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    Scientists uncover a molecule that can help coronavirus escape antibodies


    https://medicalxpress.com/news…oronavirus-antibodies.amp


    Researchers have found that a natural molecule can effectively block the binding of a subset of human antibodies to SARS-CoV-2. The discovery may help explain why some COVID-19 patients can become severely ill despite having high levels of antibodies against the virus.

    In their research, published in Science Advances today (April 22, 2021), teams from the Francis Crick Institute, in collaboration with researchers at Imperial College London, Kings College London and UCL (University College London), found that biliverdin and bilirubin, natural molecules present in the body, can suppress the binding of antibodies to the coronavirus spike.


    As vaccines are rolled out globally, understanding immunity to SARS-CoV-2 and also how the virus evades antibodies is critically important. However, there are still many unknowns. The ability of the immune system to control the infection and the quality of the antibody response are highly variable, and not well correlated, between individuals.


    The Crick researchers were involved in the development of tests that see if a person has been exposed to the virus. The scientists discovered that the SARS-CoV-2 spike protein strongly binds to biliverdin, a molecule which was giving these proteins an unusual green colouration.


    Working with teams at Imperial College London, UCL and Kings College London, they found that this natural molecule reduced antibody binding to the spike. They used blood sera and antibodies from people who were previously infected with SARS-CoV-2 and found that biliverdin could suppress the binding of human antibodies to the spike by as much as 30-50%, with some antibodies becoming ineffective at neutralizing the virus.


    Such a significant impact was completely unexpected, as biliverdin only binds to a very small patch on the virus' surface. To find out the mechanism at work, the team at the Crick used cryo-electron microscopy and X-ray crystallography to look in detail at the interactions between the spike, the antibodies and biliverdin. They found that biliverdin attaches to the spike N-terminal domain and stabilizes it so that the spike is not able to open up and expose parts of its structure. This means that some antibodies are not able to access their target sites and so cannot bind to and neutralize the virus.


    Annachiara Rosa, first author and postdoctoral training fellow in the Chromatin structure and mobile DNA Laboratory at the Crick, says: "When SARS-CoV-2 infects a patient's lungs it damages blood vessels and causes a rise in the number immune cells. Both of these effects may contribute to increasing the levels of biliverdin and bilirubin in the surrounding tissues. And with more of these molecules available, the virus has more opportunity to hide from certain antibodies. This is a really striking process, as the virus may be benefiting from a side effect of the damage it has already caused."


    Peter Cherepanov, author and a group leader of the Chromatin structure and mobile DNA Laboratory at the Crick, says: "In the first months of the pandemic, we were extremely busy churning out viral antigens for SARS-CoV-2 tests. It was a race, as these tests were urgently needed. When we finally found the time to study our green proteins, we expected a mundane answer. Instead, we were astonished to discover a new trick the virus uses to avoid antibody recognition. This is a result of a collaborative effort of several amazing teams working at the Crick and three partner universities, led purely by scientific curiosity."


    The researchers will continue this work from various angles, including measuring the levels of biliverdin and other haem metabolites in patients with COVID-19 and also exploring if it is possible to hijack the binding site used by biliverdin to potentially find new ways to target the virus.

    Watch the FLCCC update video, if ivermectin can work as a vaccine big pharma will lose emergency use for vaccine. It's all about $$$ not about saving lives and stop with the anti vax crap! Many people who believe in ivermectin have been vaccinated. I am one and would rather take a drug that has years of study behind it rather than a great world study vaccine. But that's just common sense!!!!

    Do preservative and stray proteins cause rare COVID-19 vaccine side effect?


    https://www.sciencemag.org/new…id-19-vaccine-side-effect


    Researchers in Germany and Canada have added provocative new details to their proposal for how the COVID-19 vaccine made by AstraZeneca might be causing an unusual clotting disorder in a small number of recipients. The mechanism, involving stray human proteins and a preservative in the vaccine, remains speculative. And it is not clear whether their hypothesis explains similar reactions observed in recipients of the COVID-19 vaccine made by Johnson & Johnson (J&J).


    The new data are “interesting but not a smoking gun by any means” for the group’s hypothesis, says Gowthami Arepally, a hematologist at the Duke University School of Medicine who is working as an external consultant with AstraZeneca on the issue. But figuring out what in a COVID-19 vaccine might start the sometimes fatal combination of blood clotting and low platelets is crucial for developing better treatments for the side effect and possibly for understanding who might be most at risk, says Paul Offit, a vaccine researcher at the Children’s Hospital of Philadelphia (CHOP). It could also be vital for modifying vaccines so they don’t kick-start the reaction, which researchers are calling vaccine-induced immune thrombotic thrombocytopenia (VITT).

    Vaccine regulators are struggling to balance the small risk of VITT versus the clear need to immunize people against the pandemic virus SARS-CoV-2. The European Medicines Agency (EMA) declared on Tuesday that the COVID-19 protection of the J&J vaccine significantly outweighs the danger of the rare side effect and recommended its use, with an addition to the warning label that alerts doctors and recipients to the clotting problem. That advice, which matches EMA’s verdict on the AstraZeneca vaccine, cleared the way for vaccinations with the J&J shots to begin across Europe.


    Both J&J and AstraZeneca use modified adenoviruses to deliver and express the spike protein gene of SARS-CoV-2. But new data posted Tuesday in a preprint on Research Square show that doses of the AstraZeneca vaccine also contain significant amounts of protein from human cells—presumably from the human cell line used to grow the virus during the manufacturing process. The preprint’s authors, some whom were among the first to identify the VITT side effect, propose that these proteins, together with another component of the vaccine called ethylenediaminetetraacetic acid (EDTA), may set off a dangerous response by the immune system in some vaccine recipients.


    EDTA is used in some vaccines as a preservative, but it is also known to make blood vessels a bit leaky, says Andreas Greinacher, an expert on clotting at the University of Greifswald who led the study. He said he was suprised at the concentration the group found in the AstraZeneca vaccine samples they examined: 100 micromoles, which is much higher than amounts listed for other common vaccines.


