Me and my cofounder Chris have been quietly working on Encycla for a while now. Previously, I started LocalWiki[1] and DavisWiki[2]. What I couldn't stop thinking about was: is Wikipedia really "it" in terms of web-wide knowledge sharing?
There's been lots of note-taking apps and personal knowledge sharing tools developed in the past few years. But there's a big difference between working with people you already know and collaborating with anyone on the internet.
Right now, if you're interested in, say DIY air purifiers[3], you could throw up a document or webpage. But there's no good way for people you don't already know to work on it, to make it their own. If you're writing software, the answer is obvious: publish a Git repository on GitHub/GitLab.
With Encycla, we're building a sort of "GitHub for knowledge": a place where you can create simple, topical webpages that others can fork and asynchronously push & pull changes from (without knowing about Git or anything technical).
On the backend, every page on Encycla is a git repository containing Markdown that you can clone, edit independently of the Encycla website, push to other services (such as GitHub, GitLab), etc.
I can answer that myself now: Yes, using the web login credentials it is perfectly possible to edit locally and push the changes. Markdown doesn't behave quite as expected, though.
Yes, this is one reason why an approach using a form of soluble ACE2 is so promising; mutations that would normally cause e.g. monoclonal antibodies to stop working (as detailed with the mink mutation) would in theory not stop the 'decoy receptor' approach.
Despite the fact soluble ACE2 is not looking like it'll be developed in time to impact the pandemic, there is a silver lining:
Interestingly, in this n=1 case report, it looks like the soluble ACE2 is unlikely to have worked as an antiviral; the patient already had a high level of antibodies, as you can see in the Lancet paper above. So /if/ the patient's improvements can be ascribed to the soluble ACE2 treatment, it's likely the improvement was because of the effect the soluble ACE2 had on the person's renin-angiotensin system.
And if this holds, then it's likely many of these same improvements would be possible using a common class of widely-available blood pressure medications called ARBs.
This approach would not neutralize the virus, but instead stop the body from damaging itself. That's the theory, at least.
There are ~20 trials of ARBs for COVID-19 in progress now, though almost all are underdosed.
My impression of spike attachment, via mediator, to the ACE2 is for cellular entry. I am not sure if this will exhaust the other ACE2 on other cells. That said a saturation level of spike in the blood so all cells lose spike in all areas is very unlikely, as this would, in all certaintly, be lethal??
A full blown infection - does it ever reach the level of ACE2 exhaustion - or are there many cells no reached? Heart cells - death of many heart cells would be a problem?
It was not blinded. It was open-label and the outcomes were subjective (ICU admission). The doctors involved with the trial knew who got what and may have biased their actions based on that. Given the subjective outcome and small number of participants, this is particularly important. The trial would be slightly underpowered even if it were blinded.
Other studies on Vitamin D are retrospective cohort / observational studies which are heavily biased with possible confounders with respect to Vitamin D.
My personal opinion is that Vitamin D may help in COVID-19 but this trial does not 'confirm' that. Someone should run a similar trial with more participants and/or a fully blinded trial / a trial with more outcomes (biomarkers, etc).
There may be some subjectivity at play alright when deciding if borderline patients go to ICU or not, and that certainly lowers confidence in the numbers, but the effect size is quite large.
What would be interesting would be a follow up to see if patients have suffered lasting damages as has been reported; that could be done blind if the data is collected by imaging (for say heart damage) and analyzed by a different group. Though I have no idea how common those damages are.
While it's important to acknowledge the limitations of the pilot RCT, I think calling the outcomes as "subjective" goes too far - besides ICU admission, patients were tracked until discharge or death - a pretty hard outcome, to say the least.
The ICU admission procedure is also discussed: "The patients were admitted to the ICU by applying the rigorous protocol of the Reina J Sofia University Hospital (see supplementary material). Several fundamental aspects were considered when evaluating admission to the ICU: Presence of comorbidities, either individually or quantified in the modified age Charlson Comorbidity Index; Barthel's Index
for functional assessment. It establishes the level of dependence of a patient according to his or her needs and clinical criteria: CURB-65 and SOFA scale and ATS/IDSA criteria [27]. A multidisciplinary Selection Committee was created, made up of intensivists,pulmonologists, internists and members of the ethics committee who decided on admission to the ICU."
