Simon DeDeo on Explore vs Exploit in Science

Good news everyone: I’m getting into podcasting! 

As part of my investigation into how scientific paradigms are created, I hosted a talk by Simon DeDeo, Professor Of Many Topics at Carnegie Mellon and the Santa Fe Institute, recorded at the recent ILIAD conference in Berkeley. He discusses the idea of explore vs exploit in science. Spoiler: he comes down very hard on the exploit side, based primarily on a case study of Darwin. 

For the video averse among you, here’s the transcript

I have two more episodes in editing, but am on the hunt for more guests. I’m looking to talk to scientists or ex-scientists about how ideas are created and spread in their field. Bonus points if they can talk about Chaos, Complexity, or Catastrophe Theory in particular. 

Thanks to my Lightspeed Grants and my Patreon patrons for supporting this work.

Perplexity wins my AI race

Perplexity is the first generalized AI chatbot I’ve found useful enough to integrate into any part of my daily workflow, much less across multiple domains. It speeds me up enough that I’m planning an increase in my freelancing rate.

Perplexity has three key advantages:

  1. It provides citations, cleanly, in context
  2. It has the persona of a sharp human instead of an intolerable customer service agent. 
  3. It is useful (and sufferable) across a wide variety of domains. 

The citations are a bigger deal than they sound at first. I could of course google anything ChatGPT tells me and check the results, but that’s costly. I have to spin up a new mental thread (and browser tab), sort through Google’s increasingly shitty results, remember what claim I’m trying to check… the process eats up a lot of working memory at a time when it is scarce. If I wanted to trawl a sea of content farms I would have gone to Google in the first place. 

Perplexity’s high quality inline citations solve that . Want to check if a claim is justified? Click the number next to it and look for the relevant quote. Not a perfect substitute for a 30 hour literature search, but a lot of power per minute. I don’t have to spin up a new mental thread, so the whole thing feels much lower friction.  Also thus far I’ve never caught it in a hallucination on a question of fact, although if real answers are scarce it will sometimes do the thing where it draws increasingly tenuous connections instead of just telling me no. 

I also found perplexity easier to talk to while trying to learn some math and math history. It felt about as useful as my human tutor- better at some things, worse at others. 

Test Questions

The real test was which AI do I find myself using, and the answer to that is definitively Perplexity. But just for fun or in case I was wrong, I ran a few questions Perplexity through all major engines to see what they said. 

In all cases I used the top free model available. I have Perplexity Pro thanks to a promo, but I haven’t ended up finding Pro to be much of an improvement. I do expect to use the pro-only PDF-analysis tool in the near future. 

Comments from me are in italics and [brackets]

How do fractals relate to chaos theory?

I have a project investigating chaos theory as a case study in the development of scientific/mathematical paradigms. This doesn’t require I become a mathematician, but I do need to understand how discoveries relate to each other and generally not be an idiot on the topic. Perplexity is my always available, infinitely patient tutor.

This should have been a challenging role for an AI to fill, because I have a friend who loves explaining math more than almost anything, and did his PhD in a related area. I even feel comfortable looking stupid in front of him. And yet Perplexity still had a value add, because it was never offline and I didn’t feel a need to respect its time the way I would a friend’s. 

Perplexity (link to result including citations)

Fractals and chaos theory are closely intertwined concepts in mathematics and physics, with several key connections:

Self-Similarity and Complex Patterns

Fractals are geometric objects that exhibit self-similarity across different scales, meaning smaller parts resemble the whole. This property is often found in chaotic systems, where complex patterns emerge from simple rules.

Visualization of Chaotic Processes

Fractals frequently arise as visual representations of chaotic systems:

  • The Feigenbaum diagram, which illustrates population dynamics in chaos theory, displays fractal-like structures.
  • The Mandelbrot set, a famous fractal, is closely related to chaotic processes and can be used to visualize complex number behavior in iterative functions.

