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Dennis OConnor

The proximal origin of SARS-CoV-2 | Nature Medicine - 1 views

  • Here we review what can be deduced about the origin of SARS-CoV-2 from comparative analysis of genomic data
  • Our analyses clearly show that SARS-CoV-2 is not a laboratory construct or a purposefully manipulated virus.
  • The receptor-binding domain (RBD) in the spike protein is the most variable part of the coronavirus genome1,2. Six RBD amino acids have been shown to be critical for binding to ACE2 receptors and for determining the host range of SARS-CoV-like viruses7.
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  • Theories of SARS-CoV-2 originsIt is improbable that SARS-CoV-2 emerged through laboratory manipulation of a related SARS-CoV-like coronavirus.
  • the genetic data irrefutably show that SARS-CoV-2 is not derived from any previously used virus backbone
  • we propose two scenarios that can plausibly explain the origin of SARS-CoV-2: (i) natural selection in an animal host before zoonotic transfer; and (ii) natural selection in humans following zoonotic transfer.
  • COVID-19 were linked to the Huanan market in Wuhan
  • it is likely that bats serve as reservoir hosts for its progenitor
  • Malayan pangolins (Manis javanica) illegally imported into Guangdong province contain coronaviruses similar to SARS-CoV-221
  • Although no animal coronavirus has been identified that is sufficiently similar to have served as the direct progenitor of SARS-CoV-2, the diversity of coronaviruses in bats and other species is massively undersampled
  • For a precursor virus to acquire both the polybasic cleavage site and mutations in the spike protein suitable for binding to human ACE2, an animal host would probably have to have a high population density (to allow natural selection to proceed efficiently) and an ACE2-encoding gene that is similar to the human ortholog
  • It is possible that a progenitor of SARS-CoV-2 jumped into humans, acquiring the genomic features described above through adaptation during undetected human-to-human transmission.
  • All SARS-CoV-2 genomes sequenced so
  • are thus derived from a common ancestor that had them too
  • Estimates of the timing of the most recent common ancestor of SARS-CoV-2 made with current sequence data point to emergence of the virus in late November 2019 to early December 201923,
  • compatible with the earliest retrospectively confirmed cases
  • Basic research involving passage of bat SARS-CoV-like coronaviruses in cell culture and/or animal models has been ongoing for many years in biosafety level 2 laboratories across the world27, and there are documented instances of laboratory escapes of SARS-CoV28. We must therefore examine the possibility of an inadvertent laboratory release of SARS-CoV-2.
  • The finding of SARS-CoV-like coronaviruses from pangolins with nearly identical RBDs, however, provides a much stronger and more parsimonious explanation of how SARS-CoV-2 acquired these via recombination or mutation1
  • it is reasonable to wonder why the origins of the pandemic matter
  • Detailed understanding of how an animal virus jumped species boundaries to infect humans so productively will help in the prevention of future zoonotic events.
  • More scientific data could swing the balance of evidence to favor one hypothesis over another.
Dennis OConnor

