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Tags Coronavirus , vaccination , vaccines

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Old 7th November 2021, 02:49 PM   #281
Dr.Sid
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Here at Czech Republic experts are starting to say everybody will get it now. Vaccinated will have less chance of dying, but it would be virtually impossible not to get infected, with how many cases are projected (and delta).
I mean there never was any 'zero covid' policy here, but this is basically giving up. Last wave with this case count there already was quite severe lockdown. Nothing is planed this time.
On the other hand, infection with vaccination gives best protection for future.
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Old 7th November 2021, 03:05 PM   #282
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Originally Posted by Dr.Sid View Post
Here at Czech Republic experts are starting to say everybody will get it now. Vaccinated will have less chance of dying, but it would be virtually impossible not to get infected, with how many cases are projected (and delta).
I mean there never was any 'zero covid' policy here, but this is basically giving up. Last wave with this case count there already was quite severe lockdown. Nothing is planed this time.
On the other hand, infection with vaccination gives best protection for future.
Yep. That's been pretty obvious since Delta and lots of people were saying that with Alpha. China's holding out and still claiming to have a zero Covid policy but pretty much everyone else has basically put in NPIs only to limit hospitalization resources and push to get people vaccinated which greatly helps reduce serious disease. Everyone's gonna get Covid. It's not if, it's when.

Get vaccinated and get on with life.
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Old 7th November 2021, 03:24 PM   #283
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Relevant stats from Ontario reported today:
* 636 new cases reported
* 325 unvaccinated (51%)
* 15 partially vaccinated
* 248 fully vaccinated (39%)
* 48 unknown

84.9% of the eligible population (12 and older), or 74.8% of the total population, is fully vaccinated.

So 25% of the population is responsible for at least 50% of the cases. That's a pretty stark difference.

It gets worse if you look at ICUs (73 patients):
* 59 unvaccinated (80%!)
* 2 partially vaccinated
* 12 fully vaccinated (~16%)

Sources:
https://globalnews.ca/news/8356309/o...es-november-7/
https://files.ontario.ca/moh-covid-1...21-11-05_2.pdf
https://www.publichealthontario.ca/e...d-19-data-tool
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Old 7th November 2021, 04:25 PM   #284
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SARS-CoV-2 vaccine protection and deaths among US veterans during 2021
https://www.science.org/doi/10.1126/science.abm0620

Ve against infections also at half. Ve against death is better but not as high as many other studies but still pretty good.

Abstract
We report SARS-CoV-2 vaccine effectiveness against infection (VE-I) and death (VE-D) by vaccine type (n = 780,225) in the Veterans Health Administration, covering 2.7% of the U.S. population. From February to October 2021, VE-I declined from 87.9% to 48.1%, and the decline was greatest for the Janssen vaccine resulting in a VE-I of 13.1%. Although breakthrough infection increased risk of death, vaccination remained protective against death in persons who became infected during the Delta surge. From July to October 2021, VE-D for age 65 years was 73.0% for Janssen, 81.5% for Moderna, and 84.3% for Pfizer-BioNTech; VE-D for age ≥65 years was 52.2% for Janssen, 75.5% for Moderna, and 70.1% for Pfizer-BioNTech.
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Old 7th November 2021, 06:56 PM   #285
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Originally Posted by Dr.Sid View Post
On the other hand, infection with vaccination gives best protection for future.
Originally Posted by marting View Post
Get vaccinated and get on with life.
Denmark arrived at that, and UK also did, maybe prematurely in their case.

It's the only possible answer at this time, and the sooner everyone realises that, the better.

Yes, there might be another wave, and yes, some people will die. Not huge numbers as long as your vaccine rate is high enough, and then the disease will die off to background noise.

This applies even more now we have drugs that work very well.
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Old 9th November 2021, 01:27 AM   #286
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I see Denmark has re-categorised Covid and reintroduced some measures after a surge has become apparent.

Even the jewel in the vaccination crown, Portugal, is showing signs of a possible surge.

It's not to go quietly.
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Old 9th November 2021, 09:26 AM   #287
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clinical trial of fluvoxamine contrasted with others

In his discussion of the fluvoxamine trial, Derek Lowe concluded, "It's been said before, but it needs to be said several more times: the clinical response to the pandemic, taken has a whole, has not been good, and we're going to have to take steps not to repeat these mistakes if (or when) another such infectious agent appears. That's another topic entirely, but going into what I refer to as Headless Poultry Mode shouldn't be an option. This trial and the ones listed above have been the real beacons in this area, but the US has not exactly been performing up to where it should in this area."
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Old 9th November 2021, 09:40 AM   #288
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Pfizer's reversible, covalent protease inhibitor

C&E News wrote, "PF-07321332 was developed from scratch during the current pandemic. It’s a reversible covalent inhibitor that reacts with one of the main protease’s cysteine residues."

At In the Pipeline Derek Lowe wrote, "Let’s think about some of the implications: first, an utterly obvious question is whether molnupiravir and Paxlovid can be combined into a cocktail regimen, as we have seen for other viral diseases like HIV and Hepatitis C. Those are by far the most successful small-molecule antiviral treatments ever discovered, and there seems to be no reason why this situation wouldn’t be similar."