    The group showed that in a mouse model, the vaccine did increase vascular leakage. Greinacher says this may make any free proteins in a vaccine dose more likely to encounter the red blood cell fragments known as platelets, or thrombocytes, in a recipient’s bloodstream. Platelet factor 4 (PF4), a protein secreted by these thrombocytes, could then form complexes with the residual human proteins and other components of the vaccine, thanks to its strong positive charge. Indeed, when the researchers added PF4 to the vaccine in the lab, large complexes formed. Greinacher notes that other vaccines contain human proteins, but the amount—between 70 and 80 micrograms per milliliter (mcg/mL) in the four batches they tested—was “surprisingly high,” he says. Other vaccines list amounts of 5 mcg/mL or less, although many do not specify an amount.


    In a tiny minority of people, Greinacher and his colleagues speculate, the combination of PF4 complexes and the strong inflammation triggered by the vaccine may turn on a specialized set of immune cells that can make antibodies to PF4. (This also happens in a similar clotting syndrome triggered by the blood thinner heparin. In that case, heparin forms the problematic complexes with PF4.) In an even smaller minority, the researchers say, the antibodies to PF4 are strong enough to fuel additional immune reactions in the blood that deplete platelets in the blood and cause potentially deadly clots to form in the brain, abdomen, or lungs.


    Those PF4 antibodies can be useful if the body is fighting off severe infection—but they can get out of control, Greinacher says. “It’s like waking a sleeping dragon,” he says. “In most cases, we really want to keep the dragon sleeping, and the vaccine is like a guy coming into a cave and throwing stones at it.” An AstraZeneca spokesperson said the company could not comment directly on the preprint, but that they “continue to work to understand the individual cases, epidemiology, and possible mechanisms that could explain these rare events.”


    Greinacher has asked J&J for doses of its vaccine so he can analyze its contents and see whether it might trigger the same cascade. The vaccine had not been used yet in Germany, which he says prevented him from using it in his initial experiments.


    Offit notes that other vaccines are grown in cell culture and contain cellular debris, and it isn’t clear that AstraZeneca’s contains more or different remnants. EDTA may also not be needed to trigger VITT; J&J’s COVID-19 vaccine doesn’t include it, for instance. “Adenovirus has a notorious history of being a particularly inflammatory stimulating virus,” says Mortimer Poncz, a pediatric hematologist at CHOP. “Whether the EDTA is involved, I think, is the softest part of the whole story.”


    Arepally agrees. “The virus itself, which has been given in such large amounts, is probably enough to cause an inflammatory response,” she says. Arepally suggests PF4 simply binds to the adenovirus—which could, in theory, be why the J&J vaccine produces the same side effect. She speculates that a few unlucky people “simply have higher levels of PF4 for some reason and that’s why they are forming these complexes when they get the vaccine.”


    Poncz, on the other hand, isn’t convinced PF4 complexes are actually behind the clotting problems. The complexes may be innocent bystanders, he says, although he applauds Greinacher “for leading the field and providing thought-provoking and experiment-provoking questions.”


    Rolf Marschalek, a molecular biologist at Goethe University Frankfurt, suspects that additional spike-related mechanisms may play a role once a vaccinated person’s cells start to make the viral protein, which happens in the same time frame as the clotting disorders appear, generally between 4 to 20 days following vaccination. These might then add to the PF4 antibody cascade which the Greifswald group describes, he says.


    Even as the spotlight shines on the J&J and AstraZeneca vaccines, scrutiny is widening to two other COVID-19 vaccines that rely on adenovirus vectors: Sputnik V, developed by the Russian Gamaleya National Research Institute of Epidemiology and Microbiology, and another made by the Chinese company CanSino Biologics. CanSino CEO Yu Xuefeng told journalists the company is monitoring recipients more carefully after the clotting reports emerged. The Gamaleya Institute said in a press release there had been no reports of clotting disorders following its vaccine rollout it many countries, although it’s not clear how many people have received it so far.


    Hungary is already using Sputnik V, and several other European countries are considering purchases, but EMA has not yet approved it for use. EMA Director Emer Cooke says the agency’s review of safety data for the vaccine “is at an early stage,” and it has not yet looked carefully at data regarding possible side effects. “But now that we are aware of [VITT], will make sure it’s part of the company’s responsibility to report any of these events.”

    Watch the FLCCC update I posted, kory talks of big pharma influence

    New Covid variant detected at Texas A&M lab shows signs of antibody resistance and more severe illness in young people


    https://www.cnbc.com/amp/2021/…ness-in-young-people.html


    Scientists at Texas A&M University's Global Health Research Complex say they've detected a new Covid-19 variant that shows signs of a more contagious strain that causes more severe illness and appears to be resistant to antibodies.


    The new variant, BV-1, named after its Brazos Valley origin, was found during Texas A&M's routine coronavirus screening via saliva sample in a young student who had mild cold-like symptoms. The student tested positive for Covid on March 5 and tested positive again on March 25, showing that the new strain may cause a longer infection in younger people. The student's symptoms resolved by April 2 and a third test on April 9 came back negative.

    Texas A&M scientists say that cell culture-based experiments from other labs have shown that several neutralizing antibodies had no effect in controlling other variants with the same genetic markers as BV-1.


    "We do not at present know the full significance of this variant, but it has a combination of mutations similar to other internationally notifiable variants of concern," said Texas A&M Chief Virologist Ben Neuman. "This variant combines genetic markers separately associated with rapid spread, severe disease and high resistance to neutralizing antibodies."

    FLCCC update. WHO and disinformation


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    COVID Variants Detected in Animals, May Find Hosts in Mice

    By Brenda Goodman, MA


    https://www.webmd.com/lung/new…als-may-find-host-in-mice


    March 25, 2021 -- The new coronavirus variants are not just problems for humans.


    New research shows they can also infect animals, and for the first time, variants have been able to infect mice, a development that may complicate efforts to rein in the global spread of the virus.


    In addition, two new studies have implications for pets. Veterinarians in Texas and the United Kingdom have documented infections of B.1.1.7 — the fast-spreading variant first found in the U.K. — in dogs and cats. The animals in the U.K. study also had heart damage, but it's unclear if the damage was caused by the virus or was already there and was found as a result of their infections.

    Animal studies of coronavirus and its emerging variants are urgent, Sarah Hamer, DVM, a veterinarian and epidemiologist in the Texas A&M University's College of Veterinary Medicine and Biomedical Sciences in College Station, says.


    She's part of a network of scientists who are swabbing the pets of people who are diagnosed with COVID-19 to find out how often the virus passes from people to animals.


