query: are patients taking Angiotensin-converting enzyme inhibitors (ACE) at increased risk for COVID-19?

positive: Renin-angiotensin-aldosterone system inhibitors and COVID-19 infection or hospitalization: a cohort study There are plausible mechanisms by which angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may increase the risk of COVID-19 infection or affect disease severity. To examine the association between these medications and COVID-19 infection or hospitalization, we conducted a retrospective cohort study within a US integrated healthcare system. Among people aged [≥]18 years enrolled in the health plan for at least 4 months as of 2/29/2020, current ACEI and ARB use was identified from pharmacy data, and the estimated daily dose was calculated and standardized across medications. COVID-19 infections were identified through 6/14/2020 from laboratory and hospitalization data. We used logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals. Among 322,044 individuals, 720 developed COVID-19 infection. Among people using ACEI/ARBs, 183/56,105 developed COVID-19 (3.3 per 1000 individuals) compared with 537/265,939 without ACEI/ARB use (2.0 per 1000), yielding an adjusted OR of 0.94 (95% CI 0.75-1.16). For use of < 1 defined daily dose vs. nonuse, the adjusted OR for infection was 0.89 (95% CI 0.62-1.26); for 1 to < 2 defined daily doses, 0.97 (95% CI 0.71-1.31); and for [≥]2 defined daily doses, 0.94 (95% CI 0.72-1.23). The OR was similar for ACEIs and ARBs and in subgroups by age and sex. 29% of people with COVID-19 infection were hospitalized; the adjusted OR for hospitalization in relation to ACEI/ARB use was 0.92 (95% CI 0.54-1.57), and there was no association with dose. These findings support current recommendations that individuals on these medications continue their use.

positive: [Role of age, comorbidity and renin- angiotensin-aldosterone system in COVID-19. Effects of ACE inhibitors and angiotensin receptor blockers]. The review addressed the relationship of coronavirus disease 2019 (COVID-19) with functioning of the renin-angiotensin-aldosterone axis and the causes for unfavorable prognosis depending on patients' age and comorbidities. The authors discussed in detail potential effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists on the risk of infection and the course of COVID-2019 as well as the effect of SARS-COV2 virus on the cardiovascular system.

positive: Bioinformatic characterization of angiotensin-converting enzyme 2, the entry receptor for SARS-CoV-2 The World Health Organization declared the COVID-19 epidemic a public health emergency of international concern on March 11th, 2020, and the pandemic is rapidly spreading worldwide. COVID-19 is caused by a novel coronavirus SARS-CoV-2, which enters human target cells via angiotensin converting enzyme 2 (ACE2). We used a number of bioinformatics tools to computationally characterize ACE2 by determining its cell-specific expression in trachea, lung, and small intestine, derive its putative functions, and predict transcriptional regulation. The small intestine expressed higher levels of ACE2 than any other organ. The large intestine, kidney and testis showed moderate signals, whereas the signal was weak in the lung. Single cell RNA-Seq data from trachea indicated positive signals along the respiratory tract in key protective cell types including club, goblet, proliferating, and ciliary epithelial cells; while in lung the ratio of ACE2-expressing cells was low in all cell types (<2.6%), but was highest in vascular endothelial and goblet cells. Gene ontology analysis suggested that, besides its classical role in renin-angiotensin system, ACE2 may be functionally associated with angiogenesis/blood vessel morphogenesis. Using a novel tool for the prediction of transcription factor binding sites we identified several putative binding sites within two tissue-specific promoters of the ACE2 gene. Our results also confirmed that age and gender play no significant role in the regulation of ACE2 mRNA expression in the lung. IMPORTANCE Vaccines and new medicines are urgently needed to prevent spread of COVID-19 pandemic, reduce the symptoms, shorten the duration of disease, prevent virus spread in the body, and most importantly to save lives. One of the key drug targets could be angiotensin-converting enzyme 2 (ACE2), which is a crucial receptor for the corona virus (SARS-CoV-2). It is known that SARS coronavirus infections lead to worse outcome in the elderly and in males. Therefore, one aim of the present study was to investigate whether age or sex could contribute to the regulation of ACE2 expression. We also decided to explore the transcriptional regulation of ACE2 gene expression. Since data on ACE2 distribution is still conflicting, we aimed to get a more comprehensive view of the cell types expressing the receptor of SARS-CoV-2. Finally, we studied the coexpression of ACE2 with other genes and explored its putative functions using gene ontology enrichment analysis.

positive: Angiotensin II for the Treatment of COVID-19–Related Vasodilatory Shock

positive: Should Patients Receiving ACE Inhibitors or Angiotensin Receptor Blockers be Switched to Other Antihypertensive Drugs to Prevent or Improve Prognosis of Novel Coronavirus Disease 2019 (COVID-19)?

positive: Interaction between RAAS inhibitors and ACE2 in the context of COVID-19

positive: Inhibitors of the renin–angiotensin system and SARS-CoV-2 infection

positive: Acute kidney injury in SARS-CoV-2 infected patients

positive: Angiotensin receptor blockers as tentative SARS‐CoV‐2 therapeutics At the time of writing this commentary (February 2020), the coronavirus COVID‐19 epidemic has already resulted in more fatalities compared with the SARS and MERS coronavirus epidemics combined. Therapeutics that may assist to contain its rapid spread and reduce its high mortality rates are urgently needed. Developing vaccines against the SARS‐CoV‐2 virus may take many months. Moreover, vaccines based on viral‐encoded peptides may not be effective against future coronavirus epidemics, as virus mutations could make them futile. Indeed, new Influenza virus strains emerge every year, requiring new immunizations. A tentative suggestion based on existing therapeutics, which would likely be resistant to new coronavirus mutations, is to use available angiotensin receptor 1 (AT1R) blockers, such as losartan, as therapeutics for reducing the aggressiveness and mortality from SARS‐CoV‐2 virus infections. This idea is based on observations that the angiotensin‐converting enzyme 2 (ACE2) very likely serves as the binding site for SARS‐CoV‐2, the strain implicated in the current COVID‐19 epidemic, similarly to strain SARS‐CoV implicated in the 2002–2003 SARS epidemic. This commentary elaborates on the idea of considering AT1R blockers as tentative treatment for SARS‐CoV‐2 infections, and proposes a research direction based on datamining of clinical patient records for assessing its feasibility.

positive: Cardiovascular Disease in the Post-COVID-19 Era – the Impending Tsunami?

positive: Pharmacovigilance in Patients with Diabetes: A Data-Driven Analysis Identifying Specific RAS Antagonists with Adverse Pulmonary Safety Profiles That Have Implications for COVID-19 Morbidity and Mortality ABSTRACT OBJECTIVES Current demographic information from China reports that 10-19% of patients hospitalized with COVID-19 were diabetic. Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin-II receptor blockers (ARBs) are considered first-line agents in diabetics due to their nephroprotective effects but administration of these drugs leads to upregulation of angiotensin-converting-enzyme-2 (ACE2), responsible for viral entry of severe-acute-respiratory-distress-syndrome, coronavirus-2 (SARS-CoV-2). Data is lacking to determine what pulmonary effects ACEIs/ARBs may have in patients with diabetes, which could be relevant in the management of patients infected with SARS-CoV-2. In this study, the aim was to assess the prevalence of pulmonary adverse drug effects (ADEs) in diabetic patients taking ACEI or ARBs to help provide guidance as to how these medications could affect outcomes in acute respiratory illness, such as SARS-CoV-2 infection. METHODS 1DATA, a unique data platform resulting from collaboration across veterinary and human healthcare, utilized an intelligent medicine recommender system (1DrugAssist) developed using several national and international databases, to evaluate all ADEs reported to the FDA for patients with diabetes taking ACEIs or ARBs. RESULTS Mining of this data elucidated the proportion of a cluster of pulmonary ADEs associated with specific medications in these classes, which may aid healthcare professionals in understanding how these medications could worsen or predispose patients with diabetes to infections affecting the respiratory system specifically, COVID-19. Based on this data mining, Captopril was found to have a statistically significantly higher incidence of pulmonary ADEs compared to other ACEIs (P = 0.005) as well as ARBs (P = 0.012), though other specific drugs also had important pulmonary ADEs associated with their use. CONCLUSION These analyses suggest that pharmacists and clinicians will need to consider specific medication’s adverse event profile, particularly captopril, and how this profile may affect infections and other acute disease states that alter pulmonary function, such as COVID-19.

positive: Role of ACE, ACE2 and Neprilysin in the Kidney

positive: Angiotensin converting enzyme 2 is primarily epithelial and is developmentally regulated in the mouse lung Angiotensin converting enzyme (ACE) 2 is a carboxypeptidase that shares 42% amino acid homology with ACE. Little is known about the regulation or pattern of expression of ACE2 in the mouse lung, including its definitive cellular distribution or developmental changes. Based on Northern blot and RT‐PCR data, we report two distinct transcripts of ACE2 in the mouse lung and kidney and describe a 5′ exon 1a previously unidentified in the mouse. Western blots show multiple isoforms of ACE2, with predominance of a 75–80 kDa protein in the mouse lung versus a 120 kDa form in the mouse kidney. Immunohistochemistry localizes ACE2 protein to Clara cells, type II cells, and endothelium and smooth muscle of small and medium vessels in the mouse lung. ACE2 mRNA levels peak at embryonic day 18.5 in the mouse lung, and immunostaining demonstrates protein primarily in the bronchiolar epithelium at that developmental time point. In murine cell lines ACE2 is strongly expressed in the Clara cell line mtCC, as opposed to the low mRNA expression detected in E10 (type I‐like alveolar epithelial cell line), MLE‐15 (type II alveolar epithelial cell line), MFLM‐4 (fetal pulmonary vasculature cell line), and BUMPT‐7 (renal proximal tubule cell line). In summary, murine pulmonary ACE2 appears to be primarily epithelial, is developmentally regulated, and has two transcripts that include a previously undescribed exon. J. Cell. Biochem. 101:1278–1291, 2007. © 2007 Wiley‐Liss, Inc.

positive: Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults BACKGROUND: The role of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs) in COVID-19 disease susceptibility, severity, and treatment is unclear. PURPOSE: To evaluate, on an ongoing basis, whether use of ACEIs or ARBs either increases risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or is associated with worse COVID-19 disease outcomes, and to assess the efficacy of these medications for COVID-19 treatment. DATA SOURCES: MEDLINE (Ovid) and Cochrane Database of Systematic Reviews from 2003 to 4 May 2020, with planned ongoing surveillance for 1 year; the World Health Organization database of COVID-19 publications and medRxiv.org through 17 April 2020; and ClinicalTrials.gov to 24 April 2020, with planned ongoing surveillance. STUDY SELECTION: Observational studies and trials in adults that examined associations and effects of ACEIs or ARBs on risk for SARS-CoV-2 infection and COVID-19 disease severity and mortality. DATA EXTRACTION: Single-reviewer abstraction confirmed by another reviewer, independent evaluation by 2 reviewers of study quality, and collective assessment of certainty of evidence. DATA SYNTHESIS: Two retrospective cohort studies found that ACEI and ARB use was not associated with a higher likelihood of receiving a positive SARS-CoV-2 test result, and 1 case-control study found no association with COVID-19 illness in a large community (moderate-certainty evidence). Fourteen observational studies, involving a total of 23 565 adults with COVID-19, showed consistent evidence that neither medication was associated with more severe COVID-19 illness (high-certainty evidence). Four registered randomized trials plan to evaluate ACEIs and ARBs for treatment of COVID-19. LIMITATION: Half the studies were small and did not adjust for important confounding variables. CONCLUSION: High-certainty evidence suggests that ACEI or ARB use is not associated with more severe COVID-19 disease, and moderate-certainty evidence suggests no association between use of these medications and positive SARS-CoV-2 test results among symptomatic patients. Whether these medications increase the risk for mild or asymptomatic disease or are beneficial in COVID-19 treatment remains uncertain. PRIMARY FUNDING SOURCE: None. (PROSPERO: registration number pending).

positive: Angiotensin-converting enzyme 2 in severe acute respiratory syndrome coronavirus and SARS-CoV-2: A double-edged sword? Human angiotensin-converting enzyme 2 (ACE2) facilitates cellular entry of severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 as their common receptor. During infection, ACE2-expressing tissues become direct targets, resulting in serious pathological changes and progressive multiple organ failure or even death in severe cases. However, as an essential component of renin-angiotensin system (RAS), ACE2 confers protective effects in physiological circumstance, including maintaining cardiovascular homeostasis, fluid, and electrolyte balance. The absence of protective role of ACE2 leads to dysregulated RAS and thus acute changes under multiple pathological scenarios including SARS. This potentially shared mechanism may also be the molecular explanation for pathogenesis driven by SARS-CoV-2. We reasonably speculate several potential directions of clinical management including host-directed therapies aiming to restore dysregulated RAS caused by ACE2 deficiency. Enriched knowledge of ACE2 learned from SARS and COVID-19 outbreaks can provide, despite their inherent tragedy, informative clues for emerging pandemic preparedness.

positive: New Cardiovascular and Pulmonary Therapeutic Strategies Based on the Angiotensin-Converting Enzyme 2/Angiotensin-(1–7)/Mas Receptor Axis Angiotensin (Ang)-(1–7) is now recognized as a biologically active component of the renin-angiotensin system (RAS). The discovery of the angiotensin-converting enzyme homologue ACE2 revealed important metabolic pathways involved in the Ang-(1–7) synthesis. This enzyme can form Ang-(1–7) from Ang II or less efficiently through hydrolysis of Ang I to Ang-(1–9) with subsequent Ang-(1–7) formation. Additionally, it is well established that the G protein-coupled receptor Mas is a functional ligand site for Ang-(1–7). The axis formed by ACE2/Ang-(1–7)/Mas represents an endogenous counter regulatory pathway within the RAS whose actions are opposite to the vasoconstrictor/proliferative arm of the RAS constituted by ACE/Ang II/AT(1) receptor. In this review we will discuss recent findings concerning the biological role of the ACE2/Ang-(1–7)/Mas arm in the cardiovascular and pulmonary system. Also, we will highlight the initiatives to develop potential therapeutic strategies based on this axis.

positive: [Medication and comedication in COVID-19 patients]. This paper discusses the possible effects of comedication on COVID-19 and the current treatment options for this infection. It is very doubtful that comedication has a disadvantageous effect on the course of the disease. NSAIDs should be avoided in any patient with a possible severe disease, because of potential side effects. Inhibitors of the renin-angiotensin aldosterone system should be continued when there is a solid indication, and stopped in case of hemodynamic problems. There is no preference for either ACE inhibitors or angiotensin II receptor inhibitors. Currently, chloroquine and remdesivir are possible treatment options. There is no sound evidence for either treatment. Chloroquine has side effects (nausea, QT prolongation) and there are several drug interactions. The treatment should be reconsidered in the event of side effects and when inferior medication for comorbidity must be prescribed because of possible interactions. Lopinavir/ritonavir is not effective. Supportive care is at present the mainstay of the treatment.

positive: COVID-19 in diabetic patients: related risks and specifics of management Abstract Diabetes is among the most frequently reported comorbidities in patients infected with COVID-19. According to current data, diabetic patients do not appear to be at increased risk of contracting SARS-CoV-2 compared to the general population. On the other hand, diabetes is a risk factor for developing severe and critical forms of COVID-19, the latter requiring admission to an intensive care unit and/or use of invasive mechanical ventilation, with high mortality rates. The characteristics of diabetic patients at risk for developing severe and critical forms of COVID-19, as well as the prognostic impact of diabetes on the course of COVID-19, are under current investigation. Obesity, the main risk factor for incident type 2 diabetes, is more common in patients with critical forms of COVID-19 requiring invasive mechanical ventilation. On the other hand, COVID-19 is usually associated with poor glycemic control and a higher risk of ketoacidosis in diabetic patients. There are currently no recommendations in favor of discontinuing antihypertensive medications that interact with the renin-angiotensin-aldosterone system. Metformin and SGLT2 inhibitors should be discontinued in patients with severe forms of COVID-19 owing to the risks of lactic acidosis and ketoacidosis. Finally, we advise for systematic screening for (pre)diabetes in patients with proven COVID-19 infection.

positive: Potential benefit of angiotensin II in COVID-19 patients: beyond reasonable doubt?

positive: SARS coronavirus entry into host cells through a novel clathrin- and caveolae-independent endocytic pathway While severe acute respiratory syndrome coronavirus (SARS-CoV) was initially thought to enter cells through direct fusion with the plasma membrane, more recent evidence suggests that virus entry may also involve endocytosis. We have found that SARS-CoV enters cells via pH- and receptor-dependent endocytosis. Treatment of cells with either SARS-CoV spike protein or spike-bearing pseudoviruses resulted in the translocation of angiotensin-converting enzyme 2 (ACE2), the functional receptor of SARS-CoV, from the cell surface to endosomes. In addition, the spike-bearing pseudoviruses and early endosome antigen 1 were found to colocalize in endosomes. Further analyses using specific endocytic pathway inhibitors and dominant-negative Eps15 as well as caveolin-1 colocalization study suggested that virus entry was mediated by a clathrin- and caveolae-independent mechanism. Moreover, cholesterol- and sphingolipid-rich lipid raft microdomains in the plasma membrane, which have been shown to act as platforms for many physiological signaling pathways, were shown to be involved in virus entry. Endocytic entry of SARS-CoV may expand the cellular range of SARS-CoV infection, and our findings here contribute to the understanding of SARS-CoV pathogenesis, providing new information for anti-viral drug research. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/cr.2008.15) contains supplementary material, which is available to authorized users.

positive: A Viewpoint on Angiotensin-Converting Enzyme 2, Anti-Hypertensives and Coronavirus Disease 2019 (COVID-19). TO THE EDITOR, The current life threatening pandemic outbreak of coronavirus disease 2019 (COVID-19) is hitting the whole world in terms of mortality as well as economic losses [1,2]. It has thought to be originated from Wuhan, China, in December 2019. This outbreak has link to Wuhan's seafood and exotic animal wholesale markets [3,4]. As SARS-CoV-2 is highly contagious, it has now spread to each and every corner of the world [1,2]. According to the World Health Organization (WHO) situation report (77th), updated on 6 April, 2020 there have been globally 1210956 confirmed cases and 67 594 deaths of COVID-19 [2]. This viral outbreak has now posed a global threat to healthcare systems. So many, efforts are going on to find new drugs or to repurpose already existed drugs [1,5-7]. Majoritily, it has been found that most of the COVID-19 patients belong to cardiovascular comorbidities [8-10]. It is obvious that they qualify for antihypertensive therapy. Many of them are treating with angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB)[8]. There has been considerable debate in scientific community and health professionals about whether angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) may increase attractiveness towards the COVID-19 virus infection or not ?[9-16]. One of the important concern highlighted by these studies involving antihypertensive medications suggested that these drugs might cause increments in abundance of SARS-CoV-2 receptor henceforth causing COVID-19 by entering into cells [17,18]. This suggests plausible increase in ACE2 receptors on lung and heart cells and hence offering more entry points for SARS-CoV-2[17]. However, no strong evidence has been noted. There has been more number of commentaries published explaining both sides and still they are appearing on daily basis [12-16]. Herein, we tried to summaries, clinical aspects on ACEs and ARBs based on literature and commentaries to explain both the sides. A recent published article in Nature by Zhou et al. (2020)[19], reported that the angiotensin-converting enzyme II (ACE2) is acting as receptor for SARS Coronavirus 2.This receptors was also acted as receptors for SARS-CoV and HCoV-NL63. Zhou et al. (2020), clearly wrote that "We show that 2019-nCoV (COVID-19) is able to use ACE2 proteins as an entry receptor to enter ACE2-expressing cells, but not cells that did not express ACE2, indicating that ACE2 is probably the cell receptor through which 2019-nCoV enters cells". ACE2 is aminopeptidase responsible for cleaving angiotensin I and angiotensin II into the angiotensin-(1-9) and angiotensin-(1-7) peptides[20]. Normally, ACE2 have been found to be overexpressed in clinical conditions including heart failure, arterial hypertension, etc. It has also been noted that ACE2 acts as a functional receptor for SARS-CoV-2 entry. There have been several literatures supporting the role of a cardiovascular-protective ACE2-angiotensin-(1-7)-Mas receptor axis. Recent viewpoint article published in JAMA journal by author Majd AlGhatrif exaplains[15] correlations among aging, cardiovascular diseases and COVID-19 patients. He clearly concluded important fact saying, "compared with young individuals, older persons with cardiovascular disorders (CVD); who already have reduced ACE2 levels will be expected to be more predisposed to exaggerated inflammation with further reduction in ACE2 expression in the context of COVID-19, manifesting with greater disease severity". One of well-known Austrian scientist Prof. Josef Penninger[21], Josef Penninger noted important relationship between RAS (the renin-angiotensin system) and ACE2. He is particularly focusing on ACE2 as a potential treatment approach. In one of the article by Mourad et al., (2020), explained different effects on ACE2 levels in correlation with different administrations of RAAS inhibitors and believed that chronic treatment with ACE inhibitors has no reason to influence the course of SARS-CoV-2 infection[22]. A reply to this article has also been published by Zheng et al., (2020)[23] saying that "although ACE2 has been identified as the functional receptor for SARS-CoV-2, the role of ACE2 in the progression of COVID-19 after SARS-CoV-2 infection is still controversial, so the benefits of aliskiren use in patients with COVID-19 needs further investigation". Today, many healthcare societies' especially cardiovascular societies are urging the patients suffering from CVDs (cardiovascular diseases) not to discontinue their medications[24-26]. These healthcare societies give more stress upon statement saying that there is no sound evidence to correlate ACEs and ARBs leading risk of COVID-19 infection. It has also been noted that healthcare societies do not suggest immediate starting of ACEIs/ARBs in those patients having no settlements with clinical conditions like heart failure, diabetes, hypertension, etc. As these statements adheres to current state of evidences. The same conclusion has been derived from the recent article by Ankit Patel et al., (2020)[24]. This article suggested that there has been no definitive evidence to suggest ACE inhibitors and ARBs worsening of COVID-19. A study published by Vaduganathan et al., (2020) in New England Journal of Medicine discussed the uncertain effects of RAAS blockers on ACE2 levels[27]. They also derived to conclusion that ACE2 may be beneficial in COVID-19 patients with lung injury. This team also suggests that withdrawal of RAAS inhibitors may be harmful. A very recent review published by Dr. Sanchis-Gomar and his co-authors in Mayo Clinic Proceedings[14], by analysing more than 60 articles, concluded the fact that "no studies have reported an increase in circulating ACE2 levels or expression thus far, and increased expression would not necessarily imply an increased risk of infection or disease severity". Dr. Sanchis-Gomar, studies both articles explaining that elevated levels of angiotensin II fostering acute respiratory distress syndrome (ARDS) as well as significance of RAAS inhibitors in therapy in treating patients with COVID-19. However, authors noted that more research in this regard is needed. CONCLUSION In this regards, more laboratory and clinical evidences are required in order to decide COVID-19 treatment. In conclusion to this debate, suggesting roles of antihypertensive agents and severity leading changes in ACE2 levels, may shed more light on infectivity and outcome of COVID-19.There is an urgent need to establish whether treatments with antihypertensive (ACEI's/ ARBs) needs to be determined.

positive: Therapy with agents acting on the renin-angiotensin system and risk of SARS-CoV-2 infection. Exposure to agents acting on the renin-angiotensin system was not associated to a risk increase of COVID-19 infection in two Italian matched case-control studies, one nested in hypertensive patients and the other in patients with cardiovascular diseases or diabetes.

positive: Use of renin–angiotensin–aldosterone system inhibitors and risk of COVID-19 requiring admission to hospital: a case-population study BACKGROUND: Concerns have been raised about the possibility that inhibitors of the renin–angiotensin–aldosterone system (RAAS) could predispose individuals to severe COVID-19; however, epidemiological evidence is lacking. We report the results of a case-population study done in Madrid, Spain, since the outbreak of COVID-19. METHODS: In this case-population study, we consecutively selected patients aged 18 years or older with a PCR-confirmed diagnosis of COVID-19 requiring admission to hospital from seven hospitals in Madrid, who had been admitted between March 1 and March 24, 2020. As a reference group, we randomly sampled ten patients per case, individually matched for age, sex, region (ie, Madrid), and date of admission to hospital (month and day; index date), from Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP), a Spanish primary health-care database, in its last available year (2018). We extracted information on comorbidities and prescriptions up to the month before index date (ie, current use) from electronic clinical records of both cases and controls. The outcome of interest was admission to hospital of patients with COVID-19. To minimise confounding by indication, the main analysis focused on assessing the association between COVID-19 requiring admission to hospital and use of RAAS inhibitors compared with use of other antihypertensive drugs. We calculated odds ratios (ORs) and 95% CIs, adjusted for age, sex, and cardiovascular comorbidities and risk factors, using conditional logistic regression. The protocol of the study was registered in the EU electronic Register of Post-Authorisation Studies, EUPAS34437. FINDINGS: We collected data for 1139 cases and 11 390 population controls. Among cases, 444 (39·0%) were female and the mean age was 69·1 years (SD 15·4), and despite being matched on sex and age, a significantly higher proportion of cases had pre-existing cardiovascular disease (OR 1·98, 95% CI 1·62–2·41) and risk factors (1·46, 1·23–1·73) than did controls. Compared with users of other antihypertensive drugs, users of RAAS inhibitors had an adjusted OR for COVID-19 requiring admission to hospital of 0·94 (95% CI 0·77–1·15). No increased risk was observed with either angiotensin-converting enzyme inhibitors (adjusted OR 0·80, 0·64–1·00) or angiotensin-receptor blockers (1·10, 0·88–1·37). Sex, age, and background cardiovascular risk did not modify the adjusted OR between use of RAAS inhibitors and COVID-19 requiring admission to hospital, whereas a decreased risk of COVID-19 requiring admission to hospital was found among patients with diabetes who were users of RAAS inhibitors (adjusted OR 0·53, 95% CI 0·34–0·80). The adjusted ORs were similar across severity degrees of COVID-19. INTERPRETATION: RAAS inhibitors do not increase the risk of COVID-19 requiring admission to hospital, including fatal cases and those admitted to intensive care units, and should not be discontinued to prevent a severe case of COVID-19. FUNDING: Instituto de Salud Carlos III.

positive: Practical recommendations for the management of diabetes in patients with COVID-19 Summary Diabetes is one of the most important comorbidities linked to the severity of all three known human pathogenic coronavirus infections, including severe acute respiratory syndrome coronavirus 2. Patients with diabetes have an increased risk of severe complications including Adult Respiratory Distress Syndrome and multi-organ failure. Depending on the global region, 20–50% of patients in the coronavirus disease 2019 (COVID-19) pandemic had diabetes. Given the importance of the link between COVID-19 and diabetes, we have formed an international panel of experts in the field of diabetes and endocrinology to provide some guidance and practical recommendations for the management of diabetes during the pandemic. We aim to briefly provide insight into potential mechanistic links between the novel coronavirus infection and diabetes, present practical management recommendations, and elaborate on the differential needs of several patient groups.

positive: Understanding the Renin-Angiotensin-Aldosterone-SARS-CoV-Axis: A Comprehensive Review IMPORTANCE: Coronavirus Disease 19 (COVID-19), the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been declared a global pandemic with significant morbidity and mortality since first appearing in Wuhan, China, in late 2019. As many countries are grappling with the onset of their epidemics, pharmacotherapeutics remain lacking. The window of opportunity to mitigate downstream morbidity and mortality is narrow but remains open. The renin-angiotensin-aldosterone system (RAAS) is crucial to the homeostasis of both the cardiovascular and respiratory systems. Importantly, SARS-CoV-2 utilises and interrupts this pathway directly, which could be described as the renin-angiotensin-aldosterone-SARS-CoV-2-axis (RAAS-SCoV-axis). There exists significant controversy and confusion surrounding how anti-hypertensive agents might function along this pathway. This review explores the current state of knowledge regarding the RAAS-SCoV-axis, informed by prior studies of SARS-CoV, how this relates to our currently evolving pandemic, and how these insights might guide our next steps in an evidence-based manner. OBSERVATIONS: This review discusses the role of the RAAS-SCoV-axis in acute lung injury and the effects, risks, and benefits of pharmacologic modification of this axis. There may be an opportunity to leverage the different aspects of RAAS inhibitors to mitigate indirect viral-induced lung injury. Concerns have been raised that such modulation might exacerbate the disease. While relevant preclinical, experimental models to date favor a protective effect of RAAS-SCoV-axis inhibition on both lung injury and survival, clinical data related to the role of RAAS modulation in the setting of SARS-CoV-2 remains limited. CONCLUSION: Proposed interventions for SARS-CoV-2 predominantly focus on viral microbiology and aim to inhibit viral cellular injury. While these therapies are promising, immediate use may not be feasible, and the time window of their efficacy remains a major unanswered question. An alternative approach is the modulation of the specific downstream pathophysiologic effects caused by virus that lead to morbidity and mortality. We propose a preponderance of evidence that supports clinical equipoise regarding the efficacy of RAAS-based interventions, and the imminent need for a multisite randomised controlled clinical trial to evaluate the inhibition of the RAAS-SCoV-axis on acute lung injury in COVID-19.

positive: A close-up on COVID-19 and cardiovascular diseases Abstract Aims To analyze the potential mechanism of cardiovascular dysfunctions induced by Coronavirus Disease 2019 (COVID-19) and to evaluate more effective therapeutic pathways for patients with cardiovascular diseases. Data Synthesis COVID-19 mainly invades the lungs, causing its serious damage. Studies found that COVID-19 induced the renin-angiotensin system imbalance, inflammatory storm, hypoxemia and stress response et al, all contributed to hypertension and serious myocardial damage in the process of virus pathogenesis, even increasing mortality in COVID-19 patients. Conclusions In the process of management of COVID-19 infections, close attention should be paid on both lung and cardiovascular damage, especially on those with only symptoms of cardiovascular diseases. Early identification, timely and effective treatments, maintenance of hemodynamics and electrophysiological stability are of great significance on effective treatment and long-term prognosis. The pandemic of COVID-19 has been taking lives worldwide. It caused by a novel coronavirus which human being are lack of defensive function in whole population. It targets human’s lung and causes serious damage of lungs. Based on early reports, for people with underlying heart issues, the concerns are serious. It appears people over 65 with coronary heart diseases or hypertension is more likely to be infected and to develop more severe symptoms. In addition, some of hospitalized COVID-19 patients had cardiovascular diseases in China. As characteristic analysis of COVID-19 patients, hypertension and severe myocardial damage contribute to severity [1] and mortality of COVID-19 patients [2]. Therefore, to better understand the development of COVID-19 and the impacts of cardiovascular diseases will add valuable measures to the management of COVID-19 patients.

positive: COVID-19, ACE2, and the cardiovascular consequences The novel SARS coronavirus SARS-CoV-2 pandemic may be particularly deleterious to patients with underlying cardiovascular disease (CVD). The mechanism for SARS-CoV-2 infection is the requisite binding of the virus to the membrane-bound form of angiotensin-converting enzyme 2 (ACE2) and internalization of the complex by the host cell. Recognition that ACE2 is the coreceptor for the coronavirus has prompted new therapeutic approaches to block the enzyme or reduce its expression to prevent the cellular entry and SARS-CoV-2 infection in tissues that express ACE2 including lung, heart, kidney, brain, and gut. ACE2, however, is a key enzymatic component of the renin-angiotensin-aldosterone system (RAAS); ACE2 degrades ANG II, a peptide with multiple actions that promote CVD, and generates Ang-(1-7), which antagonizes the effects of ANG II. Moreover, experimental evidence suggests that RAAS blockade by ACE inhibitors, ANG II type 1 receptor antagonists, and mineralocorticoid antagonists, as well as statins, enhance ACE2 which, in part, contributes to the benefit of these regimens. In lieu of the fact that many older patients with hypertension or other CVDs are routinely treated with RAAS blockers and statins, new clinical concerns have developed regarding whether these patients are at greater risk for SARS-CoV-2 infection, whether RAAS and statin therapy should be discontinued, and the potential consequences of RAAS blockade to COVID-19-related pathologies such as acute and chronic respiratory disease. The current perspective critically examines the evidence for ACE2 regulation by RAAS blockade and statins, the cardiovascular benefits of ACE2, and whether ACE2 blockade is a viable approach to attenuate COVID-19.

positive: Impact of Nutrition and Diet on COVID-19 Infection and Implications for Kidney Health and Kidney Disease Management

positive: Headache medication and the COVID-19 pandemic The world is currently dominated by the Corona Virus Disease 2019 (COVID-19) pandemic. Besides the obvious concerns about limitation of virus spread and providing the best possible care to infected patients, a concomitant concern has now arisen in view of a putative link between the use of certain drugs, such as Renin-Angiotensin System (RAS) inhibitors and ibuprofen, and an increased risk for COVID-19 infection. We here discuss this concern in relation to headache treatment and conclude that, based on current evidence, there is no reason to abandon treatment of headache patients with RAS inhibitors or ibuprofen.

positive: COVID-19 and the RAAS-a potential role for angiotensin II?

positive: COVID 19 and heart failure: from infection to inflammation and angiotensin II stimulation. Searching for evidence from a new disease Patients with cardiovascular disease and, namely, heart failure are more susceptible to coronavirus disease 2019 (COVID‐19) and have a more severe clinical course once infected. Heart failure and myocardial damage, shown by increased troponin plasma levels, occur in at least 10% of patients hospitalized for COVID‐19 with higher percentages, 25%–35% or more, when patients critically ill or with concomitant cardiac disease are considered. Myocardial injury may be elicited by multiple mechanisms, including those occurring with all severe infections, such as fever, tachycardia, adrenergic stimulation, as well as those caused by the exaggerated inflammatory response, endotheliitis and, in some cases, myocarditis that have been shown in patients with COVID‐19. A key role may be that of the renin–angiotensin‐aldosterone system. Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infects human cells binding to angiotensin‐converting‐enzyme 2 (ACE2), an enzyme responsible of the cleavage of angiotensin II into angiotensin 1–7, which has vasodilating and anti‐inflammatory effects. Virus‐mediated downregulation of ACE2 may increase angiotensin II stimulation and contribute to the deleterious hyper‐inflammatory reaction of COVID‐19. On the other hand, ACE2 may be upregulated in patients with cardiac disease and treated with ACE inhibitors or angiotensin receptor blockers. ACE2 upregulation may increase the susceptibility to COVID‐19 but may be also protective versus angiotensin II mediated vasoconstriction and inflammatory activation. Recent data show the lack of untoward effects of ACE inhibitors or angiotensin receptor blockers for COVID‐19 infection and severity. Prospective trials are needed to ascertain whether these drugs may have protective effects. This article is protected by copyright. All rights reserved.

positive: ACE Inhibitors and ARBs in Patients with COVID-19: Friend or Foe?

positive: A review of the 2019 Novel Coronavirus (COVID-19) based on current evidence Abstract The pneumonia caused by novel coronavirus (SARS-CoV-2) in Wuhan, China in December 2019 is a highly contagious disease. The World Health Organization (WHO) has declared the ongoing outbreak as a global public health emergency. Currently, the research on novel coronavirus is still in the primary stage. Based on the current published evidence, we systematically summarizes the epidemiology, clinical characteristics, diagnosis, treatment and prevention of knowledge surrounding COVID-19. This review in the hope of helping the public effectively recognize and deal with the 2019 novel coronavirus (SARS-CoV-2), and providing a reference for future studies.

positive: COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options The novel coronavirus disease (COVID-19) outbreak, caused by SARS-CoV-2, represents the greatest medical challenge in decades. We provide a comprehensive review of the clinical course of COVID-19, its comorbidities, and mechanistic considerations for future therapies. While COVID-19 primarily affects the lungs, causing interstitial pneumonitis and severe acute respiratory distress syndrome (ARDS), it also affects multiple organs, particularly the cardiovascular system. Risk of severe infection and mortality increase with advancing age and male sex. Mortality is increased by comorbidities: cardiovascular disease, hypertension, diabetes, chronic pulmonary disease, and cancer. The most common complications include arrhythmia (atrial fibrillation, ventricular tachyarrhythmia, and ventricular fibrillation), cardiac injury [elevated highly sensitive troponin I (hs-cTnI) and creatine kinase (CK) levels], fulminant myocarditis, heart failure, pulmonary embolism, and disseminated intravascular coagulation (DIC). Mechanistically, SARS-CoV-2, following proteolytic cleavage of its S protein by a serine protease, binds to the transmembrane angiotensin-converting enzyme 2 (ACE2) —a homologue of ACE—to enter type 2 pneumocytes, macrophages, perivascular pericytes, and cardiomyocytes. This may lead to myocardial dysfunction and damage, endothelial dysfunction, microvascular dysfunction, plaque instability, and myocardial infarction (MI). While ACE2 is essential for viral invasion, there is no evidence that ACE inhibitors or angiotensin receptor blockers (ARBs) worsen prognosis. Hence, patients should not discontinue their use. Moreover, renin–angiotensin–aldosterone system (RAAS) inhibitors might be beneficial in COVID-19. Initial immune and inflammatory responses induce a severe cytokine storm [interleukin (IL)-6, IL-7, IL-22, IL-17, etc.] during the rapid progression phase of COVID-19. Early evaluation and continued monitoring of cardiac damage (cTnI and NT-proBNP) and coagulation (D-dimer) after hospitalization may identify patients with cardiac injury and predict COVID-19 complications. Preventive measures (social distancing and social isolation) also increase cardiovascular risk. Cardiovascular considerations of therapies currently used, including remdesivir, chloroquine, hydroxychloroquine, tocilizumab, ribavirin, interferons, and lopinavir/ritonavir, as well as experimental therapies, such as human recombinant ACE2 (rhACE2), are discussed.

positive: Estimation of Renin-Angiotensin-Aldosterone-System (RAAS)-Inhibitor effect on COVID-19 outcome: A Meta-analysis BACKGROUND AND RATIONALE: Some studies of hospitalized patients suggested that the risk of death and/or severe illness due to COVID-19 is not associated with the use of angiotensin-converting enzyme inhibitors (ACEIs) and/or angiotensin II receptor type 1 blockers (ARBs). Nevertheless, some controversy still exists and there is limited information of the ACEIs/ARBs effect size on COVID-19 prognosis. AIM AND METHODS: We aimed to measure the effect of ACEIs and/or ARBs on COVID-19 severe clinical illness by a meta-analysis. Literature search included all studies published since the COVID-19 outbreak began (December 2019) until May 9, 2020. We analyzed information from studies that included tested COVID-19 patients with arterial hypertension as comorbidity prior to hospital admission and history of taking ACEIs, ARBs, or ACEIs/ARBs. RESULTS: We included 16 studies that involved 24,676 COVID-19 patients, and we compared patients with critical (nâ¯=â¯4134) vs. non-critical (nâ¯=â¯20,542) outcomes. The overall assessment by estimating random effects shows that the use of ACEIs/ARBs is not associated with higher risk of in-hospital-death and/or severe illness among hypertensive patients with COVID-19 infection. On the contrary, effect estimate shows an overall protective effect of RAAS inhibitors/blockers (ACEIs, ARBs, and/or ACEIs/ARBs) with â¼ 23 % reduced risk of death and/or critical disease (OR: 0.768, 95%CI: 0.651-0.907, p=0.0018). The use of ACEIs (OR:0.652, 95%CI:0.478-0.891, p=0.0072) but not ACEIs/ARBs (OR:0.867, 95%CI:0.638-1.179, p =NS) or ARBs alone (OR:0.810, 95%CI:0.629-1.044, p=NS) may explain the overall protection displayed by RAAS intervention combined. CONCLUSION: RAAS inhibitors might be associated with better COVID-19 prognosis.

positive: Counter-regulatory 'Renin-Angiotensin' System-based Candidate Drugs to Treat COVID-19 Diseases in SARS-CoV-2-infected patients SARS-CoV-2 / COVID-19 and the 'Renin-Angiotensin' System The ubiquitous 'Renin-Angiotensin' system (RAS), also referred to as 'Renin-Angiotensin-Aldosterone' system, plays a crucial physiological role in humans as being a key regulator of renal, cardiovascular and innate immune functions [1, 2]. It appears to work in tandem with vitamin D, a secosteroid pro-hormone which reportedly acts as a negative regulatory factor of the RAS [3-6]. A dysfunction (e.g. over-reactivity) of RAS, together with hypovitaminosis D, is likely associated with some of the various renal, cardiac, vascular and immune outcomes that might be observed in COVID-19 patients, including the cytokine storm (i.e. unopposed hyperactive immune reaction generating both pro-inflammatory and anti-inflammatory cytokines) and consequent lethal acute respiratory distress syndrome [1, 7]. Recently, SARS-CoV-2 [8, 9], the causative agent of COVID-19, has been described to interfere with the RAS [2] by interacting -via its spike (S) glycoprotein- with the metallopeptidase Angiotensin-Converting Enzyme 2 (ACE2) receptor [9, 10] that is expressed at the surface of epithelial cells from blood vessels, lung, kidney (renal tubules), intestine, and heart, as well as on cerebral neurons and immune monocytes/macrophages [11-13]. The main SARS-CoV-2-related COVID-19 symptoms/diseases reported hitherto are hypertension, atherosclerosis, thrombosis (coagulopathy), diarrhea, glaucoma, anosmia, ageusia, skin lesions (dermatitis), autoimmune inflammation of the central nervous system, and damages to various organs such as the lung, heart, kidney, and testicle [1, 2, 14]. All these diffuse COVID-19 disorders are likely linked to an over-reaction of RAS in SARS-CoV-2-infected persons. Such a RAS imbalance would be also favored by hypovitaminosis D [2-7, 11]. Since RAS appears to be central in COVID-19 symptoms/diseases, selective targeting of key component(s) of this system might be appropriate to treat RAS-dependent disorders. COVID-19 Disorders: 'Renin-Angiotensin' System (RAS) & Counter-regulatory RAS In the RAS pathway [1, 15], Renin (kidney) cleaves Angiotensinogen (liver) to give Angiotensin I (i.e. peptide DRVYIHPFHL). The latter is cleaved by the Angiotensin-Converting Enzyme (ACE) to produce Angiotensin II (i.e. peptide DRVYIHPF), which is the substrate of ACE2 (SARS-CoV-2 receptor) and key player of the RAS. The cellular targets of Angiotensin II are the vasoconstrictor type 1 (AT1R) and vasodilatator type 2 (AT2R) Angiotensin II receptors (AT1R is expressed at the surface of monocytes/macrophages and T-cells indicating that RAS acts on innate immunity in host). When cleaved by ACE2, Angiotensin II gives Angiotensin 1-7 (i.e. peptide DRVYIHP), targeting the vasodilatator proto-oncogene Mas receptor (MasR). Angiotensin 1-7 can be further transformed to Alamandine (i.e. peptide ARVYIHP) by an aspartate decarboxylase. Alamandine would bind to the vasodilatator Mas-related G protein-coupled receptor member D (MRGD) thus promoting most of the Angiotensin 1-7-like effects. Angiotensin II can produce Angiotensin A (i.e. peptide ARVYIHPF) via an aspartate decarboxylase, and Alamandine via an additional ACE2 cleavage. ACE2 can also cleave Angiotensin I to form Angiotensin 1-9 (i.e. peptide DRVYIHPFH), which targets AT2R. In the RAS pathway were finally evidenced the related Angiotensin III (i.e. peptide RVYIHPF) and Angiotensin IV (i.e. peptide VYIHPF) variants targeting the AT1R and vasodilatator AT4R, respectively. From the known molecular functioning of the RAS, Angiotensins I and II (aside Angiotensin III) are playing central roles in the activity of RAS and associated pathologies, including COVID-19 [2, 10]. Interestingly, it appears that a 'counter-regulatory' RAS does exist to modulate system homeostasis; it relies on Angiotensin 1-7, Angiotensin 1-9, Alamandine, Angiotensin A, and Angiotensin IV, which are targeting the MasR, AT2R, MRGD, ACE2 and AT4R vasodilatator receptors, respectively. These peptides were found to exhibit cardioprotective, vasoactive (anti-hypertensive), anti-hypertrophic and/or anti-inflammatory potentials [15]. Such naturally-produced molecules of the RAS are expected to counteract the SARS-CoV-2-induced over-activation of RAS and reverse, to some extent, the associated COVID-19 diseases. CONCLUDING REMARKS A recent report suggests that RAS inhibitors may act on the severity of viral infection and mortality of COVID-19 patients [14]. Whether or not RAS blockers would be beneficial to COVID-19 cases is still controversial. The RAS inhibitors likely prevent the cytokine storm as RAS is reported to control the release of pro-inflammatory cytokines [1, 7]. It appears that COVID-19 disorders of SARS-CoV-2-infected humans depend on the RAS over-reacted by the (ACE2-dependent) viral infection and vitamin D deficiency. The track for a possible COVID-19 treatment would be to target RAS using specific candidate chemotherapeutic drugs. The proposed molecules are (so far) ACE inhibitors (to prevent the production of Angiotensin II from Angiotensin I), and blockers/antagonists of AT1R such as Losartan and derivatives. Recombinant ACE2 (under clinical trials) is also considered as a decoy for the recognition and competitive binding to the spike (S) glycoprotein of SARS-CoV-2 [9, 10]. We support the use of natural candidate peptide drugs that belong to the 'counter-regulatory' RAS, i.e. Angiotensin 1-7, Angiotensin 1-9, Alamandine, Angiotensin A and/or Angiotensin IV to treat COVID-19 disorders. The targeted receptors would thus be MasR, AT2R, MRGD, ACE2 and AT4R. The authors wish to thank Bonabes De Rougé MD for fruitful discussions.

positive: Severe respiratory SARS-CoV2 infection: Does ACE2 receptor matter? Abstract SARS-CoV-2 is a novel virus of the Coronaviridiae family that represents a major global health issue. Mechanisms implicated in virus/host cells interaction are central for cell infection and replication that in turn lead to disease onset and local damage. To enter airway and lung epithelia, SARS-CoV-2 attaches to ACE2 receptors by spike (S) glycoproteins. Molecular mechanisms that promote interaction between SARS-CoV-2 virus and host with particular focus on virus cell entry receptor ACE2 are described. We further explore the impact of underlying medical conditions and therapies including renin-angiotensin inhibitors on modulating ACE 2, which is the major SARS-CoV-2 cell entry receptor.

positive: Is the ACE2 Overexpression a Risk Factor for COVID-19 Infection? In the recent coronavirus disease (COVID-19) outbreak, a higher proportion of patients with severe disease were found in older persons with comorbidities. This observation has been related to the use of drugs that can increase the cellular expression of angiotensin-converting enzyme 2 (ACE2) that has been recognized as target to which the virus bind to cells. Although this hypothesis is possible, it may also have other explanations which are discussed.

positive: Influence of inhibitors of the renin–angiotensin system on risk of acute respiratory distress syndrome in Danish hospitalized COVID-19 patients

positive: Smoking Upregulates Angiotensin-Converting Enzyme-2 Receptor: A Potential Adhesion Site for Novel Coronavirus SARS-CoV-2 (Covid-19) The epicenter of the original outbreak in China has high male smoking rates of around 50%, and early reported death rates have an emphasis on older males, therefore the likelihood of smokers being overrepresented in fatalities is high. In Iran, China, Italy, and South Korea, female smoking rates are much lower than males. Fewer females have contracted the virus. If this analysis is correct, then Indonesia would be expected to begin experiencing high rates of Covid-19 because its male smoking rate is over 60% (Tobacco Atlas). Smokers are vulnerable to respiratory viruses. Smoking can upregulate angiotensin-converting enzyme-2 (ACE2) receptor, the known receptor for both the severe acute respiratory syndrome (SARS)-coronavirus (SARS-CoV) and the human respiratory coronavirus NL638. This could also be true for new electronic smoking devices such as electronic cigarettes and “heat-not-burn” IQOS devices. ACE2 could be a novel adhesion molecule for SARS-CoV-2 causing Covid-19 and a potential therapeutic target for the prevention of fatal microbial infections, and therefore it should be fast tracked and prioritized for research and investigation. Data on smoking status should be collected on all identified cases of Covid-19.

positive: Physiological and pathological regulation of ACE2, the SARS-CoV-2 receptor The renin-angiotensin system (RAS) is crucial for the physiology and pathology of all the organs. Angiotensin-converting enzyme 2 (ACE2) maintains the homeostasis of RAS as a negative regulator. Recently, ACE2 was identified as the receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the coronavirus that is causing the pandemic of Coronavirus disease 2019 (COVID-19). Since SARS-CoV-2 must bind with ACE2 before entering the host cells in humans, the distribution and expression of ACE2 may be critical for the target organ of the SARS-CoV-2 infection. Moreover, accumulating evidence has demonstrated the implication of ACE2 in the pathological progression in tissue injury and several chronic diseases, ACE2 may also be essential in the progression and clinical outcomes of COVID-19. Therefore, we summarized the expression and activity of ACE2 in various physiological and pathological conditions, and discussed its potential implication in the susceptibility of SARS-CoV-2 infection and the progression and prognosis of COVID-19 patients in the current review.

positive: ACE inhibition and cardiometabolic risk factors, lung ACE2 and TMPRSS2 gene expression, and plasma ACE2 levels: a Mendelian randomization study Objectives: To use human genetic variants that proxy angiotensin-converting enzyme (ACE) inhibitor drug effects and cardiovascular risk factors to provide insight into how these exposures affect lung ACE2 and TMPRSS2 gene expression and circulating ACE2 levels. Design: Two-sample Mendelian randomization (MR) analysis. Setting: Summary-level genetic association data. Participants: Participants were predominantly of European ancestry. Variants that proxy ACE inhibitor drug effects and cardiometabolic risk factors (body mass index, chronic obstructive pulmonary disease, lifetime smoking index, low-density lipoprotein cholesterol, systolic blood pressure and type 2 diabetes mellitus) were selected from publicly available genome-wide association study data (sample sizes ranging from 188,577 to 898,130 participants). Genetic association estimates for lung expression of ACE2 and TMPRSS2 were obtained from the Gene-Tissue Expression (GTEx) project (515 participants) and the Lung eQTL Consortium (1,038 participants). Genetic association estimates for circulating plasma ACE2 levels were obtained from the INTERVAL study (4,947 participants). Main outcomes and measures: Lung ACE2 and TMPRSS2 expression and plasma ACE2 levels. Results: There were no association of genetically proxied ACE inhibition with any of the outcomes considered here. There was evidence of a positive association of genetic liability to type 2 diabetes mellitus with lung ACE2 gene expression in GTEx (p = 4x10-4) and with circulating plasma ACE2 levels in INTERVAL (p = 0.03), but not with lung ACE2 expression in the Lung eQTL Consortium study (p = 0.68). There were no associations between genetically predicted levels of the other cardiometabolic traits with the outcomes. Conclusions: This study does not provide evidence to support that ACE inhibitor antihypertensive drugs affect lung ACE2 and TMPRSS2 expression or plasma ACE2 levels. In the current COVID-19 pandemic, our findings do not support a change in ACE inhibitor medication use without clinical justification.

positive: COVID-19: is there a link between the course of infection and pharmacological agents in diabetes? BACKGROUND: The Coronavirus disease 2019 (COVID-19) and type 2 diabetes (T2D) are two pandemics that share the dramatic impact on global mortality and economic resources. COVID-19 largely exhibits mild to moderate clinical manifestations. However, severe pneumonia with high fatality rate may occur, especially in the elderly and in patients with underlying conditions, such as diabetes and cardiovascular disease. SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) binds to the angiotensin-converting enzyme 2 (ACE2), a ubiquitous trans-membrane carboxypeptidase, to enter the cells. AIMS: This short review discusses some open questions about the link between COVID-19 and diabetes, principally focusing on the possible effects of commonly used drugs in patients with diabetes. RESULTS: Preclinical studies have reported that angiotensin receptor blockers (ARBs) and ACE inhibitors might increase ACE2 expression in several cell types. Hence, it has been speculated that the treatment with these agents might influence the course of the infection, and both harmful and beneficial effects have been supposed. Other pharmacological agents are thought to increase ACE2 expression, including statins and proliferator-activated receptor gamma (PPAR-γ) agonists. All these drug classes are broadly adopted in T2D. Besides ACE2, other unknown co-factors might be involved in cell infection. It has been recently observed that dipeptidyl peptidase-4 (DPP4), the receptor for MERS-CoV (Middle East respiratory syndrome-related coronavirus) and ACE2 have similar expression profiles in the lung. DPP4 has important metabolic and immune functions and is a target for commonly used therapies in T2D. CONCLUSIONS: Although clinical data supporting an influence of all these drugs on the course of the disease are limited, this is an interesting background for further research that might help unravel the complex mechanisms underlying the link between COVID-19 and diabetes.

positive: Renin–Angiotensin–Aldosterone System Blockers and the Risk of Covid-19 BACKGROUND: A potential association between the use of angiotensin-receptor blockers (ARBs) and angiotensin-converting–enzyme (ACE) inhibitors and the risk of coronavirus disease 2019 (Covid-19) has not been well studied. METHODS: We carried out a population-based case–control study in the Lombardy region of Italy. A total of 6272 case patients in whom infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was confirmed between February 21 and March 11, 2020, were matched to 30,759 beneficiaries of the Regional Health Service (controls) according to sex, age, and municipality of residence. Information about the use of selected drugs and patients’ clinical profiles was obtained from regional databases of health care use. Odds ratios and 95% confidence intervals for associations between drugs and infection, with adjustment for confounders, were estimated by means of logistic regression. RESULTS: Among both case patients and controls, the mean (±SD) age was 68±13 years, and 37% were women. The use of ACE inhibitors and ARBs was more common among case patients than among controls, as was the use of other antihypertensive and non-antihypertensive drugs, and case patients had a worse clinical profile. Use of ARBs or ACE inhibitors did not show any association with Covid-19 among case patients overall (adjusted odds ratio, 0.95 [95% confidence interval {CI}, 0.86 to 1.05] for ARBs and 0.96 [95% CI, 0.87 to 1.07] for ACE inhibitors) or among patients who had a severe or fatal course of the disease (adjusted odds ratio, 0.83 [95% CI, 0.63 to 1.10] for ARBs and 0.91 [95% CI, 0.69 to 1.21] for ACE inhibitors), and no association between these variables was found according to sex. CONCLUSIONS: In this large, population-based study, the use of ACE inhibitors and ARBs was more frequent among patients with Covid-19 than among controls because of their higher prevalence of cardiovascular disease. However, there was no evidence that ACE inhibitors or ARBs affected the risk of COVID-19.

positive: The Use of Nonsteroidal Anti-inflammatory Drugs in Urological Practice in the COVID-19 Era: Is “Safe Better than Sorry”?

positive: The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The Perspectives of clinical immunologists from China Abstract The pandemic outbreak of coronavirus disease 2019 (COVID-19) is rapidly spreading all over the world. Reports from China showed that about 20% of patients developed severe disease, resulting in a fatality of 4%. In the past two months, we clinical immunologists participated in multi-rounds of MDT (multidiscipline team) discussion on the anti-inflammation management of critical COVID-19 patients, with our colleagues dispatched from Chinese leading PUMC Hospital to Wuhan to admit and treat the most severe patients. Here, from the perspective of clinical immunologists, we will discuss the clinical and immunological characteristics of severe patients, and summarize the current evidence and share our experience in anti-inflammation treatment, including glucocorticoids, IL-6 antagonist, JAK inhibitors and choloroquine/hydrocholoroquine, of patients with severe COVID-19 that may have an impaired immune system.

positive: Angiotensin receptor blockers and COVID-19 Angiotensin Receptor Blockers (ARBs) exhibit major pleiotropic protecting effects beyond their antihypertensive properties, including reduction of inflammation. ARBs directly protect the lung from the severe acute respiratory syndrome as a result of viral infections, including those from coronavirus. The protective effect of ACE2 is enhanced by ARB administration. For these reasons ARB therapy must be continued for patients affected by hypertension, diabetes and renal disease, comorbidities of the current COVID-19 pandemic. Controlled clinical studies should be conducted to determine whether ARBs may be included as additional therapy for COVID-19 patients.

positive: SARS-CoV-2 receptor ACE2 gene expression and RAAS inhibitors

positive: COVID-19 and relative angiotensin-converting enzyme 2 deficiency: role in disease severity and therapeutic response

positive: Hypothesis: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the risk of severe COVID-19 Intravenous infusions of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in experimental animals increase the numbers of angiotensin-converting enzyme 2 (ACE2) receptors in the cardiopulmonary circulation. ACE2 receptors serve as binding sites for SARS-CoV-2 virions in the lungs. Patients who take ACEIs and ARBS may be at increased risk of severe disease outcomes due to SARS-CoV-2 infections.

positive: Neurological diseases as mortality predictive factors for patients with COVID-19: a retrospective cohort study INTRODUCTION: In the current study, we evaluated factors that increase the coronavirus disease (COVID-19) patient death rate by analyzing the data from two cohort hospitals. In addition, we studied whether underlying neurological diseases are risk factors for death. METHODS: In this retrospective cohort study, we included 103 adult inpatients (aged ≥ 18 years). We evaluated differences in demographic data between surviving and non-surviving COVID-19 patients. RESULTS: In a multivariate logistic analysis, age and the presence of chronic lung disease and Alzheimer’s dementia (AD) were the only significant parameters for predicting COVID-19 non-survival (p < 0.05). However, hypertension, coronary vascular disease, dyslipidemia, chronic kidney disease, diabetes, and history of taking angiotensin II receptor blockers (ARBs) or angiotensin-converting enzyme (ACE) inhibitors, as well as nonsteroidal anti-inflammatory drugs (NSAIDs), were not significantly associated with the death of COVID-19 patients. The optimal cutoff value obtained from the maximum Youden index was 70 (sensitivity, 80.77%; specificity, 61.04%), and the odds ratio of non-survival increased 1.055 fold for every year of age. CONCLUSIONS: Clinicians should closely monitor and manage the symptoms of COVID-19 patients who are over the age of 70 years or have chronic lung disease or AD.

positive: COVID‐19 and hypertension—evidence and practical management: Guidance from the HOPE Asia Network There are several risk factors for worse outcomes in patients with coronavirus 2019 disease (COVID‐19). Patients with hypertension appear to have a poor prognosis, but there is no direct evidence that hypertension increases the risk of new infection or adverse outcomes independent of age and other risk factors. There is also concern about use of renin‐angiotensin system (RAS) inhibitors due to a key role of angiotensin‐converting enzyme 2 receptors in the entry of the SARS‐CoV‐2 virus into cells. However, there is little evidence that use of RAS inhibitors increases the risk of SARS‐CoV‐2 virus infection or worsens the course of COVID‐19. Therefore, antihypertensive therapy with these agents should be continued. In addition to acute respiratory distress syndrome, patients with severe COVID‐19 can develop myocardial injury and cytokine storm, resulting in heart failure, arteriovenous thrombosis, and kidney injury. Troponin, N‐terminal pro‐B‐type natriuretic peptide, D‐dimer, and serum creatinine are biomarkers for these complications and can be used to monitor patients with COVID‐19 and for risk stratification. Other factors that need to be incorporated into patient management strategies during the pandemic include regular exercise to maintain good health status and monitoring of psychological well‐being. For the ongoing management of patients with hypertension, telemedicine‐based home blood pressure monitoring strategies can facilitate maintenance of good blood pressure control while social distancing is maintained. Overall, multidisciplinary management of COVID‐19 based on a rapidly growing body of evidence will help ensure the best possible outcomes for patients, including those with risk factors such as hypertension.

positive: Coronavirus disease 2019 (COVID-19) and the renin-angiotensin system: A closer look at angiotensin-converting enzyme 2 (ACE2) Since the first cases of atypical pneumonia linked to the Huanan Seafood Wholesale Market in Wuhan, China, were described in late December 2019, the global landscape has changed radically. In March 2020, the World Health Organization declared COVID-19 a global pandemic, and at the time of writing this review, just over three million individuals have been infected with more than 200,000 deaths globally. Numerous countries are in 'lockdown', social distancing is the new norm, even the most advanced healthcare systems are under pressure, and a global economic recession seems inevitable. A novel coronavirus (SARS-CoV-2) was identified as the aetiological agent. From experience with previous coronavirus epidemics, namely the severe acute respiratory syndrome (SARS) and Middle East Respiratory Syndrome (MERS) in 2004 and 2012 respectively, it was postulated that the angiotensin-converting enzyme-2 (ACE2) receptor is a possible port of cell entry. ACE2 is part of the renin-angiotensin system and is also associated with lung and cardiovascular disorders and inflammation. Recent studies have confirmed that ACE2 is the port of entry for SARS-CoV-2. Male sex, advanced age and a number of associated comorbidities have been identified as risk factors for infection with COVID-19. Many high-risk COVID-19 patients with comorbidities are on ACE inhibitors and angiotensin receptor blockers, and this has sparked debate about whether to continue these treatment regimes. Attention has also shifted to ACE2 being a target for future therapies or vaccines against COVID-19. In this review, we discuss COVID-19 and its complex relationship with ACE2.

positive: Public Health Aspects of COVID-19 Infection with Focus on Cardiovascular Diseases INTRODUCTION: COVID-19 is the disease caused by an infection of the SARS-CoV-2 virus, first identified in the city of Wuhan, in China’s Hubei province in December 2019. COVID-19 was previously known as 2019 Novel Coronavirus (2019-nCoV) respiratory disease before the World Health Organization (WHO) declared the official name as COVID-19 in February 2020. AIM: The aim of this study is to search scientific literature in the biomedicine and analyzed current results of investigations regarding morbidity and mortality rates as consequences of COVID-19 infection of Cardiovascular diseases (CVD), and other most common chronic diseases which are on the top mortality and morbidity rates in almost all countries in the world. Also, to propose most useful measures how to prevent patients to keep themselves against COVID-19 infection. METHODS: We used method of descriptive analysis of the published papers with described studies about Corona virus connected with CVD, and, also, Guidelines proposed by World Health Organization (WHO) and European Society of Cardiology (ESC), and some other international associations which are included in global fighting against COVID-19 infection. RESULTS: After searching current scientific literature we have acknowledged that not any Evidence Based Medicine (EBM) study in the world during last 5 months from the time when first cases of COVID-10 infection was detected. Also, there is no unique proposed ways of treatments and drugs to protect patients, especially people over 65 years old, who are very risk group to be affected with COVID-19. Expectations that vaccine against COVID-19 will be produced optimal during at least 10 months to 2 years, and in all current Guidelines most important proposed preventive measures are the same like which one described in Strategic documents of WHO, in statements of Declaration of Primary Health Care in Alma Ata in 1978. CONCLUSION: WHO proposed preventive measures can be helpful to everybody. Physicians who work at every level of Health Care Systems, but especially at primary health care level, must follow those recommendations and teach their patients about it. But, the fact is that current focus of COVID-19 epidemic has targeted on protection of physical health of population in global, however, the influence on mental health which will be one of the important consequences of COVID-19 pandemic in the future, and which could be declared as «Post-coronavirus Stress Syndrome„ (PCSS) could be bigger challenge for Global Public Health.

positive: COVID -19 outbreak – Diabetes aspect and perspective

positive: Renin–angiotensin system inhibitors in the COVID-19 pandemic: consequences of antihypertensive drugs

positive: The Identification of a Calmodulin-Binding Domain within the Cytoplasmic Tail of Angiotensin-Converting Enzyme-2 Angiotensin-converting enzyme (ACE)-2 is a homolog of the well-characterized plasma membrane-bound angiotensin-converting enzyme. ACE2 is thought to play a critical role in regulating heart function, and in 2003, ACE2 was identified as a functional receptor for severe acute respiratory syndrome coronavirus. We have recently shown that like ACE, ACE2 undergoes ectodomain shedding and that this shedding event is up-regulated by phorbol esters. In the present study, we used gel shift assays to demonstrate that calmodulin, an intracellular calcium-binding protein implicated in the regulation of other ectodomain shedding events, binds a 16-amino acid synthetic peptide corresponding to residues 762–777 within the cytoplasmic domain of human ACE2, forming a calcium-dependent calmodulin-peptide complex. Furthermore, we have demonstrated that ACE2 expressed in Chinese hamster ovary cells specifically binds to glutathione-S-transferase-calmodulin, but not glutathione-S-transferase alone, in pull-down assays using cell lysates. Finally, to investigate whether calmodulin has any effect on ACE2 ectodomain shedding in cells that endogenously express the enzyme, cells from a human liver cell line (Huh-7) expressing ACE2 were incubated with calmodulin-specific inhibitors, trifluoperazine and calmidazolium. Both trifluoperazine (25 μmol/liter) and calmidazolium, (25 μmol/liter) significantly increased the release of ACE2 into the medium (44.1 ± 10.8%, P < 0.05, Student’s t test; unpaired, two-tailed, and 51.1 ± 7.4% P < 0.05, one-way ANOVA, respectively;), as analyzed by an ACE2-specific quenched fluorescence substrate assay. We also show that the calmodulin-specific inhibitor-stimulated shedding of ACE2 is independent from phorbol ester-induced shedding. In summary, we have demonstrated that calmodulin is able to bind ACE2 and suggest that the ACE2 ectodomain shedding and/or sheddase(s) activation regulated by calmodulin is independent from the phorbol ester-induced shedding.

positive: Corona Virus Disease 2019 (COVID-19) Presenting as Acute ST Elevation Myocardial Infarction Patients with Covid-19 disease commonly present with symptoms related to respiratory illness, and less commonly they develop cardiovascular complications either on presentation or during the course of the disease. The mortality/morbidity is high in these patients with cardiovascular involvement. Acute ST-elevation myocardial infarction (STEMI) is a medical emergency which needs immediate coronary re-perfusion for better patient outcomes. Here we present a patient who presented to the emergency room with acute STEMI and later tested positive for COVID-19. She was successfully treated with coronary revascularization and stent placement, and remains on the ventilator to date as she quickly developed acute respiratory distress syndrome. We need more research in Covid-19 patients with cardiovascular involvement for early diagnosis, prevention of exposure to health care workers and effective treatment.

positive: Review of evidence on using ACEi and ARBs in patients with hypertension and COVID-19 COVID-19 has recently become a major pandemic with associated socioeconomic dimensions. Mortality statistics suggest that COVID-19 is more lethal in aged patients with comorbid conditions including hypertension. There is ongoing debate about whether the use of angiotensin converting enzyme (ACE) inhibitors (ACEi) and angiotensin receptor blockers (ARBs) are useful or hazardous in patients with COVID-19, with both narratives supported by researchers with different hypotheses. The researchers supporting the use of these medications believe ACE2 functional blockers may block cellular entry of the SARS-CoV-2 virus and thus improve patient outcomes. The counter viewpoint argues that continuous use of these drugs results in hyperexpression of ACE2 receptors on respiratory epithelium allowing easier SARS-CoV-2 intracellular entry, resulting in enhanced viral replication and tissue damage. This short review discusses the available research on the subject with the objective to consolidate data to allow formulation of recommendations on their use or otherwise. Moreover, the authors also suggest areas for future research on the subject.

positive: Therapeutic strategies in an outbreak scenario to treat the novel coronavirus originating in Wuhan, China A novel coronavirus (2019-nCoV) originating in Wuhan, China presents a potential respiratory viral pandemic to the world population. Current efforts are focused on containment and quarantine of infected individuals. Ultimately, the outbreak could be controlled with a protective vaccine to prevent 2019-nCoV infection. While vaccine research should be pursued intensely, there exists today no therapy to treat 2019-nCoV upon infection, despite an urgent need to find options to help these patients and preclude potential death. Herein, I review the potential options to treat 2019-nCoV in patients, with an emphasis on the necessity for speed and timeliness in developing new and effective therapies in this outbreak. I consider the options of drug repurposing, developing neutralizing monoclonal antibody therapy, and an oligonucleotide strategy targeting the viral RNA genome, emphasizing the promise and pitfalls of these approaches. Finally, I advocate for the fastest strategy to develop a treatment now, which could be resistant to any mutations the virus may have in the future. The proposal is a biologic that blocks 2019-nCoV entry using a soluble version of the viral receptor, angiotensin-converting enzyme 2 (ACE2), fused to an immunoglobulin Fc domain (ACE2-Fc), providing a neutralizing antibody with maximal breath to avoid any viral escape, while also helping to recruit the immune system to build lasting immunity. The ACE2-Fc therapy would also supplement decreased ACE2 levels in the lungs during infection, thereby directly treating acute respiratory distress pathophysiology as a third mechanism of action. The sequence of the ACE2-Fc protein is provided to investigators, allowing its possible use in recombinant protein expression systems to start producing drug today to treat patients under compassionate use, while formal clinical trials are later undertaken. Such a treatment could help infected patients before a protective vaccine is developed and widely available in the coming months to year(s).

positive: Angiotensin-converting enzyme inhibitors, angiotensin II type 1 receptor blockers and risk of COVID 19: information from Bartter's and Gitelman's syndromes patients.

positive: Continuation versus discontinuation of ACE inhibitors or angiotensin II receptor blockers in COVID-19: effects on blood pressure control and mortality

positive: Coronavirus Disease 2019 (COVID-19) and its implications for cardiovascular care: expert document from the German Cardiac Society and the World Heart Federation Coronavirus diseases 2019 (COVID-19) has become a worldwide pandemic affecting people at high risk and particularly at advanced age, cardiovascular and pulmonary disease. As cardiovascular patients are at high risk but also have dyspnea and fatigue as leading symptoms, prevention, diagnostics and treatment in these patients are important to provide adequate care for those with or without COVID-19 but most importantly when comorbid cardiovascular conditions are present. Severe COVID-19 with acute respiratory distress (ARDS) is challenging as patients with elevated myocardial markers such as troponin are at enhanced high risk for fatal outcomes. As angiotensin-converting enzyme 2 (ACE2) is regarded as the viral receptor for cell entry and as the Coronavirus is downregulating this enzyme, which provides cardiovascular and pulmonary protection, there is ongoing discussions on whether treatment with cardiovascular drugs, which upregulate the viral receptor ACE2 should be modified. As most of the COVID-19 patients have cardiovascular comorbidities like hypertension, diabetes, coronary artery disease and heart failure, which imposes a high risk on these patients, cardiovascular therapy should not be modified or even withdrawn. As cardiac injury is a common feature of COVID-19 associated ARDS and is linked with poor outcomes, swift diagnostic management and specialist care of cardiovascular patients in the area of COVID-19 is of particular importance and deserves special attention.

positive: More evidence is urgently needed to confirm the relation between angiotensin-converting enzyme inhibitors and COVID-19

positive: Letter in response to the article: Comorbidities in COVID-19: outcomes in hypertensive cohort and controversies with renin angiotensin system blockers (Singh et al.)

positive: Angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 and the pathophysiology of coronavirus disease 2019 (COVID-19) Angiotensin-converting enzyme 2 (ACE2) has been established as the functional host receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the current devastating worldwide pandemic of coronavirus disease 2019 (COVID-19). ACE2 is abundantly expressed in a variety of cells residing in many different human organs. In human physiology, ACE2 is a pivotal counter-regulatory enzyme to ACE by the breakdown of angiotensin II, the central player in the renin-angiotensin-aldosterone system (RAAS) and the main substrate of ACE2. Many factors have been associated with both altered ACE2 expression and COVID-19 severity and progression, including age, sex, ethnicity, medication, and several co-morbidities, such as cardiovascular disease and metabolic syndrome. Although ACE2 is widely distributed in various human tissues and many of its determinants have been well recognised, ACE2-expressing organs do not equally participate in COVID-19 pathophysiology, implying that other mechanisms are involved in orchestrating cellular infection resulting in tissue damage. Reports of pathologic findings in tissue specimens of COVID-19 patients are rapidly emerging and confirm the established role of ACE2 expression and activity in disease pathogenesis. Identifying pathologic changes caused by SARS-CoV-2 infection is crucially important as it has major implications for understanding COVID-19 pathophysiology and the development of evidence-based treatment strategies. Currently, many interventional strategies are being explored in ongoing clinical trials, encompassing many drug classes and strategies, including antiviral drugs, biological response modifiers, and RAAS inhibitors. Ultimately, prevention is key to combat COVID-19 and appropriate measures are being taken accordingly, including development of effective vaccines. In this review, we describe the role of ACE2 in COVID-19 pathophysiology, including factors influencing ACE2 expression and activity in relation to COVID-19 severity. In addition, we discuss the relevant pathological changes resulting from SARS-CoV-2 infection. Finally, we highlight a selection of potential treatment modalities for COVID-19. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

positive: ACE2 Expression is Increased in the Lungs of Patients with Comorbidities Associated with Severe COVID-19 The pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has resulted in several thousand deaths worldwide in just a few months. Patients who died from Coronavirus disease 2019 (COVID-19) often had comorbidities, such as hypertension, diabetes, and chronic obstructive lung disease. The angiotensin-converting enzyme 2 (ACE2) was identified as a crucial factor that facilitates SARS-CoV2 to bind and enter host cells. To date, no study has assessed the ACE2 expression in the lungs of patients with these diseases. Here, we analyzed over 700 lung transcriptome samples of patients with comorbidities associated with severe COVID-19 and found that ACE2 was highly expressed in these patients, compared to control individuals. This finding suggests that patients with such comorbidities may have higher chances of developing severe COVID-19. We also found other genes, such as RAB1A, that can be important for SARS-CoV-2 infection in the lung. Correlation and network analyses revealed many potential regulators of ACE2 in the human lung, including genes related to histone modifications, such as HAT1, HDAC2, and KDM5B. In fact, epigenetic marks found in ACE2 locus were compatible to with those promoted by KDM5B. Our systems biology approach offers a possible explanation for increase of COVID-19 severity in patients with certain comorbidities.

positive: Letter to the editor: The role of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in developing a COVID-19 comorbidity-based host risk score

positive: Renin-Angiotensin-System (RAS) und COVID-19 – Zur Verordnung von RAS-Blockern Twenty years ago, an enzyme homologous to the previously known angiotensin-converting enzyme (ACE) was identified, and subsequently named ACE2. In the renin-angiotensin system (RAS), ACE2 has counter-regulatory functions against the classical effector peptide angiotensin II, for example in blood pressure regulation and cardiovascular remodeling. However, ACE2 provides an initially unexpected interesting link between virology and cardiovascular medicine. That is, ACE2 represents the binding receptor for the cellular uptake of SARS-CoV and SARS-CoV-2 viruses. Thus, ACE2 is relevant for COVID-19. In this context, it was suspected that therapy with RAS blockers might promote transmission and complications of COVID-19 by upregulation of ACE2 expression. The aim of this short review is, to describe the link between the RAS, particularly ACE2, and COVID-19. Based on our analysis and evaluation of the available findings, we justify our conclusion: important drugs such as ACE inhibitors and angiotensin receptor blockers should continue to be prescribed according to guidelines to stable patients in the context of the COVID-19 pandemic.

positive: The Association Between Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers and the Number of Covid-19 Confirmed Cases and Deaths in the United States: Geospatial Study Background: The novel coronavirus SARS-Cov2 uses the angiotensin-converting enzyme 2 (ACE2) receptor as an entry point to the cell. Cardiovascular disease (CVD) is a risk factor for the novel coronavirus disease (Covid-19) with poor outcomes. We hypothesized that the rate of ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) use is associated with the rate of Covid-19 confirmed cases and deaths. Methods: We conducted a geospatial study using publicly available county-level data. The Medicare ACEIs and ARBs prescription rate was exposure. The Covid-19 confirmed case and death rates were outcomes. Spatial autoregression models were adjusted for the percentage of Black residents, children, residents with at least some college degree, median household income, air quality index, CVD hospitalization rate in Medicare beneficiaries, and CVD death rate in a total county population. Results: The ACEI use had no effect on Covid-19 confirmed case rate. An average ACEIs use (compared to no-use) was associated with a higher Covid-19 death rate by 1.1 (95%CI 0.4-1.8)%. If the use of ACEIs increases by 0.5% for all counties, the Covid-19 death rate will drop by 0.4% to 0.7(95%CI 0.3-1.1)%; P<0.0001. An average ARBs use (compared to no-use) was associated with a higher Covid-19 confirmed case rate (by 4.2; 95%CI 4.1-4.3 %) and death rate (by 1.1; 95%CI 0.7-1.5 %). Each percent increase in ARBs use was associated with an increase in confirmed case rate by 0.2(0.03-0.4)% and death rate by 0.14(0.08-0.21)%. Conclusions: ARBs, but not ACEIs use rate, is associated with Covid-19 confirmed case rate.

positive: Current data on the cardiovascular effects of the COVID-19

positive: How Could This Happen?: Narrowing Down the Contagion of COVID-19 and Preventing Acute Respiratory Distress Syndrome (ARDS) In this rapid commentary, a mini-review is given of the present state-of-knowledge regarding the etiology and epidemiology of the new coronavirus 2019-nCoV and the risks for developing Acute respiratory distress syndrome (ARDS). The available knowledge on the viral genomics, molecular biology and pathogenicity of viruses of the Coronaviridae family and other Nidovirales, forms a helpful template for understanding the present pandemic outbreak. However, important questions remain unanswered about the underlying mechanism causing the very high case fatality ratios (CFR) and mechanisms regarding severe reactions like ARDS, fatal cardiac and renal failures, associated with a number of important comorbidity factors. Immunological reactions to lung alveoles in particular (involving lung macrophages and alveolar epithelial cell damage) in late phase ARDS in SARS-like CoV diseases, so far may not have received enough attention. Finally a shortlist of questions for high priority further research is suggested.

positive: Reply to: ‘Interaction between RAAS inhibitors and ACE2 in the context of COVID-19’

positive: Effective Use of Angiotensin II in Coronavirus Disease 19–Associated Mixed Shock State: A Case Report The rapid spread of Coronavirus Disease 2019 (COVID-19) has sparked a search for effective therapies. The discovery that the virus binds the angiotensin-converting enzyme 2 (ACE2) receptor has led to investigation of the renin–angiotensin system for possible therapeutic targets. We present a case of an elderly woman with multiple comorbidities who developed severe acute respiratory distress syndrome (ARDS), a cardiomyopathy, and vasodilatory shock secondary to COVID-19 and was treated with exogenous angiotensin II. She rapidly demonstrated significant hemodynamic improvement without noted adverse effects. Thus, we propose further investigation into possible benefits of angiotensin II in shock secondary to COVID-19.

positive: Contentious issues and evolving concepts in the clinical presentation and management of patients with COVID-19 infectionwith reference to use of therapeutic and other drugs used in Co-morbid diseases (Hypertension, diabetes etc) Abstract Background and aims Multiple issues in management of COVID have emerged, but confusion persists regarding rational interpretation. Aim of this brief review is to review these issues based on current literature. Methods This is a narrative review with Pubmed and Google Scholar search till 23 March 2020. Search terms were, COVID-19, treatment of coronavirus, COVID 19 and following terms; chloroquine, hydroxychloroquine, ibuprofen, ACE-inhibitors or angiotensin receptor blockers, cardiovascular disease, diarrhoea, liver, testis and gastrointestinal disease. Results We discuss evidence regarding role of chloroquine and hydroxychloroquine in treatment and prophylaxis, use of inhibitors of the renin angiotensin system, safety of ibuprofen, unusual clinical features like gastrointestinal symptoms and interpretation of tests for cardiac enzymes and biomarkers. Conclusions While our conclusions on management of COVID-19 patients with co-morbidities are based on current evidence, however, data is limited and there is immediate need for fast track research.

positive: Computational simulation of interactions between SARS coronavirus spike mutants and host species-specific receptors Abstract As a critical adaptive mechanism, amino acid replacements on the severe acute respiratory syndrome coronavirus (SARS-CoV) spike protein could alter the receptor-binding specificity of this envelope glycoprotein and in turn lead to the emergence or reemergence of this viral zoonosis. Based on the X-ray structures of SARS-CoV spike receptor-binding domain (RBD) in complex with its functional receptor (angiotensin-converting enzyme 2, ACE2), we perform computational simulations of interactions between three representative RBD mutants and four host species-specific receptors. The comparisons between computational predictions and experimental evidences validate our structural bioinformatics approaches. And the predictions further indicate that some viral prototypes might utilize the rat ACE2 while rats might serve as a vector or reservoir of SARS-CoV.

positive: Renin-angiotensin system inhibition in COVID-19 patients Angiotensin-converting enzyme (ACE) inhibitors (ACEIs) and angiotensin II type1 receptor blockers (ARBs) are among the most widely prescribed drugs for the treatment of arterial hypertension, heart failure and chronic kidney disease. A number of studies, mainly in animals and not involving the lungs, have indicated that these drugs can increase expression of angiotensin-converting enzyme 2 (ACE2). ACE2 is the cell entry receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19) that is currently battering the globe. This has led to the hypothesis that use of ACEIs and ARBs may increase the risk of developing severe COVID-19. In this point of view paper, possible scenarios regarding the impact of ACEI/ARB pharmacotherapy on COVID-19 are discussed in relation to the currently available evidence. Although further research on the influence of blood-pressure-lowering drugs, including those not targeting the renin-angiotensin system, is warranted, there are presently no compelling clinical data showing that ACEIs and ARBs increase the likelihood of contracting COVID-19 or worsen the outcome of SARS-CoV2 infections. Thus, unless contraindicated, use of ACEIs/ARBs in COVID-19 patients should be continued in line with the recent recommendations of medical societies.

positive: Hypothesis: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the risk of severe COVID-19

positive: Chronic Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers Is High Among Intensive Care Unit Patients With Non–COVID-19 Sepsis but Carries a Moderately Increased Risk of Death

positive: Association between chronic ACE inhibitor exposure and decreased odds of severe disease in patients with COVID-19 OBJECTIVE: Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Renin-angiotensin-aldosterone-system (RAAS) inhibitors may increase the expression of angiotensin-converting enzyme 2, which is the receptor for SARSCoV-2 Spike protein. The consequences of using angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) during the COVID-19 pandemic are unknown. METHODS: A retrospective cohort study aiming to identify the odds of severe disease (defined as either hospitalization of ≥14 days, admission to the intensive care unit, or death) associated with exposure to ACEi or ARB was conducted. Adult patients (age ≥18 years) with COVID-19 admitted to the Istanbul Faculty of Medicine Corona Center between March 9 and May 11, 2020, were included. Chronic users of ACEi, ARB, or other antihypertensive drugs were matched according to age, sex, sick days before hospitalization, comorbidities, smoking, number of antihypertensive regimens, doxazosin use, furosemide use, and serum creatinine level. Odds ratios (OR) of having severe disease were calculated. RESULTS: In total, 611 patients were admitted with COVID-19, confirmed by either reverse-transcriptase polymerase chain reaction or computed tomography (CT). There were 363 males, and the age ranged from 18 to 98 years, with an average age of 57±15 years. Of these, 165 participants had severe disease (53 deaths, case fatality rate: 8.7%). Among those with hypertension (n=249), ARB exposure was compatible with decreased odds (OR=0.60, 95% CI: 0.27-1.36, p=0.31) of severe disease though not statistically significant, while ACEi exposure significantly reduced the risk of severe disease (OR=0.37, 95% CI: 0.15-0.87, p=0.03). ACEi exposure was associated with milder infiltrations seen on baseline CT, lower C-reactive protein and ferritin, higher monocytes, shorter hospitalization, and less requirement for specific empirical treatments (favipiravir and meropenem). CONCLUSION: Our data suggest that exposure to ACEi drugs may have favorable effects in the context of COVID-19 pneumonia.

positive: Renin-Angiotensin-Aldosterone System Blockers and the Risk of Covid-19 BACKGROUND: A potential association between the use of angiotensin-receptor blockers (ARBs) and angiotensin-converting-enzyme (ACE) inhibitors and the risk of coronavirus disease 2019 (Covid-19) has not been well studied. METHODS: We carried out a population-based case-control study in the Lombardy region of Italy. A total of 6272 case patients in whom infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was confirmed between February 21 and March 11, 2020, were matched to 30,759 beneficiaries of the Regional Health Service (controls) according to sex, age, and municipality of residence. Information about the use of selected drugs and patients' clinical profiles was obtained from regional databases of health care use. Odds ratios and 95% confidence intervals for associations between drugs and infection, with adjustment for confounders, were estimated by means of logistic regression. RESULTS: Among both case patients and controls, the mean (±SD) age was 68±13 years, and 37% were women. The use of ACE inhibitors and ARBs was more common among case patients than among controls, as was the use of other antihypertensive and non-antihypertensive drugs, and case patients had a worse clinical profile. Use of ARBs or ACE inhibitors did not show any association with Covid-19 among case patients overall (adjusted odds ratio, 0.95 [95% confidence interval {CI}, 0.86 to 1.05] for ARBs and 0.96 [95% CI, 0.87 to 1.07] for ACE inhibitors) or among patients who had a severe or fatal course of the disease (adjusted odds ratio, 0.83 [95% CI, 0.63 to 1.10] for ARBs and 0.91 [95% CI, 0.69 to 1.21] for ACE inhibitors), and no association between these variables was found according to sex. CONCLUSIONS: In this large, population-based study, the use of ACE inhibitors and ARBs was more frequent among patients with Covid-19 than among controls because of their higher prevalence of cardiovascular disease. However, there was no evidence that ACE inhibitors or ARBs affected the risk of COVID-19.

positive: Risks of ACE Inhibitor and ARB Usage in COVID‐19: Evaluating the Evidence Concerns have been raised regarding the safety of angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in patients with coronavirus disease of 2019 (COVID‐19), based on the hypothesis that such medications may raise expression of ACE2, the receptor for severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2). We conducted a literature review of studies (n = 12) in experimental animals and human subjects (n = 12) and evaluated the evidence regarding the impact of administration of ACEIs and ARBs on ACE2 expression. We prioritized studies that assessed ACE2 protein expression data, measured directly or inferred from ACE2 activity assays. The findings in animals are inconsistent with respect to an increase in ACE2 expression in response to treatment with ACEIs or ARBs. Control/sham animals show little to no effect in the plurality of studies. Those studies that report increases in ACE2 expression tend to involve acute injury models and/or higher doses of ACEIs or ARBs than are typically administered to patients. Data from human studies overwhelmingly imply that administration of ACEIs/ARBs does not increase ACE2 expression. Available evidence, in particular, data from human studies, does not support the hypothesis that ACEI/ARB use increases ACE2 expression and the risk of complications from COVID‐19. We conclude that patients being treated with ACEIs and ARBs should continue their use for approved indications.

positive: The current understanding and potential therapeutic options to combat COVID-19 Abstract The ongoing wreaking global outbreak of the novel human beta coronavirus (CoV) pathogen was presumed to be from a seafood wholesale market in Wuhan, China, belongs to the Coronaviridae family in the Nidovirales order. The virus is highly contagious with potential human-human transmission which was named as the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has spread across six continents and emerged as a global pandemic in short span with alarming levels of spread and severity. This virus associated symptoms and infectious respiratory illness is designated as coronavirus disease 19 (COVID-19). The SARS-CoV-2 possesses enveloped club-like spike protein projections with positive-sense large RNA genome and has a unique replication strategy. This virus was believed to have zoonotic origin with genetical identity to bat and pangolin CoV. In the current review, we introduce a general overview about the human CoVs and the associated diseases, the origin, structure, replication and key clinical events that occur in the COVID-19 pathogenicity. Furthermore, we focused on possible therapeutic options such as repurposing drugs including antimalarials, antivirals, antiparasitic drugs, and anti-HIV drugs, as well as monoclonal antibodies, vaccines as potential treatment options. Also we have summarized the latest research progress on the usage of stem cell therapy, human convalescent serum, interferon's, in the treatment of COVID-19.

positive: Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19

positive: Association between COVID-19 and cardiovascular disease Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19) has reached a pandemic level. SARS-CoV-2 infects host cells through ACE2 receptors, leading to COVID-19-related pneumonia. The rapid increase in confirmed cases makes the prevention and control of COVID-19 extremely serious. Real-time reverse transcription-PCR (RT-PCR) assays remain the molecular test of choice for the etiologic diagnosis of SARS-CoV-2 infection while radiographic findings (chest computed tomography [CT]) and antibody-based techniques are being introduced as supplemental tools. Novel virus also cause chronic damage to the cardiovascular system, and attention should be given to cardiovascular protection during treatment for COVID-19. Acute cardiac injury determined by elevated high-sensitivity troponin levels is commonly observed in severe cases and is strongly associated with mortality. This review suggests that cardiovascular comorbidities are common in patients with COVID-19 and such patients are at higher risk of morbidity and mortality. The continuation of clinically indicated ACE inhibitor and ARB medications is recommended in COVID-19. We review the basics of coronaviruses, novel molecular targets for the coronaviruses with a focus on COVID-19, along with their effects on the cardiovascular system.

positive: Bradykinin as a Probable Aspect in SARS-Cov-2 Scenarios: Is Bradykinin Sneaking out of Our Sight? The new virus SARS-CoV-2 is savagely spreading out over the world. The biologic studies show that the target receptor for the virus might be angiotensin-converting enzyme 2 (ACE2). This peptide is responsible for converting angiotensin II (Ang II), which is a profoundly active peptide, into Ang 1-7 with quite a balancing barbell function. It is emphasized that the direct target of the virus is ACE2 underlining the obvious difference with ACE. Nevertheless, we hypothesized that a back load build up effect on Ang II may usurp the ACE capacity and subsequently leave the bradykinin system unabated. We think there are clinical clues for dry cough and the presumed aggravating role of ACE inhibitors like captopril on the disease process. Thereby, we speculated that inhibition of bradykinin synthesis and/or blockade of bradykinin B2 receptor using Aprotinin/ecallantide and Icatibant, respectively, may hold therapeutic promise in severe cases and these molecules can be advanced to clinical trials.

positive: Potential role for tissue factor in the pathogenesis of hypercoagulability associated with in COVID-19 In December 2019, a new and highly contagious infectious disease emerged in Wuhan, China. The etiologic agent was identified as a novel coronavirus, now known as Severe Acute Syndrome Coronavirus-2 (SARS-CoV-2). Recent research has revealed that virus entry takes place upon the union of the virus S surface protein with the type I transmembrane metallo-carboxypeptidase, angiotensin converting enzyme 2 (ACE-2) identified on epithelial cells of the host respiratory tract. Virus triggers the synthesis and release of pro-inflammatory cytokines, including IL-6 and TNF-α and also promotes downregulation of ACE-2, which promotes a concomitant increase in levels of angiotensin II (AT-II). Both TNF-α and AT-II have been implicated in promoting overexpression of tissue factor (TF) in platelets and macrophages. Additionally, the generation of antiphospholipid antibodies associated with COVID-19 may also promote an increase in TF. TF may be a critical mediator associated with the development of thrombotic phenomena in COVID-19, and should be a target for future study.

positive: Understanding novel COVID-19: its impact on organ failure and risk assessment for diabetic and cancer patients Abstract The current pandemic outbreak of COVID-19 originated from Wuhan, China. It is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with significant mortality and morbidity rate. The severe risk factors are commonly detected in patients of older age and with medical comorbidities like cancer and diabetes. Scientists and doctors have scrambled to gain knowledge about the novel virus and its pathophysiology in order to discover possible therapeutic regimens and vaccines for COVID-19. The therapeutic strategies like targeting the viral genome emphasize the promising approach to target COVID-19. Additionally, blocking the receptor, ACE2 via the neutralizing antibodies for viral escape that prevents it from entering into the cells provides another therapeutic regimen. In this review article, we have presented the effect of SARS-CoV-2 infection in comorbid patients and discussed organ failure caused by this virus. Based on the data available from the scientific literature and ongoing clinical trials, we have focused on therapeutic strategies. We hope that we would fill the gaps that puzzled the researchers and clinicians with the best of our knowledge collected for the betterment of the patients for the coming future.

positive: Relationship between ACE-inhibitors, ARBs and SARS-CoV-2 infection: where are we? SARS-CoV-2 is spreading rapidly all over the world. The case fatality rate seems higher in cardiovascular disease and hypertension. Other comorbidities do not seem to confer the same risk, therefore the understanding of the relationship between infection and cardiovascular system could be a crucial point for the fight against the virus. A great interest is currently directed towards the angiotensin 2 converting enzyme (ACE 2) which is the SARS-CoV-2 receptor and creates important connections between the virus replication pathway, the cardiovascular system and blood pressure. All cardiovascular conditions share an imbalance of the renin angiotensin system (RAAS) in which ACE 2 plays a central role. In the last few days, much confusion has appeared about the management of therapy with angiotensin converting enzyme inhibitors (ACE-i) and angiotensin receptor blockers (ARBs) in infected patients and in those at risk of critical illness in case of infection. In this article we will try to reorder the major opinions currently emerging on this topic.

positive: ACE inhibitors/ARB use and COVID-19. Time to change practice or keep gathering data?

positive: Antihypertensive treatment with ACEI/ARB of patients with COVID-19 complicated by hypertension

positive: The Renin-Angiotensin system and SARS-CoV-2 infection: A role for the ACE2 receptor?

positive: Commentary: COVID-19 in patients with diabetes

positive: Therapeutic strategies in an outbreak scenario to treat the novel coronavirus originating in Wuhan, China [version 1;peer review: awaiting peer review] A novel coronavirus (2019-nCoV) originating in Wuhan, China presents a potential respiratory viral pandemic to the world population Current efforts are focused on containment and quarantine of infected individuals Ultimately, the outbreak could be controlled with a protective vaccine to prevent 2019-nCoV infection While vaccine research should be pursued intensely, there exists today no therapy to treat 2019-nCoV upon infection, despite an urgent need to find options to help these patients and preclude potential death Herein, I review the potential options to treat 2019-nCoV in patients, with an emphasis on the necessity for speed and timeliness in developing new and effective therapies in this outbreak I consider the options of drug repurposing, developing neutralizing monoclonal antibody therapy, and an oligonucleotide strategy targeting the viral RNA genome, emphasizing the promise and pitfalls of these approaches Finally, I advocate for the fastest strategy to develop a treatment now, which could be resistant to any mutations the virus may have in the future The proposal is a biologic that blocks 2019-nCoV entry using a soluble version of the viral receptor, angiotensin-converting enzyme 2 (ACE2), fused to an immunoglobulin Fc domain, providing a neutralizing antibody with maximal breath to avoid any viral escape, while also helping to recruit the immune system to build lasting immunity The sequence of the ACE2-Fc protein is provided to investigators, allowing its possible use in recombinant protein expression systems to start producing drug today to treat patients under compassionate use, while formal clinical trials are later undertaken Such a treatment could help infected patients before a protective vaccine is developed and widely available in the coming months to year(s)

positive: Comparative impacts of angiotensin converting enzyme inhibitors versus angiotensin II receptor blockers on the risk of COVID-19 mortality N/A.

positive: COVID-19 and Diabetes: Knowledge in Progress Abstract Aims We aimed to briefly review the general characteristics of the novel coronavirus (SARS-CoV-2) and provide a better understanding of the coronavirus disease (COVID-19) in people with diabetes, and its management. Methods We searched for articles in PubMed and Google Scholar databases till 02 April 2020, with the following keywords: “SARS-CoV-2”, “COVID-19”, “infection”, “pathogenesis”, “incubation period”, “transmission”, “clinical features”, “diagnosis”, “treatment”, “diabetes”, with interposition of the Boolean operator “AND”. Results The clinical spectrum of COVID-19 is heterogeneous, ranging from mild flu-like symptoms to acute respiratory distress syndrome, multiple organ failure and death. Older age, diabetes and other comorbidities are reported as significant predictors of morbidity and mortality. Chronic inflammation, increased coagulation activity, immune response impairment, and potential direct pancreatic damage by SARS-CoV-2 might be among the underlying mechanisms of the association between diabetes and COVID-19. No conclusive evidence exists to support the discontinuation of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers because of COVID-19 in people with diabetes. Caution should be taken to potential hypoglycemic events with the use of chloroquine in these subjects. Patient tailored therapeutic strategies, rigorous glucose monitoring and careful consideration of drug interactions might reduce adverse outcomes. Conclusions Suggestions are made on the possible pathological mechanisms of the relationship between diabetes and COVID-19, and its management. No definite conclusions can be made based on current limited evidence. Further research regarding this relationship and its clinical management is warranted.

positive: The protein expression profile of ACE2 in human tissues The novel SARS-coronavirus 2 (SARS-CoV-2) poses a global challenge on healthcare and society. For understanding the susceptibility for SARS-CoV-2 infection, the cell type-specific expression of the host cell surface receptor is necessary. The key protein suggested to be involved in host cell entry is Angiotensin I converting enzyme 2 (ACE2). Here, we report the expression pattern of ACE2 across >150 different cell types corresponding to all major human tissues and organs based on stringent immunohistochemical analysis. The results were compared with several datasets both on the mRNA and protein level. ACE2 expression was mainly observed in enterocytes, renal tubules, gallbladder, cardiomyocytes, male reproductive cells, placental trophoblasts, ductal cells, eye and vasculature. In the respiratory system, the expression was limited, with no or only low expression in a subset of cells in a few individuals, observed by one antibody only. Our data constitutes an important resource for further studies on SARS-CoV-2 host cell entry, in order to understand the biology of the disease and to aid in the development of effective treatments to the viral infection.

positive: Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin–angiotensin–aldosterone inhibitors AIMS: The current pandemic coronavirus SARS-CoV-2 infects a wide age group but predominantly elderly individuals, especially men and those with cardiovascular disease. Recent reports suggest an association with use of renin–angiotensin–aldosterone system (RAAS) inhibitors. Angiotensin-converting enzyme 2 (ACE2) is a functional receptor for coronaviruses. Higher ACE2 concentrations might lead to increased vulnerability to SARS-CoV-2 in patients on RAAS inhibitors. METHODS AND RESULTS: We measured ACE2 concentrations in 1485 men and 537 women with heart failure (index cohort). Results were validated in 1123 men and 575 women (validation cohort). The median age was 69 years for men and 75 years for women. The strongest predictor of elevated concentrations of ACE2 in both cohorts was male sex (estimate = 0.26, P < 0.001; and 0.19, P < 0.001, respectively). In the index cohort, use of ACE inhibitors, angiotensin receptor blockers (ARBs), or mineralocorticoid receptor antagonists (MRAs) was not an independent predictor of plasma ACE2. In the validation cohort, ACE inhibitor (estimate = –0.17, P = 0.002) and ARB use (estimate = –0.15, P = 0.03) were independent predictors of lower plasma ACE2, while use of an MRA (estimate = 0.11, P = 0.04) was an independent predictor of higher plasma ACE2 concentrations. CONCLUSION: In two independent cohorts of patients with heart failure, plasma concentrations of ACE2 were higher in men than in women, but use of neither an ACE inhibitor nor an ARB was associated with higher plasma ACE2 concentrations. These data might explain the higher incidence and fatality rate of COVID-19 in men, but do not support previous reports suggesting that ACE inhibitors or ARBs increase the vulnerability for COVID-19 through increased plasma ACE2 concentrations.

positive: COVID-19 and Hypertension: The Role of ACE2 and the Renin-Angiotensin System ABSTRACT Hypertension emerged from early reports as a potential risk factor for worse outcomes for persons with coronavirus disease 2019 (COVID-19). Among the putative links between hypertension and COVID-19 is a key counter-regulatory component of the renin-angiotensin system (RAS): angiotensin-converting enzyme 2 (ACE2). ACE2 facilitates entry of SARS-CoV-2, the virus responsible for COVID-19, into host cells. Since RAS inhibitors have been suggested to increase ACE2 expression, healthcare providers and patients have grappled with the decision of whether to discontinue these medications during the COVID-19 pandemic. However, experimental models of analogous viral pneumonias suggest RAS inhibitors may exert protective effects against acute lung injury. We review how RAS and ACE2 biology may affect outcomes in COVID-19 through pulmonary and other systemic effects. In addition, we briefly detail the data for and against continuation of RAS inhibitors in persons with COVID-19 and summarize the current consensus recommendations from select specialty organizations.

positive: Coronaviruses — drug discovery and therapeutic options In humans, infections with the human coronavirus (HCoV) strains HCoV-229E, HCoV-OC43, HCoV-NL63 and HCoV-HKU1 usually result in mild, self-limiting upper respiratory tract infections, such as the common cold. By contrast, the CoVs responsible for severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), which were discovered in Hong Kong, China, in 2003, and in Saudi Arabia in 2012, respectively, have received global attention over the past 12 years owing to their ability to cause community and health-care-associated outbreaks of severe infections in human populations. These two viruses pose major challenges to clinical management because there are no specific antiviral drugs available. In this Review, we summarize the epidemiology, virology, clinical features and current treatment strategies of SARS and MERS, and discuss the discovery and development of new virus-based and host-based therapeutic options for CoV infections. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/nrd.2015.37) contains supplementary material, which is available to authorized users.

positive: Antihypertensive drugs and risk of COVID-19? – Authors' reply

positive: Plasma angiotensin-converting enzyme 2: novel biomarker in heart failure with implications for COVID-19

positive: The relationship of COVID-19 severity with cardiovascular disease and its traditional risk factors: A systematic review and meta-analysis Background: Whether cardiovascular disease (CVD) and its traditional risk factors predict severe coronavirus disease 2019 (COVID-19) is uncertain, in part, because of potential confounding by age and sex. Methods: We performed a systematic review of studies that explored pre-existing CVD and its traditional risk factors as risk factors of severe COVID-19 (defined as death, acute respiratory distress syndrome, mechanical ventilation, or intensive care unit admission). We searched PubMed and Embase for papers in English with original data (≥10 cases of severe COVID-19). Using random-effects models, we pooled relative risk (RR) estimates and conducted meta-regression analyses. Results: Of the 661 publications identified in our search, 25 papers met our inclusion criteria, with 76,638 COVID-19 patients including 11,766 severe cases. Older age was consistently associated with severe COVID-19 in all eight eligible studies, with RR >~5 in >60-65 vs. <50 years. Three studies showed no change in the RR of age after adjusting for covariate(s). In univariate analyses, factors robustly associated with severe COVID-19 were male sex (10 studies; pooled RR=1.73, [95%CI 1.50-2.01]), hypertension (8 studies; 2.87 [2.09-3.93]), diabetes (9 studies; 3.20 [2.26-4.53]), and CVD (10 studies; 4.97 [3.76-6.58]). RR for male sex was likely to be independent of age. For the other three factors, meta-regression analyses suggested confounding by age. Only four studies reported multivariable analysis, but most of them showed adjusted RR ~2 for hypertension, diabetes, and CVD. No study explored renin-angiotensin system inhibitors as a risk factor for severe COVID-19. Conclusions: Despite the potential for confounding, these results suggest that hypertension, diabetes, and CVD are independently associated with severe COVID-19 and, together with age and male sex, can be used to inform objective decisions on COVID-19 testing, clinical management, and workforce planning.

positive: Angiotensin‐converting enzyme‐2 (ACE2), SARS‐CoV‐2 and pathophysiology of coronavirus disease 2019 (COVID‐19) Angiotensin‐converting enzyme‐2 (ACE2) has been established as the functional host receptor for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the virus responsible for the current devastating worldwide pandemic of coronavirus disease 2019 (COVID‐19). ACE2 is abundantly expressed in a variety of cells residing in many different human organs. In human physiology, ACE2 is a pivotal counter‐regulatory enzyme to ACE by the breakdown of angiotensin II, the central player in the renin‐angiotensin‐aldosterone system (RAAS) and the main substrate of ACE2. Many factors have been associated with both altered ACE2 expression and COVID‐19 severity and progression, including age, sex, ethnicity, medication and several co‐morbidities, such as cardiovascular disease and metabolic syndrome. Although ACE2 is widely distributed in various human tissues and many of its determinants have been well recognised, ACE2‐expressing organs do not equally participate in COVID‐19 pathophysiology, implying that other mechanisms are involved in orchestrating cellular infection resulting in tissue damage. Reports of pathologic findings in tissue specimens of COVID‐19 patients are rapidly emerging and confirm the established role of ACE2 expression and activity in disease pathogenesis. Identifying pathologic changes caused by SARS‐CoV‐2 infection is crucially important as it has major implications for understanding COVID‐19 pathophysiology and the development of evidence‐based treatment strategies. Currently, many interventional strategies are being explored in ongoing clinical trials, encompassing many drug classes and strategies, including antiviral drugs, biological response modifiers and RAAS inhibitors. Ultimately, prevention is key to combat COVID‐19 and appropriate measures are being taken accordingly, including development of effective vaccines. In this review, we describe the role of ACE2 in COVID‐19 pathophysiology, including factors influencing ACE2 expression and activity in relation to COVID‐19 severity. In addition, we discuss the relevant pathological changes resulting from SARS‐CoV‐2 infection. Finally, we highlight a selection of potential treatment modalities for COVID‐19. This article is protected by copyright. All rights reserved.

positive: Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19 BACKGROUND: Coronavirus disease 2019 (Covid-19) may disproportionately affect people with cardiovascular disease. Concern has been aroused regarding a potential harmful effect of angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) in this clinical context. METHODS: Using an observational database from 169 hospitals in Asia, Europe, and North America, we evaluated the relationship of cardiovascular disease and drug therapy with in-hospital death among hospitalized patients with Covid-19 who were admitted between December 20, 2019, and March 15, 2020, and were recorded in the Surgical Outcomes Collaborative registry as having either died in the hospital or survived to discharge as of March 28, 2020. RESULTS: Of the 8910 patients with Covid-19 for whom discharge status was available at the time of the analysis, a total of 515 died in the hospital (5.8%) and 8395 survived to discharge. The factors we found to be independently associated with an increased risk of in-hospital death were an age greater than 65 years (mortality of 10.0%, vs. 4.9% among those ≤65 years of age; odds ratio, 1.93; 95% confidence interval [CI], 1.60 to 2.41), coronary artery disease (10.2%, vs. 5.2% among those without disease; odds ratio, 2.70; 95% CI, 2.08 to 3.51), heart failure (15.3%, vs. 5.6% among those without heart failure; odds ratio, 2.48; 95% CI, 1.62 to 3.79), cardiac arrhythmia (11.5%, vs. 5.6% among those without arrhythmia; odds ratio, 1.95; 95% CI, 1.33 to 2.86), chronic obstructive pulmonary disease (14.2%, vs. 5.6% among those without disease; odds ratio, 2.96; 95% CI, 2.00 to 4.40), and current smoking (9.4%, vs. 5.6% among former smokers or nonsmokers; odds ratio, 1.79; 95% CI, 1.29 to 2.47). No increased risk of in-hospital death was found to be associated with the use of ACE inhibitors (2.1% vs. 6.1%; odds ratio, 0.33; 95% CI, 0.20 to 0.54) or the use of ARBs (6.8% vs. 5.7%; odds ratio, 1.23; 95% CI, 0.87 to 1.74). CONCLUSIONS: Our study confirmed previous observations suggesting that underlying cardiovascular disease is associated with an increased risk of in-hospital death among patients hospitalized with Covid-19. Our results did not confirm previous concerns regarding a potential harmful association of ACE inhibitors or ARBs with in-hospital death in this clinical context. (Funded by the William Harvey Distinguished Chair in Advanced Cardiovascular Medicine at Brigham and Women's Hospital.).

positive: Drugs acting on renin angiotensin system and use in ill patients with COVID-19 Some concerns about the prescription of drugs acting on the renin-angiotensin system (angiotensin-converting enzyme 1 (ACE1) inhibitors, ACEi; angiotensin II type 1 receptor blockers, ARB) have emerged due to SARS COV2 and COVID-19 pandemic. These very legitimate questions are directly the consequence of the recent recognition of the fundamental role of ACE2 (angiotensin-converting enzyme 2) in COVID-19 infection. Indeed, SARS COV2 utilizes ACE2 as a membrane receptor to enter target cells. Consequently, the putative impact of drugs modulating the renin-angiotensin system on the risk of developing severe or fatal severe acute respiratory syndrome in case of COVID-19 infection emerged. As a membrane-bound enzyme (carboxypeptidase), ACE2 inactivates angiotensin II and therefore physiologically counters its effects. Due to a different structure compared with ACE1, ACE2 is insensitive to ACEIs. In vitro, both ARBs and ACEi appear able to upregulate ACE2 tissue expression and activity but these results were not confirmed in Humans. The exact impact of both ARBs and ACEis on COVID-19 infection is definitively known and preliminary results are even in favor of a protective role confers by these drugs. Due to the crucial role of ACE2, some groups support the hypothesis that a modulation of ACE2 expression could represent a valuable therapeutic target could confer protective properties against inflammatory tissue damage in COVID-19 infection. So, studies are currently ongoing to test the impact of elevated ACE2 membrane expression, administration of ARB and infusion of soluble ACE2. In summary, based on the currently available evidences and as recommended by several medical societies, ACEi or ARB should not be systematically discontinued because to date no safety signal was raised with the use of these drugs.

positive: Protease inhibitors and their peptidomimetic derivatives as potential drugs Abstract Precise spatial and temporal regulation of proteolytic activity is essential to human physiology. Modulation of protease activity with synthetic peptidomimetic inhibitors has proven to be clinically useful for treating human immunodeficiency virus (HIV) and hypertension and shows potential for medicinal application in cancer, obesity, cardiovascular, inflammatory, neurodegenerative diseases, and various infectious and parasitic diseases. Exploration of natural inhibitors and synthesis of peptidomimetic molecules has provided many promising compounds performing successfully in animal studies. Several protease inhibitors are undergoing further evaluation in human clinical trials. New research strategies are now focusing on the need for improved comprehension of protease-regulated cascades, along with precise selection of targets and improved inhibitor specificity. It remains to be seen which second generation agents will evolve into approved drugs or complementary therapies.

positive: Diabetes and COVID-19: evidence, current status and unanswered research questions. Patients with diabetes who get coronavirus disease 2019 (COVID-19) are at risk of a severe disease course and mortality. Several factors especially the impaired immune response, heightened inflammatory response and hypercoagulable state contribute to the increased disease severity. However, there are many contentious issues about which the evidence is rather limited. There are some theoretical concerns about the effects of different anti-hyperglycaemic drugs. Similarly, despite the recognition of angiotensin converting enzyme 2 (ACE2) as the receptor for severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), and the role of ACE2 in lung injury; there are conflicting results with the use of angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) in these patients. Management of patients with diabetes in times of restrictions on mobility poses some challenges and novel approaches like telemedicine can be useful. There is a need to further study the natural course of COVID-19 in patients with diabetes and to understand the individual, regional and ethnic variations in disease prevalence and course.

positive: Angiotensin-converting enzyme 2 protects from severe acute lung failure Acute respiratory distress syndrome (ARDS), the most severe form of acute lung injury, is a devastating clinical syndrome with a high mortality rate (30–60%) (refs 1–3). Predisposing factors for ARDS are diverse(1,3) and include sepsis, aspiration, pneumonias and infections with the severe acute respiratory syndrome (SARS) coronavirus(4,5). At present, there are no effective drugs for improving the clinical outcome of ARDS(1,2,3). Angiotensin-converting enzyme (ACE) and ACE2 are homologues with different key functions in the renin–angiotensin system(6,7,8). ACE cleaves angiotensin I to generate angiotensin II, whereas ACE2 inactivates angiotensin II and is a negative regulator of the system. ACE2 has also recently been identified as a potential SARS virus receptor and is expressed in lungs(9,10). Here we report that ACE2 and the angiotensin II type 2 receptor (AT(2)) protect mice from severe acute lung injury induced by acid aspiration or sepsis. However, other components of the renin–angiotensin system, including ACE, angiotensin II and the angiotensin II type 1a receptor (AT(1)a), promote disease pathogenesis, induce lung oedemas and impair lung function. We show that mice deficient for Ace show markedly improved disease, and also that recombinant ACE2 can protect mice from severe acute lung injury. Our data identify a critical function for ACE2 in acute lung injury, pointing to a possible therapy for a syndrome affecting millions of people worldwide every year. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/nature03712) contains supplementary material, which is available to authorized users.

positive: Current status of potential therapeutic candidates for the COVID-19 crisis Abstract As of April 15, 2020, the ongoing coronavirus disease 2019 (COVID-2019) pandemic has swept through 213 countries and infected more than 1,870,000 individuals, posing an unprecedented threat to international health and the economy. There is currently no specific treatment available for patients with COVID-19 infection. The lessons learned from past management of respiratory viral infections have provided insights into treating COVID-19. Numerous potential therapies, including supportive intervention, immunomodulatory agents, antiviral therapy, and convalescent plasma transfusion, have been tentatively applied in clinical settings. A number of these therapies have provided substantially curative benefits in treating patients with COVID-19 infection. Furthermore, intensive research and clinical trials are underway to assess the efficacy of existing drugs and identify potential therapeutic targets to develop new drugs for treating COVID-19. Herein, we summarize the current potential therapeutic approaches for diseases related to COVID-19 infection and introduce their mechanisms of action, safety, and effectiveness.

positive: Scientific statement of the Chinese Society of Cardiology (CSC) on using of renin angiotensin system blockers in patients with cardiovascular disease and COVID-19

positive: A consensus statement on the use of angiotensin receptor blockers and angiotensin converting enzyme inhibitors in relation to COVID-19 (corona virus disease 2019) There has been a lot of speculation that patients with coronavirus disease 2019 (COVID-19) who are receiving angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) may be at increased risk for adverse outcomes We reviewed the available evidence, and have not found this to be the case We recommend that patients on such medications should continue on them unless there is a clinical indication to stop their use

positive: Towards precision management of cardiovascular patients with COVID-19 to reduce mortality

positive: Colonization of Severe Acute Respiratory Syndrome-Associated Coronavirus Among Health-Care Workers Screened by Nasopharyngeal Swab Study objectives To report the efficacy and findings of a large-scale preventive screening program for severe acute respiratory syndrome-associated coronavirus (SARS-CoV) using amplification of the virus from a nasopharyngeal swab (NPS) obtained from the health-care workers (HCWs). Design A prospective observational study. Setting A medical center in Taiwan. Participants Two hundred thirty HCWs. Intervention NPS examination for the presence of SARS-CoV by two nested reverse transcription-polymerase chain reaction (RT-PCR) assays. Measurements and results During the outbreak of severe acute respiratory syndrome (SARS), NPS polymerase chain reaction screening of HCWs for SARS-CoV was performed. SARS-CoV was examined by two nested RT-PCRs and a quantitative RT-PCR. Serum-specific antibodies were assessed by enzyme immunoassay and indirect immunofluorescence. We monitored 230 HCWs, including 217 first-line HCWs and 13 non–first-line HCWs. One hundred ninety first-line HCWs and 13 non–first-line HCWs had negative results in both nested RT-PCR assays. Two first-line HCWs who were positive on both nested RT-PCR assays had SARS. They had 16,900 ± 7,920 copies (mean ± SD) of RNA per milliliter in the NPS and had detectable anti-SARS antibodies. The remaining 25 first-line HCWs were negative for the first nested RT-PCR but positive for the second nested RT-PCR. Their corresponding titers were 338 ± 227 copies of RNA per milliliter; antibodies developed in none of these 25 HCWs. The expression and function of angiotensin-converting enzyme-2 were not different among these HCWs. This study shows that colonization of SARS-CoV occurred in 25 of 217 well-protected first-line HCWs on a SARS-associated service, but they remained seronegative. Conclusion With the second RT-PCR assay more sensitive than the first RT-PCR assay, we are able to show that approximately 11.5% of well-protected HCWs exposed to SARS patients or specimens may have colonization without seroconversion. Only those with significant clinical symptoms or disease would have active immunity. Thus, regular NPS screening for nested RT-PCR assays in conjunction with a daily recording of body temperature in all first-line HCWs may provide an effective way of early detection.

positive: Susceptibility of the Elderly to SARS-CoV-2 Infection: ACE-2 Overexpression, Shedding, and Antibody-dependent Enhancement (ADE) The world is currently facing a serious SARS-CoV-2 infection pandemic. This virus is a new isolate of coronavirus, and the current infection crisis has surpassed the SARS and MERS epidemics that occurred in 2002 and 2013, respectively. SARS-CoV-2 has currently infected more than 142,000 people, causing 5,000 deaths and spreading across more than 130 countries worldwide. The spreading capacity of the virus clearly demonstrates the potential threat of respiratory viruses to human health, thereby reiterating to the governments around the world that preventive health policies and scientific research are pivotal to overcoming the crisis. Coronavirus disease (COVID-19) causes flu-like symptoms in most cases. However, approximately 15% of the patients need hospitalization, and 5% require assisted ventilation, depending on the cohorts studied. What is intriguing, however, is the higher susceptibility of the elderly, especially individuals who are older than 60 years of age, and have comorbidities, including hypertension, diabetes, and heart disease. In fact, the death rate in this group may be up to 10-12%. Interestingly, children are somehow less susceptible and are not considered as a risk group. Therefore, in this review, we discuss some possible molecular and cellular mechanisms by virtue of which the elderly subjects may be more susceptible to severe COVID-19. Toward this, we raise two main points, i) increased ACE-2 expression in pulmonary and heart tissues in users of chronic angiotensin 1 receptor (AT1R) blockers; and ii) antibody-dependent enhancement (ADE) after previous exposure to other circulating coronaviruses. We believe that these points are pivotal for a better understanding of the pathogenesis of severe COVID-19, and must be carefully addressed by physicians and scientists in the field.

positive: Liver disease and the renin–angiotensin system: Recent discoveries and clinical implications The renin–angiotensin system (RAS) is a key regulator of vascular resistance, sodium and water homeostasis and the response to tissue injury. Historically, angiotensin II (Ang II) was thought to be the primary effector peptide of this system. Ang II is produced predominantly by the effect of angiotensin converting enzyme (ACE) on angiotensin I (Ang I). Ang II acts mainly through the angiotensin II type‐1 receptor (AT(1)) and, together with ACE, these components represent the ‘classical’ axis of the RAS. Drug therapies targeting the RAS by inhibiting Ang II formation (ACE inhibitors) or binding to its receptor (angiotensin receptor blockers) are now in widespread clinical use and have been shown to reduce tissue injury and fibrosis in cardiac and renal disease independently of their effects on blood pressure. In 2000, two groups using different methodologies identified a homolog of ACE, called ACE2, which cleaves Ang II to form the biologically active heptapeptide, Ang‐(1–7). Conceptually, ACE2, Ang‐(1–7), and its putative receptor, the mas receptor represent an ‘alternative’ axis of the RAS capable of opposing the often deleterious actions of Ang II. Interestingly, ACE inhibitors and angiotensin receptor blockers increase Ang‐(1–7) production and it has been proposed that some of the beneficial effects of these drugs are mediated through upregulation of Ang‐(1–7) rather than inhibition of Ang II production or receptor binding. The present review focuses on the novel components and pathways of the RAS with particular reference to their potential contribution towards the pathophysiology of liver disease.

positive: Inhibitors of the renin-angiotensin system: The potential role in the pathogenesis of COVID-19. Coronavirus disease 2019 (COVID-19), which initially began in China, has spread to other countries of Asia, Europe, America, Africa and Oceania, with the number of confirmed cases and suspected cases increasing each day. According to recently published research, it was found that the majority of the severe cases were elderly, and many of them had at least one chronic disease, especially cardiovascular diseases. Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs) are the most widely used drugs for cardiovascular diseases. The clinical effect of ACEIs/ARBs on patients with COVID-19 is still uncertain. This paper describes their potential role in the pathogenesis of COVID-19, which may provide useful in the advice of cardiologists and physicians.

positive: The role of the exposome in promoting resilience or susceptibility after SARS-CoV-2 infection

positive: Human coronavirus NL63, a new respiratory virus From the mid-1960s onwards, it was believed that only two human coronavirus species infect humans: HCoV-229E and HCoV-OC43. Then, in 2003, a novel member of the coronavirus family was introduced into the human population: SARS-CoV, causing an aggressive lung disease. Fortunately, this virus was soon expelled from the human population, but it quickly became clear that the human coronavirus group contains more members then previously assumed, with HCoV-NL63 identified in 2004. Despite its recent discovery, ample results from HCoV-NL63 research have been described. We present an overview of the publications on this novel coronavirus.

positive: Associations between Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blocker Use, Gastrointestinal Symptoms, and Mortality among Patients with COVID-19

positive: Identification of 2019-nCoV related coronaviruses in Malayan pangolins in southern China The ongoing outbreak of viral pneumonia in China and beyond is associated with a novel coronavirus, provisionally termed 2019-nCoV. This outbreak has been tentatively associated with a seafood market in Wuhan, China, where the sale of wild animals may be the source of zoonotic infection. Although bats are likely reservoir hosts for 2019-nCoV, the identity of any intermediate host facilitating transfer to humans is unknown. Here, we report the identification of 2019-nCoV related coronaviruses in pangolins (Manis javanica) seized in anti-smuggling operations in southern China. Metagenomic sequencing identified pangolin associated CoVs that belong to two sub-lineages of 2019-nCoV related coronaviruses, including one very closely related to 2019-nCoV in the receptor-binding domain. The discovery of multiple lineages of pangolin coronavirus and their similarity to 2019-nCoV suggests that pangolins should be considered as possible intermediate hosts for this novel human virus and should be removed from wet markets to prevent zoonotic transmission.

positive: [Inhibitors of RAS Might Be a Good Choice for the Therapy of COVID-19 Pneumonia]. The novel coronavirus 2019 (COVID-19) infected patients by binding human ACE2, leading to severe pneumonia and highly mortality rate in patients. At present, there is no definite and effective treatment for COVID-19. ACE2 plays an important role in the RAS, and the imbalance between ACE/Ang II/AT1R pathway and ACE2/Ang (1-7)/Mas receptor pathway in the RAS system will lead to multi-system inflammation. Increased ACE and Ang II are poor prognostic factors for severe pneumonia. Animal studies have shown that RAS inhibitors could effectively relieve symptoms of acute severe pneumonia and respiratory failure. The binding of COVID-19 and ACE2 resulted in the exhaustion of ACE2, and then ACE2/Ang (1-7)/Mas receptor pathway was inhibited. The balance of the RAS system was broken, and this would lead to the exacerbation of acute severe pneumonia. Therefore, we speculate that ACEI and AT1R inhibitors could be used in patients with COVID-19 pneumonia under the condition of controlling blood pressure, and might reduce the pulmonary inflammatory response and mortality.

positive: COVID-19 and the RAAS—a potential role for angiotensin II?

positive: The differential expression of the ACE2 receptor across ages and gender explains the differential lethality of SARS-Cov-2 and suggests possible therapy The fatality rate of SARS-Cov-2 escalates with age and is larger in men than women. I show that these variations are strongly correlated with the levels of the ACE2 protein in the lungs but surprisingly, despite ACE2 is the viral receptor, higher levels lead to lower fatality. This behaviour is consistent with a previous mathematical model that predicts that the speed of viral progression in the organism has a maximum and then declines with the receptor level. SARS-Cov-2 degrades ACE2 and thus worsens lung injury, causes vasoconstriction, thrombotic problems, and exacerbated inflammatory response. I developed a mathematical model based on the influence of ACE2 on viral propagation and on the negative effects of its degradation. The model fits SARS-CoV-2 fatality rate across age and gender with high accuracy ($r^2>0.9$). Rescaling the model parameters with the binding rates of the spike proteins of SARS-CoV and SARS-CoV-2 allows predicting the fatality rate of SARS-CoV across age and gender, in particular its higher severity for young patients, thus linking the molecular and epidemiological levels. These results support the suggestion that drugs that enhance the expression of ACE2, such as ACE inhibitors and angiotensin receptor blockers, constitute a promising therapy against the most adverse effects of CoViD-19. Furthermore, ACE2 is a candidate prognostic factor for detecting population that needs stronger protection.

positive: Letter to the Editor in Response to article: “Clinical considerations for patients with diabetes in times of COVID-19 epidemic (Gupta et al.)

positive: Comment on "ACE inhibitors and COVID-19: We don't know yet"

positive: Relationship between the ABO Blood Group and the COVID-19 Susceptibility The novel coronavirus disease-2019 (COVID-19) has been spreading around the world rapidly and declared as a pandemic by WHO. Here, we compared the ABO blood group distribution in 2,173 patients with COVID-19 confirmed by SARS-CoV-2 test from three hospitals in Wuhan and Shenzhen, China with that in normal people from the corresponding regions. The results showed that blood group A was associated with a higher risk for acquiring COVID-19 compared with non-A blood groups, whereas blood group O was associated with a lower risk for the infection compared with non-O blood groups. This is the first observation of an association between the ABO blood type and COVID-19. It should be emphasized, however, that this is an early study with limitations. It would be premature to use this study to guide clinical practice at this time, but it should encourage further investigation of the relationship between the ABO blood group and the COVID-19 susceptibility.

positive: COVID-19 and heart failure: from infection to inflammation and angiotensin II stimulation. Searching for evidence from a new disease Patients with cardiovascular disease and, namely, heart failure are more susceptible to coronavirus disease 2019 (COVID-19) and have a more severe clinical course once infected. Heart failure and myocardial damage, shown by increased troponin plasma levels, occur in at least 10% of patients hospitalized for COVID-19 with higher percentages, 25% to 35% or more, when patients critically ill or with concomitant cardiac disease are considered. Myocardial injury may be elicited by multiple mechanisms, including those occurring with all severe infections, such as fever, tachycardia, adrenergic stimulation, as well as those caused by an exaggerated inflammatory response, endotheliitis and, in some cases, myocarditis that have been shown in patients with COVID-19. A key role may be that of the renin-angiotensin-aldosterone system. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects human cells binding to angiotensin-converting enzyme 2 (ACE2), an enzyme responsible for the cleavage of angiotensin II into angiotensin 1-7, which has vasodilating and anti-inflammatory effects. Virus-mediated down-regulation of ACE2 may increase angiotensin II stimulation and contribute to the deleterious hyper-inflammatory reaction of COVID-19. On the other hand, ACE2 may be up-regulated in patients with cardiac disease and treated with ACE inhibitors or angiotensin receptor blockers. ACE2 up-regulation may increase the susceptibility to COVID-19 but may be also protective vs. angiotensin II-mediated vasoconstriction and inflammatory activation. Recent data show the lack of untoward effects of ACE inhibitors or angiotensin receptor blockers for COVID-19 infection and severity. Prospective trials are needed to ascertain whether these drugs may have protective effects.

positive: Trilogy of ACE2: A peptidase in the renin–angiotensin system, a SARS receptor, and a partner for amino acid transporters Abstract Angiotensin-converting enzyme (ACE) 2 is a homolog to the carboxypeptidase ACE, which generates angiotensin II, the main active peptide of renin–angiotensin system (RAS). After the cloning of ACE2 in 2000, three major ACE2 functions have been described so far. First ACE2 has emerged as a potent negative regulator of the RAS counterbalancing the multiple functions of ACE. By targeting angiotensin II ACE2 exhibits a protective role in the cardiovascular system and many other organs. Second ACE2 was identified as an essential receptor for the SARS coronavirus that causes severe acute lung failure. Downregulation of ACE2 strongly contributes to the pathogenesis of severe lung failure. Third, both ACE2 and its homologue Collectrin can associate with amino acid transporters and play essential role in the absorption of amino acids in the kidney and gut. In this review, we will discuss the multiple biological functions of ACE2.

positive: Anti-RAS drugs and SARS-CoV-2 infection • There is no enough evidence to indicate that ACEIs and ARBs result in ACE2 upregulation. • The level of ACE2 expression is not completely related with the risk of COVID-19 infection. • There is currently no evidence that ACEI/ARB increase risk for COVID-19 infection from clinical trials. • It is not recommended that COVID-19 patients with hypertension or normal hypertensive patients at risk for exposure to stop using ACEI/ARB or change to other antihypertensive drugs.

positive: Design and biological activities of novel inhibitory peptides for SARS-CoV spike protein and angiotensin-converting enzyme 2 interaction Abstract Severe acute respiratory syndrome (SARS) is an emerging infectious disease caused by a novel coronavirus (SARS-CoV). The binding of SARS-CoV spike (S) protein to cellular angiotensin-converting enzyme 2 (ACE2) is the first step in SARS-CoV infection. Therefore, we assayed the inhibitory effects of small peptides derived from S protein on the binding of S protein to ACE2 and on the S-protein-pseudotyped retrovirus infectivity. SP-4 (residues 192–203), SP-8 (residues 483–494), and SP-10 (residues 668–679) significantly blocked the interaction between S protein and ACE2 by biotinylated enzyme-linked immunosorbent assay, with IC50 values of 4.30±2.18, 6.99±0.71, and 1.88±0.52nmol, respectively. Peptide scanning suggested the region spanning residues 660–683 might act as a receptor-binding domain. SP-10 blocked both binding of the S protein and infectivity of S protein-pseudotyped retrovirus to Vero E6 cells. In conclusion, this is the first report of small peptides designed to disrupt the binding of SARS-CoV S protein to ACE2. Our findings suggest that SP-10 may be developed as an anti-SARS-CoV agent for the treatment of SARS-CoV infection.

positive: Two important controversial risk factors in SARS-CoV-2 infection: Obesity and smoking The effects of obesity and smoking in the coronavirus disease 2019 (COVID-19) pandemic remain controversial. Angiotensin converting enzyme 2 (ACE2), a component of the renin-angiotensin system (RAS), is the human cell receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. ACE2 expression increases on lung alveolar epithelial cells and adipose tissue due to obesity, smoking and air pollution. A significant relationship exists between air pollution and SARS-CoV-2 infection, as more severe COVID-19 symptoms occur in smokers; comorbid conditions due to obesity or excess ectopic fat accumulation as underlying risk factors for severe COVID-19 strongly encourage the virus/ACE2 receptor-ligand interaction concept. Indeed, obesity, air pollution and smoking associated risk factors share underlying pathophysiologies that are related to the Renin-Angiotensin-System in SARS-CoV-2 infection. The aim of this review is to emphasize the mechanism of receptor-ligand interaction and its impact on the enhanced risk of death due to SARS-CoV-2 infection.

positive: Treatment with ACE-inhibitors is associated with less severe disease with SARS-Covid-19 infection in a multi-site UK acute Hospital Trust Abstract: Background: The SARS-Cov2 virus binds to the ACE2 receptor for cell entry. It has been suggested that ACE-inhibitors, which are commonly used in patients with hypertension or diabetes and which raise ACE2 levels, may increase the risk of severe COVID-19 infection. Methods: We evaluated this hypothesis in an early cohort of 205 acute inpatients with COVID-19 at King's College Hospital and Princess Royal University Hospital, London, UK with the primary endpoint being death or transfer to a critical care unit for organ support within 7-days of symptom onset. Findings: 53 patients out of 205 patients reached the primary endpoint. Contrary to the hypothesis, treatment with ACE-inhibitors was associated with a reduced risk of rapidly deteriorating severe disease. There was a lower rate of death or transfer to a critical care unit within 7 days in patients on an ACE-inhibitor OR 0.29 (CI 0.10-0.75, p<0.01), adjusting for age, gender, comorbidities (hypertension, diabetes mellitus, ischaemic heart disease and heart failure). Interpretation: Although a small sample size, we do not see evidence for ACE-inhibitors increasing the short-term severity of COVID-19 disease and patients on treatment with ACE-inhibitors should continue these drugs during their COVID-19 illness. A potential beneficial effect needs to be explored as more data becomes available.

positive: Hypertension and Renin-Angiotensin-Aldosterone System Inhibitors in Patients with Covid-19 Introduction: COVID-19 disproportionately affects those with comorbidities and the elderly. Hypertension is the most common pre-existing condition amongst COVID-19 patients. Upregulation of the renin-angiotensin-aldosterone system (RAAS) is common in hypertensive patients and may promote inflammation and ensuing cytokine storm in COVID-19. It is unknown whether RAAS inhibition with ACE1 inhibitors or angiotensin-receptor blockers (ARB) can be harmful or beneficial. Methods: Within Hackensack Meridian Health network, the largest healthcare provider in New Jersey, we performed a retrospective, multicenter, convenience sampling study of hospitalized COVID-19 patients. Demographics, clinical characteristics, treatments, and outcomes were manually abstracted. Fishers exact tests, and logistic regression were performed. Results: Among 3017 hospitalized COVID-19 patients, 1584 (52.5%) carried a diagnosis of hypertension. In the discharged or deceased cohort, the overall mortality was significantly increased at 35% vs 13% among COVID-19 patients with hypertension. However, when adjusted for age, the effect of hypertension on mortality was greatly diminished, with a reduction in odds-ratio by over half; and completely disappeared when adjusted for other major covariates. The mortality rates were lower for hypertensive patients prescribed ACE1 (27%, p=0.001) or ARBs (33%, p=0.12) compared to other anti-hypertensive agents (39%) in the unadjusted analyses. RAAS inhibitor therapy appeared protective compared to other anti-hypertensive agents (p=0.001). Conclusions: While our results are limited by the retrospective nature of our study and by potential confounders, our data argue against a harmful effect of RAAS inhibition and support the HFSA/AHA/ACC joint statement recommending continuing ACE1 and ARB therapy in hypertensive COVID-19 patients.

positive: Immunology of COVID-19: current state of the science Abstract The coronavirus disease 2019 (COVID-19) pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has affected millions of people worldwide, igniting an unprecedented effort from the scientific community to understand the biological underpinning of COVID19 pathophysiology. In this review, we summarize the current state of knowledge of innate and adaptive immune responses elicited by SARS-CoV-2 infection and the immunological pathways that likely contribute to disease severity and death. We also discuss the rationale and clinical outcome of current therapeutic strategies as well as prospective clinical trials to prevent or treat SARS-CoV-2 infection.

positive: Ramipril in High Risk Patients with COVID-19 BACKGROUND: The coronavirus disease 2019 (COVID-19) is caused by SARS-CoV2 that interfaces with the renin-angiotensin-aldosterone system (RAAS) through angiotensin-converting enzyme 2 (ACE-2). This interaction has been proposed as a potential risk factor in patients treated with RAAS-inhibitors. OBJECTIVES: To analyze if RAAS-inhibitors modify the risk for COVID-19. METHODS: RASTAVI (NCT03201185) is an ongoing randomized clinical trial randomly allocating Ramipril or control after successful transcatheter aortic valve replacement at 14 centers is Spain. We performed a non-pre-specified interim analysis to evaluate its impact on COVID-19 risk in this vulnerable population. RESULTS: As in April 1st 2020, 102 patients (50 Ramipril and 52 controls) were included in the trial. Mean age was 82.3±6.1 years, 56.9% males. Median time of Ramipril treatment was 6 months [IQR:2.9-11.4]. Eleven patients (10.8%) have been diagnosed with COVID-19 (6 in control group and 5 receiving Ramipril, HR=1.150 [95%CI: 0.351-3.768]). The risk of COVID-19 was increased in older patients (p=0.019), those with atrial fibrillation (p=0.066), lower hematocrit (p=0.084), and more comorbidities according to Society of thoracic surgeons score (p=0.065). Admission and oxygen supply was required in 4.9% (2 patients in the Ramipril and 3 in control), and 4 of them died (two in each randomized group). A higher body mass index was the only factor increasing the mortality rate (p=0.039). CONCLUSIONS: In a high risk population of old patients with cardiovascular disease, randomization to Ramipril had no impact in the incidence or severity of COVID-19. This analysis supports the maintenance of RAAS-inhibitor treatment during COVID-19 crisis.

positive: Candidate drugs against SARS-CoV-2 and COVID-19 Outbreak and pandemic of coronavirus SARS-CoV-2 in 2019/2020 will challenge global health for the future. Because a vaccine against the virus will not be available in the near future, we herein try to offer a pharmacological strategy to combat the virus. There exists a number of candidate drugs that may inhibit infection with and replication of SARS-CoV-2. Such drugs comprise inhibitors of TMPRSS2 serine protease and inhibitors of angiotensin-converting enzyme 2 (ACE2). Blockade of ACE2, the host cell receptor for the S protein of SARS-CoV-2 and inhibition of TMPRSS2, which is required for S protein priming may prevent cell entry of SARS-CoV-2. Further, chloroquine and hydroxychloroquine, and off-label antiviral drugs, such as the nucleotide analogue remdesivir, HIV protease inhibitors lopinavir and ritonavir, broad-spectrum antiviral drugs arbidol and favipiravir as well as antiviral phytochemicals available to date may limit spread of SARS-CoV-2 and morbidity and mortality of COVID-19 pandemic.

positive: Hypertension, the renin-angiotensin system, and the risk of lower respiratory tract infections and lung injury: implications for COVID-19 Systemic arterial hypertension (referred to as hypertension herein) is a major risk factor of mortality worldwide, and its importance is further emphasized in the context of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection referred to as COVID-19. Patients with severe COVID-19 infections commonly are older and have a history of hypertension. Almost 75% of patients who have died in the pandemic in Italy had hypertension. This raised multiple questions regarding a more severe course of COVID-19 in relation to hypertension itself as well as its treatment with renin-angiotensin system (RAS) blockers, e.g. angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). We provide a critical review on the relationship of hypertension, RAS, and risk of lung injury. We demonstrate lack of sound evidence that hypertension per se is an independent risk factor for COVID-19. Interestingly, ACEIs and ARBs may be associated with lower incidence and/or improved outcome in patients with lower respiratory tract infections. We also review in detail the molecular mechanisms linking the RAS to lung damage and the potential clinical impact of treatment with RAS blockers in patients with COVID-19 and a high cardiovascular and renal risk. This is related to the role of angiotensin-converting enzyme 2 (ACE2) for SARS-CoV-2 entry into cells, and expression of ACE2 in the lung, cardiovascular system, kidney, and other tissues. In summary, a critical review of available evidence does not support a deleterious effect of RAS blockers in COVID-19 infections. Therefore, there is currently no reason to discontinue RAS blockers in stable patients facing the COVID-19 pandemic.

positive: ACE inhibitors, AT1 receptor blockers and COVID-19: clinical epidemiology evidences for a continuation of treatments. The ACER-COVID study Aims: The question of interactions between the renin angiotensin aldosterone system drugs and the incidence and prognosis of COVID-19 infection has been raised by the medical community. We hypothesised that if patients treated with ACE inhibitors (ACEI) or AT1 receptor blockers (ARB) were more prone to SARS-CoV2 infection and had a worse prognosis than untreated patients, the prevalence of consumption of these drugs would be higher in patients with COVID-19 compared to the general population. Methods and results: We used a clinical epidemiology approach based on the estimation of standardised prevalence ratio (SPR) of consumption of ACEI and ARB in four groups of patients (including 187 COVID-19 positive) with increasing severity referred to the University hospital of Lille and in three French reference samples (the exhaustive North population (n=1,569,968), a representative sample of the French population (n=414,046), a random sample of Lille area (n=1,584)). The SPRs of ACEI and ARB did not differ as the severity of the COVID-19 patients increased, being similar to the regular consumption of these drugs in the North of France population with the same non-significant increase for both treatment (1.17 [0.83-1.67]). A statistically significant increase in the SPR of ARB (1.56 [1.02-2.39]) was observed in intensive care unit patients only. After stratification on obesity, this increase was limited to the high risk subgroup of obese patients. Conclusions: Our results strongly support the recommendation that ACEI and ARB should be continued in the population and in COVID-19 positive patients, reinforcing the position of several scientific societies.

positive: Potential harmful effects of discontinuing ACE-inhibitors and ARBs in COVID-19 patients The discovery of angiotensin converting enzyme-2 (ACE-2) as the receptor for SARS- CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) has implicated the renin-angiotensin-aldosterone system in acute respiratory distress syndrome (ARDS) and respiratory failure in patients with coronavirus disease-19 (COVID-19). The angiotensin converting enzyme-1–angiotensin II–angiotensin AT(1) receptor pathway contributes to the pathophysiology of ARDS, whereas activation of the ACE-2–angiotensin(1-7)-angiotensin AT(2) receptor and the ACE-2–angiotensin(1-7)–Mas receptor pathways have been shown to be protective. Here we propose and discuss therapeutic considerations how to increase soluble ACE-2 in plasma in order for ACE-2 to capture and thereby inactivate SARS-CoV-2. This could be achieved by administering recombinant soluble ACE-2. We also discuss why and how ACEIs and ARBs provide cardiovascular, renal and also pulmonary protection in SARS-CoV-2- associated ARDS. Discontinuing these medications in COVID-19 patients may therefore potentially be harmful.

positive: Renin-angiotensin-aldosterone system and COVID-19 infection Abstract With the multiplication of COVID-19 severe acute respiratory syndrome cases due to SARS COV2, some concerns about angiotensin-converting enzyme 1 (ACE1) inhibitors (ACEi) and angiotensin II type 1 receptor blockers (ARB) have emerged. Because the ACE2 (angiotensin-converting enzyme 2) enzyme is the receptor that allows SARS COV2 entry into cells, the fear was that pre-existing treatment with ACEi or ARB might increase the risk of developing severe or fatal severe acute respiratory syndrome in case of COVID-19 infection. The present article discusses these concerns. ACE2 is a membrane-bound enzyme (carboxypeptidase) that contributes to the inactivation of angiotensin II and therefore physiologically counters angiotensin II effects. ACEis do not inhibit ACE2. Although ARBs have been shown to upregulate ACE2 tissue expression in experimental animals, evidence was not always consistent in human studies. Moreover, to date there is no evidence that ACEi or ARB administration facilitates SARS COV2 cell entry by increasing ACE2 tissue expression in either animal or human studies. Finally, some studies support the hypothesis that elevated ACE2 membrane expression and tissue activity by administration of ARB and/or infusion of soluble ACE2 could confer protective properties against inflammatory tissue damage in COVID-19 infection. In summary, based on the currently available evidence and as advocated by many medical societies, ACEi or ARB should not be discontinued because of concerns with COVID-19 infection, except when the hemodynamic situation is precarious and case-by-case adjustment is required.

positive: The eye as the discrete but defensible portal of coronavirus infection Oculo-centric factors may provide a key to understanding invasion success by SARS-CoV-2, a highly contagious, potentially lethal, virus with ocular tropism. Respiratory infection transmission via the eye and lacrimal-nasal pathway elucidated during the 1918 influenza pandemic, remains to be explored in this crisis. The eye and its adnexae represent a large surface area directly exposed to airborne viral particles and hand contact. The virus may bind to corneal and conjunctival angiotensin converting enzyme 2 (ACE2) receptors and potentially to the lipophilic periocular skin and superficial tear film with downstream carriage into the nasopharynx and subsequent access to the lungs and gut. Adenoviruses and influenza viruses share this ocular tropism and despite differing ocular and systemic manifestations and disease patterns, common lessons, particularly in management, emerge. Slit lamp usage places ophthalmologists at particular risk of exposure to high viral loads (and poor prognosis) and as for adenoviral epidemics, this may be a setting for disease transmission. Local, rather than systemic treatments blocking virus binding in this pathway (advocated for adenovirus) are worth considering. This pathway is accessible with eye drops or aerosols containing drugs which appear efficacious via systemic administration. A combination such as hydroxychloroquine, azithromycin and zinc, all of which have previously been used topically in the eye and which work at least in part by blocking ACE2 receptors, may offer a safe, cost-effective and resource-sparing intervention.

positive: Plasma and tissue angiotensin‐converting enzyme 2 activity and plasma equilibrium concentrations of angiotensin peptides in dogs with heart disease BACKGROUND: Angiotensin‐converting enzyme 2 (ACE2) is a homologue of angiotensin‐converting enzyme (ACE) and produces angiotensin peptides (APs), such as angiotensin 1‐9 and 1‐7 that are vasodilatory and natriuretic, and act to counterbalance angiotensin II. HYPOTHESIS: Evidence of ACE2 can be found in tissues and plasma of dogs. Equilibrium concentrations of renin angiotensin aldosterone system (RAAS) APs differ in dogs with heart disease compared to healthy dogs and recombinant human ACE2 (rhACE2) alters relative concentrations of APs. ANIMALS: Forty‐nine dogs with and 34 dogs without heart disease. METHODS: Immunohistochemistry and assays for tissue and plasma ACE2 activity and equilibrium concentrations of plasma RAAS APs were performed. RESULTS: Immunolabeling for ACE2 was present in kidney and myocardial tissue. Median plasma ACE2 activity was significantly increased in dogs with congestive heart failure (CHF; 6.9 mU/mg; interquartile range [IQR], 5.1‐12.1) as compared to control (2.2 mU/mg; IQR, 1.8‐3.0; P = .0003). Plasma equilibrium analysis of RAAS APs identified significant increases in the median concentrations of beneficial APs, such as angiotensin 1‐7, in dogs with CHF (486.7 pg/mL; IQR, 214.2‐1168) as compared to those with preclinical disease (41.0 pg/mL; IQR, 27.4‐45.1; P < .0001) or control (11.4 pg/mL; IQR, 7.1‐25.3; P = .01). Incubation of plasma samples from dogs with CHF with rhACE2 increased beneficial APs, such as angiotensin 1‐9 (preincubation, 10.3 pg/mL; IQR, 4.4‐37.2; postincubation, 2431 pg/mL; IQR, 1355‐3037; P = .02), while simultaneously decreasing maladaptive APs, such as angiotensin II (preincubation, 53.4 pg/mL; IQR, 28.6‐226.4; postincubation, 2.4 pg/mL; IQR, 0.50‐5.8; P = .02). CONCLUSIONS AND CLINICAL IMPORTANCE: Recognition of the ACE2 system expands the conventional view of the RAAS in the dog and represents an important potential therapeutic target.

positive: Cardiovascular Complications in Patients with COVID-19: Consequences of Viral Toxicities and Host Immune Response PURPOSE OF REVIEW: Coronavirus disease of 2019 (COVID-19) is a cause of significant morbidity and mortality worldwide. While cardiac injury has been demonstrated in critically ill COVID-19 patients, the mechanism of injury remains unclear. Here, we review our current knowledge of the biology of SARS-CoV-2 and the potential mechanisms of myocardial injury due to viral toxicities and host immune responses. RECENT FINDINGS: A number of studies have reported an epidemiological association between history of cardiac disease and worsened outcome during COVID infection. Development of new onset myocardial injury during COVID-19 also increases mortality. While limited data exist, potential mechanisms of cardiac injury include direct viral entry through the angiotensin-converting enzyme 2 (ACE2) receptor and toxicity in host cells, hypoxia-related myocyte injury, and immune-mediated cytokine release syndrome. Potential treatments for reducing viral infection and excessive immune responses are also discussed. COVID patients with cardiac disease history or acquire new cardiac injury are at an increased risk for in-hospital morbidity and mortality. More studies are needed to address the mechanism of cardiotoxicity and the treatments that can minimize permanent damage to the cardiovascular system.

positive: Inhibition of SARS-CoV-2 Infections in Engineered Human Tissues Using Clinical-Grade Soluble Human ACE2 Summary We have previously provided the first genetic evidence that angiotensin converting enzyme 2 (ACE2) is the critical receptor for severe acute respiratory syndrome coronavirus (SARS-CoV), and ACE2 protects the lung from injury, providing a molecular explanation for the severe lung failure and death due to SARS-CoV infections. ACE2 has now also been identified as a key receptor for SARS-CoV-2 infections, and it has been proposed that inhibiting this interaction might be used in treating patients with COVID-19. However, it is not known whether human recombinant soluble ACE2 (hrsACE2) blocks growth of SARS-CoV-2. Here, we show that clinical grade hrsACE2 reduced SARS-CoV-2 recovery from Vero cells by a factor of 1,000–5,000. An equivalent mouse rsACE2 had no effect. We also show that SARS-CoV-2 can directly infect engineered human blood vessel organoids and human kidney organoids, which can be inhibited by hrsACE2. These data demonstrate that hrsACE2 can significantly block early stages of SARS-CoV-2 infections.

positive: Susceptibility to SARS coronavirus S protein-driven infection correlates with expression of angiotensin converting enzyme 2 and infection can be blocked by soluble receptor Abstract The angiotensin converting enzyme 2 (ACE2) has been identified as a receptor for the severe acute respiratory syndrome associated coronavirus (SARS-CoV). Here we show that ACE2 expression on cell lines correlates with susceptibility to SARS-CoV S-driven infection, suggesting that ACE2 is a major receptor for SARS-CoV. The soluble ectodomain of ACE2 specifically abrogated S-mediated infection and might therefore be exploited for the generation of inhibitors. Deletion of a major portion of the cytoplasmic domain of ACE2 had no effect on S-driven infection, indicating that this domain is not important for receptor function. Our results point to a central role of ACE2 in SARS-CoV infection and suggest a minor contribution of the cytoplasmic domain to receptor function.

positive: ACE2 in Brain Physiology and Pathophysiology: Evidence from Transgenic Animal Models Angiotensin-converting enzyme 2 (ACE2) is a protein consisting of two domains, the N-terminus is a carboxypeptidase homologous to ACE and the C-terminus is homologous to collectrin and responsible for the trafficking of the neutral amino acid transporter B(0)AT1 to the plasma membrane of gut epithelial cells. The carboxypeptidase domain not only metabolizes angiotensin II to angiotensin-(1–7), but also other peptide substrates, such as apelin, kinins and morphins. In addition, the collectrin domain regulates the levels of some amino acids in the blood, in particular of tryptophan. Therefore it is of no surprise that animals with genetic alterations in the expression of ACE2 develop a diverse pattern of phenotypes ranging from hypertension, metabolic and behavioural dysfunctions, to impairments in serotonin synthesis and neurogenesis. This review summarizes the phenotypes of such animals with a particular focus on the central nervous system.

positive: Broad Host Range of SARS-CoV-2 Predicted by Comparative and Structural Analysis of ACE2 in Vertebrates The novel coronavirus SARS-CoV-2 is the cause of Coronavirus Disease-2019 (COVID-19). The main receptor of SARS-CoV-2, angiotensin I converting enzyme 2 (ACE2), is now undergoing extensive scrutiny to understand the routes of transmission and sensitivity in different species. Here, we utilized a unique dataset of 410 vertebrates, including 252 mammals, to study cross-species conservation of ACE2 and its likelihood to function as a SARS-CoV-2 receptor. We designed a five-category ranking score based on the conservation properties of 25 amino acids important for the binding between receptor and virus, classifying all species from very high to very low. Only mammals fell into the medium to very high categories, and only catarrhine primates in the very high category, suggesting that they are at high risk for SARS-CoV-2 infection. We employed a protein structural analysis to qualitatively assess whether amino acid changes at variable residues would be likely to disrupt ACE2/SARS-CoV-2 binding, and found the number of predicted unfavorable changes significantly correlated with the binding score. Extending this analysis to human population data, we found only rare (<0.1%) variants in 10/25 binding sites. In addition, we observed evidence of positive selection in ACE2 in multiple species, including bats. Utilized appropriately, our results may lead to the identification of intermediate host species for SARS-CoV-2, justify the selection of animal models of COVID-19, and assist the conservation of animals both in native habitats and in human care.

positive: Clinical Implications of SARS-Cov2 Interaction with Renin Angiotensin System Abstract SARS-CoV2 host cell infection is mediated by the binding to angiotensin-converting enzyme 2 (ACE2). Systemic dysregulation observed in SARS-CoV was previously postulated to be due to ACE2/Ang1-7/Mas axis downregulation, increased ACE2 activity was shown to mediate disease protection. Since angiotensin II receptor blockers (ARBs), ACE inhibitors, and mineralocorticoid receptor antagonists (MRAs) increase ACE2 receptor expression, it has been tacitly believed that the use of these agents may facilitate viral disease, thus they should not be used in high-risk patients with cardiovascular disease. Based on the anti-inflammatory benefits of the upregulation of the ACE2/Ang1-7/Mas axis and previously demonstrated benefits of lung function improvement in SARS-CoV infections, we hypothesize that the benefits of treatment with renin-angiotensin system inhibitors in SARS-COV2 may outweigh the risks and at the very least should not be withheld.

positive: The renin-angiotensin system - a therapeutic target in COVID-19? COVID-19, caused by infection with SARS-CoV-2, is a disease characterised by cough, fever and fatigue, which progresses to life-threatening lung injury in approximately 5% of patients. The SARS-CoV-2 virus enters the cell via ACE2. ACE2 is a component of the renin-angiotensin system (RAS) which has an important counterregulatory effect on the classical ACE-dependent pathway. Several antihypertensives increase ACE2 expression or activity, leading to concern that this may facilitate SARS-CoV-2 entry and worsen COVID-19 disease. However, ACE2 is protective against lung injury while ANG II (which is catabolised by ACE2) is associated with lung injury both in mice and humans. We propose that medications which inhibit the RAS ACE-dependent pathway may be beneficial in treating COVID-19 and should be explored in animal models and clinical trials. Here we give an overview of the RAS pathway with respect to COVID-19 and argue that strategies which manipulate this pathway might reduce the destructive lung manifestations of COVID-19 and improve patient outcomes.

positive: Interactions of coronaviruses with ACE2, angiotensin II, and RAS inhibitors—lessons from available evidence and insights into COVID-19 The rapid spread of a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to an ongoing pandemic of coronavirus disease 2019 (COVID-19). Recently, angiotensin-converting enzyme 2 (ACE2) has been shown to be a functional receptor for SARS-CoV-2 to enter host target cells. Given that angiotensin receptor blockers (ARBs) and an ACE inhibitor (ACEI) upregulated ACE2 expression in animal studies, the concern might arise regarding whether ARBs and ACEIs would increase the morbidity and mortality of COVID-19. On the other hand, animal data suggested a potential protective effect of ARBs against COVID-19 pneumonia because an ARB prevented the aggravation of acute lung injury in mice infected with SARS-CoV, which is closely related to SARS-CoV-2. Importantly, however, there is no clinical or experimental evidence supporting that ARBs and ACEIs either augment the susceptibility to SARS-CoV-2 or aggravate the severity and outcomes of COVID-19 at present. Until further data are available, it is recommended that ARB and ACEI medications be continued for the treatment of patients with cardiovascular disease and hypertension, especially those at high risk, according to guideline-directed medical therapy based on the currently available evidence.

