Remdesivir - a possible treatment for COVID-19?

  • #26
Ygggdrasil
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This recent article suggests that rather than a "cytokine storm", COVID-19 is the result of a "bradykinin storm" initiated by the loss of the ACE2 receptor due to SARS-CoV-2.

It appears that the conclusion was reached on the basis of a super-computer analysis of samples (presumably from COVID infected patients). Here is the original paper.

I am not sure what to make of the paper.
For my thoughts on the paper see: https://www.physicsforums.com/threads/supercomputer-analysis-of-covid-virus.993135/post-6387959
 
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  • #27
Andrew Mason
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There has been much discussion in this thread about the mechanism by which SARS-CoV-2 causes respiratory disease. Since the virus enters cells via the ACE2 receptor it destroys ACE2 function. ACE2 performs a key role in regulating the level of the Angiotensin II (Ang II) enzyme.

A recent report from the University of Cincinnati published last week refers to their study of data collected in Ohio which indicates that COVID patients did not have elevated levels of Ang II. However, what they did find were very low levels of Ang-(1,7).

As mentioned on this thread, Ang-(1-7) is produced by the ACE2 receptor cleaving the Ang II enzyme. Thus ACE2 has two important functions: reducing Ang II and producing Ang-(1,7). As reported:

University of Cincinnati said:
“This is among the first substantial evidence supporting the hypothesis of a potential inhibition of ACE2 activity due to virus binding,” Henry stated. “As angiotensin (1-7) is anti-inflammatory peptide that also dilates the vessels, low levels of this peptide due to [the coronavirus] may promote ARDS. As such, supplementation with synthetic angiotensin (1-7) may be a potential therapeutic target for treating COVID-19.”
AM
 
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  • #28
Andrew Mason
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I see that Donald Trump began receiving Remdesivir shortly after being admitted to hospital, about a day after testing positive for SARS-CoV-2. This makes sense because its function is to stop viral replication and reduce viral load in the body to prevent COVID from developing. I am not sure why it was thought that Remdesivir should be given to infected patients who had already developed full blown COVID.

AM
 
  • #29
jim mcnamara
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The CDC's EUA (Emergency Use Authorization) on Remdesivir stipulates it use, which, IIRC, is for Covid-19 patients who are put on supplemental oxygen at first signs of hypoxia. Only. Not Covid-19 seropositive, and not intubated patients. This is because clinical studies show statistically significant results only for those on oxygen.

@Andrew Mason , so you are correct. :smile:
 
  • #30
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The CDC's EUA (Emergency Use Authorization) on Remdesivir stipulates it use, which, IIRC, is for Covid-19 patients who are put on supplemental oxygen at first signs of hypoxia. Only. Not Covid-19 seropositive, and not intubated patients. This is because clinical studies show statistically significant results only for those on oxygen.
The original EUA issued by the FDA on May 1, 2020 limited emergency use of remdesivir to patients with severe COVID but the revised EUA issued August 28, 2020 broadened that use:

FDA EUA Authorization Letter 1Oct20 said:
On August 28, 2020, having concluded that revising this EUA is appropriate to protect the public health or safety under Section 564(g)(2) of the Act, FDA reissued the May 1, 2020, letter in its entirety with revisions incorporated to expand the authorized use of Veklury [Gilead's trade name for remdesivir] by no longer limiting its use to the treatment of patients with severe disease.


Given that it is an anti-viral drug designed to prevent viral replication, I have trouble understanding why it was originally thought that it should be given only to patients in whom the virus had become well-established. I don't think there was evidence that the drug produced results only for those kinds of patients. In fact, evidence published in August showed that remdesivir was not effective on such patients (see post #16 above).

AM
 
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  • #31
Ygggdrasil
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Given that it is an anti-viral drug designed to prevent viral replication, I have trouble understanding why it was originally thought that it should be given only to patients in whom the virus had become well-established. I don't think there was evidence that the drug produced results only for those kinds of patients. In fact, evidence published in August showed that remdesivir was not effective on such patients (see post #16 above).
A major consideration for EUAs and drug approval is a risk-benefit analysis. Evidence for benefit can be weaker if treating a high risk population. Treating people with more mild symptoms, many of whom would recover without pharmaceutical intervention, requires a higher standard of evidence for efficacy and safety.

I agree that it is likely better to treat early with remdesivir, but I have not carefully looked at the clinical trial data to judge the EUA.
 