    The collaboration is part of the CDC’s One Health initiative. One Health aims to tackle infectious diseases by recognizing that people can't be fully protected from pathogens unless animals and the environment are also safeguarded.


    "Over 70% of emerging diseases of humans have their origins in animal populations," Hamer said. "So if we are only focusing on studying disease as it emerges in humans and ignoring where those pathogens have been transmitted or circulating for years, then we might miss the ability to detect early emergence. We might miss the ability to control these diseases before they become problems for human health.”


    Variants Move to Mice

    In new work, researchers at the Institut Pasteur in Paris have shown that the B.1.351 and P.1 variants of concern, which were first identified in South Africa and Brazil, respectively, can infect mice, giving the virus a potential new host.


    Older versions of the virus couldn't infect mice because they weren't able to bind to receptors on their cells. These two variants can.


    On one hand, that's a good thing, because it will help scientists more easily conduct experiments in mice. Before, if they wanted to do an experiment with coronavirus in mice, they had to use a special strain of mouse that was bred to carry human ACE2 receptors on their lung cells. Now that mice can become naturally infected, any breed will do, making it less costly and time-consuming to study the virus in animals.


    On the other hand, the idea that the virus could have more and different ways to spread isn't good news.


    "From the beginning of the epidemic and since human coronaviruses emerged from animals, it has been very important to establish in which species the virus can replicate, in particular the species that live close to humans," said Xavier Montagutelli, DVM, , head of the Mouse Genetics Laboratory at the Institut Pasteur. His study was published as a preprint ahead of peer review on BioRXIV.

    The search for animals harbouring coronavirus — and why it matters

    Scientists are monitoring pets, livestock and wildlife to work out where SARS-CoV-2 could hide, and whether it could resurge.


    https://www.nature.com/articles/d41586-021-00531-z


    It was the news Sophie Gryseels had been dreading for months. Almost a year into the pandemic, a seemingly healthy wild mink tested positive for SARS-CoV-2 in Utah. No free-roaming animal was known to have caught the virus before, although researchers had been watching for this closely. “It’s happened,” wrote Gryseels, an evolutionary biologist at the University of Antwerp, Belgium, in an e-mail to her colleagues.


    Ever since the coronavirus started spreading around the world, scientists have worried that it could leap from people into wild animals. If so, it might lurk in various species, possibly mutate and then resurge in humans even after the pandemic has subsided.


    That would bring the tale of SARS-CoV-2 full circle, because wild animals probably brought it to humans in the first place. Strong evidence suggests that the virus originated in horseshoe bats (Rhinolophus spp.), possibly hitching a ride on other animals before infecting people1. In the current stage of the pandemic, with hundreds of thousands of confirmed COVID-19 infections every day, people are still driving transmission of SARS-CoV-2. But years from now, when community spread has been suppressed, a reservoir of SARS-CoV-2 in free-roaming animals could become a recalcitrant source of new flare-ups.


    Wild animals are not the only ones to have drawn scrutiny. Studies have shown that SARS-CoV-2 can infect many domesticated and captive creatures, from cats and dogs, to pumas, gorillas and snow leopards in zoos, and farmed mink. Outbreaks in mink farms have already shown that infected animals can pass the virus back to humans.

    Although these cases have raised concerns, researchers are less worried about viral outbreaks in domestic and farmed animals because such eruptions can be kept in check through quarantining, vaccination and culling. If the virus spreads in wild animals, however, it will be much more difficult to control. “Then there is no hope for eradication,” says Gryseels.


    In theory, the virus could evolve as it circulates among animals — possibly in ways that threaten the efficacy of vaccines or make the pathogen more deadly and infectious to people, says Arinjay Banerjee, a coronavirus researcher at McMaster University in Hamilton, Canada. “Not to sound any alarms, but everything we don’t want to see with this virus seems to happen,” he says.


    Over the past year, scientists have tried to ascertain how credible and grave the risks are. Global efforts are under way to survey wildlife and catch spillovers as soon as possible. Researchers are testing animals from homes, zoos, shelters, veterinary clinics, farms and their surroundings. If any positive cases are detected, countries immediately notify the World Organisation for Animal Health (OIE), based in Paris. Scientists have used computational models and studied cells and whole animals to identify the species most vulnerable to infection with SARS-CoV-2.


    In one year, scientists have collected as much data about the susceptibility of different species to SARS-CoV-2 as was accumulated over the past 50 years for influenza, says Martin Beer, a virologist at the Federal Research Institute for Animal Health in Greifswald, Germany.

    Animal infections are rare, and some researchers are reassured by the data collected so far. But others are more cautious. SARS-CoV-2 is known to infect a wide range of animal species (see ‘Animal outbreaks’). This fact, says Gryseels, combined with the large number of infected people, means that, in principle, the virus has had millions of opportunities to jump from people to animals.


    Many of those jumps could be passing under the radar. Wildlife studies are difficult to do, and animal infections have not been a priority for much of the research community. The wild mink that tested positive in Utah “could just be the tip of the iceberg”, says Sarah Hamer, an epidemiologist and veterinarian at Texas A&M University in College Station. “The more we look, the more we might find.”


    Primary suspects

    Early in the pandemic, pigs were top of the watchlist. They are known to incubate other viruses, such as influenza, and they live in huge numbers in close proximity to humans — some 300 million pigs are farmed in China, where the pandemic began. “We are always afraid if pigs are involved,” says Beer.


    Pigs can also host coronaviruses. In 2018, researchers described a new bat coronavirus that had killed some 25,000 pigs in southern China2. And in February 2020, scientists working on SARS-CoV-2 showed that it could enter pig cells through the ACE2 protein — the same receptor that it uses to infect people3.


    But when researchers began artificially infecting pigs and piglets with SARS-CoV-2, they found that it did not replicate well4,5. These studies suggest that pigs are largely resistant to infection with the virus. “Thank goodness, because with the volume of pig production globally, that would have been a huge problem,” says Peter Daszak, president of the non-profit research organization Ecohealth Alliance in New York City.

    With pigs off the priority list, bats became the centre of attention. They are the purported source of SARS-CoV-2, and researchers worried that the virus could spread into new bat populations. In April, the US Fish and Wildlife Service advised scientists to suspend all research that involved capturing and hand-ling bats.