positive: Association of Renin Angiotensin System Blockers with Outcomes in Patients with Covid-19: A Systematic Review and Meta-analysis Background: Patients with cardiovascular disease are at increased risk of critical illness and mortality from Covid-19 disease. Conflicting findings have raised concerns regarding the association of angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs) use with likelihood or severity of infection during this pandemic. Objective: To study the cumulative evidence for association of ACEI/ARB use with outcomes among patients with confirmed Covid-19. Methods: The MEDLINE and EMBASE databases were thoroughly searched from November 01, 2019 to May 15, 2020 for studies reporting on outcomes based on ACEI/ARB use in patients with confirmed Covid-19. Preferred reporting items for systematic review and meta-analysis guidelines were used for the present study. Relevant data was collected and pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated using random-effects model. Main Outcome measures: In-hospital mortality was the primary end of interest. Second end-point was severe or critical illness defined as either need for intensive care unit, invasive mechanical ventilation, or mortality. Results: Fifteen studies with total of 23,822 patients (N ACEI/ARB=6,650) were included in the present analysis. Overall, prevalence of ACEI/ARB use ranged from 7.7% to 46.2% across studies. Among 10 studies, patients using ACEI/ARB had similar odds of mortality [OR 1.03 (0.69-1.55)] and severe or critical illness [1.18 (0.91-1.54)] compared to those not on ACEI/ARB. In an analysis restricted to patients with hypertension, ACEI/ARB use was associated with significantly lower mortality [0.64 (0.45-0.89)], while the odds of severe/critical illness [0.76(0.52-1.12); p=0.16] remained non-significant compared with non-ACEI/ARB users. Conclusion: There is no evidence for increased risk of severe illness or mortality in patients using ACEI/ARB compared with non-users. In patients with hypertension, ACE/ARB use might be associated with reduced mortality, however these findings need to be confirmed in prospective randomized controlled trials.

positive: The SARS-CoV-2 receptor, ACE-2, is expressed on many different cell types: implications for ACE-inhibitor- and angiotensin II receptor blocker-based cardiovascular therapies SARS-CoV-2 is characterized by a spike protein allowing viral binding to the angiotensin-converting enzyme (ACE)-2, which acts as a viral receptor and is expressed on the surface of several pulmonary and extra-pulmonary cell types, including cardiac, renal, intestinal and endothelial cells. There is evidence that also endothelial cells are infected by SARS-COV-2, with subsequent occurrence of systemic vasculitis, thromboembolism and disseminated intravascular coagulation. Those effects, together with the “cytokine storm” are involved in a worse prognosis. In clinical practice, angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin II receptor blockers (ARBs) are extensively used for the treatment of hypertension and other cardiovascular diseases. In in vivo studies, ACE-Is and ARBs seem to paradoxically increase ACE-2 expression, which could favour SARS-CoV-2 infection of host’s cells and tissues. By contrast, in patients treated with ACE-Is and ARBs, ACE-2 shows a downregulation at the mRNA and protein levels in kidney and cardiac tissues. Yet, it has been claimed that both ARBs and ACE-Is could result potentially useful in the clinical course of SARS-CoV-2-infected patients. As detected in China and as the Italian epidemiological situation confirms, the most prevalent comorbidities in deceased patients with COVID-19 are hypertension, diabetes and cardiovascular diseases. Older COVID-19-affected patients with cardiovascular comorbidities exhibit a more severe clinical course and a worse prognosis, with many of them being also treated with ARBs or ACE-Is. Another confounding factor is cigarette smoking, which has been reported to increase ACE-2 expression in both experimental models and humans. Sex also plays a role, with chromosome X harbouring the gene coding for ACE-2, which is one of the possible explanations of why mortality in female patients is lower. Viral entry also depends on TMPRSS2 protease activity, an androgen dependent enzyme. Despite the relevance of experimental animal studies, to comprehensively address the question of the potential hazards or benefits of ACE-Is and ARBs on the clinical course of COVID-19-affected patients treated by these anti-hypertensive drugs, we will need randomized human studies. We claim the need of adequately powered, prospective studies aimed at answering the following questions of paramount importance for cardiovascular, internal and emergency medicine: Do ACE-Is and ARBs exert similar or different effects on infection or disease course? Are such effects dangerous, neutral or even useful in older, COVID-19-affected patients? Do they act on multiple cell types? Since ACE-Is and ARBs have different molecular targets, the clinical course of SARS-CoV-2 infection could be also different in patients treated by one or the other of these two drug classes. At present, insufficient detailed data from trials have been made available.

positive: Will the real angiotensin converting enzyme please stand up?

positive: Highly infectious SARS-CoV pseudotyped virus reveals the cell tropism and its correlation with receptor expression Abstract Studies of SARS coronavirus (SARS-CoV)—the causative agent of severe acute respiratory syndrome (SARS)—have been hampered by its high transmission rate and the pathogenicity of this virus. To permit analysis of the host range and entry mechanism of SARS-CoV, we incorporated the humanized SARS-CoV spike (S) glycoprotein into HIV particles to generate a highly infectious SARS-CoV pseudotyped virus. The infection on Vero E6—a permissive cell line to SARS-CoV—could be neutralized by sera from convalescent SARS patients, and the entry was a pH-dependent process. With these highly infectious SARS-CoV pseudotypes, several cell lines derived from various tissues were revealed as susceptible to SARS-CoV, which were highly corresponding to the expression pattern of virus’s receptor angiotensin-converting enzyme 2 (ACE2). In addition, we also demonstrated angiotensin 1 converting enzyme (ACE)—the homologue of ACE2 could not function as a receptor for SARS-CoV.

positive: The role of angiotensin-converting enzyme 2 in coronaviruses/influenza viruses and cardiovascular disease Angiotensin-converting enzyme 2 (ACE2) has emerged as a key regulator of the renin-angiotensin system in cardiovascular (CV) disease and plays a pivotal role in infections by coronaviruses and influenza viruses. The present review is primarily focused on the findings to indicate the role of ACE2 in the relationship of coronaviruses and influenza viruses to CV disease. It is postulated that the risk of coronavirus or influenza virus infection is high, at least partly due to high ACE2 expression in populations with a high CV risk. Coronavirus and influenza virus vaccine usage in high CV risk populations could be a potential strategy to prevent both CV disease and coronavirus/influenza virus infections.

positive: Renin-Angiotensin System Inhibition in Cardiovascular Patients at the Time of COVID19: Much Ado for Nothing? A Statement of Activity from the Directors of the Board and the Scientific Directors of the Italian Society of Hypertension Cardiovascular diseases, in particular hypertension, as well as the cardiovascular treatment with Renin–Angiotensin System inhibitors such as Angiotensin Converting Enzyme (ACE) inhibitors and Angiotensin Receptor Blockers (ARBs), are claimed once again as mechanisms of Severe Acute Respiratory Syndrome (SARS) during the COVID-19 outbreak due to Cov-2 epidemics. In vitro studies are available to support the eventual role of ACE inhibitors and ARBs in both the promotion and antagonism of the disease. The available literature, indeed, presents contrasting results, all concentrated in experimental models. Evidence in humans is lacking that those mechanisms are actually occurring in the present COVID-19 outbreak. Here we present the reasoned statement of the Italian Society of Hypertension to maintain ongoing antihypertensive treatments. Furthermore, the Italian Society of Hypertension presents its own initiative to investigate the issue using an online questionnaire to collect relevant data in human disease.

positive: Year in review 2013: Acute lung injury, interstitial lung diseases, sleep and physiology

positive: Gir ACE-hemmere og angiotensinreseptorantagonister økt risiko for alvorlig covid-19?/ Gir ACE-hemmere og angiotensinreseptorantagonister økt risiko for alvorlig covid-19?/ Do ACE inhibitors and angiotensin receptor antagonists increase the risk of severe COVID-19?

positive: ACE2 fragment as a decoy for novel SARS-Cov-2 virus Novel SARS-Cov-2 enters human cells via interaction between the surface spike (S) glycoprotein and the cellular membrane receptor angiotensin-converting enzyme 2 (ACE2). Using a combination of comparative structural analyses of the binding surface of the S protein to ACE2, docking experiments, and molecular dynamics simulations we computationally identified a minimal, stable fragment of ACE2. This fragment binds to the S protein, is soluble, and appears not to bind to the physiological ligand angiotensinII. These results suggest a possible use of the ACE2 fragment as a decoy that could interfere with viral binding by competition.

positive: Pathophysiology of COVID-19: Why Children Fare Better than Adults? The world is facing Coronavirus Disease-2019 (COVID-19) pandemic, which is causing a large number of deaths and burden on intensive care facilities. It is caused by Severe Acute Respiratory Syndrome coronavirus-2 (SARS-CoV-2) originating in Wuhan, China. It has been seen that fewer children contract COVID-19 and among infected, children have less severe disease. Insights in pathophysiological mechanisms of less severity in children could be important for devising therapeutics for high-risk adults and elderly. Early closing of schools and day-care centers led to less frequent exposure and hence, lower infection rate in children. The expression of primary target receptor for SARS-CoV-2, i.e. angiotensin converting enzyme-2 (ACE-2), decreases with age. ACE-2 has lung protective effects by limiting angiotensin-2 mediated pulmonary capillary leak and inflammation. Severe COVID-19 disease is associated with high and persistent viral loads in adults. Children have strong innate immune response due to trained immunity (secondary to live-vaccines and frequent viral infections), leading to probably early control of infection at the site of entry. Adult patients show suppressed adaptive immunity and dysfunctional over-active innate immune response in severe infections, which is not seen in children. These could be related to immune-senescence in elderly. Excellent regeneration capacity of pediatric alveolar epithelium may be contributing to early recovery from COVID-19. Children, less frequently, have risk factors such as co-morbidities, smoking, and obesity. But young infants and children with pre-existing illnesses could be high risk groups and need careful monitoring. Studies describing immune-pathogenesis in COVID-19 are lacking in children and need urgent attention.

positive: Good or bad: Application of RAAS inhibitors in COVID-19 patients with cardiovascular comorbidities The coronavirus disease 2019 (COVID-19) pandemic is caused by a newly emerged coronavirus (CoV) called Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). COVID-19 patients with cardiovascular disease (CVD) comorbidities have significantly increased morbidity and mortality. The use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor type 1 blockers (ARBs) improve CVD outcomes; however, there is concern that they may worsen the prognosis of CVD patients that become infected with SARS-CoV-2 because the virus uses the ACE2 receptor to bind to and subsequently infect host cells. Thus, some health care providers and media sources have questioned the continued use of ACE inhibitors and ARBs. In this brief review, we discuss the effect of ACE inhibitor-induced bradykinin on the cardiovascular system, on the renin-angiotensin-aldosterone system (RAAS) regulation in COVID-19 patients, and analyze recent clinical studies regarding patients treated with RAAS inhibitors. We propose that the application of RAAS inhibitors for COVID-19 patients with CVDs may be beneficial rather than harmful.

positive: Comparative impacts of angiotensin converting enzyme inhibitors versus angiotensin II receptor blockers on the risk of COVID-19 mortality. N/A.

positive: Hypertension prevalence in human Coronavirus: The role of ACE system in infection spread and severity Summary The prevalence of hypertension is high in patients affected by COVID infection and it appears related to increased risk of mortality in many epidemiological studies. The ACE system is not uniformly expressed in all the human races, and current differences could hypothesize some geographical discrepancies of infection around the world. However, animal studies showed that ACE2 receptor is a potential pathway for host infection. Because two third of the hypertensive patients take ACE-i/ARB, several concerns have been raised about the detrimental role of current drugs. In this report we summarized the current evidences in favour or against the administration of ACE blockade in the COVID era.

positive: COVID-19 and Angiotensin-Converting Enzyme Inhibitor/Angiotensin-Receptor Blocker Therapy Mackey and colleagues reported a systematic review that found high-certainty evidence that angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers are not associated with greater illness severity in patients with COVID-19. The editorialist discusses the findings and emphasizes that, unless further data show otherwise, clinicians should continue to prescribe these drugs for their standard indications in patients with COVID-19.

positive: Continuing versus suspending angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: Impact on adverse outcomes in hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)--The BRACE CORONA Trial Angiotensin-converting enzyme-2 (ACE2) expression may increase due to upregulation in patients using angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs). Because renin-angiotensin system blockers increase levels of ACE2, a protein that facilitates coronavirus entry into cells, there is concern that these drugs could increase the risk of developing a severe and fatal form of COVID-19. The impact of discontinuing ACEI and ARBs in patients with COVID-19 remains uncertain. DESIGN: BRACE CORONA is a pragmatic, multicenter, randomized, phase IV, clinical trial that aims to enroll around 500 participants at 34 sites in Brazil. Participants will be identified from an ongoing national registry of suspected and confirmed cases of COVID-19. Eligible patients using renin-angiotensin system blockers (ACEI/ARBs) with a confirmed diagnosis of COVID-19 will be randomized to a strategy of continued ACEI/ARB treatment versus temporary discontinuation for 30 days. The primary outcome is the median days alive and out of the hospital at 30 days. Secondary outcomes include progression of COVID-19 disease, all-cause mortality, death from cardiovascular causes, myocardial infarction, stroke, transient ischemic attack, new or worsening heart failure, myocarditis, pericarditis, arrhythmias, thromboembolic events, hypertensive crisis, respiratory failure, hemodynamic decompensation, sepsis, renal failure, and troponin, B-type natriuretic peptide (BNP), N-terminal-proBNP, and D-dimer levels. SUMMARY: BRACE CORONA will evaluate whether the strategy of continued ACEI/ARB therapy compared with temporary discontinuation of these drugs impacts clinical outcomes among patients with COVID-19.

positive: Kidney and Lung ACE2 expression after an ACE inhibitor or an Ang II receptor blocker: implications for COVID-19 Background There have been concerns that ACE inhibitors and Ang II receptor blockers may cause an increase in ACE2, the main receptor for SARs-CoV-2. Methods Kidneys from two genetic models of kidney ACE ablation and mice treated with captopril or telmisartan were used to examine ACE2 in isolated kidney and lung membranes. Results In a global ACE KO mice, ACE2 protein abundance in kidney membranes was reduced to 42 % of wild type, p < 0.05. In ACE 8/8 mice that over-expresses cardiac ACE protein but also has no kidney ACE expression, ACE2 protein in kidney membranes was also decreased (38 % of the WT, p<0.01). In kidney membranes from mice that received captopril or telmisartan for 2 weeks there was a reduction in ACE2 protein (37% in captopril treated p<0.01) and 76% in telmisartan treated p <0.05). In lung membranes the expression of ACE2 was very low and not detected by western blotting but no significant differences in terms of ACE2 activity could be detected in mice treated with captopril (118% of control) or telmisartan (93% of control). Conclusions Genetic kidney ACE protein deficiency, suppressed enzymatic activity by Captopril or blockade of the AT1 receptor with telmisartan are all associated with a decrease in ACE2 in kidney membranes. ACE2 protein in kidney or lungs is decreased or unaffected by RAS blockers indicating that these medications can not pose a risk for SARS-CoV-2 infection related to amplification of ACE2 at these two target sites for viral entry.

positive: An Update on Current Therapeutic Drugs Treating COVID-19 The current pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has presented unprecedented challenges to the healthcare systems in almost every country around the world. Currently, there are no proven effective vaccines or therapeutic agents against the virus. Current clinical management includes infection prevention and control measures and supportive care including supplemental oxygen and mechanical ventilatory support. Evolving research and clinical data regarding the virologic SARS-CoV-2 suggest a potential list of repurposed drugs with appropriate pharmacological effects and therapeutic efficacies in treating COVID-19 patients. In this review, we will update and summarize the most common and plausible drugs for the treatment of COVID-19 patients. These drugs and therapeutic agents include antiviral agents (remdesivir, hydroxychloroquine, chloroquine, lopinavir, umifenovir, favipiravir, and oseltamivir), and supporting agents (Ascorbic acid, Azithromycin, Corticosteroids, Nitric oxide, IL-6 antagonists), among others. We hope that this review will provide useful and most updated therapeutic drugs to prevent, control, and treat COVID-19 patients until the approval of vaccines and specific drugs targeting SARS-CoV-2.

positive: Traditional Chinese medicine for COVID-19 treatment

positive: Renin-angiotensin system at the heart of COVID-19 pandemic Abstract Significant aspects of COVID-19 pandemic remain obscure. Angiotensin converting enzyme 2 (ACE2), a component of the renin-angiotensin system, whose expression dominates on lung alveolar epithelial cells, is the human cell receptor of SARS-CoV-2, the causative agent of COVID-19. We strongly encourage the concept that thorough considerations of receptor-ligand interactions should be kept at the heart of scientific debate on infection. In this idea, the whole renin-angiotensin system has to be evaluated. We hypothesize that factors related to ethnicity, environment, behaviors, associated illness, and medications involving this complex system are probably responsible for situations regarded as anomalous from both an epidemiological and a clinical point of view, but, taken together, such factors may explain most of the aspects of current outbreak. We decided to use the analogy of a play and speculate about the possible impact in this tragedy of 1) air pollution via the interference of nitrogen dioxide on ACE2 expression; 2) the dual role of nicotine; 3) the hypothetical involvement of ACE2 polymorphisms, the relationships of which with ethnic factors and susceptibility to cardiovascular disease seems intriguing; 4) the impact on the severity of infection of hypertension and related medications acting on the renin/angiotensin system, and, finally, 5) the possible helpful role of chloroquine, thanks to its capacity of modifying ACE2 affinity to the viral spike protein by altering glycosylation. This hypothesis paper is an urgent call for the development of research programs that aim at questioning whether the putative protagonists of this tragedy are real-life actors in COVID-19.

positive: Outbreak of SARS-CoV2: Pathogenesis of infection and cardiovascular involvement Since the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) has emerged from China, the infection (novel corona virus disease-2019, COVID-19) has affected many countries and led to many deaths worldwide. Like SARS-CoV, angiotencin converting enzyme (ACE)2 as a functional receptor for SARS-CoV2 is essential for the virus to make an entry into the cell. ACE2 is a part of Renin-Angiotensin-Aldosterone System, which is expressed in several organs that opposes the angiotensin (Ang) II functions by converting Ang II to Ang (1-7), the one with vasodilation effects. The death rate of COVID-19 is estimated to be approximately 3.4%; however, some comorbid conditions like underlying cardiovascular disease, hypertension, and diabetes increase the risk of mortality. In addition, cardiovascular involvement as a complication of SARS-CoV2 could be direct through either ACE2 receptors that are expressed tremendously in the heart, or by the surge of different cytokines or by acute respiratory distress syndrome-induced hypoxia. Traditional risk factors could aggravate the process of COVID-19 infection that urges the triage of these high-risk patients for SARS-CoV2. Currently, there is no effective, proven treatment or vaccination for COVID-19, but many investigators are struggling to find a treatment strategy as soon as possible. Some potential medications like chloroquine by itself or in combination with azithromycin and some protease inhibitors used for the treatment of COVID-19 have cardiovascular adverse effects, which should be kept in mind while the patients taking these medications are being closely monitored.

positive: Coronavirus Disease 2019 and Stroke: Clinical Manifestations and Pathophysiological Insights Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global health threat. Some COVID-19 patients have exhibited widespread neurological manifestations including stroke. Acute ischemic stroke, intracerebral hemorrhage, and cerebral venous sinus thrombosis have been reported in patients with COVID-19. COVID-19-associated coagulopathy is increasingly recognized as a result of acute infection and is likely caused by inflammation, including inflammatory cytokine storm. Recent studies suggest axonal transport of SARS-CoV-2 to the brain can occur via the cribriform plate adjacent to the olfactory bulb that may lead to symptomatic anosmia. The internalization of SARS-CoV-2 is mediated by the binding of the spike glycoprotein of the virus to the angiotensin-converting enzyme 2 (ACE2) on cellular membranes. ACE2 is expressed in several tissues including lung alveolar cells, gastrointestinal tissue, and brain. The aim of this review is to provide insights into the pathophysiological stroke mechanisms in COVID-19 patients. SARS-CoV-2 can down-regulate ACE2 and, in turn, over-activate the classical renin-angiotensin system (RAS) axis and decrease the activation of the alternative RAS pathway in the brain. The consequent imbalance in vasodilation, neuroinflammation, oxidative stress, and thrombotic response may contribute to the pathophysiology of stroke during SARS-CoV-2 infection.

positive: SARS-CoV-2 receptor ACE2-dependent implications on the cardiovascular system: From basic science to clinical implications The current COVID-19 pandemic started several months ago and is still exponentially growing in most parts of the world - this is the most recent and alarming update. COVID-19 requires the collaboration of nearly 200 countries to curb the spread of SARS-CoV-2 while gaining time to explore and improve treatment options especially for cardiovascular disease (CVD) and immunocompromised patients, who appear to be at high-risk to die from cardiopulmonary failure. Currently unanswered questions are why elderly people, particularly those with pre-existing comorbidities seem to exhibit higher mortality rates after SARS-CoV-2 infection and whether intensive care becomes indispensable for these patients to prevent multi-organ failure and sudden death. To face these challenges, we here summarize the molecular insights into viral infection mechanisms and implications for cardiovascular disease. Since the infection starts in the upper respiratory system, first flu-like symptoms develop that spread throughout the body. The wide range of affected organs is presumably based on the common expression of the major SARS-CoV-2 entry-receptor angiotensin-converting enzyme 2 (ACE2). Physiologically, ACE2 degrades angiotensin II, the master regulator of the renin-angiotensin-aldosterone system (RAAS), thereby converting it into vasodilatory molecules, which have well-documented cardio-protective effects. Thus, RAAS inhibitors, which may increase the expression levels of ACE2, are commonly used for the treatment of hypertension and CVD. This, and the fact that SARS-CoV-2 hijacks ACE2 for cell-entry, have spurred controversial discussions on the role of ACE2 in COVID-19 patients. In this review, we highlight the state-of-the-art knowledge on SARS-CoV-2-dependent mechanisms and the potential interaction with ACE2 expression and cell surface localization. We aim to provide a list of potential treatment options and a better understanding of why CVD is a high risk factor for COVID-19 susceptibility and further discuss the acute as well as long-term cardiac consequences.

positive: Genetic Polymorphisms in Critical Care and Illness

positive: Renin-angiotensin system blockers and susceptibility to COVID-19: a multinational open science cohort study INTRODUCTION: Angiotensin converting enzyme inhibitors (ACEs) and angiotensin receptor blockers (ARBs) could influence infection risk of coronavirus disease (COVID-19). Observational studies to date lack pre-specification, transparency, rigorous ascertainment adjustment and international generalizability, with contradictory results. METHODS: Using electronic health records from Spain (SIDIAP) and the United States (Columbia University Irving Medical Center and Department of Veterans Affairs), we conducted a systematic cohort study with prevalent ACE, ARB, calcium channel blocker (CCB) and thiazide diuretic (THZ) users to determine relative risk of COVID-19 diagnosis and related hospitalization outcomes. The study addressed confounding through large-scale propensity score adjustment and negative control experiments. RESULTS: Following over 1.1 million antihypertensive users identified between November 2019 and January 2020, we observed no significant difference in relative COVID-19 diagnosis risk comparing ACE/ARB vs CCB/THZ monotherapy (hazard ratio: 0.98; 95% CI 0.84 – 1.14), nor any difference for mono/combination use (1.01; 0.90 – 1.15). ACE alone and ARB alone similarly showed no relative risk difference when compared to CCB/THZ monotherapy or mono/combination use. Directly comparing ACE vs. ARB demonstrated a moderately lower risk with ACE, non-significant for monotherapy (0.85; 0.69 – 1.05) and marginally significant for mono/combination users (0.88; 0.79 – 0.99). We observed, however, no significant difference between drug-classes for COVID-19 hospitalization or pneumonia risk across all comparisons. CONCLUSION: There is no clinically significant increased risk of COVID-19 diagnosis or hospitalization with ACE or ARB use. Users should not discontinue or change their treatment to avoid COVID-19.

positive: ACE2, COVID19 and serum ACE as a possible biomarker to predict severity of disease

positive: Comorbidities in COVID-19: Outcomes in hypertensive cohort and controversies with renin angiotensin system blockers Abstract Background and aims COVID-19 is already a pandemic. Emerging data suggest an increased association and a heightened mortality in patients of COVID-19 with comorbidities. We aimed to evaluate the outcome in hypertensive patients with COVID-19 and its relation to the use of renin-angiotensin system blockers (RASB). Methods We have systematically searched the medical database up to March 27, 2020 and retrieved all the published articles in English language related to our topic using MeSH key words. Results From the pooled data of all ten available Chinese studies (n = 2209) that have reported the characteristics of comorbidities in patients with COVID-19, hypertension was present in nearly 21%, followed by diabetes in nearly 11%, and established cardiovascular disease (CVD) in approximately 7% of patients. Although the emerging data hints to an increase in mortality in COVID-19 patients with known hypertension, diabetes and CVD, it should be noted that it was not adjusted for multiple confounding factors. Harm or benefit in COVID-19 patients receiving RASB has not been typically assessed in these studies yet, although mechanistically and plausibly both, benefit and harm is possible with these agents, given that COVID-19 expresses to tissues through the receptor of angiotensin converting enzyme-2. Conclusion Special attention is definitely required in patients with COVID-19 with associated comorbidities including hypertension, diabetes and established CVD. Although the role of RASB has a mechanistic equipoise, patients with COVID-19 should not stop these drugs at this point of time, as recommended by various world organizations and without the advice of health care provider.

positive: Angiotensin-Converting Enzyme 2 and Antihypertensives (Angiotensin Receptor Blockers and Angiotensin-Converting Enzyme Inhibitors) in Coronavirus Disease 2019 Abstract Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2, is being defined as the worst pandemic disease of modern times. Several professional health organizations have published position papers stating that there is no evidence to change the use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) in the management of elevated blood pressure in the context of avoiding or treating COVID-19 infection. In this article, we review the evidence on the relationship between the renin-angiotensin-aldosterone system and COVID-19 infection. In agreement with current guidelines, patients with hypertension should continue taking antihypertensive medications as prescribed without interruption. Because ACEIs and ARBs are also used to retard the progression of chronic kidney disease, we suggest that these recommendations also apply to the use of these agents in chronic kidney disease. No differences generally exist between ARBs and ACEIs in terms of efficacy in decreasing blood pressure and improving other outcomes, such as all-cause mortality, cardiovascular mortality, myocardial infarction, heart failure, stroke, and end-stage renal disease. The ACEIs are associated with cough secondary to accumulation of bradykinin and angioedema, and withdrawal rates due to adverse events are lower with ARBs. Given their equal efficacy but fewer adverse events, ARBs could potentially be a more favorable treatment option in patients with COVID-19 at higher risk for severe forms of disease.

positive: Association between angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers use and the risk of infection and clinical outcome of COVID-19: a comprehensive systematic review and meta-analysis. Background The effect of using Angiotensin-converting enzyme inhibitors (ACEIs) and Angiotensin-receptor blockers (ARBs) on the risk of coronavirus disease 2019 (COVID-19) is a topic of recent debate. Although studies have examined the potential association between them, the results remain controversial. This study aims to determine the true effect of ACEI/ARBs use on the risk of infection and clinical outcome of COVID-19. Methods Five electronic databases (PubMed, Web of science, Cochrane library, China National Knowledge Infrastructure database, medRxiv preprint server) were retrieved to find eligible studies. Meta-analysis was performed to examine the association between ACEI/ARBs use and the risk of infection and clinical outcome of COVID-19. Results 22 articles containing 157,328 patients were included. Use of ACEI/ARBs was not associated with increased risk of infection (Adjusted OR: 0.96, 95% CI: 0.91-1.01, I2=5.8%) or increased severity (Adjusted OR: 0.90, 95% CI: 0.77-1.05, I2=27.6%) of COVID-19. The use of ACEI/ARBs was associated with lower risk of death from COVID-19 (Adjusted OR: 0.66, 95% CI: 0.44-0.99, I2=57.9%). Similar results of reduced risk of death were also found for ACEI/ARB use in COVID-19 patients with hypertension (Adjusted OR: 0.36, 95% CI: 0.17-0.77, I2=0). Conclusion This study provides evidence that ACEI/ARBs use for COVID-19 patients does not lead to harmful outcomes and may even provide a beneficial role and decrease mortality from COVID-19. Clinicians should not discontinue ACEI/ARBs for patients diagnosed with COVID-19 if they are already on these agents. Keywords: COVID-19; Angiotensin-converting enzyme inhibitor; Angiotensin-receptor blockers; risk; systematic review; meta-analysis

positive: Long-Term ACE Inhibitor/ARB Use Is Associated with Severe Renal Dysfunction and Acute Kidney Injury in Patients with severe COVID-19: Results from a Referral Center Cohort in the North East of France BACKGROUND: In patients with severe COVID-19, data are scarce and conflicting regarding whether chronic use of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) influences disease outcomes. In patients with severe COVID-19, we assessed the association between chronic ACEI/ARB use and the occurrence of kidney, lung, heart, and liver dysfunctions and the severity of the inflammatory reaction as evaluated by biomarkers kinetics, and their association with disease outcomes. METHODS: We performed a retrospective longitudinal cohort study on consecutive patients with newly diagnosed severe COVID-19. Independent predictors were assessed through receiver operating characteristic analysis, time-series analysis, logistic regression analysis, and multilevel modeling for repeated measures. RESULTS: On the 149 patients included in the study 30% (44/149) were treated with ACEI/ARB. ACEI/ARB use was independently associated with the following biochemical variations: phosphorus >40 mg/L (odds ratio [OR], 3.35, 95% CI, 1.83-6.14), creatinine >10.1 mg/L (OR, 3.22, 2.28-4.54), and urea nitrogen (UN) >0.52 g/L (OR, 2.65, 1.89-3.73). ACEI/ARB use was independently associated with acute kidney injury, AKI stage ≥1 (OR, 3.28, 2.17-4.94). The daily dose of ACEI/ARB was independently associated with altered kidney markers with an increased risk of +25 to +31% per each 10 mg increment of lisinopril-dose equivalent. In multivariable multilevel modeling, UN >0.52 g/L was independently associated with the risk of acute respiratory failure (OR, 3.54, 1.05-11.96). CONCLUSIONS: Patients chronically treated with ACEI/ARB who have severe COVID-19 are at increased risk of acute kidney injury. In these patients, the increase in UN associated with ACEI/ARB use could predict the development of acute respiratory failure.

positive: Commentary: What is the relationship between Covid-19 and cardiovascular disease?

positive: COVID-19 and cardiovascular diseases: viewpoint for older patients. The coronavirus disease-2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2. The link between cardiovascular disease and COVID-19 appears to be twofold. First, some reports of data indicate that certain groups of patients are more at risk of COVID-19. This includes patients with cardiovascular risk factors or pre-existing cardiovascular conditions and older patients. In addition, these patients incur disproportionately worse outcome. Second, SARS-CoV2 infection can be complicated by life-threatening cardiovascular acute diseases. Despite the rapid evolution of data on this pandemic, this review aims to highlight the cardiovascular considerations related to COVID-19 whether as comorbidities including concerns and uncertainty regarding the effect of renin-angiotensin-aldosterone system (RAAS) inhibitors on angiotensin conversion enzyme 2 or related to acute cardiovascular complications.

positive: Emodin blocks the SARS coronavirus spike protein and angiotensin-converting enzyme 2 interaction Abstract Severe acute respiratory syndrome (SARS) is an emerging infectious disease caused by a novel coronavirus (SARS-CoV). SARS-CoV spike (S) protein, a type I membrane-bound protein, is essential for the viral attachment to the host cell receptor angiotensin-converting enzyme 2 (ACE2). By screening 312 controlled Chinese medicinal herbs supervised by Committee on Chinese Medicine and Pharmacy at Taiwan, we identified that three widely used Chinese medicinal herbs of the family Polygonaceae inhibited the interaction of SARS-CoV S protein and ACE2. The IC50 values for Radix et Rhizoma Rhei (the root tubers of Rheum officinale Baill.), Radix Polygoni multiflori (the root tubers of Polygonum multiflorum Thunb.), and Caulis Polygoni multiflori (the vines of P. multiflorum Thunb.) ranged from 1 to 10μg/ml. Emodin, an anthraquinone compound derived from genus Rheum and Polygonum, significantly blocked the S protein and ACE2 interaction in a dose-dependent manner. It also inhibited the infectivity of S protein-pseudotyped retrovirus to Vero E6 cells. These findings suggested that emodin may be considered as a potential lead therapeutic agent in the treatment of SARS.

positive: Hyperinflammation and derangement of renin-angiotensin-aldosterone system in COVID-19: A novel hypothesis for clinically suspected hypercoagulopathy and microvascular immunothrombosis Abstract Early clinical evidence suggests that severe cases of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are frequently characterized by hyperinflammation, imbalance of renin-angiotensin-aldosterone system, and a particular form of vasculopathy, thrombotic microangiopathy, and intravascular coagulopathy. In this paper, we present an immunothrombosis model of COVID-19. We discuss the underlying pathogenesis and the interaction between multiple systems, resulting in propagation of immunothrombosis, which through investigation in the coming weeks, may lead to both an improved understanding of COVID-19 pathophysiology and identification of innovative and efficient therapeutic targets to reverse the otherwise unfavorable clinical outcome of many of these patients.

positive: The effects of renin-angiotensin system inhibitors (RASI) in Corona Virus Disease (COVID-19) with Hypertension: A retrospective, single-center trial Abstract Introduction and objective: A recent outbreak of Coronavirus disease 2019 (COVID-19) occurs in the worldwide. Angiotensin-converting enzyme 2 (ACE2) can mediate coronavirus entry into host cells. Therefore, renin-angiotensin system inhibitors (RASI) were suspected of contributing to the increase of coronavirus infection. We aimed to analyze the effects of RASI in COVID-19 patients with Hypertension. Patients and method: In this retrospective, single-center study, 27 COVID-19 patients with hypertension, who were admitted to the Shanghai Public Health Clinical Center from January 25, 2020 to January 31, 2020, were analyzed for clinical features, laboratory parameters, medications and the length of stay. All the patients were given antiviral and antihypertension treatment, of which 14 patients were treated with RASI and 13 patients without RASI. Results: Comparing the two groups, we did not found statistically significant differences in clinical symptoms and laboratory tests. Furthermore, cough was not aggravated. Conclusions: Through the analysis of this small sample, RASI could be deemed safe and effective to control high blood pressure of COVID-19 patients. Further analysis with a larger sampling size is required to explore the underlying mechanisms.

positive: Facts and reflections on COVID-19 and anti-hypertensives drugs. Based on some publications that associate SARS-CoV-2 infection with the use of anti-hypertensive drug groups such as angiotensin-converting-enzyme inhibitors (e.g. enalapril) or angiotensin II receptor blockers (e.g. losartan), many patients from South America, Central America or Spain, have stopped or intend to interrupt their treatments with these drugs. Hence, it may exist ominous consequences due to this drop out. For this reason, it is necessary to quickly warn about this situation and the risks associated with it.

positive: Use of RAAS inhibitors and risk of clinical deterioration in COVID-19: results from an Italian cohort of 133 hypertensives BACKGROUND: The effect of chronic use of renin–angiotensin–aldosterone system (RAAS) inhibitors on the severity of COVID-19 infection is still unclear in patients with hypertension. We aimed to investigate the association between chronic use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) and COVID-19 related outcomes in hypertensive patients. METHODS: A single center study was conducted on 133 consecutive hypertensive subjects presenting to the Emergency Department with acute respiratory symptoms and/or fever who were diagnosed with COVID-19 infection between 9(th) and 31(st) March 2020. RESULTS: All patients were grouped according to their chronic antihypertensive medications (ACEIs, N=40; ARBs, N=42; not on RAAS inhibitors, N=51). There was no statistical difference between ACEIs and ARBs groups in terms of hospital admission rate, oxygen therapy and need for non-invasive ventilation. Patients chronically treated with RAAS inhibitors showed a significantly lower rate of admission to semi-intensive/intensive care units, when compared to the non-RAAS population (odds ratio [OR] 0.25, CI95% 0.09-0.66 p=0.006). Similarly, the risk of mortality was lower in the former group, although not reaching statistical significance (OR 0.56, CI95% 0.17-1.83, p=0.341). CONCLUSIONS: Our data suggest that chronic use of RAAS inhibitors does not negatively affect clinical course of COVID-19 in hypertensive patients. Further studies are needed to confirm this finding and determine whether RAAS inhibitors may have a protective effect on COVID 19-related morbidity and mortality.

positive: Blocking angiotensin earlier with RAS blockers, statins, and heparin in high-risk COVID-19 patients: Is the remedy here?

positive: Angiotensin-Converting Enzyme 2 and the Resolution of Inflammation: In Support of Continuation of Prescribed Angiotensin-Converting Enzyme Inhibitors and Angiotensin-Receptor Blockers

positive: ACE2 and COVID-19 and the resulting ARDS This article reviews the correlation between ACE2 and COVID-19 and the resulting acute respiratory distress syndrome (ARDS). ACE2 is a crucial component of the renin-angiotensin system (RAS). The classical ACE-angiotensin â ¡ (Ang II)-angiotensin type 1 receptor (AT1R) axis and the ACE2-Ang(1-7)-Mas counter-regulatory axis play an essential role in RAS system. ACE2 antagonises the activation of the classical RAS ACE-Ang II-AT1R axis and protects against lung injury. Similar to severe acute respiratory syndrome-related coronavirus, 2019 novel coronavirus (2019-nCoV) also uses ACE2 for cell entry. ARDS is a clinical high-mortality disease which is probably due to the excessive activation of RAS caused by 2019-nCoV infection, and ACE2 has a protective effect on ARDS caused by COVID-19. Because of these protective effects of ACE2 on ARDS, the development of drugs enhancing ACE2 activity may become one of the most promising approaches for the treatment of COVID-19 in the near future. In the meantime, however, the use of RAS blockers such as ACE inhibitors and angiotensin II receptor blockers that inhibit the damaging (ACE-Ang II) arm of the RAS cascade in the lung may also be promising. Trial registration number: NCT04287686.

positive: Weathering the Cytokine Storm in Susceptible Patients with Severe SARS-CoV-2 Infection

positive: Rethinking the role of blood pressure drugs in COVID-19 All it takes is a simple cough: a sharp intake of breath, the compression of air in the lungs, and the throat flying open to spew air, spit, and mucus If the person coughing is infected with the novel coronavirus, it comes along for the ride on droplets, which can travel up to 50 miles per hour When someone breathes those droplets in, the virus can get into the lungs Once inside, it uses a spike protein on its surface to target an enzyme—ACE2—scattered over the outsides of the airway’s cells If the spike protein connects with its target, the coronavirus uses ACE2 as a door to slip inside the cell Thus begins an infection During the early days of the coronavirus outbreak, researchers hypothesized that the likelihood of contracting COVID-19, the disease caused by the novel coronavirus, could be related to the amount of ACE2 on someone’s cells—the more doors for the virus to enter through, the higher the risk That idea prompted doctors around the world in March to warn the millions of people taking two classes of blood pressure medications, angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs), of a potential danger: these medications appear to increase ACE2 levels in cells, at least in some studies, so the drugs may make their users more susceptible to the novel coronavirus, SARS-CoV-2

positive: Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review. Importance The pandemic of coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents an unprecedented challenge to identify effective drugs for prevention and treatment. Given the rapid pace of scientific discovery and clinical data generated by the large number of people rapidly infected by SARS-CoV-2, clinicians need accurate evidence regarding effective medical treatments for this infection. Observations No proven effective therapies for this virus currently exist. The rapidly expanding knowledge regarding SARS-CoV-2 virology provides a significant number of potential drug targets. The most promising therapy is remdesivir. Remdesivir has potent in vitro activity against SARS-CoV-2, but it is not US Food and Drug Administration approved and currently is being tested in ongoing randomized trials. Oseltamivir has not been shown to have efficacy, and corticosteroids are currently not recommended. Current clinical evidence does not support stopping angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in patients with COVID-19. Conclusions and Relevance The COVID-19 pandemic represents the greatest global public health crisis of this generation and, potentially, since the pandemic influenza outbreak of 1918. The speed and volume of clinical trials launched to investigate potential therapies for COVID-19 highlight both the need and capability to produce high-quality evidence even in the middle of a pandemic. No therapies have been shown effective to date.

positive: Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin-angiotensin-aldosterone inhibitors AIMS: The current pandemic coronavirus SARS-CoV-2 infects a wide age group but predominantly elderly individuals, especially men and those with cardiovascular disease. Recent reports suggest an association with use of renin-angiotensin-aldosterone system (RAAS) inhibitors. Angiotensin-converting enzyme 2 (ACE2) is a functional receptor for coronaviruses. Higher ACE2 concentrations might lead to increased vulnerability to SARS-CoV-2 in patients on RAAS inhibitors. METHODS AND RESULTS: We measured ACE2 concentrations in 1485 men and 537 women with heart failure (index cohort). Results were validated in 1123 men and 575 women (validation cohort).The median age was 69 years for men and 75 years for women. The strongest predictor of elevated concentrations of ACE2 in both cohorts was male sex (estimate = 0.26, P < 0.001; and 0.19, P < 0.001, respectively). In the index cohort, use of ACE inhibitors, angiotensin receptor blockers (ARBs), or mineralocorticoid receptor antagonists (MRAs) was not an independent predictor of plasma ACE2. In the validation cohort, ACE inhibitor (estimate = -0.17, P = 0.002) and ARB use (estimate = -0.15, P = 0.03) were independent predictors of lower plasma ACE2, while use of an MRA (estimate = 0.11, P = 0.04) was an independent predictor of higher plasma ACE2 concentrations. CONCLUSION: In two independent cohorts of patients with heart failure, plasma concentrations of ACE2 were higher in men than in women, but use of neither an ACE inhibitor nor an ARB was associated with higher plasma ACE2 concentrations. These data might explain the higher incidence and fatality rate of COVID-19 in men, but do not support previous reports suggesting that ACE inhibitors or ARBs increase the vulnerability for COVID-19 through increased plasma ACE2 concentrations.

positive: A Review: Does Complement or the Contact System Have a Role in Protection or Pathogenesis of COVID-19? INTRODUCTION: COVID-19 presentation may include a profound increase in cytokines and associated pneumonia, rapidly progressing to acute respiratory distress syndrome (ARDS). This so-called cytokine storm often leads to refractory edema, respiratory arrest, and death. At present, anti-IL-6, antiviral therapy, convalescent plasma, hydroxychloroquine, and azithromycin among others are being investigated as potential treatments for COVID-19. As the disease etiology and precise therapeutic interventions are still not definitively defined, we wanted to review the roles that complement and the contact system may have in either the treatment or pathogenesis of the disease. METHODS: We searched the recent literature (PubMed) on complement and coronavirus; contact system and coronavirus; bradykinin and coronavirus; and angiotensin receptor and coronavirus. The manuscript complies with ethics guidelines and was deemed exempt from institutional review board approval according to Human Subjects Protection Office guidelines. RESULTS: Mouse models are available for the study of coronavirus and complement. Although complement is effective in protecting against many viruses, it does not seem to be protective against coronavirus. C3 knockout mice infected with SARS-CoV had less lung disease than wild-type mice, suggesting that complement may play a role in coronavirus pathogenesis. Some evidence suggests that the observed pulmonary edema may be bradykinin-induced and could be the reason that corticosteroids, antihistamines, and other traditional interventions for edema are not effective. Angiotensin-converting enzyme 2 (ACE2) is a co-receptor for SARS-CoV-2, and studies thus far have not concluded a benefit or risk associated with the use of either ACE-inhibitors or angiotensin receptor antagonists. Activation of complement and the contact system, through generation of bradykinin, may play a role in the SARS-CoV-2-induced pulmonary edema, and our search suggests that further work is necessary to confirm our suspicions.

positive: Antihypertensive drugs and risk of COVID-19?

positive: Mortality and use of angiotensin converting enzyme inhibitors in Covid 19 disease - a systematic review. Background. Interest exits concerning the use of angiotensin converting enzyme inhibitors (ACEi) in patients with Covid-19 disease. Objectives. To perform a systematic review on mortality associated to the use of ACEi in patients with Covid 19 disease. Methods. Search in Medline (PubMed) and in ISI Web of Knowledge; use of other sources. Results. A total of 19 articles were evaluated. Four studies were selected and used to produce the meta-analyses. These four studies involved a total number of 1.423 patients treated with ACEi and 11.868 not treated with ACEi. Significant heterogeneity was seen concerning mortality associated to the use of ACEi in the context of Covid-19 disease. One report showed significantly decreased mortality associated to ACEi use, but this finding was not confirmed by the three other studies. No significant difference in mortality was seen in the meta-analysis (ACEi users versus non-users; random effects; odds ratio, 0.93; 95% confidence interval [CI], 0.44 to 1.94; P=0.84). When compared to mortality in patients treated with angiotensin receptor blockers, mortality of patients treated with ACEi was not significantly different, although a trend was noted to exist (odds ratio, 0.74; 95% confidence interval [CI], 0.41 to 1.34; P=0.32). The population studied in the report showing decreased mortality associated to ACEi use had a mean age under 50 years, whereas two other reports had a mean or median patient age over 60 years. Conclusions. The data now presented argue in favor of carrying out clinical trials studying ACEi in Covid-19 patients, to explore the hypothesis that ACEi use has a protective effect in populations with a mean age under 50 years, but not necessarily in those with a mean age over 60 years.

positive: COVID-19: Updated Data and its Relation to the Cardiovascular System. In December 2019, a new human coronavirus, called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or coronavirus disease 2019 (COVID-19) by the World Health Organization, emerged in the city of Wuhan, China. Spreading globally, it is now considered pandemic, with approximately 3 million cases worldwide at the end of April. Its symptoms include fever, cough, and headache, but the main one is shortness of breath. In turn, it is believed that there is a relationship between COVID-19 and damage to the heart muscle, and hypertensive and diabetic patients, for example, seem to have worse prognosis. Therefore, COVID-19 may worsen in individuals with underlying adverse conditions, and a not negligible number of patients hospitalized with this virus had cardiovascular or cerebrovascular diseases. Systemic inflammatory response and immune system disorders during disease progression may be behind this association. In addition, the virus uses angiotensin-converting enzyme (ACE) receptors, more precisely ACE2, to penetrate the cell; therefore, the use of ACE inhibitor drugs and angiotensin receptor blockers could cause an increase in these receptors, thus facilitating the entry of the virus into the cell. There is, however, no scientific evidence to support the interruption of these drugs. Since they are fundamental for certain chronic diseases, the risk and benefit of their withdrawal in this scenario should be carefully weighed. Finally, cardiologists and health professionals should be aware of the risks of infection and protect themselves as much as possible, sleeping properly and avoiding long working hours.

positive: ACE Inhibition in Heart Failure and Ischaemic Heart Disease

positive: Calcium channel blocker amlodipine besylate is associated with reduced case fatality rate of COVID-19 patients with hypertension The coronavirus disease (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has now spread to more than 100 countries posing as a serious threat to the public health on a global scale. Patients with comorbidity such as hypertension suffer more severe infection with elevated case fatality rate. Development of effective anti-viral drug is in urgent need to treat COVID-19 patients. Here we report that calcium channel blockers (CCBs), a type of anti-hypertension drugs that are widely used in the clinics, can significantly inhibit the post-entry replication events of SARS-CoV-2 in vitro. Comparison with two other major types of anti-hypertension drugs, the angiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB), showed that only CCBs display significant anti-SARS-CoV-2 efficacy. Combined treatment with chloroquine and CCBs significantly enhanced the anti-SARS-CoV-2 efficacy. Retrospective clinical investigation of COVID-19 patients revealed that the CCB amlodipine besylate administration distinctly reduced the case fatality rate of patients with hypertension. Results from this study suggest that CCB administration for COVID-19 patients with hypertension as the comorbidity might improve the disease outcome.

positive: Molecular targets for the rational design of drugs to inhibit SARS coronavirus Despite years of research, the precise determinants of coronavirus replication and pathogenesis remain unidentified. What is known of the pathogenesis of the severe acute respiratory syndrome coronavirus (SARS-CoV) is limited, but clinical observations suggest that both viral-induced cytotoxicity and host immune-mediated destruction contribute to the severity of disease. This summary discusses recent advances in coronavirus research that will facilitate the identification of crucial molecular targets for the rational design of SARS therapeutics. Section Editor: Anne Moscona – Department of Pediatrics, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1198, New York, NY 10029, USA When the SARS coronavirus came dramatically to attention as a fatal and potentially pandemic respiratory disease, the scientific response was swift and effective. The etiological agent was identified, the genome was cloned and sequenced, and large strides have been made in understanding key points in the viral life cycle, including recent identification of a functional host cell receptor and solution of the three-dimensional structure of the viral attachment protein. Much of this progress was possible only because a foundation of basic coronavirus biology existed. The Denison laboratory has been at the forefront of the small group of investigators who have dissected the basic features of coronaviruses. Denison has discovered critical mechanisms in the life cycle of the coronaviruses and is a key figure in the effective and urgent application of this knowledge to SARS.

positive: [Role of age, comorbidity and renin- angiotensin-aldosterone system in COVID-19. Effects of ACE inhibitors and angiotensin receptor blockers] The review addressed the relationship of coronavirus disease 2019 (COVID-19) with functioning of the renin-angiotensin-aldosterone axis and the causes for unfavorable prognosis depending on patients' age and comorbidities. The authors discussed in detail potential effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists on the risk of infection and the course of COVID-2019 as well as the effect of SARS-COV2 virus on the cardiovascular system.

positive: SARS-CoV-2 Infection and Cardiovascular Disease: COVID-19 Heart Coronavirus disease (COVID-19) is a serious illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The symptoms of the disease range from asymptomatic to mild respiratory symptoms and even potentially life-threatening cardiovascular and pulmonary complications. Cardiac complications include acute myocardial injury, arrhythmias, cardiogenic shock and even sudden death. Furthermore, drug interactions with COVID-19 therapies may place the patient at risk for arrhythmias, cardiomyopathy and sudden death. In this review, we summarise the cardiac manifestations of COVID-19 infection and propose a simplified algorithm for patient management during the COVID-19 pandemic.

positive: Angiotensin converting enzyme 2 (ACE2) and COVID-19: using antihypertensive medications, pharmacogenetic considerations COVID-19 utilizes the angiotensin-converting enzyme-2 (ACE2) pathway as a means of infection. Early data on COVID-19 suggest heterogeneity in the severity of symptoms during transmission and infection ranging from no symptoms to death. The source of this heterogeneity is likely multifaceted and may have a genetic component. Demographic and clinical comorbidities associated with the severity of infection suggest that possible variants known to influence the renin-angiotensin-aldosterone system pathway (particularly those that influence ACE2) may contribute to the heterogenous infection response. ACE2 and angiotensin(1-7) (the product of ACE2) seem to have a protective effect on the pulmonary and cardiac systems. Hypertension medication modulation, may alter ACE2 and angiotensin(1-7), particularly in variants that have been shown to influence renin-angiotensin-aldosterone system function, which could be clinically useful in patients with COVID-19.

positive: Joint HFSA/ACC/AHA Statement Addresses Concerns Re: Using RAAS Antagonists in COVID-19

positive: Unexpected BP Sensitivity to Angiotensin II in a Patient With Coronavirus Disease 2019, ARDS, and Septic Shock We report the case of an 88-year-old man with coronavirus disease 2019 (COVID-19) who presented with ARDS and septic shock. The patient had exquisite BP sensitivity to low-dose angiotensin II (Ang-2), allowing for rapid liberation from high-dose vasopressors. We hypothesize that sensitivity to Ang-2 might be related to biological effect of severe acute respiratory syndrome coronavirus 2 infection. The case is suggestive of a potential role for synthetic Ang-2 for patients with COVID-19 and septic shock. Further studies are needed to confirm our observed clinical efficacy.

positive: Coronavirus disease 2019 (COVID-19) and the renin-angiotensin system: A closer look at angiotensin-converting enzyme 2 (ACE2) Since the first cases of atypical pneumonia linked to the Huanan Seafood Wholesale Market in Wuhan, China, were described in late December 2019, the global landscape has changed radically. In March 2020, the World Health Organization declared COVID-19 a global pandemic, and at the time of writing this review, just over three million individuals have been infected with more than 200,000 deaths globally. Numerous countries are in ‘lockdown’, social distancing is the new norm, even the most advanced healthcare systems are under pressure, and a global economic recession seems inevitable. A novel coronavirus (SARS-CoV-2) was identified as the aetiological agent. From experience with previous coronavirus epidemics, namely the severe acute respiratory syndrome (SARS) and Middle East Respiratory Syndrome (MERS) in 2004 and 2012 respectively, it was postulated that the angiotensin-converting enzyme-2 (ACE2) receptor is a possible port of cell entry. ACE2 is part of the renin-angiotensin system and is also associated with lung and cardiovascular disorders and inflammation. Recent studies have confirmed that ACE2 is the port of entry for SARS-CoV-2. Male sex, advanced age and a number of associated comorbidities have been identified as risk factors for infection with COVID-19. Many high-risk COVID-19 patients with comorbidities are on ACE inhibitors and angiotensin receptor blockers, and this has sparked debate about whether to continue these treatment regimes. Attention has also shifted to ACE2 being a target for future therapies or vaccines against COVID-19. In this review, we discuss COVID-19 and its complex relationship with ACE2.

positive: What Solid Organ Transplant Healthcare Providers should know about Renin‐Angiotensin‐Aldosterone System Inhibitors and COVID‐19 The data on the outcomes of solid organ transplant recipients who have contracted coronavirus disease 2019 (COVID‐19) are still emerging. Kidney transplant recipients are commonly prescribed renin‐angiotensin‐aldosterone system (AAS) inhibitors given the prevalence of hypertension, diabetes, and cardiovascular disease. As the angiotensin‐converting enzyme 2 (ACE2) facilitates the entry of coronaviruses into target cells, there have been hypotheses that preexisting use of Renin‐Angiotensin‐Aldosterone System (RAAS) inhibitors may increase the risk of developing severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. Given the common use of RAAS inhibitors among solid organ transplant recipients, we sought to review the RAAS cascade, the mechanism of SARS‐CoV‐2 entry, and pertinent data related to the effect of RAAS inhibitors on ACE2 to guide management of solid organ transplant recipients during the COVID‐19 pandemic. At present there is no clear evidence to support the discontinuation of RAAS inhibitors in solid organ transplant recipients during the COVID‐19 pandemic.

positive: Inflammation Level Severity and Death in Patients With COVID-19: A Rapid Systematic Review and Meta-Analysis Background: An association among the use of angiotensin-converting-enzyme(ACE) inhibitors and angiotensin-receptor blockers(ARBs) with the clinical outcomes of coronavirus disease 2019 (COVID-19) is unclear. Methods: PubMed, EMBASE, and the preprint databases MedRxiv and BioRxiv were searched for relevant studies that assessed the association among inflammation level, application of ACEI/ARB, infection severity and death in patients with COVID-19. Odd risks(OR) and 95% confidence interval (CI) were combined using random-effects or fixed models depending on heterogeneity. Results: Eleven studies were included with a total of 33,483 patients. Our review showed ACEI/ARB therapy might be associated with the reduced inflammatory factor (interleukin-6) and elevated level of immune cells(CD3, CD8). Meta-analysis showed no significant increase in the risk of COVID-19 infection(OR:0.95, 95%CI:0.89-1.05) in patients receiving ACEI/ARB therapy, and ACEI/ARB therapy was associated with a decreased risk of severe COVID-19 (OR:0.75, 95%CI: 0.59-0.96) and mortality (OR:0.52, 95%CI: 0.35-0.79). Subgroup analyses showed that, among the general population, application of ACEI/ARB therapy was associated with reduced risks of all-cause death(OR:0.31, 95%CI: 0.13-0.75), and the risk of severe COVID-19(OR:0.79, 95%CI: 0.60-1.05) infection and COVID-19 infection(OR:0.85, 95% CI: 0.66-1.08) were not increased. Among patients with hypertension, the use of an ACEI/ARB was associated with a lower severity of COVID-19(OR:0.73, 95%CI: 0.51-1.03) and lower mortality(OR:0.57, 95%CI: 0.37-0.87), without evidence of an increased risk of COVID-19 infection(OR:1.00, 95%CI: 0.90-1.12). Conclusion: On the basis of the available evidence, this is the first meta-analysis showed that, in general population, the use of ACEI/ARB therapy was safe without an increased risk of COVID-19 infection and with a decreasing trend of severe COVID-19 infection and lower mortality. In patients with hypertension, the use of ACEI/ARB therapy should be encouraged, without increased risk of COVID-19 inflection, and better prognosis (a decreasing trends of severe COVID-19 and reduced all-cause death). Overall, ACEI/ARB therapy should be continued in patients who are at risk for, or have COVID-19, either in general population or hypertension patients. Our results need to be interpreted with caution considering the potential for residual confounders, and more well-designed studies that control the clinical confounders are necessary to confirm our findings. Key Words COVID-19; ACEI/ARB; SARS-COV-2; pneumonia; infectious disease; lung, hypertension

positive: On the interactions of the receptor-binding domain of SARS-CoV-1 and SARS-CoV-2 spike proteins with monoclonal antibodies and the receptor ACE2 A new betacoronavirus named SARS-CoV-2 has emerged as a new threat to global health and economy. A promising target for both diagnosis and therapeutics treatments of the new disease named COVID-19 is the coronavirus (CoV) spike (S) glycoprotein. By constant-pH Monte Carlo simulations and the PROCEEDpKa method, we have mapped the electrostatic epitopes for four monoclonal antibodies and the angiotensin-converting enzyme 2 (ACE2) on both SARS-CoV-1 and the new SARS-CoV-2 S receptor binding domain (RBD) proteins. We also calculated free energy of interactions and shown that the S RBD proteins from both SARS viruses binds to ACE2 with similar affinities. However, the affinity between the S RBD protein from the new SARS-CoV-2 and ACE2 is higher than for any studied antibody previously found complexed with SARS-CoV-1. Based on physical chemical analysis and free energies estimates, we can shed some light on the involved molecular recognition processes, their clinical aspects, the implications for drug developments, and suggest structural modifications on the CR3022 antibody that would improve its binding affinities for SARS-CoV-2 and contribute to address the ongoing international health crisis.

positive: 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.

positive: EMA: continue use of ACE inhibitors, sartans during COVID-19 pandemic

positive: Hiding in Plain Sight: an Approach to Treating Patients with Severe COVID-19 Infection Patients with COVID-19 infection are at risk of acute respiratory disease syndrome (ARDS) and death. The tissue receptor for COVID-19 is ACE2, and higher levels of ACE2 can protect against ARDS. Angiotensin receptor blockers and statins upregulate ACE2. Clinical trials are needed to determine whether this drug combination might be used to treat patients with severe COVID-19 infection.

positive: Renin-angiotensin-aldosterone system and COVID-19 infection Summary With the multiplication of COVID-19 cases due to SARS COV2, some concerns about angiotensin-converting enzyme 1 (ACE1) inhibitors (ACEi) and angiotensin II type 1 receptor blockers (ARB) have emerged. Because SARS COV2 utilizes ACE2 (angiotensin-converting enzyme 2) as a membrane receptor to enter target cells, the fear that ACEi or ARB might increase the risk of developing severe or fatal severe acute respiratory syndrome in case of COVID-19 infection emerged. The present article discusses these concerns. ACE2 is a membrane-bound enzyme (carboxypeptidase) that contributes to the inactivation of angiotensin II and therefore physiologically counters angiotensin II effects. Due to different structural structures with ACE1, ACE2 is insensitive to ACEIs. Although ARBs and ACEi have been shown to upregulate ACE2 tissue expression in experimental animals, evidence was not always consistent in human studies. Therefore, to date, the exact impact of bot ARBs and ACEis on COVID-19 infection remains unknown and preliminary results are in favor of a protective role of ACEis and ARBs. Finally, some studies support the hypothesis that elevated ACE2 membrane expression and tissue activity by administration of ARB and/or infusion of soluble ACE2 could confer protective properties against inflammatory tissue damage in COVID-19 infection. In summary, based on the currently available evidence and as recommended by several medical societies, ACEi or ARB should not be discontinued because of concerns with COVID-19 infection, except when the hemodynamic situation is precarious and case-by-case adjustment is required.

positive: Genetic Predisposition to Critical Illness in the Pediatric Intensive Care Unit Much progress has been made in the past decade in the understanding of the genetic contribution to the development of human disease in general, and critical care illness specifically. With the mapping of the human genome and on-going mapping of genetic polymorphisms and haplotypes in humans, the field of critical care is now in prime position to study the impact of genetics on common illnesses that affect children who require critical care, to examine how differences of the host defense response lead to variable outcomes in outwardly appearing similar disease states, and to study how genetic differences in response to therapy will help practitioners tailor therapeutic interventions to an individual child’s genetic composition. While we are still years away from true individualized medicine, we are now closer than ever to understanding why two might children respond to the same environmental insult in vastly different ways.

positive: Organ‐protective effect of angiotensin‐converting enzyme 2 and its effect on the prognosis of COVID‐19 This article reviews the correlation between angiotensin‐converting enzyme 2 (ACE2) and severe risk factors for coronavirus disease 2019 (COVID‐19) and the possible mechanisms. ACE2 is a crucial component of the renin‐angiotensin system (RAS). The classical RAS ACE‐Ang II‐AT1R regulatory axis and the ACE2‐Ang 1‐7‐MasR counter‐regulatory axis play an essential role in maintaining homeostasis in humans. ACE2 is widely distributed in the heart, kidneys, lungs, and testes. ACE2 antagonizes the activation of the classical RAS system and protects against organ damage, protecting against hypertension, diabetes, and cardiovascular disease. Similar to SARS‐CoV, SARS‐CoV‐2 also uses the ACE2 receptor to invade human alveolar epithelial cells. Acute respiratory distress syndrome (ARDS) is a clinical high‐mortality disease, and ACE2 has a protective effect on this type of acute lung injury. Current research shows that the poor prognosis of patients with COVID‐19 is related to factors such as sex (male), age (>60 years), underlying diseases (hypertension, diabetes, and cardiovascular disease), secondary ARDS, and other relevant factors. Because of these protective effects of ACE2 on chronic underlying diseases and ARDS, the development of spike protein‐based vaccine and drugs enhancing ACE2 activity may become one of the most promising approaches for the treatment of COVID‐19 in the future.

positive: The use of Captopril - angiotensin converting enzyme (ACE) inhibitor for cystinuria during COVID-19 pandemic

positive: Is the use of ACE inb/ARBs associated with higher in-hospital mortality in Covid-19 pneumonia patients? INTRODUCTION The present research aimed to determine the relation between the use of angiotensin-converting enzyme inhibitors (ACE inh) and angiotensinogen receptor blockers (ARBs) and in-hospital mortality of hypertensive patients diagnosed with Covid-19 pneumonia. MATERIAL AND METHOD In this retrospective study, we included 113 consecutive hypertensive patients admitted due to Covid-19 infection. In all patients, Covid-19 infection was confirmed with using reverse-transcription polymerase chain reaction. All patients were on ACE inh/ARBs or other antihypertensive therapy unless no contraindication was present. The primary outcome of the study was the in-hospital all-cause mortality. RESULTS In total, 113 hypertensive Covid-19 patients were included, of them 74 patients were using ACE inh/ARBs. During in-hospital follow up, 30.9% [n = 35 patients] of patients died. The frequency of admission to the ICU and endotracheal intubation were significantly higher in patients using ACE inh/ARBs. In a multivariable analysis, the use of ACE inh/ARBs was an independent predictor of in-hospital mortality (OR: 3.66; 95%CI: 1.11-18.18; p= .032). Kaplan-Meir curve analysis displayed that patients on ACE inh/ARBs therapy had higher incidence of in-hospital death than those who were not. CONCLUSION The present study has found that the use of ACE inh/ARBs therapy might be associated with an increased in-hospital mortality in patients who were diagnosed with Covid-19 pneumonia. It is likely that ACE inh/ARBs therapy might not be beneficial in the subgroup of hypertensive Covid-19 patients despite the fact that there might be the possibility of some unmeasured residual confounders to affect the results of the study.

positive: Pharmacotherapy in COVID-19; A narrative review for emergency providers INTRODUCTION: The COVID-19 pandemic has been particularly challenging due to a lack of established therapies and treatment guidelines. With the rapid transmission of disease, even the off-label use of available therapies has been impeded by limited availability. Several antivirals, antimalarials, and biologics are being considered for treatment at this time. The purpose of this literature review is to synthesize the available information regarding treatment options for COVID-19 and serve as a resource for health care professionals. OBJECTIVES: This narrative review was conducted to summarize the effectiveness of current therapy options for COVID-19 and address the controversial use of non-steroidal anti-inflammatory drugs (NSAIDs), angiotensin converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs). PubMed and SCOPUS were queried using a combination of the keywords “COVID 19,” “SARS-CoV-2,” and “treatment.” All types of studies were evaluated including systematic reviews, case-studies, and clinical guidelines. DISCUSSION: There are currently no therapeutic drugs available that are directly active against SARS-CoV-2; however, several antivirals (remdesivir, favipiravir) and antimalarials (chloroquine, hydroxychloroquine) have emerged as potential therapies. Current guidelines recommend combination treatment with hydroxychloroquine/azithromycin or chloroquine, if hydroxychloroquine is unavailable, in patients with moderate disease, although these recommendations are based on limited evidence. Remdesivir and convalescent plasma may be considered in critical patients with respiratory failure; however, access to these therapies may be limited. Interleukin-6 (IL-6) antagonists may be used in patients who develop evidence of cytokine release syndrome (CRS). Glucocorticoids should be avoided unless there is evidence of refractory septic shock, acute respiratory distress syndrome (ARDS), or another compelling indication for their use. ACE inhibitors and ARBs should not be discontinued at this time and ibuprofen may be used for fever. CONCLUSION: There are several ongoing clinical trials that are testing the efficacy of single and combination treatments with the drugs mentioned in this review and new agents are under development. Until the results of these trials become available, we must use the best available evidence for the prevention and treatment of COVID-19. Additionally, we can learn from the experiences of healthcare providers around the world to combat this pandemic.

positive: Reduced expression of COVID-19 host receptor, ACE2 is associated with small bowel inflammation, more severe disease, and response to anti-TNF therapy in Crohn’s disease Angiotensin-Converting Enzyme 2 (ACE2) has been identified as the host receptor for SARS-coronavirus 2 (SARS-CoV-2) which has infected millions world-wide and likely caused hundreds of thousands of deaths. Utilizing transcriptomic data from four cohorts taken from Crohn’s disease (CD) and non-inflammatory bowel disease (IBD) subjects, we observed evidence of increased ACE2 mRNA in ileum with demographic features that have been associated with poor outcomes in COVID-19 including age and raised BMI. ACE2 was downregulated in CD compared to controls in independent cohorts. Within CD, ACE2 expression was reduced in inflamed ileal tissue and also remarkably, from un-involved tissue in patients with a worse prognosis in both adult and pediatric cohorts. In active CD, small bowel ACE2 expression was restored by anti-TNF therapy particularly in anti-TNF responders. Collectively our data suggest that ACE2 downregulation is associated with inflammation and worse outcomes in CD.

positive: Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers: A Promising Medication for Chronic Obstructive Pulmonary Disease? Chronic obstructive pulmonary disease (COPD) is a complex disorder that primarily affects the lungs and is characterized not only by local pulmonary, but also by systemic inflammation which promotes the development of extrapulmonary and cardiovascular co-morbidities. Angiotensin converting enzyme (ACE) inhibitors and ARBs (angiotensin receptor blockers) are widely used drugs in the treatment of cardiovascular diseases, with growing evidence suggesting potential benefits in COPD patients. The purpose of this review is to describe the correlation of renin-angiotensin system (RAS) with COPD pathophysiology and to present the latest data regarding the potential role of RAS blockers in COPD.

positive: A systematic review to evaluate the clinical outcomes in COVID -19 patients on angiotensin converting enzyme inhibitors or angiotensin receptor blockers Introduction: Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) share their target receptor site with the SARS-CoV-2 virus, that may cause ACE2 receptor upregulation which raised concerns regarding ACEI and ARB use in COVID-19 patients. However, many medical professional societies recommended their continued use given the paucity of clinical evidence but there is need for an updated systematic review of latest clinical studies. Methods: A search was conducted on PubMed, Google Scholar, EMBASE and various preprint servers for studies comparing clinical outcomes and mortality in COVID-19 patients on ACEI and/or ARB. Results: A total of eight studies were included in the review. There were conflicting findings reported in several studies as Meng J. et al, Liu Y. et al and Feng Y. reported that patients on ACE inhibitors/ARB had lower rates of severe outcomes whereas Richardson S. et al reported higher rates of invasive ventilation and intensive care unit (ICU) admissions in patients on ACE inhibitors/ARB as compared to non-users. However, Zhang P. et al found slightly higher rates of ICU admissions in patients on ACE inhibitors and ARB as compared to non-users. Similarly, there were conflicting results in the rate of mortality reported by the various clinical studies as well. Meng J. et al, Li J. et al and Zhang P. et al reported lower rates of mortality in ACE inhibitors/ARB users versus non-users whereas Guo J. et al reported higher rates of mortality in patients on ACE inhibitors/ARB as compared to non-users. Additionally, a large study conducted in New York by Richardson S. et al raised concerns with worse mortality outcomes in patients on ACEI/ ARB. Conclusion: It is concluded that ACEI and ARB should be continued in COVID-19 patients, albeit while exercising caution until larger clinical studies and randomized controlled trials confirm their safety. Additionally, the individual patient factors like ACE2 polymorphisms which might confer higher risk of adverse outcomes need to be evaluated further.

positive: Predictors of severe or lethal COVID-19, including Angiotensin Converting Enzyme inhibitors and Angiotensin II Receptor Blockers, in a sample of infected Italian citizens AIMS: This retrospective case-control study was aimed at identifying potential independent predictors of severe/lethal COVID-19, including the treatment with Angiotensin-Converting Enzyme inhibitors (ACEi) and/or Angiotensin II Receptor Blockers (ARBs). METHODS AND RESULTS: All adults with SARS-CoV-2 infection in two Italian provinces were followed for a median of 24 days. ARBs and/or ACEi treatments, and hypertension, diabetes, cancer, COPD, renal and major cardiovascular diseases (CVD) were extracted from clinical charts and electronic health records, up to two years before infection. The sample consisted of 1603 subjects (mean age 58.0y; 47.3% males): 454 (28.3%) had severe symptoms, 192 (12.0%) very severe or lethal disease (154 deaths; mean age 79.3 years; 70.8% hypertensive, 42.2% with CVD). The youngest deceased person aged 44 years. Among hypertensive subjects (n = 543), the proportion of those treated with ARBs or ACEi were 88.4%, 78.7% and 80.6% among patients with mild, severe and very severe/lethal disease, respectively. At multivariate analysis, no association was observed between therapy and disease severity (Adjusted OR for very severe/lethal COVID-19: 0.87; 95% CI: 0.50–1.49). Significant predictors of severe disease were older age (with AORs largely increasing after 70 years of age), male gender (AOR: 1.76; 1.40–2.23), diabetes (AOR: 1.52; 1.05–2.18), CVD (AOR: 1.88; 1.32–2.70) and COPD (AOR: 1.88; 1.11–3.20). Only gender, age and diabetes also predicted very severe/lethal disease. CONCLUSION: No association was found between COVID-19 severity and treatment with ARBs and/or ACEi, supporting the recommendation to continue medication for all patients unless otherwise advised by their physicians.

positive: The Effect of Coronavirus Disease 2019 on Cardiovascular Diseases. Coronavirus disease 2019 (COVID-19) is a global pandemic affecting the world, seen in more than 1,300,000 patients. COVID-19 acts through the angiotensin-converting enzyme 2 (ACE2) receptor. Cardiovascular comorbidities are more common with COVID-19, and nearly 10% of cases develop myocarditis (22% of critical patients). Further research is needed to continue or discontinue ACE inhibitors and angiotensin receptor blockers, which are essential in hypertension and heart failure in COVID-19. Intensive research is promising for the treatment and prevention of COVID-19.

positive: Alpha 1 Antitrypsin is an Inhibitor of the SARS-CoV2–Priming Protease TMPRSS2 The transmembrane serine protease TMPRSS2 is indispensable for S protein priming of the MERS, SARS-CoV, and SARS-CoV2 coronaviruses, a process that is necessary for entry of the virus into host cells. Therefore, inhibiting TMPRSS2 holds promise as an approach toward preventing transmission of coronaviruses. Herein, we developed an in vitro system to measure TMPRSS2 activity and tested the inhibition of TMPRSS2 by several synthetic and natural protease inhibitors. Camostat mesylate and bromhexine hydrochloride (BHH) inhibited TMPRSS2 proteolytic function. In addition, we identified the small molecule 4-(2-aminomethyl)benzenesulfonyl fluoride (AEBSF) and the human, anti-inflammatory protein alpha 1 antitrypsin (A1AT) as inhibitors of TMPRSS2. AEBSF and A1AT inhibited TMPRSS2 activity in a dose-dependent manner. AEBSF and A1AT inhibited TMPRSS2 in the same range of concentrations (100-0.1 μM). We suggest that treatment with these inhibitors, particularly A1AT, which is an FDA-approved drug, might be effective in limiting SARS-CoV and SARS-CoV2 transmissibility and as a COVID-19 treatment.

positive: Response by Cohen et al to Letter Regarding Article, "Association of Inpatient Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Mortality Among Patients With Hypertension Hospitalized With COVID-19"

positive: Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and coronavirus

positive: Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are not associated with severe COVID-19 infection in a multi-site UK acute hospital trust AIMS: The SARS-CoV-2 virus binds to the angiotensin-converting enzyme 2 (ACE2) receptor for cell entry. It has been suggested that angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB), which are commonly used in patients with hypertension or diabetes and may raise tissue ACE2 levels, could increase the risk of severe COVID-19 infection. METHODS AND RESULTS: We evaluated this hypothesis in a consecutive cohort of 1200 acute inpatients with COVID-19 at two hospitals with a multi-ethnic catchment population in London (UK). The mean age was 68 ± 17 years (57% male) and 74% of patients had at least one comorbidity. Overall, 415 patients (34.6%) reached the primary endpoint of death or transfer to a critical care unit for organ support within 21 days of symptom onset. A total of 399 patients (33.3%) were taking ACEi or ARB. Patients on ACEi/ARB were significantly older and had more comorbidities. The odds ratio for the primary endpoint in patients on ACEi and ARB, after adjustment for age, sex and co-morbidities, was 0.63 (95% confidence interval 0.47-0.84, P < 0.01). CONCLUSIONS: There was no evidence for increased severity of COVID-19 in hospitalised patients on chronic treatment with ACEi or ARB. A trend towards a beneficial effect of ACEi/ARB requires further evaluation in larger meta-analyses and randomised clinical trials.

positive: B38-CAP is a bacteria-derived ACE2-like enzyme that suppresses hypertension and cardiac dysfunction Angiotensin-converting enzyme 2 (ACE2) is critically involved in cardiovascular physiology and pathology, and is currently clinically evaluated to treat acute lung failure. Here we show that the B38-CAP, a carboxypeptidase derived from Paenibacillus sp. B38, is an ACE2-like enzyme to decrease angiotensin II levels in mice. In protein 3D structure analysis, B38-CAP homolog shares structural similarity to mammalian ACE2 with low sequence identity. In vitro, recombinant B38-CAP protein catalyzed the conversion of angiotensin II to angiotensin 1–7, as well as other known ACE2 target peptides. Treatment with B38-CAP suppressed angiotensin II-induced hypertension, cardiac hypertrophy, and fibrosis in mice. Moreover, B38-CAP inhibited pressure overload-induced pathological hypertrophy, myocardial fibrosis, and cardiac dysfunction in mice. Our data identify the bacterial B38-CAP as an ACE2-like carboxypeptidase, indicating that evolution has shaped a bacterial carboxypeptidase to a human ACE2-like enzyme. Bacterial engineering could be utilized to design improved protein drugs for hypertension and heart failure.

positive: ACE‐inhibitors and Angiotensin‐2 Receptor Blockers are not associated with severe SARS‐COVID19 infection in a multi‐site UK acute Hospital Trust AIMS: The SARS‐Cov2 virus binds to the ACE2 receptor for cell entry. It has been suggested that ACE‐inhibitors (ACEi) and Angiotensin‐2 Blockers (ARB), which are commonly used in patients with hypertension or diabetes and may raise tissue ACE2 levels, could increase the risk of severe COVID19 infection. METHODS AND RESULTS: We evaluated this hypothesis in a consecutive cohort of 1200 acute inpatients with COVID19 at two hospitals with a multi‐ethnic catchment population in London (UK). The mean age was 68 ± 17 years (57% male) and 74% of patients had at least 1 comorbidity. 415 patients (34.6%) reached the primary endpoint of death or transfer to a critical care unit for organ support within 21‐days of symptom onset. 399 patients (33.3%) were taking ACEi or ARB. Patients on ACEi/ARB were significantly older and had more comorbidities. The odds ratio (OR) for the primary endpoint in patients on ACEi and ARB, after adjustment for age, sex and co‐morbidities, was 0.63 (CI 0.47–0.84, p < 0.01). CONCLUSIONS: There was no evidence for increased severity of COVID19 disease in hospitalised patients on chronic treatment with ACEi or ARB. A trend towards a beneficial effect of ACEi/ARB requires further evaluation in larger meta‐analyses and randomised clinical trials. This article is protected by copyright. All rights reserved.

positive: SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells The SARS-CoV-2 pandemic affecting the human respiratory system severely challenges public health and urgently demands for increasing our understanding of COVID-19 pathogenesis, especially host factors facilitating virus infection and replication. SARS-CoV-2 was reported to enter cells via binding to ACE2, followed by its priming by TMPRSS2. Here, we investigate ACE2 and TMPRSS2 expression levels and their distribution across cell types in lung tissue (twelve donors, 39,778 cells) and in cells derived from subsegmental bronchial branches (four donors, 17,521 cells) by single nuclei and single cell RNA sequencing, respectively. While TMPRSS2 is strongly expressed in both tissues, in the subsegmental bronchial branches ACE2 is predominantly expressed in a transient secretory cell type. Interestingly, these transiently differentiating cells show an enrichment for pathways related to RHO GTPase function and viral processes suggesting increased vulnerability for SARS-CoV-2 infection. Our data provide a rich resource for future investigations of COVID-19 infection and pathogenesis.

positive: Angiotension-converting enzyme inhibitors and angiotensin-receptor blockers are not associated with increased risk of SARS-CoV-2 infection In a large Israeli dataset of 14 520 individuals tested for SARS-CoV-2, angiotension-converting enzyme inhibitors and angiotensin-receptor blockers were not found to be associated with increased SARS-CoV-2 infection after adjusting for major confounders. Patients on these medications should not stop their medication prophylactically.

positive: Association of Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Use With COVID-19 Diagnosis and Mortality Importance: It has been hypothesized that angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) may make patients more susceptible to coronavirus disease 2019 (COVID-19) and to worse outcomes through upregulation of the functional receptor of the virus, angiotensin-converting enzyme 2. Objective: To examine whether use of ACEI/ARBs was associated with COVID-19 diagnosis and worse outcomes in patients with COVID-19. Design, Setting, and Participants: To examine outcomes among patients with COVID-19, a retrospective cohort study using data from Danish national administrative registries was conducted. Patients with COVID-19 from February 22 to May 4, 2020, were identified using ICD-10 codes and followed up from day of diagnosis to outcome or end of study period (May 4, 2020). To examine susceptibility to COVID-19, a Cox regression model with a nested case-control framework was used to examine the association between use of ACEI/ARBs vs other antihypertensive drugs and the incidence rate of a COVID-19 diagnosis in a cohort of patients with hypertension from February 1 to May 4, 2020. Exposures: ACEI/ARB use was defined as prescription fillings 6 months prior to the index date. Main Outcomes and Measures: In the retrospective cohort study, the primary outcome was death, and a secondary outcome was a composite outcome of death or severe COVID-19. In the nested case-control susceptibility analysis, the outcome was COVID-19 diagnosis. Results: In the retrospective cohort study, 4480 patients with COVID-19 were included (median age, 54.7 years [interquartile range, 40.9-72.0]; 47.9% men). There were 895 users (20.0%) of ACEI/ARBs and 3585 nonusers (80.0%). In the ACEI/ARB group, 18.1% died within 30 days vs 7.3% in the nonuser group, but this association was not significant after adjustment for age, sex, and medical history (adjusted hazard ratio [HR], 0.83 [95% CI, 0.67-1.03]). Death or severe COVID-19 occurred in 31.9% of ACEI/ARB users vs 14.2% of nonusers by 30 days (adjusted HR, 1.04 [95% CI, 0.89-1.23]). In the nested case-control analysis of COVID-19 susceptibility, 571 patients with COVID-19 and prior hypertension (median age, 73.9 years; 54.3% men) were compared with 5710 age- and sex-matched controls with prior hypertension but not COVID-19. Among those with COVID-19, 86.5% used ACEI/ARBs vs 85.4% of controls; ACEI/ARB use compared with other antihypertensive drugs was not significantly associated with higher incidence of COVID-19 (adjusted HR, 1.05 [95% CI, 0.80-1.36]). Conclusions and Relevance: Prior use of ACEI/ARBs was not significantly associated with COVID-19 diagnosis among patients with hypertension or with mortality or severe disease among patients diagnosed as having COVID-19. These findings do not support discontinuation of ACEI/ARB medications that are clinically indicated in the context of the COVID-19 pandemic.

positive: Modelling and docking of Indian SARS-CoV-2 spike protein 1 with ACE2: implications for co-morbidity and therapeutic intervention Presently, India bears amongst the highest burden of non-communicable diseases such as diabetes mellitus (DM), hypertension (HT), and cardio vascular disease (CVD) and thus represents a vulnerable target to the SARS-CoV-2/COVID-19 pandemic. Involvement of the angiotensin converting enzyme 2 (ACE2) in susceptibility to infection and pathogenesis by SARS-CoV-2 is currently an actively pursued research area. An increased susceptibility to infection in individuals with DM, HT and CVD together with higher levels of circulating ACE2 in these settings presents a scenario where interaction with soluble ACE2 may result in disseminated virus-receptor complexes that could enhance virus acquisition and pathogenesis. Thus, understanding the SARS-CoV-2 receptor binding domain-ACE2 interaction, both membrane bound and in the cell free context may contribute to elucidating the role of co-morbidities in increased susceptibility to infection and pathogenesis. Both Azithromycin and Hydroxychloroquine (HCQ) have shown efficacy in mitigating viral carriage in infected individuals. Furthermore, each of these compounds generate active metabolites which in turn may also modulate virus-receptor interaction and thus influence clinical outcomes. In this study, we model the structural interaction of S1 with both full-length and soluble ACE2. Additionally, therapeutic drugs and their active metabolites were docked with soluble ACE2 protein. Our results show that S1 from either of the reported Indian sequences can bind both full-length and soluble ACE2, albeit with varying affinity that can be attributed to a reported substitution in the RBD. Furthermore, both Azythromycin and HCQ together with their active metabolites can allosterically affect, to a range of extents, binding of S1 to ACE2.

positive: SARS-CoV-2 perturbs the renin-angiotensin system and energy metabolism The COVID-19 pandemic, caused by the novel coronavirus, SARS-CoV-2, is threating our health systems and daily lives and is responsible for causing substantial morbidity and mortality. In particular, aged individuals and individuals with comorbidities, including obesity, diabetes mellitus, and hypertension, have significantly higher risks of hospitalization and death than normal individuals. The renin-angiotensin system (RAS) plays a pivotal role in the pathogenesis of diabetes mellitus, obesity, and hypertension. Angiotensin-converting enzyme 2 (ACE2), belonging to the RAS family, has received much attention during this COVID-19 pandemic, owing to the fact that SARS-CoV-2 uses ACE2 as a receptor for cellular entry. Additionally, the RAS greatly affects energy metabolism in certain pathological conditions, including cardiac failure, diabetes mellitus, and viral infections. This article discusses the potential mechanisms by which SARS-CoV-2 modulates the RAS and energy metabolism in individuals with obesity and diabetes mellitus. The article aims to highlight the appropriate strategies for combating the COVID-19 pandemic in the clinical setting and emphasize on the areas that require further investigation in relation to COVID-19 infections in patients with obesity and diabetes mellitus from the viewpoint of endocrinology and metabolism.

positive: Renin-angiotensin system inhibitors in COVID-19 Concerns have been raised about the potential for renin-angiotensin system (RAS) inhibitors to upregulate expression of angiotensin-converting enzyme 2 (ACE2) and thus increase susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry. Currently, there is no evidence that even if RAS inhibitors increase expression and activity of ACE2, that they would increase the risk of SARS-CoV-2 infection by facilitating greater viral entry or worsen outcomes in patients with COVID-19. At this time, there is no clinical evidence to suggest that treatment with RAS inhibitors should be discontinued in stable patients with COVID-19. In hospitalized patients with severe COVID-19, decisions about these medications should be based on clinical condition, including hemodynamic status and renal function.

positive: Clinical characteristics associated with COVID-19 severity in California Given the rapidly progressing COVID-19 pandemic, this report on a US cohort of 54 COVID-19 patients from Stanford Hospital and data regarding risk factors for severe disease obtained at initial clinical presentation is of high importance and is immediately clinically relevant. We identified low presenting oxygen saturation as predictive of severe disease outcomes, such as diagnosis of pneumonia, acute respiratory distress syndrome (ARDS), and admission to the ICU, and also replicated data from China suggesting a link between hypertension and disease severity. Clinicians will benefit by tools to rapidly risk stratify patients at presentation by likelihood of progression to severe disease.

positive: ACE2, a new regulator of the renin–angiotensin system Abstract Angiotensin-converting enzyme (ACE) is a zinc metalloproteinase and a key regulator of the renin–angiotensin system (RAS). ACE2 is a newly described enzyme identified in rodents and humans with a more restricted distribution than ACE, and is found mainly in heart and kidney. ACE2 cleaves a single residue from angiotensin I (Ang I) to generate Ang 1–9, and degrades Ang II, the main effector of the RAS, to the vasodilator Ang 1–7. The importance of ACE2 in normal physiology and pathophysiological states is largely unknown. ACE2 might act in a counter-regulatory manner to ACE, modulating the balance between vasoconstrictors and vasodilators within the heart and kidney, and playing a significant role in regulating cardiovascular and renal function.

positive: COVID-19 (Novel Coronavirus 2019) - recent trends. The World Health Organization (WHO) has issued a warning that, although the 2019 novel coronavirus (COVID-19) from Wuhan City (China), is not pandemic, it should be contained to prevent the global spread. The COVID-19 virus was known earlier as 2019-nCoV. As of 12 February 2020, WHO reported 45,171 cases and 1115 deaths related to COVID-19. COVID-19 is similar to Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) virus in its pathogenicity, clinical spectrum, and epidemiology. Comparison of the genome sequences of COVID-19, SARS-CoV, and Middle East Respiratory Syndrome coronavirus (MERS-CoV) showed that COVID-19 has a better sequence identity with SARS-CoV compared to MERS CoV. However, the amino acid sequence of COVID-19 differs from other coronaviruses specifically in the regions of 1ab polyprotein and surface glycoprotein or S-protein. Although several animals have been speculated to be a reservoir for COVID-19, no animal reservoir has been already confirmed. COVID-19 causes COVID-19 disease that has similar symptoms as SARS-CoV. Studies suggest that the human receptor for COVID-19 may be angiotensin-converting enzyme 2 (ACE2) receptor similar to that of SARS-CoV. The nucleocapsid (N) protein of COVID-19 has nearly 90% amino acid sequence identity with SARS-CoV. The N protein antibodies of SARS-CoV may cross react with COVID-19 but may not provide cross-immunity. In a similar fashion to SARS-CoV, the N protein of COVID-19 may play an important role in suppressing the RNA interference (RNAi) to overcome the host defense. This mini-review aims at investigating the most recent trend of COVID-19.

positive: The use of renin angiotensin system inhibitor on mortality in patients with coronavirus disease 2019 (COVID-19): A systematic review and meta-analysis BACKGROUND: and Aims; To investigate the association between use of angiotensin-converting enzyme inhibitor (ACEI)/angiotensin-receptor blocker (ARB) and outcomes of hypertensive COVID-19 patients, a systematic review and meta-analysis were performed. METHODS: We systematically searched PubMed, EuropePMC, ProQuest, and Cochrane Central Databases using the terms “(COVID-19 OR SARS-CoV-2) AND (angiotensin converting enzyme OR angiotensin receptor blocker)”. The primary and second outcomes were mortality (non-survivor) and severe COVID-19, respectively. RESULTS: Totally, 7410 patients were included from 15 studies. Pooled analysis showed that the use of ACEI/ARB was not associated with mortality (OR 0.73 [0.38, 1.40], p = 0.34; I(2): 81%) and severity (OR 1.03 [0.73, 1.45], p = 0.87; I(2): 65%). Pooled adjusted OR showed no risk/benefit associated with ACEI/ARB use in terms of mortality (OR 0.83 [0.54, 1.27], p = 0.38; I(2): 0%). Subgroup analysis showed that the use of ARB was associated with reduced mortality (OR 0.51 [0.29, 0.90], p = 0.02; I(2): 22%) but not ACEI subgroup (OR 0.68 [0.39, 1.17], p = 0.16; I(2): 0%). Meta-regression showed that the association between ACEI/ARB use and mortality in patients with COVID-19 do not varies by gender (p = 0.104). GRADE showed a very low certainty of evidence for effect of ACEI/ARB on mortality and severity. The certainty of evidence was very low for both ACEI and ARB subgroups. CONCLUSION: Administration of a renin angiotensin system (RAS) inhibitor, was not associated with increased mortality or severity of COVID-19 in patients with hypertension. Specifically, ARB and not ACEI use, was associated with lower mortality.

positive: Angiotensin-converting enzyme inhibitors, angiotensin II type 1 receptor blockers and risk of COVID 19: information from Bartter's and Gitelman's syndromes patients

positive: ACE inhibitors and COVID‐19: We don't know yet

positive: Renin-Angiotensin System Blockers and the COVID-19 Pandemic: At Present There Is No Evidence to Abandon Renin-Angiotensin System Blockers During the spread of the severe acute respiratory syndrome coronavirus-2, some reports of data still emerging and in need of full analysis indicate that certain groups of patients are at risk of COVID-19. This includes patients with hypertension, heart disease, diabetes mellitus, and clearly the elderly. Many of those patients are treated with renin-angiotensin system blockers. Because the ACE2 (angiotensin-converting enzyme 2) protein is the receptor that facilitates coronavirus entry into cells, the notion has been popularized that treatment with renin-angiotensin system blockers might increase the risk of developing a severe and fatal severe acute respiratory syndrome coronavirus-2 infection. The present article discusses this concept. ACE2 in its full-length form is a membrane-bound enzyme, whereas its shorter (soluble) form circulates in blood at very low levels. As a mono-carboxypeptidase, ACE2 contributes to the degradation of several substrates including angiotensins I and II. ACE (angiotensin-converting enzyme) inhibitors do not inhibit ACE2 because ACE and ACE2 are different enzymes. Although angiotensin II type 1 receptor blockers have been shown to upregulate ACE2 in experimental animals, the evidence is not always consistent and differs among the diverse angiotensin II type 1 receptor blockers and differing organs. Moreover, there are no data to support the notion that ACE inhibitor or angiotensin II type 1 receptor blocker administration facilitates coronavirus entry by increasing ACE2 expression in either animals or humans. Indeed, animal data support elevated ACE2 expression as conferring potential protective pulmonary and cardiovascular effects. In summary, based on the currently available evidence, treatment with renin-angiotensin system blockers should not be discontinued because of concerns with coronavirus infection.

positive: COVID-19 pandemic: an overview of epidemiology, parthenogenesis, diagnostics and potential vaccines and therapeutics At the time of writing this review, severe acute respiratory coronavirus syndrome-2 (SARS-CoV-2) has infected more than 2,355,853 patients and resulted in more than 164,656 deaths worldwide (as of 20 April 2020). This review highlights the preventive measures, available clinical therapies and the potential of vaccine development against SARS-CoV-2 by taking into consideration the strong genetic similarities of the 2003 epidemic SARS-CoV. Recent studies are investigating the repurposing of US FDA-approved drugs as there is no available vaccine yet with many attempts under clinical evaluation. Several antivirals, antimalarials and immunomodulators that have shown activity against SARS-CoV and Middle East coronavirus respiratory syndromes are being evaluated. In particular, hydroxychloroquine, remdesivir, favipiravir, arbidol, tocilizumab and bevacizumab have shown promising results. The main aim of this review is to provide an overview of this pandemic and where we currently stand.

positive: Perspectives on monoclonal antibody therapy as potential therapeutic intervention for Coronavirus disease-19 (COVID-19). Last decade witnessed the outbreak of many life-threatening human pathogens including Nipah, Ebola, Chikungunya, Zika, Middle East respiratory syndrome coronavirus (MERS-CoV), Severe Acute respiratory syndrome coronavirus (SARS-CoV) and more recently novel coronavirus (2019-nCoV or SARS-CoV-2). The disease condition associated with novel coronavirus, referred to as Coronavirus disease (COVID-19). The emergence of novel coronavirus in 2019 in Wuhan, China marked the third highly pathogenic coronavirus infecting humans in the 21st century. The continuing emergence of coronaviruses at regular intervals poses a significant threat to human health and economy. Ironically, even after a decade of research on coronavirus, still there are no licensed vaccines or therapeutic agents to treat coronavirus infection which highlights an urgent need to develop effective vaccines or post-exposure prophylaxis to prevent future epidemics. Several clinical, genetic and epidemiological features of COVID-19 resemble SARS-CoV infection. Hence, the research advancements on SARS-CoV treatment might help scientific community in quick understanding of this virus pathogenesis and develop effective therapeutic/prophylactic agents to treat and prevent this infection. Monoclonal antibodies represent the major class of biotherapeutics for passive immunotherapy to fight against viral infection. The therapeutic potential of monoclonal antibodies has been well recognized in the treatment of many diseases. Here, we summarize the potential monoclonal antibody based therapeutic intervention for COVID-19 by considering the existing knowledge on the neutralizing monoclonal antibodies against similar coronaviruses SARS-CoV and MERS-CoV. Further research on COVID-19 pathogenesis could identify appropriate therapeutic targets to develop specific anti-virals against this newly emerging pathogen.

positive: SARS Coronavirus Redux As an atypical pneumonia began to appear in December 2019, Zhou et al . worked with remarkable speed to identify the associated virus, determine its relationship to animal viruses, and evaluate factors conferring infection susceptibility and resistance. These foundational results are being advanced to control the current worldwide human coronavirus epidemic.

positive: The modelling of COVID19 pathways sheds light on mechanisms, opportunities and on controversial interpretations of medical treatments. v2 The new coronavirus (2019-nCoV or SARS-CoV2), inducing the current pandemic disease (COVID-19) and causing pneumoniae in humans, is dramatically increasing in epidemic scale since its first appearance in Wuhan, China, in December 2019. The first infection from epidemic coronaviruses in 2003 fostered the spread of an overwhelming amount of related scientific efforts. The manifold aspects that have been raised, as well as their redundancy offer precious information that has been underexploited and needs to be critically re-evaluated, appropriately used and offered to the whole community, from scientists, to medical doctors, stakeholders and common people. These efforts will favour a holistic view on the comprehension, prevention and development of strategies (pharmacological, clinical etc) as well as common intervention against the new coronavirus spreading. Here we describe a model that emerged from our analysis that was focused on the Renin Angiotensin System (RAS) and the possible routes linking it to the viral infection. because the infection is mediated by the viral receptor on human cell membranes Angiotensin Converting Enzyme (ACE2), which is a key component in RAS signalling. The model depicts the main pathways determining the disease and the molecular framework for its establishment, and can help to shed light on mechanisms involved in the infection. It promptly gives an answer to some of the controversial, and still open, issues concerning predisposing conditions and medical treatments that protect from or favour the severity of the disease (such as the use of ACE inhibitors or ARBs/sartans), or to the sex related biases in the affected population. The model highlights novel opportunities for further investigations, diagnosis and appropriate intervention to understand and fight COVID19.

positive: Genetic Variability of Human Angiotensin-Converting Enzyme 2 (hACE2) Among Various Ethnic Populations There appears to be large regional variations for susceptibility, severity and mortality for Covid-19 infections. We set out to examine genetic differences in the human angiotensin-converting enzyme 2 (hACE2) gene, as its receptor serves as a cellular entry for SARS- CoV-2. By comparing 56,885 Non-Finnish European and 9,197 East Asians (including 1,909 Koreans) four missense mutations were noted in the hACE2 gene. Molecular dynamic demonstrated that two of these variants (K26R and I468V) may affect binding characteristics between S protein of the virus and hACE2 receptor. We also examined hACE2 gene expression in eight global populations from the HapMap3 and noted marginal differences in expression for some populations as compared to the Chinese population. However, for both of our studies, the magnitude of the difference was small and the significance is not clear in the absence of further in vitro and functional studies.

positive: Hypertension prevalence in human coronavirus disease: the role of ACE system in infection spread and severity The prevalence of hypertension is high in patients affected by coronavirus disease 2019 (COVID-2019) and it appears to be related to an increased risk of mortality, as shown in many epidemiological studies. The angiotensin-converting enzyme (ACE) system is not uniformly expressed in all of the human races, and current differences could explain some of the geographical discrepancies in infection around the world. Furthermore, animal studies have shown that the ACE2 receptor is a potential pathway for host infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. As two-thirds of hypertensive patients take ACE inhibitors/angiotensin receptor blockers, several concerns have been raised about the detrimental role of current antihypertensive drugs in COVID-19. This report summarizes the recent evidence for and against the administration of ACE blockade in the COVID-19 era.

positive: Myocyte Specific Upregulation of ACE2 in Cardiovascular Disease: Implications for SARS-CoV-2 mediated myocarditis Coronavirus disease 2019 (COVID-19) is a global pandemic caused by a novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). SARS-CoV-2 infection of host cells occurs predominantly via binding of the viral surface spike protein to the human angiotensin-converting enzyme 2 (ACE2) receptor. Hypertension and pre-existing cardiovascular disease are risk factors for morbidity from COVID-19, and it remains uncertain whether the use of angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) impacts infection and disease. Here, we aim to shed light on this question by assessing ACE2 expression in normal and diseased human myocardial samples profiled by bulk and single nucleus RNA-seq.

positive: Two hits to the renin‐angiotensin system may play a key role in severe COVID‐19 The spike glycoprotein on the virion surface docking onto the angiotensin‐converting enzyme (ACE) 2 dimer is an essential step in the process of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection in human cells—involves downregulation of ACE2 expression with systemic renin‐angiotensin system (RAS) imbalance and promotion of multi‐organ damage. In general, the RAS induces vasoconstriction, hypertension, inflammation, fibrosis, and proliferation via the ACE/Ang II/Ang II type 1 receptor (AT1R) axis and induces the opposite effects via the ACE2/Ang (1‐7)/Mas axis. The RAS may be activated by chronic inflammation in hypertension, diabetes, obesity, and cancer. SARS‐CoV‐2 induces the ACE2 internalization and shedding, leading to the inactivation of the ACE2/Ang (1‐7)/Mas axis. Therefore, we hypothesize that two hits to the RAS drives COVID‐19 progression. In brief, the first hit originates from chronic inflammation activating the ACE/Ang II/AT1R axis, and the second originates from the COVID‐19 infection inactivating the ACE2/Ang (1‐7)/Mas axis. Moreover, the two hits to the RAS may be the primary reason for increased mortality in patients with COVID‐19 who have comorbidities and may serve as a therapeutic target for COVID‐19 treatment.

positive: Modeling the molecular impact of the SARS-CoV-2 infection on the renin-angiotensin system Infection by the SARS-CoV-2 virus is mediated by the binding of its spike protein to the membrane-bound angiotensin converting enzyme 2 (ACE2), which plays a pivotal role in the renin-angiotensin system (RAS). The understanding of RAS dysregulation due to this viral infection is of fundamental importance to better understand the pathogenic mechanisms and risk factors of the coronavirus disease COVID-19, and to design effective therapeutic strategies. To address this issue, we built a mathematical model of RAS based on data about protein and peptide concentrations in normotensive and hypertensive individuals. We first tested our model on clinical data on the action of antihypertensive RAS-blocking drugs in control individuals. Despite the simplicity of our model, it reproduces very well, without any fitting of additional parameters, the impact of a series of drugs, i.e. angiotensin-converting enzyme inhibitors (ACE-I), direct renin inhibitors (DRI) and angiotensin II receptor blockers (ARB). We applied our model to analyze the impact of SARS-CoV-2 infection on the RAS system, which we modeled through a downregulation of ACE2 related to viral load. Moreover, we analyzed the effect of RAS-blockers and other RAS-targeting drugs, i.e. human recombinant ACE2 (rhACE2) and angiotensin 1-7 peptide (Ang1-7), on the RAS system of normotensive and hypertensive COVID-19 patients. We found that while ACE-I, DRI, rhACE2 and Ang1-7 tend to improve the clinical outcomes in a tension-dependent manner, the use of ARB appears to worsen it. The mathematical model that we developed offers the interesting possibility of testing in silico the RAS dysregulation upon SARS-CoV-2 infection and of predicting how risk factors as well as different drugs, alone or in combination, impact on RAS and disease severity.

positive: No association of Angiotensin-Converting enzyme 2 gene (ACE2) polymorphisms with essential hypertension Abstract Recent intriguing findings from genetic linkage, knockout, and physiologic studies in mice and rats led us to conduct the first investigation of the novel angiotensin-converting enzyme 2 gene (ACE2) in human hypertension (HT). We genotyped four single nucleotide polymorphisms (SNP) (A→G at nucleotide 1075 in intron 1, G→A at nucleotide 8790 in intron 3, C→G at nucleotide 28330 in intron 11, and G→C at nucleotide 36787 in intron 16) in HT (n = 152) and normotensive (NT, n = 193) groups having inherently high biological power (>80%) due to our inclusion only of subjects whose parents had the same BP status as themselves. The SNPs were in linkage disequilibrium (D′ = 54% to 100%, P = .05 to 0.0001). Because ACE2 is on the X chromosome, data for each sex were analyzed separately. Minor allele frequencies in HT versus NT were as follows: for the intron 1 variant 0.21 versus 0.17 in female subjects (P = .31) and 0.25 versus 0.29 in male subjects (P = .60); intron 3 variant 0.22 versus 0.18 in female subjects (P = .35) and 0.15 versus 0.20 in male subjects (P = .47); intron 11 variant 0.39 versus 0.46 in male subjects (P = 0.17) and 0.31 versus 0.30 in male subjects (P = .96); intron 16 variant 0.20 versus 0.19 in female subjects (P = .72) and 0.17 versus 0.17 in male subjects (P = .95). Haplotype analysis was also negative. These data provide little support for ACE2 in genetic predisposition to HT.

positive: Diabetes in COVID-19: Prevalence, pathophysiology, prognosis and practical considerations Abstract Background and aims High prevalence of diabetes makes it an important comorbidity in patients with COVID-19. We sought to review and analyze the data regarding the association between diabetes and COVID-19, pathophysiology of the disease in diabetes and management of patients with diabetes who develop COVID-19 infection. Methods PubMed database and Google Scholar were searched using the key terms ‘COVID-19’, ‘SARS-CoV-2’, ‘diabetes’, ‘antidiabetic therapy’ up to April 2, 2020. Full texts of the retrieved articles were accessed. Results There is evidence of increased incidence and severity of COVID-19 in patients with diabetes. COVID-19 could have effect on the pathophysiology of diabetes. Blood glucose control is important not only for patients who are infected with COVID-19, but also for those without the disease. Innovations like telemedicine are useful to treat patients with diabetes in today’s times.

positive: The SARS Coronavirus receptor ACE 2 A potential target for antiviral therapy

positive: Angiotensin II Receptors ‐ Impact for COVID‐19 Severity COVID‐19 is an outbreak of viral pneumonia which became a global health crisis, and the risk of morbidity and mortality of people with obesity are higher. SARS‐CoV‐2, the pathogen of COVID‐19, enters into cells through binding to the Angiotensin Converting Enzyme (ACE) homolog‐2 (ACE2). ACE2 is a regulator of two contrary pathways in renin angiotensin system (RAS): ACE‐Ang‐II‐AT1R axis and ACE2‐Ang 1‐7‐Mas axis. Viral entry process eventuate in downregulation of ACE2 and subsequent activation of ACE‐Ang‐II‐AT1R axis. ACE‐Ang II‐AT1R axis increases lipid storage, reduces white‐to‐beige fat conversion and plays role in obesity. Conversely, adipose tissue is an important source of angiotensin, and obesity results in increased systemic RAS. ACE‐Ang‐II‐AT1R axis, which has proinflammatory, profibrotic, prothrombotic and vasoconstrictive effects, is potential mechanism of more severe SARS‐CoV‐2 infection. The link between obesity and severe COVID‐19 may be attributed to ACE2 consumption and subsequent ACE‐Ang‐II‐AT1R axis activation. Therefore, patients with SARS‐CoV‐2 infection may benefit from therapeutic strategies that activate ACE2‐Ang 1‐7‐Mas axis, such as Ang II reseptor blockers (ARBs), ACE inhibitors (ACEIs), Mas receptor agonists and ACE2. This article is protected by copyright. All rights reserved.

positive: Structure, Evolutionary Conservation, and Functions of Angiotensin- and Endothelin-Converting Enzymes Abstract Angiotensin-converting enzyme, a member of the M2 metalloprotease family, and endothelin-converting enzyme, a member of the M13 family, are key components in the regulation of blood pressure and electrolyte balance in mammals. From this point of view, they serve as important drug targets. Recently, the involvement of these enzymes in the development of Alzheimer's disease was discovered. The existence of homologs of these enzymes in invertebrates indicates that these enzyme systems are highly conserved during evolution. Most invertebrates lack a closed circulatory system, which excludes the need for blood pressure regulators. Therefore, these organisms represent excellent targets for gaining new insights and revealing additional physiological roles of these important enzymes. This chapter reviews the structural and functional aspects of ACE and ECE and will particularly focus on these enzyme homologues in invertebrates.

positive: Effects of Angiotensin II Receptor Blockers and ACE (Angiotensin-Converting Enzyme) Inhibitors on Virus Infection, Inflammatory Status, and Clinical Outcomes in Patients With COVID-19 and Hypertension: A Single-Center Retrospective Study With the capability of inducing elevated expression of ACE2 (angiotensin-converting enzyme 2), the cellular receptor for severe acute respiratory syndrome coronavirus 2, angiotensin II receptor blockers (ARBs) or ACE inhibitors treatment may have a controversial role in both facilitating virus infection and reducing pathogenic inflammation. We aimed to evaluate the effects of ARBs/ACE inhibitors on coronavirus disease 2019 (COVID-19) in a retrospective, single-center study. One hundred twenty-six patients with COVID-19 and preexisting hypertension at Hubei Provincial Hospital of Traditional Chinese Medicine in Wuhan from January 5 to February 22, 2020, were retrospectively allocated to ARBs/ACE inhibitors group (n=43) and non-ARBs/ACE inhibitors group (n=83) according to their antihypertensive medication. One hundred twenty-five age- and sex-matched patients with COVID-19 without hypertension were randomly selected as nonhypertension controls. In addition, the medication history of 1942 patients with hypertension that were admitted to Hubei Provincial Hospital of Traditional Chinese Medicine from November 1 to December 31, 2019, before the COVID-19 outbreak were also reviewed for external comparison. Epidemiological, demographic, clinical, and laboratory data were collected, analyzed, and compared between these groups. The frequency of ARBs/ACE inhibitors usage in patients with hypertension with or without COVID-19 were comparable. Among patients with COVID-19 and hypertension, those received either ARBs/ACE inhibitors or non-ARBs/ACE inhibitors had comparable blood pressure. However, ARBs/ACE inhibitors group had significantly lower concentrations of hs-CRP (high-sensitivity C-reactive protein; P=0.049) and PCT (procalcitonin, P=0.008). Furthermore, a lower proportion of critical patients (9.3% versus 22.9%; P=0.061) and a lower death rate (4.7% versus 13.3%; P=0.216) were observed in ARBs/ACE inhibitors group than non-ARBs/ACE inhibitors group, although these differences failed to reach statistical significance. Our findings thus support the use of ARBs/ACE inhibitors in patients with COVID-19 and preexisting hypertension.

positive: Risk of severe COVID-19 in hypertensive patients treated with renin-angiotensin-aldosterone system inhibitors INTRODUCTION: There is controversy concerning the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II type-I receptor blockers (ARB) for treating hypertensive patients with Covid-19. It has been hypothesized that these drugs might increase the risk of severe Covid-19, but some authors suggested that blocking the renin-angiotensin system might actually decrease this risk. METHODS: Retrospective cohort study of all the consecutive hypertensive patients with confirmed SARS-CoV-2 infection in a health area. The outcome variable was hospitalization because of severe Covid-19. RESULTS: 539 subjects were diagnosed of SARS-CoV-2 infection. Of these, 157 (29.1%) had hypertension and were included in the study. Sixty-nine cases (43.9%) were hospitalized because of severe Covid-19. In multivariable analysis older age, diabetes and hypertensive myocadiopathy were related to a higher risk of hospital admission. ARB treatment was associated with a significantly lower risk of hospitalization (HR: 0.29, 95% CI: 0.10 - 0.88). A similar albeit not significant trend was observed for ACEI. CONCLUSION: ARB or ACEI treatment was not associated with a worse clinical outcome in consecutive hypertensive patients infected by SARS-CoV-2.

positive: COVID-19, hypertension and cardiovascular diseases: Should we change the therapy? The coronavirus disease (COVID-19) has spread all around the world in a very short period of time. Recent data are showing significant prevalence of arterial hypertension and cardiovascular diseases (CVD) among patients with COVID-19, which raised many questions about higher susceptibility of patients with these comorbidities to the novel coronavirus, as well as the role of hypertension and CVD in progression and the prognosis of COVID-19 patients. There is a very limited amount of data, usually obtained from a small population, regarding the effect of the underlying disease on the outcome in patients with COVID-19. The evaluation of the treatment of these comorbidities at baseline and during COVID-19 is scarce and the results are conflicting. Hypertension and CVD, after the adjustment for other clinical and demographic parameters, primarily age, did not remain independent predictors of the lethal outcome in COVID-19 patients. Some investigations speculated about the association between the renin-angiotensin-aldosterone system (RAAS) and susceptibility to COVID-19, as well as the relationship between RAAS inhibitors and the adverse outcome in these patients. Withdrawing or switching RAAS inhibitors would have uncertain benefits, but it would definitely have many disadvantages such as uncontrolled hypertension, cardiac function deterioration and renal function impairment, which could potentially induce more complications in patients with COVID-19 than the infection of coronavirus itself. The aim of this review article was to summarize the prevalence of hypertension and CVD in patients with COVID-19, their influence on the outcome and the effect of treatment of hypertension and CVD in COVID-19 patients.

positive: Predictive factors for disease progression in hospitalized patients with Coronavirus Disease 2019 in Wuhan, China Abstract Background A few studies have revealed the clinical characteristics of hospitalized patients with COVID-19. However, predictive factors for the outcomes remain unclear. Objective Attempted to determine the predictive factors for the poor outcomes of patients with COVID-19. Study design This is a single-center, retrospective study. Clinical, laboratory, and treatment data were collected and analyzed from 111 hospitalized patients with laboratory-confirmed COVID-19 in Union Hospital. The gathered data of discharged and deteriorated patients were compared. Results Among these 111 patients, 93 patients were discharged and 18 patients were deteriorated. The lymphocyte count (0.56 G/L [0.47-0.63] vs 1.30 G/L [0.95-1.65]) was lower in the deteriorated group than those in the discharged group. The numbers of pulmonary lobe involved (5.00 [5.00–5.00] vs 4.00 [2.00-5.00]), serum C‐reactive protein (CRP, 79.52 mg/L [61.25-102.98] vs 7.93 mg/L [3.14-22.50]), IL-6 (35.72 pg/ml [9.24-85.19] vs 5.09 pg/ml [3.16-9.72]), and IL-10 (5.35 pg/ml [4.48-7.84] vs 3.97 pg/ml [3.34-4.79]) concentrations in deteriorated patients were elevated compared with discharged patients. Multivariate logistic regression analysis showed that male gender (OR, 24.8 [1.8-342.1]), comorbidity (OR, 52.6 [3.6-776.4]), lymphopenia (OR, 17.3 [1.1-261.8]), and elevated CRP (OR, 96.5 [4.6-2017.6]) were the independent risk factors for the poor prognosis in COVID-19 patients. Conclusions This finding would facilitate the early identification of high-risk COVID-19 patients.

positive: Lectin-like Intestinal Defensin Inhibits 2019-nCoV Spike binding to ACE2 The burgeoning epidemic caused by novel coronavirus 2019 (2019-nCoV) is currently a global concern. Angiotensin-converting enzyme-2 (ACE2) is a receptor of 2019-nCoV spike 1 protein (S1) and mediates viral entry into host cells. Despite the abundance of ACE2 in small intestine, few digestive symptoms are observed in patients infected by 2019-nCoV. Herein, we investigated the interactions between ACE2 and human defensins (HDs) specifically secreted by intestinal Paneth cells. The lectin-like HD5, rather than HD6, bound ACE2 with a high affinity of 39.3 nM and weakened the subsequent recruitment of 2019-nCoV S1. The cloak of HD5 on the ligand-binding domain of ACE2 was confirmed by molecular dynamic simulation. A remarkable dose-dependent preventive effect of HD5 on 2019-nCoV S1 binding to intestinal epithelial cells was further evidenced by in vitro experiments. Our findings unmasked the innate defense function of lectin-like intestinal defensin against 2019-nCoV, which may provide new insights into the prevention and treatment of 2019-nCoV infection.

positive: Renin-Angiotensin-System (RAS) und COVID-19  Zur Verordnung von RAS-Blockern./ [Renin-Angiotensin-System (RAS) and COVID-19 - On The Prescription of RAS Blockers] Twenty years ago, an enzyme homologous to the previously known angiotensin-converting enzyme (ACE) was identified, and subsequently named ACE2. In the renin-angiotensin system (RAS), ACE2 has counter-regulatory functions against the classical effector peptide angiotensin II, for example in blood pressure regulation and cardiovascular remodeling. However, ACE2 provides an initially unexpected interesting link between virology and cardiovascular medicine. That is, ACE2 represents the binding receptor for the cellular uptake of SARS-CoV and SARS-CoV-2 viruses. Thus, ACE2 is relevant for COVID-19. In this context, it was suspected that therapy with RAS blockers might promote transmission and complications of COVID-19 by upregulation of ACE2 expression. The aim of this short review is, to describe the link between the RAS, particularly ACE2, and COVID-19. Based on our analysis and evaluation of the available findings, we justify our conclusion: important drugs such as ACE inhibitors and angiotensin receptor blockers should continue to be prescribed according to guidelines to stable patients in the context of the COVID-19 pandemic.

positive: Could renin-angiotensin-aldosterone system inhibitors be used for hypertensive patients with coronavirus disease 2019?

positive: Use of renin-angiotensin-aldosterone system inhibitors and risk of COVID-19 requiring admission to hospital: a case-population study BACKGROUND: Concerns have been raised about the possibility that inhibitors of the renin-angiotensin-aldosterone system (RAAS) could predispose individuals to severe COVID-19; however, epidemiological evidence is lacking. We report the results of a case-population study done in Madrid, Spain, since the outbreak of COVID-19. METHODS: In this case-population study, we consecutively selected patients aged 18 years or older with a PCR-confirmed diagnosis of COVID-19 requiring admission to hospital from seven hospitals in Madrid, who had been admitted between March 1 and March 24, 2020. As a reference group, we randomly sampled ten patients per case, individually matched for age, sex, region (ie, Madrid), and date of admission to hospital (month and day; index date), from Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP), a Spanish primary health-care database, in its last available year (2018). We extracted information on comorbidities and prescriptions up to the month before index date (ie, current use) from electronic clinical records of both cases and controls. The outcome of interest was admission to hospital of patients with COVID-19. To minimise confounding by indication, the main analysis focused on assessing the association between COVID-19 requiring admission to hospital and use of RAAS inhibitors compared with use of other antihypertensive drugs. We calculated odds ratios (ORs) and 95% CIs, adjusted for age, sex, and cardiovascular comorbidities and risk factors, using conditional logistic regression. The protocol of the study was registered in the EU electronic Register of Post-Authorisation Studies, EUPAS34437. FINDINGS: We collected data for 1139 cases and 11â390 population controls. Among cases, 444 (39·0%) were female and the mean age was 69·1 years (SD 15·4), and despite being matched on sex and age, a significantly higher proportion of cases had pre-existing cardiovascular disease (OR 1·98, 95% CI 1·62-2·41) and risk factors (1·46, 1·23-1·73) than did controls. Compared with users of other antihypertensive drugs, users of RAAS inhibitors had an adjusted OR for COVID-19 requiring admission to hospital of 0·94 (95% CI 0·77-1·15). No increased risk was observed with either angiotensin-converting enzyme inhibitors (adjusted OR 0·80, 0·64-1·00) or angiotensin-receptor blockers (1·10, 0·88-1·37). Sex, age, and background cardiovascular risk did not modify the adjusted OR between use of RAAS inhibitors and COVID-19 requiring admission to hospital, whereas a decreased risk of COVID-19 requiring admission to hospital was found among patients with diabetes who were users of RAAS inhibitors (adjusted OR 0·53, 95% CI 0·34-0·80). The adjusted ORs were similar across severity degrees of COVID-19. INTERPRETATION: RAAS inhibitors do not increase the risk of COVID-19 requiring admission to hospital, including fatal cases and those admitted to intensive care units, and should not be discontinued to prevent a severe case of COVID-19. FUNDING: Instituto de Salud Carlos III.

positive: Perspective: cardiovascular disease and the Covid-19 pandemic We summarize the cardiovascular risks associated with Covid-19 pandemic, discussing the risks for both infected and non-infected patients.

positive: SARS-CoV2: should inhibitors of the renin-angiotensin system be withdrawn in patients with COVID-19?

positive: Obesity: the “Achilles heel” for COVID-19?

positive: Continuing versus suspending angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: Impact on adverse outcomes in hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) BACKGROUND: Angiotensin-converting enzyme-2 (ACE2) may increase due to upregulation in patients using angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB). Because renin-angiotensin system blockers increase levels of ACE2, a protein that facilitates coronavirus entry into cells, there is concern that these drugs could increase the risk of developing a severe and fatal form of COVID-19. The impact of discontinuing ACEI and ARBs in patients with COVID-19 remains uncertain. DESIGN BRACE CORONA is a pragmatic, multicenter, randomized, phase IV, clinical trial that aims to enroll around 500 participants at 32 sites in Brazil. Participants will be identified from an ongoing national registry of suspected and confirmed cases of COVID-19. Eligible patients using renin-angiotensin system blockers (ACEI/ARBs) with a confirmed diagnosis of COVID-19 will be randomized to a strategy of continued ACEI/ARB treatment versus temporary discontinuation for 30 days. The primary outcome is the median days alive and out of the hospital at 30 days. Secondary outcomes include progression of COVID-19 disease, all-cause mortality, death from vascular causes, myocardial infarction, stroke, transient ischemic attack, new or worsening heart failure, myocarditis, pericarditis, arrhythmias, thromboembolic events, hypertensive crisis, respiratory failure, hemodynamic decompensation, sepsis, renal failure, troponin, B-type natriuretic peptide, N-terminal-pro hormone and D-dimer levels. SUMMARY: BRACE CORONA will evaluate whether the strategy of continued ACEI/ARB therapy compared with temporary discontinuation of these drugs impacts clinical outcomes among patients with COVID-19.

positive: ACE-inibitori, sartani e sindrome respiratoria acuta da coronavirus 2./ [ACE-inhibitors, angiotensin receptor blockers and severe acute respiratory syndrome caused by coronavirus] Some Authors recently suggested that angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) should be discontinued, even temporarily, given the current pandemic of SARS-CoV-2 virus. The suggestion is based on the hypothesis that ACE-inhibitors and ARBs may favor the entry and diffusion of SARS-CoV-2 virus into the human cells. ACE-inhibitors and ARBs may increase the expression of ACE2 receptors, which are the sites of viral entry into the human organism. ACE2 receptors are ubiquitous, although they are extremely abundant on the cell surface of type 2 pneumocytes. Type 2 pneumocytes are small cylindrical alveolar cells located in close vicinity to pulmonary capillaries and responsible for the synthesis of alveolar surfactant, which is known to facilitate gas exchanges. The increased expression of ACE2 for effect of ACE-inhibitors and ARBs can be detected by increased production of angiotensin1-7 and mRNA related to ACE2. There is the fear that the increased expression of ACE2 induced by ACE-inhibitors and ARBs may ultimately facilitate the entry and diffusion of the SARS-CoV-2 virus. However, there is no clinical evidence to support this hypothesis. Furthermore, available data are conflicting and some counter-intuitive findings suggest that ARBs may be beneficial, not harmful. Indeed, studies conducted in different laboratories demonstrated that ACE2 receptors show a down-regulation (i.e. the opposite of what would happen with ACE-inhibitors and ARBs) for effect of their interaction with the virus. In animal studies, down-regulation of ACE2 has been found as prevalent in the pulmonary areas infected by virus, but not in the surrounding areas. In these studies, virus-induced ACE2 down-regulation would lead to a reduced formation of angiotensin1-7 (because ACE2 degrades angiotensin II into angiotensin1-7) with consequent accumulation of angiotensin II. The excess angiotensin II would favor pulmonary edema and inflammation, a phenomenon directly associated with angiotensin II levels, along with worsening in pulmonary function. Such detrimental effects have been blocked by ARBs in experimental models. In the light of the above considerations, it is reasonable to conclude that the suggestion to discontinue ACE-inhibitors or ARBs in all patients with the aim of preventing or limiting the diffusion of SARS-CoV-2 virus is not based on clinical evidence. Conversely, experimental studies suggest that ARBs might be useful in these patients to limit pulmonary damage through the inhibition of type 1 angiotensin II receptors. Controlled clinical studies in this area are eagerly awaited. This review discusses facts and theories on the potential impact of ACE-inhibitors and ARBs in the setting of the SARS-CoV-2 pandemic.

positive: Design of potent membrane fusion inhibitors against SARS-CoV-2, an emerging coronavirus with high fusogenic activity The coronavirus disease COVID-19, caused by emerging SARS-CoV-2, has posed serious threats to global public health, economic and social stabilities, calling for the prompt development of therapeutics and prophylactics. In this study, we firstly verified that SARS-CoV-2 uses human ACE2 as a cell receptor and its spike (S) protein mediates high membrane fusion activity. Comparing to that of SARS-CoV, the heptad repeat 1 (HR1) sequence in the S2 fusion protein of SARS-CoV-2 possesses markedly increased α-helicity and thermostability, as well as a higher binding affinity with its corresponding heptad repeat 2 (HR1) site. Then, we designed a HR2 sequence-based lipopeptide fusion inhibitor, termed IPB02, which showed highly poent activities in inibibiting the SARS-CoV-2 S protein-mediated cell-cell fusion and pseudovirus infection. IPB02 also inhibited the SARS-CoV pseudovirus efficiently. Moreover, the strcuture and activity relationship (SAR) of IPB02 were characterzized with a panel of truncated lipopeptides, revealing the amino acid motifs critical for its binding and antiviral capacities. Therefore, the presented results have provided important information for understanding the entry pathway of SARS-CoV-2 and the design of antivirals that target the membrane fusion step.

positive: The Novel Coronavirus Disease (COVID-19) Threat for Patients with Cardiovascular Disease and Cancer

positive: ACE2 (Angiotensin-Converting Enzyme 2), COVID-19, and ACE Inhibitor and Ang II (Angiotensin II) Receptor Blocker Use During the Pandemic: The Pediatric Perspective Potential but unconfirmed risk factors for coronavirus disease 2019 (COVID-19) in adults and children may include hypertension, cardiovascular disease, and chronic kidney disease, as well as the medications commonly prescribed for these conditions, ACE (angiotensin-converting enzyme) inhibitors, and Ang II (angiotensin II) receptor blockers. Coronavirus binding to ACE2 (angiotensin-converting enzyme 2), a crucial component of the renin-angiotensin-aldosterone system, underlies much of this concern. Children are uniquely impacted by the coronavirus, but the reasons are unclear. This review will highlight the relationship of COVID-19 with hypertension, use of ACE inhibitors and Ang II receptor blockers, and lifetime risk of cardiovascular disease from the pediatric perspective. We briefly summarize the renin-angiotensin-aldosterone system and comprehensively review the literature pertaining to the ACE 2/Ang-(1-7) pathway in children and the clinical evidence for how ACE inhibitors and Ang II receptor blockers affect this important pathway. Given the importance of the ACE 2/Ang-(1-7) pathway and the potential differences between adults and children, it is crucial that children are included in coronavirus-related research, as this may shed light on potential mechanisms for why children are at decreased risk of severe COVID-19.

positive: ACEI/ARB Use and Risk of Infection or Severity or Mortality of COVID-19: A Systematic Review and Meta-analysis We have sparse knowledge of the effects of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) on the risk of COVID-19 infection and the progression of this disease. We systematically assessed these relationships. Unrestricted searches of the PubMed, Embase, and Cochrane Library databases were conducted, with an end date of May 9, 2020, to identify relevant studies that met predetermined inclusion criteria. Random-effects models were adopted to estimate the overall relative risk. Fourteen articles involving more than 19000 COVID-19 cases were included. Our results showed that ACEI/ARB exposure is not associated with a higher risk of COVID-19 infection (OR = 0.99; 95% CI, 0.95-1.04; P = 0.672). Among those with COVID-19 infection, ACEI/ARB exposure is not associated with a higher risk of severity (OR = 0.98; 95%CI 0.87-1.09; P = 0.69) or mortality (OR = 0.73, 95%CI 0.5-1.07; P = 0.111). However, ACEI/ARB exposure was associated with a lower risk of mortality compared those with non-ACEI/ARB antihypertensive drugs (OR = 0.48, 95% CI 0.29-0.81; P = 0.006). In conclusion, current evidence did not confirm previous concern regarding a harmful role of ACEI/ARB in COVID-19 patients. The present study support current professional society guidelines to not discontinue ACEIs or ARBs in the setting of the COVID-19 pandemic or COVID-19 patients.

positive: Diabetes and COVID-19: Global and Regional Perspectives Abstract The coronavirus disease-2019 (COVID-19) has been designated as a highly contagious infectious disease caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) since December 2019, when an outbreak of pneumonia cases emerged in Wuhan, China. The COVID-19 pandemic has led to a global health crisis, devastating the social, economic and political aspects of life. Many clinicians, health professionals, scientists, organizations, and governments have actively defeated COVID-19 and shared their experiences of the SARS-CoV2. Diabetes is one of the major risk factors for fatal outcomes from COVID-19. Patients with diabetes are vulnerable to infection because of hyperglycemia; impaired immune function; vascular complications; and comorbidities such as hypertension, dyslipidemia, and cardiovascular disease. In addition, angiotensin-converting enzyme 2 (ACE2) is a receptor for SARS-CoV-2 in the human body. Hence, the use of angiotensin-directed medications in patients with diabetes requires attention. The severity and mortality from COVID-19 was significantly higher in patients with diabetes than in those without. Thus, the patients with diabetes should take precautions during the COVID-19 pandemic. Therefore, we review the current knowledge of COVID-19 including the global and regional epidemiology, virology, impact of diabetes on COVID-19, treatment of COVID-19, and standard of care in the management of diabetes during this critical period.

positive: Pathogenesis of severe acute respiratory syndrome Severe acute respiratory syndrome (SARS) is a zoonotic infectious disease caused by a novel coronavirus (CoV). The tissue tropism of SARS-CoV includes not only the lung, but also the gastrointestinal tract, kidney and liver. Angiotensin-converting enzyme 2 (ACE2), the C-type lectin CD209L (also known L-SIGN), and DC-SIGN bind SARS-CoV, but ACE2 appears to be the key functional receptor for the virus. There is a prominent innate immune response to SARS-CoV infection, including acute-phase proteins, chemokines, inflammatory cytokines and C-type lectins such as mannose-binding lectin, which plays a protective role against SARS. By contrast there may be a lack of type 1 interferon response. Moreover, lymphopenia with decreased numbers of CD4+ and CD8+ T cells is common during the acute phase. Convalescent patients have IgG-class neutralizing antibodies that recognize amino acids 441–700 of the spike protein (S protein) as the major epitope.

positive: What’s new in the renin-angiotensin system?: Angiotensin-converting enzyme 2: a functional receptor for SARS coronavirus Cellular entry of enveloped viruses is often dependent on attachment proteins expressed on the host cell surface. Viral envelope proteins bind these receptors, and, in an incompletely understood process, facilitate fusion of the cellular and viral membranes so as to introduce the viral core into the cytoplasm. Only a small fraction of viral receptors have been identified so far. Recently, a novel coronavirus was identified as the etiological agent of severe acute respiratory syndrome (SARS). The fusion protein gene of SARS coronavirus (SARS-CoV) was cloned and characterized, and shortly thereafter, angiotensin-converting enzyme 2 (ACE2) was shown to be its functional receptor. Identification of ACE2 as a receptor for SARS-CoV will likely contribute to the development of antivirals and vaccines. It may also contribute to the development of additional animal models for studying SARS pathogenesis, and could help identify the animal reservoir of SARS-CoV.

positive: Clinical characteristics of coronavirus disease 2019 (COVID-19) patients with hypertension on renin–angiotensin system inhibitors In December 2019, COVID-19 outbroke in Wuhan, China. The current study aimed to explore the clinical characteristics of COVID-19 complicated by hypertension. In this retrospective, single-center study, we recruited 110 discharged patients with COVID-19 at Wuhan Fourth Hospital in Wuhan, China, from January 25 to February 20, 2020. All study cases were grouped according to whether they had a history of hypertension. Then, a subgroup analysis for all hypertensive patients was carried out based on whether to take ACEI or ARB drugs. The mean age of 110 patients was 57.7 years (range, 25–86 years), of which 60 (54.5%) were male patients. The main underlying diseases included hypertension [36 (32.7%)] and diabetes [11 (10.0%)]. Compared with the non-hypertensive group, the lymphocyte count was significantly lower in the hypertensive group (average value, 0.96 × 10(9)/L vs 1.26 × 10(9)/L), and analysis of clinical outcomes showed that the crude mortality rate was higher in the hypertensive group [7/36 (19.4%) vs 2/74 (2.7%)]. Patients treated with ACEI or ARB, compared with the control group, were younger (average age, 58.5 years vs 69.2 years), but there was no statistical difference in the crude cure rate [10/15 (66.7%) vs 15/21 (71.4%)] and the crude mortality rate [2/15 (13.3%) vs 5/21 (23.8%)]. In conclusions, the COVID-19 patients with a history of hypertension had a significantly lower lymphocyte count on admission. The elderly and comorbidities such as hypertension may together constitute risk factors for poor prognosis in patients with COVID-19. Taking ACEI or ARB drugs may not change the prognosis of COVID-19 patients with hypertension.

positive: Response by Gheblawi et al to Letter Regarding Article, "Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2"

positive: Antihypertensive medication uses and serum ACE2 levels: ACEIs/ARBs treatment does not raise serum levels of ACE2 IMPORTANCE: Recent reports have shown that hypertension is the most common comorbidity associated with mortality in the current coronavirus disease 2019 (COVID-19). This has been related to the use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) as animal studies indicate that these medications increase levels of ACE2, the cellular entry point for the coronavirus SARS-CoV-2. This has prompted clinicians to recommend discontinuing ACEIs and ARBs. OBJECTIVE: To examine the effect of ACEIs or ARBs treatment on serum levels of ACE2 and other key enzymes in the renin-angiotensin system (RAS). DESIGN, SETTING, AND PARTICIPANTS: A single center population-based study of 5457 Icelanders from the Age, Gene/Environment Susceptibility Reykjavik Study (AGES-RS) of the elderly (mean age 75±6 years) stratified by ACEIs (N = 699) or ARBs (N = 753) treatment. MAIN OUTCOMES AND MEASURES: The AGES-RS study population was stratified by ACEIs and ARBs medication use and compared for age, body mass index (BMI) (kg/m(2)), hypertension and type 2 diabetes (T2D) as well as serum levels of renin, ACE and ACE2. RESULTS: While renin and ACE levels were significantly raised in serum of individuals on ACEIs or ARBs treatments, the ACE2 levels remained unaffected. CONCLUSIONS AND RELEVANCE: Treatment with ACEIs or ARBs does not raise ACE2 levels in serum. Therefore, the present study does not support the proposed discontinuation of these medications among patients affected with COVID-19.

positive: Emergence of a Novel Coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2: Biology and Therapeutic Options The new decade of the 21(st) century (2020) started with the emergence of a novel coronavirus known as SARS-CoV-2 that caused an epidemic of coronavirus disease (COVID-19) in Wuhan, China. It is the third highly pathogenic and transmissible coronavirus after severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) emerged in humans. The source of origin, transmission to humans, and mechanisms associated with the pathogenicity of SARS-CoV-2 are not yet clear, however, its resemblance to SARS-CoV and several other bat coronaviruses was recently confirmed through genome sequencing-related studies. The development of therapeutic strategies is necessary in order to prevent further epidemics and cure infections. In this review, we summarize current information about the emergence, origin, diversity, and epidemiology of three pathogenic coronaviruses with a specific focus on the current outbreak in Wuhan, China. Furthermore, we discuss the clinical features and potential therapeutic options that may be effective against SARS-CoV-2.

positive: Renin-angiotensin system inhibition in COVID-19 patients Angiotensin-converting enzyme (ACE) inhibitors (ACEIs) and angiotensin II type‑1 receptor blockers (ARBs) are among the most widely prescribed drugs for the treatment of arterial hypertension, heart failure and chronic kidney disease. A number of studies, mainly in animals and not involving the lungs, have indicated that these drugs can increase expression of angiotensin-converting enzyme 2 (ACE2). ACE2 is the cell entry receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19) that is currently battering the globe. This has led to the hypothesis that use of ACEIs and ARBs may increase the risk of developing severe COVID-19. In this point of view paper, possible scenarios regarding the impact of ACEI/ARB pharmacotherapy on COVID-19 are discussed in relation to the currently available evidence. Although further research on the influence of blood-pressure-lowering drugs, including those not targeting the renin-angiotensin system, is warranted, there are presently no compelling clinical data showing that ACEIs and ARBs increase the likelihood of contracting COVID-19 or worsen the outcome of SARS-CoV‑2 infections. Thus, unless contraindicated, use of ACEIs/ARBs in COVID-19 patients should be continued in line with the recent recommendations of medical societies.

positive: Potential host range of multiple SARS-like coronaviruses and an improved ACE2-Fc variant that is potent against both SARS-CoV-2 and SARS-CoV-1 The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a currently uncontrolled pandemic and the etiological agent of coronavirus disease 2019 (COVID-19). It is important to study the host range of SARS-CoV-2 because some domestic species might harbor the virus and transmit it back to humans. In addition, insight into the ability of SARS-CoV-2 and SARS-like viruses to utilize animal orthologs of the SARS-CoV-2 receptor ACE2 might provide structural insight into improving ACE2-based viral entry inhibitors. Here we show that ACE2 orthologs of a wide range of domestic and wild animals support entry of SARS-CoV-2, as well as that of SARS-CoV-1, bat coronavirus RaTG13, and a coronavirus isolated from pangolins. Some of these species, including camels, cattle, horses, goats, sheep, pigs, cats, and rabbits may serve as potential intermediate hosts for new human transmission, and rabbits in particular may serve as a useful experimental model of COVID-19. We show that SARS-CoV-2 and SARS-CoV-1 entry could be potently blocked by recombinant IgG Fc-fusion proteins of viral spike protein receptor-binding domains (RBD-Fc) and soluble ACE2 (ACE2-Fc). Moreover, an ACE2-Fc variant, which carries a D30E mutation and has ACE2 truncated at its residue 740 but not 615, outperforms all the other ACE2-Fc variants on blocking entry of both viruses. Our data suggest that RBD-Fc and ACE2-Fc could be used to treat and prevent infection of SARS-CoV-2 and any new viral variants that emerge over the course of the pandemic.

positive: Single-cell RNA expression profiling of ACE2, the putative receptor of Wuhan 2019-nCoV, in the nasal tissue A novel coronavirus (2019-nCoV) was first identified in Wuhan, Hubei Province, and then spreads to the other Provinces of China. WHO decides to determine a Public Health Emergency of International Concern (PHEIC) of 2019-nCoV. 2019-nCov was reported to share the same receptor, Angiotensin-converting enzyme 2 (ACE2), with SARS-Cov. Here based on the public single-cell RNA-Seq datasets, we analyzed the ACE2 RNA expression profile in the tissues at different locations of the respiratory tract. The result indicates that the ACE2 expression appears in nasal epithelial cells. We found that the size of this population of ACE2-expressing nasal epithelial cells is comparable with the size of the population of ACE2-expression type II alveolar cells (AT2) in the Asian sample reported by Yu Zhao et al. We further detected 2019-nCoV by polymerase chain reaction (PCR) from the nasal-swab and throat-swab of seven suspected cases. We found that 2019-nCoV tends to have a higher concentration in the nasal-swab comparing to the throat-swab, which could attribute to the ACE2-expressing nasal epithelial cells. We hope this study could be informative for virus-prevention strategy development, especially the treatment of nasal mucus.

positive: Clinical Implications of SARS-CoV-2 Interaction With Renin Angiotensin System: JACC Review Topic of the Week Severe acute respiratory-syndrome coronavirus-2 (SARS-CoV-2) host cell infection is mediated by binding to angiotensin-converting enzyme 2 (ACE2). Systemic dysregulation observed in SARS-CoV was previously postulated to be due to ACE2/angiotensin 1-7 (Ang1-7)/Mas axis downregulation; increased ACE2 activity was shown to mediate disease protection. Because angiotensin II receptor blockers, ACE inhibitors, and mineralocorticoid receptor antagonists increase ACE2 receptor expression, it has been tacitly believed that the use of these agents may facilitate viral disease; thus, they should not be used in high-risk patients with cardiovascular disease. Based on the anti-inflammatory benefits of the upregulation of the ACE2/Ang1-7/Mas axis and previously demonstrated benefits of lung function improvement in SARS-CoV infections, it has been hypothesized that the benefits of treatment with renin-angiotensin system inhibitors in SARS-CoV-2 may outweigh the risks and at the very least should not be withheld.

positive: Angiotensin-converting enzyme 2: cardioprotective player in the renin-angiotensin system?

positive: Subchapter 29C Other Angiotensins Abstract Besides the major role of angiotensin II (Ang II) in the renin-angiotensin system (RAS), other angiotensin peptides with different lengths were recently discovered to be biologically active and they possess individual receptors and signaling pathways. Ang III stimulates AT1 and AT2 receptors and its signaling pathway is similar to that of Ang II but has a specific role on aldosterone stimulation in adrenal cortex. The Ang(1–7)/Mas receptor axis is known to antagonize the effects of the AT1 axis. These include anti-hypertrophic action, anti-thrombotic and anti-fibrotic effect, and vasodilation via stimulation of NO synthesis in endothelium and potentiation of the bradykinin effect. Ang IV stimulates insulin-regulated aminopeptidase (IRAP) or AT4 receptor and is involved in facilitation of memory such as reversing memory deficits caused by alcohol abuse and ischemia. AT4 antagonist decreases renal blood flow and increases urinary sodium excretion, and these effects are independent of the AT1 pathway.

positive: Human Angiotensin - Converting Enzyme 2 (ACE2) is a Receptor for Human Respiratory Coronavirus NL63

positive: A current review of COVID-19 for the cardiovascular specialist Abstract Although Coronavirus Disease 2019 (COVID-19) predominantly disrupts the respiratory system, there is accumulating experience that the disease, particularly in its more severe manifestations, also affects the cardiovascular system. Cardiovascular risk factors and chronic cardiovascular conditions are prevalent among patients affected by COVID-19 and associated with adverse outcomes. However, whether pre-existing cardiovascular disease is an independent determinant of higher mortality risk with COVID-19 remains uncertain. Acute cardiac injury, manifest by increased blood levels of cardiac troponin, electrocardiographic abnormalities, or myocardial dysfunction, occurs in up to ~60% of hospitalized patients with severe COVID-19. Potential contributors to acute cardiac injury in the setting of COVID-19 include 1) acute changes in myocardial demand and supply due to tachycardia, hypotension, and hypoxemia resulting in type 2 myocardial infarction; 2) acute coronary syndrome due to acute atherothrombosis in a virally-induced thrombotic and inflammatory milieu; 3) microvascular dysfunction due to diffuse microthrombi or vascular injury; 4) stress-related cardiomyopathy (Takotsubo syndrome); 5) non-ischemic myocardial injury due to a hyperinflammatory cytokine storm; or 6) direct viral cardiomyocyte toxicity and myocarditis. Diffuse thrombosis is emerging as an important contributor to adverse outcomes in patients with COVID-19. Practitioners should be vigilant for cardiovascular complications of COVID-19. Monitoring may include serial cardiac troponin and natriuretic peptides, along with fibrinogen, d-dimer, and inflammatory biomarkers. Management decisions should rely on the clinical assessment for the probability of ongoing myocardial ischemia, as well as alternative non-ischemic causes of injury, integrating the level of suspicion for COVID-19.

positive: A review on the cleavage priming of the spike protein on coronavirus by angiotensin-converting enzyme-2 and furin The widespread antigenic changes lead to the emergence of a new type of coronavirus (CoV) called as severe acute respiratory syndrome (SARS)-CoV-2 that is immunologically different from the previous circulating species. Angiotensin-converting enzyme-2 (ACE-2) is one of the most important receptors on the cell membrane of the host cells (HCs) which its interaction with spike protein (SP) with a furin-cleavage site results in the SARS-CoV-2 invasion. Hence, in this review, we presented an overview on the interaction of ACE-2 and furin with SP. As several kinds of CoVs, from various genera, have at their S1/S2 binding site a preserved site, we further surveyed the role of furin cleavage site (FCS) on the life cycle of the CoV. Furthermore, we discussed that the small molecular inhibitors can limit the interaction of ACE-2 and furin with SP and can be used as potential therapeutic platforms to combat the spreading CoV epidemic. Finally, some ongoing challenges and future prospects for the development of potential drugs to promote targeting specific activities of the CoV were reviewed. In conclusion, this review may pave the way for providing useful information about different compounds involved in improving the effectiveness of CoV vaccine or drugs with minimum toxicity against human health. Communicated by Ramaswamy H. Sarma

positive: Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV Since 2002, beta coronaviruses (CoV) have caused three zoonotic outbreaks, SARS-CoV in 2002–2003, MERS-CoV in 2012, and the newly emerged SARS-CoV-2 in late 2019. However, little is currently known about the biology of SARS-CoV-2. Here, using SARS-CoV-2 S protein pseudovirus system, we confirm that human angiotensin converting enzyme 2 (hACE2) is the receptor for SARS-CoV-2, find that SARS-CoV-2 enters 293/hACE2 cells mainly through endocytosis, that PIKfyve, TPC2, and cathepsin L are critical for entry, and that SARS-CoV-2 S protein is less stable than SARS-CoV S. Polyclonal anti-SARS S1 antibodies T62 inhibit entry of SARS-CoV S but not SARS-CoV-2 S pseudovirions. Further studies using recovered SARS and COVID-19 patients’ sera show limited cross-neutralization, suggesting that recovery from one infection might not protect against the other. Our results present potential targets for development of drugs and vaccines for SARS-CoV-2.

positive: Spike protein binding prediction with neutralizing antibodies of SARS-CoV-2 Coronavirus disease 2019 (COVID-19) is a new emerging human infectious disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2, also previously known as 2019-nCoV), originated in Wuhan seafood and animal market, China. Since December 2019, more than 69,000 cases of COVID-19 have been confirmed in China and quickly spreads to other counties. Currently, researchers put their best efforts to identify effective drugs for COVID-19. The neutralizing antibody, which binds to viral capsid in a manner that inhibits cellular entry of virus and uncoating of the genome, is the specific defense against viral invaders. In this study, we investigate to identify neutralizing antibodies that can bind to SARS-CoV-2 Sipke (S) protein and interfere with the interaction between viral S protein and a host receptor by bioinformatic methods. The sequence analysis of S protein showed two major differences in the RBD region of the SARS-CoV-2 S protein compared to SARS-CoV and SARS-CoV related bat viruses (btSARS-CoV). The insertion regions were close to interacting residues with the human ACE2 receptor. Epitope analysis of neutralizing antibodies revealed that SARS-CoV neutralizing antibodies used conformational epitopes, whereas MERS-CoV neutralizing antibodies used a common linear epitope region, which contributes to form the β-sheet structure in MERS-CoV S protein and deleted in SARS-CoV-2 S protein. To identify effective neutralizing antibodies for SARS-CoV-2, the binding affinities of neutralizing antibodies with SARS-CoV-2 S protein were predicted and compared by antibody-antigen docking simulation. The result showed that CR3022 neutralizing antibody from human may have higher binding affinity with SARS-CoV-2 S protein than SARS-CoV S protein. We also found that F26G19 and D12 mouse antibodies could bind to SARS-CoV S protein with high affinity. Our findings provide crucial clues towards the development of antigen diagnosis, therapeutic antibody, and the vaccine against SARS-CoV-2.

positive: Would ACEIs/ARBs be beneficial for COVID-19 patients without hypertension?

positive: Cardiovascular implications of the COVID-19 pandemic: a global perspective The Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), represents the pandemic of the century, with approximately 3.5 million cases and 250,000 deaths worldwide as of May 2020. Although respiratory symptoms usually dominate the clinical presentation, COVID-19 is now known to also have potentially serious cardiovascular consequences, including myocardial injury, myocarditis, acute coronary syndromes, pulmonary embolism, stroke, arrhythmias, heart failure, and cardiogenic shock. The cardiac manifestations of COVID-19 might be related to the adrenergic drive, systemic inflammatory milieu and cytokine-release syndrome caused by SARS-CoV-2, direct viral infection of myocardial and endothelial cells, hypoxia due to respiratory failure, electrolytic imbalances, fluid overload, and side effects of certain COVID-19 medications. COVID-19 has profoundly reshaped usual care of both ambulatory and acute cardiac patients, by leading to the cancellation of elective procedures and by reducing the efficiency of existing pathways of urgent care, respectively. Decreased utilization of healthcare services for acute conditions by non-COVID-19 patients has also been reported and attributed to concerns about acquiring in-hospital infection. Innovative approaches that leverage modern technologies to tackle the COVID-19 pandemic have been introduced, which include telemedicine, dissemination of educational material over social media, smartphone apps for case tracking, and artificial intelligence for pandemic modelling, among others. This article provides a comprehensive overview of the pathophysiology and cardiovascular implications of COVID-19, its impact on existing pathways of care, the role of modern technologies to tackle the pandemic, and a proposal of novel management algorithms for the most common acute cardiac conditions.

positive: Counter-regulatory 'Renin-Angiotensin' System-based Candidate Drugs to Treat COVID-19 Diseases in SARS-CoV-2-infected patients. SARS-CoV-2 / COVID-19 and the 'Renin-Angiotensin' System The ubiquitous 'Renin-Angiotensin' system (RAS), also referred to as 'Renin-Angiotensin-Aldosterone' system, plays a crucial physiological role in humans as being a key regulator of renal, cardiovascular and innate immune functions [1, 2]. It appears to work in tandem with vitamin D, a secosteroid pro-hormone which reportedly acts as a negative regulatory factor of the RAS [3-6]. A dysfunction (e.g. over-reactivity) of RAS, together with hypovitaminosis D, is likely associated with some of the various renal, cardiac, vascular and immune outcomes that might be observed in COVID-19 patients, including the cytokine storm (i.e. unopposed hyperactive immune reaction generating both pro-inflammatory and anti-inflammatory cytokines) and consequent lethal acute respiratory distress syndrome [1, 7]. Recently, SARS-CoV-2 [8, 9], the causative agent of COVID-19, has been described to interfere with the RAS [2] by interacting -via its spike (S) glycoprotein- with the metallopeptidase Angiotensin-Converting Enzyme 2 (ACE2) receptor [9, 10] that is expressed at the surface of epithelial cells from blood vessels, lung, kidney (renal tubules), intestine, and heart, as well as on cerebral neurons and immune monocytes/macrophages [11-13]. The main SARS-CoV-2-related COVID-19 symptoms/diseases reported hitherto are hypertension, atherosclerosis, thrombosis (coagulopathy), diarrhea, glaucoma, anosmia, ageusia, skin lesions (dermatitis), autoimmune inflammation of the central nervous system, and damages to various organs such as the lung, heart, kidney, and testicle [1, 2, 14]. All these diffuse COVID-19 disorders are likely linked to an over-reaction of RAS in SARS-CoV-2-infected persons. Such a RAS imbalance would be also favored by hypovitaminosis D [2-7, 11]. Since RAS appears to be central in COVID-19 symptoms/diseases, selective targeting of key component(s) of this system might be appropriate to treat RAS-dependent disorders. COVID-19 Disorders: 'Renin-Angiotensin' System (RAS) & Counter-regulatory RAS In the RAS pathway [1, 15], Renin (kidney) cleaves Angiotensinogen (liver) to give Angiotensin I (i.e. peptide DRVYIHPFHL). The latter is cleaved by the Angiotensin-Converting Enzyme (ACE) to produce Angiotensin II (i.e. peptide DRVYIHPF), which is the substrate of ACE2 (SARS-CoV-2 receptor) and key player of the RAS. The cellular targets of Angiotensin II are the vasoconstrictor type 1 (AT1R) and vasodilatator type 2 (AT2R) Angiotensin II receptors (AT1R is expressed at the surface of monocytes/macrophages and T-cells indicating that RAS acts on innate immunity in host). When cleaved by ACE2, Angiotensin II gives Angiotensin 1-7 (i.e. peptide DRVYIHP), targeting the vasodilatator proto-oncogene Mas receptor (MasR). Angiotensin 1-7 can be further transformed to Alamandine (i.e. peptide ARVYIHP) by an aspartate decarboxylase. Alamandine would bind to the vasodilatator Mas-related G protein-coupled receptor member D (MRGD) thus promoting most of the Angiotensin 1-7-like effects. Angiotensin II can produce Angiotensin A (i.e. peptide ARVYIHPF) via an aspartate decarboxylase, and Alamandine via an additional ACE2 cleavage. ACE2 can also cleave Angiotensin I to form Angiotensin 1-9 (i.e. peptide DRVYIHPFH), which targets AT2R. In the RAS pathway were finally evidenced the related Angiotensin III (i.e. peptide RVYIHPF) and Angiotensin IV (i.e. peptide VYIHPF) variants targeting the AT1R and vasodilatator AT4R, respectively. From the known molecular functioning of the RAS, Angiotensins I and II (aside Angiotensin III) are playing central roles in the activity of RAS and associated pathologies, including COVID-19 [2, 10]. Interestingly, it appears that a 'counter-regulatory' RAS does exist to modulate system homeostasis; it relies on Angiotensin 1-7, Angiotensin 1-9, Alamandine, Angiotensin A, and Angiotensin IV, which are targeting the MasR, AT2R, MRGD, ACE2 and AT4R vasodilatator receptors, respectively. These peptides were found to exhibit cardioprotective, vasoactive (anti-hypertensive), anti-hypertrophic and/or anti-inflammatory potentials [15]. Such naturally-produced molecules of the RAS are expected to counteract the SARS-CoV-2-induced over-activation of RAS and reverse, to some extent, the associated COVID-19 diseases. CONCLUDING REMARKS A recent report suggests that RAS inhibitors may act on the severity of viral infection and mortality of COVID-19 patients [14]. Whether or not RAS blockers would be beneficial to COVID-19 cases is still controversial. The RAS inhibitors likely prevent the cytokine storm as RAS is reported to control the release of pro-inflammatory cytokines [1, 7]. It appears that COVID-19 disorders of SARS-CoV-2-infected humans depend on the RAS over-reacted by the (ACE2-dependent) viral infection and vitamin D deficiency. The track for a possible COVID-19 treatment would be to target RAS using specific candidate chemotherapeutic drugs. The proposed molecules are (so far) ACE inhibitors (to prevent the production of Angiotensin II from Angiotensin I), and blockers/antagonists of AT1R such as Losartan and derivatives. Recombinant ACE2 (under clinical trials) is also considered as a decoy for the recognition and competitive binding to the spike (S) glycoprotein of SARS-CoV-2 [9, 10]. We support the use of natural candidate peptide drugs that belong to the 'counter-regulatory' RAS, i.e. Angiotensin 1-7, Angiotensin 1-9, Alamandine, Angiotensin A and/or Angiotensin IV to treat COVID-19 disorders. The targeted receptors would thus be MasR, AT2R, MRGD, ACE2 and AT4R. The authors wish to thank Bonabes De Rougé MD for fruitful discussions.

positive: Dysfunctional Coagulation in COVID-19: From Cell to Bedside Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which can induce multisystem disease. Human angiotensin-converting enzyme 2 (ACE2) widely expressing in arterial and venous endothelial cells and arterial smooth muscle cells has been identified as a functional receptor for SARS-CoV-2. Dysfunction of ACE2 leads to abnormal activation of the renin-angiotensin system and a systemic endotheliitis that may relate to abnormal coagulation and sepsis. Meanwhile, innate immune response and inflammation activation participate in dysfunctional coagulation. Previous research indicated that dysfunctional coagulation was one of the important risk factors accountable for a high risk of severe disease and death in patients with COVID-19. Understanding the possible mechanisms of dysfunctional coagulation and appropriate anticoagulation therapeutic strategies are important to prevent disease deterioration and reduce fatality rates during the ongoing COVID-19 pandemic.

positive: The effect of angiotensin converting enzyme inhibitors and angiotensin receptor blockers on death and severity of disease in patients with coronavirus disease 2019 (COVID-19): A meta-analysis Background: Effect of angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) on outcomes in patients with coronavirus disease 2019 (COVID-19) is uncertain. Available evidence is limited to a few retrospective observational studies with small number of patients. Methods: We did a meta-analysis to assess the effect of ACEi/ARB in patients with COVID-19 on severity of disease, risk for hospitalisation, and death compared to those not on ACEi/ARB. We searched the Cochrane library, PubMed, Embase, ClinicalTrial.gov and medRxiv for studies published until 21.04.2020. Inclusion criteria included all studies with patients with confirmed COVID-19 either taking, or not taking, ACEi/ARB. Depending on degree of heterogeneity, fixed or random effect model was selected to calculate effect size (Odds ratio). Findings: Five studies were eligible for meta-analysis. These included 308 patients on ACEi/ARB, and 1172 not on ACEi/ARB. Compared to patients with COVID-19 not on ACEi/ARB, there was a statistically significant 44% reduction in odds of developing severe disease (OR: 0.56; 95% CI: 0.34-1.89, I2=68.15), and 62% reduction in odds of death (OR: 0.38; 95% CI: 0.19-0.74, I2=0.000) in those on ACEi/ARB. There was a non-significant 19% (OR 0.81; 95% CI: 0.42-1.55, I2: 0.000) reduction in odds of hospitalisation among those on ACEi/ARB. Interpretation: It is safe to use ACEi/ARB in patients with COVID-19 requiring these medications for associated comorbidities. Although limited by confounding factors typical of a meta-analysis of retrospective observational studies, our data suggests that use of these medications may reduce risk of developing severe disease and death. Funding Source: None

positive: Role of Dipeptidyl Peptidase 4 Inhibitors in Diabetic Patients with Coronavirus-19 Infection. The pandemic infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is widely increasing the patients affiliated with coronavirus disease 2019 (COVID-19) from last December of 2019. It's reported that the entry receptor of SARS-CoV-2 has been confirmed to be angiotensin converting enzymes 2 (ACE2). Notably, whether the ACE-related inhibitors or drugs modulated ACE2 activity in affecting with viral activity and disease severity of SARS-CoV-2 is still an open question. Dipeptidyl peptidase 4 (DDP-4), a well-known anti-diabetic drug, has been widely used to control the glycemic condition in diabetic patients. In this article, we are focusing on the impact of ACE inhibitors (ACEI) and DPP4 inhibitors used on SARS-CoV-2 activity and discussions about those drugs that may be related to infectious condition of COVID-19 diseases.

