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Archive for the ‘Virus Infective Acute Respiratory Syndrome: SARS-CoV’ Category


How Are Cancer Researchers Fighting COVID-19? Lectures from Koch Institute @MIT

WATCH RECORDING, below

 

Reporter: Aviva Lev-Ari, PhD, RN

  • I attended Jun 29, 2020 11:30 AM Eastern Time the five presentations on

    How Are Cancer Researchers Fighting COVID-19? Lectures from Koch Institute @MIT

 

From: Koch Institute at MIT <no-reply@zoom.us>

Reply-To: <no-reply@zoom.us>

Date: Wednesday, July 1, 2020 at 11:20 AM

To: Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu>

Subject: Thank you for attending SOLUTIONS with/in/sight:

How Are Cancer Researchers Fighting COVID-19? (Part II)

 

Hi Aviva Lev-Ari,

Thank you for attending SOLUTIONS with/in/sight: How Are Cancer Researchers Fighting COVID-19? (Part II). We hope you enjoyed our event.

Please submit your questions or comments to: kievents@mit.edu.

You may view a recording of the webinar here: https://ki.mit.edu/news/events/withinsight/jun-2020

Learn more about Koch Institute cancer research and events by signing up for our mailing list here: https://ki.mit.edu/subscribe

Thank you and be safe.

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The Castleman Disease Research Network publishes Phase 1 Results of Drug Repurposing Database for COVID-19

Reporter: Stephen J. Williams, PhD.

 

From CNN at https://www.cnn.com/2020/06/27/health/coronavirus-treatment-fajgenbaum-drug-review-scn-wellness/index.html

Updated 8:17 AM ET, Sat June 27, 2020

(CNN)Every morning, Dr. David Fajgenbaum takes three life-saving pills. He wakes up his 21-month-old daughter Amelia to help feed her. He usually grabs some Greek yogurt to eat quickly before sitting down in his home office. Then he spends most of the next 14 hours leading dozens of fellow researchers and volunteers in a systematic review of all the drugs that physicians and researchers have used so far to treat Covid-19. His team has already pored over more than 8,000 papers on how to treat coronavirus patients.

The 35-year-old associate professor at the University of Pennsylvania Perelman School of Medicine leads the school’s Center for Cytokine Storm Treatment & Laboratory. For the last few years, he has dedicated his life to studying Castleman disease, a rare condition that nearly claimed his life. Against epic odds, he found a drug that saved his own life six years ago, by creating a collaborative method for organizing medical research that could be applicable to thousands of human diseases. But after seeing how the same types of flares of immune-signaling cells, called cytokine storms, kill both Castleman and Covid-19 patients alike, his lab has devoted nearly all of its resources to aiding doctors fighting the pandemic.

A global repository for Covid-19 treatment data

Researchers working with his lab have reviewed published data on more than 150 drugs doctors around the world have to treat nearly 50,000 patients diagnosed with Covid-19. They’ve made their analysis public in a database called the Covid-19 Registry of Off-label & New Agents (or CORONA for short).
It’s a central repository of all available data in scientific journals on all the therapies used so far to curb the pandemic. This information can help doctors treat patients and tell researchers how to build clinical trials.The team’s process resembles that of the coordination Fajgenbaum used as a medical student to discover that he could repurpose Sirolimus, an immunosuppressant drug approved for kidney transplant patients, to prevent his body from producing deadly flares of immune-signaling cells called cytokines.The 13 members of Fajgenbaum’s lab recruited dozens of other scientific colleagues to join their coronavirus effort. And what this group is finding has ramifications for scientists globally.
This effort by Dr. Fajgenbaum’s lab and the resultant collaborative effort shows the power and speed at which a coordinated open science effort can achieve goals. Below is the description of the phased efforts planned and completed from the CORONA website.

CORONA (COvid19 Registry of Off-label & New Agents)

Drug Repurposing for COVID-19

Our overarching vision:  A world where data on all treatments that have been used against COVID19 are maintained in a central repository and analyzed so that physicians currently treating COVID19 patients know what treatments are most likely to help their patients and so that clinical trials can be appropriately prioritized.

Phase 1: COMPLETED

Our team reviewed 2500+ papers & extracted data on over 9,000 COVID19 patients. We found 115 repurposed drugs that have been used to treat COVID19 patients and analyzed data on which ones seem most promising for clinical trials. This data is open source and can be used by physicians to treat patients and prioritize drugs for trials. The CDCN will keep this database updated as a resource for this global fight. Repurposed drugs give us the best chance to help COVID19 as quickly as possible! As disease hunters who have identified and repurposed drugs for Castleman disease, we’re applying our ChasingMyCure approach to COVID19.

Read our systematic literature review published in Infectious Diseases and Therapy at the following link: Treatments Administered to the First 9152 Reported Cases of COVID-19: A Systematic Review

From Fajgenbaum, D.C., Khor, J.S., Gorzewski, A. et al. Treatments Administered to the First 9152 Reported Cases of COVID-19: A Systematic Review. Infect Dis Ther (2020). https://doi.org/10.1007/s40121-020-00303-8

The following is the Abstract and link to the metastudy.  This study was a systematic review of literature with strict inclusion criteria.  Data was curated from these published studies and a total of 9152 patients were evaluated for treatment regimens for COVID19 complications and clinical response was curated for therapies in these curated studies.  Main insights from this study were as follows:

Key Summary Points

Why carry out this study?
  • Data on drugs that have been used to treat COVID-19 worldwide are currently spread throughout disparate publications.
  • We performed a systematic review of the literature to identify drugs that have been tried in COVID-19 patients and to explore clinically meaningful response time.
What was learned from the study?
  • We identified 115 uniquely referenced treatments administered to COVID-19 patients. Antivirals were the most frequently administered class; combination lopinavir/ritonavir was the most frequently used treatment.
  • This study presents the latest status of off-label and experimental treatments for COVID-19. Studies such as this are important for all diseases, especially those that do not currently have definitive evidence from randomized controlled trials or approved therapies.

Treatments Administered to the First 9152 Reported Cases of COVID-19: A Systematic Review

Abstract

The emergence of SARS-CoV-2/2019 novel coronavirus (COVID-19) has created a global pandemic with no approved treatments or vaccines. Many treatments have already been administered to COVID-19 patients but have not been systematically evaluated. We performed a systematic literature review to identify all treatments reported to be administered to COVID-19 patients and to assess time to clinically meaningful response for treatments with sufficient data. We searched PubMed, BioRxiv, MedRxiv, and ChinaXiv for articles reporting treatments for COVID-19 patients published between 1 December 2019 and 27 March 2020. Data were analyzed descriptively. Of the 2706 articles identified, 155 studies met the inclusion criteria, comprising 9152 patients. The cohort was 45.4% female and 98.3% hospitalized, and mean (SD) age was 44.4 years (SD 21.0). The most frequently administered drug classes were antivirals, antibiotics, and corticosteroids, and of the 115 reported drugs, the most frequently administered was combination lopinavir/ritonavir, which was associated with a time to clinically meaningful response (complete symptom resolution or hospital discharge) of 11.7 (1.09) days. There were insufficient data to compare across treatments. Many treatments have been administered to the first 9152 reported cases of COVID-19. These data serve as the basis for an open-source registry of all reported treatments given to COVID-19 patients at www.CDCN.org/CORONA. Further work is needed to prioritize drugs for investigation in well-controlled clinical trials and treatment protocols.

Read the Press Release from PennMedicine at the following link: PennMedicine Press Release

Phase 2: Continue to update CORONA

Our team continues to work diligently to maintain an updated listing of all treatments reported to be used in COVID19 patients from papers in PubMed. We are also re-analyzing publicly available COVID19 single cell transcriptomic data alongside our iMCD data to search for novel insights and therapeutic targets.

You can visit the following link to access a database viewer built and managed by Matt Chadsey, owner of Nonlinear Ventures.

If you are a physician treating COVID19 patients, please visit the FDA’s CURE ID app to report de-identified information about drugs you’ve used to treat COVID19 in just a couple minutes.

For more information on COVID19 on this Open Access Journal please see our Coronavirus Portal at

https://pharmaceuticalintelligence.com/coronavirus-portal/

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Corticosteroid, Dexamethasone Improves Survival in COVID-19: Deaths reduction by 1/3 in ventilated patients and by 1/5 in other patients receiving oxygen only

Reporter: Aviva Lev-Ari, PhD, RN – bold face and color fonts added

 

UPDATED on 6/28/2020

https://public.tableau.com/profile/matt.chadsey#!/vizhome/Corona_15895153725490/TreatmentSummary

Corona – COVID19 Treatment Registry

Viz Author: Matt Chadsey

CORONA is the COVID19 Registry of Off-Label & New Agents. A project of the Center for Cytokine Storm Treatment & Laboratory (CSTL) and the Castleman Disease Collaborative Network (CDCN).

10,553 Views  4

Inspiration:

Originally Published:

May 15, 2020

Last Updated:

Jun 27, 2020

Workbook Details:

11 Sheets

Metadata:

https://public.tableau.com/profile/matt.chadsey#!/vizhome/Corona_15895153725490/TreatmentSummary

SOURCE

The Castleman Disease Research Network publishes Phase 1 Results of Drug Repurposing Database for COVID-19

Reporter: Stephen J. Williams, PhD.

https://pharmaceuticalintelligence.com/2020/06/27/the-castleman-disease-research-network-publishes-phase-1-results-of-drug-repurposing-database-for-covid-19/

Paul Sax
@PaulSaxMD

If you’re wondering whether to use dexamethasone for patients presenting with COVID19 who need oxygen as we await the publication of the RECOVERY trial, here’s one opinion (mine): Yes. Latest post: blogs.jwatch.org/hiv-id-observa

Dexamethasone Improves Survival in COVID-19 – Why This Should Be Practice-Changing Even Before the…
When the news broke last week that the dexamethasone component of the RECOVERY randomized clinical trial was halted because those receiving the drug were significantly more likely to survive, I…
blogs.jwatch.org
8
104
239

Paul Sax
@PaulSaxMD

The favorable dexamethasone data for covid19 will likely amplify the already apparent increased risk for aspergillosis among these critically ill people. Plenty of work for experts like

and others.

Image

Paul Sax
@PaulSaxMD
– Very welcome news, dex is cheap, widely available! – Demonstrates the power of RCTs vs obs studies, which were conflicting – How will the numerous ongoing studies of immunomodulators be modified? – Rx guidelines — act now or wait for more info?
Low-cost dexamethasone reduces death by up to one third in hospitalised patients with severe…
Statement from the Chief Investigators of the Randomised Evaluation of COVid-19 thERapY (RECOVERY) Trial on dexamethasone, 16 June 2020
recoverytrial.net

Note my last point, about “guidelines”. These committees have a responsibility to get what they recommend right, and might be slower than clinicians to recommend an intervention with limited information — even if it is potentially life-saving.