    As with pigs, however, the results of studies into bats have been generally reassuring. A study of ACE2 receptors in the cells of 46 bat species found that the majority were poor hosts6. But controlled experiments have shown that some species, such as fruit bats (Rousettus aegyptiacus), can get infected and spread the infection to other bats5. And, with more than 1,400 species, “bats are more of a black box than other animals”, says Gryseels.

    In Atlanta at the Georgia Aquarium, some otters got COVID-19. The poor things showed some symptoms. They are recovering.


    https://www.ajc.com/life/georg…A3I5X5VVGZ7GGKT2IU3WPNLQ/

    This seems to be largely overlooked in the pandemic. The virus has infected domestic as well as wild animals giving the virus a huge Reservoir as well as a huge incubator for mutations as well as another new version of sars/cov. Not enough research has looked into this concerning aspect of the pandemic.

    More evidence Covid is seasonal


    Coronavirus live updates: California variant 20% more transmissible, new study findshttps://www.sfchronicle.com/coronavirus/article/Coronavirus-live-updates-Bay-Area-sees-plunge-in-15993567.php


    10:12 a.m. California variant 20% more transmissible, new study finds: The L452R spike mutation, which is present in both the California (B.1.429) and Indian (B.1.617) variants of the coronavirus, is 20% more infectious than the common virus and carries higher viral loads, according to a study published by researchers at UCSF, UCB and the California Department of Public Health. The study also found that antibody neutralization is reduced in COVID-19 patients and vaccine recipients. The variant became the dominant source of infection in the state as of Jan. 31.


    2:39 p.m. California has second lowest infection rate in the U.S.: With the seven-day average of new cases at 40.3 per 100,000 people, California has the lowest coronavirus infection rate in the nation behind Hawaii, which has 39.1 cases per 100,000 for the same period. The latest data from the Centers for Disease Control and Prevention shows the overall U.S. average is 135.3 cases, with Michigan at the top of the list with 483 cases per 100,000 people, followed by New Jersey (269.7), Delaware (264.1) and Pennsylvania (248.5).

    TEST CONFIRMS GROUP OF WA DOGS SHOW EVIDENCE OF EXPOSURE TO THE VIRUS THAT CAUSES COVID-19


    https://komonews.com/amp/news/…vid-19-antibodies-in-dogs


    OLYMPIA – The Washington State Department of Agriculture (WSDA) received confirmation yesterday of a test showing evidence of exposure to SARS-CoV-2, the virus that causes COVID-19, in a group of Washington state dogs who were sampled as part of a study by the University of Washington.

    In all, 23 samples tested positive for antibodies to SARS-CoV-2, and while these are the first cases of a pet testing positive in Washington, they are not the first in the U.S., as there have been numerous reports nationally of companion animals testing positive for SARS-CoV-2. The Centers for Disease Control and Prevention (CDC) and the U.S. Department of Agriculture (USDA) both state that there is no evidence that animals play a significant role in spreading the virus to humans.

    “These detections are not a surprise given the other cases reported across the country,” Washington State Veterinarian Dr. Brian Joseph said. “While there is no significant public health risk, we would advise pet owners who are COVID-positive to take measures to protect their pets from the virus.”

    The Washington State Department of Health recommends that people who are ill with COVID-19 and in home isolation avoid direct contact with pets. If possible, a household member should care for pets in the home. If a person with COVID-19 must care for pets or other animals, they should wear a mask and wash their hands before and after interacting with them. If an animal becomes sick, owners should contact a veterinarian.

    The samples tested in this incident were first obtained by UW researchers as part of a study the UW is leading on pets and companion animals from households where humans have tested positive for COVID-19. The COVID-19 and Pets Study began in early 2020 after the pandemic struck Washington and is being done in partnership with the Washington Animal Disease Diagnostic Laboratory (WADDL) at Washington State University.

    “These results indicate that COVID-infected humans are able to transmit the virus to animals living in the same household. While we don’t have evidence that this poses a risk to other humans, we are recommending that COVID-infected persons take steps to reduce the risk of infecting their pets,” said Dr. Peter Rabinowitz, Director of the UW Center for One Health Research and Principal Investigator for the COVID and Pets Study. “We are continuing this study as the human vaccine rollout takes place, and will be seeing whether any change in household transmission occurs.”

    WADDL advised WSDA earlier this month that their lab had found SARS-CoV-2 antibodies in the samples obtained for the UW study, indicating the animals had been exposed to the coronavirus. Last week, those samples were sent to the USDA National Veterinary Service Laboratory (NVSL), which verified WADDL’s results and provided the confirmation to WSDA.

    Visit the CDC’s Covid-19 and Animals webpage for more information on COVID-19 and animals. You can also go to the USDA Animal and Plant Health Inspection Service website for a complete list of animals that have tested positive for SARS-CoV-2.

    Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19


    https://www.nejm.org/doi/full/…irc_artType_railA_article


    BACKGROUND

    The efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear.


    METHODS

    We evaluated tocilizumab and sarilumab in an ongoing international, multifactorial, adaptive platform trial. Adult patients with Covid-19, within 24 hours after starting organ support in the intensive care unit (ICU), were randomly assigned to receive tocilizumab (8 mg per kilogram of body weight), sarilumab (400 mg), or standard care (control). The primary outcome was respiratory and cardiovascular organ support–free days, on an ordinal scale combining in-hospital death (assigned a value of −1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with predefined criteria for superiority, efficacy, equivalence, or futility. An odds ratio greater than 1 represented improved survival, more organ support–free days, or both.


    RESULTS

    Both tocilizumab and sarilumab met the predefined criteria for efficacy. At that time, 353 patients had been assigned to tocilizumab, 48 to sarilumab, and 402 to control. The median number of organ support–free days was 10 (interquartile range, −1 to 16) in the tocilizumab group, 11 (interquartile range, 0 to 16) in the sarilumab group, and 0 (interquartile range, −1 to 15) in the control group. The median adjusted cumulative odds ratios were 1.64 (95% credible interval, 1.25 to 2.14) for tocilizumab and 1.76 (95% credible interval, 1.17 to 2.91) for sarilumab as compared with control, yielding posterior probabilities of superiority to control of more than 99.9% and of 99.5%, respectively. An analysis of 90-day survival showed improved survival in the pooled interleukin-6 receptor antagonist groups, yielding a hazard ratio for the comparison with the control group of 1.61 (95% credible interval, 1.25 to 2.08) and a posterior probability of superiority of more than 99.9%. All secondary analyses supported efficacy of these interleukin-6 receptor antagonists.