positive: Angiotensin converting enzyme 2 in the brain: properties and future directions Angiotensin (Ang) converting enzyme (ACE) 2 cleaves Ang-II into the vasodilator peptide Ang-(1-7), thus acting as a pivotal element in balancing the local effects of these peptides. ACE2 has been identified in various tissues and is supposed to be a modulator of cardiovascular function. Decreases in ACE2 expression and activity have been reported in models of hypertension, heart failure, atherosclerosis, diabetic nephropathy and others. In addition, the expression level and/or activity are affected by other renin-angiotensin system components (e.g. ACE and AT1 receptors). Local inhibition or global deletion of brain ACE2 induces a reduction in baroreflex sensitivity. Moreover, ACE2-null mice have been shown to exhibit either blood pressure (BP) or cardiac dysfunction phenotypes. On the other hand, over-expression of ACE2 exerts protective effects in local tissues, including the brain. In this review, we will first summarize the major findings linking ACE2 to cardiovascular function in the periphery then focus on recent discoveries related to ACE2 in the central nervous system. Finally, we will unveil new tools designed to address the importance of central ACE2 in various diseases, and discuss the potential for this carboxypeptidase as a new target in the treatment of hypertension and other cardiovascular diseases.

positive: Prevention and management of COVID-19 among patients with diabetes: an appraisal of the literature The coronavirus disease 2019 (COVID-19) pandemic has emerged as one of the greatest challenges faced by humankind in the recent past. People with diabetes and related comorbidities are at increased risk of its complications and of COVID-19-related death. Older age, multi-morbidity, hyperglycaemia, cardiac injury and severe inflammatory response are predictors of poor outcome. The complex interplay between COVID-19, diabetes and the effects of related therapies is being explored. Most patients experience a mild illness with COVID-19, while people with diabetes are at increased risk of severe disease. Optimising glycaemic control and adopting measures to prevent disease spread are critical aspects. The management of mild disease is supportive, while very many immunomodulatory and antiviral therapies are being investigated for the treatment of severe disease. Several of these agents have specific considerations for use in people with diabetes. Since mass population lockdowns are considered a key step in controlling disease spread, it follows that, in addition to the direct vulnerability to severe COVID-19, people with diabetes can be affected by limited access to healthcare, insulin, other medications and blood glucose monitoring equipment. Measures to prevent disease spread at the individual and community level are the key to mitigating the rapidly escalating pandemic, while agents for chemoprophylaxis and vaccines are being explored. People with diabetes should be recognised as a vulnerable group for complicated disease and are at risk during times of disturbed social systems. Strategies are needed to safeguard the health of patients with diabetes during the pandemic. This review summarises the current knowledge and perceived challenges for prevention and management of COVID-19 in people with diabetes.

positive: TWIRLS, an automated topic-wise inference method based on massive literature, suggests a possible mechanism via ACE2 for the pathological changes in the human host after coronavirus infection Faced with the current large-scale public health emergency, collecting, sorting, and analyzing biomedical information related to the “coronavirus” should be done as quickly as possible to gain a global perspective, which is a basic requirement for strengthening epidemic control capacity. However, for human researchers studying the viruses and the hosts, the vast amount of information available cannot be processed effectively and in a timely manner, particularly when the scientific understanding may be limited, which can further lower the information processing efficiency. We present TWIRLS, a method that can automatically acquire, organize, and classify information. Additionally, independent functional data sources can be added to build an inference system using a machine-based approach, which can provide relevant knowledge to help human researchers quickly establish subject cognition and to make more effective decisions. TWIRLS can automatically analyze more than three million words in more than 14,000 literature articles in only 4 hours. Combining with generalized gene interaction databases creates a data interface that can help researchers to further analyze the information. Using the TWIRLS system, we found that an important regulatory factor angiotensin-converting enzyme 2 (ACE2) may be involved in the host pathological changes on binding to the coronavirus after infection. After triggering functional changes in ACE2/AT2R, an imbalance in the steady-state cytokine regulatory axis involving the Renin-Angiotensin System and IP-10 leads to a cytokine storm.

positive: [Renin-angiotensin-aldosterone blockers and Covic-19 infection : friends or enemies ?] ACE2 is not only an enzyme that counters the effects of the renin-angiotensin-aldosterone system (RAAS) but is also the entry receptor for SARS-CoV-2, the virus of the Covid-19 pandemic. Some experimental data suggest that ACE inhibitors and ARBs increase ACE2 levels, thus raising concerns on their security in Covid-19 positive patients. However, some studies have shown protection by these drugs in lower tract respiratory infections and ARDS. The actual consensus is to continue the treatment with RAAS inhibitors, abrupt withdrawal, especially in patients with cardiac or renal conditions, being hazardous in terms of cardiovascular outcomes, except in patients hospitalized in intensive care with hemodynamic instability. This position statement is actually unanimous among all international learned societies.

positive: ANGIOTENSIN CONVERTING ENZYME 2 IN THE KIDNEY 1.. Angiotensin converting enzyme 2 (ACE2) is an important homeostatic component of the renin angiotensin system (RAS). ACE2 both degrades the vasoconstrictor, angiotensin II and generates the potent vasodilator peptide, angiotensin 1–7. These actions counterbalance those of ACE. 2.. ACE2 is highly expressed in the healthy kidney, particularly in the proximal tubules, where it colocalizes with ACE and angiotensin receptors. 3.. Kidney disease and subtotal nephrectomy is associated with a reduction in renal ACE2 expression, possibly facilitating the damaging effects of angiotensin II in the failing kidney. Acquired or genetic ACE2 deficiency also appears to exacerbate renal damage and albuminuria in experimental models, supporting this hypothesis. 4.. ACE2 also has an important role in blood pressure control. Many models of hypertension are associated with reduced ACE2 expression. Although ACE2 KO animals are normotensive, in states associated with activation of the RAS, ACE2 overexpression improves blood pressure control and reduces angiotensin responsiveness.

positive: Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues BACKGROUND: Since its discovery in December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected more than 2 180 000 people worldwide and has caused more than 150 000 deaths as of April 16, 2020. SARS-CoV-2, which is the virus causing coronavirus disease 2019 (COVID-19), uses the angiotensin-converting enzyme 2 (ACE2) as a cell receptor to invade human cells. Thus, ACE2 is the key to understanding the mechanism of SARS-CoV-2 infection. This study is to investigate the ACE2 expression in various human tissues in order to provide insights into the mechanism of SARS-CoV-2 infection. METHODS: We compared ACE2 expression levels across 31 normal human tissues between males and females and between younger (ages ≤ 49 years) and older (ages > 49 years) persons using two-sided Student’s t test. We also investigated the correlations between ACE2 expression and immune signatures in various tissues using Pearson’s correlation test. RESULTS: ACE2 expression levels were the highest in the small intestine, testis, kidneys, heart, thyroid, and adipose tissue, and were the lowest in the blood, spleen, bone marrow, brain, blood vessels, and muscle. ACE2 showed medium expression levels in the lungs, colon, liver, bladder, and adrenal gland. ACE2 was not differentially expressed between males and females or between younger and older persons in any tissue. In the skin, digestive system, brain, and blood vessels, ACE2 expression levels were positively associated with immune signatures in both males and females. In the thyroid and lungs, ACE2 expression levels were positively and negatively associated with immune signatures in males and females, respectively, and in the lungs they had a positive and a negative correlation in the older and younger groups, respectively. CONCLUSIONS: Our data indicate that SARS-CoV-2 may infect other tissues aside from the lungs and infect persons with different sexes, ages, and races equally. The different host immune responses to SARS-CoV-2 infection may partially explain why males and females, young and old persons infected with this virus have markedly distinct disease severity. This study provides new insights into the role of ACE2 in the SARS-CoV-2 pandemic.

positive: Recapitulation of SARS-CoV-2 Infection and Cholangiocyte Damage with Human Liver Organoids The newly emerged pandemic coronavirus, SARS-CoV-2, has posed a significant public health threat worldwide. However, the mode of virus transmission and tissue tropism is not well established yet. Recent findings of substantial liver damage in patients and ACE2+ cholangiocytes in healthy liver tissues prompted us to hypothesize that human liver ductal organoids could serve as a model to determine the susceptibility and mechanisms underlining the liver damage upon SARS-CoV-2 infection. By single-cell RNA sequencing, we found that long-term liver ductal organoid culture preserved the human specific ACE2+ population of cholangiocytes. Moreover, human liver ductal organoids were permissive to SARS-CoV-2 infection and support robust replication. Notably, virus infection impaired the barrier and bile acid transporting functions of cholangiocytes through dysregulation of genes involved in tight junction formation and bile acid transportation, which could explain the bile acid accumulation and consequent liver damage in patients. These results indicate that control of liver damage caused directly by viral infection should be valued in treating COVID-19 patients. Our findings also provide an application of human organoids in investigating the tropism and pathogenesis of SARS-CoV-2, which would facilitate novel drug discovery.

positive: Debate on Drugs That May Aggravate COVID-19

positive: The First 75 Days of Novel Coronavirus (SARS-CoV-2) Outbreak: Recent Advances, Prevention, and Treatment The recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, previously known as 2019-nCoV) outbreak has engulfed an unprepared world amidst a festive season. The zoonotic SARS-CoV-2, believed to have originated from infected bats, is the seventh member of enveloped RNA coronavirus. Specifically, the overall genome sequence of the SARS-CoV-2 is 96.2% identical to that of bat coronavirus termed BatCoV RaTG13. Although the current mortality rate of 2% is significantly lower than that of SARS (9.6%) and Middle East respiratory syndrome (MERS) (35%), SARS-CoV-2 is highly contagious and transmissible from human to human with an incubation period of up to 24 days. Some statistical studies have shown that, on average, one infected patient may lead to a subsequent 5.7 confirmed cases. Since the first reported case of coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 on December 1, 2019, in Wuhan, China, there has been a total of 60,412 confirmed cases with 1370 fatalities reported in 25 different countries as of February 13, 2020. The outbreak has led to severe impacts on social health and the economy at various levels. This paper is a review of the significant, continuous global effort that was made to respond to the outbreak in the first 75 days. Although no vaccines have been discovered yet, a series of containment measures have been implemented by various governments, especially in China, in the effort to prevent further outbreak, whilst various medical treatment approaches have been used to successfully treat infected patients. On the basis of current studies, it would appear that the combined antiviral treatment has shown the highest success rate. This review aims to critically summarize the most recent advances in understanding the coronavirus, as well as the strategies in prevention and treatment.

positive: COVID‐19 under spotlight: A close look at the origin, transmission, diagnosis, and treatment of the 2019‐nCoV disease Months after the outbreak of a new flu‐like disease in China, the entire world is now in a state of caution. The subsequent less‐anticipated propagation of the novel coronavirus disease, formally known as COVID‐19, not only made it to headlines by an overwhelmingly high transmission rate and fatality reports, but also raised an alarm for the medical community all around the globe. Since the causative agent, SARS‐CoV‐2, is a recently discovered species, there is no specific medicine for downright treatment of the infection. This has led to an unprecedented societal fear of the newly born disease, adding a psychological aspect to the physical manifestation of the virus. Herein, the COVID‐19 structure, epidemiology, pathogenesis, etiology, diagnosis, and therapy have been reviewed.

positive: Increasing Host Cellular Receptor—Angiotensin-Converting Enzyme 2 (ACE2) Expression by Coronavirus may Facilitate 2019-nCoV Infection The ongoing outbreak of a new coronavirus (2019-nCoV) causes an epidemic of acute respiratory syndrome in humans. 2019-nCoV rapidly spread to national regions and multiple other countries, thus, pose a serious threat to public health. Recent studies show that spike (S) proteins of 2019-nCoV and SARS-CoV may use the same host cell receptor called angiotensin-converting enzyme 2 (ACE2) for entering into host cells. The affinity between ACE2 and 2019-nCoV S is much higher than ACE2 binding to SARS-CoV S protein, explaining that why 2019-nCoV seems to be more readily transmitted from the human to human. Here, we reported that ACE2 can be significantly upregulated after infection of various viruses including SARS-CoV and MERS-CoV. Basing on findings here, we propose that coronavirus infection can positively induce its cellular entry receptor to accelerate their replication and spread, thus drugs targeting ACE2 expression may be prepared for the future emerging infectious diseases caused by this cluster of viruses.

positive: Renin-angiotensin-system, a potential pharmacological candidate, in acute respiratory distress syndrome during mechanical ventilation Abstract While effective treatments for acute respiratory distress syndrome (ARDS) are lacking, mechanical lung ventilation can sustain adequate gas exchange in critically ill patients with respiratory failure due to ARDS. However, as a result of the phenomenon of ventilator-induced lung injury (VILI), there is an increasing need to seek beneficial pharmacological therapies for ARDS. Recent studies have suggested the renin-angiotensin system (RAS), which consists of the ACE/Ang-II/AT1R axis and ACE2/Ang-(1–7)/MasR axis, plays a dual role in the pathogenesis of ARDS and VILI. This review highlights the deleterious action of ACE/Ang-II/AT1R axis and the beneficial role of ACE2/Ang-(1–7)/MasR axis, as well as AT2R, in VILI and ARDS, and also discusses the possibility of targeting RAS components with pharmacological interventions to improve outcomes in ARDS.

positive: Role of brain renin angiotensin system in neurodegeneration: An update Renin angiotensin system (RAS) is an endocrine system widely known for its physiological roles in electrolyte homeostasis, body fluid volume regulation and cardiovascular control in peripheral circulation. However, brain RAS is an independent form of RAS expressed locally in the brain, which is known to be involved in brain functions and disorders. There is strong evidence for a major involvement of excessive brain angiotensin converting enzyme (ACE)/Angiotensin II (Ang II)/Angiotensin type-1 receptor (AT-1R) axis in increased activation of oxidative stress, apoptosis and neuroinflammation causing neurodegeneration in several brain disorders. Numerous studies have demonstrated strong neuroprotective effects by blocking AT1R in these brain disorders. Additionally, the angiotensin converting enzyme 2 (ACE2)/Angiotensin (1–7)/Mas receptor (MASR), is another axis of brain RAS which counteracts the damaging effects of ACE/Ang II/AT1R axis on neurons in the brain. Thus, angiotensin II receptor blockers (ARBs) and activation of ACE2/Angiotensin (1–7)/MASR axis may serve as an exciting and novel method for neuroprotection in several neurodegenerative diseases. Here in this review article, we discuss the expression of RAS in the brain and highlight how altered RAS level may cause neurodegeneration. Understanding the pathophysiology of RAS and their links to neurodegeneration has enormous potential to identify potentially effective pharmacological tools to treat neurodegenerative diseases in the brain.

positive: Comparison of renin-angiotensin-aldosterone system inhibitors with other antihypertensives in association with coronavirus disease-19 clinical outcomes: systematic review and meta-analysis Introduction: The effects of renin-angiotensin-aldosterone system (RAAS) inhibitors on the clinical outcomes of coronavirus disease-19 (COVID-19) have been conflicting in different studies. This meta-analysis was undertaken to provide more conclusive evidence. Methods: A systematic search for published articles was performed in PubMed and EMBASE from January 5 2020 till May 5 2020. Studies that reported the clinical outcomes of patients with COVID-19, stratified by the class of concomitant antihypertensive drug therapy, were included. The Mantel-Haenszel random effects model was used to estimate pooled odds ratio (OR). Results: A total of 6,997 patients with COVID-19 were included, and all of them had hypertension. The overall risk of poor patient outcomes (severe COVID-19 or death) was lower in patients taking RAAS inhibitors (OR=0.84, 95% CI: [0.73, 0.96]; P=0.017) compared with those receiving non-RAAS inhibitor antihypertensives. Patients taking angiotensin-I-converting enzyme inhibitors (ACEIs) were less likely to experience poor clinical outcomes (OR=0.73, 95% CI: [0.58-0.92]; P=0.01) compared with those receiving angiotensin-II receptor blockers (ARBs). In addition, comparison of ACEIs to the rest of non-ACEI antihypertensives gave a consistently decreased risk of poor COVID-19 outcome (OR=0.77, 95% CI: [0.63-0.93]; P=0.002). However, ARBs did not decrease the risk of poor COVID-19 outcomes compared to all other non-ARB antihypertensives (OR=1.13, 95% CI: [0.95-1.35]). Conclusion: The risk of developing severe illness or death from COVID-19 was lower in patients who received RAAS inhibitors compared with those who took non-RAAS inhibitors. ACEIs might be better in decreasing the severity and mortality of COVID-19 than ARBs.

positive: TWIRLS, an automated topic-wise inference method based on massive literature, suggests a possible mechanism via ACE2 for the pathological changes in the human host after coronavirus infection Faced with the current large-scale public health emergency, collecting, sorting, and analyzing biomedical information related to the "coronavirus" should be done as quickly as possible to gain a global perspective, which is a basic requirement for strengthening epidemic control capacity. However, for human researchers studying the viruses and the hosts, the vast amount of information available cannot be processed effectively and in a timely manner, particularly when the scientific understanding may be limited, which can further lower the information processing efficiency. We present TWIRLS, a method that can automatically acquire, organize, and classify information. Additionally, independent functional data sources can be added to build an inference system using a machine-based approach, which can provide relevant knowledge to help human researchers quickly establish subject cognition and to make more effective decisions. TWIRLS can automatically analyze more than three million words in more than 14,000 literature articles in only 4 hours. Combining with generalized gene interaction databases creates a data interface that can help researchers to further analyze the information. Using the TWIRLS system, we found that an important regulatory factor angiotensin-converting enzyme 2 (ACE2) may be involved in the host pathological changes on binding to the coronavirus after infection. After triggering functional changes in ACE2/AT2R, an imbalance in the steady-state cytokine regulatory axis involving the Renin-Angiotensin System and IP-10 leads to a cytokine storm.

positive: Is There an Association Between COVID-19 Mortality and the Renin-Angiotensin System—a Call for Epidemiologic Investigations Mortality from coronavirus disease 2019 (COVID-19) is strongly associated with cardiovascular disease, diabetes, and hypertension. These disorders share underlying pathophysiology related to the renin-angiotensin system (RAS) that may be clinically insightful. In particular, activity of the angiotensin-converting enzyme 2 (ACE2) is dysregulated in cardiovascular disease, and this enzyme is used by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to initiate the infection. Cardiovascular disease and pharmacologic RAS inhibition both increase ACE2 levels, which may increase the virulence of SARS-CoV-2 within the lung and heart. Conversely, mechanistic evidence from related coronaviruses suggests that SARS-CoV-2 infection may downregulate ACE2, leading to toxic overaccumulation of Angiotensin II that induces acute respiratory distress syndrome and fulminant myocarditis. RAS inhibition could mitigate this effect. With conflicting mechanistic evidence, we propose key clinical research priorities necessary to clarify the role of RAS inhibition in COVID-19 mortality that could be rapidly addressed by the international research community.

positive: Overview of Covid-19 regarding the cardiovascular situation in the light of current reports Nowadays coronavirus disease 2019 (Covid-19) is increasing mortality all over the world mercilessly. We are learning almost every day about its new symptoms and that it mutates quickly. This disease ties us up and leaves us desperate. Death from this disease has increased in patients who had with pre-existing medical conditions, especially cardiovascular ones, by eliminating the angiotensin-converting enzyme (ACE)-2 receptor in the lungs. Also, ACE1 and angiotensin receptor blockers (ARB) may stimulate ACE2 expression and worse the prognosis. Intravenous infusions of ACEIs and ARBs in experimental animals increase the numbers of ACE2 receptors. So, it may be one of the reasons that COVID-19 infects the cells of patients treating hypertension. However, most of the congress of cardiology do not recommend discontinue of these anti-hypertensive drugs. Therefore, this brief report evaluates Covid-19 in the view of cardiovascular diseases taking into account current reports and suggests some possible solutions to keep the virus under control.

positive: Potential harmful effects of discontinuing ACE-inhibitors and ARBs in COVID-19 patients The discovery of angiotensin converting enzyme-2 (ACE-2) as the receptor for SARS- CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) has implicated the renin-angiotensin-aldosterone system in acute respiratory distress syndrome (ARDS) and respiratory failure in patients with coronavirus disease-19 (COVID-19). The angiotensin converting enzyme-1-angiotensin II-angiotensin AT1 receptor pathway contributes to the pathophysiology of ARDS, whereas activation of the ACE-2-angiotensin(1-7)-angiotensin AT2 receptor and the ACE-2-angiotensin(1-7)-Mas receptor pathways have been shown to be protective. Here we propose and discuss therapeutic considerations how to increase soluble ACE-2 in plasma in order for ACE-2 to capture and thereby inactivate SARS-CoV-2. This could be achieved by administering recombinant soluble ACE-2. We also discuss why and how ACEIs and ARBs provide cardiovascular, renal and also pulmonary protection in SARS-CoV-2- associated ARDS. Discontinuing these medications in COVID-19 patients may therefore potentially be harmful.

positive: Coronaviridae: a review of coronaviruses and toroviruses

positive: A hypothesis for pathobiology and treatment of COVID-19: the centrality of ACE1/ACE2 imbalance. Angiotensin converting enzyme-2 (ACE2) is the receptor for the coronavirus SARS-CoV-2, which causes COVID-19. We propose the following hypothesis: Imbalance in the action of ACE1- and ACE2-derived peptides, thereby enhancing Angiotensin-II (ANG II) signaling, a primary driver of COVID-19 pathobiology. ACE1/ACE2 imbalance occurs due to the binding of SARS-CoV-2 to ACE2, reducing ACE2-mediated conversion of ANG II to ANG peptides that counteract pathophysiological effects of ACE1-generated ANGII. This hypothesis suggests several approaches to treat COVID-19 by restoring ACE1/ACE2 balance: 1) ANG II receptor blockers (ARBs); 2) ACE1 inhibitors (ACEIs); 3) Agonists of receptors activated by ACE2-derived peptides [e.g., ANG (1-7), which activates MAS1]; 4) Recombinant human ACE2 or ACE2 peptides as decoys for the virus. Reducing ACE1/ACE2 imbalance is predicted to blunt COVID-19-associated morbidity and mortality, especially in vulnerable patients. Importantly, approved ARBs and ACEIs can be rapidly repurposed to test their efficacy in treating COVID-19.

positive: Computational Design of ACE2-Based Peptide Inhibitors of SARS-CoV-2 [Image: see text] Peptide inhibitors against the SARS-CoV-2 coronavirus, currently causing a worldwide pandemic, are designed and simulated. The inhibitors are mostly formed by two sequential self-supporting α-helices (bundle) extracted from the protease domain (PD) of angiotensin-converting enzyme 2 (ACE2), which bind to the SARS-CoV-2 receptor binding domains. Molecular dynamics simulations revealed that the α-helical peptides maintain their secondary structure and provide a highly specific and stable binding (blocking) to SARS-CoV-2. To provide a multivalent binding to the SARS-CoV-2 receptors, many such peptides could be attached to the surfaces of nanoparticle carriers. The proposed peptide inhibitors could provide simple and efficient therapeutics against the COVID-19 disease.

positive: A Viewpoint on Angiotensin-Converting Enzyme 2, Anti-Hypertensives and Coronavirus Disease 2019 (COVID-19)

positive: Spontaneous Hinge-Bending Motions of Angiotensin I Converting Enzyme: Role in Activation and Inhibition The inhibition of human angiotensin I converting enzyme (ACE) has been regarded as a promising approach for the treatment of hypertension. Despite research attempts over many years, our understanding the mechanisms of activation and inhibition of ACE is still far from complete. Here, we present results of all atom molecular dynamics simulations of ACE with and without ligands. Two types of inhibitors, competitive and mixed non-competitive, were used to model the ligand bound forms. In the absence of a ligand the simulation showed spontaneous large hinge-bending motions of multiple conversions between the closed and open states of ACE, while the ligand bound forms were stable in the closed state. Our simulation results imply that the equilibrium between pre-existing backbone conformations shifts in the presence of a ligand. The hinge-bending motion of ACE is considered as an essential to the enzyme function. A mechanistic model of activation and the inhibition may provide valuable information for novel inhibitors of ACE.

positive: Cardiovascular Disease and Use of Renin-Angiotensin System Inhibitors in COVID-19 There is ongoing debate on the safety of renin-angiotensin system (RAS) inhibitors in COVID-19. Recently published studies highlight a potential relationship between cardiovascular disease (CVD) and COVID-19. This article aims to summarize the evidence on the use of RAS inhibitors in CVD patients with COVID-19, focusing on safety issues of the RAS inhibitors and their relationship with COVID-19.

positive: SARS-CoV2: should inhibitors of the renin–angiotensin system be withdrawn in patients with COVID-19?

positive: Renin-Angiotensin-Aldosterone System Inhibitors and Risk of Covid-19 BACKGROUND: There is concern about the potential of an increased risk related to medications that act on the renin-angiotensin-aldosterone system in patients exposed to coronavirus disease 2019 (Covid-19), because the viral receptor is angiotensin-converting enzyme 2 (ACE2). METHODS: We assessed the relation between previous treatment with ACE inhibitors, angiotensin-receptor blockers, beta-blockers, calcium-channel blockers, or thiazide diuretics and the likelihood of a positive or negative result on Covid-19 testing as well as the likelihood of severe illness (defined as intensive care, mechanical ventilation, or death) among patients who tested positive. Using Bayesian methods, we compared outcomes in patients who had been treated with these medications and in untreated patients, overall and in those with hypertension, after propensity-score matching for receipt of each medication class. A difference of at least 10 percentage points was prespecified as a substantial difference. RESULTS: Among 12,594 patients who were tested for Covid-19, a total of 5894 (46.8%) were positive; 1002 of these patients (17.0%) had severe illness. A history of hypertension was present in 4357 patients (34.6%), among whom 2573 (59.1%) had a positive test; 634 of these patients (24.6%) had severe illness. There was no association between any single medication class and an increased likelihood of a positive test. None of the medications examined was associated with a substantial increase in the risk of severe illness among patients who tested positive. CONCLUSIONS: We found no substantial increase in the likelihood of a positive test for Covid-19 or in the risk of severe Covid-19 among patients who tested positive in association with five common classes of antihypertensive medications.

positive: NON-WHITE ETHNICITY, MALE SEX, AND HIGHER BODY MASS INDEX, BUT NOT MEDICATIONS ACTING ON THE RENIN-ANGIOTENSIN SYSTEM ARE ASSOCIATED WITH CORONAVIRUS DISEASE 2019 (COVID-19) HOSPITALISATION: REVIEW OF THE FIRST 669 CASES FROM THE UK BIOBANK Background: Cardiometabolic morbidity and medications, specifically Angiotensin Converting Enzyme inhibitors (ACEi) and Angiotensin Receptor Blockers (ARBs), have been linked with adverse outcomes from coronavirus disease 2019 (COVID-19). This study aims to investigate factors associated with COVID-19 positivity for the first 669 UK Biobank participants; compared with individuals who tested negative, and with the untested, presumed negative, rest of the population. Methods: We studied 1,474 participants from the UK Biobank who had been tested for COVID-19. Given UK testing policy, this implies a hospital setting, suggesting at least moderate to severe symptoms. We considered the following exposures: age, sex, ethnicity, body mass index (BMI), diabetes, hypertension, hypercholesterolaemia, ACEi/ARB use, prior myocardial infarction (MI), and smoking. We undertook comparisons between: 1) COVID-19 positive and COVID-19 tested negative participants; and 2) COVID-19 tested positive and the remaining participants (tested negative plus untested, n=501,837). Logistic regression models were used to investigate univariate and mutually adjusted associations. Results: Among participants tested for COVID-19, non-white ethnicity, male sex, and greater BMI were independently associated with COVID-19 positive result. Non-white ethnicity, male sex, greater BMI, diabetes, hypertension, prior MI, and smoking were independently associated with COVID-19 positivity compared to the remining cohort (test negatives plus untested). However, similar associations were observed when comparing those who tested negative for COVID-19 with the untested cohort; suggesting that these factors associate with general hospitalisation rather than specifically with COVID-19. Conclusions: Among participants tested for COVID-19 with presumed moderate to severe symptoms in a hospital setting, non-white ethnicity, male sex, and higher BMI are associated with a positive result. Other cardiometabolic morbidities confer increased risk of hospitalisation, without specificity for COVID-19. Notably, ACE/ARB use did not associate with COVID-19 status.

positive: Antihypertensive drugs and risk of COVID-19? - Authors' reply

positive: Angiotensin-converting enzyme 2 prevents lipopolysaccharide-induced rat acute lung injury via suppressing the ERK1/2 and NF-κB signaling pathways Acute respiratory distress syndrome (ARDS) caused by severe sepsis remains a major challenge in intensive care medicine. ACE2 has been shown to protect against lung injury. However, the mechanisms of its protective effects on ARDS are largely unknown. Here, we report that ACE2 prevents LPS-induced ARDS by inhibiting MAPKs and NF-κB signaling pathway. Lentiviral packaged Ace2 cDNA or Ace2 shRNA was intratracheally administrated into the lungs of male SD rats. Two weeks after gene transfer, animals received LPS (7.5 mg/Kg) injection alone or in combination with Mas receptor antagonist A779 (10 μg/Kg) or ACE2 inhibitor MLN-4760 (1 mg/Kg) pretreatment. LPS-induced lung injury and inflammatory response were significantly prevented by ACE2 overexpression and deteriorated by Ace2 shRNA. A779 or MLN-4760 pretreatment abolished the protective effects of ACE2. Moreover, overexpression of ACE2 significantly reduced the Ang II/Ang-(1-7) ratio in BALF and up-regulated Mas mRNA expression in lung, which was reversed by A779. Importantly, the blockade of ACE2 on LPS-induced phosphorylation of ERK1/2, p38 and p50/p65 was also abolished by A779. Whereas, only the ERK1/2 inhibitor significantly attenuated lung injury in ACE2 overexpressing rats pretreated with A779. Our observation suggests that AEC2 attenuates LPS-induced ARDS via the Ang-(1-7)/Mas pathway by inhibiting ERK/NF-κB activation.

positive: Comment on “ACE inhibitors and COVID‐19: We don't know yet”

positive: The evolving role of the renin–angiotensin system in ARDS

positive: Lessons from SARS: control of acute lung failure by the SARS receptor ACE2 Angiotensin-converting enzyme 2 (ACE2), a second angiotensin-converting enzyme (ACE), regulates the renin–angiotensin system by counterbalancing ACE activity. Accumulating evidence in recent years has demonstrated a physiological and pathological role of ACE2 in the cardiovascular systems. Recently, it has been shown that severe acute respiratory syndrome (SARS) coronavirus, the cause of SARS, utilizes ACE2 as an essential receptor for cell fusion and in vivo infections in mice. Intriguingly, ACE2 acts as a protective factor in various experimental models of acute lung failure and, therefore, acts not only as a key determinant for SARS virus entry into cells but also contributes to SARS pathogenesis. Here we review the role of ACE2 in disease pathogenesis, including lung diseases and cardiovascular diseases.

positive: Controversial Relationship Between Renin-Angiotensin System Inhibitors and Severity of COVID-19: Announcing a Large Multicentre Case-Control Study in Italy

positive: Judicious Use of Sodium-Glucose Cotransporter 2 Inhibitors in Patients with Diabetes on Coronavirus-19 Pandemic. Sodium glucose cotransporter-2 inhibitors (SGLT2i), a novel anti-diabetic drug blocks the reabsorption of glucose in proximal tubules of kidney, are demonstrated to have cardiovascular and renal benefits for people with diabetes. The benefits are associated with the significant increase of intrarenal angiotensin-converting enzyme II (ACE2) expression and blood volume contraction. However, the increased ACE2 may be detrimental to patients infected with the coronavirus infection 2019 (COVID-19), which is found to invades cells via the entry receptor of ACE2. Besides, SGLT2i induced natriuretic effect may also increase the risk of acute kidney injury and affect the hemodynamic stability during systemic infection disease. In the article, we explain the mechanisms why the use of SGLT2i in people with diabetes may lead to worse outcomes and suggest clinician to judiciously use it during COVID-19 pandemic.

positive: Inhibitors of the renin-angiotensin system: The potential role in the pathogenesis of COVID-19 Coronavirus disease 2019 (COVID-19), which initially began in China, has spread to other countries of Asia, Europe, America, Africa and Oceania, with the number of confirmed cases and suspected cases increasing each day. According to recently published research, it was found that the majority of the severe cases were elderly, and many of them had at least one chronic disease, especially cardiovascular diseases. Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs) are the most widely used drugs for cardiovascular diseases. The clinical effect of ACEIs/ARBs on patients with COVID-19 is still uncertain. This paper describes their potential role in the pathogenesis of COVID-19, which may provide useful in the advice of cardiologists and physicians.

positive: Binding of SARS-CoV-2 and angiotensin-converting enzyme 2: clinical implications

positive: Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2 Angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for severe acute respiratory syndrome–coronavirus (SARS-CoV) and the new coronavirus (SARS-CoV-2) that is causing the serious coronavirus disease 2019 (COVID-19) epidemic. Here, we present cryo–electron microscopy structures of full-length human ACE2 in the presence of the neutral amino acid transporter B(0)AT1 with or without the receptor binding domain (RBD) of the surface spike glycoprotein (S protein) of SARS-CoV-2, both at an overall resolution of 2.9 angstroms, with a local resolution of 3.5 angstroms at the ACE2-RBD interface. The ACE2-B(0)AT1 complex is assembled as a dimer of heterodimers, with the collectrin-like domain of ACE2 mediating homodimerization. The RBD is recognized by the extracellular peptidase domain of ACE2 mainly through polar residues. These findings provide important insights into the molecular basis for coronavirus recognition and infection.

positive: Immunopathogenesis of coronavirus infections: implications for SARS At the end of 2002, the first cases of severe acute respiratory syndrome (SARS) were reported, and in the following year, SARS resulted in considerable mortality and morbidity worldwide. SARS is caused by a novel species of coronavirus (SARS-CoV) and is the most severe coronavirus-mediated human disease that has been described so far. On the basis of similarities with other coronavirus infections, SARS might, in part, be immune mediated. As discussed in this Review, studies of animals that are infected with other coronaviruses indicate that excessive and sometimes dysregulated responses by macrophages and other pro-inflammatory cells might be particularly important in the pathogenesis of disease that is caused by infection with these viruses. It is hoped that lessons from such studies will help us to understand more about the pathogenesis of SARS in humans and to prevent or control outbreaks of SARS in the future.

positive: The ACE-2 in COVID-19: Foe or Friend? COVID-19 is a rapidly spreading outbreak globally. Emerging evidence demonstrates that older individuals and people with underlying metabolic conditions of diabetes mellitus, hypertension, and hyperlipidemia are at higher risk of morbidity and mortality. The SARS-CoV-2 infects humans through the angiotensin converting enzyme (ACE-2) receptor. The ACE-2 receptor is a part of the dual system renin-angiotensin-system (RAS) consisting of ACE-Ang-II-AT (1) R axis and ACE-2-Ang-(1–7)-Mas axis. In metabolic disorders and with increased age, it is known that there is an upregulation of ACE-Ang-II-AT (1) R axis with a downregulation of ACE-2-Ang-(1–7)-Mas axis. The activated ACE-Ang-II-AT1R axis leads to pro-inflammatory and pro-fibrotic effects in respiratory system, vascular dysfunction, myocardial fibrosis, nephropathy, and insulin secretory defects with increased insulin resistance. On the other hand, the ACE-2-Ang-(1–7)-Mas axis has anti-inflammatory and antifibrotic effects on the respiratory system and anti-inflammatory, antioxidative stress, and protective effects on vascular function, protects against myocardial fibrosis, nephropathy, pancreatitis, and insulin resistance. In effect, the balance between these two axes may determine the prognosis. The already strained ACE-2-Ang-(1–7)-Mas in metabolic disorders is further stressed due to the use of the ACE-2 by the virus for entry, which affects the prognosis in terms of respiratory compromise. Further evidence needs to be gathered on whether modulation of the renin angiotensin system would be advantageous due to upregulation of Mas activation or harmful due to the concomitant ACE-2 receptor upregulation in the acute management of COVID-19.

positive: The potential genetic network of human brain SARS-CoV-2 infection The literature reports several symptoms of SARS-CoV-2 in humans such as fever, cough, fatigue, pneumonia, and headache. Furthermore, patients infected with similar strains (SARS-CoV and MERS-CoV) suffered testis, liver, or thyroid damage. Angiotensin-converting enzyme 2 (ACE2) serves as an entry point into cells for some strains of coronavirus (SARS-CoV, MERS-CoV, SARS-CoV-2). Our hypothesis was that as ACE2 is essential to the SARS-CoV-2 virus invasion, then brain regions where ACE2 is the most expressed are more likely to be disturbed by the infection. Thus, the expression of other genes which are also over-expressed in those damaged areas could be affected. We used mRNA expression levels data of genes provided by the Allen Human Brain Atlas (ABA), and computed spatial correlations with the LinkRbrain platform. Genes whose co-expression is spatially correlated to that of ACE2 were then clustered into 16 groups, depending on the organ in which they are the most expressed (as described by the NCBI genes database). The list of organs where genes sharing local over-expression with the ACE2 gene are the most expressed is astonishingly similar to the organs affected by Covid-19.

positive: Severe acute respiratory syndrome coronavirus 2 infection, angiotensin-converting enzyme 2 and treatment with angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers

positive: Cardiovascular Pharmacology in the Time of COVID-19: A Focus on Angiotensin-Converting Enzyme 2 Coronavirus disease-2019 (COVID-19) has emerged as a pandemic affecting millions of adults. Severe acute respiratory syndrome coronavirus-2019 (SARS-CoV-2), the causative virus of COVID-19, infects host cells through angiotensin-converting enzyme 2 (ACE2). Preclinical models suggest that ACE2 upregulation confers protective effects in acute lung injury. In addition, renin-angiotensin aldosterone system inhibitors reduce adverse atherosclerotic cardiovascular disease, heart failure, and chronic kidney disease outcomes, but may increase ACE2 levels. We review current knowledge of the role of ACE2 in cardiovascular physiology and SARS-CoV-2 virology, as well as clinical data to inform the management of patients with or at risk for COVID-19 who require renin-angiotensin-aldosterone system inhibitor therapy.

positive: The effect of RAS blockers on the clinical characteristics of COVID-19 patients with hypertension Background: Coronavirus disease 2019 (COVID-19), caused by a novel coronavirus (designated as SARS-CoV-2) has become a pandemic worldwide. Based on the current reports, hypertension may be associated with increased risk of sever condition in hospitalized COVID-19 patients. Angiotensin-converting enzyme 2 (ACE2) was recently identified to functional receptor of SARS-CoV-2. Previous experimental data revealed ACE2 level was increased following treatment with ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Currently doctors concern whether these commonly used renin-angiotensin system (RAS) blockers-ACEIs/ARBs may increase the severity of COVID-19. Methods: We extracted data regarding 50 hospitalized hypertension patients with laboratory confirmed COVID-19 in the Renmin Hospital of Wuhan University from Feb 7 to Mar 03, 2020. These patients were grouped into RAS blockers group (Group A, n=20) and non-RAS blockers group (Group B, n=30) according to the basic blood pressure medications. All patients continued to use pre-admission antihypertensive drugs. Clinical severity (symptoms, laboratory and chest CT findings, etc.), clinical course, and short time outcome were analyzed after hospital admission. Results: Ten (50%) and seventeen (56.7%) of the Group A and Group B participants were males (P=0.643), and the average age was 52.65±13.12 and 67.77±12.84 years (P=0.000), respectively. The blood pressure of both groups was under effective control. There was no significant difference in clinical severity, clinical course and in-hospital mortality between Group A and Group B. Serum cardiac troponin I (cTnI) (P=0.03), and N-terminal (NT)-pro hormone BNP (NT-proBNP) (P=0.04) showed significant lower level in Group A than in Group B. But the patients with more than 0.04ng/mL or elevated NT-proBNP level had no statistical significance between the two groups. In patients over 65 years or under 65 years, cTnI or NT-proBNP level showed no difference between the two groups. Conclusions: We observed there was no obvious difference in clinical characteristics between RAS blockers and non-RAS blockers groups. These data suggest ACEIs/ARBs may have few effects on increasing the clinical severe conditions of COVID-19.

positive: Multiomics Evaluation of Gastrointestinal and Other Clinical Characteristics of COVID-19

positive: Cardiovascular disease management during the coronavirus disease 2019 pandemic Based on clinical presentation, pathophysiology, high infectivity, high cardiovascular involvement, and therapeutic agents with cardiovascular toxicity of coronavirus disease 2019 (COVID-19), regular cardiovascular treatment is being changing greatly. Despite angiotensin-converting enzyme 2 serving as the portal for infection, the continuation of clinically indicated renin-angiotensin-aldosterone blockers is recommended according to the present evidence. Fibrinolytic therapy can be considered a reasonable option for the relatively stable ST segment elevation myocardial infarction (STEMI) patient with suspected or known COVID-19. However, primary percutaneous coronary intervention is still the standard of care in patients with definite STEMI if personal protective equipment is available and cardiac catheterization laboratory has a good infection control. In patients with elevated cardiac enzymes, it is very important to differentiate patients with Type 2 myocardial infarction or myocarditis from those with true acute coronary syndromes because invasive percutaneous intervention management in the former may be unnecessary, especially if they are hemodynamically stable. Finally, patients with baseline QT prolongation or those taking QT prolonging drugs must be cautious when treating with lopinavir/ritonavir and hydroxychloroquine for COVID-19.

positive: Relevance of enriched expression of SARS-CoV-2 binding receptor ACE2 in gastrointestinal tissue with pathogenesis of digestive symptoms, diabetes-associated mortality, and disease recurrence in COVID-19 patients Introduction COVID-19, is caused by a new strain of coronavirus called SARS-coronavirus-2 (SARS-CoV-2), which is a positive sense single strand RNA virus. In humans, it binds to angiotensin converting enzyme 2 (ACE2) with the help a structure on its surface called the S-spike. COVID-19 poses intriguing issues with imperative relevance to clinicians. The pathogenesis of GI symptoms, diabetes-associated mortality, and disease recurrence in COVID-19 are of particular relevance because they cannot be sufficiently explained from the existing knowledge of the viral diseases. Tissue specific variation of ACE2 expression in healthy individuals can help in understanding the pathophysiological basis the aforementioned collection of symptoms. Materials and Methods The data were downloaded from the Human Protein Atlas available at (https://www.proteinatlas.org/search/ACE2) and the tissue specific expression (both mRNA and protein) of ACE2 as yielded from the studies with RNA sequencing and immunohistochemistry (IHC) was analyzed as a function of the various components of the digestive tract. A digestive system specific functional enrichment map of ACE2 gene was created using g:profiler (https://biit.cs.ut.ee/gprofiler/gost) utility and the data were visualized using Cytoscape software, version 3.7.2 (https://cytoscape.org/). Results The correlated expression (genomic and proteomic) of ACE2 (to which SARS-CoV-2 binds through the S-spike) was found to be enriched in the lower gastrointestinal tract (GIT) (highest in small intestine, followed by colon and rectum), and was undetectable in the upper GIT components: mouth cavity (tongue, oral mucosa, and salivary glands), esophagus, and stomach. High expression of ACE2 was noted in the glandular cells as well as in the enterocytes in the lining epithelium (including brush border epithelium). Among other digestive system organs, gallbladder (GB) showed high expression of ACE2 in glandular cells, while any protein expression was undetectable in liver and pancreas. Conclusions Based on the findings of this study and supportive evidence from the literature we propose that a SARS-CoV-2 binding with ACE2 mediates dysregulation of the sodium dependent nutrient transporters and hence may be a plausible basis for the digestive symptoms in COVID-19 patients. ACE2 mediated dysregulation of sodium dependent glucose transporter (SGLT1 or SLC5A1) in the intestinal epithelium also links it to the pathogenesis of diabetes mellitus which can be a possible reason for the associated mortality in COVID-19 patients with diabetes. High expression of ACE2 in mucosal cells of the intestine and GB make these organs potential sites for the virus entry and replication. Continued replication of the virus at these ACE2 enriched sites may be a basis for the disease recurrence reported in some, thought to be cured, patients. Highlights SARS-CoV-2 binding receptor ACE2 expression is enriched in human intestine ACE2 regulates neutral amino acid (B0AT1) and glucose transporter (SGLT1) in intestinal epithelium Mucus secreted from GI cells may protect SARS-CoV-2 from harsh pH levels of the digestive juices Continued replication of SARS-CoV-2 in GI cells may cause disease recurrence Graphical Abstract

positive: 2019 CORONAVIRUS: What are the implications for cardiology?

positive: ACE2 X-ray structures reveal a large hinge-bending motion important for inhibitor binding and catalysis. The angiotensin-converting enzyme (ACE)-related carboxypeptidase, ACE2, is a type I integral membrane protein of 805 amino acids that contains one HEXXH + E zinc-binding consensus sequence. ACE2 has been implicated in the regulation of heart function and also as a functional receptor for the coronavirus that causes the severe acute respiratory syndrome (SARS). To gain further insights into this enzyme, the first crystal structures of the native and inhibitor-bound forms of the ACE2 extracellular domains were solved to 2.2- and 3.0-A resolution, respectively. Comparison of these structures revealed a large inhibitor-dependent hinge-bending movement of one catalytic subdomain relative to the other ( approximately 16 degrees ) that brings important residues into position for catalysis. The potent inhibitor MLN-4760 ((S,S)-2-[1-carboxy-2-[3-(3,5-dichlorobenzyl)-3H-imidazol4-yl]-ethylamino]-4-methylpentanoic acid) makes key binding interactions within the active site and offers insights regarding the action of residues involved in catalysis and substrate specificity. A few active site residue substitutions in ACE2 relative to ACE appear to eliminate the S(2)' substrate-binding subsite and account for the observed reactivity change from the peptidyl dipeptidase activity of ACE to the carboxypeptidase activity of ACE2.

positive: Management and Treatment of COVID-19: The Chinese Experience Abstract With over 1,800,000 cases and 110,000 deaths globally, COVID-19 is one of worst infectious disease outbreaks in history. The objective of this paper is to critically review the available evidence regarding the lessons learned from the Chinese experience regarding COVID-19 prevention and management. The steps that have led to a near disappearance of new cases in China included rapid sequencing of the virus to establish testing kits which allowed tracking of infected persons in and out of Wuhan. In addition, aggressive quarantine measures included the complete isolation of Wuhan and then later Hebei and the rest of the country, as well as closure of all schools and non-essential businesses. Other measures included the rapid construction of two new hospitals and the establishment of Fangcang shelter hospitals. In the absence of a vaccine, the management of COVID-19 included antivirals, high flow oxygen, mechanical ventilation, corticosteroids, hydroxychloroquine, tocilizumab, interferons, intravenous immunoglobulin and convalescent plasma infusions. These measures appeared to provide only moderate success. While some measures have been supported by weak descriptive data, their effectiveness is still unclear pending well-controlled clinical trials. In the end, it was the enforcement of drastic quarantine measures that stopped SARS-CoV-2 from spreading. The earlier the implementation, the less likely resources will be depleted. The most critical factors in stopping a pandemic are early recognition of infected individuals, carriers and contacts, and early implementation of quarantine measures with an organized, proactive and unified strategy at a national level. Delays result in significantly higher death tolls.

positive: Compensation of ACE2 Function for Possible Clinical Management of 2019-nCoV-Induced Acute Lung Injury

positive: Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may be harmful in patients with diabetes during COVID-19 pandemic The novel coronavirus disease 2019 (COVID-19) outbreak once again demonstrated the importance of the renin-angiotensin system (RAS) in patients with diabetes. Activation of the RAS increases in patients with diabetes. The virus attaches to the ACE2 enzyme at low cytosolic pH values and enters into the cell and causes infection. Especially in the presence of diabetes mellitus and accompanying comorbid conditions such as hypertension, obesity, old age, and smoking, cytosolic pH is low, thus the virus easily may enter the cell by attaching to ACE2. ACEIs and ARBs lead to a reduction in angiotensin II level by increasing the ACE2 level, thus they cause a low cytosolic pH. Increased cardiac ACE2 levels due to ACEIs and ARBs can trigger cardiac arrhythmias and myocarditis by causing the virus to easily enter the heart tissue. There is ACE2 activity in the rostral ventrolateral medulla in the brain stem. The release of angiotensin 1-7 in the brain stem leads to the activation of the sympathetic nervous system. This activation causes systemic vasoconstriction and the patient's blood pressure increases. The most important event is the increased sympathetic activity via the central stimulation, this activity increases pulmonary capillary leaking, causing the ARDS. As the cytosolic pH, which is already low in patients with diabetes will decrease further with the mechanisms mentioned above, the viral load will increase and the infection will be exacerbated. As a result, the use of ACEIs and ARBs in patients with diabetes can lead to increased morbidity and mortality of COVID-19.

positive: [2019 Novel coronavirus, renin-angiotension system imbalance and coronavirus disease 2019]. 2019 Novel coronavirus (2019-nCoV) destroys angiotensin converting enzyme 2 (ACE2) and breaks the balance of renin-angiotension system (RAS) by interacting with ACE2. The imbalance of RAS takes part in the development of organ injury of different systems through pro-inflammation, oxidative stress, cell proliferation and so on. 2019-nCoV not only attacks the lung, but also influences many other systems. It is speculated that RAS imbalance plays an important role in the development of multi-organ dysfunction caused by 2019-nCoV, and the usage of angiotensin converting enzyme inhibitor/angiotensin II receptor blocker (ACEI/ARB) may become a new treatment of 2019-nCoV-related organ injury. Further studies are need to confirm the relationship between coronavirus infection, multi-organ injury and RAS imbalance.

positive: Association of Inpatient Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Mortality Among Patients With Hypertension Hospitalized With COVID-19 RATIONALE: Use of ACEIs (angiotensin-converting enzyme inhibitors) and ARBs (angiotensin II receptor blockers) is a major concern for clinicians treating coronavirus disease 2019 (COVID-19) in patients with hypertension. OBJECTIVE: To determine the association between in-hospital use of ACEI/ARB and all-cause mortality in patients with hypertension and hospitalized due to COVID-19. METHODS AND RESULTS: This retrospective, multi-center study included 1128 adult patients with hypertension diagnosed with COVID-19, including 188 taking ACEI/ARB (ACEI/ARB group; median age 64 [interquartile range, 55-68] years; 53.2% men) and 940 without using ACEI/ARB (non-ACEI/ARB group; median age 64 [interquartile range 57-69]; 53.5% men), who were admitted to 9 hospitals in Hubei Province, China from December 31, 2019 to February 20, 2020. In mixed-effect Cox model treating site as a random effect, after adjusting for age, gender, comorbidities, and in-hospital medications, the detected risk for all-cause mortality was lower in the ACEI/ARB group versus the non-ACEI/ARB group (adjusted hazard ratio, 0.42 [95% CI, 0.19-0.92]; P=0.03). In a propensity score-matched analysis followed by adjusting imbalanced variables in mixed-effect Cox model, the results consistently demonstrated lower risk of COVID-19 mortality in patients who received ACEI/ARB versus those who did not receive ACEI/ARB (adjusted hazard ratio, 0.37 [95% CI, 0.15-0.89]; P=0.03). Further subgroup propensity score-matched analysis indicated that, compared with use of other antihypertensive drugs, ACEI/ARB was also associated with decreased mortality (adjusted hazard ratio, 0.30 [95% CI, 0.12-0.70]; P=0.01) in patients with COVID-19 and coexisting hypertension. CONCLUSIONS: Among hospitalized patients with COVID-19 and coexisting hypertension, inpatient use of ACEI/ARB was associated with lower risk of all-cause mortality compared with ACEI/ARB nonusers. While study interpretation needs to consider the potential for residual confounders, it is unlikely that in-hospital use of ACEI/ARB was associated with an increased mortality risk.

positive: COVID-19 infection in Italian people with diabetes: Lessons learned for our future (an experience to be used)

positive: Impact of hospitalised patients with COVID-19 taking Renin-Angiotensin-Aldosterone System inhibitors: a systematic review and meta-analysis Inhibitors of the Renin-Angiotensin-Aldosterone System (RAAS) notably Angiotensin-Converting Enzyme inhibitors (ACEi) or Angiotensin Receptor Blockers (ARB) have been scrutinised in hypertensive patients hospitalised with coronavirus disease 2019 (COVID-19) following some initial data they might adversely affect prognosis. With an increasing number of COVID-19 cases worldwide and the likelihood of a second wave of infection it is imperative to better understand the impact RAAS inhibitor use in antihypertensive covid positive hospitalised patients. A systematic review and meta-analysis of ACEi or ARB in patients admitted with COVID-19 was conducted. PubMed and Embase were searched and six studies were included in the meta-analysis. Pooled analysis demonstrated that 18.3% of the patients admitted with COVID-19 were prescribed ACEi/ARBs (0.183, CI 0.129 to 0.238, p<0.001). The use of RAAS inhibitors did not show any association with critical events (Pooled OR 0.833 CI 0.605 to 1.148, p=0.264) or death (Pooled OR 0.650, CI 0.356 to 1.187, p=0.161). In conclusion, our meta-analysis including critical events and mortality data on patients prescribed ACEi/ARB and hospitalised with COVID-19, found no evidence to associate ACEi/ARB with death or adverse events.

positive: Identification of critical active‐site residues in angiotensin‐converting enzyme‐2 (ACE2) by site‐directed mutagenesis Angiotensin‐converting enzyme‐2 (ACE2) may play an important role in cardiorenal disease and it has also been implicated as a cellular receptor for the severe acute respiratory syndrome (SARS) virus. The ACE2 active‐site model and its crystal structure, which was solved recently, highlighted key differences between ACE2 and its counterpart angiotensin‐converting enzyme (ACE), which are responsible for their differing substrate and inhibitor sensitivities. In this study the role of ACE2 active‐site residues was explored by site‐directed mutagenesis. Arg273 was found to be critical for substrate binding such that its replacement causes enzyme activity to be abolished. Although both His505 and His345 are involved in catalysis, it is His345 and not His505 that acts as the hydrogen bond donor/acceptor in the formation of the tetrahedral peptide intermediate. The difference in chloride sensitivity between ACE2 and ACE was investigated, and the absence of a second chloride‐binding site (CL2) in ACE2 confirmed. Thus ACE2 has only one chloride‐binding site (CL1) whereas ACE has two sites. This is the first study to address the differences that exist between ACE2 and ACE at the molecular level. The results can be applied to future studies aimed at unravelling the role of ACE2, relative to ACE, in vivo.

positive: COVID-19 for the Cardiologist: A Current Review of the Virology, Clinical Epidemiology, Cardiac and Other Clinical Manifestations and Potential Therapeutic Strategies Summary The coronavirus disease-2019 (COVID-19), a contagious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV2), has reached pandemic status. As it spreads across the world, it has overwhelmed healthcare systems, strangled the global economy and led to a devastating loss of life. Widespread efforts from regulators, clinicians and scientists are driving a rapid expansion of knowledge of the SARS-CoV2 virus and the COVID-19 disease. We review the most current data with a focus on our basic understanding of the mechanism(s) of disease and translation to the clinical syndrome and potential therapeutics. We discuss the basic virology, epidemiology, clinical manifestation, multi-organ consequences, and outcomes. With a focus on cardiovascular complications, we propose several mechanisms of injury. The virology and potential mechanism of injury form the basis for a discussion of potential disease-modifying therapies.

positive: Use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in context of COVID-19 outbreak: a retrospective analysis The possible effects of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) on COVID-19 disease severity have generated considerable debate. We performed a single-center, retrospective analysis of hospitalized adult COVID-19 patients in Wuhan, China, who had definite clinical outcome (dead or discharged) by February 15, 2020. Patients on anti-hypertensive treatment with or without ACEI/ARB were compared on their clinical characteristics and outcomes. The medical records from 702 patients were screened. Among the 101 patients with a history of hypertension and taking at least one anti-hypertensive medication, 40 patients were receiving ACEI/ARB as part of their regimen, and 61 patients were on antihypertensive medication other than ACEI/ARB. We observed no statistically significant differences in percentages of in-hospital mortality (28% vs. 34%, P = 0.46), ICU admission (20% vs. 28%, P = 0.37) or invasive mechanical ventilation (18% vs. 26%, P = 0.31) between patients with or without ACEI/ARB treatment. Further multivariable adjustment of age and gender did not provide evidence for a significant association between ACEI/ARB treatment and severe COVID-19 outcomes. Our findings confirm the lack of an association between chronic receipt of renin-angiotensin system antagonists and severe outcomes of COVID-19. Patients should continue previous anti-hypertensive therapy until further evidence is available.

positive: COVID-19 and Liver Dysfunction: Current Insights and Emergent Therapeutic Strategies The outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has attracted increasing worldwide attention. Cases of liver damage or dysfunction (mainly characterized by moderately elevated serum aspartate aminotransferase levels) have been reported among patients with COVID-19. However, it is currently uncertain whether the COVID-19-related liver damage/dysfunction is due mainly to the viral infection per se or other coexisting conditions, such as the use of potentially hepatotoxic drugs and the coexistence of systemic inflammatory response, respiratory distress syndrome-induced hypoxia, and multiple organ dysfunction. Based on the current evidence from case reports and case series, this review article focuses on the demographic and clinical characteristics, potential mechanisms, and treatment options for COVID-19-related liver dysfunction. This review also describes the geographical and demographic distribution of COVID-19-related liver dysfunction, as well as possible underlying mechanisms linking COVID-19 to liver dysfunction, in order to facilitate future drug development, prevention, and control measures for COVID-19.

positive: Boosting the arsenal against COVID-19 through computational drug repurposing

positive: COVID-19 and Inflammatory Bowel Diseases: risk assessment, shared molecular pathways and therapeutic challenges Background. The novel coronavirus SARS-CoV-2 causing COVID-19 disease is yielding a global outbreak with serious threats to public health. In this paper, we aimed to review the current knowledge about COVID-19 infectious risk status in inflammatory bowel disease (IBD) patients requiring immunosuppressive medication. Also, we focused on several molecular insights that could explain why IBD patients appear to not have higher risks of infection and worse outcome in COVID-19 than the general population, in attempt to provide scientific support for safer decisions in IBD patient care. Methods. PubMed electronic database was interogated for relevant articles involving data about common molecular pathways and shared treatment strategies between SARS-CoV-2, SARS-CoV-1, MERS-CoV and inflammatory bowel diseases. In addition, Neural Covidex, an artificial intelligence tool, was used to answer queries about pathogenic coronaviruses and possible IBD interactions using the COVID-19 Open Research Dataset (CORD-19). Discussions. Few molecular and therapeutic interactions between IBD and pathogenic coronaviruses were explored. First, we showed how the activity of soluble angiotensin-converting enzyme 2, CD209L alternate receptor and phosphorylated subunit of eukaryotic translation initiation factor 2 might exert protective impact in IBD in case of coronavirus infection. Second, IBD medication was discussed in the context of possible beneficial effects on COVID-19 pathogeny including "cytokine storm" prevention and treatment, immunomodulation, interferon signaling blocking, viral endocytosis inhibition. Conclusions. Using current understanding of SARS-CoV-2 as well as other pathogenic coronaviruses immunopathology, we showed why IBD patients should not be considered at an increased risk of infection or more severe outcomes. Whether our findings are entirely applicable to the pathogenesis, disease susceptibility and treatment management of SARS-CoV-2 infection in IBD must be further explored.

positive: Outcomes in Patients with COVID-19 Infection Taking ACEI/ARB PURPOSE OF REVIEW: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible for the aggressive coronavirus disease (COVID-19) pandemic. Recently, investigators have stipulated that COVID-19 patients receiving angiotensin-converting-enzyme inhibitors (ACEI) may be subject to poorer outcomes. This editorial presents the available evidence to guide treatment practices during this pandemic. RECENT FINDINGS: Recent studies from Wuhan cohorts provide valuable information about COVID-19. A cohort with 52 critically ill patients revealed cardiac injury in 12% of patients. Worse outcomes appear to be more prevalent in patients with hypertension and diabetes mellitus (DM), possibly due to overexpression of angiotensin-converting enzyme 2 (ACE2) receptor in airway alveolar epithelial cells. Investigators suspect that SARS-CoV-2 uses the ACE2 receptor to enter the lungs in a mechanism similar to SARS-CoV. Several hypotheses have been proposed to date regarding the net effect of ACEI/ARB on COVID-19 infections. Positive effects include ACE2 receptor blockade, disabling viral entry into the heart and lungs, and an overall decrease in inflammation secondary to ACEI/ARB. Negative effects include a possible retrograde feedback mechanism, by which ACE2 receptors are upregulated. SUMMARY: Even though physiological models of SARS-CoV infection show a theoretical benefit of ACEI/ARB, these findings cannot be extrapolated to SARS-CoV-2 causing COVID-19. Major cardiology scientific associations, including ACC, HFSA, AHA, and ESC Hypertension Council, have rejected these correlation hypotheses. After an extensive literature review, we conclude that there is no significant evidence to support an association for now, but given the rapid evolvement of this pandemic, findings may change.

positive: Angiotensin converting enzyme-2 as therapeutic target in COVID-19 The pandemic of coronavirus disease 2019 (COVID-19) is a global health emergency that poses a significant threat to world people's health. This outbreak causes major challenges to healthcare systems. Given the lack of effective treatments or vaccine for it, the identification of novel and safe drugs against COVID-19 infection is an urgent need. Angiotensin-converting enzyme 2 (ACE2) is not only an entry receptor of the SARS-CoV-2 virus, the virus that causes COVID-19, but also can protect from lung injury. In this view, we highlighted potential approaches to address ACE2-mediated SARS-CoV-2 virus, including 1) delivering an excessive soluble form of ACE2 (recombinant human ACE2: rhACE2) and 2) inhibition of the interaction between SARS-CoV-2 virus and ACE2 by some compounds with competitive effects (morphine and codeine). Further clinical trials in this regard can reveal a more definite conclusion against the COVID-19 disaster.

positive: Risk of COVID‐19 for patients with obesity

positive: Interactions of coronaviruses with ACE2, angiotensin II, and RAS inhibitors-lessons from available evidence and insights into COVID-19 The rapid spread of a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to an ongoing pandemic of coronavirus disease 2019 (COVID-19). Recently, angiotensin-converting enzyme 2 (ACE2) has been shown to be a functional receptor for SARS-CoV-2 to enter host target cells. Given that angiotensin receptor blockers (ARBs) and an ACE inhibitor (ACEI) upregulated ACE2 expression in animal studies, the concern might arise regarding whether ARBs and ACEIs would increase the morbidity and mortality of COVID-19. On the other hand, animal data suggested a potential protective effect of ARBs against COVID-19 pneumonia because an ARB prevented the aggravation of acute lung injury in mice infected with SARS-CoV, which is closely related to SARS-CoV-2. Importantly, however, there is no clinical or experimental evidence supporting that ARBs and ACEIs either augment the susceptibility to SARS-CoV-2 or aggravate the severity and outcomes of COVID-19 at present. Until further data are available, it is recommended that ARB and ACEI medications be continued for the treatment of patients with cardiovascular disease and hypertension, especially those at high risk, according to guideline-directed medical therapy based on the currently available evidence.

positive: Role of the Renin-Angiotensin System in ARDS The renin-angiotensin system (RAS) is a powerful biological system that plays an important role in regulation of systemic blood pressure through the maintenance of fluid and salt homeostasis. It is a multifactorial system since it includes different components (Fig. 1): The first, renin, was discovered in 1898 [1], whereas the discovery of the last component, angiotensin-converting enzyme 2 (ACE 2), is relatively recent, from 2000 [2, 3]. Three kinds of RAS are known: A) circulating, B) local, and C) intracellular.

positive: New agents modulating the renin-angiotensin-aldosterone system-Will there be a new therapeutic option? The renin-angiotensin-aldosterone system (RAAS) is more complex than it was originally regarded. According to the current subject knowledge, there are two main axes of the RAAS: (1) angiotensin-converting enzyme (ACE)-angiotensin II-AT1 receptor axis and (2) ACE2-angiotensin-(1-7)-Mas receptor axis. The activation of the first axis leads to deleterious effects, including vasoconstriction, endothelial dysfunction, thrombosis, inflammation, and fibrosis; therefore, blocking the components of this axis is a highly rational and commonly used therapeutic procedure. The ACE2-Ang-(1-7)-Mas receptor axis has a different role, since it often opposes the effects induced by the classical ACE-Ang II-AT1 axis. Once the positive effects of the ACE2-Ang-(1-7)-Mas axis were discovered, the alternative ways of pharmacotherapy activating this axis of RAAS appeared. This article briefly describes new molecules affecting the RAAS, namely: recombinant human ACE2, ACE2 activators, angiotensin-(1-7) peptide and non-peptide analogs, aldosterone synthase inhibitors, and the third and fourth generation of mineralocorticoid receptor antagonists. The results of the experimental and clinical studies are encouraging, which leads us to believe that these new molecules can support the treatment of cardiovascular diseases as well as cardiometabolic disorders.

positive: Treatment of patients with COVID-19 and concomitant cardiovascular diseases: Do not Forget about the Principles of Evidence-based Medicine/ Лечение больных с COVID-19 и сопутствующими сердечно-сосудистыми заболеваниями: не забывать о принципах доказательной медицины The recent discussion about the dangers of using angiotensin-converting-enzyme (ACE) inhibitors and angiotensin II receptor antagonists (ARA) in patients with COVID-19 is analyzed in the article. There is controversy over the hypothesis that these drugs can be factors contributing to an unfavorable outcome of a viral disease, as well as the absence of any clinical evidence for this hypothesis. The opinion that withdrawal of ACE inhibitors and ARA in patients with COVID-19 may increase the risk of adverse outcomes is presented.

positive: COvid MEdicaTion (COMET) study: protocol for a cohort study Various theories about drugs such as ACE inhibitors or angiotensin II receptor blockers (ARBs) in relation to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and clinical outcomes of COVID-19 are circulating in both mainstream media and medical literature. These are based on the fact that ACE2 facilitates SARS-CoV-2 cell invasion via binding of a viral spike protein to ACE2. However, the effect of ACE inhibitors, ARBs and other drugs on ACE2 is unclear and all theories are based on conflicting evidence mainly from animal studies. Therefore, clinical evidence is urgently needed. The aim of this study is to investigate the relationship between use of these drugs on clinical outcome of patients with COVID-19. Patients will be included from several hospitals in Europe. Data will be collected in a user-friendly database (Digitalis) on an external server. Analyses will be adjusted for sex, age and presence of cardiovascular disease, hypertension and diabetes. These results will enable more rational choices for randomised controlled trials for preventive and therapeutic strategies in COVID-19.

positive: Role of angiotensin-converting enzyme 2 (ACE2) in COVID-19 ABSTRACT: An outbreak of pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that started in Wuhan, China, at the end of 2019 has become a global pandemic. Both SARS-CoV-2 and SARS-CoV enter host cells via the angiotensin-converting enzyme 2 (ACE2) receptor, which is expressed in various human organs. We have reviewed previously published studies on SARS and recent studies on SARS-CoV-2 infection, named coronavirus disease 2019 (COVID-19) by the World Health Organization (WHO), confirming that many other organs besides the lungs are vulnerable to the virus. ACE2 catalyzes angiotensin II conversion to angiotensin-(1–7), and the ACE2/angiotensin-(1–7)/MAS axis counteracts the negative effects of the renin-angiotensin system (RAS), which plays important roles in maintaining the physiological and pathophysiological balance of the body. In addition to the direct viral effects and inflammatory and immune factors associated with COVID-19 pathogenesis, ACE2 downregulation and the imbalance between the RAS and ACE2/angiotensin-(1–7)/MAS after infection may also contribute to multiple organ injury in COVID-19. The SARS-CoV-2 spike glycoprotein, which binds to ACE2, is a potential target for developing specific drugs, antibodies, and vaccines. Restoring the balance between the RAS and ACE2/angiotensin-(1–7)/MAS may help attenuate organ injuries. GRAPHICAL ABSTRACT: SARS-CoV-2 enters lung cells via the ACE2 receptor. The cell-free and macrophage-phagocytosed virus can spread to other organs and infect ACE2-expressing cells at local sites, causing multi-organ injury. [Image: see text]

positive: Angiotensin converting enzyme 2 (ACE2) and COVID-19: using antihypertensive medications, pharmacogenetic considerations. COVID-19 utilizes the angiotensin-converting enzyme-2 (ACE2) pathway as a means of infection. Early data on COVID-19 suggest heterogeneity in the severity of symptoms during transmission and infection ranging from no symptoms to death. The source of this heterogeneity is likely multifaceted and may have a genetic component. Demographic and clinical comorbidities associated with the severity of infection suggest that possible variants known to influence the renin-angiotensin-aldosterone system pathway (particularly those that influence ACE2) may contribute to the heterogenous infection response. ACE2 and angiotensin(1-7) (the product of ACE2) seem to have a protective effect on the pulmonary and cardiac systems. Hypertension medication modulation, may alter ACE2 and angiotensin(1-7), particularly in variants that have been shown to influence renin-angiotensin-aldosterone system function, which could be clinically useful in patients with COVID-19.

positive: Single-cell RNA Analysis on ACE2 Expression Provides Insight into SARS-CoV-2 Blood Entry and Heart Injury COVID-19 is a global pandemic with high infectivity and pathogenicity, accounting for tens of thousands of deaths worldwide. Recent studies have found that the pathogen of COVID-19, SARS-CoV-2, shares the same cell receptor Angiotensin converting enzyme II (ACE2) with SARS-CoV. The pathological investigation of COVID-19 death showed that the lung had the characteristics of pulmonary fibrosis. However, how SARS-CoV-2 spreads from the lungs to other organs has not yet been determined. Here, we performed an unbiased evaluation of cell-type specific expression of ACE2 in healthy and fibrotic lungs, as well as in normal and failed adult human hearts, using published single-cell RNA-seq data. We found that ACE2 expression in fibrotic lungs mainly locates in arterial vascular cells, which might provide the route for bloodstream spreading of SARS-CoV-2. The failed human hearts have a higher percentage of ACE2-expressing cardiomyocytes, and SARS-CoV-2 might attack cardiomyocytes through the bloodstream in patients with heart failure. Moreover, ACE2 was highly expressed in cells infected by RSV or MERS-CoV and in mice treated by LPS. Our findings indicate that patients with pulmonary fibrosis, heart failure, and virus infection have a higher risk and are more susceptible to SARS-CoV-2 infection. SARS-CoV-2 might attack other organs by getting into the bloodstream. This work provides new insights into SARS-CoV-2 blood entry and heart injury and might propose a therapeutic strategy to prevent patients from developing severe complications.

positive: Diarrhea during COVID-19 infection: pathogenesis, epidemiology, prevention and management Abstract Background and aims The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 / COVID-19) pandemic is a worldwide emergency. An increasing number of diarrhea cases is reported. Here we investigate the epidemiology, clinical presentation, molecular mechanisms, management, and prevention of SARS-CoV-2 associated diarrhea. Methods We searched on PubMed, EMBASE, and Web of Science up to March 2020 to identify studies documenting diarrhea and mechansism of intestinal inflammation in patients with confirmed diagnosis of SARS-CoV-2 infection. Results Clinical studies show an incidence rate of diarrhea ranging from 2% to 50% of cases. It may precede or trail respiratory symptoms. A pooled analysis revealed an overall percentage of diarrhea onset of 10.4%. SARS-CoV uses the the angiotensin-converting enzyme 2 (ACE2) and the serine protease TMPRSS2 for S protein priming. ACE2 and TMPRSS2 are not only expressed in lung, but also in the small intestinal epithelia. ACE2 is expressed furthermore in the upper esophagus, liver, and colon. SARS-CoV-2 binding affinity to ACE2 is significantly higher (10-20 times) compared with SARS-CoV. Several reports indicate viral RNA shedding in stool detectable longer time period than in nasopharyngeal swabs. Current treatment is supportive, but several options appear promising and are the subject of investigation. Conclusion Diarrhea is a frequent presenting symptom in patients infected with SARS-CoV-2. Increasing evidence indicates possible fecal oral transmission, indicating the need for a rapid and effective modification of the screening and diagnostic algorithms. The optimal methods to prevent, manage, and treat diarrhea in COVID-19 infected patients are subjects of intensive research.

positive: Letter to the editors in response to: Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may be harmful in patients with diabetes during COVID-19 pandemic (Cure et al.)

positive: Correlation between renin-angiotensin system and Severe Acute Respiratory Syndrome Coronavirus 2 infection: What do we know? Abstract The first cases of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2 or COVID-19) infections were recorded in China in November 2019. Since its appearance in China at the end of last year, the virus has spread to all continents causing a “global pandemic”. To date, some aspects remain to be investigate about the pathophysiology of this viral infection. One of the aspects to be still clarified is the correlation between the renin-angiotensin system (RAS) and SARS-CoV-2 infection. RAS is a physiological system playing a key role in different human body functions regulation. SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE-2), a component of RAS, as a potential factor of cell penetration and infectivity; in addition, in the different infection stages, a functional variation of the RAS has been noted. In this article, we discuss the correlation between the role of RAS and system-modifying agents, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs) and direct renin inhibitors (DRIs), with SARS-CoV-2 infection.

positive: Inhibition of SARS-CoV-2 infection (previously 2019-nCoV) by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion The recent outbreak of coronavirus disease (COVID-19) caused by SARS-CoV-2 infection in Wuhan, China has posed a serious threat to global public health. To develop specific anti-coronavirus therapeutics and prophylactics, the molecular mechanism that underlies viral infection must first be confirmed. Therefore, we herein used a SARS-CoV-2 spike (S) protein-mediated cell-cell fusion assay and found that SARS-CoV-2 showed plasma membrane fusion capacity superior to that of SARS-CoV. We solved the X-ray crystal structure of six-helical bundle (6-HB) core of the HR1 and HR2 domains in SARS-CoV-2 S protein S2 subunit, revealing that several mutated amino acid residues in the HR1 domain may be associated with enhanced interactions with HR2 domain. We previously developed a pan-coronavirus fusion inhibitor, EK1, which targeted HR1 domain and could inhibit infection by divergent human coronaviruses tested, including SARS-CoV and MERS-CoV. We then generated a series of lipopeptides and found that the EK1C4 was the most potent fusion inhibitor against SARS-CoV-2 S protein-mediated membrane fusion and pseudovirus infection with IC50s of 1.3 and 15.8 nM, about 241- and 149-fold more potent than that of EK1 peptide, respectively. EK1C4 was also highly effective against membrane fusion and infection of other human coronavirus pseudoviruses tested, including SARS-CoV and MERS-CoV, as well as SARSr-CoVs, potently inhibiting replication of 4 live human coronaviruses, including SARS-CoV-2. Intranasal application of EK1C4 before or after challenge with HCoV-OC43 protected mice from infection, suggesting that EK1C4 could be used for prevention and treatment of infection by currently circulating SARS-CoV-2 and emerging SARSr-CoVs.

positive: Renin–angiotensin system in human coronavirus pathogenesis Although initially considered relatively harmless pathogens, human coronaviruses (HCoVs) are nowadays known to be associated with more severe clinical complications. Still, their precise pathogenic potential is largely unknown, particularly regarding the most recently identified species HCoV-NL63 and HCoV-HKU1. HCoVs need host cell proteins to successively establish infections. Proteases of the renin–angiotensin system serve as receptors needed for entry into target cells; this article describes the current knowledge on the involvement of this system in HCoV pathogenesis.

positive: Influence of blood pressure on pneumonia risk: Epidemiological association and Mendelian randomisation in the UK Biobank Objectives: To determine whether elevated blood pressure influences risk for respiratory infection. Design: Prospective, population-based epidemiological and Mendelian randomisation studies. Setting: UK Biobank. Participants: 377,143 self-identified British descent (54% women; median age 58 years) participants in the UK Biobank. Main outcome measures: First incident pneumonia over an average of 8 follow-up years. Results: 107,310 (30%) participants had hypertension at UK Biobank enrolment, and 9,969 (3%) developed a pneumonia during follow-up. Prevalent hypertension at baseline was significantly associated with increased risk for incident respiratory disease including pneumonia (hazard ratio 1.36 (95% confidence interval 1.29 to 1.43), P<0.001), acute respiratory distress syndrome or respiratory failure (1.43 (1.29 to 1.59), P<0.001), and chronic lower respiratory disease (1.30 (1.25 to 1.36), P<0.001), independent of age, age2, sex, smoking status, BMI, prevalent diabetes mellitus, prevalent coronary artery disease, and principal components of ancestry. Mendelian randomisation analyses indicated that genetic predisposition to a 5 mmHg increase in blood pressure was associated with increased risk of incident pneumonia for SBP (1.08, (1.04 to 1.13), P<0.001) and DBP (1.11 (1.03 to 1.20), P=0.005). Additionally, consistent with epidemiologic associations, increase in blood pressure genetic risk was significantly associated with reduced forced expiratory volume in the first second, forced vital capacity, and the ratio of the two (P<0.001 for all). Conclusions: These results strongly suggest that elevated blood pressure independently increases risk for pneumonia and reduces pulmonary function. Maintaining adequate blood pressure control, in addition to other measures, may reduce risk for pneumonia. Whether the present findings are generalizable to novel coronavirus disease 2019 (COVID-19) require further study.

positive: Treatment options for COVID-19: the reality and challenges Abstract An outbreak related to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in Wuhan, China in December 2019. An extremely high potential for dissemination resulted in the global coronavirus disease 2019 (COVID-19) pandemic in 2020. Despite the worsening trends of COVID-19, no drugs are validated to have significant efficacy in clinical treatment of COVID-19 patients in large-scale studies. Remdesivir is considered the most promising antiviral agent; it works by inhibiting the activity of RNA-dependent RNA polymerase (RdRp). A large-scale study investigating the clinical efficacy of remdesivir (200 mg on day 1, followed by 100 mg once daily) is on-going. The other excellent anti-influenza RdRp inhibitor favipiravir is also being clinically evaluated for its efficacy in COVID-19 patients. The protease inhibitor lopinavir/ritonavir (LPV/RTV) alone is not shown to provide better antiviral efficacy than standard care. However, the regimen of LPV/RTV plus ribavirin was shown to be effective against SARS-CoV in vitro. Another promising alternative is hydroxychloroquine (200 mg thrice daily) plus azithromycin (500 mg on day 1, followed by 250 mg once daily on day 2-5), which showed excellent clinical efficacy on Chinese COVID-19 patients and anti-SARS-CoV-2 potency in vitro. The roles of teicoplanin (which inhibits the viral genome exposure in cytoplasm) and monoclonal and polyclonal antibodies in the treatment of SARS-CoV-2 are under investigation. Avoiding the prescription of non-steroidal anti-inflammatory drugs, angiotensin converting enzyme inhibitors, or angiotensin II type I receptor blockers is advised for COVID-19 patients.

positive: What solid organ transplant healthcare providers should know about renin-angiotensin-aldosterone system inhibitors and COVID-19 The data on the outcomes of solid organ transplant recipients who have contracted coronavirus disease 2019 (COVID-19) are still emerging. Kidney transplant recipients are commonly prescribed renin-angiotensin-aldosterone system (AAS) inhibitors given the prevalence of hypertension, diabetes, and cardiovascular disease. As the angiotensin-converting enzyme 2 (ACE2) facilitates the entry of coronaviruses into target cells, there have been hypotheses that preexisting use of renin-angiotensin-aldosterone system (RAAS) inhibitors may increase the risk of developing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Given the common use of RAAS inhibitors among solid organ transplant recipients, we sought to review the RAAS cascade, the mechanism of SARS-CoV-2 entry, and pertinent data related to the effect of RAAS inhibitors on ACE2 to guide management of solid organ transplant recipients during the COVID-19 pandemic. At present, there is no clear evidence to support the discontinuation of RAAS inhibitors in solid organ transplant recipients during the COVID-19 pandemic.

positive: Important Steps to Control COVID-19/SARS-CoV-2 Infection Elderly patients are having high mortality rates from COVID-19/SARS-CoV-2 infection compared to younger patients. The SARS-CoV-2 virus uses the ACE2 receptor as the entry point to the host cells. ARBs/ACEIs which are widely used in elderly patients, have been found to be associated with overexpression of ACE2.To decrease the severity of COVID-19 infection, ARB/ACEI should be switched to another class drug not known to cause a rise in ACE2 until the COVID-19 infection subsides. Specific human immunoglobulin can be tried for COVID-19 patients with critical conditions under supervision.

positive: Human ACE2 receptor polymorphisms predict SARS-CoV-2 susceptibility Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus disease (COVID-19) that has resulted in a global pandemic. It is a highly contagious positive strand RNA virus and its clinical presentation includes severe to critical respiratory disease that appears to be fatal in ∼3-5% of the cases. The viral spike (S) coat protein engages the human angiotensin-converting enzyme2 (ACE2) cell surface protein to invade the host cell. The SARS-CoV-2 S-protein has acquired mutations that increase its affinity to human ACE2 by ∼10-15-fold compared to SARS-CoV S-protein, making it highly infectious. In this study, we assessed if ACE2 polymorphisms might alter host susceptibility to SARS-CoV-2 by affecting the ACE2 S-protein interaction. Our comprehensive analysis of several large genomic datasets that included over 290,000 samples representing >400 population groups identified multiple ACE2 protein-altering variants, some of which mapped to the S-protein-interacting ACE2 surface. Using recently reported structural data and a recent S-protein-interacting synthetic mutant map of ACE2, we have identified natural ACE2 variants that are predicted to alter the virus-host interaction and thereby potentially alter host susceptibility. In particular, human ACE2 variants S19P, I21V, E23K, K26R, T27A, N64K, T92I, Q102P and H378R are predicted to increase susceptibility. The T92I variant, part of a consensus NxS/T N-glycosylation motif, confirmed the role of N90 glycosylation in immunity from non-human CoVs. Other ACE2 variants K31R, N33I, H34R, E35K, E37K, D38V, Y50F, N51S, M62V, K68E, F72V, Y83H, G326E, G352V, D355N, Q388L and D509Y are putative protective variants predicted to show decreased binding to SARS-CoV-2 S-protein. Overall, ACE2 variants are rare, consistent with the lack of selection pressure given the recent history of SARS-CoV epidemics, however, are likely to play an important role in altering susceptibility to CoVs.

positive: Identification of Novel Small-Molecule Inhibitors of Severe Acute Respiratory Syndrome-Associated Coronavirus by Chemical Genetics Abstract The severe acute respiratory syndrome-associated coronavirus (SARS-CoV) infected more than 8,000 people across 29 countries and caused more than 900 fatalities. Based on the concept of chemical genetics, we screened 50,240 structurally diverse small molecules from which we identified 104 compounds with anti-SARS-CoV activity. Of these 104 compounds, 2 target the SARS-CoV main protease (Mpro), 7 target helicase (Hel), and 18 target spike (S) protein-angiotensin-converting enzyme 2 (ACE2)-mediated viral entry. The EC50 of the majority of the 104 compounds determined by SARS-CoV plaque reduction assay were found to be at low micromolar range. Three selected compounds, MP576, HE602, and VE607, validated to be inhibitors of SARS-CoV Mpro, Hel, and viral entry, respectively, exhibited potent antiviral activity (EC50 < 10 μM) and comparable inhibitory activities in target-specific in vitro assays.

positive: Inhibitors of the Renin–Angiotensin–Aldosterone System and Covid-19

positive: Oral epithelial expression of angiotensin converting enzyme-2: Implications for COVID-19 diagnosis and prognosis The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) uses the angiotensin converting enzyme (ACE)-2 as the host receptor for target cell entry. The extent and distribution of ACE-2 has been associated with the clinical symptoms of coronavirus disease (COVID)-19. Here we show by immunofluorescence analysis that the ACE2 is abundantly expressed in oral mucosa, particularly in the surface epithelial cells suggesting that these cells could represent sites of entry for SARS-CoV-2. Further, together with the reports on ACE2 ectodomain shedding, we discuss the rationale for the hypothesis that the ACE-2 measurement in saliva could be a marker for COVID-19 infection during early phase following SARS-CoV-2 exposure.

positive: Mutations, Recombination and Insertion in the Evolution of 2019-nCoV The 2019 novel coronavirus (2019-nCoV or SARS-CoV-2) has spread more rapidly than any other betacoronavirus including SARS-CoV and MERS-CoV. However, the mechanisms responsible for infection and molecular evolution of this virus remained unclear. We collected and analyzed 120 genomic sequences of 2019-nCoV including 11 novel genomes from patients in China. Through comprehensive analysis of the available genome sequences of 2019-nCoV strains, we have tracked multiple inheritable SNPs and determined the evolution of 2019-nCoV relative to other coronaviruses. Systematic analysis of 120 genomic sequences of 2019-nCoV revealed co-circulation of two genetic subgroups with distinct SNPs markers, which can be used to trace the 2019-nCoV spreading pathways to different regions and countries. Although 2019-nCoV, human and bat SARS-CoV share high homologous in overall genome structures, they evolved into two distinct groups with different receptor entry specificities through potential recombination in the receptor binding regions. In addition, 2019-nCoV has a unique four amino acid insertion between S1 and S2 domains of the spike protein, which created a potential furin or TMPRSS2 cleavage site. Our studies provided comprehensive insights into the evolution and spread of the 2019-nCoV. Our results provided evidence suggesting that 2019-nCoV may increase its infectivity through the receptor binding domain recombination and a cleavage site insertion. Novel 2019-nCoV sequences revealed the evolution and specificity of betacoronavirus with possible mechanisms of enhanced infectivity.

positive: Coronavirus infections and type 2 diabetes-shared pathways with therapeutic implications Individuals with diabetes are at increased risk for bacterial, mycotic, parasitic and viral infections. The severe acute respiratory syndrome (SARS)-CoV2 (also referred to as COVID-19) coronavirus pandemic highlights the importance of understanding shared disease pathophysiology potentially informing therapeutic choices in individuals with Type 2 diabetes (T2D). Two coronavirus receptor proteins, Angiotensin Converting Enzyme 2 (ACE2) and Dipeptidyl Peptidase-4 (DPP4) are also established transducers of metabolic signals and pathways regulating inflammation, renal and cardiovascular physiology, and glucose homeostasis. Moreover, glucose-lowering agents such as the DPP4 inhibitors, widely used in subjects with T2D, are known to modify the biological activities of multiple immunomodulatory substrates. Here we review the basic and clinical science spanning the intersections of diabetes, coronavirus infections, ACE2, and DPP4 biology, highlighting clinical relevance and evolving areas of uncertainty underlying the pathophysiology and treatment of T2D in the context of coronavirus infection

positive: Angiotensin receptor blockers and COVID-19 Abstract Angiotensin Receptor Blockers (ARBs) exhibit major pleiotropic protecting effects beyond their antihypertensive properties, including reduction of inflammation. ARBs directly protect the lung from the severe acute respiratory syndrome as a result of viral infections, including those from coronavirus. The protective effect of ACE2 is enhanced by ARB administration. For these reasons ARB therapy must be continued for patients affected by hypertension, diabetes and renal disease, comorbidities of the current COVID-19 pandemic. Controlled clinical studies should be conducted to determine whether ARBs may be included as additional therapy for COVID-19 patients.

positive: SAveRUNNER: a network-based algorithm for drug repurposing and its application to COVID-19 The novelty of new human coronavirus COVID-19/SARS-CoV-2 and the lack of effective drugs and vaccines gave rise to a wide variety of strategies employed to fight this worldwide pandemic. Many of these strategies rely on the repositioning of existing drugs that could shorten the time and reduce the cost compared to de novo drug discovery. In this study, we presented a new network-based algorithm for drug repositioning, called SAveRUNNER (Searching off-lAbel dRUg aNd NEtwoRk), which predicts drug-disease associations by quantifying the interplay between the drug targets and the disease-specific proteins in the human interactome via a novel network-based similarity measure that prioritizes associations between drugs and diseases locating in the same network neighborhoods. Specifically, we applied SAveRUNNER on a panel of 14 selected diseases with a consolidated knowledge about their disease-causing genes and that have been found to be related to COVID-19 for genetic similarity, comorbidity, or for their association to drugs tentatively repurposed to treat COVID-19. Focusing specifically on SARS subnetwork, we identified 282 repurposable drugs, including some the most rumored off-label drugs for COVID-19 treatments, as well as a new combination therapy of 5 drugs, actually used in clinical practice. Furthermore, to maximize the efficiency of putative downstream validation experiments, we prioritized 24 potential anti-SARS-CoV repurposable drugs based on their network-based similarity values. These top-ranked drugs include ACE-inhibitors, monoclonal antibodies, and thrombin inhibitors. Finally, our findings were in-silico validated by performing a gene set enrichment analysis, which confirmed that most of the network-predicted repurposable drugs may have a potential treatment effect against human coronavirus infections.

positive: The SARS-CoV-2 exerts a distinctive strategy for interacting with the ACE2 human receptor The COVID-19 disease has plagued over 110 countries and has resulted in over 4,000 deaths within 10 weeks. We compare the interaction between the human ACE2 receptor and the SARS-CoV-2 spike protein with that of other pathogenic coronaviruses using molecular dynamics simulations. SARS-CoV, SARS-CoV-2, and HCoV-NL63 recognize ACE2 as the natural receptor but present a distinct binding interface to ACE2 and a different network of residue-residue contacts. SARS-CoV and SARS-CoV-2 have comparable binding affinities achieved by balancing energetics and dynamics. The SARS-CoV-2–ACE2 complex contains a higher number of contacts, a larger interface area, and decreased interface residue fluctuations relative to SARS-CoV. These findings expose an exceptional evolutionary exploration exerted by coronaviruses toward host recognition. We postulate that the versatility of cell receptor binding strategies has immediate implications on therapeutic strategies. One Sentence Summary Molecular dynamics simulations reveal a temporal dimension of coronaviruses interactions with the host receptor.

positive: COVID-19 and the Renin-Angiotensin System

positive: Outcomes in Patients with COVID-19 Infection Taking ACEI/ARB PURPOSE OF REVIEW: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible for the aggressive coronavirus disease (COVID-19) pandemic. Recently, investigators have stipulated that COVID-19 patients receiving angiotensin-converting-enzyme inhibitors (ACEI) may be subject to poorer outcomes. This editorial presents the available evidence to guide treatment practices during this pandemic. RECENT FINDINGS: Recent studies from Wuhan cohorts provide valuable information about COVID-19. A cohort with 52 critically ill patients revealed cardiac injury in 12% of patients. Worse outcomes appear to be more prevalent in patients with hypertension and diabetes mellitus (DM), possibly due to overexpression of angiotensin-converting enzyme 2 (ACE2) receptor in airway alveolar epithelial cells. Investigators suspect that SARS-CoV-2 uses the ACE2 receptor to enter the lungs in a mechanism similar to SARS-CoV. Several hypotheses have been proposed to date regarding the net effect of ACEI/ARB on COVID-19 infections. Positive effects include ACE2 receptor blockade, disabling viral entry into the heart and lungs, and an overall decrease in inflammation secondary to ACEI/ARB. Negative effects include a possible retrograde feedback mechanism, by which ACE2 receptors are upregulated. Even though physiological models of SARS-CoV infection show a theoretical benefit of ACEI/ARB, these findings cannot be extrapolated to SARS-CoV-2 causing COVID-19. Major cardiology scientific associations, including ACC, HFSA, AHA, and ESC Hypertension Council, have rejected these correlation hypotheses. After an extensive literature review, we conclude that there is no significant evidence to support an association for now, but given the rapid evolvement of this pandemic, findings may change.

positive: What is the role of rheumatologists in the era of COVID-19?

positive: The double burden of disease of COVID-19 in cardiovascular patients: overlapping conditions could lead to overlapping treatments

positive: Response by Cohen et al to Letter Regarding Article, “Association of Inpatient Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Mortality Among Patients With Hypertension Hospitalized With COVID-19”

positive: [Hypertension, RAAS blockade and risk in COVID-19 patients]. SARS-coronavirus 2 (SARS-CoV-2) enters the host-cells by binding the transmembraneous angiotensin converting enzyme 2 (ACE2) when causing coronavirus disease 2019 (COVID-19). The role of angiotensin converting enzyme inhibitors (ACE) and angiotensin II receptor blockers (ARB) in COVID-19 is debated. Several well-conducted observational studies show no increased risk from RAAS blockade in COVID-19 patients and are detailed in this brief review. The Swedish Society of Hypertension, Stroke and Vascular Medicine supports current recommendations that ongoing RAAS blockade should be maintained in patients with COVID-19.

positive: The Use of Adjuvant Therapy in Preventing Progression to Severe Pneumonia in Patients with Coronavirus Disease 2019: A Multicenter Data Analysis ABSTRACT IMPORTANCE Coronavirus disease 2019 (COVID-19) is a global pandemic associated with high mortality and effective treatment to prevent clinical deterioration to severe pneumonia has not yet been well clarified. OBJECTIVE To investigate the role of several adjuvant treatments in preventing severe pneumonia in patients with COVID-19. DESIGN, SETTING, AND PARTICIPANTS Multicenter, retrospective cohort study of 564 consecutively hospitalized patients with confirmed COVID-19 at Third Xiangya Hospital of Central South University, Changsha Public Health Treatment Center, First Hospital of Yueyang, Junshan People's Hospital of Yueyang, Central Hospital of Shaoyang, Central Hospital of Xiangtan, Second Hospital of Changde, Central Hospital of Loudi, and First Affiliated Hospital of University of South China in Hunan province from January 17, 2020 to February 28, 2020; The final date of follow-up was March 15, 2020. EXPOSURES Nonspecific antivirals (arbidol, lopinavir/ritonavir, and interferon α), antihypertensives, and chloroquine. MAIN OUTCOMES AND MEASURES The development of severe COVID-19 pneumonia; Demographic, epidemiological, clinical, laboratory, radiological, and treatment data were collected and analyzed. RESULTS Of 564 patients, the median age was 47 years (interquartile range, 36-58 years), and 284 (50.4%) patients were men. Sixty-nine patients (12.2%) developed severe pneumonia. Patients who developed severe pneumonia were older (median age of 59 and 45 years, respectively), and more patients had comorbidities including hypertension (30.4% and 12.3%, respectively), diabetes (17.4% and 6.7%, respectively), and cardiovascular disease (8.7% and 3.2%, respectively) and presented with fever (84.1% and 60.4%, respectively) and shortness of breath (10.1% and 3.8%, respectively) compared with those who did not. Nonspecific antiviral therapy did not prevent clinical progression to severe pneumonia, although fewer hypertensive patients on angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers (ACEI/ARB) therapy developed severe pneumonia in contrast with those on non-ACEI/ARB antihypertensive therapy (1 of 16 [6.3%] patients and 16 of 49 [32.7%] patients, respectively [difference, 26.4%; 95% CI, 1.5% to 41.3%]). Multivariate logistic regression analysis showed that hypertension without receiving ACEI/ARB therapy was an independent risk factor (odds ratio [OR], 2.07; 95% CI, 1.07 to 4.00) for developing severe pneumonia irrespective of age. Besides, none of patients treated with chloroquine developed severe pneumonia, though without significance (difference, 12.0%; 95% CI, -3.5% to 30.0%) by propensity score matching. CONCLUSIONS AND RELEVANCE Hypertensive patients on ACEI or ARB may be protective from severe pneumonia in COVID-19 and hence these therapies should not be ceased unless there is a strong indication or further epidemiological evidence. Though none of the current antiviral and immunoregulation therapy showed benefit in preventing COVID-19 progression, chloroquine deserved further investigation.

positive: Response by Gheblawi et al to Letter Regarding Article, "Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2".

positive: Association of Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Use With COVID-19 Diagnosis and Mortality. Importance It has been hypothesized that angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) may make patients more susceptible to coronavirus disease 2019 (COVID-19) and to worse outcomes through upregulation of the functional receptor of the virus, angiotensin-converting enzyme 2. Objective To examine whether use of ACEI/ARBs was associated with COVID-19 diagnosis and worse outcomes in patients with COVID-19. Design, Setting, and Participants To examine outcomes among patients with COVID-19, a retrospective cohort study using data from Danish national administrative registries was conducted. Patients with COVID-19 from February 22 to May 4, 2020, were identified using ICD-10 codes and followed up from day of diagnosis to outcome or end of study period (May 4, 2020). To examine susceptibility to COVID-19, a Cox regression model with a nested case-control framework was used to examine the association between use of ACEI/ARBs vs other antihypertensive drugs and the incidence rate of a COVID-19 diagnosis in a cohort of patients with hypertension from February 1 to May 4, 2020. Exposures ACEI/ARB use was defined as prescription fillings 6 months prior to the index date. Main Outcomes and Measures In the retrospective cohort study, the primary outcome was death, and a secondary outcome was a composite outcome of death or severe COVID-19. In the nested case-control susceptibility analysis, the outcome was COVID-19 diagnosis. Results In the retrospective cohort study, 4480 patients with COVID-19 were included (median age, 54.7 years [interquartile range, 40.9-72.0]; 47.9% men). There were 895 users (20.0%) of ACEI/ARBs and 3585 nonusers (80.0%). In the ACEI/ARB group, 18.1% died within 30 days vs 7.3% in the nonuser group, but this association was not significant after adjustment for age, sex, and medical history (adjusted hazard ratio [HR], 0.83 [95% CI, 0.67-1.03]). Death or severe COVID-19 occurred in 31.9% of ACEI/ARB users vs 14.2% of nonusers by 30 days (adjusted HR, 1.04 [95% CI, 0.89-1.23]). In the nested case-control analysis of COVID-19 susceptibility, 571 patients with COVID-19 and prior hypertension (median age, 73.9 years; 54.3% men) were compared with 5710 age- and sex-matched controls with prior hypertension but not COVID-19. Among those with COVID-19, 86.5% used ACEI/ARBs vs 85.4% of controls; ACEI/ARB use compared with other antihypertensive drugs was not significantly associated with higher incidence of COVID-19 (adjusted HR, 1.05 [95% CI, 0.80-1.36]). Conclusions and Relevance Prior use of ACEI/ARBs was not significantly associated with COVID-19 diagnosis among patients with hypertension or with mortality or severe disease among patients diagnosed as having COVID-19. These findings do not support discontinuation of ACEI/ARB medications that are clinically indicated in the context of the COVID-19 pandemic.

positive: COVID‐19 and Older Adults: What We Know Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), a novel virus that causes COVID‐19 infection, has recently emerged and caused a deadly pandemic. Studies have shown that this virus causes worse outcomes and a higher mortality rate in older adults and those with comorbidities such as hypertension, cardiovascular disease, diabetes, chronic respiratory disease, and chronic kidney disease (CKD). A significant percentage of older American adults have these diseases, putting them at a higher risk of infection. Additionally, many adults with hypertension, diabetes, and CKD are placed on angiotensin‐converting enzyme (ACE) inhibitors and angiotensin II receptor blockers. Studies have shown that these medications upregulate the ACE‐2 receptor, the very receptor that the SARS‐CoV‐2 virus uses to enter host cells. Although it has been hypothesized that this may cause a further increased risk of infection, more studies on the role of these medications in COVID‐19 infections are necessary. In this review, we discuss the transmission, symptomatology, and mortality of COVID‐19 as they relate to older adults, and possible treatments that are currently under investigation. J Am Geriatr Soc 68:926–929, 2020

positive: Potential differential effects of renin-angiotensin system inhibitors on SARS-CoV-2 infection and lung injury in COVID-19

positive: The use of renin angiotensin system inhibitor on mortality in patients with coronavirus disease 2019 (COVID-19): A systematic review and meta-analysis BACKGROUND: and Aims; To investigate the association between use of angiotensin-converting enzyme inhibitor (ACEI)/angiotensin-receptor blocker (ARB) and outcomes of hypertensive COVID-19 patients, a systematic review and meta-analysis were performed. METHODS: We systematically searched PubMed, EuropePMC, ProQuest, and Cochrane Central Databases using the terms "(COVID-19 OR SARS-CoV-2) AND (angiotensin converting enzyme OR angiotensin receptor blocker)". The primary and second outcomes were mortality (non-survivor) and severe COVID-19, respectively. RESULTS: Totally, 7410 patients were included from 15 studies. Pooled analysis showed that the use of ACEI/ARB was not associated with mortality (OR 0.73 [0.38, 1.40], p = 0.34; I2: 81%) and severity (OR 1.03 [0.73, 1.45], p = 0.87; I2: 65%). Pooled adjusted OR showed no risk/benefit associated with ACEI/ARB use in terms of mortality (OR 0.83 [0.54, 1.27], p = 0.38; I2: 0%). Subgroup analysis showed that the use of ARB was associated with reduced mortality (OR 0.51 [0.29, 0.90], p = 0.02; I2: 22%) but not ACEI subgroup (OR 0.68 [0.39, 1.17], p = 0.16; I2: 0%). Meta-regression showed that the association between ACEI/ARB use and mortality in patients with COVID-19 do not varies by gender (p = 0.104). GRADE showed a very low certainty of evidence for effect of ACEI/ARB on mortality and severity. The certainty of evidence was very low for both ACEI and ARB subgroups. CONCLUSION: Administration of a renin angiotensin system (RAS) inhibitor, was not associated with increased mortality or severity of COVID-19 in patients with hypertension. Specifically, ARB and not ACEI use, was associated with lower mortality.

positive: Angiotensin II suppression in SARS-CoV-2 infection: a therapeutic approach()

positive: Role and mechanism of angiotensin-converting enzyme 2 in acute lung injury in coronavirus disease 2019 Coronavirus disease 2019 is a major threat to public health globally. Though its pathogenesis has not been fully elucidated, angiotensin-converting enzyme 2 (ACE2) has been recently identified as a receptor for the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into the cell. Here, we aimed to clarify the potential role of ACE2 in SARS-CoV-2-induced acute lung injury and its underlying mechanism. As a receptor for coronavirus, ACE2 mediates the entry of SARS-CoV-2 into cells in a similar way as for severe acute respiratory syndrome coronavirus (SARS-CoV). The high binding affinity of SARS-CoV-2 to ACE2 correlates with its efficient spread among humans. On the other hand, ACE2 negatively regulates the renin-angiotensin-aldosterone system (RAAS) primarily by converting angiotensin II to angiotensin 1–7, which exerts a beneficial effect on coronavirus-induced acute lung injury. Human recombinant ACE2 has been considered as a potential therapy for SARS-CoV-2 by blocking virus entry and redressing the imbalance of RAAS in SARS-CoV-2 infection. The level of ACE2 expression can be upregulated by treatment with an ACE inhibitor (ACEI) or angiotensin Ⅱ type 1 receptor blocker (ARB). To date, no evidence shows that ACEIs or ARBs increase the susceptibility and mortality of patients infected with SARS-CoV-2, and hence, it is not advisable to discontinue such drugs in patients with cardiovascular disease.

positive: Classical Renin-Angiotensin system in kidney physiology. The renin-angiotensin system has powerful effects in control of the blood pressure and sodium homeostasis. These actions are coordinated through integrated actions in the kidney, cardiovascular system and the central nervous system. Along with its impact on blood pressure, the renin-angiotensin system also influences a range of processes from inflammation and immune responses to longevity. Here, we review the actions of the "classical" renin-angiotensin system, whereby the substrate protein angiotensinogen is processed in a two-step reaction by renin and angiotensin converting enzyme, resulting in the sequential generation of angiotensin I and angiotensin II, the major biologically active renin-angiotensin system peptide, which exerts its actions via type 1 and type 2 angiotensin receptors. In recent years, several new enzymes, peptides, and receptors related to the renin-angiotensin system have been identified, manifesting a complexity that was previously unappreciated. While the functions of these alternative pathways will be reviewed elsewhere in this journal, our focus here is on the physiological role of components of the "classical" renin-angiotensin system, with an emphasis on new developments and modern concepts.

positive: COVID-19 Infection: Implications for Perioperative and Critical Care Physicians Healthcare systems worldwide are responding to Coronavirus Disease 2019 (COVID-19), an emerging infectious syndrome caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus. Patients with COVID-19 can progress from asymptomatic or mild illness to hypoxemic respiratory failure or multisystem organ failure, necessitating intubation and intensive care management. Healthcare providers, and particularly anesthesiologists, are at the frontline of this epidemic, and they need to be aware of the best available evidence to guide therapeutic management of patients with COVID-19 and to keep themselves safe while doing so. Here, the authors review COVID-19 pathogenesis, presentation, diagnosis, and potential therapeutics, with a focus on management of COVID-19–associated respiratory failure. The authors draw on literature from other viral epidemics, treatment of acute respiratory distress syndrome, and recent publications on COVID-19, as well as guidelines from major health organizations. This review provides a comprehensive summary of the evidence currently available to guide management of critically ill patients with COVID-19.

positive: ACE2 variants underlie interindividual variability and susceptibility to COVID-19 in Italian population In December 2019, an initial cluster of unexpected interstitial bilateral pneumonia emerged in Wuhan, Hubei province. A human-to-human transmission was immediately assumed and a previously unrecognized entity, termed coronavirus disease 19 (COVID-19) due to a novel coronavirus (2019-nCov) was suddenly described. The infection has rapidly spread out all over the world and Italy has been the first European Country experiencing the endemic wave with unexpected clinical severity in comparison with Asian countries. It has recently been shown that 2019-nCov utilizes host receptors namely angiotensin converting enzyme 2 (ACE2) as host receptor and host proteases for cell surface binding and internalization. Thus, a predisposing genetic background can give reason for interindividual disease susceptibility and/or severity. Taking advantage of the Network of Italian Genomes (NIG), here we mined around 7000 exomes from 5 different Centers looking for ACE2 variants. A number of variants with a potential impact on protein stability were identified. Among these, three missense changes, p.Asn720Asp, p.Lys26Arg, p.Gly211Arg (MAF 0.002 to 0.015), which have never been reported in the Eastern Asia population, were predicted to interfere with protein cleavage and stabilization. Rare truncating variants likely interfering with the internalization process and one missense variant, p.Trp69Cys, predicted to interfere with 2019-nCov spike protein binding were also observed. These findings suggest that a predisposing genetic background may contribute to the observed inter-individual clinical variability associated with COVID-19. They allow an evidence-based risk assessment opening up the way to personalized preventive measures and therapeutic options.

positive: Interactions Between Sars Coronavirus and its Receptor

positive: The use of hepatitis C virus NS3/4A and secreted alkaline phosphatase to quantitate cell–cell membrane fusion mediated by severe acute respiratory syndrome coronavirus S protein and the receptor angiotensin-converting enzyme 2 Abstract The membrane fusion process mediated by severe acute respiratory syndrome coronavirus (SARS–CoV) S protein and its cellular receptor angiotensin-converting enzyme 2 (ACE2) had been reconstituted using two Chinese hamster ovary (CHO) cell lines that constitutively express these recombinant proteins separately. This system was applied to develop a quantitative measurement of cell–cell fusion using hepatitis C virus (HCV) NS3/4A protease and a secretion-blocked EGFP-4A/4B-SEAP (EGFP: enhanced green fluorescent protein; 4A/4B: a decapeptide substrate of NS3/4A protease; SEAP: secreted alkaline phosphatase) fusion gene. Both genes were transiently expressed in either of the CHO cell lines, followed by fusion treatment. Significant SEAP activity could be detected in the culture medium only after cell–cell fusion occurred. Cell–cell fusion provides an environment in which the protease encounters its substrate 4A/4B, thereby releasing SEAP from the fusion protein. In this study, we developed a simple, sensitive, and quantitative assay to study the membrane fusion process by measuring the extracellular activity of SEAP.

positive: Potential Role of ACE2 in Coronavirus Disease 2019 (COVID-19) Prevention and Management COVID-19 is the current public health threat all over the world. Unfortunately, there is no specific prevention and treatment strategy for this disease. We aim to explore the potential role of angiotensin-converting enzyme 2 (ACE2) in this regard through this literature review. As a crucial enzyme of renin-angiotensin-aldosterone system (RAAS), ACE2 not only mediates the virus entry but also affects the pathophysiological process of virus-induced acute lung injury (ALI), as well as other organs’ damage. As interaction of COVID-19 virus spike and ACE2 is essential for virus infection, COVID-19-specific vaccine based on spike protein, small molecule compound interrupting their interaction, human monoclonal antibody based on receptor-binding domain, and recombinant human ACE2 protein (rhuACE2) have aroused the interests of researchers. Meanwhile, ACE2 could catalyze angiotensin II (Ang II) to form angiotensin 1-7 (Ang 1-7), thus alleviates the harmful effect of Ang II and amplifies the protection effect of Ang1-7. ACE inhibitor and angiotensin II receptor blocker (ARB) have been shown to increase the level of expression of ACE2 and could be potential strategies in protecting lungs, heart, and kidneys. ACE2 plays a very important role in the pathogenesis and pathophysiology of COVID-19 infection. Strategies targeting ACE2 and its ligand, COVID-19 virus spike protein, may provide novel method in the prevention and management of novel coronavirus pneumonia.

positive: Exploring the pathogenesis of severe acute respiratory syndrome (SARS): the tissue distribution of the coronavirus (SARS‐CoV) and its putative receptor, angiotensin‐converting enzyme 2 (ACE2) Severe acute respiratory syndrome (SARS) is an emerging infectious disease associated with a new coronavirus, SARS‐CoV. Pulmonary involvement is the dominant clinical feature but extra‐pulmonary manifestations are also common. Factors that account for the wide spectrum of organ system involvement and disease severity are poorly understood and the pathogenesis of SARS‐CoV infection remains unclear. Angiotensin converting enzyme 2 (ACE2) has recently been identified as the functional cellular receptor for SARS‐CoV. Studies of the tissue and cellular distribution of SARS‐CoV, and ACE2 protein expression, reveal new insights into the pathogenesis of this deadly disease. ACE2 is expressed at high level in the primary target cells of SARS‐CoV, namely pneumocytes and surface enterocytes of the small intestine. Despite the fact that SARS‐CoV can infect the lung and intestine, the tissue responses in these two organs are different. All other tissues and cell types expressing ACE2 may be potential targets of SARS‐CoV infection. Remarkably, endothelial cells, which express ACE2 to a high level, have not been shown to be infected by SARS‐CoV. There is also evidence that cell types without detectable ACE2 expression may also be infected by the virus. Furthermore, studies in a new human cell culture model have indicated that the presence of ACE2 alone is not sufficient for maintaining viral infection. Therefore, other virus receptors or co‐receptors may be required in different tissues. Moreover, the interaction between SARS‐CoV and the immunological or lymphoid system remains to be defined. It is clear that we are only at the dawn of our understanding of the pathogenesis of SARS. As our knowledge of the pathogenic mechanisms improves, a more rational approach to therapeutic and vaccine development can be designed in order to combat this new and fatal human disease. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

positive: Inpatient Care of Patients with COVID-19: A Guide for Hospitalists Abstract Since its emergence in December 2019, the virus known as severe acute respiratory syndrome coronavirus 2 has quickly caused a pandemic. This virus causes a disease now known as coronavirus disease 2019, or COVID-19. As an increasing proportion of the at-risk population becomes infected, and patients with severe illness are hospitalized, it is essential for hospitalists to remain current on how to best care for people with suspected or confirmed disease. Establishing a system for logistical planning, and accurate information sharing is strongly recommended. Infection control remains the ultimate goal. As such, healthcare workers should be educated on universal and isolation precautions, and the appropriate use of personal protective equipment. Social distancing should be encouraged to prevent the spread of infection, and creative and innovative ways to reduce contact may need to be considered. Moreover, it is imperative to prepare for contingencies as medical staff will inevitably get sick or become unavailable. Hospitalists have the difficult task of caring for patients, while also adapting to the many logistical and social elements of a pandemic.

positive: Cardiovascular Implications and Therapeutic Considerations in COVID-19 Infection The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has profoundly impacted all fields of medicine. Infection with SARS-CoV-2 and the resulting coronavirus of 2019 (COVID-19) syndrome has multiorgan effects. The pandemic has united researchers from bench to bedside in attempts to understand the pathophysiology of the disease and define optimal treatment strategies. Cardiovascular disease is highly prevalent and a leading cause of death across gender, race, and ethnic groups. As the pandemic spreads, there is increasing concern about the cardiovascular effects of the viral infection and the interaction of infection with existing cardiovascular disease. Additionally, there are concerns about the cardiac effects of the numerous treatment agents under study. It will be essential for cardiologists to understand the interplay between underlying cardiac comorbidities, acute cardiovascular effects of COVID-19 disease, and adverse effects of new treatments. Here we describe emerging evidence of the epidemiology of SARS-CoV-2 infection and underlying cardiovascular disease, the evidence for direct myocardial injury in SARS-CoV-2 infection, the specific presentations of cardiovascular involvement by SARS-CoV-2, and the cardiac effects of emerging treatments.

positive: Angiotensin-Converting Enzyme 2 and Antihypertensives (Angiotensin Receptor Blockers and Angiotensin-Converting Enzyme Inhibitors) in Coronavirus Disease 2019 Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2, is being defined as the worst pandemic disease of modern times. Several professional health organizations have published position papers stating that there is no evidence to change the use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) in the management of elevated blood pressure in the context of avoiding or treating COVID-19 infection. In this article, we review the evidence on the relationship between the renin-angiotensin-aldosterone system and COVID-19 infection. In agreement with current guidelines, patients with hypertension should continue taking antihypertensive medications as prescribed without interruption. Because ACEIs and ARBs are also used to retard the progression of chronic kidney disease, we suggest that these recommendations also apply to the use of these agents in chronic kidney disease. No differences generally exist between ARBs and ACEIs in terms of efficacy in decreasing blood pressure and improving other outcomes, such as all-cause mortality, cardiovascular mortality, myocardial infarction, heart failure, stroke, and end-stage renal disease. The ACEIs are associated with cough secondary to accumulation of bradykinin and angioedema, and withdrawal rates due to adverse events are lower with ARBs. Given their equal efficacy but fewer adverse events, ARBs could potentially be a more favorable treatment option in patients with COVID-19 at higher risk for severe forms of disease.

positive: COVID-19: A New Virus, but a Familiar Receptor and Cytokine Release Syndrome Summary Zhou et al. (Nature) and Hoffmann et al. (Cell) identify ACE2 as a SARS-CoV-2 receptor, and the latter show its entry mechanism depends on cellular serine protease TMPRSS2. These results may explain proinflammatory cytokine release via the associated angiotestin II pathway and a possible therapeutic target via the IL-6-STAT3 axis.

positive: Shotgun Transcriptome and Isothermal Profiling of SARS-CoV-2 Infection Reveals Unique Host Responses, Viral Diversification, and Drug Interactions The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused thousands of deaths worldwide, including >18,000 in New York City (NYC) alone. The sudden emergence of this pandemic has highlighted a pressing clinical need for rapid, scalable diagnostics that can detect infection, interrogate strain evolution, and identify novel patient biomarkers. To address these challenges, we designed a fast (30-minute) colorimetric test (LAMP) for SARS-CoV-2 infection from naso/oropharyngeal swabs, plus a large-scale shotgun metatranscriptomics platform (total-RNA-seq) for host, bacterial, and viral profiling. We applied both technologies across 857 SARS-CoV-2 clinical specimens and 86 NYC subway samples, providing a broad molecular portrait of the COVID-19 NYC outbreak. Our results define new features of SARS-CoV-2 evolution, nominate a novel, NYC-enriched viral subclade, reveal specific host responses in interferon, ACE, hematological, and olfaction pathways, and examine risks associated with use of ACE inhibitors and angiotensin receptor blockers. Together, these findings have immediate applications to SARS-CoV-2 diagnostics, public health, and new therapeutic targets.

positive: SARS‐CoV‐2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells The SARS‐CoV‐2 pandemic affecting the human respiratory system severely challenges public health and urgently demands for increasing our understanding of COVID‐19 pathogenesis, especially host factors facilitating virus infection and replication. SARS‐CoV‐2 was reported to enter cells via binding to ACE2, followed by its priming by TMPRSS2. Here, we investigate ACE2 and TMPRSS2 expression levels and their distribution across cell types in lung tissue (twelve donors, 39,778 cells) and in cells derived from subsegmental bronchial branches (four donors, 17,521 cells) by single nuclei and single cell RNA sequencing, respectively. While TMPRSS2 is strongly expressed in both tissues, in the subsegmental bronchial branches ACE2 is predominantly expressed in a transient secretory cell type. Interestingly, these transiently differentiating cells show an enrichment for pathways related to RHO GTPase function and viral processes suggesting increased vulnerability for SARS‐CoV‐2 infection. Our data provide a rich resource for future investigations of COVID‐19 infection and pathogenesis.

positive: A potential protective role of losartan against coronavirus-induced lung damage

positive: ACE2 and prognosis of COVID-19: Insights from Bartter's and Gitelman's syndromes patients

positive: Age and Multimorbidity Predict Death Among COVID-19 Patients: Results of the SARS-RAS Study of the Italian Society of Hypertension. Several factors have been proposed to explain the high death rate of the coronavirus disease 2019 (COVID-19) outbreak, including hypertension and hypertension-related treatment with Renin Angiotensin System inhibitors. Also, age and multimorbidity might be confounders. No sufficient data are available to demonstrate their independent role. We designed a cross-sectional, observational, multicenter, nationwide survey in Italy to verify whether renin-angiotensin system inhibitors are related to COVID-19 severe outcomes. We analyzed information from Italian patients diagnosed with COVID-19, admitted in 26 hospitals. One thousand five hundred ninety-one charts (male, 64.1%; 66±0.4 years) were recorded. At least 1 preexisting condition was observed in 73.4% of patients, with hypertension being the most represented (54.9%). One hundred eighty-eight deaths were recorded (11.8%; mean age, 79.6±0.9 years). In nonsurvivors, older age, hypertension, diabetes mellitus, chronic obstructive pulmonary disease, chronic kidney disease, coronary artery diseases, and heart failure were more represented than in survivors. The Charlson Comorbidity Index was significantly higher in nonsurvivors compared with survivors (4.3±0.15 versus 2.6±0.05; P<0.001). ACE (angiotensin-converting enzyme) inhibitors, diuretics, and β-blockers were more frequently used in nonsurvivors than in survivors. After correction by multivariate analysis, only age (P=0.0001), diabetes mellitus (P=0.004), chronic obstructive pulmonary disease (P=0.011), and chronic kidney disease (P=0.004) but not hypertension predicted mortality. Charlson Comorbidity Index, which cumulates age and comorbidities, predicts mortality with an exponential increase in the odds ratio by each point of score. In the COVID-19 outbreak, mortality is predicted by age and the presence of comorbidities. Our data do not support a significant interference of hypertension and antihypertensive therapy on COVID-19 lethality. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT04331574.

positive: Renin-Angiotensin System Inhibition in Cardiovascular Patients at the Time of COVID19: Much Ado for Nothing? A Statement of Activity from the Directors of the Board and the Scientific Directors of the Italian Society of Hypertension Cardiovascular diseases, in particular hypertension, as well as the cardiovascular treatment with Renin-Angiotensin System inhibitors such as Angiotensin Converting Enzyme (ACE) inhibitors and Angiotensin Receptor Blockers (ARBs), are claimed once again as mechanisms of Severe Acute Respiratory Syndrome (SARS) during the COVID-19 outbreak due to Cov-2 epidemics. In vitro studies are available to support the eventual role of ACE inhibitors and ARBs in both the promotion and antagonism of the disease. The available literature, indeed, presents contrasting results, all concentrated in experimental models. Evidence in humans is lacking that those mechanisms are actually occurring in the present COVID-19 outbreak. Here we present the reasoned statement of the Italian Society of Hypertension to maintain ongoing antihypertensive treatments. Furthermore, the Italian Society of Hypertension presents its own initiative to investigate the issue using an online questionnaire to collect relevant data in human disease.

positive: Use of inhibitors of the renin angiotensin system and COVID-19 prognosis: a systematic review and meta-analysis Background: controversy has arisen in the scientific community on whether the use of renin angiotensin system (RAS) inhibitors in the context of COVID-19 would be of benefit or harmful. A meta-analysis of eligible studies comparing the occurrence of severe and fatal COVID-19 in infected patients who were under treatment with angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) vs no treatment or other antihypertensives was conducted. Methods: PubMed, Google Scholar, the Cochrane Library, MedRxiv and BioRxiv were searched for relevant studies. Fixed-effect models or random-effect models were used depending on the heterogeneity between estimates. Results: a total of fifteen studies with 21,614 patients were included. The use of RAS inhibitors was associated with a non-significant 20% decreased risk of the composite outcome (death, admission to intensive care unit, mechanical ventilation requirement or progression to severe or critical pneumonia): RR 0.81 (95%CI: 0.63-1.04), p=0.10, I2=82%. In a subgroup analysis that included hypertensive subjects only, ACEI/ARB were associated with a 27% significant decrease in the risk of the composite outcome (RR 0.73 (95%CI: 0.56-0.96), p=0.02, I2=65%). Conclusion: the results of this pooled analysis suggest that the use of ACEI/ARB does not worsen the prognosis, and could even be protective in hypertensive subjects. Patients should continue these drugs during their COVID-19 illness.

positive: Interactions between antihyperglycemic drugs and the renin-angiotensin system: Putative roles in COVID-19. A mini-review Abstract Background and aims: Diabetes mellitus is associated with a more severe course of coronavirus disease 2019 (COVID-19). The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes angiotensin-converting enzyme II (ACE2) receptor for host cell entry. We aimed to assess the interactions between antihyperglycemic drugs and the renin-angiotensin system (RAS) and their putative roles in COVID-19. Methods A literature search was performed using Pubmed to review the interrelationships between hyperglycemia, RAS and COVID-19, and the effects of antihyperglycemic medications. Results The RAS has an essential role in glucose homeostasis and may have a role in COVID-19-induced lung injury. Some antihyperglycemic medications modulate RAS and might hypothetically alleviate the deleterious effect of angiotensin II on lung injury. Furthermore, most antihyperglycemic medications showed anti-inflammatory effects in animal models of lung injury. Conclusions Some antihyperglycemic medications might have protective effects against COVID-19-induced lung injury. Early insulin therapy seems very promising in alleviating lung injury.

positive: COVID-19: Therapeutics and Their Toxicities SARS-CoV-2 is a novel coronavirus that emerged in 2019 and is causing the COVID-19 pandemic. There is no current standard of care. Clinicians need to be mindful of the toxicity of a wide variety of possibly unfamiliar substances being tested or repurposed to treat COVID-19. The United States Food and Drug Administration (FDA) has provided emergency authorization for the use of chloroquine and hydroxychloroquine. These two medications may precipitate ventricular dysrhythmias, necessitating cardiac and electrolyte monitoring, and in severe cases, treatment with epinephrine and high-doses of diazepam. Recombinant protein therapeutics may cause serum sickness or immune complex deposition. Nucleic acid vaccines may introduce mutations into the human genome. ACE inhibitors and ibuprofen have been suggested to exacerbate the pathogenesis of COVID-19. Here, we review the use, mechanism of action, and toxicity of proposed COVID-19 therapeutics.

positive: A systematic review and meta-analysis to evaluate the clinical outcomes in COVID-19 patients on angiotensin-converting enzyme inhibitors or angiotensin receptor blockers INTRODUCTION: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) share their target receptor site with the SARS-CoV-2 virus, that may cause ACE2 receptor up-regulation which raised concerns regarding ACEI and ARB use in COVID-19 patients. However, many medical professional societies recommended their continued use given the paucity of clinical evidence, but there is a need for an updated systematic review and meta-analysis of the latest clinical studies. METHODS AND RESULTS: A search was conducted on PubMed, Google Scholar, EMBASE, and various preprint servers for studies comparing clinical outcomes and mortality in COVID-19 patients on ACEIs and/or ARBs, and a meta-analysis was performed. A total of 16 studies were included for the review and meta-analysis. There were conflicting findings reported in the rates of severity and mortality in several studies. In a pooled analysis of four studies, there was a statistically non-significant association of ACEI/ARB use with lower odds of developing severe disease vs. non-users [odds ratio (OR) = 0.81, 95% confidence interval (CI): 0.41-1.58, I2=50.52, P-value = 0.53). In a pooled analysis of six studies, there was a statistically non-significant association of ACEI/ARB use with lower odds of mortality as compared with non-users (OR = 0.86, 95% CI = 0.53-1.41, I2 = 79.12, P-value = 0.55). CONCLUSION: It is concluded that ACEIs and ARBs should be continued in COVID-19 patients, reinforcing the recommendations made by several medical societies. Additionally, the individual patient factors such as ACE2 polymorphisms which might confer higher risk of adverse outcomes need to be evaluated further.

positive: Role of Drugs Affecting the Renin-Angiotensin-Aldosterone System on Susceptibility and Severity of COVID-19: A Large Case-Control Study from Zheijang Province, China. Background. Medical editorials have suggested that angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) should not be given to people with arterial hypertension during the coronavirus disease 2019 (COVID-19) pandemic because of a potential increased risk of worse clinical outcomes and that calcium channel blockers (CCBs) should be used as an alternative. Methods Using a cohort of 610 COVID-19 cases and 48,667 population-based controls from Zheijang, China we have tested the role of usage of ACEIs, ARBs, CCBs and other medications on risk and severity of COVID 19. Analyses were adjusted for age, sex and BMI and for presence of relevant comorbidities. Findings: Higher BMI, diabetes and cardio/ cerebrovascular disease as independent risk factors for the development of COVID-19. Individuals with hypertension taking CCBs had significantly increased risk [odds ratio (OR)= 1.67 (95% CI 1.2-2.9)) of manifesting symptoms of COVID-19 whereas those taking ARBs and diuretics had significantly lower disease risk (OR=0.24; 95%CI 0.17-0.34 and OR=0.32; 95%CI 0.19-0.57 respectively). Other antihypertensive drugs were not associated with increased risk of severe or critical form of the infection. Use of glucocorticoids was significantly associated with a severe/critical form of COVID-19 (OR= 7.56; 95%CI 1.17-48.93). Interpretation: we found no evidence to alter ARBs or ACEIs therapy in the context of the pandemic. Patients on corticosteroids with COVID-19 are at higher risk of developing a severe form of COVID-19and therefore should be monitored closely.

positive: Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may be harmful in patients with diabetes during COVID-19 pandemic Abstract The novel coronavirus disease 2019 (COVID-19) outbreak once again demonstrated the importance of the renin-angiotensin system (RAS) in patients with diabetes. Activation of the RAS increases in patients with diabetes. The virus attaches to the ACE2 enzyme at low cytosolic pH values and enters into the cell and causes infection. Especially in the presence of diabetes mellitus and accompanying comorbid conditions such as hypertension, obesity, old age, and smoking, cytosolic pH is low, thus the virus easily may enter the cell by attaching to ACE2. ACEIs and ARBs lead to a reduction in angiotensin II level by increasing the ACE2 level, thus they cause a low cytosolic pH. Increased cardiac ACE2 levels due to ACEIs and ARBs can trigger cardiac arrhythmias and myocarditis by causing the virus to easily enter the heart tissue. There is ACE2 activity in the rostral ventrolateral medulla in the brain stem. The release of angiotensin 1-7 in the brain stem leads to the activation of the sympathetic nervous system. This activation causes systemic vasoconstriction and the patient’s blood pressure increases. The most important event is the increased sympathetic activity via the central stimulation, this activity increases pulmonary capillary leaking, causing the ARDS. As the cytosolic pH, which is already low in patients with diabetes will decrease further with the mechanisms mentioned above, the viral load will increase and the infection will be exacerbated. As a result, the use of ACEIs and ARBs in patients with diabetes can lead to increased morbidity and mortality of COVID-19.

positive: Biophysical characterization of the SARS-CoV-2 spike protein binding with the ACE2 receptor and implications for infectivity SARS-CoV-2 is a novel highly virulent pathogen which gains entry to human cells by binding with the cell surface receptor – angiotensin converting enzyme (ACE2). We computationally contrasted the binding interactions between human ACE2 and coronavirus spike protein receptor binding domain (RBD) of the 2002 epidemic-causing SARS-CoV-1, SARS-CoV-2, and bat coronavirus RaTG13 using the Rosetta energy function. We find that the RBD of the spike protein of SARS-CoV-2 is highly optimized to achieve very strong binding with human ACE2 (hACE2) which is consistent with its enhanced infectivity. SARS-CoV-2 forms the most stable complex with hACE2 compared to SARS-CoV-1 (23% less stable) or RaTG13 (11% less stable) while occupying the greatest number of residues in the ATR1 binding site. Notably, the SARS-CoV-2 RBD out-competes the angiotensin 2 receptor type I (ATR1) which is the native binding partner of ACE2 by 35% in terms of the calculated binding affinity. Strong binding is mediated through strong electrostatic attachments with every fourth residue on the N-terminus alpha-helix (starting from Ser19 to Asn53) as the turn of the helix makes these residues solvent accessible. By contrasting the spike protein SARS-CoV-2 Rosetta binding energy with ACE2 of different livestock and pet species we find strongest binding with bat ACE2 followed by human, feline, equine, canine and finally chicken. This is consistent with the hypothesis that bats are the viral origin and reservoir species. These results offer a computational explanation for the increased infectivity of SARS-CoV-2 and allude to therapeutic modalities by identifying and rank-ordering the ACE2 residues involved in binding with the virus.

positive: Focus on Receptors for Coronaviruses with Special Reference to Angiotensin-converting Enzyme 2 as a Potential Drug Target - A Perspective Coronaviruses (CoVs) possess an enveloped, single, positive-stranded RNA genome which encodes for four membrane proteins, namely spike (S), envelope (E), membrane (M) and nucleocapsid (N) proteins 3-5 [1]. With regard to pathogenicity, S proteins are essential for viral entry into host cells [2, 3]. SARS-CoV binds to the angiotensin-converting enzyme (ACE)2 which is present on nonimmune cells, such as respiratory and intestinal epithelial cells, endothelial cells, kidney cells (renal tubules) and cerebral neurons and immune cells, such as alveolar monocytes/macrophages [4-6]. Of note, CD209L or liver/lymph node special intercellular adhesion molecule-3-grabbing non-integrin (SIGN) and dendritic cell (DC)-SIGN are alternative receptors for SARS-CoV but with lower affinity [7]. In the case of MERS-CoV, S proteins bind to the host cell receptor dipeptidyl peptidase 4 (DPP4 or CD26) which is broadly expressed on intestinal, alveolar, renal, hepatic and prostate cells as well as on activated leukocytes [8]. Then, viruses replicate in target cells with release of mature virions, which, in turn, invade new target cells [9]. Evidence has been provided that SARSCoV proteins are cleaved into two subunits, S1 and S2, respectively, and the amino acids 318-510 of the S1 represent the receptor-binding domain (RBD) which binds to ACE2 [10, 11]. Quite importantly, in the context of RBD there is the receptor-binding motif (RBM) (amino acids 424- 494), which accounts for complete binding to ACE2 [11]. Moreover, by means of two residues at positions 479 and 487 RBD allows virus progression and tropism [10, 11]. In the case of MERSCoV, its RBM binds to DPP4 with residues 484-567, thus, suggesting that its RBD differs from that of SARS-CoV [12, 13]. In a very recent paper, Wan and associates [14] have investigated the receptor recognition by COVID-19 (a new term to indicate the 2019-nCoV in Wuhan) on the bases of structural studies. In this respect, the sequence of COVID-19 RBM is similar to that of SARSCoV, thus, implicating that ACE2 may represent the binding receptors for COVID-19. Furthermore, gln493 residue of COVID-19 RBM seems to allow interaction with human ACE2, thus, suggesting the ability of this virus to infect human cells. According, to Wan and associates structural analysis [14], COVID-19 binds to human ACE2 with a lesser efficiency than human SARS-CoV (2002) but with higher affinity than human SARS-CoV (2003). Furthermore, same authors predicted that a single mutation at the 501 position may enhance the COVID-19 RBD binding capacity to human ACE2 and this evolution should be monitored in infected patients [14]. These predictive findings by Wan and associates [14] are confirmed by two contemporary studies by Letko and Muster [15] and Peng and associates [16]. In particular, the report by Peng and associates [16], points out the possible origin of COVID-19 from bats [16]. From a pathogenic point of view, evidence has been provided that binding of S2 to ACE2 receptor leads to its down-regulation with subsequent lung damage in the course of SARS-CoV infection [17]. Down-regulation of ACE2 causes excessive production of angiotensin (ANG) II by the related enzyme ACE with stimulation of ANG type 1a receptor (AT1R) and enhanced lung vascular permeability [18]. In particular, same authors have reported that recombinant ACE2 could attenuate severe acute lung injury in mice [18]. Moreover, Battle and associates [19] also proposed to use already available recombinant ACE2 for intercepting COVID-19 and attenuating infection. In the previous paragraphs, the presence of ACE2 on immune cells has been pointed out and, by analogy to epithelial cells, this receptor may also be down-regulated following viral entry. Therefore, in CoV-infected animal models and in infected humans further investigations are required to clarify a possible reduced expression of ACE2 on immune cells. In fact, in the course of SARS-CoV infection, a number of immune disorders have been detected. Three reports have demonstrated the ability of CoV to inhibit interferon (IFN)-ï¢ production in the course of SARS acting as IFN antagonist [20-22]. In senescent Balb/c mice, depletion of T lymphocytes is associated to more severe interstitial pneumonitis and delayed clearance of SARS-CoV, thus, suggesting a protective role played by these cells [23]. In this connection, both SARS-CoV and MERS-CoV have been shown to induce T cell apoptosis, thus, aggravating the clinical course of disease [24, 25]. Quite interestingly, memory CD8+ T cells specific for SARS-CoV M and N proteins have been detected up to 11 years post-infection [26]. As far as humoral immune responsiveness is concerned, evidence has been provided that S1 subunit from MERS-CoV is highly immunogenic in mice [27]. Moreover, monoclonal antibodies have been shown to be highly neutralizing against MERS-CoV replication and endowed with post exposure effectiveness in susceptible mice [28, 29]. Human neutralizing antibodies have also been isolated from a recovered patient, thus, suggesting the role of humoral immunity in the control of the persistence of CoV in the host [30]. In particular, IgG response occurs early in infection and its prolonged production may serve for virus clearance during recovery also in view of the absence of viremia in convalescent sera from SARS patients [31]. According to current literature, severity of COVID-19 infection correlates with lymphopenia and patients who died from COVID-19 had lower lymphocyte counts when compared to survivors [32, 33]. These data suggest that lymphocyte-mediated anti-viral activity is poorly effective against COVID-19. Despite lymphopenia, evidence for an exaggerate release of proinflammatory cytokines [interleukin (IL)-1 and IL-6] has been reported in the course acute respiratory syndrome in COVID19 infected patients, thus, aggravating the clinical course of disease [34]. As recently reported, during COVID-19 pandemic in both Italy and China higher frequency of fatalities have been observed in the frail elderly population with previous comorbidities [35]. It is well known that decline of immunity occurs in ageing and, therefore, COVID-19 may gain easier access to the respiratory tract in frail elderly patients [36]. There is evidence that ACE2 protects from severe acute lung failure and operates as a negative regulator of the renin-angiotensin system (RAS) [18, 37]. It is well known that ANG II via activation of the AT1R promotes detrimental effects on the host, such as, vasoconstriction, reactive oxygen species generation, inflammation and matrix remodelling [38]. ACE2 counterbalances the noxious effects exhibited by ANG II and AT1R via activation of AT2R which arrests cell growth, inflammation and fibrosis [39]. In this framework, Gurwitz [40] proposed to use AT1R blockers, such as losartan, as a potential treatment of COVID-19 infection. In fact, losartan as well as olmesartan, used for treating hypertension in patients, were able to increase ACE2 expression after 28 days treatment of rats with myocardial infarction [41]. Then, Gurwitz suggests to evaluate severity of symptoms in COVID-19 infected patients under previous chronic treatment with AT1R blockers in comparison to COVID-19 infected patients who did not take AT1R blockers [40]. Quite interestingly, 75% of aged COVID-19 infected patients admitted to Italian hospitals had hypertension [unpublished data]. However, the putative effects of ACE-2 down-regulation on the cardiovascular system in the course of COVID-19 pandemic need more intensive studies. Taken together, these evidences suggest that CoV-induced down-regulation of ACE2 activates RAS with collateral damage to organs, such as lungs, in the course of SARS-related pneumonia. Then, putative therapeutic measures aimed at increasing ACE2 levels on respiratory epithelial cells should be taken into serious consideration. Quite interestingly, over the past few years, three key papers have demonstrated the ability of a polyphenol, resveratrol (RES), to experimentally deactivate the RAS system in maternal and post-weaning high fat diet, arterial ageing and high fat diet, respectively [42-44]. In all these experimental models, RES led to an increase of ACE2 with reduction of organ damage, such as liver steatosis and aorta media thickness and decrease of adipose tissue mass, respectively. As far as the mechanism of action of RES is concerned, this polyphenol is able to activate sirtuin (Sirt)1 [45-47]. In turn, Sirt1 down-regulates AT1R expression via ACE2 up-regulation [43, 48]. Of importance, Lin and associates [48] have demonstrated the ability of RES to in vitro inhibit MERS-CoV infection of Vero E6 cells, thus, prolonging cell survival in virtue of an anti-apoptotic mechanism. These findings suggest a direct antiviral effect exerted by RES. It would be very interestingly to evaluate the direct effects of RES on COVID-19, in vitro. The data above discussed strongly suggest, that RES, as an activators of ACE2, should be investigated in animal models of CoV-induced severe pneumonia, also taking into account the antioxidant, anti-inflammatory and immunomodulating effects exerted by polyphenols [49]. Then, successful animal studies may pave the way for RES-based human trials in COVID-infected patients. Note added in proof During the reviewing process of this perspective other related papers have been published. Hanff and associates [50] have discussed the possible association between COVID-19-associated cardiovascular mortality and dysregulation of the Renin Angiotensin System (RAS). From a pharmacologic point of view, RAS inhibition leads to upregulation of ACE2, thus, attenuating acute respiratory syndrome and myocarditis in COVID-19-infected patients. Conversely, increase in ACE2 expression may facilitate the access into the host of COVID-19, thus, aggravating the clinical picture. Such a dilemma would be solved byclinical trials based on RAS blockade or initiation and monitoring related effects. Contemporarily, Danser and associates [51] claim that there is no evidence to stop RAS blockers in the course of COVID-19 infection. In fact, there are no available data which support that ACE inhibitors or ANG II type I receptor blockers increase COVID-19 infection via its binding to ACE2. Finally, Kuster and associates [52] write that there are no data on the strict relationship between ACE2 activity and SARS-CoV2 mortality. Moreover, in the SARSCoV2, cells expressing ACE2 were not attacked by the virus, while cells lacking ACE2 were bound by the SARS-CoV2 virus [53]. These findings suggest that also in the case of RES effects on COVID-19 infection, the dual role of ACE2 should be taken into serious consideration.

positive: Hypertension in patients hospitalized with COVID-19 in Wuhan, China: A single-center retrospective observational study Objectives: It is unclear whether patients with hypertension are more likely to be infected with SARS-COV-2 than the general population and whether there is a difference in the severity of COVID-19 pneumonia in patients who have taken ACEI/ARB drugs to lower blood pressure compared to those who have not. Methods: This observational study included data from all patients with clinically confirmed COVID-19 who were admitted to the Hankou Hospital, Wuhan, China between January 5 and March 8, 2020. Data were extracted from clinical and laboratory records. Follow-up was cutoff on March 8, 2020. Results: A total of 274 patients, 75 with hypertension and 199 without hypertension, were included in the analysis. Patients with hypertension were older and were more likely to have pre-existing comorbidities, including chronic renal insufficiency, cardiovascular disease, diabetes mellitus, and cerebrovascular disease than patients without hypertension. Moreover, patients with hypertension tended to have higher positive COVID-19 PCR detection rates. Patients with hypertension who had previously taken ACEI/ARB drugs for antihypertensive treatment have an increased tendency to develop severe pneumonia after infection with SARS-COV-2 (P = 0.064). Conclusions: COVID-19 patients with hypertension were significantly older and were more likely to have underlying comorbidities, including chronic renal insufficiency, cardiovascular disease, diabetes mellitus, and cerebrovascular disease. Patients with hypertension who had taken ACEI/ARB drugs for antihypertensive treatment have an increased tendency to develop severe pneumonia after infection with SARS-COV-2. In future studies, a larger sample size and multi-center clinical data will be needed to support our conclusions.

positive: Functional analysis of the receptor binding domain of SARS coronavirus S1 region and its monoclonal antibody Severe acute respiratory syndrome (SARS) is caused by the SARS coronavirus (CoV). The spike protein of SARS-CoV consists of S1 and S2 domains, which are responsible for virus binding and fusion, respectively. The receptor-binding domain (RBD) positioned in S1 can specifically bind to angiotensin-converting enzyme 2 (ACE2) on target cells, and ACE2 regulates the balance between vasoconstrictors and vasodilators within the heart and kidneys. Here, a recombinant fusion protein containing 193-amino acid RBD (residues 318–510) and glutathione S-transferase were prepared for binding to target cells. Additionally, monoclonal RBD antibodies were prepared to confirm RBD binding to target cells through ACE2. We first confirmed that ACE2 was expressed in various mouse cells such as heart, lungs, spleen, liver, intestine, and kidneys using a commercial ACE2 polyclonal antibody. We also confirmed that the mouse fibroblast (NIH3T3) and human embryonic kidney cell lines (HEK293) expressed ACE2. We finally demonstrated that recombinant RBD bound to ACE2 on these cells using a cellular enzyme-linked immunosorbent assay and immunoassay. These results can be applied for future research to treat ACE2-related diseases and SARS.

positive: SARS-CoV-2 pandemic and research gaps: Understanding SARS-CoV-2 interaction with the ACE2 receptor and implications for therapy The COVID-19 pandemic is an emerging threat to global public health. While our current understanding of COVID-19 pathogenesis is limited, a better understanding will help us develop efficacious treatment and prevention strategies for COVID-19. One potential therapeutic target is angiotensin converting enzyme 2 (ACE2). ACE2 primarily catalyzes the conversion of angiotensin I (Ang I) to a nonapeptide angiotensin or the conversion of angiotensin II (Ang II) to angiotensin 1-7 (Ang 1-7) and has direct effects on cardiac function and multiple organs via counter-regulation of the renin-angiotensin system (RAS). Significant to COVID-19, ACE2 is postulated to serve as a major entry receptor for SARS-CoV-2 in human cells, as it does for SARS-CoV. Many infected individuals develop COVID-19 with fever, cough, and shortness of breath that can progress to pneumonia. Disease progression promotes the activation of immune cells, platelets, and coagulation pathways that can lead to multiple organ failure and death. ACE2 is expressed by epithelial cells of the lungs at high level, a major target of the disease, as seen in post-mortem lung tissue of patients who died with COVID-19, which reveals diffuse alveolar damage with cellular fibromyxoid exudates bilaterally. Comparatively, ACE2 is expressed at low level by vascular endothelial cells of the heart and kidney but may also be targeted by the virus in severe COVID-19 cases. Interestingly, SARS-CoV-2 infection downregulates ACE2 expression, which may also play a critical pathogenic role in COVID-19. Importantly, targeting ACE2/Ang 1-7 axis and blocking ACE2 interaction with the S protein of SARS-CoV-2 to curtail SARS-CoV-2 infection are becoming very attractive therapeutics potential for treatment and prevention of COVID-19. Here, we will discuss the following subtopics: 1) ACE2 as a receptor of SARS-CoV-2; 2) clinical and pathological features of COVID-19; 3) role of ACE2 in the infection and pathogenesis of SARS; 4) potential pathogenic role of ACE2 in COVID-19; 5) animal models for pathological studies and therapeutics; and 6) therapeutics development for COVID-19.

positive: Repurposing Therapeutics for COVID-19: Rapid Prediction of Commercially available drugs through Machine Learning and Docking Background The outbreak of the novel coronavirus disease COVID 19, caused by the SARS-CoV-2 virus has spread rapidly around the globe during the past 3 months. As the virus infected cases and mortality rate of this disease is increasing exponentially, scientists and researchers all over the world are relentlessly working to understand this new virus along with possible treatment regimens by discovering active therapeutic agents and vaccines. So, there is an urgent requirement of new and effective medications that can treat the disease caused by SARS CoV 2. Methods and findings We perform the study of drugs that are already available in the market and being used for other diseases to accelerate clinical recovery, in other words repurposing of existing drugs. The vast complexity in drug design and protocols regarding clinical trials often prohibit developing various new drug combinations for this epidemic disease in a limited time. Recently, remarkable improvements in computational power coupled with advancements in Machine Learning (ML) technology have been utilized to revolutionize the drug development process. Consequently, a detailed study using ML for the repurposing of therapeutic agents is urgently required. Here, we report the ML model based on the Naive Bayes algorithm, which has an accuracy of around 73% to predict the drugs that could be used for the treatment of COVID-19. Our study predicts around ten FDA approved commercial drugs that can be used for repurposing. Among all, we suggest that the antiretroviral drug Atazanavir (DrugBank ID DB01072) would probably be one of the most effective drugs based on the selected criterions. Conclusions Our study can help clinical scientists in being more selective in identifying and testing the therapeutic agents for COVID 19 treatment. The ML based approach for drug discovery as reported here can be a futuristic smart drug designing strategy for community applications.

positive: Soluble angiotensin-converting enzyme 2: a potential approach for coronavirus infection therapy? A new coronavirus, referred to as SARS-CoV-2, is responsible for the recent outbreak of severe respiratory disease. This outbreak first detected in Wuhan, China in December 2019, has spread to other regions of China and to 25 other countries as of January, 2020. It has been known since the 2003 SARS epidemic that the receptor critical for SARS-CoV entry into host cells is the angiotensin-converting enzyme 2 (ACE2). The S1 domain of the spike protein of SARS-CoV attaches the virus to its cellular receptor ACE2 on the host cells. We thought that it is timely to explain the connection between the SARS-CoV, SARS-CoV-2, ACE2 and the rationale for soluble ACE2 as a potential therapy.

positive: Renin-angiotensin-aldosterone system and COVID-19 infection With the multiplication of COVID-19 severe acute respiratory syndrome cases due to SARS-COV2, some concerns about angiotensin-converting enzyme 1 (ACE1) inhibitors (ACEi) and angiotensin II type 1 receptor blockers (ARB) have emerged. Since the ACE2 (angiotensin-converting enzyme 2) enzyme is the receptor that allows SARS COV2 entry into cells, the fear was that pre-existing treatment with ACEi or ARB might increase the risk of developing severe or fatal severe acute respiratory syndrome in case of COVID-19 infection. The present article discusses these concerns. ACE2 is a membrane-bound enzyme (carboxypeptidase) that contributes to the inactivation of angiotensin II and therefore physiologically counters angiotensin II effects. ACEis do not inhibit ACE2. Although ARBs have been shown to up-regulate ACE2 tissue expression in experimental animals, evidence was not always consistent in human studies. Moreover, to date there is no evidence that ACEi or ARB administration facilitates SARS-COV2 cell entry by increasing ACE2 tissue expression in either animal or human studies. Finally, some studies support the hypothesis that elevated ACE2 membrane expression and tissue activity by administration of ARB and/or infusion of soluble ACE2 could confer protective properties against inflammatory tissue damage in COVID-19 infection. In summary, based on the currently available evidence and as advocated by many medical societies, ACEi or ARB should not be discontinued because of concerns with COVID-19 infection, except when the hemodynamic situation is precarious and case-by-case adjustment is required.

positive: Calmodulin interacts with angiotensin-converting enzyme-2 (ACE2) and inhibits shedding of its ectodomain Angiotensin-converting enzyme-2 (ACE2) is a regulatory protein of the renin–angiotensin system (RAS) and a receptor for the causative agent of severe-acute respiratory syndrome (SARS), the SARS-coronavirus. We have previously shown that ACE2 can be shed from the cell surface in response to phorbol esters by a process involving TNF-α converting enzyme (TACE; ADAM17). In this study, we demonstrate that inhibitors of calmodulin also stimulate shedding of the ACE2 ectodomain, a process at least partially mediated by a metalloproteinase. We also show that calmodulin associates with ACE2 and that this interaction is decreased by calmodulin inhibitors.

positive: Association of Renin-Angiotensin System Inhibitors With Severity or Risk of Death in Patients With Hypertension Hospitalized for Coronavirus Disease 2019 (COVID-19) Infection in Wuhan, China Importance: Data are lacking whether patients with hypertension who are taking angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) have increased severity or risk of mortality during hospitalization for coronavirus disease 2019 (COVID-19). Objective: To investigate the association between ACEIs/ARBs and severity of illness and mortality in patients with hypertension hospitalized for COVID-19 infection. Design, Setting, and Participants: Retrospective, single-center case series of the 1178 hospitalized patients with COVID-19 infections at the Central Hospital of Wuhan, China, from January 15 to March 15, 2020. Main Outcomes and Measures: COVID-19 was confirmed by real-time reverse transcription-polymerase chain reaction and epidemiologic, clinical, radiologic, laboratory, and drug therapy data were analyzed in all patients. The percentage of patients with hypertension taking ACEIs/ARBs was compared between those with severe vs nonsevere illness and between survivors vs nonsurvivors. Results: Of the 1178 patients with COVID-19, the median age was 55.5 years (interquartile range, 38-67 years) and 545 (46.3%) were men. The overall in-hospital mortality was 11.0%. There were 362 patients with hypertension (30.7% of the total group; median age, 66.0 years [interquartile range, 59-73 years]; 189 [52.2%] were men), of whom 115 (31.8%) were taking ACEI/ARBs. The in-hospital mortality in the patients with hypertension was 21.3%. The percentage of patients with hypertension taking ACEIs/ARBs did not differ between those with severe and nonsevere infections (32.9% vs 30.7%; P = .65) nor did it differ between nonsurvivors and survivors (27.3% vs 33.0%; P = .34). Similar findings were observed when data were analyzed for patients taking ACEIs and those taking ARBs. Conclusions and Relevance: This study provides clinical data on the association between ACEIs/ARBs and outcomes in patients with hypertension hospitalized with COVID-19 infections, suggesting that ACEIs/ARBs are not associated with the severity or mortality of COVID-19 in such patients. These data support current guidelines and societal recommendations for treating hypertension during the COVID-19 pandemic.

positive: Angiotensin-converting enzyme 2 and new insights into the renin–angiotensin system Abstract Components of the renin–angiotensin system are well established targets for pharmacological intervention in a variety of disorders. Many such therapies abrogate the effects of the hypertensive and mitogenic peptide, angiotensin II, by antagonising its interaction with its receptor, or by inhibiting its formative enzyme, angiotensin-converting enzyme (ACE). At the turn of the millennium, a homologous enzyme, termed ACE2, was identified which increasingly shares the limelight with its better-known homologue. In common with ACE, ACE2 is a type I transmembrane metallopeptidase; however, unlike ACE, ACE2 functions as a carboxypeptidase, cleaving a single C-terminal residue from a distinct range of substrates. One such substrate is angiotensin II, which is hydrolysed by ACE2 to the vasodilatory peptide angiotensin 1–7. In this commentary we discuss the latest developments in the rapidly progressing study of the physiological and patho-physiological roles of ACE2 allied with an overview of the current understanding of its molecular and cell biology. We also discuss parallel developments in the study of collectrin, a catalytically inactive homologue of ACE2 with critical functions in the pancreas and kidney.

positive: Cardiovascular complications in COVID-19 Abstract Background The coronavirus disease of 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While systemic inflammation and pulmonary complications can result in significant morbidity and mortality, cardiovascular complications may also occur. Objective This brief report evaluates cardiovascular complications in the setting of COVID-19 infection. Discussion The current COVID-19 pandemic has resulted in over one million infected worldwide and thousands of death. The virus binds and enters through angiotensin-converting enzyme 2 (ACE2). COVID-19 can result in systemic inflammation, multiorgan dysfunction, and critical illness. The cardiovascular system is also affected, with complications including myocardial injury, myocarditis, acute myocardial infarction, heart failure, dysrhythmias, and venous thromboembolic events. Current therapies for COVID-19 may interact with cardiovascular medications. Conclusions Emergency clinicians should be aware of these cardiovascular complications when evaluating and managing the patient with COVID-19.

positive: The Outbreak of COVID-19 in Italy: Fighting the Pandemic

positive: Angiotensin-converting enzyme inhibition attenuates lipopolysaccharide-induced lung injury by regulating the balance between angiotensin-converting enzyme and angiotensin-converting enzyme 2 and inhibiting mitogen-activated protein kinase activation. Activation of the renin-angiotensin system (angiotensin-converting enzyme [ACE]/angiotensin II [Ang II] and angiotensin-converting enzyme 2 [ACE2]/Ang-1-7) has been implicated in the pathophysiology of inflammatory response and acute lung injury (ALI). Previous studies have shown that the ACE inhibitor captopril (Cap) may be a potent therapeutic drug for ALI. However, the mechanisms of its protective effects on ALI are still largely unknown. In this study, we evaluated the effects of Cap on preventing lipopolysaccharide (LPS)-induced lung injury and further investigated the underlying mechanisms of these protective effects. Rats were intraperitoneally pretreated with Cap (50 mg/kg) 30 min prior to an intravenous administration of LPS (7.5 mg/kg). Furthermore, following a 30-min pretreatment with Cap (10 mol/mL) or combined with the ACE2 inhibitor MLN4760 (10 mol/mL), rat pulmonary microvascular endothelial cells (PMVECs) were stimulated with LPS (1 mg/mL). Captopril pretreatment significantly attenuated LPS-induced pathophysiological changes in the lung, inhibited secretion of tumor necrosis factor α and interleukin 6, reduced the ratio of Ang II to Ang-1-7, and reversed the increased ratio of ACE to ACE2, which was remarkably decreased from 7.07 (LPS only) to 1.71 (LPS + Cap). The protective effects of Cap on ALI were also confirmed by in vitro studies, in which Cap suppressed LPS-induced secretion of proinflammatory cytokines and modulated the expression levels of ACE and ACE2. After Cap pretreatment, the ratio of ACE to ACE2 expression was remarkably decreased from 5.18 (LPS alone) to 1.52 (LPS + Cap). Furthermore, Cap given before LPS administration led to inhibition of p38 mitogen-activated protein kinase (MAPK), ERK (extracellular signal-regulated kinase) 1/2, and JNK (c-Jun N-terminal kinase) phosphorylation in PMVECs, whereas MLN4760 abolished the protective effects of Cap on LPS-induced secretion of proinflammatory cytokines and abolished Cap-induced blockade of p38MAPK, ERK1/2, and JNK phosphorylation. Our findings reveal that Cap exerts protective effects on LPS-induced lung injury and the cytotoxicity of PMVECs, and these effects may, at least in part, regulate the balance of ACE and ACE2 expression and inhibit the activation of MAPKs.