But my assumption was that clinical practice would change quickly, awaiting the updating of guidelines. After all, this is what we’ve been waiting for — data from a randomized trial demonstrating a clear benefit. Even better, it’s a readily available, inexpensive strategy — a course of corticosteroids — familiar to us all.

I confess the responses to my post, and comments elsewhere, surprised me. Lots of skepticism. Wow.

The comments fell into several interrelated categories:

Let’s wait for the study to be peer-reviewed and published in an established medical journal before changing clinical practice.

Really? Even when the sickest patients — those requiring oxygen or ventilatory support — were more likely to survive?

(Yes, I keep italicizing that endpoint. Emphasis, you know.)

For the record, here are the results:

Dexamethasone reduced deaths by

  • one-third in ventilated patients (rate ratio 0.65 [95% confidence interval 0.48 to 0.88]; p=0.0003) and by
  • one fifth in other patients receiving oxygen only (0.80 [0.67 to 0.96]; p=0.0021).

When a study stops because of a survival benefit for a life-threatening disease, take note. It’s because continuing the study as originally designed is unethical — those randomized to receive “usual care” would be deprived of a potentially life-saving treatment.

The steering committee has a responsibility of ensuring the safety of trial participants. And remember, they have access to all the study data, even if we don’t. Credit: NIAID

It’s critical that this information be made available as soon as possible. Patients are being treated today who might benefit, and writing papers and subsequent peer review take time — typically weeks, even with the “warp speed” of COVID-19.

To quote one of the investigators: “Dexamethasone is inexpensive, on the shelf, and can be used immediately to save lives worldwide.”

Well said.

Why are we getting critical information via press release? I’m inherently distrustful. A press release doesn’t represent actual data.

It’s reasonable to be skeptical of clinical trial press releases, especially when issued by private pharmaceutical companies with multi-million dollar marketing divisions.

These notoriously exaggerate the importance of study results, especially when focused on surrogate markers of disease that may or may not predict clinical outcome.

But consider — this isn’t a press release by a giant company, citing a minor change in an inflammatory cytokine or quality-of-life metric in an open-label study. It’s a respected clinical trials group, funded by the government of Great Britain, and they are reporting a survival benefit from their clinical trial.

To their credit, they early on started doing randomized trials of various COVID-19 interventions while the rest of the globe practiced the therapeutic equivalent of throwing drugs against the wall hoping some of them would stick.

  • Lopinavir-ritonavir!
  • Interferons!
  • Oseltamivir!
  • Hydroxychloroquine!
  • Azithromycin!
  • Ivermectin!

And it’s not just antimicrobials — virtually every immunomodulator under the sun, some extremely expensive, has found its way to off-label use for critically ill patients with COVID-19.

  • Tocilizumab!
  • Sarilumab!
  • Anakinra!
  • Ruxolitinib!
  • Eculizumab!
  • Any-other-mab! And more …

Yes, it’s hard to keep up — see Table 1 in this recent review for all the various anti-inflammatory approaches tried off-label, with many of these now under study.

If we’re using some of these unproven therapies — and many of us have — why not dexamethasone, which in the RECOVERY trial improved survival?

Here we go again! Haven’t we been burned already multiple times with research on COVID-19, only later to have this information questioned, or retracted?

Quite reasonable to be cautious in this very fast-moving area.

But the infamous research that has “burned” us involved much weaker levels of evidence — little more than anecdotal observations at one extreme and observational studies with likely falsified data at the other.

None has been a randomized clinical trial with a survival benefit.

(Have I noted that result enough times already? Nah.)

I need more details about the study. What were the primary endpoints? The specifics of the intervention? What were the patient characteristics of those enrolled? Did some subgroups benefit more than others? What were the toxicities? 

All very reasonable questions! But good news — we have the full protocol available for review. This can answer some of these queries, including the endpoints and description of the exact interventions studied.

https://blogs.jwatch.org/hiv-id-observations/index.php/dexamethasone-improves-survival-in-covid-19-why-this-should-be-practice-changing-even-before-the-paper-is-published/2020/06/21/?query=C19

 

RRFERENCES

Statement from the Chief Investigators of the Randomised Evaluation of COVid-19 thERapY (RECOVERY) Trial on dexamethasone, 16 June 2020

https://www.recoverytrial.net/news/low-cost-dexamethasone-reduces-death-by-up-to-one-third-in-hospitalised-patients-with-severe-respiratory-complications-of-covid-19

SOURCE

https://blogs.jwatch.org/hiv-id-observations/index.php/dexamethasone-improves-survival-in-covid-19-why-this-should-be-practice-changing-even-before-the-paper-is-published/2020/06/21/?query=C19

Other Related Studies

Countermeasures to COVID-19: Are immunomodulators rational treatment options — a critical review of the evidence 

Open Forum Infectious Diseases, ofaa219, https://doi.org/10.1093/ofid/ofaa219
Published:
05 June 2020

Article history

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with higher concentrations of pro-inflammatory cytokines which leads to lung damage, respiratory failure, and resultant increased mortality. Immunomodulatory therapy has the potential to inhibit cytokines and quell the immune dysregulation. Controversial data found improved oxygenation after treatment with tocilizumab, an IL-6 inhibitor, sparking a wave of interest and resultant clinical trials evaluating immunomodulatory therapies. The purpose of this article is to assess potential pro-inflammatory targets and review the safety and efficacy of immunomodulatory therapies in managing patients with acute respiratory distress syndrome associated with COVID-19.

Conclusions from PDF Full Article Version

SARS-CoV-2 leads to ALI and ARDS with increased mortality. Immunomodulatory therapies have the potential to inhibit cytokines, but the role of elevated cytokines with lung pathology is unclear. The overall lack of evidence and recommendations has forced practitioners to use their own judgment regarding use of immunomodulatory therapy. We are hopeful that as clinical trial data become available their role in managing patients with COVID-19 will emerge. For now, available evidence suggests these treatment options be reserved for use in critically ill COVID-19 patients enrolled in clinical trials. Due to the potential adverse effects, risks and benefits must be weighed and proper screening completed prior to use.

This content is only available as a PDF.

About the RECOVERY trial

The RECOVERY trial is a large, randomised controlled trial of possible treatments for patients admitted to hospital with COVID-19. Over 11,500 patients have been randomised to the following treatment arms, or no additional treatment:

  • Lopinavir-Ritonavir (commonly used to treat HIV)
  • Low-dose Dexamethasone (a type of steroid, which typically used to reduce inflammation)
  • Hydroxychloroquine (which has now been stopped due to lack of efficacy)
  • Azithromycin (a commonly used antibiotic)
  • Tocilizumab (an anti-inflammatory treatment given by injection)
  • Convalescent plasma (collected from donors who have recovered from COVID-19 and contains antibodies against the SARS-CoV-2 virus).

Overall dexamethasone reduced the 28-day mortality rate by 17% (0.83 [0.74 to 0.92]; P=0.0007) with a highly significant trend showing greatest benefit among those patients requiring ventilation (test for trend p<0.001). But it is important to recognise that we found no evidence of benefit for patients who did not require oxygen and we did not study patients outside the hospital setting. Follow-up is complete for over 94% of participants.

The RECOVERY Trial is conducted by the registered clinical trials units with the Nuffield Department of Population Health in partnership with the Nuffield Department of Medicine. The trial is supported by a grant to the University of Oxford from UK Research and Innovation/National Institute for Health Research (NIHR) and by core funding provided by NIHR Oxford Biomedical Research CentreWellcome, the Bill and Melinda Gates Foundation, the Department for International Development, Health Data Research UK, the Medical Research Council Population Health Research Unit, and NIHR Clinical Trials Unit Support Funding.

The RECOVERY trial involves many thousands of doctors, nurses, pharmacists, and research administrators at over 175 hospitals across the whole of the UK, supported by staff at the NIHR Clinical Research Network, NHS DigiTrials, Public Health England, Public Health Scotland, Department of Health & Social Care, and the NHS in England, Scotland, Wales and Northern Ireland.

About Oxford University

Oxford University has been placed number 1 in the Times Higher Education World University Rankings for the third year running, and at the heart of this success is our ground-breaking research and innovation.

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Updates on the Oxford, AstraZeneca COVID-19 Vaccine

Reporter: Stephen J. Williams, PhD

AstraZeneca’s CEO states that their COVID-19 vaccine, codeveloped with Oxford University, should provide protection for a year.

AstraZeneca’s potential coronavirus vaccine is likely to provide protection against contracting Covid-19 for about a year, the company’s chief executive told a Belgian radio station on Tuesday.

The British drugmaker has already begun human trials of the vaccine developed by the University of Oxford, with a phase I trial in Britain due to end soon and a phase III trial already begun, Pascal Soriot told broadcaster Bel RTL.

“We think that it will protect for about a year,” Soriot said.

AstraZeneca said on Saturday that it had signed contracts with France, Germany, Italy and the Netherlands to supply the European Union with up to 400 million doses of the potential vaccine.

It has also agreed deals with Britain and the United States.

“If all goes well, we will have the results of the clinical trials in August/September. We are manufacturing in parallel. We will be ready to deliver from October if all goes well,” Soriot said.

Source: https://www.cnbc.com/2020/06/16/astrazeneca-covid-19-vaccine-likely-to-protect-for-a-year-ceo-says.html

 

 

From In The Pipeline (Derek Lowe’s regular column in Science)

Criticism of the Oxford Coronavirus Vaccine

By Derek Lowe 18 May, 2020

This piece at Forbes by Bill Haseltine has set off a lot of comment – it’s a look at the Oxford group’s vaccine candidate as compared to the SinoVac candidate, and you may recall (background here) that these are the two teams that have separately reported that their vaccines appear to protect rhesus monkeys from infection after exposure to the coronavirus. Haseltine has some criticisms of the Oxford data, and as you will see from that link to his name, his opinions deserve to be taken seriously. So what’s going on? Update: here’s the take on this at BioCentury.

Looking at the preprint on the Oxford results, Haseltine has a problem with the claim that the monkeys were protected from infection by a dose of ChAdOx1 nCoV-19. The key data are in the preprint’s Figure 3. The Oxford team checked for viral RNA several different ways. One was using bronchoaveolar lavage (BAL fluid), a sampling technique that involves running a bronchoscope down into the lungs and washing out aveolar spaces – a pretty darn invasive assay, which is why you don’t hear about it all that much compared to the still-not-so-nonivasive nose swabs. BAL fluid of the virus-exposed unvaccinated animals showed coronavirus genomic RNA throughout the study, and viral subgenomic RNA (more indicative of active replication) at days 3 and 5 after exposure. Meanwhile, the vaccinated animals showed the genomic RNA in only two monkeys, and no subgenomic RNA at all.

