Correct my H5N1 research ($reward)

I love this detailed list. I've responded in-line to every one, but feel free to ask more questions, here or over email. 

1. Livestock vs. Wild Birds
   The distinction between livestock and wild birds is significant. Livestock are in much closer contact with humans and are biologically closer as well. How granular of an analysis are you interested in here?

I care about wild birds to the extent they're spreading disease to livestock or serve as reservoirs.

I've also heard a wide number of mammals have been infected. I care about this to the extent it affects humans and livestock. E.g. does this suggest it's airborne after all, or say something about the mutation rate?

1. US-specific H5N1 Trends
   It's peculiar that H5N1 seems so prevalent in the US. Could this be due to measurement bias, or does the US simply have more factory farming? How interested are you in exploring the reasons behind this trend?

I'm interested in quantifying the quality of US surveillance, but otherwise deprioritize this.  

1. Citations and Depth
   While most points aren’t cited (which is fine), it might be valuable to compile both a list of key aspects and resources for further reading. Are you looking for a more polished, thoroughly cited document?

Citations are important to the extent they let people check and build on your work. But if it's a widely known consensus such that it's easy to look up but complicated to cite, it's not important to add a citation. E.g. my fact about RNA segments is very easy to check but would have been annoying to find a citation for because I learned it 20 years ago. 

Overall citations for the current state of things (e.g. how many human infections of unknown providence) are more important than citations for basic science.

1. Biological Factors of Severity
   Binding to human receptors is just one factor controlling the severity and infectiousness of a virus. Would you like a deeper dive into the biology of respiratory infections and what makes them dangerous?

Low priority. Pass on resources if you find them but don't bother with synthesis. 

1. Tamiflu and Xofluza
   Wikipedia notes that Tamiflu has limited evidence of being worth the side effects. Are you interested in a detailed evaluation of its effectiveness? Similarly, how interested are you in assessing the likelihood of shortages and efficacy of Tamiflu/Xofluza during an H5N1 pandemic?

I'm very interested in tamiflu's efficacy. Some specific important questions: 

• is tamiflu more effective when taken very early? when did the people in the studies that found low efficacy take tamiflu? My understanding is it is effective for prophylactic use, which suggests earlier is better.
• how does the math change if the flu is more dangerous or virulent?

Not interested in assessing likelihood of shortages.

1. Over-the-counter Tests
   Is the issue a lack of over-the-counter tests specifically for H5N1, or for flu in general? General flu PCR testing is likely available—should we investigate this?

My assumption is the European OTC tests will catch H5N1, but if that's wrong I'd like to know. 

I don't care much about non-home tests, except I am interested in the national flu surveillance program and how much we can trust it. 

1. Trajectory of Illness
   For past H5N1 cases, is there a treatable "window of opportunity" before the infection becomes severe? How critical is it to determine whether mild cases might escalate and require aggressive intervention?

Very interested in this. 

1. Historical Epidemics
   I could pull together a list of relevant modern epidemics (human-to-human airborne transmission without an animal vector). Are there any specific criteria you'd like to prioritize?

The reference class is "things that got at least as far as H5N1 did this year"- widespread in livestock and with some humans infected.

1. Cross Immunity
   While cross immunity seems important, determining decision-relevant information may be challenging. Would you like a summary of existing knowledge or only actionable insights?

Medium priority for a summary of existing knowledge, bonus points for a quantitative model even if it's low confidence.

1. Respiratory Infection Dynamics
   Epidemiologists suggest that respiratory infections are deadlier lower in the lungs but more infectious higher in the system. Is this a fundamental tradeoff? Would a "both-and" virus be possible? What evolutionary advantages might viruses have in infecting the lower lungs?

If you happen to stumble on relevant information I'd like to hear it, but I don't want synthesis.

1. Government Stockpiles and Interventions
   What stockpiles of H5N1 vaccines exist? What options are available for increasing testing and vaccination of livestock? How are governments incentivizing medication, vaccine, and PPE production?

Yes to stockpiles, yes to shallow investigation of options for livestock.

1. Political Considerations
   Should we examine how a Trump presidency or similar political scenarios might influence the interaction between local and federal health agencies?