WRT to bias, the description of the study is a bit confusing to me as it is described as "open label" (treatment known to the doctors and the patients) but also "double masked" which should hide the appearance of the treatment to the patient, investigator, or medical personnel.
The study describes the masking as: "The list generated was accessible randomization only to nonmasked specialists in the study in an attempt to minimize observation bias. The patients' data were recorded in the hospital's electronic medical record, with blind access by the technical data collectors and the statistician who carried out the study."
This description still leaves me confused, so hopefully that can get clarified (since treatment was oral, should be simple to mask w/ placebo), but in any case, the results are strong enough (and in concordance not only with the prior suggestive retrospective studies on Vitamin D and COVID, but also many mechanistic and RCT studies on Vitamin D's effects on respiratory illnesses and immune function) that hopefully a more rigorous, larger scale followup is being done somewhere. (Some other things about the study that I noticed is that patients didn't have Vitamin D status collected on intake, and as mentioned in the paper, obesity, BMI, and other metabolic markers weren't measured either.)
If anyone is reading this with connections to the Gates Foundation: Please contact Dr. Robert Kruse at John Hopkins. https://twitter.com/RobertLKruse. I have been trying to get in touch with people at Gates. This announcement unfortunately features no contact email address :(
Dr. Kruse is developing an extremely promising therapeutic, ACE2-fc, which will both neutralize the virus and treat the symptoms of the disease. It has been shown to work in vitro; variants have been tested in animals models; and its been through Phase II human trials for a different indication. A variant of the therapy, soluble ACE2, is being trialed in humans now in China.
Details on the approach can be found in his paper here:
I just started working on the complementary side of the spike RBD-ACE2 interaction, making an aerosol of RBD peptide fragments to outcompete the virus for entry.
I'm the "dry lab" side of this project -- looking for peptide candidates. My other collaborators at UNC are going to do formulate the aerosol and test for safety in mice.
Normally this would be a very early stage in drug development, but it seems like we have to move quickly.
So similar shout out to the Gates Foundation folks -- if you're interested in this approach email [email protected]
This may be relevant: there's a recent (3rd March) hypothesis due to Rami Sommerstein from Department of Infectious Diseases, Bern University Hospital [0] that ACE inhibitors are a potential risk factor for fatal Covid-19 in those patients taking ACE inhibitors for hypertension/diabetes/cardiovascular disease:
>The largest Chinese study with 44,672 confirmed cases of Covid-19 shows a high overall case fatality rate (CFR) of 2.3% [2]. Important co-morbidities are hypertension (CFR 6.0%), diabetes (CFR 7.3%), cardiovascular disease (CFR 10.5%) and age >70 (CFR 10.2%) [2]. Similar co-morbidities were noted for the SARS outbreak in 2003.
> ...
>On the one hand, it has been shown that the Covid-19 agent (also known as SARS-CoV-2), uses the SARS-COV receptor angiotensin converting enzyme (ACE) 2 for entry into target cells [4]. The interface between ACE2 and the viral spike protein SARS-S has been elucidated and the efficiency of ACE2 usage was found to be a key determinant of SARS-CoV transmissibility [4].
>
>On the other hand, it could be shown in animal experiments that both the ACE-inhibitor lisinopril and the angiotensin-receptor blocker losartan can significantly increase mRNA expression of cardiac ACE2 (5-fold and 3-fold, respectively) [5]. Further, losartan also significantly increases cardiac ACE2 activity [5].
Please see my twitter account for lots on this. I'm in contact with a bunch of top researchers on this topic (renin-angiotensin system; ACE2/Ang 1-7/Mas axis; ARB usage for viral diseases) and will be posting a summary update soon:
It may be the other way around: ACEi/ARB may be protective. HTN without ACEi/ARB would be non-protective, potentially so much so that it skews the group fatality numbers. This is because people with HTN have a different renin-angiotensin system profile: more AT1R, less AT2R, more ACE, potentially less ACE2.