Characteristics of Complex Systems

Both fractals and chaos theory deal with complex systems that exhibit:

  • Non-linear behavior
  • Sensitivity to initial conditions
  • Intricate, repeating patterns

Applications in Financial Markets

In financial analysis, fractals and chaos theory are used to understand market behavior:

  • Fractals can represent underlying patterns in market movements, stripped of emotional “noise” and short-term shocks.
  • Chaos theory helps explain how markets can appear random but still follow deterministic rules.

[-1 for bringing up markets. That’s a use of both, but lots of things use two things without those things being related ]

Relationship to Complexity Theory

[This seems irrelevant but I think was prompted by context from previous questions]

While chaos and fractals are related, they are distinct concepts:

  • Chaos theory focuses on deterministic but unpredictable systems.
  • Fractals are more closely linked to complexity theory and emergent behavior.

Understanding the difference between chaos and fractals is crucial for properly characterizing complex systems like financial markets.

In essence, fractals often emerge as visual representations or outcomes of chaotic systems, providing a way to understand and analyze the complex, non-linear behavior that chaos theory describes. Both concepts contribute to our understanding of intricate, seemingly random phenomena in nature and various scientific fields.

ChatGPT 4o

  1. Fractals as Structures in Chaos: Fractals are often the geometric shapes that emerge from chaotic systems. In chaos theory, systems that appear random and unpredictable (chaotic) can produce complex patterns when visualized. These patterns are often fractal in nature, meaning they exhibit self-similarity at different scales. A classic example is the Mandelbrot set, a fractal that arises from a simple mathematical formula but exhibits infinitely complex boundary patterns.
  2. Sensitivity to Initial Conditions: One of the key aspects of chaos theory is the idea that small changes in the initial conditions of a system can lead to vastly different outcomes, a concept often described as the “butterfly effect.” When you visualize the behavior of chaotic systems, the resulting patterns often reveal fractal characteristics—structures that look similar at various levels of magnification. This sensitivity is mirrored in the recursive, infinite detail of fractals.
  3. Nonlinear Dynamics: Both chaos theory and fractals deal with nonlinear dynamics. In a chaotic system, nonlinear equations govern the evolution of the system, leading to behavior that seems random but is actually deterministic. The complexity and irregularity of fractals reflect the underlying nonlinear processes that produce them.
  4. Scale Invariance: Fractals exhibit scale invariance, meaning their structure looks similar at any magnification level. This property is often found in chaotic systems, where the same patterns or behaviors can appear at different scales of observation, whether in time or space.

In summary, fractals are often the visual and mathematical representations of the complexity inherent in chaotic systems. Chaos theory helps explain the underlying principles that lead to the formation of fractals, and fractals provide a way to visualize and understand the seemingly unpredictable nature of chaos.

Claude

Fractals and chaos theory are interconnected concepts in mathematics that deal with complex systems and their behavior. Here’s a concise overview of their relationship:

  1. Self-similarity: Fractals exhibit self-similarity at different scales, which is often seen in chaotic systems.
  2. Strange attractors: Many chaotic systems produce fractal structures called strange attractors when their behavior is mapped in phase space.
    [points to Claude on this one. It’s an important point that the others missed]
  3. Sensitivity to initial conditions: Both fractals and chaotic systems demonstrate extreme sensitivity to initial conditions.
  4. Natural phenomena: Fractals and chaos theory are used to model and explain various natural phenomena that exhibit complex, non-linear behavior.
    [again, two things being useful for a third thing doesn’t make them related]
  5. Iterative processes: Both concepts involve iterative processes that can lead to intricate patterns and unpredictable outcomes.
  6. Dimensionality: Fractal dimensions are often used to characterize chaotic attractors.

Would you like me to elaborate on any of these points or discuss a specific aspect of the relationship between fractals and chaos theory?