I don't have as much information as I would like, but it sounds as if the main protease is related to papain, and the targeted cysteine may be the nucleophile in the catalytic cycle. The warhead is the nitrile group. See for example, this paper.
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Old 9th November 2021, 11:30 AM   #289
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Originally Posted by Chris_Halkides View Post
In his discussion of the fluvoxamine trial, Derek Lowe concluded, "It's been said before, but it needs to be said several more times: the clinical response to the pandemic, taken has a whole, has not been good, and we're going to have to take steps not to repeat these mistakes if (or when) another such infectious agent appears. That's another topic entirely, but going into what I refer to as Headless Poultry Mode shouldn't be an option. This trial and the ones listed above have been the real beacons in this area, but the US has not exactly been performing up to where it should in this area."
I think the pandemic has highlighted a weakness in the US health care system in that (with the exception of the VA) it is hard to get commercially driven entities to co-operate in running proper clinical trials of drugs. The UK had a practical multicentre multidrug trial set up within days*. With the NHS committing to support the research essentially all patients admitted were offered the opportunity to recruit into clinical trials. Disproportionately to the population the UK has generated important trial data. Given the patient population size the US could have accelerated evidence based therapies instead far too many patients just seem to have been offered everything including the kitchen sink with minimal effort to collect usable data. Canada has more of a national health service and so has also been able to utilise this for good quality research. Large European nations have been surprisingly poor at producing high quality research on drugs for covid. For all the criticisms it has had at least the WHO produced the Solidarity trial.

https://www.who.int/emergencies/dise...-19-treatments

https://www.recoverytrial.net/

One thing the NIH / CDC / federal government could do is establish a system for rapid multicentre drug trials in the event of another pandemic.

*https://www.gov.uk/government/news/w...-across-the-uk
Quote:
Almost 1,000 patients from 132 different hospitals have been already recruited in just 15 days and thousands more are expected to join the Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial in the coming weeks, making it the largest randomised controlled trial of potential COVID-19 treatments in the world.
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Old 9th November 2021, 11:33 AM   #290
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Not a new variant but explaining how delta is so infectious

https://www.science.org/content/arti...et_cid=3986069

Quote:
That discovery, published today in Science, is “a big deal,” says Michael Summers, a structural biologist at the University of Maryland, Baltimore County—not just because it helps explain Delta’s ravages. The new system, developed by Nobel Prize winner Jennifer Doudna of the University of California (UC), Berkeley, and her colleagues, is a powerful tool for understanding current SARS-CoV-2 variants and exploring how future variants might affect the pandemic, he says. “The system she has developed allows you to look at any mutation and its influence on key parts of viral replication. … That can now be studied in a much easier way by a lot more scientists.”
This sounds as though it could be a very useful tool for other diseases as well
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Old 9th November 2021, 12:14 PM   #291
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Pfizer's "remarkable accomplishment"

(From the previous link to In the Pipeline) Derek Lowe wrote, "Step back for a moment and consider that this is really as fast as you could possibly expect a new, targeted small-molecule drug to ever be developed. Pfizer has a history in the antiviral protease world, so they had the expertise (and the screening collection!) to get a strong start. But here we are, less than two years after the emergence of this pathogen, with a bespoke drug against it. That's the speed record, and I think that it will be very, very hard to break - and I hope that we never have to try! It's a remarkable accomplishment."

I would only add that the fact that this is a reversible, covalent inhibitor should increase acceptance of this mode of inhibition. Covalent inhibitors used to be shunned, but there has been a renewed interest over the last dozen years or so; although they have been around for some time, reversible covalent inhibitors are just now hitting their stride as drug candidates.
EDT
Some believe that reversible covalent inhibitors will have fewer off-target effects than irreversible covalent inhibitors.
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Old 10th November 2021, 03:46 AM   #292
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I hate to keep bringing up YouTuber John Campbell, but his recent video comparing Ivermectin to the new Pfizer drug (Paxlovid) is a full-on Ivermectin Truther rant.

I watched it from beginning to end just to be sure. I don't want to criticize something without actually seeing it all. But you can also glean the gist of it from the comments under the video.

He ignores the fact that, unlike Paxlovid, there is no high quality clinical trial that shows Ivermectin to be effective either as a treatment or a prophylaxis for Covid-19. The same clinical study that found fluvoxamine to be effective, also tested Ivermectin, but did not find any positive signal, and thus that arm of the study was discontinued. Instead he focuses on the fact that it is a protease inhibitor, like Paxlovid, and some papers that seem to deal with in vitro and in silico studies. It seems almost risibly amateurish at moments, where he all but admits that he's no expert in the things he's telling his audience.

I mean, I do wish he was actually right. I wish there was a cheap drug that was already widely available and off-patent that could treat Covid-19. But unfortunately there's just not good evidence for it.