positive: Cardiovascular Pharmacology in the Time of COVID-19: A Focus on Angiotensin-Converting Enzyme 2 Coronavirus disease-2019 (COVID-19) has emerged as a pandemic affecting millions of adults. Severe acute respiratory syndrome coronavirus-2019 (SARS-CoV-2), the causative virus of COVID-19, infects host cells through angiotensin-converting enzyme 2 (ACE2). Preclinical models suggest that ACE2 upregulation confers protective effects in acute lung injury. In addition, renin–angiotensin aldosterone system inhibitors reduce adverse atherosclerotic cardiovascular disease, heart failure, and chronic kidney disease outcomes, but may increase ACE2 levels. We review current knowledge of the role of ACE2 in cardiovascular physiology and SARS-CoV-2 virology, as well as clinical data to inform the management of patients with or at risk for COVID-19 who require renin–angiotensin–aldosterone system inhibitor therapy.

positive: Dangers of ACE inhibitor and ARB usage in COVID-19: evaluating the evidence Background: Concerns have been raised regarding the safety of Angiotensin Converting Enzyme Inhibitors (ACEIs) and Angiotensin Receptor Blockers (ARBs) in patients with COVID-19, based on the hypothesis that such medications may raise expression of ACE2, the receptor for SARS-CoV-2. Methods: We conducted a literature review of studies (n=12) in experimental animals and human subjects (n=11) and evaluated the evidence regarding the impact of administration of ACEIs and ARBs on ACE2 expression. We prioritized studies that assessed ACE2 protein expression data, measured directly or inferred from ACE2 activity assays. Results: The findings in animals are inconsistent with respect to an increase in ACE2 expression in response to treatment with ACEIs or ARBs. Control/sham animals show little to no effect in the plurality of studies. Those studies that report increases in ACE2 expression tend to involve acute injury models and/or higher doses than typically administered to patients. Data from human studies overwhelmingly imply that administration of ACEIs/ARBs does not increase ACE2 expression. Conclusion: Available evidence, in particular, data from human studies, does not support the hypothesis that ACEI/ARB use increases ACE2 expression and the risk of complications from COVID-19. We conclude that patients being treated with ACEIs and ARBs should continue their use for approved indications.

positive: COVID-19 Clinical Trials: A Primer for the Cardiovascular and Cardio-Oncology Communities Abstract The COVID-19 pandemic has resulted in a proliferation of clinical trials that are designed to slow the spread of SARS-CoV-2, the virus that causes COVID-19. The overwhelming majority of cardiovascular and cancer patients are at increased risk for SARS-CoV-2 infection; accordingly, the cardiovascular and cardio-oncology communities are playing a major role in caring for COVID-19 patients. Many of the therapeutic agents that are being used to treat patients with COVID-19 are repurposed treatments for influenza, drugs that were not effective in Ebola patients, or treatments for malaria that were developed decades ago, and are unlikely to be familiar to the cardiovascular and cardio-oncology communities. Here we have provided a foundation for cardiovascular and cardio-oncology physicians who are on the frontline providing care to COVID-19 patients, so that they can better understand the emerging cardiovascular epidemiology of COVID-19, as well as the biological rationale for the clinical trials that are ongoing for the treatment of COVID-19 patients.

positive: Role of Dipeptidyl Peptidase 4 Inhibitors in Diabetic Patients with Coronavirus-19 Infection The pandemic infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is widely increasing the patients affiliated with coronavirus disease 2019 (COVID-19) from last December of 2019. It's reported that the entry receptor of SARS-CoV-2 has been confirmed to be angiotensin converting enzymes 2 (ACE2). Notably, whether the ACE-related inhibitors or drugs modulated ACE2 activity in affecting with viral activity and disease severity of SARS-CoV-2 is still an open question. Dipeptidyl peptidase 4 (DDP-4), a well-known anti-diabetic drug, has been widely used to control the glycemic condition in diabetic patients. In this article, we are focusing on the impact of ACE inhibitors (ACEI) and DPP4 inhibitors used on SARS-CoV-2 activity and discussions about those drugs that may be related to infectious condition of COVID-19 diseases.

positive: Delayed clearance of SARS-CoV2 in male compared to female patients: High ACE2 expression in testes suggests possible existence of gender-specific viral reservoirs The novel coronavirus SARS-CoV2 has been observed to cause a higher incidence and greater severity of disease in males, as seen in multiple cohorts across the globe. The reasons for gender disparity in disease severity is unclear and can be due to host factors. To determine whether males have delayed viral clearance after infection, we evaluated the time to clearance in symptomatic patients tested by serial oropharyngeal/nasopharyngeal swabs followed by RT-PCR at a reference lab in Mumbai, India. A total of 68 subjects with median age of 37 years (3-75 range) were examined and included 48 (71%) males and 20 (29%) females. We observed that females were able to achieve viral clearance significantly earlier than males, with a median difference of 2 days in achieving a negative PCR result (P value = 0.038). Furthermore, examination of 3 families with both male and female patients followed serially, demonstrated that female members of the same household cleared the SARS-CoV2 infection earlier in each family. To determine reasons for delayed clearance in males, we examined the expression patterns of the SARS-CoV2 receptor, Angiotensin-converting enzyme 2 (ACE2), in tissue specific repositories. We observed that the testes was one of the highest sites of ACE2 expression in 3 independent RNA expression databases (Human Protein Atlas, FAMTOM5 and GETx). ACE2 was also determined to be highly expressed in testicular cells at the protein levels. Interestingly, very little expression of ACE2 was seen in ovarian tissue. Taken together, these observations demonstrate for the first time that male subjects have delayed viral clearance of SARS-CoV2. High expression of ACE2 in testes raises the possibility that testicular viral reservoirs may play a role in viral persistence in males and should be further investigated.

positive: Pharmacovigilance in patients with diabetes: A data-driven analysis identifying specific RAS antagonists with adverse pulmonary safety profiles that have implications for COVID-19 morbidity and mortality OBJECTIVES: The current demographic information from China reports that 10%-19% of patients hospitalized with coronavirus disease (COVID-19) were diabetic. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are considered first-line agents in patients with diabetes because of their nephroprotective effects, but administration of these drugs leads to upregulation of angiotensin-converting enzyme 2 (ACE2), which is responsible for the viral entry of severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2). Data are lacking to determine what pulmonary effects ACEIs or ARBs may have in patients with diabetes, which could be relevant in the management of patients infected with SARS-CoV-2. This study aims to assess the prevalence of pulmonary adverse drug effects (ADEs) in patients with diabetes who were taking ACEI or ARBs to provide guidance as to how these medications could affect outcomes in acute respiratory illnesses such as SARS-CoV-2 infection. METHODS: 1DATA, a unique data platform resulting from collaboration across veterinary and human health care, used an intelligent medicine recommender system (1DrugAssist) developed using several national and international databases to evaluate all ADEs reported to the Food and Drug Administration for patients with diabetes taking ACEIs or ARBs. RESULTS: Mining of this data elucidated the proportion of a cluster of pulmonary ADEs associated with specific medications in these classes, which may aid health care professionals in understanding how these medications could worsen or predispose patients with diabetes to infections affecting the respiratory system, specifically COVID-19. Based on this data mining process, captopril was found to have a statistically significantly higher incidence of pulmonary ADEs compared with other ACEIs (P = 0.005) as well as ARBs (P = 0.012), though other specific drugs also had important pulmonary ADEs associated with their use. CONCLUSION: These analyses suggest that pharmacists and clinicians will need to consider the specific medication's adverse event profile, particularly captopril, on how it may affect infections and other acute disease states that alter pulmonary function, such as COVID-19.

positive: Hypertension, renin–angiotensin–aldosterone system inhibition, and COVID-19

positive: SARS-CoV-2 and viral sepsis: observations and hypotheses Summary Since the outbreak of coronavirus disease 2019 (COVID-19), clinicians have tried every effort to understand the disease, and a brief portrait of its clinical features have been identified. In clinical practice, we noticed that many severe or critically ill COVID-19 patients developed typical clinical manifestations of shock, including cold extremities and weak peripheral pulses, even in the absence of overt hypotension. Understanding the mechanism of viral sepsis in COVID-19 is warranted for exploring better clinical care for these patients. With evidence collected from autopsy studies on COVID-19 and basic science research on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and SARS-CoV, we have put forward several hypotheses about SARS-CoV-2 pathogenesis after multiple rounds of discussion among basic science researchers, pathologists, and clinicians working on COVID-19. We hypothesise that a process called viral sepsis is crucial to the disease mechanism of COVID-19. Although these ideas might be proven imperfect or even wrong later, we believe they can provide inputs and guide directions for basic research at this moment.

positive: Protein structure analysis of the interactions between SARS-CoV-2 spike protein and the human ACE2 receptor: from conformational changes to novel neutralizing antibodies The recent severe acute respiratory syndrome, known as Corona Virus Disease 2019 (COVID-19) has spread so much rapidly and severely to induce World Health Organization (WHO) to declare state of emergency over the new coronavirus SARS-CoV-2 pandemic. While several countries have chosen the almost complete lock-down for slowing down SARS-CoV-2 spread, scientific community is called to respond to the devastating outbreak by identifying new tools for diagnosis and treatment of the dangerous COVID-19. With this aim we performed an in silico comparative modeling analysis, which allows to gain new insights about the main conformational changes occurring in the SARS-CoV-2 spike protein, at the level of the receptor binding domain (RBD), along interactions with human cells angiotensin converting enzyme 2 (ACE2) receptor, that favour human cell invasion. Furthermore, our analysis provides i) an ideal pipeline to identify already characterized antibodies that might target SARS-CoV-2 spike RBD, for preventing interactions with the human ACE2, and ii) instructions for building new possible neutralizing antibodies, according to chemical/physical space restraints and complementary determining regions (CDR) mutagenesis of the identified existing antibodies. The proposed antibodies show in silico a high affinity for SARS-CoV-2 spike RBD and can be used as reference antibodies also for building new high affinity antibodies against present and future coronavirus able to invade human cells through interactions of their spike proteins with the human ACE2. More in general, our analysis provides indications for the set-up of the right biological molecular context for investigating spike RBD-ACE2 interactions for the development of new vaccines, diagnosis kits and other treatments based on the usage or the targeting of SARS-CoV-2 spike protein.

positive: What We Know So Far (As of March 26, 2020) About COVID-19 – An MRT Point of View

positive: Angiotensin II Receptor Blockers and Angiotensin-Converting Enzyme Inhibitors Usage is Associated with Improved Inflammatory Status and Clinical Outcomes in COVID-19 Patients With Hypertension With the capability of inducing elevated expression of ACE2, the cellular receptor for SARS-CoV-2, angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors (ARBs/ACEIs) treatment may have a controversial role in both facilitating virus infection and reducing pathogenic inflammation. We aimed to evaluate the correlation of ARBs/ACEIs usage with the pathogenesis of COVID-19 in a retrospective, single-center study. 126 COVID-19 patients with preexisting hypertension at Hubei Provincial Hospital of Traditional Chinese Medicine (HPHTCM) in Wuhan from January 5 to February 22, 2020 were retrospectively allocated to ARBs/ACEIs group (n=43) and non-ARBs/ACEIs group (n=83) according to their antihypertensive medication. 125 age- and sex-matched COVID-19 patients without hypertension were randomly selected as non-hypertension controls. In addition, the medication history of 1942 hypertension patients that were admitted to HPHTCM from November 1 to December 31, 2019 before COVID-19 outbreak were also reviewed for external comparison. Epidemiological, demographic, clinical and laboratory data were collected, analyzed and compared between these groups. The frequency of ARBs/ACEIs usage in hypertension patients with or without COVID-19 were comparable. Among COVID-19 patients with hypertension, those received either ARBs/ACEIs or non-ARBs/ACEIs had comparable blood pressure. However, ARBs/ACEIs group had significantly lower concentrations of CRP (p=0.049) and procalcitonin (PCT, p=0.008). Furthermore, much lower proportion of critical patients (9.3% vs 22.9%; p=0.061), and a lower death rate (4.7% vs 13.3%; p=0.216) were observed in ARBs/ACEIs group than non-ARBs/ACEIs group, although these differences failed to reach statistical significance. Our findings thus support the use of ARBs/ACEIs in COVID-19 patients with preexisting hypertension.

positive: 2019 Novel-coronavirus: Cardiovascular Insights about Risk Factors, Myocardial Injury, Therapy and Clinical Implications From December 31th, 2019, a novel highly pathogenic coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread worldwide, reaching at present the dimension of a pandemic. In addition to damaging the lungs, SARS-CoV-2 may also damage the heart and this is corroborated by the evidence that cardiovascular comorbidities are associated with a higher mortality and poor clinical outcomes in patient infected by the virus. During the infection myocardial injury, myocarditis and arrhythmias have also been reported, but the pathophysiological mechanisms of these complications are yet to be understood. Great attention is also being posed on the potential beneficial/harmful role of angiotensin converting enzyme (ACE) inhibitors, as far as the virus binds to angiotensin converting enzyme 2 (ACE2) to infect cells, but evidences lack. Furthermore, SARS-CoV-2 can also affect the aspect of acute coronary syndromes, not only because these two distinct pathological entities share pathogenic aspects (such as the systemic inflammatory state and cytokine release), but also and above all for the consequences that the need to contain the infection has on the management of cardiological urgencies. Aim of this review is therefore to summarize the relationship between the virus and the cardiovascular system.

positive: Candidate drugs against SARS-CoV-2 and COVID-19 Abstract Outbreak and pandemic of coronavirus SARS-CoV-2 in 2019/2020 will challenge global health for the future. Because a vaccine against the virus will not be available in the near future, we herein try to offer a pharmacological strategy to combat the virus. There exists a number of candidate drugs that may inhibit infection with and replication of SARS-CoV-2. Such drugs comprise inhibitors of TMPRSS2 serine protease and inhibitors of angiotensin-converting enzyme 2 (ACE2). Blockade of ACE2, the host cell receptor for the S protein of SARS-CoV-2 and inhibition of TMPRSS2, which is required for S protein priming may prevent cell entry of SARS-CoV-2. Further, chloroquine and hydroxychloroquine, and off-label antiviral drugs, such as the nucleotide analogue remdesivir, HIV protease inhibitors lopinavir and ritonavir, broad-spectrum antiviral drugs arbidol and favipiravir as well as antiviral phytochemicals available to date may prevent spread of SARS-CoV-2 and morbidity and mortality of COVID-19 pandemic.

positive: Predictors of severe or lethal COVID-19, including Angiotensin Converting Enzyme inhibitors and Angiotensin II Receptor Blockers, in a sample of infected Italian citizens AIMS: This retrospective case-control study was aimed at identifying potential independent predictors of severe/lethal COVID-19, including the treatment with Angiotensin-Converting Enzyme inhibitors (ACEi) and/or Angiotensin II Receptor Blockers (ARBs). METHODS AND RESULTS: All adults with SARS-CoV-2 infection in two Italian provinces were followed for a median of 24 days. ARBs and/or ACEi treatments, and hypertension, diabetes, cancer, COPD, renal and major cardiovascular diseases (CVD) were extracted from clinical charts and electronic health records, up to two years before infection. The sample consisted of 1603 subjects (mean age 58.0y; 47.3% males): 454 (28.3%) had severe symptoms, 192 (12.0%) very severe or lethal disease (154 deaths; mean age 79.3 years; 70.8% hypertensive, 42.2% with CVD). The youngest deceased person aged 44 years. Among hypertensive subjects (n = 543), the proportion of those treated with ARBs or ACEi were 88.4%, 78.7% and 80.6% among patients with mild, severe and very severe/lethal disease, respectively. At multivariate analysis, no association was observed between therapy and disease severity (Adjusted OR for very severe/lethal COVID-19: 0.87; 95% CI: 0.50-1.49). Significant predictors of severe disease were older age (with AORs largely increasing after 70 years of age), male gender (AOR: 1.76; 1.40-2.23), diabetes (AOR: 1.52; 1.05-2.18), CVD (AOR: 1.88; 1.32-2.70) and COPD (AOR: 1.88; 1.11-3.20). Only gender, age and diabetes also predicted very severe/lethal disease. CONCLUSION: No association was found between COVID-19 severity and treatment with ARBs and/or ACEi, supporting the recommendation to continue medication for all patients unless otherwise advised by their physicians.

positive: Is Hypertension a Real Risk Factor for Poor Prognosis in the COVID-19 Pandemic? PURPOSE OF REVIEW: There is increasing evidence indicating an association between several risk factors and worse prognosis in patients with coronavirus disease 2019 (COVID-19), including older age, hypertension, heart failure, diabetes, and pulmonary disease. Hypertension is of particular interest because it is common in adults and there are concerns related to the use of renin-angiotensin system (RAS) inhibitors in patients with hypertension infected with COVID-19. Levels of angiotensin-converting enzyme 2 (ACE2), a protein that facilitates entry of coronavirus into cells, may increase in patients using RAS inhibitors. Thus, chronic use of RAS inhibition could potentially lead to a more severe and fatal form of COVID-19. In this review, we provide a critical review to the following questions: (1) Does hypertension influence immunity or ACE2 expression favoring viral infections? (2) Are the risks of complications in hypertension mediated by its treatment? (3) Is aging a major factor associated with worse prognosis in patients with COVID-19 and hypertension? RECENT FINDINGS: Despite the potential involvement of immune responses in the pathogenesis of hypertension, there is no evidence supporting that hypothesis that hypertension or RAS inhibitors contributes to unfavorable outcomes in viral infections. Future investigations adopting a strict protocol for confirming hypertension status as well as assessing associated comorbidities that may influence outcomes are necessary. From the therapeutic perspective, recombinant ACE2 may serve as a potential therapy, but relevant studies in humans are lacking. Definitive evidence regarding the use of RAS inhibitors in patients with COVID-19 is needed; 5 randomized trials examining this issue are currently underway. SUMMARY: There is no current scientific support for claiming that hypertension or its treatment with RAS inhibitors contribute to unfavorable outcomes in COVID-19.

positive: Predictors of severe or lethal COVID-19, including Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers, in a sample of infected Italian citizens Aims: This retrospective case-control study was aimed at identifying potential independent predictors of severe/lethal COVID-19, including the treatment with Angiotensin-Converting Enzyme inhibitors (ACEi) and/or Angiotensin II Receptor Blockers (ARBs). Methods and Results: All adults with SARS-CoV-2 infection in two Italian provinces were followed for a median of 24 days. ARBs and/or ACEi treatments, and hypertension, diabetes, cancer, COPD, renal and major cardiovascular diseases (CVD) were extracted from clinical charts and electronic health records, up to two years before infection. The sample consisted of 1603 subjects (mean age 58.0y; 47.3% males): 454 (28.3%) had severe symptoms, 192 (12.0%) very severe or lethal disease (154 deaths; mean age 79.3 years; 70.8% hypertensive, 42.2% with CVD). The youngest deceased person aged 44 years. Among hypertensive subjects (n=543), the proportion of those treated with ARBs or ACEi were 88.4%, 78.7% and 80.6% among patients with mild, severe and very severe/lethal disease, respectively. At multivariate analysis, no association was observed between therapy and disease severity (Adjusted OR for very severe/lethal COVID-19: 0.87; 95% CI: 0.50-1.49). Significant predictors of severe disease were older age (with AORs largely increasing after 70 years of age), male gender (AOR: 1.76; 1.40-2.23), diabetes (AOR: 1.52; 1.05-2.18), CVD (AOR: 1.88; 1.32-2.70) and COPD (1.88; 1.11-3.20). Only gender, age and diabetes also predicted very severe/lethal disease. Conclusion: No association was found between COVID-19 severity and treatment with ARBs and/or ACEi, supporting the recommendation to continue medication for all patients unless otherwise advised by their physicians.

positive: Might renin–angiotensin system blockers play a role in the COVID-19 pandemic? Since December 2019, a new coronavirus, named SARS-CoV-2, has spread globally, affecting >200 000 people worldwide with the so-called COVID-19 disease. The scientific community is actively and constantly working to identify the mechanisms involved in the diffusion of this virus and the pathogenesis of the infection, with its most frequent and severe complication, namely interstitial pneumonia. To date, SARS-CoV-2 is known to enter the host cells via the angiotensin-converting enzyme 2 protein. For this reason, the hypothesis that drugs capable of increasing the expression of this protein may have a role in the spread of the virus and in the symptomatology of affected patients has taken hold. The purpose of this Editorial is to briefly show the evidence currently available in this regard and to provide ideas for future research.

positive: Membrane ectopeptidases targeted by human coronaviruses Six coronaviruses, including the recently identified Middle East respiratory syndrome coronavirus, are known to target the human respiratory tract causing mild to severe disease. Their interaction with receptors expressed on cells located in the respiratory tract is an essential first step in the infection. Thus far three membrane ectopeptidases, dipeptidyl peptidase 4 (DPP4), angiotensin-converting enzyme 2 (ACE2) and aminopeptidase N (APN), have been identified as entry receptors for four human-infecting coronaviruses. Although the catalytic activity of the ACE2, APN, and DPP4 peptidases is not required for virus entry, co-expression of other host proteases allows efficient viral entry. In addition, evolutionary conservation of these receptors may permit interspecies transmissions. Because of the physiological function of these peptidase systems, pathogenic host responses may be potentially amplified and cause acute respiratory distress.

positive: Missense variants in ACE2 are predicted to encourage and inhibit interaction with SARS-CoV-2 Spike and contribute to genetic risk in COVID-19 SARS-CoV-2 invades host cells via an endocytic pathway that begins with the interaction of the SARS-CoV-2 Spike glycoprotein (S-protein) and human Angiotensin-converting enzyme 2 (ACE2). Genetic variability in ACE2 may be one factor that mediates the broad-spectrum severity of SARS-CoV-2 infection and COVID-19 outcomes. We investigated the capacity of ACE2 variation to influence SARS-CoV-2 infection with a focus on predicting the effect of missense variants on the ACE2 SARS-CoV-2 S-protein interaction. We validated the mCSM-PPI2 variant effect prediction algorithm with 26 published ACE2 mutant SARS-CoV S-protein binding assays and found it performed well in this closely related system (True Positive Rate = 0.7, True Negative Rate = 1). Application of mCSM-PPI2 to ACE2 missense variants from the Genome Aggregation Consortium Database (gnomAD) identified three that are predicted to strongly inhibit or abolish the S-protein ACE2 interaction altogether (p.Glu37Lys, p.Gly352Val and p.Asp355Asn) and one that is predicted to promote the interaction (p.Gly326Glu). The S-protein ACE2 inhibitory variants are expected to confer a high degree of resistance to SARS-CoV-2 infection whilst the S-protein ACE2 affinity enhancing variant may lead to additional susceptibility and severity. We also performed in silico saturation mutagenesis of the S-protein ACE2 interface and identified a further 38 potential missense mutations that could strongly inhibit binding and one more that is likely to enhance binding (Thr27Arg). A conservative estimate places the prevalence of the strongly protective variants between 12-70 per 100,000 population but there is the possibility of higher prevalence in local populations or those underrepresented in gnomAD. The probable interplay between these ACE2 affinity variants and ACE2 expression polymorphisms is highlighted as well as gender differences in penetrance arising from ACE2’s situation on the X-chromosome. It is also described how our data can help power future genetic association studies of COVID-19 phenotypes and how the saturation mutant predictions can help design a mutant ACE2 with tailored S-protein affinity, which may be an improvement over a current recombinant ACE2 that is undergoing clinical trial. Key results 1 ACE2 gnomAD missense variant (p.Gly326Glu) and one unobserved missense mutation (Thr27Arg) are predicted to enhance ACE2 binding with SARS-CoV-2 Spike protein, which could result in increased susceptibility and severity of COVID-19 3 ACE2 missense variants in gnomAD plus another 38 unobserved missense mutations are predicted to inhibit Spike binding, these are expected to confer a high degree of resistance to infection The prevalence of the strongly protective variants is estimated between 12-70 per 100,000 population but higher prevalence may exist in local populations or those underrepresented in gnomAD A strategy to design a recombinant ACE2 with tailored affinity towards Spike and its potential therapeutic value is presented The predictions were extensively validated against published ACE2 mutant binding assays for SARS-CoV Spike protein

positive: Covid-19 and cardiovascular risk: Susceptibility to infection to SARS-CoV-2, severity and prognosis of Covid-19 and blockade of the renin-angiotensin-aldosterone system. An evidence-based viewpoint The presence of cardiovascular co-morbidities and the known effects of coronaviruses on the cardiovascular system have called attention to the potential implications for patients with cardiovascular risk factors. This evidence-based viewpoint will address two questions: (a) are individuals with underlying cardiovascular risk factors (e.g. high blood pressure or diabetes) or overt disease (e.g. coronary heart disease, heart failure, kidney disease) more likely to develop severe Covid-19 and to die than those without underlying conditions? (b) does the regular use of angiotensin-converting enzyme inhibitors (ACE-i) or angiotensin-receptor blockers (ARB) make patients more likely to get infected and to die of Covid-19? With a necessary cautionary note that the evidence around the links between Covid-19 and cardiovascular disease is accruing at a fast pace, to date we can conclude that: (a) the greater susceptibility of individuals with underlying cardiovascular conditions to develop more severe Covid-19 with higher mortality rate is likely to be confounded, in part, by age and the type of co-morbidities. Patients with heart failure or chronic kidney disease might show an excess risk; (b) neither ACE-i nor ARB are associated with greater risk of SARS-Cov2 infection, or severity or risk of death in patients with Covid-19. Patients on these drugs should not stop them, unless under strict medical supervision and with the addition of a suitable replacement medicine.

positive: Recombinant human ACE2: acing out angiotensin II in ARDS therapy

positive: Relationship Between ACE2 and Other Components of the Renin-Angiotensin System PURPOSE OF THE REVIEW: Angiotensin-converting enzyme 2 (ACE2) is a key counter-regulatory component of the renin-angiotensin system. Here, we briefly review the mechanistic and target organ effects related to ACE2 activity, and the importance of ACE2 in SARS-CoV-2 infection. RECENT FINDINGS: ACE2 converts angiotensin (Ang) II to Ang-(1–7), which directly opposes the vasoconstrictive, proinflammatory, and prothrombotic effects of Ang II. ACE2 also facilitates SARS-CoV-2 viral entry into host cells. Drugs that interact with the renin-angiotensin system may impact ACE2 expression and COVID-19 pathogenesis; however, the magnitude and direction of these effects are unknown at this time. SUMMARY: High quality research is needed to improve our understanding of how agents that act on the renin-angiotensin system impact ACE2 and COVID-19-related disease outcomes.

positive: SARS-CoV-2 and SARS-CoV Spike-RBD Structure and Receptor Binding Comparison and Potential Implications on Neutralizing Antibody and Vaccine Development SARS-CoV-2 and SARS-CoV share a common human receptor ACE2. Protein-protein interaction structure modeling indicates that spike-RBD of the two viruses also has similar overall binding conformation and binding free energy to ACE2. In vitro assays using recombinant ACE2 proteins and ACE2 expressing cells confirmed the two coronaviruses’ similar binding affinities to ACE2. The above studies provide experimental supporting evidences and possible explanation for the high transmissibility observed in the SARS-CoV-2 outbreak. Potent ACE2-blocking SARS-CoV neutralizing antibodies showed limited cross-binding and neutralizing activities to SARS-CoV-2. ACE2-non-blocking SARS-CoV RBD antibodies, though with weaker neutralizing activities against SARS-CoV, showed positive cross-neutralizing activities to SARS-CoV-2 with an unknown mechanism. These findings suggest a trade-off between the efficacy and spectrum for therapeutic antibodies to different coronaviruses, and hence highlight the possibilities and challenges in developing broadly protecting antibodies and vaccines against SARS-CoV-2 and its future mutants.

positive: Covid-19 and the angiotensin-converting enzyme (ACE2): Areas for research

positive: Angiotensin-converting enzyme-2 (ACE2), SARS-CoV-2 and pathophysiology of coronavirus disease 2019 (COVID-19) Angiotensin-converting enzyme-2 (ACE2) has been established as the functional host receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the current devastating worldwide pandemic of coronavirus disease 2019 (COVID-19). ACE2 is abundantly expressed in a variety of cells residing in many different human organs. In human physiology, ACE2 is a pivotal counter-regulatory enzyme to ACE by the breakdown of angiotensin II, the central player in the renin-angiotensin-aldosterone system (RAAS) and the main substrate of ACE2. Many factors have been associated with both altered ACE2 expression and COVID-19 severity and progression, including age, sex, ethnicity, medication and several co-morbidities, such as cardiovascular disease and metabolic syndrome. Although ACE2 is widely distributed in various human tissues and many of its determinants have been well recognised, ACE2-expressing organs do not equally participate in COVID-19 pathophysiology, implying that other mechanisms are involved in orchestrating cellular infection resulting in tissue damage. Reports of pathologic findings in tissue specimens of COVID-19 patients are rapidly emerging and confirm the established role of ACE2 expression and activity in disease pathogenesis. Identifying pathologic changes caused by SARS-CoV-2 infection is crucially important as it has major implications for understanding COVID-19 pathophysiology and the development of evidence-based treatment strategies. Currently, many interventional strategies are being explored in ongoing clinical trials, encompassing many drug classes and strategies, including antiviral drugs, biological response modifiers and RAAS inhibitors. Ultimately, prevention is key to combat COVID-19 and appropriate measures are being taken accordingly, including development of effective vaccines. In this review, we describe the role of ACE2 in COVID-19 pathophysiology, including factors influencing ACE2 expression and activity in relation to COVID-19 severity. In addition, we discuss the relevant pathological changes resulting from SARS-CoV-2 infection. Finally, we highlight a selection of potential treatment modalities for COVID-19. This article is protected by copyright. All rights reserved.

positive: Angiotensin-converting enzyme 2, a SARS-CoV-2 receptor, is upregulated by interleukin-6 via STAT3 signaling in rheumatoid synovium Detected in December 2019, the coronavirus disease 2019 (COVID-19) has since spread all over the world, resulting in a global pandemic. The disease is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), and its symptoms usually include cough, fever, and gastrointestinal problems. Although the prevalence of rheumatoid arthritis (RA) is about 1 % of the global population and RA patients naturally have a chance of acquiring COVID-19 in this pandemic, no studies have considered the expression of angiotensin-converting enzyme 2 (ACE2) (a receptor for SARS-CoV-2) in synovial tissues. Our presenting data revealed that ACE2 expression was elevated in active rheumatoid synovium, and siRNA against STAT3 was able to downregulate ACE2 expression, which was in turn induced by IL-6 signaling.

positive: Integrated analyses of single-cell atlases reveal age, gender, and smoking status associations with cell type-specific expression of mediators of SARS-CoV-2 viral entry and highlights inflammatory programs in putative target cells The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, creates an urgent need for identifying molecular mechanisms that mediate viral entry, propagation, and tissue pathology. Cell membrane bound angiotensin-converting enzyme 2 (ACE2) and associated proteases, transmembrane protease serine 2 (TMPRSS2) and Cathepsin L (CTSL), were previously identified as mediators of SARS-CoV2 cellular entry. Here, we assess the cell type-specific RNA expression of ACE2, TMPRSS2, and CTSL through an integrated analysis of 107 single-cell and single-nucleus RNA-Seq studies, including 22 lung and airways datasets (16 unpublished), and 85 datasets from other diverse organs. Joint expression of ACE2 and the accessory proteases identifies specific subsets of respiratory epithelial cells as putative targets of viral infection in the nasal passages, airways, and alveoli. Cells that co-express ACE2 and proteases are also identified in cells from other organs, some of which have been associated with COVID-19 transmission or pathology, including gut enterocytes, corneal epithelial cells, cardiomyocytes, heart pericytes, olfactory sustentacular cells, and renal epithelial cells. Performing the first meta-analyses of scRNA-seq studies, we analyzed 1,176,683 cells from 282 nasal, airway, and lung parenchyma samples from 164 donors spanning fetal, childhood, adult, and elderly age groups, associate increased levels of ACE2, TMPRSS2, and CTSL in specific cell types with increasing age, male gender, and smoking, all of which are epidemiologically linked to COVID-19 susceptibility and outcomes. Notably, there was a particularly low expression of ACE2 in the few young pediatric samples in the analysis. Further analysis reveals a gene expression program shared by ACE2+TMPRSS2+ cells in nasal, lung and gut tissues, including genes that may mediate viral entry, subtend key immune functions, and mediate epithelial-macrophage cross-talk. Amongst these are IL6, its receptor and co-receptor, IL1R, TNF response pathways, and complement genes. Cell type specificity in the lung and airways and smoking effects were conserved in mice. Our analyses suggest that differences in the cell type-specific expression of mediators of SARS-CoV-2 viral entry may be responsible for aspects of COVID-19 epidemiology and clinical course, and point to putative molecular pathways involved in disease susceptibility and pathogenesis.

positive: Recommendations for coronavirus infection in rheumatic diseases treated with biologic therapy Abstract The Coronavirus-associated disease, that was first identified in 2019 in China (CoViD-19), is a pandemic caused by a bat-derived beta-coronavirus, named SARS-CoV2. It shares homology with SARS and MERS-CoV, responsible for past outbreaks in China and in Middle East. SARS-CoV2 spread from China where the first infections were described in December 2019 and is responsible for the respiratory symptoms that can lead to acute respiratory distress syndrome. A cytokine storm has been shown in patients who develop fatal complications, as observed in past coronavirus infections. The management includes ventilatory support and broad-spectrum antiviral drugs, empirically utilized, as a targeted therapy and vaccines have not been developed. Based upon our limited knowledge on the pathogenesis of CoViD-19, a potential role of some anti-rheumatic drugs may be hypothesized, acting as direct antivirals or targeting host immune response. Antimalarial drugs, commonly used in rheumatology, may alter the lysosomal proteases that mediates the viral entry into the cell and have demonstrated efficacy in improving the infection. Anti-IL-1 and anti-IL-6 may interfere with the cytokine storm in severe cases and use of tocilizumab has shown good outcomes in a small cohort. Baricitinib has both antiviral and anti-inflammatory properties. Checkpoints inhibitors such as anti-CD200 and anti-PD1 could have a role in the treatment of CoViD-19. Rheumatic disease patients taking immunosuppressive drugs should be recommended to maintain the chronic therapy, prevent infection by avoiding social contacts and pausing immunosuppressants in case of infection. National and international registries are being created to collect data on rheumatic patients with CoViD-19.

positive: Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2 ACE2 (angiotensin-converting enzyme 2) has a multiplicity of physiological roles that revolve around its trivalent function: a negative regulator of the renin-angiotensin system, facilitator of amino acid transport, and the severe acute respiratory syndrome-coronavirus (SARS-CoV) and SARS-CoV-2 receptor. ACE2 is widely expressed, including, in the lungs, cardiovascular system, gut, kidneys, central nervous system, and adipose tissue. ACE2 has recently been identified as the SARS-CoV-2 receptor, the infective agent responsible for coronavirus disease 2019, providing a critical link between immunity, inflammation, ACE2, and cardiovascular disease. Although sharing a close evolutionary relationship with SARS-CoV, the receptor-binding domain of SARS-CoV-2 differs in several key amino acid residues, allowing for stronger binding affinity with the human ACE2 receptor, which may account for the greater pathogenicity of SARS-CoV-2. The loss of ACE2 function following binding by SARS-CoV-2 is driven by endocytosis and activation of proteolytic cleavage and processing. The ACE2 system is a critical protective pathway against heart failure with reduced and preserved ejection fraction including, myocardial infarction and hypertension, and against lung disease and diabetes mellitus. The control of gut dysbiosis and vascular permeability by ACE2 has emerged as an essential mechanism of pulmonary hypertension and diabetic cardiovascular complications. Recombinant ACE2, gene-delivery of Ace2, Ang 1–7 analogs, and Mas receptor agonists enhance ACE2 action and serve as potential therapies for disease conditions associated with an activated renin-angiotensin system. rhACE2 (recombinant human ACE2) has completed clinical trials and efficiently lowered or increased plasma angiotensin II and angiotensin 1-7 levels, respectively. Our review summarizes the progress over the past 20 years, highlighting the critical role of ACE2 as the novel SARS-CoV-2 receptor and as the negative regulator of the renin-angiotensin system, together with implications for the coronavirus disease 2019 pandemic and associated cardiovascular diseases.

positive: Estimation of RAAS-Inhibitor effect on the COVID-19 outcome: A Meta-analysis BACKGROUND AND RATIONALE: Some studies of hospitalized patients suggested that the risk of death and/or severe illness due to COVID-19 is not associated with the use of angiotensin-converting enzyme inhibitors (ACEIs) and/or angiotensin II receptor type 1 blockers (ARBs). Nevertheless, some controversy still exists and there is limited information of the ACEIs/ARBs effect size on COVID-19 prognosis. AIM AND METHODS: We aimed to measure the effect of ACEIs and/or ARBs on COVID-19 severe clinical illness by a meta-analysis. Literature search included all studies published since the COVID-19 outbreak began (December 2019) until May 9, 2020. We analyzed information from studies that included tested COVID-19 patients with arterial hypertension as comorbidity prior to hospital admission and history of taking ACEIs, ARBs, or ACEIs/ARBs. RESULTS: We included 16 studies that involved 24,676 COVID-19 patients, and we compared patients with critical (n = 4134) vs. non-critical (n = 20,542) outcomes. The overall assessment by estimating random effects shows that the use of ACEIs/ARBs is not associated with higher risk of in-hospital-death and/or severe illness among hypertensive patients with COVID-19 infection. On the contrary, effect estimate shows an overall protective effect of RAAS inhibitors/blockers (ACEIs, ARBs, and/or ACEIs/ARBs) with ∼ 23 % reduced risk f death and/or critical disease (OR: 0.768, 95%CI: 0.651-0.907, p=0.0018). The use of ACEIs (OR:0.652, 95%CI:0.478-0.891, p=0.0072) but not ACEIs/ARBs (OR:0.867, 95%CI:0.638-1.179, p =NS) or ARBs alone (OR:0.810, 95%CI:0.629-1.044, p=NS) may explain the overall protection displayed by RAAS intervention combined. CONCLUSION: RAAS inhibitors might be associated with better COVID-19 prognosis.

positive: Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?

positive: Targeting of Renin-Angiotensin System In COVID-19 Patients Affected by Stroke: Emerging Concerns About Detrimental vs. Benefit Effect OBJECTIVE: The present short report summarizes some clinical characteristics of six patients affected by stroke while being on angiotensin-converting enzyme (ACE)2 inhibitors and angiotensin II receptor blockers (ARBs) before and during COVID-19. METHODS: Medical charts and images of six patients affected by stroke while being on ACE-Is and ARBs therapy before and during COVID-19 outbreak in Lombardy region, Italy, were reviewed. RESULTS: Three patients had a dural sinus thrombosis, whereas the remaining suffered by an arterial ischemia, which was a middle cerebral artery occlusion in one case, and a posterior-inferior cerebellar artery occlusion in the remaining two. All patients showed clinical features typical of SARS-CoV-2 infection and positive chest CT scan, and were treated with ACE-Is as needed. Hypercoagulability panel was negative in any case. A recovery was achieved in all cases, although in a variable manner. CONCLUSIONS: Whether or not and in which manner the pharmacomodulation of the renin-angiotensin system may had affect the clinical course of the reported six COVID-19 patients affected by stroke has to be still clarified. An urgent need of randomized clinical trials aimed to assess the safety profile and neuroprotective properties of ACE-Is and ARBs in COVID-19 patients diagnosed with stroke does exists.

positive: RAAS inhibitors do not increase the risk of COVID-19 According to five new studies, therapy with angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs) is not associated with an increased risk of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or with an increased risk of severe disease or in-hospital death among patients with COVID-19.

positive: Anti-hypertensive Angiotensin II receptor blockers associated to mitigation of disease severity in elderly COVID-19 patients Summary Background The novel coronavirus (CoV) severe acute respiratory syndrome (SARS)-CoV-2 outbreak started at the end of 2019 in Wuhan, China, and spread over 100 countries. SARS-CoV-2 uses the membrane protein Angiotensin I converting enzyme 2(ACE2) as a cell entry receptor. Indeed, it was reported that the balance of Renin-Angiotensin System (RAS), regulated by both ACE and ACE2, was altered in COVID-19 patients. It is controversial, however, whether commonly used anti-hypertensive drugs Angiotensin I converting enzyme inhibitor (ACEI) and Angiotensin II receptor blocker (ARB) shall be continued in the confirmed COVID-19 patients. This study was designed to investigate any difference in disease severity between COVID-19 patients with hypertension comorbidity. The included COVID-19 patients used ACEI, ARB, calcium channel blockers (CCB), beta blockers (BB), or thiazide to treat preexisting hypertension prior to the hospital were compared to patients who did not take any of those drugs. Methods In this multicentre retrospective study, clinical data of 511 COVID-19 patients were analyzed. Patients were categorized into six sub-groups of hypertension comorbidity based on treatment using one of anti-hypertension drugs (ACEI, ARB, CCB, BB, thiazide), or none. A meta-analysis was performed to evaluate the use of ACEI and ARB associated with pneumonia using published studies. Findings Among the elderly (age>65) COVID-19 patients with hypertension comorbidity, the risk of COVID-19-S (severe disease) was significantly decreased in patients who took ARB drugs prior to hospitalization compared to patients who took no drugs (OR=0.343, 95% CI 0.128-0.916, p=0.025). The meta-analysis showed that ARB use has positive effects associated with morbidity and mortality of pneumonia. Interpretation Elderly (age>65) COVID-19 patients with hypertension comorbidity who are taking ARB anti-hypertension drugs may be less likely to develop severe lung disease compared to patients who take no anti-hypertension drugs. Funding National Natural Science Foundation of China, Chinese Academy of Medical Sciences

positive: COVID-19 and cardiovascular disease: What we know, what we think we know, and what we need to know

positive: COVID-19, diabetes mellitus and ACE2: The conundrum

positive: COVID-19 pandemic and therapy with ibuprofen or renin-angiotensin system blockers: no need for interruptions or changes in ongoing chronic treatments Scientists hypothesized that drugs such as ibuprofen or renin-angiotensin system (RAS) blockers could exacerbate the novel coronavirus disease COVID-19 by upregulating the angiotensin-converting enzyme 2 (ACE2), which serves as an entry receptor for the coronavirus SARS-CoV-2. This hypothesis was taken up by the lay press and led to concerns among doctors and patients whether the use of these drugs was still safe and justified against the background of the pandemic spread of SARS-CoV-2 with an increasing number of cases and deaths. In this article, we summarize what is known about the effect of RAS blockers or non-steroidal anti-inflammatory drugs (NSAIDs) on the course of COVID-19 disease. In the case of RAS inhibition, we also find evidence for the opposite hypothesis, namely, that RAS inhibition in COVID-19 could be protective. In view of the inconsistent and limited evidence and after weighing up the benefits and risks, we would not currently recommend discontinuing or switching an effective treatment with RAS blockers. NSAIDs should be used at the lowest effective dose for the shortest possible period. The choice of drug to treat COVID-19-associated fever or pain should be based on a benefit-risk assessment for known side effects (e.g., kidney damage, gastrointestinal ulceration).

positive: Angiotensin-converting-enzyme inhibitors (ACE inhibitors) and angiotensin II receptor blocker (ARB) use in COVID-19 prevention or treatment: A paradox

positive: COVID-19 – Does This Disease Kill Due to Imbalance of the Renin Angiotensin System (RAS) Caused by Genetic and Gender Differences in the Response to Viral ACE 2 Attacks? ABSTRACT Debate continues in the medical literature on the role of the renin angiotensin system (RAS) in Coronavirus disease 2019 (COVID-19) pathophysiology and the implications for the use of cardiovascular drugs acting on the RAS. Could these drugs – which include angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptors blockers (ARBs) – be harmful or potential key therapeutic agents in COVID-19?

positive: Renin–Angiotensin–Aldosterone System Inhibitors and Risk of Covid-19 BACKGROUND: There is concern about the potential of an increased risk related to medications that act on the renin–angiotensin–aldosterone system in patients exposed to coronavirus disease 2019 (Covid-19), because the viral receptor is angiotensin-converting enzyme 2 (ACE2). METHODS: We assessed the relation between previous treatment with ACE inhibitors, angiotensin-receptor blockers, beta-blockers, calcium-channel blockers, or thiazide diuretics and the likelihood of a positive or negative result on Covid-19 testing as well as the likelihood of severe illness (defined as intensive care, mechanical ventilation, or death) among patients who tested positive. Using Bayesian methods, we compared outcomes in patients who had been treated with these medications and in untreated patients, overall and in those with hypertension, after propensity-score matching for receipt of each medication class. A difference of at least 10 percentage points was prespecified as a substantial difference. RESULTS: Among 12,594 patients who were tested for Covid-19, a total of 5894 (46.8%) were positive; 1002 of these patients (17.0%) had severe illness. A history of hypertension was present in 4357 patients (34.6%), among whom 2573 (59.1%) had a positive test; 634 of these patients (24.6%) had severe illness. There was no association between any single medication class and an increased likelihood of a positive test. None of the medications examined was associated with a substantial increase in the risk of severe illness among patients who tested positive. CONCLUSIONS: We found no substantial increase in the likelihood of a positive test for Covid-19 or in the risk of severe Covid-19 among patients who tested positive in association with five common classes of antihypertensive medications.

positive: An epidemiological study exploring a possible impact of treatment with ACE inhibitors or angiotensin receptor blockers on ACE2 plasma concentrations

positive: SARS-CoV-2 receptor ACE2-dependent implications on the cardiovascular system: From basic science to clinical implications Abstract The current COVID-19 pandemic started several months ago and is still exponentially growing in most parts of the world – this is the most recent and alarming update. COVID-19 requires the collaboration of nearly 200 countries to curb the spread of SARS-CoV-2 while gaining time to explore and improve treatment options especially for cardiovascular disease (CVD) and immunocompromised patients, who appear to be at high-risk to die from cardiopulmonary failure. Currently unanswered questions are why elderly people, particularly those with pre-existing comorbidities seem to exhibit higher mortality rates after SARS-CoV-2 infection and whether intensive care becomes indispensable for these patients to prevent multi-organ failure and sudden death. To face these challenges, we here summarize the molecular insights into viral infection mechanisms and implications for cardiovascular disease. Since the infection starts in the upper respiratory system, first flu-like symptoms develop that spread throughout the body. The wide range of affected organs is presumably based on the common expression of the major SARS-CoV-2 entry-receptor angiotensin-converting enzyme 2 (ACE2). Physiologically, ACE2 degrades angiotensin II, the master regulator of the renin-angiotensin-aldosterone system (RAAS), thereby converting it into vasodilatory molecules, which have well-documented cardio-protective effects. Thus, RAAS inhibitors, which may increase the expression levels of ACE2, are commonly used for the treatment of hypertension and CVD. This, and the fact that SARS-CoV-2 hijacks ACE2 for cell-entry, have spurred controversial discussions on the role of ACE2 in COVID-19 patients. In this review, we highlight the state-of-the-art knowledge on SARS-CoV-2-dependent mechanisms and the potential interaction with ACE2 expression and cell surface localization. We aim to provide a list of potential treatment options and a better understanding of why CVD is a high risk factor for COVID-19 susceptibility and further discuss the acute as well as long-term cardiac consequences.

positive: ACE2 correlated with immune infiltration serves as a prognostic biomarker in endometrial carcinoma and renal papillary cell carcinoma: implication for COVID-19 Angiotensin-converting enzyme 2 (ACE2) is a member of the renin-angiotension system, however, the correlation between ACE2 and prognosis in UCEC (Uterine Corpus Endometrial Carcinoma) and KIRP (Kidney Renal Papillary Cell Carcinoma) is not clear. We analyzed the expression levels of ACE2 in the Oncomine and TIMER databases, the correlation between ACE2 and overall survival in the PrognoScan, GEPIA and Kaplan-Meier plotter databases. The correlation between ACE2 and immune infiltration level and the type markers of immune cells was investigated in TIMER database. A prognosis analysis based on the expression levels of ACE2 was further performed in related immune cells subgroup. The ACE2 promoter methylation profile was tested in the UALCAN database. In addition, we used GSE30589 and GSE52920 databases to elucidate the changes of ACE2 expression in vivo and in vitro after SARS-CoV infection. ACE2 was elevated in UCEC and KIRP, and high ACE2 had a favorable prognosis. The expression of ACE2 was positively correlated with the level of immune infiltration of macrophage in KIRP, B cell, CD4+T cell, neutrophil and dendritic cell immune infiltration levels in UCEC. ACE2 was significantly positively correlated with the type markers of B cells and neutrophils, macrophages in UCEC, while ACE2 in KIRP was positively correlated with the type markers of macrophages. High ACE2 expression level had a favorable prognosis in different enriched immune cells subgroups in UCEC and KIRP. And the promoter methylation levels of ACE2 in UCEC and KIRP were significantly reduced. What's more, we found that the expression of ACE2 decreased in vivo and in vitro after SARS-CoV infection. In conclusion, ACE2 expression increased significantly in UCEC and KIRP, elevated ACE2 was positively correlated with immune infiltration and prognosis. Moreover, tumor tissues may be more susceptible to SARS-CoV-2 infection in COVID-19 patients with UCEC and KIRP, which may worsen the prognosis.

positive: The role of angiotensin-converting enzyme 2 in the pathogenesis of COVID-19: the villain or the hero? Angiotensin-converting enzyme 2 (ACE 2) is the entry receptor for the novel coronavirus SARS-CoV-2, the aetiological agent of COVID-19. At the same time, ACE 2 expression decreases during COVID-19. Two seemingly contradictory relationships between the expression of ACE 2 and COVID-19 have been reported. Increased level of expression of ACE 2 may be a risk factor for the development of COVID-19 infection, while reduced ACE 2 expression during COVID-19 leads to acute respiratory distress syndrome. This article provides a comprehensive overview of available scientific knowledge about the role of ACE 2 in the pathogenesis of COVID-19, which is available up to current day. Also, it discusses unknown factors that we will have to reveal in order to understand the whole role of ACE 2 in the pathogenesis of COVID-19.

positive: Will children reveal their secret? The coronavirus dilemma

positive: Angiotensin II administration to COVID-19 patients is not advisable

positive: Association of Renin-Angiotensin System Inhibitors With Severity or Risk of Death in Patients With Hypertension Hospitalized for Coronavirus Disease 2019 (COVID-19) Infection in Wuhan, China. Importance Data are lacking whether patients with hypertension who are taking angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) have increased severity or risk of mortality during hospitalization for coronavirus disease 2019 (COVID-19). Objective To investigate the association between ACEIs/ARBs and severity of illness and mortality in patients with hypertension hospitalized for COVID-19 infection. Design, Setting, and Participants Retrospective, single-center case series of the 1178 hospitalized patients with COVID-19 infections at the Central Hospital of Wuhan, China, from January 15 to March 15, 2020. Main Outcomes and Measures COVID-19 was confirmed by real-time reverse transcription-polymerase chain reaction and epidemiologic, clinical, radiologic, laboratory, and drug therapy data were analyzed in all patients. The percentage of patients with hypertension taking ACEIs/ARBs was compared between those with severe vs nonsevere illness and between survivors vs nonsurvivors. Results Of the 1178 patients with COVID-19, the median age was 55.5 years (interquartile range, 38-67 years) and 545 (46.3%) were men. The overall in-hospital mortality was 11.0%. There were 362 patients with hypertension (30.7% of the total group; median age, 66.0 years [interquartile range, 59-73 years]; 189 [52.2%] were men), of whom 115 (31.8%) were taking ACEI/ARBs. The in-hospital mortality in the patients with hypertension was 21.3%. The percentage of patients with hypertension taking ACEIs/ARBs did not differ between those with severe and nonsevere infections (32.9% vs 30.7%; P = .65) nor did it differ between nonsurvivors and survivors (27.3% vs 33.0%; P = .34). Similar findings were observed when data were analyzed for patients taking ACEIs and those taking ARBs. Conclusions and Relevance This study provides clinical data on the association between ACEIs/ARBs and outcomes in patients with hypertension hospitalized with COVID-19 infections, suggesting that ACEIs/ARBs are not associated with the severity or mortality of COVID-19 in such patients. These data support current guidelines and societal recommendations for treating hypertension during the COVID-19 pandemic.

positive: Genotype and phenotype of COVID-19: Their roles in pathogenesis Abstract COVID-19 is a novel coronavirus with an outbreak of unusual viral pneumonia in Wuhan, China, and then pandemic. Based on its phylogenetic relationships and genomic structures the COVID-19 belongs to genera Betacoronavirus. Human Betacoronaviruses (SARS-CoV-2, SARS-CoV, and MERS-CoV) have many similarities, but also have differences in their genomic and phenotypic structure that can influence their pathogenesis. COVID-19 is containing single-stranded (positive-sense) RNA associated with a nucleoprotein within a capsid comprised of matrix protein. A typical CoV contains at least six ORFs in its genome. All the structural and accessory proteins are translated from the sgRNAs of CoVs. Four main structural proteins are encoded by ORFs 10, 11 on the one-third of the genome near the 3′-terminus. The genetic and phenotypic structure of COVID-19 in pathogenesis is important. This article highlights the most important of these features compared to other Betacoronaviruses.

positive: The S proteins of human coronavirus NL63 and severe acute respiratory syndrome coronavirus bind overlapping regions of ACE2 The cellular receptor for human coronavirus NL63 (HCoV-NL63), a group I coronavirus, is angiotensin-converting enzyme2 (ACE2). ACE2 is also the receptor for the SARS coronavirus (SARS-CoV), a group II coronavirus. Here we describe the ability of HCoV-NL63 to utilize a number of ACE2 variants previously characterized as SARS-CoV receptors. Several ACE2 variants that reduced SARS-CoV S-protein association similarly reduced that of HCoV-NL63, whereas alteration of a number of solvent-exposed ACE2 residues did not interfere with binding by either S protein. One notable exception is ACE2 residue 354, at the boundary of the SARS-CoV binding site, whose alteration markedly inhibited utilization by the HCoV-NL63 but not SARS-CoV S proteins. In addition, the SARS-CoV S-protein receptor-binding domain inhibited entry mediated by the HCoV-NL63 S protein. These studies indicate that HCoV-NL63, like SARS-CoV, associates region of human ACE2 that includes a key loop formed by β-strands 4 and 5.

positive: Identification and characterisation of the angiotensin converting enzyme-3 (ACE3) gene: a novel mammalian homologue of ACE BACKGROUND: Mammalian angiotensin converting enzyme (ACE) plays a key role in blood pressure regulation. Although multiple ACE-like proteins exist in non-mammalian organisms, to date only one other ACE homologue, ACE2, has been identified in mammals. RESULTS: Here we report the identification and characterisation of the gene encoding a third homologue of ACE, termed ACE3, in several mammalian genomes. The ACE3 gene is located on the same chromosome downstream of the ACE gene. Multiple sequence alignment and molecular modelling have been employed to characterise the predicted ACE3 protein. In mouse, rat, cow and dog, the predicted protein has mutations in some of the critical residues involved in catalysis, including the catalytic Glu in the HEXXH zinc binding motif which is Gln, and ESTs or reverse-transcription PCR indicate that the gene is expressed. In humans, the predicted ACE3 protein has an intact HEXXH motif, but there are other deletions and insertions in the gene and no ESTs have been identified. CONCLUSION: In the genomes of several mammalian species there is a gene that encodes a novel, single domain ACE-like protein, ACE3. In mouse, rat, cow and dog ACE3, the catalytic Glu is replaced by Gln in the putative zinc binding motif, indicating that in these species ACE3 would lack catalytic activity as a zinc metalloprotease. In humans, no evidence was found that the ACE3 gene is expressed and the presence of deletions and insertions in the sequence indicate that ACE3 is a pseudogene.

positive: Angiotensin-converting enzyme 2 and angiotensin 1–7: novel therapeutic targets The renin–angiotensin system (RAS) has pivotal roles in the regulation of normal physiology and the pathogenesis of cardiovascular disease. Angiotensin-converting enzyme (ACE) 2, and its product angiotensin 1–7, are thought to have counteracting effects against the adverse actions of other, better known and understood, members of the RAS. The physiological and pathological importance of ACE2 and angiotensin 1–7 in the cardiovascular system are not completely understood, but numerous experimental studies have indicated that these components have protective effects in the heart and blood vessels. Here, we provide an overview on the basic properties of ACE2 and angiotensin 1–7 and a summary of the evidence from experimental and clinical studies of various pathological conditions, such as hypertension, atherosclerosis, myocardial remodelling, heart failure, ischaemic stroke, and diabetes mellitus. ACE2-mediated catabolism of angiotensin II is likely to have a major role in cardiovascular protection, whereas the relevant functions and signalling mechanisms of actions induced by angiotensin 1–7 have not been conclusively determined. The ACE2–angiotensin 1–7 pathway, however, might provide a useful therapeutic target for the treatment of cardiovascular disease, especially in patients with overactive RAS. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/nrcardio.2014.59) contains supplementary material, which is available to authorized users.

positive: Expression of SARS-CoV-2 receptor ACE2 and the spike protein processing enzymes in developing human embryos The novel coronavirus disease, COVID-19 caused by Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2), has resulted in thousands of critically ill patients and poses a serious threat globally. To investigate if SARS-CoV-2 can affect early human embryos, we analysed scRNA-seq datasets of human embryos for the SARS-CoV-2 receptors ACE2 and BSG (CD147), the serine protease TMPRSS2 for viral spike protein priming, and the endosomal protease CTSL for spike protein activation via the endosomal route. The results reveal that ACE2 and TMPRSS2 are co-expressed in a proportion of epiblast cells, and both BSG and CTSL are expressed in all the stages of embryonic development. The cells of the blastocysts express genes encoding for other coronavirus receptors such as DPP4 and ANPEP as well. Interestingly, the cells of the epiblast also express genes involved in viral endocytosis and replication. We further identified 194 genes that are differentially expressed in ACE2- and TMPRSS2-positive cells as compared to ACE2- and TMPRSS2-negative cells of the epiblast. Our results show that developing human embryos express the receptors for SARS-CoV-2 and other coronaviruses; embryos also harbour the necessary machinery for viral internalization and replication. We suggest that couples be advised to avoid conceiving during the pandemic and that IVF procedures be kept to a minimum to prevent any possible hazard to the developing embryos.

positive: Age and Multimorbidity Predict Death Among COVID-19 Patients: Results of the SARS-RAS Study of the Italian Society of Hypertension Several factors have been proposed to explain the high death rate of the coronavirus disease 2019 (COVID-19) outbreak, including hypertension and hypertension-related treatment with Renin Angiotensin System inhibitors. Also, age and multimorbidity might be confounders. No sufficient data are available to demonstrate their independent role. We designed a cross-sectional, observational, multicenter, nationwide survey in Italy to verify whether renin-angiotensin system inhibitors are related to COVID-19 severe outcomes. We analyzed information from Italian patients diagnosed with COVID-19, admitted in 26 hospitals. One thousand five hundred ninety-one charts (male, 64.1%; 66±0.4 years) were recorded. At least 1 preexisting condition was observed in 73.4% of patients, with hypertension being the most represented (54.9%). One hundred eighty-eight deaths were recorded (11.8%; mean age, 79.6±0.9 years). In nonsurvivors, older age, hypertension, diabetes mellitus, chronic obstructive pulmonary disease, chronic kidney disease, coronary artery diseases, and heart failure were more represented than in survivors. The Charlson Comorbidity Index was significantly higher in nonsurvivors compared with survivors (4.3±0.15 versus 2.6±0.05; P<0.001). ACE (angiotensin-converting enzyme) inhibitors, diuretics, and ß-blockers were more frequently used in nonsurvivors than in survivors. After correction by multivariate analysis, only age (P=0.0001), diabetes mellitus (P=0.004), chronic obstructive pulmonary disease (P=0.011), and chronic kidney disease (P=0.004) but not hypertension predicted mortality. Charlson Comorbidity Index, which cumulates age and comorbidities, predicts mortality with an exponential increase in the odds ratio by each point of score. In the COVID-19 outbreak, mortality is predicted by age and the presence of comorbidities. Our data do not support a significant interference of hypertension and antihypertensive therapy on COVID-19 lethality. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT04331574.

positive: Renin-angiotensin system inhibitors in COVID-19. Concerns have been raised about the potential for renin-angiotensin system (RAS) inhibitors to upregulate expression of angiotensin-converting enzyme 2 (ACE2) and thus increase susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry. Currently, there is no evidence that even if RAS inhibitors increase expression and activity of ACE2, that they would increase the risk of SARS-CoV-2 infection by facilitating greater viral entry or worsen outcomes in patients with COVID-19. At this time, there is no clinical evidence to suggest that treatment with RAS inhibitors should be discontinued in stable patients with COVID-19. In hospitalized patients with severe COVID-19, decisions about these medications should be based on clinical condition, including hemodynamic status and renal function.

positive: The two faces of ACE2: The Role of ACE2 receptor and its polymorphisms in hypertension and COVID-19 Abstract The mechanism for the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection requires the binding of the virus to the angiotensin-converting enzyme 2 (ACE2) receptor, well-known for its role in counteracting ACE. ACE2 is involved in modulating blood pressure and establishing blood pressure homeostasis. Recently, a critical debatable question has risen, whether using antihypertensive medications will have a favorable impact on people infected with SARS-CoV-2 or a deleterious one, mainly since ACEIs and ARBs therapy can modulate the expression of ACE2 protein. The concern is that the use of ACEIs and ARBs will increase the expression of ACE2 and increase patient susceptibility to viral host cell entry and propagation. On the other hand, several genetic association studies have examined the relationship between ACE2 genetic variants and the risk of developing hypertension in different ethnic populations. In this review, we discuss the ongoing arguments in the literature about ACE2’s role in mortality rate among COVID-19 people comorbid with hypertension and critically evaluate the current debate about the usage or discontinuation of ACEI/ARB antihypertensive drugs. Moreover, we explore the two opposing roles that ACE2 genetic variants might be playing in COVID-19 disease by reducing ACE2 receptor effectiveness and mitigating SARS-CoV-2 infectivity.

positive: Inhaled modified angiotensin converting enzyme 2 (ACE2) as a decoy to mitigate SARS-CoV-2 infection. COVID-19 is a new zoonotic disease caused by the SARS-CoV-2 virus. Since its emergence in Wuhan City, China, the virus has rapidly spread across the globe causing calamitous health, economic and societal consequences. It causes disproportionately severe disease in the elderly and those with co-morbidities, such as hypertension and diabetes. There is currently no proven treatment for COVID-19 and a safe and effective vaccine is at least a year away. The virus gains access to the respiratory epithelium through cell surface angiotensin converting enzyme 2 (ACE2). The receptor binding domain (RBD) of the virus is unlikely to mutate without loss of pathogenicity and thus represents an attractive target for antiviral treatment. Inhaled modified recombinant human ACE2, may bind SARS-CoV-2 and mitigate lung damage. This decoy strategy is unlikely to provoke an adverse immune response and may reduce morbidity and mortality in high-risk groups.

positive: Long-Term ACE Inhibitor/ARB Use Is Associated with Severe Renal Dysfunction and Acute Kidney Injury in Patients with severe COVID-19: Results from a Referral Center Cohort in the North East of France. BACKGROUND In patients with severe COVID-19, data are scarce and conflicting regarding whether chronic use of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) influences disease outcomes. In patients with severe COVID-19, we assessed the association between chronic ACEI/ARB use and the occurrence of kidney, lung, heart, and liver dysfunctions and the severity of the inflammatory reaction as evaluated by biomarkers kinetics, and their association with disease outcomes. METHODS We performed a retrospective longitudinal cohort study on consecutive patients with newly diagnosed severe COVID-19. Independent predictors were assessed through receiver operating characteristic analysis, time-series analysis, logistic regression analysis, and multilevel modeling for repeated measures. RESULTS On the 149 patients included in the study 30% (44/149) were treated with ACEI/ARB. ACEI/ARB use was independently associated with the following biochemical variations: phosphorus >40 mg/L (odds ratio [OR], 3.35, 95% CI, 1.83-6.14), creatinine >10.1 mg/L (OR, 3.22, 2.28-4.54), and urea nitrogen (UN) >0.52 g/L (OR, 2.65, 1.89-3.73). ACEI/ARB use was independently associated with acute kidney injury, AKI stage ≥1 (OR, 3.28, 2.17-4.94). The daily dose of ACEI/ARB was independently associated with altered kidney markers with an increased risk of +25 to +31% per each 10 mg increment of lisinopril-dose equivalent. In multivariable multilevel modeling, UN >0.52 g/L was independently associated with the risk of acute respiratory failure (OR, 3.54, 1.05-11.96). CONCLUSIONS Patients chronically treated with ACEI/ARB who have severe COVID-19 are at increased risk of acute kidney injury. In these patients, the increase in UN associated with ACEI/ARB use could predict the development of acute respiratory failure.

positive: Effects of Renin-Angiotensin Inhibition on ACE2 and TMPRSS2 Expression: Insights into COVID-19 Angiotensin-converting enzyme 2 (ACE2), a component of the renin-angiotensin system, is a receptor for SARS-CoV-2, the virus that causes COVID-19. To determine whether the renin-angiotensin inhibition regulates ACE2 expression, either enalapril (an angiotensin-converting enzyme inhibitor) or losartan (an AT1 receptor blocker) was infused subcutaneously to male C57BL/6J mice for two weeks. Neither enalapril nor losartan changed abundance of ACE2 mRNA in lung, ileum, kidney, and heart. Viral entry also depends on transmembrane protease serine 2 (TMPRSS2) to prime the S protein. TMPRSS2 mRNA was abundant in lungs and ileum, modest in kidney, but barely detectable in heart. TMPRSS2 mRNA abundance was not altered by either enalapril or losartan in any of the 4 tissues. Next, we determined whether depletion of angiotensinogen (AGT), the unique substrate of the renin-angiotensin system, changes ACE2 and TMPRSS2 mRNA abundance. AGT antisense oligonucleotides (ASO) were injected subcutaneously to male C57BL/6J mice for 3 weeks. Abundance of ACE2 mRNA was unchanged in any of the 4 tissues, but TMPRSS2 mRNA was significantly decreased in lungs. Our data support that the renin-angiotensin inhibition does not regulate ACE2 and hence are not likely to increase risk for COVID-19.

positive: Cardiac drugs and outcome in COVID-19: Reply

positive: COVID-19 and diabetes: The why, the what and the how BACKGROUND: The novel coronavirus SARS-CoV-2 has taken the world by storm. Alongside COVID-19, diabetes is a long-standing global epidemic. The diabetes population has been reported to suffer adverse outcomes if infected by COVID-19. The aim was to summarise information and resources available on diabetes and COVID-19, highlighting special measures that individuals with diabetes need to follow. METHODS: A search using keywords “COVID-19” and “Diabetes” was performed using different sources, including PubMed and World Health Organization. RESULTS: COVID-19 may enhance complications in individuals with diabetes through an imbalance in angiotension-converting enzyme 2 (ACE2) activation pathways leading to an inflammatory response. ACE2 imbalance in the pancreas causes acute β-cell dysfunction and a resultant hyperglycemic state. These individuals may be prone to worsened COVID-19 complications including vasculopathy, coagulopathy as well as psychological stress. Apart from general preventive measures, remaining hydrated, monitoring blood glucose regularly and monitoring ketone bodies in urine if on insulin is essential. All this while concurrently maintaining physical activity and a healthy diet. Different supporting entities are being set up to help this population. CONCLUSION: COVID-19 is a top priority. It is important to remember that a substantial proportion of the world's population is affected by other co-morbidities such as diabetes. These require special attention during this pandemic to avoid adding on to the burden of countries' healthcare systems.

positive: Decreased Mortality of COVID-19 with Renin-Angiotensin-Aldosterone System Inhibitors Therapy in Patients with Hypertension: A Meta-Analysis. The coronavirus disease 2019 (COVID-19) is caused by the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), having gradually developed into a pandemic and endangered global health. The continued use of angiotensin converting enzyme inhibitor (ACEIs) and angiotensin II receptor blockers (ARBs) which are part of renin-angiotensin-aldosterone system (RAAS) inhibitors in COVID-19 patients with hypertension has become controversial. We conducted a meta-analysis by searching Pubmed, Web of Science, Scopus and Embase up to 13 May 2020. Data analyses were performed by the Cochrane Collaboration's Review Manager 5.3 software. Finally, we included 9 studies comprising 3936 patients with hypertension and COVID-19 infection. Compared with non-ACEI/ARB treatment, ACEI/ARB treatment was not associated with disease severity (OR 0.71, 95 % CI 0.46-1.08, P 0.11, I2 59%) but was related to lower mortality of COVID-19 in patients with hypertension (OR 0.57, 95 % CI 0.38-0.84, P 0.004, I2 0). In summary, ACEI/ARB therapy did not aggravate disease severity of COVID-19. Besides, ACEI/ARB therapy can decrease the mortality of COVID-19. Current evidence suggested that RAAS inhibitors should be continued in COVID-19 patients with hypertension. Future well-designed randomized controlled trials are needed to confirm these findings.

positive: A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injury During several months of 2003, a newly identified illness termed severe acute respiratory syndrome (SARS) spread rapidly through the world(1,2,3). A new coronavirus (SARS-CoV) was identified as the SARS pathogen(4,5,6,7), which triggered severe pneumonia and acute, often lethal, lung failure(8). Moreover, among infected individuals influenza such as the Spanish flu(9,10) and the emergence of new respiratory disease viruses(11,12) have caused high lethality resulting from acute lung failure(13). In cell lines, angiotensin-converting enzyme 2 (ACE2) has been identified as a potential SARS-CoV receptor(14). The high lethality of SARS-CoV infections, its enormous economic and social impact, fears of renewed outbreaks as well as the potential misuse of such viruses as biologic weapons make it paramount to understand the pathogenesis of SARS-CoV. Here we provide the first genetic proof that ACE2 is a crucial SARS-CoV receptor in vivo. SARS-CoV infections and the Spike protein of the SARS-CoV reduce ACE2 expression. Notably, injection of SARS-CoV Spike into mice worsens acute lung failure in vivo that can be attenuated by blocking the renin-angiotensin pathway. These results provide a molecular explanation why SARS-CoV infections cause severe and often lethal lung failure and suggest a rational therapy for SARS and possibly other respiratory disease viruses. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/nm1267) contains supplementary material, which is available to authorized users.

positive: Controversial Relationship between Renin-Angiotensin System Inhibitors and Severity of COVID-19: Announcing a Large Multicentre Case-Control Study in Italy. The hypothesis has been proposed that patients COVID-19 positive, under anti-hypertensive treatment with angiotensin enzyme inhibitors or angiotensin receptor-blockers, might have a worse or a better clinical prognosis. This might be due to the fact that ACE2 is the receptor for the virus to enter human cells, but, on the contrary, that ACE2 expression is downregulated following SARS-1 infection, resulting in disproportionate activation of renin-angiotensin-aldosterone system and exacerbated pneumonia progression. However, no solid clinical data are available at the present moment to support or disprove such hypotheses. We announce in this letter that a large multicentre case-control study has been started in Italy that is the country with a very high impact of COVID-19 infection. We hope that our letter will encourage other clinical centres, even outside Italy, to join our study.

positive: Association of Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Testing Positive for Coronavirus Disease 2019 (COVID-19). Importance The role of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) in the setting of the coronavirus disease 2019 (COVID-19) pandemic is hotly debated. There have been recommendations to discontinue these medications, which are essential in the treatment of several chronic disease conditions, while, in the absence of clinical evidence, professional societies have advocated their continued use. Objective To study the association between use of ACEIs/ARBs with the likelihood of testing positive for COVID-19 and to study outcome data in subsets of patients taking ACEIs/ARBs who tested positive with severity of clinical outcomes of COVID-19 (eg, hospitalization, intensive care unit admission, and requirement for mechanical ventilation). Design, Setting, and Participants Retrospective cohort study with overlap propensity score weighting was conducted at the Cleveland Clinic Health System in Ohio and Florida. All patients tested for COVID-19 between March 8 and April 12, 2020, were included. Exposures History of taking ACEIs or ARBs at the time of COVID-19 testing. Main Outcomes and Measures Results of COVID-19 testing in the entire cohort, number of patients requiring hospitalizations, intensive care unit admissions, and mechanical ventilation among those who tested positive. Results A total of 18 472 patients tested for COVID-19. The mean (SD) age was 49 (21) years, 7384 (40%) were male, and 12 725 (69%) were white. Of 18 472 patients who underwent COVID-19 testing, 2285 (12.4%) were taking either ACEIs or ARBs. A positive COVID-19 test result was observed in 1735 of 18 472 patients (9.4%). Among patients who tested positive, 421 (24.3%) were admitted to the hospital, 161 (9.3%) were admitted to an intensive care unit, and 111 (6.4%) required mechanical ventilation. Overlap propensity score weighting showed no significant association of ACEI and/or ARB use with COVID-19 test positivity (overlap propensity score-weighted odds ratio, 0.97; 95% CI, 0.81-1.15). Conclusions and Relevance This study found no association between ACEI or ARB use and COVID-19 test positivity. These clinical data support current professional society guidelines to not discontinue ACEIs or ARBs in the setting of the COVID-19 pandemic. However, further study in larger numbers of hospitalized patients receiving ACEI and ARB therapy is needed to determine the association with clinical measures of COVID-19 severity.

positive: The SARS-CoV-2 receptor, ACE-2, is expressed on many different cell types: implications for ACE-inhibitor- and angiotensin II receptor blocker-based cardiovascular therapies SARS-CoV-2 is characterized by a spike protein allowing viral binding to the angiotensin-converting enzyme (ACE)-2, which acts as a viral receptor and is expressed on the surface of several pulmonary and extra-pulmonary cell types, including cardiac, renal, intestinal and endothelial cells. There is evidence that also endothelial cells are infected by SARS-COV-2, with subsequent occurrence of systemic vasculitis, thromboembolism and disseminated intravascular coagulation. Those effects, together with the "cytokine storm" are involved in a worse prognosis. In clinical practice, angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin II receptor blockers (ARBs) are extensively used for the treatment of hypertension and other cardiovascular diseases. In in vivo studies, ACE-Is and ARBs seem to paradoxically increase ACE-2 expression, which could favour SARS-CoV-2 infection of host's cells and tissues. By contrast, in patients treated with ACE-Is and ARBs, ACE-2 shows a downregulation at the mRNA and protein levels in kidney and cardiac tissues. Yet, it has been claimed that both ARBs and ACE-Is could result potentially useful in the clinical course of SARS-CoV-2-infected patients. As detected in China and as the Italian epidemiological situation confirms, the most prevalent comorbidities in deceased patients with COVID-19 are hypertension, diabetes and cardiovascular diseases. Older COVID-19-affected patients with cardiovascular comorbidities exhibit a more severe clinical course and a worse prognosis, with many of them being also treated with ARBs or ACE-Is. Another confounding factor is cigarette smoking, which has been reported to increase ACE-2 expression in both experimental models and humans. Sex also plays a role, with chromosome X harbouring the gene coding for ACE-2, which is one of the possible explanations of why mortality in female patients is lower. Viral entry also depends on TMPRSS2 protease activity, an androgen dependent enzyme. Despite the relevance of experimental animal studies, to comprehensively address the question of the potential hazards or benefits of ACE-Is and ARBs on the clinical course of COVID-19-affected patients treated by these anti-hypertensive drugs, we will need randomized human studies. We claim the need of adequately powered, prospective studies aimed at answering the following questions of paramount importance for cardiovascular, internal and emergency medicine: Do ACE-Is and ARBs exert similar or different effects on infection or disease course? Are such effects dangerous, neutral or even useful in older, COVID-19-affected patients? Do they act on multiple cell types? Since ACE-Is and ARBs have different molecular targets, the clinical course of SARS-CoV-2 infection could be also different in patients treated by one or the other of these two drug classes. At present, insufficient detailed data from trials have been made available.

positive: Angiotensin Converting Enzyme Inhibitor and Angiotensin II Receptor Blocker Use Among Outpatients Diagnosed with COVID-19 Coronavirus disease 2019 (COVID-19) is a viral pandemic precipitated by the severe acute respiratory syndrome coronavirus 2. Since previous reports suggested that viral entry into cells may involve angiotensin converting enzyme 2, there has been growing concern that angiotensin converting enzyme inhibitor (ACEI) and angiotensin II receptor blocker (ARB) use may exacerbate the disease severity. In this retrospective, single-center US study of adult patients diagnosed with COVID-19, we evaluated the association of ACEI/ARB use with hospital admission. Secondary outcomes included: ICU admission, mechanical ventilation, length of hospital stay, use of inotropes, and all-cause mortality. Propensity score matching was performed to account for potential confounders. Among 590 unmatched patients diagnosed with COVID-19, 78 patients were receiving ACEI/ARB (median age 63 years and 59.7% male) and 512 patients were non-users (median age 42 years and 47.1% male). In the propensity matched population, multivariate logistic regression analysis adjusting for age, gender and comorbidities demonstrated that ACEI/ARB use was not associated with hospital admission (OR 1.2, 95% CI 0.5-2.7, p = 0.652). CAD and CKD/ESRD remained independently associated with admission to hospital. All-cause mortality, ICU stay, need for ventilation, and inotrope use was not significantly different between the 2 study groups. In conclusion, among patients who were diagnosed with COVID-19, ACEI/ARB use was not associated with increased risk of hospital admission.

positive: Teicoplanin potently blocks the cell entry of 2019-nCoV Since December 2019, the outbreak of a new coronavirus, named 2019-nCoV, has greatly threatened the public health in China and raised great concerns worldwide. No specific treatment for this infection is currently available. We previously reported that teicoplanin, a glycopeptide antibiotic which has routinely been used in the clinic to treat bacterial infection with low toxicity, significantly inhibits the invasion of cells by Ebola virus, SARS-CoV and MERS-CoV, via specifically inhibiting the activity of cathepsin L. Here, we tested the efficacy of teicoplanin against 2019-nCoV virus infection and found that teicoplanin potently prevents the entrance of 2019-nCoV-Spike-pseudoviruses into the cytoplasm, with an IC50 of 1.66 μM. Although the inhibitory effect upon the replication of wildtype viruses ex vivo and in vivo remains to be determined, our preliminary result indicates that the potential antiviral activity of teicoplanin could be applied for the treatment of 2019-nCoV virus infection.

positive: Severe acute respiratory syndrome coronavirus 2 infection, angiotensin-converting enzyme 2 and treatment with angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers.

positive: Regulation of angiotensin converting enzyme 2 (ACE2) in obesity: implications for COVID-19 The ongoing COVID-19 pandemic is caused by the novel coronavirus SARS-CoV-2. Age, smoking, obesity, and chronic diseases such as cardiovascular disease and diabetes have been described as risk factors for severe complications and mortality in COVID-19. Obesity and diabetes are usually associated with dysregulated lipid synthesis and clearance which can initiate or aggravate pulmonary inflammation and injury. It has been shown that for viral entry into the host cell, SARS-CoV-2 utilizes the angiotensin converting enzyme 2 (ACE2) receptors present on the cells. We aimed to characterize how SARS-CoV-2 dysregulates lipid metabolism pathways in the host and the effect of dysregulated lipogenesis on the regulation of ACE2, specifically in obesity. In our study, through the re-analysis of publicly available transcriptomic data, we first found that lung epithelial cells infected with SARS-CoV-2 showed upregulation of genes associated with lipid metabolism, including the SOC3 gene which is involved in regulation of inflammation and inhibition of leptin signaling. This is of interest as viruses may hijack host lipid metabolism to allow completion of their viral replication cycles. Furthermore, a mouse model of diet-induced obesity showed a significant increase in Ace2 expression in the lungs which negatively correlated with the expression of genes that code for sterol response element binding proteins 1 and 2 (SREBP). Suppression of Srebp1 showed a significant increase in Ace2 expression in the lung. Together our results suggest that the dysregulated lipogenesis and the subsequently high ACE2 expression in obese patients might be the mechanism underlying the increased risk for severe complications in those patients when infected by SARS-CoV-2.

positive: Development of a homogeneous screening assay for automated detection of antiviral agents active against severe acute respiratory syndrome-associated coronavirus Abstract The severity and global spread of the 2003 outbreak of the severe acute respiratory syndrome-associated coronavirus (SARS-CoV) highlighted the risks to human health posed by emerging viral diseases and emphasized the need for specific therapeutic agents instead of relying on existing broadly active antiviral compounds. The development of rapid screening assays is essential for antiviral drug discovery. Thus, a screening system for anti-SARS-CoV agents was developed, which evaluated compound potency, specificity and cytotoxicity at the initial screening phase. Cell lines were engineered to constitutively express an enhanced green fluorescent protein (EGFP) and used to detect (1) antiviral potency in SARS-CoV infection tests; (2) antiviral specificity in tests using the porcine coronavirus transmissible gastroenteritis virus (TGEV); and (3) cytotoxicity in the same assays without virus challenge. The assay system involves minimal manipulation after assay set-up, facilitates automated read-out and minimizes risks associated with hazardous viruses. The suitability of this assay system in drug discovery was demonstrated by screening of 3388 small molecule compounds. The results show that these assays can be applied to high-throughput screening for identification of inhibitors selectively active against SARS-CoV.

positive: Organ-specific distribution of ACE2 mRNA and correlating peptidase activity in rodents Biochemical analysis revealed that angiotensin-converting enzyme related carboxy-peptidase (ACE2) cleaves angiotensin (Ang) II to Ang-(1–7), a heptapeptide identified as an endogenous ligand for the G protein-coupled receptor Mas. No data are currently available that systematically describe ACE2 distribution and activity in rodents. Therefore, we analyzed the ACE2 expression in different tissues of mice and rats on mRNA (RNase protection assay) and protein levels (immunohistochemistry, ACE2 activity, western blot). Although ACE2 mRNA in both investigated species showed the highest expression in the ileum, the mouse organ exceeded rat ACE2, as also demonstrated in the kidney and colon. Corresponding to mRNA, ACE2 activity was highest in the ileum and mouse kidney but weak in the rat kidney, which was also confirmed by immunohistochemistry. Contrary to mRNA, we found weak activity in the lung of both species. Our data demonstrate a tissue- and species-specific pattern for ACE2 under physiological conditions.

positive: Should ACE Inhibitors and Angiotensin Receptor Blockers Be Withdrawn in the Current Setting of COVID-19 Infection?

positive: SARS-CoV-2 infection and obesity: Common inflammatory and metabolic aspects Abstract Backround and aims According to the World Obesity Federation, “obesity-related conditions seem to worsen the effect of Covid-19 (SARS-CoV-2)”; additionally the Centres for Disease Control and Prevention reported that “people with heart disease and diabetes are at higher risk of SARS-CoV-2 complications and that severe obesity poses a higher risk for severe illness”. Recent reports have shown elevated levels of cytokines due to increased inflammation in patients with SARS-CoV-2 disease. On the other hand, obesity represents a state of low-grade inflammation, with various inflammatory products directly excreted by adipose tissue. In this concise report we aimed to assess common elements of obesity and SARS-CoV-2 infection. Methods Literature search on obesity and SARS-CoV-2 infection. Results We present “mechanistic” obesity-related problems that aggravate SARS-CoV-2 infection as well as tentative inflammatory/metabolic links between these diseases. Conclusion Obesity and SARS-CoV-2 share common elements of the inflammatory process (and possibly also metabolic disturbances), exacerbating SARS-CoV-2 infection in the obese.

positive: Local renin-angiotensin II systems, angiotensin-converting enzyme and its homologue ACE2: their potential role in the pathogenesis of chronic obstructive pulmonary diseases, pulmonary hypertension and acute respiratory distress syndrome. Renin-angiotensin II-aldosterone axis has long been known as a regulator of blood pressure and fluid homeostasis. Yet, local renin-angiotensin II systems have been discovered and novel actions of angiotensin II (AngII) have emerged among which its ability to act as a immunomodulator and profibrotic molecule. The enzyme responsible for its synthesis, Angiotensin-converting-enzyme (ACE), is present in high concentrations in lung tissue. In the present paper, we review data from studies of the past decade that implicate AngII and functional polymorphisms of the ACE gene that increase ACE activity with increased susceptibility for asthma and chronic obstructive pulmonary disease (COPD) and for pulmonary hypertension. Moreover, drugs that inhibit the synthesis of AngII (ACE inhibitors) or that antagonize its actions on its receptors (Angiotensin II receptor blockers -ARBs) have been shown to provide beneficial effects. Another recent discovery reviewed is the presence of a homologue of ACE, ACE2, which cleaves a single amino acid from AngII and forms a heptapeptide with vasodilatory actions, Ang 1-7. The balance between ACE and ACE2 is crucial for controlling AngII levels. ACE and ACE2 also appear to modify the severity of Acute Respiratory Distress Syndrome (ARDS), with ACE2 playing a protective role. Finally, mention is made to the recent discovery of ACE2 as a receptor for the SARS Corona Virus.

positive: Searching therapeutic strategy of new coronavirus pneumonia from angiotensin-converting enzyme 2: the target of COVID-19 and SARS-CoV Since December 2019, the infection of the new coronavirus (COVID-19) caused an outbreak of new coronavirus pneumonia in Wuhan, China, and caused great public concern. Both COVID-19 and SARS-CoV belong to the coronavirus family and both invade target cells through ACE2. An in-depth understanding of ACE2 and a series of physiological and physiological changes caused by the virus invading the human body may help to discover and explain the corresponding clinical phenomena and then deal with them timely. In addition, ACE2 is a potential therapeutic target. This article will summarize the role of ACE2 in multiple organ damage caused by COVID-19 and SARS-CoV, targeted blocking drugs against ACE2, and drugs that inhibit inflammation in order to provide the basis for subsequent related research, diagnosis and treatment, and drug development.

positive: Renin‐angiotensin system revisited New components and functions of the renin‐angiotensin system (RAS) are still being unravelled. The classical RAS as it looked in the middle 1970s consisted of circulating renin, acting on angiotensinogen to produce angiotensin I, which in turn was converted into angiotensin II (Ang II) by angiotensin‐converting enzyme (ACE). Ang II, still considered the main effector of RAS was believed to act only as a circulating hormone via angiotensin receptors, AT1 and AT2. Since then, an expanded view of RAS has gradually emerged. Local tissue RAS systems have been identified in most organs. Recently, evidence for an intracellular RAS has been reported. The new expanded view of RAS therefore covers both endocrine, paracrine and intracrine functions. Other peptides of RAS have been shown to have biological actions; angiotensin 2–8 heptapeptide (Ang III) has actions similar to those of Ang II. Further, the angiotensin 3–8 hexapeptide (Ang IV) exerts its actions via insulin‐regulated amino peptidase receptors. Finally, angiotensin 1–7 (Ang 1–7) acts via mas receptors. The discovery of another ACE2 was an important complement to this picture. The recent discovery of renin receptors has made our view of RAS unexpectedly complex and multilayered. The importance of RAS in cardiovascular disease has been demonstrated by the clinical benefits of ACE inhibitors and AT1 receptor blockers. Great expectations are now generated by the introduction of renin inhibitors. Indeed, RAS regulates much more and diverse physiological functions than previously believed.

positive: Angiotensin II Receptors - Impact for COVID-19 Severity COVID-19 is an outbreak of viral pneumonia which became a global health crisis, and the risk of morbidity and mortality of people with obesity are higher. SARS-CoV-2, the pathogen of COVID-19, enters into cells through binding to the Angiotensin Converting Enzyme (ACE) homolog-2 (ACE2). ACE2 is a regulator of two contrary pathways in renin angiotensin system (RAS): ACE-Ang-II-AT1R axis and ACE2-Ang 1-7-Mas axis. Viral entry process eventuate in downregulation of ACE2 and subsequent activation of ACE-Ang-II-AT1R axis. ACE-Ang II-AT1R axis increases lipid storage, reduces white-to-beige fat conversion and plays role in obesity. Conversely, adipose tissue is an important source of angiotensin, and obesity results in increased systemic RAS. ACE-Ang-II-AT1R axis, which has proinflammatory, profibrotic, prothrombotic and vasoconstrictive effects, is potential mechanism of more severe SARS-CoV-2 infection. The link between obesity and severe COVID-19 may be attributed to ACE2 consumption and subsequent ACE-Ang-II-AT1R axis activation. Therefore, patients with SARS-CoV-2 infection may benefit from therapeutic strategies that activate ACE2-Ang 1-7-Mas axis, such as Ang II reseptor blockers (ARBs), ACE inhibitors (ACEIs), Mas receptor agonists and ACE2. This article is protected by copyright. All rights reserved.

positive: A hypothesis for pathobiology and treatment of COVID-19: The centrality of ACE1/ACE2 imbalance Angiotensin Converting Enzyme2 is the cell surface binding site for the coronavirus SARS-CoV-2, which causes COVID-19. We propose that an imbalance in the action of ACE1- and ACE2-derived peptides, thereby enhancing angiotensin II (Ang II) signalling is primary driver of COVID-19 pathobiology. ACE1/ACE2 imbalance occurs due to the binding of SARS-CoV-2 to ACE2, reducing ACE2-mediated conversion of Ang II to Ang peptides that counteract pathophysiological effects of ACE1-generated ANG II. This hypothesis suggests several approaches to treat COVID-19 by restoring ACE1/ACE2 balance: (a) AT receptor antagonists; (b) ACE1 inhibitors (ACEIs); (iii) agonists of receptors activated by ACE2-derived peptides (e.g. Ang (1-7), which activates MAS1); (d) recombinant human ACE2 or ACE2 peptides as decoys for the virus. Reducing ACE1/ACE2 imbalance is predicted to blunt COVID-19-associated morbidity and mortality, especially in vulnerable patients. Importantly, approved AT antagonists and ACEIs can be rapidly repurposed to test their efficacy in treating COVID-19.

positive: [Clinical characteristics and outcomes of 112 cardiovascular disease patients infected by 2019-nCoV]. Objective: To explore the clinical characteristics and prognosis of the new coronavirus 2019-nCoV patients combined with cardiovascular disease (CVD). Methods: A retrospective analysis was performed on 112 COVID-19 patients with CVD admitted to the western district of Union Hospital in Wuhan, from January 20, 2020 to February 15, 2020. They were divided into critical group (ICU, n=16) and general group (n=96) according to the severity of the disease and patients were followed up to the clinical endpoint. The observation indicators included total blood count, C-reactive protein (CRP), arterial blood gas analysis, myocardial injury markers, coagulation function, liver and kidney function, electrolyte, procalcitonin (PCT), B-type natriuretic peptide (BNP), blood lipid, pulmonary CT and pathogen detection. Results: Compared with the general group, the lymphocyte count (0.74×10(9) (0.34×10(9), 0.94×10(9))/L vs. 0.99×10(9) (0.71×10(9), 1.29×10(9))/L, P=0.03) was extremely lower in the critical group, CRP (106.98 (81.57, 135.76) mg/L vs. 34.34 (9.55,76.54) mg/L, P<0.001) and PCT (0.20 (0.15,0.48) μg/L vs. 0.11 (0.06,0.20)μg/L, P<0.001) were significantly higher in the critical group. The BMI of the critical group was significantly higher than that of the general group (25.5 (23.0, 27.5) kg/m(2) vs. 22.0 (20.0, 24.0) kg/m(2), P=0.003). Patients were further divided into non-survivor group (17, 15.18%) group and survivor group (95, 84.82%). Among the non-survivors, there were 88.24% (15/17) patients with BMI> 25 kg/m(2), which was significantly higher than that of survivors (18.95% (18/95), P<0.001). Compared with the survived patients, oxygenation index (130 (102, 415) vs. 434 (410, 444), P<0.001) was significantly lower and lactic acid (1.70 (1.30, 3.00) mmol/L vs. 1.20 (1.10, 1.60) mmol/L, P<0.001) was significantly higher in the non-survivors. There was no significant difference in the proportion of ACEI/ARB medication between the critical group and the general group or between non-survivors and survivors (all P>0.05). Conclusion: COVID-19 patients combined with CVD are associated with a higher risk of mortality. Critical patients are characterized with lower lymphocyte counts. Higher BMI are more often seen in critical patients and non-survivor. ACEI/ARB use does not affect the morbidity and mortality of COVID-19 combined with CVD. Aggravating causes of death include fulminant inflammation, lactic acid accumulation and thrombotic events.

positive: Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target

positive: Diabetes and metabolic syndrome as risk factors for COVID-19 BACKGROUND AND AIMS: Clinical evidence exists that patients with diabetes are at higher risk for Coronavirus disease 2019 (COVID-19). We investigated the physiological origins of this clinical observation linking diabetes with severity and adverse outcome of COVID-19. METHODS: Publication mining was applied to reveal common physiological contexts in which diabetes and COVID-19 have been investigated simultaneously. Overall, we have acquired 1,121,078 publications from PubMed in the time span between 01 and 01-2000 and 17-04-2020, and extracted knowledge graphs interconnecting the topics related to diabetes and COVID-19. RESULTS: The Data Mining revealed three pathophysiological pathways linking diabetes and COVID-19. The first pathway indicates a higher risk for COVID-19 because of an upregulation of Angiotensin-converting enzyme 2. The other two important physiological links between diabetes and COVID-19 are liver dysfunction and chronic systemic inflammation. A deep network analysis has suggested clinical biomarkers predicting the higher risk: Hypertension, elevated serum Alanine aminotransferase, high Interleukin-6, and low Lymphocytes count. CONCLUSIONS: The revealed biomarkers can be applied directly in clinical practice. For newly infected patients, the medical history needs to be checked for evidence of a long-term, chronic dysregulation of these biomarkers. In particular, patients with diabetes, but also those with prediabetic state, deserve special attention.

positive: Angiotensin-converting enzymes and drug discovery in cardiovascular diseases. Angiotensin-converting enzyme (ACE) is a major target in the treatment of cardiovascular diseases (CVDs). In addition to ACE, ACE2 - which is a homolog of ACE and promotes the degradation of angiotensin II (Ang II) to Ang (1-7) - has been recognized recently as a potential therapeutic target in the management of CVDs. This article reviews different metabolic pathways of ACE and ACE2 (Ang I-Ang II-AT1 receptors and Ang I-Ang (1-7)-Mas receptors) in the regulation of cardiovascular function and their potential in new drug development in the therapy of CVDs. In addition, recent progress in the study of angiotensin and ACE in fetal origins of CVD, which might present an interesting field in perinatal medicine and preventive medicine, is briefly summarized.

positive: Should Angiotensin-Converting Enzyme Inhibitors ever Be Used for the Management of Hypertension? PURPOSE OF REVIEW: Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are commonly used anti-hypertensive medications in a number of clinical settings. They are often used interchangeably, but we pose the provocative question as to whether they should be. We review the literature to evaluate for any differences in efficacy between the two classes in order to determine if the greater side effects associated with angiotensin-converting enzyme inhibitors are offset by any advantageous effects on outcomes to warrant their use over angiotensin receptor blockers. RECENT FINDINGS: In many clinical scenarios, the data supports similar efficacy between ACE inhibitors and ARBs, while in a minority of others, there are murky signals from previous trials that suggest ACE inhibitors may be better. However, when reviewing the literature in its entirety, and taking into account recently published pooled analysis and head to head trials, it is reasonable to conclude that ACE inhibitors and ARBs have similar efficacy. This is in contrast to data on adverse effects, which consistently favors the use of ARBs. SUMMARY: From the available data, it is reasonable to conclude that ACE inhibitors and ARBs have equal efficacy yet unequal adverse effects. It is in this context that we take the provocative stance that ACE inhibitors should not be used to treat hypertension.

positive: Obesity and COVID-19: ACE 2, the Missing Tile

positive: COVID-19: Immunology and treatment options Abstract The novel coronavirus SARS-CoV2 causes COVID-19, a pandemic threatening millions. As protective immunity does not exist in humans and the virus is capable of escaping innate immune responses, it can proliferate, unhindered, in primarily infected tissues. Subsequent cell death results in the release of virus particles and intracellular components to the extracellular space, which result in immune cell recruitment, the generation of immune complexes and associated damage. Infection of monocytes/macrophages and/or recruitment of uninfected immune cells can result in massive inflammatory responses later in the disease. Uncontrolled production of pro-inflammatory mediators contributes to ARDS and cytokine storm syndrome. Antiviral agents and immune modulating treatments are currently being trialled. Understanding immune evasion strategies of SARS-CoV2 and the resulting delayed massive immune response will result in the identification of biomarkers that predict outcomes as well as phenotype and disease stage specific treatments that will likely include both antiviral and immune modulating agents.

positive: Renin–angiotensin system and SARS-CoV-2 infection: there is a before and after

positive: Angiotensin converting enzyme: A review on expression profile and its association with human disorders with special focus on SARS-CoV-2 infection Angiotensin-converting enzyme (ACE) and its homologue, ACE2, have been mostly associated with hypertensive disorder. However, recent pandemia of SARS-CoV-2 has put these proteins at the center of attention, as this virus has been shown to exploit ACE2 protein to enter cells. Clear difference in the response of affected patients to this virus has urged researchers to find the molecular basis and pathophysiology of the cell response to this virus. Different levels of expression and function of ACE proteins, underlying disorders, consumption of certain medications and the existence of certain genomic variants within ACE genes are possible explanations for the observed difference in the response of individuals to the SARS-CoV-2 infection. In the current review, we discuss the putative mechanisms for this observation.

positive: Risk Factors Associated with Disease Severity and Length of Hospital Stay in COVID-19 Patients

positive: High rate of increased level of plasma Angiotensin II and its gender difference in COVID-19: an analysis of 55 hospitalized patients with COVID-19 in a single hospital, WuHan, China Background: 2019 Novel coronavirus disease (COVID-19) is turning into a pandemic globally lately. Angiotensin-converting enzyme 2 (ACE2) is identified as an important functional receptor for SARS-Cov-2. ACE2 and ACE are homologues with inverse functions in the renin-angiotensin system. ACE converts angiotensin I into a vital vasoactive peptide called angiotensin II(AngII), whereas ACE2 hydrolyzes AngII into a series of vasodilators. There were few reports illustrated the expression of AngII in COVID-19. This study aimed to demonstrate the expression of angiotensin II in COVID-19 and how it correlated to the disease. Methods: We enrolled 55 patients with COVID-19 admitted to renmin Hospital of Wuhan University from January 21st to February 21st, 2020. Demographic data were collected upon admission. COVID-19 nuclear acid, plasma AngII, Renin and aldosterone in the lying position without sodium restriction, and other laboratory indicators were together measured by the laboratory department of our hospital. Findings: Of the 55 patients with COVID-19, 34(61.8%) had an increased level of AngII. The severity of COVID-19 and male is positively related with the level of AngII. The level of blood lymphocyte, PCT, ALT, and AST were remarkably severe with those of normal level of AngII (P < 0.05). CD4/CD8 cells ratio was significantly higher whereas CD3+CD8+ cells amount, CD3+CD8+ cells proportion, CD56+CD16+CD3- cells amount and CD19+CD3- cells amount were considerably lower than those of normal level of AngII (P < 0.05). Abnormal rates of blood lymphocyte and PCT were significantly higher in Patients with elevated AngII level. The results of binary logistic regression analysis showed that the severity of COVID-19 (OR=4.123) and CD4/CD8 ratio(OR=4.050) were the co-directional impact factor while female(OR=0.146) was inverse impact factor of elevated AngII level. Interpretation: High rate of increased level of AngII was detected in COVID-19 patients. Patients with elevated AngII level were more likely to be critically ill with COVID-19. Considering the gender differences in ACE2 expression and no gender differences in angiotensin expression, the gender differences in AngII level might indicate less loss of ACE2 in female patients. Elevated AngII level was correlated with CD4/CD8 ratio, suggesting it might involve in immune disorder. Keywords: 2019 Novel coronavirus disease(COVID-19), Angiotensin-converting enzyme 2 (ACE2), Angiotensin II(AngII), gender differences

positive: Potential Mechanisms of Cardiac Injury and Common Pathways of Inflammation in Patients With COVID-19 Due to the lack of prospective, randomized, controlled clinical studies on inflammation and cardiovascular involvement, the exact mechanism of cardiac injury among patients with Coronavirus Disease 2019 (COVID-19) still remains uncertain. It was demonstrated that there is a high and significantly positive linear correlation between troponin T and plasma high-sensitivity C-reactive protein levels, biomarkers of cardiac injury and systemic inflammation, respectively. Cardiac injury and inflammation is a relatively common association among patients hospitalized with COVID-19, and it is related to higher risk of in-hospital mortality. In our literature search, we identified several potential mechanisms of myocardial tissue damage, namely, coronavirus-associated acute myocarditis, angiotensin-converting enzyme 2 receptor binding affinity to the virus Spike protein, increased cytokine secretion, and hypoxia-induced cardiac myocyte apoptosis. Elucidation of the disease pathogenesis and prospective histopathological studies are crucial for future proper treatment in case of renewed outbreaks. Of interest is that with hundred of thousands of bodies available for autopsy studies, no prospective investigation has been reported so far. Strong efforts and continued research of the cardiovascular complications and identification of risk factors for poor prognosis in COVID-19 are steadily needed. The high morbidity and mortality of COVID-19, its monumental economic burden and social impact, the despair of a new pandemic outbreak, and the thread of potential utilization of novel severe acute respiratory syndrome coronavirus 2 as biologic weapons make it a preponderant necessity to better comprehend the therapeutic management of this lethal disease. Emerging as an acute infectious disease, COVID-19 may become a chronic epidemic because of genetic recombination. Therefore, we should be ready for the reemergence of COVID-19 or other coronaviruses.

positive: Epidemiology and clinical features of COVID-19: A review of current literature Abstract Coronavirus disease 2019 is a pandemic influencing the first half of the year 2020. The virus has rapidly spread to many countries. Studies are rapidly published to share information regarding epidemiology, clinical and diagnostic patterns, and prognosis. The following review condenses the surge of information into an organized format.

positive: Natural History of COVID-19 and Current Knowledge on Treatment Therapeutic Options Despite intense research there is currently no effective vaccine available against the new severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged in the later 2019 and responsible for the COVID-19 pandemic. This infectious and communicable disease has become one of the major public health challenges in the world. The clinical management of COVID-19 has been limited to infection prevention and control measures associated with supportive care such as supplemental oxygen and mechanical ventilation. Meanwhile efforts to find an effective treatment to inhibit virus replication, mitigate the symptoms, increase survival and decrease mortality rate are ongoing. Several classes of drugs, many of them already in use for other diseases, are being evaluated based on the body of clinical knowledge obtained from infected patients regarding to the natural history and evolution of the infection. Herein we will provide an updated overview of the natural history and current knowledge on drugs and therapeutic agents being tested for the prevention and treatment of COVID-19. These include different classes of drugs such as antiviral agents (chloroquine, ivermectin, nitazoxanide, hydroxychloroquine, lopinavir, remdesivir, tocilizumab), supporting agents (Vitamin C, Vitamin D, azithromycin, corticosteroids) and promising investigational vaccines. Considering the controversies and excessive number of compounds being tested and reported in the literature we hope that this review can provide useful and updated consolidated information on potential drugs used to prevent, control and treat COVID-19 patients worldwide.

positive: Continue ACE inhibitors/ ARB’S till further evidence in Coronavirus disease 2019 (COVID-19)

positive: COVID‐19 and renin‐angiotensin system inhibition: role of angiotensin converting enzyme 2 (ACE2) ‐ Is there any scientific evidence for controversy? Renin–angiotensin system (RAS) blockers are extensively used worldwide to treat many cardiovascular disorders, where they are effective in reducing both mortality and morbidity. These drugs are known to induce an increased expression of angiotensin‐converting enzyme 2 (ACE2). ACE2 acts as receptor for the novel SARS coronavirus‐2 (SARS‐CoV‐2) which raising the important issue of possible detrimental effects that RAS blockers could exert on the natural history and pathogenesis of the coronavirus disease‐19 (COVID‐19) and associated excessive inflammation, myocarditis and cardiac arrhythmias. We review the current knowledge on the interaction between SARS‐CoV‐2 infection and RAS blockers and suggest a scientific rationale for continuing RAS blockers therapy in patients with COVID‐19 infection.

positive: Association of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers with the Risk of Hospitalization and Death in Hypertensive Patients with Coronavirus Disease-19 BACKGROUND: Whether angiotensin-converting enzyme (ACE) Inhibitors and angiotensin receptor blockers (ARBs) mitigate or exacerbate SARS-CoV-2 infection remains uncertain. In a national study, we evaluated the association of ACE inhibitors and ARB with coronavirus disease-19 (COVID-19) hospitalization and mortality among individuals with hypertension. METHODS: Among Medicare Advantage and commercially insured individuals, we identified 2,263 people with hypertension, receiving ≥1 antihypertensive agents, and who had a positive outpatient SARS-CoV-2 test (outpatient cohort). In a propensity score-matched analysis, we determined the association of ACE inhibitors and ARBs with the risk of hospitalization for COVID-19. In a second study of 7,933 individuals with hypertension who were hospitalized with COVID-19 (inpatient cohort), we tested the association of these medications with in-hospital mortality. We stratified all our assessments by insurance groups. RESULTS: Among individuals in the outpatient and inpatient cohorts, 31.9% and 29.8%, respectively, used ACE inhibitors and 32.3% and 28.1% used ARBs. In the outpatient study, over a median 30.0 (19.0 - 40.0) days after testing positive, 12.7% were hospitalized for COVID-19. In propensity score-matched analyses, neither ACE inhibitors (HR, 0.77 [0.53, 1.13], P = 0.18), nor ARBs (HR, 0.88 [0.61, 1.26], P = 0.48), were significantly associated with risk of hospitalization. In analyses stratified by insurance group, ACE inhibitors, but not ARBs, were associated with a significant lower risk of hospitalization in the Medicare group (HR, 0.61 [0.41, 0.93], P = 0.02), but not the commercially insured group (HR: 2.14 [0.82, 5.60], P = 0.12; P-interaction 0.09). In the inpatient study, 14.2% died, 59.5% survived to discharge, and 26.3% had an ongoing hospitalization. In propensity score-matched analyses, neither use of ACE inhibitor (0.97 [0.81, 1.16]; P = 0.74) nor ARB (1.15 [0.95, 1.38]; P = 0.15) was associated with risk of in-hospital mortality, in total or in the stratified analyses. CONCLUSIONS: The use of ACE inhibitors and ARBs was not associated with the risk of hospitalization or mortality among those infected with SARS-CoV-2. However, there was a nearly 40% lower risk of hospitalization with the use of ACE inhibitors in the Medicare population. This finding merits a clinical trial to evaluate the potential role of ACE inhibitors in reducing the risk of hospitalization among older individuals, who are at an elevated risk of adverse outcomes with the infection.

positive: The novel coronavirus 2019 (2019-nCoV) uses the SARS-coronavirus receptor ACE2 and the cellular protease TMPRSS2 for entry into target cells The emergence of a novel, highly pathogenic coronavirus, 2019-nCoV, in China, and its rapid national and international spread pose a global health emergency. Coronaviruses use their spike proteins to select and enter target cells and insights into nCoV-2019 spike (S)-driven entry might facilitate assessment of pandemic potential and reveal therapeutic targets. Here, we demonstrate that 2019-nCoV-S uses the SARS-coronavirus receptor, ACE2, for entry and the cellular protease TMPRSS2 for 2019-nCoV-S priming. A TMPRSS2 inhibitor blocked entry and might constitute a treatment option. Finally, we show that the serum form a convalescent SARS patient neutralized 2019-nCoV-S-driven entry. Our results reveal important commonalities between 2019-nCoV and SARS-coronavirus infection, which might translate into similar transmissibility and disease pathogenesis. Moreover, they identify a target for antiviral intervention. One sentence summary The novel 2019 coronavirus and the SARS-coronavirus share central biological properties which can guide risk assessment and intervention.

positive: 2019-nCoV (Wuhan virus), a novel Coronavirus: human-to-human transmission, travel-related cases, and vaccine readiness. On 31 December 2019 the Wuhan Health Commission reported a cluster of atypical pneumonia cases that was linked to a wet market in the city of Wuhan, China. The first patients began experiencing symptoms of illness in mid-December 2019. Clinical isolates were found to contain a novel coronavirus with similarity to bat coronaviruses. As of 28 January 2020, there are in excess of 4,500 laboratory-confirmed cases, with > 100 known deaths. As with the SARS-CoV, infections in children appear to be rare. Travel-related cases have been confirmed in multiple countries and regions outside mainland China including Germany, France, Thailand, Japan, South Korea, Vietnam, Canada, and the United States, as well as Hong Kong and Taiwan. Domestically in China, the virus has also been noted in several cities and provinces with cases in all but one provinence. While zoonotic transmission appears to be the original source of infections, the most alarming development is that human-to-human transmission is now prevelant. Of particular concern is that many healthcare workers have been infected in the current epidemic. There are several critical clinical questions that need to be resolved, including how efficient is human-to-human transmission? What is the animal reservoir? Is there an intermediate animal reservoir? Do the vaccines generated to the SARS-CoV or MERS-CoV or their proteins offer protection against 2019-nCoV? We offer a research perspective on the next steps for the generation of vaccines. We also present data on the use of in silico docking in gaining insight into 2019-nCoV Spike-receptor binding to aid in therapeutic development. Diagnostic PCR protocols can be found at https://www.who.int/health-topics/coronavirus/laboratory-diagnostics-for-novel-coronavirus.

positive: Angiotensin‐converting enzyme 2 in severe acute respiratory syndrome coronavirus and SARS‐CoV‐2: A double‐edged sword? Human angiotensin‐converting enzyme 2 (ACE2) facilitates cellular entry of severe acute respiratory syndrome coronavirus (SARS‐CoV) and SARS‐CoV‐2 as their common receptor. During infection, ACE2‐expressing tissues become direct targets, resulting in serious pathological changes and progressive multiple organ failure or even death in severe cases. However, as an essential component of renin‐angiotensin system (RAS), ACE2 confers protective effects in physiological circumstance, including maintaining cardiovascular homeostasis, fluid, and electrolyte balance. The absence of protective role of ACE2 leads to dysregulated RAS and thus acute changes under multiple pathological scenarios including SARS. This potentially shared mechanism may also be the molecular explanation for pathogenesis driven by SARS‐CoV‐2. We reasonably speculate several potential directions of clinical management including host‐directed therapies aiming to restore dysregulated RAS caused by ACE2 deficiency. Enriched knowledge of ACE2 learned from SARS and COVID‐19 outbreaks can provide, despite their inherent tragedy, informative clues for emerging pandemic preparedness.

positive: A systematic review and meta-analysis to evaluate the clinical outcomes in COVID-19 patients on angiotensin-converting enzyme inhibitors or angiotensin receptor blockers INTRODUCTION: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) share their target receptor site with the SARS-CoV-2 virus, that may cause ACE2 receptor up-regulation which raised concerns regarding ACEI and ARB use in COVID-19 patients. However, many medical professional societies recommended their continued use given the paucity of clinical evidence, but there is a need for an updated systematic review and meta-analysis of the latest clinical studies. METHODS AND RESULTS: A search was conducted on PubMed, Google Scholar, EMBASE, and various preprint servers for studies comparing clinical outcomes and mortality in COVID-19 patients on ACEIs and/or ARBs, and a meta-analysis was performed. A total of 16 studies were included for the review and meta-analysis. There were conflicting findings reported in the rates of severity and mortality in several studies. In a pooled analysis of four studies, there was a statistically non-significant association of ACEI/ARB use with lower odds of developing severe disease vs. non-users [odds ratio (OR) = 0.81, 95% confidence interval (CI): 0.41–1.58, I(2)=50.52, P-value = 0.53). In a pooled analysis of six studies, there was a statistically non-significant association of ACEI/ARB use with lower odds of mortality as compared with non-users (OR = 0.86, 95% CI = 0.53–1.41, I(2) = 79.12, P-value = 0.55). CONCLUSION: It is concluded that ACEIs and ARBs should be continued in COVID-19 patients, reinforcing the recommendations made by several medical societies. Additionally, the individual patient factors such as ACE2 polymorphisms which might confer higher risk of adverse outcomes need to be evaluated further.

positive: Analysis of the susceptibility of lung cancer patients to SARS-CoV-2 infection Recent studies have reported that COVID-19 patients with lung cancer have a higher risk of severe events than patients without cancer. In this study, we investigated the gene expression of angiotensin I-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) with prognosis in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Lung cancer patients in each age stage, subtype, and pathological stage are susceptible to SARS-CoV-2 infection, except for the primitive subtype of LUSC. LUAD patients are more susceptible to SARS-CoV-2 infection than LUSC patients. The findings are unanimous on tissue expression in gene and protein levels.

positive: COVID-19 and the Cerebro-Cardiovascular Systems: What do we Know so Far? The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic of 2019-2020 has resulted in multiple hospitalizations, deaths and economic hardships worldwide. Though respiratory involvement in patients with coronavirus disease 2019 (COVID-19) is well-known, the potential cardiovascular and cerebrovascular manifestations are less-understood. We performed a PubMed and Google Scholar search and reviewed relevant literature regarding COVID-19 and cardiovascular system involvement. SARS-CoV-2 possesses high-affinity for angiotensin converting enzyme 2 (ACE2) receptor, which is highly concentrated in the lungs and cardiovascular tissue, thereby provoking concern for cardiovascular involvement in COVID-19 cases. Pre-existing cardiovascular and cerebrovascular disease has been shown in previous reports to be a risk-factor for severe infection. Based on our review of published studies, COVID-19 patients may be more likely to experience acute cardiac injury, arrhythmia, coagulation defects and acute stroke and are likely to have poorer outcomes as a result. As the COVID-19 pandemic continues, more data regarding potential cardiovascular and cerebrovascular manifestations of the disease is required.

positive: AT2 receptors: Functional relevance in cardiovascular disease Abstract The renin angiotensin system (RAS) is intricately involved in normal cardiovascular homeostasis. Excessive stimulation by the octapeptide angiotensin II contributes to a range of cardiovascular pathologies and diseases via angiotensin type 1 receptor (AT1R) activation. On the other hand, tElsevier Inc.he angiotensin type 2 receptor (AT2R) is thought to counter-regulate AT1R function. In this review, we describe the enhanced expression and function of AT2R in various cardiovascular disease settings. In addition, we illustrate that the RAS consists of a family of angiotensin peptides that exert cardiovascular effects that are often distinct from those of Ang II. During cardiovascular disease, there is likely to be an increased functional importance of AT2R, stimulated by Ang II, or even shorter angiotensin peptide fragments, to limit AT1R-mediated overactivity and cardiovascular pathologies.

positive: Renin-Angiotensin-Aldosterone Inhibitors and COVID-19 The Corona Virus Disease 2019 (COVID-19) outbreak has rapidly spread throughout the world, accounting for significant morbidity and mortality. There is a concern that renin-angiotensin-aldosterone inhibitors increase susceptibility to COVID-19. Currently there are no clinical data demonstrating beneficial or adverse effects of these medications on COVID-19 outcomes. Renin-angiotensin-aldosterone inhibitors should be continued in patients in otherwise stable conditions who are at risk for or having COVID-19.

positive: The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2 A new type of pneumonia caused by a novel coronavirus SARS-CoV-2 outbreaks recently in China and spreads into many other countries. This disease, named as COVID-19, is similar to patients infected by SARS-CoV and MERS-CoV, and nearly 20% of patients developed severe condition. Cardiac injury is a prevalent complication of severe patients, exacerbating the disease severity in coronavirus disease 2019 (COVID-19) patients. Angiotensin-converting enzyme 2 (ACE2), the key host cellular receptor of SARS-CoV-2, has been identified in multiple organs, but its cellular distribution in human heart is not illuminated clearly. This study performed the first state-of-art single cell atlas of adult human heart, and revealed that pericytes with high expression of ACE2 might act as the target cardiac cell of SARS-CoV-2. The pericytes injury due to virus infection may result in capillary endothelial cells dysfunction, inducing microvascular dysfunction. And patients with basic heart failure disease showed increased ACE2 expression at both mRNA and protein levels, meaning that if infected by the virus these patients may have higher risk of heart attack and critically ill condition. The finding of this study explains the high rate of severe cases among COVID-19 patients with basic cardiovascular disease; and these results also perhaps provide important reference to clinical treatment of cardiac injury among severe patients infected by SARS-CoV-2.

positive: What is the Role of Angiotensin Converting Enzyme 2 (ACE2) in COVID-19 Infection in Hypertensive, Diabetic Patients?

positive: Diabetes and COVID-19: evidence, current status and unanswered research questions Patients with diabetes who get coronavirus disease 2019 (COVID-19) are at risk of a severe disease course and mortality. Several factors especially the impaired immune response, heightened inflammatory response and hypercoagulable state contribute to the increased disease severity. However, there are many contentious issues about which the evidence is rather limited. There are some theoretical concerns about the effects of different anti-hyperglycaemic drugs. Similarly, despite the recognition of angiotensin converting enzyme 2 (ACE2) as the receptor for severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), and the role of ACE2 in lung injury; there are conflicting results with the use of angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) in these patients. Management of patients with diabetes in times of restrictions on mobility poses some challenges and novel approaches like telemedicine can be useful. There is a need to further study the natural course of COVID-19 in patients with diabetes and to understand the individual, regional and ethnic variations in disease prevalence and course.

positive: COVID-19: A promising cure for the global panic Abstract The novel Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2, which is the causative agent of a potentially fatal disease that is of great global public health concern. The outbreak of COVID-19 is wreaking havoc worldwide due to inadequate risk assessment regarding the urgency of the situation. The COVID-19 pandemic has entered a dangerous new phase. When compared with SARS and MERS, COVID-19 has spread more rapidly, due to increased globalization and adaptation of the virus in every environment. Slowing the spread of the COVID-19 cases will significantly reduce the strain on the healthcare system of the country by limiting the number of people who are severely sick by COVID-19 and need hospital care. Hence, the recent outburst of COVID-19 highlights an urgent need for therapeutics targeting SARS-CoV-2. Here, we have discussed the structure of virus; varying symptoms among COVID-19, SARS, MERS and common flu; the probable mechanism behind the infection and its immune response. Further, the current treatment options, drugs available, ongoing trials and recent diagnostics for COVID-19 have been discussed. We suggest traditional Indian medicinal plants as possible novel therapeutic approaches, exclusively targeting SARS-CoV-2 and its pathways.

positive: Angiotensin Converting Enzyme 2 May Mediate Disease Severity In COVID-19 Identification of vulnerability to severe coronavirus disease 2019 (COVID-19) is extremely important and might allow optimised shielding and easing of lockdown. The disease is attributed to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which enters host cells through binding to angiotensin converting enzyme 2 (ACE2) on the cell surface. Clinical syndromes such as hypertension that display reduced ACE2 expression tend to correlate with a more severe disease course, whereas treatments which upregulate ACE2 such as the use of angiotensin converting enzyme inhibitors (ACE-i) appear to have a protective effect against COVID-19. Pre-clinical studies have shown that plasma soluble ACE2 could render SARS-CoV-2 inactive in a dose-dependent manner. The association of clinical syndromes or treatments that impact ACE2 expression and clinical severity of COVID-19 infection combined with the reduction in viral load with human recombinant serum ACE2 shown in pre-clinical studies indicate a key role for ACE2 in determining COVID-19 severity. In conclusion, we propose that measurement of ACE2 level may help identify individuals at risk of severe infection where targeted shielding can be used and could provide a novel therapeutic target.

positive: Myocardial injury and COVID-19: Possible mechanisms Coronavirus Disease 2019 (COVID-19) has quickly progressed to a global health emergency. Respiratory illness is the major cause of morbidity and mortality in these patients with the disease spectrum ranging from asymptomatic subclinical infection, to severe pneumonia progressing to acute respiratory distress syndrome. There is growing evidence describing pathophysiological resemblance of SARS-CoV-2 infection with other coronavirus infections such as Severe Acute Respiratory Syndrome coronavirus and Middle East Respiratory Syndrome coronavirus (MERS-CoV). Angiotensin Converting Enzyme-2 receptors play a pivotal role in the pathogenesis of the virus. Disruption of this receptor leads to cardiomyopathy, cardiac dysfunction, and heart failure. Patients with cardiovascular disease are more likely to be infected with SARS-CoV-2 and they are more likely to develop severe symptoms. Hypertension, arrhythmia, cardiomyopathy and coronary heart disease are amongst major cardiovascular disease comorbidities seen in severe cases of COVID-19. There is growing literature exploring cardiac involvement in SARS-CoV-2. Myocardial injury is one of the important pathogenic features of COVID-19. As a surrogate for myocardial injury, multiple studies have shown increased cardiac biomarkers mainly cardiac troponins I and T in the infected patients especially those with severe disease. Myocarditis is depicted as another cause of morbidity amongst COVID-19 patients. The exact mechanisms of how SARS-CoV-2 can cause myocardial injury are not clearly understood. The proposed mechanisms of myocardial injury are direct damage to the cardiomyocytes, systemic inflammation, myocardial interstitial fibrosis, interferon mediated immune response, exaggerated cytokine response by Type 1 and 2 helper T cells, in addition to coronary plaque destabilization, and hypoxia.

positive: Substituting Angiotensin-(1-7) to Prevent Lung Damage in SARS-CoV-2 Infection?

positive: Contentious issues and evolving concepts in the clinical presentation and management of patients with COVID-19 infectionwith reference to use of therapeutic and other drugs used in Co-morbid diseases (Hypertension, diabetes etc) BACKGROUND AND AIMS: Multiple issues in management of COVID have emerged, but confusion persists regarding rational interpretation. Aim of this brief review is to review these issues based on current literature. METHODS: This is a narrative review with Pubmed and Google Scholar search till 23 March 2020. Search terms were, COVID-19, treatment of coronavirus, COVID 19 and following terms; chloroquine, hydroxychloroquine, ibuprofen, ACE-inhibitors or angiotensin receptor blockers, cardiovascular disease, diarrhoea, liver, testis and gastrointestinal disease. RESULTS: We discuss evidence regarding role of chloroquine and hydroxychloroquine in treatment and prophylaxis, use of inhibitors of the renin angiotensin system, safety of ibuprofen, unusual clinical features like gastrointestinal symptoms and interpretation of tests for cardiac enzymes and biomarkers. CONCLUSIONS: While our conclusions on management of COVID-19 patients with co-morbidities are based on current evidence, however, data is limited and there is immediate need for fast track research.

positive: Clinical considerations for patients with diabetes in times of COVID-19 pandemic

positive: Guidance for the care of neuromuscular patients during the COVID-19 pandemic outbreak from the French Rare Health Care for Neuromuscular Diseases Network Abstract In France, the epidemic phase of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began in February 2020 and resulted in the implementation of emergency measures and a degradation in the organization of neuromuscular reference centers. In this special context, the French Rare Health Care for Neuromuscular Diseases Network (FILNEMUS) has established guidance in an attempt to homogenize the management of neuromuscular (NM) patients within the French territory. Hospitalization should be reserved for emergencies, the conduct of treatments that cannot be postponed, check-ups for which the diagnostic delay may result in a loss of survival chance, and cardiorespiratory assessments for which the delay could be detrimental to the patient. A national strategy was adopted during a period of 1 to 2 months concerning treatments usually administered in hospitalization. NM patients treated with steroid/ immunosuppressants for a dysimmune pathology should continue all of their treatments in the absence of any manifestations suggestive of COVID-19. A frequently asked questions (FAQ) sheet has been compiled and updated on the FILNEMUS website. Various support systems for self-rehabilitation and guided exercises have been also provided on the website. In the context of NM diseases, particular attention must be paid to two experimental COVID-19 treatments, hydroxycholoroquine and azithromycin: risk of exacerbation of myasthenia gravis and QT prolongation in patients with pre-existing cardiac involvement. The unfavorable emergency context related to COVID-19 may specially affect the potential for intensive care admission (ICU) for people with NMD. In order to preserve the fairest medical decision, a multidisciplinary working group has listed the neuromuscular diseases with a good prognosis, usually eligible for resuscitation admission in ICU and, for other NM conditions, the positive criteria suggesting a good prognosis. Adaptation of the use of noninvasive ventilation (NIV) make it possible to limit nebulization and continue using NIV in ventilator-dependent patients.

positive: Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension The dysfunction of the renin-angiotensin system (RAS) has been observed in coronavirus infection disease (COVID-19) patients, but whether RAS inhibitors, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs), are associated with clinical outcomes remains unknown. COVID-19 patients with hypertension were enrolled to evaluate the effect of RAS inhibitors. We observed that patients receiving ACEI or ARB therapy had a lower rate of severe diseases and a trend toward a lower level of IL-6 in peripheral blood. In addition, ACEI or ARB therapy increased CD3 and CD8 T cell counts in peripheral blood and decreased the peak viral load compared to other antihypertensive drugs. This evidence supports the benefit of using ACEIs or ARBs to potentially contribute to the improvement of clinical outcomes of COVID-19 patients with hypertension.

positive: Assessing ACE2 expression patterns in lung tissues in the pathogenesis of COVID-19 It has been reported that SARS-CoV-2 may use ACE2 as a receptor to gain entry into human cells, in a way similar to that of SARS-CoV. Analyzing the distribution and expression level of ACE2 may therefore help reveal underlying mechanisms of viral susceptibility and post-infection modulation. In this study, we utilized previously uploaded information on ACE2 expression in various conditions including SARS-CoA to evaluate the role of ACE2 in SARS-CoV and extrapolate that to COVID-19. We found that the expression of ACE2 in healthy populations and patients with underlying diseases was not significantly different. However, based on the elevated expression of ACE2 in cigarette smokers, we speculate that long-term smoking may be a risk factor for COVID-19. Analysis of ACE2 in SARS-CoV infected cells suggests that ACE2 is not only a receptor but is also involved in post-infection regulation, including immune response, cytokine secretion, and viral genome replication. Moreover, we constructed Protein-protein interaction (PPI) networks and identified hub genes in viral activity and cytokine secretion. Our findings may help clinicians and researchers gain more insight into the pathogenesis of SARS-CoV-2 and design therapeutic strategies for COVID-19.

positive: The renin–angiotensin system in acute respiratory distress syndrome Angiotensin-converting enzyme 2 (ACE2) counterbalances with ACE and functions as a negative regulator of the renin–angiotensin system (RAS). The importance of RAS in acute respiratory distress syndrome (ARDS) has recently re-emerged owing to the identification of ACE2 as a receptor for the SARS-coronavirus. Recent studies have demonstrated that ACE2 protects mice from acute lung injury as well as SARS-mediated lung injury. We review the role of the RAS, in particular ACE2, in the pathogenesis of ARDS. Section editors: Terry Delovitch – The John P. Robarts Research Institute, London, Ont., Canada David Scott – University of Maryland School of Medicine, Baltimore, MD, USA

positive: Angiotensin-converting enzyme 2 autoantibodies: further evidence for a role of the renin-angiotensin system in inflammation Traditionally viewed as important in the regulation of blood pressure, the renin-angiotensin system - and specifically the angiotensin-converting enzyme (ACE)-angiotensin (Ang) II-AT(1 )receptor axis - may play a prominent role to promote inflammation and fibrosis. ACE2, a new component of the renin-angiotensin system, has emerged as a key enzyme that selectively degrades Ang II and generates Ang-(1-7), a bioactive peptide with anti-inflammatory and anti-fibrotic actions. Takahashi and colleagues demonstrate circulating titers of inhibitory autoantibodies against ACE2 in patients with systemic sclerosis. The current study reveals a potentially novel mechanism to attenuate the catalytic activity of ACE2, thereby promoting the actions of Ang II.

positive: Angiotensin-converting enzyme 2 (ACE2) mediates influenza H7N9 virus-induced acute lung injury Since March 2013, the emergence of an avian-origin influenza A (H7N9) virus has raised concern in China. Although most infections resulted in respiratory illness, some severe cases resulted in acute respiratory distress syndrome (ARDS), which is a severe form of acute lung injury (ALI) that further contributes to morbidity. To date, no effective drugs that improve the clinical outcome of influenza A (H7N9) virus-infected patients have been identified. Angiotensin-converting enzyme (ACE) and ACE2 are involved in several pathologies such as cardiovascular functions, renal disease, and acute lung injury. In the current study, we report that ACE2 could mediate the severe acute lung injury induced by influenza A (H7N9) virus infection in an experimental mouse model. Moreover, ACE2 deficiency worsened the disease pathogenesis markedly, mainly by targeting the angiotensin II type 1 receptor (AT1). The current findings demonstrate that ACE2 plays a critical role in influenza A (H7N9) virus-induced acute lung injury, and suggest that might be a useful potential therapeutic target for future influenza A (H7N9) outbreaks.

positive: Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury The outbreak of the 2019-nCoV infection began in December 2019 in Wuhan, Hubei province, and rapidly spread to many provinces in China as well as other countries. Here we report the epidemiological, clinical, laboratory, and radiological characteristics, as well as potential biomarkers for predicting disease severity in 2019-nCoV-infected patients in Shenzhen, China. All 12 cases of the 2019-nCoV-infected patients developed pneumonia and half of them developed acute respiratory distress syndrome (ARDS). The most common laboratory abnormalities were hypoalbuminemia, lymphopenia, decreased percentage of lymphocytes (LYM) and neutrophils (NEU), elevated C-reactive protein (CRP) and lactate dehydrogenase (LDH), and decreased CD8 count. The viral load of 2019-nCoV detected from patient respiratory tracts was positively linked to lung disease severity. ALB, LYM, LYM (%), LDH, NEU (%), and CRP were highly correlated to the acute lung injury. Age, viral load, lung injury score, and blood biochemistry indexes, albumin (ALB), CRP, LDH, LYM (%), LYM, and NEU (%), may be predictors of disease severity. Moreover, the Angiotensin II level in the plasma sample from 2019-nCoV infected patients was markedly elevated and linearly associated to viral load and lung injury. Our results suggest a number of potential diagnosis biomarkers and angiotensin receptor blocker (ARB) drugs for potential repurposing treatment of 2019-nCoV infection. ELECTRONIC SUPPLEMENTARY MATERIAL: Supplementary material is available for this article at 10.1007/s11427-020-1643-8 and is accessible for authorized users.

positive: Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review Importance: The pandemic of coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents an unprecedented challenge to identify effective drugs for prevention and treatment. Given the rapid pace of scientific discovery and clinical data generated by the large number of people rapidly infected by SARS-CoV-2, clinicians need accurate evidence regarding effective medical treatments for this infection. Observations: No proven effective therapies for this virus currently exist. The rapidly expanding knowledge regarding SARS-CoV-2 virology provides a significant number of potential drug targets. The most promising therapy is remdesivir. Remdesivir has potent in vitro activity against SARS-CoV-2, but it is not US Food and Drug Administration approved and currently is being tested in ongoing randomized trials. Oseltamivir has not been shown to have efficacy, and corticosteroids are currently not recommended. Current clinical evidence does not support stopping angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in patients with COVID-19. Conclusions and Relevance: The COVID-19 pandemic represents the greatest global public health crisis of this generation and, potentially, since the pandemic influenza outbreak of 1918. The speed and volume of clinical trials launched to investigate potential therapies for COVID-19 highlight both the need and capability to produce high-quality evidence even in the middle of a pandemic. No therapies have been shown effective to date.

positive: The role of angiotensin-converting enzyme 2 in coronaviruses/influenza viruses and cardiovascular disease Angiotensin-converting enzyme 2 (ACE2) has emerged as a key regulator of the renin–angiotensin system in cardiovascular (CV) disease and plays a pivotal role in infections by coronaviruses and influenza viruses. The present review is primarily focused on the findings to indicate the role of ACE2 in the relationship of coronaviruses and influenza viruses to CV disease. It is postulated that the risk of coronavirus or influenza virus infection is high, at least partly due to high ACE2 expression in populations with a high CV risk. Coronavirus and influenza virus vaccine usage in high CV risk populations could be a potential strategy to prevent both CV disease and coronavirus/influenza virus infections.

positive: What could be the better choice between ACE inhibitors and AT1R antagonists in coronavirus disease 2019 (COVID-19) patients?

positive: Myocardial injury and COVID-19: Possible mechanisms Abstract Coronavirus Disease 2019 (COVID-19) has quickly progressed to a global health emergency. Respiratory illness is the major cause of morbidity and mortality in these patients with the disease spectrum ranging from asymptomatic subclinical infection, to severe pneumonia progressing to acute respiratory distress syndrome. There is growing evidence describing pathophysiological resemblance of SARS-CoV-2 infection with other coronavirus infections such as Severe Acute Respiratory Syndrome coronavirus and Middle East Respiratory Syndrome coronavirus (MERS-CoV). Angiotensin Converting Enzyme-2 receptors play a pivotal role in the pathogenesis of the virus. Disruption of this receptor leads to cardiomyopathy, cardiac dysfunction, and heart failure. Patients with cardiovascular disease are more likely to be infected with SARS-CoV-2 and they are more likely to develop severe symptoms. Hypertension, arrhythmia, cardiomyopathy and coronary heart disease are amongst major cardiovascular disease comorbidities seen in severe cases of COVID-19. There is growing literature exploring cardiac involvement in SARS-CoV-2. Myocardial injury is one of the important pathogenic features of COVID-19. As a surrogate for myocardial injury, multiple studies have shown increased cardiac biomarkers mainly cardiac troponins I and T in the infected patients especially those with severe disease. Myocarditis is depicted as another cause of morbidity amongst COVID-19 patients. The exact mechanisms of how SARS-CoV-2 can cause myocardial injury are not clearly understood. The proposed mechanisms of myocardial injury are direct damage to the cardiomyocytes, systemic inflammation, myocardial interstitial fibrosis, interferon mediated immune response, exaggerated cytokine response by Type 1 and 2 helper T cells, in addition to coronary plaque destabilization, and hypoxia.

positive: Detection of soluble angiotensin-converting enzyme 2 in heart failure: insights into the endogenous counter-regulatory pathway of the renin-angiotensin-aldosterone system. OBJECTIVES We sought to determine whether circulating soluble angiotensin-converting enzyme 2 (sACE2) is increased in the plasma of patients with heart failure (HF). BACKGROUND Angiotensin-converting enzyme 2 (ACE2) is an integral membrane protein that antagonizes the actions of angiotensin II and prevents the development of HF in animal models. However, because of the need for invasive cardiac tissue sampling, little is known about whether ACE2 is involved in the pathophysiology of HF in humans. METHODS We developed a sensitive and specific assay to measure sACE2 activity in human plasma and screened a heterogeneous group of patients suspected of having clinical HF. RESULTS Increasing sACE2 plasma activity strongly correlated with a clinical diagnosis of HF (p = 0.0002), worsening left ventricular ejection fraction (p < 0.0001), and increasing B-type natriuretic peptide levels (p < 0.0001). Similar to B-type natriuretic peptide, sACE2 activity reflected the severity of HF, with increasing levels associated with worsening New York Heart Association functional class (p < 0.0001). These associations were independent of other disease states and medication use. We found that sACE2 activity was increased in patients with both ischemic and nonischemic cardiomyopathies and also in patients with clinical HF but a preserved left ventricular ejection fraction. CONCLUSIONS Soluble ACE2 activity is increased in patients with HF and correlates with disease severity, suggesting that a cardioprotective arm of the renin-angiotensin-aldosterone system is active in HF.

positive: The Lung, the Heart, the Novel Coronavirus, and the Renin-Angiotensin System; The Need for Clinical Trials Angiotensin-converting enzyme 2 (ACE2) is the receptor for COVID-19 (SARs-CoV-2). ACE2 protects the lung and heart from acute respiratory distress syndrome (ARDS) and acute myocarditis and arrhythmias, because it breaks down Angiotensin II, which has inflammatory effects in the lung and heart as well as in the kidney. When SARS-CoV-2 binds to ACE2, it suppresses it, so this protective action of ACE2 is lost. Death from COVID-19 is due to ARDS and also heart failure and acute cardiac injury. Drugs that prevent the inflammatory actions of Angiotensin II (i.e., Angiotensin receptor blockers, ARBs) prevent acute lung injury caused by SARS-CoV. Clinical trials are underway to test the risks and benefits of ARBs and angiotensin-converting enzyme inhibitors (ACEIs) in COVID-19 patients requiring hospitalization. Other potential treatments are also discussed.

positive: Losartan and enalapril decrease viral absorption and interleukin 1 beta production by macrophages in an experimental dengue virus infection The role of angiotensin II (Ang II) in dengue virus infection remains unknown. The aim of this study was to determine the effect of losartan, an antagonist of the angiotensin II type 1 receptor (AT1 receptor), and enalapril, an inhibitor of angiotensin I-converting enzyme (ACE), on viral antigen expression and IL-1β production in peritoneal macrophages infected with dengue virus type 2. Mice treated with losartan or enalapril and untreated controls were infected intraperitoneally with the virus, and macrophages were analyzed. Infection resulted in increased IL-1β production and a high percentage of cells expressing viral antigen, and this was decreased by treatment with anti-Ang II drugs, suggesting a role for Ang II in dengue virus infection.

positive: Response to recent commentaries regarding the involvement of angiotensin-converting enzyme 2 (ACE2) and renin-angiotensin system blockers in SARS-CoV-2 infections

positive: Sex-Specific Modulation of Blood Pressure and the Renin-Angiotensin System by ACE (Angiotensin-Converting Enzyme) 2. We showed ACE (angiotensin-converting enzyme) 2 is higher in the kidney of male compared with female mice. To further investigate this sex difference, we examined the role of ACE2 in Ang-[1-8] (angiotensin [1-8])-induced hypertension and regulation of the renin-angiotensin system in the kidney of WT (wild type) and Ace2 KO (knockout) mice. Mean arterial pressure rose faster in WT male than WT female mice after Ang-[1-8] infusion. This sex difference was attenuated in ACE2 KO mice. Ang-[1-8] infusion reduced glomerular AT1R (angiotensin type 1 receptor) binding in WT female mice by 30%, and deletion of Ace2 abolished this effect. In contrast, Ang-[1-8] infusion increased glomerular AT1R binding in WT male mice by 1.2-fold, and this effect of Ang-[1-8] persisted in Ace2 KO male mice (1.3-fold). ACE2 also had an effect on renal protein expression of the neutral endopeptidase NEP (neprilysin), the enzyme that catabolizes Ang-[1-10] (angiotensin [1-10]), the precursor of Ang-[1-8]. Ang-[1-8] infusion downregulated NEP protein expression by 20% in WT male, whereas there was a slight increase in NEP expression in WT female mice. Deletion of Ace2 resulted in lowered NEP expression after Ang-[1-8] infusion in both sexes. These findings suggest sex-specific ACE2 regulation of the renin-angiotensin system contributes to female protection from Ang-[1-8]-induced hypertension. These findings have ramifications for the current coronavirus disease 2019 (COVID-19) pandemic, especially in hypertension since ACE2 is the SARS-CoV-2 receptor and hypertension is a major risk factor for poor outcomes.

positive: Functional Immune Deficiency Syndrome via Intestinal Infection in COVID-19 Using a Systems Biology approach, we integrated genomic, transcriptomic, proteomic, and molecular structure information to provide a holistic understanding of the COVID-19 pandemic. The expression data analysis of the Renin Angiotensin System indicates mild nasal, oral or throat infections are likely and that the gastrointestinal tissues are a common primary target of SARS-CoV-2. Extreme symptoms in the lower respiratory system likely result from a secondary-infection possibly by a comorbidity-driven upregulation of ACE2 in the lung. The remarkable differences in expression of other RAS elements, the elimination of macrophages and the activation of cytokines in COVID-19 bronchoalveolar samples suggest that a functional immune deficiency is a critical outcome of COVID-19. We posit that using a non-respiratory system as a major pathway of infection is likely determining the unprecedented global spread of this coronavirus. One Sentence Summary A Systems Approach Indicates Non-respiratory Pathways of Infection as Key for the COVID-19 Pandemic

positive: New understanding of the damage of SARS-CoV-2 infection outside the respiratory system Abstract Since early December 2019, a number of pneumonia cases associated with unknown coronavirus infection were identified in Wuhan, China, and many additional cases were identified in other regions of China and in other countries within 3 months. Currently, more than 80,000 cases have been diagnosed in China, including more than 3,000 deaths. The epidemic is spreading to the rest of the world, posing a grave challenge to prevention and control. On February 12, 2020, the International Committee on Taxonomy of Viruses and the World Health Organization officially named the novel coronavirus and associated pneumonia as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 2019 (COVID-19), respectively. According to the recent research on SARS-CoV-2, the virus mainly infects the respiratory system but may cause damage to other systems. In this paper, we will systematically review the pathogenic features, transmission routes, and infection mechanisms of SARS-CoV-2, as well as any adverse effects on the digestive system, urogenital system, central nervous system, and circulatory system, in order to provide a theoretical and clinical basis for the diagnosis, classification, treatment, and prognosis assessment of SARS-CoV-2 infection.

positive: The two fACEs of the tissue renin-angiotensin systems: implication in cardiovascular diseases. The implication of the renin-angiotensin system (RAS) in the regulation of the cardiovascular system has been well known for many years. Accordingly, many pharmaceutical inhibitors have been developed to treat several pathologies, like hypertension and heart failure, and angiotensin converting enzyme (ACE) became one of the major target in the treatment of these cardiovascular diseases. In the last decade however, it has become apparent that the classical view of the RAS was not quite accurate. For instance, ACE has been shown to work not only by generating angiotensin-II but also by interacting with receptors outside the renin-angiotensin system. Moreover, it has been shown that many local RAS are present in different tissues, such as the heart, brain, kidney and vasculature. However, in the past, it was impossible to determine the role of these local systems as they were pharmacologically indistinguishable from the systemic RAS. Hence, in recent years, the development of transgenic animals has allowed us to determine that these local systems are implicated in the roles that had been originally attributed exclusively to the systemic action of the RAS. However, with almost 30% of the medicated hypertensive patients harboring an uncontrolled blood pressure, a need for new drugs and new targets appears necessary. With the new century came the discovery of a new homolog of ACE, called ACE2, and early studies suggest that it may play a pivotal role in the RAS by controlling the balance between the vasoconstrictor effects of angiotensin-II and the vasodilatory properties of the angiotensin(1-7) peptide. Like ACE, ACE2 appears to hydrolyze peptides not related with the RAS and the enzyme has also been identified as a receptor for the severe acute respiratory syndrome (SARS) coronavirus. Although the tissue localization of ACE2 was originally though to be very restricted, new studies have emerged showing a more widespread distribution. Therefore, the whole dynamics of the RAS has to be re-evaluated in light of this new information. In this review, we will compare the structures, distributions and properties of ACE and its new homologue in the context of cardiovascular function, focusing on the autocrine/paracrine cardiac and brain renin-angiotensin systems and we will present recent data from the literature and our laboratory offering a new perspective on this potential target for the treatment of cardiovascular diseases.

positive: Advanced bioinformatics rapidly identifies existing therapeutics for patients with coronavirus disease-2019 (COVID-19) BACKGROUND: The recent global pandemic has placed a high priority on identifying drugs to prevent or lessen clinical infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), caused by Coronavirus disease-2019 (COVID-19). METHODS: We applied two computational approaches to identify potential therapeutics. First, we sought to identify existing FDA approved drugs that could block coronaviruses from entering cells by binding to ACE2 or TMPRSS2 using a high-throughput AI-based binding affinity prediction platform. Second, we sought to identify FDA approved drugs that could attenuate the gene expression patterns induced by coronaviruses, using our Disease Cancelling Technology (DCT) platform. RESULTS: Top results for ACE2 binding iincluded several ACE inhibitors, a beta-lactam antibiotic, two antiviral agents (Fosamprenavir and Emricasan) and glutathione. The platform also assessed specificity for ACE2 over ACE1, important for avoiding counterregulatory effects. Further studies are needed to weigh the benefit of blocking virus entry against potential counterregulatory effects and possible protective effects of ACE2. However, the data herein suggest readily available drugs that warrant experimental evaluation to assess potential benefit. DCT was run on an animal model of SARS-CoV, and ranked compounds by their ability to induce gene expression signals that counteract disease-associated signals. Top hits included Vitamin E, ruxolitinib, and glutamine. Glutathione and its precursor glutamine were highly ranked by two independent methods, suggesting both warrant further investigation for potential benefit against SARS-CoV-2. CONCLUSIONS: While these findings are not yet ready for clinical translation, this report highlights the potential use of two bioinformatics technologies to rapidly discover existing therapeutic agents that warrant further investigation for established and emerging disease processes.

positive: What could be the better choice between ACE inhibitors and AT1R antagonists in coronavirus disease 2019 (COVID-19) patients? Angiotensin-converting enzyme 2 (ACE2) removes a single residue from Ang I to yield Ang (1-9) and cleaves a single residue from Ang II to generate Ang (1-7). Thus ACE2 counterbalances ACE function decreasing Ang II levels1 . Consequently, this enzyme has a protective role against excessively high blood pressure values and high level of renin-angiotensin system (RAS) activation2 . This article is protected by copyright. All rights reserved.

positive: Functional assessment of cell entry and receptor usage for lineage B β-coronaviruses, including 2019-nCoV Over the past 20 years, several coronaviruses have crossed the species barrier into humans, causing outbreaks of severe, and often fatal, respiratory illness. Since SARS- CoV was first identified in animal markets, global viromics projects have discovered thousands of coronavirus sequences in diverse animals and geographic regions. Unfortunately, there are few tools available to functionally test these novel viruses for their ability to infect humans, which has severely hampered efforts to predict the next zoonotic viral outbreak. Here we developed an approach to rapidly screen lineage B betacoronaviruses, such as SARS-CoV and the recent 2019-nCoV, for receptor usage and their ability to infect cell types from different species. We show that host protease processing during viral entry is a significant barrier for several lineage B viruses and that bypassing this barrier allows several lineage B viruses to enter human cells through an unknown receptor. We also demonstrate how different lineage B viruses can recombine to gain entry into human cells and confirm that human ACE2 is the receptor for the recently emerging 2019-nCoV.

positive: Overview of Covid-19 regarding the cardiovascular situation in the light of current reports. Nowadays coronavirus disease 2019 (Covid-19) is increasing mortality all over the world mercilessly. We are learning almost every day about its new symptoms and that it mutates quickly. This disease ties us up and leaves us desperate. Death from this disease has increased in patients who had with pre-existing medical conditions, especially cardiovascular ones, by eliminating the angiotensin-converting enzyme (ACE)-2 receptor in the lungs. Also, ACE1 and angiotensin receptor blockers (ARB) may stimulate ACE2 expression and worse the prognosis. Intravenous infusions of ACEIs and ARBs in experimental animals increase the numbers of ACE2 receptors. So, it may be one of the reasons that COVID-19 infects the cells of patients treating hypertension. However, most of the congress of cardiology do not recommend discontinue of these anti-hypertensive drugs. Therefore, this brief report evaluates Covid-19 in the view of cardiovascular diseases taking into account current reports and suggests some possible solutions to keep the virus under control.

positive: Diabetes mellitus is associated with increased mortality and severity of disease in COVID-19 pneumonia – A systematic review, meta-analysis, and meta-regression Abstract Background and aims Diabetes Mellitus (DM) is chronic conditions with devastating multi-systemic complication and may be associated with severe form of Coronavirus Disease 2019 (COVID-19). We conducted a systematic review and meta-analysis in order to investigate the association between DM and poor outcome in patients with COVID-19 pneumonia. Methods Systematic literature search was performed from several electronic databases on subjects that assess DM and outcome in COVID-19 pneumonia. The outcome of interest was composite poor outcome, including mortality, severe COVID-19, acute respiratory distress syndrome (ARDS), need for intensive care unit (ICU) care, and disease progression. Results There were a total of 6452 patients from 30 studies. Meta-analysis showed that DM was associated with composite poor outcome (RR 2.38 [1.88, 3.03], p < 0.001; I2: 62%) and its subgroup which comprised of mortality (RR 2.12 [1.44, 3.11], p < 0.001; I2: 72%), severe COVID-19 (RR 2.45 [1.79, 3.35], p < 0.001; I2: 45%), ARDS (RR 4.64 [1.86, 11.58], p = 0.001; I2: 9%), and disease progression (RR 3.31 [1.08, 10.14], p = 0.04; I2: 0%). Meta-regression showed that the association with composite poor outcome was influenced by age (p = 0.003) and hypertension (p < 0.001). Subgroup analysis showed that the association was weaker in studies with median age ≥55 years-old (RR 1.92) compared to <55 years-old (RR 3.48), and in prevalence of hypertension ≥25% (RR 1.93) compared to <25% (RR 3.06). Subgroup analysis on median age <55 years-old and prevalence of hypertension <25% showed strong association (RR 3.33) Conclusion DM was associated with mortality, severe COVID-19, ARDS, and disease progression in patients with COVID-19.

positive: Inhaled modified angiotensin converting enzyme 2 (ACE2) as a decoy to mitigate SARS-CoV-2 infection COVID-19 is a new zoonotic disease caused by the SARS-CoV-2 virus Since its emergence in Wuhan City, China, the virus has rapidly spread across the globe causing calamitous health, economic and societal consequences It causes disproportionately severe disease in the elderly and those with co-morbidities, such as hypertension and diabetes There is currently no proven treatment for COVID-19 and a safe and effective vaccine is at least a year away The virus gains access to the respiratory epithelium through cell surface angiotensin converting enzyme 2 (ACE2) The receptor binding domain (RBD) of the virus is unlikely to mutate without loss of pathogenicity and thus represents an attractive target for antiviral treatment Inhaled modified recombinant human ACE2, may bind SARS-CoV-2 and mitigate lung damage This decoy strategy is unlikely to provoke an adverse immune response and may reduce morbidity and mortality in high-risk groups

positive: The 2019 Novel Coronavirus Outbreak - A Global Threat. The 2019 Novel Corona virus infection (COVID 19) is an ongoing public health emergency of international significance. There are significant knowledge gaps in the epidemiology, transmission dynamics, investigation tools and management. In this article, we review the available evidence about this disease. Every decade has witnessed the evolution of a new coronavirus epidemic since the last three decades. The varying transmission patterns, namely, nosocomial transmission and spread through mildly symptomatic cases is an area of concern. There is a spectrum of clinical features from mild to severe life threatening disease with major complications like severe pneumonia, ARDS, acute cardiac injury and septic shock. Presence of bilateral ground glass opacity and consolidation on imaging in appropriate clinical background should raise a suspicion about COVID 19. Poor prognostic factors include Multilobular infiltration on chest imaging, Lymphopenia, Bacterial co-infection, Smoking history, Chronic medical conditions like Hypertension and age >60 years (MuLBSTA score). Diagnosis is confirmed with PCR based testing of appropriate respiratory samples. Management is primarily supportive, with newer antivirals (lopinavir ritonavir and Remdesivir) under investigation. Role of steroids is still inconclusive. Standard infection control and prevention techniques should be followed. Vigilant screening of suspected cases and their contacts is important. Isolation of symptomatic cases and home quarantine of asymptomatic contacts is recommended. To conclude, controlling this highly transmissible disease requires international co-ordination.

positive: Age, frailty and diabetes – triple jeopardy for vulnerability to COVID-19 infection

positive: Association Between ACEIs or ARBs Use and Clinical Outcomes in COVID-19 Patients: A Systematic Review and Meta-analysis Importance: There is a controversy regarding whether or not to continue angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in patients with coronavirus disease 2019 (COVID-19). Objective: To evaluate the association between ACEIs or ARBs use and clinical outcomes in COVID-19 patients. Data Sources: Systematic search of the PubMed, Embase, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials from database inception to May 31, 2020. We also searched the preprint servers medRxiv and SSNR for additional studies. Study Selection: Observational studies and randomized controlled trials reporting the effect of ACEIs or ARBs use on clinical outcomes of adult patients with COVID-19. Data Extraction and Synthesis: Risk of bias of observational studies were evaluated using the Newcastle-Ottawa Scale. Meta-analyses were performed using a random-effects models and effects expressed as Odds ratios (OR) and mean differences with their 95% confidence interval (95%CI). If available, adjusted effects were pooled. Main Outcomes and Measures: The primary outcome was all-cause mortality and secondary outcomes were COVID-19 severity, hospital discharge, hospitalization, intensive care unit admission, mechanical ventilation, length of hospital stay, and troponin, creatinine, procalcitonin, C-reactive protein (CRP), interleukin-6 (IL-6), and D-dimer levels. Results: 40 studies (21 cross-sectional, two case-control, and 17 cohorts) involving 50615 patients were included. ACEIs or ARBs use was not associated with all-cause mortality overall (OR 1.11, 95%CI 0.77-1.60, p=0.56), in subgroups by study design and using adjusted effects. ACEI or ARB use was independently associated with lower COVID-19 severity (aOR 0.56, 95%CI 0.37-0.87, p<0.01). No significant associations were found between ACEIs or ARBs use and hospital discharge, hospitalization, mechanical ventilation, length of hospital stay, and biomarkers. Conclusions and Relevance: ACEIs or ARBs use was not associated with higher all-cause mortality in COVID-19. However, ACEI or ARB use was independently associated with lower COVID-19 severity. Our results support the current international guidelines to continue the use of ACEIs and ARBs in COVID-19 patients with hypertension.