    CONCLUSIONS

    In critically ill patients with Covid-19 receiving organ support in ICUs, treatment with the interleukin-6 receptor antagonists tocilizumab and sarilumab improved outcomes, including survival. (REMAP-CAP ClinicalTrials.gov number, NCT02735707.

    India’s massive COVID surge puzzles scientists


    https://www.nature.com/articles/d41586-021-01059-y


    The pandemic is sweeping through India at a pace that has staggered scientists. Daily case numbers have exploded since early March: the government reported 273,810 new infections nationally on 18 April. High numbers in India have also helped drive global cases to a daily high of 854,855 in the past week, almost breaking a record set in January.


    Just months earlier, antibody data had suggested that many people in cities such as Delhi and Chennai had already been infected, leading some researchers to conclude that the worst of the pandemic was over in the country.


    Researchers in India are now trying to pinpoint what is behind the unprecedented surge, which could be due to an unfortunate confluence of factors, including the emergence of particularly infectious variants, a rise in unrestricted social interactions, and low vaccine coverage. Untangling the causes could be helpful to governments trying to suppress or prevent similar surges around the world.


    European countries such as France and Germany are also currently experiencing large outbreaks relative to their size, and nations including Brazil and the United States are reporting high infection rates at around 70,000 a day. But India’s daily totals are now some of the highest ever recorded for any country, and are not far off a peak of 300,000 cases seen in the United States on 2 January.


    ‘Ripple in a bathtub’

    COVID-19 case numbers started to drop in India last September, after a high of around 100,000 daily infections. But they began to rise again in March and the current peak is more than double the previous one.


    “The second wave has made the last one look like a ripple in a bathtub,” says Zarir Udwadia, a clinician-researcher in pulmonary medicine at P D Hinduja Hospital & Medical Research Centre in Mumbai, who spoke to Nature during a break from working in the intensive-care unit. He describes a “nightmarish” situation at hospitals, where beds and treatments are in extremely short supply.


    Shahid Jameel, a virologist at Ashoka University in Sonipat, agrees that the intensity of the current wave is startling. “I was expecting fresh waves of infection, but I would not have dreamt that it would be this strong,” he says.

    FLCCC update, listen to the doctors treating the virus


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    In evolving to infect mink, SARS-CoV-2’s risk for humans changes


    https://arstechnica.com/scienc…ions-found-in-mink/?amp=1


    We've always needed to limit the total SARS-CoV-2 infections for reasons beyond the immediate risk they pose to the infected. Each new infected individual is a chance for the virus to evolve in a way that makes it more dangerous—more infective or more lethal. This is true even when an individual has a completely symptom-free infection. The more the virus replicates, the more mutations it will experience and the greater chance that something threatening will evolve.


    One of the disturbing discoveries of the past year has been that it's not just the human population we have to worry about. SARS-CoV-2 has been found in a number of species, notably cats and mink, that we spend a lot of time around. It has even spread from there to the wild mink population, and the virus has jumped back and forth between humans and farmed mink. These animal reservoirs provide added opportunities for COVID to evolve in ways that make it more dangerous to us—perhaps via mutations that allow it to adapt to the new species.

    A group of German researchers has now tested some of the mutations that have appeared in viruses circulating in mink populations, and the news is mixed. One specific mutation makes the virus somewhat less infectious to humans but reduces the probability that antibodies raised against the virus will recognize it.


    A bit different

    When we first reported on the virus appearing in mink, all we really knew was that it picked up mutations while infecting the animals; we were still too early to even put together a list of mutations commonly seen in mink. That has now changed, and the research team has a list to work with; there's now a catalog of mutations found in European mink farms but not circulating in humans. The researchers focused on mutations in the Spike protein, which the virus uses to latch on to human cells and infect them. Spike is important both because it determines which cells the virus can infect, and it's often the target of antibodies that can block the virus from entering cells.


    To look into these mutations, the researchers engineered different versions of the Spike protein into a harmless virus and tested whether the engineered virus could infect cells. They found that certain mutations made it harder for Spike to get the virus into some human cells. There were still some types of human cells it could infect—notably intestine and lung cells, two major sites of SARS-CoV-2 infection. But the virus had a harder time infecting others.

    Separately, the researchers looked at how these mutations fared against the antibody response mounted after SARS-CoV-2 infection using serum obtained from 14 people who had been infected previously. They focused on a single mutation located in the part of the Spike protein that latches on to the surface of human cells (as opposed to the part that opens up the cells' membrane).


    All but one of the 14 serum samples were able to block infection by the engineered virus without any Spike mutations. But all the sera were less effective at blocking infections by viruses that carried a Spike protein altered by a single mutation found in mink. All of them could still block the virus; it just took more serum to do so.


    Looking into this more carefully, the researchers checked the two antibodies used in a potential COVID-19 therapy made by Regeneron. Either of these antibodies is capable of blocking infection of cultured human cells by SARS-CoV-2 on their own. But when tested against Spike carrying the mutation found in mink, only one of the two antibodies still neutralized it. Again, this is consistent with the mutation altering Spike's profile from the immune system's perspective.


    What does this mean?

    The specific mutation that alters the immune response has also been seen in strains that have adapted to circulate in ferrets, and it's at a location that physically interacts with a human protein. So, in all likelihood, this mutation has been selected for enabling more efficient infection of mink. By contrast, the mutation has rarely been seen in humans—just one report of it being found in a person with a persistent infection.


    The same virus seems to infect human cells somewhat less well. This suggests that current adaptations to mink don't seem to make the virus more dangerous to humans in this regard, although we can't rule out that further evolution won't have different implications for humans.

    Clinical Trial Conducted by MedinCell Confirms the Safety of Continuous Administration of ivermectin


    https://www.businesswire.com/n…inistration-of-ivermectin


    MONTPELLIER, France--(BUSINESS WIRE)--Regulatory News:


    MedinCell (Paris:MEDCL):


    Clinical trial validates the safety of ivermectin taken daily in oral form, to simulate the continuous release of the active substance by a long-acting injection.