I wish someone with actual expertise would debunk this.
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Old 10th November 2021, 05:01 AM   #293
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binding affinity to the protease

To do a full analysis of the Campbell video, one would need to read the papers. I got about halfway through the video, and one thing that jumped out at me was that one of the papers was using ivermectin at 50 µM in concentration. It gave substantial but not complete inhibition. That does not strike me as being anywhere near strong enough affinity. Another thing: docking is a useful, in silico tool, but it is no substitute for measuring the affinity properly. Given that ivermectin and remdesivir bind to different enzymes altogether, I don't see the point of comparing their docking affinities.
EDT
I got all the way through. One problem is that he is taking docking studies, which are done in silico, way too seriously. I am not an expert in docking, however. It is odd that he did not know what nsp14 was.
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Old 10th November 2021, 06:16 AM   #294
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Originally Posted by Puppycow View Post
I hate to keep bringing up YouTuber John Campbell, but his recent video comparing Ivermectin to the new Pfizer drug (Paxlovid) is a full-on Ivermectin Truther rant.

I watched it from beginning to end just to be sure. I don't want to criticize something without actually seeing it all. But you can also glean the gist of it from the comments under the video.

He ignores the fact that, unlike Paxlovid, there is no high quality clinical trial that shows Ivermectin to be effective either as a treatment or a prophylaxis for Covid-19. The same clinical study that found fluvoxamine to be effective, also tested Ivermectin, but did not find any positive signal, and thus that arm of the study was discontinued. Instead he focuses on the fact that it is a protease inhibitor, like Paxlovid, and some papers that seem to deal with in vitro and in silico studies. It seems almost risibly amateurish at moments, where he all but admits that he's no expert in the things he's telling his audience.

I mean, I do wish he was actually right. I wish there was a cheap drug that was already widely available and off-patent that could treat Covid-19. But unfortunately there's just not good evidence for it.

I wish someone with actual expertise would debunk this.
Yeah, I have filed him away as a crank.
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Old 10th November 2021, 06:51 AM   #295
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Originally Posted by Chris_Halkides View Post
To do a full analysis of the Campbell video, one would need to read the papers.
Indeed. There's links to all of them in the video description. At least he's usually pretty good in that respect. So here's my attempt to review each of his cited papers:

OK, the first link is to the Pfizer press release about their new drug. No evidence for Ivermectin there.

The second link:
Identification of SARS-CoV-2 3CL Protease Inhibitors by a Quantitative High-Throughput Screening

I can't even find the word Ivermectin appearing anywhere in this paper.
Quote:
We performed a quantitative high-throughput screening (qHTS) of 10 755 compounds consisting of approved and investigational drugs, and bioactive compounds using a SARS-CoV-2 3CLpro assay. Twenty-three small molecule inhibitors of SARS-CoV-2 3CLpro have been identified with IC50s ranging from 0.26 to 28.85 μM. Walrycin B (IC50 = 0.26 μM), hydroxocobalamin (IC50 = 3.29 μM), suramin sodium (IC50 = 6.5 μM), Z-DEVD-FMK (IC50 = 6.81 μM), LLL-12 (IC50 = 9.84 μM), and Z-FA-FMK (IC50 = 11.39 μM) are the most potent 3CLpro inhibitors. The activity of the anti-SARS-CoV-2 viral infection was confirmed in 7 of 23 compounds using a SARS-CoV-2 cytopathic effect assay. The results demonstrated a set of SARS-CoV-2 3CLpro inhibitors that may have potential for further clinical evaluation as part of drug combination therapies to treating COVID-19 patients and as starting points for chemistry optimization for new drug development.
Was Ivermectin among the 10,755 compounds they screened? It does not appear to be among those which they call the "most potent". Nor does that word appear anywhere in the paper as far as I can tell.
BTW, those compounds were:
Quote:
A primary screen of 10 755 compounds in the libraries containing approved drugs, investigational drug candidates, and bioactive compounds yielded 161 hits in which the hit rate was 1.5% (Figure S1).

The next link, now we finally get a paper about Ivermectin:
Microscopic interactions between ivermectin and key human and viral proteins involved in SARS-CoV-2 infection

But it's all about a computer simulation. It's way too technical for me to understand, but I was able to discern that it is about a computer model of how these molecules would interact.

Next link:
Identification of 3-chymotrypsin like protease (3CLPro) inhibitors as potential anti-SARS-CoV-2 agents

Seems like promising early-stage research, involving in vitro testing as well as computer simulations. It's very technical, but it doesn't involve any actual clinical trial of ivermectin in patients.
Quote:
in this study, we have reported that ivermectin inhibits the enzymatic activity of SARS-CoV-2 3CLpro and thus may potentially inhibit the replication of RNA viruses including SARS-CoV-2. These studies suggest that ivermectin could be a potential drug candidate to inhibit the SARS-CoV-2 replication and the proposed anti-viral mechanism of ivermectin presented in Fig. 8 and in vivo efficacy of ivermectin towards COVID-19 is currently been evaluated in clinical trials
So the paper is far from claiming that ivermectin would actually be a clinically effective therapeutic.