So far, so good. But both vaccinated and unvaccinated monkeys showed the same amount of viral genomic RNA from nose swab samples (Figure 3c). That’s the test that’s used out in the human population, and that means that the vaccinated animals would still be declared as positive for the coronavirus after being exposed to it. And the other thing that Haseltine notes is that the amount (the “titer”, in the lingo) of neutralizing antibodies in the blood of the vaccinated animals does not appear to be that high. You’d like to be able to dilute the blood antibody samples down by hundreds of times or even a thousandfold and still see antiviral activity in an in vitro assay, but in the Oxford case the activity started disappearing at about fortyfold dilution (Figure 2b).

On the positive side, 2/3 of the unvaccinated animals showed clear evidence of viral pneumonia at autopsy, but none of the vaccinated ones did. The conclusion is that the vaccinated animals were indeed infected – the vaccine did not protect against that – but that the disease was definitely less severe. But these results mean that the virus might well still be transmissible from people who had been so vaccinated, even if the disease course itself was not as deadly. You’d want to do better than that, if you can. Haseltine’s take is “Time will tell if this is the best approach. I wouldn’t bet on it.

Haseltine compares these results to the SinoVac inactivated virus vaccine, and finds that that one looks better – at its highest dose, no viral RNA was recovered from the tissues of the vaccinated animals, for example. This sort of “sterilizing immunity” is what you’d want to aim for – it gives the virus nowhere to go in the human population if you can vaccinate enough people. But it’s worth noting that the SinoVac results were from three doses of their vaccine (versus one of the Oxford candidate), and the viral exposure challenge was about half as strong (total viral particles) as what the Oxford paper used. The Oxford group also inoculated their monkeys in both the upper and lower respiratory tract, while the SinoVac team used a single inoculation in the trachea. So I agree with that tweet linked from AndyBiotech; I don’t think that a head-to-head comparison is fair. But Haseltine’s point stands, that the results as we have them from the ChAdOx1 nCoV-19 vaccine did not actually protect monkeys from infection.

Source: https://blogs.sciencemag.org/pipeline/archives/2020/05/18/criticism-of-the-oxford-coronavirus-vaccine

 

Please see other Articles on COVID-19 on our Coronavirus Portal Including Late Breaking News at:

https://pharmaceuticalintelligence.com/coronavirus-portal/

 

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COVID-19: Pandemic Surgery Guidance published by a Global Consortium initiated effort by Björn L.D.M. Brücher, MD, PhD, Prof. Of Surgery, Carl-Thiem-Klinikum, Cottbus, Germany

Reporter: Aviva Lev-Ari, PhD, RN

This video interview with the corresponding author, Björn L.D.M. Brücher, considers the changing landscape of surgery as a result of COVID-19, and explores the process of creating this guidance in an innovative and collaborative way. A ‘Key Summary’ has also been produced in an easy to understand Q&A format.

Watch the full video: https://bit.ly/2AkEgLm
Read the ‘Key Summary’: https://bit.ly/2MNtK20

 

Issue
4open
Volume 3, 2020
Article Number 1
Number of page(s) 19
DOI https://doi.org/10.1051/fopen/2020002
Published online 10 April 2020

© B.L.M.D. Brücher et al., Published by EDP Sciences, 2020

Licence Creative Commons
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

SOURCE

https://www.4open-sciences.org/articles/fopen/full_html/2020/01/fopen200002s/fopen200002s.html

 

Other related articles published on this Open Access Online Scientific Journal include the following:

EIGHT pages on the Coronavirus Portal:

https://pharmaceuticalintelligence.com/coronavirus-portal/

Coronavirus Pandemic: RESEARCH CATEGORIES in JOURNAL ONTOLOGY

  • Population genetics
  •  Population Health Management
    •  U.S. Employment-to-Population Ratio

OPEN TO GUEST AUTHORS

on Seven Selected Topics & Lead Curator for Contact:

BREAKING NEWS CORNER

June 2020

 

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New Coronavirus Passive Vaccine Developed by Israeli Researchers

Reporter: Irina Robu, PhD

Researchers at Bar-Ilan University have identified short amino acid sequences that could help the development of a vaccine against COVID-19 virus. Of the 25 epitopes that were discovered to be 100% identical to SARS, seven are theoretically efficient vaccine candidates. Their research indicate that they could cover as much as 87% of the world population

Their study has identified a set of immunodominant epitopes from the SARS-CoV-2 proteome, which are capable of generating antibody and cell mediated immune responses. The epitopes, known as antigenic determinants, are the part of the antigen that binds to a specific antigen receptor on the surface of B cells or T cells and are able to provoke an immune response.

It is known that immune response occurs within an organism for the purpose of defending against foreign invaders such as viruses, bacteria, parasites and fungi. The immune responses that are based on specific immunodominant epitopes contain the generation of both antibody- and cell-mediated immunity against pathogens. Such immunity can facilitate fast and effective elimination of the pathogen. The end result is a passive vaccine capable of capable of activating both cellular and humoral immune responses in humans.

According to the team at Bar-Ilan University, the mapped coronavirus epitopes with those of the influenza virus. And they found that 85% of the sequence identity with experimentally detected epitopes of Severe Acute Respiratory Syndrome-related coronavirus (SARS-CoV).

Additional analysis indicated that the epitopes are non-allergic and non-toxic to humans and have very low risk for generating autoimmune responses. The team is looking to partner with companies to build vaccine constructs and test them in-vitro and on animal trials before starting any clinical trials.

SOURCE

https://www.jpost.com/health-science/israeli-researchers-on-road-to-new-covid-19-passive-vaccine-630988?utm_source=ActiveCampaign

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COVID-19’s seasonal cycle to be estimated at Lawrence Berkeley National Laboratory (Berkeley Lab) by Artificial Intelligence and Machine Learning Algorithms: Will A Fall and Winter resurgence be Likely??

Reporter: Aviva Lev-Ari, PhD, RN

Using machine learning to estimate COVID-19’s seasonal cycle

Woman walks down empty city street wearing a mask

Credit: Ivan Marc/Shutterstock

Berkeley Lab researchers have launched a project to determine if the novel coronavirus might be seasonal, waning in summer months and resurging in fall and winter.

One of the many unanswered scientific questions about COVID-19 is whether it is seasonal like the flu — waning in warm summer months then resurging in the fall and winter.

Now scientists at Lawrence Berkeley National Laboratory (Berkeley Lab) are launching a project to apply machine-learning methods to a plethora of health and environmental datasets, combined with high-resolution climate models and seasonal forecasts, to tease out the answer.

“Environmental variables, such as temperature, humidity, and UV [ultraviolet radiation] exposure, can have an effect on the virus directly, in terms of its viability. They can also affect the transmission of the virus and the formation of aerosols,” said Berkeley Lab scientist Eoin Brodie, the project lead. “We will use state-of-the-art machine-learning methods to separate the contributions of social factors from the environmental factors to attempt to identify those environmental variables to which disease dynamics are most sensitive.

The research team will take advantage of an abundance of health data available at the county level — such as the severity, distribution and duration of the COVID-19 outbreak, as well as what public health interventions were implemented when — along with demographics, climate and weather factors, and, thanks to smartphone data, population mobility dynamics. The initial goal of the research is to predict — for each county in the United States — how environmental factors influence the transmission of the SARS-CoV-2 virus, which causes COVID-19.

Multidisciplinary team for a complex problem

Untangling environmental factors from social and health factors is a knotty problem with a large number of variables, all interacting in different ways. On top of that, climate and weather affect not only the virus but also human physiology and behavior. For example, people may spend more or less time indoors, depending on the weather; and their immune systems may also change with the seasons.

It’s a complex data problem similar to others tackled by Berkeley Lab’s researchers studying systems like watersheds and agriculture; the challenge involves integrating data across scales to make predictions at the local level. “Downscaling of climate information is something that we routinely do to understand how climate impacts ecosystem processes,” Brodie said. “It involves the same types of variables — temperature, humidity, solar radiation.”

Brodie, deputy director of Berkeley Lab’s Climate and Ecosystem Sciences Division, is leading a cross-disciplinary team of Lab scientists with expertise in climate modeling, data analytics, machine learning, and geospatial analytics. Ben Brown, a computational biologist in Berkeley Lab’s Biosciences Area, is leading the machine-learning analysis. One of their main aims is to understand how climate and weather interact with societal factors.

“We don’t necessarily expect climate to be a massive or dominant effect in and of itself. It’s not going to trump which city shut down when,” Brown said. “But there may be some really important interactions [between the variables]. Looking at New York and California for example, even accounting for the differences between the timing of state-instituted interventions, the death rate in New York may be four times higher than in California — though additional testing on random samples of the population is needed to know for sure. Understanding the environmental interactions may help explain why these patterns appear to be emerging. This is a quintessential problem for machine learning and AI [artificial intelligence].”

The computing work will be conducted at the National Energy Research Scientific Computing Center (NERSC), a DOE Office of Science user facility located at Berkeley Lab.

Signs of climatic influences

map of the worldwide incidence rate of COVID-19
The worldwide incidence rate of COVID-19.
Credit: Center for Systems Science and Engineering at Johns Hopkins University

Already, geographical differences in how the disease behaves have been reported, the researchers point out. Temperature, humidity, and the UV Index have all been statistically associated with rates of COVID-19 transmission — although contact rates are still the dominant influence on the spread of disease. In the southern hemisphere, for example, where it’s currently fall, disease spread has been slower than in the northern hemisphere. “There’s potentially other factors associated with that,” Brodie said. “The question is, when the southern hemisphere moves into winter, will there be an increase in transmission rate, or will fall and winter 2020 lead to a resurgence across the U.S. in the absence of interventions?”

India is another place where COVID-19 does not yet appear to be as virulent. “There are cities where it behaves as if it’s the most infectious disease in recorded history. Then there are cities where it behaves more like influenza,” Brown said. “It is really critical to understand why we see those massive differences.”

Brown notes other experiments suggesting the SARS-CoV-2 virus could be seasonal. In particular, the National Biodefense Analysis and Countermeasures Center (NBACC) assessed the longevity of the virus on various surfaces. “Under sunlight and humidity, they found that the virus loses viability in under 60 minutes,” Brown said. “But in darkness and low temperatures it’s stable for eight days. There’s some really serious differences that need investigating.”

The Berkeley Lab team believes that enough data may now be available to determine what environmental factors may influence the virulence of the virus. “Now we should have enough data from around the world to really make an assessment,” Brown said.

The team hopes to have the first phase of their analysis available by late summer or early fall. The next phase will be to make projections under different scenarios, which could aid in public health decisions.

“We would use models to project forward, with different weather scenarios, different health intervention scenarios — such as continued social distancing or whether there are vaccines or some level of herd immunity — in different parts of the country. For example, we hope to be able to say, if you have kids going back to school under this type of environment, the climate and weather in this zone will influence the potential transmission by this amount,” Brodie explained. “That will be a longer-term task for us to accomplish.”