  • #32
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As Andrew Mason said, and the way I read it, the EUA has been updated. . .

eua-fda-authorization-letter.pdf

On October 1, 2020, having concluded that revising this EUA is appropriate to protect the public health or safety under Section 564(g)(2) of the Act, FDA is reissuing the August 28, 2020, letter in its entirety with revisions incorporated to the scope and conditions of authorization designating Gilead Sciences, Inc. and its authorized distributors as the responsible parties for the distribution of Velkury.



Carry on. . .

.
 
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  • #33
Andrew Mason
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I see that Gilead has suspended trials that combine antibody treatment and remdesevir. They were combining Lilly's antibody treatment (which is similar to Regeneron's antibody treatment) with remdesivir. According to this report:
Marketwatch 13Oct20 said:
The pause is notable for two reasons. Lilly's investigational antibody drug is similar to the Regeneron Pharmaceuticals Inc.'s experimental antibody treatment that was prescribed to President Donald Trump. It is also the third major clinical trial in this pandemic to be paused for safety reasons, which experts say is a common occurrence but likely one being scrutinized given the lack of treatment or prevention options against the coronavirus.
This may be a reference to a recent case in which combined antibody/remdesivir treatment was given, after which the patient experienced delusions of absolute immunity as well as exacerbation of pre-existing delusions of grandeur and invincibility.:cool:

AM
 
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  • #34
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A new large randomized controlled trial from the WHO finds no evidence that remdesivir decreases COVID-19 mortality:
One of the world’s biggest trials of COVID-19 therapies released its long-awaited interim results yesterday—and they’re a letdown. None of the four treatments in the Solidarity trial, which enrolled more than 11,000 patients in 400 hospitals around the globe, increased survival—not even the much-touted antiviral drug remdesivir. Scientists at the World Health Organization (WHO) released the data as a preprint on medRxiv last night, ahead of its planned publication in The New England Journal of Medicine.
https://www.sciencemag.org/news/202...fall-flat-who-s-megastudy-covid-19-treatments

On remdesivir specifically, the Science news piece says:
Remdesivir, which attacks a specific enzyme in several RNA viruses and was previously tested against Ebola, was initially seen as a promising candidate. In a U.S. trial with more than 1000 COVID-19 patients published last week, those who received remdesivir had a shorter recovery time than patients in the control group, but there was no significant difference in mortality. Two smaller trials found few significant benefits. Remdesivir received an emergency use authorization from the U.S. Food and Drug Administration (FDA) in May for severe COVID-19 patients that was later expanded to include all patients.

But the Solidarity trial suggests the drug does little in severe cases. Of 2743 hospitalized patients who received the drug, 11% died, versus 11.2% in a control group of roughly the same size. The difference is so small it could have arisen by chance.

When the authors pooled Solidarity’s data with those from the three other trials, they found a slight reduction in mortality that wasn’t statistically significant either. "This absolutely excludes the suggestion that remdesivir can prevent a substantial fraction of all deaths,“ the authors write. "The confidence interval is comfortably compatible with prevention of a small fraction of all deaths but is also comfortably compatible with prevention of no deaths.”
Here's the non-peer-reviewed pre-print posted on medRxiv:

Repurposed antiviral drugs for COVID-19; interim WHO SOLIDARITY trial results
https://www.medrxiv.org/content/10.1101/2020.10.15.20209817v1

Abstract:
BACKGROUND WHO expert groups recommended mortality trials in hospitalized COVID-19 of four re-purposed antiviral drugs.

METHODS Study drugs were Remdesivir, Hydroxychloroquine, Lopinavir (fixed-dose combination with Ritonavir) and Interferon-β1a (mainly subcutaneous; initially with Lopinavir, later not). COVID-19 inpatients were randomized equally between whichever study drugs were locally available and open control (up to 5 options: 4 active and local standard-of-care). The intent-to-treat primary analyses are of in-hospital mortality in the 4 pairwise comparisons of each study drug vs its controls (concurrently allocated the same management without that drug, despite availability). Kaplan-Meier 28-day risks are unstratified; log-rank death rate ratios (RRs) are stratified for age and ventilation at entry.