Next link:
Ilimaquinone (marine sponge metabolite) as a novel inhibitor of SARS-CoV-2 key target proteins in comparison with suggested COVID-19 drugs: designing, docking and molecular dynamics simulation study
Quote:
In the present study, the inhibitory prospects of ilimaquinone (marine sponge metabolite) were assessed in comparison with hydroxychloroquine, azithromycin, favipiravir, ivermectin and remdesivir at the active binding pockets of nine different vital SARS-CoV-2 target proteins (spike receptor binding domain, RNA-dependent RNA polymerase, Nsp10, Nsp13, Nsp14, Nsp15, Nsp16, main protease, and papain-like-protease), employing an in silico molecular interaction based approach. In addition, molecular dynamics (MD) simulations of the SARS-CoV-2 papain-like protease (PLpro)–ilimaquinone complex were also carried out to calculate various structural parameters including root mean square fluctuation (RMSF), root mean square deviation (RMSD), radius of gyration (Rg) and hydrogen bond interactions.
So another paper using computer-based modeling. Campbell keys in on this quote:
Quote:
From the docking analysis, ivermectin showed the highest docking score with an average energy of −8.5 kcal mol−1 among all the compounds. Remdesivir showed the lowest binding energy and highest docking score of −9.9 kcal mol−1
He admits he doesn't really understand this, but thinks this means ivermectin is better than Remdesivir.

I have absolutely no idea, and I doubt that most of his audience does either.

The next link is only available to users in the United Kingdom, so I'll skip it. (that's not the link, it's the URL I got redirected to)

Next link:
Exploring the binding efficacy of ivermectin against the key proteins of SARS-CoV-2 pathogenesis: an in silico approach

More computer modeling.

The next link is the Pfizer press release again.

And finally:
Molecular Docking Reveals Ivermectin and Remdesivir as Potential Repurposed Drugs Against SARS-CoV-2
Quote:
Molecular docking of these drugs with different SARS-CoV-2 target proteins, including spike and membrane proteins, RdRp, nucleoproteins, viral proteases, and nsp14, was performed. Moreover, the binding affinities of the human ACE-2 receptor and TMPRSS2 to the different drugs were evaluated. Molecular dynamics simulation and MM-PBSA calculation were also conducted. Ivermectin and remdesivir were found to be the most promising drugs. Our results suggest that both these drugs utilize different mechanisms at the entry and post-entry stages and could be considered potential inhibitors of SARS-CoV-2 replication.
Right. So that's all of the links that I could access.

No clinical trials, just early-stage drug discovery research.


Quote:
I got about halfway through the video, and one thing that jumped out at me was that one of the papers was using ivermectin at 50 µM in concentration. It gave substantial but not complete inhibition. That does not strike me as being anywhere near good enough affinity. Another thing: docking is a useful, in silico tool, but it is no substitute for measuring the affinity properly. Given that ivermectin and remdesivir bind to different enzymes altogether, I don't see the point of comparing their docking affinities.
EDT
I got all the way through. One problem is that he is taking docking studies, which are done in silico, way too seriously. I am not an expert in docking, however.
I come to the same conclusions, but I too am not an expert. No clinical trials, mostly computer-based modeling and hypothesizing.

But the way he packages this stuff, it's as if it proves that Ivermectin is just as effective as Paxlovid, but none of this shows anything like that. Actually clinical studies are needed to prove that, and the ones that have been done (the ones not fraudulent anyway) did not find a similar therapeutic effect.
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Old 10th November 2021, 08:53 AM   #296
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more negative values and binding strength

There is another problem with his analysis. I assume that the reaction in question is

L + R ---> L•R

where L is the ligand (the inhibitor), and R is the receptor in the broad sense of the term (which could be one of the proteases). The complex between the inhibitor and the protease is L•R. If my assumption is correct, the value of -9.9 (which is for remdesivir binding to PLPro, as shown in Table 2 of this link, the paper on Ilimaquinone) is actually the strongest binding.
EDT
The authors wrote, "Remdesivir showed the lowest binding energy and highest docking score of −9.9 kcal mol−1 which was followed by ilimaquinone having the second highest binding energy of −8.1 kcal mol−1." I infer that they authors use of the word "lowest" means "most negative." This might confuse the unwary; Dr. Campbell says that remdesivir doesn't work very well in this analysis (starting near the 14;20 time in the video). I would also point out that remdesivir is not thought to be a protease inhibitor; it is believed to work by interfering with the replication of RNA.
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Old 10th November 2021, 09:01 AM   #297
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Which protease?

There may be another problem, but it would take time to tease it out. There are at least two proteases in the viral genome. Both contain a cysteine residue, and I not sure that people are using the same terminology when discussing them, which is what is taking up my time to figure out. If we compare inhibitors of protease A and rank them on the basis of calculated or (preferably) measured affinity, that is fine. If we start comparing an inhibitor of protease A to an inhibitor of protease B, things get more complex. For example, I am very doubtful that one should compare docking energies between two compounds binding to two different receptors.
EDT
Based partially on this link, my preliminary assessment is that the main protease is the one that is described as chymotrypsin-like. It is also the target of the new Pfizer drug. Therefore, it is OK for Dr. Campbell to focus on it, although the other protease might also be a worthwhile target.
EDT2
I remember taking a shallow dive into the following question a few months ago: Does the size of the molecule introduce a bias in the calculated affinity in a docking experiment? I found some references which suggested that the answer was yes, but that there were ways to compensate for this bias. Given that the sizes of ivermectin, remdesivir, etc. are different, ideally one should factor this into a comparison.
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Old 10th November 2021, 11:29 AM   #298
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Originally Posted by Dr.Sid View Post
I'm just using current data from here https://www.covdata.cz/cesko.php infections 65+, which have 80% vaccination rate. So I just take number of vaccinated infections, divide by 4 to correct for 4:1 vaccination ratio in population, and then divide by number by non vaccinated infections. For recent days it's about 60%, to weeks back it was closer to 50%. It would be better to do it with exact age group size and counts of vaccinated and non-vaccinated, but for rough estimate this should be enough.

