The ‘End’ of COVID Is Still Far Worse Than We Imagined

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ChicagoGranny
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Re: The ‘End’ of COVID Is Still Far Worse Than We Imagined

Post by ChicagoGranny » Thu Sep 29, 2022 7:49 am

joepublic23 wrote:
Wed Sep 28, 2022 8:59 pm
I did return the CPAP machine. Good riddance to the insomnia box. Next week I am seeing a Doctor who is both an ENT AND a Dentist. My gut feeling is surgery is the only solution for me, although I am hoping that the eXciteOSA device might be a viable solution for me. I am not opposed to trying a dental device but I am concerned that it will also cause insomnia. I might buy a real cheap one just to see if I can sleep with it.
Since this is a CPAP forum, it's time for you to move on.

tisket
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Re: The ‘End’ of COVID Is Still Far Worse Than We Imagined

Post by tisket » Sun Oct 09, 2022 12:23 am

joepublic23 wrote:
Wed Sep 28, 2022 3:39 pm
You have a choice to make:

You can wear a mask everywhere you go, everyday for the rest of your life and limit attending indoor public gatherings drastically.
This is extremist thinking. I am surrounded by people who think and talk like this. It's like they have amnesia and forget how the pandemic has changed significantly over time. "The rest of your life" implies a static situation when the pandemic has been anything but.

2020 was a very bad time. The health authorities embarrassed themselves with "stop buying masks people, they won't work for you unless you're a medical professional!" and "it's not airborne" and ended up losing a lot of credibility. One thing the ghastly death stats revealed is the number one risk factor by far is age. Older people have hundreds of times the risk of younger people. So even if you feel safe now due to age, you get older every day and it is waiting for you when your immune system loses its efficiency. Yes it doesn't kill everybody. Neither does ebola or smallpox. Even HIV has a few people immune to it. But taking your chances with it over and over is asking for trouble, especially since you age a little more every day. Flu is pretty harmless when you're 30. Not so when you're 70.

2021 was the year of the vaccine. It was amazingly effective. For awhile even the most cautious people felt free to resume normal life. It was also the year of monoclonal antibodies as a treatment option. Then came Delta, which changed everything for the worse, along with evidence of waning immunity due to antibody decline. Then came the first booster, which repaired the damaged immune armor. I ate out again and flew on a plane. Then came Omicron, immune escape, and the incredibly short incubation time which meant lifetime immunity would be impossible, unlike some diseases, because the virus can multiply much faster than even a trained immune system can gear up. This means current antibody levels are incredibly important but they do not last, and multiple boosters per year will be required with the current technology. N95s became widely available, however the variants became much more transmissible, rivaling measles.

2022 was the year of Paxlovid, people pretending it's over, people getting it again and again, and endless studies showing long term effects and risks even years after initial infection, and a labor shortage caused by millions with long covid. Medical authorities would frequently state that "the virus was gone from the body" for people with long covid, or people in the ICU for long periods of time, despite a total lack of evidence that this was the case. Saying it's gone because a nasal swab is negative is like saying syphilis is gone because the chancres on the genitals have healed. I recall how they could not find HIV in the blood and could not understand how it could persist until finally someone found it inside T cells in the lymph nodes. Long term effects of covid remain unknown since there hasn't been a long term yet. Also the year politicians and health experts decided to follow the crowd and stop trying to prevent spread, and instead get back to business as normal, everybody take their chances and just treat it like the risk of a car accident, don't have to isolate very long and can return to work or travel during the infectious period etc. CDC avoids talking about long covid and remains laser focused on "severe disease and death" (acute lung distress), and they change their map to feature "community levels" instead of "community transmission" to make everything look better than it is. Administration talks about "one shot per year" as if covid was a seasonal disease like flu (it isn't). It was also the year of free rapid tests, I have taken at least two every week since January. Altogether I have taken 4 PCRs and probably over a hundred rapid tests during the pandemic.

