19 vaccines. Investigating the mechanistic basis underlying these clinical findings, an analysis of bulk RNA-sequencing data from 12,158 human blood samples (8626 female, 3532 male) reveals 85 genes that are not only significantly different in their gene expression between females and males at baseline, but also have established literature-based associations to COVID-19 as well as the vaccine-related adverse events of clinical consequence. The NLRP3 inflammasome and the NR3C1 glucocorticoid receptor emerge as particularly promising baseline links to sex-associated vaccine adverse events, warranting targeted investigation of these signaling pathways and associated cell types. From a public health standpoint, our clinical findings shall aid in educating patients on the sex-associated risks they should expect for COVID-19 vaccines, and promote better clinical management of vaccine-associated adverse events.Funding Statement: None to declare. Declaration of Interests: AJV, PK, ES, MS, RS, PL, EG, EL, and VS are employees of nference and have financial interests in the company and in the successful application of this research. JCO receives personal fees from Elsevier and Bates College, and receives small grants from nference, Inc, outside the submitted work. ADB is a consultant for Abbvie, is on scientific advisory boards for nference and Zentalis, and is founder and President of Splissen therapeutics. JCO, GJG, AWW, AV, MDS, and ADB are employees of the Mayo Clinic. The Mayo Clinic may stand to gain financially from the successful outcome of the research. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic Conflict of Interest policies. All other authors have nothing to declare. Ethics Approval Statement: This study was reviewed by the Mayo Clinic Institutional Review Board (IRB) and determined to be exempt from the requirement for IRB approval (45 CFR 46.104d, category 4).

Female-male differences in COVID vaccine adverse events have precedence in seasonal flu shots: a potential link to sex-associated baseline gene expression patterns (preprint)

Nearly 150 million doses of FDA-authorized COVID vaccines have been administered in the United States. Sex-based differences of adverse events remain poorly understood, mandating the need for real-world investigation from Electronic Health Records (EHRs) and broader epidemiological data sets. Based on an augmented curation of EHR clinical notes of 31,064 COVID-vaccinated individuals (19,321 females and 11,743 males) in the Mayo Clinic, we find that nausea and vomiting were documented significantly more frequently in females than males after both vaccine doses (nausea: RRDose 1 = 1.67, pDose 1 <0.001, RRDose 2 = 2.2, pDose 1 < 0.001; vomiting: RRDose 1 = 1.58, pDose 1 < 0.001, RRDose 2 = 1.88, pDose 1 = 3.4x10-2). Conversely, fever, fatigue, and lymphadenopathy were more common in males after the first dose vaccination (fever RR = 0.62; p = 8.65x10-3; fatigue RR = 0.86, p = 2.89x10-2; lymphadenopathy RR = 0.61, p = 3.45x10-3). Analysis of the Vaccine Adverse Events Reporting System (VAERS) database further confirms that nausea comprises a larger fraction of total reports among females than males (RR: 1.58; p<0.001), while fever comprises a larger fraction of total reports among males than females (RR: 0.84; p<0.001). Importantly, increased reporting of nausea and fever among females and males, respectively, is also observed for prior influenza vaccines in the VAERS database, establishing that these differences are not unique to the recently developed COVID-19 vaccines. Investigating the mechanistic basis underlying these clinical findings, an analysis of bulk RNA-sequencing data from 12,158 human blood samples (8626 female, 3532 male) reveals 85 genes that are not only significantly different in their gene expression between females and males at baseline, but also have established literature-based associations to COVID-19 as well as the vaccine-related adverse events of clinical consequence. The NLRP3 inflammasome and the NR3C1 glucocorticoid receptor emerge as particularly promising baseline links to sex-associated vaccine adverse events, warranting targeted investigation of these signaling pathways and associated cell types. From a public health standpoint, our clinical findings shall aid in educating patients on the sex-associated risks they should expect for COVID-19 vaccines and also promote better clinical management of vaccine-associated adverse events.

Market capitalization: Pre and post COVID-19 analysis.

This research paper focuses on the impact of COVID-19 on Indian Stock Market and shares performance. In other words, the article analyses the market capitalization correlation between the performances of shares and the growth of the share market, using the stock market data of Pre and post COVID-19 status by comparing the data from Jan'20 to Jun'20. The variables have positive and statistically strong significance on the changes in the market's performance and the value of its market capitalization.

Coronavirus Disease (COVID-19) and the Liver: A comprehensive systematic review and meta-analysis (preprint)

Background: Liver function derangements have been reported in coronavirus disease (COVID-19) but reported rates are variable. Methods: We searched Pubmed and Embase with terms COVID and SARS-COV-2 from December 1, 2019 till April 5, 2020. We estimated overall prevalence, stratified prevalence based on severity, estimated risk ratio (RR) and estimated standardized mean difference (SMD) of liver function parameters in severe as compared to nonsevere COVID. Random effect method utilizing inverse variance approach was used for pooling the data. Results: In all, 128 studies were included. The most frequent abnormalities were hypoalbuminemia [61.27% (48.24 - 72.87)], elevations of gamma-glutamyl transferase (GGT) [27.94%(18.22 -40.27)], alanine aminotransferase (ALT) [23.28%(19.92 - 27.01)] and aspartate aminotransferase (AST) [23.41%(18.84 - 28.70)]. Further the relative risk of these abnormalities was higher in the patients with severe COVID-19 when compared to non-severe disease [Hypoalbuminemia - 2.65(1.38 - 5.07); GGT - 2.31(1.6 - 3.33); ALT - 1.76(1.44 - 2.15); AST 2.30(1.82 - 2.90)]. The SMD of hypoalbuminemia, GGT, ALT and AST elevation in severe as compared to nonsevere were -1.05(-1.27 - -0.83), 0.76(0.40 - 1.12), 0.42(0.27 - 0.56) and 0.69 (0.52 - 0.86) respectively. The pooled prevalence and RR of chronic liver disease as a comorbidity was 2.64% (1.73- 4) and 1.69(1.05-2.73) respectively. Conclusion: The most frequent abnormality in liver functions was hypoalbuminemia followed by derangements in gamma-glutamyl transferase and aminotransferases and these abnormalities were more frequent in severe disease.  The systematic review was, however, limited by heterogeneity in definitions of severity and liver function derangements.