This is being looked at now. But the key is that in every study ever done on viral lung disease, etc, AT1R blockade was highly beneficial, and we know that ACE2-knockout basically screws up lungs, makes viral lung disease way worse, etc. Please see my twitter posts.
The virus eats up ACE2, downregulating it as it binds. This would have delirious effects. Check out the linked "essential reading" twitter post.
I'm fairly out of my depth here, but it's somewhat relevant to my personal situation:
When this came up for discussion on HN a few days ago, I was initially confused, as some of what I read seemed to suggest that taking e.g. lisinopril could possibly increase the risk of an infection because it seems to increase the expression of ACE2 receptors that are used by the virus to infect cells.
On the other hand, some of what I read seemed to suggest that ACE inhibitors (e.g. lisinopril) could have a therapeutic benefit. The virus is going to inactivate a bunch of ACE2 receptors through the course of infection. Since ACE2 receptors inactivate angiotensin, that would leave a lot of active angiotensin floating around, which is potentially very bad. ACE inhibitors would seem to help here because they inhibit the active form of angiotensin from being created in the first place.
Now I'm wondering: Is it possible that taking lisinopril could increase the risk of serious infection for those of us not yet infected, but also could reduce the severity of an active infection?
I agree. There is a +6% increase in COVID-19 mortality for those with hypertension. Assume all were on BP meds. They're cheap, & doctors usually insist. If ACEs or ARBs were protective, it should be more like -6%. Right? Losartan = 400% more ACE2, Lisinopril = 100% more ACE2.
Elderly people are usually on BP meds.
Diabetics are frequently prescribed Losartan to protect their kidneys. I know. I am a diabetic, and was prescribed it for that reason and also for high BP.
As a diabetic over 50 with high BP I have a greater interest than most. Especially since my wife was exposed to coronavirus, is sick, and I am starting to feel unwell.
Stopped taking losartan yesterday. Have some tenofovir lying around and might start taking it. It's the only antiviral I was able to get my hands on. Hopefully my chloroquine arrives in the mail soon.
I read a paper that suggested caffeic acid was the anti-viral component of elderberry extract that was actually inhibiting HCoV-NL63 viral attachment and infection of human lung cells in vitro (Virus Research, 273 (2019)197767). This paper speculated that caffeic acid binds to ACE2 and inhibits viral attachment and infection via this route. Another paper suggested 95% absorption in humans dosed with 500 mg in 200 mL of hot water. A third paper that looked at 2-year study in SD rats suggested pro-carcinogenic properties, but many other papers suggest anti-oxidant/anti-inflammatory/anti-carcinogenic properties. If I start to come down with it, I think I'm going to do a 500 mg caffeic acid dose.
I am propably among the most ardent critics of twitter and social media when it comes to Corona. And then comes a guy like you. Stuff like that should be among every top comment, everywhere when it comes to this. Along side the WHO situation reports and guidelines. So, thank you!
I think the table in that paper is just confusing. The parenthesized numbers are for portion of the total number of people, rather than the portion of that category.
For instance, there are 137 current smokers. 108 are listed as non-severe. 29 are listed as severe. This means 108/137 = 79% non-severe, 29/137 21% severe.
Never smoked: 927 total, 793/927 non-severe (86%), 134/927 severe (14%).
Hope that makes sense. That table confused me too. Don't start smoking!
For context, around 60% of men in China smoke. Your proximate interpretation of the numbers is correct, but I think the real question is where are there so few smokers in the data. (And whether smoking confers some sort of protective effect by upregulating ACE2 receptors.)
A few days ago I started taking a low dose of an OTC ACE inhibitor in order to upregulate my ACE2 receptors. This is what the literature that was written before the current epidemic about surviving novel Coronavirus pandemics says to do, and the new evidence that comes out each day is actually validating this strategy.
