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Thread: Disease and pandemics thread (because it's science)

  1. #2401
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    In other news, the Oxford/AstraZeneca trials are back on.

    https://m.fark.com/goto/10949185/www...%3Dlink%26ICID


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  2. #2402
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    According to BBC Travel, the 17th Century’s wine portals are back in use. Nice article about that, nanoclays greening the desert and the beauty of the Italian language this month.

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    Quote Originally Posted by Extravoice View Post
    Based on my understanding, it seemed likely to be the case. However, I learned long ago that I shouldn’t assume I know all the variables that might be at play. Thanks for the clarification.
    The problem is that this disease keeps on spawning mutually inconsistent narratives. On this occasion we have the "Everyone will lose immunity really quickly" narrative, and the "Herd immunity is already being achieved" narrative. We have information that undermines both, but that doesn't seem to dim their popularity.

    Grant Hutchison

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    Grant, as a doctor, do you believe that herd immunity can be achieved other than through vaccination; in other words by enough people getting infected? I keep seeing different stories; such as that that was what Sweden was planning on.
    Cum catapultae proscriptae erunt tum soli proscript catapultas habebunt.

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    Anders Tegnell is on record saying that Sweden's aim was never to achieve herd immunity, in the sense of deliberately setting out to get everyone infected. I've no reason to doubt him. (Sweden, of course, is the subject of another set of mutual contradictory narratives.)

    In general, I think people became hypnotized from very early on by the naive calculation of the herd immunity threshold, (R0-1)/R0, which comes out to 2/3 of your population if R0=3. From that, they looked at the infection fatality rate, did a little arithmetic, and start yelling about hundreds of thousands of deaths. So from March to August this year, no-one has really been able to say the words "herd immunity" without becoming the focus of a toxic reflex twitter-storm.
    But we know that infection is not distributed at random throughout the population (which is a key assumption of the naive calculation); and we know that R doesn't really resemble R0 in any society in the world at present, because we've made huge social changes specifically to achieve that end. So we know that the 2/3 threshold is an overestimate.
    People who carry out more realistic modelling exercises of how populations actually behave are coming up with "effective herd immunity" levels as low as 20%. There's a recent preprint here, for instance. To that, we can add recent observations that there appears to be a degree of cross-immunity between common cold coronaviruses and SARS-CoV-2, which means that some individuals may be immune without having been infected with Covid-19.
    Now, there are already places in the world with seroprevalence of Covid-19 antibodies of 20%. (Bit of wiggle room there, however, in that we still don't know what level and kind of antibodies are protective, and we do know that some people may have cell-mediated immunity in the absence of antibodies.) And there is suggestive epidemiology--the way the case rate in Sweden is declining without any changes in disease control measures, and while still far short of that 2/3 seroprevalence everyone got so exercised about; the way London seems to have (so far) avoided becoming a UK hotspot as lockdown relaxes, despite being earliest and worst hit in the first wave.
    That said, there are places where seroprevalence is higher than 20%. If 20% was some sort of magic herd immunity wall, then that wouldn't have happened. But we'd need to model the social structure in those places to estimate the effective herd immunity threshold for those places, before we could truly understand the figures.

    So, basically, I don't know. What I do know is that it's complicated and messy, and that "60-70% for herd immunity" is a figure that only makes sense if you're planning to vaccinate a population at random, not if you're dealing with a real disease transmitting through a real population. I think we're seeing a little scintilla of evidence that in some settings "useful herd immunity" might already be occurring, while in other settings it very much isn't. And I know that, by any reasonable expectation, we're going to see a lot more cases this winter, so we're going to get more evidence, one way or another, of how close some societies are to helpful levels of seroprevalence developing in their populations.

    Grant Hutchison
    Last edited by grant hutchison; 2020-Sep-13 at 05:44 PM. Reason: missing word

  6. #2406
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    Quote Originally Posted by grant hutchison View Post
    Anders Tegnell is on record saying that Sweden's aim was never to achieve herd immunity, in the sense of deliberately setting out to get everyone infected. I've no reason to doubt him. (Sweden, of course, is the subject of another set of mutual contradictory narratives.)

