SARS-CoV-2; CoVID-19; Coronavirus; Updates and Information

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(1) by late March, 1k+ patients received compassionate use of remdesivir. However, clinical report was very limited. It is understandable that front line doctors are very busy and it takes time to analyze data.
https://www.gilead.com/stories/articles/an-open-letter-from-our-chairman-and-ceo
March 28, 2020



(2) a report of compassionate use of remdesivir was published on NEJM. Good news: Lower mortality on ventilated patients compared to standard of care? Bad news: adverse events quite common
Compassionate Use of Remdesivir for Patients with Severe Covid-19
https://www.nejm.org/doi/full/10.1056/NEJMoa2007016


36 of 53 patients (68%) showed clinical improvement. A total of 25 patients (47%) were discharged, and 7 patients (13%) died; Mortality was 18% (6 of 34) among patients receiving invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation.


A total of 32 patients (60%) reported adverse events during follow-up. The most common adverse events were increased hepatic enzymes, diarrhea, rash, renal impairment, and hypotension. A total of 12 patients (23%) had serious adverse events. The most common serious adverse events — multiple-organ-dysfunction syndrome, septic shock, acute kidney injury, and hypotension. Four patients (8%) discontinued remdesivir treatment prematurely.


(3) in early April, Gilead had supply of 140k treatment courses to distribute. TBH, it doesn't seem that it is widely used on severe patients in US if it is the game-changer. Maybe many doctors don't have access to it or are reluctant to use it without further data.
https://www.gilead.com/stories/articles/an-update-on-covid-19-from-our-chairman-and-ceo
April 04, 2020


(4) by late Apr, we can expect Gilead's severe patient trial result (open-label, over SOC, 400+ patients) and China's severe patient trial result (double-blinded, over placebo, 200+ patients)

https://www.gilead.com/stories/articles/an-open-letter-from-our-chairman-and-ceo-april-10
April 10, 2020
A summary of remdesivir trials with upcoming data readouts can be found
https://www.gilead.com/stories/-/media/gilead-blog/files/clinical-trials-infographic.pdf
 
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https://www.sciencemag.org/news/202...ace-ferocious-rampage-through-body-brain-toes

The best article I’ve read so far about how coronavirus would kill. It’s definitely worthy of a few minutes of your time. One of the more baffling symptoms is the loss of taste and smell. Scientists are at a total loss as to explain how the virus would invade olfactory bulb and other neural regions.

Thats is not the part that baffles me. The virus doesnt need to go to the olfactory bulb (in brain) to suppress olfaction. The peripheral sensory elements of olfactory receptor neurons are found in specialized folds of upper respiratory epithelium called turbinates (in your nose). The cells have little tufts of cilia that bind odorant molecules in inspired air. They are right next to mucus-secreting goblet cells that have a supportive role, and it is likely that some of them have ACE-2. SARS-CoV-2 could cause loss of those cells. Fortunately those cells regenerate in about 28 days and can rewire up to the brain (which is itself an interesting mystery in neuriscience).

What is surprising to me is the big effect to prevent O2 transfer to blood even when air is moving in and out of lungs pretty well. That seems different from SARS and influenza. The thrombosis is clearly a big issue not seen previously.

The confusion etc. could be partly from electrolyte and acid base disturbance which can also drive arrythmias. But there may be more going on.

It is a good article.
 
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(1) by late March, 1k+ patients received compassionate use of remdesivir. However, clinical report was very limited. It is understandable that front line doctors are very busy and it takes time to analyze data.
https://www.gilead.com/stories/articles/an-open-letter-from-our-chairman-and-ceo
March 28, 2020



(2) a report of compassionate use of remdesivir was published on NEJM. Good news: Lower mortality on ventilated patients compared to standard of care? Bad news: adverse events quite common
Compassionate Use of Remdesivir for Patients with Severe Covid-19
https://www.nejm.org/doi/full/10.1056/NEJMoa2007016


36 of 53 patients (68%) showed clinical improvement. A total of 25 patients (47%) were discharged, and 7 patients (13%) died; Mortality was 18% (6 of 34) among patients receiving invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation.