Israel showed between 60-70% when the last wave started, but it went up
rapidly with introduction of 3rd dose. When the wave peaked, it was above 80%. I used same method, data from here: https://datadashboard.health.gov.il/...edium=referral
Unfortunately I can't control the page well enough to get to historical data, as it is in Hebrew and google fails to translate it. Maybe you will have less problems.
I found some datasets from Israel.
https://data.gov.il/dataset/covid-19

May be they are the ones you were looking for.

As for rest: I'd say ~60% protection against infection by delta using vaccine against original strain is pretty good, considering that original criterium for vaccine was 50% protection against hospitalization.

Looking at my corner of Republic (Královehradecký kraj), we're doing pretty good... (But then, we were ran over by Covid in winter)

But I do see where are you coming from.

Originally Posted by marting View Post
Here's recent study in Nature (Nov. 2) That shows Ve against infection around 50%

https://www.nature.com/articles/s41591-021-01583-4

BNT162b2 effectiveness against any, symptomatic or asymptomatic, Delta infection was 45.3% (95% CI, 22.0–61.6%) ≥14 d after the first vaccine dose, but only 51.9% (95% CI, 47.0–56.4%) ≥14 d after the second dose, with 50% of fully vaccinated individuals receiving their second dose before 11 May 2021.

Lancet Preprint. Consistent with the Nature piece above.
Effectiveness of Covid-19 Vaccination Against Risk of Symptomatic Infection, Hospitalization, and Death Up to 9 Months: A Swedish Total-Population Cohort Study
https://papers.ssrn.com/sol3/papers....act_id=3949410

Findings: Vaccine effectiveness of BNT162b2 against infection waned progressively from 92% (95% CI, 92-93, P<0·001) at day 15-30 to 47% (95% CI, 39-55, P<0·001) at day 121-180, and from day 211 and onwards no effectiveness could be detected (23%; 95% CI, -2-41, P=0·07).
Hm, I would ignore that last part about no protection. P-value is high. (Null hypothesis cannot be dismissed)

But then there is this French study:
https://www.epi-phare.fr/app/uploads...s_50_74ans.pdf

Although it seems they were more interested in hospitalizations.

From brief search there don't seem top be any other studies of similar nature. (And I can't use more time into this)
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Old 10th November 2021, 12:34 PM   #299
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Originally Posted by The Atheist View Post
I see Denmark has re-categorised Covid and reintroduced some measures after a surge has become apparent.


Yes, but still not enough measures, in my opinion. The vaccination pass will be reintroduced from this Friday - mainly as a way to make life more difficult for the unvaccinated, I think. It already seems to be working. They should reintroduce face masks, but I guess the elections for city councils next Tuesday have put a damper on the politicians' willingness to advocate for more restrictions for the time being.

The number of infections is still rising: 3,017 today (pop. 5.8 million).
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Old 10th November 2021, 01:14 PM   #300
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Originally Posted by Klimax View Post
Quote:
Findings: Vaccine effectiveness of BNT162b2 against infection waned progressively from 92% (95% CI, 92-93, P<0·001) at day 15-30 to 47% (95% CI, 39-55, P<0·001) at day 121-180, and from day 211 and onwards no effectiveness could be detected (23%; 95% CI, -2-41, P=0·07).
Hm, I would ignore that last part about no protection. P-value is high. (Null hypothesis cannot be dismissed)
It's really standard stat. speak when p > .05. The last part does indicate waning after 211 days with a point Ve of 23% but a large CI. For that matter, detecting no protection is never possible. At best one can determine that a benefit or harm is statistically likely. Actually determining no effect can't be done. So what the paper is saying is that the p value is to high to exclude no efficacy in the 95% sense. But it does show some efficacly is likely but with a broad range.

Also, these studies are observational with all the associated confounding issues. Are vaccinated people more likely to get tested because they are more health aware or are they less likely because they ascribe any symptoms to something other than Covid-19 since they are vaccinated? That's a big potential confounder.
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Old 10th November 2021, 04:58 PM   #301
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Interesting but long paper exploring cross reactivity of other infectious agents including seasonal coronaviruses on increasing immunity among health care workers.

Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV-2
https://www.nature.com/articles/s415..._reference.pdf

I wonder if any studies have been done among other groups such as teachers that are exposed frequently? Might be interesting to see if Covid-19 incidence impacts different professions more than others.
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Old 10th November 2021, 07:31 PM   #302
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Originally Posted by Chris_Halkides View Post
There is another problem with his analysis. I assume that the reaction in question is

L + R ---> L•R

where L is the ligand (the inhibitor), and R is the receptor in the broad sense of the term (which could be one of the proteases). The complex between the inhibitor and the protease is L•R. If my assumption is correct, the value of -9.9 (which is for remdesivir binding to PLPro, as shown in Table 2 of this link, the paper on Ilimaquinone) is actually the strongest binding.
EDT
The authors wrote, "Remdesivir showed the lowest binding energy and highest docking score of −9.9 kcal mol−1 which was followed by ilimaquinone having the second highest binding energy of −8.1 kcal mol−1." I infer that they authors use of the word "lowest" means "most negative." This might confuse the unwary; Dr. Campbell says that remdesivir doesn't work very well in this analysis (starting near the 14;20 time in the video). I would also point out that remdesivir is not thought to be a protease inhibitor; it is believed to work by interfering with the replication of RNA.
Yeah, I did have the impression that he might be completely misunderstanding the significance of that quote he pulled.

Is lowest binding energy good or bad? It also had the "highest docking score". And from the paper it looked like they were talking different docking sites.
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Old 10th November 2021, 07:52 PM   #303
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Originally Posted by dann View Post
Yes, but still not enough measures, in my opinion...

The number of infections is still rising: 3,017 today (pop. 5.8 million).
That's quite a lot.

People are in mild panic here because we're having 150 a day, but we're still in major lockdown - 12 weeks of it so far.

Schools go back next week, so we'll look more like you shortly, I'd say.

How are the hospital numbers? I see deaths haven't gone above an average of 3, but it's early days.

Originally Posted by marting View Post
Interesting but long paper exploring cross reactivity of other infectious agents including seasonal coronaviruses on increasing immunity among health care workers.
I was reading that this morning, and all it did for me is emphasise yet again the crap statistical analysis going on. The idea was raised 18 months ago and it's only now we see some results, not that they're very helpful, because we don't know what infection caused the T-cell response.

Originally Posted by Puppycow View Post
It also had the "highest docking score".
Rule 34 says they need a new name for it.
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Old 10th November 2021, 08:06 PM   #304
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Originally Posted by angrysoba View Post
Yeah, I have filed him away as a crank.
You are wrong to do so. He may have fallen a bit for the Ivermectin hype, but is still, as are we all, waiting for the clinical trial data that will come from the UK study, and has made it clear that evidence trumps all.

He has gleefully reported the results of the new Pfizer therapeutic and hopes as we all do that it will be a game changer.

From the beginning of the pandemic, he has been providing clear, informative science based reporting of the vaccines and health recommendations.

He was pushing for the universal use of masks long before anyone else was, and is as pro-vaccine as it is possible to be.

Each to your own of course, but he is by no means a crank.
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Old 10th November 2021, 08:18 PM   #305
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Binding energy

Originally Posted by Puppycow View Post
Yeah, I did have the impression that he might be completely misunderstanding the significance of that quote he pulled.

Is lowest binding energy good or bad? It also had the "highest docking score". And from the paper it looked like they were talking different docking sites.
Now that you mention it, the -9.9 value is for remdesivir binding to the papain-like protease, which is the other protease. My interpretation is that the tabulated values are the standard Gibbs' free energies of binding, where (delta)G°' = (-1)RTln(Keq). The equilibrium constant Keq is the association constant for the formation of the complex. The more negative the value, the larger the value of the equilibrium constant and the stronger the binding is. Elsewhere in the paper they mention predicted binding energy.

I would say that my reservations about the video revolve around misinterpretations such as these. What you highlighted earlier is more fundamental: this study (and presumably the others--which I have not looked at as closely yet) are in the discovery stage.
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Old 10th November 2021, 11:53 PM   #306
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Originally Posted by The Atheist View Post
That's quite a lot.

People are in mild panic here because we're having 150 a day, but we're still in major lockdown - 12 weeks of it so far.

Schools go back next week, so we'll look more like you shortly, I'd say.

How are the hospital numbers? I see deaths haven't gone above an average of 3, but it's early days.

Hospitalization (and ICU!) numbers are rising. So is the death toll, but more slowly - maybe because 0-9 and 10-19 are the two age groups with the highest rates of infection.
Schools shouldn't have been open until all children were vaccinated. And students should have have been wearing face masks. It is as if European countries consider children to be invulnerable and as if there is no such thing as long covid.
That is one of the things I admire about Cuba. They didn't open schools until children had had three jabs and they're still masking up.
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Old 11th November 2021, 01:43 AM   #307
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Originally Posted by dann View Post
Schools shouldn't have been open until all children were vaccinated.
That's the exact trap we're walking into next week, with all schools back from Wednesday, and virtually no kids under 12 have been vaccinated yet.

I agree with the policy, but it's going to cause a surge here, I'm sure, although the hot summer might help.
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Old 11th November 2021, 02:43 AM   #308
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Originally Posted by The Atheist View Post
That's the exact trap we're walking into next week, with all schools back from Wednesday, and virtually no kids under 12 have been vaccinated yet.

