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Archive for the ‘Treatment Protocols for COVID-19’ Category

COVID and the brain: researchers zero in on how damage occurs

Reporter: Danielle Smolyar

Research Assistant 3 – Text Analysis for 2.0 LPBI Group’s TNS #1 – 2020/2021 Academic Internship in Medical Text Analysis (MTA)

Recent evidence has indicated that coronavirus can cause brain fog and also lead to different neurological symptoms. 

Since the beginning of the pandemic, researchers have been trying to understand how the coronavirus SARS-CoV-2 affects the brain

Image Credit: Stanislav Krasilnikov/TASS/Getty

image source:https://www.nature.com/articles/d41586-021-01693-6?utm_source=Nature+Briefing

New evidence has shown how coronavirus has caused much damage to the brain. There is a new evidence that shows that COVID-19 assault on the brain I has the power to be multipronged. What this means is that it can attack on certain Brain cells such as reduce the amount of blood flow that the brain needs to the brain tissue.

Along with brain damage COVID-19 has also caused strokes and memory loss. A neurologist at yell University Serena Spudich says, “Can we intervene early to address these abnormalities so that people don’t have long-term problems?”

We’re on 80% of the people who have been hospitalized due to COVID-19 have showed brain symptoms which seem to be correlated to coronavirus.

At the start of the pandemic a group of researchers speculated that coronavirus they can damage the brain by infecting the neurons in the cells which are important in the process of transmitting information. After further studies they found out that coronavirus has a harder time getting past the brains defense system and the brain barrier and that it does not affect the neurons in anyway.

An expert in this study indicated that a way in which SARS-CoV-2 may be able to get to the brain is by going through the olfactory mucosa which is the lining of the nasal cavity. It is found that this virus can be found in the nasal cavity which is why we swab the nose one getting tested for COVID-19.

Spudich quotes, “there’s not a tonne of virus in the brain”.

Recent studies indicate that SARS-CoV-2 have ability to infect astrocytes which is a type of cell found in the brain. Astrocytes do quite a lot that supports normal brain function,” including providing nutrients to neurons to keep them working, says Arnold Kriegstein, a neurologist at the University of California, San Francisco.

Astrocytes are star-shaped cells in the central nervous system that perform many functions, including providing nutrients to neurons.

Image Credit: David Robertson, ICR/SPL

image source: https://www.nature.com/articles/d41586-021-01693-6?utm_source=Nature+Briefing

Kriegstein and his fellow colleagues have found that SARS-CoV-2 I mostly infects the astrocytes over any of the other brain cells present. In this research they expose brain organoids which is a miniature brain that are grown from stem cells into the virus.

As quoted in the article” a group including Daniel Martins-de-Souza, head of proteomics at the University of Campinas in Brazil, reported6 in a February preprint that it had analysed brain samples from 26 people who died with COVID-19. In the five whose brain cells showed evidence of SARS-CoV-2 infection, 66% of the affected cells were astrocytes.”

The infected astrocytes could indicate the reasoning behind some of the neurological symptoms that come with COVID-19. Specifically, depression, brain fog and fatigue. Kreigstein quotes, “Those kinds of symptoms may not be reflective of neuronal damage but could be reflective of dysfunctions of some sort. That could be consistent with astrocyte vulnerability.”

A study that was published on June 21 they compared eight different brands of deceased people who did have COVID-19 along with 14 brains as the control. The results of this research were that they found that there was no trace of coronavirus Brain infected but they found that the gene expression was affected in some of the astrocytes.

As a result of doing all this research and the findings the researchers want to know more about this topic and how many brain cells need to be infected for there to be neurological symptoms says Ricardo Costa.

Further evidence has also been done on how SARS-CoV-2 can affect the brain by reducing its blood flow which impairs the neurons’ function which ends up killing them.

Pericytes can be found on the small blood vessels which are called capillaries and are found all throughout the body and in the brain. In a February pre-print there was a report about how SARS-CoV-2 can infect the pericyte in the brain organoids. 

David Atwell, a neuroscientist at the University College London, along with his other colleagues had published a pre-print which has evidence to show that SARS-CoV-2 odes In fact pericytes behavior. I researchers saw that in the different part of the hamsters brain SARS-CoV-2 blocks the function of receptors on the pericytes which ultimately causes the capillaries found inside the tissues to constrict.

As stated in the article, It’s a “really cool” study, says Spudich. “It could be something that is determining some of the permanent injury we see — some of these small- vessel strokes.”

Attwell brought to the attention that the drugs that are used to treat high blood pressure may in fact be used in some cases of COVID-19. Currently there are two clinical trials that are being done to further investigate this idea.

There is further evidence showing that the neurological symptoms and damage could in fact be happening because of the bodies on immune system reacting or misfiring after having COVID-19.

Over the past 15 years it has become evident that people’s immune system’s make auto antibodies which attack their own tissues says Harald Prüss in the article who has a Neuroimmunologist at the German Center for neurogenerative Diseases in Berlin. This may cause neuromyelitis optica which is when you can experience loss of vision or weakness in limbs. Harald Prüss summarized that the autoantibodies can pass through the blood brain barrier and ultimately impact neurological disorders such as psychosis.

Prüss and his colleagues published a study last year that focused on them isolating antibodies against SARS-CoV-2 from people. They found that one was able to protect hamsters from lung damage and other infections. The purpose of this was to come up with and create new treatments. During this research they found that some of the antibodies from people. They found that one was able to protect hamsters from lung damage and other infections. The purpose of this was to come up with and create new treatments. During this research they found that some of the antibodies can bind to the brain tissue which can ultimately damage it. Prüss states, “We’re currently trying to prove that clinically and experimentally,” says Prüss.

Was published online in December including Prüss sorry the blood and cerebrospinal fluid of 11 people who were extremely sick with COVID-19. These 11 people had neurological symptoms as well. All these people were able to produce auto antibodies which combined to neurons. There is evidence that when the patients were given intravenous immunoglobin which is a type of antibody it was successful.

Astrocytes, pericytes and autoantibodies we’re not the only  pathways. However it is likely that people with COVID-19 experience article symptoms for many reasons. As stated, In the article, Prüss says a key question is what proportion of cases is caused by each of the pathways. “That will determine treatment,” he says.

SOURCE: https://www.nature.com/articles/d41586-021-01693-6?utm_source=Nature+Briefing

Original article: 

Marshall, M. (2021, July 7). COVID and the brain: researchers zero in on how damage occurs. Nature News. https://www.nature.com/articles/d41586-021-01693-6

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

Covid-19 and its implications on pregnancy

Reporter and Curator: Mr. Srinjoy Chakraborty (Junior Research Felllow) and Dr. Sudipta Saha, Ph.D.

Nir Hacohen and Marcia Goldberg, Researchers at MGH and the Broad Institute identify protein “signature” of severe COVID-19

Reporter and Curator:2012pharmaceutical

Identification of Novel genes in human that fight COVID-19 infection

Reporter and Curator: Amandeep Kaur

Comparing COVID-19 Vaccine Schedule Combinations, or “Com-COV” – First-of-its-Kind Study will explore the Impact of using eight different Combinations of Doses and Dosing Intervals for Different COVID-19 Vaccines

Reporter and Curator: 2012pharmaceutical

Early Details of Brain Damage in COVID-19 Patients

Reporter and Curator: Irina Robu, PhD

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Ramatroban, a Thromboxane A2/TPr and PGD2/DPr2 receptor antagonist for Acute and Long haul COVID-19

Author: Ajay Gupta, MD

From: “Gupta, Ajay” <ajayg1@hs.uci.edu>
Date: Wednesday, July 7, 2021 at 1:10 PM
To: Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu>
Cc: “Dr. Saul Yedgar” <saulye@ekmd.huji.ac.il>
Subject: Ramatroban, a Thromboxane A2/TPr and PGD2/DPr2 receptor antagonist for Acute and Long haul COVID-19

While corticosteroids may have a role in about 5% of hospitalized patients who have the cytokine storm, currently there is no effective treatment for mild or moderate COVID and long haul COVID. Massive increase in respiratory and plasma thromboxane A2 (TxA2) plays a key role in thromboinflammation and microvascular thrombosis, while an increase in respiratory and plasma PGD2 potentially suppresses innate interferon response, and acquired Th1 anti-viral response, while promoting a maladaptive type 2, anti-helminthic like immune response. Ramatroban is a potent dual receptor antagonist of Thromboxane A2/TPr and PGD2/DPr2 that has been used in Japan for the treatment of allergic rhinitis for past 20 years (Baynas®, Bayer Japan). We first disclosed use of ramatroban for COVID in a provisional patent application filed on 31st March, 2020; followed by the publication Gupta et al, J Mol Genet Med, 2020

Several experts, as outlined below in yellow highlighted text, have supported the idea of using ramatroban as an anti-thrombotic and immunomodulator in COVID-19.

1.     Prof. Louis Flamand, Nicolas Flamand, Eric Boilard Laval Univ. Quebec, Canada: There is a lipid-mediator storm in COVID-19 characterized by massive increases in thromboxane A2 and PGD2 in the lungs and plasma.  “Blocking the deleterious effects of             PGD2 and TxA2 with the dual DPr2/TPr antagonist Ramatroban might be beneficial in COVID-19 Archambault et al, FASEB, June 2021, doi: https://doi.org/10.1096/fj.202100540R

2. Prof. Garret A FitzGerald, Univ. Of Pennsylvania, Member National Academy of Sciences.https://en.wikipedia.org/wiki/Garret_A._FitzGerald “In the current pandemic there may be utility in targeting eicosanoids with existing drugs.  These approaches would likely be most effective early in the disease before the development of ARDS, where cytokines and chemokines dominate. Dexamethasone limits COX-2 expression and might diminish COVID-19 severity and mortality at least in part, by diminishing COX metabolites… Dexamethasone might improve severe COVID-19 by diminishing the prostaglandins / thromboxane storm in the lungs”. “Treatment with a PGD2/DPr2 inhibitor decreased viral load and improved morbidity by upregulating IFN-lambda expression. …..  Antagonism of the thromboxane receptor (TPr) prevents ARDS…. Early administration of well-tolerated TPr antagonists may limit progress to severe COVID-19 (Theken and FitzGerald, Science, 2021)

4.     Prof. Simon Phipps, Univ. of Queensland, Brisbane Australia “It has been hypothesized that DP2 antagonists be repurposed as a novel immunotherapy for the treatment of COVID-19, and this may be appropriate in mild to moderate cases where Th1 immunity is impaired.” (Ullah et al, Mucosal Immunology, 2021)

5.     Prof. Bruce D. Hammock, Distinguished Professor, Univ of California DavisMember US National Academy of Sciences and National Academy of Inventors; April 25, 2021. https://www.entsoc.org/fellows/hammock “I find your idea of blocking specific thromboxane receptors in preventing or reducing some of the devastating co-morbidity of COVID-19 very compelling. … A DPr2 receptor blocker is conceptually attractive in offering the potential of effective therapy and low risk due to a high therapeutic index.” E mail dated April 25, 2021.  (https://ajp.amjpathol.org/action/showPdf?pii=S0002-9440%2820%2930332-1    and http://ucanr.edu/sites/hammocklab/files/328012.pdf)

6. Ann E Eakin, PhD, Senior Scientific Officer, NIH-NIAID “very compelling data supporting potential benefits of ramatroban in both reducing viral load as well as modulating host responses” E Mail dated Nov 20, 2020

7. Prof. James Ritter, MA, DPhil, FRCP, FMedSci, Hon FBPhS https://www.trinhall.cam.ac.uk/contact-us/contact-directory/fellows-and-academics-directory/james-ritter/ “Very impressive, and fascinating” referring to ramatroban for COVID-19 in an e-mail dated Dec 21, 2020

Ramatroban is expected to reduce lung fibrosis in COVID-19 and therefore diminish clinical manifestations of Long haul COVID. Pang et al, 2021 “examined the effect of Ramatroban, a clinical antagonist of both PGD2 and TXA2 receptors, on treating silicosis using a mouse model. The results showed that Ramatroban significantly alleviated silica-induced pulmonary inflammation, fibrosis, and cardiopulmonary dysfunction compared with the control group.” https://www.thno.org/v11p2381.htm

Unfortunately, the animal models of COVID-19 are harsh, lack microvascular thrombosis and immune perturbations characteristic of human disease. These models may be good for testing antivirals but not for testing immunomodulators or anti-thrombotics. There is highly positive anecdotal experience with use of ramatroban in moderately severe COVID-19 (https://www.researchsquare.com/article/rs-474882/v1

Additionally, Ramatroban holds great promise in sickle cell disease, cardiovascular disease https://doi.org/10.1111/j.1527-3466.2004.tb00132.x, and community acquired pneumonia.