It's only the scientists who didn't start studying Coronaviruses until two weeks ago who seem to think that having ACE2 receptors is dangerous.
That definitely could be true, but from what I've read it probably isn't. One of the ways the virus kills people is by destroying their ACE2 receptors, which your lung cells need to function. If you blocked them all, your lung cells would die anyway. So as long as the virus can enter your lung cells, you might as well prevent it from killing them by making extra ACE2 receptors. That's the theory anyway.
There are also many other ways you can block the virus from entering your lungs that don't involve downregulating your ACE2 receptors.
I think Hawthorn or hibiscus. You can get them certified as USP or cGMP, and/or independently tested by Consumer Labs.
I'm not 100% sure on the mechanism of action on Hawthorn. I've read that it's an ACE inhibitor, but I don't have a good source. But I can see at the very least that it's an elastase inhibitor, which is supposed to be protective against ARDS.
edit: I think proanthocyanidin is the component that is supposed to be an ACE inhibitor.
I'm just taking some expired Hawthorn pills that I happened to have lying around the house. In my case I don't have high blood pressure to begin with, so I'm just taking about 1/3rd of the recommended dose and then periodically checking to ensure that my blood pressure isn't getting dangerously low.
People make their own hawthorn jam and jelly though, so it isn't excessively dangerous, but on principle it's probably better to take a conservative approach, or at least one that's commensurate with the initial risk.
Because I'm in NYC we actually have them growing everywhere because they are one of a handful of approved small-sized street trees, and they're in all the parks, but regardless it's easier just to buy as a supplement.
It is related, but it's pretty complicated. For some information on this and the potential relationship, see my twitter account: https://twitter.com/__philipn__
The latest is that ACE2 and TMPRSS2 are both needed to infect humans. There are already two compounds identified to block these pathways, one of which is already a medication used in Japan. Both are very safe with huge LD50's.
That's where Angiotensin I (ACE = Angiotensin Converting Enzyme) is converted to Angiotensin II, which acts on tons of blood vessels to increase blood pressure. That's essentially why ACE inhibitors have a blood pressure effect. On top of that, Bradykinin is an inflammatory mediator that is degraded by ACE. It's heavily implicated in the side effect ACE inhibitors have of dry cough.
Now that is a very interesting question! Unfortunately, I don't think that we have a complete answer. A couple of notes, that perhaps can provide some perspective:
1. lungs are highly vascularised areas with a large amount of vascular endothelium, making them a great location to express ACE if you want to convert as much angiotensin I as you can in the space of a heartbeat (which you'd like to do if your blood pressure dropped, for example).
2. ACE is not specific for angiotensin, it acts on a variety of peptides. Bradykinin is a good example as it can provide more perspective on why ACE is expressed mainly in lung tissue. Bradykinin acts to contract smooth muscle in your airways. Thus, degrading bradykinin via ACE is a good way to improve your breathing.
I’m not a doctor, but fusing a complement activator to a natural enzyme and megadosing it is a horrible idea because it’s gonna trigger complement activation in the context of a self protein, which could cause major autoimmunity, and ACE2 overload is gonna overactivate the angiotensin-aldosterone axis and deactivate renin via negative feedback, screw up your electrolytes which could cause arrhythmias, and give you high blood pressure.
To avoid side effects, a therapy ought to be as orthogonal as possible to natural systems. A high dose of a hormone activator smushed together with an immune activator is definitely not orthogonal to natural systems.
More useful to focus on genomic smart bombs like CRISPR Cas13 ( cough, https://github.com/bionicles/coronavirus ) or RNAi because they’re way, way, way, less likely to have side effects, they can last forever, can easily be retargeted to future germs hella quick, etc etc
We'll never know. If it works then Covid-19 will be a footnote in history, a temporary problem that was quickly solved. We won't know if it would have become an extinction-threatening event or if it would have fizzled out on it's own, or anything in between. If it doesn't work then YC's input wasn't important and didn't help.
This take is too pessimistic. Eventually we will have enough data to project what could have happened without treatments like this. We will know the rate of infection, the rate of death without treatment, etc. There will be many different groups globally trying to find out these answers and apply them to preventing future pandemics.