RESULTS In 405 hospitals in 30 countries 11,266 adults were randomized, with 2750 allocated Remdesivir, 954 Hydroxychloroquine, 1411 Lopinavir, 651 Interferon plus Lopinavir, 1412 only Interferon, and 4088 no study drug. Compliance was 94-96% midway through treatment, with 2-6% crossover. 1253 deaths were reported (at median day 8, IQR 4-14). Kaplan-Meier 28-day mortality was 12% (39% if already ventilated at randomization, 10% otherwise). Death rate ratios (with 95% CIs and numbers dead/randomized, each drug vs its control) were: Remdesivir RR=0.95 (0.81-1.11, p=0.50; 301/2743 active vs 303/2708 control), Hydroxychloroquine RR=1.19 (0.89-1.59, p=0.23; 104/947 vs 84/906), Lopinavir RR=1.00 (0.79-1.25, p=0.97; 148/1399 vs 146/1372) and Interferon RR=1.16 (0.96-1.39, p=0.11; 243/2050 vs 216/2050). No study drug definitely reduced mortality (in unventilated patients or any other subgroup of entry characteristics), initiation of ventilation or hospitalisation duration.

CONCLUSIONS These Remdesivir, Hydroxychloroquine, Lopinavir and Interferon regimens appeared to have little or no effect on hospitalized COVID-19, as indicated by overall mortality, initiation of ventilation and duration of hospital stay. The mortality findings contain most of the randomized evidence on Remdesivir and Interferon, and are consistent with meta-analyses of mortality in all major trials.
 
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  • #35
Andrew Mason
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A new large randomized controlled trial from the WHO finds no evidence that remdesivir decreases COVID-19 mortality:
If remdesivir is effective in blocking viral RNA transcription and, therefore, viral replication, what these trials suggest is that once the virus has infected enough cells (through the ACE2 entry mechanism), the serious potentially fatal COVID pneumonia that develops cannot be stopped by just attacking the virus.

But it may also be that remdesivir by itself - just blocking RNA transcription - is not enough to stop the virus since it will not block 100% of the time. Since the SARS-CoV-2 virus replicates very quickly inside infected cells, remdesivir will just slow down replication. This article suggests that to also stop the virus one also has to block the proof-reading function that the virus employs after RNA transcription.

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  • #36
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Another potential interpretation of the data is that remdesivir is not effective if administered late in the course of the infection (e.g. at the point at which patients need to be hospitalized), which is consistent with our experience with other antivirals like Tamiflu. For example, Tamiflu is effective at decreasing the duration and severity of illness for the influenza virus, but only if taken within 36-48 hours of the onset of symptoms.
 
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  • #37
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Another potential interpretation of the data is that remdesivir is not effective if administered late in the course of the infection (e.g. at the point at which patients need to be hospitalized), . . .
I would agree, and looking at the earliest trials, most if not all were severe cases require oxygen or ventilation. Remdesivir may be more effective at the onset of symptoms, and perhaps one still needs something like Regeneron's monoclonal antibody cocktail.

When I had the flu, I received Tamiflu between 18 to 24 hours after symptoms developed. It was Sunday night when I awoke with a fever measuring about 102-103°F and a mild cough. Earlier I had started coughing but thought it might be an allergy. I saw a doctor on Monday morning, but didn't get Tamiflu until the afternoon, which was the soonest the pharmacy could do whatever they did to get it. I still had a fever and the cough had become stronger. The fever started to break Monday night and was much less on Tuesday morning. The cough persisted though through Thursday. I was quarantined until Friday, and only went to work for half a day, wore a mask and socially distanced.

Where we were in May - Potential Treatments for SARS‐CoV‐2 Infection
https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/cld.969
Lots of choices, and lots of unknowns.
 
  • #38
Andrew Mason
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Another potential interpretation of the data is that remdesivir is not effective if administered late in the course of the infection (e.g. at the point at which patients need to be hospitalized), which is consistent with our experience with other antivirals like Tamiflu. For example, Tamiflu is effective at decreasing the duration and severity of illness for the influenza virus, but only if taken within 36-48 hours of the onset of symptoms.
Yes, but why would remdesivir be effective only if administered early? Why does Tamiflu work that way? I can see two reasonable interpretations of such a result but there may be others.

AM
 
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  • #39
Tom.G
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Yes, but why would remdesivir be effective only if administered early? Why does Tamiflu work that way? I can see two reasonable interpretations of such a result but there may be others.

AM
https://www.sciencemag.org/news/202...fall-flat-who-s-megastudy-covid-19-treatments

In a U.S. trial with more than 1000 COVID-19 patients published last week, those who received remdesivir had a shorter recovery time than patients in the control group, but there was no significant difference in mortality.