    In general, I think people became hypnotized from very early on by the naive calculation of the herd immunity threshold, (R0-1)/R0, which comes out to 2/3 of your population if R0=3. From that, they looked at the infection fatality rate, did a little arithmetic, and start yelling about hundreds of thousands of deaths. So from March to August this year, no-one has really been able to say the words "herd immunity" without becoming the focus of a toxic reflex twitter-storm.
    But we know that infection is not distributed at random throughout the population (which is a key assumption of the naive calculation); and we know that R doesn't really resemble R0 in any society in the world at present, because we've made huge social changes specifically to achieve that end. So we know that the 2/3 threshold is an overestimate.
    People who carry out more realistic modelling exercises of how populations actually behave are coming up with "effective herd immunity" levels as low as 20%. There's a recent preprint here, for instance. To that, we can add recent observations that there appears to be a degree of cross-immunity between common cold coronaviruses and SARS-CoV-2, which means that some individuals may be immune without having been infected with Covid-19.
    Now, there are already places in the world with seroprevalence of Covid-19 antibodies of 20%. (Bit of wiggle room there, however, in that we still don't know what level and kind of antibodies are protective, and we do know that some people may have cell-mediated immunity in the absence of antibodies.) And there is suggestive epidemiology--the way the case rate in Sweden is declining without any changes in disease control measures, and while still far short of that 2/3 seroprevalence everyone got so exercised about; the way London seems to have (so far) avoided becoming a UK hotspot as lockdown relaxes, despite being earliest and worst hit in the first wave.
    That said, there are places where seroprevalence is higher than 20%. If 20% was some sort of magic herd immunity wall, then that wouldn't have happened. But we'd need to model the social structure in those places to estimate the effective herd immunity threshold for those places, before we could truly understand the figures.

    So, basically, I don't know. What I do know is that it's complicated and messy, and that "60-70% for herd immunity" is a figure that only makes sense if you're planning to vaccinate a population at random, not if you're dealing with a real disease transmitting through a real population. I think we're seeing a little scintilla of evidence that in some settings "useful herd immunity" might already be occurring, while in other settings it very much isn't. And I know that, by any reasonable expectation, we're going to see a lot more cases this winter, so we're going to get more evidence, one way or another, of how close some societies are to helpful levels of seroprevalence developing in their populations.

    Grant Hutchison
    Thanks Grant, this is what I have been trying to point out for awhile.
    The moment an instant lasted forever, we were destined for the leading edge of eternity.

  7. #2407
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    I am curious about the dose effect. It seems the way to catch this virus, like many, is to hang around with infected people indoors for fifteen minutes. I am excluding being coughed upon in clinical situations. So there must be a regular smaller dose when shopping carefully, for example. Does our immune system cope with small doses without developing cell or antigen immunity? Or do we in fact develop immunity from these small doses?

    This impinges on the mask policy because as discussed earlier, in a shop for example, a mask can obviously become a source. But maybe a low dose source?
    sicut vis videre esto
    When we realize that patterns don't exist in the universe, they are a template that we hold to the universe to make sense of it, it all makes a lot more sense.
    Originally Posted by Ken G

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    Quote Originally Posted by profloater View Post
    Does our immune system cope with small doses without developing cell or antigen immunity? Or do we in fact develop immunity from these small doses?
    I think it’s a really good question. But I don’t think it’s been definitively answered.
    As above, so below