Best regards,

Ajay

Ajay Gupta, M.B.,B.S., M.D.

Clinical Professor,

Division of Nephrology, Hypertension and Kidney Transplantation

University of California Irvine  

President & CSO, KARE Biosciences (www.karebio.com)

E-mail:     ajayg1@hs.uci.edu

Cell:         1 (562) 412-6259

Office:     1 (562) 419-7029

Please see some of our recent publications in the COVID area.  

https://assets.researchsquare.com/files/rs-474882/v1/6d209040-e94b-4adf-80a9-3a9eddf93def.pdf?c=1619795476

https://www.uni-muenster.de/Ejournals/index.php/fnp/article/view/3395

https://www.tandfonline.com/doi/full/10.1080/13543784.2021.1950687

https://www.amjmed.com/article/S0002-9343(20)30872-X/fulltext

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Covid-19 and its implications on pregnancy

Reporter and Curator: Mr. Srinjoy Chakraborty (Junior Research Felllow) and Dr. Sudipta Saha, Ph.D.

Coronavirus disease 2019 (COVID-19), which is caused by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has emerged as a serious global health issue with high transmission rates affecting millions of people worldwide. The SARS-CoV-2 is known to damage cells in the respiratory system, thus causing viral pneumonia. The novel SARS-CoV-2 is a close relative to the previously identified severe acute respiratory syndrome-coronavirus (SARS-CoV) and Middle East respiratory syndrome-coronavirus (MERS-CoV) which affected several people in 2002 and 2012, respectively. Ever since the outbreak of covid-19, several reports have poured in about the impact of Covid-19 on pregnancy. A few studies have highlighted the impact of the viral infection in pregnant women and how they are more susceptible to the infection because of the various physiological changes of the cardiopulmonary and immune systems during pregnancy. It is known that SARS-CoV and MERS-CoV diseases have influenced the fatality rate among pregnant women. However, there are limited studies on the impact of the novel corona virus on the course and outcome of pregnancy.

Figure: commonly observed clinical symptoms of COVID-19 in the general population: Fever and cough, along with dyspnoea, diarrhoea, and malaise are the most commonly observed symptoms in pregnant women, which is similar to that observed in the normal population.

The WHO and the Indian Council of Medical Research (ICMR) have proposed detailed guidelines for treating pregnant women; these guidelines must be strictly followed by the pregnant individual and their families. According to the guidelines issued by the ICMR, the risk of pregnant women contracting the virus to that of the general population. However, the immune system and the body’s response to a viral infection is altered during pregnancy. This may result in the manifestation of more severe symptoms. The ICMR guidelines also state that the reported cases of COVID-19 pneumonia in pregnancy are milder and with good recovery. However, by observing the trends of the other coronavirus infection (SARS, MERS), the risks to the mother appear to increase in particular during the last trimester of pregnancy. Cases of preterm birth in women with COVID-19 have been mentioned in a few case report, but it is unclear whether the preterm birth was always iatrogenic, or whether some were spontaneous. Pregnant women with heart disease are at highest risk of acquiring the infection, which is similar to that observed in the normal population. Most importantly, the ICMR guidelines highlights the impact of the coronavirus epidemic on the mental health of pregnant women. It mentions that the since the pandemic has begun, there has been an increase in the risk of perinatal anxiety and depression, as well as domestic violence. It is critically important that support for women and families is strengthened as far as possible; that women are asked about mental health at every contact.

With the available literature available on the impact of SARS and MERS on reproductive outcome, it has been mentioned that SARS infection did increase the risk of miscarriage, preterm birth and, intrauterine foetal growth restriction. However, the same has not been demonstrated in early reports from COVID-19 infection in pregnancy. According to a study that included 8200 participants conducted by the centre for disease control and prevention, pregnant women may be at a higher risk of acquiring severe infection and need for ICU admissions as compared to their non-pregnant counterparts. However, a detailed and thorough study involving a larger proportion of the population is needed today.

References:

https://www.news-medical.net/news/20210614/COVID-19-in-pregnancy-could-be-less-severe-than-previously-thought-A-Danish-case-study.aspx

https://obgyn.onlinelibrary.wiley.com/doi/10.1111/jog.14696

https://www.nature.com/articles/s41577-021-00525-y

https://www.tandfonline.com/doi/full/10.1080/14767058.2020.1759541

https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/special-populations/pregnancy-data-on-covid-19/what-cdc-is-doing.html

https://economictimes.indiatimes.com/news/india/why-is-covid-19-killing-so-many-pregnant-women-in-india/articleshow/82902194.cms?from=mdr

https://content.iospress.com/download/international-journal-of-risk-and-safety-in-medicine/jrs200060?id=international-journal-of-risk-and-safety-in-medicine%2Fjrs200060

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C.D.C. Reviewing Cases of Heart Problem in Youngsters After Getting Vaccinated and AHA Reassures that Benefits Overwhelm the Risks of Vaccination

Reporter: Amandeep Kaur, B.Sc. , M.Sc.

The latest article in New York times reported by Apoorva Mandavilli outlines the statement of officials that C.D.C. agency is investigating few cases of young adults and teenagers who might have developed myocarditis after getting vaccinated. It is not confirmed by the agency that whether this condition is caused by vaccine or not.

According to the vaccine safety group of the Centers for Disease Control and Prevention, the reports of heart problems experienced by youngsters is relatively very small in number. The group stated that these cases could be unlinked to vaccination. The condition of inflammation of heart muscle which can occur due to certain infections is known as myocarditis.

Moreover, the agency still has to determine any evidence related to vaccines causing the heart issues. The C.D.C. has posted on its website the updated guidance for doctors and clinicians, urging them to be alert to uncommon symptoms related to heart cases among teenagers who are vaccine recipients.

In New York, Dr. Celine Gounder, an infectious disease specialist at Bellevue Hospital Center stated that “It may simply be a coincidence that some people are developing myocarditis after vaccination. It’s more likely for something like that to happen by chance, because so many people are getting vaccinated right now.”

The article reported that the cases appeared mainly in young adults after about four days of their second shot of mRNA vaccines, made by Moderna and Pfizer-BioNTech. Such cases are more prevalent in males as compared to females.

The vaccine safety group stated “Most cases appear to be mild, and follow-up of cases is ongoing.” It is strongly recommended by C.D.C. that American young adults from the age of 12 and above should get vaccinated against COVID-19.

Dr. Yvonne Maldonado, chair of the American Academy of Pediatrics’s Committee on Infectious Diseases stated “We look forward to seeing more data about these cases, so we can better understand if they are related to the vaccine or if they are coincidental. Meanwhile, it’s important for pediatricians and other clinicians to report any health concerns that arise after vaccination.”

Experts affirmed that the potentially uncommon side effects of myocarditis get insignificant compared to the potential risks of SARS-CoV-2 infection, including the continuous syndrome known as “long Covid.” It is reported in the article that acute Covid can lead to myocarditis.

According to the data collected by A.A.P, about 16 thousand children were hospitalized and more than 3.9 million children were infected by coronavirus till the second week of May. In the United States, about 300 children died of SARS-CoV-2 infection, which makes it among the top 10 death causes in children since the start of pandemic.

Dr. Jeremy Faust, an emergency medicine physician at Brigham and Women’s Hospital in Boston stated that “And that’s in the context of all the mitigation measures taken.”

According to researchers, about 10 to 20 of every 1 lakh people each year develop myocarditis in the general population, facing symptoms from fatigue and chest pain to arrhythmias and cardiac arrest, whereas some have mild symptoms which remain undiagnosed.

Currently, the number of reports of myocarditis after vaccination is less than that reported normally in young adults, confirmed by C.D.C. The article reported that the members of vaccine safety group felt to communicate the information about upcoming cases of myocarditis to the providers.

The C.D.C. has not yet specified the ages of the patients involved in reporting. Since December 2020, the Pfizer-BioNTech vaccine was authorized for young people of age 16 and above. The Food and Drug Administration extended the authorization to children of age 12 to 15 years, by the starting of this month.

On 14th May, the clinicians have been alerted by C.D.C. regarding the probable link between myocarditis and vaccination. Within three days, the team started reviewing data on myocarditis, reports filed with the Vaccine Adverse Event Reporting System and others from the Department of Defense.

A report on seven cases has been submitted to the journal Pediatrics for review and State health departments in Washington, Oregon and California have notified emergency providers and cardiologists about the potential problem.

In an interview, Dr. Liam Yore, past president of the Washington State chapter of the American College of Emergency Physicians detailed a case of teenager with myocarditis after vaccination. The patient was provided treatment for mild inflammation of the inner lining of the heart and was discharged afterwards. Later, the young adult returned for care due to decrease in the heart’s output. Dr. Yore reported that still he had come across worse cases in youngsters with Covid, including in a 9-year-old child who arrived at the hospital after a cardiac arrest last winter.

He stated that “The relative risk is a lot in favor of getting the vaccine, especially considering how coronavirus vaccine have been administered.”

In the United States, more than 161 million people have received their first shot of vaccine in which about 4.5 million people were between the age 12 to 18 years.

Benefits Overwhelm Risks of COVID Vaccination, AHA Reassures

The latest statement of American Heart Association (AHA)/ American Stroke Association (ASA) on May 23rd states that the benefits of COVID-19 vaccination enormously outweigh the rare risk for myocarditis cases, which followed the C.D.C. report that the agency is tracking the Vaccine Adverse Events Reporting System (VAERS) and the Vaccine Safety Datalink (VSD) for myocarditis cases linked with mRNA vaccines against coronavirus.

The myocarditis cases in young adults are more often observed after the second dose of vaccine rather than the first one, and have more cases of males than females. The CDC’s COVID-19 Vaccine Safety Technical Work Group (VaST) observed such heart complications after 4 days of vaccination.

CDC reported that “Within CDC safety monitoring systems, rates of myocarditis reports in the window following COVID-19 vaccination have not differed from expected baseline rates.”

The CDC team stated that “The evidence continues to indicate that the COVID-19 vaccines are nearly 100% effective at preventing death and hospitalization due to COVID-19 infection, and Strongly urged all young adults and children 12 years and above to get vaccinated as soon as possible.”