This research is supported by Berkeley Lab’s Laboratory Directed Research and Development (LDRD) program. Other team members include Dan Feldman, Zhao Hao, Chaincy Kuo, Haruko Wainwright, and Nicola Falco. Berkeley Lab mobilized quickly to provide LDRD funding for several research projects to address the COVID-19 pandemic, including one on text mining scientific literature and another on indoor transmission of the virus.

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SAR-Cov-2 is probably a vasculotropic RNA virus affecting the blood vessels: Endothelial cell infection and endotheliitis in COVID-19

Reporter: Aviva Lev-Ari, PhD, RN – Bold face and colors are my addition

From: “Dr. Larry Bernstein” <larry.bernstein@gmail.com>

Reply-To: “Dr. Larry Bernstein” <larry.bernstein@gmail.com>

Date: Tuesday, June 2, 2020 at 8:50 AM

To: Aviva Lev-Ari <aviva.lev-ari@comcast.net>

Subject: Re: Coronavirus May Be a Vascular Disease, Which Explains Everything | Elemental

“I don’t think the conclusion is fully validated. I would want to see autopsy reports, like that found in China. It can be done safely, and the tools could be discarded.”

Larry

UPDATED on 6/29/2020

Another duality and paradox in the Treatment of COVID-19 Patients in ICUs was expressed by Mike Yoffe, MD, PhD, David H. Koch Professor of Biology and Biological Engineering, Massachusetts Institute of Technology. Dr. Yaffe has a joint appointment in Acute Care Surgery, Trauma, and Surgical Critical Care, and in Surgical Oncology @BIDMC

on 6/29 at SOLUTIONS with/in/sight at Koch Institute @MIT

How Are Cancer Researchers Fighting COVID-19? (Part II)” Jun 29, 2020 11:30 AM EST

Mike Yoffe, MD, PhD 

In COVID-19 patients: two life threatening conditions are seen in ICUs:

  • Blood Clotting – Hypercoagulability or Thrombophilia
  • Cytokine Storm – immuno-inflammatory response
  • The coexistence of 1 and 2 – HINDERS the ability to use effectively tPA as an anti-clotting agent while the cytokine storm is present.

Mike Yoffe’s related domain of expertise:

Signaling pathways and networks that control cytokine responses and inflammation

Misregulation of cytokine feedback loops, along with inappropriate activation of the blood clotting cascade causes dysregulation of cell signaling pathways in innate immune cells (neutrophils and macrophages), resulting in tissue damage and multiple organ failure following trauma or sepsis. Our research is focused on understanding the role of the p38-MK2 pathway in cytokine control and innate immune function, and on cross-talk between cytokines, clotting factors, and neutrophil NADPH oxidase-derived ROS in tissue damage, coagulopathy, and inflammation, using biochemistry, cell biology, and mouse knock-out/knock-in models.  We recently discovered a particularly important link between abnormal blood clotting and the complement pathway cytokine C5a which causes excessive production of extracellular ROS and organ damage by neutrophils after traumatic injury.

SOURCE

https://www.bidmc.org/research/research-by-department/surgery/acute-care-surgery-trauma-and-surgical-critical-care/michael-b-yaffe

 

SAR-Cov-2 is probably a vasculotropic RNA virus affecting the blood vessels: Endothelial cell infection and endotheliitis in COVID-19

Mandeep Mehra, MD, medical director of the Brigham and Women’s Hospital Heart and Vascular Center.

“All these Covid-associated complications were a mystery. We see blood clotting, we see kidney damage, we see inflammation of the heart, we see stroke, we see encephalitis [swelling of the brain],” says William Li, MD, president of the Angiogenesis Foundation. “A whole myriad of seemingly unconnected phenomena that you do not normally see with SARS or H1N1 or, frankly, most infectious diseases.”

“If you start to put all of the data together that’s emerging, it turns out that this virus is probably a vasculotropic virus, meaning that it affects the [blood vessels],”

Mehra explains. “Then it starts to infect endothelial cell after endothelial cell, creates a local immune response, and inflames the endothelium.”

Benhur Lee, MD, a professor of microbiology at the Icahn School of Medicine at Mount Sinai:

“In SARS1, the protein that’s required to cleave it is likely present only in the lung environment, so that’s where it can replicate. To my knowledge, it doesn’t really go systemic,” Lee says. “[SARS-CoV-2] is cleaved by a protein called furin, and that’s a big danger because furin is present in all our cells, it’s ubiquitous.”

Sanjum Sethi, MD, MPH, an interventional cardiologist at Columbia University Irving Medical Center:

“The endothelial cell layer is in part responsible for [clot] regulation, it inhibits clot formation through a variety of ways, If that’s disrupted, you could see why that may potentially promote clot formation.” Damage to endothelial cells causes inflammation in the blood vessels, and that can cause any plaque that’s accumulated to rupture, causing a heart attack. “Inflammation and endothelial dysfunction promote plaque rupture. Endothelial dysfunction is linked towards worse heart outcomes, in particular myocardial infarction or heart attack.”

https://elemental.medium.com/coronavirus-may-be-a-blood-vessel-disease-which-explains-everything-2c4032481ab2

Endothelial cell dysfunction: pre-existing conditions like high blood pressure, high cholesterol, diabetes, and heart disease are at a higher risk for severe complications from a virus that’s supposed to just infect the lungs. Why ventilation often isn’t enough to help many Covid-19 patients breathe better. Moving air into the lungs, which ventilators help with, is only one part of the equation. The exchange of oxygen and carbon dioxide in the blood is just as important to provide the rest of the body with oxygen, and that process relies on functioning blood vessels in the lungs.

William Li, MD, president of the Angiogenesis Foundation:

“If you have blood clots within the blood vessels that are required for complete oxygen exchange, even if you’re moving air in and out of the airways, [if] the circulation is blocked, the full benefits of mechanical ventilatory support are somewhat thwarted,” “We were observing virus particles filling up the endothelial cell like filling up a gumball machine. The endothelial cell swells and the cell membrane starts to break down, and now you have a layer of injured endothelium.” “Endothelial cells connect the entire circulation [system], 60,000 miles worth of blood vessels throughout our body,” says Li. “Is this one way that Covid-19 can impact the brain, the heart, the Covid toe? Does SARS-CoV-2 traffic itself through the endothelial cells or get into the bloodstream this way? We don’t know the answer to that.”

https://elemental.medium.com/coronavirus-may-be-a-blood-vessel-disease-which-explains-everything-2c4032481ab2

If Covid-19 is a vascular disease, the best antiviral therapy might not be antiviral therapy

“I suspect from what we see and what our preliminary data show is that this virus has an additional risk factor for blood clots, but I can’t prove that yet,” Sethi says. An alternative theory is that the blood clotting and symptoms in other organs are caused by inflammation in the body due to an over-reactive immune response — the so-called cytokine storm

SARS-CoV-2 virus can infect the endothelial cells that line the inside of blood vessels. Endothelial cells protect the cardiovascular system, and they release proteins that influence everything from blood clotting to the immune response. In the paper, the scientists showed damage to endothelial cells in the lungs, heart, kidneys, liver, and intestines in people with Covid-19.

Treatment Protocol for COVID-19

The good news is that if Covid-19 is a vascular disease, there are existing drugs that can help protect against endothelial cell damage. In another New England Journal of Medicine paper that looked at nearly 9,000 people with Covid-19, Mehra showed that the use of statins and ACE inhibitors were linked to higher rates of survival. Statins reduce the risk of heart attacks not only by lowering cholesterol or preventing plaque, they also stabilize existing plaque, meaning they’re less likely to rupture if someone is on the drugs.

“It turns out that both statins and ACE inhibitors are extremely protective on vascular dysfunction,” Mehra says. “Most of their benefit in the continuum of cardiovascular illness — be it high blood pressure, be it stroke, be it heart attack, be it arrhythmia, be it heart failure — in any situation the mechanism by which they protect the cardiovascular system starts with their ability to stabilize the endothelial cells.”

  • The best therapy might actually be a drug that stabilizes the vascular endothelial.

Endothelial cell infection and endotheliitis in COVID-19

Cardiovascular complications are rapidly emerging as a key threat in coronavirus disease 2019 (COVID-19) in addition to respiratory disease. The mechanisms underlying the disproportionate effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on patients with cardiovascular comorbidities, however, remain incompletely understood.
SARS-CoV-2 infects the host using the angiotensin converting enzyme 2 (ACE2) receptor, which is expressed in several organs, including the lung, heart, kidney, and intestine. ACE2 receptors are also expressed by endothelial cells.
Whether vascular derangements in COVID-19 are due to endothelial cell involvement by the virus is currently unknown. Intriguingly, SARS-CoV-2 can directly infect engineered human blood vessel organoids in vitro.
Here we demonstrate endothelial cell involvement across vascular beds of different organs in a series of patients with COVID-19 (further case details are provided in the appendix).
Patient 1 was a male renal transplant recipient, aged 71 years, with coronary artery disease and arterial hypertension. The patient’s condition deteriorated following COVID-19 diagnosis, and he required mechanical ventilation. Multisystem organ failure occurred, and the patient died on day 8.

Post-mortem analysis of the transplanted kidney by electron microscopy revealed viral inclusion structures in endothelial cells (figure A, B). In histological analyses, we found an accumulation of inflammatory cells associated with endothelium, as well as apoptotic bodies, in the heart, the small bowel (figure C) and lung (figure D). An accumulation of mononuclear cells was found in the lung, and most small lung vessels appeared congested.

See Figures in https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30937-5/fulltext

Findings
We found evidence of direct viral infection of the endothelial cell and diffuse endothelial inflammation. Although the virus uses ACE2 receptor expressed by pneumocytes in the epithelial alveolar lining to infect the host, thereby causing lung injury, the ACE2 receptor is also widely expressed on endothelial cells, which traverse multiple organs.
Recruitment of immune cells, either by direct viral infection of the endothelium or immune-mediated, can result in widespread endothelial dysfunction associated with apoptosis (figure D).
The vascular endothelium is an active paracrine, endocrine, and autocrine organ that is indispensable for the regulation of vascular tone and the maintenance of vascular homoeostasis.
Endothelial dysfunction is a principal determinant of microvascular dysfunction by shifting the vascular equilibrium towards more vasoconstriction with subsequent organ ischaemia, inflammation with associated tissue oedema, and a pro-coagulant state.
Our findings show the presence of viral elements within endothelial cells and an accumulation of inflammatory cells, with evidence of endothelial and inflammatory cell death. These findings suggest that SARS-CoV-2 infection facilitates the induction of endotheliitis in several organs as a direct consequence of viral involvement (as noted with presence of viral bodies) and of the host inflammatory response. In addition, induction of apoptosis and pyroptosis might have an important role in endothelial cell injury in patients with COVID-19.
COVID-19-endotheliitis could explain the systemic impaired microcirculatory function in different vascular beds and their clinical sequelae in patients with COVID-19. This hypothesis provides a rationale for therapies to stabilise the endothelium while tackling viral replication, particularly with anti-inflammatory anti-cytokine drugs, ACE inhibitors, and statins., , , ,
This strategy could be particularly relevant for vulnerable patients with pre-existing endothelial dysfunction, which is associated with male sex, smoking, hypertension, diabetes, obesity, and established cardiovascular disease, all of which are associated with adverse outcomes in COVID-19.