What We Know So Far About SARS-CoV-2 - The Atlantic - 0 views

  • March 20, 2020
  • One of the few mercies during this crisis is that, by their nature, individual coronaviruses are easily destroyed.
  • These viruses don’t endure in the world. They need bodies.
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  • To be clear, SARS-CoV-2 is not the flu. It causes a disease with different symptoms, spreads and kills more readily,
  • his family, the coronaviruses, includes just six other members that infect humans
  • OC43, HKU1, NL63, and 229E—have been gently annoying humans for more than a century, causing a third of common colds
  • MERS and SARS (or “SARS-classic,” as some virologists have started calling it)—both cause far more severe disease.
  • hy was this seventh coronavirus the one to go pandemic?
  • The structure of the virus provides some clues about its success. In shape, it’s essentially a spiky ball. Those spikes recognize and stick to a protein called ACE2
  • This is the first step to an infection
  • he exact contours of SARS-CoV-2’s spikes allow it to stick far more strongly to ACE2 than SARS-classic did
  • But in SARS-CoV-2, the bridge that connects the two halves can be easily cut by an enzyme called furin, which is made by human cells and—crucially—is found across many tissues. “This is probably important for some of the really unusual things we see in this virus,” says Kristian Andersen of Scripps Research Translational Institute.
  • SARS-CoV-2 seems to infect both upper and lower airways,
  • his double whammy could also conceivably explain why the virus can spread between people before symptoms show up
  • All of this is plausible but totally hypothetical; the virus was only discovered in January, and most of its biology is still a mystery.
  • The closest wild relative of SARS-CoV-2 is found in bats, which suggests it originated in a bat, then jumped to humans either directly or through another species.
  • Another coronavirus found in wild pangolins also resembles SARS-CoV-2
  • Indeed, why some coronaviruses are deadly and some are not is unclear. “There’s really no understanding at all of why SARS or SARS-CoV-2 are so bad but OC43 just gives you a runny nose,” Frieman says.
  • Once in the body, it likely attacks the ACE2-bearing cells that line our airways.
  • The immune system fights back and attacks the virus; this is what causes inflammation and fever
  • in extreme cases, the immune system goes berserk
  • These damaging overreactions are called cytokine storms.
  • they’re probably behind the most severe cases of COVID-19.
  • During a cytokine storm, the immune system isn’t just going berserk but is also generally off its game, attacking at will without hitting the right targets.
  • But why do some people with COVID-19 get incredibly sick, while others escape with mild or nonexistent symptoms
  • Age is a factor.
  • other factors—a person’s genes, the vagaries of their immune system, the amount of virus they’re exposed to, the other microbes in their bodies
  • “it’s a mystery why some people have mild disease, even within the same age group,”
  • Coronaviruses, much like influenza, tend to be winter viruses.
  • In the heat and humidity of summer, both trends reverse, and respiratory viruses struggle to get a foothold.
  • irus is tearing through a world of immunologically naive people, and that vulnerability is likely to swamp any seasonal variations.
  • And one recent modeling study concluded that “SARS-CoV-2 can proliferate at any time of year.
  • Unless people can slow the spread of the virus by sticking to physical-distancing recommendations, the summer alone won’t save us.
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    Dr. Michael Kurisu D.O.: We've known about SARS-CoV-2 for only three months, but scientists can make some educated guesses about where it came from and why it's behaving in such an extreme way.
Dennis OConnor

Using influenza surveillance networks to estimate state-specific prevalence of SARS-CoV... - 0 views

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    "Abstract Detection of SARS-CoV-2 infections to date has relied heavily on RT-PCR testing. However, limited test availability, high false-negative rates, and the existence of asymptomatic or sub-clinical infections have resulted in an under-counting of the true prevalence of SARS-CoV-2. Here, we show how influenza-like illness (ILI) outpatient surveillance data can be used to estimate the prevalence of SARS-CoV-2. We found a surge of non-influenza ILI above the seasonal average in March 2020 and showed that this surge correlated with COVID-19 case counts across states. If 1/3 of patients infected with SARS-CoV-2 in the US sought care, this ILI surge would have corresponded to more than 8.7 million new SARS-CoV-2 infections across the US during the three-week period from March 8 to March 28, 2020. Combining excess ILI counts with the date of onset of community transmission in the US, we also show that the early epidemic in the US was unlikely to have been doubling slower than every 4 days. Together these results suggest a conceptual model for the COVID-19 epidemic in the US characterized by rapid spread across the US with over 80% infected patients remaining undetected. We emphasize the importance of testing these findings with seroprevalence data and discuss the broader potential to use syndromic surveillance for early detection and understanding of emerging infectious diseases."
Dennis OConnor

Finding Antibodies that Neutralize SARS-CoV-2 - NIH Director's Blog - 0 views

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    "It's now clear that nearly everyone who recovers from coronavirus disease 2019 (COVID-19) produces antibodies that specifically target SARS-CoV-2, the novel coronavirus that causes the infection. Yet many critical questions remain. A major one is: just how well do those particular antibodies neutralize the virus to fight off the infection and help someone recover from COVID-19? Fortunately, most people get better-but should the typical antibody response take the credit?"
Dennis OConnor

FAQs on Diagnostic Testing for SARS-CoV-2 | FDA - 0 views

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    Explanation from DeAunne Denmark, MD, PhD : And just to clarify for all, since all of the testing jargon and landscape can be *extremely* confusing, especially now: The FDA has currently relaxed regulations for COVID diagnostics under "Emergency Use" (EUA). This authorizes, not approves, test kits, machines and devices to run those kits, and all other aspects involved in diagnostic testing. Authorize vs approve are very different animals under FDA. And you will see this repeatedly emphasized on the FDA site. But most often neglected, skipped over, mistaken in the wider press. Many articles and press releases use "approve" which is technically wrong - they mean authorize, or "grant use", or "use will not be objected to by FDA." If you have the stamina, I highly recommended reading as much of this as you can: https://www.fda.gov/medical-devices/emergency-situations-medical-devices/faqs-diagnostic-testing-sars-cov-2 "Validation" is yet an additional aspect that is probably the grayest zone of all, since it is left to each company/testing entity how exactly this is done. Validation can range from excellent to pretty cruddy science and still meet FDA "standards". These will be the devilish details we need to sort out re: collaborating with partners. And will unfortunately likely be a big mess for many outpatient Drs trying to figure out which test to order.
Dennis OConnor