Even though the analysis of myocarditis reports related to coronavirus vaccine is in progress, the AHA/ASA stated that “myocarditis is typically the result of an actual viral infection, and it is yet to be determined if these cases have any correlation to receiving a COVID-19 vaccine.”

Richard Besser, MD, president and CEO of the Robert Wood Johnson Foundation (RWJF) and former acting director of the CDC stated on ABC’s Good Morning America “We’ve lost hundreds of children and there have been thousands who have been hospitalized, thousands who developed an inflammatory syndrome, and one of the pieces of that can be myocarditis.” He added “still, from my perspective, the risk of COVID is so much greater than any theoretical risk from the vaccine.”

After COVID-19 vaccination the symptoms that occur include tiredness, muscle pain, headaches, chills, nausea and fever. The AHA/ASA stated that “typically appear within 24 to 48 hours and usually pass within 36-48 hours after receiving the vaccine.”

All healthcare providers are suggested to be aware of the rare adverse symptoms such as myocarditis, low platelets, blood clots, and severe inflammation. The agency stated that “Healthcare professionals should strongly consider inquiring about the timing of any recent COVID vaccination among patients presenting with these conditions, as needed, in order to provide appropriate treatment quickly.”

President Mitchell S.V. Elkind, M.D., M.S., FAHA, FAAN, Immediate Past President Robert A. Harrington, M.D., FAHA, President-Elect Donald M. Lloyd-Jones, M.D., Sc.M., FAHA, Chief Science and Medical Officer Mariell Jessup, M.D., FAHA, and Chief Medical Officer for Prevention Eduardo Sanchez, M.D, M.P.H., FAAFP are science leaders of AHA/ASA and reflected their views in the following statements:

We strongly urge all adults and children ages 12 and older in the U.S. to receive a COVID vaccine as soon as they can receive it, as recently approved by the U.S. Food and Drug Administration and the CDC. The evidence continues to indicate that the COVID-19 vaccines are nearly 100% effective at preventing death and hospitalization due to COVID-19 infection. According to the CDC as of May 22, 2021, over 283 million doses of COVID-19 vaccines have been administered in the U.S. since December 14, 2020, and more than 129 million Americans are fully vaccinated (i.e., they have received either two doses of the Pfizer-BioNTech or Moderna COVID-19 vaccine, or the single-dose Johnson & Johnson/Janssen COVID-19 vaccine).

We remain confident that the benefits of vaccination far exceed the very small, rare risks. The risks of vaccination are also far smaller than the risks of COVID-19 infection itself, including its potentially fatal consequences and the potential long-term health effects that are still revealing themselves, including myocarditis. The recommendation for vaccination specifically includes people with cardiovascular risk factors such as high blood pressure, obesity and type 2 diabetes, those with heart disease, and heart attack and stroke survivors, because they are at much greater risk of an adverse outcome from the COVID-19 virus than they are from the vaccine.

We commend the CDC’s continual monitoring for adverse events related to the COVID-19 vaccines through VAERS and VSD, and the consistent meetings of ACIP’s VaST Work Group, demonstrating transparent and robust attention to any and all health events possibly related to a COVID-19 vaccine. The few cases of myocarditis that have been reported after COVID-19 vaccination are being investigated. However, myocarditis is usually the result of a viral infection, and it is yet to be determined if these cases have any correlation to receiving a COVID-19 vaccine, especially since the COVID-19 vaccines authorized in the U.S. do not contain any live virus.

We also encourage everyone to keep in touch with their primary care professionals and seek care immediately if they have any of these symptoms in the weeks after receiving the COVID-19 vaccine: chest pain including sudden, sharp, stabbing pains; difficulty breathing/shortness of breath; abnormal heartbeat; severe headache; blurry vision; fainting or loss of consciousness; weakness or sensory changes; confusion or trouble speaking; seizures; unexplained abdominal pain; or new leg pain or swelling.

We will stay up to date with the CDC’s recommendations regarding all potential complications related to COVID-19 vaccines, including myocarditis, pericarditis, central venous sinus thrombosis (CVST) and other blood clotting events, thrombosis thrombocytopenia syndrome (TTS), and vaccine-induced immune thrombosis thrombocytopenia (VITT).

The American Heart Associationrecommends all health care professionals be aware of these very rare adverse events that may be related to a COVID-19 vaccine, including myocarditis, blood clots, low platelets, or symptoms of severe inflammation. Health care professionals should strongly consider inquiring about the timing of any recent COVID vaccination among patients presenting with these conditions, as needed, in order to provide appropriate treatment quickly. As detailed in last month’s AHA/ASA statement, all suspected CVST or blood clots associated with the COVID-19 vaccine should be treated initially using non-heparin anticoagulants. Heparin products should not be administered in any dose if TTS/VITT is suspected, until appropriate testing can be done to exclude heparin-induced antibodies. In addition, health care professionals are required to report suspected vaccine-related adverse events to the Vaccine Adverse Event Reporting System, in accordance with federal regulations.

Individuals should refer to their local and state health departments for specific information about when and where they can get vaccinated. We implore everyone ages 12 and older to get vaccinated so we can return to being together, in person – enjoying life with little to no risk of severe COVID-19 infection, hospitalization or death.

We also support the CDC recommendations last week that loosen restrictions on mask wearing and social distancing for people who are fully vaccinated. For those who are unable to be vaccinated, we reiterate the importance of handwashing, social distancing and wearing masks, particularly for people at high risk of infection and/or severe COVID-19. These simple precautions remain crucial to protecting people who are not vaccinated from the virus that causes COVID-19.

Source:

Other related articles were published in this Open Access Online Scientific Journal, including the following:

Thriving Vaccines and Research: Weizmann Institute Coronavirus Research Development

Reporter: Amandeep Kaur, B.Sc., M.Sc.

https://pharmaceuticalintelligence.com/2021/05/04/thriving-vaccines-and-research-weizmann-coronavirus-research-development/

Identification of Novel genes in human that fight COVID-19 infection

Reporter: Amandeep Kaur, B.Sc., M.Sc.

https://pharmaceuticalintelligence.com/2021/04/19/identification-of-novel-genes-in-human-that-fight-covid-19-infection/

Fighting Chaos with Care, community trust, engagement must be cornerstones of pandemic response

Reporter: Amandeep Kaur, B.Sc., M.Sc. 

https://pharmaceuticalintelligence.com/2021/04/13/fighting-chaos-with-care/

T cells recognize recent SARS-CoV-2 variants

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2021/03/30/t-cells-recognize-recent-sars-cov-2-variants/

Need for Global Response to SARS-CoV-2 Viral Variants

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2021/02/12/need-for-global-response-to-sars-cov-2-viral-variants/

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Nir Hacohen and Marcia Goldberg, Researchers at MGH and the Broad Institute identify protein “signature” of severe COVID-19

Curator and Reporter: Aviva Lev-Ari, PhD, RN

Longitudinal proteomic analysis of plasma from patients with severe COVID-19 reveal patient survival-associated signatures, tissue-specific cell death, and cell-cell interactions

Open AccessPublished:April 30, 2021DOI:https://doi.org/10.1016/j.xcrm.2021.100287

Highlights

  • 16% of COVID-19 patients display an atypical low-inflammatory plasma proteome
  • Severe COVID-19 is associated with heterogeneous plasma proteomic responses
  • Death of virus-infected lung epithelial cells is a key feature of severe disease
  • Lung monocyte/macrophages drive T cell activation, together promoting epithelial damage

Summary

Mechanisms underlying severe COVID-19 disease remain poorly understood. We analyze several thousand plasma proteins longitudinally in 306 COVID-19 patients and 78 symptomatic controls, uncovering immune and non-immune proteins linked to COVID-19. Deconvolution of our plasma proteome data using published scRNAseq datasets reveals contributions from circulating immune and tissue cells. Sixteen percent of patients display reduced inflammation yet comparably poor outcomes. Comparison of patients who died to severely ill survivors identifies dynamic immune cell-derived and tissue-associated proteins associated with survival, including exocrine pancreatic proteases. Using derived tissue-specific and cell type-specific intracellular death signatures, cellular ACE2 expression, and our data, we infer whether organ damage resulted from direct or indirect effects of infection. We propose a model in which interactions among myeloid, epithelial, and T cells drive tissue damage. These datasets provide important insights and a rich resource for analysis of mechanisms of severe COVID-19 disease.

Graphical Abstract

Figure thumbnail fx1

Image Source: DOI: https://doi.org/10.1016/j.xcrm.2021.100287

https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(21)00115-4

The quest to identify mechanisms that might be contributing to death in COVID-19: Why do some patients die from this disease, while others — who appear to be just as ill do not?

Researchers at Massachusetts General Hospital (MGH) and the Broad Institute of MIT and Harvard have identified the protein “signature” of severe COVID-19

Interest was to develop methods for studying human immune responses to infections, which they had applied to the condition known as bacterial sepsis. The three agreed to tackle this new problem with the goal of understanding how the human immune system responds to SARS-CoV-2, the novel pathogen that causes COVID-19.

How scientists launched a study in days to probe COVID-19’s unpredictability

Collecting these specimens required a large team of collaborators from many departments, which worked overtime for five weeks to amass blood samples from 306 patients who tested positive for COVID-19, as well as from 78 patients with similar symptoms who tested negative for the coronavirus.

Alexandra-Chloé Villani

Credit : Alexandra-Chloé VillaniResearch associates at Mass General who worked countless hours to process blood samples for the COVID Acute Cohort Study (from left to right: Anna Gonye, Irena Gushterova, and Tom Lasalle)By Leah Eisenstadt

https://www.broadinstitute.org/news/how-scientists-launched-study-days-probe-covid-19%E2%80%99s-unpredictability

As the COVID-19 surge began in March, Mass General and Broad researchers worked around the clock to begin learning why some patients fare worse with the disease than others

Protein signatures in the blood

https://www.broadinstitute.org/news/researchers-identify-protein-%E2%80%9Csignature%E2%80%9D-severe-covid-19

The study found that most patients with COVID-19 have a consistent protein signature, regardless of disease severity; as would be expected, their bodies mount an immune response by producing proteins that attack the virus. “But we also found a small subset of patients with the disease who did not demonstrate the pro-inflammatory response that is typical of other COVID-19 patients,” Filbin said, yet these patients were just as likely as others to have severe disease. Filbin, who is also an assistant professor of emergency medicine at Harvard Medical School (HMS), noted that patients in this subset tended to be older people with chronic diseases, who likely had weakened immune systems.

Among other revelations, this showed that the most prevalent severity-associated protein, a pro-inflammatory protein called interleukin-6 (IL-6) rose steadily in patients who died, while it rose and then dropped in those with severe disease who survived. Early attempts by other groups to treat COVID-19 patients experiencing acute respiratory distress with drugs that block IL-6 were disappointing, though more recent studies show promise in combining these medications with the steroid dexamethasone.

Hacohen, who is a professor of medicine at HMS and director of the Broad’s Cell Circuits Program:

“You can ask which of the many thousands of proteins that are circulating in your blood are associated with the actual outcome,” he said, “and whether there is a set of proteins that tell us something.”

Goldberg, who is a professor of emergency medicine at HMS:

They are highly likely to be useful in figuring out some of the underlying mechanisms that lead to severe disease and death in COVID-19,” she said, noting her gratitude to the patients involved in the study. Their samples are already being used to study other aspects of COVID-19, such as identifying the qualities of antibodies that patients form against the virus.