References

    • Zhou F
    • Yu T
    • Du R
    • et al.
    Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.

    Lancet.2020; 3951054-1062

    • Horton R
  1. Offline: COVID-19—bewilderment and candour.

    Lancet.2020; 3951178

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  2. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2.

    Circulation.2005; 1112605-2610

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  3. Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2.

    Cell.2020; (published online in press.)

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  4. The assessment of endothelial function: from research into clinical practice.

    Circulation.2012; 126753-767

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  5. Endothelial dysfunction – a marker of atherosclerotic risk.

    Arterioscl Throm Vas.2003; 23168-175

    • Anderson TJ
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  6. The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion.

    N Engl J Med.1995; 332488-493

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  8. Angiotensin-converting enzyme inhibition improves vascular function in rheumatoid arthritis.

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  10. Trials of anti-tumour necrosis factor therapy for COVID-19 are urgently needed.

    Lancet.2020; (published online April 9.)

Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19

List of authors.

  • Mandeep R. Mehra, M.D.,
  • Sapan S. Desai, M.D., Ph.D.,
  • SreyRam Kuy, M.D., M.H.S.,
  • Timothy D. Henry, M.D.,
  • and Amit N. Patel, M.D.

Metrics

Abstract

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.

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.)

As the coronavirus disease 2019 (Covid-19) pandemic has spread around the globe, there has been growing recognition that persons with underlying increased cardiovascular risk may be disproportionately affected.1-3 Several studies of case series have noted cardiac arrhythmias, cardiomyopathy, and cardiac arrest as terminal events in patients with Covid-19.1-4 Higher incidences of cardiac arrhythmias, acute coronary syndromes, and heart failure–related events have also been reported during seasonal influenza outbreaks, which suggests that acute respiratory infections may result in activation of coagulation pathways, proinflammatory effects, and endothelial cell dysfunction.5 In addition, however, concern has been expressed that medical therapy for cardiovascular disease might specifically contribute to the severity of illness in patients with Covid-19.6,7

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Covid-19, has been shown to establish itself in the host through the use of angiotensin-converting enzyme 2 (ACE2) as its cellular receptor.8 ACE2 is a membrane-bound monocarboxypeptidase found ubiquitously in humans and expressed predominantly in heart, intestine, kidney, and pulmonary alveolar (type II) cells.7,9 Entry of SARS-CoV-2 into human cells is facilitated by the interaction of a receptor-binding domain in its viral spike glycoprotein ectodomain with the ACE2 receptor.10

ACE2 is counterregulatory to the activity of angiotensin II generated through ACE1 and is protective against detrimental activation of the renin–angiotensin–aldosterone system. Angiotensin II is catalyzed by ACE2 to angiotensin-(1–7), which exerts vasodilatory, antiinflammatory, antifibrotic, and antigrowth effects.11 It has been suggested that ACE inhibitors and angiotensin-receptor blockers (ARBs) may increase the expression of ACE2, which has been shown in the heart in rats,12 and thereby may confer a predisposition to more severe infection and adverse outcomes during Covid-19.6,7 Others have suggested that ACE inhibitors may counter the antiinflammatory effects of ACE2. However, in vitro studies have not shown direct inhibitory activity of ACE inhibitors against ACE2 function.9,13

Despite these uncertainties, some have recommended cessation of treatment with ACE inhibitors and ARBs in patients with Covid-19.6 However, several scientific societies, including the American Heart Association, the American College of Cardiology, the Heart Failure Society of America, and the Council on Hypertension of the European Society of Cardiology, have urged that these important medications should not be discontinued in the absence of clear clinical evidence of harm.14,15 We therefore undertook a study to investigate the relationship between underlying cardiovascular disease and Covid-19 outcomes and to evaluate the association between cardiovascular drug therapy and mortality in this illness.

Discussion

Our investigation confirms previous reports of the independent relationship of older age, underlying cardiovascular disease (coronary artery disease, heart failure, and cardiac arrhythmias), current smoking, and COPD with death in Covid-19. Our results also suggest that women are proportionately more likely than men to survive the infection. Neither harmful nor beneficial associations were noted for antiplatelet therapy, beta-blockers, or hypoglycemic therapy. It is important to note that we were not able to confirm previous concerns regarding a potential harmful association of either ACE inhibitors or ARBs with in-hospital mortality in this clinical context.

In viral infections such as influenza, older age is associated with an increased risk of cardiovascular events and death.5 In the 2003 epidemic of severe acute respiratory syndrome (SARS, caused by SARS-CoV-1 infection), sex differences in the risk of death similar to those we observed were noted.17 Women have stronger innate and adaptive immunity and greater resistance to viral infections than men.18 In animal models of SARS-CoV-1 infection, higher susceptibility of male mice to SARS-CoV-1 and greater accumulation of macrophages and neutrophils in the lungs have been described.19 Ovariectomy or the use of estrogen-receptor antagonists increased mortality from SARS-CoV-1 infection in female animals. Furthermore, the difference in risk between the sexes increased with advancing age.19 These findings may support the observation in our investigation that suggested an association between survival and female sex, independent of older age.

Infection with SARS-CoV-2 is a mild disease in most people, but in some the disease progresses to a severe respiratory illness characterized by a hyperinflammatory syndrome, multiorgan dysfunction, and death.20 In the lung, the viral spike glycoprotein of SARS-CoV-2 interacts with cell-surface ACE2, and the virus is internalized by endocytosis. The endocytic event up-regulates the activity of ADAM metallopeptidase domain 17 (ADAM17), which cleaves ACE2 from the cell membrane, resulting in a loss of ACE2-mediated protection against the effects of activation of the tissue renin–angiotensin–aldosterone system while mediating the release of proinflammatory cytokines into the circulation.21 The stress of critical illness and inflammation may unite in destabilizing preexisting cardiovascular illness. Vascular endothelial cell dysfunction, inflammation-associated myocardial depression, stress cardiomyopathy, direct viral infection of the heart and its vessels, or the host response may cause or worsen heart failure, demand-related ischemia, and arrhythmias.22 These factors may underlie the observed associations between cardiovascular disease and death in Covid-19.

In our analyses, use of either ACE inhibitors or statins was associated with better survival among patients with Covid-19. However, these associations should be considered with extreme caution. Because our study was not a randomized, controlled trial, we cannot exclude the possibility of confounding. In addition, we examined relationships between many variables and in-hospital death, and no primary hypothesis was prespecified; these factors increased the probability of chance associations being found. Therefore, a cause-and-effect relationship between drug therapy and survival should not be inferred. These data also offer no information concerning the potential effect of initiation of ACE inhibitor or statin therapy in patients with Covid-19 who do not have an appropriate indication for these medications. Randomized clinical trials evaluating the role of ACE inhibitors and statins will be necessary before any conclusion can be reached regarding a potential benefit of these agents in patients with Covid-19.

In this multinational observational study involving patients hospitalized with Covid-19, we confirmed previous observations suggesting that underlying cardiovascular disease is independently associated with an increased risk of in-hospital death. We were not able to confirm previous concerns regarding a potential harmful association of ACE inhibitors or ARBs with in-hospital mortality in this clinical context.

Supported by the William Harvey Distinguished Chair in Advanced Cardiovascular Medicine at Brigham and Women’s Hospital. The development and maintenance of the Surgical Outcomes Collaborative database was funded by Surgisphere.

This article was published on May 1, 2020, and updated on May 8, 2020, at NEJM.org.

Author Affiliations

From Brigham and Women’s Hospital Heart and Vascular Center and Harvard Medical School, Boston (M.R.M.); Surgisphere, Chicago (S.S.D.); Baylor College of Medicine and Department of Veterans Affairs, Houston (S.K.); Christ Hospital, Cincinnati (T.D.H.); the Department of Biomedical Engineering, University of Utah, Salt Lake City (A.N.P.); and HCA Research Institute, Nashville (A.N.P.).

References

1. Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med 2020 March 3 (Epub ahead of print).

2. Shi S, Qin M, Shen B, et al. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiol 2020 March 25 (Epub ahead of print).

3. Guo T, Fan Y, Chen M, et al. Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19). JAMA Cardiol 2020 March 27 (Epub ahead of print).

4. Arentz M, Yim E, Klaff L, et al. Characteristics and outcomes of 21 critically ill patients with COVID-19 in Washington State. JAMA 2020 March 19 (Epub ahead of print).

5. Nguyen JL, Yang W, Ito K, Matte TD, Shaman J, Kinney PL. Seasonal influenza infections and cardiovascular disease mortality. JAMA Cardiol 2016;1:274-81.

6. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med 2020;8(4): e21.

7. Nicin L, Abplanalp WT, Mellentin H, et al. Cell type-specific expression of the putative SARS-CoV-2 receptor ACE2 in human hearts. Eur Heart J 2020 April 15 (Epub ahead of print).

8. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020;181(2):271.e8-280.e8.

9. Rice GI, Thomas DA, Grant PJ, Turner AJ, Hooper NM. Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism. Biochem J 2004;383: 45-51.

10. Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, function, and antigenicity of the SARSCoV-2 spike glycoprotein. Cell 2020; 181(2):281.e6-292.e6.

11. Li XC, Zhang J, Zhuo JL. The vasoprotective axes of the renin-angiotensin system: physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases. Pharmacol Res 2017;125:21-38.

12. Ferrario CM, Jessup J, Chappell MC, et al. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation 2005;111: 2605-10.

13. Patel AB, Verma A. COVID-19 and angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: what is the evidence? JAMA 2020 March 24 (Epub ahead of print).

14. American College of Cardiology. HFSA/ACC/AHA statement addresses concerns re: using RAAS antagonists in COVID-19. March 17, 2020 (https://www .acc.org/latest-in-cardiology/articles/ 2020/03/17/08/59/hfsa-acc-aha-statement -addresses-concerns-re-using-raas -antagonists-in-covid-19).

15. European Society of Cardiology. Position statement of the ESC Council on Hypertension on ACE-inhibitors and angiotensin receptor blockers. March 13, 2020 (https://www.escardio.org/Councils/ Council-on-Hypertension-(CHT)/News/ position-statement-of-the-esc-council-on -hypertension-on-ace-inhibitors-and-ang).

16. World Health Organization. Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected: interim guidance. March 13, 2020 (https://www.who.int/docs/default -source/coronaviruse/clinical -management-of-novel-cov.pdf).

17. Karlberg J, Chong DSY, Lai WYY. Do men have a higher case fatality rate of severe acute respiratory syndrome than women do? Am J Epidemiol 2004;159:229- 31. The New England Journal of Medicine Downloaded from nejm.org on June 1, 2020. For personal use only. No other uses without permission. Copyright © 2020 Massachusetts Medical Society. All rights reserved. 8 n engl j med nejm.org The new england journal o f medicine

18. Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol 2016;16:626-38.