No.

1. Species-to-Species Spread
   The rapid spread of H5N1 to multiple bird and mammal species raises the question of whether humans will inevitably be affected. Is this worth exploring in-depth?

Yes.

1. Mortality and Long-term Effects
   What demographics do other flu strains tend to affect most? Are there long-term side effects comparable to "long COVID"?

We know who normally gets hit hardest by diseases, I'm only interested in deviation from that.

No to "long flu", because I am already convinced it exists but the data on it is bad.

1. Mutation and Vaccine Efficacy
   How quickly do flu strains, especially H5N1, tend to mutate? What implications does this have for vaccine efficacy and cross-reactivity? How much asymptomatic spread occurs with flu, and how long does it remain airborne?

Yes to mutation rate, especially if you can quantify what's needed to allow human-to-human transfer.

Yes to general flu knowledge like asymptomatic period and time airborne.

1. No Deaths Yet
   How should we update based on the fact that, contrary to past occurrences of H5N1 that had a ~50% CFR, none of the 58 confirmed cases have died?

 

This paper says there has been one death from the current clade. I'm very interested in knowing if that's correct. It also says tamiflu was found to reduce mortality in earlier, more deadly forms of H5N1.

That's a lot, so here are my top three priorities: vaccine efficacy (wide confidence intervals are fine), treatment efficacy, and likelihood of human-to-human transmission.

I'm having trouble parsing but I think the first point is about the mutation rate in humans? I don't expect that to be informative about flu virus except as a floor.

How sure are you that flu is generally spread through fluids? It seems like the medical system is ~prejudiced against the concept of airborne transmission. 

The use case is a lesswrong post people use to make decisions (which could be written by me, or you, but it's looking like @DirectedEvolution [LW · GW]).

This is outside the reference class I intended (needed at least one human case), but since I didn't specify that I'll award a token $10. Please let me know what your paypal is.

"Is there something better than tamiflu?" - Thank you for posing this question, I enjoyed researching it. 

I'm going to propose two candidates that could be superior against H5N1: Aspirin (acetylsalicylic acid) and Methylene blue (methylthioninium chloride). 

Aspirin 

First, consider aspirin’s safety profile. For short-term use—relevant in acute infections—the risks are minimal for most individuals. GI upset, often cited as a concern, is only marginally higher than placebo (source: PMC3586117). The notable exception is its association with Reye's syndrome in children, but this is exceptionally rare. The risk-benefit calculus remains favorable for adults, particularly in acute scenarios.

Efficacy-wise, aspirin’s NF-κB-inhibiting activity shows promise as an antiviral. It has demonstrated robust effects against H5N1 in vitro and in vivo (source: Wiley). This pathway is a compelling mechanism of action that Tamiflu does not directly address, positioning aspirin as a strong candidate for consideration.

Methylene blue

Next, methylene blue is another plausible alternative. Its safety profile for short-term use is generally acceptable, barring contraindications such as risk of serotonin syndrome, hypersensitivity, or severe renal impairment (source: Medsafe). For those without contraindications, it represents a well-tolerated option.

Methylene blue's broad-spectrum antiviral properties are underappreciated. It has shown potent virucidal activity against H1N1 (source: PMC8275569), and while H5N1-specific data is lacking, the mechanism of action suggests potential efficacy. Notably, there’s already a patent application exploring its antiviral indications (source: WO2007086995A2). Given this, methylene blue is a viable contender worthy of further clinical study.

Comparing with Tamiflu 

Tamiflu has well-documented side effects—nausea, vomiting, diarrhea, and abdominal pain—that overlap with the profiles of both aspirin and methylene blue (source: Medsafe Tamiflu). While tolerable for most, its mild benefits against H5N1 are unlikely to significantly outperform the mechanistic potential of aspirin or methylene blue (source: JHEOR).

Conclusion 

In a pandemic preparedness scenario, Aspirin and Methylene blue deserve serious consideration alongside Tamiflu. They offer distinct mechanisms of action, robust preliminary data, and manageable safety profiles. If you're prioritizing interventions that maximize cost-effectiveness and theoretical efficacy, these "old drugs" might hold the key to new antiviral strategies. Rational prioritization of research and clinical trials could unlock their full potential.