    No side effects were observed with the three doses of ivermectin tested up to 100 µg / kg.


    MedinCell develops several long-acting injectable formulations of ivermectin, the most advanced aims at preventing infection from Covid-19 and its mutants for several months.


    Positive results of the safety study


    "All our programs are developed in accordance with the highest ethical standards and on the basis of reliable scientific principles with a view to potential massive deployment. Proving the safety of ivermectin in regular daily administration over a long period was an essential step for our ivermectin programs, in particular mdc-TTG in Covid-19," said Joël Richard, Chief Development Officer at MedinCell.


    Ivermectin has already been administered as a once-daily treatment to hundreds of millions of patients worldwide. Its safety as a once-daily treatment has been demonstrated and documented. MedinCell tested ivermectin taken daily in oral form to simulate the continuous release of the active substance by a long-acting injectable. After completion, the study confirms the safety of ivermectin up to a dose of 100 µg / kg / day in continuous administration over 1 month in healthy volunteers. No significant difference was observed between the treated volunteers and the placebo volunteers in the three cohorts studied successively (daily doses of 50 µg / kg, 75 µg / kg and 100 µg / kg respectively).


    The pharmacokinetic data of the three cohorts shows a limited peak circulating plasma concentration in the first 12 hours (Cmax between 25-60 ng / mL) and the rapid achievement of a stationary regime and a regular plasma concentration of between approximately 10 and 30 ng / mL for 28 days, depending on the dose administered. These preliminary results are considered positive and live up to Company expectations based on the data in the literature. The dose-response relationship has not yet been established.


    After study completion and in regard of the expert review conducted by Professor Jacques Descotes1 (March 2021), the safety profile of ivermectin supports the progress of MedinCell programs using this molecule, in particular mdc-TTG against Covid-19 and mdc-STM against malaria.


    Covid-19: The prophylactic strategy


    "Our hypotheses are being confirmed, says Christophe Douat, CEO of MedinCell: the pandemic continues, and vaccination may not be enough to stop it. The body of clinical data and scientific knowledge supporting the efficacy of ivermectin at a therapeutic dose against Covid-19, in particular as a prophylaxis, continues to grow. In this context, our treatment, based on a widely known molecule, which could be stored at room temperature and which aims to offer protection for several months after a simple injection against Covid-19 and its variants, could become a key tool of the anti-Covid arsenal. Our goal is still to have a product ready in 2022. "


    Currently in regulatory development, the mdc-TTG program aims to offer an injectable treatment in the form of a pre-filled syringe, ready to use, and stable for 24 months at room temperature. MedinCell’s BEPO® technology will allow the formation of a small subcutaneous deposit at the time of injection. It will act as a mini pump that releases ivermectin regularly until it disappears completely.


    The long-acting formulation of ivermectin in the mdc-TTG program could provide protection against Covid-19 and its mutants for several months after a single injection. It could also be administered to people identified as Covid-19 contact cases to protect them.


    About the clinical safety study


    Study title


    Exploratory phase 1, randomized, double-blind trial assessing the pharmacokinetic profile, safety and tolerability of a regime of continuous daily administration of Ivermectin to healthy volunteers


    Participants


    3 successive cohorts of 8 healthy volunteers (one cohort per dose)


    Administration


    Daily dose of Ivermectin or placebo taken orally for 4 weeks by each cohort


    Doses tested


    Cohort 1: 200 μg/kg (day 1) + 50 μg/kg daily (day 2 to 28)


    Cohort 2: 200 μg/kg (day 1) + 75 μg/kg daily (Day 2 to 28)


    Cohort 3: 200 μg/kg (day 1) + 100 μg/kg daily (day 2 to 28)


    Authorization of clinical trials


    MHRA (Medicines & Healthcare products Regulatory Agency – United Kingdom)


    Study period


    September 2020 – March 2021


    About MedinCell


    MedinCell is a clinical stage pharmaceutical company that develops a portfolio of long-acting injectable products in various therapeutic areas by combining its proprietary BEPO® technology with active ingredients already known and marketed. Through the controlled and extended release of the active pharmaceutical ingredient, MedinCell makes medical treatments more efficient, particularly thanks to improved compliance, i.e. compliance with medical prescriptions, and to a significant reduction in the quantity of medication required as part of a one-off or chronic treatment. The BEPO® technology makes it possible to control and guarantee the regular delivery of a drug at the optimal therapeutic dose for several days, weeks or months starting from the subcutaneous or local injection of a simple deposit of a few millimeters, fully bioresorbable. Based in Montpellier, MedinCell currently employs more than 140 people representing over 25 different nationalities.


    This press release may contain forward-looking statements, especially on the Company’s progress of its clinical trials. Although the Company believes that its expectations are based on reasonable assumptions, any statements other than statements of historical facts that may be contained in this press release relating to future events are subject to change without notice, factors beyond the Company's control and the Company's financial capabilities.


    These statements may include, but are not limited to, any statement beginning with, followed by or including words or phrases such as "objective", "believe", "anticipate", "foresee", "aim", "intend", "may", "anticipate", "estimate", "plan", "project", "will", "may", "probably", "should", "could" and other words and phrases of the same meaning or used in negative form. Forward-looking statements are subject to inherent risks and uncertainties beyond the Company's control that may, if any, cause actual results, performance or achievements to differ materially from those anticipated or expressed explicitly or implicitly by such forward-looking statements. A list and description of these risks, contingencies and uncertainties can be found in the documents filed by the Company with the Autorité des Marchés Financiers (AMF) pursuant to its regulatory obligations, including the Company's registration document, registered with the AMF on September 4, 2018 under number I. 18-062, as well as in the documents and reports to be published subsequently by the Company. In addition, these forward-looking statements speak only as of the date of this press release. Readers are cautioned not to place undue reliance on these forward-looking statements. Except as required by law, the Company does not undertake any obligation to publicly update these forward-looking statements or to update the reasons why actual results could differ materially from those anticipated by the forward-looking statements, including in the event that new information becomes available. The Company's update of one or more forward-looking statements does not imply that the Company will make any further updates to such forward-looking statements or other forward-looking statements.