Substantial undocumented infection facilitates the rapid dissemination of novel coronav... - 0 views

  • AbstractEstimation of the prevalence and contagiousness of undocumented novel coronavirus (SARS-CoV2) infections is critical for understanding the overall prevalence and pandemic potential of this disease. Here we use observations of reported infection within China, in conjunction with mobility data, a networked dynamic metapopulation model and Bayesian inference, to infer critical epidemiological characteristics associated with SARS-CoV2, including the fraction of undocumented infections and their contagiousness. We estimate 86% of all infections were undocumented (95% CI: [82%–90%]) prior to 23 January 2020 travel restrictions. Per person, the transmission rate of undocumented infections was 55% of documented infections ([46%–62%]), yet, due to their greater numbers, undocumented infections were the infection source for 79% of documented cases. These findings explain the rapid geographic spread of SARS-CoV2 and indicate containment of this virus will be particularly challenging.
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    Recommended by Jessica Block
Dennis OConnor

A serological assay to detect SARS-CoV-2 seroconversion in humans | medRxiv - 0 views

  • While molecular assays to directly detect the viral genetic material are available for the diagnosis of acute infection, we currently lack serological assays suitable to specifically detect SARS-CoV-2 antibodies.
  • Methods: Here we describe serological enzyme-linked immunosorbent assays (ELISA) that we developed using recombinant antigens derived from the spike protein of SARS-CoV-2.
  • Conclusion: Serological assays are of critical importance to determine seroprevalence in a given population, define previous exposure and identify highly reactive human donors for the generation of convalescent serum as therapeutic.
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    Recommended by DeAunne Denmark, MD, PhD: This study is under peer review. Published via the medRxiv preprint server for health sciences.
Dennis OConnor

Coronavirus Hub: Cell Press - 0 views

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    Recommended by DeAunne Denmark MD Phd, "At Cell Press, we recognize the urgent need to quickly share information about SARS-CoV-2, the coronavirus that causes COVID-19. On this hub page, curated by members of our editorial team, you'll find the latest content about the outbreak as it appears in Cell Press journals."
Dennis OConnor

A global effort to define the human genetics of protective immunity to SARS-CoV-2 infec... - 0 views

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    Recommended by Meg Sweeney: "Abstract SARS-CoV-2 infection displays immense inter-individual clinical variability, ranging from silent infection to lethal disease. The role of human genetics in determining clinical response to the virus remains unclear. Studies of outliers - individuals remaining uninfected despite viral exposure and healthy young patients with life-threatening disease - presents a unique opportunity to reveal human genetic determinants of infection and disease."
Dennis OConnor