A total of 32 patients (60%) reported adverse events during follow-up. The most common adverse events were increased hepatic enzymes, diarrhea, rash, renal impairment, and hypotension. A total of 12 patients (23%) had serious adverse events. The most common serious adverse events — multiple-organ-dysfunction syndrome, septic shock, acute kidney injury, and hypotension. Four patients (8%) discontinued remdesivir treatment prematurely.


(3) in early April, Gilead had supply of 140k treatment courses to distribute. TBH, it doesn't seem that it is widely used on severe patients in US if it is the game-changer. Maybe many doctors don't have access to it or are reluctant to use it without further data.
https://www.gilead.com/stories/articles/an-update-on-covid-19-from-our-chairman-and-ceo
April 04, 2020


(4) by late Apr, we can expect Gilead's severe patient trial result (open-label, over SOC, 400+ patients) and China's severe patient trial result (double-blinded, over placebo, 200+ patients)

https://www.gilead.com/stories/articles/an-open-letter-from-our-chairman-and-ceo-april-10
April 10, 2020
A summary of remdesivir trials with upcoming data readouts can be found
https://www.gilead.com/stories/-/media/gilead-blog/files/clinical-trials-infographic.pdf

Yes. Some guys I know in Houston are part of one of the remdesivir trials. The info from Univ Chicago was not supposed to be leaked. Maybe somebody was trying to manipulate the Gilead stock price?
 
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There are some studies in vitro suggesting that SARS-CoV-2 can enter cells by direct fusion other than by binding to ACE2 on cell surface. MERS has a similar mechanism. ACE2 is already widely expressed among tissues and that fusion mechanism makes things even worse.
It is still too early but I expect to see some GWAS, RNA-seq studies to show why some people get covid and some not, why some people are asymptomatic. I guess I may also conduct some covid-related studies once my institution reopens :p
 
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I think there are funded studies going on in USA about HCQ. One of them is using as a placebo something that is effective vs virus, so go figure. I wouldn't be surprised if ultimately, the major funded studies favor the more expensive options.

One thing about Corona in USA is that there is mostly no treatment very early on. When a person feels they have corona, it is very difficult to get tested (as if the tests are actually 100% accurate). Often, a person CALLS the doctor, tells doc about symptoms, severity and duration... doc often tells person to self-isolate 14 days and call back.

Now 7-14 days later person is very much along the way of corona infection and at a point where the treatments discussed will be much less effective.

The HCQ and HQC w/Zinc and others are way more effective if performed very early on.

There are reasons why doctors en mass are reluctant to start with those early on.

Yet, treatment early on is more higher percentage than treating later, when one is days away from a respirator. There are more and more doctors with private practices publicly stating this.
 
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One thing, us the increase in Singapore real, or have they just been doing more testing?
Back in March, Singapore tested even more than South Korea, after adjusting for population. 6800 vs 6500 tests/million. Hong Kong was behind in testing initially but quickly ramped up from February, testing ~2100 samples per day in March, comparable to Singapore.

Despite the aggressive tracing, the second wave in Singapore is now dominated by multiple big clusters in dormitories housing foreign workers, which were largely neglected by government policy.

As for Hong Kong, the second wave mostly consists of students studying abroad(US, UK, Germany etc.) and some smartasses who insist on ignoring the travel warnings, only to get stranded, infected and then "ask" the government to bring them back by charter planes.