Google Search AI Summary

  • Fractal dimension
  • The fractal dimension of an attractor can indicate how deterministic a system is. A low fractal dimension means the data was generated by a deterministic system, while a high fractal dimension indicates a random system. 
  • Self-similarity
  • Fractals are infinitely complex patterns that repeat themselves at different scales, which is similar to the principles of chaos theory. Chaos theory studies how small changes in initial conditions can lead to large-scale, unpredictable outcomes. 
  • Geometry of chaos
  • Fractals are the geometry of chaos, and can be found in nature, such as snowflakes, ferns, and coastlines, as well as in human-made structures, such as architecture, art, and music. For example, the Voyager spacecraft noticed that Jupiter has complicated turbulent vortices that are chaotic geometry, and any geometrical object with that structure is called a fractal. 
  • Visual identity
  • Fractals are part of the visual identity of chaos theory. For example, the Mandelbrot set is a way of ordering all the Julia sets, which have a fractal-like structure. The Mandelbrot set is infinitely complex, but it also displays self-similarity with regions that look like the outline of the entire set. 

What a cool set of random facts with the word “fractal” in them, Google. 

How long after antibiotics is bordatello not contagious in cats? 

[note: misspelled, the real spelling is Bordatella]

I was supposed to adopt a kitten at the beginning of August. On the day I was supposed to take him home, the breeder found Bordatella in another cat in the home (this is the bacteria that causes kennel cough in dogs and whooping cough in humans; it doesn’t have a common name in cats). It was early in the morning, this was a stressful topic and, due to travel times, I had an hour to figure out if I would take him that day (and risk spreading Bordatella to my existing elderly cat) or wait. Perplexity really hit this one out of the park, but it was a complicated back and forth that doesn’t make for a good example here. 

I’m instead going to share this question I asked two weeks later, when I was trying to figure out if it was safe to bring the symptomatic-but-in-treatment kitten home.

ChatGPT was especially bad here. It was factually incorrect and spent 4 paragraphs reminding me to respect authority and eat my vegetables.

Perplexity (link to results including citations)

Based on the search results, there is no specific information about how long Bordetella remains contagious in humans after antibiotic treatment. However, we can draw some relevant insights from the information about Bordetella in cats and humans:

  1. For Bordetella pertussis (whooping cough) in humans, patients treated with antibiotics may be contagious for only 5 to 10 days after starting treatment.
  2. In cats, Bordetella bronchiseptica infections typically cause symptoms that persist for 7-10 days.
  3. Cats infected with Bordetella can shed the bacteria for an extended period, even after clinical signs have resolved. Some cats have been shown to shed the bacteria for at least 19 weeks after initial exposure.
  4. Antibiotics like doxycycline are usually effective in treating Bordetella infections in cats.

While these points don’t provide a definitive answer for humans, they suggest that the contagious period may be reduced to around 5-10 days after starting antibiotic treatment [this is what the source says, although I haven’t verified with other sources]. However, it’s important to note that this is an extrapolation from limited information, and the actual duration may vary depending on the specific Bordetella species and individual factors.

For accurate information about the contagious period of Bordetella in humans after antibiotic treatment, it would be best to consult with a medical professional or refer to guidelines from health authorities.

ChatGPT-4o

Bordetella bronchiseptica, the bacterium responsible for respiratory infections in humans, is less common in humans than in animals but can still be transmitted. The duration of contagiousness after starting antibiotics can vary depending on the individual, the severity of the infection, and the specific antibiotic used.

Generally, with many bacterial infections, including Bordetella, a person is often considered less contagious after 24 to 48 hours of appropriate antibiotic therapy [this is contradicted by the only source I checked, and dangerous. If ChatGPT gave sources maybe I could compare them]. This period allows the antibiotic to reduce the bacterial load to a level where the risk of transmission is significantly lowered.

However, it’s important to follow these guidelines:

  1. Complete the Antibiotic Course: Even if symptoms improve and contagiousness decreases, it’s crucial to finish the entire prescribed antibiotic course to fully eradicate the bacteria.
  2. Follow Medical Advice: Always consult with a healthcare provider to understand the specific recommendations based on your case, as the contagious period can vary.
  3. Hygiene Practices: Continue practicing good hygiene, such as covering your mouth when coughing and washing hands frequently, to minimize the risk of spreading the infection.