In the case of .org, non-uniform renewal pricing is only allowed if "the applicable registrant expressly agreed in its registration agreement with registrar to higher Renewal Pricing at the time of the initial registration of the domain name following clear and conspicuous disclosure of such Renewal Pricing to such registrant"
So Ethos wouldn't be able to screw over existing registrants with non-uniform renewal pricing.
This depends on the TLD (top level domain) in question.
For .com, .net, .org it has historically not been possible to price discriminate like this.
For the "new TLDs" (the explosion of new extensions we have seen in recent years), the registry contract is different and they are indeed allowed to do this. They call it "premium pricing".
Part of the big outcry about the recent changes to .org is that it brings it closer to the "new TLD" model, which disfavors the registrant.
One reason is constitutionality. The "One man, one vote" principal likely has to be upheld for a voting system used in the US to be ruled as constitutional.
Ranked Choice Voting is sometimes called Instant Runoff Voting when used in a single-winner election. But it can be used in multi-winner elections.
If it's used for a multi-winner election, it gives results that are proportional in representation. For instance, this is how it's used in the city council elections in Cambridge, MA. Sometimes it's referred to as "Single Transferable Vote" when used for multi-winner elections.
"Ranked Choice Voting" is an umbrella term that refers to the ranked ballots, round-by-round elimination of candidates, etc.
"..There was zero overlap between the provers and the bulldogs. I was expecting at least some overlap: somebody who mocked me but also provided a valid solution, or even tried but failed. But that didn’t happen.
I normally assume these people are “brilliant jerks”: they’re assholes online, but I still have to listen to them in case they say something important. This really cracked that assumption: none of the “brilliant jerks” were willing to put any skin in the game. You don’t have to listen if they have nothing to say."
I came to a similar realization a few years ago. I followed a number of people who were/are widely followed in parts of the FP community that are generally caustic, but I assumed their popularity implied that they had something useful to say. I eventually unfollowed/muted/blocked many of them because I reached a point where I realized I'm not dumb, I actually do know the domain pretty well, and I'm well regarded in that community, yet I think these people are just spewing hot air (either aggressively negative, confrontational, or self-promoting). To be honest, I don't think I've missed anything of any consequence since my block/mute/unfollow-fest. It does disappoint me when I look and see that some of these toxic personalities are still widely followed and still spewing the same garbage, even though I can't see any tangible contribution that they've made.
There are many who are good at making noise and opining, and even talking about wonderful "tech" that they are working on, but most of the "brilliant jerks" ultimately produce nothing of value and contribute nothing to the ecosystem.
To be a brilliant jerk (BJ) is a social phenomenon. I think everybody (brilliant) is a BJ sometimes. In academy one does that to protect own field of research, or virtue signalling. A BJ can recognize a good idea and use it later without attribution (and perhaps in a better version, because he's brilliant). A BJ can bark at the stranger's idea and later become a supporter of the same idea, done by one of the friends. So in conclusion I think it is not constructive to NOT listen a BJ, instead treat them like an evolved form of a troll, face them with evidence and do what they don't: learn their field.
There's been lots of note-taking apps and personal knowledge sharing tools developed in the past few years. But there's a big difference between working with people you already know and collaborating with anyone on the internet.
Right now, if you're interested in, say DIY air purifiers[3], you could throw up a document or webpage. But there's no good way for people you don't already know to work on it, to make it their own. If you're writing software, the answer is obvious: publish a Git repository on GitHub/GitLab.
With Encycla, we're building a sort of "GitHub for knowledge": a place where you can create simple, topical webpages that others can fork and asynchronously push & pull changes from (without knowing about Git or anything technical).
On the backend, every page on Encycla is a git repository containing Markdown that you can clone, edit independently of the Encycla website, push to other services (such as GitHub, GitLab), etc.
1. https://localwiki.org
2. https://localwiki.org/davis
3. https://encycla.com/Corsi-Rosenthal_Cube