What Went Wrong with Coronavirus Testing in the U.S. | The New Yorker - 0 views

  • n February 5th, sixteen days after a Seattle resident who had visited relatives in Wuhan, China, was diagnosed as having the first confirmed case of COVID-19 in the United States, the Centers for Disease Control, in Atlanta, began sending diagnostic tests to a network of about a hundred state, city, and county public-health laboratories⁠. Up to that point, all testing for COVID-19 in the U.S. had been done at the C.D.C.; of some five hundred suspected cases⁠ tested at the Centers, twelve had confirmed positive. The new test kits would allow about fifty thousand patients to be tested, and they would also make testing much faster, as patient specimens would no longer have to be sent to Atlanta to be evaluated.
  • Before a state or local lab could use the C.D.C.-developed tests on actual patients
  • verification
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  • larger number, about thirty-six of them, received inconclusive⁠ results from one of the reagents.
  • Another five,
  • had problems with two reagents
  • On February 8th
  • we’re looking at exponential growth, and we need to figure out how to meet an exponential demand.”
  • the verification problems were “part of the normal procedures⁠.” In the meantime, she said, until new reagents could be manufactured, all COVID-19 testing in the United States would continue to take place exclusively at the C.D.C⁠.
  • The public-health-laboratory network was never intended to provide widespread testing in the event of a pandemic.
  • the three-week delay caused by the C.D.C.’s failure to get working test kits into the hands of the public-health labs came at a crucial time.
  • The void created by the C.D.C.’s faulty tests made it impossible for public-health authorities to get an accurate picture of how far and how fast the disease was spreadin
  • In hotspots like Seattle, and probably elsewhere, COVID-19 spread undetected for several weeks, which in turn only multiplied the need for more tests.
  • The problem was that containment was not done very well.
  • e cascading effects that they’ve had on the country’s COVID-19 preparations suggest a much larger problem with the way the United States has structured its pandemic response.
  • Yet flexibility was not what Jerome and his lab found when they tried to get an E.U.A. for their COVID-19 test.
  • problem was exacerbated by a President who has simultaneously underplayed the severity of the outbreak and overpromised the means available to fight it
  • problems with COVID-19 testing in the United States have obscured
  • triumph of modern medical science
  • Chinese scientists uploaded a copy of the virus’s genome to an online repository⁠, and virologists around the world set to work to develop diagnostic tests for the new disease
  • January 21st, a team in Berlin, led by Christian Drosten, one of the scientists who discovered the original SARS virus, in 2003, submitted the first paper to describe a protocol for testing for SARS-CoV-2.
  • That protocol would form the basis for a test disseminated, early on, by the World Health Organization
  • That same day, Messonnier announced that the C.D.C. had finalized its own test⁠, which it used to confirm the first known case of COVID-19 in the U.S.
  • The U.W. virology lab
  • started, probably in earnest in mid-January, to prepare what we call a laboratory-developed test,⁠
  • It took a team at the lab, working under the direction of Alex Greninger, about two weeks to develop a working version
  • But, as soon as Alex Azar, the Secretary of Health and Human Services, declared a public-health emergency, on February 4th, a new regulatory regime took effect. From that point on, any lab that wanted to conduct its own tests for the new coronavirus would first need to secure something called an Emergency Use Authorization from the F.D.A.
  • This shift in the regulations sounds perverse, since it restricts the use of new tests at precisely the moment they’re most needed.
  • E.U.A. process is supremely flexible.
  • several labs reported their problems to the C.D.C. In a briefing a few days later,
  • hen there’s a big emergency and we feel like we should really do something, it gets hard. It’s a little frustrating. We’ve got a lot of scientists and doctors and laboratory personnel who are incredibly good at making assays. What we’re not so good at is figuring out all the forms and working with the bureaucracy of the federal government.”
  • At one point, he was very frustrated because he’d e-mailed them what we were doing so they could review it,”
  • Here we are in this SARS-CoV-2 crisis, and you have to send them something through the United States Postal Service. It’s just shocking.
  • Despite these difficulties, Jerome said, the F.D.A. ultimately proved responsive to the lab’s entreaties. “They had good and substantive feedback that made our testing better, and the response time was typically just a couple of days.”
  • believe it was, February 29th,” he said. “And then we got a specimen from one of the people who were the two original cases in Washington
  • The E.U.A. regulations, however, prohibited the lab from reporting the results to the doctors who had ordered the tests for their patients.
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    "Sharfstein, too, thinks that it's fair to criticize the federal government for not recognizing that its pandemic plans had a single point of failure. The C.D.C. quickly developed a working test, and it was understandable, at some level, that people at the Centers thought that fixing the faulty reagents for the public-health labs would be faster than shifting to an entirely different protocol. Nevertheless, Sharfstein said, "Why are we relying only on the C.D.C.? What the F.D.A. could have done, and eventually did do, is say, 'You can use other approaches.' " Even so, he said, "I don't think it's quite fair to totally blame the F.D.A. for this. The F.D.A. can design an approach to support the public-health strategy, but someone has to tell F.D.A. the public-health goal." The delay in clearly establishing those goals, he said, shows why the decision to shut down the N.S.C. directorate was so consequential. "People talk about, like, why does it matter that they closed the White House office on pandemic preparedness? This is one reason.""
Dennis OConnor

Up-to-Date Coronavirus (SARS-CoV-2 / COVID-19) Information - Peter Attia MD - 0 views

  • Currently, my entire clinical and research team are working on trying to make sense of the SARS-CoV-2 / COVID-19 pandemic.
  • We’re constantly in contact with leading experts and doctors working on this issue around the world,
  • We will tell you what we know, when we know it, and what we don’t know.
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  • Information will continue to be passed through podcasts, patient memos, and videos.
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    Recommended by Vicky Newman & Erin Raskin
Dennis OConnor

The Challenge of Tracking COVID-19's Stealthy Spread - NIH Director's Blog - 0 views

  • The first thing that testing may help us do is to identify those SARS-CoV-2-infected individuals who have no symptoms, but who are still capable of transmitting the virus.
  • The second way we can use testing is to identify individuals who’ve already been infected with SARS-CoV-2, but who didn’t get seriously ill and can no longer transmit the virus to others.
Dennis OConnor