This was also the year (or maybe late 2021) that scientists figured out how covid kills most people that it kills - by infecting macrophages, a type of immune cell, and causing the cells to self-destruct and release a barrage of inflammatory chemicals via little sacs called "inflammasomes." This occurs when certain antibodies, which are non-neutralizing, attach to the virus and the macrophage then tries to eat it, but gets infected by the still active virus. Its fiery death summons more immune cells which in turn get infected and the inflammation in the lungs gets totally out of control and your lungs turn to concrete as connective scar tissue replaces the delicate alveoli. It's no accident the "cytokine storm" tends to occur around days 8-10 after symptoms start (with the old variants anyway) because that is when antibody production kicks in, with the unfortunate chain of events involving macrophages. This is a type of antibody-dependent enhancement (ADE) like that seen in dengue and HIV, but it does not require exposure to different strains, instead it triggers off of early, poorly matching antibodies or non-neutralizing ones like nucleocapsid antibodies. Concern about exactly this kind of situation is why the mRNA and viral vector DNA vaccines code only for the spike protein (to produce neutralizing antibodies) and not the nucleocapsid or other proteins which induce non-neutralizing antibodies. The vaccine makers are a clever bunch. For viruses like this, non-neutralizing antibodies are actually dangerous. They learned this from the RSV vaccine attempts, along with the need to freeze the spike protein in the pre-fusion configuration. The details of the vaccines fascinate me.

2023 may be the year of the pan-coronavirus vaccine which will produce neutralizing antibodies even against variants which don't exist yet, maybe even against common cold coronaviruses and SARS, but which cannot give lifetime immunity because of the short incubation period problem. Still, they could allow us to get vaccines without concern of them suffering from immune escape from some new variant a month later. Maybe it will be the year of the next really bad variant. We don't know.

I am the only one I know in my department who has not had covid. I am also the only one who does not eat out, and wears an N95 anytime I am around other people besides my girlfriend. (She also wears N95s anytime she is around other people and we test before seeing each other.) I time my dental and medical visits around boosters and maximum antibody levels. Are these "lifetime" behaviors? Hopefully not but it depends on what happens. Nobody knows what the future holds. Saying "for the rest of your life" is an indication of rigid, extremist thinking in what is actually a very fluid situation. I go by the data. There have been times, after the initial vaccines and after the first booster, when I felt safe enough to be able to return to restaurants. Each time the situation deteriorated, and I changed my behavior accordingly.

Covid is not a respiratory disease. It is a multi system inflammatory disease that attacks cells all over the body and by attacking cells lining blood vessels, can cause clots in any organ. I know people who don't take covid seriously, and some of them died, horribly, from covid. I know people who had to retire prematurely due to long covid - they were lucky to be able to afford to do that. I can't afford to do that so I am trying my best to avoid it. I have found people tend to keep their long covid symptoms to themselves if they can, but the few I know well enough to share, have told me that it has affected their sense of smell (all meat smells rotten, all milk smells sour) from infections 18 months or more ago. This seems permanent. One told me she got it in August and ever since her visual field is severely distorted in one eye, no doubt due to retinal clots or bleeding. She was headed to an eye exam last time I spoke with her. I know someone else who ended up in the ICU with a collapsed lung from it, it ate a hole right through his lung, and has suffered personality changes from the experience (can no longer enjoy whiskey for example, gets a panic attack). I know tons of people who have had to take weeks and weeks off work every year due to covid, exhausting all their paid time off, not on vacations, but on covid, and then having to go unpaid due to having no PTO left. Then they get it again.

A lot of diseases have long term effects that only show up over long periods of time. Epstein Barr was shown this year to almost definitely be the cause of multiple sclerosis - 5 years after infection. I recall the start of the AIDS epidemic where people would get a rash and then they were "recovered" until a few years later their T cells got destroyed and they started dying. I know someone blind in one eye due to shingles from a chickenpox infection 40 years before. People talking about "recovering" from covid really have no idea what they are talking about, nobody does, because there is absolutely zero long term data about it. There is a lot of rationalization going on out there and a lot of people who really want to believe they're ok, and they really want to eat out, they want to travel, they want to have gatherings, so they construct a mindset where the virus isn't that dangerous, despite all the evidence to the contrary. Many of them seem to be getting away with it, but it's still very early in this story.