Cheers,
Tom

p.s. It may have been in another article; around the same time the above appeared I stumbled across the speculation that remdesivir can inhibit the free virus but when the virus gets into a cell all bets are off. That could explain the early usefulness.
 
  • #40
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https://www.sciencemag.org/news/202...fall-flat-who-s-megastudy-covid-19-treatments

In a U.S. trial with more than 1000 COVID-19 patients published last week, those who received remdesivir had a shorter recovery time than patients in the control group, but there was no significant difference in mortality.

Cheers,
Tom

p.s. It may have been in another article; around the same time the above appeared I stumbled across the speculation that remdesivir can inhibit the free virus but when the virus gets into a cell all bets are off. That could explain the early usefulness.
If I understand it correctly, remdesivir interferes with RNA replication by interfering the the function of the RNA polymerase (RdRP) in transcribing viral RNA. See the drawing in post #11 above, for example. It does this by delivering a nucleoside analogue that is similar to adenosine which is then taken up by the RdRP molecule and inserted into the RNA transcript instead of normal adenosine. This, apparently, terminates further replication so the proteins essential for viral replication cannot be made with the defective RNA transcripts.

Since RNA replication occurs in the nucleus of the host cell, one would need to ensure that a good supply of the therapeutic nucleoside analogue in remdesivir is present in the nucleus of the host cell. If that can be accomplished by having enough of the remdesivir nucleoside taken up by the virus prior to cell entry, that might work, perhaps even better. I am not qualified to say whether viral uptake of remdesivir prior to cell entry occurs or is even possible and I was unable to find anything on this.

AM
 
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  • #41
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Since RNA replication occurs in the nucleus of the host cell, one would need to ensure that a good supply of the therapeutic nucleoside analogue in remdesivir is present in the nucleus of the host cell. If that can be accomplished by having enough of the remdesivir nucleoside taken up by the virus prior to cell entry, that might work, perhaps even better. I am not qualified to say whether viral uptake of remdesivir prior to cell entry occurs or is even possible and I was unable to find anything on this.
Like most nucleoside analogs, remdesivir is a pro-drug that is administered in an inactive form that is able to enter cells by crossing the plasma membrane. Once inside the cell, cellular enzymes will convert the drug into its active form, where it can incorporated into viral RNA by the virus's RdRp. See the diagram here for more information: https://en.wikipedia.org/wiki/Remdesivir#Pharmacology

Also, viral RNA replication occurs in the cytoplasm.
 
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  • #42
Andrew Mason
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Like most nucleoside analogs, remdesivir is a pro-drug that is administered in an inactive form that is able to enter cells by crossing the plasma membrane. Once inside the cell, cellular enzymes will convert the drug into its active form, where it can incorporated into viral RNA by the virus's RdRp. See the diagram here for more information: https://en.wikipedia.org/wiki/Remdesivir#Pharmacology
According to the Wikipedia article and this paper, much of the time remdesivir is converted outside the cell, removing the pro-drug part and leaving the active nucleotide part GS-441524 in the extracellular plasma rather than inside the cell. According to the authors, that may explain why remdesivir is not as effective as originally hoped.

Also, viral RNA replication occurs in the cytoplasm.
Thanks for that. I found this paper which explains that RNA viruses that replicate in the cytoplasm appear to make their own little organelles in the cytoplasm in which to carry out RNA replication:
Cytoplasmic Viral Replication Complexes said:
Whereas eukaryotic cells sequester and organize their genome replication and transcription in the nucleus, many RNA and some DNA viruses carry out viral genome replication and transcription in the cytoplasm. To establish efficient genome replication and shield it from host defenses, including crucial intrinsic and innate defenses, many or most of these cytoplasmically replicating viruses organize their genome replication and transcription in organelle-like compartments (Novoa et al., 2005). These replication compartments or factories often are associated with the sites of subsequent stages in the viral replication cycle, including particle formation and virus budding.

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  • #43
Andrew Mason
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I see that remdesivir has just been given approval by the FDA for persons over 12 years of age and 40 kg. in weight who are hospitalized. This appears to be based mainly on one trial that appears to show that remdesivir reduces recovery times by about a third. Pediatric use will continue to be under a modified Emergency Use Authorization.

