Updated, peer reviewed and published https://link.springer.com/article/10.1007/s10787-021-00896-7#Sec7 Aspirin has been recently suggested to be independently associated with reduced risk of mechanical ventilation, ICU admission and in-hospital mortality of COVID-19. However, we claim that the molecular interpretation of these important results was not scientifically valid, and we provide our academic interpretation that is also basing on our real-life practice using non-steroidal anti-inflammatory drugs in management of COVID-19 and we suggest that inhibition of COX-1 and/or COX-2 enzymes might play a lifesaving role in COVID-19 management, and we further discuss the potential of aspirin triggered lipoxins and resolivns in the same context.

We have previously suggested numerous immunomodulatory and anti-inflammatory benefits when NSAIDs are administered to manage COVID-19 and in this commentary, we add other potential benefits related to SARS CoV-2 ORF proteins dependent activation of caspases with subsequent mitochondrial dysfunction, endoplasmic reticulum stress and necroptosis that were described with complicated COVID-19 as NSAIDs are known to be caspase inhibitors. Moreover, NSAIDs might independently inhibit other COVID-19 associated downstream pathological signaling mechanisms. We also postulate that CARD-14, a caspase recruitment domain-containing protein, polymorphisms might play a role in development of severe and critical COVID-19. We believe that it is very unfortunate that for more than one year of relentless struggle, our recommendation to adopt NSAIDs as first choice COVID-19 therapy has not adopted while lives are lost are succumbed every day.

A document by Mina Kelleni. Click on the document to view its contents.

Nucleic acid based - mRNA based and adenovirus vectored - vaccines, were first ever or first commercially ever approved for the public, respectively. However, these newly emergency approved types possess a potential risk to induce auto-immune diseases e.g., thrombocytopenia, myocarditis and immune induced thrombosis and thromboembolism that might be fatal and could reason for some of the post vaccination sudden death reports. Moreover, all SARS CoV-2 types of vaccines, depending on the spike protein immunogenicity, especially the conventional inactivated ones might increase the likelihood of COVID-19 severity upon re-infection through antibody dependent enhancement which might reason for the recently described abundance of hospital admissions within seven days of vaccination and might also reason for some of the serious adverse effects encountered with administration of convalescent plasma to COVID-19 patients as well as they might share in development of some lethal SARS CoV-2 variants. Importantly, we suggest that SARS CoV-2 mass vaccination campaigns were the worst ever decision made and that making these COVID-19 vaccines compulsory or administering them to children or pregnant participants might be considered as a crime against humanity to the extent that no prior companies- governmental agreements would ever secure impunity. Finally, a full informed personalized risk benefit ratio especially for some described high-risk groups must be secured while suggesting that the subunit vaccines are the least hazardous ones.

This preprint has been published: https://juniperpublishers.com/ijoprs/IJOPRS.MS.ID.555658.php Nucleic acid based - mRNA based and adenovirus vectored - vaccines, were first ever or first commercially ever approved for the public, respectively. However, these newly emergency approved types possess a potential risk to induce auto-immune diseases e.g., thrombocytopenia, myocarditis and immune induced thrombosis and thromboembolism that might be fatal and could reason for some of the post vaccination sudden death reports. Moreover, all SARS CoV-2 types of vaccines, depending on the spike protein immunogenicity, especially the conventional inactivated ones might increase the likelihood of COVID-19 severity upon re-infection through antibody dependent enhancement which might reason for the recently described abundance of hospital admissions within seven days of vaccination and might also reason for some of the serious adverse effects encountered with administration of convalescent plasma to COVID-19 patients as well as they might share in development of some lethal SARS CoV-2 variants. Importantly, we suggest that SARS CoV-2 mass vaccination campaigns were the worst ever decision made and that making these COVID-19 vaccines compulsory or administering them to children or pregnant participants might be considered as a crime against humanity to the extent that no prior companies- governmental agreements would ever secure impunity. Finally, a full informed personalized risk benefit ratio especially for some described high-risk groups must be secured while suggesting that the subunit vaccines are the least hazardous ones.