positive: COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options The novel coronavirus disease (COVID-19) outbreak, caused by SARS-CoV-2, represents the greatest medical challenge in decades. We provide a comprehensive review of the clinical course of COVID-19, its comorbidities, and mechanistic considerations for future therapies. While COVID-19 primarily affects the lungs, causing interstitial pneumonitis and severe acute respiratory distress syndrome (ARDS), it also affects multiple organs, particularly the cardiovascular system. Risk of severe infection and mortality increase with advancing age and male sex. Mortality is increased by comorbidities: cardiovascular disease, hypertension, diabetes, chronic pulmonary disease, and cancer. The most common complications include arrhythmia (atrial fibrillation, ventricular tachyarrhythmia, and ventricular fibrillation), cardiac injury [elevated highly sensitive troponin I (hs-cTnI) and creatine kinase (CK) levels], fulminant myocarditis, heart failure, pulmonary embolism, and disseminated intravascular coagulation (DIC). Mechanistically, SARS-CoV-2, following proteolytic cleavage of its S protein by a serine protease, binds to the transmembrane angiotensin-converting enzyme 2 (ACE2) -a homologue of ACE-to enter type 2 pneumocytes, macrophages, perivascular pericytes, and cardiomyocytes. This may lead to myocardial dysfunction and damage, endothelial dysfunction, microvascular dysfunction, plaque instability, and myocardial infarction (MI). While ACE2 is essential for viral invasion, there is no evidence that ACE inhibitors or angiotensin receptor blockers (ARBs) worsen prognosis. Hence, patients should not discontinue their use. Moreover, renin-angiotensin-aldosterone system (RAAS) inhibitors might be beneficial in COVID-19. Initial immune and inflammatory responses induce a severe cytokine storm [interleukin (IL)-6, IL-7, IL-22, IL-17, etc.] during the rapid progression phase of COVID-19. Early evaluation and continued monitoring of cardiac damage (cTnI and NT-proBNP) and coagulation (D-dimer) after hospitalization may identify patients with cardiac injury and predict COVID-19 complications. Preventive measures (social distancing and social isolation) also increase cardiovascular risk. Cardiovascular considerations of therapies currently used, including remdesivir, chloroquine, hydroxychloroquine, tocilizumab, ribavirin, interferons, and lopinavir/ritonavir, as well as experimental therapies, such as human recombinant ACE2 (rhACE2), are discussed.

positive: COVID-19 and RAS: Unravelling an Unclear Relationship The renin-angiotensin system (RAS) plays a main role in regulating blood pressure and electrolyte and liquid balance. Previous evidence suggests that RAS may represent an important target for the treatment of lung pathologies, especially for acute respiratory distress syndrome and chronic fibrotic disease. The scientific community has recently focused its attention on angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor 1 (AT1R) inhibitors and their possible benefit/harms for patients infected by Coronavirus disease (COVID-19) who experience pneumonia, but there are still some doubts about the effects of these drugs in this setting.

positive: The Cell Biology of the SARS Coronavirus Receptor, Angiotensin-Converting Enzyme 2 The identification of angiotensin-converting enzyme 2 (ACE2) as a cellular receptor for the SARS coronavirus (SARS-CoV) rejuvenated research into what was regarded by some as a minor player in the renin–angiotensin system. The discovery of its double life led to breathtaking advances in the understanding of virtually all aspects of its biology, including its structure, physiological and pathophysiological roles and cell biology. ACE2, like its well-known homologue, ACE, is a metallopeptidase which resides on the cell surface of the epithelial, and sometimes endothelial, cells of the heart, kidney, testes, lung and gastrointestinal tract. It is a type I transmembrane protein with a large catalytic extracellular domain which acts as both a peptidase and a viral receptor. This extracellular domain can be cleaved from the cell surface by other peptidases, modulating its activity. The levels of the enzyme on the cell surface are also thought to be regulated by internalisation on S-protein binding and by clustering in membrane microdomains known as lipid rafts. This chapter summarises the current understanding of how the cell biology of ACE2 is regulated and may influence and determine its function, and concludes by discussing the future challenges and opportunities for studies of this increasingly important enzyme.

positive: Identification of angiotensin converting enzyme 2 in the rodent retina. PURPOSE An active renin-angiotensin system has been found in the retina of rats and humans. Angiotensin-converting enzyme 2 (ACE2) is a recently discovered enzymatic homologue of Angiotensin-converting enzyme (ACE) that may be an important new component of the renin-angiotensin system (RAS). This study assesses the involvement of ACE2 in the normal and diabetic rodent retina and its modulation by ACE inhibition. METHODS Sprague-Dawley rats were randomised into three groups, control, diabetes, and diabetes plus ramipril, with diabetes induced with the cell toxin streptozocin and the study run for 24 weeks. ACE2 and ACE gene levels were measured using quantitative real-time polymerase chain reaction (QRT-PCR), ACE2 protein expression was confirmed by Western blotting, and ACE and ACE2 catalytic activity were measured using specific activity assays in the rat retina. Localisation of ACE2 mRNA and protein were determined by in situ hybridisation and immunohistochemistry, respectively. RESULTS ACE mRNA levels were decreased to approximately 50% in the diabetic retina, but ACE2 mRNA levels were not significantly changed. ACE but not ACE2 gene expression was influenced by ramipril treatment. Following immunostaining, both ACE2 and ACE protein were localised predominantly to the inner nuclear layer (INL) but also to photoreceptors. In the diabetic retina, ACE enzyme activity was decreased, whereas ACE2 enzyme activity was increased. CONCLUSIONS This study has identified ACE2 gene and catalytically active protein in the rodent retina. In diabetes, the major changes were a decrease in ACE but an increase in ACE2 enzymatic activity. The ACE inhibitor ramipril did not reduce ACE2 enzymatic activity.

positive: Psoriasis and risk of the COVID-19 infection: Is there a role for Angiotensin Converting Enzyme (ACE)? Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first appeared in Wuhan, China in December 2019 resulting in the COVID-19 pandemic. It has been shown that SARS-CoV-2 spike protein shares a high similarity with SARS-CoV spike protein with a strong binding affinity to human Angiotensin Converting Enzyme 2 (ACE2) receptor. Skin tissue may be a possible specific target for the SARS-CoV-2. Preliminary reports from the COVID-19 infection have shown cutaneous manifestation, including erythematous rash, widespread urticaria, and chickenpox-like vesicles. Moreover, many studies have shown the role of ACE in the development, severity, and complications of psoriasis. Herein, we discuss a possible shared mechanism of psoriasis with SARS-CoV-2; also, we propose a therapeutic approach to balance the effect of ACE activity in these patients.

positive: Pathophysiological Characteristics and Therapeutic Approaches for Pulmonary Injury and Cardiovascular Complications of Coronavirus Disease 2019 Abstract The pandemic of coronavirus disease 2019 (COVID-19) has emerged as a major health crisis, with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) having infected over a million people around the world within a few months of its identification as a human pathogen. Initially, SARS-CoV-2 infects cells in the respiratory system and causes inflammation and cell death. Subsequently, the virus spreads out and damages other vital organs and tissues, triggering a complicated spectrum of pathophysiological changes and symptoms, including cardiovascular complications. Acting as the receptor for SARS-CoV entering mammalian cells, angiotensin converting enzyme-2 (ACE2) plays a pivotal role in the regulation of cardiovascular cell function. Diverse clinical manifestations and laboratory abnormalities occur in patients with cardiovascular injury in COVID-19, characterizing the development of this complication, as well as providing clues to diagnosis and treatment. This review provides a summary of the rapidly appearing laboratory and clinical evidence for the pathophysiology and therapeutic approaches to COVID-19 pulmonary and cardiovascular complications.

positive: Potential role for tissue factor in the pathogenesis of hypercoagulability associated with in COVID-19 In December 2019, a new and highly contagious infectious disease emerged in Wuhan, China. The etiologic agent was identified as a novel coronavirus, now known as Severe Acute Syndrome Coronavirus-2 (SARS-CoV-2). Recent research has revealed that virus entry takes place upon the union of the virus S surface protein with the type I transmembrane metallo-carboxypeptidase, angiotensin converting enzyme 2 (ACE-2) identified on epithelial cells of the host respiratory tract. Virus triggers the synthesis and release of pro-inflammatory cytokines, including IL-6 and TNF-α and also promotes downregulation of ACE-2, which promotes a concomitant increase in levels of angiotensin II (AT-II). Both TNF-α and AT-II have been implicated in promoting overexpression of tissue factor (TF) in platelets and macrophages. Additionally, the generation of antiphospholipid antibodies associated with COVID-19 may also promote an increase in TF. TF may be a critical mediator associated with the development of thrombotic phenomena in COVID-19, and should be a target for future study.

positive: Good ACE, bad ACE do battle in lung injury, SARS Two studies show how the enzyme ACE2 protects against lung injury caused by SARS and other agents. ACE2 seems to counteract the effects of ACE, which are more damaging (pages 875–879).

positive: Prioritisation of potential anti-SARS-CoV-2 drug repurposing opportunities based on ability to achieve adequate target site concentrations derived from their established human pharmacokinetics Many papers are emerging that describe the in vitro antiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against SARS-CoV-2. However, no comprehensive evaluation of these molecules in the context of the achievable plasma pharmacokinetics after administration of approved doses and schedules to humans has been conducted. Moreover, most publications have focussed on 50% maximum effective concentrations (EC50), which may be an insufficiently robust indicator of antiviral activity because of marked differences in the slope of the concentration-response curve between drugs. Accordingly, in vitro anti-SARS-CoV-2 activity data was digitised from all available publications up to 13th April 2020 and used to recalculate an EC90 value for each drug. EC90 values were then expressed as a ratio to the achievable maximum plasma concentrations (Cmax) reported for each drug after administration of the approved dose to humans (Cmax/EC90 ratio). Only 14 of the analysed drugs achieved a Cmax/EC90 ratio above 1 meaning that plasma Cmax concentrations exceeded those necessary to inhibit 90% of SARS-CoV-2 replication. A more in-depth assessment of these drugs demonstrated that only nitazoxanide, nelfinavir, tipranavir (boosted with ritonavir) and sulfadoxine achieved plasma concentrations above their anti-SARS-CoV-2 activity across their entire approved dosing interval at their approved human dose. For all drugs reported, the unbound lung to plasma tissue partition coefficient (KpUlung) was also simulated and used along with reported Cmax and fraction unbound in plasma to derive a lung Cmax/EC50 as a better indicator of potential human efficacy (lung Cmax/EC90 ratio was also calculable for a limited number of drugs). Using this parameter hydroxychloroquine, chloroquine, mefloquine, atazanavir (boosted with ritonavir), tipranavir (boosted with ritonavir), ivermectin, azithromycin and lopinavir (boosted with ritonavir) were all predicted to achieve lung concentrations over 10-fold higher than their reported EC50. This analysis was not possible for nelfinavir because insufficient data were available to calculate KpUlung but nitozoxanide and sulfadoxine were also predicted to exceed their reported EC50 by 3.1- and 1.5-fold in lung, respectively. The antiviral activity data reported to date is of variable quality and conducted under different conditions by different investigators. However, this analysis has prioritised candidates with the best chance for success in therapy or chemoprevention of Covid-19 based upon the currently available in vitro activity and human plasma pharmacokinetic data. Future studies should focus on EC90 values and discuss findings in the context of achievable exposures in humans, especially within target compartments such as the lung, in order to maximise the potential for success of proposed human clinical trials.

positive: Mechanisms of increased morbidity and mortality of SARS-CoV-2 infection in individuals with diabetes: what this means for an effective management strategy

positive: angiotensin-converting enzyme 2 3.4.17.23 EC number 3.4.17.23 Recommended name angiotensin-converting enzyme 2 Synonyms ACE <4> [12] ACE 2 <10,12,13> [74] ACE-2 <2,3,4,9> [38,68] ACE-related carboxypeptidase <9> [3] ACE2 <1,2,3,4,5,6,9,10,11,12,13> [1,2,3,5,6,9,14,15,16,17,19,20,22,25,26,30,37,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,65,66,67,68,69,70,71,72,73,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97] ACE2 homologue <2> [41] ACEH <9> [7] Ang converting enzyme 2 <10,12,13> [74] angiotensin II converting enzyme 2 <3> [81] angiotensin converting enzyme 2 <2,3,4,6,9,10,11,12,13> (<3> functions as a carboxypeptidase [41]) [14,41,43,46,47,51,55,57,58,60,63,74,78,84] angiotensin converting enzyme II <9> [95] angiotensin converting enzyme-2 <2,3,4> [38] angiotensin-converting enzyme <4,9> [22] angiotensin-converting enzyme 2 <4,8,9,10,12,13> [10,19,67,68,70,76] angiotensin-converting enzyme homolog <9> [7] angiotensin-converting enzyme homologue <9> [6] angiotensin-converting enzyme type 2 <13> [79] angiotensin-converting enzyme-2 <3,4> [37,53,97] angiotensin-converting enzyme-like protein <9> [7] angiotensin-converting enzyme-related carboxypeptidase <9> [1,6] angiotensinase <9> [4] hACE2 <3,10,13> [36,67,74] CAS registry number 328404-18-8

positive: Impact of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on COVID-19 in a western population. CARDIOVID registry ABSTRACT Introduction and objectives: Coronavirus disease (COVID-19) has been designated a global pandemic by the World Health Organization. It is unclear whether previous treatment with angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) affects the prognosis of COVID-19 patients. The aim of this study was to evaluate the clinical implications of previous treatment with ACEI/ARB on the prognosis of patients with COVID-19 infection. Methods: Single-center, retrospective, observational cohort study based on all the inhabitants of our health area. Analyses of main outcomes (mortality, heart failure, hospitalization, intensive care unit [ICU] admission, and major acute cardiovascular events [a composite of mortality and heart failure]) were adjusted by multivariate logistic regression and propensity score matching models. Results: Of the total population, 447 979 inhabitants, 965 patients (0.22%) were diagnosed with COVID-19 infection, and 210 (21.8%) were under ACEI or ARB treatment at the time of diagnosis. Treatment with ACEI/ARB (combined and individually) had no effect on mortality (OR, 0.62; 95%CI, 0.17-2.26; P = .486), heart failure (OR, 1.37; 95%CI, 0.39-4.77; P = .622), hospitalization rate (OR, 0.85; 95%CI, 0.45-1.64; P = .638), ICU admission (OR, 0.87; 95%CI, 0.30-2.50; P = .798), or major acute cardiovascular events (OR, 1.06; 95%CI, 0.39-2.83; P = .915). This neutral effect remained in a subgroup analysis of patients requiring hospitalization. Conclusions: Previous treatment with ACEI/ARB in patients with COVID-19 had no effect on mortality, heart failure, requirement for hospitalization, or ICU admission. Withdrawal of ACEI/ARB in patients testing positive for COVID-19 would not be justified, in line with current recommendations of scientific societies and government agencies.

positive: ACE2, COVID-19, and ACE Inhibitor and ARB Use during the Pandemic: The Pediatric Perspective. Potential but unconfirmed risk factors for coronavirus disease 2019 in adults and children may include hypertension, cardiovascular disease, and chronic kidney disease, as well as the medications commonly prescribed for these conditions, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers. Coronavirus binding to angiotensin-converting enzyme 2, a crucial component of the renin-angiotensin-aldosterone system, underlies much of this concern. Children are uniquely impacted by the coronavirus but the reasons are unclear. This review will highlight the relationship of coronavirus disease 2019 with hypertension, use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, and lifetime risk of cardiovascular disease from the pediatric perspective. We briefly summarize the renin-angiotensin-aldosterone system and comprehensively review the literature pertaining to the angiotensin-converting enzyme 2/angiotensin-(1-7) pathway in children and the clinical evidence for how angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers affect this important pathway. Given the importance of the angiotensin-converting enzyme 2/angiotensin-(1-7) pathway and the potential differences between adults and children, it is crucial that children are included in coronavirus-related research, as this may shed light on potential mechanisms for why children are at decreased risk of severe coronavirus disease 2019.

positive: The angiotensin-converting enzyme 2 (ACE2) receptor in the prevention and treatment of COVID-19 are distinctly different paradigms There is current debate concerning the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II type 1 receptor blockers (ARBs), for hypertension management, during COVID-19 infection. Specifically, the suggestion has been made that ACE inhibitors or ARBs could theoretically contribute to infection via increasing ACE2 receptor expression and hence increase viral load. The ACE2 receptor is responsible for binding the SAR-CoV2 viral spike and causing COVID-19 infection. What makes the argument somewhat obtuse for ACE inhibitors or ARBs is that ACE2 receptor expression can be increased by compounds that activate or increase the expression of SIRT1. Henceforth common dietary interventions, vitamins and nutrients may directly or indirectly influence the cellular expression of the ACE2 receptor. There are many common compounds that can increase the expression of the ACE2 receptor including Vitamin C, Metformin, Resveratrol, Vitamin B3 and Vitamin D. It is important to acknowledge that down-regulation or blocking the cellular ACE2 receptor will likely be pro-inflammatory and may contribute to end organ pathology and mortality in COVID-19. In conclusion from the perspective of the ACE2 receptor, COVID-19 prevention and treatment are distinctly different. This letter reflects on this current debate and suggests angiotensin-converting enzyme inhibitors and ARBs are likely beneficial during COVID-19 infection for hypertensive and normotensive patients.

positive: Ramipril in High Risk Patients with COVID-19 Abstract Background The coronavirus disease 2019 (COVID-19) is caused by SARS-CoV2 that interfaces with the renin-angiotensin-aldosterone system (RAAS) through angiotensin-converting enzyme 2 (ACE-2). This interaction has been proposed as a potential risk factor in patients treated with RAAS-inhibitors. Objectives To analyze if RAAS-inhibitors modify the risk for COVID-19. Methods RASTAVI (NCT03201185) is an ongoing randomized clinical trial randomly allocating Ramipril or control after successful transcatheter aortic valve replacement at 14 centers is Spain. We performed a non-pre-specified interim analysis to evaluate its impact on COVID-19 risk in this vulnerable population. Results As in April 1st 2020, 102 patients (50 Ramipril and 52 controls) were included in the trial. Mean age was 82.3±6.1 years, 56.9% males. Median time of Ramipril treatment was 6 months [IQR:2.9-11.4]. Eleven patients (10.8%) have been diagnosed with COVID-19 (6 in control group and 5 receiving Ramipril, HR=1.150 [95%CI: 0.351-3.768]). The risk of COVID-19 was increased in older patients (p=0.019), those with atrial fibrillation (p=0.066), lower hematocrit (p=0.084), and more comorbidities according to Society of thoracic surgeons score (p=0.065). Admission and oxygen supply was required in 4.9% (2 patients in the Ramipril and 3 in control), and 4 of them died (two in each randomized group). A higher body mass index was the only factor increasing the mortality rate (p=0.039). Conclusions In a high risk population of old patients with cardiovascular disease, randomization to Ramipril had no impact in the incidence or severity of COVID-19. This analysis supports the maintenance of RAAS-inhibitor treatment during COVID-19 crisis.

positive: Hypertension and renin-angiotensin system blockers are not associated with expression of Angiotensin Converting Enzyme 2 (ACE2) in the kidney Angiotensin converting enzyme 2 (ACE2) is the cellular entry point for severe acute respiratory syndrome coronavirus (SARS-CoV-2) - the cause of COVID-19 disease. It has been hypothesized that use of renin-angiotensin system (RAS) inhibiting medications in patients with hypertension, increases the expression of ACE2 and thereby increases the risk of COVID-19 infection and severe outcomes or death. However, the effect of RAS-inhibition on ACE2 expression in human tissues of key relevance to blood pressure regulation and COVID-19 infection has not previously been reported. We examined how hypertension, its major metabolic co-phenotypes and antihypertensive medications relate to ACE2 renal expression using information from up to 436 patients whose kidney transcriptomes were characterised by RNA-sequencing. We further validated some of the key observations in other human tissues and/or a controlled experimental model. Our data reveal increasing expression of ACE2 with age in both human lungs and the kidney. We show no association between renal expression of ACE2 and either hypertension or common types of RAS inhibiting drugs. We demonstrate that renal abundance of ACE2 is positively associated with a biochemical index of kidney function and show a strong enrichment for genes responsible for kidney health and disease in ACE2 co-expression analysis. Collectively, our data indicate that neither hypertension nor antihypertensive treatment are likely to alter individual risk of SARS-CoV-2 infection or influence clinical outcomes in COVID-19 through changes of ACE2 expression. Our data further suggest that in the absence of SARS-CoV-2 infection, kidney ACE2 is most likely nephro-protective but the age-related increase in its expression within lungs and kidneys may be relevant to the risk of SARS-CoV-2 infection.

positive: Association of Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Testing Positive for Coronavirus Disease 2019 (COVID-19) Importance: The role of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) in the setting of the coronavirus disease 2019 (COVID-19) pandemic is hotly debated. There have been recommendations to discontinue these medications, which are essential in the treatment of several chronic disease conditions, while, in the absence of clinical evidence, professional societies have advocated their continued use. Objective: To study the association between use of ACEIs/ARBs with the likelihood of testing positive for COVID-19 and to study outcome data in subsets of patients taking ACEIs/ARBs who tested positive with severity of clinical outcomes of COVID-19 (eg, hospitalization, intensive care unit admission, and requirement for mechanical ventilation). Design, Setting, and Participants: Retrospective cohort study with overlap propensity score weighting was conducted at the Cleveland Clinic Health System in Ohio and Florida. All patients tested for COVID-19 between March 8 and April 12, 2020, were included. Exposures: History of taking ACEIs or ARBs at the time of COVID-19 testing. Main Outcomes and Measures: Results of COVID-19 testing in the entire cohort, number of patients requiring hospitalizations, intensive care unit admissions, and mechanical ventilation among those who tested positive. Results: A total of 18â¯472 patients tested for COVID-19. The mean (SD) age was 49 (21) years, 7384 (40%) were male, and 12â¯725 (69%) were white. Of 18â¯472 patients who underwent COVID-19 testing, 2285 (12.4%) were taking either ACEIs or ARBs. A positive COVID-19 test result was observed in 1735 of 18â¯472 patients (9.4%). Among patients who tested positive, 421 (24.3%) were admitted to the hospital, 161 (9.3%) were admitted to an intensive care unit, and 111 (6.4%) required mechanical ventilation. Overlap propensity score weighting showed no significant association of ACEI and/or ARB use with COVID-19 test positivity (overlap propensity score-weighted odds ratio, 0.97; 95% CI, 0.81-1.15). Conclusions and Relevance: This study found no association between ACEI or ARB use and COVID-19 test positivity. These clinical data support current professional society guidelines to not discontinue ACEIs or ARBs in the setting of the COVID-19 pandemic. However, further study in larger numbers of hospitalized patients receiving ACEI and ARB therapy is needed to determine the association with clinical measures of COVID-19 severity.

positive: Immunomodulatory therapy for the management of severe COVID-19. Beyond the anti-viral therapy: A comprehensive review Severe Acute Respiratory Syndrome related to Coronavirus-2 (SARS-CoV-2), coronavirus disease-2019 (COVID-19) may cause severe illness in 20% of patients. This may be in part due to an uncontrolled immune-response to SARS-CoV-2 infection triggering a systemic hyperinflammatory response, the so-called “cytokine storm”. The reduction of this inflammatory immune-response could be considered as a potential therapeutic target against severe COVID-19. The relationship between inflammation and clot activation must also be considered. Furthermore, we must keep in mind that currently, no specific antiviral treatment is available for SARS-CoV-2. While moderate-severe forms need in-hospital surveillance plus antivirals and/or hydroxychloroquine; in severe and life-threating subsets a high intensity anti-inflammatory and immunomodulatory therapy could be a therapeutic option. However, right data on the effectiveness of different immunomodulating drugs are scarce. Herein, we discuss the pathogenesis and the possible role played by drugs such as: antimalarials, anti-IL6, anti-IL-1, calcineurin and JAK inhibitors, corticosteroids, immunoglobulins, heparins, angiotensin-converting enzyme agonists and statins in severe COVID-19.

positive: Effects of hypertension, diabetes and coronary heart disease on COVID-19 diseases severity: a systematic review and meta-analysis Background: COVID-19 patients with chronic diseases such as hypertension, diabetes and coronary heart diseases is more likely to worsen, but with mixed results for COVID-19 severity. This meta-analysis is to analyze the correlation between hypertension, diabetes, coronary heart disease and COVID-19 disease severity. Methods: Available data from PubMed, Web of Science, China National Knowledge Infrastructure Database, WanFang Database and VIP Database, were analyzed using a fixed effects model meta-analysis to derive overall odds ratios (OR) with 95% CIs. Funnel plots and Begg's were used to assess publication bias. Findings: Of 182 articles found following our initial search, we assessed 34 full-text articles, of which 9 articles with 1936 COVID-19 patients met all selection criteria for our meta-analysis. No significant heterogeneity between studies. There were significant correlations between COVID-19 severity and hypertension [OR=2.3 [95% CI (1.76, 3.00), P<0.01], diabetes [OR=2.67, 95% CI (1.91, 3.74), P<0.01], coronary heart disease [OR=2.85 [95% CI (1.68, 4.84), P<0.01]. Most of the studies in the funnel plot are on the upper part and few on the base part, and are roughly symmetrical left and right. Begg's test: hypertension (Z=-0.1, P=1.0), diabetes (Z=0.73, P=0.466), coronary heart disease (Z=0.38, P=0.707), all found no publication bias. Interpretation: Hypertension, diabetes, and coronary heart disease can affect the severity of COVID-19. It may be related to the imbalance of angiotensin-converting enzyme 2 (ACE2) and the cytokine storm induced by Glucolipid metabolic disorders (GLMD).

positive: Brief Review on COVID-19: The 2020 Pandemic Caused by SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible for the coronavirus disease of 2019 (COVID-19). First identified in Wuhan (Hubei, China) in December of 2019, it has since been declared a pandemic by the World Health Organization in March of 2020. In this study, we will provide a brief review of viral origin, identification, symptoms, transmission, diagnosis, and potential treatment strategies for the newly identified SARS-CoV-2 strain.

positive: ACEI/ARB use and risk of infection or severity or mortality of COVID-19: A systematic review and meta-analysis The effects of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) on the risk of COVID-19 infection and disease progression are yet to be investigated. The relationship between ACEI/ARB use and COVID-19 infection was systematically reviewed. To identify relevant studies that met predetermined inclusion criteria, unrestricted searches of the PubMed, Embase, and Cochrane Library databases were conducted. The search strategy included clinical date published until May 9, 2020. Twelve articles involving more than 19,000 COVID-19 cases were included. To estimate overall risk, random-effects models were adopted. Our results showed that ACEI/ARB exposure was not associated with a higher risk of COVID-19 infection (OR = 0.99; 95 % CI, 0-1.04; P = 0.672). Among those with COVID-19 infection, ACEI/ARB exposure was also not associated with a higher risk of having severe infection (OR = 0.98; 95 % CI, 0.87-1.09; P = 0.69) or mortality (OR = 0.73, 95 %CI, 0.5-1.07; P = 0.111). However, ACEI/ARB exposure was associated with a lower risk of mortality compared to those on non-ACEI/ARB antihypertensive drugs (OR = 0.48, 95 % CI, 0.29-0.81; P = 0.006). In conclusion, current evidence did not confirm the concern that ACEI/ARB exposure is harmful in patientswith COVID-19 infection. This study supports the current guidelines that discourage discontinuation of ACEIs or ARBs in COVID-19 patients and the setting of the COVID-19 pandemic.

positive: Increasing Host Cellular Receptor—Angiotensin‐Converting Enzyme 2 (ACE2) Expression by Coronavirus may Facilitate 2019‐nCoV (or SARS‐CoV‐2) Infection The ongoing outbreak of a new coronavirus (2019‐nCoV, or SARS‐CoV‐2) has caused an epidemic of the acute respiratory syndrome known as COVID‐19 in humans. SARS‐CoV‐2 rapidly spread to multiple regions of China and multiple other countries, posing a serious threat to public health. The spike (S) proteins of SARS‐CoV‐1 and SARS‐CoV‐2 may use the same host cellular receptor, angiotensin‐converting enzyme 2 (ACE2), for entering into host cells. The affinity between ACE2 and the SARS‐CoV‐2 S protein is much higher than that of ACE2 binding to the SARS‐CoV S protein, explaining why SARS‐CoV‐2 seems to be more readily transmitted from the human to human. Here, we report that ACE2 can be significantly upregulated after infection of various viruses, including SARS‐CoV‐1 and SARS‐CoV‐2, or by the stimulation with inflammatory cytokines such as interferons. We propose that SARS‐CoV‐2 may positively induce its cellular entry receptor, ACE2, to accelerate its replication and spread; high inflammatory cytokine levels increase ACE2 expression and act as high‐risk factors for developing COVID‐19, and the infection of other viruses may increase the risk of SARS‐CoV‐2 infection. Therefore, drugs targeting ACE2 may be developed for the future emerging infectious diseases caused by this cluster of coronaviruses. This article is protected by copyright. All rights reserved.

positive: Status presens of antiviral drugs and strategies: Part II: RNA VIRUSES (EXCEPT RETROVIRUSES) More than 40 compounds have been formally licensed for clinical use as antiviral drugs, and half of these are used for the treatment of HIV infections. The others have been approved for the therapy of herpesvirus (HSV, VZV, CMV), hepadnavirus (HBV), hepacivirus (HCV) and myxovirus (influenza, RSV) infections. New compounds are in clinical development or under preclinical evaluation, and, again, half of these are targeting HIV infections. Yet, quite a number of important viral pathogens (i.e. HPV, HCV, hemorrhagic fever viruses) remain in need of effective and/or improved antiviral therapies.

positive: Controversies of renin–angiotensin system inhibition during the COVID-19 pandemic The current COVID-19 pandemic is associated with unprecedented morbidity and mortality. Early reports suggested an association between disease severity and hypertension but did not account for sources of confounding. However, the responsible virus — SARS-CoV-2 — gains entry to host cells via angiotensin-converting enzyme 2 (ACE2), highlighting the need to understand the relationship between the virus and the renin–angiotensin system (RAS) and how this might be affected by RAS inhibitors.

positive: Multiple functions of angiotensin-converting enzyme 2 and its relevance in cardiovascular diseases. Angiotensin-converting enzyme 2 (ACE2) is a negative regulator of the renin-angiotensin system, and functions as the key SARS coronavirus receptor and stabilizer of neutral amino acid transporters. ACE2 catalyzes the conversion of angiotensin II to angiotensin 1-7, thereby counterbalancing ACE activity. Accumulating evidence indicates that the enzymatic activity of ACE2 has a protective role in cardiovascular diseases. Loss of ACE2 can be detrimental, as it leads to functional deterioration of the heart and progression of cardiac, renal, and vascular pathologies. Recombinant soluble human ACE2 protein has been demonstrated to exhibit beneficial effects in various animal models, including cardiovascular diseases. ACE2 is a multifunctional enzyme and thus potentially acts on other vasoactive peptides, such as Apelin, a vital regulator of blood pressure and myocardium contractility. In addition, ACE2 is structurally a chimeric protein that has emerged from the duplication of 2 genes: homology with ACE at the carboxypeptidase domain and homology with Collectrin in the transmembrane C-terminal domain. ACE2 has been implicated in the pathology of Hartnup's disease, a disorder of amino acid homeostasis, and, via its function in amino acid transport, it has been recently revealed that ACE2 controls intestinal inflammation and diarrhea, thus regulating the gut microbiome. This review summarizes and discusses the structure and multiple functions of ACE2 and the relevance of this key enzyme in disease pathogenesis.

positive: SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.

positive: Metalloproteases and Proteolytic Processing Proteolytic enzymes constitute around 2% of the human genome and are involved in all stages of cell and organism development from fertilization through to cell death. In the human genome the major classes of peptidases are represented by cysteine-, serine- and metalloenzymes, which possess a wide spectrum of substrate specificity and physiological functions. The identification of many novel peptidases from genome sequencing programmes has suggested potential new therapeutic targets. In addition, several well characterised peptidases were recently shown to possess new and unexpected biological roles in neuroinflammation, cancer and angiogenesis, cardiovascular diseases and neurodegeneration. This chapter will briefly characterize the main classes of metallopeptidases and their roles in health and disease. Particular attention will be paid to the angiotensin-converting enzyme (ACE), neprilysin (NEP) and adamalysin (ADAM) families of proteases and their pathophysiological roles with a particular emphasis on cancer and neurodegeneration. The roles and mechanisms of protein shedding which primarily involve the ADAMs family of metallopeptidases will be explained using amyloid protein precursor (APP) processing cascades as a well characterized example. The therapeutic significance of modulating (activating or inhibiting) metallopeptidase activity will be a particular focus of this chapter.

positive: The pivotal link between ACE2 deficiency and SARS-CoV-2 infection Abstract Angiotensin converting enzyme-2 (ACE2) receptors mediate the entry into the cell of three strains of coronavirus: SARS-CoV, NL63 and SARS-CoV-2. ACE2 receptors are ubiquitous and widely expressed in the heart, vessels, gut, lung (particularly in type 2 pneumocytes and macrophages), kidney, testis and brain. ACE2 is mostly bound to cell membranes and only scarcely present in the circulation in a soluble form. An important salutary function of membrane-bound and soluble ACE2 is the degradation of angiotensin II to angiotensin1-7. Consequently, ACE2 receptors limit several detrimental effects resulting from binding of angiotensin II to AT1 receptors, which include vasoconstriction, enhanced inflammation and thrombosis. The increased generation of angiotensin1-7 also triggers counter-regulatory protective effects through binding to G-protein coupled Mas receptors. Unfortunately, the entry of SARS-CoV2 into the cells through membrane fusion markedly down-regulates ACE2 receptors, with loss of the catalytic effect of these receptors at the external site of the membrane. Increased pulmonary inflammation and coagulation have been reported as unwanted effects of enhanced and unopposed angiotensin II effects via the ACE→Angiotensin II→AT1 receptor axis. Clinical reports of patients infected with SARS-CoV-2 show that several features associated with infection and severity of the disease (i.e., older age, hypertension, diabetes, cardiovascular disease) share a variable degree of ACE2 deficiency. We suggest that ACE2 down-regulation induced by viral invasion may be especially detrimental in people with baseline ACE2 deficiency associated with the above conditions. The additional ACE2 deficiency after viral invasion might amplify the dysregulation between the ‘adverse’ ACE→Angiotensin II→AT1 receptor axis and the ‘protective’ ACE2→Angiotensin1-7→Mas receptor axis. In the lungs, such dysregulation would favor the progression of inflammatory and thrombotic processes triggered by local angiotensin II hyperactivity unopposed by angiotensin1-7. In this setting, recombinant ACE2, angiotensin1-7 and angiotensin II type 1 receptor blockers could be promising therapeutic approaches in patients with SARS-CoV-2 infection.

positive: Angiotensin-Converting Enzyme 2 as the Molecular Bridge Between Epidemiologic and Clinical Features of COVID-19

positive: Angiotensin-converting enzyme 2 (ACE2) proteins of different bat species confer variable susceptibility to SARS-CoV entry The discovery of SARS-like coronavirus in bats suggests that bats could be the natural reservoir of SARS-CoV. However, previous studies indicated the angiotensin-converting enzyme 2 (ACE2) protein, a known SARS-CoV receptor, from a horseshoe bat was unable to act as a functional receptor for SARS-CoV. Here, we extended our previous study to ACE2 molecules from seven additional bat species and tested their interactions with human SARS-CoV spike protein using both HIV-based pseudotype and live SARS-CoV infection assays. The results show that ACE2s of Myotis daubentoni and Rhinolophus sinicus support viral entry mediated by the SARS-CoV S protein, albeit with different efficiency in comparison to that of the human ACE2. Further, the alteration of several key residues either decreased or enhanced bat ACE2 receptor efficiency, as predicted from a structural modeling study of the different bat ACE2 molecules. These data suggest that M. daubentoni and R. sinicus are likely to be susceptible to SARS-CoV and may be candidates as the natural host of the SARS-CoV progenitor viruses. Furthermore, our current study also demonstrates that the genetic diversity of ACE2 among bats is greater than that observed among known SARS-CoV susceptible mammals, highlighting the possibility that there are many more uncharacterized bat species that can act as a reservoir of SARS-CoV or its progenitor viruses. This calls for continuation and expansion of field surveillance studies among different bat populations to eventually identify the true natural reservoir of SARS-CoV. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00705-010-0729-6) contains supplementary material, which is available to authorized users.

positive: COVID-19 and Older Adults: What We Know Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel virus that causes COVID-19 infection, has recently emerged and caused a deadly pandemic. Studies have shown that this virus causes worse outcomes and a higher mortality rate in older adults and those with comorbidities such as hypertension, cardiovascular disease, diabetes, chronic respiratory disease, and chronic kidney disease (CKD). A significant percentage of older American adults have these diseases, putting them at a higher risk of infection. Additionally, many adults with hypertension, diabetes, and CKD are placed on angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers. Studies have shown that these medications upregulate the ACE-2 receptor, the very receptor that the SARS-CoV-2 virus uses to enter host cells. Although it has been hypothesized that this may cause a further increased risk of infection, more studies on the role of these medications in COVID-19 infections are necessary. In this review, we discuss the transmission, symptomatology, and mortality of COVID-19 as they relate to older adults, and possible treatments that are currently under investigation. J Am Geriatr Soc 68:926-929, 2020.

positive: Target Virus or Target Ourselves for COVID-19 Drugs Discovery?-Lessons learned from anti-influenzas virus therapies Abstract The COVID-19 pandemic, after it was reported in December 2019, is a highly contagious and now spreading to over 190 countries, causing a severe public health burden. Currently, there is no vaccine or specific drug to treat COVID-19, which is caused by a novel coronavirus, SARS-2-CoV. For this emergency, the FDA has approved Remdesivir and Hydroxychloroquine for treatment of COVID-19 as Emergency Use Authorization. However, even after this pandemic, COVID-19 may still have a chance to come back. Therefore, we need to come out with new strategies for drug discovery for combating COVID-19 in the future.

positive: Renin–angiotensin–aldosterone system dysregulation and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection

positive: ARB/ACEI use and severe COVID-19: a nationwide case-control study Background: Angiotensin receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACEIs) have anti-inflammatory effects. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses the membrane protein angiotensin-converting enzyme 2 (ACE2), which is increased by ARB/ACEI treatment, as a cell entry receptor. Therefore, the use of ARBs/ACEIs for COVID-19 remains controversial. Methods: A retrospective case-control study was conducted using COVID-19 patients previously diagnosed with hypertension before COVID-19 onset. The primary outcome was severe infection or all-cause mortality. Cases included ARB/ACEI use for 30 days or longer during the 6 months before COVID-19 onset. Primary controls included antihypertensive use other than ARBs/ACEIs (narrow control); secondary controls included all other hypertension patients (broad control). We investigated ARB/ACEI association with outcomes in general and by subgroups (age, sex, and presence of diabetes) using logistic regression models with propensity score matching. Findings: Of 234427 suspected COVID-19 patients we screened, 1585 hypertension patients were analyzed. In the 892 cases, 428 narrow controls, and 693 broad controls, severe infection or death occurred in 8.6%, 22.2%, and 16.7%, respectively. ARB/ACEI use was associated with a reduced risk of severe infection or death relative to the narrow control group (adjusted odds ratio [aOR] 0.43, 95% confidence interval [CI] 0.28-0.65) and broad control group (aOR 0.49, 95% CI 0.33-0.71). The association was smaller for newly diagnosed hypertension patients (aOR 0.11, 95% CI 0.03-0.42 compared to narrow control group). ARB/ACEI protective effects against severe infection or death were significantly observed in male and diabetic patients. Interpretation: ARB/ACEI use was associated with a lower risk of severe infection or mortality compared to other antihypertensives or ARB/ACEI nonuse.

positive: A Comprehensive Literature Review on the Clinical Presentation, and Management of the Pandemic Coronavirus Disease 2019 (COVID-19) Coronavirus disease 2019 (COVID-19) is a declared global pandemic. There are multiple parameters of the clinical course and management of the COVID-19 that need optimization. A hindrance to this development is the vast amount of misinformation present due to scarcely sourced manuscript preprints and social media. This literature review aims to presents accredited and the most current studies pertaining to the basic sciences of SARS-CoV-2, clinical presentation and disease course of COVID-19, public health interventions, and current epidemiological developments. The review on basic sciences aims to clarify the jargon in virology, describe the virion structure of SARS-CoV-2 and present pertinent details relevant to clinical practice. Another component discussed is the brief history on the series of experiments used to explore the origins and evolution of the phylogeny of the viral genome of SARS-CoV-2. Additionally, the clinical and epidemiological differences between COVID-19 and other infections causing outbreaks (SARS, MERS, H1N1) are elucidated. Emphasis is placed on evidence-based medicine to evaluate the frequency of presentation of various symptoms to create a stratification system of the most important epidemiological risk factors for COVID-19. These can be used to triage and expedite risk assessment. Furthermore, the limitations and statistical strength of the diagnostic tools currently in clinical practice are evaluated. Criteria on rapid screening, discharge from hospital and discontinuation of self-quarantine are clarified. Epidemiological factors influencing the rapid rate of spread of the SARS-CoV-2 virus are described. Accurate information pertinent to improving prevention strategies is also discussed. The penultimate portion of the review aims to explain the involvement of micronutrients such as vitamin C and vitamin D in COVID19 treatment and prophylaxis. Furthermore, the biochemistry of the major candidates for novel therapies is briefly reviewed and a summary of their current status in the clinical trials is presented. Lastly, the current scientific data and status of governing bodies such as the Center of Disease Control (CDC) and the WHO on the usage of controversial therapies such as angiotensin-converting enzyme (ACE) inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs) (Ibuprofen), and corticosteroids usage in COVID-19 are discussed. The composite collection of accredited studies on each of these subtopics of COVID-19 within this review will enable clarification and focus on the current status and direction in the planning of the management of this global pandemic.

positive: COVID-19, ACE2 and the Cardiovascular Consequences. The novel SARS coronavirus SARS-CoV-2 pandemic may be particularly deleterious to patients with underlying cardiovascular disease (CVD). The mechanism for SARS-CoV-2 infection is the requisite binding of the virus to the membrane-bound form of angiotensin-converting enzyme 2 (ACE2) and internalization of the complex by the host cell. Recognition that ACE2 is the co-receptor for the coronavirus has prompted new therapeutic approaches to block the enzyme or reduce its expression to prevent the cellular entry and SARS-CoV-2 infection in tissues that express ACE2 including lung, heart, kidney, brain, and gut. ACE2, however, is a key enzymatic component of the renin-angiotensin-aldosterone system (RAAS); ACE2 degrades Ang II, a peptide with multiple actions that promote CVD, and generates Ang-(1-7) which antagonizes the effects of Ang II. Moreover, experimental evidence suggests that RAAS blockade by ACE inhibitors, AT1 receptor antagonists and mineralocorticoid antagonists, as well as statins enhance ACE2 that, in part, contribute to the benefit of these regimens. In lieu of the fact that many older patients with hypertension or other CVDs are routinely treated with RAAS blockers and statins, new clinical concerns have developed regarding whether these patients are at greater risk for SARS-CoV-2 infection, whether RAAS and statin therapy should be discontinued, and the potential consequences of RAAS blockade to COVID-19-related pathologies such as acute and chronic respiratory disease. The current perspective critically examines the evidence for ACE2 regulation by RAAS blockade and statins, the cardiovascular benefits of ACE2, and whether ACE2 blockade is a viable approach to attenuate COVID-19.

positive: Renin-angiotensin-aldosterone system inhibitors and mortality in patients with hypertension hospitalized for COVID-19: a systematic review and meta-analysis Objective: The association between renin-angiotensin-aldosterone (RAAS) inhibitors and Coronavirus diseases 2019 (COVID-19) mortality is unclear. We aimed to explore the association of RAAS inhibitors, including angiotensin-converting inhibitors (ACEi) and angiotensin II receptor blockers (ARBs) with COVID-19 mortality in patients with hypertension. Methods: MEDLINE, SCOPUS, OVID, and Cochrane Library were searched for the period of January 1, 2020 to May 20, 2020. Studies reporting the association of RAAS inhibitors (ACEi and ARBs) and mortality in patients with hypertension, hospitalized for COVID-19 were extracted. Two reviewers independently extracted appropriate data of interest and assessed the risk of bias. All analyses were performed using random-effects models on log-transformed risk ratio estimates, and heterogeneity was quantified. Results: Data were collected on 2,065,805 individuals (mean age, 58.73 years; 53.4% male). Patients with hypertension taking RAAS inhibitors were 35% less likely to die from COVID-19 compared to patients with hypertension not taking RAAS inhibitors (pooled RR= 0.65, 95% Confidence Intervals (CI): 0.45-0.94). To explore the association of COVID-19 and specific classes of RAAS inhibitors, we conducted a subgroup analysis of ARBs and ACEi separately from studies that provided them. Pooled risk ratio estimates from ARBs and ACEi showed a lower but not significant risk of death from COVID-19 (RR=0.93, 95% CI: 0.70-1.22) and ACEi (RR=0.65, 95% CI: 0.32-1.30). Conclusions: In this meta-analysis, it was discovered that taking RAAS inhibitors, significantly decreased the risk of COVID-19 mortality in patients with hypertension. This indicates a potential protective role that RAAS-inhibitors may have in COVID-19 patients with hypertension.

positive: Focus on Receptors for Coronaviruses with Special Reference to Angiotensin-converting Enzyme 2 as a Potential Drug Target - A Perspective. Coronaviruses (CoVs) possess an enveloped, single, positive-stranded RNA genome which encodes for four membrane proteins, namely spike (S), envelope (E), membrane (M) and nucleocapsid (N) proteins 3-5 [1]. With regard to pathogenicity, S proteins are essential for viral entry into host cells [2, 3]. SARS-CoV binds to the angiotensin-converting enzyme (ACE)2 which is present on nonimmune cells, such as respiratory and intestinal epithelial cells, endothelial cells, kidney cells (renal tubules) and cerebral neurons and immune cells, such as alveolar monocytes/macrophages [4-6]. Of note, CD209L or liver/lymph node special intercellular adhesion molecule-3-grabbing non-integrin (SIGN) and dendritic cell (DC)-SIGN are alternative receptors for SARS-CoV but with lower affinity [7]. In the case of MERS-CoV, S proteins bind to the host cell receptor dipeptidyl peptidase 4 (DPP4 or CD26) which is broadly expressed on intestinal, alveolar, renal, hepatic and prostate cells as well as on activated leukocytes [8]. Then, viruses replicate in target cells with release of mature virions, which, in turn, invade new target cells [9]. Evidence has been provided that SARSCoV proteins are cleaved into two subunits, S1 and S2, respectively, and the amino acids 318-510 of the S1 represent the receptor-binding domain (RBD) which binds to ACE2 [10, 11]. Quite importantly, in the context of RBD there is the receptor-binding motif (RBM) (amino acids 424- 494), which accounts for complete binding to ACE2 [11]. Moreover, by means of two residues at positions 479 and 487 RBD allows virus progression and tropism [10, 11]. In the case of MERSCoV, its RBM binds to DPP4 with residues 484-567, thus, suggesting that its RBD differs from that of SARS-CoV [12, 13]. In a very recent paper, Wan and associates [14] have investigated the receptor recognition by COVID-19 (a new term to indicate the 2019-nCoV in Wuhan) on the bases of structural studies. In this respect, the sequence of COVID-19 RBM is similar to that of SARSCoV, thus, implicating that ACE2 may represent the binding receptors for COVID-19. Furthermore, gln493 residue of COVID-19 RBM seems to allow interaction with human ACE2, thus, suggesting the ability of this virus to infect human cells. According, to Wan and associates structural analysis [14], COVID-19 binds to human ACE2 with a lesser efficiency than human SARS-CoV (2002) but with higher affinity than human SARS-CoV (2003). Furthermore, same authors predicted that a single mutation at the 501 position may enhance the COVID-19 RBD binding capacity to human ACE2 and this evolution should be monitored in infected patients [14]. These predictive findings by Wan and associates [14] are confirmed by two contemporary studies by Letko and Muster [15] and Peng and associates [16]. In particular, the report by Peng and associates [16], points out the possible origin of COVID-19 from bats [16]. From a pathogenic point of view, evidence has been provided that binding of S2 to ACE2 receptor leads to its down-regulation with subsequent lung damage in the course of SARS-CoV infection [17]. Down-regulation of ACE2 causes excessive production of angiotensin (ANG) II by the related enzyme ACE with stimulation of ANG type 1a receptor (AT1R) and enhanced lung vascular permeability [18]. In particular, same authors have reported that recombinant ACE2 could attenuate severe acute lung injury in mice [18]. Moreover, Battle and associates [19] also proposed to use already available recombinant ACE2 for intercepting COVID-19 and attenuating infection. In the previous paragraphs, the presence of ACE2 on immune cells has been pointed out and, by analogy to epithelial cells, this receptor may also be down-regulated following viral entry. Therefore, in CoV-infected animal models and in infected humans further investigations are required to clarify a possible reduced expression of ACE2 on immune cells. In fact, in the course of SARS-CoV infection, a number of immune disorders have been detected. Three reports have demonstrated the ability of CoV to inhibit interferon (IFN)- production in the course of SARS acting as IFN antagonist [20-22]. In senescent Balb/c mice, depletion of T lymphocytes is associated to more severe interstitial pneumonitis and delayed clearance of SARS-CoV, thus, suggesting a protective role played by these cells [23]. In this connection, both SARS-CoV and MERS-CoV have been shown to induce T cell apoptosis, thus, aggravating the clinical course of disease [24, 25]. Quite interestingly, memory CD8+ T cells specific for SARS-CoV M and N proteins have been detected up to 11 years post-infection [26]. As far as humoral immune responsiveness is concerned, evidence has been provided that S1 subunit from MERS-CoV is highly immunogenic in mice [27]. Moreover, monoclonal antibodies have been shown to be highly neutralizing against MERS-CoV replication and endowed with post exposure effectiveness in susceptible mice [28, 29]. Human neutralizing antibodies have also been isolated from a recovered patient, thus, suggesting the role of humoral immunity in the control of the persistence of CoV in the host [30]. In particular, IgG response occurs early in infection and its prolonged production may serve for virus clearance during recovery also in view of the absence of viremia in convalescent sera from SARS patients [31]. According to current literature, severity of COVID-19 infection correlates with lymphopenia and patients who died from COVID-19 had lower lymphocyte counts when compared to survivors [32, 33]. These data suggest that lymphocyte-mediated anti-viral activity is poorly effective against COVID-19. Despite lymphopenia, evidence for an exaggerate release of proinflammatory cytokines [interleukin (IL)-1 and IL-6] has been reported in the course acute respiratory syndrome in COVID19 infected patients, thus, aggravating the clinical course of disease [34]. As recently reported, during COVID-19 pandemic in both Italy and China higher frequency of fatalities have been observed in the frail elderly population with previous comorbidities [35]. It is well known that decline of immunity occurs in ageing and, therefore, COVID-19 may gain easier access to the respiratory tract in frail elderly patients [36]. There is evidence that ACE2 protects from severe acute lung failure and operates as a negative regulator of the renin-angiotensin system (RAS) [18, 37]. It is well known that ANG II via activation of the AT1R promotes detrimental effects on the host, such as, vasoconstriction, reactive oxygen species generation, inflammation and matrix remodelling [38]. ACE2 counterbalances the noxious effects exhibited by ANG II and AT1R via activation of AT2R which arrests cell growth, inflammation and fibrosis [39]. In this framework, Gurwitz [40] proposed to use AT1R blockers, such as losartan, as a potential treatment of COVID-19 infection. In fact, losartan as well as olmesartan, used for treating hypertension in patients, were able to increase ACE2 expression after 28 days treatment of rats with myocardial infarction [41]. Then, Gurwitz suggests to evaluate severity of symptoms in COVID-19 infected patients under previous chronic treatment with AT1R blockers in comparison to COVID-19 infected patients who did not take AT1R blockers [40]. Quite interestingly, 75% of aged COVID-19 infected patients admitted to Italian hospitals had hypertension [unpublished data]. However, the putative effects of ACE-2 down-regulation on the cardiovascular system in the course of COVID-19 pandemic need more intensive studies. Taken together, these evidences suggest that CoV-induced down-regulation of ACE2 activates RAS with collateral damage to organs, such as lungs, in the course of SARS-related pneumonia. Then, putative therapeutic measures aimed at increasing ACE2 levels on respiratory epithelial cells should be taken into serious consideration. Quite interestingly, over the past few years, three key papers have demonstrated the ability of a polyphenol, resveratrol (RES), to experimentally deactivate the RAS system in maternal and post-weaning high fat diet, arterial ageing and high fat diet, respectively [42-44]. In all these experimental models, RES led to an increase of ACE2 with reduction of organ damage, such as liver steatosis and aorta media thickness and decrease of adipose tissue mass, respectively. As far as the mechanism of action of RES is concerned, this polyphenol is able to activate sirtuin (Sirt)1 [45-47]. In turn, Sirt1 down-regulates AT1R expression via ACE2 up-regulation [43, 48]. Of importance, Lin and associates [48] have demonstrated the ability of RES to in vitro inhibit MERS-CoV infection of Vero E6 cells, thus, prolonging cell survival in virtue of an anti-apoptotic mechanism. These findings suggest a direct antiviral effect exerted by RES. It would be very interestingly to evaluate the direct effects of RES on COVID-19, in vitro. The data above discussed strongly suggest, that RES, as an activators of ACE2, should be investigated in animal models of CoV-induced severe pneumonia, also taking into account the antioxidant, anti-inflammatory and immunomodulating effects exerted by polyphenols [49]. Then, successful animal studies may pave the way for RES-based human trials in COVID-infected patients. Note added in proof During the reviewing process of this perspective other related papers have been published. Hanff and associates [50] have discussed the possible association between COVID-19-associated cardiovascular mortality and dysregulation of the Renin Angiotensin System (RAS). From a pharmacologic point of view, RAS inhibition leads to upregulation of ACE2, thus, attenuating acute respiratory syndrome and myocarditis in COVID-19-infected patients. Conversely, increase in ACE2 expression may facilitate the access into the host of COVID-19, thus, aggravating the clinical picture. Such a dilemma would be solved by clinical trials based on RAS blo

positive: Renin-angiotensin system inhibitors in management of hypertension during the COVID-19 pandemic. COVID-19, which is caused by the single-stranded RNA severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), has introduced significant therapeutic dilemmas in several areas. One of these is concern regarding the use of renin-angiotensin system (RAS) inhibitors. Dysfunction of the RAS has been observed in COVID-19 patients, but whether RAS inhibitors, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor blockers (ARBs), are associated with improved or worse clinical outcomes, remains unclear. RAS inhibitors are currently widely used in the treatment of hypertension. Emerging data suggest an increased association and a heightened mortality in patients of COVID-19 with co-morbidities such as hypertension, coronary heart disease, and diabetes mellitus, particularly in the elderly. Therefore, several recently published research papers have focused on the management of hypertension during the COVID-19 pandemic, as this co-morbidity was found to be the most common in patients with coronavirus infections. SARS-CoV-2 viral surface protein is known to attach angiotensin converting enzyme-2 (ACE-2) on the cell membrane to facilitate viral entry into the cytoplasm. While the SARS-CoV-2 viral load remains the highest in upper respiratory tract of COVID-19 patients, it has also been reported in multiple sites in COVID-19, and patients not infrequently require the Intensive Care Units (ICU) admission. However, despite the theoretical concerns of possible increased ACE2 expression by RAS blockade, there is no evidence that RAS inhibitors are harmful during COVID-19 infection, and indeed they have been shown to be beneficial in some animal studies. In this review we summarise the pathophysiology of the interaction between RAS, ACEIs/ARBs inhibitors and COVID-19, and conclude, on the basis of current data, that RAS blockade should be maintained during the current coronavirus pandemic.

positive: SARS-CoV2: should inhibitors of the renin–angiotensin system be withdrawn in patients with COVID-19? ;European Heart Journal ;Oxford Academic In a rapid response published online by the British Medical Journal, Sommerstein and Gräni1 pushed forward the hypothesis that angiotensin-converting enzyme (ACE) inhibitors (ACE-Is) could act as a potential risk factor for fatal Corona virus disease 2019 (COVID-19) by up-regulating ACE2 This notion was quickly picked up by the lay press and sparked concerns among physicians and patients regarding the intake of inhibitors of the renin–angiotensin–aldosterone system (RAAS) by severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infected individuals 1 In this article, we try to shed light on what is known and unknown regarding the RAAS and SARS-CoV2 interaction We find translational evidence for diverse roles of the RAAS, which allows to formulate also the opposite hypothesis, i e that inhibition of the RAAS might be protective in COVID-19 [Truncated]

positive: The host’s angiotensin-converting enzyme polymorphism may explain epidemiological findings in COVID-19 infections

positive: Use of RAAS inhibitors and risk of clinical deterioration in COVID-19: results from an Italian cohort of 133 hypertensives BACKGROUND: The effect of chronic use of renin-angiotensin-aldosterone system (RAAS) inhibitors on the severity of COVID-19 infection is still unclear in patients with hypertension. We aimed to investigate the association between chronic use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) and COVID-19 related outcomes in hypertensive patients. METHODS: A single center study was conducted on 133 consecutive hypertensive subjects presenting to the Emergency Department with acute respiratory symptoms and/or fever who were diagnosed with COVID-19 infection between 9th and 31st March 2020. RESULTS: All patients were grouped according to their chronic antihypertensive medications (ACEIs, N=40; ARBs, N=42; not on RAAS inhibitors, N=51). There was no statistical difference between ACEIs and ARBs groups in terms of hospital admission rate, oxygen therapy and need for non-invasive ventilation. Patients chronically treated with RAAS inhibitors showed a significantly lower rate of admission to semi-intensive/intensive care units, when compared to the non-RAAS population (odds ratio [OR] 0.25, CI95% 0.09-0.66 p=0.006). Similarly, the risk of mortality was lower in the former group, although not reaching statistical significance (OR 0.56, CI95% 0.17-1.83, p=0.341). CONCLUSIONS: Our data suggest that chronic use of RAAS inhibitors does not negatively affect clinical course of COVID-19 in hypertensive patients. Further studies are needed to confirm this finding and determine whether RAAS inhibitors may have a protective effect on COVID 19-related morbidity and mortality.

positive: Analysis of the susceptibility to COVID-19 in pregnancy and recommendations on potential drug screening To analyze the susceptibility of SARS-CoV-2 in pregnancy and the drugs that can be used to treat pregnancy with COVID-19, so as to provide evidence for drug selection in clinic. By reviewing the existing literature, this paper analyzes the susceptibility of pregnant women to virus, especially to SARS-CoV-2, from the aspects of anatomical, reproductive endocrine and immune changes during pregnancy and screens effective and fetal-safe treatments from the existing drugs. The anatomical structure of the respiratory system is changed during pregnancy, and the virus transmitted by droplets and aerosols is more easily inhaled by pregnant women and is difficult to remove. Furthermore, the prognosis is worse after infection when compared with non-pregnancy women. And changes in reproductive hormones and immune systems during pregnancy collectively make them more susceptible to certain infections. More importantly, angiotensin-converting enzyme (ACE)-2, the SARS-CoV-2 receptor, has been proven highly increased during pregnancy, which may contribute to the susceptibility to SARS-CoV-2. When it comes to treatment, specific drugs for COVID-19 have not been found at present, and taking old drugs for new use in treating COVID-19 has become an emergency method for the pandemic. Particularly, drugs that show superior maternal and fetal safety are worthy of consideration for pregnant women with COVID-19, such as chloroquine, metformin, statins, lobinavir/ritonavir, glycyrrhizic acid, and nanoparticle-mediated drug delivery (NMDD), etc. Pregnant women are susceptible to COVID-19, and special attention should be paid to the selection of drugs that are both effective for maternal diseases and friendly to the fetus. However, there are still many deficiencies in the study of drug safety during pregnancy, and broad-spectrum, effective and fetal-safe drugs for pregnant women need to be developed so as to cope with more infectious diseases in the future.

positive: Interaction of severe acute respiratory syndrome-coronavirus and NL63 coronavirus spike proteins with angiotensin converting enzyme-2 Although in different groups, the coronaviruses severe acute respiratory syndrome-coronavirus (SARS-CoV) and NL63 use the same receptor, angiotensin converting enzyme (ACE)-2, for entry into the host cell. Despite this common receptor, the consequence of entry is very different; severe respiratory distress in the case of SARS-CoV but frequently only a mild respiratory infection for NL63. Using a wholly recombinant system, we have investigated the ability of each virus receptor-binding protein, spike or S protein, to bind to ACE-2 in solution and on the cell surface. In both assays, we find that the NL63 S protein has a weaker interaction with ACE-2 than the SARS-CoV S protein, particularly in solution binding, but the residues required for contact are similar. We also confirm that the ACE-2-binding site of NL63 S lies between residues 190 and 739. A lower-affinity interaction with ACE-2 might partly explain the different pathological consequences of infection by SARS-CoV and NL63.

positive: Managing hypertension during the COVID-19 pandemic

positive: Management of hypertension in COVID-19 The ACE2 receptor plays a central role in severe acute respiratory syndrome coronavirus 2 host cell entry and propagation. It has therefore been postulated that angiotensin converting enzyme inhibitors and angiotensin receptor blockers may upregulate ACE2 expression and thus increase susceptibility to infection. We suggest that alternative anti-hypertensive agents should be preferred among individuals who may be exposed to this increasingly common and potentially lethal virus.

positive: Hypertension and Diabetes Delay the Viral Clearance in COVID-19 Patients Objectives: Comorbidities have significant indications for the disease outcome of COVID-19, however which underlying diseases that contribute the most to aggravate the conditions of COVID-19 patients is still largely unknown. SARS-CoV-2 viral clearance is a golden standard for defining the recovery of COVID-19 infections. To dissect the underlying diseases that could impact on viral clearance, we enrolled 106 COVID-19 patients who were hospitalized in the Zhongnan Hospital of Wuhan University, Wuhan, China between Jan 5 and Feb 25, 2020. Methodology: We comprehensively analyzed demographic, clinical and laboratory data, as well as patient treatment records. Survival analyses with Kaplan-Meier and Cox regression modelling were employed to identify factors influencing the viral clearance negatively. Results: We found that increasing age, male gender, and angiotensin-converting enzyme 2 (ACE2) associated factors (including hypertension, diabetes, and cardiovascular diseases) adversely affected the viral clearance. Furthermore, analysis by a random forest survival model pointed out hypertension, cortisone treatment, gender, and age as the four most important variables. Conclusions: We conclude that patients at old age, males, and/or having diseases associated with high expression of ACE2 will have worse prognosis during a COVID-19 infections.

positive: Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus Spike (S) proteins of coronaviruses, including the coronavirus that causes severe acute respiratory syndrome (SARS), associate with cellular receptors to mediate infection of their target cells(1,2). Here we identify a metallopeptidase, angiotensin-converting enzyme 2 (ACE2)(3,4), isolated from SARS coronavirus (SARS-CoV)-permissive Vero E6 cells, that efficiently binds the S1 domain of the SARS-CoV S protein. We found that a soluble form of ACE2, but not of the related enzyme ACE1, blocked association of the S1 domain with Vero E6 cells. 293T cells transfected with ACE2, but not those transfected with human immunodeficiency virus-1 receptors, formed multinucleated syncytia with cells expressing S protein. Furthermore, SARS-CoV replicated efficiently on ACE2-transfected but not mock-transfected 293T cells. Finally, anti-ACE2 but not anti-ACE1 antibody blocked viral replication on Vero E6 cells. Together our data indicate that ACE2 is a functional receptor for SARS-CoV. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/nature02145) contains supplementary material, which is available to authorized users.

positive: Receptor recognition and cross-species infections of SARS coronavirus Abstract Receptor recognition is a major determinant of the host range, cross-species infections, and pathogenesis of the severe acute respiratory syndrome coronavirus (SARS-CoV). A defined receptor-binding domain (RBD) in the SARS-CoV spike protein specifically recognizes its host receptor, angiotensin-converting enzyme 2 (ACE2). This article reviews the latest knowledge about how RBDs from different SARS-CoV strains interact with ACE2 from several animal species. Detailed research on these RBD/ACE2 interactions has established important principles on host receptor adaptations, cross-species infections, and future evolution of SARS-CoV. These principles may apply to other emerging animal viruses, including the recently emerged Middle East respiratory syndrome coronavirus (MERS-CoV). This paper forms part of a series of invited articles in Antiviral Research on “From SARS to MERS: 10years of research on highly pathogenic human coronaviruses”.

positive: COVID and the Renin-Angiotensin System: Are Hypertension or Its Treatments Deleterious?

positive: Renin-angiotensin system inhibitors in management of hypertension during the COVID-19 pandemic COVID-19, which is caused by the single-stranded RNA severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), has introduced significant therapeutic dilemmas in several areas. One of these is concern regarding the use of renin-angiotensin system (RAS) inhibitors. Dysfunction of the RAS has been observed in COVID-19 patients, but whether RAS inhibitors, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor blockers (ARBs), are associated with improved or worse clinical outcomes, remains unclear. RAS inhibitors are currently widely used in the treatment of hypertension. Emerging data suggest an increased association and a heightened mortality in patients of COVID-19 with co-morbidities such as hypertension, coronary heart disease, and diabetes mellitus, particularly in the elderly. Therefore, several recently published research papers have focused on the management of hypertension during the COVID-19 pandemic, as this co-morbidity was found to be the most common in patients with coronavirus infections. SARS-CoV-2 viral surface protein is known to attach angiotensin converting enzyme-2 (ACE-2) on the cell membrane to facilitate viral entry into the cytoplasm. While the SARS-CoV-2 viral load remains the highest in upper respiratory tract of COVID-19 patients, it has also been reported in multiple sites in COVID-19, and patients not infrequently require the Intensive Care Units (ICU) admission. However, despite the theoretical concerns of possible increased ACE2 expression by RAS blockade, there is no evidence that RAS inhibitors are harmful during COVID-19 infection, and indeed they have been shown to be beneficial in some animal studies. In this review we summarise the pathophysiology of the interaction between RAS, ACEIs/ARBs inhibitors and COVID-19, and conclude, on the basis of current data, that RAS blockade should be maintained during the current coronavirus pandemic.

positive: Insertion/Deletion Polymorphism of Angiotensin Converting Enzyme Gene in Kawasaki Disease Polymorphism of angiotensin converting enzyme (ACE) gene is reported to be associated with ischemic heart disease, hypertrophic cardiomyopathy, and idiopathic dilated cardiomyopathy. In this study, we investigated the relationship between Kawasaki disease and insertion/deletion polymorphism of ACE gene. Fifty five Kawasaki disease patients and 43 healthy children were enrolled. ACE genotype was evaluated from each of the subjects' DNA fragments through polymerase chain reaction (PCR). Frequencies of ACE genotypes (DD, ID, II) were 12.7%, 60.0%, 27.3% in Kawasaki group, and 41.9%, 30.2%, 27.9% in control group respectively, indicating low rate of DD and high rate of ID genotype among Kawasaki patients (p<0.01). Comparing allelic (I, D) frequencies, I allele was more prevalent in Kawasaki group than in control group (57.3% vs. 43.0%, p<0.05). In Kawasaki group, both genotype and allelic frequencies were not statistically different between those with coronary dilatations and those without. ACE gene I/D polymorphism is thought to be associated with Kawasaki disease but not with the development of coronary dilatations.

positive: ACE2, Much More Than Just a Receptor for SARS-COV-2 The rapidly evolving pandemic of severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection worldwide cost many lives. The angiotensin converting enzyme-2 (ACE-2) has been identified as the receptor for the SARS-CoV-2 viral entry. As such, it is now receiving renewed attention as a potential target for anti-viral therapeutics. We review the physiological functions of ACE2 in the cardiovascular system and the lungs, and how the activation of ACE2/MAS/G protein coupled receptor contributes in reducing acute injury and inhibiting fibrogenesis of the lungs and protecting the cardiovascular system. In this perspective, we predominantly focus on the impact of SARS-CoV-2 infection on ACE2 and dysregulation of the protective effect of ACE2/MAS/G protein pathway vs. the deleterious effect of Renin/Angiotensin/Aldosterone. We discuss the potential effect of invasion of SARS-CoV-2 on the function of ACE2 and the loss of the protective effect of the ACE2/MAS pathway in alveolar epithelial cells and how this may amplify systemic deleterious effect of renin-angiotensin aldosterone system (RAS) in the host. Furthermore, we speculate the potential of exploiting the modulation of ACE2/MAS pathway as a natural protection of lung injury by modulation of ACE2/MAS axis or by developing targeted drugs to inhibit proteases required for viral entry.

positive: Risk of severe COVID-19 in hypertensive patients treated with renin-angiotensin-aldosterone system inhibitors: Abstract Introduction There is controversy concerning the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II type-I receptor blockers (ARB) for treating hypertensive patients with Covid-19. It has been hypothesized that these drugs might increase the risk of severe Covid-19, but some authors suggested that blocking the renin-angiotensin system might actually decrease this risk. Methods Retrospective cohort study of all the consecutive hypertensive patients with confirmed SARS-CoV-2 infection in a health area. The outcome variable was hospitalization because of severe Covid-19. Results 539 subjects were diagnosed of SARS-CoV-2 infection. Of these, 157 (29.1%) had hypertension and were included in the study. Sixty-nine cases (43.9%) were hospitalized because of severe Covid-19. In multivariable analysis older age, diabetes and hypertensive myocadiopathy were related to a higher risk of hospital admission. ARB treatment was associated with a significantly lower risk of hospitalization (HR: 0.29, 95% CI: 0.10 – 0.88). A similar albeit not significant trend was observed for ACEI. Conclusion ARB or ACEI treatment was not associated with a worse clinical outcome in consecutive hypertensive patients infected by SARS-CoV-2.

positive: [2019 Novel coronavirus, renin-angiotension system imbalance and coronavirus disease 2019] 2019 Novel coronavirus (2019-nCoV) destroys angiotensin converting enzyme 2 (ACE2) and breaks the balance of renin-angiotension system (RAS) by interacting with ACE2. The imbalance of RAS takes part in the development of organ injury of different systems through pro-inflammation, oxidative stress, cell proliferation and so on. 2019-nCoV not only attacks the lung, but also influences many other systems. It is speculated that RAS imbalance plays an important role in the development of multi-organ dysfunction caused by 2019-nCoV, and the usage of angiotensin converting enzyme inhibitor/angiotensin II receptor blocker (ACEI/ARB) may become a new treatment of 2019-nCoV-related organ injury. Further studies are need to confirm the relationship between coronavirus infection, multi-organ injury and RAS imbalance.

positive: Residues affecting the chloride regulation and substrate selectivity of the angiotensin‐converting enzymes (ACE and ACE2) identified by site‐directed mutagenesis Angiotensin‐converting enzyme (ACE) and its homologue angiotensin‐converting enzyme 2 (ACE2) are critical counter‐regulatory enzymes of the renin–angiotensin system, and have been implicated in cardiac function, renal disease, diabetes, atherosclerosis and acute lung injury. Both ACE and ACE2 have catalytic activity that is chloride sensitive and is caused by the presence of the CL1 and CL2 chloride‐binding sites in ACE and the CL1 site in ACE2. The chloride regulation of activity is also substrate dependent. Site‐directed mutagenesis was employed to elucidate which of the CL1 and CL2 site residues are responsible for chloride sensitivity. The CL1 site residues Arg186, Trp279 and Arg489 of testicular ACE and the equivalent ACE2 residues Arg169, Trp271 and Lys481 were found to be critical to chloride sensitivity. Arg522 of testicular ACE was also confirmed to be vital to the chloride regulation mediated by the CL2 site. In addition, Arg514 of ACE2 was identified as a residue critical to substrate selectivity, with the R514Q mutant, relative to the wild‐type, possessing a fourfold greater selectivity for the formation of the vasodilator angiotensin‐(1–7) from the vasoconstrictor angiotensin II. The enhancement of angiotensin II cleavage by R514Q ACE2 was a result of a 2.5‐fold increase in V (max) compared with the wild‐type. Inhibition of ACE2 was also found to be chloride sensitive, as for testicular ACE, with residues Arg169 and Arg514 of ACE2 identified as influencing the potency of the ACE2‐specific inhibitor MLN‐4760. Consequently, important insights into the chloride sensitivity, substrate selectivity and inhibition of testicular ACE and ACE2 were elucidated.

positive: Authors’ reply to correspondence in response to “Will children reveal their secret? The coronavirus dilemma” The role of ACE2 receptor in SARS-CoV-2 infection and in COVID-19 outcomes is still debated, especially in children.

positive: COVID-19 presenting as stroke Abstract Objective Acute stroke remains a medical emergency even during the COVID-19 pandemic. Most patients with COVID-19 present with constitutional and respiratory symptoms, some patients present with atypical symptoms including gastrointestinal, cardiovascular, or neurological symptoms. Here we present a series of four COVID-19 patients with acute stroke as a presenting symptom. Methods We searched the hospital databases for patients presenting with acute strokes and suspected COVID-19 features. All patients that had imaging confirmed strokes and PCR confirmed COVID-19 were included in the study. Patients admitted to the hospital with PCR confirmed COVID-19 disease whose hospital course was complicated with acute stroke while inpatient were excluded from the study. Retrospective patient data were obtained from electronic medical records. Informed consent was obtained. Results We identified four patients presenting with imaging confirmed acute strokes and PCR confirmed SARS-CoV-2 infection. We elucidate the clinical characteristics, imaging findings, and the clinical course. Conclusions Timely assessment and hyperacute treatment is the key to minimize mortality and morbidity of patients with acute stroke. Stroke teams should be wary of the fact that COVID-19 patients can present with cerebrovascular accidents and dawn appropriate personal protective equipment in every suspected patient. Further studies are urgently needed for a comprehensive understanding of the neurological pathology of COVID-19 and its effects on the nervous system.

positive: Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers and Outcome of COVID-19 : A Systematic Review and Meta-analysis Importace: There is conflicting evidence about the role of angiotensin converting enzymes inhibitors (ACEIs) and angiotensin receptors blockers (ARBs) in the pathogenesis and outcome of patients infected with acute severe respiratory syndrome coronavirus 2 (SASR-CoV-2) virus and growing public concern. Methods: We systematically reviewed the literature and performed a meta-analysis using inverse variance random effect models including all studies that evaluate the role of ACEIs/ARBs and reported adjusted odds ratio. Results: Nine studies met our eligibility criteria that enrolled a population of 58615 patients infected with SASR-CoV-2. Prior use of ACEIs/ARBs were associated with significant reduction of inpatient mortality among infected patients with SASR-CoV-2, adjusted odds ratio from 4 studies 0.33, 95% confidence interval ( 0.22,0.49) with zero in between studies heterogeneity and with significant reduction of critical or fatal outcome , pooled adjusted odds ratio from 5 studies 0.32,95% confidence interval ( 0.22,0.46) with no in between studies heterogeneity. Conclusion: Our findings suggest that prior use ACEIs /ARBs is associated with a decreased risk of death or critical outcome among SASR-CoV-2 infected patients.This findings is limited by the observational nature of included studies.However, it provides a reassurance to the public not to stop prescribed ACEIs /ARBs due to fear of severe COVID-19. It also calls upon investigators and ethics committee to reconsider the ongoing randomized trials of discontinuation of these drugs.

positive: The sweeter side of ACE2: Physiological evidence for a role in diabetes Diabetes mellitus is a growing problem in all parts of the world. Both clinical trials and animal models of type I and type II diabetes have shown that hyperactivity of angiotensin-II (Ang-II) signaling pathways contribute to the development of diabetes and diabetic complications. Of clinical relevance, blockade of the renin–angiotensin system prevents new-onset diabetes and reduces the risk of diabetic complications. Angiotensin-converting enzyme (ACE) 2 is a recently discovered mono-carboxypeptidase and the first homolog of ACE. It is thought to inhibit Ang-II signaling cascades mostly by cleaving Ang-II to generate Ang-(1−7), which effects oppose Ang-II and are mediated by the Mas receptor. The enzyme is present in the kidney, liver, adipose tissue and pancreas. Its expression is elevated in the endocrine pancreas in diabetes and in the early phase during diabetic nephropathy. ACE2 is hypothesized to act in a compensatory manner in both diabetes and diabetic nephropathy. Recently, we have shown the presence of the Mas receptor in the mouse pancreas and observed a reduction in Mas receptor immuno-reactivity as well as higher fasting blood glucose levels in ACE2 knockout mice, indicating that these mice may be a new model to study the role of ACE2 in diabetes. In this review we will examine the role of the renin–angiotensin system in the physiopathology and treatment of diabetes and highlight the potential benefits of the ACE2/Ang-(1−7)/Mas receptor axis, focusing on recent data about ACE2.

positive: Structural modeling of 2019-novel coronavirus (nCoV) spike protein reveals a proteolytically-sensitive activation loop as a distinguishing feature compared to SARS-CoV and related SARS-like coronaviruses The 2019 novel coronavirus (2019-nCoV) is currently causing a widespread outbreak centered on Hubei province, China and is a major public health concern. Taxonomically 2019-nCoV is closely related to SARS-CoV and SARS-related bat coronaviruses, and it appears to share a common receptor with SARS-CoV (ACE-2). Here, we perform structural modeling of the 2019-nCoV spike glycoprotein. Our data provide support for the similar receptor utilization between 2019-nCoV and SARS-CoV, despite a relatively low amino acid similarity in the receptor binding module. Compared to SARS-CoV, we identify an extended structural loop containing basic amino acids at the interface of the receptor binding (S1) and fusion (S2) domains, which we predict to be proteolytically-sensitive. We suggest this loop confers fusion activation and entry properties more in line with MERS-CoV and other coronaviruses, and that the presence of this structural loop in 2019-nCoV may affect virus stability and transmission.

positive: Warning Against the Use of Anti-Inflammatory Medicines to Cure COVID-19: Building Castles in the Air

positive: Association between renin–angiotensin system inhibitors and COVID-19 complications AIMS: To describe the characteristics of patients hospitalized with COVID-19 (including their long-term at-home medication use), and compare them with regard to the course of the disease. To assess the association between renin–angiotensin system inhibitors (RASIs) and disease progression and critical outcomes. METHODS AND RESULTS: All consecutive hospitalized patients with laboratory-confirmed COVID-19 in a university hospital in Amiens (France) were included in this study. The primary composite endpoint was admission to an intensive care unit (ICU) or death before ICU admission. Univariable and multivariable logistic regression models were used to identify factors associated with the composite endpoint. Between 28 February 2020 and 30 March 2020, a total of 499 local patients tested positive for SARS-CoV-2. Of these, 231 were not hospitalized {males 33%; median [interquartile range (IQR)] age: 44 (32–54)}, and 268 were hospitalized [males 58%; median (IQR) age: 73 (61–84)]. A total of 116 patients met the primary endpoint: 47 died before ICU admission, and 69 were admitted to the ICU. Patients meeting the primary endpoint were more likely than patients not meeting the primary endpoint to have coronary heart disease and to have been taking RASIs; however, the two subsets of patients did not differ with regard to median age. After adjustment for other associated variables, the risk of meeting the composite endpoint was 1.73 times higher (odds ratio 1.73, 95% confidence interval 1.02–2.93) in patients treated at baseline with a RASI than in patients not treated with this drug class. This association was confirmed when the analysis was restricted to patients treated with antihypertensive agents. CONCLUSIONS: We highlighted a potential safety signal for RASIs, the long-term use of which was independently associated with a higher risk of severe COVID-19 and a poor outcome. Due to the widespread use of this important drug class, formal proof based on clinical trials is needed to better understand the association between RASIs and complications of COVID-19.

positive: Hypokalemia and Clinical Implications in Patients with Coronavirus Disease 2019 (COVID-19) BACKGROUND: SARS-CoV-2 has caused a series of COVID-19 globally. SARS-CoV-2 binds angiotensin I converting enzyme 2 (ACE2) of renin-angiotensin system (RAS) and causes prevalent hypokalemia METHODS: The patients with COVID-19 were classified into severe hypokalemia, hypokalemia, and normokalemia group. The study aimed to determine the relationship between hypokalemia and clinical features, the underlying causes and clinical implications of hypokalemia. RESULTS: By Feb 15, 2020, 175 patients with COVID-19 (92 women and 83 men; median age, 46 [IQR, 34-54] years) were admitted to hospital in Wenzhou, China, consisting 39 severe hypokalemia-, 69 hypokalemia-, and 67 normokalemia patients. Gastrointestinal symptoms were not associated with hypokalemia among 108 hypokalemia patients (P>0.05). Body temperature, CK, CK-MB, LDH, and CRP were significantly associated with the severity of hypokalemia (P<0.01). 93% of severe and critically ill patients had hypokalemia which was most common among elevated CK, CK-MB, LDH, and CRP. Urine K+ loss was the primary cause of hypokalemia. severe hypokalemia patients was given 3 g/day, adding up to an average of 34 (SD=4) g potassium during hospital stay. The exciting finding was that patients responded well to K+ supplements when they were inclined to recovery. CONCLUSIONS: Hypokalemia is prevailing in patients with COVID-19. The correction of hypokalemia is challenging because of continuous renal K+ loss resulting from the degradation of ACE2. The end of urine K+ loss indicates a good prognosis and may be a reliable, in-time, and sensitive biomarker directly reflecting the end of adverse effect on RAS system.

positive: Sex-Specific Modulation of Blood Pressure and the Renin-Angiotensin System by ACE (Angiotensin-Converting Enzyme) 2 We showed ACE (angiotensin-converting enzyme) 2 is higher in the kidney of male compared with female mice. To further investigate this sex difference, we examined the role of ACE2 in Ang-[1-8] (angiotensin [1-8])-induced hypertension and regulation of the renin-angiotensin system in the kidney of WT (wild type) and Ace2 KO (knockout) mice. Mean arterial pressure rose faster in WT male than WT female mice after Ang-[1-8] infusion. This sex difference was attenuated in ACE2 KO mice. Ang-[1-8] infusion reduced glomerular AT1R (angiotensin type 1 receptor) binding in WT female mice by 30%, and deletion of Ace2 abolished this effect. In contrast, Ang-[1-8] infusion increased glomerular AT1R binding in WT male mice by 1.2-fold, and this effect of Ang-[1-8] persisted in Ace2 KO male mice (1.3-fold). ACE2 also had an effect on renal protein expression of the neutral endopeptidase NEP (neprilysin), the enzyme that catabolizes Ang-[1-10] (angiotensin [1-10]), the precursor of Ang-[1-8]. Ang-[1-8] infusion downregulated NEP protein expression by 20% in WT male, whereas there was a slight increase in NEP expression in WT female mice. Deletion of Ace2 resulted in lowered NEP expression after Ang-[1-8] infusion in both sexes. These findings suggest sex-specific ACE2 regulation of the renin-angiotensin system contributes to female protection from Ang-[1-8]-induced hypertension. These findings have ramifications for the current coronavirus disease 2019 (COVID-19) pandemic, especially in hypertension since ACE2 is the SARS-CoV-2 receptor and hypertension is a major risk factor for poor outcomes.

positive: Cardiovascular Complications in Patients with COVID-19: Consequences of Viral Toxicities and Host Immune Response PURPOSE OF REVIEW: Coronavirus disease of 2019 (COVID-19) is a cause of significant morbidity and mortality worldwide. While cardiac injury has been demonstrated in critically ill COVID-19 patients, the mechanism of injury remains unclear. Here, we review our current knowledge of the biology of SARS-CoV-2 and the potential mechanisms of myocardial injury due to viral toxicities and host immune responses. RECENT FINDINGS: A number of studies have reported an epidemiological association between history of cardiac disease and worsened outcome during COVID infection. Development of new onset myocardial injury during COVID-19 also increases mortality. While limited data exist, potential mechanisms of cardiac injury include direct viral entry through the angiotensin-converting enzyme 2 (ACE2) receptor and toxicity in host cells, hypoxia-related myocyte injury, and immune-mediated cytokine release syndrome. Potential treatments for reducing viral infection and excessive immune responses are also discussed. SUMMARY: COVID patients with cardiac disease history or acquire new cardiac injury are at an increased risk for in-hospital morbidity and mortality. More studies are needed to address the mechanism of cardiotoxicity and the treatments that can minimize permanent damage to the cardiovascular system.

positive: Risks of ACE Inhibitor and ARB Usage in COVID-19: Evaluating the Evidence Concerns have been raised regarding the safety of angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in patients with coronavirus disease of 2019 (COVID-19), based on the hypothesis that such medications may raise expression of ACE2, the receptor for severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). We conducted a literature review of studies (n = 12) in experimental animals and human subjects (n = 12) and evaluated the evidence regarding the impact of administration of ACEIs and ARBs on ACE2 expression. We prioritized studies that assessed ACE2 protein expression data, measured directly or inferred from ACE2 activity assays. The findings in animals are inconsistent with respect to an increase in ACE2 expression in response to treatment with ACEIs or ARBs. Control/sham animals show little to no effect in the plurality of studies. Those studies that report increases in ACE2 expression tend to involve acute injury models and/or higher doses of ACEIs or ARBs than are typically administered to patients. Data from human studies overwhelmingly imply that administration of ACEIs/ARBs does not increase ACE2 expression. Available evidence, in particular, data from human studies, does not support the hypothesis that ACEI/ARB use increases ACE2 expression and the risk of complications from COVID-19. We conclude that patients being treated with ACEIs and ARBs should continue their use for approved indications.

positive: Angiotensin-converting enzyme (ACE1, ACE2) gene variants are associated with COVID19 severity depending on the hypertension status. Background: The Angiotensin system is implicated in the pathogenesis of COVID19. First, ACE2 is the cellular receptor for SARS-COv-2, and expression of the ACE2 gene could regulate the individuals susceptibility to infection. In addition, the balance between ACE1 and ACE activity has been implicated in the pathogenesis of respiratory diseases and could play a role in the severity of COVID19. Functional ACE1 and ACE2 gene polymorphisms have been associated with the risk of cardiovascular and pulmonary diseases, and could thus also contribute to the outcome of COVID19. Methods: We studied 204 COVID19 patients (137 non-severe and 67 severe-ICU cases) and 536 age-matched controls. The ACE1 indel and ACE2 rs2285666 polymorphism were determined. Variables frequencies were compared between the groups by logistic regression. We also sequenced the ACE2 coding nucleotides in a group of patients. Results: Severe COVID19 was associated with hypertension male gender (p<0.001), hypertension (p=0.006), hypercholesterolaemia (p=0.046), and the ACE1-DD genotype (p=0.049). In the multiple logistic regression hypertension (p=0.02, OR=2.26, 95CI=1.12-4.63) and male gender (p=0.002; OR=3.15, 95CI=1.56-6.66) remained as independent significant predictors of severity. The ACE2 polymorphism was not associated with the disease outcome. The ACE2 sequencing showed no coding sequence variants that could explain an increased risk of developing COVID19. Conclusions: Adverse outcome of COVID19 was associated with male gender, hypertension, hypercholesterolemia and the ACE1 genotype. The ACE1-indel was a significant risk factor for severe COVID19, but the effect was dependent on the hypertensive status.

positive: Risk of Covid-19 with renin-angiotensin-aldosterone system medications

positive: TACE antagonists blocking ACE2 shedding caused by the spike protein of SARS-CoV are candidate antiviral compounds Abstract Because outbreaks of severe acute respiratory syndrome coronavirus (SARS-CoV) might reemerge, identifying antiviral compounds is of key importance. Previously, we showed that the cellular factor TNF-α converting enzyme (TACE), activated by the spike protein of SARS-CoV (SARS-S protein), was positively involved in viral entry, implying that TACE is a possible target for developing antiviral compounds. To demonstrate this possibility, we here tested the effects of TACE inhibitors on viral entry. In vitro and in vivo data revealed that the TACE inhibitor TAPI-2 attenuated entry of both pseudotyped virus expressing the SARS-S protein in a lentiviral vector backbone and infectious SARS-CoV. TAPI-2 blocked both the SARS-S protein-induced shedding of angiotensin-converting enzyme 2 (ACE2), a receptor of SARS-CoV, and TNF-α production in lung tissues. Since the downregulation of ACE2 by SARS-S protein was proposed as an etiological event in the severe clinical manifestations, our data suggest that TACE antagonists block SARS-CoV infection and also attenuate its severe clinical outcome.

positive: ACE2 expression by colonic epithelial cells is associated with viral infection, immunity and energy metabolism Respiratory disease caused by the 2019 novel coronavirus (2019-nCoV) pneumonia first emerged in Wuhan, Hubei Province, China, in December 2019 and spread rapidly to other provinces and other countries. Angiotensin-converting enzyme 2 (ACE2) is the receptor for SARS-CoV and has been suggested to be also the receptor for 2019-nCoV. Paradoxically, ACE2 expression in the lung protects mice from SARS-CoV spike protein induced lung injury by attenuating the renin-angiotensin system. In the intestine, ACE2 also suppresses intestinal inflammation by maintaining amino acid homeostasis, antimicrobial peptide expression and ecology of the gut microbiome. Upon analysis of single cell-RNA sequencing data from control subjects and those with colitis or inflammatory bowel disease (IBD), we found that ACE2 expression in the colonocytes was positively associated with genes regulating viral infection, innate and cellular immunity, but was negatively associated with viral transcription, protein translation, humoral immunity, phagocytosis and complement activation. In summary, we suggest that ACE2 may play dual roles in mediating the susceptibility and immunity of 2019-nCoV infection.

positive: Elucidating the differences in the molecular mechanism of receptor binding between 2019-nCoV and the SARS-CoV viruses using computational tools The outbreak of the 2019-nCoV coronavirus causing severe acute respiratory syndrome which can be fatal, especially in elderly population, has been declared a pandemic by the World Health Organization. Many biotechnology laboratories are rushing to develop therapeutic antibodies and antiviral drugs for treatment of this viral disease. The viral CoV spike (S) glycoprotein is one of the main targets for pharmacological intervention. Its receptor-binding domain (RBD) interacts with the human ACE2 receptor ensuring the entry of the viral genomes into the host cell. In this work, we report on the differences in the binding of the RBD of the previous coronavirus SARS-CoV and of the newer 2019-nCoV coronavirus to the human ACE2 receptor using atomistic molecular dynamics techniques. Our results show major mutations in the 2019-nCoV RBD with respect to the SARS-CoV RBD occurring at the interface of RBD-ACE2 complex. These mutations make the 2019-nCoV RBD protein backbone much more flexible, hydrophobic interactions are reduced and additional polar/charged residues appear at the interface. We observe that higher flexibility of the 2019-nCoV RBD with respect to the SARS-CoV RBD leads to a bigger binding interface between the 2019-nCoV RBD and ACE2 and to about 20% more contacts between them in comparison with SARS-CoV. Taken together, the 2019-nCoV RBD shows more stable binding interface and higher binding affinity for the ACE2 receptor. The mutations not only stabilize the binding interface, they also lead to overall more stable 2019-nCoV RBD protein structure, even far from the binding interface. Our results on the molecular differences in the binding between the two viruses can provide important inputs for development of appropriate antiviral treatments of the new viruses, addressing the necessity of ongoing pandemics.

positive: Genetic Profiles in Pharmacogenes Indicate Personalized Drug Therapy for COVID-19 Background: The coronavirus disease 2019 (COVID-19) has become a global pandemic currently. Many drugs showed potential for COVID-19 therapy. However, genetic factors which can lead to different drug efficiency and toxicity among populations are still undisclosed in COVID-19 therapy. Methods: We selected 67 potential drugs for COVID-19 therapy (DCTs) from clinical guideline and clinical trials databases. 313 pharmaco-genes related to these therapeutic drugs were included. Variation information in 125,748 exomes were collected for racial differences analyses. The expression level of pharmaco-genes in single cell resolution was evaluated from single-cell RNA sequencing (scRNA-seq) data of 17 healthy adults. Results: Pharmacogenes, including CYP3A4, ABCB1, SLCO1B1, ALB, CYP3A5, were involved in the process of more than multi DCTs. 224 potential drug-drug interactions (DDI) of DCTs were predicted, while 112 of them have been reported. Racial discrepancy of common nonsynonymous mutations was found in pharmacogenes including: VDR, ITPA, G6PD, CYP3A4 and ABCB1 which related to DCTs including ribavirin, -interferon, chloroquine and lopinavir. Moreover, ACE2, the target of 2019-nCoV, was only found in parts of lung cells, which makes drugs like chloroquine that prevent virus binding to ACE2 more specific than other targeted drugs such as camostat mesylate. Conclusions: At least 17 drugs for COVID-19 therapy with predictable pharmacogenes should be carefully utilized in risk races which are consisted of more risk allele carriers. At least 29 drugs with potential of DDIs are reported to be affected by other DDIs, they should be replaced by similar drugs without interaction if it is possible. Drugs which specifically targeted to infected cells with ACE2 such as chloroquine are preferred in COVID-19 therapy.

positive: SARS-CoV-2 (COVID 19) Infection in Hypertensive Patients and in Patients With Cardiac Disease COVID 19, caused by the SARS-CoV-2 virus, a newly discovered coronavirus, has caused the global pandemic of early 2020. The first case was described in December 2019 in Wuhan, China, and by March 2020, most countries around the world have put in place some of the strictest restrictions seen in decades in order to slow down the spread of the disease. Patients with pre-existing hypertension and cardiovascular comorbidities were reported to be at an increased risk of serious infections caused by SARS-CoV-2. Considering that those are among the most common chronic medical conditions in the Western world, the potential impact of it is huge. The proposed mechanism behind those associations is the expression of angiotensin converting enzyme II (ACE II) in those patients. Furthermore, the association between ACE inhibitors/AR blockers, which are among the most frequently prescribed medications, and serious cases of COVID 19 has been studied with the same mechanism in mind. The reports on the association between hypertension and COVID 19 morbidity and mortality are less clear, and the International Society of Hypertension even claims that there is none. The reports on the association between heart failure or coronary disease and COVID 19 are more uniform, and all seem to point to a greater risk from serious infections faced by patients with those comorbidities. A significant effort will need to be invested by the scientific community into finding strategies for protecting those patients from contracting the virus in the first place and then, once infected, into developing management plans aimed at preserving cardiac function as much as possible.

positive: Recent discovery and development of inhibitors targeting coronaviruses Human coronaviruses (CoVs) are enveloped viruses with a positive-sense single-stranded RNA genome. Currently, six human CoVs have been reported including human coronavirus 229E (HCoV-229E), OC43 (HCoV-OC43), NL63 (HCoV-NL63), HKU1 (HCoV-HKU1), severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV), and MiddleEast respiratory syndrome (MERS) coronavirus (MERS-CoV). They cause moderate to severe respiratory and intestinal infections in humans. In this review, we focus on recent advances in the research and development of small-molecule anti-human coronavirus therapies targeting different stages of the CoV life cycle.

positive: Computational View toward the Inhibition of SARS-CoV-2 Spike Glycoprotein and the 3CL Protease Since the outbreak of the 2019 novel coronavirus disease (COVID-19), the medical research community is vigorously seeking a treatment to control the infection and save the lives of severely infected patients. The main potential candidates for the control of viruses are virally targeted agents. In this short letter, we report our calculations on the inhibitors for the SARS-CoV-2 3CL protease and the spike protein for the potential treatment of COVID-19. The results show that the most potent inhibitors of the SARS-CoV-2 3CL protease include saquinavir, tadalafil, rivaroxaban, sildenafil, dasatinib, etc. Ergotamine, amphotericin b, and vancomycin are most promising to block the interaction of the SARS-CoV-2 S-protein with human ACE-2.

positive: Marked Up-Regulation of ACE2 in Hearts of Patients with Obstructive Hypertrophic Cardiomyopathy: Implications for SARS-CoV-2-Mediated COVID-19 Abstract Objective To explore the transcriptomic differences between patients with hypertrophic cardiomyopathy (HCM) and controls. Patients and Methods RNA was extracted from cardiac tissue flash frozen at therapeutic surgical septal myectomy for 106 patients with HCM and from 39 healthy donor hearts. Expression profiling of 37,846 genes was performed using the Illumina Human HT-12v3 Expression BeadChip. All HCM patients were genotyped for pathogenic variants causing HCM. Technical validation was performed using quantitative real-time PCR (qRT-PCR) and Western blot. This study was started on January 1, 1999 and final analysis was completed on April 20, 2020. Results Overall, 22% of the transcriptome (8443 genes) was expressed differentially between HCM and control tissues. Analysis by genotype revealed that gene expression changes were similar among genotypic subgroups of HCM, with only 4-6% of the transcriptome exhibiting differential expression between genotypic subgroups. qRT-PCR confirmed differential expression in 92% of tested transcripts. Notably, in the context of COVID-19, the transcript for ACE2, a negative regulator of the angiotensin system, was the single most up-regulated gene in HCM (fold-change 3.53, q-value=1.30x10-23), which was confirmed with qRT-PCR in triplicate (fold-change 3.78; p=5.22x10-4), and Western blot confirmed a >5-fold over-expression of ACE2 protein (fold-change 5.34, p=1.66x10-6). Conclusions Over 20% of the transcriptome is expressed differentially between HCM and control tissues. Importantly, ACE2 was the most up-regulated gene in HCM indicating perhaps the heart’s compensatory effort to mount an anti-hypertrophic, anti-fibrotic response. However, given that the SARS-CoV-2 uses ACE2 for viral entry, this 5-fold increase in ACE2 protein may confer increased risk for COVID-19 manifestations and outcomes in patients with increased ACE2 transcript expression and protein levels in the heart.

positive: Cell-based antiviral screening against coronaviruses: Developing virus-specific and broad-spectrum inhibitors To combat the public health threat from emerging coronaviruses (CoV), the development of antiviral therapies with either virus-specific or pan-CoV activities is necessary. An important step in antiviral drug development is the screening of potential inhibitors in cell-based systems. The recent emergence of the Middle East respiratory syndrome (MERS)-CoV necessitates adapting methods that have been used to identify antivirals against the severe, acute respiratory syndrome (SARS)-CoV and developing new approaches to more efficiently screen antiviral drugs. In this article we review cell-based assays using infectious virus (BSL-3) and surrogate assays (BSL-2) that can be implemented to accelerate antiviral development against MERS-CoV and future emergent coronaviruses. This paper forms part of a series of invited articles in Antiviral Research on “From SARS to MERS: 10 years of research on highly pathogenic human coronaviruses.”

positive: Hypertension, the renin–angiotensin system, and the risk of lower respiratory tract infections and lung injury: implications for COVID-19: European Society of Hypertension COVID-19 Task Force Review of Evidence Systemic arterial hypertension (referred to as hypertension herein) is a major risk factor of mortality worldwide, and its importance is further emphasized in the context of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection referred to as COVID-19. Patients with severe COVID-19 infections commonly are older and have a history of hypertension. Almost 75% of patients who have died in the pandemic in Italy had hypertension. This raised multiple questions regarding a more severe course of COVID-19 in relation to hypertension itself as well as its treatment with renin–angiotensin system (RAS) blockers, e.g. angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). We provide a critical review on the relationship of hypertension, RAS, and risk of lung injury. We demonstrate lack of sound evidence that hypertension per se is an independent risk factor for COVID-19. Interestingly, ACEIs and ARBs may be associated with lower incidence and/or improved outcome in patients with lower respiratory tract infections. We also review in detail the molecular mechanisms linking the RAS to lung damage and the potential clinical impact of treatment with RAS blockers in patients with COVID-19 and a high cardiovascular and renal risk. This is related to the role of angiotensin-converting enzyme 2 (ACE2) for SARS-CoV-2 entry into cells, and expression of ACE2 in the lung, cardiovascular system, kidney, and other tissues. In summary, a critical review of available evidence does not support a deleterious effect of RAS blockers in COVID-19 infections. Therefore, there is currently no reason to discontinue RAS blockers in stable patients facing the COVID-19 pandemic.

positive: Comparisons of Staphylococcus aureus infection and other outcomes between users of angiotensin-converting-enzyme inhibitors and angiotensin II receptor blockers: lessons for COVID-19 from a nationwide cohort study Background: Mice receiving angiotensin converting enzyme inhibitor (ACEI) drugs show increased susceptibility to infection by Staphylococcus aureus ( S. aureus). We sought to investigate whether humans using ACEI were at increased risk of S. aureus infection, comparing them to users of Angiotensin II Receptor Blockers (ARB) with multiple control outcomes to assess the potential for residual confounding. Methods: Using the UK Clinical Practice Research Datalink linked to Hospital Episode Statistics between 1997 and 2017, we identified adults starting ACEI or ARB (as an active comparator drug). We regarded prescription of ACEI or ARB as time-dependent exposure and used a Cox regression model to compare incidence of first hospitalisation with infection due to S. aureus in periods with ACEI to periods with ARB prescriptions. We repeated the analysis using control outcomes that we did not expect to be associated with use of ACEI versus ARB (Gram-negative sepsis, hip fracture and herpes zoster) and one that we did (dry cough). Results: We identified 445,341 new users of ACEI (mean age 64.0±14.0, male 51.7%) and 41,824 new users of ARB (mean age 64.1±14.0, male 45.5%). The fully adjusted hazard ratio for S. aureus infection (ACEI vs. ARB) was 1.18 (95% CI 1.10–1.27), consistent across sensitivity analyses. However, we also found associations with all control outcomes; rates of Gram-negative sepsis, hip fracture and dry cough were also increased during periods of time treated with ACEI compared to ARB while herpes zoster was more common during time treated with ARB. Conclusions: Our results suggest that although ARB users appear an ideal control for analyses of ACEI effects, there is residual confounding even after multivariable adjustment. This has implications for observational analyses comparing users of these drug classes, in particular the effect of these drugs in relation to COVID-19 infection.

positive: Smoking Cessation as a Public Health Measure to Limit the Coronavirus Disease 2019 Pandemic The novel coronavirus disease 2019 (COVID-19) has already evolved into a rapidly expanding pandemic. Risk factors for COVID-19, such as cardiovascular disease, chronic obstructive pulmonary disease and diabetes, are all strongly associated with smoking habits. The effects of cigarette smoking on the transmission of the virus and worsening of COVID-19 have been less addressed. Emerging data indicate that smoking history is the major determinant of worsening COVID-19 outcomes. Smoking cessation recovers airway ciliary clearance and immune function. Thus, smoking cessation awareness is strongly encouraged as a public health measure to limit the global impact of COVID-19.

positive: Angiotensin converting enzyme 2 abrogates bleomycin-induced lung injury Despite substantial progress, mortality and morbidity of the acute respiratory distress syndrome (ARDS), a severe form of acute lung injury (ALI), remain unacceptably high. There is no effective treatment for ARDS/ALI. The renin–angiotensin system (RAS) through Angiotensin-converting enzyme (ACE)-generated Angiotensin II contributes to lung injury. ACE2, a recently discovered ACE homologue, acts as a negative regulator of the RAS and counterbalances the function of ACE. We hypothesized that ACE2 prevents Bleomycin (BLM)-induced lung injury. Fourteen to 16-week-old ACE2 knockout mice—male (ACE2(−/y)) and female (ACE2(−/−))—and age-matched wild-type (WT) male mice received intratracheal BLM (1.5U/kg). Male ACE2(−/y) BLM injured mice exhibited poorer exercise capacity, worse lung function and exacerbated lung fibrosis and collagen deposition compared with WT. These changes were associated with increased expression of the profibrotic genes α-smooth muscle actin (α-SMA) and Transforming Growth Factor ß1. Compared with ACE2(−/y) exposed to BLM, ACE2(−/−) exhibited better lung function and architecture and decreased collagen deposition. Treatment with intraperitoneal recombinant human (rh) ACE2 (2 mg/kg) for 21 days improved survival, exercise capacity, and lung function and decreased lung inflammation and fibrosis in male BLM-WT mice. Female BLM WT mice had mild fibrosis and displayed a possible compensatory upregulation of the AT2 receptor. We conclude that ACE2 gene deletion worsens BLM-induced lung injury and more so in males than females. Conversely, ACE2 protects against BLM-induced fibrosis. rhACE2 may have therapeutic potential to attenuate respiratory morbidity in ALI/ARDS.

positive: Speculation is not evidence: antihypertensive therapy and COVID-19

positive: Predicting the angiotensin converting enzyme 2 (ACE2) utilizing capability as the receptor of SARS-CoV-2 Abstract SARS-CoV-2, the newly identified human coronavirus causing severe pneumonia pandemic, was probably originated from Chinese horseshoe bats. However, direct transmission of the virus from bats to humans is unlikely due to lack of direct contact, implying the existence of unknown intermediate hosts. Angiotensin converting enzyme 2 (ACE2) is the receptor of SARS-CoV-2, but only ACE2s of certain species can be utilized by SARS-CoV-2. Here, we evaluated and ranked the receptor-utilizing capability of ACE2s from various species by phylogenetic clustering and sequence alignment with the currently known ACE2s utilized by SARS-CoV-2. As a result, we predicted that SARS-CoV-2 tends to utilize ACE2s of various mammals, except murines, and some birds, such as pigeon. This prediction may help to screen the intermediate hosts of SARS-CoV-2.

positive: COVID-19, ACE -inhibitors and angiotensin receptor blockers-: The need to differentiate between early infection and acute lung injury

positive: In Reply - Angiotensin-Converting Enzyme 2 and the Resolution of Inflammation: In Support of Continuation of Prescribed Angiotensin-Converting Enzyme Inhibitors and Angiotensin-Receptor Blockers

positive: Is the use of RAS inhibitors safe in the current era of COVID-19 pandemic? Antihypertensive drugs are one of the most widely used pharmacologic agent in the world and it is predominantly used in the elderly subjects. Pneumonia is the most common cause of death in the extremely old subject. During infection and its complication such as sepsis, hypotension could be exacerbated by antihypertensive drugs because homeostasis mechanisms such as sodium balance, renin angiotensin aldosterone system and/or sympathetic nervous system can be mitigated by antihypertensive drug therapy. Severe Acute Respiratory Syndrome-Coronavirus-1 and 2 viral surface protein is known to attach angiotensin converting enzyme 2 (ACE2) on the cell membrane to facilitate viral entry into the cytoplasm. Despite the theoretical concerns of increased ACE2 expression by Renin-Angiotensin-Aldosterone system (RAS) blockade, there is no evidence that RAS inhibitors are harmful during COVID-19 infection and have in fact been shown to be beneficial in animal studies. Therefore, it is recommended to maintain RAS blockade during the current corona virus pandemic.

positive: COVID-19 and Multi-Organ Response Abstract Since the outbreak and rapid spread of COVID-19 starting late December 2019, it has been apparent that disease prognosis has largely been influenced by multi-organ involvement. Comorbidities such as cardiovascular diseases have been the most common risk factors for severity and mortality. The hyperinflammatory response of the body, coupled with the plausible direct effects of SARS-CoV-2 on body-wide organs via ACE2, has been associated with complications of the disease. Acute respiratory distress syndrome, heart failure, renal failure, liver damage, shock and multi-organ failure have precipitated death. Acknowledging the comorbidities and potential organ injuries throughout the course of COVID-19 is therefore crucial in the clinical management of patients. This paper aims to add onto the ever-emerging landscape of medical knowledge on COVID-19, encapsulating its multi-organ impact.

positive: COVID-19: Dados Atualizados e sua Relação Com o Sistema Cardiovascular./ COVID-19: Dados Atualizados e sua Relação Com o Sistema Cardiovascular./ COVID-19: Updated Data and its Relation to the Cardiovascular System In December 2019, a new human coronavirus, called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or coronavirus disease 2019 (COVID-19) by the World Health Organization, emerged in the city of Wuhan, China. Spreading globally, it is now considered pandemic, with approximately 3 million cases worldwide at the end of April. Its symptoms include fever, cough, and headache, but the main one is shortness of breath. In turn, it is believed that there is a relationship between COVID-19 and damage to the heart muscle, and hypertensive and diabetic patients, for example, seem to have worse prognosis. Therefore, COVID-19 may worsen in individuals with underlying adverse conditions, and a not negligible number of patients hospitalized with this virus had cardiovascular or cerebrovascular diseases. Systemic inflammatory response and immune system disorders during disease progression may be behind this association. In addition, the virus uses angiotensin-converting enzyme (ACE) receptors, more precisely ACE2, to penetrate the cell; therefore, the use of ACE inhibitor drugs and angiotensin receptor blockers could cause an increase in these receptors, thus facilitating the entry of the virus into the cell. There is, however, no scientific evidence to support the interruption of these drugs. Since they are fundamental for certain chronic diseases, the risk and benefit of their withdrawal in this scenario should be carefully weighed. Finally, cardiologists and health professionals should be aware of the risks of infection and protect themselves as much as possible, sleeping properly and avoiding long working hours.

positive: COVID-19 and intracerebral haemorrhage: causative or coincidental? Pneumonia appears to be the most common manifestation of coronavirus disease 2019 (COVID-19), but some extrapulmonary involvement, such as gastrointestinal, cardiac and renal, has been reported. The limited clinical data about the virus's behavior to date, especially extrapulmonary symptoms, suggest that we should be aware of the possibility of initial cerebrovascular manifestations of COVID-19.

positive: Covid-19 and cardiovascular risk: susceptibility to infection to SARS-CoV-2, severity and prognosis of Covid-19 and blockade of the renin-angiotensin-aldosterone system. An evidence-based viewpoint Abstract The presence of cardiovascular co-morbidities and the known effects of coronaviruses on the cardiovascular system have called attention to the potential implications for patients with cardiovascular risk factors. This evidence-based viewpoint will address two questions: (a) are individuals with underlying cardiovascular risk factors (e.g. high blood pressure or diabetes) or overt disease (e.g. coronary heart disease, heart failure, kidney disease) more likely to develop severe Covid-19 and to die than those without underlying conditions? (b) does the regular use of angiotensin-converting enzyme inhibitors (ACE-i) or angiotensin-receptor blockers (ARB) make patients more likely to get infected and to die of Covid-19? With a necessary cautionary note that the evidence around the links between Covid-19 and cardiovascular disease is accruing at a fast pace, to date we can conclude that: (a) the greater susceptibility of individuals with underlying cardiovascular conditions to develop more severe Covid-19 with higher mortality rate is likely to be confounded, in part, by age and the type of co-morbidities. Patients with heart failure or chronic kidney disease might show an excess risk; (b) neither ACE-i nor ARB are associated with greater risk of SARS-Cov2 infection, or severity or risk of death in patients with Covid-19. Patients on these drugs should not stop them, unless under strict medical supervision and with the addition of a suitable replacement medicine.

positive: Coronavirus Disease 2019 and the Cerebrovascular-Cardiovascular Systems: What Do We Know So Far? The severe acute respiratory syndrome coronavirus 2 pandemic of 2019 to 2020 has resulted in multiple hospitalizations, deaths, and economic hardships worldwide. Although respiratory involvement in patients with coronavirus disease 2019 (COVID-19) is well known, the potential cardiovascular and cerebrovascular manifestations are less understood. We performed a PubMed and Google Scholar search and reviewed relevant literature on COVID-19 and cardiovascular system involvement. Severe acute respiratory syndrome coronavirus 2 possesses high affinity for angiotensin-converting enzyme 2 receptor, which is highly concentrated in the lungs and cardiovascular tissue, thereby provoking concern for cardiovascular involvement in COVID-19 cases. Preexisting cardiovascular and cerebrovascular disease has been shown in previous reports to be a risk factor for severe infection. On the basis of our review of published studies, COVID-19 patients may be more likely to experience acute cardiac injury, arrhythmia, coagulation defects, and acute stroke and are likely to have poorer outcomes as a result. As the COVID-19 pandemic continues, more data about potential cardiovascular and cerebrovascular manifestations of the disease are required.

positive: The COVID-19 outbreak and the angiotensin-converting enzyme 2: too little or too much?

positive: Activation of renin–angiotensin–aldosterone system (RAAS) in the lung of smoking-induced pulmonary arterial hypertension (PAH) rats OBJECTIVES: To explore the role of the renin–angiotensin–aldosterone system (RAAS) in the pathogenesis of pulmonary arterial hypertension (PAH) induced by chronic exposure to cigarette smoke. METHODS: 48 healthy male SD rats were randomly divided into four groups (12/group): control group (group A); inhibitor alone group (group B); cigarette induction group (group C); cigarette induction + inhibitor group (group D). After the establishment of smoking-induced PAH rat model, the right ventricular systolic pressure (RVSP) was detected using an inserted catheter; western blotting was used to detect the protein expression of angiotensin-converting enzyme-2 (ACE2) and angiotensin-converting enzyme (ACE); expression levels of angiotensin II (AngII) in lung tissue were measured by radioimmunoassay. RESULTS: After six months of cigarette exposure, the RVSP of chronic cigarette induction group was significantly higher than that of the control group; expression levels of AngII and ACE increased in lung tissues, but ACE2 expression levels reduced. Compared with cigarette exposure group, after losartan treatment, RVSP, ACE and AngII obviously decreased (P<0.05), and ACE2 expression levels significantly increased. CONCLUSION: Chronic cigarette exposure may result in PAH and affect the protein expression of ACE2 and ACE in lung tissue, suggesting that ACE2 and ACE play an important role in the pathogenesis of smoking-induced PAH.

positive: Does the direct renin inhibitor have a role to play in attenuating severity of the outbreak coronavirus disease 2019 (COVID-19)?

positive: A model of the ACE2 structure and function as a SARS-CoV receptor Abstract The angiotensin-converting enzyme 2 (ACE2) is an important regulator of the renin–angiotensin system and was very recently identified as a functional receptor for the SARS virus. The ACE2 sequence is similar (sequence identities 43% and 35%, and similarities 61% and 55%, respectively) to those of the testis-specific form of ACE (tACE) and the Drosophila homolog of ACE (AnCE). The high level of sequence similarity allowed us to build a robust homology model of the ACE2 structure with a root-mean-square deviation from the aligned crystal structures of tACE and AnCE less than 0.5Å. A prominent feature of the model is a deep channel on the top of the molecule that contains the catalytic site. Negatively charged ridges surrounding the channel may provide a possible binding site for the positively charged receptor-binding domain (RBD) of the S-glycoprotein, which we recently identified [Biochem. Biophys. Res. Commun. 312 (2003) 1159]. Several distinct patches of hydrophobic residues at the ACE2 surface were noted at close proximity to the charged ridges that could contribute to binding. These results suggest a possible binding region for the SARS-CoV S-glycoprotein on ACE2 and could help in the design of experiments to further elucidate the structure and function of ACE2.

positive: Cell type-specific expression of the putative SARS-CoV-2 receptor ACE2 in human hearts

positive: Cardiovascular and Logistic Issues Associated With COVID-19 Pandemic

positive: Coronavirus Disease (COVID-19): A primer for emergency physicians INTRODUCTION: Rapid worldwide spread of Coronavirus Disease 2019 (COVID-19) has resulted in a global pandemic. OBJECTIVE: This review article provides emergency physicians with an overview of the most current understanding of COVID-19 and recommendations on the evaluation and management of patients with suspected COVID-19. DISCUSSION: Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for causing COVID-19, is primarily transmitted from person-to-person through close contact (approximately 6 ft) by respiratory droplets. Symptoms of COVID-19 are similar to other viral upper respiratory illnesses. Three major trajectories include mild disease with upper respiratory symptoms, non-severe pneumonia, and severe pneumonia complicated by acute respiratory distress syndrome (ARDS). Emergency physicians should focus on identifying patients at risk, isolating suspected patients, and informing hospital infection prevention and public health authorities. Patients with suspected COVID-19 should be asked to wear a facemask. Respiratory etiquette, hand washing, and personal protective equipment are recommended for all healthcare personnel caring for suspected cases. Disposition depends on patient symptoms, hemodynamic status, and patient ability to self-quarantine. CONCLUSION: This narrative review provides clinicians with an updated approach to the evaluation and management of patients presenting to the emergency department with suspected COVID-19.

positive: Response to recent commentaries regarding the involvement of angiotensin‐converting enzyme 2 (ACE2) and renin‐angiotensin system blockers in SARS‐CoV‐2 infections

positive: Robust ACE2 protein expression localizes to the motile cilia of the respiratory tract epithelia and is not increased by ACE inhibitors or angiotensin receptor blockers We investigated the expression and subcellular localization of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), within the upper (nasal) and lower (pulmonary) respiratory tracts of healthy human donors. We detected ACE2 protein expression within the cilia organelle of ciliated airway epithelial cells, which likely represents the initial or early subcellular site of SARS-CoV-2 viral entry during respiratory transmission. We further determined whether ACE2 expression in the cilia of upper respiratory cells was influenced by patient demographics, clinical characteristics, co-morbidities, or medication use, and found no evidence that the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs) increases ACE2 protein expression.

positive: Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults: A Living Systematic Review BACKGROUND: The role of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs) in COVID-19 disease susceptibility, severity, and treatment is unclear. PURPOSE: To evaluate, on an ongoing basis, whether use of ACEIs or ARBs either increases risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or is associated with worse COVID-19 disease outcomes, and to assess the efficacy of these medications for COVID-19 treatment. DATA SOURCES: MEDLINE (Ovid) and Cochrane Database of Systematic Reviews from 2003 to 4 May 2020, with planned ongoing surveillance for 1 year; the World Health Organization database of COVID-19 publications and medRxiv.org through 17 April 2020; and ClinicalTrials.gov to 24 April 2020, with planned ongoing surveillance. STUDY SELECTION: Observational studies and trials in adults that examined associations and effects of ACEIs or ARBs on risk for SARS-CoV-2 infection and COVID-19 disease severity and mortality. DATA EXTRACTION: Single-reviewer abstraction confirmed by another reviewer, independent evaluation by 2 reviewers of study quality, and collective assessment of certainty of evidence. DATA SYNTHESIS: Two retrospective cohort studies found that ACEI and ARB use was not associated with a higher likelihood of receiving a positive SARS-CoV-2 test result, and 1 case–control study found no association with COVID-19 illness in a large community (moderate-certainty evidence). Fourteen observational studies, involving a total of 23 565 adults with COVID-19, showed consistent evidence that neither medication was associated with more severe COVID-19 illness (high-certainty evidence). Four registered randomized trials plan to evaluate ACEIs and ARBs for treatment of COVID-19. LIMITATION: Half the studies were small and did not adjust for important confounding variables. CONCLUSION: High-certainty evidence suggests that ACEI or ARB use is not associated with more severe COVID-19 disease, and moderate-certainty evidence suggests no association between use of these medications and positive SARS-CoV-2 test results among symptomatic patients. Whether these medications increase the risk for mild or asymptomatic disease or are beneficial in COVID-19 treatment remains uncertain. PRIMARY FUNDING SOURCE: None. (PROSPERO: registration number pending)

positive: A consensus statement on the use of angiotensin receptor blockers and angiotensin converting enzyme inhibitors in relation to COVID-19 (corona virus disease 2019). There has been a lot of speculation that patients with coronavirus disease 2019 (COVID-19) who are receiving angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) may be at increased risk for adverse outcomes. We reviewed the available evidence, and have not found this to be the case. We recommend that patients on such medications should continue on them unless there is a clinical indication to stop their use.

positive: Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2 ACE2 (angiotensin-converting enzyme 2) has a multiplicity of physiological roles that revolve around its trivalent function: a negative regulator of the renin-angiotensin system, facilitator of amino acid transport, and the severe acute respiratory syndrome-coronavirus (SARS-CoV) and SARS-CoV-2 receptor. ACE2 is widely expressed, including, in the lungs, cardiovascular system, gut, kidneys, central nervous system, and adipose tissue. ACE2 has recently been identified as the SARS-CoV-2 receptor, the infective agent responsible for coronavirus disease 2019, providing a critical link between immunity, inflammation, ACE2, and cardiovascular disease. Although sharing a close evolutionary relationship with SARS-CoV, the receptor-binding domain of SARS-CoV-2 differs in several key amino acid residues, allowing for stronger binding affinity with the human ACE2 receptor, which may account for the greater pathogenicity of SARS-CoV-2. The loss of ACE2 function following binding by SARS-CoV-2 is driven by endocytosis and activation of proteolytic cleavage and processing. The ACE2 system is a critical protective pathway against heart failure with reduced and preserved ejection fraction including, myocardial infarction and hypertension, and against lung disease and diabetes mellitus. The control of gut dysbiosis and vascular permeability by ACE2 has emerged as an essential mechanism of pulmonary hypertension and diabetic cardiovascular complications. Recombinant ACE2, gene-delivery of Ace2, Ang 1-7 analogs, and Mas receptor agonists enhance ACE2 action and serve as potential therapies for disease conditions associated with an activated renin-angiotensin system. rhACE2 (recombinant human ACE2) has completed clinical trials and efficiently lowered or increased plasma angiotensin II and angiotensin 1-7 levels, respectively. Our review summarizes the progress over the past 20 years, highlighting the critical role of ACE2 as the novel SARS-CoV-2 receptor and as the negative regulator of the renin-angiotensin system, together with implications for the coronavirus disease 2019 pandemic and associated cardiovascular diseases.

positive: Role of the Backbenchers of the Renin-Angiotensin System ACE2 and AT2 Receptors in COVID-19: Lessons From SARS The novel coronaviruses causing severe acute respiratory syndrome (SARS) and coronavirus disease 2019 (COVID-19) have been shown to utilize angiotensin-converting enzyme 2 (ACE2) as the receptor for entry into the host cells. The involvement of the renin-angiotensin system (RAS) in the evolution and pathogenesis of lung diseases has been implicated in recent years. The two enzymes of RAS, angiotensin-converting enzyme (ACE) and ACE2, serve a contrasting function. ACE helps in the formation of angiotensin II (AGII) from angiotensin I (AGI), and ACE2 cleaves AGI and AGII into AG (1-9) and AG (1-7) respectively. The ACE-induced AGII has vasoconstrictor and pro-inflammatory properties via AT1R, whereas ACE2 has been shown to protect against lung injury. The less spoken about AGII receptor, angiotensin receptor type 2 (AT2R), has anti-inflammatory and anti-fibrotic effects in lung tissue and may be of significance in light of the lung pathology presentation in COVID-19. A review of articles searched in PubMed and peer-reviewed journals of importance was done using search terms “ACE2,” “AT2,” “SARS,” and COVID-19.” Lung involvement in both SARS and COVID-19 has been very severe and suggestive of severe inflammatory and immune reactions. Animal studies have shown that ACE2 and AT2 receptors counter the pro-inflammatory and other effects mediated by angiotensin II by their vasodilator, anti-inflammatory, anti-fibrotic, and anti-proliferative effects. They have been shown to protect against and revert acute lung injuries. The instrumental role of recombinant ACE2, AT2 receptor agonists, and AT1 receptor blockers may be helpful in the treatment of COVID-19.

positive: Potential therapies for coronaviruses Coronavirus replication offers several attractive targets for chemotherapy. These include: viral entry (inhibited by chloroquine and peptides); viral RNA (targeted by antisense approaches/RNAi); the main protease 3CLpro (inhibited by peptidic molecules such as HIV-1 protease inhibitors and miscellaneous compounds); the accessory protease(s) PLpro(s) (inhibited by zinc ions); RNA-dependent RNA polymerase (inhibited by aurintricarboxylic acid and antisense approaches); and helicase (inhibited by bananins). Chloroquine and HIV-1 protease inhibitors (with well-known toxicity profiles) should be considered for clinical tests if severe acute respiratory syndrome (SARS) re-emerges; however, there are other attractive compounds. Lessons should be learnt from AIDS research for choosing the best strategies.

positive: Association between chronic ACE inhibitor exposure and decreased odds of severe disease in patients with COVID-19. OBJECTIVE Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Renin-angiotensin-aldosterone-system (RAAS) inhibitors may increase the expression of angiotensin-converting enzyme 2, which is the receptor for SARSCoV-2 Spike protein. The consequences of using angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) during the COVID-19 pandemic are unknown. METHODS A retrospective cohort study aiming to identify the odds of severe disease (defined as either hospitalization of ≥14 days, admission to the intensive care unit, or death) associated with exposure to ACEi or ARB was conducted. Adult patients (age ≥18 years) with COVID-19 admitted to the İstanbul Faculty of Medicine Corona Center between March 9 and May 11, 2020, were included. Chronic users of ACEi, ARB, or other antihypertensive drugs were matched according to age, sex, sick days before hospitalization, comorbidities, smoking, number of antihypertensive regimens, doxazosin use, furosemide use, and serum creatinine level. Odds ratios (OR) of having severe disease were calculated. RESULTS In total, 611 patients were admitted with COVID-19, confirmed by either reverse-transcriptase polymerase chain reaction or computed tomography (CT). There were 363 males, and the age ranged from 18 to 98 years, with an average age of 57±15 years. Of these, 165 participants had severe disease (53 deaths, case fatality rate: 8.7%). Among those with hypertension (n=249), ARB exposure was compatible with decreased odds (OR=0.60, 95% CI: 0.27-1.36, p=0.31) of severe disease though not statistically significant, while ACEi exposure significantly reduced the risk of severe disease (OR=0.37, 95% CI: 0.15-0.87, p=0.03). ACEi exposure was associated with milder infiltrations seen on baseline CT, lower C-reactive protein and ferritin, higher monocytes, shorter hospitalization, and less requirement for specific empirical treatments (favipiravir and meropenem). CONCLUSION Our data suggest that exposure to ACEi drugs may have favorable effects in the context of COVID-19 pneumonia.

positive: Good or bad: Application of RAAS inhibitors in COVID-19 patients with cardiovascular comorbidities The coronavirus disease 2019 (COVID-19) pandemic is caused by a newly emerged coronavirus (CoV) called Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). COVID-19 patients with cardiovascular disease (CVD) comorbidities have significantly increased morbidity and mortality. The use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor type 1 blockers (ARBs) improve CVD outcomes; however, there is concern that they may worsen the prognosis of CVD patients that become infected with SARS-CoV-2 because the virus uses the ACE2 receptor to bind to and subsequently infect host cells. Thus, some health care providers and media sources have questioned the continued use of ACE inhibitors and ARBs. In this brief review, we discuss the effect of ACE inhibitor-induced bradykinin on the cardiovascular system, on the renin–angiotensin–aldosterone system (RAAS) regulation in COVID-19 patients, and analyze recent clinical studies regarding patients treated with RAAS inhibitors. We propose that the application of RAAS inhibitors for COVID-19 patients with CVDs may be beneficial rather than harmful.

positive: COVID-19 and Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers: What Is the Evidence?

positive: COVID-19-related cardiac involvement and potential implications for cardiothoracic imaging

positive: Lipid-lowering therapy and renin-angiotensin-aldosterone system inhibitors in the era of the COVID-19 pandemic

positive: Association of Inpatient Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Mortality Among Patients With Hypertension Hospitalized With COVID-19 RATIONALE: Use of ACEIs (angiotensin-converting enzyme inhibitors) and ARBs (angiotensin II receptor blockers) is a major concern for clinicians treating coronavirus disease 2019 (COVID-19) in patients with hypertension. OBJECTIVE: To determine the association between in-hospital use of ACEI/ARB and all-cause mortality in patients with hypertension and hospitalized due to COVID-19. METHODS AND RESULTS: This retrospective, multi-center study included 1128 adult patients with hypertension diagnosed with COVID-19, including 188 taking ACEI/ARB (ACEI/ARB group; median age 64 [interquartile range, 55–68] years; 53.2% men) and 940 without using ACEI/ARB (non-ACEI/ARB group; median age 64 [interquartile range 57–69]; 53.5% men), who were admitted to 9 hospitals in Hubei Province, China from December 31, 2019 to February 20, 2020. In mixed-effect Cox model treating site as a random effect, after adjusting for age, gender, comorbidities, and in-hospital medications, the detected risk for all-cause mortality was lower in the ACEI/ARB group versus the non-ACEI/ARB group (adjusted hazard ratio, 0.42 [95% CI, 0.19–0.92]; P=0.03). In a propensity score-matched analysis followed by adjusting imbalanced variables in mixed-effect Cox model, the results consistently demonstrated lower risk of COVID-19 mortality in patients who received ACEI/ARB versus those who did not receive ACEI/ARB (adjusted hazard ratio, 0.37 [95% CI, 0.15–0.89]; P=0.03). Further subgroup propensity score-matched analysis indicated that, compared with use of other antihypertensive drugs, ACEI/ARB was also associated with decreased mortality (adjusted hazard ratio, 0.30 [95% CI, 0.12–0.70]; P=0.01) in patients with COVID-19 and coexisting hypertension. CONCLUSIONS: Among hospitalized patients with COVID-19 and coexisting hypertension, inpatient use of ACEI/ARB was associated with lower risk of all-cause mortality compared with ACEI/ARB nonusers. While study interpretation needs to consider the potential for residual confounders, it is unlikely that in-hospital use of ACEI/ARB was associated with an increased mortality risk.

positive: Thiol-based angiotensin-converting enzyme 2 inhibitors: P1′ modifications for the exploration of the S1′ subsite Abstract Explorations of the S1′ subsite of ACE2 via modifications of the P1′ methylene biphenyl moiety of thiol-based metalloprotease inhibitors led to improvements in ACE2 selectivity versus ACE and NEP, while maintaining potent ACE2 inhibition.

negative: Late‐onset Pneumocystis jirovecii pneumonia post–fludarabine, cyclophosphamide and rituximab: implications for prophylaxis OBJECTIVE: Fludarabine, cyclophosphamide and rituximab (FCR) therapy for lymphoid malignancies has historically been associated with a low reported incidence of Pneumocystis jirovecii pneumonia (PJP). However, prophylaxis was routinely used in early studies, and molecular diagnostic tools were not employed. The objective of this study was to review the incidence of PJP during and post‐FCR in the era of highly sensitive molecular diagnostics and (18)F‐fluorodeoxyglucose (FDG) positron emission tomography (PET)–computerised tomography (CT). METHODS: All patients treated with standard FCR at the Peter MacCallum Cancer Centre (March 2009 to June 2012) were identified from a medications management database. Laboratory‐confirmed PJP cases during this time were identified from an electronic database. RESULTS: Overall, 66 patients were treated with a median of 5.5 FCR cycles. Eight PJP cases were identified, 6 of whom had received chemotherapy prior to FCR. In 5 cases, (18)F‐FDG PET demonstrated bilateral ground‐glass infiltrates. Median CD4(+) lymphocyte counts at time of PJP diagnosis and 9–12 months following FCR were 123 and 400 cells/μL, respectively. In patients receiving no prophylaxis, 9.1% developed PJP during FCR. The rate following FCR was 18.4%, with median onset at 6 months (2.4–24 months). CONCLUSION: Given the high rate of late‐onset PJP, consideration should be given for extended PJP prophylaxis for up to 12 months post‐FCR, particularly in pretreated patients. Further evaluation of the role of CD4(+) monitoring is warranted to quantify risk of disease development and to guide duration of prophylaxis.

negative: Full spectrum of COVID-19 severity still being depicted

negative: Characterizing Eckol as a Therapeutic Aid: A Systematic Review The marine biosphere is a treasure trove of natural bioactive secondary metabolites and the richest source of structurally diverse and unique compounds, such as phlorotannins and halo-compounds, with high therapeutic potential. Eckol is a precursor compound representing the dibenzo-1,4-dioxin class of phlorotannins abundant in the Ecklonia species, which are marine brown algae having a ubiquitous distribution. In search of compounds having biological activity from macro algae during the past three decades, this particular compound has attracted massive attention for its multiple therapeutic properties and health benefits. Although several varieties of marine algae, seaweed, and phlorotannins have already been well scrutinized, eckol deserves a place of its own because of the therapeutic properties it possesses. The relevant information about this particular compound has not yet been collected in one place; therefore, this review focuses on its biological applications, including its potential health benefits and possible applications to restrain diseases leading to good health. The facts compiled in this review could contribute to novel insights into the functions of eckol and potentially enable its use in different uninvestigated fields.

negative: Genetic diversity and evolution of SARS-CoV-2 Abstract COVID-19 is a viral respiratory illness caused by a new coronavirus called SARS-CoV-2. The World Health Organization declared the SARS-CoV-2 outbreak a global public health emergency. We performed genetic analyses of eighty-six complete or near-complete genomes of SARS-CoV-2 and revealed many mutations and deletions on coding and non-coding regions. These observations provided evidence of the genetic diversity and rapid evolution of this novel coronavirus.

negative: May patients receiving 5-alpha-reductase inhibitors be in higher risk of COVID-19 complications ? Abstract COVID-19 pandemic is a major challenge for global and national healthcare providers. Number of new cases is continuously increasing with an emerging trend showing worse prognosis in males in comparison to females. Based on this observation, our proposed hypothesis is that 5-alpha-reductase inhibitors, that are commonly used for BPH treatment, may be one of the factors contributing to poorer prognosis in males. Background With increasing number of COVID-19 cases, an evident sex- dependent difference in disease outcomes can be observed. Based on published studies with short term follow-up, males have 65% higher mortality rate (1). The question remains, whether long term observational studies will confirm improved recovery in females.

negative: Characterization of Angiotensin Converting Enzyme-2 (ACE2) in Human Urine Angiotensin converting enzyme-2 (ACE2) is a recently described membrane-bound carboxypeptidase identified by its homology to ACE, the enzyme responsible for the formation of the potent vasoconstrictor angiotensin II (Ang II). ACE2 inactivates Ang II and is thus thought to act in a counter-regulatory fashion to ACE. ACE2 is highly expressed in epithelial cells of distal renal tubules, and recent evidence indicates that expression is increased in a range of renal diseases. A soluble form of ACE, generated by proteolytic cleavage of the membrane-bound form, has been shown to be present in urine; although evidence for a similar release of ACE2 has been reported in cell culture, it is not yet known whether this occurs in vivo. The present study has identified ACE2 in human urine, both by a sensitive fluorescence-based activity assay and by Western immunoblot. Levels of ACE2 were surprisingly higher than ACE, which may reflect preferential targeting of the enzyme to the luminal surface of the renal epithelium. Future studies will determine whether increased expression of ACE2 in renal diseases are reflected in higher urinary levels of this novel enzyme.

negative: Diseases of the Liver and Hepatobiliary System

negative: Improvement in Mortality and End-Stage Renal Disease in Patients With Type 2 Diabetes After Acute Kidney Injury Who Are Prescribed Dipeptidyl Peptidase-4 Inhibitors Abstract Objective To focus on the potential beneficial effects of the pleiotropic effects of dipeptidyl peptidase-4 inhibitors (DPP4is) on attenuating progression of diabetic kidney disease in reducing the long-term effect of the acute kidney injury (AKI) to chronic kidney disease (CKD) transition. Patients and Methods Data from the National Health Insurance Research Database from January 1, 1999, to July 31, 2011, were analyzed, and patients with diabetes weaning from dialysis-requiring AKI were identified. Cox proportional hazards models and inverse-weighted estimates of the probability of treatment were used to adjust for treatment selection bias. The outcomes were incident end-stage renal disease (ESRD) and mortality, major adverse cardiovascular events, and hospitalized heart failure. Results Of a total of 6165 patients with diabetes weaning from dialysis-requiring AKI identified, 5635 (91.4%) patients were DPP4i nonusers and 530 (8.6%) patients were DPP4i users. Compared with DPP4i nonusers, DPP4i users had a lower risk of ESRD (hazard ratio, 0.81; 95% CI, 0.70-0.94; P=.04) and all-cause mortality (hazard ratio, 0.28; 95% CI, 0.23-0.34; P<.001) after adjustments for CKD, advanced CKD, and angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker use. In contrast, the risk of major adverse cardiovascular events and hospitalized heart failure did not differ significantly between groups. Conclusion Dipeptidyl peptidase-4 inhibitor users had a lower risk of ESRD and mortality than did nonusers among patients with diabetes after weaning from dialysis-requiring AKI. Therefore, a prospective study of AKI to CKD transitions after episodes of AKI is needed to optimally target DPP4i interventions.

negative: Clinical considerations for patients with diabetes in times of COVID-19 epidemic

negative: Investigation into SARS-CoV-2 Resistance of Compounds in Garlic Essential Oil [Image: see text] Eighteen active substances, including 17 organosulfur compounds found in garlic essential oil (T), were identified by GC–MS analysis. For the first time, using the molecular docking technique, we report the inhibitory effect of the considered compounds on the host receptor angiotensin-converting enzyme 2 (ACE2) protein in the human body that leads to a crucial foundation about coronavirus resistance of individual compounds on the main protease (PDB6LU7) protein of SARS-CoV-2. The results show that the 17 organosulfur compounds, accounting for 99.4% contents of the garlic essential oil, have strong interactions with the amino acids of the ACE2 protein and the main protease PDB6LU7 of SARS-CoV-2. The strongest anticoronavirus activity is expressed in allyl disulfide and allyl trisulfide, which account for the highest content in the garlic essential oil (51.3%). Interestingly, docking results indicate the synergistic interactions of the 17 substances, which exhibit good inhibition of the ACE2 and PDB6LU7 proteins. The results suggest that the garlic essential oil is a valuable natural antivirus source, which contributes to preventing the invasion of coronavirus into the human body.

negative: Computers and viral diseases. Preliminary bioinformatics studies on the design of a synthetic vaccine and a preventative peptidomimetic antagonist against the SARS-CoV-2 (2019-nCoV, COVID-19) coronavirus Abstract This paper concerns study of the genome of the Wuhan Seafood Market isolate believed to represent the causative agent of the disease COVID-19. This is to find a short section or sections of viral protein sequence suitable for preliminary design proposal for a peptide synthetic vaccine and a peptidomimetic therapeutic, and to explore some design possibilities. The project was originally directed towards a use case for the Q-UEL language and its implementation in a knowledge management and automated inference system for medicine called the BioIngine, but focus here remains mostly on the virus itself. However, using Q-UEL systems to access relevant and emerging literature, and to interact with standard publically available bioinformatics tools on the Internet, did help quickly identify sequences of amino acids that are well conserved across many coronaviruses including 2019-nCoV. KRSFIEDLLFNKV was found to be particularly well conserved in this study and corresponds to the region around one of the known cleavage sites of the SARS virus that are believed to be required for virus activation for cell entry. This sequence motif and surrounding variations formed the basis for proposing a specific synthetic vaccine epitope and peptidomimetic agent. The work can, nonetheless, be described in traditional bioinformatics terms, and readily reproduced by others, albeit with the caveat that new data and research into 2019-nCoV is emerging and evolving at an explosive pace. Preliminary studies using molecular modeling and docking, and in that context the potential value of certain known herbal extracts, are also described.

negative: Clinical characteristics of COVID-19-infected cancer patients: a retrospective case study in three hospitals within Wuhan, China BACKGROUND: Cancer patients are regarded as a highly vulnerable group in the current Coronavirus Disease 2019 (COVID-19) pandemic. To date, the clinical characteristics of COVID-19-infected cancer patients remain largely unknown. PATIENTS AND METHODS: In this retrospective cohort study, we included cancer patients with laboratory-confirmed COVID-19 from three designated hospitals in Wuhan, China. Clinical data were collected from medical records from 13 January 2020 to 26 February 2020. Univariate and multivariate analyses were carried out to assess the risk factors associated with severe events defined as a condition requiring admission to an intensive care unit, the use of mechanical ventilation, or death. RESULTS: A total of 28 COVID-19-infected cancer patients were included; 17 (60.7%) patients were male. Median (interquartile range) age was 65.0 (56.0–70.0) years. Lung cancer was the most frequent cancer type (n = 7; 25.0%). Eight (28.6%) patients were suspected to have hospital-associated transmission. The following clinical features were shown in our cohort: fever (n = 23, 82.1%), dry cough (n = 22, 81%), and dyspnoea (n = 14, 50.0%), along with lymphopaenia (n = 23, 82.1%), high level of high-sensitivity C-reactive protein (n = 23, 82.1%), anaemia (n = 21, 75.0%), and hypoproteinaemia (n = 25, 89.3%). The common chest computed tomography (CT) findings were ground-glass opacity (n = 21, 75.0%) and patchy consolidation (n = 13, 46.3%). A total of 15 (53.6%) patients had severe events and the mortality rate was 28.6%. If the last antitumour treatment was within 14 days, it significantly increased the risk of developing severe events [hazard ratio (HR) = 4.079, 95% confidence interval (CI) 1.086–15.322, P = 0.037]. Furthermore, patchy consolidation on CT on admission was associated with a higher risk of developing severe events (HR = 5.438, 95% CI 1.498–19.748, P = 0.010). CONCLUSIONS: Cancer patients show deteriorating conditions and poor outcomes from the COVID-19 infection. It is recommended that cancer patients receiving antitumour treatments should have vigorous screening for COVID-19 infection and should avoid treatments causing immunosuppression or have their dosages decreased in case of COVID-19 coinfection.

negative: COVID-19: What Should Interventional Radiologists Know and What Can They Do? The outbreak of coronavirus disease 2019 (COVID-19) in late December 2019 in Wuhan, China, has been characterized as a “pandemic” by the World Health Organization and has resulted in 81,603 confirmed cases in China, among the 334,981 cases confirmed in 189 countries as of 09:00 am, March 24, 2020 (China central standard time). During the past 3 months, hundreds of thousands of Chinese health care workers, including interventional radiologists (IRs), have been fighting this battle against the horrifying COVID-19 disease. As IRs, what should we know and what can we do when facing this challenge? This paper shares the experience we have gone through.

negative: Origin, Potential Therapeutic Targets and Treatment for Coronavirus Disease (COVID-19) The ongoing episode of coronavirus disease 19 (COVID-19) has imposed a serious threat to global health and the world economy. The disease has rapidly acquired a pandemic status affecting almost all populated areas of the planet. The causative agent of COVID-19 is a novel coronavirus known as SARS-CoV-2. The virus has an approximate 30 kb single-stranded positive-sense RNA genome, which is 74.5% to 99% identical to that of SARS-CoV, CoV-pangolin, and the coronavirus the from horseshoe bat. According to available information, SARS-CoV-2 is inferred to be a recombinant virus that originated from bats and was transmitted to humans, possibly using the pangolin as the intermediate host. The interaction of the SARS-CoV-2 spike protein with the human ACE2 (angiotensin-converting enzyme 2) receptor, and its subsequent cleavage by serine protease and fusion, are the main events in the pathophysiology. The serine protease inhibitors, spike protein-based vaccines, or ACE2 blockers may have therapeutic potential in the near future. At present, no vaccine is available against COVID-19. The disease is being treated with antiviral, antimalarial, anti-inflammatory, herbal medicines, and active plasma antibodies. In this context, the present review article provides a cumulative account of the recent information regarding the viral characteristics, potential therapeutic targets, treatment options, and prospective research questions.

negative: The SARS-CoV-2 receptor ACE2 expression of maternal-fetal interface and fetal organs by single cell transcriptome study The new type of pneumonia caused by the SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) has been declared as a global public health concern by WHO. Thousands of human infections have been diagnosed in China along with many other countries, which exhibited apparent person-to-person transmission characteristics of this virus. The capacity of vertical transmission in SARS-CoV-2 remains controversial recently. Angiotensin-converting enzyme 2 (ACE2) is now confirmed as the receptor of SARS-CoV-2 and plays essential roles in human infection and transmission. In present study, we collected the online available single-cell RNA sequencing (scRNA-seq) data to evaluate the cell specific expression of ACE2 in maternal-fetal interface as well as in multiple fetal organs. Our results revealed that ACE2 was highly expressed in maternal-fetal interface cells including stromal cells and perivascular cells of decidua, and cytotrophoblast and syncytiotrophoblast in placenta. Meanwhile, ACE2 was also expressed in specific cell types of human fetal heart, liver and lung, but not in kidney. And in a study containing series fetal and post-natal mouse lung, we observed ACE2 was dynamically changed over the time, and ACE2 was extremely high in neonatal mice at post-natal day 1~3. In summary, this study revealed that the SARS-CoV-2 receptor ACE2 was widely spread in specific cell types of maternal-fetal interface and fetal organs. Although previous clinical studies have not observed vertical transmission of SARS-COV-2 among limited cases, this phenomenon still needs to be further carefully investigated in clinical practice.

negative: Still puzzling questions in immunology (infection and immunity)

negative: Mechanisms of Hypersensitivity Allergic reactions to drugs are not always the result of the drug’s protein-binding capacity, biotransformation, or degradation. Mediator release may occur via cross-linking of cell-bound IgE by di-(multi-) valent free drug. Physiological and pharmacological effects of histamine are mediated through four receptors, H(1), H(2), H(3), and H(4.) The H(3) receptor has a regulatory role in the release of neurotransmitters such as serotonin and dopamine; the H(4) receptor exerts a chemotactic effect on several cell types associated with allergy and asthma. Cysteinyl leukotrienes and PAF are powerful mediators of anaphylaxis, asthma, and shock. Sphingosine-1-phosphate, elevated in the lungs of asthmatics, regulates pulmonary epithelium permeability and contributes to the pathogenesis of anaphylaxis. Urticaria is a heterogeneous disease with many subtypes. Both ACE inhibitors and angiotensin II receptor blockers may cause angioedema. Abacavir changes the shape of the HLA antigen-binding cleft producing an alteration in the repertoire of self-peptides that bind HLA-B*57:01 and a T cell response to self-proteins. Drug-induced delayed-type cutaneous hypersensitivity reactions are mediated by CD4+ and CD8+ CD3+ T cells in the dermis and epidermis. Granulysin appears to be a key molecule for keratinocyte killing in TEN/SJS. Drugs provide good examples of types II (immune hemolytic anemia, drug-induced thrombocytopenia) and III (serum sickness-like) hypersensitivities.

negative: Globalized low-income countries may experience higher COVID-19 mortality rates Understanding the factors underpinning COVID-19 infection and mortality rates is essential in order to implement actions that help mitigate the current pandemia. Here we evaluate how a suit of 15 climatic and socio-economic variables influence COVID-19 exponential growth-phase infection and mortality rates across 36 countries. We found that imports of goods and services, international tourism and the number of published scientific papers are good predictors of COVID-19 infection rates, indicating that more globalized countries may have experienced multiple and recurrent introductions of the virus. However, high-income countries showed lower mortality rates, suggesting that the consequences of the current pandemia will be worse for globalized low-income countries. International aid agencies could use this information to help mitigate the consequences of the current pandemia in the most vulnerable countries.

negative: [Angiotensin-converting enzyme 2 and coronavirus: research update on pathogenesis of the infection induced by this indissoluble bond]

negative: A New, Simple Projection Model for COVID-19 Pandemic With the worldwide outbreak of COVID-19, an accurate model to predict how the coronavirus pandemic will evolve becomes important and urgent to help policy makers in different countries address the epidemic outbreak and determine policies to control spread more efficiently and effectively. Unlike the classic public health and virus propagation models, this new projection model takes government intervention and public response into account to make reliable projections of the outbreak 10 days to 2 weeks in advance.

negative: Global rheumatology in the time of COVID-19

negative: The anti-viral facet of anti-rheumatic drugs: Lessons from COVID-19 Abstract The outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has posed the world at a pandemic risk. Coronavirus-19 disease (COVID-19) is an infectious disease caused by SARS-CoV-2, which causes pneumonia, requires intensive care unit hospitalization in about 10% of cases and can lead to a fatal outcome. Several efforts are currently made to find a treatment for COVID-19 patients. So far, several anti-viral and immunosuppressive or immunomodulating drugs have demonstrated some efficacy on COVID-19 both in vitro and in animal models as well as in cases series. In COVID-19 patients a pro-inflammatory status with high levels of interleukin (IL)-1B, IL-1 receptor (R)A and tumor necrosis factor (TNF)-α has been demonstrated. Moreover, high levels of IL-6 and TNF-α have been observed in patients requiring intensive-care-unit hospitalization. This provided rationale for the use of anti-rheumatic drugs as potential treatments for this severe viral infection. Other agents, such as hydroxychloroquine and chloroquine might have a direct anti-viral effect. The anti-viral aspect of immunosuppressants towards a variety of viruses has been known since long time and it is herein discussed in the view of searching for a potential treatment for SARS-CoV-2 infection.

negative: Are COVID-19 patients with hypertension at higher risk in China?

negative: Potent MERS-CoV Fusion Inhibitory Peptides Identified from HR2 Domain in Spike Protein of Bat Coronavirus HKU4 The Middle East respiratory syndrome coronavirus (MERS-CoV) emerged in 2012 and caused continual outbreaks worldwide with high mortality. However, no effective anti-MERS-CoV drug is currently available. Recently, numerous evolutionary studies have suggested that MERS-CoV originated from bat coronavirus (BatCoV). We herein reported that three peptides derived from the HR2 region in spike protein of BatCoV HKU4, including HKU4-HR2P1, HKU4-HR2P2 and HKU4-HR2P3, could bind the MERS-CoV HR1-derived peptide to form a six-helix bundle (6-HB) with high stability. Moreover, these peptides, particularly HKU4-HR2P2 and HKU4-HR2P3, exhibited potent inhibitory activity against MERS-CoV S-mediated cell–cell fusion and viral infection, suggesting that these HKU4 HR2-derived peptides could be candidates for futher development as antiviral agents against MERS-CoV infection.

negative: Review on Machine and Deep Learning Models for the Detection and Prediction of Coronavirus The novel Coronavirus disease has increased rapidly in the Wuhan city of China in December 2019. This fatal virus has spread across the whole world like a fire in different stages and affecting millions of population and thousands of deaths worldwide. Therefore, it is essential to classify the infected people, so that they can take the precaution in the earlier stages. Also, due to the increasing cases spread of Coronavirus, there are only limited numbers of polymerase change reaction kits available in the hospitals for testing Coronavirus patients. That why it is extremely important to develop artificial intelligence-based automatic diagnostic tools to classify the Coronavirus outbreak. The objective of this paper is to know the novel disease epidemiology, major prevention from spreading of Coronavirus Severe Acute Respiratory Syndrome, and to assess the machine and deep learning-based architectures performance that is proposed in the present year for classification of Coronavirus images such as, X-Ray and computed tomography. Specifically, advanced deep learning-based algorithms known as the Convolutional neural network, which plays a great effect on extracting highly essential features, mostly in terms of medical images. This technique, with using CT and X-Ray image scans, has been adopted in most of the recently published articles on the Coronavirus with remarkable results. Furthermore, according to this paper, this can be noted and said that deep learning technology has potential clinical applications.

negative: Epidemiological and clinical features of COVID-19 patients with and without pneumonia in Beijing, China Background:SARS-CoV-2-caused coronavirus disease (COVID-19) is posinga large casualty. The features of COVID-19patients withand without pneumonia,SARS-CoV-2 transmissibility in asymptomatic carriers, and factors predicting disease progression remain unknown. Methods: We collected information on clinical characteristics, exposure history, andlaboratory examinations of all laboratory-confirmed COVID-19 patients admitted to PLA General Hospital. Cox regression analysis was applied to identify prognostic factors. The last follow-up was February 18, 2020. Results:We characterized 55 consecutive COVID-19 patients. The mean incubation was 8.42(95% confidence interval [CI], 6.55-10.29) days. The mean SARS-CoV-2-positive duration from first positive test to clearance was 9.71(95%CI, 8.21-11.22) days. COVID-19 course was approximately 2 weeks. Asymptomatic carriers might transmit SARS-CoV-2. Compared with patients without pneumonia, those with pneumonia were 15 years older and had a higher rate of hypertension, higher frequencies of having a fever and cough, and higher levels of interleukin-6 (14.61 vs. 8.06pg/mL, P=0.040), B lymphocyte proportion (13.0% vs.10.0%, P=0.024), low account (<190/μL) of CD8+ T cells (33.3% vs. 0, P=0.019). Multivariate Cox regression analysis indicated that circulating interleukin-6 andlactate independently predicted COVID-19 progression, with a hazard ratio (95%CI) of 1.052 (1.000-1.107) and 1.082 (1.013-1.155), respectively. During disease course,T lymphocytes were generally lower,neutrophils higher, in pneumonia patients than in pneumonia-free patients. CD8+ lymphocytes did not increase at the 20th days after illness onset. Conclusion: The epidemiological features areimportant for COVID-19 prophylaxis. Circulating interleukin-6 and lactateare independent prognostic factors. CD8+ T cell exhaustion might be critical in the development of COVID-19.

negative: Immune environment modulation in pneumonia patients caused by coronavirus: SARS-CoV, MERS-CoV and SARS-CoV-2 Currently, we are on a global pandemic of Coronavirus disease-2019 (COVID-19) which causes fever, dry cough, fatigue and acute respiratory distress syndrome (ARDS) that may ultimately lead to the death of the infected. Current researches on COVID-19 continue to highlight the necessity for further understanding the virus-host synergies. In this study, we have highlighted the key cytokines induced by coronavirus infections. We have demonstrated that genes coding interleukins (Il-1α, Il-1β, Il-6, Il-10), chemokine (Ccl2, Ccl3, Ccl5, Ccl10), and interferon (Ifn-α2, Ifn-β1, Ifn2) upsurge significantly which in line with the elevated infiltration of T cells, NK cells and monocytes in SARS-Cov treated group at 24 hours. Also, interleukins (IL-6, IL-23α, IL-10, IL-7, IL-1α, IL-1β) and interferon (IFN-α2, IFN2, IFN-γ) have increased dramatically in MERS-Cov at 24 hours. A similar cytokine profile showed the cytokine storm served a critical role in the infection process. Subsequent investigation of 463 patients with COVID-19 disease revealed the decreased amount of total lymphocytes, CD3+, CD4+, and CD8+ T lymphocytes in the severe type patients which indicated COVID-19 can impose hard blows on human lymphocyte resulting in lethal pneumonia. Thus, taking control of changes in immune factors could be critical in the treatment of COVID-19.

negative: Celiac and non-celiac gluten sensitivity: a review on the association with schizophrenia and mood disorders An association between many psychiatric and gluten-related disorders has been known for some time. In the case of schizophrenia and mood disorders, the major psychiatric disorders, there is much evidence, not without contradictions, of a possible association between schizophrenia and celiac disease. The association between mood disorders and gluten-related disorders, especially celiac disease, has only been studied for depression, often coupled with anxiety, and very recently for bipolar disorder. Since non-celiac gluten sensitivity is now known to be different from celiac disease, many studies have shown that gluten sensitivity is also associated with major psychiatric disorders. Here we review the literature on the association between schizophrenia/mood disorders and celiac disease/gluten sensitivity, pointing out the differences between these associations.