19. Channappanavar R, Fett C, Mack M, Ten Eyck PP, Meyerholz DK, Perlman S. Sex-based differences in susceptibility to severe acute respiratory syndrome coronavirus infection. J Immunol 2017;198: 4046-53.

20. Siddiqi HK, Mehra MR. COVID-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal. J Heart Lung Transplant 2020;39:405-7.

21. Wang K, Gheblawi M, Oudit GY. Angiotensin converting enzyme 2: a double edged sword. Circulation 2020 March 26 (Epub ahead of print).

22. Mehra MR, Ruschitzka F. COVID-19 illness and heart failure: a missing link? JACC Heart Fail (in press). Copyright © 2020 Massachusetts Medical Society

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SARS-CoV-2 is pre-adapted to Human Transmission, branches of evolution stemming from a less well-adapted human SARS-CoV-2-like virus have been found: The Role of SARS-CoV-2 Virus Progenitors for Future Virus Disease Transmission and Pandemic Re-Emergence

Reporter and Curator: Aviva Lev-Ari, PhD, RN – all bold face and colors are my additions

 

UPDATED on 6/4/2020

Former MI6 head claims COVID-19 was made in a Chinese lab

Sir Richard Dearlove said there was good evidence that the virus was engineered, but that it’s escape from the laboratory was accidental.

A former head of the British intelligence agency MI6 has said that he believes the COVID-19 virus was created in a lab and spread accidentally. Speaking to The Telegraph‘s Planet Normal podcast, Sir Richard Dearlove cited recent research which claimed to have found key evidence that the virus had been manipulated to bind to humans.

If accurate, the research would have far-reaching political effects as governments around the world re-examined their dealings with the Communist state, including raising the question of reparation payments from China to the rest of the world for the damage caused by the virus.

A former head of the British intelligence agency MI6 has said that he believes the COVID-19 virus was created in a lab and spread accidentally. Speaking to The Telegraph‘s Planet Normal podcast, Sir Richard Dearlove cited recent research which claimed to have found key evidence that the virus had been manipulated to bind to humans.

If accurate, the research would have far-reaching political effects as governments around the world re-examined their dealings with the Communist state, including raising the question of reparation payments from China to the rest of the world for the damage caused by the virus.

“I do think that this started as an accident,” Sir Richard told the Telegraph, citing a peer-reviewed paper by Professor Angus Dalgleish of St George’s Hospital at the University of London, and the Norwegian virologist Birger Sorensen.

According to Sir Richard, the pair claimed to have identified “inserted sections placed on the SARS-CoV-2 Spike surface,” which allow the virus to bind to human cells, in contrast to alternate theories that the virus originated in animals, likely bats and pangolins, and mutated naturally to make the jump to human hosts. And they warn that current efforts to develop a vaccine are likely to be unsuccessful, as the true causation of the virus’s effects are being misunderstood by other scientists. The researchers are therefore working on their own vaccine, produced by Immunor AS, a Norwegian pharmaceutical company led by Mr Sorensen according to the Telegraph.

The research paper was “a very important contribution to a debate which is now starting about how the virus evolved and how it got out and broke out as a pandemic”, Sir Richard said, adding: “I think this particular article is very important, and I think it will shift the debate.”

Dalgleish and Sorensen’s article was re-written a number of times after early versions failed to achieve publication. An early version seen by the Telegraph suggested COVID-19 be known as the “Wuhan virus,” and said that it was “beyond reasonable doubt that the Covid-19 virus is engineered.” The authors originally noted: “We are aware that these findings could have political significance and raise troubling questions.”

However, the paper was not accepted for publication until the authors had re-drafted to remove explicit claims against China. Following the edits, the science presented within the paper was deemed of sufficient worth for publication in the Quarterly Review of Biophysics Discovery, chaired by leading Stanford University and University of Dundee scientists.

SOURCE

https://www.jpost.com/health-science/former-mi6-head-covid-19-was-made-in-a-chinese-lab-630346?from=groupmessage

LPBI Position Statement

A.  SARS-CoV-2 is pre-adapted to Human Transmission

B.  Branches of evolution stemming from a less well-adapted human SARS-CoV-2-like virus have been found

C.  The Role of SARS-CoV-2 Virus Progenitors – ARE CLEAR

D. Virus Progenitors will potentiate Future Virus Disease Transmission

E.  Pandemic Re-Emergence – Is  InEVITABLE and Virus Progenitors will be the subject for 2nd generation of virus genetic engineering technologies for human infectivity

 

  • Top vaccine scientist says coronavirus is ‘almost perfectly human adapted’

The coronavirus that causes COVID-19 is “almost perfectly human adapted” — lending credence to the possibility it was man-made in a Chinese lab, a top Australian vaccine researcher says.

Nikolai Petrovsky was shocked when research found that the virus was more virulent in humans than any other animal, the Daily Mail reported.

He said it was like the new strain of coronavirus, called SARS-CoV-2, was “completely optimized from day one without the need to evolve” like other viruses.

“This is a new virus that has never been in humans before, but it has an extraordinarily high binding to human receptors, which is very surprising,” Petrovsky told the Mail. “It is almost perfectly human adapted, it couldn’t do any better.”

He said it is possible the virus was created in a lab in China — deepening suspicions that the global pandemic originated in Wuhan.

“We have to ask how that happened. Was it a complete fluke? It can be as nature has many shots at goal and you only see the ones that land,” Petrovsky said.

SOURCE

https://nypost.com/2020/05/27/top-vaccine-scientist-covid-19-is-almost-perfectly-human-adapted/

  • No known animal host and ‘almost perfect’ human adaption: Top Australian vaccine scientist reveals how COVID-19’s unique structure means it’s either man-made – or a ‘complete fluke’ of nature
  • Professor Nikolai Petrovsky said virus was better at attaching itself to human cells than to any other animal
  • It is so ‘perfectly adapted’ to infect humans that the possibility it was made in a Chinese lab can’t be ignored
  • Wuhan Institute of Virology studied bat coronaviruses and is theorised to have accidentally leaked COVID-19
  • Virus could have been formed naturally by mixing bat and pangolin versions, but this is statistically unlikely
  • Professor Petrovsky said the inquiry into virus origins needed urgently and should have started months ago

“This, plus the fact that no corresponding virus has been found to exist in nature, leads to the possibility that COVID-19 is a human-created virus. It is therefore entirely plausible that the virus was created in the biosecurity facility in Wuhan [WIV] by selection on cells expressing human ACE2 [receptor], a laboratory that was known to be cultivating exotic bat coronaviruses at the time.” https://www.washingtontimes.com/news/2020/may/21/australian-researchers-see-virus-design-manipulati/

Scientist in protective overall

“We can’t exclude the possibility that this came from a laboratory experiment rather than from an animal” – Prof Nikolai Petrovsky

Genetic engineering the quicker way to human infectivity

Commenting on Prof Petrovsky’s conclusion that SARS-CoV-2 could have originated from culture of a wild virus and selection in human cells, the London-based molecular geneticist Dr Michael Antoniou agreed that this scenario was plausible: “You can certainly develop a human-infective virus like SARS-CoV-2 by repeatedly passing a wild bat virus through human cells, in the way that Prof Petrovsky describes. You culture human cells with the virus, allowing the virus to replicate, and harvest the resulting viruses. This selects for the most human-infective viruses, which you use to re-infect more cells. By going through successive rounds of this process, you are gradually selecting for viruses that have acquired mutations leading to enhancement of human infectivity. Eventually you end up with a virus that is optimized for human infectivity.”

However, Dr Antoniou added that there are far quicker and more efficient ways to achieve this aim.

For example, if you start with little information about what your human-infective virus looks like, you can genetically engineer a large number of SARS-CoV spike protein variants within phages. Phages are viruses that can infect bacteria. Phages can be genetically engineered to express on their exterior coat the CoV spike protein with a different variant of the receptor binding domain (RBD) – the part of the spike protein that allows the virus to bind to the ACE2 protein on human cell surfaces and thus enables infection to take place. This collection of phage variants with different RBDs is called a “phage display library”. The “library” of variants is then cultured with human cells in order to select for those phages with spike protein variants that bind to the ACE2 receptor.

Then the DNA is extracted from the phage with the best-binding spike protein and sequenced. Based on the sequence, a whole virus optimized for human infectivity can be synthesized.

Alternatively, Dr Antoniou explained, if you start with some information, as is likely with a group of researchers experienced in coronavirus gain-of-function research, there is an even quicker way to create a human-infective virus. Given that past research indicates that the nature of the spike protein alone doesn’t determine infectivity, it seems sensible to generate a library of spike mutant proteins directly within a whole coronavirus, which would also contain any other components necessary for infectivity.

In this case, you would take a DNA clone of a coronavirus that you know to be close to human infectivity, based on the sequence of its RBD. (Manipulation of DNA clones of coronaviruses is the standard procedure used to generate mutant viruses, including chimeras, in gain-of-function experiments, such as those carried out by scientists at the University of North Carolina and the Wuhan Institute of Virology.) You would then use the genetic engineering technique of DNA synthesis to generate a large number of randomly mutated versions of the spike protein RBD. The RBD mutations that you engineer could be more narrowly targeted by focusing on those regions encoding the amino acids whose nature and positions you know to be most critical for docking onto the human ACE2 receptor. The mutant versions of the RBD would then be selected for strong binding to the ACE2 receptor and consequently high infectivity of human cells.

Both methods described above would not leave any “signature” of genetic engineering. That’s an important consideration, given that Prof Petrovsky believes that genetic engineering was not involved in the development of SARS-CoV-2 due to the absence of such a signature.

Genetic engineering likely

In GMWatch’s view, to bypass the efficient genetic engineering-based methods described by Dr Antoniou in favour of the more laborious culture and selection-only method suggested by Prof Petrovsky would seem a curious decision for any laboratory committed to investigating coronavirus gain-of-function, such as the WIV.

The conclusions that we draw from these two new papers and Dr Antoniou’s input are that the “zoonosis” theory of SARS-CoV-2’s origin looks increasingly open to question, that the lab escape theory appears to be a solidly based scenario and, if that is what happened, genetic engineering is highly likely to have played a part in the development of the virus.

Report by Claire Robinson

SOURCE

https://www.gmwatch.org/en/news/latest-news/19412-lab-escape-theory-of-sars-cov-2-origin-gaining-scientific-support

  • Why Was Wuhan Lab Locked Down When Outbreak Began?
Analysis by Dr. Joseph Mercola Fact Checked

GAs reported in “Bioweapon Labs Must Be Shut Down and Scientists Prosecuted,” there’s mounting evidence suggesting SARS-CoV-2 may have been leaked (whether inadvertently or not) from the biosafety level (BSL) 4 laboratory in Wuhan, China.1,2I’ve also interviewed bioweapons expert Francis Boyle and molecular biologist Judy Mikovits, both of whom have cited evidence that strongly points toward SARS-CoV-2 being an escaped laboratory creation.