I agree with the policy, but it's going to cause a surge here, I'm sure, although the hot summer might help.
Didn't help in Israel this summer.
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Old 11th November 2021, 09:05 AM   #309
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The official daily figures in the UK have stopped going down, and may be going up again. On the other hand, the ZOE Covid symptom figures are still going down.
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Old 11th November 2021, 09:26 AM   #310
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Dr. Campbell

Originally Posted by GraculusTheGreenBird View Post
Each to your own of course, but he is by no means a crank.
You raise a fair point. I give Dr. Campbell credit for reading the primary literature. I would say that he does not have the right kind experience to perform a critical evaluation of the papers he discusses. I also think that he is engaging in a little bit of motivated reasoning concerning ivermectin. All of the compounds bind to all of the targets in Table 2 of the paper that we have been discussing, which is in silico docking. IMO this suggests that one should take these numbers with a grain of salt.

My own work has made me familiar with docking studies, but I am hesitant to offer strong opinions about the work described in these papers (my previous comments bear this out). It would be different if I performed my own docking docking studies on a weekly basis.
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Old 11th November 2021, 11:36 AM   #311
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Originally Posted by Dr.Sid View Post
Didn't help in Israel this summer.
No, but it seems to be in Aussie.

A huge part of the problem is the vaccine decline in efficacy. The key is to get people vaccinated as fast as possible, then open up while protection is at the highest point.

NZ's strategy of a long, slow, rollout is going to bite us right in the arse, with all vulnerable people having been vaccinated well over 6 months ago. We are starting booster shots, however, so as long as do that fast enough we might be able to keep a cap on it.

Originally Posted by zooterkin View Post
The official daily figures in the UK have stopped going down, and may be going up again. On the other hand, the ZOE Covid symptom figures are still going down.
At least deaths appear to be tapering off, and there can't be many people left to infect, so you might be ok and the past couple of days just a blip.
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Old 11th November 2021, 12:48 PM   #312
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Originally Posted by The Atheist View Post
No, but it seems to be in Aussie.

A huge part of the problem is the vaccine decline in efficacy. The key is to get people vaccinated as fast as possible, then open up while protection is at the highest point.

NZ's strategy of a long, slow, rollout is going to bite us right in the arse, with all vulnerable people having been vaccinated well over 6 months ago. We are starting booster shots, however, so as long as do that fast enough we might be able to keep a cap on it.



At least deaths appear to be tapering off, and there can't be many people left to infect, so you might be ok and the past couple of days just a blip.
Phase plot of rolling 7-day hospitalisations vs cases since September 2020, and same data against time




To me it looks like it's been bumping around a similar level of infections and hospital admissions since July.
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Old 11th November 2021, 03:25 PM   #313
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lead compounds

The authors of the paper "Identification of 3-chymotrypsin like protease (3CLPro) inhibitors as potential anti-SARS-CoV-2 agents" stated, "The calculated IC50 values for ivermectin, tipranavir, boceprevir, micafungin, paritaprevir, and ombitasvir were found to be 21.5, 27.7, 31.4, 47.6, 73.4, and 75.5 µM, respectively (Table 2). Taken together, these studies suggest that the molecules listed above exhibited inhibitory activity against 3CLpro enzyme of SARS-CoV-2."

IC50 values can be converted into dissociation constants if one knows the type of inhibition, competitive, uncompetitive, or noncompetitive. A dissociation constant is simply the inverse of an association constant. But for argument's sake, let us assume that the dissociation constant for ivermectin is 10 µM (10 micro molar) and that all the compounds bind in a reversible manner. That sounds like what I would expect of a hit or a lead compound, not a compound that is actually a drug. "Whatever the screening paradigm, the output of the hit discovery phase of a lead identification programme is a so-called ‘hit’ molecule, typically with a potency of 100 nM–5 µM at the drug target. A chemistry programme is initiated to improve the potency of this molecule." link
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Old 13th November 2021, 03:40 AM   #314
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Originally Posted by marting View Post
Interesting but long paper exploring cross reactivity of other infectious agents including seasonal coronaviruses on increasing immunity among health care workers.

Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV-2
https://www.nature.com/articles/s415..._reference.pdf

I wonder if any studies have been done among other groups such as teachers that are exposed frequently? Might be interesting to see if Covid-19 incidence impacts different professions more than others.
Probably those with greatest occupational exposure will be teachers / child care workers. Occupational mortality for teachers despite high risk of infection was not above average as compared with care workers dealing with the elderly, who had high risk of infection, but not necessarily a high risk of prior infection by other coronaviruses.

https://www.ons.gov.uk/peoplepopulat...28december2020

There was some work suggesting that the less severe impact in places like Korea, Taiwan was not simply because of greater mask wearing or better public health response but because a significant proportion of the community had been exposed to a related coronavirus and had some cross reactive immunity.