SOURCES

Original Research

Filbin MR, Mehta A, et al. Longitudinal proteomic analysis of plasma from patients with severe COVID-19 reveal patient survival-associated signatures, tissue-specific cell death, and cell-cell interactionsCell Reports Medicine. Online April 30, 2021. DOI: 10.1016/j.xcrm.2021.100287.

Adapted from a press release originally issued by Massachusetts General Hospital.

https://www.broadinstitute.org/news/researchers-identify-protein-%E2%80%9Csignature%E2%80%9D-severe-covid-19

https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(21)00115-4

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Thriving Vaccines and Research: Weizmann Institute Coronavirus Research Development

Reporter: Amandeep Kaur, B.Sc., M.Sc.

In early February, Prof. Eran Segal updated in one of his tweets and mentioned that “We say with caution, the magic has started.”

The article reported that this statement by Prof. Segal was due to decreasing cases of COVID-19, severe infection cases and hospitalization of patients by rapid vaccination process throughout Israel. Prof. Segal emphasizes in another tweet to remain cautious over the country and informed that there is a long way to cover and searching for scientific solutions.

A daylong webinar entitled “COVID-19: The epidemic that rattles the world” was a great initiative by Weizmann Institute to share their scientific knowledge about the infection among the Israeli institutions and scientists. Prof. Gideon Schreiber and Dr. Ron Diskin organized the event with the support of the Weizmann Coronavirus Response Fund and Israel Society for Biochemistry and Molecular Biology. The speakers were invited from the Hebrew University of Jerusalem, Tel-Aviv University, the Israel Institute for Biological Research (IIBR), and Kaplan Medical Center who addressed the molecular structure and infection biology of the virus, treatments and medications for COVID-19, and the positive and negative effect of the pandemic.

The article reported that with the emergence of pandemic, the scientists at Weizmann started more than 60 projects to explore the virus from different range of perspectives. With the help of funds raised by communities worldwide for the Weizmann Coronavirus Response Fund supported scientists and investigators to elucidate the chemistry, physics and biology behind SARS-CoV-2 infection.

Prof. Avi Levy, the coordinator of the Weizmann Institute’s coronavirus research efforts, mentioned “The vaccines are here, and they will drastically reduce infection rates. But the coronavirus can mutate, and there are many similar infectious diseases out there to be dealt with. All of this research is critical to understanding all sorts of viruses and to preempting any future pandemics.”

The following are few important projects with recent updates reported in the article.

Mapping a hijacker’s methods

Dr. Noam Stern-Ginossar studied the virus invading strategies into the healthy cells and hijack the cell’s systems to divide and reproduce. The article reported that viruses take over the genetic translation system and mainly the ribosomes to produce viral proteins. Dr. Noam used a novel approach known as ‘ribosome profiling’ as her research objective and create a map to locate the translational events taking place inside the viral genome, which further maps the full repertoire of viral proteins produced inside the host.

She and her team members grouped together with the Weizmann’s de Botton Institute and researchers at IIBR for Protein Profiling and understanding the hijacking instructions of coronavirus and developing tools for treatment and therapies. Scientists generated a high-resolution map of the coding regions in the SARS-CoV-2 genome using ribosome-profiling techniques, which allowed researchers to quantify the expression of vital zones along the virus genome that regulates the translation of viral proteins. The study published in Nature in January, explains the hijacking process and reported that virus produces more instruction in the form of viral mRNA than the host and thus dominates the translation process of the host cell. Researchers also clarified that it is the misconception that virus forced the host cell to translate its viral mRNA more efficiently than the host’s own translation, rather high level of viral translation instructions causes hijacking. This study provides valuable insights for the development of effective vaccines and drugs against the COVID-19 infection.

Like chutzpah, some things don’t translate

Prof. Igor Ulitsky and his team worked on untranslated region of viral genome. The article reported that “Not all the parts of viral transcript is translated into protein- rather play some important role in protein production and infection which is unknown.” This region may affect the molecular environment of the translated zones. The Ulitsky group researched to characterize that how the genetic sequence of regions that do not translate into proteins directly or indirectly affect the stability and efficiency of the translating sequences.

Initially, scientists created the library of about 6,000 regions of untranslated sequences to further study their functions. In collaboration with Dr. Noam Stern-Ginossar’s lab, the researchers of Ulitsky’s team worked on Nsp1 protein and focused on the mechanism that how such regions affect the Nsp1 protein production which in turn enhances the virulence. The researchers generated a new alternative and more authentic protocol after solving some technical difficulties which included infecting cells with variants from initial library. Within few months, the researchers are expecting to obtain a more detailed map of how the stability of Nsp1 protein production is getting affected by specific sequences of the untranslated regions.

The landscape of elimination

The article reported that the body’s immune system consists of two main factors- HLA (Human Leukocyte antigen) molecules and T cells for identifying and fighting infections. HLA molecules are protein molecules present on the cell surface and bring fragments of peptide to the surface from inside the infected cell. These peptide fragments are recognized and destroyed by the T cells of the immune system. Samuels’ group tried to find out the answer to the question that how does the body’s surveillance system recognizes the appropriate peptide derived from virus and destroy it. They isolated and analyzed the ‘HLA peptidome’- the complete set of peptides bound to the HLA proteins from inside the SARS-CoV-2 infected cells.

After the analysis of infected cells, they found 26 class-I and 36 class-II HLA peptides, which are present in 99% of the population around the world. Two peptides from HLA class-I were commonly present on the cell surface and two other peptides were derived from coronavirus rare proteins- which mean that these specific coronavirus peptides were marked for easy detection. Among the identified peptides, two peptides were novel discoveries and seven others were shown to induce an immune response earlier. These results from the study will help to develop new vaccines against new coronavirus mutation variants.

Gearing up ‘chain terminators’ to battle the coronavirus

Prof. Rotem Sorek and his lab discovered a family of enzymes within bacteria that produce novel antiviral molecules. These small molecules manufactured by bacteria act as ‘chain terminators’ to fight against the virus invading the bacteria. The study published in Nature in January which reported that these molecules cause a chemical reaction that halts the virus’s replication ability. These new molecules are modified derivates of nucleotide which integrates at the molecular level in the virus and obstruct the works.

Prof. Sorek and his group hypothesize that these new particles could serve as a potential antiviral drug based on the mechanism of chain termination utilized in antiviral drugs used recently in the clinical treatments. Yeda Research and Development has certified these small novel molecules to a company for testing its antiviral mechanism against SARS-CoV-2 infection. Such novel discoveries provide evidences that bacterial immune system is a potential repository of many natural antiviral particles.

Resolving borderline diagnoses

Currently, Real-time Polymerase chain reaction (RT-PCR) is the only choice and extensively used for diagnosis of COVID-19 patients around the globe. Beside its benefits, there are problems associated with RT-PCR, false negative and false positive results and its limitation in detecting new mutations in the virus and emerging variants in the population worldwide. Prof. Eran Elinavs’ lab and Prof. Ido Amits’ lab are working collaboratively to develop a massively parallel, next-generation sequencing technique that tests more effectively and precisely as compared to RT-PCR. This technique can characterize the emerging mutations in SARS-CoV-2, co-occurring viral, bacterial and fungal infections and response patterns in human.

The scientists identified viral variants and distinctive host signatures that help to differentiate infected individuals from non-infected individuals and patients with mild symptoms and severe symptoms.

In Hadassah-Hebrew University Medical Center, Profs. Elinav and Amit are performing trails of the pipeline to test the accuracy in borderline cases, where RT-PCR shows ambiguous or incorrect results. For proper diagnosis and patient stratification, researchers calibrated their severity-prediction matrix. Collectively, scientists are putting efforts to develop a reliable system that resolves borderline cases of RT-PCR and identify new virus variants with known and new mutations, and uses data from human host to classify patients who are needed of close observation and extensive treatment from those who have mild complications and can be managed conservatively.

Moon shot consortium refining drug options

The ‘Moon shot’ consortium was launched almost a year ago with an initiative to develop a novel antiviral drug against SARS-CoV-2 and was led by Dr. Nir London of the Department of Chemical and Structural Biology at Weizmann, Prof. Frank von Delft of Oxford University and the UK’s Diamond Light Source synchroton facility.

To advance the series of novel molecules from conception to evidence of antiviral activity, the scientists have gathered support, guidance, expertise and resources from researchers around the world within a year. The article reported that researchers have built an alternative template for drug-discovery, full transparency process, which avoids the hindrance of intellectual property and red tape.

The new molecules discovered by scientists inhibit a protease, a SARS-CoV-2 protein playing important role in virus replication. The team collaborated with the Israel Institute of Biological Research and other several labs across the globe to demonstrate the efficacy of molecules not only in-vitro as well as in analysis against live virus.

Further research is performed including assaying of safety and efficacy of these potential drugs in living models. The first trial on mice has been started in March. Beside this, additional drugs are optimized and nominated for preclinical testing as candidate drug.

Source: https://www.weizmann.ac.il/WeizmannCompass/sections/features/the-vaccines-are-here-and-research-abounds

Other related articles were published in this Open Access Online Scientific Journal, including the following:

Identification of Novel genes in human that fight COVID-19 infection

Reporter: Amandeep Kaur, B.Sc., M.Sc. (ept. 5/2021)

https://pharmaceuticalintelligence.com/2021/04/19/identification-of-novel-genes-in-human-that-fight-covid-19-infection/

Fighting Chaos with Care, community trust, engagement must be cornerstones of pandemic response

Reporter: Amandeep Kaur, B.Sc., M.Sc. (ept. 5/2021)

https://pharmaceuticalintelligence.com/2021/04/13/fighting-chaos-with-care/

T cells recognize recent SARS-CoV-2 variants

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2021/03/30/t-cells-recognize-recent-sars-cov-2-variants/

Need for Global Response to SARS-CoV-2 Viral Variants

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2021/02/12/need-for-global-response-to-sars-cov-2-viral-variants/

Mechanistic link between SARS-CoV-2 infection and increased risk of stroke using 3D printed models and human endothelial cells

Reporter: Adina Hazan, PhD

https://pharmaceuticalintelligence.com/2020/12/28/mechanistic-link-between-sars-cov-2-infection-and-increased-risk-of-stroke-using-3d-printed-models-and-human-endothelial-cells/

Read Full Post »

Identification of Novel genes in human that fight COVID-19 infection

Reporter: Amandeep Kaur, B.Sc., M.Sc. (ept. 5/2021)

Scientists have recognized human genes that fight against the SARS-CoV-2 viral infection. The information about genes and their function can help to control infection and aids the understanding of crucial factors that causes severe infection. These novel genes are related to interferons, the frontline fighter in our body’s defense system and provide options for therapeutic strategies.

The research was published in the journal Molecular Cell.

Sumit K. Chanda, Ph.D., professor and director of the Immunity and Pathogenesis Program at Sanford Burnham Prebys reported in the article that they focused on better understanding of the cellular response and downstream mechanism in cells to SARS-CoV-2, including the factors which causes strong or weak response to viral infection. He is the lead author of the study and explained that in this study they have gained new insights into how the human cells are exploited by invading virus and are still working towards finding any weak point of virus to develop new antivirals against SARS-CoV-2.

With the surge of pandemic, researchers and scientists found that in severe cases of COVID-19, the response of interferons to SARS-CoV-2 viral infection is low. This information led Chanda and other collaborators to search for interferon-stimulated genes (ISGs), are genes in human which are triggered by interferons and play important role in confining COVID-19 infection by controlling their viral replication in host.