I believe covid is the most contagious and rapidly mutating dangerous virus with the shortest incubation period ever found, it is uniquely bad, but if there's another I'd be interested in hearing what it is.

I think it's likely that like many other diseases, it will severely affect a certain percentage of people, affect other people less severely but still change their life for the worse, and seemingly leave some people untouched, at least in the medium term. (Again we have no long term data at all.) And we know it hits older people much harder and we all get old eventually. For comparison polio only paralyzes about 1 in 400 children who catch it, yet we take it far more seriously than covid, whose death and disability rate is far higher. No effort was spared to stop polio in its tracks. But covid is politicized. I have been to medical and dental offices recently where the staff did not wear masks, and know of several doctors who do not wear masks when seeing patients. I have walked into a medical office wearing a mask and been told "Oh you don't have to wear that if you don't want to" by the staff - a strange message to be sure. Patients are not required to wear them except in a handful of offices I have been to. There is a giant Emperor's New Clothes going on right now with people pretending it's all over. If only it were.

I'm just trying to stay safe until we get completely effective treatments, understand and can treat (and hopefully prevent) long covid, get better vaccines like nasal vaccines that block infection at the contact point and pan-coronavirus vaccines that do not fall behind the constant flow of new variants. I read exciting research all the time and am confident that more breakthroughs will emerge, such as treatment for persistent microclots that appear to be caused by covid causing clotting proteins to assume unusual shapes and resist breakdown by the body. I also read of biopsy studies where covid virus is found in organs hundreds of days after infection. I think a lot more data will be coming and I hope we can get covid under control. My main concern is that with the administration wanting to push a "back to normal" message, and the public wanting to pretend it's over, that the resources and commitment will not be there to produce multiple shots per year, which I feel will be needed. As it is, the bivalent booster has very low uptake and a lot of people don't even know it exists.
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ChicagoGranny
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Re: The ‘End’ of COVID Is Still Far Worse Than We Imagined

Post by ChicagoGranny » Sun Oct 09, 2022 11:24 am

tisket wrote:
Sun Oct 09, 2022 12:23 am
tisket
Good, comprehensive summary.

tisket wrote:
Sun Oct 09, 2022 12:23 am
This is extremist thinking.
It simplifies the brain. Reading, thinking, analyzing, and listening to others are all hard work.

tyrinryan
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Re: The ‘End’ of COVID Is Still Far Worse Than We Imagined

Post by tyrinryan » Sun Oct 09, 2022 11:33 am

Terrific and so well written! Could you expand on the paragraph "This was the year....". Macrophages, I guess, only attack the infected regular cells? are there other immune cells or even regular cells that are part of the equation to create the cytokine storm? etc.? or is it only these macrophage explosions? What would be the purpose of a non-neutralizing antibody?

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Re: The ‘End’ of COVID Is Still Far Worse Than We Imagined

Post by lazarus » Sun Oct 09, 2022 12:46 pm

I have zero disagreements with your points or the way you made them, tisket. In fact, it may be the first time I've read anyone express that much on those subjects and for me not to have had a different position or conclusion on something.

The only small observation I might make is that although I do not hold the same personal position as Mr. Public, I do recognize that communication styles can differ quite a bit in the informal vernacular in forums, so I see a fairly fine line between the intent behind the following two statements:
joepublic23 wrote:
Wed Sep 28, 2022 3:39 pm
You can wear a mask everywhere you go, everyday for the rest of your life and limit attending indoor public gatherings drastically.
and
tisket wrote:
Sun Oct 09, 2022 12:23 am
I am also the only one who does not eat out, and wears an N95 anytime I am around other people besides my girlfriend. (She also wears N95s anytime she is around other people and we test before seeing each other.) I time my dental and medical visits around boosters and maximum antibody levels. Are these "lifetime" behaviors? Hopefully not but it depends on what happens. Nobody knows what the future holds.
(Underline added by me.)

The first statement uses a shorthand form of hyperbole; the second is clearer and more nuanced and more forward-looking, but . . . well, you know.

I personally am prepared to wear an N95 indoors whenever in a crowd of strangers and to do so 'for the rest of my life,' for my benefit and for the benefit of others--although I, too, hope circumstances change and that it doesn't come down to that long-term.