    This press release is for information purposes only. The information contained herein does not constitute an offer to sell or a solicitation of an offer to buy or subscribe for the Company's shares in any jurisdiction, in particular in France. Similarly, this press release does not constitute investment advice and should not be treated as such. It is not related to the investment objectives, financial situation or specific needs of any recipient. It should not deprive the recipients of the opportunity to exercise their own judgment. All opinions expressed in this document are subject to change without notice. The distribution of this press release may be subject to legal restrictions in certain jurisdictions. Persons who come to know about this press release are required to inquire about and comply with these restrictions.

    The Great Barrington Declaration and Ad Hominem Argumentation


    https://www.aier.org/article/t…ominem-argumentation/amp/


    In my previous column I promised that today’s column would continue a discussion of vaccine passports. Alas, I’m breaking that promise in order to promote a different cause, one whose urgency was raised, at least from my vantage point, in the past week. The cause is the fight against ad hominem argumentation, and specifically, the use of such argumentation to disparage AIER generally and, specifically, the Great Barrington Declaration.


    Ad Hominem

    Loosely, the Latin phrase ad hominem translates as “to the man.” And according to the Oxford English Dictionary, the adjective “ad hominem” – as in “That’s an ad hominem argument” – is an argument or reaction “directed against a person rather than the position they are maintaining.”


    Every semester near the start of my Principles of Microeconomics course I identify six logical fallacies that occur with great frequency in discussions of economics and economic policy. The ad hominem fallacy is among these six. (The other five are [1] the post hoc, ergo propter hoc fallacy; [2] the naturalistic fallacy; [3] what Matt Ridley calls the “reverse naturalistic fallacy;” [4] the fallacy of confusing the mean or median of a group with any individual in the group; and [5] the fallacy of composition.) I perform this exercise in order to warn students both to avoid committing these fallacies themselves, and to avoid being misled by these fallacies when these are committed by others.


    While always widely used, ad hominem argumentation has seemingly become not only acceptable, but de rigueur, in arguments used by pro-lockdowners and anti-anti-lockdowners.


    Not surprisingly, although no less unfortunately, AIER has been bombarded of late by ad hominem attacks. I say “not surprisingly” because no organization has been as visibly out in front as has AIER in challenging lockdowns in particular, and the hysteria over Covid-19 more generally. Politicians, government officials, and pundits who are committed to lockdowns and to opposing us anti-lockdowners are angry at AIER’s unrelenting exposure of the countless exaggerations, half-truths, and outright lies about lockdowns, mask mandates, school closures, and Covid’s dangers.


    But of course the single most significant of AIER’s efforts is the Great Barrington Declaration.


    AIER arranged for the October 2020 meeting that led to this document’s drafting, and the Declaration is hosted on a website maintained by AIER. It’s important to note, however, that no AIER personnel – no board member, columnist, intern, accountant, receptionist, or groundskeeper – played any role in writing this document. The Declaration is co-written by Prof. Jay Bhattacharya of the Stanford medical school, Prof. Sunetra Gupta, a theoretical epidemiologist at Oxford University, and Prof. Martin Kulldorff of the Harvard medical school.


    Because this clear and concise anti-lockdown Declaration is not only infused with much good sense, but also proposes, as a response to SARS-CoV-2, what was regarded as mainstream public-health practice until early 2020 – and even well-regarded by SAGE as recently as May of last year – pro-lockdowners and anti-anti-lockdowners cannot easily attack the Declaration’s substance. And so pro-lockdowers and anti-anti-lockdowners resort to ad hominem argumentation.


    Some of these logically fallacious arguments are attempts to discredit the Declaration by pointing to mistaken predictions made by its authors. Some other of these logically fallacious arguments are attempts to discredit the Declaration by smearing AIER. Let’s consider each of these attempts.


    Science Is a Human Enterprise

    Science is carried out by non-omniscient human beings who seek greater knowledge and understanding through trial-and-error processes unobstructed by dogma. Hypotheses are offered and then tested as best as is humanly possible with logic, against the data, and against competing hypotheses. Less-successful hypotheses are replaced by more-successful ones. Thus does science advance.


    The results are never perfect. Error is inseparable from trial and error. A scientist who makes a faulty prediction no more thereby becomes an unreliable scientist than does a baseball pitcher become an unreliable pitcher merely by walking a batter or by giving up a grand slam. Just as what matters for assessing the quality of a baseball pitcher is his performance over many innings on the mound, what matters for assessing someone’s quality as a scientist is that person’s performance over many years in the lab, at the observatory, or at wherever a particular scientist does his or her work.


    Obviously, a scientist with a record of making an unusually large number of poor predictions rightly loses credibility, especially relative to scientists with better track records. And because time and effort are scarce, it’s legitimate to screen out of consideration claims made by scientists with poor reputations. Such a screening process is not ad hominem; it’s a useful rule of thumb.


    What’s not legitimate is to attempt to discredit an esteemed scientist on the basis of one or a handful of poor predictions. Even less legitimate is the attempt to discredit a substantive piece of work by an esteemed scientist – a piece of work that can be judged on its own merits – by pointing to one or a handful of that scientist’s poor predictions.


    Sadly, some of the ‘arguments’ against the Great Barrington Declaration are of this sort. Each of its co-authors is an esteemed scientist, and none of these scientists has the reputation of being an ideologue. Yet some opponents of the Declaration nevertheless say, in effect, “Look! This GBD co-author made this mistaken prediction. Gotcha! The Great Barrington Declaration therefore is faulty and should be ignored.”


    The irony in this sort of logically fallacious argumentation is that those who engage in it put their own credibility as scientists in jeopardy. Making predictions that turn out to be faulty is a legitimate and unavoidable feature of the scientific process; ad hominem argumentation is not.


    It’s notable that those who are quick to disparage the Great Barrington Declaration by pointing to some faulty predictions made by its co-authors do not hold pro-lockdown scientists to the same exacting standards. Anthony Fauci in 1983, writing about AIDS, suggested (as quoted by Phil Magness) “the possibility that routine close contact, as within a family household, can spread the disease.” Is Fauci’s penning of this claim – known now (but not then) to be a howler – sufficient to discredit him as a scientist?


    And let’s not overlook Neil Ferguson’s several faulty predictions, as summarized by Matt Ridley:


    In various years in the early 2000s Ferguson predicted up to 136,000 deaths from mad cow disease, 200 million from bird flu and 65,000 from swine flu. The final death toll in each case was in the hundreds.