The investigators have developed laboratory experiments to identify ISGs based on the previous knowledge gathered by the outbreak of SARS-CoV-1 from 2002-2004 which was similar to COVID-19 pandemic caused by SARS-CoV-2 virus.

The article reports that Chanda mentioned “we found that 65 ISGs controlled SAR-CoV-2 infection, including some that inhibited the virus’ ability to enter cells, some that suppressed manufacture of the RNA that is the virus’s lifeblood, and a cluster of genes that inhibited assembly of the virus.” They also found an interesting fact about ISGs that some of these genes revealed control over unrelated viruses, such as HIV, West Nile and seasonal flu.

Laura Martin-Sancho, Ph.D., a senior postdoctoral associate in the Chanda lab and first author of the study reported in the article that they identified 8 different ISGs that blocked the replication of both SARS-CoV-1 and CoV-2 in the subcellular compartments responsible for packaging of proteins, which provide option to exploit these vulnerable sites to restrict infection. They are further investigating whether the genetic variability within the ISGs is associated with COVID-19 severity.

The next step for researchers will be investigating and observing the biology of variants of SARS-CoV-2 that are evolving and affecting vaccine efficacy. Martin-Sancho mentioned that their lab has already started gathering all the possible variants for further investigation.

“It’s vitally important that we don’t take our foot off the pedal of basic research efforts now that vaccines are helping control the pandemic,” reported in the article by Chanda.

“We’ve come so far so fast because of investment in fundamental research at Sanford Burnham Prebys and elsewhere, and our continued efforts will be especially important when, not if, another viral outbreak occurs,” concluded Chanda.

Source: https://medicalxpress.com/news/2021-04-covid-scientists-human-genes-infection.html

Reference: Laura Martin-Sancho et al. Functional Landscape of SARS-CoV-2 Cellular Restriction, Molecular Cell (2021). DOI: 10.1016/j.molcel.2021.04.008

Other related articles were published in this Open Access Online Scientific Journal, including the following:

Fighting Chaos with Care, community trust, engagement must be cornerstones of pandemic response

Reporter: Amandeep Kaur

https://pharmaceuticalintelligence.com/2021/04/13/fighting-chaos-with-care/

Mechanism of Thrombosis with AstraZeneca and J & J Vaccines: Expert Opinion by Kate Chander Chiang & Ajay Gupta, MD

Reporter & Curator: Dr. Ajay Gupta, MD

https://pharmaceuticalintelligence.com/2021/04/14/mechanism-of-thrombosis-with-astrazeneca-and-j-j-vaccines-expert-opinion-by-kate-chander-chiang-ajay-gupta-md/

T cells recognize recent SARS-CoV-2 variants

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2021/03/30/t-cells-recognize-recent-sars-cov-2-variants/

Need for Global Response to SARS-CoV-2 Viral Variants

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2021/02/12/need-for-global-response-to-sars-cov-2-viral-variants/

Mechanistic link between SARS-CoV-2 infection and increased risk of stroke using 3D printed models and human endothelial cells

Reporter: Adina Hazan, PhD

https://pharmaceuticalintelligence.com/2020/12/28/mechanistic-link-between-sars-cov-2-infection-and-increased-risk-of-stroke-using-3d-printed-models-and-human-endothelial-cells/

Read Full Post »

 

 

Mechanism of thrombosis with AstraZeneca and J & J vaccines: Expert Opinion by Kate Chander Chiang & Ajay Gupta, MD

UPDATED on 4/15/2021


Atul Gawande@Atul_Gawande
·

Why wait for more info? A new case of cerebral sinus venus thrombosis was reported in a 25 year old man who became critically ill from a cerebral hemorrhage. And for women age 20-50, CSVT occurred in 1 in 13,000, or 4-15X higher than background.

UPDATED on 4/14/2021

How UK doctor linked rare blood-clotting to AstraZeneca Covid jab

https://www.theguardian.com/society/2021/apr/13/how-uk-doctor-marie-scully-blood-clotting-link-astrazeneca-covid-jab-university-college-london-hospital

From: “Gupta, Ajay” <ajayg1@hs.uci.edu>

Date: Wednesday, April 14, 2021 at 10:33 AM

To: “Aviva Lev-Ari, PhD, RN” <AvivaLev-Ari@alum.berkeley.edu>

Cc: Kate Chiang <kcscience777@gmail.com>

Subject: Mechanism of thrombosis with AstraZeneca and J & J vaccines

https://www.fda.gov/news-events/press-announcements/joint-cdc-and-fda-statement-johnson-johnson-covid-19-vaccine

We have put together the following mechanism for thrombosis including central vein sinus thrombosis as a complication of both J&J and the AstraZeneca vaccines. This unifying mechanism explains the predilection of cerebral veins and higher risk in younger women. Please share your thoughts on the proposed mechanism.

We have submitted the attached manuscript to SSRN.  Sharing this promptly considering the public health significance.

Thanks

Figure 1. AstraZeneca or Janssen COVID-19 vaccine induced thromboinflammation and cerebral venous sinus thrombosis (CVST)-Proposed Mechanisms: Adenovirus carrier delivers SARS-CoV-2 DNA encoding the Spike (S) protein to the lung megakaryocytes via the coxsackie-adenovirus receptor (CAR). Spike protein induces COX-2 expression in megakaryocytes leading to megakaryocyte activation, biogenesis of activated platelets that express COX-2 and generate thromboxane A2 (TxA2). Cerebral vein sinus endothelial cells express podoplanin, a natural ligand for CLEC2 receptors on platelets. Platelets traversing through the cerebral vein sinuses would be further activated by TxA2 dependent podoplanin-CLEC2 signaling, leading to release of extracellular vesicles, thereby promoting CLEC5A and TLR2 mediated neutrophil activation, thromboinflammation, CVST, and thromboembolism in other vascular beds. Young age and female gender are associated with increased TxA2 generation and platelet activation respectively, and hence increased risk of thromboembolic complications following vaccination.

Best regards,

Ajay

Ajay Gupta, M.B.,B.S., M.D.

Clinical Professor,

Division of Nephrology, Hypertension and Kidney Transplantation

University of California Irvine  

President & CSO, KARE Biosciences (www.karebio.com)

E-mail:     ajayg1@hs.uci.edu

Cell:         1 (562) 412-6259

Office:     1 (562) 419-7029

PERSPECTIVE 

Title: SARS-CoV-2 vaccination induced thrombosis: Is chemoprophylaxis with antiplatelet agents warranted? 

Guest Authors: 

Kate Chander Chiang1 

Ajay Gupta, MBBS, MD1,2 

Affiliations 

(1) KARE Biosciences, Orange, CA 92869 

(2) Department of Medicine, University of California Irvine (UCI) School of Medicine, Orange, CA 92868 

*Corresponding author: 

Ajay Gupta, MBBS, MD 

Clinical Professor of Medicine, 

Division of Nephrology, Hypertension and Kidney Transplantation 

University of California Irvine (UCI) School of Medicine, 

Orange, CA 92868 

Tel: +1 (562) 412-6259 

E-mail: ajayg1@hs.uci.edu 

Word Count 

Abstract: 359 

Main Body: 1,648 

Funding: No funding was required. 

Conflict of Interest: AG and KCC have filed a patent for use of Ramatroban as an anti-thrombotic and immune modulator in SARS-CoV-2 infection. The patents have been licensed to KARE Biosciences. KCC is an employee of KARE Biosciences. 

Author Contributions: AG and KCC conceptualized, created the framework, wrote and reviewed the manuscript. 

Abbreviations: TxA2, thromboxane A2; DIC, disseminated intravascular coagulopathy; COX, cyclooxygenase; TTP, thrombotic thrombocytopenic purpura; CVST, cerebral venous sinus thrombosis; CLEC, C-type lectin-like receptor; TLR, toll-like receptor; CAR, coxsackievirus and adenovirus receptor; COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2 2 

ABSTRACT 

The COVID-19 vaccines, Vaxzevria® (AstraZeneca) and the Janssen vaccine (Johnson & Johnson) are highly effective but associated with rare thrombotic complications. These vaccines are comprised of recombinant, replication incompetent, chimpanzee adenoviral vectors encoding the Spike (S) glycoprotein of SARS-CoV-2. The adenovirus vector infects epithelial cells expressing the coxsackievirus and adenovirus receptor (CAR). The S glycoprotein of SARS-CoV-2 is expressed locally stimulating neutralizing antibody and cellular immune responses, which protect against COVID-19. The immune responses are highly effective in preventing symptomatic disease in adults irrespective of age, gender or ethnicity. However, both vaccines have been associated with thromboembolic events including cerebral venous sinus thrombosis (CVST). Megakaryocytes also express CAR, leading us to postulate adenovirus vector uptake and expression of spike glycoprotein by megakaryocytes. Spike glycoprotein induces expression of cyclooxygenase -2 (COX-2), leading to generation of thromboxane A2 (TxA2). TxA2 promotes megakaryocyte activation, biogenesis of activated platelets and thereby increased thrombogenicity. Cerebral vein sinus endothelial cells express podoplanin, a natural ligand for CLEC2 receptors on platelets. Platelets traversing through the cerebral vein sinuses would be further activated by TxA2 dependent podoplanin-CLEC2 signaling, leading to CVST. The mechanisms proposed are consistent with the following clinical observations. First, a massive increase in TxA2 generation promotes platelet activation and thromboinflammation in COVID-19 patients. Second, TxA2 generation and platelet activation is increased in healthy women compared to men, and in younger mice compared to older mice; and, younger age and female gender appear to be associated with increased risk of thromboembolism as a complication of adenoviral vector based COVID-19 vaccine. The roll out of both AstraZeneca and Janssen vaccines has been halted for adults under 30-60 years of age in many countries. We propose that antiplatelet agents targeting TxA2 receptor signaling should be considered for chemoprophylaxis when administering the adenovirus based COVID-19 vaccines to adults under 30-60 years of age. In many Asian and African countries, only adenovirus-based COVID-19 vaccines are available at present. A short course of an antiplatelet agent such as aspirin could allow millions to avail of the benefits of the AstraZeneca and Janssen COVID-19 vaccines which could be otherwise either denied to them or put them at undue risk of thromboembolic complications. 