Governments are often more concerned with the short-term economic repercussions of public policy than with individual health and quality of life and the long-term economic repurcussions. So we have to recognize that individual responsibility comes into play as we each research risks and make personal decisions.

That said, I am personally confused that in some places it can be illegal to smoke in an enclosed public space (such as an elevator) but perfectly acceptable behavior not to be masked. Which action presently has a greater likelihood for damaging other people's health most seriously for brief amounts of time but repeated exposure?

But, hey, there's a lot of stuff that confuses me these days in this ongoing episode of The Twilight Zone. I still plan to tune in next week in case there is a sequel that makes more sense to me.
The people who confuse "entomology" and "etymology" really bug me beyond words.
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tisket
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Re: The ‘End’ of COVID Is Still Far Worse Than We Imagined

Post by tisket » Sun Oct 09, 2022 11:37 pm

tyrinryan wrote:
Sun Oct 09, 2022 11:33 am
Terrific and so well written! Could you expand on the paragraph "This was the year....". Macrophages, I guess, only attack the infected regular cells? are there other immune cells or even regular cells that are part of the equation to create the cytokine storm? etc.? or is it only these macrophage explosions? What would be the purpose of a non-neutralizing antibody?
The immune system is enormously complicated and I don't pretend to understand all of it. But I think I can give a little summary. I am not going to cover things like interferon, by which an infected cell can tell its neighbors to shut down their machinery because there are viruses around, but am going to concentrate on the immune cells themselves. I will just note there was a fascinating study in a petri dish with nasal cells which showed they cleared rhinovirus (a type of common cold) infections by themselves - with no immune cells present.


Your immune system has two "teams" called the innate immune system and the adaptive immune system. The innate immune system is designed to be a first responder to anything bad going on, but is not particularly specific. It has a number of different kinds of cells, like neutrophils, which attack bacteria, and natural killer cells, which attack human cells which appear infected, and macrophages, which are monocytes which travel in the blood to an infected organ and then turn into macrophages ("big eaters") which go around trying to eat bad things, like viruses or the detritus of dead cells. The innate immune system has ways of causing "inflammation" which is actually part of the damage response and healing process, it brings more blood, and thus more oxygen, nutrients, immune cells etc to a trouble spot to stop the problem and begin repairs. If you've sprained your ankle, the resulting swelling is your innate immune system bringing in repair crews to fix the damage.

The innate immune system also produces symptoms. The purpose of this is to make you lie down and rest. The way the body's energy budget works is active tasks, like thinking and moving muscles, spend energy from the daily budget immediately as they occur. The immune system gets what is "left over" as a budget surplus so to speak. That is why you will do worse if you try to remain active through an illness. Feeling bad is the innate immune system's way of forcing you to lie down and not do anything so it has plenty of energy from the surplus. Those muscle aches, headache, fatigue etc? They're the innate immune system trying to get you to hand over the energy. Of course you can override this (what if there's a lion over there?) but you shouldn't unless you have no choice.

Other less pleasant symptoms like nausea, vomiting and diarrhea are the body's way of trying to flush bad things out of the digestive system and make you stop eating whatever noxious substances you ate.

Fever has a special purpose, it changes the body temperature which in turn impacts enzymes (organic catalysts). Enzymes are designed to operate at a particular temperature and biological processes are absolutely dependent on them. Warm blooded animals have mostly enzymes which work at a particular temperature and they regulate their body temperature to maximize enzyme activity by keeping things at the ideal temperature for their enzymes. Cold blooded animals have groups of enzymes, some of which work at this temperature, some at that, so they can tolerate a wide range of internal temperatures and their metabolism does not stop if they get cold (like ours does), but on the other hand, when they get cold only a portion of their enzyme set works so they are sluggish, while our bodies would spend energy to maintain our temperature at a constant point and remain just as active when it's cold out as when it's warm since all our enzymes are always available at full capacity. Make us too cold internally and all the machinery stops though.