Background: The current pandemic of coronavirus disease 2019 has necessitated trial of several drugs searching for a potential cure. We have published an article to justify adoption of nitazoxanide/azithromycin for early cases of COVID-19 followed by two other articles providing the theoretical basis to add non-steroidal anti-inflammatory drugs to the protocol which is described in this manuscript. Patients and methods: Twenty-two consented confirmed and highly suspected COVID-19 Egyptian patients including 11 adult males, 6 adult females, 2 pregnant patients as well as 3 children. All patients have received a 5-day-regimen of NSAIDs (diclofenac potassium, ibuprofen or ketoprofen)/nitazoxanide/azithromycin either in full or in part as illustrated in the manuscript. The primary endpoint of this protocol was full relief of all significant/hazardous COVID-19 symptoms and signs like fever, progressive cough, moderate/severe dyspnea or disturbed level of consciousness. Results: The primary endpoint of this protocol was fully achieved in all patients within two weeks. Most of the patients treated early with the protocol have recovered during the five days; the lymphocytic count was significantly improved for those with prior lymphopenia. No significant adverse effects were reported. Conclusion: A novel short course COVID-19 protocol using inexpensive FDA approved drugs is illustrated.

Updated, peer reviewed and published at Immunologic Research https://link.springer.com/article/10.1007%2Fs12026-021-09219-y   

Until recently, ibuprofen has been avoided in all COVID-19 protocols world-wide. The author has been trying since March, 2020 to publish a paper that disputes this unfortunate incident and he finally managed since May 2020 to publish two manuscripts that not only prove non-steroidal anti-inflammatory drugs not harmful for COVID-19, rather they were shown to possess a potential to cure the disease based on a unique new theory suggested to explain COVID-19 pathogenesis and he suggested NSAIDs to be added to unique protocol he suggested using nitazoxanide/azithromycin to manage early cases of COVID-19. In this manuscript, considered the fourth related to the subject, the author represents the first clinical results of using NSAIDs/Nitazoxanide/Azithromycin protocol, used partly or fully, that includes relatively cheap FDA approved drugs used in seventeen Egyptian patients, whether confirmed or suspected, including children, adults and two pregnant ladies whom have been mostly symptoms-free in five days. The manuscripts also presents a road-map to illustrate how to deal efficiently with early cases of COVID-19 according to the author’s clinical experience.

Updated, peer reviewed and published at Canadian journal of medicinehttps://cjm.cikd.ca/article_60573.htmlIntroduction: COVID-19 management still lacks a protocol of proven efficacy and we present a novel COVID-19 immunomodulatory protocol basing on our early pioneering article that justified repurposing nitazoxanide/azithromycin combination for early COVID-19 which was followed by two articles to justify addition of non-steroidal anti-inflammatory drugs to nitazoxanide/azithromycin as well as by our recent article that illustrates the potential immunomodulatory mechanisms by which all the drugs used in this manuscript might benefit COVID-19 patients.Methods: We present a case series of 38 confirmed and highly suspected COVID-19 consented native Arabic speaking patients, including 12 confirmed by PCR, and the others diagnosed by other measures who were managed by telemedicine. The patients included 15 adult males including an immunocompromised patient, 16 adult females including one lactating, 3 pregnant patients including one confirmed by PCR as well as 4 children. All patients have received a short 5-day-regimen of NSAIDs / nitazoxanide/ azithromycin +/- cefoperazone either in full or in part. The primary endpoint of this protocol was a full relief of all serious COVID-19 clinical manifestations. Results: The primary endpoint was fully achieved within two weeks. Most of the patients who were treated early, have fully recovered during its described five days; the leucocytic/lymphocytic count was significantly improved for those with prior leucopenia or leucocytosis/lymphopenia. Neither significant adverse effects, nor post/para COVID syndrome was reported. Conclusions: a novel 5-day-protocol to safely and effectively cure COVID-19 using repurposed immunomodulatory safe and inexpensive FDA approved drugs is illustrated and we recommend performing sufficiently powered double-blind randomized clinical trials.