Keywords: SARS-CoV-2, COVID-19, Vaxzevria, COVISHIELD, Janssen COVID-19 vaccine, Johnson & Johnson vaccine, AstraZeneca vaccine, AZD1222, thrombosis, cerebral venous sinus thrombosis, thromboembolism, aspirin, antiplatelet agents, thromboxane, COX-2, disseminated intravascular coagulation, thrombocytopenia, thrombotic thrombocytopenia, CLEC2, megakaryocyte 3 

COVID-19 disease is caused by a novel positive-strand RNA coronavirus (SARS-CoV-2), which belongs to the Coronaviridae family, along with the severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS) coronaviruses.1 The genome of these viruses encodes several non-structural and structural proteins, including spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins.2 The majority of the vaccines for COVID-19 that employ administration of viral antigens or viral gene sequences aim to induce neutralizing antibodies against the viral spike protein (S), preventing uptake through the ACE2 receptor, and thereby blocking infection.3 

The Janssen COVID-19 vaccine (Johnson & Johnson) is comprised of a recombinant, replication- incompetent Ad26 vector, encoding a stabilized variant of the SARS-CoV-2 Spike (S) protein. The ChAdOx1 nCoV-19 vaccine (AZD1222, Vaxzevria®) was developed at Oxford University and consists of a replication-deficient chimpanzee adenoviral vector ChAdOx1, encoding the S protein.4 In US Phase III trials, Vaxzevria has been demonstrated to have 79% efficacy at preventing symptomatic COVID-19, and 100% efficacy against severe or critical disease and hospitalization, with comparable efficacy across ethnicity, gender and age.5 However, Vaxzevria has been associated with thrombotic and embolic events including disseminated intravascular coagulation (DIC) and cerebral venous sinus thrombosis (CVST), occurring within 14 days after vaccination, mostly in people under 55 years of age, the majority of whom have been women.6 Data from Europe suggests that the event rate for thromboembolic events may be about 10 per million vaccinated. Antibodies to platelet factor 4/heparin complexes have been recently reported in a few patients.7 However, the significance of this finding remains to be established. As of April 12, 2021, about 6.8 million doses of the Janssen vaccine have been administered in the U.S.8 CDC and FDA are reviewing data involving six reported U.S. cases of CVST in combination with thrombocytopenia.8 All six cases occurred among women between the ages of 18 and 48, and symptoms occurred 6 to 13 days after vaccination.8 

SARS-CoV-2 is known to cause thromboinflammation leading to thrombotic microangiopathy, pulmonary thrombosis, pedal acro-ischemia (“COVID-toes”), arterial clots, strokes, cardiomyopathy, coronary and systemic vasculitis, deep venous thrombosis, pulmonary embolism, and microvascular thrombosis in renal, cardiac and brain vasculature.9-14 Cerebral venous sinus thrombosis (CVST) has also been reported in COVID-19 patients.15 Amongst 34,331 hospitalized COVID-19 patients, CVST was diagnosed in 28.16 In a multicenter, multinational, cross sectional, retrospective study of 8 patients diagnosed with CVST and COVID-19, seven were women.17 In another series of 41 patients with COVID-19 and CVST, the average age was about 50 years (SD, 16.5 years).17 The pathobiology of thrombotic events associated with the AstraZeneca vaccine should be viewed in the context of mechanisms underlying thromboinflammation that complicates SARS-CoV-2 infection and COVID-19 disease. 

A. Role of COX-2 and thromboxane A2 in thromboinflammation complicating adenovirus based COVID-19 vaccine encoding the Spike protein of SARS-CoV-2 

Thromboinflammation in COVID-19 seems to be primarily caused by endothelial, platelet and neutrophil activation, platelet-neutrophil aggregates and release of neutrophil extracellular traps (NETs).13,18 Platelet activation in COVID-19 is fueled by a lipid storm characterized by massive increases in thromboxane A2 (TxA2) levels in the blood and bronchoalveolar lavage fluid.19,20 Cyclooxygenase (COX) enzymes catalyze the first step in the biosynthesis of TxA2 from arachidonic acid, and COX-2 expression is induced by the spike (S) protein of coronaviruses.21 We postulate that an aberrant increase in TxA2 generation induced by the spike protein expression from the AstraZeneca vaccine leads to thromboinflammation, thromboembolism and CVST. 4 

The support for the above proposed mechanism comes from the following observations. First, when mice of different age groups were infected with SARS-CoV virus, the generation of TxA2 was markedly increased in younger mice compared to middle aged mice.22 Furthermore, in children with asymptomatic or mildly symptomatic SARS-CoV-2 infection, microvascular thrombosis and thrombotic microangiopathy occur early in infection.20 These observations are consistent with the higher risk for thrombosis in adults under 60 years of age, compared with the older age group.6,7 Second, platelets from female mice are much more reactive than from male mice.23 Furthermore, TxA2 generation, TxA2-platelet interaction and activation is increased in women compared to men.24,25 These observations are consistent with disproportionately increased risk of thrombosis in women following AstraZeneca and Janssen COVID-19 vaccines. 

The adenoviral vector ChAdOx1, containing nCoV-19 spike protein gene, infects host cells through the coxsackievirus and adenovirus receptor (CAR).26 CAR-dependent cell entry of the viral vector allows insertion of the SARS-CoV-2 spike protein gene and expression of Spike protein by host cells (Figure 1). CAR is primarily expressed on epithelial tight junctions.27 CAR expression has also been reported in platelets,28 and since platelets are anucleate cells CAR expression by megakaryocytes can be inferred. Therefore, AstraZeneca and Janssen vaccines would be expected to induce expression of Spike protein in megakaryocytes and platelets (Figure 1). 

Spike protein of coronaviruses in known to induce COX-2 gene expression.21,29 COX-2 expression is induced during normal human megakaryopoiesis and characterizes newly formed platelets.30 While in healthy controls <10% of circulating platelets express COX-2, in patients with high platelet generation, up to 60% of platelets express COX-2.30 Generation of TxA2 by platelets is markedly suppressed by COX-2 inhibition in patients with increased megakaryopoiesis versus healthy subjects.30 Therefore, we postulate that expression of Spike protein induces COX-2 expression and generation of thromboxane A2 by megakaryocytes. TxA2 promotes biogenesis of activated platelets expressing COX-2. Platelet TxA2 generation leads to platelet activation and aggregation, and thereby thromboinflammation (Figure 1). 

Extravascular spaces of the lungs comprise populations of mature and immature megakaryocytes that originate from the bone marrow, such that lungs are a major site of platelet biogenesis, accounting for approximately 50% of total platelet production or about 10 million platelets per hour.31 More than 1 million extravascular megakaryocytes have been observed in each lung of transplant mice.31 Following intramuscular injection of the AstraZeneca and Janssen vaccines, the adenovirus vector will traverse the veins and lymphatics to be delivered to the pulmonary circulation thereby exposing lung megakaryocytes in the first pass. Interestingly, under thrombocytopenic conditions, haematopoietic progenitors migrate out of the lung to repopulate the bone marrow and completely reconstitute blood platelet counts.31 

B. Predilection of cerebral venous sinuses for thrombosis following vaccination 

Recent studies have demonstrated that arterial, venous and sinusoidal endothelial cells in the brain uniquely express markers of the lymphatic endothelium including podoplanin.32 Podoplanin serves as a ligand for CLEC2 receptors on platelets.33 Thromboxane A2 dependent CLEC2 signaling leads to platelet activation (Figure 1), while a TxA2 receptor antagonist nearly abolish CLEC2 signaling and platelet activation.33 TxA2 dependent CLEC2 signaling promotes release of exosomes and microvesicles from platelets, leading to activation of CLEC5A and TLR2 receptors respectively on neutrophils, neutrophil activation and release of neutrophil extracellular traps (NETs) (Figure 1).34 Neutrophil activation, more than platelet activation, is associated with thrombotic complications in COVID-19.13,18,35 As proposed above, the expression of podoplanin, a unique molecular signature of cerebral endothelial cells, may be responsible for the predilection of brain vascular bed to thromboinflammation and CVST as a complication of COVID-19 vaccines. 5 

C. Chemoprophylaxis with antiplatelet agents 

In animal models of endotoxin mediated endothelial injury and thromboinflammation, antagonism of TxA2 signaling prevents ARDS, reduces myocardial damage and increases survival.36-38 

Considering the key role played by platelets in thromboinflammation, we propose consideration of antiplatelet agents, either aspirin or TxA2 receptor antagonists, as chemoprophylactic agents when the AstraZeneca vaccine is administered to adults between 18 and 60 years of age.39 High bleeding risk because of another medical condition or medication would be contraindications to use of antiplatelet agents.39 Medical conditions that increase bleeding risk include previous gastrointestinal bleeding, peptic ulcer disease, blood clotting problems, and kidney disease.39 Medications that increase bleeding risk include nonsteroidal anti-inflammatory drugs, steroids, and other anticoagulants or anti-platelet agents.39 Aspirin appears to be safe in COVID-19. In a retrospective observational study in hospitalized patients with COVID-19, low-dose aspirin was found to be effective in reducing morbidity and mortality; and was not associated with any safety issues including major bleeding.40 Therefore, aspirin is likely to be safe as an adjunct to COVID-19 vaccines even in the event of a subsequent infection with SARS-CoV-2 virus. 

Can aspirin influence the host immune response to the COVID-19 vaccines? This issue merits further investigation. When healthy adults > 65 years of age were given influenza vaccine and randomized to receive 300 mg aspirin or placebo on days 1, 2, 3, 5 and 7, the aspirin group showed 4-fold or greater rise in influenza specific antibodies.41 The risk-benefit analysis, based on above information, suggests that a one to three week course of low-dose aspirin merits consideration in order to prevent the thromboembolic events associated with the AstraZeneca vaccine. 

SUMMARY 

Thromboembolic disease including disseminated intravascular coagulation and cerebral venous sinus thrombosis have been reported in association with AstraZeneca and Janssen COVID-19 vaccines. Many countries have halted use of these vaccines either entirely or for adults under 30 to 60 years of age. European and North American countries generally have access to mRNA vaccines. However, in Asian and African countries the choices are limited to adenovirus based COVID-19 vaccines. The governments in such countries are forging ahead with vaccinating all adults, including those under 60 years of age, with Vaxzevria, Covishield (the version of Vaxzevria manufactured by the Serum Institute of India) or the Janssen vaccines. This has led to grave concern and anxiety amongst the citizens and medical professionals. Considering the profound global public health implications of limiting the use of these vaccines, it is critical to understand the pathobiology of vaccination induced thrombotic events in order to guide strategies aimed at prevention. In this regard, studies are urgently needed to examine lipid mediators and thromboxane A2 – platelet axis following vaccination with these vaccines, compared with mRNA vaccines. The risk-benefit analysis based on information presented here suggests that chemoprophylaxis using a short course of low-dose aspirin in adults under 60 years of age may be justified in conjunction with adenovirus based COVID-19 vaccines in order to prevent thromboembolic events and enhance safety. 6 

Figure 1. AstraZeneca or Janssen COVID-19 vaccine induced thromboinflammation and cerebral venous sinus thrombosis (CVST)-Proposed Mechanisms: Adenovirus carrier delivers SARS-CoV-2 DNA encoding the Spike (S) protein to the lung megakaryocytes via the coxsackie-adenovirus receptor (CAR). Spike protein induces COX-2 expression in megakaryocytes leading to megakaryocyte activation, biogenesis of activated platelets that express COX-2 and generate thromboxane A2 (TxA2). Cerebral vein sinus endothelial cells express podoplanin, a natural ligand for CLEC2 receptors on platelets. Platelets traversing through the cerebral vein sinuses would be further activated by TxA2 dependent podoplanin-CLEC2 signaling, leading to release of extracellular vesicles, thereby promoting CLEC5A and TLR2 mediated neutrophil activation, thromboinflammation, CVST, and thromboembolism in other vascular beds. Young age and female gender are associated with increased TxA2 generation and platelet activation respectively, and hence increased risk of thromboembolic complications following vaccination. 

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16. Baldini T, Asioli GM, Romoli M, et al. Cerebral venous thrombosis and severe acute respiratory syndrome coronavirus-2 infection: A systematic review and meta-analysis. Eur J Neurol. 2021. 

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18. Petito E, Falcinelli E, Paliani U, et al. Association of Neutrophil Activation, More Than Platelet Activation, With Thrombotic Complications in Coronavirus Disease 2019. The Journal of Infectious Diseases. 2020. 8 

19. Archambault A-S, Zaid Y, Rakotoarivelo V, et al. Lipid storm within the lungs of severe COVID-19 patients: Extensive levels of cyclooxygenase and lipoxygenase-derived inflammatory metabolites. medRxiv. 2020:2020.2012.2004.20242115. 