https://en.wikipedia.org/wiki/COVID-19_testing#Virus_testing_statistics_by_country
Code:
                 Date     Tests      +ve      %     Tests/mln.   +ve/mln.  
 ------------- -------- ---------- -------- ------ ------------ ---------- 
  Hong Kong     14 Apr    131,786    1,012   0.77       17,613        135  
  South Korea   18 Apr    554,834   10,653    1.9       10,730        206  
  Singapore     17 Apr     59,737    5,050    8.5       10,474        885  
  Japan         18 Apr    111,325    9,795    8.8          882         78  
  Tokyo         13 Apr      6,743    2,158   32.0          484        155

https://www.scmp.com/week-asia/expl...-worker-dormitories-become-singapores-biggest
caa1b322-8097-11ea-8736-98edddd9b5ca_972x_190352.jpg
 
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There is a growing body of clinical experience now in the US (but as yet no published studies) especially from New York, suggesting that ventilators are at the least less helpful for this disease than one would expect and may even make things worse unless used at the lowest possible pressures (or even then). This is very surprising. However, Covid-19 is not really producing a classical acute respiratory syndrome like what one sees in influenza or even in SARS previously. Anecdotally, some ICU physicians saying that simply placing a patient on their stomach (proning) can in many cases increase blood oxygenation percentage. This is coming from so many places now that it is almost certainly true.
 
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There is a growing body of clinical experience now in the US (but as yet no published studies) especially from New York, suggesting that ventilators areat the least less helpful for this disease than one would expect and may even make things worse unless used at the lowest possible pressures (or even then). This is very surprising. However, Covid-19 is not really producing a classical acute respiratory syndrome like what one sees in influenza or even in SARS previously. Anecdotally, some ICU physicians saying that simply placing a patient on their stomach (proning) can in many cases increase blood oxygenation percentage. This is coming from so many places now that it is almost certainly true.
Yes, seems like this report from New Orleans backed up what many docs had already been thinking. A major part of the presentation can involve damage to small blood vessels (a thrombotic microangiopathy) rather than or in addition to more typical ARDS pathology. This could account for some of the unusual clinical presentation, including severe hypoxemia with normal compliance, easily recruitable lungs (so CPAP may be more useful than a vent), as well as multisystem organ damage, weird rashes, etc.
 
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As I've said before, I am not personally convinced that Dr. Evil is actually evil and I am even starting to suspect that this is not his real name.

Translating his post into everyday English:

Hypoxemia with normal compliance is a weird combination compared to what one would expect in a life threatening viral respiratory infection. Hypoxemia means low levels of oxygen in blood. Normal compliance means that the smallest airways (called alveoli) have their normal "stretchy" mechanical properties. Those properties depend on secretion of a complex mixture called pulmonary surfactant from a population of cells in the lung that also express the SARS-CoV-2 receptor (ACE-2). In influenza and in the original SARS there is usually a loss of surfactant which makes it hard for people to breathe, and so the ventilator helped. What seems to be happening in Covid-19 is that lots of little blood clots are forming in the pulmonary blood vessels, so that blood is not making it to quite a few of the places in the lungs where it can unload CO2 and pick up O2. However the lung mechanical properties are surprisingly normal. In fact, trying to force air in and out in some of these patients is actually damaging the remaining tiny airways and the delicate capillaries that surround them, leading to fluid leaking out. So there is a growing sense that ventilators are a last resort in these patients.

The clotting issues may be due to the virus infecting cells called megakaryocytes that ultimately give rise to platelets that are needed for clotting, but that has not been proven.

Also, the damage in sickest people is clearly not limited to the lungs, all sorts of other strange things are occurring, as Free Bird noted in the article in Science he linked to up the thread a bit.

And as Rain noted just as bit above, it may be that SARS-CoV-2 has more than one way of getting into cells, at least in some people. The details of what that might be are not known.
 