If you or someone you know is dealing with Bordetella bronchiseptica, it’s best to consult a healthcare professional for personalized advice on managing the infection and understanding when it is safe to resume normal activities without the risk of spreading the bacteria.

Claude 3.5

The contagious period for Bordetella (also known as kennel cough) in cats typically decreases significantly after starting antibiotic treatment. However, the exact timeline can vary. Here’s a general guideline:

  1. Typically, cats become less contagious within 2-3 days of starting antibiotic treatment.
  2. Most veterinarians recommend keeping infected cats isolated for at least 7-10 days after beginning antibiotics.
  3. The full course of antibiotics (usually 10-14 days) should be completed to ensure the infection is fully cleared.
  4. Some cats may continue shedding the bacteria for several weeks after treatment, even if they no longer show symptoms.

It’s important to note that individual cases may vary, and you should follow your veterinarian’s specific advice. They may recommend a different isolation period based on the severity of the infection and the cat’s response to treatment.

If you need more specific information about your cat’s situation, I recommend consulting with your veterinarian directly. They can provide tailored advice based on your pet’s individual case and current condition.

[This is a better written result than Perplexity but doesn’t cite sources and isn’t reliable enough to trust so doesn’t save me much work]

Google Search AI summary

No AI response, first page of results did not answer the question

Is the Aegis Shield Playful?

This one is kind of goofy; I was considering naming the new kitten Aegis but also wanted a name to signal playfulness. I knew the answer was going to be “no, are you insane?” but Perplexity made it feel cheap to check. 

All three engines got the right answer, but Perplexity took a stand and ChatGPT weaseled to avoid telling me no.

Perplexity

The term “playful” is subjective, but the Aegis Shield in gaming contexts often refers to its protective capabilities rather than a playful nature. For instance, in Final Fantasy, it provides strong defense against various status effects, while in Fire Emblem, it is valued for its strategic advantages despite some drawbacks. Overall, the Aegis Shield is more about utility and defense than playfulness.

ChatGPT 4o

The Aegis shield, rooted in Greek mythology, is not typically associated with playfulness. It is more often connected with protection, power, and divine authority. The Aegis was originally described as a protective cloak or shield carried by Zeus and Athena, symbolizing their might and the fear they could instill in their enemies.

However, in a creative or metaphorical sense, you could interpret the Aegis shield as playful if it’s part of a story, game, or artwork that reimagines it in a lighter or more whimsical context. Typically, though, its traditional associations are with seriousness, protection, and strength rather than playfulness.

Claude 3.5

I apologize, but I’m not familiar with a specific item or concept called an “Aegis Shield Playful.” There could be a few possibilities:

  1. If you’re referring to the mythological Aegis shield associated with Zeus and Athena in Greek mythology, it’s not typically described as playful. It’s usually portrayed as a powerful protective device.
  2. If this is related to a video game item, toy, or product, I don’t have specific information about it. Many games or products create their own versions of mythological items, sometimes with unique attributes.
  3. There might be a misunderstanding or typo in the question.

To provide an accurate answer, I would need more context about where you encountered this term or what specific item or concept you’re referring to. Could you provide more details or clarify the context of your question?

[Correct, but miserable to read]

Google Search AI summary

No AI response

Conclusion

I’m jinxing things a little by writing this after 3-4 weeks of work, but Perplexity has genuinely sped up my work in ways no other chatbot has managed. I am both delighted and scared of where we are on the AGI curve.

Acknowledgements and (lack of) COI

This post was financially supported by my Patreon patrons (thanks guys!) but not by any of the companies in question. Unless you count Uber One giving me a Perplexity Pro subscription that didn’t feature in this review. I have friends who work at Anthropic (which produces Claude) and a few other AI orgs, but AFAIK no one at Perplexity. 

Quick look: applications of chaos theory

Introduction

Recently we (Elizabeth Van Nostrand and Alex Altair) started a project investigating chaos theory as an example of field formation.[1] The number one question you get when you tell people you are studying the history of chaos theory is “does that matter in any way?”[2]. Books and articles will list applications, but the same few seem to come up a lot, and when you dig in, application often means “wrote some papers about it” rather than “achieved commercial success”. 