Disclaimer: I am not your doctor, please see a medical professional for personalized advice. The information presented is only for the interests of research and should not be interpreted as clinical advice. 

↑ comment by Elizabeth (pktechgirl) · 2024-12-11T18:36:10.068Z · LW(p) · GW(p)

Is this partially AI written? The reference to further clinical study seems weird.

Replies from: haotian-huang, haotian-huang

↑ comment by Haotian (haotian-huang) · 2024-12-15T13:22:51.356Z · LW(p) · GW(p)

I have posted this and following the advice of lesswrong members will clarify, the research was performed by me entirely late at night and passed through an LLM for readability. 

You can view the original here, I believe it fulfils your criteria for being credible suggestions:

Before:

Aspirin is a credible better candidate than Tamiflu. First off safety profile because you need to weigh up risks and benefits. Short term usage (what you're interested in for acute viral infections) is associated with GI upset, but only marginally more than placebo. There are of course other considerations that should be taken into account, but for the majority of users short term usage of aspirin is safe. Special note here about the association with aspirin and Reye's syndrome in children, the incidence of this is extremely low, but it is worth considering if your patient is under 16. In terms of efficacy against H5N1, it has demonstrated great success in vitro and in vivo acting via its NF-κB-inhibiting activity.

Methylene blue is also a credible better candidate than Tamiflu. Starting again with safety profile the gist is short term usage is generally safe unless you happen to be contraindicated. There are a few reasons and these briefly (NOT comprehensive do not take medicine based off this comment alone) (i) if you are at risk of serotonin syndrome (ii) known hypersensitivity (iii) severe renal impairment. If you are considering this medication I implore you to read at least the following data sheet. With that out of the way, how well does it work against H5N1? Efficacy-wise it has little-appreciated broad-spectrum antiviral properties. and has specifically demonstrated potent virucidal activity against H1N1 (H5N1 not yet tested to my knowledge). Interestingly, there is also a patent application for this indication. Taken together it could credibly be better. 

For balance, Tamiflu is also associated with many of the same common adverse side effects including nausea, vomiting, diarrhoea or abdominal pain. Side effects typically occur along a distribution of individual susceptibility and should be tolerable for most for all three drugs. However, efficacy wise, aspirin and methylene blue are both credible candidates at outperforming the benefits of Tamiflu against H5N1.

Replies from: pktechgirl

↑ comment by Elizabeth (pktechgirl) · 2024-12-19T18:13:26.325Z · LW(p) · GW(p)

Thank you for the explanation.

Is there a reason you deflected when I originally asked about AI assistance? To me that's a much bigger deal than the AI assistance itself.

Replies from: haotian-huang

↑ comment by Haotian (haotian-huang) · 2024-12-20T00:31:03.822Z · LW(p) · GW(p)

Yes. I have copied my shortform [LW · GW] here in its entirety: 

LessWrong, is this rational? I wrote a reply to Elizabeth's open bid for answers to her research questions in good faith. She replies not with anything substantive, but to claim it is written with AI. I'm happy for her to disagree with my answer, but flagging a difference in style to suggest low quality is not what I thought this community was supposed to be about. Cynically, one could suggest she doesn't want to make good on her offer ... For the record, I wrote it late at night and ran the response through an LLM to improve readability for her benefit. 

If you don't know what I'm talking about, see the most disliked comment on her post :) 

https://www.lesswrong.com/posts/bFvEpE4atK4pPEirx/correct-my-h5n1-research-usdreward [LW · GW]

To be clear, I no longer think you were trying to avoid making good on your offer. But at the moment I was irked and that's what it felt like from my perspective. 

↑ comment by Haotian (haotian-huang) · 2024-12-11T21:43:53.706Z · LW(p) · GW(p)

Why is reference to further clinical study weird? It is a credible alternative not a mainstream, thoroughly researched alternative. 

Replies from: pktechgirl

↑ comment by Elizabeth (pktechgirl) · 2024-12-12T03:06:05.411Z · LW(p) · GW(p)