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There are some studies in vitro suggesting that SARS-CoV-2 can enter cells by direct fusion other than by binding to ACE2 on cell surface. MERS has a similar mechanism. ACE2 is already widely expressed among tissues and that fusion mechanism makes things even worse.
It is still too early but I expect to see some GWAS, RNA-seq studies to show why some people get covid and some not, why some people are asymptomatic. I guess I may also conduct some covid-related studies once my institution reopens :p

Not sure how fusion would work without binding first. Recently scientists have been able to study the structure and conformations of the S protein and its bind to the ACE2 receptor using high resolution Cryo-EM (3.5 angstroms). The S2 subunit, which is responsible for membrane fusion, is not accessible in pre-fusion conformations. The binding of S1 subunit to the receptor triggers a series of interactions including some host proteases acting on a couple of cleavage sites in the S protein. The shedding of S1 induces a dramatic conformational change in S2 from a folded multi helices to an extended one. This enables S2 “stab” host cell in membrane and triggers fusion.
 
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Thats is not the part that baffles me. The virus doesnt need to go to the olfactory bulb (in brain) to suppress olfaction. The peripheral sensory elements of olfactory receptor neurons are found in specialized folds of upper respiratory epithelium called turbinates (in your nose). The cells have little tufts of cilia that bind odorant molecules in inspired air. They are right next to mucus-secreting goblet cells that have a supportive role, and it is likely that some of them have ACE-2. SARS-CoV-2 could cause loss of those cells. Fortunately those cells regenerate in about 28 days and can rewire up to the brain (which is itself an interesting mystery in neuriscience).

What is surprising to me is the big effect to prevent O2 transfer to blood even when air is moving in and out of lungs pretty well. That seems different from SARS and influenza. The thrombosis is clearly a big issue not seen previously.

The confusion etc. could be partly from electrolyte and acid base disturbance which can also drive arrythmias. But there may be more going on.

It is a good article.

Good info. I think what baffles scientists is the total loss of taste including salt, bitter, sweet, and sour. These would activate taste buds in your tongue and signals get to brain directly.
 
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Yes the taste part is more surprising.

But as Rain says, even though we know the virus binds with high affinity to ACE-2 this absolutely does not exclude that it could bind to some other surface protein that is then internalized. Maybe a pattern-sensing receptor like TolR or RAGE, or maybe a megalin or cubilin variant, or even one or more of the hundreds of G protein-coupled receptors. Or something else. Could be anything. Maybe it even has to do with why some people get sicker.
 
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The major viral entry route is thought to be ACE2-mediated endocytosis and CQ/HCQ disrupts endosome function (as well as lysosome function) in vitro.
As you mentioned, there are findings suggest that in addition to ACE2, host protease such as TMPRSS2 is involved to cleave S protein into S1/S2; the latter mediates membrane fusion. TMPRSS2 inhibitors are tested in clinical trial. https://www.sciencedirect.com/science/article/pii/S0092867420302294
However, the cleavage of S protein into S1/S2 does not necessarily take place on cell surface. It can happen inside the cell (like furin cleavage in Golgi). In the Cell paper below, the authors found S1/S2 cleavage during S biosynthesis was not necessary for S-mediated entry in their experimental setting. https://www.sciencedirect.com/science/article/pii/S0092867420302622. But I heard that furin-mediated cleavage enabled viral entry in cell lines lack of ACE2 expression (personal communication). Again, in vitro assays all have limitations. That's a lot to do for basic researchers to understand the molecular pathology of COVID, but I don't think it has immediate or direct impact on COVID prevention and treatment.


Not sure how fusion would work without binding first. Recently scientists have been able to study the structure and conformations of the S protein and its bind to the ACE2 receptor using high resolution Cryo-EM (3.5 angstroms). The S2 subunit, which is responsible for membrane fusion, is not accessible in pre-fusion conformations. The binding of S1 subunit to the receptor triggers a series of interactions including some host proteases acting on a couple of cleavage sites in the S protein. The shedding of S1 induces a dramatic conformational change in S2 from a folded multi helices to an extended one. This enables S2 “stab” host cell in membrane and triggers fusion.
 
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Taste is definitely an interesting field and not heavily explored. I have been in particular interested in taste loss during ageing and taste-modifying molecules; maybe it is time to think of COVID related projects for the sake of funding :p

I didn't find report on ACE2 expression in human taste buds; in mice taste buds, ACE2 is widely expressed. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770651/ . Saliva COVID test is in use now and I won't be surprised that taste buds can be infected when viral load is high in saliva.