In this post we checked a few commonly cited applications to see if they pan out. We didn’t do deep dives to prove the mathematical dependencies, just sanity checks.

Our findings: Big Chaos has a very good PR team, but the hype isn’t unmerited either. Most of the commonly touted applications never received wide usage, but chaos was at least instrumental in several important applications that are barely mentioned on wikipedia. And it was as important for weather as you think it is. 

[1] This is a follow up to Elizabeth’s 2022 work on plate tectonics

[2] The second most popular is “oh you should read that book by Gleick”

Applications

Cryptography and random number generators- Strong No (Alex)

The wikipedia page for Chaos theory has a prominent section on cryptography. This sounds plausible; you certainly want your encryption algorithm to display sensitive dependence on initial conditions in the sense that changing a bit of your input randomizes the bits of your output. Similarly, one could imagine using the sequence of states of a chaotic system as a random number generator. However a quick google search makes me (Alex) think this is not a serious application.

I’ve seen it claimed [Footnote: in Chaos: a very short introduction, page 44, and in this youtube video] that one of the earliest pseudo-random number generators used the logistic map, but I was unable to find a primary reference to this from a quick search.

Some random number generators use physical entropy from outside the computer (rather than a pseudo-random mathematical computation). There are some proposals to do this by taking measurements from a physical chaotic system, such as an electronic circuit or lasers. This seems to be backward, and not actually used in practice. The idea is somewhat roasted in the Springer volume “Open Problems in Mathematics and Computational Science” 2014, chapter “True Random Number Generators” by Mario Stipčević and Çetin Kaya Koç.

Other sources that caused me to doubt the genuine application of chaos to crypto include this Crypto StackExchange question, and my friend who has done done cryptography research professionally.

As a final false positive example, a use of lava lamps as a source of randomness once gained some publicity. Though this was patented under an explicit reference to chaotic systems, it was only used to generate a random seed, which doesn’t really make use of the chaotic dynamics. It sounds to me like it’s just a novelty, and off-the-shelf crypto libraries would have been just fine.

Anesthesia, Fetal Monitoring, and Approximate Entropy- No (Elizabeth)

Approximate Entropy (ApEn) is a measurement designed to assess how regular and predictable a system is, a simplification of Kolmogorov-Sinai entropy. ApEn was originally invented for analyzing medical data, such as brain waves under anesthesia or fetal heart rate. It has several descendents, including Sample Entropy; for purposes of this article I’m going to refer to them all as ApEn. Researchers have since applied the hammer of ApEn and its children to many nails, but as far as I (Elizabeth) can tell it has never reached widespread usage.

ApEn’s original application was real time fetal heart monitoring; however as far as I can tell it never achieved commercial success and modern doctors use simpler algorithms to evaluate fetal monitoring data. 

ApEn has also been extensively investigated for monitoring brain waves under anesthesia. However commercially available products only offer Spectral Entropy (based purely on information theory, no chaos) and Bispectral Index

ApEn has been tried out in other fields, including posture, neurological issues, finance, and weather. I was unable to find any evidence any of these made it into practice, although if some day trader was making money with ApEn I wouldn’t expect them to tell me. 

Empirical Dynamical Modeling– Unproven (Elizabeth)

EDM is a framework for modeling chaotic systems without attempting to use parameters. It was first created by George Sugihara and Robert May (a prominent early advocate and developer of chaos theory), but Stephen Munch is the scientist most putting the tool into practice. Munch has an excellent-looking experiment in which he applies EDM to wild shrimp management (fisheries being one of two places you can make money with theoretical ecology[3]) and compares his output with other models. Alas, his results will not be available until 2041. At least they’ll be thorough.

Sugihara himself applied the framework across numerous fields (including a stint as a quant manager at Deutsche Bank), however his website for his consulting practice only mentions systems he’s modeled, not instances his work was put into practice. His work as an investment quant sounds like exactly the kind of thing that could show a decisive success, except there’s no evidence he was successful and mild evidence he wasn’t. 