negative: High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa It has been reported that ACE2 is the main host cell receptor of 2019-nCoV and plays a crucial role in the entry of virus into the cell to cause the final infection. To investigate the potential route of 2019-nCov infection on the mucosa of oral cavity, bulk RNA-seq profiles from two public databases including The Cancer Genome Atlas (TCGA) and Functional Annotation of The Mammalian Genome Cap Analysis of Gene Expression (FANTOM5 CAGE) dataset were collected. RNA-seq profiling data of 13 organ types with para-carcinoma normal tissues from TCGA and 14 organ types with normal tissues from FANTOM5 CAGE were analyzed in order to explore and validate the expression of ACE2 on the mucosa of oral cavity. Further, single-cell transcriptomes from an independent data generated in-house were used to identify and confirm the ACE2-expressing cell composition and proportion in oral cavity. The results demonstrated that the ACE2 expressed on the mucosa of oral cavity. Interestingly, this receptor was highly enriched in epithelial cells of tongue. Preliminarily, those findings have explained the basic mechanism that the oral cavity is a potentially high risk for 2019-nCoV infectious susceptibility and provided a piece of evidence for the future prevention strategy in dental clinical practice as well as daily life.

negative: Patients with advanced basal cell carcinomas in treatment with sonic hedgehog inhibitors during the coronavirus disease 2019 (COVID-19) period: Management and adherence to treatment

negative: Differential Diagnosis of Common Acute Toxicologic Versus Nontoxicologic Illness This table outlines common toxicologic versus nontoxicologic rule outs based on clinical abnormalities seen in an acutely ill animal. The purpose is to provide an initial guideline for considering toxicologic versus nontoxicologic rule outs when a patient is presented to a practicing veterinarian. Major clinical abnormalities followed by common toxicologic rule outs and non-toxicologic rule outs have been listed so that practicing veterinarians can narrow down an etiology quickly. Based on history, physical examination findings, and blood work changes, once a reasonable etiology has been narrowed down or established, the reader is encouraged to review a more detailed discussion on management of the particular poisoning or disease listed in this or other references.

negative: Angiotensin-converting enzyme 2: Possible role in hypertension and kidney disease The discovery of angiotensin-converting enzyme (ACE) 2 adds a new level of complexity to the understanding of the renin-angiotensin system. The high catalytic efficiency of ACE2 for the generation of angiotensin (ANG)-1-7 from ANG II suggests an important role of ACE2 in preventing ANG II accumulation, while at the same time enhancing ANG-1-7 formation. ACE and ACE2 may have counterbalancing functions and a regulatory role in fine-tuning the rate at which ANG peptides are formed and degraded. By counterregulating the actions of ACE on ANG II formation, ACE2 may play a role in maintaining a balanced status of the renninangiotensin system. This review focuses on the function of ACE2 and its possible roles in kidney disease and hypertension. Studies using models of ACE2 ablation and the pharmacologic administration of an ACE2 inhibitor suggest that decreased ACE2 activity alone or in combination with increased ACE activity may play a role in both diseases.

negative: The interaction between severe acute respiratory syndrome coronavirus 3C-like proteinase and a dimeric inhibitor by capillary electrophoresis Abstract 3C-like proteinase of severe acute respiratory syndrome (SARS) coronavirus has been demonstrated to be a key target for drug design against SARS. The interaction between SARS coronavirus 3C-like (3CL) proteinase and an octapeptide interface inhibitor was studied by affinity capillary electrophoresis (ACE). The binding constants were estimated by the change of migration time of the analytes in the buffer solution containing different concentrations of SARS 3CL proteinase. The results showed that SARS 3CL proteinase was able to complex with the octapeptide competitively, with binding constants of 2.44×104 M−1 at 20°C and 2.11×104 M−1 at 37°C. In addition, the thermodynamic parameters deduced reveal that hydrophobic interaction might play major roles, along with electrostatic force, in the binding process. The ACE method used here could be developed to be an effective and simple way of applying large-scale drug screening and evaluation.

negative: A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing An outbreak of the novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 290,000 people since the end of 2019, killed over 12,000, and caused worldwide social and economic disruption(1,2). There are currently no antiviral drugs with proven efficacy nor are there vaccines for its prevention. Unfortunately, the scientific community has little knowledge of the molecular details of SARS-CoV-2 infection. To illuminate this, we cloned, tagged and expressed 26 of the 29 viral proteins in human cells and identified the human proteins physically associated with each using affinity- purification mass spectrometry (AP-MS), which identified 332 high confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 existing FDA-approved drugs, drugs in clinical trials and/or preclinical compounds, that we are currently evaluating for efficacy in live SARS-CoV-2 infection assays. The identification of host dependency factors mediating virus infection may provide key insights into effective molecular targets for developing broadly acting antiviral therapeutics against SARS-CoV-2 and other deadly coronavirus strains.

negative: TREC-COVID: Constructing a Pandemic Information Retrieval Test Collection TREC-COVID is a community evaluation designed to build a test collection that captures the information needs of biomedical researchers using the scientific literature during a pandemic. One of the key characteristics of pandemic search is the accelerated rate of change: the topics of interest evolve as the pandemic progresses and the scientific literature in the area explodes. The COVID-19 pandemic provides an opportunity to capture this progression as it happens. TREC-COVID, in creating a test collection around COVID-19 literature, is building infrastructure to support new research and technologies in pandemic search.

negative: Decades-old renin inhibitors are still struggling to find a niche in antihypertensive therapy. A fleeting look at the old and the promising new molecules Abstract Hypertension is a diverse illness interlinked with cerebral, cardiovascular (CVS) and renal abnormalities. Presently, the malady is being treated by focusing on Renin- angiotensin system (RAS), voltage-gated calcium channels, peripheral vasodilators, renal and sympathetic nervous systems. Cardiovascular and renal abnormalities are associated with the overactivation of RAS, which can be constrained by angiotensin- converting enzyme inhibitors (ACEIs), angiotensin II (Ang-II) -AT1 receptor blockers (ARBs) and renin inhibitors. The latter is a new player in the old system. The renin catalyzes the conversion of angiotensinogen to Angiotensin I (Ang-I). This can be overcome by inhibiting renin, a preliminary step, eventually hinders the occurrence of the cascade of events in the RAS. Various peptidomimetics, the first-generation renin inhibitors developed six decades ago have limited drug-like properties as they suffered from poor intestinal absorption, high liver first-pass metabolism and low oral bioavailability. The development of chemically diverse molecules from peptides to nonpeptides expanded the horizon to achieving direct renin inhibition. Aliskiren, a blockbuster drug that emerged as a clinical candidate and got approved by the US FDA in 2007 was developed by molecular modeling studies. Aliskiren indicated superior to average efficacy and with minor adverse effects relative to other RAS inhibitors. However, its therapeutic use is limited by poor oral bioavailability of less than 2% that is similar to first-generation peptidic compounds. In this review, we present the development of direct renin inhibitors (DRIs) from peptidic to nonpeptidics that lead to the birth of aliskiren, its place in the treatment of cardiovascular diseases and its limitations.

negative: Cardiovascular disease and COVID-19: implications for prevention, surveillance and treatment.

negative: Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody The newly identified 2019 novel coronavirus (2019-nCoV) has caused more than 11,900 laboratory-confirmed human infections, including 259 deaths, posing a serious threat to human health. Currently, however, there is no specific antiviral treatment or vaccine. Considering the relatively high identity of receptor-binding domain (RBD) in 2019-nCoV and SARS-CoV, it is urgent to assess the cross-reactivity of anti-SARS CoV antibodies with 2019-nCoV spike protein, which could have important implications for rapid development of vaccines and therapeutic antibodies against 2019-nCoV. Here, we report for the first time that a SARS-CoV-specific human monoclonal antibody, CR3022, could bind potently with 2019-nCoV RBD (KD of 6.3 nM). The epitope of CR3022 does not overlap with the ACE2 binding site within 2019-nCoV RBD. These results suggest that CR3022 may have the potential to be developed as candidate therapeutics, alone or in combination with other neutralizing antibodies, for the prevention and treatment of 2019-nCoV infections. Interestingly, some of the most potent SARS-CoV-specific neutralizing antibodies (e.g. m396, CR3014) that target the ACE2 binding site of SARS-CoV failed to bind 2019-nCoV spike protein, implying that the difference in the RBD of SARS-CoV and 2019-nCoV has a critical impact for the cross-reactivity of neutralizing antibodies, and that it is still necessary to develop novel monoclonal antibodies that could bind specifically to 2019-nCoV RBD.

negative: Retinal pathology in multiple sclerosis: insight into the mechanisms of neuronal pathology

negative: Pathology of infectious diseases: new agents, opportunistic, neglectable, emergent, reemergent diseases and why not super resistant nosocomial bacteria?

negative: Caring for persons in detention suffering with mental illness during the Covid-19 outbreak

negative: Role of the ACE2/Angiotensin 1-7 Axis of the Renin-Angiotensin System in Heart Failure. Heart failure (HF) remains the most common cause of death and disability, and a major economic burden, in industrialized nations. Physiological, pharmacological, and clinical studies have demonstrated that activation of the renin-angiotensin system is a key mediator of HF progression. Angiotensin-converting enzyme 2 (ACE2), a homolog of ACE, is a monocarboxypeptidase that converts angiotensin II into angiotensin 1-7 (Ang 1-7) which, by virtue of its actions on the Mas receptor, opposes the molecular and cellular effects of angiotensin II. ACE2 is widely expressed in cardiomyocytes, cardiofibroblasts, and coronary endothelial cells. Recent preclinical translational studies confirmed a critical counter-regulatory role of ACE2/Ang 1-7 axis on the activated renin-angiotensin system that results in HF with preserved ejection fraction. Although loss of ACE2 enhances susceptibility to HF, increasing ACE2 level prevents and reverses the HF phenotype. ACE2 and Ang 1-7 have emerged as a key protective pathway against HF with reduced and preserved ejection fraction. Recombinant human ACE2 has been tested in phase I and II clinical trials without adverse effects while lowering and increasing plasma angiotensin II and Ang 1-7 levels, respectively. This review discusses the transcriptional and post-transcriptional regulation of ACE2 and the role of the ACE2/Ang 1-7 axis in cardiac physiology and in the pathophysiology of HF. The pharmacological and therapeutic potential of enhancing ACE2/Ang 1-7 action as a novel therapy for HF is highlighted.

negative: A Tale of Two Communities: Characterizing Reddit Response to COVID-19 through /r/China_Flu and /r/Coronavirus The COVID-19 pandemic has deeply impacted people's lives around the globe. During the extended lockdowns caused by the pandemic, online communities are crucial for people to access information and share experiences. In particular, two"new"communities have emerged on Reddit: /r/China_flu and /r/Coronavirus. By studying activities and users in these two communities, we provide a characterization of people's responses to COVID-19 on Reddit. First, we find that user activity peaks around March 17, when the World Health Organization (WHO) announced COVID-19 as a pandemic. Shortly after that, the activity levels of both communities have been declining week by week. We further illustrate the central role of these two communities in the emergence of COVID-related communities. Second, we study the differences between these two communities. /r/Coronavirus is recommended as the official community for COVID-19 on Reddit, while /r/China_flu adopts a loose moderation practice. As a result, we observe that these two communities are gradually growing apart and more extremism is being found in /r/China_flu. Finally, we examine the spillover effect of the COVID-19 pandemic on user activity across the entire Reddit platform. Our results show significant changes in user activities outside COVID-related communities. In subreddits related to finance, food, and countries/cities, user activity is recovering to the pre-pandemic level in late April and May as countries reopen, but subreddits related to travel and sports remain highly impacted and show lower activity levels than the pre-pandemic period. Our work highlights the strength of Reddit as a source for understanding public reactions to COVID-19 and the importance of content moderation on the Internet during a pandemic.

negative: Chest CT features and their role in COVID-19 Abstract Since December 2019, the novel coronavirus disease (COVID-19) has spread rapidly throughout China. This article reviews the chest CT features of COVID-19 and analyzes the role of chest CT in this health emergency.

negative: Incidence, risk factors and clinical outcomes of acute kidney injury associated with scrub typhus: a retrospective study of 510 consecutive patients in South Korea (2001–2013) OBJECTIVES: Renal involvement in scrub typhus ranges from simple urinary abnormalities to acute kidney injury (AKI) leading to death. This study evaluated the incidence, predictors and prognosis of AKI associated with scrub typhus according to the RIFLE (risk, injury, failure, loss, end-stage kidney disease) criteria. METHODS: We retrospectively evaluated the medical records of patients diagnosed with scrub typhus from January 2001 to November 2013 in Gyeongsang National University Hospital. RESULTS: During the study period, 510 patients were diagnosed with scrub typhus and the incidence of AKI was 35.9%. There were 132 (25.9%) patients at risk, 37 (7.3%) with injury and 14 (2.7%) with failure. In comparison with the non-AKI group, the AKI group was older (73.9 vs 63.4 years, p<0.001) and had more comorbidities such as hypertension, diabetes mellitus and chronic kidney disease (CKD). AKI frequently occurs in hypertensive patients taking angiotensin receptor blockers or ACE inhibitors (p=0.002), and in patients with diabetes with higher glycated haemoglobin levels (p=0.033). Haematuria and proteinuria were more frequent in the AKI group. There was no relationship between the severity of proteinuria and occurrence of AKI. Intensive care unit admission and death were more frequent in the AKI group. The renal function of most patients with AKI recovered without sequelae, except for 1 patient who had underlying CKD. Multivariate analysis showed that age, presence of CKD, serum albumin level and time to hospital presentation after symptom onset were independent predictors of AKI in patients with scrub typhus. CONCLUSIONS: Our current results suggest that the presence of underlying CKD, older age, lower serum albumin level and time to hospital presentation after symptom onset were important risk factors to determine occurrence of AKI. Whether earlier diagnosis and treatment in patients with the above risk factors reduce the incidence and severity of AKI deserves to be investigated.

negative: A comprehensive Chinese experience against SARS-CoV-2 in ophthalmology The 2019 novel coronavirus disease (COVID-19) has now swept through the continents and poses a global threat to public health. Several investigations have been conducted to identify whether COVID-19 can be transmitted through the ocular route, and the conclusion is that it is a potential route but remains uncertain. Due to the face-to-face communication with patients, frequent exposure to tears and ocular discharge, and the unavoidable use of equipment which requires close proximity, ophthalmologists carry a high risk of contracting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Based on 33 articles published by Chinese scholars, guidelines and clinical practice experience in domestic hospitals, we have summarized the Chinese experience through the lens of ophthalmology, hoping to make a contribution to protecting ophthalmologists and patients around the world.

negative: Targeting the Vasoprotective Axis of the Renin-Angiotensin System: A Novel Strategic Approach to Pulmonary Hypertensive Therapy A decade has passed since the discovery of angiotensin-converting enzyme 2 (ACE2), a component of the ACE2–angiotensin (Ang)-(1-7)–Mas counterregulatory axis of the renin angiotensin system (RAS). ACE2 is considered an endogenous regulator of the vasoconstrictive, proliferative, fibrotic, and proinflammatory effects of the ACE–Ang II–angiotensin II type 1 receptor (AT(1)R) axis. Both animal and clinical studies have emerged to define a role for ACE2 in pulmonary arterial hypertension (PAH). There is scientific evidence supporting the concept that ACE2 maintains the RAS balance and plays a protective role in PAH. The activation of pulmonary ACE2 could influence the pathogenesis of PAH and serve as a novel therapeutic target in PAH. Current therapeutic strategies and interventions have limited success, and PAH remains a fatal disease. Thus, more research that establishes the novel therapeutic potential and defines the mechanism of the ACE2–Ang-(1-7)–Mas counterregulatory axis in PAH is needed.

negative: Do checkpoint inhibitors compromise the cancer patients’ immunity and increase the vulnerability to COVID-19 infection? The severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) has been declared a pandemic by the WHO that claimed the lives of thousands of people within a few months. Cancer patients represent a vulnerable population due to the acquired immunodeficiency associated with anti-cancer therapy. Immune checkpoint inhibitors have largely impacted the prognosis of a multitude of malignancies with significant improvement in survival outcomes and a different, tolerable toxicity profile. In this paper, we assess the safety of ICI administration in cancer patients during the coronavirus pandemic in order to guide the usage of these highly efficacious agents.

negative: Evolutionary origins of epidemic potential among human RNA viruses To have epidemic potential, a pathogen must be able to spread in human populations, but of human-infective RNA viruses only a minority can do so. We investigated the evolution of human transmissibility through parallel analyses of 1755 virus genome sequences from 39 RNA virus genera. We identified 57 lineages containing human-transmissible species and estimated that at least 74% of these lineages have evolved directly from non-human viruses in other mammals or birds, a public health threat recently designated “Disease X”. Human-transmissible viruses rarely evolve from virus lineages that can infect but not transmit between humans. This result cautions against focussing surveillance and mitigation efforts narrowly on currently known human-infective virus lineages and supports calls for a better understanding of RNA virus diversity in non-human hosts.

negative: Automated Real-Time Collection of Pathogen-Specific Diagnostic Data: Syndromic Infectious Disease Epidemiology BACKGROUND: Health care and public health professionals rely on accurate, real-time monitoring of infectious diseases for outbreak preparedness and response. Early detection of outbreaks is improved by systems that are comprehensive and specific with respect to the pathogen but are rapid in reporting the data. It has proven difficult to implement these requirements on a large scale while maintaining patient privacy. OBJECTIVE: The aim of this study was to demonstrate the automated export, aggregation, and analysis of infectious disease diagnostic test results from clinical laboratories across the United States in a manner that protects patient confidentiality. We hypothesized that such a system could aid in monitoring the seasonal occurrence of respiratory pathogens and may have advantages with regard to scope and ease of reporting compared with existing surveillance systems. METHODS: We describe a system, BioFire Syndromic Trends, for rapid disease reporting that is syndrome-based but pathogen-specific. Deidentified patient test results from the BioFire FilmArray multiplex molecular diagnostic system are sent directly to a cloud database. Summaries of these data are displayed in near real time on the Syndromic Trends public website. We studied this dataset for the prevalence, seasonality, and coinfections of the 20 respiratory pathogens detected in over 362,000 patient samples acquired as a standard-of-care testing over the last 4 years from 20 clinical laboratories in the United States. RESULTS: The majority of pathogens show influenza-like seasonality, rhinovirus has fall and spring peaks, and adenovirus and the bacterial pathogens show constant detection over the year. The dataset can also be considered in an ecological framework; the viruses and bacteria detected by this test are parasites of a host (the human patient). Interestingly, the rate of pathogen codetections, on average 7.94% (28,741/362,101), matches predictions based on the relative abundance of organisms present. CONCLUSIONS: Syndromic Trends preserves patient privacy by removing or obfuscating patient identifiers while still collecting much useful information about the bacterial and viral pathogens that they harbor. Test results are uploaded to the database within a few hours of completion compared with delays of up to 10 days for other diagnostic-based reporting systems. This work shows that the barriers to establishing epidemiology systems are no longer scientific and technical but rather administrative, involving questions of patient privacy and data ownership. We have demonstrated here that these barriers can be overcome. This first look at the resulting data stream suggests that Syndromic Trends will be able to provide high-resolution analysis of circulating respiratory pathogens and may aid in the detection of new outbreaks.

negative: In Vitro Reconstitution of SARS-Coronavirus mRNA Cap Methylation SARS-coronavirus (SARS-CoV) genome expression depends on the synthesis of a set of mRNAs, which presumably are capped at their 5′ end and direct the synthesis of all viral proteins in the infected cell. Sixteen viral non-structural proteins (nsp1 to nsp16) constitute an unusually large replicase complex, which includes two methyltransferases putatively involved in viral mRNA cap formation. The S-adenosyl-L-methionine (AdoMet)-dependent (guanine-N7)-methyltransferase (N7-MTase) activity was recently attributed to nsp14, whereas nsp16 has been predicted to be the AdoMet-dependent (nucleoside-2′O)-methyltransferase. Here, we have reconstituted complete SARS-CoV mRNA cap methylation in vitro. We show that mRNA cap methylation requires a third viral protein, nsp10, which acts as an essential trigger to complete RNA cap-1 formation. The obligate sequence of methylation events is initiated by nsp14, which first methylates capped RNA transcripts to generate cap-0 (7Me)GpppA-RNAs. The latter are then selectively 2′O-methylated by the 2′O-MTase nsp16 in complex with its activator nsp10 to give rise to cap-1 (7Me)GpppA(2′OMe)-RNAs. Furthermore, sensitive in vitro inhibition assays of both activities show that aurintricarboxylic acid, active in SARS-CoV infected cells, targets both MTases with IC(50) values in the micromolar range, providing a validated basis for anti-coronavirus drug design.

negative: Preliminary Estimates of the Prevalence of Selected Underlying Health Conditions Among Patients with Coronavirus Disease 2019 — United States, February 12–March 28, 2020 On March 11, 2020, the World Health Organization declared Coronavirus Disease 2019 (COVID-19) a pandemic (1). As of March 28, 2020, a total of 571,678 confirmed COVID-19 cases and 26,494 deaths have been reported worldwide (2). Reports from China and Italy suggest that risk factors for severe disease include older age and the presence of at least one of several underlying health conditions (3,4). U.S. older adults, including those aged ≥65 years and particularly those aged ≥85 years, also appear to be at higher risk for severe COVID-19-associated outcomes; however, data describing underlying health conditions among U.S. COVID-19 patients have not yet been reported (5). As of March 28, 2020, U.S. states and territories have reported 122,653 U.S. COVID-19 cases to CDC, including 7,162 (5.8%) for whom data on underlying health conditions and other known risk factors for severe outcomes from respiratory infections were reported. Among these 7,162 cases, 2,692 (37.6%) patients had one or more underlying health condition or risk factor, and 4,470 (62.4%) had none of these conditions reported. The percentage of COVID-19 patients with at least one underlying health condition or risk factor was higher among those requiring intensive care unit (ICU) admission (358 of 457, 78%) and those requiring hospitalization without ICU admission (732 of 1,037, 71%) than that among those who were not hospitalized (1,388 of 5,143, 27%). The most commonly reported conditions were diabetes mellitus, chronic lung disease, and cardiovascular disease. These preliminary findings suggest that in the United States, persons with underlying health conditions or other recognized risk factors for severe outcomes from respiratory infections appear to be at a higher risk for severe disease from COVID-19 than are persons without these conditions.

negative: Association between insertion/deletion polymorphism in angiotensin-converting enzyme gene and acute lung injury/acute respiratory distress syndrome: a meta-analysis BACKGROUND: A previous meta-analysis reported a positive association between an insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme gene (ACE) and the risk of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Here, we updated this meta-analysis and additionally assessed the association of this polymorphism with ALI/ARDS mortality. METHODS: We searched electronic databases through October 2011 for the terms “angiotensin-converting enzyme gene”, “acute lung injury”, and “acute respiratory distress syndrome,” and reviewed all studies that reported the relationship of the I/D polymorphism in ACE with ALI/ARDS in humans. Seven studies met the inclusion criteria, comprising 532 ALI/ARDS patients, 3032 healthy controls, and 1432 patients without ALI/ARDS. We used three genetic models: the allele, dominant, and recessive models. RESULTS: The ACE I/D polymorphism was not associated with susceptibility to ALI/ARDS for any genetic model. However, the ACE I/D polymorphism was associated with the mortality risk of ALI/ARDS in Asian subjects ( P(allele) < 0.0001, P(dominant) = 0.001, P(recessive) = 0.002). This finding remained significant after correction for multiple comparisons. CONCLUSIONS: There is a possible association between the ACE I/D polymorphism genotype and the mortality risk of ALI/ARDS in Asians.

negative: Approaches to the management of patients in oral and maxillofacial surgery during COVID-19 pandemic Oral and maxillofacial surgery is correlated with a high risk of SARS-CoV-2 transmission. Therefore, the aim of the review is to collect and discuss aspects of the management of patients in oral and maxillofacial surgery during the COVID-19 pandemic. In order to save resources and to avoid unnecessary exposure to infected patients, there is the need to schedule interventions depending on their priority. During the peak of the pandemic, no elective surgery should be performed. Even urgent procedures might be postponed if there is a view to recovery of a COVID-19 patient within a few days. Emergency procedures do not allow any delay. Specialties with overlap in therapies should have well defined arrangements among each other concerning the treatment spectra in order to avoid redundancy and loss of resources. Inpatient and outpatient units have to be organized in such a way that the risk of cross-infection among patients is reduced to a minimum. Especially, testing of patients for SARS-CoV-2 is important to detect the infected patients at an early stage. When surgery is performed on COVID-19 patients, adequate personal protective equipment is crucial. There must be negative pressure in the operating room, and aerosol formation must be reduced to a minimum. In order to address the COVID-19 challenge adequately, significant changes in the infrastructure of outpatient units, inpatient units, and operating rooms are needed. In addition, the demands concerning personal protective equipment increase significantly. The major aim is to protect patients as well as the medical staff from unnecessary infection, and to keep the healthcare system running effectively. Therefore, every effort should be taken to make the necessary investments.

negative: Angiotensin-converting enzyme 2 and renal disease. PURPOSE OF REVIEW The renin-angiotensin system (RAS) is a pivotal player in the physiology and pathophysiology of cardiovascular and renal systems. Discovery of angiotensin-converting enzyme 2 (ACE2), capable of cleaving RAS effector peptide angiotensin (Ang) II into biologically active Ang-(1-7), has increased the complexity of our knowledge of the RAS. ACE2 expression is abundant in the kidney and is thought to provide protection against injury. This review emphasizes current experimental and clinical findings that examine ACE2 in the context of kidney injury and its potential therapeutic impact for treatment of kidney disease. RECENT FINDINGS Clinical studies have reported upregulation of ACE2 in urine from diabetic patients, which may be reflective of pathological shedding of renal ACE2 as suggested by mechanistic experiments. Studies in experimental models have investigated the feasibility of pharmacological induction of ACE2 for improvement of renal function, inflammation, and fibrosis. SUMMARY Emerging concepts about the RAS indicate that ACE2 is a critical regulator of angiotensin peptide metabolism and the pathogenesis of renal disease. Human recombinant ACE2 is available and may be a practical clinical approach to enzyme replacement. Elucidating precise roles of ACE2 throughout disease progression will enrich our view of the RAS and help identify novel targets and appropriate strategies for intervention.

negative: Modulation of angiotensin II signaling in the prevention of fibrosis Over the last decade, it has become clear that the role of angiotensin II extends far beyond recognized renal and cardiovascular effects. The presence of an autologous renin-angiotensin system has been demonstrated in almost all tissues of the body. It is now known that angiotensin II acts both independently and in synergy with TGF-beta to induce fibrosis via the angiotensin type 1 receptor (AT(1)) in a multitude of tissues outside of the cardiovascular and renal systems, including pulmonary fibrosis, intra-abdominal fibrosis, and systemic sclerosis. Interestingly, recent studies have described a paradoxically regenerative effect of the angiotensin system via stimulation of the angiotensin type 2 receptor (AT(2)). Activation of AT(2) has been shown to ameliorate fibrosis in animal models of skeletal muscle, gastrointestinal, and neurologic diseases. Clinical reports suggest a beneficial role for modulation of angiotensin II signaling in cutaneous scarring. This article reviews current knowledge on the role that angiotensin II plays in tissue fibrosis, as well as current and potential therapies targeting this system.

negative: Guidelines for prevention of hospital acquired infections These guidelines, written for clinicians, contains evidence-based recommendations for the prevention of hospital acquired infections Hospital acquired infections are a major cause of mortality and morbidity and provide challenge to clinicians. Measures of infection control include identifying patients at risk of nosocomial infections, observing hand hygiene, following standard precautions to reduce transmission and strategies to reduce VAP, CR-BSI, CAUTI. Environmental factors and architectural lay out also need to be emphasized upon. Infection prevention in special subsets of patients - burns patients, include identifying sources of organism, identification of organisms, isolation if required, antibiotic prophylaxis to be used selectively, early removal of necrotic tissue, prevention of tetanus, early nutrition and surveillance. Immunodeficient and Transplant recipients are at a higher risk of opportunistic infections. The post tranplant timetable is divided into three time periods for determining risk of infections. Room ventilation, cleaning and decontamination, protective clothing with care regarding food requires special consideration. Monitoring and Surveillance are prioritized depending upon the needs. Designated infection control teams should supervise the process and help in collection and compilation of data. Antibiotic Stewardship Recommendations include constituting a team, close coordination between teams, audit, formulary restriction, de-escalation, optimizing dosing, active use of information technology among other measure. The recommendations in these guidelines are intended to support, and not replace, good clinical judgment. The recommendations are rated by a letter that indicates the strength of the recommendation and a Roman numeral that indicates the quality of evidence supporting the recommendation, so that readers can ascertain how best to apply the recommendations in their practice environments.

negative: Sudden Death from Pulmonary Causes This chapter seeks to survey many of the common pathological entities identified in the lungs at autopsy and the potential role of pulmonary disease in formulating an opinion regarding the cause of death. Appreciation of pulmonary pathology in the medicolegal context is important as it frequently contributes to the immediate or underlying mechanisms of death. The primacy of the lungs in breathing and their coordinated function with the cardiovascular system means that pulmonary failure can rapidly compromise tissue oxygenation and body chemistry, leading to an alteration in blood pH, hypoxic damage to downstream tissues and ultimately multiorgan failure and death. Moreover, given that the lungs have direct contact with the environment through inhalation and receive approximately 50% of the cardiac output with each beat of the heart, they may be adversely affected by hazardous agents from the outside world or other pathologic processes not primarily located in the lungs. The range of topics discussed herein is limited by design to deaths due to disease and largely foregoes discussion of more forensically relevant issues relating to toxicology or trauma. Furthermore, the content and format of this chapter is not intended to be encyclopedic, but rather attempts to highlight selected issues regarding pulmonary disease of potential relevance to surgical or forensic pathologists who perform medicolegal postmortem examinations.

negative: ACE2: from vasopeptidase to SARS virus receptor Abstract The zinc metallopeptidase angiotensin-converting enzyme 2 (ACE2) is the only known human homologue of the key regulator of blood pressure angiotensin-converting enzyme (ACE). Since its discovery in 2000, ACE2 has been implicated in heart function, hypertension and diabetes, with its effects being mediated, in part, through its ability to convert angiotensin II to angiotensin-(1–7). Unexpectedly, ACE2 also serves as the cellular entry point for the severe acute respiratory syndrome (SARS) virus and the enzyme is therefore a prime target for pharmacological intervention on several disease fronts.

negative: Informational needs assessment of non‐Hodgkin lymphoma survivors and their physicians

negative: Renin-angiotensin system: The unexpected flaw inside the human immune system revealed by SARS-CoV-2

negative: Angiotensin-Converting Enzyme 2 (ACE2) Is a Key Modulator of the Renin Angiotensin System in Health and Disease Angiotensin-converting enzyme 2 (ACE2) shares some homology with angiotensin-converting enzyme (ACE) but is not inhibited by ACE inhibitors. The main role of ACE2 is the degradation of Ang II resulting in the formation of angiotensin 1–7 (Ang 1–7) which opposes the actions of Ang II. Increased Ang II levels are thought to upregulate ACE2 activity, and in ACE2 deficient mice Ang II levels are approximately double that of wild-type mice, whilst Ang 1–7 levels are almost undetectable. Thus, ACE2 plays a crucial role in the RAS because it opposes the actions of Ang II. Consequently, it has a beneficial role in many diseases such as hypertension, diabetes, and cardiovascular disease where its expression is decreased. Not surprisingly, current therapeutic strategies for ACE2 involve augmenting its expression using ACE2 adenoviruses, recombinant ACE2 or compounds in these diseases thereby affording some organ protection.

negative: The RNA Virus Database http://virus.zoo.ox.ac.uk/rnavirusdb; http://hivweb.sanbi.ac.za/rnavirusdb; http://bioinf.cs.auckland.ac.nz/rnavirusdb; http://tree.bio.ed.ac.uk/rnavirusdb.

negative: Association between Serum Angiotensin-converting Enzyme 2 Level with Postoperative Morbidity and Mortality after Major Pulmonary Resection in Non-small Cell Lung Cancer Patients Background To explore the association between serum angiotensin-converting enzyme 2 (ACE2) levels and postoperative morbidity and mortality after major pulmonary resection in non-small cell lung cancer (NSCLC) patients. Methods Preoperative and postoperative serum ACE2 levels in 320 NSCLC patients who underwent major pulmonary resection were measured. The serum ACE2 levels on postoperative day 1 were divided into quartile categories. Results After adjustment for age, sex, body mass index, current smoking status, forced expiratory volume in 1 second, coronary heart disease, hypertension, diabetes mellitus, chronic obstructive pulmonary disease, and tumour clinical stages, the risk of developing postoperative morbidities was significantly higher in the lowest serum ACE2 level quartile than in the highest quartile (hazard ratio, 2.12; 95% CI, 1.57-6.23; p=0.008). NSCLC patients with a serum ACE2 level ≤3.21 ng/mL had significantly higher rates of pneumonia, pleural effusion, atrial fibrillation as well as higher in-hospital mortality after major pulmonary resection, compared with those with a serum ACE2 level >3.21ng/mL. Conclusions The serum ACE2 level one day post surgery is an independent risk factor for postoperative morbidities after major pulmonary resection in NSCLC patients. Thus, it could be used as a prognostic factor for postoperative morbidities after major pulmonary resection in NSCLC patients.

negative: A novel coronavirus (2019-nCoV) causing pneumonia-associated respiratory syndrome

negative: From SARS coronavirus to novel animal and human coronaviruses. In 2003, severe acute respiratory syndrome coronavirus (SARS-CoV) caused one of the most devastating epidemics known to the developed world. There were two important lessons from this epidemic. Firstly, coronaviruses, in addition to influenza viruses, can cause severe and rapidly spreading human infections. Secondly, bats can serve as the origin and natural animal reservoir of deadly human viruses. Since then, researchers around the world, especially those in Asia where SARS-CoV was first identified, have turned their focus to find novel coronaviruses infecting humans, bats, and other animals. Two human coronaviruses, HCoV-HKU1 and HCoV-NL63, were identified shortly after the SARS-CoV epidemic as common causes of human respiratory tract infections. In 2012, a novel human coronavirus, now called Middle East respiratory syndrome coronavirus (MERS-CoV), has emerged in the Middle East to cause fatal human infections in three continents. MERS-CoV human infection is similar to SARS-CoV in having a high fatality rate and the ability to spread from person to person which resulted in secondary cases among close contacts including healthcare workers without travel history to the Middle East. Both viruses also have close relationships with bat coronaviruses. New cases of MERS-CoV infection in humans continue to occur with the origins of the virus still unknown in many cases. A multifaceted approach is necessary to control this evolving MERS-CoV outbreak. Source identification requires detailed epidemiological studies of the infected patients and enhanced surveillance of MERS-CoV or similar coronaviruses in humans and animals. Early diagnosis of infected patients and appropriate infection control measures will limit the spread in hospitals, while social distancing strategies may be necessary to control the outbreak in communities if it remained uncontrolled as in the SARS epidemic.

negative: Angiotensin-converting enzyme insertion/deletion polymorphism associated with acute respiratory distress syndrome among caucasians. Studies investigating the association between angiotensin-converting enzyme (ACE) insertion/deletion polymorphisms and the risk of acute respiratory distress syndrome (ARDS) report conflicting results. The objective of the present study was to summarize quantitatively the evidence for such a relationship. Two investigators independently searched the MEDLINE (January 1966 - October 2009) and EMBASE (January 1980 - October 2009) databases. This meta-analysis included six case-control studies, which included 514 ARDS cases and 2619 controls. The combined results based on all studies showed that patients with ARDS had a significantly higher frequency of the ACE deletion/deletion (DD) genotype (odds ratio [OR] 1.56; 95% confidence interval [CI] 1.22, 2.00) than controls. When stratifying for race, no significant differences in genotype distribution were found except that Caucasian patients with ARDS had a significantly higher frequency of the DD genotype (OR 1.65; 95% CI 1.27, 2.13) than controls. This meta-analysis suggests that ACE insertion/deletion polymorphisms may be associated with ARDS among Caucasians.

negative: Abstracts from the 37th Annual Meeting of the Society of General Internal Medicine

negative: Devil and angel in the renin–angiotensin system: ACE–angiotensin II–AT(1) receptor axis vs. ACE2–angiotensin-(1–7)–Mas receptor axis Recent studies have established a new regulatory axis in the renin–angiotensin system (RAS). In this axis, angiotensin (Ang)-(1–7) is finally produced from Ang I or Ang II by the catalytic activity of angiotensin-converting enzyme 2 (ACE2). Ang-(1–7) shows actions different from those of AT(1) receptor stimulation, such as vasodilatation, natriuresis, anti-proliferation and an increase in the bradykinin–NO (nitric oxide) system. As the catalytic efficiency of ACE2 is approximately 400-fold higher with Ang II as a substrate than with Ang I, this axis is possibly acting as a counter-regulatory system against the ACE/Ang II/AT(1) receptor axis. The signaling pathway of the ACE2–Ang-(1–7) axis has not yet been totally and clearly understood. However, a recent report suggests that the Mas oncogene acts as a receptor for Ang-(1–7). Intracellular signaling through Mas is not clear yet. Several factors such as Akt phosphorylation, protein kinase C activation and mitogen-activated protein (MAP) kinase inhibition seem to be involved in this signaling pathway. Further investigations are needed to clarify the regulation and mechanism of action of ACE2 and Ang-(1–7). However, this second axis through ACE2 and Ang-(1–7) in RAS can be an important target for the therapy of cardiovascular and metabolic disorders.

negative: The phenotypic changes of Î³Î´ T cells in COVID-19 patients A novel pneumonia-associated respiratory syndrome named coronavirus disease-2019 (COVID-19), which caused by SARS-CoV-2 and broken in Wuhan, China in the end of 2019. Unfortunately, there is no specific antiviral agent or vaccine available to treat SARS-CoV-2 infections. Also, information regarding the immunological characteristics in COVID-19 patients remains limited. Here we collected the blood samples from 18 healthy donors (HD) and 38 COVID-19 patients to analyze changes in {gamma}{delta} T cells. In comparison to HD, the {gamma}{delta} T cells percentage was decreased. {gamma}{delta} T cells are able to immediately respond to SARS-CoV-2 infection and upregulate the activation marker CD25. In addition, the increased expression of CD4 in {gamma}{delta} T cells may serve as a biomarker for the assessment of SARS-CoV-2 infection.

negative: Hyperoxia downregulates angiotensin-converting enzyme-2 in human fetal lung fibroblasts BACKGROUND: Angiotensin (ANG) II is involved in experimental hyperoxia-induced lung fibrosis. Angiotensin-converting enzyme-2 (ACE-2) degrades ANG II and is thus protective, but is downregulated in adult human and experimental lung fibrosis. Hyperoxia is a known cause of chronic fibrotic lung disease in neonates, but the role of ACE-2 in neonatal lung fibrosis is unknown. We hypothesized that ACE-2 in human fetal lung cells might be downregulated by hyperoxic gas. METHODS: Fetal human lung fibroblast IMR90 cells were exposed to hyperoxic (95% O(2)/5% CO(2)) or normoxic (21% O(2)/5% CO(2)) gas in vitro. Cells and culture media were recovered separately for assays of ACE-2 enzymatic activity, mRNA, and immunoreactive protein. RESULTS: Hyperoxia decreased ACE-2 immunoreactive protein and enzyme activity in IMR90 cells (both P < 0.01), but did not change ACE-2 mRNA. ACE-2 protein was increased in the cell supernatant, suggesting protease-mediated ectodomain shedding. TAPI-2, an inhibitor of TNF-α−converting enzyme (TACE/ADAM17), prevented both the decrease in cellular ACE-2 and the increase in soluble ACE-2 (both P < 0.05). CONCLUSION: These data show that ACE-2 is expressed in fetal human lung fibroblasts but is significantly decreased by hyperoxic gas. They also suggest that hyperoxia decreases ACE-2 through a shedding mechanism mediated by ADAM17/TACE. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/pr.2015.27) contains supplementary material, which is available to authorized users.

negative: A systematic review of lopinavir therapy for SARS coronavirus and MERS coronavirus—A possible reference for coronavirus disease‐19 treatment option In the past few decades, coronaviruses have risen as a global threat to public health. Currently, the outbreak of coronavirus disease‐19 (COVID‐19) from Wuhan caused a worldwide panic. There are no specific antiviral therapies for COVID‐19. However, there are agents that were used during the severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) epidemics. We could learn from SARS and MERS. Lopinavir (LPV) is an effective agent that inhibits the protease activity of coronavirus. In this review, we discuss the literature on the efficacy of LPV in vitro and in vivo, especially in patients with SARS and MERS, so that we might clarify the potential for the use of LPV in patients with COVID‐19.

negative: Chapter 25 ACE2 Cell Biology, Regulation, and Physiological Functions Abstract Angiotensin-converting enzyme 2 (ACE2), discovered as a homologue of ACE, acts as its physiological counterbalance providing homeostatic regulation of circulating angiotensin II (Ang II) levels. ACE2 is a zinc metalloenzyme and carboxypeptidase located as an ectoenzyme on the surface of endothelial and other cells. While its primary substrate appears to be Ang II, it can hydrolyze a number of other physiological substrates. Additionally, ACE2 functions in other noncatalytic cellular roles including the regulation of intestinal neutral amino acid transport. It also serendipitously acts as the receptor for the severe acute respiratory syndrome virus. Upregulation of ACE2 expression and function is increasingly recognized as a potential therapeutic strategy in hypertension and cardiovascular disease, diabetes, lung injury, and fibrotic disorders. ACE2 is regulated at multiple levels including transcriptional, posttranscriptional (miRNA and epigenetic), and posttranslational through its shedding from the cell surface.

negative: 2018 ACVIM Forum Research Abstract Program: Seattle, Washington, June 14 ‐ 15, 2018

negative: Angiotensin converting enzyme-2 (ACE2) and its possible roles in hypertension, diabetes and cardiac function Angiotensin converting enzyme-2 (ACE2) is a recently described homologue of the vasoactive peptidase, angiotensin converting enzyme (ACE). Like ACE, ACE2 is an integral (type I) membrane zinc metallopeptidase, which exists as an ectoenzyme. ACE2 is less widely distributed than ACE in the body, being expressed at highest concentrations in the heart, kidney and testis. ACE2 also differs from ACE in its substrate specificity, functioning exclusively as a carboxypeptidase rather than a peptidyl dipeptidase. A key role for ACE2 appears to be emerging in the conversion of angiotensin II to angiotensin (1–7), allowing it to act as a counter-balance to the actions of ACE. ACE2 has been localised to the endothelial and epithelial cells of the heart and kidney where it may have a role at the cell surface in hydrolysing bioactive peptides such as angiotensin II present in the circulation. A role for ACE2 in the metabolism of other biologically active peptides also needs to be considered. ACE2 also serendipitously appears to act as a receptor for the severe acute respiratory syndrome (SARS) coronavirus. Studies usingace2 (−/−) mice, and other emerging studiesin vivo andin vitro, have revealed that ACE2 has important functions in cardiac regulation and diabetes. Together with its role as a SARS receptor, ACE2 is therefore likely to be an important therapeutic target in a diverse range of disease states.

negative: COVID-19 and diabetes: Can DPP4 inhibition play a role?

negative: Protein Crystallography in Drug Discovery

negative: Structure analysis of the receptor binding of 2019-nCoV Abstract 2019-nCoV is a newly identified coronavirus with high similarity to SARS-CoV. We performed a structural analysis of the receptor binding domain (RBD) of spike glycoprotein responsible for entry of coronaviruses into host cells. The RBDs from the two viruses share 72% identity in amino acid sequences, and molecular simulation reveals highly similar ternary structures. However, 2019-nCoV has a distinct loop with flexible glycyl residues replacing rigid prolyl residues in SARS-CoV. Molecular modeling revealed that 2019-nCoV RBD has a stronger interaction with angiotensin converting enzyme 2 (ACE2). A unique phenylalanine F486 in the flexible loop likely plays a major role because its penetration into a deep hydrophobic pocket in ACE2. ACE2 is widely expressed with conserved primary structures throughout the animal kingdom from fish, amphibians, reptiles, birds, to mammals. Structural analysis suggests that ACE2 from these animals can potentially bind RBD of 2019-nCoV, making them all possible natural hosts for the virus. 2019-nCoV is thought to be transmitted through respiratory droplets. However, since ACE2 is predominantly expressed in intestines, testis, and kidney, fecal-oral and other routes of transmission are also possible. Finally, antibodies and small molecular inhibitors that can block the interaction of ACE2 with RBD should be developed to combat the virus.

negative: Nelfinavir inhibits replication of severe acute respiratory syndrome coronavirus 2 in vitro In December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, Hubei Province, China. No specific treatment has been established against coronavirus disease-2019 (COVID-19) so far. Therefore, it is urgently needed to identify effective antiviral agents for the treatment of this disease, and several approved drugs such as lopinavir have been evaluated. Here, we report that nelfinavir, an HIV-1 protease inhibitor, potently inhibits replication of SARS-CoV-2. The effective concentrations for 50% and 90% inhibition (EC50 and EC90) of nelfinavir were 1.13 µM and 1.76 µM respectively, the lowest of the nine HIV-1 protease inhibitors including lopinavir. The trough and peak serum concentrations of nelfinavir were three to six times higher than EC50 of this drug. These results suggest that nelfinavir is a potential candidate drug for the treatment of COVID-19 and should be assessed in patients with COVID-19.

negative: Lack of Antiviral Activity of Darunavir against SARS-CoV-2 Given the high need and the absence of specific antivirals for treatment of COVID-19 (the disease caused by severe acute respiratory syndrome-associated coronavirus-2 [SARS-CoV-2]), human immunodeficiency virus (HIV) protease inhibitors are being considered as therapeutic alternatives. Prezcobix/Rezolsta is a fixed-dose combination of 800 mg of the HIV protease inhibitor darunavir (DRV) and 150 mg cobicistat, a CYP3A4 inhibitor, which is indicated in combination with other antiretroviral agents for the treatment of HIV infection. There are currently no definitive data on the safety and efficacy of DRV/cobicistat for treatment of COVID-19. The in vitro antiviral activity of darunavir against a clinical isolate from a patient infected with SARS-CoV-2 was assessed. DRV showed no activity against SARS-CoV-2 at clinically relevant concentrations (EC50 >100 μM). Remdesivir, used as a positive control, showed potent antiviral activity (EC50 = 0.38 μM). Overall, the data do not support the use of DRV for treatment of COVID-19.

negative: ACE2-Ang-(1-7)-Mas Axis in Brain: A Potential Target for Prevention and Treatment of Ischemic Stroke The renin-angiotensin system (RAS) in brain is a crucial regulator for physiological homeostasis and diseases of cerebrovascular system, such as ischemic stroke. Overactivation of brain Angiotensin-converting enzyme (ACE) - Angiotensin II (Ang II) - Angiotensin II type 1 receptor (AT(1)R) axis was found to be involved in the progress of hypertension, atherosclerosis and thrombogenesis, which increased the susceptibility to ischemic stroke. Besides, brain Ang II levels have been revealed to be increased in ischemic tissues after stroke, and contribute to neural damage through elevating oxidative stress levels and inducing inflammatory response in the ischemic hemisphere via AT(1)R. In recent years, new components of RAS have been discovered, including ACE2, Angiotensin-(1–7) [Ang-(1-7)] and Mas, which constitute ACE2-Ang-(1-7)-Mas axis. ACE2 converts Ang II to Ang-(1-7), and Ang-(1-7) binds with its receptor Mas, exerting benefical effects in cerebrovascular disease. Through interacting with nitric oxide and bradykinin, Ang-(1-7) could attenuate the development of hypertension and the pathologic progress of atherosclerosis. Besides, its antithrombotic activity also prevents thrombogenic events, which may contribute to reduce the risk of ischemic stroke. In addition, after ischemia insult, ACE2-Ang-(1-7)-Mas has been shown to reduce the cerebral infarct size and improve neurological deficits through its antioxidative and anti-inflammatory effects. Taken together, activation of the ACE2-Ang-(1-7)-Mas axis may become a novel therapeutic target in prevention and treatment of ischemia stroke, which deserves further investigations.

negative: Meplazumab treats COVID-19 pneumonia: an open-labelled, concurrent controlled add-on clinical trial Background: SARS-CoV-2 is a novel human coronavirus, there is no specific antiviral drugs. It has been proved that host-cell-expressed CD147 could bind spike protein of SARS-CoV-2 and involve in host cell invasion. Antibody against CD147 could block the infection of SARS-CoV-2. We aimed to assess the efficacy and safety of meplazumab, a humanized anti-CD147 antibody, as add-on therapy in patients with COVID-19 pneumonia. Methods: All patients received recommended strategy from Diagnosis and Treatment for 2019 Novel Coronavirus Diseases released by National Health Commission of China. Eligible patients were add-on administered 10 mg meplazumab intravenously at days 1, 2, and 5. Patients hospitalized in the same period were observed as concurrent control. The endpoints include virological clearance rate, case severity, chest radiographic, and laboratory test. This trial was approved by the Ethics Committee of Institution at the Tangdu hospital, and registered with ClinicalTrials.gov, NCT 04275245. Findings:17 patients were enrolled and assigned to meplazumab group between Feb 3, 2020 and Feb 10, 2020. 11 hospitalized patients served as concurrent control. Baseline characteristics were generally balanced across two groups. Compared to control group, meplazumab treatment significantly improved the discharged (p=0.006) and case severity (p=0.021) in critical and severe patients. The time to virus negative in meplazumab group was reduced than that in control group (median 3, 95%CI[1.5-4.5] vs. 13, [6.5-19.5]; p=0.014, HR=0.37, 95%CI[0.155-0.833]). The percentages of patients recovered to the normal lymphocyte count and CRP concentration were also increased remarkably and rapidly in meplazumab group. No adverse effect was found in meplazumab-treated patients. Interpretation:Meplazumab efficiently improved the recovery of patients with SARS-CoV-2 pneumonia with a favorable safety profile. Our results support to carry out a large-scale investigation of meplazumab as a treatment for COVID-19 pneumonia. Funding:National Science and Technology Major Project.

negative: Alterations in Gene Expression of Components of the Renin-Angiotensin System and Its Related Enzymes in Lung Cancer OBJECTIVES: The study assessed the existence and significance of associations between the expression of fifteen renin-angiotensin system component genes and lung adenocarcinoma. MATERIALS AND METHODS: NCBI's built-in statistical tool, GEO2R, was used to calculate Student's t-tests for the associations found in a DNA expression study of adenocarcinoma and matched healthy lung tissue samples. The raw data was processed with GeneSpring™ and then used to generate figures with and without Sidak's multiple comparison correction. RESULTS: Ten genes were found to be significantly associated with adenocarcinoma. Seven of these associations remained statistically significant after correction for multiple comparisons. Notably, AGTR2, which encodes the AT(2) angiotensin II receptor subtype, was significantly underexpressed in adenocarcinoma tissue (p < 0.01). AGTR1, ACE, ENPEP, MME, and PRCP, which encode the AT(1) angiotensin II receptor, angiotensin-converting enzyme, aminopeptidase N, neprilysin, and prolylcarboxypeptidase, respectively, were also underexpressed. AGT, which encodes angiotensinogen, the angiotensin peptide precursor, was overexpressed in adenocarcinoma tissue. CONCLUSION: The results suggest an association between the expression of the genes for renin-angiotensin system-related proteins and adenocarcinoma. While further research is necessary to conclusively demonstrate a link between the renin-angiotensin system and lung cancers, the results suggest that the renin-angiotensin system plays a role in the pathology of adenocarcinoma.

negative: The site of origin of the 1918 influenza pandemic and its public health implications

negative: COVID-19 control in China during mass population movements at New Year

negative: Quantifying tetrahedral adduct formation and stabilization in the cysteine and the serine proteases Abstract Two new papain inhibitors have been synthesized where the terminal α-carboxyl groups of Z-Phe-Ala-COOH and Ac-Phe-Gly-COOH have been replaced by a proton to give Z-Phe-Ala-H and Ac-Phe-Gly-H. We show that for papain, replacing the terminal carboxylate group of a peptide inhibitor with a hydrogen atom decreases binding 3–4 fold while replacing an aldehyde or glyoxal group with a hydrogen atom decreases binding by 300,000–1,000,000 fold. Thiohemiacetal formation by papain with aldehyde or glyoxal inhibitors is shown to be ~10,000 times more effective than hemiacetal or hemiketal formation with chymotrypsin. It is shown using effective molarities, that for papain, thiohemiacetal stabilization is more effective with aldehyde inhibitors than with glyoxal inhibitors. The effective molarity obtained when papain is inhibited by an aldehyde inhibitor is similar to the effective molarity obtained when chymotrypsin is inhibited by glyoxal inhibitors showing that both enzymes can stabilize tetrahedral adducts by similar amounts. Therefore the greater potency of aldehyde and glyoxal inhibitors with papain is not due to greater thiohemiacetal stabilization by papain compared to the hemiketal and hemiacetal stabilization by chymotrypsin, instead it reflects the greater intrinsic reactivity of the catalytic thiol group of papain compared to the catalytic hydroxyl group of chymotrypsin. It is argued that while the hemiacetals and thiohemiacetals formed with the serine and cysteine proteases respectively can mimic the catalytic tetrahedral intermediate they are also analogues of the productive and non-productive acyl intermediates that can be formed with the cysteine and serine proteases.

negative: Sequence variation among SARS-CoV-2 isolates in Taiwan Taiwan experienced two waves of imported cases of coronavirus disease 2019 (COVID-19), first from China in January to late February, followed by those from other countries starting in early March. Additionally, several cases could not be traced to any imported cases and were suspected as sporadic local transmission. Twelve full viral genomes were determined in this study by Illumina sequencing either from virus isolates or directly from specimens, among which 5 originated from clustered infections. Phylogenetic tree analysis revealed that these sequences were in different clades, indicating that no major strain has been circulating in Taiwan. A deletion in open reading frame 8 was found in one isolate. Only a 4-nucleotide difference was observed among the 5 genomes from clustered infections.

negative: A rate equation approach to model the denaturation or replication behavior of the SARS coronavirus As a newly emerging virus, little is known about the SARS coronavirus, whose outbreak has brought away several hundred people’s lives over the world in the year of 2003 and is seriously imperiling the human health. Revealing the denaturation and replication mechanisms of SARS coronavirus has great importance for successfully fighting SARS. However, experiments related to SARS coronavirus are extremely dangerous and therefore restricted only to certain specific labs with high safety standard. Clearly, predicting the behaviors of SARS coronavirus in a wide variety of environmental conditions, which are not easily accessible, are thus critically necessary. In this study, we proposed to quantify the survival time of SARS coronavirus either in vitro or in vivo, through introducing thermal rate process models established from the well-known Arrhenius law. The complex physical and chemical behaviors of the SARS coronavirus can then be attributed to its activation energy, frequency factor, damage function as well as the surrounding environmental conditions. Based on the first data on stability and resistance of SARS coronavirus measured by members of WHO laboratory network, the rate coefficients involved in the above equations were estimated for the first time. Predictions on the survival time of SARS coronavirus in different temperature scale were then performed. It was found theoretically that, such survival time falls in an extremely wide range, say from several seconds in high temperature to an almost infinitely long time in a low temperature environment, which has already or is being supported by the currently available tests data. Applications of the present theory to interpret several existing phenomena were presented and their implementations in developing new technical ways for SARS prevention and clinical therapy were discussed. Uncertainties involved in the theoretical models were also analyzed and predicted. Parametric studies were performed to test the effects of the rate coefficients to the survival time of SARS coronavirus. Some important factors, which can significantly vary the denaturation or replication process of SARS coronavirus were pointed out. Through regulating the parameters involved in the equation, certain potential therapies either through drug delivery or engineering approach to treat the SARS disease can possibly be established. Extension of the present model for further studies was also suggested. This study opens a new theoretical way for probing into the complex behaviors of SARS coronavirus. Modellierung der Denaturierung oder Repliziryng von SARS-Korona-Viren Zusammenfassung Der Kenntnisstand über die Eigenschaften des in 2003 neu aufgetretenen SARS Korona Virus, der einige Hundert Menschenleben gekostet hat, ist relativ gering. Die Ermittlung des Denaturierungs- und Replizierungsmechanismuses des SARS Virus ist für seine Bekämpfung von hoher Bedeutung. Experimentelle Untersuchungen an diesem extrem gefährlichen Virus dürfen nur durch Laboratorien mit einem hohen Sicherheitsstandard erfolgen. Die Vorhersage des Verhaltens des SARS Virus in unterschiedlichen Umgebungsbedingungen ist dabei erforderlich. In der vorliegenden Studie wird die überlebensdauer des Virus unter Labor- und realen Bedingungen durch Anwendung der bekannten Arrhenius-Beziehung für temperaturabhängige Vorgänge ermittelt. Das physikalische und chemische Verhalten des SARS Virus wird anhand der zugrundeliegenden Modell- Parameter beschrieben. Basierend auf den ersten Messungen von Mitgliedern des WHO-laboratory-network über die Stabilität und Widerstandsfähigkeit des Virus wurden erstmalig die Geschwindigkeitskoeffizienten des Berechnungsmodells bestimmt. Vorhersagen der Überlebensdauer des SARS-Virus unter unterschiedlichen Temperaturbedingungen wurden ausgeführt. Das sich hieraus ergebende, sehr unterschiedliche Ausmaß der Überlebensfähigkeit in Abhängigkeit der Umgebungstemperatur ist durch den Vergleich mit verfügbaren experimentellen Ergebnissen bestätigt worden. Die Anwendung der vorgestellten Modellierung zur Interpretation realer Phänomene und zur Entwicklung technischer Maßnahmen zur Vorbeugung und klinischen Therapierung von SARS wird diskutiert. Der Einfluß von Unsicherheiten des Modells wird analysiert und abgeschätzt. Parametrische Studien sind durchgeführt worden, um den Einfluß der Geschwindigkeitskoeffizienten auf die Überlebensdauer des SARS Virus darzustellen. Einige wichtige Einflußgrößen auf die Denaturierung und Replikationsfähigkeit des SARS Virus werden aufgezeigt. Durch eine Variation der Modellparameter kann die potentielle Wirksamkeit medikamentöser oder physikalischer Therapien abgeschätzt werden. Erweiterungsmöglichkeiten des vorgestellten Modells werden vorgeschlagen. Die vorliegende Studie ermöglicht neue, theoretische Vorgehensweisen zur Untersuchung des komplexen Verhaltensmusters des SARS Virus.

negative: Highly ACE2 Expression in Pancreas May Cause Pancreas Damage After SARS-CoV-2 Infection The ongoing outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) started in the end of 2019 in China has triggered a global public health crisis. Previous studies have shown that SARS-CoV-2 infects cells by binding angiotensin-converting enzyme 2 (ACE2), which is the same as SARS-CoV. The expression and distribution of ACE2 in the pancreas are unknown. At the same time, the injury of pancreas after SARS-CoV-2 infection has not been concerned. Here, we collected public datasets (bulk RNA-seq and single-cell RNA-seq) to indicate the expression and the distribution of ACE2 in pancreas (in both exocrine glands and islets). And further, clinical data including mild and severe patients with COVID-19 demonstrated there existed mild pancreatitis. In the 67 severe cases, 11 patients (16.41%) showed elevated levels of both amylase and lipase, and 5 patients (7.46%) showed imaging alterations. Only one patient (1.85%) showed elevated levels of both amylase and lipase in 54 mild cases, without imaging changes. Our study revealed the phenomenon and possible cause of mild pancreatic injury in patients with COVID-19. This suggests that pancreatitis after SARS-CoV-2 infection should also be paid attention in clinical work.

negative: Host-microbial interactions in patients with chronic rhinosinusitis There has been considerable investigation of host-microbial interactions in patients with chronic rhinosinusitis (CRS) in hopes of elucidating mechanisms of disease and better treatment. Most attention has been paid to bacterial infection and potential underlying defects in innate immunity. Bacterial biofilm is present in most patients with CRS undergoing surgical intervention, and its presence is associated with more severe disease and worse surgical outcomes. A role for viral or fungal infection in patients with CRS is less clear. There is no evidence for a primary defect in mucociliary clearance in most patients with CRS. Decreased levels of certain antimicrobial proteins, most notably lactoferrin, have been found in sinus secretions, whereas levels of other antimicrobial proteins have been found to be normal. No primary defects in Toll-like receptors have been found in patients with CRS, although a 50% reduced expression of Toll-like receptor 9 was reported in patients with recalcitrant nasal polyps. A polymorphism in a bitter taste receptor was recently associated with refractory CRS and persistent Pseudomonas aeruginosa infection. A downregulation of innate immunity by maladaptive TH2 tissue inflammation has also been described in patients with recalcitrant nasal polyps, suggesting a link to persistent infection. To date, an effective means of restoring host-microbial balance and mitigating disease in patients with CRS remains elusive.

negative: Absence of association between angiotensin converting enzyme polymorphism and development of adult respiratory distress syndrome in patients with severe acute respiratory syndrome: a case control study BACKGROUND: It has been postulated that genetic predisposition may influence the susceptibility to SARS-coronavirus infection and disease outcomes. A recent study has suggested that the deletion allele (D allele) of the angiotensin converting enzyme (ACE) gene is associated with hypoxemia in SARS patients. Moreover, the ACE D allele has been shown to be more prevalent in patients suffering from adult respiratory distress syndrome (ARDS) in a previous study. Thus, we have investigated the association between ACE insertion/deletion (I/D) polymorphism and the progression to ARDS or requirement of intensive care in SARS patients. METHOD: One hundred and forty genetically unrelated Chinese SARS patients and 326 healthy volunteers were recruited. The ACE I/D genotypes were determined by polymerase chain reaction and agarose gel electrophoresis. RESULTS: There is no significant difference in the genotypic distributions and the allelic frequencies of the ACE I/D polymorphism between the SARS patients and the healthy control subjects. Moreover, there is also no evidence that ACE I/D polymorphism is associated with the progression to ARDS or the requirement of intensive care in the SARS patients. In multivariate logistic analysis, age is the only factor associated with the development of ARDS while age and male sex are independent factors associated with the requirement of intensive care. CONCLUSION: The ACE I/D polymorphism is not directly related to increased susceptibility to SARS-coronavirus infection and is not associated with poor outcomes after SARS-coronavirus infection.

negative: Angiotensin II treatment in COVID-19 patients: more risk than benefit? A single-center experience

negative: Rethinking the Renin-Angiotensin System and Its Role in Cardiovascular Regulation Angiotensin-converting enzyme (ACE) plays a pivotal role in the renin-angiotensin system (RAS) and ACE-inhibitors are widely used in several clinical conditions, including hypertension and heart failure. Recently, a homologue of ACE, ACE(2) has been discovered. Both ACE and ACE(2) are emerging as key enzymes of the RAS, where ACE(2) may play a role as negative regulator of ACE. Moreover, ACE(2) appears to be an important enzyme outside the classical RAS, as it hydrolyzes apelins, dynorphin A 1-13, des-Arg-bradykinin and other peptide substrates. The precise interplay between tissue ACE, ACE(2), and their substrates and by-products are presently still unclear. ACE-inhibitors reduce angiotensin II formation and bradykinin degradation, but do not inhibit ACE(2) activity. Moreover, ACE-inhibitors differ in their affinity for tissue ACE, and it has been suggested that tissue ACE affinity might be responsible for some of the beneficial properties of these drugs. ACE-inhibitors also increase nitric oxide availability, and activate several kinases that may regulate protein synthesis by interacting with the nucleus of the cells (outside-in signaling). The outside-in signaling may also be activated by bradykinin itself. Although, the precise significance of the outside-in signaling is still unclear, this new role of ACE-inhibitors may represent a discriminant factor versus angiotensin II receptors antagonists. This mini review will summarize some new aspects concerning the recently discovered biological functions of RAS and in particular of ACE, ACE(2) and ACE-inhibitors in cardiovascular system.

negative: The COVID-19 pandemic: Important considerations for contact lens practitioners A novel coronavirus (CoV), the Severe Acute Respiratory Syndrome Coronavirus - 2 (SARS-CoV-2), results in the coronavirus disease 2019 (COVID-19). As information concerning the COVID-19 disease continues to evolve, patients look to their eye care practitioners for accurate eye health guidance. There is currently no evidence to suggest an increased risk of contracting COVID-19 through contact lens (CL) wear compared to spectacle lens wear and no scientific evidence that wearing standard prescription spectacles provides protection against COVID-19 or other viral transmissions. During the pandemic there will potentially be significant changes in access to local eyecare. Thus, it is imperative CL wearers are reminded of the steps they should follow to minimise their risk of complications, to reduce their need to leave isolation and seek care. Management of adverse events should be retained within optometric systems if possible, to minimise the impact on the wider healthcare service, which will be stretched. Optimal CL care behaviours should be the same as those under normal circumstances, which include appropriate hand washing (thoroughly with soap and water) and drying (with paper towels) before both CL application and removal. Daily CL cleaning and correct case care for reusable CL should be followed according to appropriate guidelines, and CL exposure to water must be avoided. Where the availability of local clinical care is restricted, practitioners should consider advising patients to reduce or eliminate sleeping in their CL (where patients have the appropriate knowledge about correct daily care and access to suitable lens-care products) or consider the option of moving patients to daily disposable lenses (where patients have appropriate lens supplies available). Patients should also avoid touching their face, including their eyes, nose and mouth, with unwashed hands and avoid CL wear altogether if unwell (particularly with any cold or flu-like symptoms).

negative: Peptide aldehyde inhibitors challenge the substrate specificity of the SARS-coronavirus main protease Abstract SARS coronavirus main protease (SARS-CoV Mpro) is essential for the replication of the virus and regarded as a major antiviral drug target. The enzyme is a cysteine protease, with a catalytic dyad (Cys-145/His-41) in the active site. Aldehyde inhibitors can bind reversibly to the active-site sulfhydryl of SARS-CoV Mpro. Previous studies using peptidic substrates and inhibitors showed that the substrate specificity of SARS-CoV Mpro requires glutamine in the P1 position and a large hydrophobic residue in the P2 position. We determined four crystal structures of SARS-CoV Mpro in complex with pentapeptide aldehydes (Ac-ESTLQ-H, Ac-NSFSQ-H, Ac-DSFDQ-H, and Ac-NSTSQ-H). Kinetic data showed that all of these aldehydes exhibit inhibitory activity towards SARS-CoV Mpro, with Ki values in the μM range. Surprisingly, the X-ray structures revealed that the hydrophobic S2 pocket of the enzyme can accommodate serine and even aspartic-acid side-chains in the P2 positions of the inhibitors. Consequently, we reassessed the substrate specificity of the enzyme by testing the cleavage of 20 different tetradecapeptide substrates with varying amino-acid residues in the P2 position. The cleavage efficiency for the substrate with serine in the P2 position was 160-times lower than that for the original substrate (P2=Leu); furthermore, the substrate with aspartic acid in the P2 position was not cleaved at all. We also determined a crystal structure of SARS-CoV Mpro in complex with aldehyde Cm-FF-H, which has its P1-phenylalanine residue bound to the relatively hydrophilic S1 pocket of the enzyme and yet exhibits a high inhibitory activity against SARS-CoV Mpro, with Ki =2.24±0.58μM. These results show that the stringent substrate specificity of the SARS-CoV Mpro with respect to the P1 and P2 positions can be overruled by the highly electrophilic character of the aldehyde warhead, thereby constituting a deviation from the dogma that peptidic inhibitors need to correspond to the observed cleavage specificity of the target protease.

negative: Systematic Comparison of Two Animal-to-Human Transmitted Human Coronaviruses: SARS-CoV-2 and SARS-CoV After the outbreak of the severe acute respiratory syndrome (SARS) in the world in 2003, human coronaviruses (HCoVs) have been reported as pathogens that cause severe symptoms in respiratory tract infections. Recently, a new emerged HCoV isolated from the respiratory epithelium of unexplained pneumonia patients in the Wuhan seafood market caused a major disease outbreak and has been named the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This virus causes acute lung symptoms, leading to a condition that has been named as “coronavirus disease 2019” (COVID-19). The emergence of SARS-CoV-2 and of SARS-CoV caused widespread fear and concern and has threatened global health security. There are some similarities and differences in the epidemiology and clinical features between these two viruses and diseases that are caused by these viruses. The goal of this work is to systematically review and compare between SARS-CoV and SARS-CoV-2 in the context of their virus incubation, originations, diagnosis and treatment methods, genomic and proteomic sequences, and pathogenic mechanisms.

negative: Robotic-assisted spleen preserving distal pancreatectomy: a technical review. Minimally-invasive spleen-preserving distal pancreatectomy is indicated for benign or borderline malignant lesions confined to the pancreatic body and tail. With the introduction of the da Vinci robotic system, preliminary case series have suggested an improved spleen preservation rate, higher rate of margin negative resections and improved lymph node yield versus the standard laparoscopic approach. In this article, we described our approach to robotic-assisted distal pancreatectomy with both vessel-conserving (Kimura) and vessel-sacrificing (Warshaw) variations.

negative: Upregulation of hepatic angiotensin-converting enzyme 2 (ACE2) and angiotensin-(1–7) levels in experimental biliary fibrosis Background/Aims Angiotensin-converting enzyme 2 (ACE2), its product, angiotensin-(1–7) and its receptor, Mas, may moderate the adverse effects of angiotensin II in liver disease. We examined the expression of these novel components of the renin angiotensin system (RAS) and the production and vasoactive effects of angiotensin-(1–7) in the bile duct ligated (BDL) rat. Methods BDL or sham-operated rats were sacrificed at 1, 2, 3 and 4 weeks. Tissue and blood were collected for gene expression, enzyme activity and peptide measurements. In situ perfused livers were used to assess angiotensin peptide production and their effects on portal resistance. Results Hepatic ACE2 gene and activity (P <0.0005), plasma angiotensin-(1–7) (P <0.0005) and Mas receptor expression (P <0.01) were increased following BDL compared to shams. Perfusion experiments confirmed that BDL livers produced increased angiotensin-(1–7) (P <0.05) from angiotensin II and this was augmented (P <0.01) by ACE inhibition. Whilst angiotensin II increased vasoconstriction in cirrhotic livers, angiotensin-(1–7) had no effect on portal resistance. Conclusions RAS activation in chronic liver injury is associated with upregulation of ACE2, Mas and hepatic conversion of angiotensin II to angiotensin-(1–7) leading to increased circulating angiotensin-(1–7). These results support the presence of an ACE2-angiotensin-(1–7)-Mas axis in liver injury which may counteract the effects of angiotensin II.

negative: No evidence of SARS-CoV-2 in semen of males recovering from COVID-19 Abstract Objective To describe detection of SARS-CoV-2 in seminal fluid of patients recovering from COVID-19 and describe the expression profile of ACE2 and TMPRSS2 within the testicle. Design observational, cross-sectional study Setting Tertiary referral center Patients Thirty-four adult Chinese males diagnosed with COVID-19 through confirmatory quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) from pharyngeal swab samples Intervention None Main Outcome Measures Identification of SARS-CoV-2 on qRT-PCR of single ejaculated semen samples. Semen quality was not assessed. Expression patterns of ACE2 and TMPRSS2 in the human testis are explored through previously published single-cell transcriptome datasets. Results Six patients (19%) demonstrated scrotal discomfort concerning for viral orchitis around the time of COVID-19 confirmation. SARS-CoV-2 was not detected in semen after a median of 31 days (IQR: 29-36 days) from COVID-19 diagnosis. Single-cell transcriptome analysis demonstrates sparse expression of ACE2 and TMPRSS2, with almost no overlapping gene expression. Conclusions SARS-CoV-2 was not detected in the semen of patients recovering from COVID-19 one month after COVID-19 diagnosis. ACE2-mediated viral entry of SARS-CoV-2 into target host cells is unlikely to occur within the human testicle based on ACE2 and TMPRSS2 expression. The long-term effects of SARS-CoV-2 on male reproductive function remain unknown.

negative: From SARS to MERS, Thrusting Coronaviruses into the Spotlight Coronaviruses (CoVs) have formerly been regarded as relatively harmless respiratory pathogens to humans. However, two outbreaks of severe respiratory tract infection, caused by the severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV), as a result of zoonotic CoVs crossing the species barrier, caused high pathogenicity and mortality rates in human populations. This brought CoVs global attention and highlighted the importance of controlling infectious pathogens at international borders. In this review, we focus on our current understanding of the epidemiology, pathogenesis, prevention, and treatment of SARS-CoV and MERS-CoV, as well as provides details on the pivotal structure and function of the spike proteins (S proteins) on the surface of each of these viruses. For building up more suitable animal models, we compare the current animal models recapitulating pathogenesis and summarize the potential role of host receptors contributing to diverse host affinity in various species. We outline the research still needed to fully elucidate the pathogenic mechanism of these viruses, to construct reproducible animal models, and ultimately develop countermeasures to conquer not only SARS-CoV and MERS-CoV, but also these emerging coronaviral diseases.

negative: Membrane-associated zinc peptidase families: comparing ACE and ACE2 Abstract In contrast to the relatively ubiquitous angiotensin-converting enzyme (ACE), expression of the mammalian ACE homologue, ACE2, was initially described in the heart, kidney and testis. ACE2 is a type I integral membrane protein with its active site domain exposed to the extracellular surface of endothelial cells and the renal tubular epithelium. Here ACE2 is poised to metabolise circulating peptides which may include angiotensin II, a potent vasoconstrictor and the product of angiotensin I cleavage by ACE. To this end, ACE2 may counterbalance the effects of ACE within the renin–angiotensin system (RAS). Indeed, ACE2 has been implicated in the regulation of heart and renal function where it is proposed to control the levels of angiotensin II relative to its hypotensive metabolite, angiotensin-(1–7). The recent solution of the structure of ACE2, and ACE, has provided new insight into the substrate and inhibitor profiles of these two key regulators of the RAS. As the complexity of this crucial pathway is unravelled, there is a growing interest in the therapeutic potential of agents that modulate the activity of ACE2.

negative: Angiotensin-converting enzyme 2 in lung diseases The renin-angiotensin system (RAS) plays a key role in maintaining blood pressure homeostasis, as well as fluid and salt balance. Angiotensin II, a key effector peptide of the system, causes vasoconstriction and exerts multiple biological functions. Angiotensin-converting enzyme (ACE) plays a central role in generating angiotensin II from angiotensin I, and capillary blood vessels in the lung are one of the major sites of ACE expression and angiotensin II production in the human body. The RAS has been implicated in the pathogenesis of pulmonary hypertension and pulmonary fibrosis, both commonly seen in chronic lung diseases such as chronic obstructive lung disease. Recent studies indicate that the RAS also plays a critical role in acute lung diseases, especially acute respiratory distress syndrome (ARDS). ACE2, a close homologue of ACE, functions as a negative regulator of the angiotensin system and was identified as a key receptor for SARS (severe acute respiratory syndrome) coronavirus infections. In the lung, ACE2 protects against acute lung injury in several animal models of ARDS. Thus, the RAS appears to play a critical role in the pathogenesis of acute lung injury. Indeed, increasing ACE2 activity might be a novel approach for the treatment of acute lung failure in several diseases.

negative: The old but new: Can unfractioned heparin and low molecular weight heparins inhibit proteolytic activation and cellular internalization of SARS-CoV2 by inhibition of host cell proteases? Currently, our world is facing the 2019 Novel Coronavirus (COVID-19) outbreak and tremendous efforts are made for developing drugs to treat and vaccines to prevent the disease. At present, there is no specific antiviral drug or vaccine for COVID-19. The pathogenic infectivity of the virus requires the S1 subunit of the spike (S) protein to bind the host cell receptor, angiontensin converting enzyme (ACE2). While the binding to host cell receptor is the first step of infection, the entrance of the virus into the cell needs the cleavage of S1–S2 subunits to expose S2 for fusion to cell membrane via host proteases including cathepsins, cell surface transmembrane protease/serine (TMPRSS) proteases, furin, trypsin and factor Xa. Previous in vitro studies have shown that factor Xa inhibition can decrease viral infectivity. We suppose that host cell proteases including furin (as expressed highly in lungs), factor Xa and cathepsin are possible targets to decrease viral burden, therefore unfractioned heparin and low molecular weight heparin-LMWH (specifically dalteparin and tinzaparin for their anti inflammatory action) can be potential inhibitors of multiple endoproteases involved in virus infectivity. Our hypothesis needs to be tested in in vitro and clinical studies, however as we are in an urgent situation as the burden of SARS-CoV2 is increasing all around the world, we recommend the usage of unfractioned heparin or LMWH in intensive care unit (ICU) and non-ICU hospitalized patients with the risk–benefit judgement of the clinician. Whether our hypothesis is clinically applicable and successful in decreasing viral infection will be evaluated for further studies.

negative: Brain angiotensin‐converting enzymes: role of angiotensin‐converting enzyme 2 in processing angiotensin II in mice Angiotensin (Ang)‐converting enzyme 2 (ACE2) metabolizes Ang II to the vasodilatory peptide Ang(1–7), while neprilysin (NEP) generates Ang(1–7) from Ang I. Experiments used novel Surface Enhanced Laser Desorption Ionization‐Time of Flight (SELDI‐TOF) mass spectroscopic (MS) assays to study Ang processing. Mass spectroscopy was used to measure proteolytic conversion of Ang peptide substrates to their specific peptide products. We compared ACE/ACE2 activity in plasma, brain and kidney from C57BL/6 and NEP (−/−) mice. Plasma or tissue extracts were incubated with Ang I or Ang II (1296 or 1045, m/z, respectively), and generated peptides were monitored with MS. Angiotensin‐converting enzyme 2 activity was detected in kidney and brain, but not in plasma. Brain ACE2 activity was highest in hypothalamus. Angiotensin‐converting enzyme 2 activity was inhibited by the specific ACE2 inhibitor, DX600 (10 μm, 99% inhibition), but not by the ACE inhibitor, captopril (10 μm). Both MS and colorimetric assays showed high ACE activity in plasma and kidney with low levels in brain. To extend these findings, ACE measurements were made in ACE overexpressing mice. Angiotensin‐converting enzyme four‐copy mice showed higher ACE activity in kidney and plasma with low levels in hypothalamus. In hypothalamus from NEP (−/−) mice, generation of Ang(1–7) from Ang I was decreased, suggesting a role for NEP in Ang metabolism. With Ang II as substrate, there was no difference between NEP (−/−) and wild‐type control mice, indicating that other enzymes may contribute to generation of Ang(1–7). The data suggest a predominant role of hypothalamic ACE2 in the processing of Ang II, in contrast to ACE, which is most active in plasma.

negative: The potential SARS-CoV-2 entry inhibitor Outbreak of coronavirus disease 2019 (COVID-19) occurred in Wuhan and has rapidly spread to almost all parts of world. In coronaviruses, the receptor binding domain (RBD) in the distal part of S1 subunit of SARS-CoV-2 spike protein can directly bind to angiotensin converting enzyme 2 (ACE2). RBD promote viral entry into the host cells and is an important therapeutic target. In this study, we discovered that theaflavin showed the lower idock score (idock score: −7.95 kcal/mol). To confirm the result, we discovered that theaflavin showed FullFitness score of −991.21 kcal/mol and estimated ΔG of −8.53 kcal/mol for the most favorable interaction with contact area of SARS-CoV-2 RBD by SwissDock service. Regarding contact modes, hydrophobic interactions contribute significantly in binding and additional hydrogen bonds were formed between theaflavin and Arg454, Phe456, Asn460, Cys480, Gln493, Asn501 and Val503 of SARS-CoV-2 RBD, near the direct contact area with ACE2. Our results suggest that theaflavin could be the candidate of SARS-CoV-2 entry inhibitor for further study.

negative: Metabolism of Bradykinin by Peptidases in Health and Disease This chapter provides an overview of the metabolism of bradykinin (BK) by peptidases in health and disease. The enzymatic breakdown of kinins affects the duration of their biological actions as the plasma half-life of intravenously injected BK is in the range of seconds. Kinins are cleaved in vitro and in vivo by enzymes that belong to families, such as zinc-metallopeptidases, astacin-like metallopeptidases, and catheptic enzymes. Vane noted the importance of the pulmonary circulation in the metabolism of vasoactive substances, such as BK as well as angiotensin 1 and 5- hydroxytryptamine. It is clear after decades of research that angiotensin 1-converting enzyme (ACE) on the vascular endothelial cell surface is the most important inactivator of blood-borne BK. BK may act primarily in an autocrine and paracrine fashion, establishing the importance of local regulation of its activity by enzymes on cell surfaces. Thus, the assortment of other enzymes that can inactivate BK is important in a variety of physiological and pathological situations. Most physiological systems have redundant pathways of metabolism so that the abolishment of one pathway is compensated for by the presence of others. This is demonstrated by the pharmacological inhibition of ACE in hypertension.

negative: Scorpion venom components as potential candidates for drug development Abstract Scorpions are well known for their dangerous stings that can result in severe consequences for human beings, including death. Neurotoxins present in their venoms are responsible for their toxicity. Due to their medical relevance, toxins have been the driving force in the scorpion natural compounds research field. On the other hand, for thousands of years, scorpions and their venoms have been applied in traditional medicine, mainly in Asia and Africa. With the remarkable growth in the number of characterized scorpion venom components, several drug candidates have been found with the potential to tackle many of the emerging global medical threats. Scorpions have become a valuable source of biologically active molecules, from novel antibiotics to potential anticancer therapeutics. Other venom components have drawn attention as useful scaffolds for the development of drugs. This review summarizes the most promising candidates for drug development that have been isolated from scorpion venoms.

negative: Risk assessment of progression to severe conditions for patients with COVID-19 pneumonia: a single-center retrospective study Background: Management of high mortality risk due to significant progression requires prior assessment of time-to-progression. However, few related methods are available for COVID-19 pneumonia. Methods: We retrospectively enrolled 338 adult patients admitted to one hospital between Jan 11, 2020 to Feb 29, 2020. The final follow-up date was March 8, 2020. We compared characteristics between patients with severe and non-severe outcome, and used multivariate survival analyses to assess the risk of progression to severe conditions. Results: A total of 76 (31.9%) patients progressed to severe conditions and 3 (0.9%) died. The mean time from hospital admission to severity onset is 3.7 days. Age, body mass index (BMI), fever symptom on admission, co-existing hypertension or diabetes are associated with severe progression. Compared to non-severe group, the severe group already demonstrated, at an early stage, abnormalities in biomarkers indicating organ function, inflammatory responses, blood oxygen and coagulation function. The cohort is characterized with increasing cumulative incidences of severe progression up to 10 days after admission. Competing risks survival model incorporating CT imaging and baseline information showed an improved performance for predicting severity onset (mean time-dependent AUC = 0.880). Conclusions: Multiple predisposition factors can be utilized to assess the risk of progression to severe conditions at an early stage. Multivariate survival models can reasonably analyze the progression risk based on early-stage CT images that would otherwise be misjudged by artificial analysis.

negative: What’s new in the renin-angiotensin system?: Angiotensin-converting enzyme-2: a molecular and cellular perspective Angiotensin-converting enzyme-2 (ACE2) is the first human homologue of ACE to be described. ACE2 is a type I integral membrane protein which functions as a carboxypeptidase, cleaving a single hydrophobic/basic residue from the C-terminus of its substrates. ACE2 efficiently hydrolyses the potent vasoconstrictor angiotensin II to angiotensin (1–7). It is a consequence of this action that ACE2 participates in the renin-angiotensin system. However, ACE2 also hydrolyses dynorphin A (1–13), apelin-13 and des-Arg(9) bradykinin. The role of ACE2 in these peptide systems has yet to be revealed. A physiological role for ACE2 has been implicated in hypertension, cardiac function, heart function and diabetes, and as a receptor of the severe acute respiratory syndrome coronavirus. This paper reviews the biochemistry of ACE2 and discusses key findings such as the elucidation of crystal structures for ACE2 and testicular ACE and the development of ACE2 inhibitors that have now provided a basis for future research on this enzyme.

negative: Discovering drugs to treat coronavirus disease 2019 (COVID-19). The SARS-CoV-2 virus emerged in December 2019 and then spread rapidly worldwide, particularly to China, Japan, and South Korea. Scientists are endeavoring to find antivirals specific to the virus. Several drugs such as chloroquine, arbidol, remdesivir, and favipiravir are currently undergoing clinical studies to test their efficacy and safety in the treatment of coronavirus disease 2019 (COVID-19) in China; some promising results have been achieved thus far. This article summarizes agents with potential efficacy against SARS-CoV-2.

negative: A Multicentre Study of 2019 Novel Coronavirus Disease Outcomes of Cancer Patients in Wuhan, China Background: At present, there is a global pandemic of coronavirus disease 2019 (COVID-19) pneumonia. Two previous case series from China have suggested that cancer patients are at a higher risk of COVID-19 pneumonia, but the reports were limited by small numbers and few clinical information. Objective: To study clinical characteristics and outcomes of cancer patients infected with COVID-19. Design: Retrospective study. Setting: Four designated COVID-16 hospitals in Wuhan, Hubei province, China. Participants: Medical records of 67 cancer patients admitted to hospitals between Jan 5, 2020 to Feb 18, 2020 were included. Measurements: Demographic, clinical, laboratory, radiological and treatment data were collected. Survival data of the cohort was cut-off on Mar 10, 2020. Results: Of the 67 patients (median age: 66 years), the median age of patients who had severe illness was older than that of patients who had mild symptoms (P<0.001). Forty-three (64.2%) patients had other concurrent chronic diseases, and the proportion of severe patients had co-morbidities was higher than patients with mild disease (P=0.004). Twenty-three (34.3%) patients were still at the anticancer treatment phase, but no tumour progression and recurrence was observed for all the patients during the treatment of COVID-19 pneumonia. About 70% of these patients had fever (n=53, 79.1%) and/or cough (n=50, 74.6%). Lymphocytopenia was the main laboratory finding accompanying increased C-reactive protein and procalcitonin in cancer patients, especially in severe cases. By Mar 10, 2020, 18 (26.9%) patients died from COVID-19, and 39 (58.2%) patients have been discharged. The median age of survivors was younger than that of deaths (P=0.014). Lung cancer (n=15, 22.4%) with COVID-19 was the most common cancer type and accounted for the highest proportion COVID-19 resulted deaths (33.3%, 5/15). We observed a tendency that patients at the follow-up phase had a better prognosis than that at anticancer treatment phase (P=0.095). Limitation: This is a retrospective study with only 67 cases from four hospitals. And some specific clinical information was insufficient. Conclusion: This study showed COVID-19 patients with cancer seem to have a higher proportion of severe cases and poorer prognosis. The tendency of poor prognosis was more obvious in patients at anticancer treatment phase. We should pay more intensive attentions to cancer patients infected with COVID-19.

negative: Achievements and highlights for Infection, Disease and Health

negative: Reply to “Comments on Fouchier’s Calculation of Risk and Elapsed Time for Escape of a Laboratory-Acquired Infection from His Laboratory”

negative: Coronavirus 2019-nCoV: A brief perspective from the front line Abstract A novel coronavirus, designated as 2019-nCoV, hit the central Chinese city of Wuhan in late December 2019, and subsequently spread rapidly to all provinces of China and multiple countries. As of 0:00 am February 9, 2020, a total of 37,287 cases have been confirmed infection of 2019-nCoV in China mainland, and 302 cases have also been cumulatively reported from 24 countries. According to the latest data, a total of 813 deaths occurred in China mainland, with the mortality reaching approximately 2.2%. At present, there is no vaccine or specific drugs for the human coronavirus. Therefore, it is critical to understand the nature of the virus and its clinical characteristics, in order to respond to the 2019-nCoV outbreak. Thus, the present study briefly but comprehensively summarizes the not much but timely reports on the 2019-nCoV.

negative: Nicotianamine is a novel angiotensin-converting enzyme 2 inhibitor in soybean. Angiotensin-converting enzyme 2 (ACE2) is a carboxypeptidase which is highly homologous to angiotensin-converting enzyme (ACE). ACE2 produces vasodilator peptides angiotensin 1-7 from angiotensin II. In the present study, we synthesized various internally quenched fluorogenic (IQF) substrates (fluorophore-Xaa-Pro-quencher) based on the cleavage site of angiotensin II introducing N-terminal fluorophore N-methylanthranilic acid (Nma) and C-terminal quencher N(ε)-2,4- dinitrophenyl-lysine [Lys(Dnp)]. The synthesized mixed substrates "Nma-Xaa-Pro-Lys(Dnp)" were hydrolyzed by recombinant human (rh) ACE2. The amount of each product was determined by liquid chromatography mass spectrometry (LC-MS) with fluorescence detection and it was found that Nma-His-Pro-Lys(Dnp) is the most suitable substrate for rhACE2. The K(m), k(cat), and k(cat)/K(m) values of Nma-His-Pro-Lys(Dnp) on rhACE2 were determined to be 23.3 μM, 167 s(-1), and 7.17 μM(-1) s(-1), respectively. Using the rhACE2 and the newly developed IQF substrate, we found rhACE2 inhibitory activity in soybean and isolated the active compound soybean ACE2 inhibitor (ACE2iSB). The physicochemical data on the isolated ACE2iSB were identical to those of nicotianamine. ACE2iSB strongly inhibited rhACE2 activity with an IC50 value of 84 nM. This is the first demonstration of an ACE2 inhibitor from foodstuffs.

negative: Right ventricular aneurysm and atrial septal defect in a cat Abstract This case report shows the development of a right ventricular aneurysm in a cat with a large atrial septal defect. Despite this complex cardiac pathology, the cat lived normally for more than 4 years and developed fatal congestive heart failure.

negative: Any possible role of phosphodiesterase type 5 inhibitors in the treatment of severe COVID19 infections? A lesson from urology

negative: Current knowledge about the antivirals remdesivir (GS-5734) and GS-441524 as therapeutic options for coronaviruses Abstract Recent international epidemics of coronavirus-associated illnesses underscore the urgent medical and public health need for vaccine development and regulatory body approved therapies. In particular, the current coronavirus disease 2019 (COVID-19) pandemic has quickly intensified interest in developing treatment options to mitigate impact on human life. Remdesivir (GS-5734™) is a broad-spectrum antiviral drug that is now being tested as a potential treatment for COVID-19 in international, multi-site clinical trials. Currently available evidence about the antiviral effects of remdesivir against coronaviruses is primarily based on in vitro and in vivo studies (including some on a chemically related compound, GS-441524™), which have demonstrated largely favorable findings. As the pandemic progresses, information from human compassionate use cases will continue to accumulate before the clinical trials are concluded. It is imperative for public health practitioners and the One Health community to stay up to date on the most promising potential therapeutic options that are under investigation. Thus, the purpose of this review is to synthesize the knowledge to date about remdesivir as a therapeutic option for coronaviruses, with a special focus on information relevant to the One Health community.

negative: Spike protein recognition of mammalian ACE2 predicts the host range and an optimized ACE2 for SARS-CoV-2 infection Abstract SARS-CoV-2 causes the recent global COVID-19 public health emergency. ACE2 is the receptor for both SARS-CoV-2 and SARS-CoV. To predict the potential host range of SARS-CoV-2, we analyzed the key residues of ACE2 for recognizing S protein. We found that most of the selected mammals including pets (dog and cat), pangolin and Circetidae mammals remained the most of key residues for association with S protein from SARS-CoV and SARS-CoV-2. The interaction interface between cat/dog/pangolin/Chinese hamster ACE2 and SARS-CoV/SARS-CoV-2 S protein was simulated through homology modeling. We identified that N82 in ACE2 showed a closer contact with SARS-CoV-2 S protein than M82 in human ACE2. Our finding will provide important insights into the host range of SARS-CoV-2 and a new strategy to design an optimized ACE2 for SARS-CoV-2 infection.

negative: Evolution of Bcl-2 homology (BH) motifs – homology versus homoplasy Bcl-2 family proteins regulate apoptosis in animals. This protein family includes several homologous proteins and a collection of other proteins lacking sequence similarity except for a BH3 motif. Thus, membership in the Bcl-2 family requires only one of the four BH (Bcl-2 homology) motifs. On this basis, a growing number of diverse BH3-only proteins are being reported. While compelling cell biological and biophysical evidence validates many BH3-only proteins, claims about significant BH3 sequence similarity are often unfounded. Computational and phylogenetic analyses suggest that only some BH3 motifs arose by divergent evolution from a common ancestor (homology), while others arose by convergent evolution or random coincidence (homoplasy), challenging current assumptions about which proteins constitute the extended Bcl-2 family.

negative: COVID-19: Epidemiology, Evolution, and Cross-Disciplinary Perspectives The recent outbreak of COVID-19 in Wuhan turned into a public health emergency of international concern. With no antiviral drugs nor vaccines, and the presence of carriers without obvious symptoms, traditional public health intervention measures are significantly less effective. Here, we report the epidemiological and virological characteristics of the COVID-19 outbreak. Originated in bats, 2019-nCoV/ severe acute respiratory syndrome coronavirus (SARS-CoV)-2 likely experienced adaptive evolution in intermediate hosts before transfer to humans at a concentrated source of transmission. Similarities of receptor sequence binding to 2019-nCoV between humans and animals suggest a low species barrier for transmission of the virus to farm animals. We propose, based on the One Health model, that veterinarians and animal specialists should be involved in a cross-disciplinary collaboration in the fight against this epidemic.

negative: Characterization of the first angiotensin-converting like enzyme in bacteria: Ancestor ACE is already active Abstract Angiotensin-converting enzyme (ACE) is a metallopeptidase that converts angiotensin I into angiotensin II. ACE is crucial in the control of cardiovascular and renal homeostasis and fertility in mammals. In vertebrates, both transmembrane and soluble ACE, containing one or two active sites, have been characterized. So far, only soluble, single domain ACEs from invertebrates have been cloned, and these have been implicated in reproduction in insects. Furthermore, an ACE-related carboxypeptidase was recently characterized in Leishmania, a unicellular eukaryote, suggesting the existence of ACE in more distant organisms. Interestingly, in silico databank analysis revealed that bacterial DNA sequences could encode putative ACE-like proteins, strikingly similar to vertebrates' enzymes. To gain more insight into the bacterial enzymes, we cloned the putative ACE from the phytopathogenic bacterium, Xanthomonas axonopodis pv. citri, named XcACE. The 2 kb open reading frame encodes a 672-amino-acid soluble protein containing a single active site. In vitro expression and biochemical characterization revealed that XcACE is a functional 72 kDa dipeptidyl-carboxypeptidase. As in mammals, this metalloprotease hydrolyses angiotensin I into angiotensin II. XcACE is sensitive to ACE inhibitors and chloride ions concentration. Variations in the active site residues, highlighted by structural modelling, can account for the different substrate selectivity and inhibition profile compared to human ACE. XcACE characterization demonstrates that ACE is an ancestral enzyme, provoking questions about its appearance and structure/activity specialisation during the course of evolution.

negative: Neuropeptidases Neuropeptides are neurotransmitters and modulators distributed in the central nervous system (CNS) and peripheral nervous system. Their abnormalities cause neurological and mental diseases. Neuropeptidases are enzymes crucial for the biosynthesis and biodegradation of neuropeptides. We here focus on the peptidases involved in the metabolism of the well-studied opioid peptides. Bioactive enkephalins are formed from propeptides by processing enzymes—prohormone thiol protease, prohormone convertase 1 and 2 (PC 1 and 2), carboxypeptidase H/E, and Arg/Lys aminopeptidase. After they exert their biological effects, enkephalins are likely to be inactivated by degrading enzymes—angiotensin-converting enzyme (ACE), aminopeptidase N (APN), puromycin-sensitive aminopeptidase (PSA), and endopeptidase 24.11. Recently, a neuron-specific aminopeptidase (NAP), which was a putative enkephalin-inactivating enzyme at the synapses, was found. Neuropeptidases are useful drug targets and their inhibitors can be therapeutic. Synthetic anti-enkephalinases and anti-aminopeptidases are being developed. They are potent analgesics but have fewer side effects than the opiates.

negative: Topographic Changes in SARS Coronavirus–infected Cells at Late Stages of Infection Scanning electron and atomic force microscopy was used for the first time to view the maturation of the severe acute respiratory syndrome–associated coronavirus at the cell surface. The surface form of the cells at advanced infection displayed prolific pseudopodia that, in addition to the rest of the plasma membrane, were also active sites of virus release. High magnification of the maturing virus particles showed a rosette appearance with short knoblike spikes under both the scanning electron and atomic force microscopes. The final expulsion step of the maturing virus particles seemed to result in some disruptions to the plasma membrane. The cytoskeletal network along the edge of the infected cells was enhanced and could be involved in transporting and expelling the progeny virus particles. Thickening of the actin filaments at the cell edge provided the bending force to extrude the virus particles.

negative: COVID-19: combining antiviral and anti-inflammatory treatments

negative: Validation of a novel severe acute respiratory syndrome scoring system() STUDY OBJECTIVE: In a pilot study conducted during March 14 to April 2, 2003, 2 severe acute respiratory syndrome (SARS) screening scores were developed for predicting SARS among febrile patients presenting to the emergency department (ED). The objective of this study is to validate these scoring systems with a different set of patients. METHODS: All adult patients with documented fever, measured at home or at the hospital, and presenting to the ED of National Taiwan University Hospital, a 2,400-bed tertiary care teaching hospital in northern Taiwan, were prospectively enrolled. Two previously developed SARS screening scores were applied to all patients. The final diagnosis of SARS was made by the Expert Committee of the Center for Disease Control Taiwan, Republic of China, according to the criteria of Centers for Disease Control and Prevention, Atlanta, GA. RESULTS: A total of 239 adult patients, including 117 men and 122 women, were enrolled. Eighty-two patients were finally diagnosed with SARS. Compared with the SARS patients in the derivation cohort, those in the validation cohort were older (44.5±15.9 versus 33.9±15.9 years), more likely to acquire the disease locally (76.8% versus 37.5%), and more likely to have cough before or during fever. For the non-SARS patients, cases in the validation cohort presented with less cough and coryza but more diarrhea. For the 4-item symptom score, the sensitivity reached 96.3% (95% confidence interval [CI] 89.7% to 98.7%) and the specificity 51.6% (95% CI 43.8% to 59.3%). For the 6-item clinical score, the sensitivity reached 92.6% (95% CI 84.8% to 96.6%) and the specificity 71.2% (95% CI 63.6% to 77.7%). When the clinical score was applied to patients with a positive symptom score, the combined sensitivity reached 90.2% (95% CI 82.0% to 95.0%), and the combined specificity reached 80.1% (95% CI 73.2% to 85.6%). CONCLUSION: This prospective study validated the scoring system previously developed by using a different cohort. The scoring systems could be applied to settings where mass screening of SARS is needed during future outbreaks.

negative: COVID-19 infection and rheumatoid arthritis: Faraway, so close! Abstract The outbreak of the new coronavirus infections COVID-19 in December 2019 in China has quickly become a global health emergency. Given the lack of specific anti-viral therapies, the current management of severe acute respiratory syndrome coronaviruses (SARS-CoV-2) is mainly supportive, even though several compounds are now under investigation for the treatment of this life-threatening disease. COVID-19 pandemic is certainly conditioning the treatment strategy of a complex disorder as rheumatoid arthritis (RA), whose infectious risk is increased compared to the general population because of an overall impairment of immune system typical of autoimmune diseases combined with the iatrogenic effect generated by corticosteroids and immunosuppressive drugs. However, the increasing knowledge about the pathophysiology of SARS-CoV-2 infection is leading to consider some anti-rheumatic drugs as potential treatment options for the management of COVID-19. In this review we will critically analyse the evidences on either positive or negative effect of drugs commonly used to treat RA in this particular scenario, in order to optimize the current approach to RA patients.

negative: Influenza pathogenesis: lessons learned from animal studies with H5N1, H1N1 Spanish, and pandemic H1N1 2009 influenza. Because cases of highly pathogenic influenza are rare, no systematic clinical studies have evaluated different therapeutic approaches. Instead, treatment recommendations are aimed at the alleviation of clinical signs and symptoms, especially the restoration of respiratory function, and at the inhibition of virus replication, assuming viral load is responsible for disease phenotype. Studies of highly pathogenic influenza in different animal models, especially nonhuman primates and ferrets, reproduce many of the key observations from clinical cases. Host-response kinetics reveal a delayed but broad activation of genes involved in the innate and acquired immune responses (innate responses produce inflammatory responses), which continue after the virus has been cleared and may contribute importantly to the clinical signs observed. Experimental animal models point to an important role for immune dysregulation in the pathogenesis of highly pathogenic influenza. The use of these models to develop and validate therapeutic approaches is just beginning, but published studies reveal the importance of early treatment with antivirals and show the potential and limitations of approaches aimed at the host response.

negative: PCR sequencing of the spike genes of geographically and chronologically distinct human coronaviruses 229E Abstract A reverse transcription nested PCR (RT-PCR) sequencing methodology was developed and used to generate sequence data from the spike genes of three geographically and chronologically distinct human coronaviruses 229E. These three coronaviruses were isolated originally from the USA in the 1960s (human coronavirus 229E strain ATCC VR-74), the UK in the 1990s (human coronavirus 229E LRI 281) and Ghana (human coronavirus 229E A162). Upon translation and alignment with the published spike protein sequence of human coronavirus 229E ‘LP’ (isolated in the UK in the 1970s), it was found that variation within the translated protein sequences was rather limited. In particular, minimal variation was observed between the translated spike protein sequence of human coronaviruses 229E LP and ATCC VR-74 (1/1012 amino acid differences), whilst most variation was observed between the translated spike protein sequence of human coronaviruses 229E LP and A162 (47/1012 amino acid changes). Further, the translated spike protein sequence of human coronavirus 229E A162 showed three clusters of amino acid changes, situated within the 5′ half of the translated spike protein sequence.

negative: Perspectives on therapeutic neutralizing antibodies against the Novel Coronavirus SARS-CoV-2 A newly identified novel coronavirus (SARS-CoV-2) is causing pneumonia-associated respiratory syndrome across the world. Epidemiology, genomics, and pathogenesis of the SARS-CoV-2 show high homology with that of SARS-CoV. Current efforts are focusing on development of specific antiviral drugs. Therapeutic neutralizing antibodies (NAbs) against SARS-CoV-2 will be greatly important therapeutic agents for the treatment of coronavirus disease 2019 (COVID-19). Herein, the host immune responses against SARS-CoV discussed in this review provide implications for developing NAbs and understanding clinical interventions against SARS-CoV-2. Further, we describe the benefits, challenges and considerations of NAbs against SARS-CoV-2. Although many challenges exist, NAbs still offer a therapeutic option to control the current pandemic and the possible re-emergence of the virus in the future, and their development therefore remains a high priority.

negative: Clinical and Laboratory Profiles of 75 Hospitalized Patients with Novel Coronavirus Disease 2019 in Hefei, China The outbreak of the novel coronavirus disease 2019 (COVID-19) infection began in December 2019 in Wuhan, and rapidly spread to many provinces in China. The number of cases has increased markedly in Anhui, but information on the clinical characteristics of patients is limited. We reported 75 patients with COVID-19 in the First Affiliated Hospital of USTC from Jan 21 to Feb 16, 2020, Hefei, Anhui Province, China. COVID-19 infection was confirmed by real-time RT-PCR of respiratory nasopharyngeal swab samples. Epidemiological, clinical and laboratory data were collected and analyzed. Of the 75 patients with COVID-19, 61 (81.33%) had a direct or indirect exposure history to Wuhan. Common symptoms at onset included fever (66 [88.0%] of 75 patients) and dry cough (62 [82.67%]). Of the patients without fever, cough could be the only or primary symptom. The most prominent laboratory abnormalities were lymphopenia, decreased percentage of lymphocytes (LYM%), decreased CD4+ and CD8+ T cell counts, elevated C-reactive protein (CRP) and lactate dehydrogenase (LDH). Patients with elevated interleukin 6 (IL-6) showed significant decreases in the LYM%, CD4+ and CD8+ T cell counts. Besides, the percentage of neutrophils, CRP, LDH and Procalcitonin levels increased significantly. We concluded that COVID-19 could cause different degrees of hematological abnormalities and damage of internal organs. Hematological profiles including LYM, LDH, CRP and IL-6 could be indicators of diseases severity and evaluation of treatment effectiveness. Antiviral treatment requires a comprehensive and supportive approach. Further targeted therapy should be determined based on individual clinical manifestations and laboratory indicators.

negative: Impact of anti-tnfα antibodies on the risk of Covid-19 and its severity in patients with inflammatory Bowel Diseases

negative: Angiotensin-converting enzyme is a GPI-anchored protein releasing factor crucial for fertilization The angiotensin-converting enzyme (ACE) is a key regulator of blood pressure. It is known to cleave small peptides, such as angiotensin I and bradykinin and changes their biological activities, leading to upregulation of blood pressure. Here we describe a new activity for ACE: a glycosylphosphatidylinositol (GPI)-anchored protein releasing activity (GPIase activity). Unlike its peptidase activity, GPIase activity is weakly inhibited by the tightly binding ACE inhibitor and not inactivated by substitutions of core amino acid residues for the peptidase activity, suggesting that the active site elements for GPIase differ from those for peptidase activity. ACE shed various GPI-anchored proteins from the cell surface, and the process was accelerated by the lipid raft disruptor filipin. The released products carried portions of the GPI anchor, indicating cleavage within the GPI moiety. Further analysis by high-performance liquid chromatography–mass spectrometry predicted the cleavage site at the mannose-mannose linkage. GPI-anchored proteins such as TESP5 and PH-20 were released from the sperm membrane of wild-type mice but not in Ace knockout sperm in vivo. Moreover, peptidase-inactivated E414D mutant ACE and also PI-PLC rescued the egg-binding deficiency of Ace knockout sperms, implying that ACE plays a crucial role in fertilization through this activity. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/nm1179) contains supplementary material, which is available to authorized users.

negative: Genetic evolution analysis of 2019 novel coronavirus and coronavirus from other species The Corona Virus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a Public Health Emergency of International Concern. However, so far, there are still controversies about the source of the virus and its intermediate host. Here, we found the novel coronavirus was closely related to coronaviruses derived from five wild animals, including Paguma larvata, Paradoxurus hermaphroditus, Civet, Aselliscus stoliczkanus and Rhinolophus sinicus, and was in the same branch of the phylogenetic tree. However, genome and ORF1a homology show that the virus is not the same coronavirus as the coronavirus derived from these five animals, whereas the virus has the highest homology with Bat coronavirus isolate RaTG13.

negative: Angiotensin converting enzyme-2 is protective but downregulated in human and experimental lung fibrosis. Earlier work from this laboratory showed that local generation of angiotensin (ANG) II is required for the pathogenesis of experimental pulmonary fibrosis and that ANG peptides are expressed robustly in the lungs of patients with idiopathic pulmonary fibrosis (IPF). Angiotensin converting enzyme-2 (ACE-2) degrades the octapeptide ANG II to form the heptapeptide ANG1-7 and thereby limits ANG II accumulation. On this basis, we hypothesized that ACE-2 would be protective against experimental lung fibrogenesis and might be downregulated in human and experimental lung fibrosis. In lung biopsy specimens from patients with IPF, ACE-2 mRNA and enzyme activity were decreased by 92% (P<0.01) and 74% (P<0.05), respectively. ACE-2 mRNA and activity were also decreased similarly in the lungs of bleomycin-treated rats and C57-BL6 mice. In mice exposed to low doses of bleomycin, lung collagen accumulation was enhanced by intratracheal administration of either ACE-2-specific small interfering RNAs (siRNAs) or the peptide DX(600), a competitive inhibitor of ACE-2 (P<0.05). Administration of either ACE-2 siRNA or DX(600) significantly increased the ANG II content of mouse lung tissue above the level induced by bleomycin alone. Coadministration of the ANG II receptor antagonist saralasin blocked the DX(600)-induced increase in lung collagen. Moreover, purified recombinant human ACE-2, delivered to mice systemically by osmotic minipump, attenuated bleomycin-induced lung collagen accumulation. Together, these data show that ACE-2 mRNA and activity are severely downregulated in both human and experimental lung fibrosis and suggest that ACE-2 protects against lung fibrogenesis by limiting the local accumulation of the profibrotic peptide ANG II.

negative: Impact of antibacterials on subsequent resistance and clinical outcomes in adult patients with viral pneumonia: an opportunity for stewardship INTRODUCTION: Respiratory viruses are increasingly recognized as significant etiologies of pneumonia among hospitalized patients. Advanced technologies using multiplex molecular assays and polymerase-chain reaction increase the ability to identify viral pathogens and may ultimately impact antibacterial use. METHOD: This was a single-center retrospective cohort study to evaluate the impact of antibacterials in viral pneumonia on clinical outcomes and subsequent multidrug-resistant organism (MDRO) infections/colonization. Patients admitted from March 2013 to November 2014 with positive respiratory viral panels (RVP) and radiographic findings of pneumonia were included. Patients transferred from an outside hospital or not still hospitalized 72 hours after the RVP report date were excluded. Patients were categorized based on exposure to systemic antibacterials: less than 3 days representing short-course therapy and 3 to 10 days being long-course therapy. RESULTS: A total of 174 patients (long-course, n = 67; short-course, n = 28; mixed bacterial-viral infection, n = 79) were included with most being immunocompromised (56.3 %) with active malignancy the primary etiology (69.4 %). Rhinovirus/Enterovirus (23 %), Influenza (19 %), and Parainfluenza (15.5 %) were the viruses most commonly identified. A total of 13 different systemic antibacterials were used as empiric therapy in the 95 patients with pure viral infection for a total of 466 days-of-therapy. Vancomycin (50.7 %), cefepime (40.3 %), azithromycin (40.3 %), meropenem (23.9 %), and linezolid (20.9 %) were most frequently used. In-hospital mortality did not differ between patients with viral pneumonia in the short-course and long-course groups. Subsequent infection/colonization with a MDRO was more frequent in the long-course group compared to the short-course group (53.2 vs 21.1 %; P = 0.027). CONCLUSION: This study found that long-course antibacterial use in the setting of viral pneumonia had no impact on clinical outcomes but increased the incidence of subsequent MDRO infection/colonization.

negative: Potential Broad Spectrum Inhibitors of the Coronavirus 3CL(pro): A Virtual Screening and Structure-Based Drug Design Study Human coronaviruses represent a significant disease burden; however, there is currently no antiviral strategy to combat infection. The outbreak of severe acute respiratory syndrome (SARS) in 2003 and Middle East respiratory syndrome (MERS) less than 10 years later demonstrates the potential of coronaviruses to cross species boundaries and further highlights the importance of identifying novel lead compounds with broad spectrum activity. The coronavirus 3CL(pro) provides a highly validated drug target and as there is a high degree of sequence homology and conservation in main chain architecture the design of broad spectrum inhibitors is viable. The ZINC drugs-now library was screened in a consensus high-throughput pharmacophore modeling and molecular docking approach by Vina, Glide, GOLD and MM-GBSA. Molecular dynamics further confirmed results obtained from structure-based techniques. A highly defined hit-list of 19 compounds was identified by the structure-based drug design methodologies. As these compounds were extensively validated by a consensus approach and by molecular dynamics, the likelihood that at least one of these compounds is bioactive is excellent. Additionally, the compounds segregate into 15 significantly dissimilar (p < 0.05) clusters based on shape and features, which represent valuable scaffolds that can be used as a basis for future anti-coronaviral inhibitor discovery experiments. Importantly though, the enriched subset of 19 compounds identified from the larger library has to be validated experimentally.

negative: Amino acid residues critical for RNA-binding in the N-terminal domain of the nucleocapsid protein are essential determinants for the infectivity of coronavirus in cultured cells The N-terminal domain of the coronavirus nucleocapsid (N) protein adopts a fold resembling a right hand with a flexible, positively charged β-hairpin and a hydrophobic palm. This domain was shown to interact with the genomic RNA for coronavirus infectious bronchitis virus (IBV) and severe acute respiratory syndrome coronavirus (SARS-CoV). Based on its 3D structure, we used site-directed mutagenesis to identify residues essential for the RNA-binding activity of the IBV N protein and viral infectivity. Alanine substitution of either Arg-76 or Tyr-94 in the N-terminal domain of IBV N protein led to a significant decrease in its RNA-binding activity and a total loss of the infectivity of the viral RNA to Vero cells. In contrast, mutation of amino acid Gln-74 to an alanine, which does not affect the binding activity of the N-terminal domain, showed minimal, if any, detrimental effect on the infectivity of IBV. This study thus identifies residues critical for RNA binding on the nucleocapsid surface, and presents biochemical and genetic evidence that directly links the RNA binding capacity of the coronavirus N protein to the viral infectivity in cultured cells. This information would be useful in development of preventive and treatment approaches against coronavirus infection.

negative: Serological Evidence of Influenza A Viruses in Frugivorous Bats from Africa Bats are likely natural hosts for a range of zoonotic viruses such as Marburg, Ebola, Rabies, as well as for various Corona- and Paramyxoviruses. In 2009/10, researchers discovered RNA of two novel influenza virus subtypes – H17N10 and H18N11 – in Central and South American fruit bats. The identification of bats as possible additional reservoir for influenza A viruses raises questions about the role of this mammalian taxon in influenza A virus ecology and possible public health relevance. As molecular testing can be limited by a short time window in which the virus is present, serological testing provides information about past infections and virus spread in populations after the virus has been cleared. This study aimed at screening available sera from 100 free-ranging, frugivorous bats (Eidolon helvum) sampled in 2009/10 in Ghana, for the presence of antibodies against the complete panel of influenza A haemagglutinin (HA) types ranging from H1 to H18 by means of a protein microarray platform. This technique enables simultaneous serological testing against multiple recombinant HA-types in 5μl of serum. Preliminary results indicate serological evidence against avian influenza subtype H9 in about 30% of the animals screened, with low-level cross-reactivity to phylogenetically closely related subtypes H8 and H12. To our knowledge, this is the first report of serological evidence of influenza A viruses other than H17 and H18 in bats. As avian influenza subtype H9 is associated with human infections, the implications of our findings from a public health context remain to be investigated.

negative: Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion The recent outbreak of coronavirus disease (COVID-19) caused by SARS-CoV-2 infection in Wuhan, China has posed a serious threat to global public health. To develop specific anti-coronavirus therapeutics and prophylactics, the molecular mechanism that underlies viral infection must first be defined. Therefore, we herein established a SARS-CoV-2 spike (S) protein-mediated cell–cell fusion assay and found that SARS-CoV-2 showed a superior plasma membrane fusion capacity compared to that of SARS-CoV. We solved the X-ray crystal structure of six-helical bundle (6-HB) core of the HR1 and HR2 domains in the SARS-CoV-2 S protein S2 subunit, revealing that several mutated amino acid residues in the HR1 domain may be associated with enhanced interactions with the HR2 domain. We previously developed a pan-coronavirus fusion inhibitor, EK1, which targeted the HR1 domain and could inhibit infection by divergent human coronaviruses tested, including SARS-CoV and MERS-CoV. Here we generated a series of lipopeptides derived from EK1 and found that EK1C4 was the most potent fusion inhibitor against SARS-CoV-2 S protein-mediated membrane fusion and pseudovirus infection with IC50s of 1.3 and 15.8 nM, about 241- and 149-fold more potent than the original EK1 peptide, respectively. EK1C4 was also highly effective against membrane fusion and infection of other human coronavirus pseudoviruses tested, including SARS-CoV and MERS-CoV, as well as SARSr-CoVs, and potently inhibited the replication of 5 live human coronaviruses examined, including SARS-CoV-2. Intranasal application of EK1C4 before or after challenge with HCoV-OC43 protected mice from infection, suggesting that EK1C4 could be used for prevention and treatment of infection by the currently circulating SARS-CoV-2 and other emerging SARSr-CoVs.

negative: Current status and progress of 2019 novel coronavirus pneumonia/ 中华危重病急救医学 Recently, the 2019 novel coronavirus (2019-nCoV) pneumonia outbroke in Wuhan and rapidly spread to all over China and even the world. Because of the strong infectivity and various clinical symptoms, it has brought certain difficulties to the epidemic prevention and control. Currently there is no specific drug for 2019-nCoV. Previous drugs used to treat other coronaviruses may be effective, but further clinical trials remain needed. We reviewed literature on the epidemiology, etiology, clinical manifestations, imaging manifestations, laboratory examination, diagnosis, complications, treatment and outcome of 2019-nCoV pneumonia.

negative: Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods SARS-CoV-2 has caused tens of thousands of infections and more than one thousand deaths. There are currently no registered therapies for treating coronavirus infections. Because of time consuming process of new drug development, drug repositioning may be the only solution to the epidemic of sudden infectious diseases. We systematically analyzed all the proteins encoded by SARS-CoV-2 genes, compared them with proteins from other coronaviruses, predicted their structures, and built 19 structures that could be done by homology modeling. By performing target-based virtual ligand screening, a total of 21 targets (including two human targets) were screened against compound libraries including ZINC drug database and our own database of natural products. Structure and screening results of important targets such as 3-chymotrypsin-like protease (3CLpro), Spike, RNA-dependent RNA polymerase (RdRp), and papain like protease (PLpro) were discussed in detail. In addition, a database of 78 commonly used anti-viral drugs including those currently on the market and undergoing clinical trials for SARS-CoV-2 was constructed. Possible targets of these compounds and potential drugs acting on a certain target were predicted. This study will provide new lead compounds and targets for further in vitro and in vivo studies of SARS-CoV-2, new insights for those drugs currently ongoing clinical studies, and also possible new strategies for drug repositioning to treat SARS-CoV-2 infections.

negative: First Clinical Study Using HCV Protease Inhibitor Danoprevir to Treat Naive and Experienced COVID-19 Patients As coronavirus disease 2019 (COVID-19) outbreak, caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), started in China in January, 2020, repurposing approved drugs is emerging as important therapeutic options. We reported here the first clinical study using hepatitis C virus (HCV) protease inhibitor, danoprevir, to treat COVID-19 patients. Danoprevir (Ganovo) is a potent HCV protease (NS3/4A) inhibitor (IC50 = 0.29 nM), which was approved and marketed in China since 2018 to treat chronic hepatitis C patients. Ritonavir is a CYP3A4 inhibitor to enhance plasma concentration of danoprevir while it also acts as a human immunodeficiency virus (HIV) protease inhibitor at high doses. The chymotrypsin-like protease of SARS-CoV-2 shares structure similarity with HCV and HIV proteases. In the current clinical study (NCT04291729) conducted at the Nineth Hospital of Nanchang, we evaluated therapeutic effects of danoprevir, boosted by ritonavir, on treatment naive and experienced COVID-19 patients. The data from this small-sample clinical study showed that danoprevir boosted by ritonavir is safe and well tolerated in all patients. After 4 to 12-day treatment of danoprevir boosted by ritonavir, all eleven patients enrolled, two naive and nine experienced, were discharged from the hospital as they met all four conditions as follows: (1) normal body temperature for at least 3 days; (2) significantly improved respiratory symptoms; (3) lung imaging shows obvious absorption and recovery of acute exudative lesion; and (4) two consecutive RT-PCR negative tests of SARS-CoV-2 nucleotide acid (respiratory track sampling with interval at least one day). Our findings suggest that repurposing danoprevir for COVID-19 is a promising therapeutic option.

negative: Dynamic change process of target genes by RT-PCR testing of SARS-Cov-2 during the course of a Coronavirus Disease 2019 patient Abstract We report the dynamic change process of target genes by RT-PCR testing of SARS-Cov-2 during the course of a COVID-19 patient: from successive negative results to successive single positive nucleocapsid gene, to two positive target genes (orf1ab and nucleocapsid) by RT-PCR testing of SARS-Cov-2, and describe the diagnosis, clinical course, and management of the case. In this case, negative results of RT-PCR testing was not excluded to diagnose a suspected COVID-19 patient, clinical signs and symptoms, other laboratory findings, and chest CT images should be taken into account for the absence of enough positive evidence. This case highlights the importance of successive sampling and testing SARS-Cov-2 by RT-PCR as well as the increased value of single positive target gene from pending to positive in two specimens to diagnose laboratory-confirmed COVID-19.

negative: The effects of injection of bovine vaccine into a human digit: a case report BACKGROUND: The incidence of needlestick injuries in farmers and veterinary surgeons is significant and the consequences of such an injection can be serious. CASE PRESENTATION: We report accidental injection of bovine vaccine into the base of the little finger. This resulted in increased pressure in the flexor sheath causing signs and symptoms of ischemia. Amputation of the digit was required despite repeated surgical debridement and decompression. CONCLUSION: There have been previous reports of injection of oil-based vaccines into the human hand resulting in granulomatous inflammation or sterile abscess and causing morbidity and tissue loss. Self-injection with veterinary vaccines is an occupational hazard for farmers and veterinary surgeons. Injection of vaccine into a closed compartment such as the human finger can have serious sequelae including loss of the injected digit. These injuries are not to be underestimated. Early debridement and irrigation of the injected area with decompression is likely to give the best outcome. Frequent review is necessary after the first procedure because repeat operations may be required.

negative: Moving-average based index to timely evaluate the current epidemic situation after COVID-19 outbreak A pneumonia outbreak caused by a novel coronavirus (COVID-19) occurred in Wuhan, China at the end of 2019 and then spread rapidly to the whole country. A total of 81,021 laboratory-confirmed cases, including 3,194 deaths (3.9%) had been reported in China by March 14, 2020, meanwhile, 61,518 laboratory-confirmed cases and 2,199 deaths were reported outside China. Common symptoms of COVID-19 pneumonia included fever, fatigue and dry cough. Faced with such a sudden outbreak of new infectious diseases, we have no history to learn from and no evidence to count on. Traditional models often predict inconsistent results. Aiming at estimate the epidemic trend timely after the outbreak, we mainly used 7-day moving average of log-transformed daily new cases (LMA) to establish a new index named "epidemic trend index", which will be used to predict the evolutionary trend of the epidemic situation and support epidemic control decision making processes. We used SARS epidemic data from Hong Kong in 2003 to verify the practicability of the new index, which shows that the index is acceptable. The epidemic trend index was then applied to the COVID-19 epidemic analysis in China. The results show that during the epidemic, the trend direction of different districts of China changed on different date. In the whole country and in Hubei Province alone, the epidemic reached the peak on February 9. While the peak appeared earlier, i.e. on February 5 in other provinces. It indicated that decisive outbreak control measures of the Chinese government are effective. While local governments should adjust management measures based on local risk level of epidemic. Although the epidemic has eased since late February, continued efforts in epidemic control are still needed to accelerate the end of the epidemic in China. However, the global COVID-19 epidemic outside China continues to expand as indicated by the epidemic trend index we proposed. In order to cope with the novel coronavirus pandemic, people all over the world should work together and governments of all countries should take efficient measures in the light of China's experience and according to national circumstances and local conditions.

negative: Dozens of coronavirus drugs are in development - what happens next?

negative: Society of General Internal Medicine: 28th Annual Meeting New Orleans, LA May 11–14, 2005: Out of Chaos: The Critical Role of Generalists, ABSTRACTS OF SUBMISSIONS ACCEPTED FOR PRESENTATIOIN

negative: Discovery of Bat Coronaviruses through Surveillance and Probe Capture-Based Next-Generation Sequencing Coronaviruses (CoVs) of bat origin have caused two pandemics in this century. Severe acute respiratory syndrome (SARS)-CoV and Middle East respiratory syndrome (MERS)-CoV both originated from bats, and it is highly likely that bat coronaviruses will cause future outbreaks. Active surveillance is both urgent and essential to predict and mitigate the emergence of these viruses in humans. Next-generation sequencing (NGS) is currently the preferred methodology for virus discovery to ensure unbiased sequencing of bat CoVs, considering their high genetic diversity. However, unbiased NGS is an expensive methodology and is prone to missing low-abundance CoV sequences due to the high background level of nonviral sequences present in surveillance field samples. Here, we employ a capture-based NGS approach using baits targeting most of the CoV species. Using this technology, we effectively reduced sequencing costs by increasing the sensitivity of detection. We discovered nine full genomes of bat CoVs in this study and revealed great genetic diversity for eight of them. IMPORTANCE Active surveillance is both urgent and essential to predict and mitigate the emergence of bat-origin CoV in humans and livestock. However, great genetic diversity increases the chance of homologous recombination among CoVs. Performing targeted PCR, a common practice for many surveillance studies, would not reflect this diversity. NGS, on the other hand, is an expensive methodology and is prone to missing low-abundance CoV sequences. Here, we employ a capture-based NGS approach using baits targeting all CoVs. Our work demonstrates that targeted, cost-effective, large-scale, genome-level surveillance of bat CoVs is now highly feasible.

negative: Les antirétroviraux ont-ils une place dans le traitement du syndrome respiratoire aigu sévère ? Points essentiels L’inhibition d’une protéase ou d’une protéine de fusion est une approche générale en chimiothérapie antivirale et n’est pas spécifique du VIH. Les molécules qui provoquent ces phénomènes sont, en général, très spécifiques d’un virus ou d’une famille virale. Dans le traitement du syndrome respiratoire aigu sévère (SRAS) liés à severe acute respiratory syndrome-Coronavirus (SARS-CoV), l’évaluation de l’efficacité des anti-VIH était essentiellement motivée par l’absence d’alternatives thérapeutiques devant un virus émergent, dans un contexte épidémique inquiétant. Aucun des traitements commercialisés dans la prise en charge des patients vivant avec le VIH ne semble efficace dans le traitement du du SARS-CoV. Les données in vitro sont non concluantes et les données cliniques fragiles. Des résultats préliminaires sur les inhibiteurs de protéase et les inhibiteurs d’entrée à un stade précoce de développement, très en amont des phases cliniques, ouvrent des perspectives intéressantes. Key points Inhibition of viral assembly (protease inhibitors) and of fusion of viral and target membranes (fusion inhibitors) are general approaches to antiviral treatment, not specific for HIV. Nonetheless, the agents that induce these phenomena are most often specific for a given virus or virus family. Drugs developed for HIV treatment were reevaluated for use against severe acute respiratory syndrome-coronavirus (SARS-CoV) during and after the epidemic in 2003, in view of the absence of any other available treatment. Of the protease and entry inhibitors approved for treating HIV-infected patients, none was effective against SARS-CoV, although in vitro activity against this virus was reported for the protease inhibitor lopinavir/ritonavir, in results that have not been confirmed in the most recent studies. The epidemiologic methods used to assess this drug's efficacy are not robust. Preliminary results for SARS treatment with protease and entry inhibitors, although at early stages of development, are promising.

negative: Harmonizing heterogeneous endpoints in COVID-19 trials without loss of information - an essential step to facilitate decision making Background: Many trials are now underway to inform decision-makers on potential effects of treatments for COVID-19. To provide sufficient information for all involved decision-makers (clinicians, public health authorities, drug regulatory agencies) a multiplicity of endpoints must be considered. It is a challenge to generate detailed high quality evidence from data while ensuring fast availability and evaluation of the results. Methods: We reviewed all interventional COVID-19 trials on Remdesivir, Lopinavir/ritonavir and Hydroxychloroquine registered in the National Library of Medicine (NLM) at the National Institutes of Health (NIH) and summarized the endpoints used to assess treatment effects. We propose a multistate model that harmonizes heterogeneous endpoints and differing lengths of follow-up within and between trials. Results: There are currently, March 27, 2020, 23 registered interventional trials investigating the potential benefits of Remdesivir, Lopinavir/ritonavir and Hydroxychloroquine. The endpoints are highly heterogeneous. Follow-up for the primary endpoints ranges from four to 168 days. A detailed precisely defined endpoint has been proposed by the global network REMAP-CAP, which is specialized on community-acquired pneumonia. Their seven-category endpoint accounts for major clinical events informative for all decision-makers. Moreover, the Core Outcome Measures in Effectiveness Trials (COMET) Initiative is currently working on a core outcome set. We propose a multistate model that accommodates analysis of these recommended endpoints. The model allows for a detailed investigation of treatment effects for various endpoints over the course of time thereby harmonizing differing endpoints and lengths of follow-up. Conclusion: Multistate model analysis is a powerful tool to study clinically heterogeneous endpoints (mortality, discharge) as well as endpoints influencing hospital capacities (duration of hospitalization and ventilation) simultaneously over time. Our proposed model extracts all information available in the data and is - by harmonizing endpoints within and between trials - a step towards faster decision making. All ongoing clinical trials, especially those with severe cases, should accommodate primary analysis with a stacked probability plot of the major events mechanical ventilation, discharge alive and death.

negative: COVID-19 clinical characteristics, and sex-specific risk of mortality: Systematic Review and Meta-analysis Objectives: The rapidly evolving coronavirus disease 2019 (COVID-19), was declared a pandemic by the World Health Organization on March 11, 2020. It was first detected in the city of Wuhan in China and has spread globally resulting in substantial health and economic crisis in many countries. Observational studies have partially identified the different aspects of this disease. Up to this date, no comprehensive systematic review for the clinical, laboratory, epidemiologic and mortality findings has been published. We conducted this systematic review and meta-analysis for a better understanding of COVID-19. Methods: We reviewed the scientific literature published from January 1, 2019 to March 3, 2020. Statistical analyses were performed with STATA (version 14, IC; Stata Corporation, College Station, TX, USA). The pooled frequency with 95% confidence intervals (CI) was assessed using random effect model. Publication bias was assessed and p <0.05 was considered a statistically significant publication bias. Results: Out of 1102 studies, 32 satisfied the inclusion criteria. A total of 4789 patients with a mean age of 49 years were evaluated. Fever (83.0%, CI 77.5 to 87.6), cough (65.2%, CI 58.6 to 71.2) and myalgia/fatigue (34.7, CI 26.0 to 44.4) were the most common symptoms. The most prevalent comorbidities were hypertension (18.5 %, CI 12.7 to 24.4) and Cardiovascular disease (14.9 %, CI 6.0 to 23.8). Among the laboratory abnormalities, elevated C-Reactive Protein (CRP) (72.0% (CI 54.3 to 84.6) and lymphopenia (50.1%, CI 38.0 to 62.4) were the most common findings. Bilateral ground-glass opacities (66.0%, CI 51.1 to 78.0) was the most common CT-Scan presentation. Pooled mortality rate was 6.6%, with males having significantly higher mortality compared to females (OR 3.4; 95% CI 1.2 to 9.1, P = 0.01). Conclusion: COVID-19 commonly presented with a progressive course of cough and fever with more than half of hospitalized patients showing leukopenia or a high CRP on their laboratory findings. Mortality associated with COVID19 was higher than that reported in studies in China with Males having a 3-fold higher risk of mortality in COVID19 compared to females.

negative: Gastrointestinal tract symptoms in coronavirus disease 2019: Analysis of clinical symptoms in adult patients Objective: To investigate the clinical presentation of coronavirus disease 2019 (COVID-19), particularly the incidence of gastrointestinal tract symptoms. Design: We enrolled adult COVID-19 patients from a mobile cabin hospital in Wuhan with a definitive diagnosis by SARS-CoV-2 nucleic acid testing. Face-to-face interviews were conducted in which the patient selected COVID-19-related symptoms and report the time of onset and duration of symptoms. Results: A total of 212 adults were enrolled in this study, of which 127 (59.9%) were females, mean age was 48.50 (range: 17-79) years, and mean disease course was 26.78 (3-60) days. Fever and cough were the most common and earliest clinical symptoms of COVID-19. Diarrhoea occurred in 43.8% (93/212) of patients, of which 86.0% (80/93) had mushy stools. Nausea and vomiting were also common (20.7%). Diarrhoea lasted for 4.00(2.00-8.85) days and mostly occurred 5.00(0.25-11.00) days after the emergence of the first symptoms. Multiple logistic regression analysis found that diarrhoea was significantly correlated with fatigue [OR2.900,95%CI (1.629-5.164), p<0.0001]. Conclusions: Gastrointestinal tract symptoms are common in COVID-19 and most occur during the middle stage of the disease and lasts for a short period of time. Clinicians need to pay greater attention to gastrointestinal tract symptoms of COVID-19.

negative: Hyperglycemia and the novel Covid-19 infection: Possible pathophysiologic mechanisms

negative: Renal ACE2 expression and activity is unaltered during established hypertension in adult SHRSP and TGR(mREN2)27. Differential renal expression of a homolog of the angiotensin-converting enzyme (ACE), that is, ACE2, has been implicated as a genetic basis of polygenetic hypertension in the stroke-prone spontaneously hypertensive rat model. However, data on the role of ACE2 in hypertension are still inconclusive. Therefore, we analyzed kidney ACE2 mRNA, ACE2 protein and ACE2 enzyme activities in the adult polygenetic stroke-prone spontaneously hypertensive rat (SHRSP) and the monogenetic TGR(mREN2)27 rat models, in comparison with their normotensive reference strains, Wistar-Kyoto (WKY) and Spraque-Dawley (SD) rats, respectively. Kidney ACE2 mRNA was studied using quantitative real-time reverse transcriptase-PCR (RT-PCR) in cortex and medulla, whereas protein expression was scored semiquantitatively in detail in different renal structures using immunohistochemistry. Furthermore, total renal tissue ACE2 activity was measured using a fluorimetric assay that was specified by the ACE2 inhibitor DX600. In SHRSP and homozygous TGR(mREN2)27 rats with established hypertension, kidney ACE2 mRNA, protein and tissue ACE2 activities were not different from their respective WKY and SD reference strain, respectively. In addition, when we looked at renal localization, we found ACE2 protein to be predominantly present in glomeruli and endothelium with weak staining in distal and negative staining in proximal tubuli. Thus, our data challenge previous work that implicates ACE2 as a candidate gene for hypertension in SHRSP by reporting a significant reduction of ACE2 in the kidneys of SHRSP. Taken together, renal ACE2 is not altered in the SHRSP and TGR(mREN2)27 genetic rat models with established hypertension.

negative: SARS-CoV-2 outbreak: How can pharmacists help? Coronaviruses (CoVs) are a large family of viruses that cause disorders ranging from a mild cold to severe disease. Some of the CoVs are zoonotic, meaning they can be transmitted from animals to humans. In December 2019, the world awoke to a new zoonotic strain of CoV that was named SARS-CoV-2 (standing for severe acute respiratory syndrome coronavirus 2), which has been classified as a high-consequence infectious disease. In addition, serious complications related to COVID-19 have been reported in some patients. These include acute respiratory distress syndrome, acute renal failure, septic shock and ventilator-associated pneumonia. The pharmacist, as a healthcare practitioner, can play an important role in hindering the spread of COVID-19, and can be an active participant in national and community efforts to fight and contain this outbreak.

negative: Functional Cell Receptors for Human Coronavirus Viruses infect host cells by binding to receptors on thesurface of cells Receptor is an important factor affecting host range and interspecific transmission In December 2019, an outbreak of unexplained pneumonia occurred in Wuhan, Hubei province The pathogen was a new coronavirus, named 2019 NovelCoronavirus (2019-nCoV) by WHO Angiotensin-converting enzyme 2 (ACE2) was found to be the receptor of 2019-nCoV This review provides a brief overview of human coronavirus receptors and their applications, with a view to providing references for the tracing, cross-species transmission, epidemiological analysis and antiviral and vaccine studies of 2019-nCoV

negative: Predicting the receptor-binding domain usage of the coronavirus based on kmer frequency on spike protein

negative: Reverse Logistics Network Design for Effective Management of Medical Waste in Epidemic Outbreaks: Insights from the Coronavirus Disease 2019 (COVID-19) Outbreak in Wuhan (China) The outbreak of an epidemic disease may pose significant treats to human beings and may further lead to a global crisis. In order to control the spread of an epidemic, the effective management of rapidly increased medical waste through establishing a temporary reverse logistics system is of vital importance. However, no research has been conducted with the focus on the design of an epidemic reverse logistics network for dealing with medical waste during epidemic outbreaks, which, if improperly treated, may accelerate disease spread and pose a significant risk for both medical staffs and patients. Therefore, this paper proposes a novel multi-objective multi-period mixed integer program for reverse logistics network design in epidemic outbreaks, which aims at determining the best locations of temporary facilities and the transportation strategies for effective management of the exponentially increased medical waste within a very short period. The application of the model is illustrated with a case study based on the outbreak of the coronavirus disease 2019 (COVID-19) in Wuhan, China. Even though the uncertainty of the future COVID-19 spread tendency is very high at the time of this research, several general policy recommendations can still be obtained based on computational experiments and quantitative analyses. Among other insights, the results suggest installing temporary incinerators may be an effective solution for managing the tremendous increase of medical waste during the COVID-19 outbreak in Wuhan, but the location selection of these temporary incinerators is of significant importance. Due to the limitation on available data and knowledge at present stage, more real-world information are needed to assess the effectiveness of the current solution.

negative: Practical insights for paediatric otolaryngology surgical cases and performing microlaryngobronchoscopy during the COVID-19 pandemic Abstract Paediatric otolaryngology practice involves examining and operating in anatomical locations with high levels of aerosol generation and transmission of COVID-19 to treating clinicians, especially from the asymptomatic patient populations including children. During the COVID-19 pandemic all emergent otolaryngological conditions affecting the airway, oral, and nasal cavities should be managed medically where possible and any operating deferred. We present guidelines for operating on paediatric otolaryngological patients when necessary during the COVID-19 pandemic, and incorporate experience gathered during microlaryngobronchoscopy on a COVID-19 positive infant at our institution.

negative: Comparison of risk factors for viral and nonviral asthma exacerbations

negative: Viral Pathogens and Acute Lung Injury: Investigations Inspired by the SARS Epidemic and the 2009 H1N1 Influenza Pandemic Acute viral pneumonia is an important cause of acute lung injury (ALI), although not enough is known about the exact incidence of viral infection in ALI. Polymerase chain reaction-based assays, direct fluorescent antigen (DFA) assays, and viral cultures can detect viruses in samples from the human respiratory tract, but the presence of the virus does not prove it to be a pathogen, nor does it give information regarding the interaction of viruses with the host immune response and bacterial flora of the respiratory tract. The severe acute respiratory syndrome (SARS) epidemic and the 2009 H1N1 influenza pandemic provided a better understanding of how viral pathogens mediate lung injury. Although the viruses initially infect the respiratory epithelium, the relative role of epithelial damage and endothelial dysfunction has not been well defined. The inflammatory host immune response to H1N1 infection is a major contributor to lung injury. The SARS coronavirus causes lung injury and inflammation in part through actions on the nonclassical renin angiotensin pathway. The lessons learned from the pandemic outbreaks of SARS coronavirus and H1N1 capture key principles of virally mediated ALI. There are pathogen-specific pathways underlying virally mediated ALI that converge onto a common end pathway resulting in diffuse alveolar damage. In terms of therapy, lung protective ventilation is the cornerstone of supportive care. There is little evidence that corticosteroids are beneficial, and they might be harmful. Future therapeutic strategies may be targeted to specific pathogens, the pathogenetic pathways in the host immune response, or enhancing repair and regeneration of tissue damage.

negative: Critical care management of adults with community-acquired severe respiratory viral infection With the expanding use of molecular assays, viral pathogens are increasingly recognized among critically ill adult patients with community-acquired severe respiratory illness; studies have detected respiratory viral infections (RVIs) in 17–53% of such patients. In addition, novel pathogens including zoonotic coronaviruses like the agents causing Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS) and the 2019 novel coronavirus (2019 nCoV) are still being identified. Patients with severe RVIs requiring ICU care present typically with hypoxemic respiratory failure. Oseltamivir is the most widely used neuraminidase inhibitor for treatment of influenza; data suggest that early use is associated with reduced mortality in critically ill patients with influenza. At present, there are no antiviral therapies of proven efficacy for other severe RVIs. Several adjunctive pharmacologic interventions have been studied for their immunomodulatory effects, including macrolides, corticosteroids, cyclooxygenase-2 inhibitors, sirolimus, statins, anti-influenza immune plasma, and vitamin C, but none is recommended at present in severe RVIs. Evidence-based supportive care is the mainstay for management of severe respiratory viral infection. Non-invasive ventilation in patients with severe RVI causing acute hypoxemic respiratory failure and pneumonia is associated with a high likelihood of transition to invasive ventilation. Limited existing knowledge highlights the need for data regarding supportive care and adjunctive pharmacologic therapy that is specific for critically ill patients with severe RVI. There is a need for more pragmatic and efficient designs to test different therapeutics both individually and in combination. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00134-020-05943-5) contains supplementary material, which is available to authorized users.

negative: Importance of cholesterol-rich membrane microdomains in the interaction of the S protein of SARS-coronavirus with the cellular receptor angiotensin-converting enzyme 2 Abstract Cholesterol present in the plasma membrane of target cells has been shown to be important for the infection by SARS-CoV. We show that cholesterol depletion by treatment with methyl-β-cyclodextrin (mβCD) affects infection by SARS-CoV to the same extent as infection by vesicular stomatitis virus-based pseudotypes containing the surface glycoprotein S of SARS-CoV (VSV-ΔG-S). Therefore, the role of cholesterol for SARS-CoV infection can be assigned to the S protein and is unaffected by other coronavirus proteins. There have been contradictory reports whether or not angiotensin-converting enzyme 2 (ACE2), the cellular receptor for SARS-CoV, is present in detergent-resistant membrane domains. We found that ACE2 of both Vero E6 and Caco-2 cells co-purifies with marker proteins of detergent-resistant membranes supporting the notion that cholesterol-rich microdomains provide a platform facilitating the efficient interaction of the S protein with the cellular receptor ACE2. To understand the involvement of cholesterol in the initial steps of the viral life cycle, we applied a cell-based binding assay with cells expressing the S protein and cells containing angiotensin-converting enzyme 2 (ACE2). Alternatively, we used a soluble S protein as interaction partner. Depletion of cholesterol from the ACE2-expressing cells reduced the binding of S-expressing cells by 50% whereas the binding of soluble S protein was not affected. This result suggests that optimal infection requires a multivalent interaction between viral attachment protein and cellular receptors.

negative: Angiotensin-Converting Enzyme 2: The First Decade The renin-angiotensin system (RAS) is a critical regulator of hypertension, primarily through the actions of the vasoactive peptide Ang II, which is generated by the action of angiotensin-converting enzyme (ACE) mediating an increase in blood pressure. The discovery of ACE2, which primarily metabolises Ang II into the vasodilatory Ang-(1-7), has added a new dimension to the traditional RAS. As a result there has been huge interest in ACE2 over the past decade as a potential therapeutic for lowering blood pressure, especially elevation resulting from excess Ang II. Studies focusing on ACE2 have helped to reveal other actions of Ang-(1-7), outside vasodilation, such as antifibrotic and antiproliferative effects. Moreover, investigations focusing on ACE2 have revealed a variety of roles not just catalytic but also as a viral receptor and amino acid transporter. This paper focuses on what is known about ACE2 and its biological roles, paying particular attention to the regulation of ACE2 expression. In light of the entrance of human recombinant ACE2 into clinical trials, we discuss the potential use of ACE2 as a therapeutic and highlight some pertinent questions that still remain unanswered about ACE2.

negative: Current Understanding of Molecular Pathology and Treatment of Cardiomyopathy in Duchenne Muscular Dystrophy Duchenne muscular dystrophy (DMD) is a genetic muscle disorder caused by mutations in the Dmd gene resulting in the loss of the protein dystrophin. Patients do not only experience skeletal muscle degeneration, but also develop severe cardiomyopathy by their second decade, one of the main causes of death. The absence of dystrophin in the heart renders cardiomyocytes more sensitive to stretch-induced damage. Moreover, it pathologically alters intracellular calcium (Ca(2+)) concentration, neuronal nitric oxide synthase (nNOS) localization and mitochondrial function and leads to inflammation and necrosis, all contributing to the development of cardiomyopathy. Current therapies only treat symptoms and therefore the need for targeting the genetic defect is immense. Several preclinical therapies are undergoing development, including utrophin up-regulation, stop codon read-through therapy, viral gene therapy, cell-based therapy and exon skipping. Some of these therapies are undergoing clinical trials, but these have predominantly focused on skeletal muscle correction. However, improving skeletal muscle function without addressing cardiac aspects of the disease may aggravate cardiomyopathy and therefore it is essential that preclinical and clinical focus include improving heart function. This review consolidates what is known regarding molecular pathology of the DMD heart, specifically focusing on intracellular Ca(2+), nNOS and mitochondrial dysregulation. It briefly discusses the current treatment options and then elaborates on the preclinical therapeutic approaches currently under development to restore dystrophin thereby improving pathology, with a focus on the heart.

negative: Anti-HCV, nucleotide inhibitors, repurposing against COVID-19 Abstract Aims A newly emerged Human Coronavirus (HCoV) is reported two months ago in Wuhan, China (COVID-19). Until today >2700 deaths from the 80,000 confirmed cases reported mainly in China and 40 other countries. Human to human transmission is confirmed for COVID-19 by China a month ago. Based on the World Health Organization (WHO) reports, SARS HCoV is responsible for >8000 cases with confirmed 774 deaths. Additionally, MERS HCoV is responsible for 858 deaths out of about 2500 reported cases. The current study aims to test anti-HCV drugs against COVID-19 RNA dependent RNA polymerase (RdRp). Materials and methods In this study, sequence analysis, modeling, and docking are used to build a model for Wuhan COVID-19 RdRp. Additionally, the newly emerged Wuhan HCoV RdRp model is targeted by anti-polymerase drugs, including the approved drugs Sofosbuvir and Ribavirin. Key findings The results suggest the effectiveness of Sofosbuvir, IDX-184, Ribavirin, and Remidisvir as potent drugs against the newly emerged HCoV disease. Significance The present study presents a perfect model for COVID-19 RdRp enabling its testing in silico against anti-polymerase drugs. Besides, the study presents some drugs that previously proved its efficiency against the newly emerged viral infection.

negative: Maladies respiratoires, allergies et infections à COVID-19. Premières nouvelles de Wuhan

negative: Conducting phase 1 cancer clinical trials during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–related disease pandemic

negative: Host Factors in Coronavirus Replication Coronaviruses are pathogens with a serious impact on human and animal health. They mostly cause enteric or respiratory disease, which can be severe and life threatening, e.g., in the case of the zoonotic coronaviruses causing severe acute respiratory syndrome (SARS) and Middle East Respiratory Syndrome (MERS) in humans. Despite the economic and societal impact of such coronavirus infections, and the likelihood of future outbreaks of additional pathogenic coronaviruses, our options to prevent or treat coronavirus infections remain very limited. This highlights the importance of advancing our knowledge on the replication of these viruses and their interactions with the host. Compared to other +RNA viruses, coronaviruses have an exceptionally large genome and employ a complex genome expression strategy. Next to a role in basic virus replication or virus assembly, many of the coronavirus proteins expressed in the infected cell contribute to the coronavirus-host interplay. For example, by interacting with the host cell to create an optimal environment for coronavirus replication, by altering host gene expression or by counteracting the host’s antiviral defenses. These coronavirus–host interactions are key to viral pathogenesis and will ultimately determine the outcome of infection. Due to the complexity of the coronavirus proteome and replication cycle, our knowledge of host factors involved in coronavirus replication is still in an early stage compared to what is known for some other +RNA viruses. This review summarizes our current understanding of coronavirus–host interactions at the level of the infected cell, with special attention for the assembly and function of the viral RNA-synthesising machinery and the evasion of cellular innate immune responses.

negative: Recombinant Vaccines against T. gondii: Comparison between Homologous and Heterologous Vaccination Protocols Using Two Viral Vectors Expressing SAG1 The use of recombinant viral vectors expressing T. gondii antigens is a safe and efficient approach to induce immune response against the parasite and a valuable tool for vaccine development. We have previously protected mice from toxoplasmosis by immunizing the animals with an adenovirus expressing the protein SAG1 (AdSAG1) of T. gondii. We are now looking for ways to improve the vaccination strategy and enhance protection. One limitation of homologous vaccinations (sequential doses of the same vector) is induction of anti-vector immune response that blocks cell transduction, restricts transgene expression and, consequently, compromises the overall outcome of vaccination. One way to avert the effects of anti-vector response is to use different viruses in prime and boost (heterologous vaccination). Bearing this in mind, we generated a modified Vaccinia Virus Ankara encoding SAG1 (MVASAG1), to be tested as boost agent after prime with AdSAG1. Although minor differences were observed in the magnitude of the anti-SAG1 immune response induced by each vaccination protocol, the heterologous immunization with AdSAG1 followed by MVASAG1 resulted in improved capacity to control brain cyst formation in a model of chronic toxoplasmosis in C57BL/6 mice.

negative: ACE for all – a molecular perspective Angiotensin-I converting enzyme (ACE, EC 3.4.15.1) is a zinc dependent dipeptidyl carboxypeptidase with an essential role in mammalian blood pressure regulation as part of the renin-angiotensin aldosterone system (RAAS). As such, it has long been targeted in the treatment of hypertension through the use of ACE inhibitors. Although ACE has been studied since the 1950s, only recently have the full range of functions of this enzyme begun to truly be appreciated. ACE homologues have been found in a host of other organisms, and are now known to be conserved in insects. Insect ACE homologues typically share over 30 % amino acid sequence identity with human ACE. Given that insects lack a mammalian type circulatory system, they must have crucial roles in other physiological processes. The first ACE crystal structures were reported during the last decade and have enabled these enzymes to be studied from an entirely different perspective. Here we review many of these key developments and the implications that they have had on our understanding of the diverse functions of these enzymes. Specifically, we consider how structural information is being used in the design of a new generation of ACE inhibitors with increased specificity, and how the structures of ACE homologues are related to their functions. The Anopheles gambiae genome is predicted to code for ten ACE homologues, more than any genome studied so far. We have modelled the active sites of some of these as yet uncharacterised enzymes to try and infer more about their potential roles at the molecular level.

negative: Pneumonia Abstract Pneumonia remains the main cause of morbidity and mortality from infectious diseases in the world. The important reason for the increased global mortality is the impact of pneumonia on chronic diseases especially in the elderly population and the virulence factors of the causative microorganisms. Because elderly individuals present with comorbidities, particular attention should be paid for multidrug-resistant pathogens. Streptococcus pneumoniae remains the most frequently encountered pathogen. Enteric gram-negative rods, as well as anaerobes, should be considered in patients with aspiration pneumonia. Interventions for modifiable risk factors will reduce the risk of this infection. The adequacy of the initial antimicrobial therapy and determination of patients’ follow-up place is a key factor for prognosis. Also, vaccination is one of the most important preventive measures. In this section it was focused on several aspects, including the atypical presentation of pneumonia in the elderly, the methods to evaluate the severity of illness, the appropriate take care place and the management with prevention strategies.

negative: Nucleotide Analogues as Inhibitors of Viral Polymerases Coronaviruses such as the newly discovered virus from Wuhan, China, 2019-nCoV, and the viruses that cause SARS and MERS, have resulted in regional and global public health emergencies. Based on our molecular insight that the hepatitis C virus and the coronavirus use a similar viral genome replication mechanism, we reasoned that the FDA-approved drug EPCLUSA (Sofosbuvir/Velpatasvir) for the treatment of hepatitis C will also inhibit the above coronaviruses, including 2019-nCoV. To develop broad spectrum anti-viral agents, we further describe a novel strategy to design and synthesize viral polymerase inhibitors, by combining the ProTide Prodrug approach used in the development of Sofosbuvir with the use of 3’-blocking groups that we have previously built into nucleotide analogues that function as polymerase terminators.

negative: Role of cardiac renin angiotensin system in ischemia reperfusion injury and preconditioning of heart Cardio-vascular diseases are the leading cause of morbidity and mortality. Ischemia is a state of oxygen deprivation in tissues, whereas reperfusion is restoration of blood flow in ischemic tissues. Myocardial damage of tissue during reperfusion after ischemic insult is known as myocardial ischemia–reperfusion (I/R) injury. It induces damage to cardiac muscle via increasing expression of oxygen, sodium and calcium ions which are responsible in the activation of proteases and cell death. Heart renin angiotensin system (RAS) plays an important role in the myocardial ischemia and reperfusion injury. Angiotensin (1–7) is responsible for vasodilation and angiotensin II for vasoconstriction. Here-in we reviewed how myocardial I/R injury sets in by up-regulation of angiotensin II that leads to increased infarct size, which can be reduced by the use of ACE inhibitors, ACE2 activators and angiotensin II antagonist.

negative: Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use is associated with reduced major adverse cardiovascular events among patients with critical limb ischemia. Angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) are recommended for secondary prevention in peripheral artery disease, but their effectiveness in patients with critical limb ischemia (CLI) is uncertain. We reviewed 464 patients with CLI who underwent diagnostic angiography or endovascular intervention from 2006-2013 at a multidisciplinary vascular center. ACEI or ARB use was assessed at the time of angiography. Major adverse cardiovascular events (MACE), mortality, and major adverse limb events (MALE) were assessed during three-year follow-up. Propensity weighting was used to adjust for baseline differences between patients taking and not taking ACEIs or ARBs. ACEIs or ARBs were prescribed to 269 (58%) patients. Patients prescribed ACEIs or ARBs had more baseline comorbidities including diabetes and hypertension (p<0.05). Patients prescribed ACEIs or ARBs had lower three-year unadjusted rates of MACE (40% versus 47%) and mortality (33% versus 43%). After propensity weighting, ACEI or ARB use was associated with significantly lower rates of MACE (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.58-0.99, p=0.04) and overall mortality (HR 0.71, 95% CI 0.53-0.95, p=0.02). There was no significant association between ACEI or ARB use and MALE (HR 0.97, 95% CI 0.69-1.35, p=0.2) or major amputation (HR 0.74, 95% CI 0.47-1.18, p=0.1). ACEI/ARB use is associated with lower MACE and mortality in patients with CLI, but there was no effect on limb-related outcomes.

negative: Interferon alfacon 1 inhibits SARS-CoV infection In human bronchial epithelial Calu-3 cells The primary targets for SARS-CoV infection are the epithelial cells in the respiratory and intestinal tract. The angiotensin-converting enzyme 2 (ACE-2) has been identified as a functional receptor for SARS-CoV. ACE-2 has been shown to be expressed at the apical domain of polarized Calu-3 cells. In this report, interferon alfacon 1 was examined for inhibitory activities against SARS-CoV on human lung carcinoma epithelial Calu-3 cell line and the other three African green monkey kidney epithelial cell lines. Interferon alfacon 1 demonstrated significant antiviral activity in neutral red uptake assay and virus yield reduction assay. The data might provide an important insight into the mechanism of pathogenesis of SARS-CoV allowing further development of antiviral therapies for treating SARS infections.

negative: The COVID-19 outbreak and psychiatric hospitals in China: managing challenges through mental health service reform Recently, more than 300 Chinese patients with psychiatric disorders were diagnosed with the 2019 novel coronavirus disease (COVID-19). Possible reasons quoted in the report were the lack of caution regarding the COVID-19 outbreak in January and insufficient supplies of protective gear. We outlined major challenges for patients with psychiatric disorders and mental health professionals during the COVID-19 outbreak, and also discussed how to manage these challenges through further mental health service reform in China.