The race for coronavirus vaccines: a graphical guide - 0 views

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    "Eight ways in which scientists hope to provide immunity to SARS-CoV-2 ."
Dennis OConnor

The Prime Cellular Targets for the Novel Coronavirus - NIH Director's Blog - 0 views

  • Posted on May 5th, 2020 by Dr. Francis Collins
  • it has been remarkable and gratifying to watch researchers from around the world pull together and share their time, expertise, and hard-earned data in the urgent quest to control this devastating virus.
  • a recent study that characterized the specific human cells that SARS-CoV-2 likely singles out for infection [1
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  • This work was driven by the mostly shuttered labs of Alex K. Shalek, Massachusetts Institute of Technology, Ragon Institute of MGH, MIT, and Harvard, and Broad Institute of MIT and Harvard, Cambridge; and Jose Ordovas-Montanes at Boston Children’s Hospital. In the end, it brought together (if only remotely) dozens of their colleagues in the Human Cell Atlas Lung Biological Network and others across the U.S., Europe, and South Africa.
  • The discovery suggests that SARS-CoV-2 and potentially other coronaviruses that rely on ACE2 may take advantage of the immune system’s natural defenses.
  • t’s clear that these new findings, from data that weren’t originally generated with COVID-19 in mind, contained several potentially important new leads. This is another demonstration of the value of basic science.
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    "Posted on May 5th, 2020 by Dr. Francis Collins"
Dennis OConnor

Sewage-handling robots help predict COVID-19 outbreaks in San Diego | EurekAlert! Scien... - 0 views

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    "From July to November 2020, Karthikeyan and team, led by Rob Knight, PhD, professor and director of the Center for Microbiome Innovation at UC San Diego, sampled sewage water to see if they could detect SARS-CoV-2, the virus that causes COVID-19. They could. But concentrating the wastewater proved to be a bottleneck -- it's a slow and laborious multi-step process."
Dennis OConnor

Rogue antibodies could be driving severe COVID-19 - 0 views

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    DeAunne Denmark MD, PhD; Very interesting developments. Really hope this will start pointing toward more effective, targeted treatments. "Evidence is growing that self-attacking 'autoantibodies' could be the key to understanding some of the worst cases of SARS-CoV-2 infection."
Dennis OConnor

Swimming with the High-Tech Sharks to Improve COVID-19 Testing - NIH Director's Blog - 0 views

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    "So much has been reported over the past six months about testing for coronavirus disease 2019 (COVID-19) that keeping up with the issue can be a real challenge. To discuss the latest progress on new technologies for SARS-CoV-2 diagnostic testing in the United States, I spoke recently with NIH's Dr. Bruce Tromberg, director of the National Institute of Biomedical Imaging and Bioengineering (NIBIB). Not only does Bruce run a busy NIH institute, he is helping to coordinate the national response for expanded testing during the COVID-19 pandemic."
Dennis OConnor

'AeroNabs' Promise Powerful, Inhalable Protection Against COVID-19 | UC San Francisco - 0 views

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    Recommended by Janice O'Connor: "As the world awaits vaccines to bring the COVID-19 pandemic under control, UC San Francisco scientists have devised a novel approach to halting the spread of SARS-CoV-2, the virus that causes the disease."
Dennis OConnor

Study of Healthcare Workers Shows COVID-19 Immunity Lasts Many Months - NIH Director's ... - 0 views

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    "New findings from a study of thousands of healthcare workers in England show that those who got COVID-19 and produced antibodies against the virus are highly unlikely to become infected again, at least over the several months that the study was conducted. In the rare instances in which someone with acquired immunity for SARS-CoV-2 subsequently tested positive for the virus within a six month period, they never showed any signs of being ill."
Dennis OConnor

PMWC 2021 COVID-19 Conference Jan. 25-27 - Prec. Med. World Conf. - 1 views

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    The COVID-19 pandemic makes it necessary for leading experts from across disciplines and geographies to come together to jointly address the challenges we are facing when coping with the disruptive nature of the coronavirus SARS-CoV-2 pandemic is having on our healthcare system and our society as a whole. The tasks upon us are enormous and include besides decoding the virus and scaling diagnostics, tackling COVID-19 within existing healthcare systems, building health data platforms that support COVID-19 focused health care, accommodating clinical trials in the era of COVID-19, and developing functional vaccines and therapeutics. The next PMWC 2021 on January 25-27 would be a virtual conference and will touch upon these critical developments and ongoing activities while also including the regulatory and investment sides that influence clinical advancements.
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