Process note: one of the reasons I believed in the story of Chaos Theory as told in the classic Gleick book was that I (Elizabeth) studied theoretical ecology in college, and distinctly remembered learning chaos theory in that context. This let me confirm a lot of Gleick’s claims about ecology, which made me trust his claims about other fields more. I recently talked to the professor who taught me and learned that in the mid 00s he was one of only 2 or 3 ecologists taking chaos really seriously. If I’d gone to almost any other university at the time, I would not have walked out respecting chaos theory as a tool for ecology. 

[3] The other is epidemiology

Weather forecasting- Yes (Alex)

Weather forecasting seems to be a domain where ideas from chaos theory had substantial causal impact. That said, it is still unclear to me (Alex) how much this impact depended on the exact mathematical content of chaos theory; it’s not like current weather modeling software is importing a library called chaos.cpp. I think I can imagine a world where people realized early on that weather was pretty complicated, and that predicting it required techniques that didn’t rely on common simplifying assumptions, like locally linear approximations, or using maximum likelihood estimates.

Here is a brief historical narrative, to give you a sense of the entanglement between these two fields. Most of the below can be found in “Roots of Ensemble Forecasting” (Lewis 2004), although I have seen much of it corroborated across many other sources.

By the 1940s, weather forecasting was still being done manually, and there was not much ability to predict that far into the future. As large electronic computers were being developed, it became clear that they could provide substantially more computation for this purpose, perhaps making longer predictions feasible. John von Neumann was especially vocally optimistic on this front.

Initially people assumed that we would make useful weather predictions by doing the following; 1) formulate a dynamical model of the weather based on our knowledge of physics 2) program that model into the computer 3) take measurements of current conditions, and 4) feed those measurements into the computer to extrapolate a prediction for a reasonable timespan into the future. People knew this would be very challenging, and they expected to have to crank up the amount of compute, the number of measurements, and the accuracy of their model in order to improve their forecasts. These efforts began to acquire resources and governmental bodies to give it a serious go. Researchers developed simple models, which would have systematic errors, and then people would go on to attempt to find corrections to these errors. It sounds like these efforts were very much in the spirit of pragmatism, though not entirely consistent with known physical principles (like conservation of energy).

After a decade or so, various scientists began to suggest that there was something missing from the above scheme. Perhaps, instead of using our best-guess deterministic model run on our best-guess set of observations, we should instead run multiple forecasts, with variations in the models and input data. In case our best guess failed to predict some key phenomenon like a storm, this “ensemble” strategy may at least show the storm in one of its outputs. That would at least let us know to start paying attention to that possibility.

It sounds like there was some amount of resistance to this, though not a huge amount. Further work was done to make estimates of the limits of predictability based on the growth rate of errors (Philip Thompson, E. Novikov) and construct more physically principled models.

Around this point (the mid 1950s) enters Edward Lorenz, now known as one of the founding fathers of chaos theory. The oft-related anecdote is that he accidentally noticed sensitive dependence on initial conditions while doing computer simulations of weather. But in addition to this discovery, he was actively trying to convince people in weather forecasting that their simplifying assumptions were problematic. He impacted the field both by producing much good work and by being an active proponent of these new ideas. It is especially notable that the Lorenz system, a paradigmatic chaotic system, came from his deliberate attempt to take a real weather model (of convection cells in a temperature differential) and simplify it down to the smallest possible system that maintained both the chaotic behavior and the reflection of reality. By cutting it down to three dimensions, he allowed people to see how a deterministic system could display chaotic behavior, with spectacular visuals.

Through continued work (especially Edward Epstein’s 1969 paper “Stochastic Dynamic Prediction”) people became convinced that weather forecasting needed to be done with some kind of ensemble method (i.e. not just using one predicted outcome). However, unlike the Lorenz system, useful weather models are *very* complicated. It is not feasible to use a strategy where, for example, you input a prior probability distribution over your high-dimensional observation vector and then analytically calculate out the mean and standard deviation etc. of each of the desired future observations. Instead, you need to use a technique like Monte Carlo, where you randomly sample from the prior distribution, and run each of those individual data points through the model, producing a distribution of outputs.