It is likely that any pre-existing immunity from other coronavirus infections will be predominantly T-cell mediated against epitopes other than the spike protein. So immunity will not stop infection but will modify post infection disease (not necessarily in a good way e.g. Dengue).

https://www.nature.com/articles/s41577-020-00460-4
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Old 13th November 2021, 07:33 AM   #315
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Originally Posted by angrysoba View Post
Yeah, I have filed him away as a crank.
I unsubscribed from his channel after that video, but the YouTube algorithm keeps recommending his videos to me. Apparently his latest one is a diatribe because he got fact-checked by Facebook.
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Old 13th November 2021, 09:43 AM   #316
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UK official figures have been up week-on-week for the last three days, which I'm pretty sure indicates a real increase. I would guess the previous dip was largely due to the schools being on half-term, and they've been back two weeks now.~

The ZOE Covid numbers are still dropping, though, but that may be, as always, a reflection of their data set which I suspect doesn't have a lot of school-age children.
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Old 13th November 2021, 10:39 AM   #317
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Pfizer's new protease inhibitor

A crystal structure of PF-07321332 in complex with the main protease is available. The resolution is 1.6 angstroms.
EDT
The detailed mechanism of action is that a covalent bond is formed between a cysteine residue of the enzyme and the inhibitor. Not all protease inhibitors work in the same way. A nitrile group on the inhibitor forms a reversible covalent bond with the enzyme.
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Old 13th November 2021, 11:31 AM   #318
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some thoughts on Dr. Campbell's video

Originally Posted by Puppycow View Post
I unsubscribed from his channel after that video, but the YouTube algorithm keeps recommending his videos to me. Apparently his latest one is a diatribe because he got fact-checked by Facebook.
I could not make it all the way through this video, but I did skip around a bit. Two compounds that are protease inhibitors may differ in their details. There are reversible, reversible covalent, and irreversible (typically covalent) protease inhibitors. That may be something of a quibble, but there is also the question of differing affinities. In addition even high affinity is no guarantee that an inhibitor will be a successful drug.

Regarding how we know that a compound binds to a particular enzyme in vitro, there are computational methods (including docking), determination of the structure (usually by X-ray crystallography), and kinetic methods that examine the rate at which the enzyme converts its substrate into products.
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Old 13th November 2021, 01:46 PM   #319
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CDC: This is embarrassing!

One thing about the fringe, is they tend to be more alert to things that make no sense. @Covid19Crusher posted a screenshot of the latest Covid-19 Disease Burden which contained an obvious impossibility. Specifically that, for Covid-19, the total number of estimated infections was lower than the total number of estimated symptomatic cases for ages 0-17.

Here's a link: https://www.cdc.gov/coronavirus/2019...es/burden.html

Infections per 100,000 for 0-17 y/o: 29885
Symptomatics per 100,000 for 0-17 y/o: 30253

I figured the CDC would correct an obvious typo or error in a few days. I was wrong. So I took a closer look and in a few minutes noticed multiple discrepancies which indicate no one bothered to even review the document for sanity before posting it.

The not so bad:
In Table 1 they list numbers of people in each of the age groups together with all ages. The age groups don't add up to the all ages group. But at least they are close. Since these are estimates, perhaps they included estimates of a small group with unknown ages. Problem is some of the columns would require a negative number of unknown ages. But I give them a pass on this. Their models for each age group could be different for their models for all ages and produce small differences so they don't add up.

The truly egregious:
In Table 2 listing a higher rate for infections v. symptomatics, which @Covid19Crusher caught ranks right up their with splendidly wrong. But was it a typo or did they copy the wrong entry? Hard to tell. Here's another glaring error from Table 1's entry of the 0-17 y/o:

Point Number: 25,844,005
Conf. Interval: 18,861,476 – 25,408,407

Wow! The Point number (central estimate) is above the upper limit on the CI. Must be some sort of new math. Grr.

So egregiously wrong data in both Table 1 and Table 2. And it's something that should have been noticed by anyone reviewing it. Thanks a lot for feeding the deniers claiming the CDC's data can't be trusted. Grrrr.
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Old 13th November 2021, 03:10 PM   #320
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Originally Posted by Planigale View Post
Probably those with greatest occupational exposure will be teachers / child care workers. Occupational mortality for teachers despite high risk of infection was not above average as compared with care workers dealing with the elderly, who had high risk of infection, but not necessarily a high risk of prior infection by other coronaviruses.
That's very much in line with what was being said almost 18 months ago.

My mind boggles that we don't know for sure what it is.

Originally Posted by zooterkin View Post
UK official figures have been up week-on-week for the last three days, which I'm pretty sure indicates a real increase. I would guess the previous dip was largely due to the schools being on half-term, and they've been back two weeks now.~

The ZOE Covid numbers are still dropping, though, but that may be, as always, a reflection of their data set which I suspect doesn't have a lot of school-age children.
Sounds right. And the good news is, if infections are mainly kids, your hospital and death rates should fall down a cliff.

Let's hope.

Originally Posted by marting View Post
So egregiously wrong data in both Table 1 and Table 2. And it's something that should have been noticed by anyone reviewing it. Thanks a lot for feeding the deniers claiming the CDC's data can't be trusted. Grrrr.
Jesus mate, if you're spotting these errors that easily, they should be being stopped long before publication. Have you contacted them?

Always the damned numbers.
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