Bacteria and viruses tend to like it colder than we do in terms of their enzyme activity. If you raise the temperature via a fever, their activity tends to slow. They reproduce more slowly. Thus a fever can often slow down a disease by interfering with the activity level of the enzymes the pathogen uses to infect cells and reproduce itself. This is why fever reducers are seldom a good idea. They are making things more pleasant for the disease organism. One study showed that people who took aspirin during a common cold had a 50% longer duration of the cold than people who didn't.


Which brings us to the main point of the innate immune system in a situation like a viral infection: to buy time. The innate immune system is not "smart" and just tries to attack obviously bad things, increase the temperature, make you feel crappy so you rest, and create inflammation in attacked areas to bring in reinforcements. It is just stalling for time for the other team to do its thing.

Calling for backup is another job of the innate immune system. There are innate immune cells, called antigen-presenting cells, such as dendritic cells, whose job it is to patrol the body and look for alien stuff, namely antigens, floating around. Anytime there are viruses or bacteria there are pieces of protein, lipoproteins etc from them floating around for various reasons. Antigen is short for "antibody generating." It is a substance defined by the fact it evokes a response from the adaptive immune system because the body recognizes it as alien. Dendritic cells like to hang out in muscles among other places which is why intramuscular shots are given for many vaccines.


The adaptive immune system is the precise one. It contains two general classes of cells, T cells and B cells. You could think of the innate immune cells as street cops walking beats all over the body and the adaptive immune system as a SWAT team in reserve, much more powerful but it has to be summoned to where the trouble is and told what it is so it can prepare.

When an antigen-presenting cell like a dendritic cell finds something weird and alien, like a viral protein, it goes to the lymph nodes where the T cells and B cells hang out. If I recall correctly it hands off what it found to a type of T cell called a helper T cell. Then this cell goes looking for what are called naive T and B cells. Naive cells are not specialized, they are essentially recruits who have not been trained yet. But they each have a unique pattern on their outside. The helper cells holds out a chemical signal which corresponds to the antigen that was found, to find naive cells who "match" it to some degree. You can think of this like a peg and hole sort of arrangement, or a lock and key. The helper cell tries to find T and B cells whose surface pattern roughly fits the antigen. This pattern is a protein called an immunoglobulin and the T and B cells display it on their surfaces so the helper cells can try to find cells that match the antigen the helper cell is carrying around.

Matching cells become "activated" and begin a remarkable process called somatic hypermutation and affinity selection. This means they begin dividing and deliberately inducing very high rates of mutation in the sections of their DNA that code for their unique immunoglobulin. This produces lots of slightly different cells with a huge array of variations of their immunoglobulin, some of which will fit the antigen better and some worse. The helper cells keep fitting their little key to the locks of the immunglobulins of these new cells. If a cell is a bad fit, it is told to self destruct and it drops out of the competition. If it is a good fit, it continues in this process, which simulates mutation and natural selection in the environment, producing generation after generation of these mutated cells, trying by chance to get better and better fits to the antigen, with the losers of each round self destructing and the winners dividing again with more mutations. This goes on for days, even weeks. At some point cells whose immunoglobulins are a more or less perfect match, along with other ones which are close, are produced. The body has thus produced immune cells whose immunoglobulins match the antigen almost exactly, along with variations just in case the virus mutates. These cells now follow one of two paths: they become memory cells to keep in reserve for the next time this antigen is seen so the process goes much faster, or they go to war.

(This process actually continues over time after the infection is over, and again upon re exposure, such as a second vaccine shot, but that's another story.)

T cells that go to war are called cytotoxic T cells and their job is to look for their matching antigen or a fragment of it (they are very good at recognizing variants of their immunoglobulin) on the surface of a human cell. Human cells always have a little escalator inside that runs up samples of everything it is making and displays them on its surface in something called the major histocompatibility complex or MHC. The T cells float around and sample the MHCs of everything they bump into to see if anything there matches their immunoglobulin. If it does - it means the cell is making viral proteins! It is infected! The T cell has ways of destroying human cells, such as apoptosis, where the infected cell is ordered to self destruct. The T cells go around killing the human cells which have been co-opted into becoming viral factories. This is the only way to end an infection - destroy all the infected cells. T cells stop the infection at its source, the infected cells which are making more viruses.