But now we have another problem; instead of calculating one prediction, you are calculating many. There is an inherent trade-off in how to use your limited compute budget. So for something like two decades, people continued to use the one-best-guess method while computing got faster, cheaper and more parallelized. During this wait, researchers worked on technical issues, like just how much uncertainty they should expect from specific weather models, and how exactly to choose the ensemble members. (It turns out that people do not even use the “ideal” Monte Carlo method mentioned above, and instead use heuristical techniques involving things like “singular vectors” and “breeding vectors”)

In the early 1990s, the major national weather forecast agencies finally switched to delivering probabilistic forecasts from ensemble prediction systems. The usefulness of these improved predictions is universally recognized; they are critical not just for deciding whether to pack an extra jacket, but also for evacuation planning, deciding when to harvest crops, and staging military operations.

Fractals- Yes (Elizabeth)

Fractals have been credited for a number of advancements, including better mapping software, better antennas, and Nassim Taleb’s investing strategy. I (Elizabeth) am unclear how much the mathematics of fractals were absolutely necessary for these developments (and would bet against for that last one), but they might well be on the causal path in practice.

Mandelbrot’s work on phone line errors is more upstream than downstream of fractals, but produced legible economic value by demonstrating that phone companies couldn’t solve errors via their existing path of more and more powerful phone lines. Instead, they needed redundancy to compensate for the errors that would inevitably occur. Again I feel like it doesn’t take a specific mathematical theory to consider redundancy as a solution, but that may be because I grew up in a post-fractal world where the idea was in the water supply. And then I learned the details of TCP/IP where redundancy is baked in. 

Final thoughts

Every five hours we spent on this, we changed our mind about how important chaos theory was. Elizabeth discovered the fractals applications after she was officially done and waiting for Alex to finish his part.

We both find the whole brand of chaos confusing. The wikipedia page on fractals devotes many misleading paragraphs to applications that never made it into practice. But nowhere does it mention fractal antennas, which first created economic value 30 years ago and now power cell phones and wifi. It’s almost like unproductive fields rush to invoke chaos to improve their PR, while productive applications don’t bother. It’s not that they hide it, they just don’t go out of their way to promote themselves and chaos. 

Another major thread that came up was that there are a number of cases that benefited from the concepts of uncertainty and unpredictability, but didn’t use any actual chaos math. I have a hunch that chaos may have provided cover to many projects whose funders and bosses would otherwise have demanded an impossible amount of predictability. Formal chaos shouldn’t have been necessary for this, but working around human stupidity is an application. 

Acknowledgements

Thank you to Lightspeed Grants and Elizabeth’s Patreon patrons for supporting her part of this work. Did you know it’s pledge drive week at AcesoUnderGlass.com?

Please support this blog (with money)

Short version

It has always felt like a gift that people read things I write, and I enjoyed reciprocating that by sharing my writing for free.  Until recently I had enough income to pull that off and still cover material needs. That is no longer true, and while it is not an urgent problem, I would like to solve it while that is still true. However it’s important to me to keep this blog free. To square this, I’m asking for your support. If you value this blog and can comfortably do so, please consider sending some of that value back my way via Patreon or Paypal.

Long version

I love my work and this blog. Clients paying me to learn interesting things that they immediately use to help people would be amazing on its own, but then grantmakers pay me to do more speculative EV projects of my choosing. Then I get to publish my work and help more people. I’m incredibly fortunate to do this, and at a wage that supports a good lifestyle in a reasonable number of hours.