In the first version, I have made a mistake SARS COV-2 Vaccines have not shared in development of the original SARS CoV-2 B.1.617 variants in India (yet they might have shared in the evolution of the more virulent delta plus variant). I have updated the manuscript, thanks to Authorea, and in the updated versions Remdesivir, Favipiravir and Dexamethasone are suggested as potential crucial causes that led to B.1.617 variants in India and elsewhere. Moreover, SARS CoV-2 mass vaccination programs and the unfortunately anticipated Molnupiravir are suggested to share in evolution of potentially more virulent variants e.g. delta plus and the catastrophic Indian surge of mortality is also anticipated to be repeated elsewhere unless some prompt interventions are considered.

A document by Mina Kelleni. Click on the document to view its contents.

A heavily updated version would be find here:https://www.authorea.com/users/318758/articles/522100-ace2-polymorphisms-reflected-on-the-immune-and-apelinergic-peptide-systems-potential-covid-19-tools-for-risk-stratification-and-therapyShort communicationThe apelinergic peptide system link with ACE2 polymorphisms: novel insights in COVID-19 managementMina T. Kelleni, MD, PhDAssistant Professor of Pharmacology, College of Medicine, Minia University, Egypt.Mobile: [email protected], [email protected]://orcid.org/0000-0001-6290-6025HighlightsACE2 polymorphisms have been previously linked to increased susceptibility to multiple diseases and are currently linked to SARS CoV-2 susceptibility and complicationsACE2 transcribed or regulated proteins including the activity of metaloproteinsase-2 and apelin-13 and 36 cleavage, might be linked to abnormal immune responses and complicationsA potential genetic or serological test might be developed to detect the higher vulnerable groups to SARS CoV-2 complications and/or mortality including health care professionalsInfusion of apelin-13 to treat critical cases of COVID-19, especially those complaining of advanced heart failure, might prove beneficialAbstract:Aiming to decrease the unexplained COVID-19 mortality in some young and otherwise healthy patients, including health care professionals, we hypothesize that ACE2 polymorphisms might be reflected through under/overexpression of ACE2 transcribed or regulated proteins including the activity of metaloproteinsase-2 and apelin-13 and 36 cleavage, leading to unexpected immune responses and complications. We might detect the higher vulnerable groups if a genetic test to detect potential associated variant ACE2 alleles, or a serological test to detect the suggested associated proteins, could be developed and linked to those cases of unexpected complications and/or mortality. Furthermore, basing on the same hypothesis, we suggest testing infusion of apelin-13 to treat critical cases of COVID-19, especially those complaining of advanced heart failure. Keywords:SARS CoV-2, COVID-19, ACE2 polymorphisms, apelin-13. Recent studies have demonstrated that the expression, polymorphism and/or mutations in the receptor binding domain of ACE2, the receptor of SARS CoV-2, could influence both the susceptibility of people and populations to SARS CoV-2 infection as well as the potential clinical manifestations and outcomes of COVID-19(Azer, 2020; Devaux, Rolain & Raoult, 2020; Hou et al., 2020; Khayat et al., 2020). As an example, a study showed that East Asian populations have a much higher  ACE2 allelic fraction in expression quantitative trait loci variants which may suggest different susceptibilities or response to SARS CoV-2 from other populations (Cao et al., 2020). Thus, thorough exploration of the relationship ACE2 polymorphisms with COVID-19 might help to save lives, especially those belonging to the minority of unexplainable complications and/or mortality of young patients, including health care professionals.  