Why Was Wuhan Lab Shut Down?

Fueling suspicions that SARS-CoV-2 escaped from the lab in Wuhan — and that it began far earlier than admitted — is an analysis3 of commercial telemetry (i.e., cellphone) data showing a significant and unusual reduction in device activity in and around the Wuhan Institute of Virology’s (WIV) National Biosafety Laboratory during October 2019.4,5,6According to the open source telemetry report,7 “Beginning on October 11, there was a substantial decrease in activity,” and “the last time a device is active prior to October 11 is October 6.”Between October 14 and October 19, there was no device activity in the area around the laboratory at all. “During this time, it is believed that roadblocks were put in place to prevent traffic from coming near the facility,” the report states. What’s more, between October 7 and October 24, there was no activity within the facility itself.While not concrete proof of a biohazard leak, the absence of cellphone traffic in and around the laboratory in October 2019 suggests the lab may have been shut down for a period, and the roads around it blocked off. The question is why?Amid accusations that the World Health Organization helped suppress information about the pandemic on behalf of China, a review of its handling of the COVID-19 pandemic will be conducted,8 although it is still unclear which body will conduct the review and when. Many are also asking just how independent such a review will or can be.According to Martenson, the fact that SARS-CoV-2’s spike protein has a furin cleavage site is “the smoking gun” that proves it was created in a lab. I invite you to review his easy-to-follow analysis in “The Smoking Gun Proving SARS-CoV-2 Is an Engineered Virus.”If the Nerd Has Power blogger is correct, and the bat virus RaTG13 was in fact fabricated in order to give the natural evolution theory of SARS-CoV-2 some credence, then the evidence for a man-made pandemic becomes all the more compelling. There’s also other evidence that raise serious questions about the origin of this pandemic virus. Other Evidence of ManipulationIn an earlier blog post, dated March 15, 2020, Nerd Has Power explains the importance of the S1 and S2 spikes of a given virus.38 In that post, the blogger also details significant changes found in the S1 portion of the SARS-CoV-2 spike protein, “which dictates which host a coronavirus targets,” whereas much of the rest of the spike is very similar to the bat coronaviruses ZC45 and ZXC21. According to the blogger:39

“… the details of these differences and the way the human and the bat viruses differ from each other here in S1, in my and many other people’s eyes, practically spell out the origin of the Wuhan coronavirus — it is created by people, not by nature.”

In my opinion, the strongest pieces of evidence so far all point toward SARS-CoV-2 being a laboratory creation. How it got released, however, and why, remains to be determined.The fact that the people responsible would want to cover it up is obvious, however, when you consider that the punishment in such an event could include life in prison for violating the Biological Weapons Anti-Terrorism Act of 1989.40

Sources & References

wuhan bio lab shut down

STORY AT-A-GLANCE

  • Fueling suspicions that SARS-CoV-2 escaped from the Wuhan lab is an analysis of commercial telemetry (i.e., cellphone) data showing a significant and unusual reduction in device activity in and around the Wuhan Institute of Virology’s National Biosafety Laboratory during October 2019
  • Between October 14 and October 19, there was no device activity in the area around the laboratory at all, and between October 7 and October 24, there was no activity within the facility itself
  • While not concrete proof of a biohazard leak, the absence of cellphone traffic in and around the laboratory in October 2019 suggests the lab may have been shut down for a period, and the roads around it blocked off
  • A crucial piece of the lab release hypothesis that is missing from media reports and scientific opinion is a clear description of the experiments being conducted at the Wuhan Institute of Virology
  • Researchers have engineered chimeric viruses where the gene for the cell entry protein (S protein receptor-binding domain) from one virus is replaced by that of another virus
  • Bioweapon Labs Must Be Shut Down and Scientists Prosecuted
Analysis by Dr. Joseph Mercola Fact Checked
  • Gain of Function Research at NIH

https://osp.od.nih.gov/biotechnology/gain-of-function-research/

 

  • A pneumonia outbreak associated with a new coronavirus of probable bat origin

Nature volume 579, pages270–273(2020)Cite this article

https://www.nature.com/articles/s41586-020-2012-7

 

  • A pneumonia outbreak associated with a new coronavirus of probable bat origin.

Zhou, P., Yang, X., Wang, X. et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270–273 (2020). https://doi.org/10.1038/s41586-020-2012-7

Abstract

Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats1,2,3,4. Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans5,6,7. Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor—angiotensin converting enzyme II (ACE2)—as SARS-CoV.

References

  1. Li, W. et al. Bats are natural reservoirs of SARS-like coronaviruses. Science310, 676–679 (2005).
  2. Ge, X.-Y. et al. Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor. Nature503, 535–538 (2013).
  3. Yang, L. et al. Novel SARS-like betacoronaviruses in bats, China, 2011. Emerg. Infect. Dis19, 989–991 (2013).
  4. Hu, B. et al. Discovery of a rich gene pool of bat SARS-related coronaviruses provides new insights into the origin of SARS coronavirus. PLoS Pathog13, e1006698 (2017).

 

  • A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence

Menachery, V., Yount, B., Debbink, K. et al. A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence. Nat Med 21, 1508–1513 (2015). https://doi.org/10.1038/nm.3985

Abstract

The emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome (MERS)-CoV underscores the threat of cross-species transmission events leading to outbreaks in humans. Here we examine the disease potential of a SARS-like virus, SHC014-CoV, which is currently circulating in Chinese horseshoe bat populations1. Using the SARS-CoV reverse genetics system2, we generated and characterized a chimeric virus expressing the spike of bat coronavirus SHC014 in a mouse-adapted SARS-CoV backbone. The results indicate that group 2b viruses encoding the SHC014 spike in a wild-type backbone can efficiently use multiple orthologs of the SARS receptor human angiotensin converting enzyme II (ACE2), replicate efficiently in primary human airway cells and achieve in vitro titers equivalent to epidemic strains of SARS-CoV. Additionally, in vivo experiments demonstrate replication of the chimeric virus in mouse lung with notable pathogenesis. Evaluation of available SARS-based immune-therapeutic and prophylactic modalities revealed poor efficacy; both monoclonal antibody and vaccine approaches failed to neutralize and protect from infection with CoVs using the novel spike protein. On the basis of these findings, we synthetically re-derived an infectious full-length SHC014 recombinant virus and demonstrate robust viral replication both in vitro and in vivo. Our work suggests a potential risk of SARS-CoV re-emergence from viruses currently circulating in bat populations.

https://www.nature.com/articles/nm.3985/#citeas

 

Donato Gemmati, Barbara Bramanti, […] & Veronica Tisato

International Journal of Molecular Sciences (2020)

 

  • Evolutionary arms race between virus and host drives genetic diversity in bat SARS related coronavirus spike genes

Hua Guo, Bing-Jie Hu, Xing-Lou Yang, Lei-Ping Zeng, Bei Li, Song-Ying Ouyang, Zheng-Li Shi

doi: https://doi.org/10.1101/2020.05.13.093658

https://www.biorxiv.org/content/10.1101/2020.05.13.093658v1

 

LPBI Position 

A.  SARS-CoV-2 is pre-adapted to Human Transmission

B.  Branches of evolution stemming from a less well-adapted human SARS-CoV-2-like virus have been found

C.  The Role of SARS-CoV-2 Virus Progenitors – ARE CLEAR

D. Virus Progenitors will potentiate Future Virus Disease Transmission

E.  Pandemic Re-Emergence – Is  InEVITABLE and Virus Progenitors will be the subject for 2nd generation of genetic engineering technologies

Read Full Post »


COVID-19: Novel Treatment Protocols using Approved drugs vs Standard of Care vs Vaccine and Antiviral new drug discovery and development – An LPBI Group Response and An LPBI Group & Affiliates Response

Curator: Aviva Lev-Ari, PhD, RN

 

On 5/26/2020 LPBI organized a Symposium on New Therapeutics for COVID-19

AGENDA included presentations by:

  • Dr. Raphael Nir, PhD, CSO, SBH, Sciences, Inc. – Drug Concept to mitigate Cytokine Storm in COVID-19 – ATTACHMENT
  • Dr. Ajay Gupta, MD, Professor & Entrepreneur – Rhinitis drug approved in Japan – REPURPOSED for COVID-19 and Application for FDA Approval
  • Dr. Yigal Blum, PhD, ex-SRI Int’l VP and Entrepreneur –  AMORPHOUS CALCIUM CARBONATE (ACC) TREATMENT FOR COVID-19
  • Dr. Orna Harel, PhD, Managing Partner, Agbiopro – Representation for – Prof. Saul Yedgar on the concept and state of preclinical efforts for COVID-19 drug development 
  • Aviva Lev-Ari, PhD, RN – The Potential of REVIVAL of Drug Discovery Initiative and Explorations of Joint Ventures with Biotech companies – An Interim Phase toward POST Coronavirus Pandemic Exit

DISCUSSION – Where and What is the INTERFACE between what our External Relations attempt to accomplish and the Capabilities of LPBI Group’s Team

In the concluding remarks, Dr. Lev-Ari discussed the importance of TREATMENT PROTOCOLS vs. one Therapeutics at a time vs. Combination Drug therapies.

Dr. Lev-Ari pointed the Symposium attendees to the following two points:

1.  The State of Science been endorsed by LPBI Group

RNA from the SARS-CoV-2 virus taking over the cells it infects: Virulence – Pathogen’s ability to infect a Resistant Host: The Imbalance between Controlling Virus Replication versus Activation of the Adaptive Immune Response
Curator: Aviva Lev-Ari, PhD, RN – I added colors and bold face
https://pharmaceuticalintelligence.com/2020/05/23/rna-from-the-sars-cov-2-virus-taking-over-the-cells-it-infects-virulence-pathogens-ability-to-infect-a-resistant-host-the-imbalance-between-controlling-virus-replication-versus-activation-of-the/

2.  LPBI Group’s Position for Treatment Protocol(s)

In continuation to 5/26/2020 Symposium on New Therapeutics for COVID-19, we will follow up with an AGENDA for 6/16/2020 

Part I: Therapeutics for COVID-19

  • Prof. Saul Yedgar – Holder of US Patents on Rhinitis, anti-inflatation and other indications – 40 minutes
  • Dr. Ajay Gupta, MD – Rhinitis drug approved in Japan – FDA Application for Approval of Repurpusing to COVID-19 in the US – 40 minutes
  • Discussion – 20 minutes

 

On 5/29/2020 Dr. Lev-Ari read the article, COVID-19 Critical Care

Analysis by Dr. Joseph Mercola

STORY AT-A-GLANCE

  • Despite the fact that many critical care specialists are using treatment protocols that differ from standard of care, information about natural therapeutics in particular are still being suppressed by the media and is not received by critical care physicians
  • Five critical care physicians have formed the Front Line COVID-19 Critical Care Working Group (FLCCC). The group has developed a highly effective treatment protocol known as MATH+
  • Of the more than 100 hospitalized COVID-19 patients treated with the MATH+ protocol as of mid-April, only two died. Both were in their 80s and had advanced chronic medical conditions
  • The protocols call for the use of intravenous methylprednisolone, vitamin C and subcutaneous heparin within six hours of admission into the hospital, along with high-flow nasal oxygen. Optional additions include thiamine, zinc and vitamin D
  • COVID-19 kills by triggering hyperinflammation, hypercoagulation and hypoxia. The MATH+ protocol addresses these three core pathological processes

COVID-19 Early Intervention Protocol

According to Kory, the FLCCCs MATH+ protocol has been delivered to the White House on four occasions, yet no interest has been shown. Worse, he says they continue to be stonewalled by the U.S. Centers for Disease Control and the National Institute for Health. Why?