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    Not an answer to the question, but the body does have various nonspecific defenses against viruses, more likely to be effective with a smaller viral load. Some details here:

    https://www.ncbi.nlm.nih.gov/books/NBK8348/

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  10. #2410
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    The barrier component to innate immunity makes it harder for viruses to gain access to cells. But it only takes one cell to be infected for massive viral replication to take place, at which point you have a viral infection. The other components of the innate system then slow the rate at which the virus replicates, buying time until a specific immune response is invoked. That early non-specific inflammatory process kicking in is what makes you feel terrible while you have the infection, and then it goes away when the immune response starts clearing the virus. (Except we know that Covid-19 can, in some people, trigger an overwhelming inflammatory response which is what makes them end up in hospital.)
    The median infectious dose is a measure of how many viable virions you need to be exposed to in order to have a 50% chance of becoming infected. Estimates are on the order of hundreds for most respiratory viruses, IIRC. There's presumably a stochastic element to that ("just one virion in the wrong place"), but I do wonder if there's isn't also a concentration effect--that it requires a little cluster of virions to overcome barrier defences that might easily deal with a single virion. I don't know if that is so, and have never been able to track down any data on the topic. But obviously that would make a difference to risk--a cloud of 1000 individual virions, landing at 1000 different places in your respiratory tract, might be dealt with more effectively than 1000 virions in a blob on a tiny patch of mucosa.
    Another consideration is that, despite all the horrific computer animations of aerosols spreading through supermarkets we've been treated to of late, the epidemiology still suggests that (like other coronaviruses) aerosols are not the primary mode of transmission of SARS-CoV-2 in the community, though there's evidence it occasionally happens. That may be because the virions are usually less viable in community aerosols (despite PCR-detectible viral RNA being present), or because community aerosol droplets don't usually deliver virion in sufficient local numbers to overwhelm barrier defences. But despite all the laboratory and theoretical work about Covid aerosols that has been published, what's being reported about observed transmission by real infected people is more compatible with larger droplets being the major mode of transmission.

    So, anyway, the upshot of all that would be that, when "shopping carefully" we might not actually be encountering any viable virions, or we may be encountering virions presented in a manner that the barrier defences of our innate system deals with before a single cell can be infected. Either way, we're not going to trigger antibodies under those circumstances.

  11. #2411
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    Thank you Grant for that detailed answer. Near my home we had an outbreak, at Banham chicken processor factory. It is chilled so the air takes no vapour. In that situation with workers sweating and closely adjacent, droplets will survive a long time. A large proportion of the workers tested positive but none (I think) hospitalised. The fate of droplets in warm breezy conditions is very different. I like your swarm hypothesis because it is a numbers issue per cell, it seems to me. Similarly, I guess, droplets on masks evaporate in warm low RH conditions.

    When colder nights arrive, it is easy to get high RH and therefore higher risk for careful shoppers. It is too complex to be public policy but thinking about RH in chilled or twilight cooled spaces makes sense to me. Plus avoiding handshakes.
    sicut vis videre esto
    When we realize that patterns don't exist in the universe, they are a template that we hold to the universe to make sense of it, it all makes a lot more sense.
    Originally Posted by Ken G

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    Quote Originally Posted by Van Rijn View Post
    Not an answer to the question, but the body does have various nonspecific defenses against viruses, more likely to be effective with a smaller viral load. Some details here:

    https://www.ncbi.nlm.nih.gov/books/NBK8348/
    Thank you for that very interesting reference
    sicut vis videre esto
    When we realize that patterns don't exist in the universe, they are a template that we hold to the universe to make sense of it, it all makes a lot more sense.
    Originally Posted by Ken G

  13. #2413
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    If you have experience of ultrasonic humidifiers you see in a ventilated room a cloud of fog which disperses within half a metre. But if you run one in either cold or hot high RH conditions, it can fill a room. The difference is evaporation rate.
    sicut vis videre esto
    When we realize that patterns don't exist in the universe, they are a template that we hold to the universe to make sense of it, it all makes a lot more sense.
    Originally Posted by Ken G

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    There's a good review of potential mechanisms linking relative humidity and transmissibility here. For reference, SARS-CoV-2 is an enveloped virus, and therefore falls into the group that seems to transmit better at low RH.