Yes the taste part is more surprising.

But as Rain says, even though we know the virus binds with high affinity to ACE-2 this absolutely does not exclude that it could bind to some other surface protein that is then internalized. Maybe a pattern-sensing receptor like TolR or RAGE, or maybe a megalin or cubilin variant, or even one or more of the hundreds of G protein-coupled receptors. Or something else. Could be anything. Maybe it even has to do with why some people get sicker.
 
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That's extremely interesting Rain.

Years ago I worked at a place where literally everybody around me worked on chemical senses, about half on olfaction and about half on taste. I always wondered why they hired me. Later, oddly enough after I moved from that place, I collaborated with a geneticist and have co-authored three papers on olfaction in Drosophila. That was a couple of decades ago. (Two were in Nature though). Sadly he left my department and got a better job elsewhere (he is an amazing scientist) and so that was the end of my brief career in chemical senses and I resumed my life sticking microelectrodes into other things, and then later made yet another weird career change in terms of what I worked on. Depending on what happens with my latest RO1 application, I may be needing to make another one.... :(

I certainly did not suspect that there would be ACE-2 in taste buds. But upon thinking a bit about it, it kind of makes sense. There is a really old literature showing that Ang II regulates salt appetite (and also drinking behavior, more acutely), and while it has generally been thought that these behavioral responses are driven by central effects, one thing about Ang II is that it produces effects all over the place, so in that context the expression of all of the RAAS components in cells that sense salt taste is not that surprising. (I actually have several papers that touch on Ang II).

There are actually two different kinds of cells in taste buds, plus nerve terminals that receive input from them. One of them, the so-called sustentacular cell, may be a bit like the type II cells in respiratory epithelium? But the entire sensory modality is insanely complicated and there has been a ton of stuff discovered since I last read anything about it. I just found a good review written by an old friend of mine I haven't seen in quite a few years. This is literally the only thing I have read about taste since about 2001.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958546/

 
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Hey Free Bird, this just came out. It suggests that SARS-CoV-2 infects the supporting cells in the olfactory epithelium, and not the ciliated olfactory receptor neurons themselves. Some of those epithelial cells will actually turn into olfactory receptor neurons (which turn over about every 28 days throughout our live), and some of them play a supporting role, so that if you lose them the neurons will not function.

https://www.biorxiv.org/content/10.1101/2020.03.25.009084v3.full.pdf+html
 
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An interview that explains the logic behind the approach in Sweden.

https://youtu.be/bfN2JWifLCY

While there are similarly argued and to some extent more detailed arguments from another researcher I have listened to, I think the length of this interview and the insider status of the interviewee makes it a better choice to understand why the Swedes did what they did and to truly understand the pros and cons of a lockdown.
 
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- UK policy on lockdown and other European countries are not evidence-based
- The correct policy is to protect the old and the frail only
- This will eventually lead to herd immunity as a “by-product”
...
The Swedes want to embrace an evidence-based approach and past evidence for herd immunity is...

https://www.jacksonville.com/opinion/20200202/herd-immunity-is-key-to-preventing-infections
When European explorers came to the New World, they brought viruses such as measles, mumps, rubella, and smallpox with them. The Native Americans had never been exposed to these viral diseases. They had no natural immunity and no herd immunity at all.

An estimated ninety percent of the indigenous Indians perished within a few years of this exposure. The New World was virtually emptied of its original inhabitants by the invisible hand of deadly viral disease.

Anger in Sweden as elderly pay price for coronavirus strategy
https://www.theguardian.com/world/2...as-elderly-pay-price-for-coronavirus-strategy
Tegnell’s colleague AnnaSara Carnahan on Friday told Sveriges Radio that the number of deaths reported from old people’s homes was “probably an underestimate”, as regional health infectious diseases units were reporting that many elderly who died were not being tested.
 
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