Isn’t saving lives, right now, and by any means possible, more important than pushing for a vaccine? If the MATH+ protocol works with near-100% effectiveness, a vaccine may not even be necessary. The MATH+ protocol gets its name from:

Intravenous Methylprednisolone

High-dose intravenous Ascorbic acid

Plus optional treatments Thiamine, zinc and vitamin D

Full dose low molecular weight Heparin

Kory’s testimony transcript reviews and summarizes the MATH+ protocol, and explains why the timing of the treatment is so important. As explained by Kory, there are two distinct yet overlapping phases of COVID-19 infection.

  1. Phase 1 is the viral replication phase. Typically, patients will only experience mild symptoms, if any, during this phase. At this time, it’s important to focus on antiviral therapies.
  2. In Phase 2, the hyperinflammatory immune response sets in, which can result in organ failures (lungs, brain, heart and kidneys). The MATH+ protocol is designed to treat this active phase, but it needs to be administered early enough.

The MATH+ Protocol

The MATH+ protocol7 calls for the use of three medicines, all of which need to be started within six hours of hospital admission:

  • Intravenous methylprednisolone, to suppress the immune system and prevent organ damage from cytokine storms — For mild hypoxia, 40 milligrams (mg) daily until off oxygen; moderate to severe illness, 80 mg bolus followed by 20 mg per day for seven days. On Day 8, switch to oral prednisone and taper down over the next six days.
  • Intravenous ascorbic acid (vitamin C), to control inflammation and prevent the development of leaky blood vessels in the lungs — 3 grams/100 ml every six hours for up to seven days.
  • Subcutaneous heparin (enoxaparin), to thin the blood and prevent blood clots — For mild to moderate illness, 40 mg to 60 mg daily until discharged.

Optional additions include thiamine, zinc and vitamin D. In addition to these medications, the protocol calls for high-flow nasal oxygen to avoid mechanical ventilation, “which itself damages the lungs and is associated with a mortality rate approaching nearly 90% in some centers,” Kory notes.8

Together, this approach addresses the three core pathological processes seen in COVID-19, namely hyperinflammation, hypercoagulability of the blood, and hypoxia (shortness of breath due to low oxygenation).

COVID-19 Should Not Be Treated as ARDS

In the video, Dr. Paul Marik points out that it’s crucial for doctors to treat each patient as an individual case, as COVID-19 is not conventional acute respiratory distress syndrome (ARDS).

If the patient is assumed to have ARDS and placed on a ventilator, you’re likely going to damage their lungs. Indeed, research has now shown that patients placed on mechanical ventilation have far higher mortality rates than patients who are not ventilated. While not discussed here, some doctors are also incorporating hyperbaric oxygen treatment in lieu of ventilation, with great success.

The reason for this is because the primary problem is inflammation, not fluid in the lungs. So, Marik says, they need anti-inflammatory drugs. “It’s not the virus that is hurting the host, it’s the acute inflammatory dysregulated response,” he says. “That’s why you need to use vitamin C and steroids.” He points out that steroids play a crucial role, as it creates synergy with vitamin C.

COVID-19 patients also have a hypercoagulation problem, so they need anticoagulants. In addition to using the proper medication, they must also be treated early. “You have to intervene early and aggressively to prevent them from deteriorating,” Marik says.

Methylprednisolone May Be a Crucial Component

Kory expresses concerns over the fact that health organizations around the world are warning doctors against the use of corticosteroids, calling this a “tragic error”9 as “COVID-19 is a steroid-responsive disease.”10 In his testimony, he points out:11

“Sorin Draghici, CEO of Advaita Bioinformatics, just reported12 that their incredibly sophisticated Artificial Intelligence platform called iPathwayGuide, using cultured human cell lines infected with COVID-19, is able to map all the human genes which are activated by this virus …

Note almost all the activated genes are those that express triggers of inflammation. With this knowledge of the specific COVID inflammatory gene activation combined with knowledge of the gene suppression activity of all known medicines they were able to match the most effective drug for COVID-19 human gene suppression, and that drug is methylprednisolone.

This must be recognized, as the ability of other corticosteroids to control inflammation in COVID-19 was much less impactful. This is, we believe, an absolutely critical and historic finding. Many centers are using similar but less effective agents such as dexamethasone or prednisone.”

As noted by Kory in his senate testimony, Marik, chief of pulmonary and critical care medicine at the Eastern Virginia Medical School in Norfolk, Virginia, is a member of the FLCCC.13 You may recall that Marik was the one who in 2017 announced he had developed an extraordinarily effective treatment against sepsis.

Marik’s sepsis protocol also calls for intravenous vitamin C and a steroid, in this case hydrocortisone, along with thiamine. I for one am not surprised that the two protocols are so similar, seeing how sepsis is also a major cause of death in severe COVID-19 cases.

Safe and Effective Treatments Must Not Be Ignored

As noted by Marik in the video, COVID-19 is not regular ARDS and should not be treated as such. What kills people with COVID-19 is the inflammation, and steroids in combination with vitamin C work synergistically together to control and regulate that inflammation. The heparin, meanwhile, addresses the hypercoagulation that causes blood clots, which is a unique feature of COVID-19. As for the “lack of studies” supporting their protocol, FLCCC notes:14

“A number of official guidelines, such as those of the WHO and several other U.S. agencies, recommend limiting treatment for … critically ill patients to ‘supportive care only’ — and to allow the therapies described here to be studied in randomized controlled trials where half of the patients would receive placebo and where the results would come in months or years.

Our physicians agree that while a randomized controlled trial (RCT), under normal circumstances, might be considered, the early provisions of MATH+, which must be given within hours of critical illness, would inevitably be delayed by such a study design, rendering the validity of the RCT questionable.

Furthermore, while the results of an RCT would not be available for months or more, well-designed observational studies of the protocol could yield timely feedback during this pandemic, to improve the treatment process much more quickly.”

I believe this information needs to be shared far and wide, if we are to prevent more people from dying unnecessarily. More and more, as doctors are starting to speak openly about their clinical findings, we’re seeing that there are quite a few different ways to tackle this illness without novel antivirals or vaccines, using older, inexpensive and readily available medications that are already known to be safe.

References

SOURCE

https://blogs.mercola.com/sites/vitalvotes/archive/2020/05/28/lab-escape-theory-of-sarscov2-origin-gaining-scientific-support.aspx

 

A Response by LPBI Group and a Potential Response by LPBI Group and its Affiliates

 

LPBI Group’s Components in Novel Treatment Protocol Definition

 

  • Forthcoming by Stephen J. Williams, PhD – Immuno-theraphy boosting Protocol

based on

T cells found in COVID-19 patients ‘bode well’ for long-term immunity | Science | AAAS
https://www.sciencemag.org/news/2020/05/t-cells-found-covid-19-patients-bode-well-long-term-immunity

 

  • Forthcoming by Aviva Lev-Ari, PhD, RN and Stephen J. Williams, PhD – Nitric Oxide Inhaler OR Bystolic® (nebivolol) www.bystolicpro.com
  • Two alternatives per stage of COVID-19 infections: Severe or Moderate

based on

 

  • LPBI Group’s Affiliates:

If you wish your Therapeutic solution to be included in the NEW DEFINITION of Treatment Protocol(s), then propose your component for inclusion in the Novel Treatment Protocol to be discussed on June 16, 2020

LPBI Group’s Affiliates Components in the Novel Treatment Protocol(s) Definition

  • Prof. Saul Yedgar – Holder of US Patents on Rhinitis, anti-inflammation and other indications – 40 minutes
  • Dr. Ajay Gupta, MD – Rhinitis drug approved in Japan – FDA Application for Approval of Repurposing to COVID-19 in the US – 40 minutes
  • Dr. Raphael Nir, PhD, CSO, SBH, Sciences, Inc. – Drug Concept to mitigate Cytokine Storm in COVID-19 
  • Dr. Yigal Blum, PhD, ex-SRI Int’l VP and Entrepreneur –  AMORPHOUS CALCIUM CARBONATE (ACC) TREATMENT FOR COVID-19

References on Nitric Oxide on PharmaceuticalIntellige.com – Open Access Online Scientific Journal include 299 articles

https://pharmaceuticalintelligence.com/?s=Nitric+Oxide

Of note

 

Included in the 299 articles

  • Transposon-mediated Gene Therapy improves Pulmonary Hemodynamics and attenuates Right Ventricular Hypertrophy: eNOS gene therapy reduces Pulmonary vascular remodeling and Arterial wall hyperplasia

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/05/31/transposon-mediated-gene-therapy-improves-pulmonary-hemodynamics-and-attenuates-right-ventricular-hypertrophy-enos-gene-therapy-reduces-pulmonary-vascular-remodeling-and-arterial-wall-hyperplasia/

 

Author and Curator of an Investigator Initiated Study: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/10/04/endothelin-receptors-in-cardiovascular-diseases-the-role-of-enos-stimulation/

 

  • Inhibition of ET-1, ETA and ETA-ETB, Induction of NO production,  stimulation of eNOS and Treatment Regime with PPAR-gamma agonists (TZD): cEPCs Endogenous Augmentation for Cardiovascular Risk Reduction – A Bibliography

Curator of an Investigator Initiated Study: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/10/04/inhibition-of-et-1-eta-and-eta-etb-induction-of-no-production-and-stimulation-of-enos-and-treatment-regime-with-ppar-gamma-agonists-tzd-cepcs-endogenous-augmentation-for-cardiovascular-risk-reduc/

 

  • Cardiovascular Disease (CVD) and the Role of Agent Alternatives in endothelial Nitric Oxide Synthase (eNOS) Activation and Nitric Oxide Production

Curator and Investigator Initiated Study: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/07/19/cardiovascular-disease-cvd-and-the-role-of-agent-alternatives-in-endothelial-nitric-oxide-synthase-enos-activation-and-nitric-oxide-production/

 

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