AM
 
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  • #44
Andrew Mason
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Further to the second part of my post 42 above, the dynamics of coronavirus replication seems to be an area that is getting some attention. The coronavirus creates a double membrane replication organelle in the cell cytoplasm to a create a sealed replication compartment where the RNA transcription takes place. This recent paper provides a graphical explanation of the complex processes that take place.

It appears, therefore, that unless remdesivir's active nucleotide is present in these organelles, it will not be able to affect viral RNA transcription. So a big question would seem to me to be: "how does remdesivir get transported into these double membrane organelles?". I suspect that unless the active part of remdesivir is already present in the cytosol of the host cell when the cell gets infected by the SARS-CoV-2 virus, it will not likely be present inside these organelles and will, therefore, be ineffective in blocking RNA transcription. If that is the situation, then administering remdesivir to prevent infection or at a very early stage of infection might be the better course.

The paper (also available here) focuses on the exit pathway from these replication organelles (to allow the viral RNA transcripts to exit to permit protein synthesis in the host cell ) and a particular double membrane-spanning pore that the authors discovered. They suggest that this pore could be a key structure for viral replication and may be a good drug target:

Wolff et al Science 11Sept20 said:
The double-membrane–spanning molecular pore revealed here may constitute the exit pathway for coronaviral RNA products from the DMV’s interior toward the cytosol, with the large and multifunctional nsp3 being its central component. Although the exact mode of function of this molecular pore remains to be elucidated, it seems to be a key structure in the viral replication cycle that is likely conserved among coronaviruses and thus may offer a coronavirus-specific drug target.
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  • #45
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Further to the second part of my post 42 above, the dynamics of coronavirus replication seems to be an area that is getting some attention. The coronavirus creates a double membrane replication organelle in the cell cytoplasm to a create a sealed replication compartment where the RNA transcription takes place. This recent paper provides a graphical explanation of the complex processes that take place.

It appears, therefore, that unless remdesivir's active nucleotide is present in these organelles, it will not be able to affect viral RNA transcription. So a big question would seem to me to be: "how does remdesivir get transported into these double membrane organelles?". I suspect that unless the active part of remdesivir is already present in the cytosol of the host cell when the cell gets infected by the SARS-CoV-2 virus, it will not likely be present inside these organelles and will, therefore, be ineffective in blocking RNA transcription. If that is the situation, then administering remdesivir to prevent infection or at a very early stage of infection might be the better course.
Remdesivir is a pretty small molecule and if pores are visible by electron microscopy and allow RNA molecules to pass through, I suspect nucleotides like remdesivir's activated form would be able to freely diffuse into the compatments as well.

The paper (also available here) focuses on the exit pathway from these replication organelles (to allow the viral RNA transcripts to exit to permit protein synthesis in the host cell ) and a particular double membrane-spanning pore that the authors discovered. They suggest that this pore could be a key structure for viral replication and may be a good drug target:
How would a drug target such a complex? Are there any other drugs that act in a similar way?
 
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  • #46
Andrew Mason
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Remdesivir is a pretty small molecule and if pores are visible by electron microscopy and allow RNA molecules to pass through, I suspect nucleotides like remdesivir's activated form would be able to freely diffuse into the compartments as well.
In order to carry out RNA transcription, there must be an abundant supply of A, C, G, and U nucleotides available inside the double-membrane compartment. I was thinking, however, that these would be present and acquired when the membranes are formed in the cytoplasm.

As I understand it, the portal that allows RNA molecules to exit the viral endosome is not an open door. It is opened, presumably, to let RNA transcripts out but remains closed to molecules in the cytoplasm entering.
How would a drug target such a complex? Are there any other drugs that act in a similar way?
If one could determine the molecular structure of the molecules that make up the portal, could a drug developer fashion a protein complex that could attach to the portal and block it? One could then determine corresponding mRNA template(s) and manufacture the blocking molecule as a drug.

AM
 
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  • #47
Filip Larsen
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From an article on Arstechnica, I understand that WHO last week issued the results of a large study finding no benefit from Remdesivir treatment.

https://arstechnica.com/science/202...vid-19-but-global-study-finds-it-doesnt-work/
According to preliminary results from the Solidarity trial—reported online last week ahead of its planned publication in the New England Journal of Medicine—remdesivir was given to 2,743 patients, and their outcomes were compared with those of 2,708 patients given standard treatments. Between the two groups, WHO found that remdesivir did not reduce mortality. It also did not change how many patients progressed to needing mechanical ventilation, nor did it change the proportion of patients discharged after seven days of hospitalization.
 

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