    What logic leads anyone to continue to give credence to Fauci and Ferguson while simultaneously pointing to faulty predictions by, say, Prof. Gupta as a legitimate reason for dismissing the substance of the Great Barrington Declaration?


    Guilt by Association

    An even weaker argument against the Great Barrington Declaration is the observation that some people associated with AIER say, write, or tweet some things that other people find to be beyond the pale.


    I don’t wish here to assess, and much less to defend, everything ever said or written by everyone affiliated with AIER. Undoubtedly, were I to survey it all I’d find much with which I disagree. But the same is true for every organization under the moon and stars.


    Of relevance here is the irrelevance to the merits of the Great Barrington Declaration of what AIER associates Mr. X and Ms. Y said or tweeted.


    Had the Great Barrington Declaration been penned by individuals known chiefly for their membership in the Libertarian Party, by Fox News interns, or by Miss Grundy’s sixth graders as a class project, dismissing it merely by pointing to the identities and affiliations of its authors would be acceptable. But this Declaration is co-authored by world-renowned scientists, each of whom is expert in the public-health challenges presented by Covid-19. Furthermore, this Declaration has been endorsed by a large number of other credible scientists. Under these circumstances, ad hominem dismissals of the Declaration simply carry no credibility.


    Substantively criticizing parts or the whole of the Great Barrington Declaration is legitimate. Indeed, such criticism is welcome; it’s part of the scientific process. But in far too many cases people dismiss the Declaration with nothing more than ad hominem assertions and attempts to establish guilt by association. The conclusion that I draw from these sorts of dismissals is that those who offer them actually have no substantive criticism of the Declaration. After all, because substantive criticisms would carry more weight even with Miss Grundy’s sixth graders, anyone with such criticisms to offer would present them front and center rather than resort to ad hominem argumentation.


    The greatest compliment paid to the Great Barrington Declaration, therefore, is one wholly unintended: Many of its staunchest opponents offer against it nothing beyond ad hominem attacks and accusations of guilt by association. This Declaration must indeed be powerful!

    Substantial Differences in SARS-CoV-2 Antibody Responses Elicited by Natural Infection and mRNA Vaccination


    https://www.biorxiv.org/content/10.1101/2021.04.15.440089v2


    Abstract

    We analyzed data from two ongoing serologic surveys, a longitudinal cohort of health care workers (HCW) from the University of California Irvine Medical Center (Orange County, CA, USA), collected from May and December 2020 through March 2021, and a cross sectional county-wide study in July 2020 (actOC; Orange County, CA) and a more focused community study in the city of Santa Ana (Santa Ana Cares; Orange County, CA, USA), collected in December 2020 - in order to compare the antibody responses to SARS-CoV-2 natural infection and vaccination. In addition, we serially tested 9 volunteers at multiple time points to analyze the time course of vaccine-induced antibody response in more detail. In May 2020, 1060 HCW were enrolled and had finger stick samples collected. Finger stick samples were again collected in December 2020, before vaccination, as well as January, February and March 2021 during vaccination campaign. A total of 8,729 finger stick blood specimens were probed and analyzed for IgG and IgM antibodies using a coronavirus antigen microarray (COVAM). The microarray contained 10 SARS-CoV-2 antigens including nucleocapid protein (NP) and several varying fragments of the spike protein, as well as 4 SARS, 3 MERS, 12 Common CoV, and 8 Influenza antigens.Based on a random forest based prediction algorithm, between May and December, prior to vaccine rollout, we observed that seropositivity in the HCW cohort increased from 4.5% to 13%. An intensive vaccination campaign with mRNA vaccines was initiated on December 16, 2020 and 6,724 healthcare workers were vaccinated within 3 weeks. The observed seropositivity of the HCW specimens taken in the last week of January 2021 jumped to 78%, and by the last week in February it reached 93%, and peaked at 98% seropositive in March. The antibody profile induced by natural exposure differed from the profile induced after mRNA vaccination. Messenger RNA vaccines induced elevated antibody (Ab) reactivity levels against the Receptor Binding Domain (RBD) domain of SARS-CoV-2 spike, and cross-reactive responses against SARS and MERS RBD domains. Nucleocapsid protein (NP), which is an immunodominant antigen induced after natural exposure, is not present in the vaccine and can be used as a biomarker of past exposure. The results show that naturally-exposed individuals mount a stronger anti-spike response upon vaccination than individuals that were not previously exposed. Longitudinal specimens taken at approximately weekly intervals from 9 individuals show variation in the response to the mRNA vaccine, with some showing a vigorous response to the first dose (prime) and others requiring a subsequent dose (boost) to reach high anti-SARS-CoV-2 levels. Antibody titers determined by serial dilution of the specimens were used to accurately compare antibody levels in these samples. mRNA vaccinees after the boost have higher Ab titers (up to 10 times higher) than convalescent plasmas from donors who recovered from natural infection. The results of this study exemplify the time course and outcomes expected from similar mRNA mass vaccination campaigns conducted in other institutions.

    J&J to resume rollout of COVID-19 vaccine in Europe with safety warning


    https://www.reuters.com/busine…vaccine-sales-2021-04-20/


    Johnson & Johnson (JNJ.N) said on Tuesday it will resume rolling out its COVID-19 vaccine in Europe after the region’s medical regulator said the benefits of the shot outweigh the risk of very rare, potentially lethal blood clots.


    Europe’s health regulator, the European Medicines Agency (EMA), on Tuesday recommended adding a warning about rare blood clots with low blood platelet count to the vaccine’s product label and said the benefits of the one-dose shot outweigh its risks.

    Interesting. The CDC just recently asked providers to hold off TB testing on vaccinated patients


    https://www.cdc.gov/tb/publica…letters/covid19-mrna.html


    For healthcare personnel or patients who require baseline TB testing (at onboarding or entry into facilities) at the same time they are to receive a COVID-19 mRNA vaccine, CDC recommends:


    Perform TB symptom screening on all healthcare personnel or patients.

    If using IGRA, draw blood prior to COVID-19 mRNA vaccination.

    If using TST, place prior to COVID-19 mRNA vaccination.

    If COVID-19 mRNA vaccination has already occurred, defer TST or IGRA until 4 weeks after completion of 2-dose COVID-19 mRNA vaccination.