negative: ACE2 – From the renin–angiotensin system to gut microbiota and malnutrition Abstract The renin–angiotensin system (RAS) is a complex network that regulates blood pressure, electrolyte and fluid homeostasis, as well as the function of several organs. Angiotensin-converting enzyme 2 (ACE2) was identified as an enzyme that negatively regulates the RAS by converting Ang II, the main bioactive molecule of the RAS, to Ang 1–7. Thus, ACE2 counteracts the role of angiotensin-converting enzyme (ACE) which generates Ang II from Ang I. ACE and ACE2 have been implicated in several pathologies such as cardiovascular and renal disease or acute lung injury. In addition, ACE2 has functions independent of the RAS: ACE2 is the receptor for the SARS coronavirus and ACE2 is essential for expression of neutral amino acid transporters in the gut. In this context, ACE2 modulates innate immunity and influences the composition of the gut microbiota, which can explain diarrhea and intestinal inflammation observed in Hartnup disorder, Pellagra, or under conditions of severe malnutrition. Here we review and discuss the diverse functions of ACE2 and its relevance to human pathologies.

negative: Reduced plasma ACE2 activity in dialysis patients: another piece in the conundrum of factors involved in hypertension and cardiovascular morbidity? the reduction in plasma ACE2 activity reported in ESRD patients treated by dialysis, particularly in female subjects, could limit Ang II degradation leading to increased levels of this peptide, which could contribute to the high prevalence of hypertension and cardiovascular morbidity that afflicts the dialysis population

negative: Demographic, etiological, and histological pulmonary analysis of patients with acute respiratory failure: a study of 19 years of autopsies INTRODUCTION: Acute respiratory failure has been one of the most important causes of death in intensive care units, and certain aspects of its pulmonary pathology are currently unknown. OBJECTIVES: The objective was to describe the demographic data, etiology, and pulmonary histopathological findings of different diseases in the autopsies of patients with acute respiratory failure. METHOD: Autopsies of 4,710 patients with acute respiratory failure from 1990 to 2008 were reviewed, and the following data were obtained: age, sex, and major associated diseases. The pulmonary histopathology was categorized as diffuse alveolar damage, pulmonary edema, alveolar hemorrhage, and lymphoplasmacytic interstitial pneumonia. The odds ratio of the concordance between the major associated diseases and specific autopsy findings was calculated using logistic regression. RESULTS: Bacterial bronchopneumonia was present in 33.9% of the cases and cancer in 28.1%. The pulmonary histopathology showed diffuse alveolar damage in 40.7% (1,917) of the cases. A multivariate analysis showed a significant and powerful association between diffuse alveolar damage and bronchopneumonia, HIV/AIDS, sepsis, and septic shock, between liver cirrhosis and pulmonary embolism, between pulmonary edema and acute myocardial infarction, between dilated cardiomyopathy and cancer, between alveolar hemorrhage and bronchopneumonia and pulmonary embolism, and between lymphoplasmacytic interstitial pneumonia and HIV/AIDS and liver cirrhosis. CONCLUSIONS: Bronchopneumonia was the most common diagnosis in these cases. The most prevalent pulmonary histopathological pattern was diffuse alveolar damage, which was associated with different inflammatory conditions. Further studies are necessary to elucidate the complete pathophysiological mechanisms involved with each disease and the development of acute respiratory failure.

negative: Ectopeptidases in pathophysiology Ectopeptidases are transmembrane proteins present in a wide variety of tissues and cell types. Dysregulated expression of certain ectopeptidases in human malignancies suggests their value as clinical markers. Ectopeptidase interaction with agonistic antibodies or their inhibitors has revealed that these ectoenzymes are able to modulate bioactive peptide responses and to influence growth, apoptosis and differentiation, as well as adhesion and motility, all functions involved in normal and tumoral processes. There is evidence that ectopeptidase‐mediated signal transduction frequently involves tyrosine phosphorylation. Combined analyses of gene organization and regulation of ectopeptidases by various physiological factors have provided insights into their structure–function relationships. Understanding the roles of ectopeptidases in pathophysiology may have implications in considering them as therapeutic targets. BioEssays 23:251–260, 2001. © 2001 John Wiley & Sons, Inc.

negative: À propos de chirurgie et COVID-19 : quelques précautions complémentaires. Réponse à : « Stratégie pour la pratique de la chirurgie digestive et oncologique en situation d’épidémie de COVID-19 »()

negative: Retrovirus Entry by Endocytosis and Cathepsin Proteases Retroviruses include infectious agents inducing severe diseases in humans and animals. In addition, retroviruses are widely used as tools to transfer genes of interest to target cells. Understanding the entry mechanism of retroviruses contributes to developments of novel therapeutic approaches against retrovirus-induced diseases and efficient exploitation of retroviral vectors. Entry of enveloped viruses into host cell cytoplasm is achieved by fusion between the viral envelope and host cell membranes at either the cell surface or intracellular vesicles. Many animal retroviruses enter host cells through endosomes and require endosome acidification. Ecotropic murine leukemia virus entry requires cathepsin proteases activated by the endosome acidification. CD4-dependent human immunodeficiency virus (HIV) infection is thought to occur via endosomes, but endosome acidification is not necessary for the entry whereas entry of CD4-independent HIVs, which are thought to be prototypes of CD4-dependent viruses, is low pH dependent. There are several controversial results on the retroviral entry pathways. Because endocytosis and endosome acidification are complicatedly controlled by cellular mechanisms, the retrovirus entry pathways may be different in different cell lines.

negative: Repurposing the mucolytic cough suppressant and TMPRSS2 protease inhibitor bromhexine for the prevention and management of SARS-CoV-2 infection

negative: Angiotensin converting enzyme 2 and the kidney. PURPOSE OF REVIEW Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase that metabolizes angiotensin II (AngII). AngII levels can be modulated by ACE2 in tissues where the enzyme is highly expressed, such as the kidney. In the kidney, ACE2 has the potential to regulate the intrarenal renin-angiotensin system (RAS), which can impact blood pressure and renal injury. Thus, in disease states where the RAS is often upregulated, the function of ACE2 plays a particularly important role. This review highlights the results of recent studies that demonstrate the interplay between ACE2 and the kidney under normal and pathological conditions. RECENT FINDINGS ACE2 has been reported to play a key role in renal and cardiovascular function. Recent studies have implicated shedding of the membrane-bound ectodomain of ACE2 as one way in which the enzyme can be regulated and enzymatic activity altered. This posttranslational modification releases a fragment which retains enzymatic activity, and thus provides a novel mechanism by which the RAS can be altered in response to physiological stimuli. Decreased ACE2 activity is associated with increased blood pressure, diabetes, and oxidative stress, whereas, increased levels of ACE2 appear to be renoprotective. SUMMARY A growing body of evidence, involving both experimental and human studies, points out the crucial role that ACE2 plays on the modulation of renal injury. Thus, therapeutic targets aiming to increase ACE2 activity and the ACE2-Ang(1-7)-MasR axis could potentially become clinically relevant, especially in disease states where the renal RAS is upregulated.

negative: Assessment of PaO(2)/FiO(2) for stratification of patients with moderate and severe acute respiratory distress syndrome OBJECTIVES: A recent update of the definition of acute respiratory distress syndrome (ARDS) proposed an empirical classification based on ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO(2)/FiO(2)) at ARDS onset. Since the proposal did not mandate PaO(2)/FiO(2) calculation under standardised ventilator settings (SVS), we hypothesised that a stratification based on baseline PaO(2)/FiO(2) would not provide accurate assessment of lung injury severity. DESIGN: A prospective, multicentre, observational study. SETTING: A network of teaching hospitals. PARTICIPANTS: 478 patients with eligible criteria for moderate (100<PaO(2)/FiO(2)≤200) and severe (PaO(2)/FiO(2)≤100) ARDS and followed until hospital discharge. INTERVENTIONS: We examined physiological and ventilator parameters in association with the PaO(2)/FiO(2) at ARDS onset, after 24 h of usual care and at 24 h under a SVS. At 24 h, patients were reclassified as severe, moderate, mild (200<PaO(2)/FiO(2)≤300) ARDS and non-ARDS (PaO(2)/FiO(2)>300). PRIMARY AND SECONDARY OUTCOMES: Group severity and hospital mortality. RESULTS: At ARDS onset, 173 patients had a PaO(2)/FiO(2)≤100 but only 38.7% met criteria for severe ARDS at 24 h under SVS. When assessed under SVS, 61.3% of patients with severe ARDS were reclassified as moderate, mild and non-ARDS, while lung severity and hospital mortality changed markedly with every PaO(2)/FiO(2) category (p<0.000001). Our model of risk stratification outperformed the stratification using baseline PaO(2)/FiO(2) and non-standardised PaO(2)/FiO(2) at 24 h, when analysed by the predictive receiver operating characteristic (ROC) curve: area under the ROC curve for stratification at baseline was 0.583 (95% CI 0.525 to 0.636), 0.605 (95% CI 0.552 to 0.658) at 24 h without SVS and 0.693 (95% CI 0.645 to 0.742) at 24 h under SVS (p<0.000001). CONCLUSIONS: Our findings support the need for patient assessment under SVS at 24 h after ARDS onset to assess disease severity, and have implications for the diagnosis and management of ARDS patients. TRIAL REGISTRATION NUMBERS: NCT00435110 and NCT00736892.

negative: Design, synthesis and crystallographic analysis of nitrile-based broad-spectrum peptidomimetic inhibitors for coronavirus 3C-like proteases Coronaviral infection is associated with up to 5% of respiratory tract diseases. The 3C-like protease (3CL(pro)) of coronaviruses is required for proteolytic processing of polyproteins and viral replication, and is a promising target for the development of drugs against coronaviral infection. We designed and synthesized four nitrile-based peptidomimetic inhibitors with different N-terminal protective groups and different peptide length, and examined their inhibitory effect on the in-vitro enzymatic activity of 3CL(pro) of severe-acute-respiratory-syndrome-coronavirus. The IC(50) values of the inhibitors were in the range of 4.6–49 μM, demonstrating that the nitrile warhead can effectively inactivate the 3CL(pro) autocleavage process. The best inhibitor, Cbz-AVLQ-CN with an N-terminal carbobenzyloxy group, was ∼10x more potent than the other inhibitors tested. Crystal structures of the enzyme–inhibitor complexes showed that the nitrile warhead inhibits 3CL(pro) by forming a covalent bond with the catalytic Cys145 residue, while the AVLQ peptide forms a number of favourable interactions with the S1–S4 substrate-binding pockets. We have further showed that the peptidomimetic inhibitor, Cbz-AVLQ-CN, has broad-spectrum inhibition against 3CL(pro) from human coronavirus strains 229E, NL63, OC43, HKU1, and infectious bronchitis virus, with IC(50) values ranging from 1.3 to 3.7 μM, but no detectable inhibition against caspase-3. In summary, we have shown that the nitrile-based peptidomimetic inhibitors are effective against 3CL(pro), and they inhibit 3CL(pro) from a broad range of coronaviruses. Our results provide further insights into the future design of drugs that could serve as a first line defence against coronaviral infection.

negative: Perception of emergent epidemic of COVID-2019 / SARS CoV-2 on the Polish Internet Problem: Due to the spread of SARS CoV-2 virus infection and COVID-2019 disease, there is an urgent need to analyze COVID-2019 epidemic perception in Poland. This would enable authorities for preparation of specific actions minimizing public health and economic risks. Methods: We study the perception of COVID-2019 epidemic in Polish society using quantitative analysis of its digital footprints on the Internet (on Twitter, Google, YouTube, Wikipedia and electronic media represented by Event Registry) from January 2020 to 12.03.2020 (before and after official introduction to Poland on 04.03.2020). To this end we utilize data mining, social network analysis, natural language processing techniques. Each examined internet platform was analyzed for representativeness and composition of the target group. Results: We identified three major cluster of the interest before disease introduction on the topic COVID-2019: China- and Italy-related peaks on all platforms, as well as a peak on social media related to the recent special law on combating COVID-2019. Besides, there was a peak in interest on the day of officially confirmed introduction as well as an exponential increase of interest when the Polish government declared war against disease with a massive mitigation program. From sociolingistic perspective, we found that concepts and issues of threat, fear and prevention prevailed before introduction. After introduction, practical concepts about disease and epidemic dominate. Twitter reflected the clear, structural division of the Polish political sphere. We were able to identify potential sources of misinformation as well as key actors (especially early adopters) and influencers. Conclusions: Traditional and social media not only reflect reality, but also create it. Polish authorities, having a reliable analysis of the perception of the problem, could optimally prepare and manage the social dimension of the current epidemic and future ones. Due to filter bubbles observed on Twitter, public information campaigns might have less impact on society than expected. For greater penetration, it might be necessary to diversify information channels to reach as many people as possible which might already be happening. Moreover, it might be necessary to prevent the spread of disinformation, which is now possible due to the special law on combating COVID-2019.

negative: Fast assessment of human receptor-binding capability of 2019 novel coronavirus (2019-nCoV) The outbreaks of 2002/2003 SARS, 2012/2015 MERS and 2019/2020 Wuhan respiratory syndrome clearly indicate that genome evolution of an animal coronavirus (CoV) may enable it to acquire human transmission ability, and thereby to cause serious threats to global public health. It is widely accepted that CoV human transmission is driven by the interactions of its spike protein (S-protein) with human receptor on host cell surface; so, quantitative evaluation of these interactions may be used to assess the human transmission capability of CoVs. However, quantitative methods directly using viral genome data are still lacking. Here, we perform large-scale protein-protein docking to quantify the interactions of 2019-nCoV S-protein receptor-binding domain (S-RBD) with human receptor ACE2, based on experimental SARS-CoV S-RBD-ACE2 complex structure. By sampling a large number of thermodynamically probable binding conformations with Monte Carlo algorithm, this approach successfully identified the experimental complex structure as the lowest-energy receptor-binding conformations, and hence established an experiment-based strength reference for evaluating the receptor-binding affinity of 2019-nCoV via comparison with SARS-CoV. Our results show that this binding affinity is about 73% of that of SARS-CoV, supporting that 2019-nCoV may cause human transmission similar to that of SARS-CoV. Thus, this study presents a method for rapidly assessing the human transmission capability of a newly emerged CoV and its mutant strains, and demonstrates that post-genome analysis of protein-protein interactions may provide early scientific guidance for viral prevention and control.

negative: ACE-2 Expression in the Small Airway Epithelia of Smokers and COPD Patients: Implications for COVID-19 Introduction: Coronavirus disease 2019 (COVID-19) is a respiratory infection caused by the severe acute respiratory syndrome coronavirus2 (SARSCoV-2). This virus uses the angiotensin converting enzyme II (ACE2) as the cellular entry receptor to infect the lower respiratory tract. Because individuals with chronic obstructive pulmonary disease (COPD) are at increased risk of severe COVID19, we determined whether ACE2 expression in the lower airways was related to COPD and cigarette smoking. Methods: Using RNAseq, we determined gene expression levels in bronchial epithelia obtained from cytologic brushings of 6th to 8th generation airways in individuals with and without COPD. We externally validated these results from two additional independent cohorts, which used microarray technologies to measure gene expression levels from 6th to 12th generation airways. Results: In the discovery cohort (n=42 participants), we found that ACE2 expression levels were increased by 48% in the airways of COPD compared with non-COPD subjects (COPD=2.52 (0.66) log2 counts per million reads (CPM) versus non-COPD= 1.70 (0.51) CPM , p=.000762). There was a significant inverse relationship between ACE2 gene expression and FEV1% of predicted (r=negative 0.24; p=0.035). Current smoking also significantly increased ACE2 expression levels compared with never smokers (never current smokers=2.77 (90.91) CPM versus smokers=1.78 (0.39) CPM, p=0.024). These findings were replicated in the two external cohorts. Conclusions: ACE2 expression in lower airways is increased in patients with COPD and with current smoking. These data suggest that these two subgroups are at increased risk of serious COVID19 infection and highlight the importance of smoking cessation in reducing the risk.

negative: Vasculitis and anaphylactoid shock induced in mice by cell wall extract of the fungus Candida metapsilosis. To investigate whether cell wall mannan from Candida metapsilosis induces vasculitis similar to that in Kawasaki syndrome and anaphylactoid shock in mice, we examined the pathogenic effects of C. metapsilosis cell wall extracts. Our results show that intraperitoneal injection of cell wall extracts induced severe coronary arteritis, and intravenous injection induced acute anaphylactoid shock similar to extracts from Candida albicans (C. albicans). Structural analysis of cell wall mannan from C. metapsilosis using NMR spectroscopy showed it to contain only a-mannan, indicating that a-mannan might be contributing to Candida pathogenicity by inducing coronary arteritis and acute shock.

negative: Advances in disease diagnosis, vaccine development and other emerging methods to control pathogens in aquaculture Disease is still regarded as a major constraint to aquaculture production globally. Rapid disease diagnosis and vaccination play a huge part in the control of bacterial diseases, and there has been significant progress in both of these areas. This chapter considers the limitations of existing methods and reviews recent advances made in pathogen detection technologies and vaccine development methodologies. Future directions are discussed, including nanotechnology and reversed vaccinology.

negative: 15 What factors predispose patients to acute respiratory distress syndrome? Abstract: Sepsis, pneumonia, and shock are the most common conditions predisposing to acute respiratory distress syndrome (ARDS) and certain host genetic variants have been associated with the development of ARDS. Risk modifiers include abuse of alcohol and tobacco, malnutrition, and obesity. The Lung Injury Prediction Score (LIPS) and the simplified Early Acute Lung Injury Score predict ARDS based on clinical and investigational criteria. Hospital-acquired ARDS may result from a medley factors of which high tidal volume ventilation, high oxygen concentration, and plasma transfusion are most commonly implicated. The Checklist for Lung Injury Prevention (CLIP) has been developed to ensure compliance with evidence-based practice that may affect ARDS occurrence. To date, no pharmacologic intervention has been shown to prevent ARDS

negative: X-ray Structure and Enzymatic Activity Profile of a Core Papain-like Protease of MERS Coronavirus with utility for structure-based drug design Ubiquitin-like domain 2 (Ubl2) is immediately adjacent to the N-terminus of the papain-like protease (PLpro) domain in coronavirus polyproteins, and it may play a critical role in protease regulation and stability as well as in viral infection. However, our recent cellular studies reveal that removing the Ubl2 domain from MERS PLpro has no effect on its ability to process the viral polyprotein or act as an interferon antagonist, which involves deubiquitinating and deISGylating cellular proteins. Here, we test the hypothesis that the Ubl2 domain is not required for the catalytic function of MERS PLpro in vitro. The X-ray structure of MERS PLpro-∆Ubl2 was determined to 1.9 Å and compared to PLpro containing the N-terminal Ubl2 domain. While the structures were nearly identical, the PLpro-∆Ubl2 enzyme revealed the intact structure of the substrate-binding loop. Moreover, PLpro-∆Ubl2 catalysis against different substrates and a purported inhibitor revealed no differences in catalytic efficiency, substrate specificity, and inhibition. Further, no changes in thermal stability were observed between enzymes. We conclude that the catalytic core of MERS PLpro, i.e. without the Ubl2 domain, is sufficient for catalysis and stability in vitro with utility to evaluate potential inhibitors as a platform for structure-based drug design.

negative: Society of Cardiovascular Computed Tomography Guidance for Use of Cardiac Computed Tomography Amidst the COVID-19 Pandemic Abstract The world is currently suffering through a pandemic outbreak of severe respiratory syndrome coronavirus 2 (SARS-CoV-2) known as Coronavirus Disease 2019 (COVID-19). The United States (US) Centers for Disease Control and Prevention (CDC) currently advises medical facilities to “reschedule non-urgent outpatient visits as necessary” (1). The European Centre for Disease Prevention and Control, the United Kingdom National Health Service and several other international agencies covering Asia, North America and most regions of the world have recommended similar “social distancing” measures(2, 3). The Society of Cardiovascular Computed Tomography (SCCT) offers guidance for cardiac CT (CCT) practitioners to help implement these international recommendations in order to decrease the risk of COVID-19 transmission in their facilities while deciding on the timing of outpatient and inpatient CCT exams. This document also emphasizes SCCT’s commitment to the health and well-being of CCT technologists, imagers, trainees, and research community, as well as the patients served by CCT.

negative: Association between Angiotensin-Converting Enzyme Inhibitors and Lung Cancer-A Nationwide, Population-Based, Propensity Score-Matched Cohort Study BACKGROUND: Direct evidence of lung cancer risk in Asian users of angiotensin-converting enzyme inhibitors (ACEIs) is lacking. METHODS: The ACEI cohort comprised 22,384 patients aged ≥ 18 years with a first prescription of ACEI. The comparison angiotensin receptor blocker (ARB) cohort consisted of age-, sex- and comorbidity-matched patients at a ratio of 1:1. The primary outcome was the incidence of lung cancer, which was evaluated using a proportional hazard model. RESULTS: The overall incidence rates of lung cancer in the ACEI and ARB cohorts were 16.6 and 12.2 per 10,000 person-years, respectively. The ACEI cohort had a significantly higher risk of lung cancer than the ARB cohort (adjusted hazard ratio [aHR]. = 1.36; 95% confidence interval [CI]. = 1.11-1.67). Duration-response and dose-response analyses revealed that compared with patients who did not receive ACEIs, patients who received ACEIs for more than 45 days per year (aHR = 1.87; 95% CI = 1.48-2.36) and patients who received more than 540 defined daily doses of ACEIs per year (aHR =1.80; 95% CI = 1.43--2.27) had a significantly higher risk of lung cancer. The cumulative incidence of lung cancer was also significantly higher in the ACEI cohort than in the ARB cohort (log-rank test, p = 0.002). CONCLUSIONS: ACEI use is associated with an increased risk of lung cancer compared with ARB use. Patients using ARBs have a significantly lower risk of lung cancer than non-ARB users.

negative: A chimeric virus-mouse model system for evaluating the function and inhibition of papain-like proteases of emerging coronaviruses. To combat emerging coronaviruses, developing safe and efficient platforms to evaluate viral protease activities and the efficacy of protease inhibitors is a high priority. Here, we exploit a biosafety level 2 (BSL-2) chimeric Sindbis virus system to evaluate protease activities and the efficacy of inhibitors directed against the papain-like protease (PLpro) of severe acute respiratory syndrome coronavirus (SARS-CoV), a biosafety level 3 (BSL-3) pathogen. We engineered Sindbis virus to coexpress PLpro and a substrate, murine interferon-stimulated gene 15 (ISG15), and found that PLpro mediates removal of ISG15 (deISGylation) from cellular proteins. Mutation of the catalytic cysteine residue of PLpro or addition of a PLpro inhibitor blocked deISGylation in virus-infected cells. Thus, deISGylation is a marker of PLpro activity. Infection of alpha/beta interferon receptor knockout (IFNAR(-/-)) mice with these chimeric viruses revealed that PLpro deISGylation activity removed ISG15-mediated protection during viral infection. Importantly, administration of a PLpro inhibitor protected these mice from lethal infection, demonstrating the efficacy of a coronavirus protease inhibitor in a mouse model. However, this PLpro inhibitor was not sufficient to protect the mice from lethal infection with SARS-CoV MA15, suggesting that further optimization of the delivery and stability of PLpro inhibitors is needed. We extended the chimeric-virus platform to evaluate the papain-like protease/deISGylating activity of Middle East respiratory syndrome coronavirus (MERS-CoV) to provide a small-animal model to evaluate PLpro inhibitors of this recently emerged pathogen. This platform has the potential to be universally adaptable to other viral and cellular enzymes that have deISGylating activities. Importance: Evaluating viral protease inhibitors in a small-animal model is a critical step in the path toward antiviral drug development. We modified a biosafety level 2 chimeric virus system to facilitate evaluation of inhibitors directed against highly pathogenic coronaviruses. We used this system to demonstrate the in vivo efficacy of an inhibitor of the papain-like protease of severe acute respiratory syndrome coronavirus. Furthermore, we demonstrate that the chimeric-virus system can be adapted to study the proteases of emerging human pathogens, such as Middle East respiratory syndrome coronavirus. This system provides an important tool to rapidly assess the efficacy of protease inhibitors targeting existing and emerging human pathogens, as well as other enzymes capable of removing ISG15 from cellular proteins.

negative: Subchapter 29D Angiotensin Converting Enzymes Abstract Angiotensin converting enzyme (ACE) is well known for its dual actions in converting inactive Ang I to active Ang II and degrade active bradykinin (BK), which play an important role in the control of blood pressure. Since the bottle neck step is the production of pressor Ang II, this was targeted pharmacologically in 1970s and successful ACE inhibitors such as captopril were produced to treat hypertension. Researches on domain specific ACE inhibitors are continuing to produce effective hypertension controlling drugs with fewer side effects. ACE2 was discovered in 2000; it converts Ang II into Ang(1–7), thereby reducing the concentration of Ang II as well as increasing that of Ang(1–7), an important enzyme for Ang(1–7)/Mas receptor signaling. ACE2 also acts as the receptor in the lung for the coronavirus causing the infamous severe acute respiratory syndrome (SARS) in 2003.

negative: Expression of feline angiotensin converting enzyme 2 and its interaction with SARS-CoV S1 protein Abstract Feline angiotensin converting enzyme 2 (fACE2) gene was amplified from domestic cat lung with RT-PCR, cloned and sequenced. The complete coding region is 2418bp in length and is the closest to human ACE2 among known ACE2 homologs of non-primate animals. The N terminal fragment 19– 367 aa was expressed in Escherishia coli. Both Western blotting and ELISA demonstrated that fACE2 could react with SARS-CoV S1 protein as efficiently as ACE2 of Vero E6 cells did.

negative: Susceptibility to mouse hepatitis virus strain 3 in BALB/cJ mice: failure of immune cell proliferation and interleukin 2 production.

negative: An approach to the photocatalytic mechanism in the TiO(2)-nanomaterials microorganism interface for the control of infectious processes The approach of this timely review considers the current literature that is focused on the interface nanostructure/cell-wall microorganism to understand the annihilation mechanism. Morphological studies use optical and electronic microscopes to determine the physical damage on the cell-wall and the possible cell lysis that confirms the viability and microorganism death. The key parameters of the tailoring the surface of the photoactive nanostructures such as the metal functionalization with bacteriostatic properties, hydrophilicity, textural porosity, morphology and the formation of heterojunction systems, can achieve the effective eradication of the microorganisms under natural conditions, ranging from practical to applications in environment, agriculture, and so on. However, to our knowledge, a comprehensive review of the microorganism/nanomaterial interface approach has rarely been conducted. The final remarks point the ideal photocatalytic way for the effective prevention/eradication of microorganisms, considering the resistance that the microorganism could develop without the appropriate regulatory aspects for human and ecosystem safety.

negative: [Health protection guideline of mobile cabin hospitals during Novel Coronavirus Pneumonia (NPC) outbreak]. This guideline is applicable to the health protection requirements of large indoor stadiums which are reconstructed as treatment sites for the Novel Coronavirus Pneumonia (NPC) patients with mild symptoms during the outbreak. Focusing on the health emergency scenario of severe virus infectious diseases and atypical places where NPC patients with mild symptom gather, from perspectives of functional zones, hygiene facilities, personal protection, and management system, health risk protection recommendations and countermeasures are comprehensively proposed to mainly protect staffs and surrounding environment. The implementation of this guideline will provide technique support for emergency requirements of indoor stadiums reconstructed as mobile cabin hospitals.

negative: Not just angiotensinases: new roles for the angiotensin-converting enzymes The renin-angiotensin system (RAS) is a critical regulator of blood pressure and fluid homeostasis. Angiotensin II, the primary bioactive peptide of the RAS, is generated from angiotensin I by angiotensin-converting enzyme (ACE). A homologue of ACE, ACE2, is able to convert angiotensin II to a peptide with opposing effects, angiotensin-(1-7). It is proposed that disturbance of the balance of ACE and ACE2 expression and/or function is important in pathologies in which angiotensin II plays a role. These include cardiovascular and renal disease, lung injury and liver fibrosis. The critical roles of ACE and ACE2 in regulating angiotensin II levels have traditionally focussed attention on their activities as angiotensinases. Recent discoveries, however, have illuminated the roles of these enzymes and of the ACE2 homologue, collectrin, in intracellular trafficking and signalling. This paper reviews the key literature regarding both the catalytic and non-catalytic roles of the angiotensin-converting enzyme gene family.

negative: Do chronic respiratory diseases or their treatment affect the risk of SARS-CoV-2 infection?

negative: [Potential antiviral therapeutics for 2019 Novel Coronavirus]. The recent outbreak of respiratory illness in Wuhan, China is caused by a novel coronavirus, named 2019-nCoV, which is genetically close to a bat-derived coronavirus. 2019-nCoV is categorized as beta genus coronavirus, same as the two other strains - severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). Antiviral drugs commonly used in clinical practice, including neuraminidase inhibitors (oseltamivir, paramivir, zanamivir, etc.), ganciclovir, acyclovir and ribavirin, are invalid for 2019-nCoV and not recommended. Drugs are possibly effective for 2019-nCoV include: remdesivir, lopinavir / ritonavir, lopinavir / ritonavir combined with interferon-β, convalescent plasma, and monoclonal antibodies. But the efficacy and safety of these drugs for 2019-nCoV pneumonia patients need to be assessed by further clinical trials.

negative: 3CLpro inhibitors as a potential therapeutic option for COVID-19: Available evidence and ongoing clinical trials

negative: Coronavirus spreads The deadly virus that emerged in Wuhan, China, may be much more contagious than initially thought. Jessica Hamzelou reports

negative: Sars and Other Coronaviruses in Humans and Animals

negative: Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely associated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients Background: Although the SARS-CoV-2 viral load detection of respiratory specimen has been widely used for novel coronavirus disease (COVID-19) diagnosis, it is undeniable that serum SARS-CoV-2 nucleic acid (RNAaemia) could be detected in a fraction of the COVID-19 patients. However, it is not clear that if the incidence of RNAaemia could be correlated with the occurrence of cytokine storm or with the specific class of patients. Methods: This study enrolled 48 patients with COVID-19 admitted to the General Hospital of Central Theater Command, PLA, a designated hospital in Wuhan, China. The patients were divided into three groups according to the Diagnosis and Treatment of New Coronavirus Pneumonia (version 6) published by the National Health Commission of China. The clinical and laboratory data were collected. The serum viral load detection and serum IL-6 levels were determined. Except for routine statistical analysis, Generalized Linear Models (GLMs) analysis was used to establish a patient status prediction model based on real-time RT-PCR Ct value. Findings: The Result showed that cases with RNAaemia were exclusively confirmed in critically ill patients group and appeared to reflect the illness severity. Further more, the inflammatory cytokine IL-6 levels were significantly elevated in critically ill patients, which is almost 10-folds higher than those in other patients. More importantly, the extremely high IL-6 level was closely correlated with the incidence of RNAaemia (R=0.902) and the vital signs of COVID-19 patients (R= -0.682). Interpretation: Serum SARS-CoV-2 viral load (RNAaemia) is strongly associated with cytokine storm and can be used to predict the poor prognosis of COVID-19 patients. Moreover, our results strongly suggest that cytokine IL-6 should be considered as a therapeutic target in critically ill patients with excessive inflammatory response.

negative: Care of patients with liver disease during the COVID-19 pandemic: EASL-ESCMID position paper The coronavirus disease 2019 (COVID-19) pandemic poses an enormous challenge to healthcare systems in affected communities. Older patients and those with pre-existing medical conditions have been identified as populations at risk of a severe disease course. It remains unclear at this point to what extent chronic liver diseases should be considered as risk factors, due to a shortage of appropriate studies. However, patients with advanced liver disease and those after liver transplantation represent vulnerable patient cohorts with an increased risk of infection and/or a severe course of COVID-19. In addition, the current pandemic requires unusual allocation of healthcare resources which may negatively impact the care of patients with chronic liver disease that continue to require medical attention. Thus, the challenge hepatologists are facing is to promote telemedicine in the outpatient setting, prioritise outpatient contacts, avoid nosocomial dissemination of the virus to patients and healthcare providers, and at the same time maintain standard care for patients who require immediate medical attention.

negative: Pneumopathies dites atypiques à coronavirus Résumé La nouvelle pneumopathie, appelée pneumonie atypique, revêt dans 20 % de cas l’aspect d’une forme grave (severe acute respiratory syndrome, SARS). C’est parmi ces cas que l’on trouve surtout les 5 % de mortalité. C’est le diagnostic et le traitement tardif qui entraînent ces formes sévères. Il faut donc traiter tôt en se fondant sur le tableau clinique, la notion de contage, l’identification du virus. ribavirine et corticoïdes en sont les éléments principaux. Abstract A new respiratory illness, designated as atypical pneumonia, produces in 20% of the cases a much more serious disease termed severe acute respiratory syndrome (SARS), which can be fatal in 5% of the cases. Delayed diagnosis and treatment are the underlying causes for the development of SARS. Measures for the management of the disease should be taken swiftly, based on clinical symptoms, definite contact and isolation of the virus. Current treatment of SARS involves antiviral agents, such as ribavirin, and corticosteroids.

negative: Risk perception and behavioral change during epidemics: Comparing models of individual and collective learning Modern societies are exposed to a myriad of risks ranging from disease to natural hazards and technological disruptions. Exploring how the awareness of risk spreads and how it triggers a diffusion of coping strategies is prominent in the research agenda of various domains. It requires a deep understanding of how individuals perceive risks and communicate about the effectiveness of protective measures, highlighting learning and social interaction as the core mechanisms driving such processes. Methodological approaches that range from purely physics-based diffusion models to data-driven environmental methods rely on agent-based modeling to accommodate context-dependent learning and social interactions in a diffusion process. Mixing agent-based modeling with data-driven machine learning has become popularity. However, little attention has been paid to the role of intelligent learning in risk appraisal and protective decisions, whether used in an individual or a collective process. The differences between collective learning and individual learning have not been sufficiently explored in diffusion modeling in general and in agent-based models of socio-environmental systems in particular. To address this research gap, we explored the implications of intelligent learning on the gradient from individual to collective learning, using an agent-based model enhanced by machine learning. Our simulation experiments showed that individual intelligent judgement about risks and the selection of coping strategies by groups with majority votes were outperformed by leader-based groups and even individuals deciding alone. Social interactions appeared essential for both individual learning and group learning. The choice of how to represent social learning in an agent-based model could be driven by existing cultural and social norms prevalent in a modeled society.

negative: Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study Summary Background A cluster of patients with coronavirus disease 2019 (COVID-19) pneumonia caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were successively reported in Wuhan, China. We aimed to describe the CT findings across different timepoints throughout the disease course. Methods Patients with COVID-19 pneumonia (confirmed by next-generation sequencing or RT-PCR) who were admitted to one of two hospitals in Wuhan and who underwent serial chest CT scans were retrospectively enrolled. Patients were grouped on the basis of the interval between symptom onset and the first CT scan: group 1 (subclinical patients; scans done before symptom onset), group 2 (scans done ≤1 week after symptom onset), group 3 (>1 week to 2 weeks), and group 4 (>2 weeks to 3 weeks). Imaging features and their distribution were analysed and compared across the four groups. Findings 81 patients admitted to hospital between Dec 20, 2019, and Jan 23, 2020, were retrospectively enrolled. The cohort included 42 (52%) men and 39 (48%) women, and the mean age was 49·5 years (SD 11·0). The mean number of involved lung segments was 10·5 (SD 6·4) overall, 2·8 (3·3) in group 1, 11·1 (5·4) in group 2, 13·0 (5·7) in group 3, and 12·1 (5·9) in group 4. The predominant pattern of abnormality observed was bilateral (64 [79%] patients), peripheral (44 [54%]), ill-defined (66 [81%]), and ground-glass opacification (53 [65%]), mainly involving the right lower lobes (225 [27%] of 849 affected segments). In group 1 (n=15), the predominant pattern was unilateral (nine [60%]) and multifocal (eight [53%]) ground-glass opacities (14 [93%]). Lesions quickly evolved to bilateral (19 [90%]), diffuse (11 [52%]) ground-glass opacity predominance (17 [81%]) in group 2 (n=21). Thereafter, the prevalence of ground-glass opacities continued to decrease (17 [57%] of 30 patients in group 3, and five [33%] of 15 in group 4), and consolidation and mixed patterns became more frequent (12 [40%] in group 3, eight [53%] in group 4). Interpretation COVID-19 pneumonia manifests with chest CT imaging abnormalities, even in asymptomatic patients, with rapid evolution from focal unilateral to diffuse bilateral ground-glass opacities that progressed to or co-existed with consolidations within 1–3 weeks. Combining assessment of imaging features with clinical and laboratory findings could facilitate early diagnosis of COVID-19 pneumonia. Funding None.

negative: Thiol-based angiotensin-converting enzyme 2 inhibitors: P1 modifications for the exploration of the S1 subsite Abstract Screening of a metalloprotease library led to the identification of a thiol-based dual ACE/NEP inhibitor as a potent ACE2 inhibitor. Modifications of the P1 benzyl moiety led to improvements in ACE2 potency as well as to increased selectivity versus ACE and NEP.

negative: Angiotensin-converting enzyme 2 is reduced in Alzheimer’s disease in association with increasing amyloid-β and tau pathology BACKGROUND: Hyperactivity of the classical axis of the renin-angiotensin system (RAS), mediated by angiotensin II (Ang II) activation of the angiotensin II type 1 receptor (AT1R), is implicated in the pathogenesis of Alzheimer’s disease (AD). Angiotensin-converting enzyme-2 (ACE-2) degrades Ang II to angiotensin 1–7 (Ang (1-7)) and counter-regulates the classical axis of RAS. We have investigated the expression and distribution of ACE-2 in post-mortem human brain tissue in relation to AD pathology and classical RAS axis activity. METHODS: We measured ACE-2 activity by fluorogenic peptide substrate assay in mid-frontal cortex (Brodmann area 9) in a cohort of AD (n = 90) and age-matched non-demented controls (n = 59) for which we have previous data on ACE-1 activity, amyloid β (Aβ) level and tau pathology, as well as known ACE1 (rs1799752) indel polymorphism, apolipoprotein E (APOE) genotype, and cerebral amyloid angiopathy severity scores. RESULTS: ACE-2 activity was significantly reduced in AD compared with age-matched controls (P < 0.0001) and correlated inversely with levels of Aβ (r = −0.267, P < 0.001) and phosphorylated tau (p-tau) pathology (r = −0.327, P < 0.01). ACE-2 was reduced in individuals possessing an APOE ε4 allele (P < 0.05) and was associated with ACE1 indel polymorphism (P < 0.05), with lower ACE-2 activity in individuals homozygous for the ACE1 insertion AD risk allele. ACE-2 activity correlated inversely with ACE-1 activity (r = −0.453, P < 0.0001), and the ratio of ACE-1 to ACE-2 was significantly elevated in AD (P < 0.0001). Finally, we show that the ratio of Ang II to Ang (1–7) (a proxy measure of ACE-2 activity indicating conversion of Ang II to Ang (1–7)) is reduced in AD. CONCLUSIONS: Together, our findings indicate that ACE-2 activity is reduced in AD and is an important regulator of the central classical ACE-1/Ang II/AT1R axis of RAS, and also that dysregulation of this pathway likely plays a significant role in the pathogenesis of AD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13195-016-0217-7) contains supplementary material, which is available to authorized users.

negative: A noncovalent class of papain-like protease/deubiquitinase inhibitors blocks SARS virus replication. We report the discovery and optimization of a potent inhibitor against the papain-like protease (PLpro) from the coronavirus that causes severe acute respiratory syndrome (SARS-CoV). This unique protease is not only responsible for processing the viral polyprotein into its functional units but is also capable of cleaving ubiquitin and ISG15 conjugates and plays a significant role in helping SARS-CoV evade the human immune system. We screened a structurally diverse library of 50,080 compounds for inhibitors of PLpro and discovered a noncovalent lead inhibitor with an IC(50) value of 20 microM, which was improved to 600 nM via synthetic optimization. The resulting compound, GRL0617, inhibited SARS-CoV viral replication in Vero E6 cells with an EC(50) of 15 microM and had no associated cytotoxicity. The X-ray structure of PLpro in complex with GRL0617 indicates that the compound has a unique mode of inhibition whereby it binds within the S4-S3 subsites of the enzyme and induces a loop closure that shuts down catalysis at the active site. These findings provide proof-of-principle that PLpro is a viable target for development of antivirals directed against SARS-CoV, and that potent noncovalent cysteine protease inhibitors can be developed with specificity directed toward pathogenic deubiquitinating enzymes without inhibiting host DUBs.

negative: Role of angiotensin-converting enzyme (ACE) and ACE2 in a rat model of smoke inhalation induced acute respiratory distress syndrome Abstract Smoke inhalation induced acute respiratory distress syndrome (ARDS) has become more and more common throughout the world and it is hard to improve the outcome. The present research was to investigate possible roles of angiotensin-converting enzyme (ACE) and ACE2 in lung injury resulted from smoke exposure. Rats were exposed to dense smoke to induce ARDS. Histological changes, blood gases, bronchoalveolar lavage fluids (BALF) and wet-to-dry weight were analyzed to evaluate lung injury after smoke inhalation; beside, we also measured the expression of ACE and ACE2 at different time points to explore the possible mechanism of those changes. The results showed that pH of arterial blood, partial blood oxygen (PaO2) and blood oxygen saturation (SO2) decreased after smoke inhalation at different time points (P <0.01); while, partial blood carbon dioxide (PaCO2), wet-to-dry weight ratio, leukocytes count, protein concentration and inflammatory cytokines in BALF increased after smoke exposure (P <0.01). More importantly, both immunohistochemical staining and Western blot results showed that ACE and ACE2 expression in lungs from the experimental groups significantly increased compared with that of the control group (P <0.05). This study indicated that inflammation pulmonary edema and histological changes resulted from smoke inhalation induced lung injury were possibly attributed to abnormal expression of ACE and ACE2 related pathway.

negative: The role of ACE2 in pulmonary diseases—relevance for the nephrologist

negative: Inhibitors of SARS-3CLpro: virtual screening, biological evaluation, and molecular dynamics simulation studies. SARS-CoV from the coronaviridae family has been identified as the etiological agent of Severe Acute Respiratory Syndrome (SARS), a highly contagious upper respiratory disease that reached epidemic status in 2002. SARS-3CL(pro), a cysteine protease indispensible to the viral life cycle, has been identified as one of the key therapeutic targets against SARS. A combined ligand and structure-based virtual screening was carried out against the Asinex Platinum collection. Multiple low micromolar inhibitors of the enzyme were identified through this search, one of which also showed activity against SARS-CoV in a whole cell CPE assay. Furthermore, multinanosecond explicit solvent simulations were carried out using the docking poses of the identified hits to study the overall stability of the binding site interactions as well as identify important changes in the interaction profile that were not apparent from the docking study. Cumulative analysis of the evaluated compounds and the simulation studies led to the identification of certain protein-ligand interaction patterns which would be useful in further structure based design efforts.

negative: Molecular and functional insights into a novel teleost malectin from big-belly seahorse Hippocampus abdominalis Abstract Malectin is a carbohydrate-binding lectin protein found in the endoplasmic reticulum (ER). It selectivity binds to Glc2-N-glycan and is involved in a glycoprotein quality control mechanism. Even though malectin may play a role in immunity, its role in innate immunity is not fully known. In the present study, we identified and characterized the malectin gene from Hippocampus abdominalis (HaMLEC). We analyzed sequence features, spatial expression levels, temporal expression profiles upon immune responses, bacterial and carbohydrate binding abilities and anti-viral properties to investigate the potential role of HaMLEC in innate immunity. The molecular weight and isoelectric point (pI) were estimated to be 31.99 kDa and 5.17, respectively. The N-terminal signal peptide, malectin superfamily domain and C-terminal transmembrane region were identified from the amino acid sequence of HaMLEC. The close evolutionary relationship of HaMLEC with other teleosts was identified by phylogenetic analysis. According to quantitative PCR (qPCR) results, HaMLEC expression was observed in all the examined tissues and high expression was observed in the ovary and brain, compared to other tested tissues. Temporal expression of HaMLEC in liver and blood tissues were significant modulated upon exposure to immunogens Edwardasiella tarda, Streptococcus iniae, polyinosinic:polycytidylic and lipopolysaccharide. The presence of carbohydrate binding modules (CBMs) of bacterial glycosyl hydrolases were functionally confirmed by a bacterial binding assay. Anti-viral activity significantly reduced viral hemorrhagic septicemia virus (VHSV) replication in cells overexpressing HaMLEC. The observed results suggested that HaMLEC may have a significant role in innate immunity in Hippocampus abdominalis.

negative: Potential effect of blood purification therapy in reducing cytokine storm as a late complication of critically ill COVID-19

negative: Docking study of Chloroquine and Hydroxychloroquine interaction with SARS-CoV-2 spike glycoprotein-An in silico insight into the comparative efficacy of repurposing antiviral drugs. Recent outbreak of novel Coronavirus disease (Covid-19) pandemic around the world is associated with severe acute respiratory syndrome. The death toll associated with the pandemic is increasing day by day. SARS-CoV-2 is an enveloped virus and there are ample evidences that its Spike protein (S-protein) is mainly associated with pathogenesis as it is surface-exposed and mediates entry into host cells by binding to angiotensin-converting enzyme-2 (ACE-2) receptor. Therefore, it is the main target of neutralizing antibodies upon infection and there is always a quest to inhibit the S-protein which in turn may help in controlling diseases caused by SARS-CoV-2 in humans. The role of Chloroquine and Hydroxychloroquine as potential treatments for Covid-19 is still under debate globally because of some side effects associated with it. This study involves the In silico interactions of Chloroquine and Hydroxychloroquine with the S-protein of SARS-CoV-2. With the help of various computational methods, we have re-explored the potential role of both of these antiviral drugs for the treatment of Covid-19 patients by comparing the efficacy of both of the drugs to bind to S-protein at its host receptor region. In our research Hydroxychloroquine exhibited potential inhibitory effectsof S-protein with binding energy -7.28 kcal/mol than Chloroquine (-6.30 kcal/mol) at SARS-CoV-2 receptor recognition of susceptible cells. The outcomes of this research strongly appeal for in vivo trials of Hydroxychloroquine for the patients infected with Covid-19. Furthermore, the recommended doses of Hydroxychloroquine may reduce the chances of catching Covid-19 to the healthcare workers and staff who are in contact with or delivering direct care to coronavirus patients as long as they have not been diagnosed with Covid-19. We further hypothesize that the comparative S-protein-drug docking interactions may help to understand the comparative efficacy of other candidate repurposing drugs until discovery of a proper vaccine.

negative: Novel Therapeutic Approaches Targeting the Renin-Angiotensin System and Associated Peptides in Hypertension and Heart Failure Despite the success of renin-angiotensin system (RAS) blockade by angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 receptor (AT(1)R) blockers, current therapies for hypertension and related cardiovascular diseases are still inadequate. Identification of additional components of the RAS and associated vasoactive pathways, as well as new structural and functional insights into established targets, have led to novel therapeutic approaches with the potential to provide improved cardiovascular protection and better blood pressure control and/or reduced adverse side effects. The simultaneous modulation of several neurohumoral mediators in key interconnected blood pressure–regulating pathways has been an attractive approach to improve treatment efficacy, and several novel approaches involve combination therapy or dual-acting agents. In addition, increased understanding of the complexity of the RAS has led to novel approaches aimed at upregulating the ACE2/angiotensin-(1-7)/Mas axis to counter-regulate the harmful effects of the ACE/angiotensin II/angiotensin III/AT(1)R axis. These advances have opened new avenues for the development of novel drugs targeting the RAS to better treat hypertension and heart failure. Here we focus on new therapies in preclinical and early clinical stages of development, including novel small molecule inhibitors and receptor agonists/antagonists, less conventional strategies such as gene therapy to suppress angiotensinogen at the RNA level, recombinant ACE2 protein, and novel bispecific designer peptides.

negative: Long-Term Toxicity of Immunosuppressive Therapy

negative: Pharmacologic modulation of ACE2 expression Angiotensin-converting enzyme 2 (ACE2) is an enzymatically active homologue of angiotensin-converting enzyme that degrades angiotensin I, angiotensin II, and other peptides. Recent studies have shown that under pathologic conditions, ACE2 expression in the kidney is altered. In this review, we briefly summarize recent studies dealing with pharmacologic interventions that modulate ACE2 expression. ACE2 amplification may have a potential therapeutic role for kidney disease and hypertension.

negative: Computer simulations of protein–membrane systems The interactions between proteins and membranes play critical roles in signal transduction, cell motility, and transport, and they are involved in many types of diseases. Molecular dynamics (MD) simulations have greatly contributed to our understanding of protein–membrane interactions, promoted by a dramatic development of MD-related software, increasingly accurate force fields, and available computer power. In this chapter, we present available methods for studying protein–membrane systems with MD simulations, including an overview about the various all-atom and coarse-grained force fields for lipids, and useful software for membrane simulation setup and analysis. A large set of case studies is discussed.

negative: Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19 BACKGROUND: Coronavirus disease 2019 (Covid-19) may disproportionately affect people with cardiovascular disease. Concern has been aroused regarding a potential harmful effect of angiotensin-converting–enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) in this clinical context. METHODS: Using an observational database from 169 hospitals in Asia, Europe, and North America, we evaluated the relationship of cardiovascular disease and drug therapy with in-hospital death among hospitalized patients with Covid-19 who were admitted between December 20, 2019, and March 15, 2020, and were recorded in the Surgical Outcomes Collaborative registry as having either died in the hospital or survived to discharge as of March 28, 2020. RESULTS: Of the 8910 patients with Covid-19 for whom discharge status was available at the time of the analysis, a total of 515 died in the hospital (5.8%) and 8395 survived to discharge. The factors we found to be independently associated with an increased risk of in-hospital death were an age greater than 65 years (mortality of 10.0%, vs. 4.9% among those ≤65 years of age; odds ratio, 1.93; 95% confidence interval [CI], 1.60 to 2.41), coronary artery disease (10.2%, vs. 5.2% among those without disease; odds ratio, 2.70; 95% CI, 2.08 to 3.51), heart failure (15.3%, vs. 5.6% among those without heart failure; odds ratio, 2.48; 95% CI, 1.62 to 3.79), cardiac arrhythmia (11.5%, vs. 5.6% among those without arrhythmia; odds ratio, 1.95; 95% CI, 1.33 to 2.86), chronic obstructive pulmonary disease (14.2%, vs. 5.6% among those without disease; odds ratio, 2.96; 95% CI, 2.00 to 4.40), and current smoking (9.4%, vs. 5.6% among former smokers or nonsmokers; odds ratio, 1.79; 95% CI, 1.29 to 2.47). No increased risk of in-hospital death was found to be associated with the use of ACE inhibitors (2.1% vs. 6.1%; odds ratio, 0.33; 95% CI, 0.20 to 0.54) or the use of ARBs (6.8% vs. 5.7%; odds ratio, 1.23; 95% CI, 0.87 to 1.74). CONCLUSIONS: Our study confirmed previous observations suggesting that underlying cardiovascular disease is associated with an increased risk of in-hospital death among patients hospitalized with Covid-19. Our results did not confirm previous concerns regarding a potential harmful association of ACE inhibitors or ARBs with in-hospital death in this clinical context. (Funded by the William Harvey Distinguished Chair in Advanced Cardiovascular Medicine at Brigham and Women’s Hospital.)

negative: Renal ACE and ACE2 expression in early diabetic rats. BACKGROUND/AIM The role of angiotensin-converting enzyme (ACE)-related carboxypeptidase-2 (ACE2) in the regulation of the renin-angiotensin system is not well characterized. This study investigated the changes in the expression of ACE and ACE2 in the kidney in early diabetic rats. METHODS Streptozotocin-induced diabetic rats were examined. The concentrations of angiotensin II in plasma, urine, and renal cortex were measured by radioimmunoassay. The mRNA expression of ACE, ACE2, angiotensin II type 1 receptor (AT1R), and Mas receptor (MasR) in glomeruli and cortex was assessed using real-time PCR. The glomerular and cortical expression of ACE and ACE2 was assessed by immunohistochemistry. RESULTS For renal cortical tissue, the angiotensin II level was more intensified in the 8-week diabetic rats. Immunohistochemical experiments showed that ACE was increased, but ACE2 was decreased in the glomeruli of 8-week diabetic rats, while both ACE and ACE2 in the tubules were increased. The AT1R mRNA in the glomeruli was decreased, while the MasR mRNA was increased in 2-week diabetic rats. CONCLUSION The combined effects of increased ACE and decreased ACE2 in glomeruli may be associated with the activation of the renin-angiotensin system in early diabetic rats, which is known to increase proteinuria.

negative: [Analysis of variation and evolution of SARS-CoV-2 genome]. OBJECTIVE To analyze the evolution and variation of SARS-CoV-2 during the epidemic starting at the end of 2019. METHODS We downloaded the full-length genome sequence of SARS-CoV-2 from the databases of GISAID and NCBI. Using the software for bioinformatics including MEGA-X, BEAST, and TempEst, we constructed the genomic evolution tree, inferred the time evolution signal of the virus, calculated the tMRCA time of the virus and analyzed the selection pressure of the virus during evolution. RESULTS The phylogenetic tree showed that SARS-CoV-2 belonged to the Sarbecovirus subgenus of β Coronavirus genus together with bat coronavirus BetaCoV/bat/Yunnan/RaTG13/2013, bat-SL-CoVZC45, bat-SL-CoVZXC21 and SARS-CoV. The genomic sequences of SARS-CoV-2 isolated from the ongoing epidemic showed a weak time evolution signal with an average tMRCA time of 73 days (95% CI: 38.9-119.3 days). No positive time evolution signal was found between SARS-CoV-2 and BetaCoV/bat/Yunnan/RaTG13/2013, but the former virus had a strong positive temporal evolution relationship with bat-SL-CoVZC45 and SARS-CoV. The major cause for mutations of SARS-CoV-2 was the pressure of purification selection during the epidemic. CONCLUSIONS SARS-CoV-2 may have emerged as early as November, 2019, originating most likely from bat-associated coronavirus. This finding may provide evidence for tracing the sources and evolution of the virus.

negative: [Angiotensin-converting enzyme 2 and coronavirus: research update on pathogenesis of the infection induced by this indissoluble bond]. 与严重急性呼吸系统综合征冠状病毒（SARS-CoV）一样，2019新型冠状病毒（2019-nCoV）亦是以血管紧张素转化酶2（ACE2）为受体感染细胞。ACE2作为肾素-血管紧张素系统（RAS）的重要成员，与ACE互为拮抗，二者的平衡与失衡在维护心血管系统生理功能、机体炎症反应、肺损伤等过程中均发挥着重要作用，而其在冠状病毒感染与致病机制中亦发挥着非常重要的作用。目前为止，在7种人畜共患的冠状病毒中有3种以ACE2为受体感染细胞，即SARS-CoV、人类冠状病毒NL63（HCoV-NL63）和2019-nCoV，了解这些病毒与ACE2的相互作用对于冠状病毒感染的预防和治疗意义重大。本文对相关文献进行了梳理，总结了ACE2及RAS系统在冠状病毒感染、致病过程中发挥的作用，对于2019-nCoV防治过程中存在的争议进行了归纳，针对ACE2和RAS系统中可能存在的2019-nCoV的治疗靶点进行了展望。.

negative: The effect of N-terminal acetylation and the inhibition activity of acetylated enkephalins on the aminopeptidase M-catalyzed hydrolysis of enkephalins☆() High performance liquid chromatography and high performance liquid chromatography/electrospray ionization-mass spectrometry were used to study the effect of N-terminal acetylation and the inhibition activity of acetylated enkephalins on the aminopeptidase M (EC 3.4.11.2)-catalyzed hydrolysis of methionine (Met-enk) and leucine enkephalins (Leu-enk). Acetylation imparts a significant enhancement in the proteolytic stability of these two peptides. After 30 min of the reaction, <10% of both acetylated enkephalins was hydrolyzed. In an 8-h incubation period, only a maximum of 54% acetylated (Ac)-Met-enk and 38% Ac-Leu-enk was hydrolyzed. V(max) and K(m [infi]) for the degradation of Ac-Met-enk were 1.4 nmol/min/50 ng and 2.2 mM, respectively. The corresponding values for the reaction of Ac-Leu-enk were 0.5 nmol/min/50 ng and 0.9 mM. Also, the aminopeptidase M activity on Met-enk can be inhibited in the presence of Ac-Met-enk, which acts as a mixed-type inhibitor with the inhibition constant (K(i)) of 1 × 10(−3) M.

negative: Hereditary and acquired angioedema: Problems and progress: Proceedings of the third C1 esterase inhibitor deficiency workshop and beyond Hereditary angioedema (HAE), a rare but life-threatening condition, manifests as acute attacks of facial, laryngeal, genital, or peripheral swelling or abdominal pain secondary to intra-abdominal edema. Resulting from mutations affecting C1 esterase inhibitor (C1-INH), inhibitor of the first complement system component, attacks are not histamine-mediated and do not respond to antihistamines or corticosteroids. Low awareness and resemblance to other disorders often delay diagnosis; despite availability of C1-INH replacement in some countries, no approved, safe acute attack therapy exists in the United States. The biennial C1 Esterase Inhibitor Deficiency Workshops resulted from a European initiative for better knowledge and treatment of HAE and related diseases. This supplement contains work presented at the third workshop and expanded content toward a definitive picture of angioedema in the absence of allergy. Most notably, it includes cumulative genetic investigations; multinational laboratory diagnosis recommendations; current pathogenesis hypotheses; suggested prophylaxis and acute attack treatment, including home treatment; future treatment options; and analysis of patient subpopulations, including pediatric patients and patients whose angioedema worsened during pregnancy or hormone administration. Causes and management of acquired angioedema and a new type of angioedema with normal C1-INH are also discussed. Collaborative patient and physician efforts, crucial in rare diseases, are emphasized. This supplement seeks to raise awareness and aid diagnosis of HAE, optimize treatment for all patients, and provide a platform for further research in this rare, partially understood disorder.

negative: Nucleotide Analogues as Inhibitors of SARS-CoV Polymerase SARS-CoV-2, a member of the coronavirus family, has caused a global public health emergency.1 Based on our analysis of hepatitis C virus and coronavirus replication, and the molecular structures and activities of viral inhibitors, we previously reasoned that the FDA-approved heptatitis C drug EPCLUSA (Sofosbuvir/Velpatasvir) should inhibit coronaviruses, including SARS-CoV-2.2 Here, using model polymerase extension experiments, we demonstrate that the activated triphosphate form of Sofosbuvir is incorporated by low-fidelity polymerases and SARS-CoV RNA-dependent RNA polymerase (RdRp), and blocks further incorporation by these polymerases; the activated triphosphate form of Sofosbuvir is not incorporated by a host-like high-fidelity DNA polymerase. Using the same molecular insight, we selected two other anti-viral agents, Alovudine and AZT (an FDA approved HIV/AIDS drug) for evaluation as inhibitors of SARS-CoV RdRp. We demonstrate the ability of two HIV reverse transcriptase inhibitors, 3’-fluoro-3’-deoxythymidine triphosphate and 3’-azido-3’-deoxythymidine triphosphate (the active triphosphate forms of Alovudine and AZT), to be incorporated by SARS-CoV RdRp where they also terminate further polymerase extension. Given the 98% amino acid similarity of the SARS-CoV and SARS-CoV-2 RdRps, we expect these nucleotide analogues would also inhibit the SARS-CoV-2 polymerase. These results offer guidance to further modify these nucleotide analogues to generate more potent broad-spectrum anti-coronavirus agents.

negative: Pandémie COVID-19 : impact sur le systeme cardiovasculaire. Données disponibles au 1er avril 2020 Résumé Le syndrome respiratoire aigu sévère coronavirus 2 (SARS-CoV-2) infecte les cellules hôtes par les récepteurs de l’angiotensine, conduisant à une pneumonie liée au COVID-19. À un niveau cardiaque, le virus a un double impact ; en effet, l’infection sera plus grave si l’hôte possède des comorbidités cardiovasculaires, et le virus peut causer des lésions cardiovasculaires pouvant engager le pronostic vital. Les thérapeutiques associées au COVID-19 peuvent avoir des effets indésirables cardiovasculaires. Une attention particulière doit être accordée à la protection cardiovasculaire pendant l’infection au COVID-19. Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects host cells with angiotensin receptors, leading to pneumonia linked to COVID-19. The virus has a double impact on the cardiovascular system, the infection will be more intense if the host has cardiovascular co-morbidities and the virus can cause life-threatening cardiovascular lesions. Therapies associated with COVID-19 may have adverse cardiovascular effects. Therefore, special attention should be given to cardiovascular protection during COVID-19 infection.

negative: Heart Transplantation for Advanced Heart Failure

negative: Social Media as a Sensor of Air Quality and Public Response in China BACKGROUND: Recent studies have demonstrated the utility of social media data sources for a wide range of public health goals, including disease surveillance, mental health trends, and health perceptions and sentiment. Most such research has focused on English-language social media for the task of disease surveillance. OBJECTIVE: We investigated the value of Chinese social media for monitoring air quality trends and related public perceptions and response. The goal was to determine if this data is suitable for learning actionable information about pollution levels and public response. METHODS: We mined a collection of 93 million messages from Sina Weibo, China’s largest microblogging service. We experimented with different filters to identify messages relevant to air quality, based on keyword matching and topic modeling. We evaluated the reliability of the data filters by comparing message volume per city to air particle pollution rates obtained from the Chinese government for 74 cities. Additionally, we performed a qualitative study of the content of pollution-related messages by coding a sample of 170 messages for relevance to air quality, and whether the message included details such as a reactive behavior or a health concern. RESULTS: The volume of pollution-related messages is highly correlated with particle pollution levels, with Pearson correlation values up to .718 (n=74, P<.001). Our qualitative results found that 67.1% (114/170) of messages were relevant to air quality and of those, 78.9% (90/114) were a firsthand report. Of firsthand reports, 28% (32/90) indicated a reactive behavior and 19% (17/90) expressed a health concern. Additionally, 3 messages of 170 requested that action be taken to improve quality. CONCLUSIONS: We have found quantitatively that message volume in Sina Weibo is indicative of true particle pollution levels, and we have found qualitatively that messages contain rich details including perceptions, behaviors, and self-reported health effects. Social media data can augment existing air pollution surveillance data, especially perception and health-related data that traditionally requires expensive surveys or interviews.

negative: Novel and potent inhibitors targeting DHODH, a rate-limiting enzyme in de novo pyrimidine biosynthesis, are broad-spectrum antiviral against RNA viruses including newly emerged coronavirus SARS-CoV-2 Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of coronavirus SARS-CoV-2. Existing direct-acting antiviral (DAA) drugs cannot be applied immediately to new viruses because of virus-specificity, and the development of new DAA drugs from the beginning is not timely for outbreaks. Thus, host-targeting antiviral (HTA) drugs have many advantages to fight against a broad spectrum of viruses, by blocking the viral replication and overcoming the potential viral mutagenesis simultaneously. Herein, we identified two potent inhibitors of DHODH, S312 and S416, with favorable drug-like and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus (H1N1, H3N2, H9N2), Zika virus, Ebola virus, and particularly against the recent novel coronavirus SARS-CoV-2. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knocking-out cells. We also proposed the drug combination of DAA and HTA was a promising strategy for anti-virus treatment and proved that S312 showed more advantageous than Oseltamivir to treat advanced influenza diseases in severely infected animals. Notably, S416 is reported to be the most potent inhibitor with an EC50 of 17nM and SI value >5882 in SARS-CoV-2-infected cells so far. This work demonstrates that both our self-designed candidates and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-repression may have clinical potentials not only to influenza but also to COVID-19 circulating worldwide, no matter such viruses mutate or not.

negative: Transmission Parameters of the 2001 Foot and Mouth Epidemic in Great Britain Despite intensive ongoing research, key aspects of the spatial-temporal evolution of the 2001 foot and mouth disease (FMD) epidemic in Great Britain (GB) remain unexplained. Here we develop a Markov Chain Monte Carlo (MCMC) method for estimating epidemiological parameters of the 2001 outbreak for a range of simple transmission models. We make the simplifying assumption that infectious farms were completely observed in 2001, equivalent to assuming that farms that were proactively culled but not diagnosed with FMD were not infectious, even if some were infected. We estimate how transmission parameters varied through time, highlighting the impact of the control measures on the progression of the epidemic. We demonstrate statistically significant evidence for assortative contact patterns between animals of the same species. Predictive risk maps of the transmission potential in different geographic areas of GB are presented for the fitted models.

negative: Structure and Function of Angiotensin Converting Enzyme and Its Inhibitors Abstract Angiotensin converting enzyme (ACE, EC 3.4.15.1) is a membrane-bound, zinc dependent dipeptidase that catalyzes the conversion of the decapeptide angiotensin I to the potent vasopressor octapeptide angiotensin II by removing the two C-terminal amino acids. ACE is well known to be a key part of the rennin-angiotensin system that regulates blood pressure. The inhibitors of ACE have the potency of treating hypertension. This article reviews the structure-function relationship of ACE as well as its gene polymorphism and inhibitor development. In particular, it has been found that the catalytic mechanisms of the two active sites of somatic ACE in the cleavage of angiotensin I and bradykin are different. Therefore, by specifically targeting the individual active sites of somatic ACE, it will likely offer a new way to develop novel ACE inhibitors with fewer side effects.

negative: Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome: Current Therapeutic Options and Potential Targets for Novel Therapies No specific antivirals are currently available for two emerging infectious diseases, Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS). A literature search covering pathogenesis, clinical features and therapeutics, clinically developed drugs for repurposing and novel drug targets was performed. This review presents current knowledge on the epidemiology, pathogenesis and clinical features of the SARS and MERS coronaviruses. The rationale for and outcomes with treatments used for SARS and MERS is discussed. The main focus of the review is on drug development and the potential that drugs approved for other indications provide for repurposing. The drugs we discuss belong to a wide range of different drug classes, such as cancer therapeutics, antipsychotics, and antimalarials. In addition to their activity against MERS and SARS coronaviruses, many of these approved drugs have broad-spectrum potential and have already been in clinical use for treating other viral infections. A wealth of knowledge is available for these drugs. However, the information in this review is not meant to guide clinical decisions, and any therapeutic described here should only be used in context of a clinical trial. Potential targets for novel antivirals and antibodies are discussed as well as lessons learned from treatment development for other RNA viruses. The article concludes with a discussion of the gaps in our knowledge and areas for future research on emerging coronaviruses.

negative: Ace revisited: A new target for structure-based drug design Current-generation angiotensin-converting enzyme (ACE) inhibitors are widely used for cardiovascular diseases, including high blood pressure, heart failure, heart attack and kidney failure, and have combined annual sales in excess of US $6 billion. However, the use of these ACE inhibitors, which were developed in the late 1970s and early 1980s, is hampered by common side effects. Moreover, we now know that ACE actually consists of two parts (called the N- and C-domains) that have different functions. Therefore, the design of specific domain-selective ACE inhibitors is expected to produce next-generation drugs that might be safer and more effective. Here we discuss the structural features of current inhibitors and outline how next-generation ACE inhibitors could be designed by using the three-dimensional molecular structure of human testis ACE. The ACE structure provides a unique opportunity for rational drug design, based on a combination of in silico modelling using existing inhibitors as scaffolds and iterative lead optimization to drive the synthetic chemistry.

negative: Knocking Out Angiotensin II in the Heart Despite ongoing medical advances, cardiovascular disease continues to be a leading health concern. The renin-angiotensin system (RAS) plays an important role in regulating cardiovascular function, and is, therefore, the subject of extensive study. Several drugs currently used to treat hypertension and heart failure are designed to target angiotensin II synthesis and function, but thus far, none have been able to completely block the effects of RAS signaling. This review discusses current and emerging approaches towards inhibiting cardiac RAS function in order to further improve cardiovascular disease outcomes.

negative: Corona Virus International Public Health Emergencies: Implications for Radiology Management The outbreak of 2019 novel coronavirus (2019-nCoV) pneumonia was reported in Wuhan, Hubei Province, China in December 2019 and has spread internationally. This article discusses how radiology departments can most effectively respond to this public health emergency.

negative: Hospital pharmacists’ pharmaceutical care for hospitalized patients with COVID-19: Recommendations and guidance from clinical experience Abstract Objective To discuss hospital pharmacists’ role in providing pharmaceutical care for hospitalized patients with COVID-19 to promote patient care and management during the pandemic. Method Based on the method of evidence-based pharmacy, clinical evidence of therapeutical drugs for COVID-19 were retrieved and summarized. Based on clinical experience Chinese hospital pharmacists gained from providing pharmaceutical care services during COVID-19 pandemic, taking COVID-19 hospitalized patients’ needs into consideration, the methods and strategies hospital pharmacists shall use to provide pharmaceutical care were analyzed and summarized. Results Hospital pharmacists shall support pharmaceutical care services by participating in making evidence-based decisions for medication, monitoring and evaluation of medication safety and efficacy, providing strengthened care for special population and patients with combined underlying diseases, monitoring and management of convalescent plasma therapy, providing emotional counselling and psychological support, and providing scientific information about COVID-19 vaccines. Conclusion The need of pharmaceutical care services in COVID-19 hospitalized patients during this pandemic was quite distinguished from the past. Hospital pharmacists shall join the collaborative multidisciplinary team to improve COVID-19 patients’ outcome and reduce mortality, and to facilitate the pandemic control.

negative: Knowledge and Beliefs towards Universal Safety Precautions to flatten the curve during Novel Coronavirus Disease (nCOVID-19) Pandemic among general Public in India: Explorations from a National Perspective Background: The novel Coronavirus disease (COVID-19) is being considered as the most serious health threat that the world has never witnessed in the recent times and significantly affecting the daily routine of mankind by emerging as a global pandemic. Yet, as there is no treatment nor a vaccine that was approved so far, universal safety precautions (USPs) and mitigating strategies are the only way to deal with this emergency crisis. However, knowledge and beliefs towards USPs among the general public in countries such as India with a large population are lacking. Methods: A prospective, cross-sectional, web-based online survey was conducted among the general public in India during March 2020. A 20-items self-administered survey questionnaire was developed and randomly distributed among the public using google document forms through social media networks. Descriptive statistics were used in representing the study characteristics, and the Chi-square test was used in assessing the associations among the study variables with a p-value of < 0.05 was considered as statistically significant. Results: Of 1287 participants, 1117 have given their consent of willingness and completed the questionnaire with a response rate of 86.8%. The mean age of the study participants was 28.8 ± 10.9 years, where the majority of them belong to the age category <25 years, and sex was equally distributed. Based upon the socio-demographic information, the majority were post-graduates (32.9%), professional job holders (45%) and belonged to the upper-middle (40%) economic class. Overall, the knowledge and beliefs towards USPs and mitigating strategies among participants varied between moderate to high, with statistically significant associations with their socio-demographic characteristics. Conclusions: Although the knowledge and beliefs of the general public in India towards USPs are encouraging, there is a need for long-term educational interventions as the dynamics and severity of COVID-19 have been changing day-by-day rapidly. The findings of this study could guide the public health authorities in making and implementing decisions to combat this pandemic. Keywords: Coronavirus, COVID-19, outbreak, Pandemic, universal precautions, SARS-CoV-2.

negative: Treatment of 2019 novel coronavirus pneumonia based on the theory of 'three syndromes and three methods'/ 中华危重病急救医学 The latest diagnosis and treatment plan (4th edition) of 2019 novel coronavirus pneumonia has been issued. The diagnosis and treatment plan highlights the concept of integrated traditional Chinese and Western medicine, and Xuebijing injection was referred for three times. Xuebijing injection was successfully developed based on the theory of 'three syndromes and three methods'. The theory of 'three syndromes and three methods' is a theoretical system of integrated traditional Chinese and Western medicine on critical diseases proposed by Professor Wang Jinda and his team in the 1970s, and it is one of the main contents of Wang Jinda's academic thought. The theory of 'three syndromes and three methods' has a deep foundation of traditional Chinese medicine theory, and it is still being continuously enriched and improved. It is also supported by multiple evidence-based data. Therefore, 'three syndromes and three methods' has rich theoretical connotation and tenacious vitality.

negative: Low serum 25-hydroxyvitamin D levels are associated with increased risk of viral coinfections in wheezing children

negative: Invited review: A systematic review of the effects of early separation on dairy cow and calf health ABSTRACT Concern from the public is growing regarding early cow-calf separation, yet proponents of this practice maintain that artificial rearing is critical for cow and calf health. Early separation is assumed to reduce the risk of transfer of pathogens from dam to neonatal calf, but a wide range of health benefits associated with extended cow-calf contact has also been documented. The aim of this systematic review was to report and synthesize conclusions from the literature on dairy cow and calf health in conventional rearing versus cow-calf contact systems. Peer-reviewed, published manuscripts, written in English, directly comparing dairy cow or calf health in artificial versus suckling systems, were eligible for inclusion. We conducted 7 targeted searches using Web of Science to identify key literature on important health conditions. The resulting manuscripts underwent a 4-step appraisal process, and further manuscripts were sourced from reference lists. This process resulted in a final sample of 70 articles that addressed cow and calf health. Sufficient literature was available to assess mastitis in cows, and scours, cryptosporidiosis, Johne's disease, pneumonia, immunity, and mortality in calves. The results for cryptosporidiosis, pneumonia, immunity, and mortality were mixed, with some differences between studies likely attributable to flawed comparisons between cohorts. Overall, the articles addressing calf scours and mastitis pointed to beneficial or no effects of suckling. The studies addressing Johne's disease did not find cow-calf contact to be a significant risk factor. In conclusion, the scientific peer-reviewed literature on cow and calf health provides no consistent evidence in support of early separation.

negative: An Overview of Severe Acute Respiratory Syndrome–Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy [Image: see text] Severe acute respiratory syndrome (SARS) is caused by a newly emerged coronavirus that infected more than 8000 individuals and resulted in more than 800 (10–15%) fatalities in 2003. The causative agent of SARS has been identified as a novel human coronavirus (SARS-CoV), and its viral protease, SARS-CoV 3CL(pro), has been shown to be essential for replication and has hence been recognized as a potent drug target for SARS infection. Currently, there is no effective treatment for this epidemic despite the intensive research that has been undertaken since 2003 (over 3500 publications). This perspective focuses on the status of various efficacious anti-SARS-CoV 3CL(pro) chemotherapies discovered during the last 12 years (2003–2015) from all sources, including laboratory synthetic methods, natural products, and virtual screening. We describe here mainly peptidomimetic and small molecule inhibitors of SARS-CoV 3CL(pro). Attempts have been made to provide a complete description of the structural features and binding modes of these inhibitors under many conditions.

negative: Degradation of Lung Protective Angiotensin Converting Enzyme-2 by Meconium in Human Alveolar Epithelial Cells: A Potential Pathogenic Mechanism in Meconium Aspiration Syndrome BACKGROUND: Pancreatic digestive enzymes present in meconium might be responsible for meconium-induced lung injury. The local Renin Angiotensin System plays an important role in lung injury and inflammation. Particularly, angiotensin converting enzyme-2 (ACE-2) has been identified as a protective lung enzyme against the insult. ACE-2 converts pro-apoptotic Angiotensin II to anti-apoptotic Angiotensin 1–7. However, the effect of meconium on ACE-2 has never been studied before. OBJECTIVE: To study the effect of meconium on ACE-2, and whether inhibition of proteolytic enzymes present in the meconium reverses its effects on ACE-2. METHODS: Alveolar epithelial A549 cells were exposed to F-12 medium, 2.5% meconium, meconium + a protease inhibitor cocktail (PIc) and PIc alone for 16 h. At the end of incubation, apoptosis was measured with a nuclear fragmentation assay and cell lysates were collected for ACE-2 immunoblotting and enzyme activity. RESULTS: Meconium caused a fourfold increase in apoptotic nuclei (p < 0.001). The pro-apoptotic effect of meconium can be reversed by PIc. Meconium reduced ACE-2 enzyme activity by cleaving ACE-2 into a fragment detected at ~ 37 kDa by immunoblot. PIc prevented the degradation of ACE-2 and restored 50% of ACE-2 activity (p < 0.05). CONCLUSION: These data suggest that meconium causes degradation of lung protective ACE-2 by proteolytic enzymes present in meconium, since the effects of meconium can be reversed by PIc.

negative: A case report of neonatal COVID-19 infection in China ;Clinical Infectious Diseases ;Oxford Academic Abstract In December 2019, the 2019 novel coronavirus disease (COVID-19) caused by SARS-CoV-2 emerged in China and now has spread in many countries Pregnant women are susceptible population of COVID-19 which are more likely to have complications and even progresse to severe illness We report a case of neonatal COVID-19 infection in China with pharyngeal swabs tested positive by rRT-PCR assay 36 hours after birth However, whether the case is a vertical transmission from mother to child remains to be confirmed

negative: Development of Small-Molecule MERS-CoV Inhibitors Middle East respiratory syndrome coronavirus (MERS-CoV) with potential to cause global pandemics remains a threat to the public health, security, and economy. In this review, we focus on advances in the research and development of small-molecule MERS-CoV inhibitors targeting different stages of the MERS-CoV life cycle, aiming to prevent or treat MERS-CoV infection.

negative: Informed Consent in the (Mis) Information Age Recent studies suggest that large numbers of healthcare consumers are turning to the Internet as a source of health information. This article considers the potential impact of on-line health information on women’s health-care decisions, and the role of physicians relating to their patients’ use of the Internet as an information source. In particular, the article examines the effect of on-line health information on the informed consent process. Physicians’ disclosure obligations (their legal duty to provide information to patients) and the law of informed consent are briefly described. The article then considers the Internet as a source of health information, and instances and types of misinformation. Finally, the article suggests steps physicians may take to help their patients benefit from Internet health information and to become critical consumers who do not fall victim to inaccurate or misleading information. The article concludes by suggesting that physicians make a practice of asking their patients about alternate sources of information they may have accessed, in order to help ensure that patients’ health-care decisions are based on current accurate and complete information.

negative: Angiotensin-(1-7) and Mas: A Brief History Angiotensin-(1-7) is a vasoactive peptide of the renin–angiotensin system (RAS), which is generated mainly by angiotensin-converting enzyme 2 (ACE2) and exerts its actions via activation of its receptor Mas. The Ang-(1-7)/ACE2/Mas axis is nowadays considered to be a main mechanism, which counterbalances the vasoconstrictive actions of classical RAS, which includes renin, ACE, ANG II, and its receptors AT(1) and AT(2). Whereas the classical RAS has been known for more than 100 years, the protective arm of the RAS was relatively recently discovered. Both Mas and Ang-(1-7) were first described almost 30 years ago; however, it took an additional 15 years until the interaction of these components was revealed. Here, we will describe the story of Mas and Ang-(1-7), which was full of errors and uncertainty at the beginning, until the interrelationship between the two was unveiled in 2003.

negative: Cats, coronaviruses and coronavirus antibody tests Feline infectious peritonitis and other coronavirus infections of cats are briefly reviewed. Interpretation and applications of feline coronavirus antibody tests are described, and general recommendations are provided for practitioners. Some of the major unresolved questions regarding coronavirus infections of cats are delineated.

negative: Effective containment explains sub-exponential growth in confirmed cases of recent COVID-19 outbreak in Mainland China The recent outbreak of COVID-19 in Mainland China is characterized by a distinctive algebraic, sub-exponential increase of confirmed cases with time during the early phase of the epidemic, contrasting an initial exponential growth expected for an unconstrained outbreak with sufficiently large reproduction rate. Although case counts vary significantly between affected provinces in Mainland China, the scaling law t^μ is surprisingly universal, with a range of exponents μ = 2.1 ± 0.3. The universality of this behavior indicates that, in spite of social, regional, demographical, geographical, and socio-economical heterogeneities of affected Chinese provinces, this outbreak is dominated by fundamental mechanisms that are not captured by standard epidemiological models. We show that the observed scaling law is a direct consequence of containment policies that effectively deplete the susceptible population. To this end we introduce a parsimonious model that captures both, quarantine of symptomatic infected individuals as well as population wide isolation in response to mitigation policies or behavioral changes. For a wide range of parameters, the model reproduces the observed scaling law in confirmed cases and explains the observed exponents. Quantitative fits to empirical data permit the identification of peak times in the number of asymptomatic or oligo-symptomatic, unidentified infected individuals, as well as estimates of local variations in the basic reproduction number. The model implies that the observed scaling law in confirmed cases is a direct signature of effective contaiment strategies and/or systematic behavioral changes that affect a substantial fraction of the susceptible population. These insights may aid the implementation of containment strategies in potential export induced COVID-19 secondary outbreaks elsewhere or similar future outbreaks of other emergent infectious diseases.

negative: [An increased neutrophil/lymphocyte ratio is an early warning signal of severe COVID-19]. OBJECTIVE To identify the biomarkers as early warning signals for severe COVID-19. METHODS We retrospectively analyzed the clinical data of 63 patients with COVID- 19 from Hubei Provincial Hospital of Integrated Chinese and Western Medicine, including 32 moderate cases and 31 severe cases. The demographic data, underlying diseases, clinical manifestations and laboratory test results were compared between the two groups. Logistic regression analysis was performed to identify the factors that predicted the severity of COVID-19. The receiver- operating characteristic curve (ROC) of neutrophil/lymphocyte ratio (NLR) was calculated, and the area under the curve (AUC) was determined to estimate the optimal threshold of NLR for predicting severe cases of COVID-19. RESULTS The patients with moderate and server COVID-19 showed significant differences in the rate of diabetes, NLR, serum amyloid A (SSA), C-reactive protein (CRP) and serum albumin (ALB) levels (P < 0.05). The co- morbidity of diabetes, NLR, SSA and CRP were found to positively correlate and ALB to inversely correlate with the severity of COVID-19 (P < 0.05). Multivariate logistic regression analysis showed that NLR was an independent risk factor for severe COVID-19 (OR=1.264, 95% CI: 1.046-1.526, P=0.015) with an AUC of 0.831 (95% CI: 0.730-0.932), an optimal diagnostic threshold of 4.795, a sensitivity of 0.839, and a specificity of 0.750. CONCLUSIONS An increased NLR can serve as an early warning signal of severe COVID-19.

negative: Coronavirus disease 2019 (COVID-19): current status and future perspectives ABSTRACT Coronavirus disease 2019 (COVID-19) originated in the city of Wuhan, Hubei Province, Central China, and has spread quickly to 72 countries to date. COVID-19 is caused by a novel coronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [previously provisionally known as 2019 novel coronavirus (2019-nCoV)]. At present, the newly identified SARS-CoV-2 has caused a large number of deaths with tens of thousands of confirmed cases worldwide, posing a serious threat to public health. However, there are no clinically approved vaccines or specific therapeutic drugs available for COVID-19. Intensive research on the newly emerged SARS-CoV-2 is urgently needed to elucidate the pathogenic mechanisms and epidemiological characteristics and to identify potential drug targets, which will contribute to the development of effective prevention and treatment strategies. Hence, this review will focus on recent progress regarding the structure of SARS-CoV-2 and the characteristics of COVID-19, such as the aetiology, pathogenesis and epidemiological characteristics.

negative: Suppression of innate antiviral response by severe acute respiratory syndrome coronavirus M protein is mediated through the first transmembrane domain Coronaviruses have developed various measures to evade innate immunity. We have previously shown that severe acute respiratory syndrome (SARS) coronavirus M protein suppresses type I interferon (IFN) production by impeding the formation of functional TRAF3-containing complex. In this study, we demonstrate that the IFN-antagonizing activity is specific to SARS coronavirus M protein and is mediated through its first transmembrane domain (TM1) located at the N terminus. M protein from human coronavirus HKU1 does not inhibit IFN production. Whereas N-linked glycosylation of SARS coronavirus M protein has no influence on IFN antagonism, TM1 is indispensable for the suppression of IFN production. TM1 targets SARS coronavirus M protein and heterologous proteins to the Golgi apparatus, yet Golgi localization is required but not sufficient for IFN antagonism. Mechanistically, TM1 is capable of binding with RIG-I, TRAF3, TBK1 and IKKε, and preventing the interaction of TRAF3 with its downstream effectors. Our work defines the molecular architecture of SARS coronavirus M protein required for suppression of innate antiviral response.

negative: A Case Study Evaluating the Risk of Infection from Middle Eastern Respiratory Syndrome Coronavirus (MERS‐CoV) in a Hospital Setting Through Bioaerosols Middle Eastern respiratory syndrome, an emerging viral infection with a global case fatality rate of 35.5%, caused major outbreaks first in 2012 and 2015, though new cases are continuously reported around the world. Transmission is believed to mainly occur in healthcare settings through aerosolized particles. This study uses Quantitative Microbial Risk Assessment to develop a generalizable model that can assist with interpreting reported outbreak data or predict risk of infection with or without the recommended strategies. The exposure scenario includes a single index patient emitting virus‐containing aerosols into the air by coughing, leading to short‐ and long‐range airborne exposures for other patients in the same room, nurses, healthcare workers, and family visitors. Aerosol transport modeling was coupled with Monte Carlo simulation to evaluate the risk of MERS illness for the exposed population. Results from a typical scenario show the daily mean risk of infection to be the highest for the nurses and healthcare workers (8.49 × 10(−4) and 7.91 × 10(−4), respectively), and the lowest for family visitors and patients staying in the same room (3.12 × 10(−4) and 1.29 × 10(−4), respectively). Sensitivity analysis indicates that more than 90% of the uncertainty in the risk characterization is due to the viral concentration in saliva. Assessment of risk interventions showed that respiratory masks were found to have a greater effect in reducing the risks for all the groups evaluated (>90% risk reduction), while increasing the air exchange was effective for the other patients in the same room only (up to 58% risk reduction).

negative: Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis BACKGROUND: Hydroxychloroquine or chloroquine, often in combination with a second-generation macrolide, are being widely used for treatment of COVID-19, despite no conclusive evidence of their benefit. Although generally safe when used for approved indications such as autoimmune disease or malaria, the safety and benefit of these treatment regimens are poorly evaluated in COVID-19. METHODS: We did a multinational registry analysis of the use of hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19. The registry comprised data from 671 hospitals in six continents. We included patients hospitalised between Dec 20, 2019, and April 14, 2020, with a positive laboratory finding for SARS-CoV-2. Patients who received one of the treatments of interest within 48 h of diagnosis were included in one of four treatment groups (chloroquine alone, chloroquine with a macrolide, hydroxychloroquine alone, or hydroxychloroquine with a macrolide), and patients who received none of these treatments formed the control group. Patients for whom one of the treatments of interest was initiated more than 48 h after diagnosis or while they were on mechanical ventilation, as well as patients who received remdesivir, were excluded. The main outcomes of interest were in-hospital mortality and the occurrence of de-novo ventricular arrhythmias (non-sustained or sustained ventricular tachycardia or ventricular fibrillation). FINDINGS: 96 032 patients (mean age 53·8 years, 46·3% women) with COVID-19 were hospitalised during the study period and met the inclusion criteria. Of these, 14 888 patients were in the treatment groups (1868 received chloroquine, 3783 received chloroquine with a macrolide, 3016 received hydroxychloroquine, and 6221 received hydroxychloroquine with a macrolide) and 81 144 patients were in the control group. 10 698 (11·1%) patients died in hospital. After controlling for multiple confounding factors (age, sex, race or ethnicity, body-mass index, underlying cardiovascular disease and its risk factors, diabetes, underlying lung disease, smoking, immunosuppressed condition, and baseline disease severity), when compared with mortality in the control group (9·3%), hydroxychloroquine (18·0%; hazard ratio 1·335, 95% CI 1·223–1·457), hydroxychloroquine with a macrolide (23·8%; 1·447, 1·368–1·531), chloroquine (16·4%; 1·365, 1·218–1·531), and chloroquine with a macrolide (22·2%; 1·368, 1·273–1·469) were each independently associated with an increased risk of in-hospital mortality. Compared with the control group (0·3%), hydroxychloroquine (6·1%; 2·369, 1·935–2·900), hydroxychloroquine with a macrolide (8·1%; 5·106, 4·106–5·983), chloroquine (4·3%; 3·561, 2·760–4·596), and chloroquine with a macrolide (6·5%; 4·011, 3·344–4·812) were independently associated with an increased risk of de-novo ventricular arrhythmia during hospitalisation. INTERPRETATION: We were unable to confirm a benefit of hydroxychloroquine or chloroquine, when used alone or with a macrolide, on in-hospital outcomes for COVID-19. Each of these drug regimens was associated with decreased in-hospital survival and an increased frequency of ventricular arrhythmias when used for treatment of COVID-19. FUNDING: William Harvey Distinguished Chair in Advanced Cardiovascular Medicine at Brigham and Women's Hospital.

negative: Angiotensin-converting enzyme polymorphism affects outcome of local Chinese with acute lung injury Summary Introduction Acute Lung Injury (ALI) with genetic predisposition is fatal. Relationship between angiotensin-converting enzyme insertion/deletion (ACE I/D) polymorphism and the prognosis of local Chinese patients with ALI was investigated; meanwhile, the mechanisms involved were explored. Methods 101 ALI patients, 408 non-ALI patients and 236 healthy blood donors were enrolled. ACE I/D polymorphism was detected by polymerase chain reaction, then ACE genotype (II, ID, DD) and allele (I, D) frequencies were compared. Clinical data of ALI patients was calculated. Also, peripheral blood mononuclear cells (PBMC) were isolated from healthy volunteers with different ACE genotypes. Lipopolysaccharide (LPS)-induced ACE gene mRNA expression and ACE activity was measured. Results There was no significant difference in the frequencies of the genotypes and alleles. Acute Physiology and Chronic Health Evaluation (APACHE) II score was higher in DD subgroup than in II subgroup (19.7 ± 8.7 and 15.6 ± 6.2; P < 0.05). The 28-day mortality was significantly different (17.4%, 26.8%, and 64.3% for II, ID, and DD; P = 0.013). DD genotype was the independent prognostic factor for 28-day outcome. Furthermore, LPS-induced ACE mRNA expression and ACE activity from PBMC in DD genotype subgroup were both significantly higher than those in the other two subgroups. Conclusions ACE I/D polymorphism is a prognostic factor for ALI. Patients with the DD genotype have higher mortality of ALI. Polymorphism influences the expression of ACE gene in LPS-stimulated PBMC, DD genotype leads to higher level of mRNA and enzyme activity. It may be one of the mechanisms involved.

negative: Safety of Ibuprofen in Patients With COVID-19 Causal or Confounded?

negative: Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study BACKGROUND: Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. METHODS: In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. FINDINGS: 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p<0·0001), and d-dimer greater than 1 μg/mL (18·42, 2·64–128·55; p=0·0033) on admission. Median duration of viral shedding was 20·0 days (IQR 17·0–24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors. The longest observed duration of viral shedding in survivors was 37 days. INTERPRETATION: The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. FUNDING: Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

negative: Potential therapeutic effects of dipyridamole in the severely ill patients with COVID-19 Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can cause acute respiratory distress syndrome, hypercoagulability, hypertension, and multiorgan dysfunction. Effective antivirals with safe clinical profile are urgently needed to improve the overall prognosis. In an analysis of a randomly collected cohort of 124 patients with Corona Virus Disease 2019 (COVID-19), we found that hypercoagulability as indicated by elevated concentrations of D-dimers was associated with disease severity. By virtual screening of a U.S. Food and Drug Administration (FDA) approved drug library, we identified an anticoagulation agent dipyridamole (DIP) in silico, which suppressed SARS-CoV-2 replication in vitro. In a proof-of-concept trial involving 31 patients with COVID-19, DIP supplementation was associated with significantly decreased concentrations of D-dimers (P<0.05), increased lymphocyte and platelet recovery in the circulation, and markedly improved clinical outcomes in comparison to the control patients. In particular, all 8 of the DIP-treated severely ill patients showed remarkable improvement: 7 patients (87.5%) achieved clinical cure and were discharged from the hospitals while the remaining 1 patient (12.5%) was in clinical remission.

negative: Angiotensin Converting Enzyme (ACE) and ACE2 Bind Integrins and ACE2 Regulates Integrin Signalling The angiotensin converting enzymes (ACEs) are the key catalytic components of the renin-angiotensin system, mediating precise regulation of blood pressure by counterbalancing the effects of each other. Inhibition of ACE has been shown to improve pathology in cardiovascular disease, whilst ACE2 is cardioprotective in the failing heart. However, the mechanisms by which ACE2 mediates its cardioprotective functions have yet to be fully elucidated. Here we demonstrate that both ACE and ACE2 bind integrin subunits, in an RGD-independent manner, and that they can act as cell adhesion substrates. We show that cellular expression of ACE2 enhanced cell adhesion. Furthermore, we present evidence that soluble ACE2 (sACE2) is capable of suppressing integrin signalling mediated by FAK. In addition, sACE2 increases the expression of Akt, thereby lowering the proportion of the signalling molecule phosphorylated Akt. These results suggest that ACE2 plays a role in cell-cell interactions, possibly acting to fine-tune integrin signalling. Hence the expression and cleavage of ACE2 at the plasma membrane may influence cell-extracellular matrix interactions and the signalling that mediates cell survival and proliferation. As such, ectodomain shedding of ACE2 may play a role in the process of pathological cardiac remodelling.

negative: Fatalism in the context of COVID-19: Perceiving coronavirus as a death sentence predicts reluctance to perform recommended preventative behaviors() To manage the spread of coronavirus, health entities have urged the public to take preventative measures such as social distancing and handwashing. Yet, many appear reluctant to take these measures. Research is needed to understand factors underlying such reluctance, with the aim of developing targeted health interventions. We identify associating coronavirus with death as one such factor. 590 participants completed surveys in mid-March 2020, which included attitudes toward coronavirus, preventative behavioral intentions, and sociodemographic factors. Associating coronavirus with death negatively predicted intentions to perform preventative behaviors. Further, associating coronavirus with death was not evenly distributed throughout the sample and was related with a number of sociodemographic factors including age, race, and availability of sick leave. Following recommended preventative measures to slow the spread of coronavirus appears to relate to the degree to which people associate coronavirus with death. These findings can be used by public health researchers and practitioners to identify those for whom targeted health communication and interventions would be most beneficial, as well as to frame health messaging in ways that combat fatalism.

negative: Hydrolysis of angiotensin peptides by human angiotensin I-converting enzyme and the resensitization of B2 kinin receptors. We measured the cleavage of angiotensin I (Ang I) metabolites by angiotensin I-converting enzyme (ACE) in cultured cells and examined how they augment actions of bradykinin B2 receptor agonists. Monolayers of Chinese hamster ovary cells transfected to stably express human ACE and bradykinin B2 receptors coupled to green fluorescent protein (B2GFP) or to express only coupled B2GFP receptors. We used 2 ACE-resistant bradykinin analogues to activate the B2 receptors. We used high-performance liquid chromatography to analyze the peptides cleaved by ACE on cell monolayers and found that Ang 1-9 was hydrolyzed 18x slower than Ang I and &30% slower than Ang 1-7. Ang 1-7 was cleaved to Ang 1-5. Although micromol/L concentrations of slowly cleaved substrates Ang 1-7 and Ang 1-9 inhibit ACE, they resensitize the desensitized B2GFP receptors in nmol/L concentration, independent of ACE inhibition. This is reflected by release of arachidonic acid through a mechanism involving cross-talk between ACE and B2 receptors. When ACE was not expressed, the Ang 1-9, Ang 1-7 peptides were inactive. Inhibitors of protein kinase C-alpha, phosphatases and Tyr-kinase blocked this resensitization activity, but not basal B2 activation by bradykinin. Ang 1-9 and Ang 1-7 enhance bradykinin activity, probably by acting as endogenous allosteric modifiers of the ACE and B2 receptor complex. Consequently, when ACE inhibitors block conversion of Ang I, other enzymes can still release Ang I metabolites to enhance the efficacy of ACE inhibitors.

negative: Cardiovascular safety of dipeptidyl peptidase-4 inhibitors: recent evidence on heart failure. The cardiovascular safety of DPP4 inhibitors as a class, especially in regards to heart failure, has been questioned after the publication of first trials (SAVOR-TIMI 53 and EXAMINE) assessing the cardiovascular risks of DPP4 inhibitors alogliptin and sitagliptin in 2013. Although there were no increased risks in composite cardiovascular outcomes, the SAVOR-TIMI 53 trial reported a 27% increase in hospitalization for heart failure in diabetic patients who received the DPP4 inhibitor saxagliptin. There has been substantial increase in knowledge on the heart failure effect of DPP4 inhibition since 2013. This review will summarize the role of the DPP4/incretin axis in heart failure and discuss the findings from recent large scale clinical trials assessing the effects of DPP4 inhibitors on heart failure.

negative: Structure of alphacoronavirus transmissible gastroenteritis virus nsp1 has implications for coronavirus nsp1 function and evolution. Coronavirus nsp1 has been shown to induce suppression of host gene expression and to interfere with the host immune response. However, the mechanism is currently unknown. The only available structural information on coronavirus nsp1 is the nuclear magnetic resonance (NMR) structure of the N-terminal domain of nsp1 from severe acute respiratory syndrome coronavirus (SARS-CoV) from the betacoronavirus genus. Here we present the first nsp1 structure from an alphacoronavirus, transmissible gastroenteritis virus (TGEV) nsp1. It displays a six-stranded β-barrel fold with a long alpha helix on the rim of the barrel, a fold shared with SARS-CoV nsp1(13-128). Contrary to previous speculation, the TGEV nsp1 structure suggests that coronavirus nsp1s have a common origin, despite the lack of sequence homology. However, comparisons of surface electrostatics, shape, and amino acid conservation between the alpha- and betacoronaviruses lead us to speculate that the mechanism for nsp1-induced suppression of host gene expression might be different in these two genera.

negative: Rapid and accurate identification of COVID-19 infection through machine learning based on clinical available blood test results Since the sudden outbreak of coronavirus disease 2019 (COVID-19), it has rapidly evolved into a momentous global health concern. Due to the lack of constructive information on the pathogenesis of COVID-19 and specific treatment, it highlights the importance of early diagnosis and timely treatment. In this study, 11 key blood indices were extracted through random forest algorithm to build the final assistant discrimination tool from 49 clinical available blood test data which were derived by commercial blood test equipments. The method presented robust outcome to accurately identify COVID-19 from a variety of suspected patients with similar CT information or similar symptoms, with accuracy of 0.9795 and 0.9697 for the cross-validation set and test set, respectively. The tool also demonstrated its outstanding performance on an external validation set that was completely independent of the modeling process, with sensitivity, specificity, and overall accuracy of 0.9512, 0.9697, and 0.9595, respectively. Besides, 24 samples from overseas infected patients with COVID-19 were used to make an in-depth clinical assessment with accuracy of 0.9167. After multiple verification, the reliability and repeatability of the tool has been fully evaluated, and it has the potential to develop into an emerging technology to identify COVID-19 and lower the burden of global public health. The proposed tool is well-suited to carry out preliminary assessment of suspected patients and help them to get timely treatment and quarantine suggestion. The assistant tool is now available online at http://lishuyan.lzu.edu.cn/COVID2019_2/.

negative: Protocolo diagnóstico y tratamiento de la rinitis

negative: Perspectives on the death investigation during the COVID-19 pandemic Abstract The pandemic of COVID-19 caused by 2019-nCoV outbreaks in most of the countries, which has subsequently spread rapidly and become a pandemic worldwide. Due to the strong infectivity of COVID-19 and lack of experience of performing an autopsy to infectious disease-induced death, the pandemic created some challenges for forensic practitioners. In this article, we summarize the experience of how we handle the confirmed or suspected infectious cases, and give some perspectives for the future.

negative: Localization to the nucleolus is a common feature of coronavirus nucleoproteins, and the protein may disrupt host cell division. The subcellular localization of transmissible gastroenteritis virus (TGEV) and mouse hepatitis virus (MHV) (group I and group II coronaviruses, respectively) nucleoproteins (N proteins) were examined by confocal microscopy. The proteins were shown to localize either to the cytoplasm alone or to the cytoplasm and a structure in the nucleus. This feature was confirmed to be the nucleolus by using specific antibodies to nucleolin, a major component of the nucleolus, and by confocal microscopy to image sections through a cell expressing N protein. These findings are consistent with our previous report for infectious bronchitis virus (group III coronavirus) (J. A. Hiscox et al., J. Virol. 75:506-512, 2001), indicating that nucleolar localization of the N protein is a common feature of the coronavirus family and is possibly of functional significance. Nucleolar localization signals were identified in the domain III region of the N protein from all three coronavirus groups, and this suggested that transport of N protein to the nucleus might be an active process. In addition, our results suggest that the N protein might function to disrupt cell division. Thus, we observed that approximately 30% of cells transfected with the N protein appeared to be undergoing cell division. The most likely explanation for this is that the N protein induced a cell cycle delay or arrest, most likely in the G(2)/M phase. In a fraction of transfected cells expressing coronavirus N proteins, we observed multinucleate cells and dividing cells with nucleoli (which are only present during interphase). These findings are consistent with the possible inhibition of cytokinesis in these cells.

negative: iGPCR-Drug: A Web Server for Predicting Interaction between GPCRs and Drugs in Cellular Networking Involved in many diseases such as cancer, diabetes, neurodegenerative, inflammatory and respiratory disorders, G-protein-coupled receptors (GPCRs) are among the most frequent targets of therapeutic drugs. It is time-consuming and expensive to determine whether a drug and a GPCR are to interact with each other in a cellular network purely by means of experimental techniques. Although some computational methods were developed in this regard based on the knowledge of the 3D (dimensional) structure of protein, unfortunately their usage is quite limited because the 3D structures for most GPCRs are still unknown. To overcome the situation, a sequence-based classifier, called “iGPCR-drug”, was developed to predict the interactions between GPCRs and drugs in cellular networking. In the predictor, the drug compound is formulated by a 2D (dimensional) fingerprint via a 256D vector, GPCR by the PseAAC (pseudo amino acid composition) generated with the grey model theory, and the prediction engine is operated by the fuzzy K-nearest neighbour algorithm. Moreover, a user-friendly web-server for iGPCR-drug was established at http://www.jci-bioinfo.cn/iGPCR-Drug/. For the convenience of most experimental scientists, a step-by-step guide is provided on how to use the web-server to get the desired results without the need to follow the complicated math equations presented in this paper just for its integrity. The overall success rate achieved by iGPCR-drug via the jackknife test was 85.5%, which is remarkably higher than the rate by the existing peer method developed in 2010 although no web server was ever established for it. It is anticipated that iGPCR-Drug may become a useful high throughput tool for both basic research and drug development, and that the approach presented here can also be extended to study other drug – target interaction networks.

negative: Microbial and fungal protease inhibitors—current and potential applications Proteolytic enzymes play essential metabolic and regulatory functions in many biological processes and also offer a wide range of biotechnological applications. Because of their essential roles, their proteolytic activity needs to be tightly regulated. Therefore, small molecules and proteins that inhibit proteases can be versatile tools in the fields of medicine, agriculture and biotechnology. In medicine, protease inhibitors can be used as diagnostic or therapeutic agents for viral, bacterial, fungal and parasitic diseases as well as for treating cancer and immunological, neurodegenerative and cardiovascular diseases. They can be involved in crop protection against plant pathogens and herbivorous pests as well as against abiotic stress such as drought. Furthermore, protease inhibitors are indispensable in protein purification procedures to prevent undesired proteolysis during heterologous expression or protein extraction. They are also valuable tools for simple and effective purification of proteases, using affinity chromatography. Because there are such a large number and diversity of proteases in prokaryotes, yeasts, filamentous fungi and mushrooms, we can expect them to be a rich source of protease inhibitors as well.

negative: Guidelines for preventing respiratory illness in older adults aged 60 years and above living in long-term care: A rapid review of clinical practice guidelines Background: The overall objective of this rapid review was to identify infection protection and control recommendations from published clinical practice guidelines (CPGs) for adults aged 60 years and older in long-term care settings Methods: Comprehensive searches in MEDLINE, EMBASE, the Cochrane Library, and relevant CPG publishers/repositories were carried out in early March 2020. Title/abstract and full-text screening, data abstraction, and quality appraisal (AGREE-II) were carried out by single reviewers. Results: A total of 17 relevant CPGs were identified, published in the USA (n=8), Canada (n=6), Australia (n=2), and the United Kingdom (n=1). All of the CPGs dealt with infection control in long-term care facilities (LTCF) and addressed various types of viral respiratory infections (e.g., influenza, COVID-19, severe acute respiratory syndrome). Ten or more CPGs recommended the following infection control measures in LTCF: hand hygiene (n=13), wearing personal protective equipment (n=13), social distancing or isolation (n=13), disinfecting surfaces (n=12), droplet precautions (n=12), surveillance and evaluation (n=11), and using diagnostic testing to confirm illness (n=10). While only two or more CPGs recommended these infection control measures: policies and procedures for visitors, staff and/or residents (n=9), respiratory hygiene/cough etiquette (n=9), providing supplies (n=9), staff and/or residents education (n=8), increasing communication (n=6), consulting or notifying health professionals (n=6), appropriate ventilation practices (n=2), and cohorting equipment (n=2). Ten CPGs also addressed management of viral respiratory infections in LTCF and recommended antiviral chemoprophylaxis (n=10) and one CPG recommended early mobilization of residents. Conclusion: The recommendations from current guidelines overall seem to support environmental measures for infection prevention and antiviral chemoprophylaxis for infection management as the most appropriate first-line response to viral respiratory illness in long-term care.

negative: Altered Lipid Metabolism in Recovered SARS Patients Twelve Years after Infection Severe acute respiratory syndrome-coronavirus (SARS-CoV) and SARS-like coronavirus are a potential threat to global health. However, reviews of the long-term effects of clinical treatments in SARS patients are lacking. Here a total of 25 recovered SARS patients were recruited 12 years after infection. Clinical questionnaire responses and examination findings indicated that the patients had experienced various diseases, including lung susceptibility to infections, tumors, cardiovascular disorders, and abnormal glucose metabolism. As compared to healthy controls, metabolomic analyses identified significant differences in the serum metabolomes of SARS survivors. The most significant metabolic disruptions were the comprehensive increase of phosphatidylinositol and lysophospha tidylinositol levels in recovered SARS patients, which coincided with the effect of methylprednisolone administration investigated further in the steroid treated non-SARS patients with severe pneumonia. These results suggested that high-dose pulses of methylprednisolone might cause long-term systemic damage associated with serum metabolic alterations. The present study provided information for an improved understanding of coronavirus-associated pathologies, which might permit further optimization of clinical treatments.

negative: The cardiovascular burden of coronavirus disease 2019 (COVID-19) with a focus on congenital heart disease Abstract Coronavirus disease 2019 (COVID-19), caused by a novel betacoronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first described in a cluster of patients presenting with pneumonia symptoms in Wuhan, China, in December of 2019. Over the past few months, COVID-19 has developed into a worldwide pandemic, with over 400,000 documented cases globally as of March 24, 2020. The SARS-CoV-2 virus is most likely of zoonotic origin, but has been shown to have effective human-to-human transmission. COVID-19 results in mild symptoms in the majority of infected patients, but can cause severe lung injury, cardiac injury, and death. Given the novel nature of COVID-19, no established treatment beyond supportive care exists currently, but extensive public-health measures to reduce person-to-person transmission of COVID-19 have been implemented globally to curb the spread of disease, reduce the burden on healthcare systems, and protect vulnerable populations, including the elderly and those with underlying medical comorbidities. Since this is an emerging infectious disease, there is, as of yet, limited data on the effects of this infection on patients with cardiovascular disease, particularly so for those with congenital heart disease. We summarize herewith the early experience with COVID-19 and consider the potential applicability to and implications for patients with cardiovascular disease in general and congenital heart disease in particular.

negative: The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus Antiviral drugs for managing infections with human coronaviruses are not yet approved, posing a serious challenge to current global efforts aimed at containing the outbreak of severe acute respiratory syndrome–coronavirus 2 (CoV-2). Remdesivir (RDV) is an investigational compound with a broad spectrum of antiviral activities against RNA viruses, including severe acute respiratory syndrome–CoV and Middle East respiratory syndrome (MERS–CoV). RDV is a nucleotide analog inhibitor of RNA-dependent RNA polymerases (RdRps). Here, we co-expressed the MERS–CoV nonstructural proteins nsp5, nsp7, nsp8, and nsp12 (RdRp) in insect cells as a part a polyprotein to study the mechanism of inhibition of MERS–CoV RdRp by RDV. We initially demonstrated that nsp8 and nsp12 form an active complex. The triphosphate form of the inhibitor (RDV-TP) competes with its natural counterpart ATP. Of note, the selectivity value for RDV-TP obtained here with a steady-state approach suggests that it is more efficiently incorporated than ATP and two other nucleotide analogs. Once incorporated at position i, the inhibitor caused RNA synthesis arrest at position i + 3. Hence, the likely mechanism of action is delayed RNA chain termination. The additional three nucleotides may protect the inhibitor from excision by the viral 3′–5′ exonuclease activity. Together, these results help to explain the high potency of RDV against RNA viruses in cell-based assays.

negative: Identifying factors and target preventive therapies for Middle East Respiratory Syndrome sucsibtable patients BACKGROUND: Middle East Respiratory Syndrome (MERS) is a respiratory disease caused by a novel coronavirus that was identified in 2012 in Saudi Arabia. It is associated with significant mortality and morbidity. We identified factors associated with the Middle East Respiratory Syndrome-Coronavirus (MERS‐CoV) infection among suspected cases presented with sign and symptoms of upper respiratory infection or exposure to the virus. We also looked at the impact of medication history on virus transmission. METHOD: We included subjects with suspected MERS-CoV infection and confirmed cases of MERS infection. Subjects were excluded if there were any missing data that prevent the final analysis. Descriptive statistics were used to report demographic data. Percentages and frequencies were used to summarize the categorical variables, while means and standard deviations were calculated for continuous variables. Logistic regression was used to assess the risk of MERS-CoV infection among the suspected cases. A value of p < 0.05 was considered statistically significant. RESULTS: A total of 16,189 suspected cases were identified, complete data were analyzed for 3154 to assess factors that are independently associated with MERS-CoV infection. MERS-CoV infection was associated with age (adjusted odds ratio [AOR] = 1.06; 95% CI [1.02–1.098], P-value = 0.004), male gender (AOR = 1.617; 95% CI [1.365–1.77], P-value < 0.001) and diabetes (AOR = 1.68; 95% CI [1.346–1.848], P-value = 0.002. There was no significant association with the other comorbidities. Medication history was not associated with an increase or decrease the likelihood of the infection. CONCLUSIONS: MERS-Cov infection is more common in male, advanced age and diabetes. No medications were associated with an increase or decrease the likelihood of the infection. This is important to focus on screening and detection to this patient population.

negative: Can we contain the COVID-19 outbreak with the same measures as for SARS? Summary The severe acute respiratory syndrome (SARS) outbreak in 2003 resulted in more than 8000 cases and 800 deaths. SARS was eventually contained by means of syndromic surveillance, prompt isolation of patients, strict enforcement of quarantine of all contacts, and in some areas top-down enforcement of community quarantine. By interrupting all human-to-human transmission, SARS was effectively eradicated. By contrast, by Feb 28, 2020, within a matter of 2 months since the beginning of the outbreak of coronavirus disease 2019 (COVID-19), more than 82 000 confirmed cases of COVID-19 have been reported with more than 2800 deaths. Although there are striking similarities between SARS and COVID-19, the differences in the virus characteristics will ultimately determine whether the same measures for SARS will also be successful for COVID-19. COVID-19 differs from SARS in terms of infectious period, transmissibility, clinical severity, and extent of community spread. Even if traditional public health measures are not able to fully contain the outbreak of COVID-19, they will still be effective in reducing peak incidence and global deaths. Exportations to other countries need not result in rapid large-scale outbreaks, if countries have the political will to rapidly implement countermeasures.

negative: Abstracts from the 36th Annual Meeting of the Society of General Internal Medicine

negative: Triage Considerations for Patients Referred for Structural Heart Disease Intervention During the Coronavirus Disease 2019 (COVID-19) Pandemic: An ACC /SCAI Consensus Statement Abstract The COVID-19 pandemic has strained health care resources around the world causing many institutions to curtail or stop elective procedures. This has resulted in the inability to care for patients valvular and structural heart disease (SHD) in a timely fashion potentially placing these patients at increased risk for adverse cardiovascular complications including congestive heart failure and death. The effective triage of these patients has become challenging in the current environment as clinicians have had to weigh the risk of bringing susceptible patients into the hospital environment during the COVID-19 pandemic versus the risk of delaying a needed procedure. In this document, we suggest guidelines as to how to triage patients in need of SHD interventions and provide a framework of how to decide when it may be appropriate to proceed with intervention despite the ongoing pandemic. In particular, we address the triage of patients in need of trans-catheter aortic valve replacement and percutaneous mitral valve repair. We also address procedural issues and considerations for the function of structural heart disease teams during the COVID-19 pandemic.

negative: How will country-based mitigation measures influence the course of the COVID-19 epidemic?

negative: A review of cardiac manifestations and predictors of outcome in patients with COVID – 19 Abstract Coronavirus disease (COVID-19) pandemic has so far involved 184 countries and more than 2.79 million patients worldwide. Over the past three months, it has attributed to more than 196, 000 deaths, with more than 50, 000 deaths in the United States alone. Pulmonary manifestations are predominant and have been well identified. Cardiac involvement is also common. Acute cardiac injury, the most common cardiac manifestation of this disease can be seen in patients even without prior cardiac comorbidities. Established cardiovascular risk factors such as diabetes mellitus, hypertension, and coronary artery disease predispose to cardiac injury, the severity of illness and mortality. Non-ischemic myocardial injury secondary to cytokine storm is thought to be the predominant mechanism of acute cardiac injury associated with COVID-19. Multiple mechanisms and processes contribute to cardiac injury resulting in a poor outcome. Some of these are not clearly understood. Clinical and diagnostic details of cardiovascular involvement in these patients are mostly limited to biochemical markers. Multiple therapeutic agents have been tried with questionable efficacy and without clinical evidence. Interactions of comorbidities, cardiovascular drugs, the cardiac effect of therapeutic agents on the illness continue to be under investigation. With an increasing number of patients, newer promising therapies, and ongoing clinical trials, the exact mechanisms and extent to which these risk factors contribute to outcomes will be clearer in the future.

negative: Testing Case Number of Coronavirus Disease 2019 in China with Newcomb-Benford Law The coronavirus disease 2019 bursted out about two months ago in Wuhan has caused the death of more than a thousand people. China is fighting hard against the epidemics with the helps from all over the world. On the other hand, there appear to be doubts on the reported case number. In this article, we propose a test of the reported case number of coronavirus disease 2019 in China with Newcomb-Benford law. We find a $p$-value of $92.8\%$ in favour that the cumulative case numbers abide by the Newcomb-Benford law. Even though the reported case number can be lower than the real number of affected people due to various reasons, this test does not seem to indicate the detection of frauds.

negative: Midwives in a pandemic: A call for solidarity and compassion

negative: Insight Derived from Molecular Docking and Molecular Dynamics Simulations into the Binding Interactions Between HIV-1 Protease Inhibitors and SARS-CoV-2 3CLpro A novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) was identified from respiratory illness patients in Wuhan, Hubei Province, China, which has recently emerged as a serious threat to the world public health Hower, no approved drugs have been found to effectively inhibit the virus Since it has been reported that the HIV-1 protease inhibitors can be used as anti-SARS drugs by tegarting SARS-CoV 3CLpro, we choose six approved anti-HIV-1 drugs to investigate their binding interactions between 3CLpro, and to evaluate their potential to become clinical drugs for the new coronavirus pneumonia (COVID19) caused by SARS-CoV-2 infection The molecular docking results indicate that, the 3CLpro of SARS-CoV-2 has a higher binding affinity for all the studied inhibitors than its SARS homologue Two docking complexes (indinavir and darunavir) with high docking scores were futher subjected to MM-PBSA binding free energy calculations to detail the molecular interactions between these two proteinase inhibitors and the 3CLpro Our results show that darunavir has the best binding affinity with SARS-CoV-2 and SARS-CoV 3CLpro among all inhibitors, indicating it has the potential to become an anti-COVID-19 clinical drug The likely reason behind the increased binding affinity of HIV-1 protease inhibitors toward SARS-CoV2 3CLpro than that of SARS-CoV were investigated by MD simulations Our study provides insight into the possible role of structural flexibility during interactions between 3CLpro and inhibitors, and sheds light on the structure-based design of anti-COVID-19 drugs targeting the SARS-CoV-2 3CLpro

negative: Attachment Factor and Receptor Engagement of Sars Coronavirus and Human Coronavirus NL63

negative: Rapid random access detection of the novel SARS-coronavirus-2 (SARS-CoV-2, previously 2019-nCoV) using an open access protocol for the Panther Fusion • Detection of SARS-CoV-2 within 3.5 h (sample-to-answer-time) by random access real time PCR. • Adaption of an already published real time PCR for SARS-CoV-2 to a fully automatic, random access PCR system. • Detection of all SARS-CoV (from 2002, which may be soon labelled as SARS-CoV-1, and SARS-CoV-2) with a PCR for the highly conserved E gene region. • Differentiation of SARS-CoV-2 with a PCR for the RdRp Gene.

negative: Short- and long-term efficacy of prednisolone for first acute rhinovirus-induced wheezing episode Background Rhinovirus-induced wheezing is an important risk factor for recurrent wheezing. There are no randomized controlled trials on the effect of systemic corticosteroids in patients with this disease. Objective We sought to study the short- and long-term effects of prednisolone treatment of the first acute, moderate-to-severe, rhinovirus-induced wheezing episode in young children. Methods After confirming rhinovirus from nasopharyngeal aspirate by using PCR, 79 children with a first wheezing episode at age 3 to 23 months were randomized to receive oral prednisolone (first dose of 2 mg/kg, followed by 2 mg/kg/d in 2 divided doses for 3 days) or placebo. The trial was double blind throughout the 12-month follow-up. The primary outcomes were long term: new physician-confirmed wheezing episode within 2 months, number of physician-confirmed wheezing episodes within 12 months, and initiation of regular controller medication for asthma symptoms within 12 months. The primary interaction analysis examined rhinovirus load. Results Seventy-four patients completed the study (mean age, 13 months; 28% atopic). Long-term outcomes did not differ between groups (all P ≥ .30). For short-term outcomes, the prednisolone group had less cough, rhinitis, noisy breathing, severe breathing difficulties, and nocturnal respiratory symptoms at home within 2 weeks (all P < .05). The 25 children with greater than 7000 rhinovirus copies/mL (most sensitive cutoff) benefitted from prednisolone in terms of less risk of physician-confirmed recurrence within 2 and 12 months compared with placebo (both P < .05). Conclusions Prednisolone cannot be routinely recommended for all young children experiencing their first acute, moderate-to-severe, rhinovirus-induced wheezing episode. Prednisolone might be beneficial in a subgroup of children with high viral loads.

negative: ACR Appropriateness Criteria® acute respiratory illness in immunocompetent patients. Acute respiratory illness is defined as one or more of the following: cough, sputum production, chest pain, or dyspnea (with or without fever). The workup of these patients depends on many factors, including clinical presentation and the suspected etiology. This study reviews the literature on the indications and usefulness of radiologic studies for the evaluation of acute respiratory illness in the immunocompetent patient. The following recommendations are the result of evidence-based consensus by the American College of Radiology Appropriateness Criteria Expert Panel on Thoracic Radiology. Chest radiographs are usually appropriate in (1) patients with positive physical examination or risk factors for pneumonia, (2) for the assessment of complicated pneumonia, or (3) in cases of emerging infections and biological warfare agents such as severe acute respiratory syndrome, H1N1, and anthrax. Computed tomography, although having a more limited role, is usually appropriate (1) in the assessment of complicated pneumonia and (2) in patients with suspected severe acute respiratory syndrome, H1N1, or anthrax and a normal radiograph.

negative: COVID-19 randomised trial protocols: rapid publication without barriers

negative: Effect of specific humoral immunity and some non-specific factors on resistance of volunteers to respiratory coronavirus infection. Thirty-three volunteers were inoculated intranasally with coronavirus 229 E, and their responses monitored by antibody rises, symptomatology and virus excretion. These were related to their pre-trial immune status as indicated by concentrations of specific antibodies and non-specific proteins in serum and nasal washings. Both circulating and local specific antibodies were associated with protection from infection and disease, but only specific IgA antibodies of either type appeared to shorten the period of virus shedding. Although total secretory IgA was significantly associated only with reduction of symptoms, total protein in nasal washings appeared to protect against infection also, indicating that other locally produced proteins, not identified, may be associated with resistance. Two of the many factors which may affect the concentration of circulating and local protective proteins and thus influence the outcome of virus inoculation, namely, sex of the volunteer and the interval since the previous cold, were examined. Male volunteers or volunteers who had had evidence of a recent respiratory infection were less likely to be infected, but if they were infected, they had lower clinical scores and stopped shedding virus earlier than the rest. These groups possessed higher concentrations of specific antibodies and non-specific proteins in their pre-challenge sera and/or nasal washings. The significance of these findings is discussed.

negative: [ACE-inhibitors, angiotensin receptor blockers and severe acute respiratory syndrome caused by coronavirus]. Some Authors recently suggested that angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) should be discontinued, even temporarily, given the current pandemic of SARS-CoV-2 virus. The suggestion is based on the hypothesis that ACE-inhibitors and ARBs may favor the entry and diffusion of SARS-CoV-2 virus into the human cells. ACE-inhibitors and ARBs may increase the expression of ACE2 receptors, which are the sites of viral entry into the human organism. ACE2 receptors are ubiquitous, although they are extremely abundant on the cell surface of type 2 pneumocytes. Type 2 pneumocytes are small cylindrical alveolar cells located in close vicinity to pulmonary capillaries and responsible for the synthesis of alveolar surfactant, which is known to facilitate gas exchanges. The increased expression of ACE2 for effect of ACE-inhibitors and ARBs can be detected by increased production of angiotensin1-7 and mRNA related to ACE2. There is the fear that the increased expression of ACE2 induced by ACE-inhibitors and ARBs may ultimately facilitate the entry and diffusion of the SARS-CoV-2 virus. However, there is no clinical evidence to support this hypothesis. Furthermore, available data are conflicting and some counter-intuitive findings suggest that ARBs may be beneficial, not harmful. Indeed, studies conducted in different laboratories demonstrated that ACE2 receptors show a down-regulation (i.e. the opposite of what would happen with ACE-inhibitors and ARBs) for effect of their interaction with the virus. In animal studies, down-regulation of ACE2 has been found as prevalent in the pulmonary areas infected by virus, but not in the surrounding areas. In these studies, virus-induced ACE2 down-regulation would lead to a reduced formation of angiotensin1-7 (because ACE2 degrades angiotensin II into angiotensin1-7) with consequent accumulation of angiotensin II. The excess angiotensin II would favor pulmonary edema and inflammation, a phenomenon directly associated with angiotensin II levels, along with worsening in pulmonary function. Such detrimental effects have been blocked by ARBs in experimental models. In the light of the above considerations, it is reasonable to conclude that the suggestion to discontinue ACE-inhibitors or ARBs in all patients with the aim of preventing or limiting the diffusion of SARS-CoV-2 virus is not based on clinical evidence. Conversely, experimental studies suggest that ARBs might be useful in these patients to limit pulmonary damage through the inhibition of type 1 angiotensin II receptors. Controlled clinical studies in this area are eagerly awaited. This review discusses facts and theories on the potential impact of ACE-inhibitors and ARBs in the setting of the SARS-CoV-2 pandemic.

negative: Associations between media use and health information-seeking behavior on vaccinations in South Korea BACKGROUND: Although vaccinations are critical for preventing emerging infectious diseases, scant research has been conducted on risk communication. With socio-economic characteristics, health behavior, and underlying diseases under control, we investigated associations between media use, health information-seeking behavior, health information type, and vaccination in the population. METHODS: This study relied on a national survey of Korean adults (n = 1367). Participants were adult males and females age 20 and older. Web and face-to-face surveys were conducted throughout July 2014. The main outcome was vaccination (categorized as yes or no). Independent variables were time spent on media, frequency of health information-seeking behavior, and types of health information sought. RESULTS: Controlling for co-variates, logistic regression analysis was conducted to identify factors that influence Korean adults being vaccinated. Results revealed that accessible information about emerging infectious diseases, listening to the radio, and reading the newspaper were associated with increased odds of being vaccinated. Active seeking health information as well as being female and of higher socio-economic status were positively correlated with Korean adults being vaccinated. CONCLUSION: It is critical to promote health information-seeking behavior and use diverse media channels to increase acceptance and awareness of emerging infectious diseases and vaccinations. Because there are differences in vaccination awareness depending on social class, it is critical to reduce communication inequality, strengthen accessibility to vaccinations, and devise appropriate risk communication strategies that ensure Korean adults receive vaccinations.

negative: Pathophysiology of Portal Hypertension The bases of our current knowledge on the physiology of the hepatic portal system are largely owed to the work of three pioneering vascular researchers from the sixteenth and the seventeenth centuries: A. Vesalius, W. Harvey, and F. Glisson. Vesalius is referred to as the founder of modern human anatomy, and in his influential book, De humani corporis fabrica libri septem, he elaborated the first anatomical atlas of the hepatic portal venous system (Vesalius 2013). Sir William Harvey laid the foundations of modern cardiovascular research with his Exercitatio Anatomica de Motu Cordis et Sanguinis in Animalibus (Harvey 1931) in which he established the nature of blood circulation. Finally, F. Glisson characterized the gastrointestinal-hepatic vascular system (Child 1955). These physiological descriptions were later complemented with clinical observations. In the eighteenth and nineteenth centuries, Morgagni, Puckelt, Cruveilhier, and Osler were the first to make the connection between common hepatic complications – ascites, splenomegaly, and gastrointestinal bleeding – and obstruction of the portal system (Sandblom 1993). These were the foundations that allowed Gilbert, Villaret, and Thompson to establish an early definition of portal hypertension at the beginning of the twentieth century. In this period, Thompson performed the first direct measurement of portal pressure by laparotomy in some patients (Gilbert and Villaret 1906; Thompson et al. 1937). Considering all these milestones, and paraphrasing Sir Isaac Newton, if hepatologists have seen further, it is by standing on the shoulders of giants. Nowadays, our understanding of the pathogenesis of portal hypertension has largely improved thanks to the progress in preclinical and clinical research. However, this field is ever-changing and hepatologists are continually identifying novel pathological mechanisms and developing new therapeutic strategies for this clinical condition. Hence, the aim of this chapter is to summarize the current knowledge about this clinical condition.

negative: Rapid implementation of mobile technology for real-time epidemiology of COVID-19 The rapid pace of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic (COVID-19) presents challenges to the robust collection of population-scale data to address this global health crisis. We established the COronavirus Pandemic Epidemiology (COPE) consortium to bring together scientists with expertise in big data research and epidemiology to develop a COVID-19 Symptom Tracker mobile application that we launched in the UK on March 24, 2020 and the US on March 29, 2020 garnering more than 2.25 million users to date. This mobile application offers data on risk factors, herald symptoms, clinical outcomes, and geographical hot spots. This initiative offers critical proof-of-concept for the repurposing of existing approaches to enable rapidly scalable epidemiologic data collection and analysis which is critical for a data-driven response to this public health challenge.

negative: Structural and Evolutionary Analysis Indicate that the SARS-CoV-2 Mpro is an Inconvenient Target for Small-Molecule Inhibitors Design The novel coronavirus whose outbreak took place in December 2019 continues to spread at a rapid rate worldwide. In the absence of an effective vaccine, inhibitor repurposing or de novo drug design may offer a longer-term strategy to combat this and future infections due to similar viruses. Here, we report on detailed classical and mix-solvent molecular dynamics simulations of the main protease (Mpro) enriched by evolutionary and stability analysis of the protein. The results were compared with those for a highly similar SARS Mpro protein. In spite of a high level of sequence similarity, the active sites in both proteins show major differences in both shape and size indicating that repurposing SARS drugs for COVID-19 may be futile. Furthermore, analysis of the binding site’s conformational changes during the simulation time indicates its flexibility and plasticity, which dashes hopes for rapid and reliable drug design. Conversely, structural stability of the protein with respect to flexible loop mutations indicates that the virus’ mutability will pose a further challenge to the rational design of small-molecule inhibitors. However, few residues contribute significantly to the protein stability and thus can be considered as key anchoring residues for Mpro inhibitor design.

negative: Respiratory Emergencies Causes of cough: Acute cough (<3 weeks): Respiratory tract infections: viral upper respiratory tract infection, viral rhinosinusitis, common cold, acute bacterial sinusitis, acute bronchitis, pneumonia, acute exacerbation of COPD; pertussis. Inhalation of direct irritants: dust, smoke, ozone, air pollutants. Inhalation of specific allergen in the asthmatic: pollen, or low concentration of non-specific irritants: cigarette smoke, perfume; house dust mites. Allergic rhinitis. Chemical exposure: chloramines in swimming pools. Medication: ACE inhibitors. Subacute cough (3–8 weeks): Post-infectious cough: prior viral upper respiratory tract infection. Bordetella pertussis infection. Subacute bacterial sinusitis. Asthma. Neoplasm. Chronic cough (>8 weeks): Persistent airway inflammation: COPD, asthma, bronchiectasis. Smoking. Neoplasm. Interstitial lung disease: pulmonary fibrosis. Persistent infection: tuberculosis; bronchiectasis. Raised left atrial pressure: mitral stenosis, left ventricular failure. Inhaled foreign body. Iatrogenic: ACE inhibitors, radiation pneumonitis, steroid aerosols. Aspiration syndrome: gastro-oesophageal reflux disease; bulbar dysfunction; oesophageal dysmotility. Psychogenic. Post-nasal drip syndrome (posterior nasal discharge and night cough): sinusitis; rhinitis (allergic; non-allergic; vasomotor). Primary ciliary dyskinesia.

negative: Estimation of SARS-CoV-2 mortality during the early stages of an epidemic: a modelling study in Hubei, China and northern Italy Background. The epidemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that originated in Wuhan, China in late 2019 is now pandemic. Reliable estimates of death from coronavirus disease 2019 (COVID-19) are essential to guide control efforts and to plan health care system requirements. The objectives of this study are to: 1) simulate the transmission dynamics of SARS-CoV-2 using publicly available surveillance data; 2) give estimates of SARS-CoV-2 mortality adjusted for bias in the two regions with the world's highest numbers of confirmed Covid-19 deaths: Hubei province, China and northern Italy. Method and Findings. We developed an age-stratified susceptible-exposed-infected-removed (SEIR) compartmental model describing the dynamics of transmission and mortality during the SARS-CoV-2 epidemic. Our model accounts for two biases; preferential ascertainment of severe cases and delayed mortality (right-censoring). We fitted our transmission model to surveillance data from Hubei province (1 January to 11 February 2020) and northern Italy (8 February to 3 March 2020). Overall mortality among all symptomatic and asymptomatic infections was estimated to be 3.0% (95% credible interval: 2.6-3.4%) in Hubei province and 3.3% (2.0-4.7%) in northern Italy. Mortality increased with age; we estimate that among 80+ year olds, 39.0% (95%CrI: 31.1-48.9%) in Hubei province and 89.0% (95%CrI: 56.2-99.6%) in northern Italy dies or will die. Limitations are that the model requires data recorded by date of onset and that sex-disaggregated mortality was not available. Conclusions. We developed a mechanistic approach to correct the crude CFR for bias due to right-censoring and preferential ascertainment and provide adjusted estimates of mortality due to SARS-CoV-2 infection by age group. While specific to the situation in Hubei, China and northern Italy during these periods, these findings will help the mitigation efforts and planning of resources as other regions prepare for SARS-CoV-2 epidemics.

negative: Middle East Respiratory Syndrome: Emergence of a Pathogenic Human Coronavirus. In 2012, a zoonotic coronavirus was identified as the causative agent of Middle East respiratory syndrome and was named MERS coronavirus (MERS-CoV). As of August 11, 2016, the virus has infected 1,791 patients, with a mortality rate of 35.6%. Although MERS-CoV generally causes subclinical or mild disease, infection can result in serious outcomes, including acute respiratory distress syndrome and multi-organ failure in patients with comorbidities. The virus is endemic in camels in the Arabian Peninsula and Africa and thus poses a consistent threat of frequent reintroduction into human populations. Disease prevalence will increase substantially if the virus mutates to increase human-to-human transmissibility. No therapeutics or vaccines are approved for MERS; thus, development of novel therapies is needed. Further, since many MERS cases are acquired in healthcare settings, public health measures and scrupulous attention to infection control are required to prevent additional MERS outbreaks.

negative: Modelling of potentially promising SARS protease inhibitors In many cases, at the beginning of a high throughput screening experiment some information about active molecules is already available. Active compounds (such as substrate analogues, natural products and inhibitors of related proteins) are often identified in low throughput validation studies on a biochemical target. Sometimes the additional structural information is also available from crystallographic studies on protein and ligand complexes. In addition, the structural or sequence similarity of various protein targets yields a novel possibility for drug discovery. Co-crystallized compounds from homologous proteins can be used to design leads for a new target without co-crystallized ligands. In this paper we evaluate how far such an approach can be used in a real drug campaign, with severe acute respiratory syndrome (SARS) coronavirus providing an example. Our method is able to construct small molecules as plausible inhibitors solely on the basis of the set of ligands from crystallized complexes of a protein target, and other proteins from its structurally homologous family. The accuracy and sensitivity of the method are estimated here by the subsequent use of an electronic high throughput screening flexible docking algorithm. The best performing ligands are then used for a very restrictive similarity search for potential inhibitors of the SARS protease within the million compounds from the Ligand.Info small molecule meta-database. The selected molecules can be passed on for further experimental validation.

negative: Aminopeptidase N is a major receptor for the enteropathogenic coronavirus TGEV CORONAVIRUSES, like many animal viruses, are characterized by a restricted host range and tissue tropism(1). Transmissible gastroenteritis virus (TGEV), a major pathogen causing a fatal diarrhoea in newborn pig, replicates selectively in the differentiated enterocytes covering the villi of the small intestine(2). To investigate the molecular determinants of the infection, we characterized the surface molecule used by the virus for binding and entry into host cells. Here we report that aminopeptidase N, an ectoenzyme abundantly expressed at the apical membrane of the enterocytes, serves as a receptor for TGEV. Monoclonal antibodies were selected for their ability to block infection by TGEV of porcine cell lines. They recognized a brush-border membrane protein of M(r), 150K, which was identified as aminopeptidase N by ammo-terminal sequencing. Two lines of evidence supported the view that the peptidase itself acts as a receptor. First, virions bound specifically to aminopep-tidase N that was purified to homogeneity. Second, recombinant expression of aminopeptidase N conferred infectivity by TGEV to an otherwise non-permissive cell line.

negative: From gene to protein—experimental and clinical studies of ACE2 in blood pressure control and arterial hypertension Hypertension is a major risk factor for stroke, coronary events, heart and renal failure, and the renin-angiotensin system (RAS) plays a major role in its pathogenesis. Within the RAS, angiotensin converting enzyme (ACE) converts angiotensin (Ang) I into the vasoconstrictor Ang II. An “alternate” arm of the RAS now exists in which ACE2 counterbalances the effects of the classic RAS through degradation of Ang II, and generation of the vasodilator Ang 1-7. ACE2 is highly expressed in the heart, blood vessels, and kidney. The catalytically active ectodomain of ACE2 undergoes shedding, resulting in ACE2 in the circulation. The ACE2 gene maps to a quantitative trait locus on the X chromosome in three strains of genetically hypertensive rats, suggesting that ACE2 may be a candidate gene for hypertension. It is hypothesized that disruption of tissue ACE/ACE2 balance results in changes in blood pressure, with increased ACE2 expression protecting against increased blood pressure, and ACE2 deficiency contributing to hypertension. Experimental hypertension studies have measured ACE2 in either the heart or kidney and/or plasma, and have reported that deletion or inhibition of ACE2 leads to hypertension, whilst enhancing ACE2 protects against the development of hypertension, hence increasing ACE2 may be a therapeutic option for the management of high blood pressure in man. There have been relatively few studies of ACE2, either at the gene or the circulating level in patients with hypertension. Plasma ACE2 activity is low in healthy subjects, but elevated in patients with cardiovascular risk factors or cardiovascular disease. Genetic studies have investigated ACE2 gene polymorphisms with either hypertension or blood pressure, and have produced largely inconsistent findings. This review discusses the evidence regarding ACE2 in experimental hypertension models and the association between circulating ACE2 activity and ACE2 polymorphisms with blood pressure and arterial hypertension in man.

negative: Manipulating angiotensin metabolism with angiotensin converting enzyme 2 (ACE2) in heart failure Angiotensin converting enzyme 2 (ACE2), is a monocarboxypeptidase which metabolizes several peptides including the degradation of Ang II, a peptide with vasoconstrictive/proliferative/effects, to generate Ang 1–7, which acting through its receptor Mas exerts vasodilatory/anti-proliferative actions. The classical pathway of the RAS involving the ACE-Ang II-AT1 receptor axis is antagonized by the second arm constituted by the ACE2-Ang 1–7/Mas receptor axis. Loss of ACE2 enhances the adverse pathological remodeling susceptibility to pressure-overload and myocardial infarction. Human recombinant ACE2 is also a negative regulator of Ang II-induced myocardial hypertrophy, fibrosis and diastolic dysfunction and suppresses pressure-overload induced heart failure. Due to its characteristics, the ACE2-Ang 1–7/Mas axis may represent new possibilities for developing novel therapeutic strategies for the treatment of heart failure. Human recombinant ACE2 has been safely administered to healthy human volunteers intravenously resulting in sustained lowering of plasma Ang II levels. In this review, we will summarize the beneficial effects of ACE2 in heart disease and the potential use of human recombinant ACE2 as a novel therapy for heart failure.

negative: Characterization of SARS main protease and inhibitor assay using a fluorogenic substrate Abstract SARS main protease is essential for life cycle of SARS coronavirus and may be a key target for developing anti-SARS drugs. Recently, the enzyme expressed in Escherichia coli was characterized using a HPLC assay to monitor the formation of products from 11 peptide substrates covering the cleavage sites found in the SARS viral genome. This protease easily dissociated into inactive monomer and the deduced K d of the dimer was 100μM. In order to detect enzyme activity, the assay needed to be performed at micromolar enzyme concentration. This makes finding the tight inhibitor (nanomolar range IC50) impossible. In this study, we prepared a peptide with fluorescence quenching pair (Dabcyl and Edans) at both ends of a peptide substrate and used this fluorogenic peptide substrate to characterize SARS main protease and screen inhibitors. The fluorogenic peptide gave extremely sensitive signal upon cleavage catalyzed by the protease. Using this substrate, the protease exhibits a significantly higher activity (k cat=1.9s−1 and K m =17 μ M) compared to the previously reported parameters. Under our assay condition, the enzyme stays as an active dimer without dissociating into monomer and reveals a small K d value (15nM). This enzyme in conjunction with fluorogenic peptide substrate provides us a suitable tool for identifying potent inhibitors of SARS protease.

negative: Opportunities and challenges in utilizing electronic health records for infection surveillance, prevention, and control

negative: Host protein interactions with the 3' end of bovine coronavirus RNA and the requirement of the poly(A) tail for coronavirus defective genome replication. RNA viruses have 5' and 3' untranslated regions (UTRs) that contain specific signals for RNA synthesis. The coronavirus genome is capped at the 5' end and has a 3' UTR that consists of 300 to 500 nucleotides (nt) plus a poly(A) tail. To further our understanding of coronavirus replication, we have begun to examine the involvement of host factors in this process for two group II viruses, bovine coronavirus (BCV) and mouse hepatitis coronavirus (MHV). Specific host protein interactions with the BCV 3' UTR [287 nt plus poly(A) tail] were identified using gel mobility shift assays. Competition with the MHV 3' UTR [301 nt plus poly(A) tail] suggests that the interactions are conserved for the two viruses. Proteins with molecular masses of 99, 95, and 73 kDa were detected in UV cross-linking experiments. Less heavily labeled proteins were also detected in the ranges of 40 to 50 and 30 kDa. The poly(A) tail was required for binding of the 73-kDa protein. Immunoprecipitation of UV-cross-linked proteins identified the 73-kDa protein as the cytoplasmic poly(A)-binding protein (PABP). Replication of the defective genomes BCV Drep and MHV MIDI-C, along with several mutants, was used to determine the importance of the poly(A) tail. Defective genomes with shortened poly(A) tails consisting of 5 or 10 A residues were replicated after transfection into helper virus-infected cells. BCV Drep RNA that lacked a poly(A) tail did not replicate, whereas replication of MHV MIDI-C RNA with a deleted tail was detected after several virus passages. All mutants exhibited delayed kinetics of replication. Detectable extension or addition of the poly(A) tail to the mutants correlated with the appearance of these RNAs in the replication assay. RNAs with shortened poly(A) tails exhibited less in vitro PABP binding, suggesting that decreased interactions with the protein may affect RNA replication. The data strongly indicate that the poly(A) tail is an important cis-acting signal for coronavirus replication.

negative: Seroprevalence, cross antigenicity and circulation sphere of bat-borne hantaviruses revealed by serological and antigenic analyses Bats are newly identified reservoirs of hantaviruses (HVs) among which very divergent HVs have been discovered in recent years. However, their significance for public health remains unclear since their seroprevalence as well as antigenic relationship with human-infecting HVs have not been investigated. In the present study archived tissues of 1,419 bats of 22 species from 6 families collected in 5 south and southwest provinces in China were screened by pan-HV RT-PCR following viral metagenomic analysis. As a result nine HVs have been identified in two bat species in two provinces and phylogenetically classified into two species, Laibin virus (LAIV, ICTV approved species, 1 strain) and Xuan son virus (XSV, proposed species, 8 strains). Additionally, 709 serum samples of these bats were also analyzed by ELISA to investigate the seroprevalence and cross-reactivity between different HVs using expressed recombinant nucleocapsid proteins (rNPs) of LAIV, XSV and Seoul virus (SEOV). The cross-reactivity of some bat sera were further confirmed by western blot (WB) using three rNPs followed by fluorescent antibody virus neutralization test (FAVNT) against live SEOV. Results showed that the total HV seropositive rate of bat sera was 18.5% (131/709) with many cross reacting with two or all three rNPs and several able to neutralize SEOV. WB analysis using the three rNPs and their specific hyperimmune sera demonstrated cross-reactivity between XSV/SEOV and LAIV/XSV, but not LAIV/SEOV, indicating that XSV is antigenically closer to human-infecting HVs. In addition a study of the distribution of the viruses identified an area covering the region between Chinese Guangxi and North Vietnam, in which XSV and LAIV circulate within different bat colonies with a high seroprevalence. A circulation sphere of bat-borne HVs has therefore been proposed.

negative: Protease inhibitors broadly effective against feline, ferret and mink coronaviruses Abstract Ferret and mink coronaviruses typically cause catarrhal diarrhea in ferrets and minks, respectively. In recent years, however, systemic fatal coronavirus infection has emerged in ferrets, which resembles feline infectious peritonitis (FIP) in cats. FIP is a highly fatal systemic disease caused by a virulent feline coronavirus infection in cats. Despite the importance of coronavirus infections in these animals, there are no effective commercial vaccines or antiviral drugs available for these infections. We have previously reported the efficacy of a protease inhibitor in cats with FIP, demonstrating that a virally encoded 3C-like protease (3CLpro) is a valid target for antiviral drug development for coronavirus infections. In this study, we extended our previous work on coronavirus inhibitors and investigated the structure-activity relationships of a focused library of protease inhibitors for ferret and mink 3CLpro. Using the fluorescence resonance energy transfer assay, we identified potent inhibitors broadly effective against feline, ferret and mink coronavirus 3CLpro. Multiple amino acid sequence analysis and modelling of 3CLpro of ferret and mink coronaviruses were conducted to probe the structural basis for these findings. The results of this study provide support for further research to develop broad-spectrum antiviral agents for multiple coronavirus infections. To the best of our knowledge, this is the first report on small molecule inhibitors of ferret and mink coronaviruses.

negative: Serology characteristics of SARS-CoV-2 infection since the exposure and post symptoms onset Background Timely diagnosis of SARS-CoV-2 infection is the prerequisite for treatment and preventive quarantine. The serology characteristics and complement diagnosis value of antibody test to RNA test needs to be demonstrated. Method A patient cohort study was conducted at the first affiliated hospital of Zhejiang University, China. Serial sera of COVID-19 patients were collected and total antibody (Ab), IgM and IgG antibody against SARS-CoV-2 were detected. The antibody dynamics during the infection were described. Results The seroconversion rate for Ab, IgM and IgG in COVID-19 patients was 98.8% (79/80), 93.8% (75/80) and 93.8% (75/80), respectively. The first detectible serology marker is total antibody and followed by IgM and IgG, with a median seroconversion time of 15, 18 and 20 day post exposure (d.p.e) or 9, 10 and 12 days post onset, separately. The antibody levels increased rapidly since 6 d.p.o and accompanied with the decline of viral load. For patients in the early stage of illness (0-7d.p.o),Ab showed the highest sensitivity (64.1%) compared to the IgM and IgG (33.3% for both, p<0.001). The sensitivities of Ab, IgM and IgG detection increased to 100%, 96.7% and 93.3% two weeks later, respectively. Conclusions Typical acute antibody response is induced during the SARS-CoV-2 infection. The serology testing provides important complementation to RNA test for pathogenic specific diagnosis and helpful information to evaluate the adapted immunity status of patient. It should be strongly recommended to apply well-validated antibody tests in the clinical management and public health practice to improve the control of COVID-19 infection.

negative: [2019 novel coronavirus, angiotensin converting enzyme 2 and cardiovascular drugs]. 2019年底，武汉出现了由2019新型冠状病毒（2019-nCoV）引发的新型冠状病毒肺炎（COVID-19）。该疫情在短时间内迅速蔓延，严重威胁着公共卫生安全，目前，COVID-19尚无有效的治疗手段。血管紧张素转化酶2（ACE2）作为受体介导2019-nCoV进入细胞，是目前最有可能防治COVID-19的靶点之一。中老年人是COVID-19的易感人群，多伴有基础疾病，且大部分为心血管疾病，因此这部分人更容易发展为重症和危重症，造成严重的临床后果。ACE2是肾素-血管紧张素系统重要的组成部分，以此系统为靶点的ACE抑制剂和血管紧张素受体阻断剂等药物，是目前临床治疗高血压、心肌重构和心力衰竭等心血管疾病的最主要的药物之一。本文系统的介绍了COVID-19以及肾素-血管紧张素系统相关药物及其临床应用，并且分析了肾素-血管紧张素系统相关药物在COVID-19防治中的价值，以及并发心血管疾病的COVID-19患者用药方面需要注意的问题。.

negative: Destruction of microbial collections in response to select agent and toxin list regulations. In this study we have followed up on anecdotal and hearsay evidence that microbial collections were destroyed in the United States following the imposition of the regulations associated with the Select Agents and Toxins List, to validate or refute that information. Using a questionnaire, we documented 13 episodes of microbial collection destruction involving viral, bacterial, and fungal strains, which we believe is almost certainly an underestimate of the number of collections destroyed. In every case, the motivation for the destruction of the collection was a desire to avoid the perceived burdens of the regulatory environment associated with operating under the Select Agent Regulations. Some institutions that destroyed isolates considered, and in some cases tried, transferring their collections to registered institutions prior to collection destruction but desisted when confronted with transport regulations. Destruction of microbial collections represents a loss of strains and biological diversity available for biomedical research and future mechanistic, forensic, and epidemiologic investigations. Given the rapid evolution of microbial strains, the destruction of archival collections is a potentially irretrievable loss that was an unintended consequence of regulations to protect society against the nefarious use of biological agents. Furthermore, unregistered institutions continue to destroy newly acquired clinical isolates, thus preventing the establishment of new repository collections. We recommend that government agencies develop plans to ensure that microbial collections are preserved when considering future additions to microbial threat lists under which the possession of certain microbes is criminalized.

negative: Extracellular superoxide dismutase, a molecular transducer of health benefits of exercise Extracellular superoxide dismutase (EcSOD) is the only extracellular scavenger of superoxide anion (O(2)(.-)) with unique binding capacity to cell surface and extracellular matrix through its heparin-binding domain. Enhanced EcSOD activity prevents oxidative stress and damage, which are fundamental in a variety of disease pathologies. In this review we will discuss the findings in humans and animal studies supporting the benefits of EcSOD induced by exercise training in reducing oxidative stress in various tissues. In particularly, we will highlight the importance of skeletal muscle EcSOD, which is induced by endurance exercise and redistributed through the circulation to the peripheral tissues, as a molecular transducer of exercise training to confer protection against oxidative stress and damage in various disease conditions.

negative: Coronavirus Disease 2019 (COVID-19) Pneumonia in a Hemodialysis Patient Coronavirus disease 2019 (COVID-19) is a highly infective disease caused by the severe acute respiratory syndrome coronavirus 2 virus (SARS-CoV-2). Previous studies of the COVID-19 pneumonia outbreak were based on information from the general population. Limited data are available for hemodialysis patients with COVID-19 pneumonia. This report describes the clinical characteristics of COVID-19 in an in-center hemodialysis patient, as well as our experience in implementing steps to prevent the spread of COVID-19 pneumonia among in-center hemodialysis patients. The diagnosis, infection control, and treatment of COVID-19 in hemodialysis patients are discussed in this report, and we conclude with recommendations for how a dialysis facility can respond to COVID-19 based on our experiences.

negative: Circulating angiotensin-converting enzyme 2 activity in patients with chronic kidney disease without previous history of cardiovascular disease BACKGROUND: Patients with cardiovascular (CV) disease have an increased circulating angiotensin-converting enzyme 2 (ACE2) activity, but there is little information about changes in ACE2 in chronic kidney disease (CKD) patients without history of CV disease. We examined circulating ACE2 activity in CKD patients at stages 3–5 (CKD3-5) and in dialysis (CKD5D) without any history of CV disease. METHODS: Circulating ACE2 activity was measured in human ethylenediamine-tetraacetic acid (EDTA)-plasma samples from the NEFRONA study (n = 2572): control group (CONT) (n = 568), CKD3-5 (n = 1458) and CKD5D (n = 546). Different clinical and analytical variables such as gender; age; history of diabetes mellitus (DM), dyslipidemia and hypertension; glycaemic, renal, lipid and anaemia profiles; vitamin D analogues treatment and antihypertensive treatments (angiotensin-converting enzyme inhibitor and angiotensin receptor blockade) were analysed. Circulating ACE2 and ACE activities were measured using modified fluorimetric assay for EDTA-plasma samples, where zinc chloride was added to recover enzymatic activity. RESULTS: In CKD3-5 and CKD5D, significant decrease in circulating ACE2 activity was observed when compared with CONT, but no differences were found between CKD3-5 and CKD5 when performing paired case-control studies. By multivariate linear regression analysis, male gender and advanced age were identified as independent predictors of ACE2 activity in all groups. Diabetes was identified as independent predictor of ACE2 activity in CKD3-5. Significant increase in the activity of circulating ACE was found in CKD3-5 and CKD5D when compared with CONT and in CKD5D when compared with CKD3-5. By multiple regression analysis, female gender and younger age were identified as independent predictors of ACE activity in CONT and CKD3-5. Diabetes was also identified as an independent predictor of ACE activity in CKD3-5 patients. CONCLUSIONS: Circulating ACE2 and ACE activities can be measured in human EDTA-plasma samples with zinc added to recover enzymatic activity. In a CKD population without previous history of CV disease, ACE2 activity from human EDTA-plasma samples directly correlated with the classical CV risk factors namely older age, diabetes and male gender. Our data suggest that circulating ACE2 is altered in CKD patients at risk for CV event.

negative: Social distancing strategies for curbing the COVID-19 epidemic The SARS-CoV-2 pandemic is straining healthcare resources worldwide, prompting social distancing measures to reduce transmission intensity. The amount of social distancing needed to curb the SARS-CoV-2 epidemic in the context of seasonally varying transmission remains unclear. Using a mathematical model, we assessed that one-time interventions will be insufficient to maintain COVID-19 prevalence within the critical care capacity of the United States. Seasonal variation in transmission will facilitate epidemic control during the summer months but could lead to an intense resurgence in the autumn. Intermittent distancing measures can maintain control of the epidemic, but without other interventions, these measures may be necessary into 2022. Increasing critical care capacity could reduce the duration of the SARS-CoV-2 epidemic while ensuring that critically ill patients receive appropriate care.

negative: EZH2-mediated H3K27me3 inhibits ACE2 expression Abstract The outbreak of corona virus disease 2019 (COVID-19) caused by SARS-CoV-2 infection is spreading globally and quickly, leading to emerging health issues. SARS-CoV-2 enters into and infects host cells through its spike glycoprotein recognizing the cell receptor Angiotensin-converting enzyme II (ACE2). Here, we noticed that ACE2 was further enhanced by SARS-CoV-2 infection. Human germ cells and early embryos express high level of ACE2. Notably, RNA-seq result showed that reduction of H3K27me3, but not H3K4/9/36me3, led to upregulation of Ace2 expression in mouse germ cell line GC-2. In agreement with this result, we found in human embryonic stem cells that ACE2 expression was significantly increased in absence of EZH2, the major enzyme catalyzing H3K27me3. ChIP-seq analysis further confirmed decrease of H3K27me3 signal and increase of H3K27ac signal at ACE2 promoter upon EZH2 knockout. Therefore, we propose that EZH2-mediated H3K27me3 at ACE2 promoter region inhibits ACE2 expression in mammalian cells. This regulatory pattern may also exist in other human cells and tissues. Our discovery provides clues for pathogenesis and targeted drug therapy towards ACE2 expression for prevention and adjuvant therapy of COVID-19.

negative: Endovascular management of giant middle cerebral artery aneurysms. BACKGROUND This article reported the experience of endovascular treatment in giant middle cerebral artery (MCA) aneurysms with parent artery occlusion or stent-assisted coiling. MATERIAL AND METHODS Eleven consecutive patients with giant MCA aneurysms were included. The aneurysms predominantly involved the M1 segment in two cases, bifurcation in four cases, and M2 in five cases. Four M2 fusiform aneurysms were treated with parent artery sacrifice after balloon occlusion test. The seven unruptured aneurysms and one ruptured one were treated with stent-assisted coiling. The post-operation and long-term follow-up angiographic and clinical outcomes were analyzed. RESULTS Endovascular coiling was performed successfully in all 11 cases. All four M2 fusiform cases using parent artery occlusion strategy achieved complete occlusion of aneurysms. In the seven cases with stent-assisted coiling, four were completely occluded, two were partially occluded and one remained small residue. Mild perioperative complications occurred in six patients. The follow-up angiography taken at a mean of 13.5 months of eight patients showed that seven aneurysms remained stable or improved and one M1 aneurysms relapsed and needed further treatment. CONCLUSION Stent-assisted coiling or parent artery occlusion of selected giant MCA aneurysms is an option to consider.