B cells that go to war are called plasma cells. They begin manufacturing enormous quantities of their immunoglobulins and releasing them into the bloodstream. These free floating immunoglobulins are more widely known as "antibodies." They have been crafted through the mutation and selection process to chemically match and stick onto the antigen. The blood becomes filled with these antibodies and viruses displaying the antigen find themselves covered in a fuzz of antibodies blanketing them like iron filings on a magnet.

Now the B cells produce antibodies to whatever they are shown by the helper cells. Some antigens, like the tip of the fusion proteins of viruses like covid, are required to be functional and exposed for the virus to be able to infect a cell. If you cover them with antibodies, the virus is neutralized and cannot infect anything. However, other antigens, like other substances on the virus surface, or parts of the spike protein not near the tip which are not essential to have exposed in order to infect a cell, are not used in the infection process and it doesn't neutralize the virus to cover them. The B cells have been shown all sorts of antigens by helper cells and make antibodies to them all. Some are neutralizing, some are not, depending on exactly what antigens they were shown, which is going to be a wide array of fragments of various substances produced by the virus.

Macrophages know what antibodies are, if they see something with antibodies sticking to it, they know it is something alien to be eaten and dissolved. This works fairly well most of the time, but there are certain viruses like dengue and HIV which use something called "antibody dependent enhancement" or ADE. For them, this means the person was infected with one strain, produced antibodies to it, and then later was infected by another strain. The antibodies to the old strain are close enough to the new strain to stick to it, but not well enough to neutralize it. This results in "marked" viruses that immune cells try to eat, but the virus is still active and infectious, so it infects the immune cell. This is bad. This is why a second dengue infection is often far worse than the first. This also happened when researchers tried to make a vaccine for RSV - to make a long story short the vaccine produced lots of antibodies which were not neutralizing, and children getting the vaccine actually did far worse than the control group. The RSV debacle gave a lot of lessons which made the covid vaccines possible.

Covid, to my knowledge (which is limited) is the first virus to use ADE in the initial infection, such that early antibodies (which might not fit as well as later, more refined versions, or else target unessential parts of the virus) enable the virus to infect macrophages. The virus gets eaten, but it breaks out of the endosome the macrophage stores it in, so instead of being destroyed, it infects the macrophage. Macrophages know this trick and self destruct rather than let themselves be used as a virus factory, but in doing so they send up a big flare that hey, this is serious, this pathogen is infecting the immune system itself, send help now. This is a major form of inflammation which results in more immune cells coming in, some of which get infected the same way and it's like a chain reaction in a nuclear bomb. Innate immune cells are not the trained snipers of the adaptive immune system, and in a situation like this with flares going up saying "Emergency!" and without the specificity of the trained T cells, they can start killing everything in sight, including uninfected lung cells, and "destroy the village in order to save it."

I should note that one of the things the adaptive immune system does, when it is ready to fight, which is typically 14 days after infection, is tell the innate immune system to stand down. Turn off the fever, the inflammation, the body aches etc the situation is now under control, we got this. Except this doesn't work in a cytokine storm of the type produced by the infected macrophages. It can be very difficult or impossible for both the body and for doctors to stop the runaway cytokine storm once it starts. I don't think covid is the only virus that can cause this situation but it certainly is the first widespread one that I know of.

Future infections by the same pathogen result in a similar but shorter process where the antigen presenting cells find an army of memory cells already waiting and trained on this particular antigen. Chances are the virus has mutated a bit since last time so some more refinement might be needed, but the antibodies start getting churned out in days rather than weeks. For most viruses, this response is faster than the virus' incubation time, which means the body gets it under control before the virus can reproduce enough to trigger symptoms and you never know you even were reinfected. This is what the "lifetime immunity" we associate with things like measles and smallpox is. You don't get these diseases twice, once your immune system is trained it can squash any future infections quickly. Covid unfortunately now has such a short incubation time that it can outrun even a trained immune system before the memory cells can get fully into gear, although your chances are still much better of avoiding a bad outcome if you have had prior exposure to the antigen and have memory cells standing by.

Hope that was helpful and that I didn't make too many mistakes. I think the immune system is second only to the brain in terms of complexity, it truly is amazing and I am not an immunologist.
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