    Grant Hutchison

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    Quote Originally Posted by grant hutchison View Post
    There's a good review of potential mechanisms linking relative humidity and transmissibility here. For reference, SARS-CoV-2 is an enveloped virus, and therefore falls into the group that seems to transmit better at low RH.

    Grant Hutchison
    Another fascinating reference. At the end they mention the unknown role of temperature, while the role of pH reduction is both interesting and complex. Thinking in boundary layer terms is always difficult and devilish to research. I would like to see discussion of the latent heat effects within the boundary layer where the lipid surfaces are exposed to those surface tension and pH challenges. In order to evaporate the tiny droplet must cool because the boundary layer also limits heat transfer. This effect is therefore dependent both on RH and temperature, not to mention salt content.

    It seems from that review that infectivity will vary with time once the droplet is ejected, for several inter-related reasons. I have mentioned before, without any reference that surfaces also affect boundary layer RH in some circumstances and for some substrates, which might explain how virions can remain infective on surfaces.

    The only practical take is that distance is important as we already know!
    sicut vis videre esto
    When we realize that patterns don't exist in the universe, they are a template that we hold to the universe to make sense of it, it all makes a lot more sense.
    Originally Posted by Ken G

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    If I read the article linked below correctly, Eli Lilly has a drug made of synthesized antibodies from an early COVID-19 patient.

    Anyone know why only the middle dose had the desired result? I would think that if 2800 mg of antibodies is good, 7000 would work at least as well.

    https://news.google.com/articles/CAI...S&ceid=US%3Aen


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    It's just an interim report on the primary outcome measure of the BLAZE-1 trial. We'll need to see full details of the secondary outcomes, the data analysis, and the results of peer review.
    There could be all sorts of reasons for the reported outcome, some relating to the real world and some relating to the data collection and analysis, But you can bet that any report from the drug company itself (like this one) will highlight the best possible interpretation.

    Grant Hutchison
    Last edited by grant hutchison; 2020-Sep-17 at 12:22 AM. Reason: typo

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    Now the CDC is revising their guidelines. https://www.yahoo.com/news/cdc-says-...034950288.html
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    And now they reverted it, saying it was posted in error, but apparently are planning on making some change in guidelines.

    "The problem with quotes on the Internet is that it is hard to verify their authenticity." — Abraham Lincoln

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    CDC in "Saying Something Generally Acknowledged To Be True" scandal!

    Whatever next.

    Grant Hutchison

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    Fair enough, but it is astonishing that they would accidentally put a draft out and almost immediately pull it back. It doesn’t inspire confidence - mine at least - in their organization and makes me think of questions we can’t discuss.

    "The problem with quotes on the Internet is that it is hard to verify their authenticity." — Abraham Lincoln

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    I am very curious what the guidance will say once they revise it and if it will have any significant changes over current.
    Last edited by Van Rijn; 2020-Sep-21 at 09:48 PM.

    "The problem with quotes on the Internet is that it is hard to verify their authenticity." — Abraham Lincoln

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    The page that was inadvertently updated simply acknowledged the possibility that community aerosol transmission may occur, which has been blamed for sporadic superspreader events. (The WHO and ECDC has remained unpersuaded, if we can judge from the fact that they haven't updated their unpersuaded webpages in a month or two.)
    Presumably the "How Covid Spreads" update by the CDC was intended to go out at the same time as an updated guidance note, addressing how to limit the likelihood of such events. I'm not expecting any surprises from the associated guidance (I think it'll say a lot of stuff that's already being widely discussed and adopted).

    But then again, the nature of surprises is that you don't expect them.