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26. Cohen CJ, Xiang ZQ, Gao G-P, Ertl HCJ, Wilson JM, Bergelson JM. Chimpanzee adenovirus CV-68 adapted as a gene delivery vector interacts with the coxsackievirus and adenovirus receptor. Journal of General Virology. 2002;83(1):151-155. 

27. Cohen CJ, Shieh JT, Pickles RJ, Okegawa T, Hsieh JT, Bergelson JM. The coxsackievirus and adenovirus receptor is a transmembrane component of the tight junction. Proc Natl Acad Sci U S A. 2001;98(26):15191-15196. 

28. Assinger A. Platelets and infection – an emerging role of platelets in viral infection. Front Immunol. 2014;5:649. 

29. Yan X, Hao Q, Mu Y, et al. Nucleocapsid protein of SARS-CoV activates the expression of cyclooxygenase-2 by binding directly to regulatory elements for nuclear factor-kappa B and CCAAT/enhancer binding protein. Int J Biochem Cell Biol. 2006;38(8):1417-1428. 

30. Rocca B, Secchiero P, Ciabattoni G, et al. Cyclooxygenase-2 expression is induced during human megakaryopoiesis and characterizes newly formed platelets. Proc Natl Acad Sci U S A. 2002;99(11):7634-7639. 

31. Lefrançais E, Ortiz-Muñoz G, Caudrillier A, et al. The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors. Nature. 2017;544(7648):105-109. 

32. Mezey É, Szalayova I, Hogden CT, et al. An immunohistochemical study of lymphatic elements in the human brain. Proceedings of the National Academy of Sciences. 2021;118(3):e2002574118. 

33. Badolia R, Inamdar V, Manne BK, Dangelmaier C, Eble JA, Kunapuli SP. G(q) pathway regulates proximal C-type lectin-like receptor-2 (CLEC-2) signaling in platelets. J Biol Chem. 2017;292(35):14516-14531. 9 

34. Sung P-S, Huang T-F, Hsieh S-L. Extracellular vesicles from CLEC2-activated platelets enhance dengue virus-induced lethality via CLEC5A/TLR2. Nature Communications. 2019;10(1). 

35. Ng H, Havervall S, Rosell A, et al. Circulating Markers of Neutrophil Extracellular Traps Are of Prognostic Value in Patients With COVID-19. Arteriosclerosis, Thrombosis, and Vascular Biology. 2021;41(2):988-994. 

36. Carey MA, Bradbury JA, Seubert JM, Langenbach R, Zeldin DC, Germolec DR. Contrasting Effects of Cyclooxygenase-1 (COX-1) and COX-2 Deficiency on the Host Response to Influenza A Viral Infection. The Journal of Immunology. 2005;175(10):6878-6884. 

37. Kuhl PG, Bolds JM, Loyd JE, Snapper JR, FitzGerald GA. Thromboxane receptor-mediated bronchial and hemodynamic responses in ovine endotoxemia. Am J Physiol. 1988;254(2 Pt 2):R310-319. 

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39. Peters AT, Mutharasan RK. Aspirin for Prevention of Cardiovascular Disease. JAMA. 2020;323(7):676. 

40. Chow JH, Khanna AK, Kethireddy S, et al. Aspirin Use Is Associated With Decreased Mechanical Ventilation, Intensive Care Unit Admission, and In-Hospital Mortality in Hospitalized Patients With Coronavirus Disease 2019. Anesthesia & Analgesia. 2021;132(4). 

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SOURCE

From: “Gupta, Ajay” <ajayg1@hs.uci.edu>

Date: Wednesday, April 14, 2021 at 10:33 AM

To: “Aviva Lev-Ari, PhD, RN” <AvivaLev-Ari@alum.berkeley.edu>

This EXPERT OPINION is in response to:

From: Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu>
Date: Tuesday, April 13, 2021 at 9:03 AM
To: “Joel Shertok, PhD” <jshertok@yahoo.com>, “Stephen Williams, PhD” <sjwilliamspa@comcast.net>, “Prof. Marcus W Feldman” <mfeldman@stanford.edu>, “Irina Robu, PhD” <irina.stefania@gmail.com>, “Dr. Sudipta Saha” <sudiptasaha1977@gmail.com>, Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu>, “Dr. Larry Bernstein” <larry.bernstein@gmail.com>, “Ofer Markman, PhD” <oferm2020@gmail.com>, “Daniel Menzin (gmail)” <dmenzin@gmail.com>, Pnina Abir-Am <pnina.abiram@gmail.com>, Alan <alanalanf@gmail.com>, Justin MDMEPhD <jdpmdphd@gmail.com>, Inbar Ofer <ofer.i@northeastern.edu>, Aviva Lev-Ari <aviva.lev-ari@comcast.net>, Madison Davis <madisond2302@gmail.com>, Danielle Smolyar <dsmolyar@syr.edu>, “Adina Hazan, PhD” <adinathazan@gmail.com>, Gail Thornton <gailsthornton@yahoo.com>, Amandeep kaur <662amandeep@gmail.com>, Premalata Pati <premalata09@gmail.com>, “Ajay Gupta, MD” <charaklabs@outlook.com>, Saul Yedgar <saulye@ekmd.huji.ac.il>, Yigal Blum <yigalblum@gmail.com>, a el <AElRoeiy@gmail.com>, “Dr. Raphael Nir” <rnir@sbhsciences.com>, “George Tetz, MD, PhD” <gtetz@clstherapeutics.com>, “Dr. Martin R Schiller (CEO, Heligenics)” <heligenics@gmail.com>, “Jea Asio (Heligenics)” <JAsio@Heligenics.com>, Yakov Kogan <ykogan@tgv-biomed.com>, Haim Levkowitz <haim@cs.UML.edu>

Subject: APRIL 13. 2021 – J&J Statement – Out of an abundance of caution, the CDC and FDA have recommended a pause in the use of our vaccine. ->> Are there relations between these FINDINGS?

Johnson & Johnson Statement on COVID-19 Vaccine

NEW BRUNSWICK, N.J., April 13, 2021– The safety and well-being of the people who use our products is our number one priority. We are aware of an extremely rare disorder involving people with blood clots in combination with low platelets in a small number of individuals who have received our COVID-19 vaccine. The United States Centers for Disease Control (CDC) and Food and Drug Administration (FDA) are reviewing data involving six reported U.S. cases out of more than 6.8 million doses administered. Out of an abundance of caution, the CDC and FDA have recommended a pause in the use of our vaccine.

In addition, we have been reviewing these cases with European health authorities. We have made the decision to proactively delay the rollout of our vaccine in Europe.

We have been working closely with medical experts and health authorities, and we strongly support the open communication of this information to healthcare professionals and the public.

The CDC and FDA have made information available about proper recognition and management due to the unique treatment required with this type of blood clot. The health authorities advise that people who have received our COVID-19 vaccine and develop severe headache, abdominal pain, leg pain, or shortness of breath within three weeks after vaccination should contact their health care provider.

For more information on the Janssen COVID-19 vaccine, click here.

Please All send me your Expert Opinion on the relations between these FINDINGS?

Linking Thrombotic Thrombocytopenia to ChAdOx1 nCov-19 Vaccination, AstraZeneca | Leaders in Pharmaceutical Business Intelligence (LPBI) Group

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2021/04/12/linking-thrombotic-thrombocytopenia-to-chadox1-ncov-19-vaccination-astrazeneca/

Is SARS-COV2 Hijacking the Complement and Coagulation Systems?

Reporter: Stephen J. Williams, PhD

https://pharmaceuticalintelligence.com/2020/08/04/is-sars-cov2-hijacking-the-complement-and-coagulation-systems/

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 

https://pharmaceuticalintelligence.com/2020/06/01/sar-cov-2-is-probably-a-vasculotropic-rna-virus-affecting-the-blood-vessels-endothelial-cell-infection-and-endotheliitis-in-covid-19/

THANK YOU

Best regards,

Aviva

Aviva Lev-Ari, PhD, RN

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Fighting Chaos with care, community trust, engagement must be cornerstones of pandemic response

Reporter: Amandeep Kaur, BSc, MSc (Exp. 6/2021)

According to the Global Health Security Index released by Johns Hopkins University in October 2019 in collaboration with Nuclear Threat Initiative (NTI) and The Economist Intelligence Unit (EIU), the United States was announced to be the best developed country in the world to tackle any pandemic or health emergency in future.

The table turned within in one year of outbreak of the novel coronavirus COVID-19. By the end of March 2021, the country with highest COVID-19 cases and deaths in the world was United States. According to the latest numbers provided by World Health Organization (WHO), there were more than 540,000 deaths and more than 30 million confirmed cases in the United States.

Joia Mukherjee, associate professor of global health and social medicine in the Blavatnik Institute at Harvard Medical School said,

“When we think about how to balance control of an epidemic over chaos, we have to double down on care and concern for the people and communities who are hardest hit”.

She also added that U.S. possess all the necessary building blocks required for a health system to work, but it lacks trust, leadership, engagement and care to assemble it into a working system.

Mukherjee mentioned about the issues with the Index that it undervalued the organized and integrated system which is necessary to help public meet their needs for clinical care. Another necessary element for real health safety which was underestimated was conveying clear message and social support to make effective and sustainable efforts for preventive public health measures.

Mukherjee is a chief medical officer at Partners In Health, an organization focused on strengthening community-based health care delivery. She is also a core member of HMS community members who play important role in constructing a more comprehensive response to the pandemic in all over the U.S. With years of experience, they are training global health care workers, analyzing the results and constructing an integrated health system to fight against the widespread health emergency caused by coronavirus all around the world.

Mukherjee encouraged to strengthen the consensus among the community to constrain this infectious disease epidemic. She suggested that validation of the following steps are crucial such as testing of the people with symptoms of infection with coronavirus, isolation of infected individuals by providing them with necessary resources and providing clinical treatment and care to those people who are in need. Mukherjee said, that community engagement and material support are not just idealistic goal rather these are essential components for functioning of health care system during an outburst of coronavirus.

Continued alertness such as social distancing and personal contact with infected individual is important because it is not possible to rapidly replace the old-school public health approaches with new advanced technologies like smart phone applications or biomedical improvements.

Public health specialists emphasized that the infection limitation is the only and most vital strategy for controlling the outbreak in near future, even if the population is getting vaccinated. It is crucial to slowdown the spread of disease for restricting the natural modification of more dangerous variants as that could potentially escape the immune protection mechanism developed by recently generated vaccines as well as natural immune defense systems.

Making Crucial connections

The treatment is more expensive and complicated in areas with less health facilities, said Paul Farmer, the Kolokotrones University Professor at Harvard and chair of the HMS Department of Global Health and Social Medicine. He called this situation as treatment nihilism. Due to shortage of resources, the maximum energy is focused in public health care and prevention efforts. U.S. has resources to cope up with the increasing demand of hospital space and is developing vaccines, but there is a form of containment nihilism- which means prevention and infection containment are unattainable- said by many experts.

Farmer said, integration of necessary elements such as clinical care, therapies, vaccines, preventive measures and social support into a single comprehensive plan is the best approach for a better response to COVID-19 disease. He understands the importance of community trust and integrated health care system for fighting against this pandemic, as being one of the founders of Partners In Health and have years of experience along with his colleagues from HMS and PIH in fighting epidemics of HIV, Ebola, cholera, tuberculosis, other infectious and non-infectious diseases.