ACE2 polymorphisms and their induced mutations have been previously linked to enhanced susceptibility to heart diseases including coronary heart disease and myocardial infarction as have been revealed both clinically and experimentally(Wang et al., 2014; Yang et al., 2006). Importantly, the ACE2 rs4646188 variant was suggested as a potential and optimal genetic susceptibility marker for essential hypertension, dyslipidemia and its related ischemic stroke(Pan et al., 2018). Similarly, three other ACE2 variants (rs4240157, rs4646155, and rs4830542) were found to be associated with essential hypertension and hypertension-related atrial fibrillation and left atrial remodeling(Luo et al., 2019). Similarly, genetic variants in the ACE2 gene have been suggested to be associated with left ventricular mass, septal wall thickness and left ventricular hypertrophy in hemizygous men(Lieb et al., 2006) and genetic variants in the ACE2 gene were significantly associated with diastolic blood pressure responses to cold stress in the Chinese female population(Huang et al., 2012). Thus, ACE2 polymorphisms were logically suggested and later showed to be linked with SARS CoV-2 variable clinical manifestations and outcomes. Notably, a study showed that six out of ten eQTL variants in ACE2 have been associated with altered ACE2 tissue expression and linked with the need for hospitalization due to COVID-19, suggesting that ACE2 genotype may inform both COVID-19 risk stratification and the need for more intense therapy(Wooster, Nicholson, Sigurslid, Lino Cardenas & Malhotra, 2020). Furthermore, a significant ACE2‐mRNA expression was observed in the classical human monocyte subpopulation (CD14++CD16− cells)(Rutkowska-Zapała et al., 2015), thus, a variable immune response associated with some ACE2 variants might prove beneficial when thoroughly examined. Taken together, it is likely that ACE2 polymorphisms might explain at least some cases of the otherwise unexplained COVID-19 induced mortality encountered in some healthy adults/health care professionals(Kelleni). Moreover, several apelin peptides have been shown to inhibit human immunodeficiency virus into cells expressing the G protein coupled apelin receptor to which they act as endogenous ligands (Read et al., 2019; Zou, Liu, Haraguchi, Soda, Tatemoto & Hoshino, 2000) and apelin-13 has been shown to act as a  positive regulator of ACE2 mRNA transcription(Gheblawi et al., 2020). Similarly, it is well established that downregulation of ACE2 receptors triggers important inflammatory lesions in the respiratory tree and has been suggested to play a central role in the pathogenesis of SARS-CoV-2 infection(Verdecchia, Cavallini, Spanevello & Angeli, 2020). Moreover, a negative correlation between ACE2 expression and COVID‐19 fatality at both the population and molecular levels has been shown (Chen et al., 2020). Thus, we recommend exploring our suggested hypothesis to detect potential varian ACE2 alleles and their suggested over/underexpression or altered abnormal activity of some transcribed/regulated proteins including metallopeptidase-2 activity(Kuan et al., 2013) and apelin-13 and apelin-36 peptide cleavage (Gheblawi et al., 2020; Yang et al., 2017) wishing to develop potential genetic tests to detect variant ACE2 alleles as well as serological tests to detect the suggested abnormal levels or activities of the suggested and other associated proteins. Bronchoscopy/CT guided lung biopsies and autopsies might be considered to directly examine those markers to be compared in different groups of COVID-19 patients. Interestingly, apelin peptides were shown to ameliorate acute lung injury by several mechanisms that are also associated with COVID-19 associated acute respiratory distress syndrome(Saeedi Saravi & Beer, 2020) and apelin-13 continuous infusion at 1 mg/kg/d by an osmotic pump upregulated ACE2 expression, improved heart functions and reduced heart weight in AT1R-deficient mice under transverse aortic constriction(Sato et al., 2013) and we recommend to test apelin-13 infusion for critical cases of COVID-19, especially those complaining of advanced heart failure. Finally, we would like to recommend that the continuous exploration of this type of genetic research should never be abandoned even if a valid cure and/or vaccine has been developed, we should learn from this COVID-19 pandemic to prepare in the morning to what might newly arise before the end of the day.             Conflict of interests:The author has no conflicts of interest to declare.Funding/Financial disclosure:None.References: Azer SA (2020). COVID-19: pathophysiology, diagnosis, complications and investigational therapeutics. New Microbes and New Infections 37: 100738. Cao Y, Li L, Feng Z, Wan S, Huang P, Sun X, et al. (2020). Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations. Cell Discovery 6: 11. Chen J, Jiang Q, Xia X, Liu K, Yu Z, Tao W, et al. (2020). Individual variation of the SARS-CoV-2 receptor ACE2 gene expression and regulation. Aging Cell 19. Devaux CA, Rolain J-M, & Raoult D (2020). 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