    Grant Hutchison

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    Quote Originally Posted by Van Rijn View Post
    I am very curious what the guidance will say once they revise it and if it will have any significant changes over current.
    In that case we should just follow the authoritative science!
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    The reality with regard to authoritative science is this:
    While it is always helpful to have more data and more evidence, we caution that in this complex and fast-moving pandemic, certainty is likely to remain elusive. “Facts” will be differently valued and differently interpreted by different experts and different interest groups. A research finding that is declared “best evidence” or “robust evidence” by one expert will be considered marginal or flawed by another expert. It is more important than ever to consider multiple perspectives on the issues and encourage interdisciplinary debate and peer review. While government must continue to support research, some decisions—as you will be well aware—will need to be made pragmatically in the face of uncertainty.
    Those are the closing remarks from an open letter sent to the UK's chief medical officers yesterday, urging a particular approach to the pandemic, and signed by twenty-odd authoritative scientists.
    By a splendid coincidence, as if to demonstrate precisely the points raised in the quote above, another group of twenty-odd authoritative scientists signed another open letter to the same recipients on the same day, urging essentially the opposite course of action to that urged by the first group of authoritative scientists.
    So, as the quote above concludes, it's evident that "some decisions [...] need to be made pragmatically in the face of uncertainty."

    That's the context in which we need to consider the pronouncements made by national public health authorities.

    Grant Hutchison

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    Quote Originally Posted by Copernicus View Post
    In that case we should just follow the authoritative science!
    As Grant's letter implies, science is a method of analysis and a learning process. The specific results change as new and ongoing research and data are integrated.

    We have to get in the habit of not getting into habits, as the authoritative guidance will be continually adjusted for some time.
    "I'm planning to live forever. So far, that's working perfectly." Steven Wright

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    Indeed. While the last six or eight months have been a lifetime in terms of the changes wrought on our lives, they haven't been remotely long enough for a scientific consensus to form. In part that's because we keep seeing contradictory experimental and epidemiological results (that's entirely to be expected in medicine during the early stages of understanding a new disease or treatment), and in part it's because the situation is still evolving. Things we did at the start of the pandemic are not necessarily things we should be doing now.

    (On that last point, I'm unutterable weary of journalists talking about "U-turns" in policy, and vox pops that feature people moaning about "first they tell us one thing, then they tell us another". Surely it should be evident to everyone who's been awake for any length of time recently, that what's happening now is not what was happening two months, four months or six months ago.)

    Grant Hutchison

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    Quote Originally Posted by grant hutchison View Post
    "first they tell us one thing, then they tell us another".
    In the US, they're telling us one thing and another simultaneously, but not because of science.

    Quote Originally Posted by grant hutchison View Post
    Surely it should be evident to everyone who's been awake for any length of time recently, that what's happening now is not what was happening two months, four months or six months ago.)
    Well, there's the problem! In my experience too many people are plunging through this crisis eyes and minds closed, hoping it'll just go away.
    "I'm planning to live forever. So far, that's working perfectly." Steven Wright

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    The AstraZeneca trial is still on hold in the US. While the main takeaway from the following article seems to be that the FDA is being careful, I wonder about AstraZeneca changing the protocol mid-trial. Is that at all common?


    https://www.reuters.com/article/uk-h...-idINKBN26L3T8
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    Quote Originally Posted by Extravoice View Post
    The AstraZeneca trial is still on hold in the US. While the main takeaway from the following article seems to be that the FDA is being careful, I wonder about AstraZeneca changing the protocol mid-trial. Is that at all common?
    Very common to make minor protocol changes like the one reported. I recall seeing a report that, in a particular setting, more than half of large drug trials had midstream protocol changes.
    This one simply pushes back the timing of the first interim data analysis. These early analyses allow trials to be halted early if there is overwhelming evidence of harm or benefit before the originally planned recruitment target is reached. They're setting themselves a later trigger for the first interim analysis, and I'd guess that's to allow more time for any further adverse events to appear, before they analyse for benefit. It's just good practice, if you've seen an adverse event, to give yourself longer for another adverse event to appear. All this stuff usually goes on without anyone but the researchers and the regulatory organizations knowing about it, but of course everything Covid-related is being carried out in the full glare of media attention.

    Grant Hutchison

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