PIH launched the Massachusetts Community Tracing Collaborative (CTC), which is an initiative of contact tracing statewide in partnership with several other state bodies, local boards of Health system and PIH. The CTC was setup in April 2020 in U.S. by Governor Charlie Baker, with leadership from HMS faculty, to build a unified response to COVID-19 and create a foundation for a long-term movement towards a more integrated community-based health care system.

The contact tracing involves reaching out to individuals who are COVID-19 positive, then further detect people who came in close contact with infected individuals and screen out people with coronavirus symptoms and encourage them to seek testing and take necessary precautions to break the chain of infection into the community.

In the initial phase of outbreak, the CTC group comprises of contact tracers and health care coordinators who spoke 23 different languages, including social workers, public health practitioners, nurses and staff members from local board health agencies with deep links to the communities they are helping. The CTC worked with 339 out of 351 state municipalities with local public health agencies relied completely on CTC whereas some cities and towns depend occasionally on CTC backup. According to a report, CTC members reached up to 80 percent of contact tracking in hard-hit and resource deprived communities such as New Bedford.

Putting COVID-19 in context

Based on generations of experience helping people surviving some of the deadliest epidemic and endemic outbreaks in places like Haiti, Mexico, Rwanda and Peru, the staff was alert that people with bad social and economic condition have less space to get quarantined and follow other public health safety measures and are most vulnerable people at high risk in the pandemic situation.

Infected individuals or individuals at risk of getting infected by SARS-CoV-2 had many questions regarding when to seek doctor’s help and where to get tested, reported by contact tracers. People were worried about being evicted from work for two weeks and some immigrants worried about basic supplies as they were away from their family and friends.

The CTC team received more than 7,000 requests for social support assistance in the initial three months. The staff members and contact tracers were actively connecting the resourceful individuals with the needy people and filling up the gap when there was shortage in their own resources.

Farmer said, “COVID is a misery-seeking missile that has targeted the most vulnerable.”

The reality that infected individuals concerned about lacking primary household items, food items and access to childcare, emphasizes the urgency of rudimentary social care and community support in fighting against the pandemic. Farmer said, to break the chain of infection and resume society it is mandatory to meet all the elementary needs of people.

“What kinds of help are people asking for?” Farmer said and added “it’s important to listen to what your patients are telling you.”

An outbreak of care

The launch of Massachusetts CTC with the support from PIH, started receiving requests from all around the country to assist initiating contact tracing procedures. In May, 2020 the organization announced the launch of a U.S. public health accompaniment to cope up with the asked need.

The unit has included team members in nearly 24 states and municipal health departments in the country and work in collaboration with local organizations. The technical support on things like choosing and implementing the tools and software for contact tracing was provided by PIH. To create awareness and provide new understanding more rapidly, a learning collaboration was established with more than 200 team members from more than 100 different organizations. The team worked to meet the needs of population at higher risk of infection by advocating them for a stronger and more reliable public health response.

The PIH public health team helped to train contact trackers in the Navajo nation and operate to strengthen the coordination between SARS-CoV-2 testing, efforts for precaution, clinical health care delivery and social support in vulnerable communities around the U.S.

“For us to reopen our schools, our churches, our workplaces,” Mukherjee said, “we have to know where the virus is spreading so that we don’t just continue on this path.”

SOURCE:

https://hms.harvard.edu/news/fighting-chaos-care?utm_source=Silverpop&utm_medium=email&utm_term=field_news_item_1&utm_content=HMNews04052021

Other related articles were published in this Open Access Online Scientific Journal, including the following:

T cells recognize recent SARS-CoV-2 variants

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2021/03/30/t-cells-recognize-recent-sars-cov-2-variants/

The WHO team is expected to soon publish a 300-page final report on its investigation, after scrapping plans for an interim report on the origins of SARS-CoV-2 — the new coronavirus responsible for killing 2.7 million people globally

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2021/03/27/the-who-team-is-expected-to-soon-publish-a-300-page-final-report-on-its-investigation-after-scrapping-plans-for-an-interim-report-on-the-origins-of-sars-cov-2-the-new-coronavirus-responsibl/

Need for Global Response to SARS-CoV-2 Viral Variants

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2021/02/12/need-for-global-response-to-sars-cov-2-viral-variants/

Mechanistic link between SARS-CoV-2 infection and increased risk of stroke using 3D printed models and human endothelial cells

Reporter: Adina Hazan, PhD

https://pharmaceuticalintelligence.com/2020/12/28/mechanistic-link-between-sars-cov-2-infection-and-increased-risk-of-stroke-using-3d-printed-models-and-human-endothelial-cells/

Artificial intelligence predicts the immunogenic landscape of SARS-CoV-2

Reporter: Irina Robu, PhD

https://pharmaceuticalintelligence.com/2021/02/04/artificial-intelligence-predicts-the-immunogenic-landscape-of-sars-cov-2/

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COVID-19 Sequel: Neurological Impact of Social isolation been linked to poorer physical and mental health

Reporter: Aviva Lev-Ari, PhD, RN

UPDATED on 4/13/2021

Toward Understanding COVID-19 Recovery: National Institutes of Health Workshop on Postacute COVID-19

 

Abstract

Over the past year, the SARS-CoV-2 pandemic has swept the globe, resulting in an enormous worldwide burden of infection and mortality. However, the additional toll resulting from long-term consequences of the pandemic has yet to be tallied. Heterogeneous disease manifestations and syndromes are now recognized among some persons after their initial recovery from SARS-CoV-2 infection, representing in the broadest sense a failure to return to a baseline state of health after acute SARS-CoV-2 infection. On 3 to 4 December 2020, the National Institute of Allergy and Infectious Diseases, in collaboration with other Institutes and Centers of the National Institutes of Health, convened a virtual workshop to summarize existing knowledge on postacute COVID-19 and to identify key knowledge gaps regarding this condition.

Over the past year, the SARS-CoV-2 pandemic has swept the globe, resulting in more than 113 million persons infected and 2.5 million deaths (1). However, the additional toll resulting from long-term consequences of the pandemic has yet to be tallied. Heterogeneous disease manifestations and syndromes are now recognized among some persons after their initial recovery from SARS-CoV-2 infection. Although a standardized case definition does not yet exist for these manifestations, in the broadest sense they represent a failure to return to a baseline state of health after acute SARS-CoV-2 infection. The various terms used to describe this condition have included postacute (or late) sequelae of COVID-19, post-COVID condition or syndrome, long COVID, and long-haul COVID. In this article, we use the general umbrella term of “postacute COVID-19” to refer to multiple disease processes that may have varying degrees of overlap (including but not limited to sequelae of critical illness and hospitalization in persons with COVID-19) and the entity of long COVID, which refers to prolonged health abnormalities in persons previously infected with SARS-CoV-2 who may or may not have required hospitalization. Of note, there is not yet a consensus on terminology, which will likely evolve with a better understanding of this condition.

Reported symptoms are wide-ranging and may involve nearly all organ systems, with fatigue, dyspnea, cognitive dysfunction, anxiety, and depression often described (2–5). Although abnormalities in imaging studies and functional testing have been reported, the long-term clinical significance of some of these findings is not yet clear (367). Postacute manifestations of COVID-19 have been seen in persons of all demographic groups and include reports of multisystem inflammatory syndrome in children (89). Although the epidemiology of the diverse manifestations of postacute COVID-19 is not yet known, the expansive global burden of SARS-CoV-2 infection suggests that the potential public health effects of postacute COVID-19 are significant if even a small proportion of persons with SARS-CoV-2 infection have prolonged recovery or do not return to their baseline health.

On 3 to 4 December 2020, the National Institute of Allergy and Infectious Diseases, in collaboration with other Institutes and Centers of the National Institutes of Health, convened a virtual workshop (available via videocast at https://videocast.nih.gov/watch=38878 and https://videocast.nih.gov/watch=38879) to summarize existing knowledge on postacute COVID-19 and to identify key knowledge gaps. The speakers and participants included epidemiologists, clinicians, clinical and basic scientists, and members of the affected community. The videocast was open to the general public and had more than 1200 registered participants.

SOURCE

UPDATED on 4/7/2021

‘Beyond a Reasonable Doubt’: COVID-19 Brain Health Fallout Is Real, Severe

Sarah Edmonds

April 07, 2021

Editor’s note: Find the latest COVID-19 news and guidance in Medscape’s Coronavirus Resource Center.

START QUOTE

COVID-19 survivors face a sharply elevated risk of developing psychiatric or neurologic disorders in the six months after they contract the virus — a danger that mounts with symptom severity, new research shows.

In what is purported to be the largest study of its kind to-date, results showed that among 236,379 COVID-19 patients, one third were diagnosed with at least one of 14 psychiatric or neurologic disorders within a 6-month span.

The rate of illnesses, which ranged from depression to stroke, rose sharply among those with COVID-19 symptoms acute enough to require hospitalization.  

“If we look at patients who were hospitalized, that rate increased to 39%, and then increased to about just under 1 in 2 patients who needed ICU admission at the time of the COVID-19 diagnosis,” Maxime Taquet, PhD, University of Oxford Department of Psychiatry, Oxford, United Kingdom, told a media briefing.

Incidence jumps to almost two thirds in patients with encephalopathy at the time of COVID-19 diagnosis, he added.

The study, which examined the brain health of 236,379 survivors of COVID-19 via a US database of 81 million electronic health records, was published online April 6 in The Lancet Psychiatry.

High Rate of Neurologic, Psychiatric Disorders

The research team looked at the first-time diagnosis or recurrence of 14 neurologic and psychiatric outcomes in patients with confirmed SARS-CoV-2 infections. They also compared the brain health of this cohort with a control group of those with influenza or with non-COVID respiratory infections over the same period. 

SOURCE

The Effects of Loneliness and Our Brain function: poorer physical and mental health

One review of the science of loneliness found that people with stronger social relationships have a 50 per cent increased likelihood of survival over a set period of time compared with those with weaker social connections. Other studies have linked loneliness to cardiovascular disease, inflammation, and depression.

For loneliness researchers the pandemic has provided an unprecedented natural experiment in the impact that social isolation might have on our brains. As millions of people across the world emerge from months of reduced social contact, a new neuroscience of loneliness is starting to figure out why social relationships are so crucial to our health.

Neural basis of Emotion

Desire for Social Interaction

Are there neurological differences between people who experience short-term isolation and those who have been isolated for long stretches of time? What kinds of social interactions satisfy our social cravings? Is a video call enough to quell our need for social contact, or do some people require an in-person connection to really feel satiated?

START QUOTE

Julianne Holt-Lunstad, a psychology professor at Brigham Young University in the US and the author of two major studies on social isolation and health. “We have a lot of data that very robustly shows that both isolation and loneliness put us at increased risk for premature mortality—and conversely, that being socially connected is protective and reduces our risk,” she says.

START QUOTE

“Trying to investigate isolation or loneliness is not as straightforward in humans. In humans, being lonely is not necessarily correlated with how many people are around you,” says Tomova. She is particularly interested in the impact that the pandemic might have had on young people whose cognitive and social skills are still developing. “I think we will see potentially some differences in how their social behavior developed or things like that,” she says. But as is always the case in the uncertain world of loneliness research, the opposite could be true. “It could also be that most people are fine, because maybe social media does fulfill our social needs really well.”

SOURCE

https://www.wired.co.uk/article/lockdown-loneliness-neuroscience

The Weird Science of Loneliness and Our Brains – Social isolation as been linked to poorer physical and mental health, but scientists are finally starting to understand its neurological impact

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