negative: Loss of Angiotensin-Converting Enzyme-2 Leads to the Late Development of Angiotensin II-Dependent Glomerulosclerosis Angiotensin-converting enzyme-2 (ACE2), a membrane-bound carboxymonopeptidase highly expressed in the kidney, functions as a negative regulator of the renin-angiotensin system. Here we report early accumulation of fibrillar collagen in the glomerular mesangium of male ACE2 mutant (ACE2(−/y)) mice followed by development of glomerulosclerosis by 12 months of age whereas female ACE2 mutant (ACE2(−/−)) mice were relatively protected. Progressive kidney injury was associated with increased deposition of collagen I, collagen III and fibronectin in the glomeruli and increased urinary albumin excretion compared to age-matched control mice. These structural and functional changes in the glomeruli of male ACE2 mutant mice were prevented by treatment with the angiotensin II type-1 receptor antagonist irbesartan. Loss of ACE2 was associated with a marked increase in renal lipid peroxidation product formation and activation of mitogen-activated protein kinase and extracellular signal-regulated kinases 1 and 2 in glomeruli, events that are also prevented by angiotensin II type-1 receptor blockade. We conclude that deletion of the ACE2 gene leads to the development of angiotensin II-dependent glomerular injury in male mice. These findings have important implications for our understanding of ACE2, the renin-angiotensin system, and gender in renal injury, with ACE2 likely to be an important therapeutic target in kidney disease.

negative: The use of nucleic acid hybridization to detect human coronaviruses We have applied an RNA: RNA hybridization test for the detection of human coronavirus 229E. This test is undergoing further development but already allows a diagnosis of HCV 229E infection within 48 hours.

negative: Effect of Heat Moisture Exchanger on Aerosol Drug Delivery and Airway Resistance in Simulated Ventilator-Dependent Adults Using Jet and Mesh Nebulizers. BACKGROUND Placement of a heat moisture exchanger (HME) between aerosol generator and patient has been associated with greatly reduced drug delivery. The purpose of this study was to evaluate the effect of filtered and nonfiltered HMEs placed between nebulizer and patient on aerosol deposition and airway resistance (Raw) in simulated ventilator-dependent adults. METHODS An in vitro lung model was developed to simulate a mechanically ventilated adult (Vt 500 mL, RR 15/min, and PEEP 5 cmH2O, using two inspiratory flow rates 40 and 50 L/min) using an intubated adult manikin with an endotracheal tube (8 mmID). The bronchi of the manikin were connected to a Y-adapter through a collecting filter (Respirgard II) attached to a test lung through a heated humidifier (37°C producing 100% relative humidity) to simulate exhaled humidity. For treatment conditions, a nonfiltered HME (ThermoFlo™ 6070; ARC Medical) and filtered HMEs (ThermoFlo™ Filter; ARC Medical and PALL Ultipor; Pall Medical) were placed between the ventilator circuit at the endotracheal tube and allowed to acclimate to the exhaled heat and humidity for 30 minutes before aerosol administration. Airway resistance (cmH2O/L/s) was taken at 0, 10, 20, and 30 minutes after HME placement and after each of four aerosol treatments. Albuterol sulfate (2.5 mg/3 mL) was administered with jet (Misty Max 10; Airlife) and mesh (Aerogen Solo; Aerogen) nebulizers positioned in the inspiratory limb proximal to the Y-adapter. Control consisted of nebulization with no HME. Drug was eluted from filter at the end of the trachea and measured using spectrophotometry (276 nm). RESULTS Greater than 60% of the control dose was delivered through the ThermoFlo. No significant difference was found between the first four treatments given by the jet (p = 0.825) and the mesh (p = 0.753) nebulizers. There is a small increase in Raw between pre- and post-four treatments with the jet (p = 0.001) and mesh (p = 0.015) nebulizers. Aerosol delivery through filtered HMEs was similar (<0.5%) across the four treatments. Airway resistance was similar using the ThermoFlo Filter. With the PALL Ultipor, changes in Raw increased with mesh nebulizer after treatment (p = 0.005). Changes in resistance pre- and post-treatment were similar with both filtered HMEs. CONCLUSION The ThermoFlo™ nonfilter HME allowed the majority of the control dose to be delivered to the airway. Increases in Raw would likely not be outside of a tolerable range in ventilated patients. In contrast, filtered HMEs should not be placed between nebulizers and patient airways. Further research with other HMEs and materials is warranted.

negative: Dissecting racial disparities in multiple myeloma-clues from differential immunoglobulin levels.

negative: Failure in initial stage containment of global COVID‐19 epicenters With multiple virus epicenters, COVID‐19 has been declared a pandemic by the World Health Organization. Consequently, many countries have implemented different policies to manage this crisis including curfew and lockdown. However, the efficacy of individual policies remains unclear with respect to COVID‐19 case development. We analyzed available data on COVID‐19 cases of eight majorly affected countries, including China, Italy, Iran, Germany, France, Spain, South Korea, and Japan. Growth rates and doubling time of cases were calculated for the first 6 weeks after the initial cases were declared for each respective country and put into context with implemented policies. Although the growth rate of total confirmed COVID‐19 cases in China has decreased, those for Japan have remained constant. For European countries, the growth rate of COVID‐19 cases considerably increased during the second time interval. Interestingly, the rates for Germany, Spain, and France are the highest measured in the second interval and even surpass the numbers in Italy. Although the initial data in Asian countries are encouraging with respect to case development at the initial stage, the opposite is true for European countries. Based on our data, disease management in the 2 weeks following the first reported cases is of utmost importance.

negative: Intranasal treatment with poly(I•C) protects aged mice from lethal respiratory virus infections. In the 2002-2003 severe acute respiratory syndrome coronavirus (SARS-CoV) epidemic, no patients under 24 years of age died, while mortality was greater than 50% in those over 65 years. Greater than 90% of all deaths from influenza A virus (IAV) occur in the elderly (>65 years of age). To address this age-related susceptibility to SARS-CoV and IAV, we infected C57BL/6 (B6) mice with mouse-adapted SARS-CoV (MA15) or IAV (PR8), both of which cause severe disease in aged mice. Intranasal pretreatment of aged mice with poly(I·C) (a TLR3 agonist) and, to a lesser extent, CpG, R848, or lipopolysaccharide (TLR9, TLR7/8, or TLR4 agonists), provided a high level of protection [90% to 100% survival rate after poly(I·C) treatment] against lethal MA15 or IAV challenge and reduced pathological changes and virus loads in the lungs at early times after infection. Poly(I·C) pretreatment upregulated beta interferon (IFN-β), IFN-γ, IL-1β, and tumor necrosis factor (TNF) gene expression in the lungs. Intranasal pretreatment with IFN-β or IFN-γ but not IL-1β or TNF also protected aged mice, consistent with the notion that poly(I·C) pretreatment functioned, at least in part, by inducing IFN-β and IFN-γ. We also identified a potential cellular target for poly(I·C) by showing that treatment inhibited virus replication in primary human airway epithelial cells. These results suggest that intranasal poly(I·C) should be evaluated as a prophylactic agent in aged individuals at high risk for contracting SARS-CoV or IAV infections.

negative: The Economic Impact of the COVID-19 Pandemic on Radiology Practices The COVID-19 pandemic will have a profound impact on Radiology practices across the country. Policy measures adopted to slow the transmission of disease are decreasing the demand for imaging independent of COVID-19. Hospital preparations to expand crisis capacity are further diminishing the amount of appropriate medical imaging that can be safely performed. While economic recessions generally tend to result in decreased health care expenditures, radiology groups have never experienced an economic shock that is simultaneously exacerbated by the need to restrict the availability of imaging. Outpatient heavy practices will feel the biggest impact of these changes, but all imaging volumes will decrease. Anecdotal experience suggests that radiology practices should anticipate 50%-70% decreases in imaging volume that will last a minimum of 3-4 months, depending on the location of practice and the severity of the COVID-19 pandemic in each region. The CARES Act provides multiple means of direct and indirect aid to healthcare providers and small businesses. The final allocation of this funding is not yet clear, and it is likely that additional congressional action will be necessary to stabilize health care markets. Administrators and practice leaders need to be proactive with practice modifications and financial maneuvers that can position them to emerge from this pandemic in the most viable economic position. It is possible that this crisis will have lasting effects on the structure of the radiology field.

negative: Targeting Membrane-Bound Viral RNA Synthesis Reveals Potent Inhibition of Diverse Coronaviruses Including the Middle East Respiratory Syndrome Virus Coronaviruses raise serious concerns as emerging zoonotic viruses without specific antiviral drugs available. Here we screened a collection of 16671 diverse compounds for anti-human coronavirus 229E activity and identified an inhibitor, designated K22, that specifically targets membrane-bound coronaviral RNA synthesis. K22 exerts most potent antiviral activity after virus entry during an early step of the viral life cycle. Specifically, the formation of double membrane vesicles (DMVs), a hallmark of coronavirus replication, was greatly impaired upon K22 treatment accompanied by near-complete inhibition of viral RNA synthesis. K22-resistant viruses contained substitutions in non-structural protein 6 (nsp6), a membrane-spanning integral component of the viral replication complex implicated in DMV formation, corroborating that K22 targets membrane bound viral RNA synthesis. Besides K22 resistance, the nsp6 mutants induced a reduced number of DMVs, displayed decreased specific infectivity, while RNA synthesis was not affected. Importantly, K22 inhibits a broad range of coronaviruses, including Middle East respiratory syndrome coronavirus (MERS–CoV), and efficient inhibition was achieved in primary human epithelia cultures representing the entry port of human coronavirus infection. Collectively, this study proposes an evolutionary conserved step in the life cycle of positive-stranded RNA viruses, the recruitment of cellular membranes for viral replication, as vulnerable and, most importantly, druggable target for antiviral intervention. We expect this mode of action to serve as a paradigm for the development of potent antiviral drugs to combat many animal and human virus infections.

negative: The role of the neutral amino acid transporter B(0)AT1 (SLC6A19) in Hartnup disorder and protein nutrition Hartnup disorder (OMIM 234500) is an autosomal recessive disorder, which was first described in 1956 as an aminoaciduria of neutral amino acids accompanied by a variety of symptoms, such as a photo‐sensitive skin‐rash and cerebellar ataxia. The disorder is caused by mutations in the neutral amino acid transporter B(0)AT1 (SLC6A19). To date 21 mutations have been identified in more than twenty families. SLC6A19 requires either collectrin or angiotensin‐converting enzyme 2 for surface expression in the kidney and intestine, respectively. This ties SLC6A19 together with more complex functions such as blood‐pressure control, glomerular structure, and exocytosis. © 2009 IUBMB IUBMB Life, 61(6): 591–599, 2009

negative: 2019 Novel Coronavirus Disease (COVID-19): Paving the Road for Rapid Detection and Point-of-Care Diagnostics We believe a point-of-care (PoC) device for the rapid detection of the 2019 novel Coronavirus (SARS-CoV-2) is crucial and urgently needed. With this perspective, we give suggestions regarding a potential candidate for the rapid detection of the coronavirus disease 2019 (COVID-19), as well as factors for the preparedness and response to the outbreak of the COVID-19.

negative: A Social Network Model of the COVID-19 Pandemic In the COVID-19 coronavirus pandemic, currently vaccines and specific anti-viral treatment are not yet available. Thus, preventing viral transmission by case isolation, quarantine, and social distancing is essential to slowing its spread. Here we model social networks using weighted graphs, where vertices represent individuals and edges represent contact. As public health measures are implemented, connectivity in the graph decreases, resulting in lower effective reproductive numbers, and reduced viral transmission. For COVID-19, model parameters were derived from the coronavirus epidemic in China, validated by epidemic data in Italy, then applied to the United States. We calculate that, in the U.S., the public is able to contain viral transmission by limiting the average number of contacts per person to less than 7 unique individuals over each 5 day period. This increases the average social distance between individuals to 10 degrees of separation.

negative: Characterization of ACE and ACE2 Expression within Different Organs of the NOD Mouse Renin angiotensin system (RAS) is known to play a key role in several diseases such as diabetes, and renal and cardiovascular pathologies. Its blockade has been demonstrated to delay chronic kidney disease progression and cardiovascular damage in diabetic patients. In this sense, since local RAS has been described, the aim of this study is to characterize angiotensin converting enzyme (ACE) and ACE2 activities, as well as protein expression, in several tissues of the non-obese diabetic (NOD) mice model. After 21 or 40 days of diabetes onset, mouse serums and tissues were analyzed for ACE and ACE2 enzyme activities and protein expression. ACE and ACE2 enzyme activities were detected in different tissues. Their expressions vary depending on the studied tissue. Thus, whereas ACE activity was highly expressed in lungs, ACE2 activity was highly expressed in pancreas among the studied tissues. Interestingly, we also observed that diabetes up-regulates ACE mainly in serum, lung, heart, and liver, and ACE2 mainly in serum, liver, and pancreas. In conclusion, we found a marked serum and pulmonary alteration in ACE activity of diabetic mice, suggesting a common regulation. The increase of ACE2 activity within the circulation in diabetic mice may be ascribed to a compensatory mechanism of RAS.

negative: Monocytic angiotensin-converting enzyme 2 relates to atherosclerosis in patients with chronic kidney disease Background: Increased levels of monocytic angiotensin-converting enzyme (ACE) found in haemodialysis (HD) patients may directly participate in the pathogenesis of atherosclerosis. We demonstrated recently that uremia triggers the development of highly pro-atherogenic monocytes via an angiotensin II (AngII)–dependent mechanism. Opposing actions of the AngII-degrading ACE2 remain largely unknown. We examined the status of both ACEs and related receptors in circulating leukocytes of HD, not-dialyzed CKD and healthy individuals. Furthermore, we tested the possible impact of monocytic ACEs on atherogenesis and behaviour of the cells under conditions mimicking chronic renal failure. Methods: Expression of ACE, ACE2, AT1R, AT2R and MASR was investigated on circulating leukocytes from 71 HD (62 ± 14 years), 24 CKD stage 3–5 (74 ± 10 years) patients and 37 healthy control subjects (53 ± 6 years) and isolated healthy monocytes treated with normal and uremic serum. Analyses of ACE, ACE2, ICAM-1, VCAM-1, MCSF and endothelial adhesion were tested on ACE-overexpressing THP-1 monocytes treated with captopril or losartan. ACE2-overexpressing monocytes were subjected to transmigration and adhesion assays and investigated for MCP-1, ICAM-1, VCAM-1, MCSF, AT1R and AT2R expression. Results: The ACE mRNA level was significantly increased in HD and CKD stage 3–5 leukocytes. Correspondingly, ACE2 was downregulated and AngII as well as MAS receptor expression was upregulated in these cells. Healthy monocytes preconditioned with uremic serum reflected the same expressional regulation of ACE/ACE2, MAS and AngII receptors as those observed in HD and CKD stage 3–5 leukocytes. Overexpression of monocytic ACE dramatically decreased levels of ACE2 and induced a pro-atherogenic phenotype, partly reversed by AngII-modifying treatments, leading to an increase in ACE2. Overexpression of ACE2 in monocytes led to reduced endothelial adhesion, transmigration and downregulation of adhesion-related molecules. Conclusions: HD and not-dialyzed CKD stage 3–5 patients show enhanced ACE and decreased ACE2 expression on monocytes. This constellation renders the cells endothelial adhesive and likely supports the development of atherosclerosis.

negative: Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2): An Update Coronaviruses (CoVs) belong to the family of Coronaviridae, the order Nidovirales, and the genus Coronavirus. They are the largest group of viruses causing respiratory and gastrointestinal infections. Morphologically, CoVs are enveloped viruses containing a non-segmented positive-sense, single-stranded ribonucleic acid (RNA) viruses. CoVs are categorized into four important genera that include Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus. A novel member of human CoV that has recently emerged in Wuhan, China, is now formally named as SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). This is a unique strain of RNA viruses that have not been previously observed in humans. The virus has wide host adaptability and is capable of causing severe diseases in humans, masked palm civets, mice, dogs, cats, camels, pigs, chickens, and bats. The SARS-CoV-2 typically causes respiratory and gastrointestinal sickness in both humans and animals. It can be transmitted through aerosols and direct/indirect contact, as well as during medical cases and laboratory sample handling. Specific structural proteins, which might be found on the surface of the virus, play an important role in the pathogenesis and development of the complications. The disease is characterized by distinct medical signs and symptoms that include high fever, chills, cough, and shortness of breath or difficulty in breathing. The infected people may also present with other symptoms such as diarrhea, myalgia, fatigue, expectoration, and hemoptysis. It is important from the public health and economic point of view as it affects the growth of the country, which is majorly attributed to the restriction in the movement of the people and the cost associated with the control and prevention of the disease. Since there is no specific therapeutic intervention nor a vaccine available against the virus, supportive management and treatment with non-specific therapeutic agents (repurposed drugs) may provide relief to the patients. Some preventive strategies of the disease include blocking the routes of transmission of the infections, disinfection of instruments used during medical case handling, using personal protective equipment, proper and early diagnosis of the disease, avoiding contact with the sick patients, and quarantine of the infected/exposed people.

negative: In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds Abstract Effective antiviral agents are urgently needed to combat the possible return of severe acute respiratory syndrome (SARS). Commercial antiviral agents and pure chemical compounds extracted from traditional Chinese medicinal herbs were screened against 10 clinical isolates of SARS coronavirus by neutralisation tests with confirmation by plaque reduction assays. Interferon-beta-1a, leukocytic interferon-alpha, ribavirin, lopinavir, rimantadine, baicalin and glycyrrhizin showed antiviral activity. The two interferons were only active if the cell lines were pre-incubated with the drugs 16h before viral inoculation. Results were confirmed by plaque reduction assays. Antiviral activity varied with the use of different cell lines. Checkerboard assays for synergy were performed showing combinations of interferon beta-1a or leukocytic interferon-alpha with ribavirin are synergistic. Since the clinical and toxicity profiles of these agents are well known, they should be considered either singly or in combination for prophylaxis or treatment of SARS in randomised placebo controlled trials in future epidemics.

negative: α-Ketoamides as Broad-Spectrum Inhibitors of Coronavirus and Enterovirus Replication: Structure-Based Design, Synthesis, and Activity Assessment [Image: see text] The main protease of coronaviruses and the 3C protease of enteroviruses share a similar active-site architecture and a unique requirement for glutamine in the P1 position of the substrate. Because of their unique specificity and essential role in viral polyprotein processing, these proteases are suitable targets for the development of antiviral drugs. In order to obtain near-equipotent, broad-spectrum antivirals against alphacoronaviruses, betacoronaviruses, and enteroviruses, we pursued a structure-based design of peptidomimetic α-ketoamides as inhibitors of main and 3C proteases. Six crystal structures of protease–inhibitor complexes were determined as part of this study. Compounds synthesized were tested against the recombinant proteases as well as in viral replicons and virus-infected cell cultures; most of them were not cell-toxic. Optimization of the P2 substituent of the α-ketoamides proved crucial for achieving near-equipotency against the three virus genera. The best near-equipotent inhibitors, 11u (P2 = cyclopentylmethyl) and 11r (P2 = cyclohexylmethyl), display low-micromolar EC(50) values against enteroviruses, alphacoronaviruses, and betacoronaviruses in cell cultures. In Huh7 cells, 11r exhibits three-digit picomolar activity against the Middle East Respiratory Syndrome coronavirus.

negative: Dilated cardiomyopathy Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left ventricular or biventricular dilation and impaired contraction that is not explained by abnormal loading conditions (for example, hypertension and valvular heart disease) or coronary artery disease. Mutations in several genes can cause DCM, including genes encoding structural components of the sarcomere and desmosome. Nongenetic forms of DCM can result from different aetiologies, including inflammation of the myocardium due to an infection (mostly viral); exposure to drugs, toxins or allergens; and systemic endocrine or autoimmune diseases. The heterogeneous aetiology and clinical presentation of DCM make a correct and timely diagnosis challenging. Echocardiography and other imaging techniques are required to assess ventricular dysfunction and adverse myocardial remodelling, and immunological and histological analyses of an endomyocardial biopsy sample are indicated when inflammation or infection is suspected. As DCM eventually leads to impaired contractility, standard approaches to prevent or treat heart failure are the first-line treatment for patients with DCM. Cardiac resynchronization therapy and implantable cardioverter–defibrillators may be required to prevent life-threatening arrhythmias. In addition, identifying the probable cause of DCM helps tailor specific therapies to improve prognosis. An improved aetiology-driven personalized approach to clinical care will benefit patients with DCM, as will new diagnostic tools, such as serum biomarkers, that enable early diagnosis and treatment.

negative: Pulmonary Pathology of Early-Phase 2019 Novel Coronavirus (COVID-19) Pneumonia in Two Patients With Lung Cancer Abstract There is currently a lack of pathologic data on the novel coronavirus (severe acute respiratory syndrome coronavirus 2) pneumonia, or coronavirus disease 2019 (COVID-19), from autopsy or biopsy. Two patients who recently underwent lung lobectomies for adenocarcinoma were retrospectively found to have had COVID-19 at the time of the operation. These two cases thus provide important first opportunities to study the pathology of COVID-19. Pathologic examinations revealed that apart from the tumors, the lungs of both patients exhibited edema, proteinaceous exudate, focal reactive hyperplasia of pneumocytes with patchy inflammatory cellular infiltration, and multinucleated giant cells. Hyaline membranes were not prominent. Because both patients did not exhibit symptoms of pneumonia at the time of operation, these changes likely represent an early phase of the lung pathology of COVID-19 pneumonia.

negative: Recommendations and guidance for providing pharmaceutical care services during COVID-19 pandemic: A China perspective Abstract Background The novel coronavirus pneumonia (COVID-19), which was first detected in Wuhan City, has now became a pandemic that affecting patients around the world. Particularly, the community patient population are at high risk of infection and are facing potential failure of proper medication use during the pandemic. Objective To discuss community pharmacists’ role and the content of pharmaceutical care (PC) during the novel coronavirus pandemic to promote effective prevention and control and safe drug use of the community patient population. Method Collect and summarize the experience Chinese community pharmacies gained from providing pharmacy services during the COVID-19 outbreak, and taking patients' PC needs into consideration, analyze and discuss the methods and strategies that community pharmacies and pharmacists shall use to provide PC during the pandemic. Results Community pharmacy management teams shall support PC services by providing adequate supply of COVID-19 related medications and preventative products, following environment regulations, and providing sufficient staff trainings. Pharmacists shall use various approaches to provide PC services in drug dispensing, consulting and referrals, chronic disease management, safe use of infusions, patient education, home care guidance and psychological support to promote the COVID-19 pandemic control and ensure safe medication use of community patients during the pandemic. Conclusion PC services in communities during the COVID-19 shall possess different properties due to disease characteristics and related change in patients' need. Community pharmacies shall work as a strong supporter of patient's medication and protective equipment supply. Community pharmacists shall be prepared to provide skilled and effective PC services for community patient population to ensure medication safety and promote the overall COVID-19 pandemic control.

negative: Coexistence of angiotensin II type-1 receptor A1166C and angiotensin-converting enzyme D/D polymorphism suggests susceptibility for small-vessel-associated ischemic stroke The renin-angiotensin system plays an important role in the maintenance of blood pressure homeostasis. The angiotensin-converting enzyme (ACE) converts angiotensin I into angiotensin II. Angiotensin II, which binds the angiotensin II type-1 receptor (AT1R), is a potent vasoconstrictor. On a pathophysiological basis, both ACE I/D and AT1R A1166C polymorphism lead to an enhanced activity of the angiotensin II-AT1R axis, thereby possibly contributing to circulatory disturbances. A mutually facilitatory effect may be presumed between the two polymorphisms. We examined whether this synergistic effect is involved in the evolution of different types of ischemic stroke. Genetic and clinical data on 308 consecutive patients with acutely developing ischemic stroke were analyzed. A total of 272 stroke and neuroimaging alteration-free subjects served as a control group. Univariate and logistic regression statistical approaches were used. The ACE D allele combined with the AT1R 1166C allele did not yield a risk of ischemic stroke. However, the co-occurrence of the homozygous ACE D/D and at least one AT1R 1166C allele was more frequent in the ischemic stroke group than in the control group (22.4 vs 11%, p<0.005, OR, 2.33; 95% CI, 1.46–3.7). After specific subgroup analysis, this synergistic association was even stronger for small-vessel ischemic stroke (OR, 3.44; 95% CI, 1.9–6.24; p<0.0005). Multivariate logistic regression analysis of the data confirmed this association (adjusted OR, 3.54, 95% CI, 1.88–7.16; p<0.0005). Our results demonstrate that ACE D/D and AT1R 1166C polymorphism were associated with the development of small-vessel ischemic stroke through a mutually facilitatory interplay between them. Genetic interactions might contribute to the altered functional network in renin-angiotensin system in vascular disorders.

negative: Hipertensión y COVID-19: cuidados con los manguitos de presión arterial./ [Hypertension and COVID 19: Warnings regarding blood pressure cuffs]

negative: New therapeutic opportunities for COVID-19 patients with Tocilizumab: Possible correlation of interleukin-6 receptor inhibitors with osteonecrosis of the jaws

negative: NetNCSP: Nonoverlapping closed sequential pattern mining Abstract Sequential pattern mining (SPM) has been applied in many fields. However, traditional SPM neglects the pattern repetition in sequence. To solve this problem, gap constraint SPM was proposed and can avoid finding too many useless patterns. Nonoverlapping SPM, as a branch of gap constraint SPM, means that any two occurrences cannot use the same sequence letter in the same position as the occurrences. Nonoverlapping SPM can make a balance between efficiency and completeness. The frequent patterns discovered by existing methods normally contain redundant patterns. To reduce redundant patterns and improve the mining performance, this paper adopts the closed pattern mining strategy and proposes a complete algorithm, named Nettree for Nonoverlapping Closed Sequential Pattern (NetNCSP) based on the Nettree structure. NetNCSP is equipped with two key steps, support calculation and closeness determination. A backtracking strategy is employed to calculate the nonoverlapping support of a pattern on the corresponding Nettree, which reduces the time complexity. This paper also proposes three kinds of pruning strategies, inheriting, predicting, and determining. These pruning strategies are able to find the redundant patterns effectively since the strategies can predict the frequency and closeness of the patterns before the generation of the candidate patterns. Experimental results show that NetNCSP is not only more efficient but can also discover more closed patterns with good compressibility. Furtherly, in biological experiments NetNCSP mines the closed patterns in SARS-CoV-2 and SARS viruses. The results show that the two viruses are of similar pattern composition with different combinations.

negative: Chapter 100 Angiotensin-Converting Enzyme-2 The third edition of the Handbook of Proteolytic Enzymes aims to be a comprehensive reference work for the enzymes that cleave proteins and peptides, and contains over 850 chapters. Each chapter is organized into sections describing the name and history, activity and specificity, structural chemistry, preparation, biological aspects, and distinguishing features for a specific peptidase. The subject of Chapter 100 is Angiotensin-Converting Enzyme-2. Keywords: Angiotensin, angiotensin-converting enzyme 2 (ACE2), apelin, bradykinin, carboxypeptidase, cardiovascular, collectrin, renin-angiotensin system, SARS virus, shedding, transmembrane, vasoactive, zinc-binding motif.

negative: Loss of Apelin Augments Angiotensin II-Induced Cardiac Dysfunction and Pathological Remodeling Apelin is an inotropic and cardioprotective peptide that exhibits beneficial effects through activation of the APJ receptor in the pathology of cardiovascular diseases. Apelin induces the expression of angiotensin-converting enzyme 2 (ACE2) in failing hearts, thereby improving heart function in an angiotensin 1–7-dependent manner. Whether apelin antagonizes the over-activation of the renin–angiotensin system in the heart remains elusive. In this study we show that the detrimental effects of angiotensin II (Ang II) were exacerbated in the hearts of aged apelin-gene-deficient mice. Ang II-mediated cardiac dysfunction and hypertrophy were augmented in apelin knockout mice. The loss of apelin increased the ratio of angiotensin-converting enzyme (ACE) to ACE2 expression in the Ang II-stressed hearts, and Ang II-induced cardiac fibrosis was markedly enhanced in apelin knockout mice. mRNA expression of pro-fibrotic genes, such as transforming growth-factor beta (TGF-β) signaling, were significantly upregulated in apelin knockout hearts. Consistently, treatment with the ACE-inhibitor Captopril decreased cardiac contractility in apelin knockout mice. In vitro, apelin ameliorated Ang II-induced TGF-β expression in primary cardiomyocytes, accompanied with reduced hypertrophy. These results provide direct evidence that endogenous apelin plays a crucial role in suppressing Ang II-induced cardiac dysfunction and pathological remodeling.

negative: SARS-CoV-2 transmission in cancer patients of a tertiary hospital in Wuhan In December 2019, an outbreak of atypical pneumonia known as 2019 novel coronavirus disease (COVID-19) occurred in Wuhan, China. This new type of pneumonia is characterized by rapid human-to-human transmission. Among the different disease types, cancer patients are often recalled to the hospital for treatment and disease surveillance, and the majority of cancer treatments such as chemotherapy and radiotherapy are immunosuppressive. This prompts us to consider if cancer patients were at an elevated risk of SARS-CoV-2 infection. A total of 1,524 cancer patients who were managed at our tertiary cancer institution-Zhongnan hospital of Wuhan University were reviewed during the period of Dec 30, 2019 to Feb 17, 2020. It was found that cancer patients had an estimated 2-fold increased risk of COVID-19 than the general population. We identified twelve patients who were infected with SARS-CoV-2, with two recorded deaths (16.7%), albeit one patient passed away from a COVID-19 unrelated cause. Interestingly, only five of these patients were ongoing treatment at the time of contracting the virus, suggesting that hospital visitation was the likely factor contributing to the elevated incidence in cancer patients. Moreover, we also observed that the incidence of severe COVID-19 was not higher than in the general population. Consequently, for cancer patients who require treatment, proper isolation protocols must be in place to mitigate the risk of SARS-CoV-2 infection.

negative: Research and Development on Therapeutic Agents and Vaccines for COVID-19 and Related Human Coronavirus Diseases Since the outbreak of the novel coronavirus disease COVID-19, caused by the SARS-CoV-2 virus, this disease has spread rapidly around the globe. Considering the potential threat of a pandemic, scientists and physicians have been racing to understand this new virus and the pathophysiology of this disease to uncover possible treatment regimens and discover effective therapeutic agents and vaccines. To support the current research and development, CAS has produced a special report to provide an overview of published scientific information with an emphasis on patents in the CAS content collection. It highlights antiviral strategies involving small molecules and biologics targeting complex molecular interactions involved in coronavirus infection and replication. The drug-repurposing effort documented herein focuses primarily on agents known to be effective against other RNA viruses including SARS-CoV and MERS-CoV. The patent analysis of coronavirusrelated biologics includes therapeutic antibodies, cytokines, and nucleic acid-based therapies targeting virus gene expression as well as various types of vaccines. More than 500 patents disclose methodologies of these four biologics with the potential for treating and preventing coronavirus infections, which may be applicable to COVID-19. The information included in this report provides a strong intellectual groundwork for the ongoing development of therapeutic agents and vaccines.

negative: ESICM 2013 - Abstracts of Oral Presentations and Poster Sessions

negative: Peptidases in human bronchoalveolar lining fluid, macrophages, and epithelial cells: Dipeptidyl (amino)peptidase IV, aminopeptidase N, and dipeptidyl (carboxy)peptidase (angiotensin-converting enzyme)() The modulation of proteolytic activity is an important factor in regulating the metabolism and function of peptide hormones. In this study, the activities of dipeptidyl (carboxy)peptidase (angiotensin-converting enzyme (ACE)), aminopeptidase N (APN), and dipeptidyl (amino)peptidase IV (DPP IV) were measured in the blood, the human bronchial epithelial and alveolar cells, bronchoalveolar macrophages, and the soluble phase of bronchoalveolar lavage (BAL) samples obtained from normal human volunteers and patients with pulmonary pathologic conditions. BAL fluid expressed ACE activity and very low levels of APN and DPP IV activities in the volunteer population, but higher levels could be measured in samples from patients. In patients, increased APN corresponded to a high granulocyte count, while DPP IV and ACE were associated with a high percentage of lymphocytes. Neither AIDS nor smoking induced an increased level of these enzymes. Immunohistochemical staining of bronchoalveolar smears with anti-human ACE monoclonal antibody showed that only macrophages expressed this enzyme. Enzyme histochemistry for DPP IV and APN showed that all leukocytes expressed these activities. APN, DPP IV, and ACE activities were also found in cell extracts of bronchoalveolar macrophages. In extracts of bronchial epithelial and alveolar cells, only APN and DPP IV activities were detected. Kinetic properties of the soluble enzymes in lavage supernatants were comparable to those of serum enzymes. These results demonstrate that soluble forms of cellular enzymes found in BAL fluid are regulated independently of blood and that different cell types may release these enzymes.

negative: Effectiveness and safety of antiviral or antibody treatments for coronavirus: A rapid review Background: To identify safe and effective medical countermeasures (e.g., antivirals/antibodies) to address the current outbreak of a novel coronavirus (COVID-19) Methods: Comprehensive literature searches were developed by an experienced librarian for MEDLINE, EMBASE, the Cochrane Library, and biorxiv.org/medrxiv.org; additional searches for ongoing trials and unpublished studies were conducted in clinicaltrials.gov and the Global Infectious Diseases and Epidemiology Network (GIDEON). Title/abstract and full-text screening, data abstraction, and risk of bias appraisal were carried out by single reviewers. Results: 54 studies were included in the review: three controlled trials, 10 cohort studies, seven retrospective medical record/database studies, and 34 case reports or series. These studies included patients with severe acute respiratory syndrome (SARs, n=33), middle east respiratory syndrome (MERS, n=16), COVID-19 (n=3), and unspecified coronavirus (n=2). The most common treatment was ribavirin (n=41), followed by oseltamivir (n=10) and the combination of lopinavir/ritonavir (n=7). Additional therapies included broad spectrum antibiotics (n=30), steroids (n=39) or various interferons (n=12). No eligible studies examining monoclonal antibodies for COVID-19 were identified. One trial found that ribavirin prophylactic treatment statistically significantly reduced risk of MERS infection in people who had been exposed to the virus. Of the 21 studies reporting rates of ICU admission in hospitalized SARS or MERS patients, none reported statistically significant results in favour of or against antiviral therapies. Of the 40 studies reporting mortality rates in hospitalized SARS or MERS patients, one cohort study (MERS) and one retrospective study (SARS) found a statistically significant increase in the mortality rate for patients treated with ribavirin. Eighteen studies reported potential drug-related adverse effects including gastrointestinal symptoms, anemia, and altered liver function in patients receiving ribavirin. Conclusion: The current evidence for the effectiveness and safety of antiviral therapies for coronavirus is inconclusive and suffers from a lack of well-designed prospective trials or observational studies, preventing any treatment recommendations from being made. However, it is clear that the existing body of evidence is weighted heavily towards ribavirin (41/54 studies), which has not shown conclusive evidence of effectiveness and may cause harmful adverse events so future investigations may consider focusing on other candidates for antiviral therapy.

negative: Coronavirus S protein-induced fusion is blocked prior to hemifusion by Abl kinase inhibitors Enveloped viruses gain entry into host cells by fusing with cellular membranes, a step required for virus replication. Coronaviruses, including the severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and infectious bronchitis virus (IBV), fuse at the plasma membrane or use receptor-mediated endocytosis and fuse with endosomes depending on the cell or tissue type. The virus Spike (S) protein mediates fusion with the host cell membrane. We have shown previously that an Abl kinase inhibitor, imatinib, significantly reduces SARS-CoV and MERS-CoV viral titers and prevents endosomal entry by HIV SARS S and MERS S pseudotyped virions. SARS-CoV and MERS-CoV are classified as BSL-3 viruses, which can make experimentation into the cellular mechanisms involved in infection more challenging. Here, we use IBV, a BSL-2 virus, as a model for studying the role of Abl kinase activity during coronavirus infection. We found that imatinib and two specific Abl kinase inhibitors, GNF2 and GNF5, reduce IBV titers by blocking the first round of virus infection. Additionally, all three drugs prevented IBV S-induced syncytia formation prior to the hemifusion step. Our results indicate that membrane fusion (both virus-cell and cell-cell) is blocked in the presence of Abl kinase inhibitors. Studying the effects of Abl kinase inhibitors on IBV will be useful in identifying host cell pathways required for coronavirus infection. This will provide insight into possible therapeutic targets to treat infections by current as well as newly emerging coronaviruses.

negative: A fast and simple one-step duplex PCR assay for canine distemper virus (CDV) and canine coronavirus (CCoV) detection The one-step polymerase chain reaction (one-step PCR) detection assay is an innovative PCR detection method, eliminating nucleic acid extraction steps, in which samples can be directly added to PCR reagents for testing. For simultaneous detection of CDV and CCoV, a sensitive and specific one-step duplex PCR (one-step dPCR) assay was developed with two pairs of primers that were designed based on H and M gene sequences of CDV and CCoV, respectively. The one-step dPCR with optimized detection conditions has high specificity and sensitivity; independent sequencing assays further verified these results.

negative: Cigarette smoke exposure and inflammatory signaling increase the expression of the SARS-CoV-2 receptor ACE2 in the respiratory tract The factors mediating fatal SARS-CoV-2 infections are poorly understood. Here, we show that cigarette smoke causes a dose-dependent upregulation of Angiotensin Converting Enzyme 2 (ACE2), the SARS-CoV-2 receptor, in rodent and human lungs. Using single-cell sequencing data, we demonstrate that ACE2 is expressed in a subset of secretory cells in the respiratory tract. Chronic smoke exposure triggers the expansion of this cell population and a concomitant increase in ACE2 expression. In contrast, quitting smoking decreases the abundance of these secretory cells and reduces ACE2 levels. Finally, we demonstrate that ACE2 expression is responsive to inflammatory signaling and can be upregulated by viral infections or interferon treatment. Taken together, these results may partially explain why smokers are particularly susceptible to severe SARS-CoV-2 infections. Furthermore, our work identifies ACE2 as an interferon-stimulated gene in lung cells, suggesting that SARS-CoV-2 infections could create positive-feedback loops that increase ACE2 levels and facilitate viral dissemination.

negative: Ethical Alternatives to Experiments with Novel Potential Pandemic Pathogens Please see later in the article for the Editors' Summary

negative: Unrevealing sequence and structural features of novel coronavirus using in silico approaches: The main protease as molecular target Direct-acting antivirals are effective tools to control viral infections. SARS-CoV-2 is a coronavirus associated with the epidemiological outbreak in late 2019. Previous reports showed that HIV-1 protease inhibitors could block SARS-CoV main protease. Based on that and using an in silico approach, we evaluated SARS-CoV-2 main protease as a target for HIV-1 protease inhibitors to reveal the structural features related to their antiviral effect. Our results showed that several HIV inhibitors such as lopinavir, ritonavir, and saquinavir produce strong interaction with the active site of SARS-CoV-2 main protease. Furthermore, broad library protease inhibitors obtained from PubChem and ZINC (www.zinc.docking.org) were evaluated. Our analysis revealed 20 compounds that could be clustered into three groups based on their chemical features. Then, these structures could serve as leading compounds to develop a series of derivatives optimizing their activity against SARS-CoV-2 and other coronaviruses. Altogether, the results presented in this work contribute to gain a deep understanding of the molecular pharmacology of SARS-CoV-2 treatment and validate the use of protease inhibitors against SARS-CoV-2.

negative: Catalytic function and substrate specificity of the papain-like protease domain of nsp3 from the Middle East respiratory syndrome coronavirus. UNLABELLED The papain-like protease (PLpro) domain from the deadly Middle East respiratory syndrome coronavirus (MERS-CoV) was overexpressed and purified. MERS-CoV PLpro constructs with and without the putative ubiquitin-like (UBL) domain at the N terminus were found to possess protease, deubiquitinating, deISGylating, and interferon antagonism activities in transfected HEK293T cells. The quaternary structure and substrate preferences of MERS-CoV PLpro were determined and compared to those of severe acute respiratory syndrome coronavirus (SARS-CoV) PLpro, revealing prominent differences between these closely related enzymes. Steady-state kinetic analyses of purified MERS-CoV and SARS-CoV PLpros uncovered significant differences in their rates of hydrolysis of 5-aminomethyl coumarin (AMC) from C-terminally labeled peptide, ubiquitin, and ISG15 substrates, as well as in their rates of isopeptide bond cleavage of K48- and K63-linked polyubiquitin chains. MERS-CoV PLpro was found to have 8-fold and 3,500-fold higher catalytic efficiencies for hydrolysis of ISG15-AMC than for hydrolysis of the Ub-AMC and Z-RLRGG-AMC substrates, respectively. A similar trend was observed for SARS-CoV PLpro, although it was much more efficient than MERS-CoV PLpro toward ISG15-AMC and peptide-AMC substrates. MERS-CoV PLpro was found to process K48- and K63-linked polyubiquitin chains at similar rates and with similar debranching patterns, producing monoubiquitin species. However, SARS-CoV PLpro much preferred K48-linked polyubiquitin chains to K63-linked chains, and it rapidly produced di-ubiquitin molecules from K48-linked chains. Finally, potent inhibitors of SARS-CoV PLpro were found to have no effect on MERS-CoV PLpro. A homology model of the MERS-CoV PLpro structure was generated and compared to the X-ray structure of SARS-CoV PLpro to provide plausible explanations for differences in substrate and inhibitor recognition. IMPORTANCE Unlocking the secrets of how coronavirus (CoV) papain-like proteases (PLpros) perform their multifunctional roles during viral replication entails a complete mechanistic understanding of their substrate recognition and enzymatic activities. We show that the PLpro domains from the MERS and SARS coronaviruses can recognize and process the same substrates, but with different catalytic efficiencies. The differences in substrate recognition between these closely related PLpros suggest that neither enzyme can be used as a generalized model to explain the kinetic behavior of all CoV PLpros. As a consequence, decoding the mechanisms of PLpro-mediated antagonism of the host innate immune response and the development of anti-CoV PLpro enzyme inhibitors will be a challenging undertaking. The results from this study provide valuable information for understanding how MERS-CoV PLpro-mediated antagonism of the host innate immune response is orchestrated, as well as insight into the design of inhibitors against MERS-CoV PLpro.

negative: A data-driven drug repositioning framework discovered a potential therapeutic agent targeting COVID-19 The global spread of SARS-CoV-2 requires an urgent need to find effective therapeutics for the treatment of COVID-19. We developed a data-driven drug repositioning framework, which applies both machine learning and statistical analysis approaches to systematically integrate and mine large-scale knowledge graph, literature and transcriptome data to discover the potential drug candidates against SARS-CoV-2. The retrospective study using the past SARS-CoV and MERS-CoV data demonstrated that our machine learning based method can successfully predict effective drug candidates against a specific coronavirus. Our in silico screening followed by wet-lab validation indicated that a poly-ADP-ribose polymerase 1 (PARP1) inhibitor, CVL218, currently in Phase I clinical trial, may be repurposed to treat COVID-19. Our in vitro assays revealed that CVL218 can exhibit effective inhibitory activity against SARS-CoV-2 replication without obvious cytopathic effect. In addition, we showed that CVL218 is able to suppress the CpG-induced IL-6 production in peripheral blood mononuclear cells, suggesting that it may also have anti-inflammatory effect that is highly relevant to the prevention immunopathology induced by SARS-CoV-2 infection. Further pharmacokinetic and toxicokinetic evaluation in rats and monkeys showed a high concentration of CVL218 in lung and observed no apparent signs of toxicity, indicating the appealing potential of this drug for the treatment of the pneumonia caused by SARS-CoV-2 infection. Moreover, molecular docking simulation suggested that CVL218 may bind to the N-terminal domain of nucleocapsid (N) protein of SARS-CoV-2, providing a possible model to explain its antiviral action. We also proposed several possible mechanisms to explain the antiviral activities of PARP1 inhibitors against SARS-CoV-2, based on the data present in this study and previous evidences reported in the literature. In summary, the PARP1 inhibitor CVL218 discovered by our data-driven drug repositioning framework can serve as a potential therapeutic agent for the treatment of COVID-19.

negative: Infections in Travelers Travel medicine continues to grow as international tourism and patient medical complexity increases. This article reflects the state of the current field, but new recommendations on immunizations, resistance patterns, and treatment modalities constantly change. The US Centers for Disease Control and the World Health Organization maintain helpful Web sites for both patient and physician. With thoughtful preparation and prevention, risks can be minimized and travel can continue as safely as possible.

negative: Angiotensin Converting Enzyme-2 (ACE2) and its Possible Roles in Hypertension, Diabetes and Cardiac Function Angiotensin converting enzyme-2 (ACE2) is a recently described homologue of the vasoactive peptidase, angiotensin converting enzyme (ACE). Like ACE, ACE2 is an integral (type I) membrane zinc metallopeptidase, which exists as an ectoenzyme. ACE2 is less widely distributed than ACE in the body, being expressed at highest concentrations in the heart, kidney and testis. ACE2 also differs from ACE in its substrate specificity, functioning exclusively as a carboxypeptidase rather than a peptidyl dipeptidase. A key role for ACE2 appears to be emerging in the conversion of angiotensin II to angiotensin (1–7), allowing it to act as a counter-balance to the actions of ACE. ACE2 has been localised to the endothelial and epithelial cells of the heart and kidney where it may have a role at the cell surface in hydrolysing bioactive peptides such as angiotensin II present in the circulation. A role for ACE2 in the metabolism of other biologically active peptides also needs to be considered. ACE2 also serendipitously appears to act as a receptor for the severe acute respiratory syndrome (SARS) coronavirus. Studies using ace2 (-/-) mice, and other emerging studies in vivo and in vitro, have revealed that ACE2 has important functions in cardiac regulation and diabetes. Together with its role as a SARS receptor, ACE2 is therefore likely to be an important therapeutic target in a diverse range of disease states.

negative: Active surveillance for suspected COVID-19 cases in inpatients with information technology

negative: Protective Role of the ACE2/Ang-(1–9) Axis in Cardiovascular Remodeling Despite reduction in cardiovascular (CV) events and end-organ damage with the current pharmacologic strategies, CV disease remains the primary cause of death in the world. Pharmacological therapies based on the renin angiotensin system (RAS) blockade are used extensively for the treatment of hypertension, heart failure, and CV remodeling but in spite of their success the prevalence of end-organ damage and residual risk remain still high. Novel approaches must be discovered for a more effective treatment of residual CV remodeling and risk. The ACE2/Ang-(1–9) axis is a new and important target to counterbalance the vasoconstrictive/proliferative RAS axis. Ang-(1–9) is hydrolyzed slower than Ang-(1–7) and is able to bind the Ang II type 2 receptor. We review here the current experimental evidence suggesting that activation of the ACE2/Ang-(1–9) axis protects the heart and vessels (and possibly the kidney) from adverse cardiovascular remodeling in hypertension as well as in heart failure.

negative: What are the risks of COVID-19 infection in pregnant women?

negative: Actualización de la situación epidemiológica de la infección por SARS-CoV-2 en España. Comentarios a las recomendaciones de manejo de la infección en pediatría

negative: Serodiagnostic Aids and Management Practice for Feline Retrovirus and Coronavirus Infections

negative: Challenges in paediatric inflammatory bowel diseases in the COVID-19 time

negative: Emerging and re-emerging coronaviruses in pigs Porcine epidemic diarrhea virus (PEDV), porcine deltacoronavirus (PDCoV), and swine acute diarrhea syndrome-coronavirus (SADS-CoV) are emerging/reemerging coronaviruses (CoVs). They cause acute gastroenteritis in neonatal piglets. Sequence analyses suggest that PEDV and SADS-CoV may have originated from bat CoVs and PDCoV from a sparrow CoV, reaffirming the interspecies transmission of CoVs. The clinical signs and pathogenesis of the three viruses are similar. Necrosis of infected intestinal epithelial cells occurs, causing villous atrophy that results in malabsorptive diarrhea. The severe diarrhea and vomiting may lead to dehydration and death of piglets. Natural infection induces protective immunity, but there is no cross-protection among the three viruses. Besides strict biosecurity measures, individual vaccines are needed for each virus for disease prevention and control.

negative: Crystal structure of SARS-CoV-2 nucleocapsid protein RNA binding domain reveals potential unique drug targeting sites The outbreak of coronavirus disease (COVID-19) in China caused by SARS-CoV-2 virus continually lead to worldwide human infections and deaths. It is currently no specific viral protein targeted therapeutics yet. Viral nucleocapsid protein is a potential antiviral drug target, serving multiple critical functions during the viral life cycle. However, the structural information of SARS-CoV-2 nucleocapsid protein is yet to be clear. Herein, we have determined the 2.7 Å crystal structure of the N-terminal RNA binding domain of SARS-CoV-2 nucleocapsid protein. Although overall structure is similar with other reported coronavirus nucleocapsid protein N-terminal domain, the surface electrostatic potential characteristics between them are distinct. Further comparison with mild virus type HCoV-OC43 equivalent domain demonstrates a unique potential RNA binding pocket alongside the β-sheet core. Complemented by in vitro binding studies, our data provide several atomic resolution features of SARS-CoV-2 nucleocapsid protein N-terminal domain, guiding the design of novel antiviral agents specific targeting to SARS-CoV-2.

negative: Increased Urinary Angiotensin-Converting Enzyme 2 in Renal Transplant Patients with Diabetes Angiotensin-converting enzyme 2 (ACE2) is expressed in the kidney and may be a renoprotective enzyme, since it converts angiotensin (Ang) II to Ang-(1-7). ACE2 has been detected in urine from patients with chronic kidney disease. We measured urinary ACE2 activity and protein levels in renal transplant patients (age 54 yrs, 65% male, 38% diabetes, n = 100) and healthy controls (age 45 yrs, 26% male, n = 50), and determined factors associated with elevated urinary ACE2 in the patients. Urine from transplant subjects was also assayed for ACE mRNA and protein. No subjects were taking inhibitors of the renin-angiotensin system. Urinary ACE2 levels were significantly higher in transplant patients compared to controls (p = 0.003 for ACE2 activity, and p≤0.001 for ACE2 protein by ELISA or western analysis). Transplant patients with diabetes mellitus had significantly increased urinary ACE2 activity and protein levels compared to non-diabetics (p<0.001), while ACE2 mRNA levels did not differ. Urinary ACE activity and protein were significantly increased in diabetic transplant subjects, while ACE mRNA levels did not differ from non-diabetic subjects. After adjusting for confounding variables, diabetes was significantly associated with urinary ACE2 activity (p = 0.003) and protein levels (p<0.001), while female gender was associated with urinary mRNA levels for both ACE2 and ACE. These data indicate that urinary ACE2 is increased in renal transplant recipients with diabetes, possibly due to increased shedding from tubular cells. Urinary ACE2 could be a marker of renal renin-angiotensin system activation in these patients.

negative: The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade Abstract In 2019, a new coronavirus (2019-nCoV) infecting Humans has emerged in Wuhan, China. Its genome has been sequenced and the genomic information promptly released. Despite a high similarity with the genome sequence of SARS-CoV and SARS-like CoVs, we identified a peculiar furin-like cleavage site in the Spike protein of the 2019-nCoV, lacking in the other SARS-like CoVs. In this article, we discuss the possible functional consequences of this cleavage site in the viral cycle, pathogenicity and its potential implication in the development of antivirals.

negative: Chapter 33 Avian Coronavirus: Case of Infectious Bronchitis Virus Pathogenesis, Diagnostic Approaches, and Phylogenetic Relationship Among Emerging Strains in Middle East and North Africa Regions Abstract Infectious bronchitis (IB) virus (IBV) is a very dynamic and evolving virus, causing severe diseases in poultry with significant economic consequences to the poultry industry worldwide, affecting chickens of all ages and possessing a major threat to the poultry industry. IBV is well studied worldwide; nevertheless, in Middle East and North Africa (MENA) regions, epidemiological and scientific data are poor and not updated. In spite of regular vaccination with Massachusetts (Mass) strain has been available to control IB for many decades in MENA regions, which it is most commonly used, the protection is not occurred. However, the continuity of the spread of IBV has shown the emergence of multiple variant strains due to the frequent point of mutations and recombination events in the S1 gene hypervariable regions. All the reported IBV variants circulate in the form of several serotypes/genotypes that can be partially or poorly neutralized by current vaccines. This emergence remains a problem for the poultry industry and vaccine manufacturers. Therefore the objective of this present chapter, which is reported for the first time, aims to establish phylogenic relationship among emerging strains in MENA regions.

negative: Low expression of dendritic cell-specific intercellular adhesion molecule-grabbing nonintegrin-related protein in lung cancer and significant correlations with brain metastasis and natural killer cells Dendritic cell-specific intercellular adhesion molecule-grabbing nonintegrin-related protein (DC-SIGNR) is a type II transmembrane protein which has been reported to bind a variety of pathogens as well as participate in immunoregulation. But the association between the level of DC-SIGNR and lung cancer is unknown. To investigate the clinical diagnostic significance of DC-SIGNR in lung cancer, we investigated serum DC-SIGNR levels in 173 lung cancer patients and 134 healthy individuals using enzyme-linked immunosorbent assay (ELISA). Results showed that serum DC-SIGNR levels in lung cancer patients were lower than that in healthy controls (P = 0.0003). A cut-off value of 3.8998 ng/L for DC-SIGNR predicted the presence of lung cancer with 78.03 % sensitivity and 49.25 % specificity (area under the curve = 0.6212, P = 0.0003). Strikingly, serum DC-SIGNR levels were significantly higher in lung cancer patients with brain metastasis compared to those without metastasis (P = 0.0283). Moreover, the serum concentrations of DC-SIGNR in lung cancer patients also correlated significantly with serum natural killer cells percentage (P = 0.0017). In addition, immunohistochemistry assay demonstrated that the expression of DC-SIGNR in lung tissues of 31 lung cancer patients and 13 tuberculosis patients was significantly lower than that in 18 normal lung tissues (P = 0.0418, 0.0289), and there is no significant difference between tuberculosis tissues and lung cancer tissues (P = 0.2696). These results suggest that DC-SIGNR maybe a promising biological molecule that has the potential for clinical research of lung cancer, whereas its underlying roles are needed to be investigated in further studies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11010-015-2465-4) contains supplementary material, which is available to authorized users.

negative: First genome sequences of buffalo coronavirus from water buffaloes in Bangladesh We report the complete genome sequences of a buffalo coronavirus (BufCoV HKU26) detected from the faecal samples of two domestic water buffaloes (Bubalus bubalis) in Bangladesh. They possessed 98–99% nucleotide identities to bovine coronavirus (BCoV) genomes, supporting BufCoV HKU26 as a member of Betacoronavirus 1. Nevertheless, BufCoV HKU26 possessed distinct accessory proteins between spike and envelope compared to BCoV. Sugar-binding residues in the N-terminal domain of S protein in BCoV are conserved in BufCoV HKU26.

negative: Angiotensin‐converting enzyme 2 catalytic activity in human plasma is masked by an endogenous inhibitor Angiotensin‐converting enzyme 2 (ACE2) is thought to act in an opposing manner to its homologue, angiotensin‐converting enzyme (ACE), by inactivating the vasoconstrictor peptide angiotensin II and generating the vasodilatory fragment, angiotensin(1–7). Both ACE and ACE2 are membrane‐bound ectoenzymes and may circulate in plasma as a consequence of a proteolytic shedding event. In this study, we show that ACE2 circulates in human plasma, but its activity is suppressed by the presence of an endogenous inhibitor. Partial purification of this inhibitor indicated that the inhibitor is small, hydrophilic and cationic, but not a divalent metal cation. These observations led us to develop a method for removal of the inhibitor, thus allowing detection of plasma ACE2 levels using a sensitive quenched fluorescent substrate‐based assay. Using this technique, ACE2 activity measured in plasma from healthy volunteers (n= 18) ranged from 1.31 to 8.69 pmol substrate cleaved min(−1) ml(−1) (mean ±s.e.m., 4.44 ± 0.56 pmol min(−1) ml(−1)). Future studies of patients with cardiovascular, renal and liver disease will determine whether plasma ACE2 is elevated in parallel with increased tissue levels observed in these conditions.

negative: Remdesivir and SARS-CoV-2: structural requirements at both nsp12 RdRp and nsp14 Exonuclease active-sites Abstract The rapid global emergence of SARS-CoV-2 has been the cause of significant health concern, highlighting the immediate need for antivirals. Viral RNA-dependent RNA polymerases (RdRp) play essential roles in viral RNA synthesis, and thus remains the target of choice for the prophylactic or curative treatment of several viral diseases, due to high sequence and structural conservation. To date, the most promising broad-spectrum class of viral RdRp inhibitors are nucleoside analogues (NAs), with over 25 approved for the treatment of several medically important viral diseases. However, Coronaviruses stand out as a particularly challenging case for NA drug design due to the presence of an exonuclease (ExoN) domain capable of excising incorporated NAs and thus providing resistance to many of these available antivirals. Here we use the available structures of the SARS-CoV RdRp and ExoN proteins, as well as Lassa virus N exonuclease to derive models of catalytically competent SARS-CoV-2 enzymes. We then map a promising NA candidate, GS-441524 (the active metabolite of Remdesivir) to the nucleoside active site of both proteins, identifying the residues important for nucleotide recognition, discrimination, and excision. Interestingly, GS-441524 addresses both enzyme active sites in a manner consistent with significant incorporation, delayed chain termination, and altered excision due to the ribose 1'-CN group, which may account for the increased antiviral effect compared to other available analogues. Additionally, we propose structural and function implications of two previously identified RdRp resistance mutations in relation to resistance against Remdesivir. This study highlights the importance of considering the balance between incorporation and excision properties of NAs between the RdRp and ExoN.

negative: COVID-19 Pandemic and the Crisis of Health Systems: The Experience of the Apulia Cancer Network and of the Comprehensive Cancer Center Istituto Tumori “Giovanni Paolo II” of Bari On 11 March 2020, the World Health Organization declared a new disease caused by a novel virus characterized by rapid human-to-human transmission and named severe acute respiratory syndrome coronoavirus-2 (SARS-CoV-2) a pandemic. In terms of this ongoing international scenario, we report the situation in Apulia, a region of southern Italy that, as of April 2, has not yet been overwhelmed by this health emergency. In particular, we consider the care models that have been adopted, especially those that manage the requests of cancer patients.

negative: Three key proteases – angiotensin-I-converting enzyme (ACE), ACE2 and renin – within and beyond the renin-angiotensin system Summary The discovery of angiotensin-I-converting enzyme 2 (ACE2) and a (pro)renin receptor has renewed interest in the physiology of the renin-angiotensin system (RAS). Through the ACE2/angiotensin-(1–7)/Mas counter-regulatory axis, ACE2 balances the vasoconstrictive, proliferative, fibrotic and proinflammatory effects of the ACE/angiotensin II/AT1 axis. The (pro)renin receptor system shows an angiotensin-dependent function related to increased generation of angiotensin I, and an angiotensin-independent aspect related to intracellular signalling. Activation of ACE2 and inhibition of ACE and renin have been at the core of the RAS regulation. The aim of this review is to discuss the biochemistry and biological functions of ACE, ACE2 and renin within and beyond the RAS, and thus provide a perspective for future bioactives from natural plant and/or food resources related to the three proteases.

negative: Cryo-EM structure of infectious bronchitis coronavirus spike protein reveals structural and functional evolution of coronavirus spike proteins As cell-invading molecular machinery, coronavirus spike proteins pose an evolutionary conundrum due to their high divergence. In this study, we determined the cryo-EM structure of avian infectious bronchitis coronavirus (IBV) spike protein from the γ-genus. The trimeric IBV spike ectodomain contains three receptor-binding S1 heads and a trimeric membrane-fusion S2 stalk. While IBV S2 is structurally similar to those from the other genera, IBV S1 possesses structural features that are unique to different other genera, thereby bridging these diverse spikes into an evolutionary spectrum. Specifically, among different genera, the two domains of S1, the N-terminal domain (S1-NTD) and C-terminal domain (S1-CTD), diverge from simpler tertiary structures and quaternary packing to more complex ones, leading to different functions of the spikes in receptor usage and membrane fusion. Based on the above structural and functional comparisons, we propose that the evolutionary spectrum of coronavirus spikes follows the order of α-, δ-, γ-, and β-genus. This study has provided insight into the evolutionary relationships among coronavirus spikes and deepened our understanding of their structural and functional diversity.

negative: ElaD, a Deubiquitinating Protease Expressed by E. coli BACKGROUND: Ubiquitin and ubiquitin-like proteins (Ubl) are designed to modify polypeptides in eukaryotes. Covalent binding of ubiquitin or Ubls to substrate proteins can be reversed by specific hydrolases. One particular set of cysteine proteases, the CE clan, which targets ubiquitin and Ubls, has homologs in eukaryotes, prokaryotes, and viruses. FINDINGS: We have cloned and analyzed the E. coli protein elaD, which is distantly related to eukaryotic CE clan members of the ULP/SENP protease family that are specific for SUMO and Nedd8. Previously misannotated as a putative sulfatase/phosphatase, elaD is an efficient and specific deubiquitinating enzyme in vitro. Interestingly, elaD is present in all intestinal pathogenic E. coli strains, but conspicuously absent from extraintestinal pathogenic strains (ExPECs). Further homologs of this protease can be found in Acanthamoeba Polyphaga Mimivirus, and in Alpha-, Beta-and Gammaproteobacteria. CONCLUSION: The expression of ULP/SENP-related hydrolases in bacteria therefore extends to plant pathogens and medically relevant strains of Escherichia coli, Legionella pneumophila, Rickettsiae, Chlamydiae, and Salmonellae, in which the elaD ortholog sseL has recently been identified as a virulence factor with deubiquitinating activity. As a counterpoint, our phylogenetic and functional examination reveals that ancient eukaryotic ULP/SENP proteases also have the potential of ubiquitin-specific hydrolysis, suggesting an early common origin of this peptidase clan.

negative: Virtual Screening of Natural Products against Type II Transmembrane Serine Protease (TMPRSS2), the Priming Agent of Coronavirus 2 (SARS-CoV-2) Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused about 2 million infections and is responsible for more than 100,000 deaths worldwide. To date, there is no specific drug registered to combat the disease it causes, named coronavirus disease 2019 (COVID-19). In the current study, we used an in silico approach to screen natural compounds to find potent inhibitors of the host enzyme transmembrane protease serine 2 (TMPRSS2). This enzyme facilitates viral particle entry into host cells, and its inhibition blocks virus fusion with angiotensin-converting enzyme 2 (ACE2). This, in turn, restricts SARS-CoV-2 pathogenesis. A three-dimensional structure of TMPRSS2 was built using SWISS-MODEL and validated by RAMPAGE. The natural compounds library Natural Product Activity and Species Source (NPASS), containing 30,927 compounds, was screened against the target protein. Two techniques were used in the Molecular Operating Environment (MOE) for this purpose, i.e., a ligand-based pharmacophore approach and a molecular docking-based screening. In total, 2140 compounds with pharmacophoric features were retained using the first approach. Using the second approach, 85 compounds with molecular docking comparable to or greater than that of the standard inhibitor (camostat mesylate) were identified. The top 12 compounds with the most favorable structural features were studied for physicochemical and ADMET (absorption, distribution, metabolism, excretion, toxicity) properties. The low-molecular-weight compound NPC306344 showed significant interaction with the active site residues of TMPRSS2, with a binding energy score of −14.69. Further in vitro and in vivo validation is needed to study and develop an anti-COVID-19 drug based on the structures of the most promising compounds identified in this study.

negative: Chloroquine diphosphate: a risk factor for herpes zoster in patients with dermatomyositis/polymyositis OBJECTIVES: Herpes zoster has been widely described in the context of different systemic autoimmune diseases but not dermatomyositis/polymyositis. Therefore, we analyzed the prevalence, risk factors and herpes zoster outcomes in this population. METHOD: A retrospective cohort study of herpes zoster infections in dermatomyositis/polymyositis patients was performed. The patients were followed at a tertiary center from 1991 to 2012. For the control group, each patient with herpes zoster was paired with two patients without herpes zoster. Patients were matched by gender and the type of myositis, age at myositis onset and disease duration. RESULTS: Of 230 patients, 24 (10.4%) had a histories of herpes zoster (19 with dermatomyositis and five with polymyositis, two-thirds female). The mean age of the patients with herpes zoster was 44.6±16.8 years. No difference between the groups was found regarding cumulative clinical manifestations. Disease activity, autoantibody, muscle and leukogram parameters were also comparable between the groups. No differences in immunosuppressive (alone or in association with other immunosuppressive therapies) or glucocorticoid (current use, medium dose and cumulative dose in the last two months) therapies were found between patients with and without herpes zoster. However, a higher proportion of patients in the herpes zoster group received chloroquine diphosphate compared to the control group. All of the patients received acyclovir; 58.3% of patients had postherpetic neuralgia and no cases of recurrence were reported. Furthermore, individuals who were taking high prednisone doses at the time of the herpes zoster diagnosis had reduced levels of postherpetic neuralgia. CONCLUSIONS: These data suggest that chloroquine diphosphate could predispose patients with dermatomyositis/polymyositis to developing herpes zoster, particularly women and dermatomyositis patients.

negative: Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study Summary Background Coronavirus disease 2019 (COVID-19) causes severe community and nosocomial outbreaks. Comprehensive data for serial respiratory viral load and serum antibody responses from patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are not yet available. Nasopharyngeal and throat swabs are usually obtained for serial viral load monitoring of respiratory infections but gathering these specimens can cause discomfort for patients and put health-care workers at risk. We aimed to ascertain the serial respiratory viral load of SARS-CoV-2 in posterior oropharyngeal (deep throat) saliva samples from patients with COVID-19, and serum antibody responses. Methods We did a cohort study at two hospitals in Hong Kong. We included patients with laboratory-confirmed COVID-19. We obtained samples of blood, urine, posterior oropharyngeal saliva, and rectal swabs. Serial viral load was ascertained by reverse transcriptase quantitative PCR (RT-qPCR). Antibody levels against the SARS-CoV-2 internal nucleoprotein (NP) and surface spike protein receptor binding domain (RBD) were measured using EIA. Whole-genome sequencing was done to identify possible mutations arising during infection. Findings Between Jan 22, 2020, and Feb 12, 2020, 30 patients were screened for inclusion, of whom 23 were included (median age 62 years [range 37–75]). The median viral load in posterior oropharyngeal saliva or other respiratory specimens at presentation was 5·2 log10 copies per mL (IQR 4·1–7·0). Salivary viral load was highest during the first week after symptom onset and subsequently declined with time (slope −0·15, 95% CI −0·19 to −0·11; R 2=0·71). In one patient, viral RNA was detected 25 days after symptom onset. Older age was correlated with higher viral load (Spearman's ρ=0·48, 95% CI 0·074–0·75; p=0·020). For 16 patients with serum samples available 14 days or longer after symptom onset, rates of seropositivity were 94% for anti-NP IgG (n=15), 88% for anti-NP IgM (n=14), 100% for anti-RBD IgG (n=16), and 94% for anti-RBD IgM (n=15). Anti-SARS-CoV-2-NP or anti-SARS-CoV-2-RBD IgG levels correlated with virus neutralisation titre (R 2>0·9). No genome mutations were detected on serial samples. Interpretation Posterior oropharyngeal saliva samples are a non-invasive specimen more acceptable to patients and health-care workers. Unlike severe acute respiratory syndrome, patients with COVID-19 had the highest viral load near presentation, which could account for the fast-spreading nature of this epidemic. This finding emphasises the importance of stringent infection control and early use of potent antiviral agents, alone or in combination, for high-risk individuals. Serological assay can complement RT-qPCR for diagnosis. Funding Richard and Carol Yu, May Tam Mak Mei Yin, The Shaw Foundation Hong Kong, Michael Tong, Marina Lee, Government Consultancy Service, and Sanming Project of Medicine.

negative: Experimental and numerical investigation of micro-environmental conditions in public transportation buses Abstract This study examines both numerically and experimentally the micro-environmental conditions in public transportation buses. A Computational Fluid Dynamics (CFD) model was developed and experimentally validated. The developed CFD model was used to calculate the spatial distributions of the mean age and mean residual lifetime of air in the bus environment and evaluate the efficiency of the bus ventilation system. Additionally, the passengers’ exposures to a variety of environmental conditions were experimentally monitored in “real world” field campaigns using the Harvard University shuttle bus system. Real time continuous monitoring systems were used to assess indoor environmental quality in the buses. It was found that CO levels were very low, while the levels of particulate matter varied and were influenced by the ambient air penetrated into the bus through the operation of the doors and the ventilation system. The CO2 level was found elevated and greatly affected by occupancy conditions. The elevated CO2 level indicates that the current bus ventilation is insufficient to dilute air pollutants in the bus especially under heavy occupancy conditions. This lack of sufficient ventilation indicates an elevated risk for airborne transmitted diseases in such a popular public transportation system.

negative: New Perspectives in the Renin-Angiotensin-Aldosterone System (RAAS) IV: Circulating ACE2 as a Biomarker of Systolic Dysfunction in Human Hypertension and Heart Failure BACKGROUND: Growing evidence exists for soluble Angiotensin Converting Enzyme-2 (sACE2) as a biomarker in definitive heart failure (HF), but there is little information about changes in sACE2 activity in hypertension with imminent heart failure and in reverse remodeling. METHODS, FINDINGS: Patients with systolic HF (NYHAII-IV, enrolled for cardiac resynchronisation therapy, CRT, n = 100) were compared to hypertensive patients (n = 239) and to a healthy cohort (n = 45) with preserved ejection fraction (EF>50%) in a single center prospective clinical study. The status of the heart failure patients were checked before and after CRT. Biochemical (ACE and sACE2 activity, ACE concentration) and echocardiographic parameters (EF, left ventricular end-diastolic (EDD) and end-systolic diameter (ESD) and dP/dt) were measured. sACE2 activity negatively correlated with EF and positively with ESD and EDD in all patient's populations, while it was independent in the healthy cohort. sACE2 activity was already increased in the hypertensive group, where signs for imminent heart failure (slightly decreased EF and barely increased NT-proBNP levels) were detected. sACE2 activities further increased in patients with definitive heart failure (EF<50%), while sACE2 activities decreased with the improvement of the heart failure after CRT (reverse remodeling). Serum angiotensin converting enzyme (ACE) concentrations were lower in the diseased populations, but did not show a strong correlation with the echocardiographic parameters. CONCLUSIONS: Soluble ACE2 activity appears to be biomarker in heart failure, and in hypertension, where heart failure may be imminent. Our data suggest that sACE2 is involved in the pathomechanism of hypertension and HF.

negative: COVID-19 pneumonia with hemoptysis: Acute segmental pulmonary emboli associated with novel coronavirus infection Abstract Recent retrospective studies from Wuhan, China suggest Novel Coronavirus Disease 2019 (COVID-19) may be associated with a hypercoagulable state and increased risk for venous thromboembolism. The overlap in the signs and symptoms of COVID-19 associated Acute Respiratory Distress Syndrome (ARDS) and COVID-19 with concurrent pulmonary embolism creates a diagnostic challenge for emergency medicine physicians in patients already at risk for renal impairment. However, identifying features atypical for COVID-19 alone may play a role in the judicious use of Computed Tomography Angiography among these patients. Hemoptysis is seen in roughly 13% of pulmonary embolism cases and infrequently reported among COVID-19 infections. Additionally, the presence of right heart strain on electrocardiography (EKG) is a well described clinical presentations of pulmonary embolism not reported commonly with COVID-19 infections.

negative: Current status of treatment for 2019 novel coronavirus pneumonia/ 中华微生物学和免疫学杂志 2019 novel coronavirus (2019-nCoV) is a new member of coronavirus family that can cause serious respiratory diseases after the emergence of severe acute respiratory syndrome-coronavirus (SARS-CoV) and middle east respiratory syndrome-coronavirus (MERS-CoV). At present, there is no specific antiviral drug targeting 2019-nCoV. In facing of the increasingly serious epidemic of 2019 novel coronavirus pneumonia and the urgent needs in drug treatment strategies, this paper reviewed the current research situation and progress in antiviral treatment for the newly identified disease.

negative: Efficient replication of severe acute respiratory syndrome coronavirus in mouse cells is limited by murine angiotensin-converting enzyme 2. Replication of viruses in species other than their natural hosts is frequently limited by entry and postentry barriers. The coronavirus that causes severe acute respiratory syndrome (SARS-CoV) utilizes the receptor angiotensin-converting enzyme 2 (ACE2) to infect cells. Here we compare human, mouse, and rat ACE2 molecules for their ability to serve as receptors for SARS-CoV. We found that, compared to human ACE2, murine ACE2 less efficiently bound the S1 domain of SARS-CoV and supported less-efficient S protein-mediated infection. Rat ACE2 was even less efficient, at near background levels for both activities. Murine 3T3 cells expressing human ACE2 supported SARS-CoV replication, whereas replication was less than 10% as efficient in the same cells expressing murine ACE2. These data imply that a mouse transgenically expressing human ACE2 may be a useful animal model of SARS.

negative: A brief review of antiviral drugs evaluated in registered clinical trials for COVID-19 Background: Although a number of antiviral agents have been evaluated for coronaviruses there are no approved drugs available. To provide an overview of the landscape of therapeutic research for COVID-19, we conducted a review of registered clinical trials. Methods: A review of currently registered clinical trials was performed on registries, including the Chinese (chictr.org.cn) and US (clinicaltrials.gov) databases to identify relevant studies up to March, 7th 2020. The search was conducted using the search terms “2019-nCoV”, “COVID-19”, “SARS-CoV-2”, “Hcov-19”, “new coronavirus”, “novel coronavirus”. We included interventional clinical trials focusing on patients with COVID-19 and assessing antiviral drugs or agents. Findings: Out of the 353 studies identified, 115 clinical trials were selected for data extraction. Phase IV trials were the most commonly reported study type (n=27, 23%). However, 62 trials (54%) did not describe the phase of the study. Eighty percent (n=92) of the trials were randomized with parallel assignment and the median number of planned inclusions was 63 (IQR, 36-120). Open-label studies were the most frequent (46%) followed by double-blind (13%) and single blind studies (10%). The most frequently assessed therapies were: stem cells therapy (n=23 trials), lopinavir/ritonavir (n=15), chloroquine (n=11), umifenovir (n=9), hydroxychloroquine (n=7), plasma treatment (n=7), favipiravir (n=7), methylprednisolone (n=5), and remdesivir (n=5). Remdesivir was tested in 5 trials with a median of 400 (IQR, 394-453) planned inclusions per trial, while stem cells therapy was tested in 23 trials, but had a median of 40 (IQR, 23-60) planned inclusions per trial. Lopinavir/ritonavir was associated with the highest total number of planned inclusions (2606) followed by remdesivir (2155). Only 52% of the clinical trials reported the treatment dose (n=60) and only 34% (n=39) the duration. The primary outcome was clinical in 76 studies (66%), virological in 27 (23%); radiological in 9 (8%) or immunological in three studies (3%). Interpretation: Numerous clinical trials have been registered since the beginning of the COVID-19 outbreak, however, a number of information regarding drugs or trial design were lacking. Funding: None

negative: Tabagisme et maladie à coronavirus 2019 (COVID-19)

negative: Social and administrative issues related to the COVID-19 pandemic in Pakistan: better late than never The study critically reviewed Pakistan’s provincial updates of coronavirus disease 2019 (COVID-19) and discussed the current challenges faced by the government in a given context. The coronavirus-associated death tolls have been increasing rapidly in a country. The provincial status of confirmed cases of coronavirus is higher in Punjab, followed by the Sindh, Khyber Pakhtunkhwa (KPK), and Balochistan. The case fatality ratio shows that KPK has a higher ratio, i.e., 5.11%, followed by the Punjab, i.e., 1.82%; Sindh, i.e., 1.80%; Balochistan, i.e., 1.28%; Gilgit-Baltistan, i.e., 0.71%; and Federal territory, i.e., 0.66%. The country has a less testing capacity to identify more suspected coronavirus patients. The study calculated that if we increase five times our testing capacity from the current date, the total registered cases will be reached to 137,370 and death tolls will increase up to 3090. It is highly needed to increase testing capacity across Pakistan in order to minimize the outbreak of coronavirus. The provincial government should follow the Federal Government instructions to contain coronavirus by increasing testing capacities, tracing suspected patients, smart lockdowns, emergency relief to the poor, and vigilant monitoring system.

negative: Antigenic Relationship between Human Coronavirus Strain DC 43 and Hemagglutinating Encephalomyelitis Virus Strain 67N of Swine: Antibody Responses in Human and Animal Sera Hemagglutinating encephalomyelitis virus of swine (HEV) was adapted to growth in suckling mouse brain. Electron micrographs of HEV-infected suckling mouse brain, prepared by negative staining and thin-section techniques, exhibited typical morphological characteristics shared with other members of the Coronaviridae. The adaptation of HEV to suckling mouse brain facilitated serologic testing by the use of common host reagents and compatible animal systems. With hemagglutination inhibition, complement-fixation, and neutralization tests, an antigenic relationship was demonstrated between human coronavirus OC 43 and HEV in specific immune and hyperimmune animal sera. Children and adults with seroconversion to OC 43 antigen had diagnostic rises in titer of antibody to HEV antigens. Individuals with seroconversion to human coronaviruses 229E and B814 demonstrated antibody to HEV but not diagnostic rises in titer. Swine with titers of antibody to HEV had lower or no detectable titers of antibody to coronavirus OC 43. Although the prevalence and geometric mean titer of antibody to DC 43 were higher than the titer of antibody to HEV in every group of normal humans tested, significant differences in antibody response to coronavirus DC 43 and HEV were seen between populations that did or did not have possible contact with swine. The evidence suggested that antibody to HEV in humans probably represented a heterologous response to infection with coronavirus DC 43. However, a heterotypic response to unknown or uncharacterized strains of coronavirus cannot be excluded.

negative: Tanshinone IIA Attenuates Bleomycin-Induced Pulmonary Fibrosis via Modulating Angiotensin-Converting Enzyme 2/ Angiotensin-(1-7) Axis in Rats Pulmonary fibrosis (PF) is a common complication in those interstitial lung diseases patients, which will result in poor prognosis and short survival. Traditional therapeutic methods such as glucocorticoid and cytotoxic drugs are insufficient for treating PF and may cause severe side effects. Recent studies showed that traditional Chinese herbal abstraction such as Tanshinone IIA (TIIA) was displayed significant anti-PF effects in animal models. However, the exact mechanisms underlying the protective effects of TIIA were not fully understood. Here we further investigated the protective effects of TIIA and its mechanisms underlying. PF models of rat were induced by bleomycin (BLM); TIIA was administered subsequently. The PF changes were identified by histopathological analyses. The results showed that BLM resulted in severe PF and alveolar inflammation; together with significant elevation of transforming growth factor-β 1 (TGF-β1). Angiotensin-converting enzyme 2 (ACE-2) together with angiotensin-(1-7) [ANG-(1-7)] were both greatly reduced after BLM administration. TIIA treatment notably attenuated BLM induced PF and inflammation, decreased expression of TGF-β1 and reversed ACE-2 and ANG-(1-7) production in rat lungs. Thus we may draw the conclusion that TIIA may exert protective effects on BLM induced PF in rats, and the ACE-2/ANG-(1-7) axis may ascribe to those protective effects.

negative: Why are pregnant women susceptible to COVID-19? An immunological viewpoint Abstract The 2019 novel coronavirus disease (COVID-19) was first detected in December 2019 and became epidemic in Wuhan, Hubei Province, China. COVID-19 has been rapidly spreading out in China and all over the world. The virus causing COVID-19, SARS-CoV-2 has been known to be genetically similar to severe acute respiratory syndrome coronavirus (SARS-CoV) but distinct from it. Clinical manifestation of COVID-19 can be characterized by mild upper respiratory tract infection, lower respiratory tract infection involving non-life threatening pneumonia, and life-threatening pneumonia with acute respiratory distress syndrome. It affects all age groups, including newborns, to the elders. Particularly, pregnant women may be more susceptible to COVID-19 since pregnant women, in general, are vulnerable to respiratory infection. In pregnant women with COVID-19, there is no evidence for vertical transmission of the virus, but an increased prevalence of preterm deliveries has been noticed. The COVID-19 may alter immune responses at the maternal-fetal interface, and affect the well-being of mothers and infants. In this review, we focused on the reason why pregnant women are more susceptible to COVID-19 and the potential maternal and fetal complications from an immunological viewpoint.

negative: Genetic, Transcriptome, Proteomic, and Epidemiological Evidence for Blood-Brain Barrier Disruption and Polymicrobial Brain Invasion as Determinant Factors in Alzheimer’s Disease Diverse pathogens are detected in Alzheimer’s disease (AD) brains. A bioinformatics survey showed that AD genome-wide association study (GWAS) genes (localized in bone marrow, immune locations and microglia) relate to multiple host/pathogen interactomes (Candida albicans, Cryptococcus neoformans, Bornavirus, Borrelia burgdorferri, cytomegalovirus, Ebola virus, HSV-1, HERV-W, HIV-1, Epstein-Barr, hepatitis C, influenza, Chlamydia pneumoniae, Porphyrymonas gingivalis, Helicobacter pylori, Toxoplasma gondii, Trypanosoma cruzi). These interactomes also relate to the AD hippocampal transcriptome and to plaque or tangle proteins. Upregulated AD hippocampal genes match those upregulated by multiple bacteria, viruses, fungi, or protozoa in immunocompetent cells. AD genes are enriched in GWAS datasets reflecting pathogen diversity, suggesting selection for pathogen resistance, as supported by the old age of AD patients, implying resistance to earlier infections. APOE4 is concentrated in regions of high parasitic burden and protects against childhood tropical infections and hepatitis C. Immune/inflammatory gain of function applies to APOE4, CR1, and TREM2 variants. AD genes are also expressed in the blood-brain barrier (BBB), which is disrupted by AD risk factors (age, alcohol, aluminum, concussion, cerebral hypoperfusion, diabetes, homocysteine, hypercholesterolemia, hypertension, obesity, pesticides, pollution, physical inactivity, sleep disruption, smoking) and by pathogens, directly or via olfactory routes to basal-forebrain BBB control centers. The BBB benefits from statins, NSAIDs, estrogen, melatonin, memantine, and the Mediterranean diet. Polymicrobial involvement is supported by upregulation of bacterial, viral, and fungal sensors/defenders in the AD brain, blood, or cerebrospinal fluid. AD serum amyloid-β autoantibodies may attenuate its antimicrobial effects favoring microbial survival and cerebral invasion leading to activation of neurodestructive immune/inflammatory processes, which may also be augmented by age-related immunosenescence. AD may thus respond to antibiotic, antifungal, or antiviral therapy.

negative: Navigating the challenges of the COVID-19 outbreak: perspectives from the radiation oncology service in singapore Abstract In December 2019, pneumonia of unknown cause was reported by China to WHO. The outbreak was found to be caused by a coronavirus which was officially named “severe acute respiratory syndrome coronavirus 2” (SARS-CoV-2), and the disease caused by it was named ‘COVID-19’. The first case in Singapore was confirmed on 23rd January 2020. With lessons learnt from the SARS epidemic in 2003 and the H1N1 flu pandemic in 2009, Singapore was much better prepared to deal with the virus outbreak. The government has taken swift measures to contain and break the chain of transmission. Healthcare workers face the challenge of keeping patients and staff safe from the disease. There is a higher risk of mortality of COVID-19 in cancer patients and hence unique considerations for a radiation oncology department operating in an infectious disease outbreak. This article is the recommendations and adapted workflow from the two National Cancer Centres in Singapore with the endorsement by the working committee of the Chapter of Radiation Oncology, Academy of Medicine, Singapore. It highlights the challenges that radiation oncology departments in Singapore face and the appropriate recommended responses. This includes interventions, business continuity plans and workflow in managing a COVID-19 positive patient on radiotherapy.

negative: Association of Population Migration and Coronavirus Disease 2019 Epidemic Control Background and Objective To analyze the impact of different patterns of migration flow in two cities, Hefei and Shenzhen, on the epidemic and disease control of Coronavirus Disease 2019 (COVID-19), in order to provide insight for making differentiated controlling policies. Methods We collected demographic and epidemiological information of confirmed COVID-19 cases in Hefei and Shenzhen between January 19 and February 11, 2020, from data officially published by the provincial and municipal Centers for Disease Control and Prevention (CDC). From these data we calculated basic reproduction number R0 to reflect the rate of spread of COVID-19 in these cities. Aggregated data of population migration during the same period was extracted from Baidu Migration. The change of R0 in the two cites were analyzed and compared. Spearman correlation analysis between R0 and population inflow from epidemic focus were performed. Results A total of 157 confirmed cases was identified in Hefei by 24:00 February 11, 2020, with an average age of 44.4±15.6 years, 74 female (47.1%) and 386 confirmed cases were identified in Shenzhen, with an average age of 45.15±17.99 years, 202 female (52.3%). Significant difference in the proportion of imported cases between the two cities was observed (Hefei vs Shenzhen, 24.2% vs 74.9%, p=0.000). Before January 31 2020, during the initial stage of the Level 1 Response to Major Public Health Emergencies, there was no significant association observed in Shenzhen between R0 and the proportion of population inflow from the epidemic focus (P =0.260, r=-0.452); meanwhile in Hefei, such association was strong (P =0.000, r=1.0). However, after the initial stage of response, the situation reversed. A weak association was observed in Shenzhen between be R0 and the proportion of population inflow from the epidemic focus (P=0.073, r=0.536) but not in Hefei (P =0.498, r=0.217). Conclusion Following Level 1 Response, consistent decline of R0 of COVID-19 was observed in both Hefei and Shenzhen. Different patterns of disease spread were observed in the two cities, driven by different patterns of population migration. This indicated that population migration should be taken into consideration when we set controlling policy of a novel infectious disease.

negative: Recent progress in understanding 2019 novel coronavirus (SARS-CoV-2) associated with human respiratory disease: detection, mechanisms and treatment ABSTRACT Viral respiratory diseases such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) always pose a severe threat to people. First identified in late December 2019, a novel coronavirus (2019-nCoV; SARS-CoV-2) has affected many provinces in China and multiple countries worldwide. The viral outbreak has aroused panic and a public-health emergency around the world, and the number of infections continues to rise. However, the causes and consequences of the pneumonia remain unknown. To effectively implement epidemic prevention, early identification and diagnosis are critical to disease control. Here we scrutinise a series of available studies by global scientists on the clinical manifestations, detection methods and treatment options for the disease caused by SARS-CoV-2, named coronavirus disease 2019 (COVID-19), and also propose potential strategies for preventing the infection.

negative: Reversal of the Progression of Fatal Coronavirus Infection in Cats by a Broad-Spectrum Coronavirus Protease Inhibitor Coronaviruses infect animals and humans causing a wide range of diseases. The diversity of coronaviruses in many mammalian species is contributed by relatively high mutation and recombination rates during replication. This dynamic nature of coronaviruses may facilitate cross-species transmission and shifts in tissue or cell tropism in a host, resulting in substantial change in virulence. Feline enteric coronavirus (FECV) causes inapparent or mild enteritis in cats, but a highly fatal disease, called feline infectious peritonitis (FIP), can arise through mutation of FECV to FIP virus (FIPV). The pathogenesis of FIP is intimately associated with immune responses and involves depletion of T cells, features shared by some other coronaviruses like Severe Acute Respiratory Syndrome Coronavirus. The increasing risks of highly virulent coronavirus infections in humans or animals call for effective antiviral drugs, but no such measures are yet available. Previously, we have reported the inhibitors that target 3C-like protease (3CLpro) with broad-spectrum activity against important human and animal coronaviruses. Here, we evaluated the therapeutic efficacy of our 3CLpro inhibitor in laboratory cats with FIP. Experimental FIP is 100% fatal once certain clinical and laboratory signs become apparent. We found that antiviral treatment led to full recovery of cats when treatment was started at a stage of disease that would be otherwise fatal if left untreated. Antiviral treatment was associated with a rapid improvement in fever, ascites, lymphopenia and gross signs of illness and cats returned to normal health within 20 days or less of treatment. Significant reduction in viral titers was also observed in cats. These results indicate that continuous virus replication is required for progression of immune-mediated inflammatory disease of FIP. These findings may provide important insights into devising therapeutic strategies and selection of antiviral compounds for further development for important coronaviruses in animals and humans.

negative: Angiotensin-converting enzyme 2 in acute respiratory distress syndrome Angiotensin-converting enzyme (ACE) and ACE2 are highly homologous metalloproteases that provide essential catalytic functions in the renin-angiotensin system (RAS). Angiotensin II is one key effector peptide of the RAS, inducing vasoconstriction and exerting multiple biological functions. ACE cleaves angiotensin I to generate angiotensin II, whereas ACE2 reduces angiotensin II levels. Accumulating evidence has demonstrated a physiological and pathological role of ACE2 in the cardiovascular systems. Intriguingly, the SARS coronavirus, the cause of severe acute respiratory syndrome (SARS), utilizes ACE2 as an essential receptor for cell fusion and in vivo infections. Moreover, recent studies have demonstrated that ACE2 protects murine lungs from acute lung injury as well as SARS-Spike protein-mediated lung injury, suggesting a dual role of ACE2 in SARS infections and protection from ARDS.

negative: Biopsychopharmacosocial approach to assess impact of social distancing and isolation on mental health in older adults It is impossible to predict or comprehend the impact of the ongoing COVID-19 pandemic. The UK Government's advice for vulnerable people, including older adults, to move towards self-isolation and social distancing is likely to reduce rates of transmission, the risk of severe illness and the impact on the acute health services. Although justified and necessary, this process of isolation is likely to have a negative impact on the mental health of these vulnerable groups, especially older people. It will become increasingly important for community health professionals to assess subtle changes in older persons' mental health, as the duration of this period of isolation remains unclear. The biopsychopharmacosocial model provides one method of assessing mental health and planning health and social care needs. This article hopes to guide community health professionals through the specifics of this assessment model in relation to the growing COVID-19 pandemic.

negative: Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein The emergence of SARS-CoV-2 has resulted in >90,000 infections and >3,000 deaths. Coronavirus spike (S) glycoproteins promote entry into cells and are the main target of antibodies. We show that SARS-CoV-2 S uses ACE2 to enter cells and that the receptor-binding domains of SARS-CoV-2 S and SARS-CoV S bind with similar affinities to human ACE2, correlating with the efficient spread of SARS-CoV-2 among humans. We found that the SARS-CoV-2 S glycoprotein harbors a furin cleavage site at the boundary between the S(1)/S(2) subunits, which is processed during biogenesis and sets this virus apart from SARS-CoV and SARS-related CoVs. We determined cryo-EM structures of the SARS-CoV-2 S ectodomain trimer, providing a blueprint for the design of vaccines and inhibitors of viral entry. Finally, we demonstrate that SARS-CoV S murine polyclonal antibodies potently inhibited SARS-CoV-2 S mediated entry into cells, indicating that cross-neutralizing antibodies targeting conserved S epitopes can be elicited upon vaccination.

negative: Coronavirus pandemic and tourism: Dynamic stochastic general equilibrium modeling of infectious disease outbreak • We propose a DSGE model to examine the impact of the coronavirus outbreak on tourism. • The model is generalizable to any epidemic. • The model supports the policy of providing tourism consumption vouchers for residents.

negative: Understanding of guidance for acupuncture and moxibustion interventions on COVID-19 (Second edition) issued by CAAM Abstract At present, the situation of global fight against COVID-19 is serious. WHO (World Health Organization)-China Joint Mission fully confirms the success of “China's model” against COVID-19 in the report. In fact, one particular power in “China's model” is acupuncture and moxibustion of traditional Chinese medicine. To better apply “non-pharmaceutic measures”—the external technique of traditional Chinese medicine, in the article, the main content of Guidance for acupuncture and moxibustion interventions on COVID-19 (Second edition) issued by China Association of Acupuncture–Moxibution is introduced and the discussion is stressed on the selection of moxibustion device and the duration of its exertion.

negative: Ebola Viral Disease in West Africa: A Threat to Global Health, Economy and Political Stability The West African sub-continent is currently experiencing its first, and ironically, the largest and longest Ebola viral diseases (EVD) outbreak ever documented in modern medical history. The current outbreak is significant in several ways, including longevity, magnitude of morbidity and mortality, occurrence outside the traditional niches, rapid spread and potential of becoming a global health tragedy. The authors provided explicit insights into the current and historical background, drivers of the epidemic, societal impacts, status of vaccines and drugs development and proffered recommendations to halt and prevent future occurrences. The authors reviewed mainly five databases and a hand search of key relevant literature. We reviewed 51 articles that were relevant up until the 18(th) of August 2014. The authors supplemented the search with reference list of relevant articles and grey literature as well as relevant Internet websites. Article searches were limited to those published either in English or French. There are strong indications that the EVD may have been triggered by increased human activities and encroachment into the forest ecosystem spurred by increasing population and poverty-driven forest-dependent local economy. Containment efforts are being hampered by weak and fragile health systems, including public health surveillance and weak governance, certain socio-anthropological factors, fast travels (improved transport systems) and globalization. The societal impacts of the EBV outbreak are grave, including economic shutdown, weakening of socio-political systems, psychological distress, and unprecedented consumption of scarce health resources. The research and development (R&D) pipeline for product against EBV seems grossly insufficient. The outbreak of Ebola and the seeming difficulty to contain the epidemic is simply a reflection of the weak health system, poor surveillance and emergency preparedness/response, poverty and disconnect between the government and the people in many West African countries. Although interventions by the United Nations and other international development agencies could ultimately halt the epidemic, local communities must be engaged to build trust and create demand for the public health interventions being implemented in the Ebola-ravaged populations. In the intermediate and long term, post-Ebola rehabilitation should focus on strengthening of health systems, improving awareness about zoonosis and health behaviors, alleviating poverty and mitigating the impact of triggering factors. Finally, national governments and international development partners should mobilize huge resources and investments to spur or facilitate R&D of disease control tools for emerging and pernicious infectious diseases (not limited to EVD).

negative: Analysis of murine coronavirus surface glycoprotein functions by using monoclonal antibodies. The murine coronavirus surface glycoprotein gene was expressed as a fusion protein in bacteria, and the expressed protein was used to generate S protein-specific monoclonal antibodies (MAbs). Three of the MAbs, 11F, 30B, and 10G, were able to neutralize virus infectivity, and two of them, 11F and 10G, were able to block virus-induced, cell-to-cell fusion. The binding sites of the 11F, 30B, and 10G MAbs were determined by Western immunoblotting and epitope mapping. The 11F and 30B MAbs bound to sites located, respectively, between amino acids 33 to 40 and 395 to 406 in the amino-terminal (S1) subunit of the S protein, and the 10G MAb bound to a site located between amino acids 1123 and 1137 in the carboxy-terminal (S2) subunit. These data define more precisely the interactions between the S1 and S2 subunits of the murine coronavirus S protein and provide further insights into its structure and function.

negative: Comment on “Epidemiological and clinical characteristics of heart transplant recipients during the 2019 coronavirus outbreak in Wuhan, China” by Ren et al

negative: Yeast Kex1p is a Golgi-associated membrane protein: deletions in a cytoplasmic targeting domain result in mislocalization to the vacuolar membrane We have investigated the localization of Kex1p, a type I transmembrane carboxypeptidase involved in precursor processing within the yeast secretory pathway. Indirect immunofluorescence demonstrated the presence of Kex1p in a punctate organelle resembling the yeast Golgi apparatus as identified by Kex2p and Sec7p (Franzusoff, A., K. Redding, J. Crosby, R. S. Fuller, and R. Schekman. 1991. J. Cell Biol. 112:27- 37). Glycosylation studies of Kex1p were consistent with a Golgi location, as Kex1p was progressively N-glycosylated in an MNN1- dependent manner. To address the basis of Kex1p targeting to the Golgi apparatus, we examined the cellular location of a series of carboxy- terminal truncations of the protein. The results indicate that a cytoplasmically exposed carboxy-terminal domain is required for retention of this membrane protein within the Golgi apparatus. Deletions of the retention region or overproduction of wild-type Kex1p led to mislocalization of Kex1p to the vacuolar membrane. This unexpected finding is discussed in terms of models involving either the vacuole as a default destination for membrane proteins, or by endocytosis to the vacuole following their default localization to the plasma membrane.

negative: In silico approach to screen compounds active against parasitic nematodes of major socio-economic importance BACKGROUND: Infections due to parasitic nematodes are common causes of morbidity and fatality around the world especially in developing nations. At present however, there are only three major classes of drugs for treating human nematode infections. Additionally the scientific knowledge on the mechanism of action and the reason for the resistance to these drugs is poorly understood. Commercial incentives to design drugs that are endemic to developing countries are limited therefore, virtual screening in academic settings can play a vital role is discovering novel drugs useful against neglected diseases. In this study we propose to build robust machine learning model to classify and screen compounds active against parasitic nematodes. RESULTS: A set of compounds active against parasitic nematodes were collated from various literature sources including PubChem while the inactive set was derived from DrugBank database. The support vector machine (SVM) algorithm was used for model development, and stratified ten-fold cross validation was used to evaluate the performance of each classifier. The best results were obtained using the radial basis function kernel. The SVM method achieved an accuracy of 81.79% on an independent test set. Using the model developed above, we were able to indentify novel compounds with potential anthelmintic activity. CONCLUSION: In this study, we successfully present the SVM approach for predicting compounds active against parasitic nematodes which suggests the effectiveness of computational approaches for antiparasitic drug discovery. Although, the accuracy obtained is lower than the previously reported in a similar study but we believe that our model is more robust because we intentionally employed stringent criteria to select inactive dataset thus making it difficult for the model to classify compounds. The method presents an alternative approach to the existing traditional methods and may be useful for predicting hitherto novel anthelmintic compounds.

negative: Angiotensin-converting enzyme 2/angiotensin-(1–7)/Mas axis prevents lipopolysaccharide–induced apoptosis of pulmonary microvascular endothelial cells by inhibiting JNK/NF–κB pathways ACE2 and Ang–(1–7) have important roles in preventing acute lung injury. However, it is not clear whether upregulation of the ACE2/Ang–(1–7)/Mas axis prevents LPS–induced injury in pulmonary microvascular endothelial cells (PMVECs) by inhibiting the MAPKs/NF–κB pathways. Primary cultured rat PMVECs were transduced with lentiviral–borne Ace2 or shRNA–Ace2, and then treated or not with Mas receptor blocker (A779) before exposure to LPS. LPS stimulation resulted in the higher levels of AngII, Ang–(1–7), cytokine secretion, and apoptosis rates, and the lower ACE2/ACE ratio. Ace2 reversed the ACE2/ACE imbalance and increased Ang–(1–7) levels, thus reducing LPS–induced apoptosis and inflammation, while inhibition of Ace2 reversed all these effects. A779 abolished these protective effects of Ace2. LPS treatment was associated with activation of the ERK, p38, JNK, and NF–κB pathways, which were aggravated by A779. Pretreatment with A779 prevented the Ace2–induced blockade of p38, JNK, and NF–κB phosphorylation. However, only JNK inhibitor markedly reduced apoptosis and cytokine secretion in PMVECs with Ace2 deletion and A779 pretreatment. These results suggest that the ACE2/Ang–(1–7)/Mas axis has a crucial role in preventing LPS–induced apoptosis and inflammation of PMVECs, by inhibiting the JNK/NF–κB pathways.

negative: Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered patient cohort and their implications Background The COVID-19 pandemic caused by SARS-CoV-2 coronavirus threatens global public health. Currently, neutralizing antibodies (NAbs) versus this virus are expected to correlate with recovery and protection of this disease. However, the characteristics of these antibodies have not been well studied in association with the clinical manifestations in patients. Methods Plasma collected from 175 COVID-19 recovered patients with mild symptoms were screened using a safe and sensitive pseudotyped-lentiviral-vector-based neutralization assay. Spike-binding antibody in plasma were determined by ELISA using RBD, S1, and S2 proteins of SARS-CoV-2. The levels and the time course of SARS-CoV-2-specific NAbs and the spike-binding antibodies were monitored at the same time. Findings SARS-CoV-2 NAbs were unable to cross-reactive with SARS-CoV virus. SARS-CoV-2-specific NAbs were detected in patients from day 10-15 after the onset of the disease and remained thereafter. The titers of NAb among these patients correlated with the spike-binding antibodies targeting S1, RBD, and S2 regions. The titers of NAbs were variable in different patients. Elderly and middle-age patients had significantly higher plasma NAb titers (P<0.0001) and spike-binding antibodies (P=0.0003) than young patients. Notably, among these patients, there were ten patients whose NAb titers were under the detectable level of our assay (ID50: < 40); while in contrast, two patients, showed very high titers of NAb, with ID50 :15989 and 21567 respectively. The NAb titers were positive correlated with plasma CRP levels but negative correlated with the lymphocyte counts of patients at the time of admission, indicating an association between humoral response and cellular immune response. Interpretation The variations of SARS-CoV-2 specific NAbs in recovered COVID-19 patients may raise the concern about the role of NAbs on disease progression. The correlation of NAb titers with age, lymphocyte counts, and blood CRP levels suggested that the interplay between virus and host immune response in coronavirus infections should be further explored for the development of effective vaccine against SARS-CoV-2 virus. Furthermore, titration of NAb is helpful prior to the use of convalescent plasma for prevention or treatment. Funding Ministry of Science and Technology of China, National Natural Science Foundation of China, Shanghai Municipal Health Commission, and Chinese Academy of Medical Sciences

negative: The membrane-bound basic carboxypeptidase from hog intestinal mucosa The carboxypeptidase activity occurring in hog intestinal mucosa is apparently due to two distinct enzymes which may be responsible for the release of basic COOH-terminal amino acids from short peptides. The plasma membrane-bound carboxypeptidase activity which occurs at neutral optimum pH levels was found to be enhanced by CoCl(2) and inhibited by guanidinoethylmercaptosuccinic acid, o-phenanthroline, ethylenediamine tetraacetic acid and cadmium acetate; whereas the soluble carboxypeptidase activity which occurs at an optimum pH level of 5.0 was not activated by CoCl(2) and only slightly inhibited by o-phenanthroline, ethylenediamine tetraacetic acid, NiCl(2) and CdCl(2). The latter activity was presumably due to lysosomal cathepsin B, which is known to be present in the soluble fraction of hog intestinal mucosa. Although the membrane-bound enzyme was evenly distributed along the small intestine, it was not anchored in the phospholipidic bilayer via a glycosyl-phosphatidylinositol moiety, as carboxypeptidase M from human placenta is. The enzyme was not solubilized by phosphatidylinositol-specific phospholipase C, but was solubilized to practically the same extent by several detergents. The purified trypsin-solubilized form is a glycoprotein with a molecular mass of 200 kDa, as determined by performing SDS–PAGE and gel filtration, which differs considerably from the molecular mass of human placental carboxypeptidase M (62 kDa). It was found to cleave lysyl bonds more rapidly than arginyl bonds, which is not so in the case of carboxypeptidase M, and immunoblotting analysis provided further evidence that hog intestinal and human placental membrane-bound carboxypeptidases do not bear much resemblance to each other. Since the latter enzyme has been called carboxypeptidase M, it is suggested that the former might be carboxypeptidase D, the recently described new member of the carboxypeptide B-type family.

negative: Enzima conversiva de la angiotensina 2 y su papel emergente en la regulación del sistema renina-angiotensina El sistema renina-angiotensina-aldosterona (SRAA) es un importante regulador de la función cardiovascular y renal. Su bloqueo mediante los inhibidores de la enzima conversiva de la angiotensina (ECA) y/o los antagonistas del receptor de la angiotensina II se acompaña de una reducción de los valores de presión arterial, reducción del riesgo cardiovascular y enlentecimiento de la progresión de la insuficiencia renal. El descubrimiento de la ECA2, una enzima homóloga de la ECA encargada de la degradación de la angiotensina II a angiotensina 1-7, ofrece una nueva línea de estudio en el SRAA. La presente revision expone la importancia de la ECA2 en diferentes órganos: el corazón, el pulmón y el riñón. A su vez, se detalla la importancia de dicha enzima mediante los diversos estudios realizados en modelos genéticamente manipulados con deleción del gen de la ECA2 y mediante la administración de un inhibidor de la ECA2. Los resultados de dichos estudios apuntan a un papel emergente de la ECA2 como una nueva diana terapéutica del SRAA. The renin-angiotensin system (RAS) plays a key role in the regulation of cardiovascular and renal function. Thus, RAS blockade with an angiotensin- converting enzyme (ACE) and/or angiotensin receptor blocker decreases blood pressure, cardiovascular events, and delays the progression of kidney disease. The discovery of ACE2, a homologue of ACE, capable of degrading angiotensin II to angiotensin 1-7, may offer new insights into the RAS. In this review we discuss the possible protective role of ACE2 in different organs, namely heart, lungs and kidneys. The role of this enzyme is inferred from recent studies performed using genetically manipulated mice that lack the ACE2 gene and also mice treated with pharmacological ACE2 inhibitors. These results suggest that ACE2 might be a new therapeutic target within the RAS.

negative: Design of the first highly potent and selective aminopeptidase N (EC 3.4.11.2) inhibitor A series of phosphinic compounds mimicking the transition state of substrates hydrolysed by aminopeptidase N (EC 3.4.11.2) were synthesized. These new compounds have potent inhibitory activities with Ki values in the nanomolar range. These derivatives behave as the most potent APN inhibitors designed to date.

negative: Concerns for activated breathing control (ABC) with breast cancer in the era of COVID-19: Maximizing infection control while minimizing heart dose

negative: Coagulation modifiers targeting SARS-CoV-2 main protease Mpro for COVID-19 treatment: an in silico approach Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection depends on viral polyprotein processing, catalysed by the main proteinase (Mpro). The solution of the SARS-CoV-2 Mpro structure allowed the investigation of potential inhibitors. This work aims to provide first evidences of the applicability of commercially approved drugs to treat coronavirus disease-19 (COVID-19). We screened 4,334 compounds to found potential inhibitors of SARS-CoV-2 replication using an in silico approach. Our results evidenced the potential use of coagulation modifiers in COVID-19 treatment due to the structural similarity of SARS-CoV-2 Mpro and human coagulation factors thrombin and Factor Xa. Further in vitro and in vivo analysis are needed to corroborate these results.

negative: Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A meta-analysis BACKGROUND: Coronavirus disease 2019 (COVID-19) is a novel infectious disease with lack of established laboratory markers available to evaluate illness severity. In this study, we investigate whether platelet count could differentiate between COVID-19 patients with or without severe disease. Additionally, we evaluate if thrombocytopenia is associated with severe COVID-19. METHODS: An electronic search in Medline, Scopus and Web of Science was performed to identify studies reporting data on platelet count in COVID-19 patients. A meta-analysis was performed, with calculation of weighted mean difference (WMD) of platelet number in COVID-19 patients with or without severe disease and odds ratio (OR) of thrombocytopenia for severe form of COVID-19. RESULTS: Nine studies with 1779 COVID-19 patients, 399 (22.4%) with severe disease, were included in the meta-analysis. The pooled analysis revealed that platelet count was significantly lower in patients with more severe COVID-19 (WMD -31×10(9)/L; 95% CI, from -35 to -29×10(9)/L). A subgroup analysis comparing patients by survival, found an even lower platelet count was observed with mortality (WMD, -48×10(9)/L; 95% CI, -57 to -39×10(9)/L. In the four studies (n=1427) which reported data on rate of thrombocytopenia, a low platelet count was associated with over fivefold enhanced risk of severe COVID-19 (OR, 5.1; 95% CI, 1.8-14.6). CONCLUSIONS: Low platelet count is associated with increased risk of severe disease and mortality in patients with COVID-19, and thus should serve as clinical indicator of worsening illness during hospitalization.

negative: COVID-19, A Clinical Syndrome Manifesting as Hypersensitivity Pneumonitis

negative: Coronavirus Epidemic and Extracorporeal Therapies in Intensive Care: si vis pacem para bellum

negative: The SARS-Coronavirus papain-like protease: Structure, function and inhibition by designed antiviral compounds Over ten years have passed since the deadly human coronavirus that causes severe acute respiratory syndrome (SARS-CoV) emerged from the Guangdong Province of China. Despite the fact that the SARS-CoV pandemic infected over 8,500 individuals, claimed over 800 lives and cost billions of dollars in economic loss worldwide, there still are no clinically approved antiviral drugs, vaccines or monoclonal antibody therapies to treat SARS-CoV infections. The recent emergence of the deadly human coronavirus that causes Middle East respiratory syndrome (MERS-CoV) is a sobering reminder that new and deadly coronaviruses can emerge at any time with the potential to become pandemics. Therefore, the continued development of therapeutic and prophylactic countermeasures to potentially deadly coronaviruses is warranted. The coronaviral proteases, papain-like protease (PLpro) and 3C-like protease (3CLpro), are attractive antiviral drug targets because they are essential for coronaviral replication. Although the primary function of PLpro and 3CLpro are to process the viral polyprotein in a coordinated manner, PLpro has the additional function of stripping ubiquitin and ISG15 from host-cell proteins to aid coronaviruses in their evasion of the host innate immune responses. Therefore, targeting PLpro with antiviral drugs may have an advantage in not only inhibiting viral replication but also inhibiting the dysregulation of signaling cascades in infected cells that may lead to cell death in surrounding, uninfected cells. This review provides an up-to-date discussion on the SARS-CoV papain-like protease including a brief overview of the SARS-CoV genome and replication followed by a more in-depth discussion on the structure and catalytic mechanism of SARS-CoV PLpro, the multiple cellular functions of SARS-CoV PLpro, the inhibition of SARS-CoV PLpro by small molecule inhibitors, and the prospect of inhibiting papain-like protease from other coronaviruses. This paper forms part of a series of invited articles in Antiviral Research on “ From SARS to MERS: 10 years of research on highly pathogenic human coronaviruses.”

negative: Cardiovascular Considerations for Patients, Health Care Workers, and Health Systems During the Coronavirus Disease 2019 (COVID-19) Pandemic Abstract The coronavirus disease-2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 that has significant implications for the cardiovascular care of patients. First, those with COVID-19 and preexisting cardiovascular disease (CVD) have an increased risk of severe disease and death. Second, infection has been associated with multiple direct and indirect cardiovascular complications including acute myocardial injury, myocarditis, arrhythmias and venous thromboembolism. Third, therapies under investigation for COVID-19 may have cardiovascular side effects. Fourth, the response to COVID-19 can compromise the rapid triage of non-COVID-19 patients with cardiovascular conditions. Finally, the provision of cardiovascular care may place health care workers in a position of vulnerability as they become host or vectors of virus transmission. We hereby review the peer-reviewed and preprint literature pertaining to cardiovascular considerations related to COVID-19 and highlight gaps in knowledge that require further study pertinent to patients, health care workers, and health systems.

negative: Medical imaging informatics research and development trends—an editorial

negative: In silico identification of clinically approved medicines against the main protease of SARS-CoV-2, causative agent of covid-19 The COVID-19 pandemic triggered by SARS-CoV-2 is a worldwide health disaster. Main protease is an attractive drug target among coronaviruses, due to its vital role in processing the polyproteins that are translated from the viral RNA. There is presently no exact drug or treatment for this diseases caused by SARS-CoV-2. In the present study, we report the potential inhibitory activity of some FDA approved drugs against SARS-CoV-2 main protease by molecular docking study to investigate their binding affinity in protease active site. Docking studies revealed that drug Oseltamivir (anti-H1N1 drug), Rifampin (anti-TB drug), Maraviroc, Etravirine, Indinavir, Rilpivirine (anti-HIV drugs) and Atovaquone, Quinidine, Halofantrine, Amodiaquine, Tetracylcine, Azithromycin, hydroxycholoroquine (anti-malarial drugs) among others binds in the active site of the protease with similar or higher affinity. However, the in-silico abilities of the drug molecules tested in this study, further needs to be validated by carrying out in vitro and in vivo studies. Moreover, this study spreads the potential use of current drugs to be considered and used to comprise the fast expanding SARS-CoV-2 infection.

negative: Chapter 20 Ethics, Legality, and Education in the Practice of Cardiology Advances in diagnostics, drugs, and devices have revolutionized cardiology practice, and improved quality of life of the patients. However, awareness, achievements, and advances in cardiac health care have enhanced the demands and expectations of the community, which lacks awareness about the social, economic, administrative, professional, and technical constraints or limitations of implementation. Being unfamiliar with medical ethics and legal aspects of care, and suboptimal virtues among physicians, have led to patients and the public utilizing legal remedies. In addition, sophistication of medical practice, increasing costs of health care, involvement of insurance systems, increased awareness and high expectations from the community and patients, and increased participation of the media have altered the attitude toward claiming compensation and acquisition of health care delivery among the public. In view of the changing trends of consumers and emerging areas in health care, providers must get accustomed to patient empowerment and come up to their expectations. Interactive programs on these aspects in medical education will help students understand not only the intricacies of medical ethics and the laws and shortcomings of health professionals and/or health systems, but also strengthen their knowledge of ethics and laws to improve their practice. Principles of ethics and legal issues have to be discussed at every stage of medical education. To improve the quality of the physician–patient encounter, we need to develop formal and informal curricula about effective communication skills. This chapter also highlights preventive measures and educational aspects of cardiology practice.

negative: Inhibitor Recognition Specificity of MERS-CoV Papain-like Protease May Differ from That of SARS-CoV [Image: see text] The Middle East Respiratory Syndrome coronavirus (MERS-CoV) papain-like protease (PLpro) blocking loop 2 (BL2) structure differs significantly from that of SARS-CoV PLpro, where it has been proven to play a crucial role in SARS-CoV PLpro inhibitor binding. Four SARS-CoV PLpro lead inhibitors were tested against MERS-CoV PLpro, none of which were effective against MERS-CoV PLpro. Structure and sequence alignments revealed that two residues, Y269 and Q270, responsible for inhibitor binding to SARS-CoV PLpro, were replaced by T274 and A275 in MERS-CoV PLpro, making critical binding interactions difficult to form for similar types of inhibitors. High-throughput screening (HTS) of 25 000 compounds against both PLpro enzymes identified a small fragment-like noncovalent dual inhibitor. Mode of inhibition studies by enzyme kinetics and competition surface plasmon resonance (SPR) analyses suggested that this compound acts as a competitive inhibitor with an IC(50) of 6 μM against MERS-CoV PLpro, indicating that it binds to the active site, whereas it acts as an allosteric inhibitor against SARS-CoV PLpro with an IC(50) of 11 μM. These results raised the possibility that inhibitor recognition specificity of MERS-CoV PLpro may differ from that of SARS-CoV PLpro. In addition, inhibitory activity of this compound was selective for SARS-CoV and MERS-CoV PLpro enzymes over two human homologues, the ubiquitin C-terminal hydrolases 1 and 3 (hUCH-L1 and hUCH-L3).

negative: HATRIC: a study of Pelargonium sidoides root extract EPs®7630 (Kaloba®) for the treatment of acute cough due to lower respiratory tract infection in adults—study protocol for a double blind, placebo-controlled randomised feasibility trial BACKGROUND: Acute lower respiratory tract infection is a common acute infection managed in primary care. The current dominant management strategy in the UK is antibiotics, despite widespread publicity regarding antimicrobial resistance and evidence that the small benefits of antibiotics do not outweigh the harms. There is a need to address the rising problem of antibiotic resistance by providing credible alternative strategies, which reduce symptom burden. There is sufficient evidence to recommend the use of Pelargonium sidoides root extract in order to warrant undertaking an independent clinical trial. We propose a feasibility study to demonstrate our ability to recruit and retain patients and conduct a placebo-controlled trial of Pelargonium sidoides extract EPs®7630 in lower respiratory tract infection where pneumonia is not suspected. Both the tablet and liquid formulations will be included. METHODS: The HATRIC trial is a double-blind randomised placebo-controlled feasibility study aiming to determine the potential to conduct a fully powered trial of Pelargonium sidoides root extract as an alternative to the inappropriate use of antibiotics for acute bronchitis in UK primary care. Primary care sites will be equally randomised to one of two formulation groups (tablet or liquid preparation). Additionally, within each site, patients will be evenly randomised to active or placebo treatment. Antibiotic consumption will be monitored during the trial, but the use of a delayed prescription strategy is encouraged. The target sample size for this study is 160 patients overall or 40 per arm, recruited from approximately 20 primary care sites. The analysis will be descriptive focusing on estimation with no formal comparison of groups taking place. DISCUSSION: If this trial demonstrates the feasibility of recruitment and delivery, we will seek funding for a fully powered placebo-controlled trial of Pelargonium sidoides root extract for the treatment of lower respiratory tract infections in primary care. TRIAL REGISTRATION: HATRIC was registered on the ISRCTN registry (ISRCTN17672884) on 16 August 2018.

negative: Episodic evolution mediates interspecies transfer of a murine coronavirus. Molecular mechanisms permitting the establishment and dissemination of a virus within a newly adopted host species are poorly understood. Mouse hepatitis virus (MHV) strains (MHV-A59, MHV-JHM, and MHV-A59/MHV-JHM) were passaged in mixed cultures containing progressively increasing concentrations of nonpermissive Syrian baby hamster kidney (BHK) cells and decreasing concentrations of permissive murine DBT cells. From MHV-A59/MHV-JHM mixed infection, variant viruses (MHV-H1 and MHV-H2) which replicated efficiently in BHK cells were isolated. Under identical treatment conditions, the parental MHV-A59 or MHV-JHM strains failed to produce infectious virus or transcribe detectable levels of viral RNA or protein. The MHV-H isolates were polytrophic, replicating efficiently in normally nonpermissive Syrian hamster smooth muscle (DDT-1), Chinese hamster ovary (CHO), human adenocarcinoma (HRT), primate kidney (Vero), and murine 17Cl-1 cell lines. Little if any virus replication was detected in feline kidney (CRFK) and porcine testicular (ST) cell lines. The variant virus, MHV-H2, transcribed seven mRNAs equivalent in relative abundance and size to those synthesized by the parental virus strains. MHV-H2 was an RNA recombinant virus containing a crossover site in the S glycoprotein gene. At the molecular level, episodic evolution and positive Darwinian natural selection were apparent within the MHV-H2 S and HE glycoprotein genes. These findings differ from the hypothesis that neutral changes are the predominant feature of molecular evolution and argue that changing ecologies actuate episodic evolution in the MHV spike glycoprotein genes that govern interspecies transfer and spread into alternative hosts.

negative: Controversias sobre el tratamiento con IECA/ARA-II y Covid-19

negative: Cerebrovascular Accident in a Pediatric Patient Presenting With Influenza Abstract Background Acute ischemic stroke (AIS) in pediatric populations accounts for more than half of pediatric strokes and is associated with significant morbidity and mortality. Pediatric AIS can present with nonspecific symptoms or symptoms that mimic alternate pathology. Case Report A 4-month-old female presented to the emergency department for fever, decreased oral intake, and “limp” appearance after antibiotic administration. She was febrile, tachypneic, and hypoxic. Her skin was mottled with 3-s capillary refill, her anterior fontanelle was tense, and she had mute Babinski reflex bilaterally but was moving all extremities. The patient was hyponatremic, thrombocytopenic, and tested positive for influenza A. A computed tomography scan of the brain revealed an acute infarction involving the right frontal, parietal, temporal, and occipital lobes in addition to hyperdensities concerning for thrombosed cortical veins. The patient was transferred for specialty evaluation and was discharged 2 weeks later on levetiracetam. Why Should an Emergency Physician be Aware of This? Pediatric AIS can present with nonspecific symptoms that mimic alternate pathology. A high level of suspicion is needed so as not to miss the diagnosis of pediatric AIS in the emergency department. A thorough neurologic assessment is warranted, and subtle abnormalities should be investigated further.

negative: Cardiovascular disease and COVID-19 Abstract Background and aims Many patients with coronavirus disease 2019 (COVID-19) have underlying cardiovascular (CV) disease or develop acute cardiac injury during the course of the illness. Adequate understanding of the interplay between COVID-19 and CV disease is required for optimum management of these patients. Methods A literature search was done using PubMed and Google search engines to prepare a narrative review on this topic. Results Respiratory illness is the dominant clinical manifestation of COVID-19; CV involvement occurs much less commonly. Acute cardiac injury, defined as significant elevation of cardiac troponins, is the most commonly reported cardiac abnormality in COVID-19. It occurs in approximately 8–12% of all patients. Direct myocardial injury due to viral involvement of cardiomyocytes and the effect of systemic inflammation appear to be the most common mechanisms responsible for cardiac injury. The information about other CV manifestations in COVID-19 is very limited at present. Nonetheless, it has been consistently shown that the presence of pre-existing CV disease and/or development of acute cardiac injury are associated with significantly worse outcome in these patients. Conclusions Most of the current reports on COVID-19 have only briefly described CV manifestations in these patients. Given the enormous burden posed by this illness and the significant adverse prognostic impact of cardiac involvement, further research is required to understand the incidence, mechanisms, clinical presentation and outcomes of various CV manifestations in COVID-19 patients.

negative: Impact of Congestive Heart Failure and Role of Cardiac Biomarkers in COVID-19 patients: A Systematic Review and Meta-Analysis Background: Coronavirus disease 2019 (COVID-19) has been reported to cause worse outcomes in patients with underlying cardiovascular disease, especially in patients with acute cardiac injury, which is determined by elevated levels of high-sensitivity troponin. There is a paucity of data on the impact of congestive heart failure (CHF) on outcomes in COVID-19 patients. Methods: We conducted a literature search of PubMed/Medline, EMBASE, and Google Scholar databases from 11/1/2019 till 06/07/2020, and identified all relevant studies reporting cardiovascular comorbidities, cardiac biomarkers, disease severity, and survival. Pooled data from the selected studies were used for metanalysis to identify the impact of risk factors and cardiac biomarker elevation on disease severity and/or mortality. Results: We collected pooled data on 5,967 COVID-19 patients from 20 individual studies. We found that both non-survivors and those with severe disease had an increased risk of acute cardiac injury and cardiac arrhythmias, our pooled relative risk (RR) was - 8.52 (95% CI 3.63-19.98) (p<0.001); and 3.61 (95% CI 2.03-6.43) (p=0.001), respectively. Mean difference in the levels of Troponin-I, CK-MB, and NT-proBNP was higher in deceased and severely infected patients. The RR of in-hospital mortality was 2.35 (95% CI 1.18-4.70) (p=0.022) and 1.52 (95% CI 1.12-2.05) (p=0.008) among patients who had pre-existing CHF and hypertension, respectively. Conclusion: Cardiac involvement in COVID-19 infection appears to significantly adversely impact patient prognosis and survival. Pre-existence of CHF and high cardiac biomarkers like NT-pro BNP and CK-MB levels in COVID-19 patients correlates with worse outcomes. Keywords: Acute cardiac injury; cardiac arrhythmia; mortality risk; cardiac biomarkers, COVID-19.

negative: Cough Pharmacists play an important role in the assessment and management of patients with cough. By obtaining a focused clinical history from the patient, they can identify patients who need to be referred to their physician or to the emergency room, as well as which patients can be managed at home. Red flags that prompt referral include severe systemic illness, respiratory distress, hemoptysis, and altered level of consciousness. Patients with underlying chronic illnesses such as chronic obstructive pulmonary disease, asthma, and heart failure who present with cough should be assessed for possible exacerbation of their illness and should be referred if this is suspected. Determining the duration of cough is an important step, as this helps identify possible etiologies. Cough <3-week duration is categorized as acute, 3- to 8-week duration is subacute, and > 8-week duration is a chronic cough. Patients with cough lasting >3 weeks should generally be referred for further evaluation and management. Acute cough is often infectious but can also be due to exacerbation of underlying illness or could be medication-related. Upper airway cough syndrome (UACS) is one of the most common causes of subacute and chronic cough. Several different etiologies lead to UACS, which is thought to be caused by postnasal drip ± sensitization of cough receptors in the respiratory tract. First-generation antihistamines or decongestants are therapeutic options when UACS is suspected. It is important to note that antitussive medications such as dextromethorphan can actually prolong illness in patients with a productive cough and are thus not recommended. Monitoring parameters and frequency of follow-up depend on underlying cause, severity of illnesses, past medical history, as well as medication changes.

negative: Epigenetic dysregulation of ACE2 and interferon-regulated genes might suggest increased COVID-19 susceptibility and severity in lupus patients Abstract Infection caused by SARS-CoV-2 can result in severe respiratory complications and death. Patients with a compromised immune system are expected to be more susceptible to a severe disease course. In this report we suggest that patients with systemic lupus erythematous might be especially prone to severe COVID-19 independent of their immunosuppressed state from lupus treatment. Specifically, we provide evidence in lupus to suggest hypomethylation and overexpression of ACE2, which is located on the X chromosome and encodes a functional receptor for the SARS-CoV-2 spike glycoprotein. Oxidative stress induced by viral infections exacerbates the DNA methylation defect in lupus, possibly resulting in further ACE2 hypomethylation and enhanced viremia. In addition, demethylation of interferon-regulated genes, NFκB, and key cytokine genes in lupus patients might exacerbate the immune response to SARS-CoV-2 and increase the likelihood of cytokine storm. These arguments suggest that inherent epigenetic dysregulation in lupus might facilitate viral entry, viremia, and an excessive immune response to SARS-CoV-2. Further, maintaining disease remission in lupus patients is critical to prevent a vicious cycle of demethylation and increased oxidative stress, which will exacerbate susceptibility to SARS-CoV-2 infection during the current pandemic. Epigenetic control of the ACE2 gene might be a target for prevention and therapy in COVID-19.

negative: The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak Abstract Coronavirus disease (COVID-19) is caused by SARS-COV2 and represents the causative agent of a potentially fatal disease that is of great global public health concern. Based on the large number of infected people that were exposed to the wet animal market in Wuhan City, China, it is suggested that this is likely the zoonotic origin of COVID-19. Person-to-person transmission of COVID-19 infection led to the isolation of patients that were subsequently administered a variety of treatments. Extensive measures to reduce person-to-person transmission of COVID-19 have been implemented to control the current outbreak. Special attention and efforts to protect or reduce transmission should be applied in susceptible populations including children, health care providers, and elderly people. In this review, we highlights the symptoms, epidemiology, transmission, pathogenesis, phylogenetic analysis and future directions to control the spread of this fatal disease.

negative: The 1-Year Impact of Severe Acute Respiratory Syndrome on Pulmonary Function, Exercise Capacity, and Quality of Life in a Cohort of Survivors Objective To examine pulmonary function, exercise capacity, and health-related quality of life (HRQoL) among severe acute respiratory syndrome (SARS) survivors. Methods We evaluated survivors with confirmed SARS at the Prince of Wales Hospital, Hong Kong, at 3, 6, and 12 months after symptom onset. Our assessment included: lung volume (total lung capacity [TLC], vital capacity, residual volume, functional residual capacity), spirometry (FVC, FEV1), diffusing capacity of the lung for carbon monoxide (Dlco), inspiratory and expiratory respiratory muscle strength, 6-min walk distance (6MWD), chest radiographs (CXRs), and HRQoL by Medical Outcomes Study 36-Item Short-Form General Health Survey questionnaire. Results Ninety-seven patients completed the serial assessments. There were 39 male and 58 female patients, and 63 patients (70%) were health-care workers (mean age, 36.9 years [SD, 9.5 years]; body mass index, 23.7 kg/m2 [SD, 4.0 kg/m2]). At 1 year, 27 patients (27.8%) had abnormal CXR findings. Four patients (4.1%), 5 patients (5.2%), and 23 patients (23.7%) had FVC, TLC, and Dlco values < 80% of predicted values, respectively. The 6MWD at 12 months was 511.0 m (SD, 89.8 m), which was higher than at 3 months (mean difference, 47.0 m; 95% confidence interval [CI], 31.8 to 62.1 m; p < 0.01) but not different from 6 months (mean difference, 9.7 m; 95% CI, − 4.4 to 23.8 m; p = 0.18). The 6MWD was lower than that for normal control subjects of the same age groups, and there was impairment of HRQoL at 12 months. Patients who required ICU admission (n = 31) showed higher CXR scores (1.6 [SD, 3.1]; vs 0.4 [SD, 1.1]; p = 0.04) and lower percentage of predicted FVC, TLC, and Dlco than those who did not, but there were no differences in 6MWD and health status. Conclusion Significant impairment in Dlco was noted in 23.7% of survivors 1 year after illness onset. Exercise capacity and health status of SARS survivors were remarkably lower than those of a normal population.

negative: COVID-19 Coronavirus spike protein analysis for synthetic vaccines, a peptidomimetic antagonist, and therapeutic drugs, and analysis of a proposed achilles’ heel conserved region to minimize probability of escape mutations and drug resistance Abstract This paper continues a recent study of the spike protein sequence of the COVID-19 virus (SARS-CoV-2). It is also in part an introductory review to relevant computational techniques for tackling viral threats, using COVID-19 as an example. Q-UEL tools for facilitating access to knowledge and bioinformatics tools were again used for efficiency, but the focus in this paper is even more on the virus. Subsequence KRSFIEDLLFNKV of the S2′ spike glycoprotein proteolytic cleavage site continues to appear important. Here it is shown to be recognizable in the common cold coronaviruses, avian coronaviruses and possibly as traces in the nidoviruses of reptiles and fish. Its function or functions thus seem important to the coronaviruses. It might represent SARS-CoV-2 Achilles’ Heel, less likely to acquire resistance by mutation, as has happened in some early SARS vaccine studies discussed in the previous paper. Preliminary conformational analysis of the receptor (ACE2) binding site of the spike protein is carried suggesting that while it is somewhat conserved, it appears to be more variable than KRSFIEDLLFNKV. However compounds like emodin that inhibit SARS entry, apparently by binding ACE2, might also have functions at several different human protein binding studies. The enzyme 11β-hydroxysteroid dehydrogenase type 1 is again argued to be a convenient model pharmacophore perhaps representing an ensemble of targets, and it is noted that it occurs both in lung and alimentary tract. Perhaps it benefits the virus to block an inflammatory response by inhibiting the dehydrogenase, but a fairly complex web involves several possible targets.

negative: Molecular biology of severe acute respiratory syndrome coronavirus The worldwide epidemic of severe acute respiratory syndrome (SARS) in 2003 was caused by a novel coronavirus called SARS-CoV. Coronaviruses and their closest relatives possess extremely large plus-strand RNA genomes and employ unique mechanisms and enzymes in RNA synthesis that separate them from all other RNA viruses. The SARS epidemic prompted a variety of studies on multiple aspects of the coronavirus replication cycle, yielding both rapid identification of the entry mechanisms of SARS-CoV into host cells and valuable structural and functional information on SARS-CoV proteins. These recent advances in coronavirus research have important implications for the development of anti-SARS drugs and vaccines.

negative: Rapid surveillance of COVID-19 in the United States using a prospective space-time scan statistic: Detecting and evaluating emerging clusters Abstract Coronavirus disease 2019 (COVID-19) was first identified in Wuhan, China in December 2019, and is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 is a pandemic with an estimated death rate between 1% and 5%; and an estimated R 0 between 2.2 and 6.7 according to various sources. As of March 28th, 2020, there were over 649,000 confirmed cases and 30,249 total deaths, globally. In the United States, there were over 115,500 cases and 1891 deaths and this number is likely to increase rapidly. It is critical to detect clusters of COVID-19 to better allocate resources and improve decision-making as the outbreaks continue to grow. Using daily case data at the county level provided by Johns Hopkins University, we conducted a prospective spatial-temporal analysis with SaTScan. We detect statistically significant space-time clusters of COVID-19 at the county level in the U.S. between January 22nd-March 9th, 2020, and January 22nd-March 27th, 2020. The space-time prospective scan statistic detected “active” and emerging clusters that are present at the end of our study periods – notably, 18 more clusters were detected when adding the updated case data. These timely results can inform public health officials and decision makers about where to improve the allocation of resources, testing sites; also, where to implement stricter quarantines and travel bans. As more data becomes available, the statistic can be rerun to support timely surveillance of COVID-19, demonstrated here. Our research is the first geographic study that utilizes space-time statistics to monitor COVID-19 in the U.S.

negative: Conformational Fingerprinting Using Monoclonal Antibodies (on the Example of Angiotensin I-Converting Enzyme-ACE) During the past 30 years my laboratory has generated 40+ monoclonal antibodies (mAbs) directed to structural and conformational epitopes on human ACE as well as ACE from rats, mice and other species. These mAbs were successfully used for detection and quantification of ACE by ELISA, Western blotting, flow cytometry and immunohistochemistry. In all these applications mainly single mAbs were used. We hypothesized that we can obtain a completely new kind of information about ACE structure and function if we use the whole set of mAbs directed to different epitopes on the ACE molecule. When we finished epitope mapping of all mAbs to ACE (and especially, those recognizing conformational epitopes), we realized that we had obtained a new tool to study ACE. First, we demonstrated that binding of some mAbs is very sensitive to local conformational changes on the ACE surface—due to local denaturation, inactivation, ACE inhibitor or mAbs binding or due to diseases. Second, we were able to detect, localize and characterize several human ACE mutations. And, finally, we established a new concept—conformational fingerprinting of ACE using mAbs that in turn allowed us to obtain evidence for tissue specificity of ACE, which has promising scientific and diagnostic perspectives. The initial goal for the generation of mAbs to ACE 30 years ago was obtaining mAbs to organ-specific endothelial cells, which could be used for organ-specific drug delivery. Our systematic work on characterization of mAbs to numerous epitopes on ACE during these years has lead not only to the generation of the most effective mAbs for specific drug/gene delivery into the lung capillaries, but also to the establishment of the concept of conformational fingerprinting of ACE, which in turn gives a theoretical base for the generation of mAbs, specific for ACE from different organs. We believe that this concept could be applicable for any glycoprotein against which there is a set of mAbs to different epitopes.

negative: Angiotensin-converting enzyme 2: implications for blood pressure and kidney disease. PURPOSE OF REVIEW Angiotensin-converting enzyme 2 (ACE 2), the main product of which is Ang 1-7, which binds to its receptor, Mas, is an important member of the renin-angiotensin system. RECENT FINDINGS A substantial body of research indicates that ACE2 is cardioprotective and renoprotective. ACE2 participates in a pathway that is counterregulatory to the effects of angiotensin II (Ang II). The mechanisms by which the protective effects of ACE2 occur are just beginning to be elucidated. SUMMARY As ACE2 appears to exert protective effects within the kidney and vasculature, recent data indicate that how it is expressed, what regulates it, and how it interacts with other biological systems may ultimately have clinical implications.

negative: What Have We Learned About Middle East Respiratory Syndrome Coronavirus Emergence in Humans? A Systematic Literature Review Background: Middle East respiratory syndrome coronavirus (MERS-CoV) was first identified in humans in 2012. A systematic literature review was conducted to synthesize current knowledge and identify critical knowledge gaps. Materials and Methods: We conducted a systematic review on MERS-CoV using PRISMA guidelines. We identified 407 relevant, peer-reviewed publications and selected 208 of these based on their contributions to four key areas: virology; clinical characteristics, outcomes, therapeutic and preventive options; epidemiology and transmission; and animal interface and the search for natural hosts of MERS-CoV. Results: Dipeptidyl peptidase 4 (DPP4/CD26) was identified as the human receptor for MERS-CoV, and a variety of molecular and serological assays developed. Dromedary camels remain the only documented zoonotic source of human infection, but MERS-like CoVs have been detected in bat species globally, as well as in dromedary camels throughout the Middle East and Africa. However, despite evidence of camel-to-human MERS-CoV transmission and cases apparently related to camel contact, the source of many primary cases remains unknown. There have been sustained health care-associated human outbreaks in Saudi Arabia and South Korea, the latter originating from one traveler returning from the Middle East. Transmission mechanisms are poorly understood; for health care, this may include environmental contamination. Various potential therapeutics have been identified, but not yet evaluated in human clinical trials. At least one candidate vaccine has progressed to Phase I trials. Conclusions: There has been substantial MERS-CoV research since 2012, but significant knowledge gaps persist, especially in epidemiology and natural history of the infection. There have been few rigorous studies of baseline prevalence, transmission, and spectrum of disease. Terms such as “camel exposure” and the epidemiological relationships of cases should be clearly defined and standardized. We strongly recommend a shared and accessible registry or database. Coronaviruses will likely continue to emerge, arguing for a unified “One Health” approach.

negative: Human monoclonal IgG selection of Plasmodium falciparum for the expression of placental malaria-specific variant surface antigens Pregnancy-associatedPlasmodium falciparum malaria (PAM) is a major cause of morbidity and mortality in African women and their offspring. PAM is characterized by accumulation of infected erythrocytes (IEs) that adhere to chondroitin sulphate A (CSA) in the placental intervillous space. We show here that human monoclonal IgG antibodies with specificity for variant surface antigens (VSA) specifically expressed by CSA-adhering IEs (VSA(PAM)) can be used in vitro to select parasites from nonpregnant donors to express VSA(PAM) and that this selection for VSA(PAM) expression results in preferential transcription of var2csa. The results corroborate current efforts to develop PAM-specific vaccines based on VAR2CSA.

negative: Potential inhibitors for 2019-nCoV coronavirus M protease from clinically approved medicines Starting from December 2019, a novel coronavirus, named 2019-nCoV, was found to cause Severe Acute Respiratory (SARI) symptoms and rapid pandemic in China. With the hope to identify candidate drugs for 2019-nCoV, we adopted a computational approach to screen for available commercial medicines which may function as inhibitors for the Mpro of 2019-nCoV. Up to 10 commercial medicines that may form hydrogen bounds to key residues within the binding pocket of 2019-nCoV Mpro were identified, which may have higher mutation tolerance than lopinavir/ritonavir and may also function as inhibitors for other coronaviruses with similar Mpro binding sites and pocket structures.

negative: Teicoplanin: an alternative drug for the treatment of coronavirus COVID-19? In December 2019, a new coronavirus, named SARS-CoV-2, has emerged from China causing pneumonia outbreaks first in the Wuhan region and have now spread worldwide because of its probable high transmission efficiency. Due to the lack of efficient and specific treatments and the need to contain the epidemic, drug repurposing appears to be the best tool to find therapeutic solution. Chloroquine, remdesivir, lopinavir, ribavirin or ritonavir have shown efficacy to inhibit coronavirus in vitro. Teicoplanin, an antibiotic used to treat staphylococci infection, previously showed efficacy to inhibit the first stage of MERS-coronarivus viral cycle in human cells. This activity is conserved on the SARS-Cov-2, thus placing teicoplanin as a potential treatment for patients with this virus.

negative: Inhibidores de la enzima convertidora de angiotensina y antagonistas del receptor de angiotensina II: ¿Aumentan el riesgo de padecer COVID-19? Abstract A new coronavirus, called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was discovered in December 2019 in Wuhan, China; the virus escalated rapidly and on March 11, 2020, the World Health Organization declared it a pandemic.Emerging data suggests that older patients with COVID-19 associated with other comorbid conditions such as diabetes, hypertension, heart and lung diseases are particularly more susceptible, compared to general populations, and have higher mortality. It is not yet clear whether this increased association of high blood pressure with COVID-19 and the increased risk of mortality are directly related to high blood pressure or other associated comorbidities, or to antihypertensive treatment.Although the underlying pathogenic mechanism linking hypertension and severity of COVID-19 infection remains to be elucidated, it has been hypothesized that excessive activation of the renin-angiotensin system (RAS) could contribute to the progression of COVID-19 related lung injury.Concern about whether angiotensin II receptor blockers (ARBs) and angiotensin converting enzyme (ACE) inhibitors may have deleterious effects on morbidity and mortality in patients with COVID-19 is based on speculation that these drugs would increase the regulation of angiotensin II converting enzyme (ACE2), a receptor for SARS-CoV-2, which would increase viral load and lung damage.Recent studies are consistent with the recommendations of scientific societies that propose avoiding the suspension or change of antihypertensive medication, as there is no evidence that shows that these can be taken as risk factors for severity or mortality from COVID-19.

negative: Chapter 7 Coronaviridae: 100,000 Years of Emergence and Reemergence Abstract The coronavirus family (Coronaviridae) is a positive-sense single-stranded RNA, with a size of 27kb. These viruses have a potential species specificity and interspecies transmission. The interspecies transmission of viruses from one host species to another is a major factor responsible for the majority of emerging and reemerging infections. The Coronaviridae is one of the most popular emerging viral families that threaten to the public health.

negative: The role of chemokines and chemokine receptors in multiple sclerosis Abstract Multiple sclerosis (MS) is a chronic inflammatory disease that is characterized by leukocyte infiltration and subsequent axonal damage, demyelinating inflammation, and formation of sclerosing plaques in brain tissue. The results of various studies in patients indicate that autoimmunity and inflammation make an important impact on the pathogenesis of MS. Chemokines are key mediators of inflammation development and cell migration, mediating various immune cell responses, including chemotaxis and immune activation, and are important in immunity and inflammation, therefore we focus on chemokines and their receptors in multiple sclerosis. In this article, we summarize the study of the role of prominent chemokines and their receptors in MS patients and MS animal modelsand discuss their potential significance in inflammatory injury and repair of MS. We have also summarized the progress in the treatment of multiple sclerosis antagonists in recent years with chemokine receptors as targets.

negative: Synergistic activation of p53 by actinomycin D and nutlin-3a is associated with the upregulation of crucial regulators and effectors of innate immunity Abstract Actinomycin D and nutlin-3a (A + N) activate p53, partly through induction of phosphorylation on Ser392. The death of A549 cells induced by A + N morphologically resembles inflammation-inducing pyroptosis - cell destruction triggered by activated caspase-1. The treatment with A + N (or camptothecin) strongly upregulated caspase-1 and its two activators: IFI16 and NLRP1, however, caspase-1 activation was not detected. A549 cells may have been primed for pyroptosis, with the absence of a crucial trigger. The investigation of additional innate immunity elements revealed that A + N (or camptothecin) stimulated the expression of NLRX1, STING (stimulator of interferon genes) and two antiviral proteins, IFIT1 and IFIT3. IFI16 and caspase-1 are coded by p53-regulated genes which led us to investigate regulation of NLRP1, NLRX1, STING, IFIT1 and IFIT3 in p53-dependent mode. The upregulation of NLRP1, NLRX1 and STING was attenuated in p53 knockdown cells. The upsurge of the examined genes, and activation of p53, was inhibited by C16, an inhibitor of PKR kinase. PKR was tested due to its ability to phosphorylate p53 on Ser392. Surprisingly, C16 was active even in PKR knockdown cells. The ability of C16 to prevent activation of p53 and expression of innate immunity genes may be the source of its strong anti-inflammatory action. Moreover, cells exposed to A + N can influence neighboring cells in paracrine fashion, for instance, they shed ectodomain of COL17A1 protein and induce, in p53-dependent mode, the expression of gene for interleukin-7. Further, the activation of p53 also spurred the expression of SOCS1, an inhibitor of interferon triggered STAT1-dependent signaling. We conclude that, stimulation of p53 primes cells for the production of interferons (through upregulation of STING), and may activate negative-feedback within this signaling system by enhancing the production of SOCS1.

negative: Lower airway sampling greatly increases detection of respiratory viruses in critically ill patients: the COURSE study

negative: OP4-5 Genetic variants of human parvovirus B19 in South Africa: co-circulation of three genotypes and identification of a novel subtype of genotype 1.

negative: Positive rate of RT-PCR detection of SARS-CoV-2 infection in 4880 cases from one hospital in Wuhan, China, from Jan to Feb 2020 Abstract Background There’s an outbreak of a novel coronavirus (SARS-CoV-2) infection since December 2019, first in China, and currently with more than 80 thousand confirmed infection globally in 29 countries till March 2, 2020. Identification, isolation and caring for patients early are essential to limit human-to-human transmission including reducing secondary infections among close contacts and health care workers, preventing transmission amplification events. The RT-PCR detection of viral nucleic acid test (NAT) was one of the most quickly established laboratory diagnosis method in a novel viral pandemic, just as in this COVID-19 outbreak. Methods 4880 cases that had respiratory infection symptoms or close contact with COVID-19 patients in hospital in Wuhan, China, were tested for SARS-CoV-2 infection by use of quantitative RT-PCR (qRT-PCR) on samples from the respiratory tract. Positive rates were calculated in groups divided by genders or ages. Results The positive rate was about 38% for the total 4880 specimens. Male and older population had a significant higher positive rates. However, 57% was positive among the specimens from the Fever Clinics. Binary logistic regression analysis showed that age, not gender, was the risk factor for SARS-CoV-2 infection in fever clinics. Conclusions Therefore, we concluded that viral NAT played an important role in identifying SARS-CoV-2 infection.

negative: Chapter 38 Angiotensin-Converting Enzyme 2/Angiotensin-(1-7)/Mas Receptor Axis Emerging Pharmacological Target for Pulmonary Diseases Abstract Experimental and clinical evidence supports an active role of the renin–angiotensin system (RAS) in the pathogenesis and progression of lung diseases. Angiotensin II (Ang II), a key vasoactive peptide of the RAS, has been implicated in pulmonary disorders such as pulmonary arterial hypertension, lung fibrosis, chronic obstructive pulmonary disease, and acute respiratory distress syndrome. Over the past few years, the classical concept of the RAS has undergone substantial changes to include several new active components. Among them, the identification of angiotensin-converting enzyme 2 (ACE2), its metabolic product angiotensin-(1-7) (Ang-(1-7)), and the Mas receptor has been of biological significance since these components form a counterregulatory axis (ACE2/Ang-(1-7)/Mas) that opposes the detrimental actions of Ang II. In this chapter, we will discuss the role of the ACE2/Ang-(1-7)/Mas axis in lung diseases and describe novel therapeutic approaches to activate this axis for the treatment of pulmonary disorders.

negative: Associations between immune-suppressive and stimulating drugs and novel COVID-19—a systematic review of current evidence BACKGROUND: Cancer and transplant patients with COVID-19 have a higher risk of developing severe and even fatal respiratory diseases, especially as they may be treated with immune-suppressive or immune-stimulating drugs. This review focuses on the effects of these drugs on host immunity against COVID-19. METHODS: Using Ovid MEDLINE, we reviewed current evidence for immune-suppressing or -stimulating drugs: cytotoxic chemotherapy, low-dose steroids, tumour necrosis factorα (TNFα) blockers, interlukin-6 (IL-6) blockade, Janus kinase (JAK) inhibitors, IL-1 blockade, mycophenolate, tacrolimus, anti-CD20 and CTLA4-Ig. RESULTS: 89 studies were included. Cytotoxic chemotherapy has been shown to be a specific inhibitor for severe acute respiratory syndrome coronavirus in in vitro studies, but no specific studies exist as of yet for COVID-19. No conclusive evidence for or against the use of non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of COVID-19 patients is available, nor is there evidence indicating that TNFα blockade is harmful to patients in the context of COVID-19. COVID-19 has been observed to induce a pro-inflammatory cytokine generation and secretion of cytokines, such as IL-6, but there is no evidence of the beneficial impact of IL-6 inhibitors on the modulation of COVID-19. Although there are potential targets in the JAK-STAT pathway that can be manipulated in treatment for coronaviruses and it is evident that IL-1 is elevated in patients with a coronavirus, there is currently no evidence for a role of these drugs in treatment of COVID-19. CONCLUSION: The COVID-19 pandemic has led to challenging decision-making about treatment of critically unwell patients. Low-dose prednisolone and tacrolimus may have beneficial impacts on COVID-19. The mycophenolate mofetil picture is less clear, with conflicting data from pre-clinical studies. There is no definitive evidence that specific cytotoxic drugs, low-dose methotrexate for auto-immune disease, NSAIDs, JAK kinase inhibitors or anti-TNFα agents are contraindicated. There is clear evidence that IL-6 peak levels are associated with severity of pulmonary complications.

negative: Clinical characteristics and outcomes of 112 cardiovascular disease patients infected by 2019-nCoV/ 中华心血管病杂志 Objective@#To explore the clinical characteristics and prognosis of the new coronavirus 2019-nCoV patients combined with cardiovascular disease (CVD).@*Methods@#A retrospective analysis was performed on 112 COVID-19 patients with CVD admitted to the western district of Union Hospital in Wuhan, from January 20, 2020 to February 15, 2020. They were divided into critical group (ICU, n=16) and general group (n=96) according to the severity of the disease and patients were followed up to the clinical endpoint. The observation indicators included total blood count, C-reactive protein (CRP), arterial blood gas analysis, myocardial injury markers, coagulation function, liver and kidney function, electrolyte, procalcitonin (PCT), B-type natriuretic peptide (BNP), blood lipid, pulmonary CT and pathogen detection.@*Results@#Compared with the general group, the lymphocyte count (0.74×109 (0.34×109, 0.94×109)/L vs. 0.99×109 (0.71×109, 1.29×109)/L, P=0.03) was extremely lower in the critical group, CRP (106.98 (81.57, 135.76) mg/L vs. 34.34 (9.55,76.54) mg/L, P<0.001) and PCT (0.20 (0.15,0.48) μg/L vs. 0.11 (0.06,0.20)μg/L, P<0.001) were significantly higher in the critical group. The BMI of the critical group was significantly higher than that of the general group (25.5 (23.0, 27.5) kg/m2 vs. 22.0 (20.0, 24.0) kg/m2, P=0.003). Patients were further divided into non-survivor group (17, 15.18%) group and survivor group (95, 84.82%). Among the non-survivors, there were 88.24% (15/17) patients with BMI> 25 kg/m2, which was significantly higher than that of survivors (18.95% (18/95), P<0.001). Compared with the survived patients, oxygenation index (130 (102, 415) vs. 434 (410, 444), P<0.001) was significantly lower and lactic acid (1.70 (1.30, 3.00) mmol/L vs. 1.20 (1.10, 1.60) mmol/L, P<0.001) was significantly higher in the non-survivors. There was no significant difference in the proportion of ACEI/ARB medication between the critical group and the general group or between non-survivors and survivors (all P>0.05).@*Conclusion@#COVID-19 patients combined with CVD are associated with a higher risk of mortality. Critical patients are characterized with lower lymphocyte counts. Higher BMI are more often seen in critical patients and non-survivor. ACEI/ARB use does not affect the morbidity and mortality of COVID-19 combined with CVD. Aggravating causes of death include fulminant inflammation, lactic acid accumulation and thrombotic events.

negative: Spiking the MERS-coronavirus receptor A novel coronavirus, the Middle East respiratory syndrome coronavirus, recently emerged through zoonotic transmission, causing a severe lower respiratory tract infection in humans. In two recent papers, one published in Cell Research, the crystal structure of the viral receptor-binding domain in complex with the host CD26/dipeptidyl peptidase 4 receptor has now been characterized.

negative: ACE/ACE2 Ratio and MMP-9 Activity as Potential Biomarkers in Tuberculous Pleural Effusions Objective: Pleural effusion is common problem, but the rapid and reliable diagnosis for specific pathogenic effusions are lacking. This study aimed to identify the diagnosis based on clinical variables to differentiate pleural tuberculous exudates from other pleural effusions. We also investigated the role of renin-angiotensin system (RAS) and matrix metalloproteinase (MMPs) in the pathogenesis of pleural exudates. Experimental design: The major components in RAS and extracellular matrix metabolism, including angiotensin converting enzyme (ACE), ACE2, MMP-2 and MMP-9 activities, were measured and compared in the patients with transudative (n = 45) and exudative (n = 80) effusions. The exudative effusions were come from the patients with tuberculosis (n = 20), pneumonia (n = 32), and adenocarcinoma (n = 28). Results: Increased ACE and equivalent ACE2 activities, resulting in a significantly increased ACE/ACE2 ratio in exudates, were detected compared to these values in transudates. MMP-9 activity in exudates was significantly higher than that in transudates. The significant correlation between ACE and ACE2 activity that was found in transudates was not found in exudates. Advanced analyses showed significantly increased ACE and MMP-9 activities, and decreased ACE2 activity in tuberculous pleural effusions compared with those in pneumonia and adenocarcinoma effusions. The results indicate that increased ACE and MMP-9 activities found in the exudates were mainly contributed from a higher level of both enzyme activities in the tuberculous pleural effusions. Conclusion: Interplay between ACE and ACE2, essential functions in the RAS, and abnormal regulation of MMP-9 probably play a pivotal role in the development of exudative effusions. Moreover, the ACE/ACE2 ratio combined with MMP-9 activity in pleural fluid may be potential biomarkers for diagnosing tuberculous pleurisy.

negative: Association between Angiotensin-Converting Enzyme Inhibitors and Lung Cancer—A Nationwide, Population-Based, Propensity Score-Matched Cohort Study Background: Direct evidence of lung cancer risk in Asian users of angiotensin-converting enzyme inhibitors (ACEIs) is lacking. Methods: The ACEI cohort comprised 22,384 patients aged ≥ 18 years with a first prescription of ACEI. The comparison angiotensin receptor blocker (ARB) cohort consisted of age-, sex- and comorbidity-matched patients at a ratio of 1:1. The primary outcome was the incidence of lung cancer, which was evaluated using a proportional hazard model. Results: The overall incidence rates of lung cancer in the ACEI and ARB cohorts were 16.6 and 12.2 per 10,000 person-years, respectively. The ACEI cohort had a significantly higher risk of lung cancer than the ARB cohort (adjusted hazard ratio [aHR]. = 1.36; 95% confidence interval [CI]. = 1.11–1.67). Duration–response and dose–response analyses revealed that compared with patients who did not receive ACEIs, patients who received ACEIs for more than 45 days per year (aHR = 1.87; 95% CI = 1.48–2.36) and patients who received more than 540 defined daily doses of ACEIs per year (aHR =1.80; 95% CI = 1.43–-2.27) had a significantly higher risk of lung cancer. The cumulative incidence of lung cancer was also significantly higher in the ACEI cohort than in the ARB cohort (log-rank test, p = 0.002). Conclusions: ACEI use is associated with an increased risk of lung cancer compared with ARB use. Patients using ARBs have a significantly lower risk of lung cancer than non-ARB users.