Unfortunately, I can’t work a reasonable number of hours. It’s been years since I could work a full work-week, but until recently I could still work enough. That stopped being true this winter (short version: furniture grew mold leading to a devastating health cascade).  I spent months barely able to work while firehosing money at the medical system (ballpark total cost: $100,000, plus an intense desire to own my own home). I’m doing much better although not fully healed now and God willing this was a one time thing, but 10 years ago I needed a year off work for dental surgery, and I’ll consider myself lucky if it takes 10 years before my next “one off” multi-month health problem. My limited hours in good times aren’t enough to make up for the total absence of hours in bad times. Disability insurance refused to sell to me at any price back when I had an excellent work attendance record and very minor medical issues, so I assume they’d use a flamethrower if I tried now. This has me interested in finding ways to decouple my income from my working hours.

The obvious thing to do is monetize this blog. Except I hate gating zero-marginal-cost content, especially health content. It keeps out the people who most need the help. It’s also hard to match price to value – any given post could be a waste of your time or a life changing intervention, and you may not know which for years. So I don’t want to do any kind of paywall. Instead, I’m asking for voluntary contributions, based on your evaluation of the value my work has provided you. That way you can match price to value, no one gets locked out of content they need, and I can invest in this blog while staying financially secure. 

How to give me money

If you’d like to make a one-time payment, you can paypal me at acesounderglass@gmail.com. This will get me caught up on this winter’s lost income and medical expenses. If your generosity exceeds Paypal’s petty limitations or you just prefer a different format, email me at that same address and we’ll work something out. 

If you would like to give ongoing support, you can join my Patreon. This will let me spend more time on my top-choice project and invest more in this blog on an ongoing basis. I’ve recently added real rewards to my patreon, including a discord, live calls for each post, and for the most discerning of patrons, all the plankton you can eat. For the moment these are experimental, and you can help me out by telling me what you’d like to see. 

If you’re already a Patreon patron – first of all, thank you. Second, take a look at the new tiers. I’m not allowed to switch you to reward tiers even if you’re already giving enough to qualify for them, and the $1 tier has been removed. 

If you would like to give one-time support to specific projects: watch this space. Once my current projects wrap up, I plan on putting some projects on Manifund, which is nonprofit Kickstarter with an impact certificate market attached. 

Current and Potential Projects

If you’re providing forward-looking money, you might care about what kinds of things that money will go towards. I don’t want to make promises, but this list should give you some idea of what I am working on now and might do in the near future: 

  • I have at least one more investigation (salt water gargle) in my series on interventions for upper respiratory infection.
  • I am investigating the development of mathematical and scientific paradigms. Right now the nominal focus is a case study of chaos theory, but the current winds are blowing it towards something more like “when science became uncertain”.
    • In my dream world there are lots of follow-ups to this project. 
  • Research on stimulant usage. I originally conceived of this as a lit review, but based on preliminary work I think my frame might be more like “stimulant usage as a learnable skill”.
    • The lit review version of this received a grant from Lightspeed Grants, but I redirected it (with permission) to the respiratory infection work. Lightspeed is alas no longer with us so can’t fund the project a second time.
  • Oops health becomes my full time job again and I have to spend 10 hours/day taking care of myself and another 10 sleeping.
  • I have at least six drafts in a series on cults and eucults. This never gets to the top of my list because untangling the dependencies is very time consuming.
  • Every year or two I have a fantastic post on something random. I don’t know what the next Luck Based Medicine or Power Buys You Distance From The Crime is but I’m confident there will be one. 
  • Feedback loops for exercise.
  • Compare AI-based research tools. 
  • Improve my writing. For the in-the-weeds science-y posts I’d qualify my writing as “fine”. I’d like to do better, but the world is full of things that are more fun or more income generating so it never reaches the top of the list. Patreon would create more incentive and more slack to pursue this. 

Counterarguments

Fungibility

One reason you might choose not to contribute is if you think this will funge against money from institutions with deep pockets.  I think funging
will be minimal because:

  • I asked two grantmakers if this was a risk. Both said the median impact was zero, one put the 99th percentile funging at 20-30%
  • There may not be grant funding available for me at all. My biggest granter, Lightspeed, no longer exists, and other grantmakers who’ve funded me are not good fits for upcoming projects. 
  • Assuming there was a grantmaker, I don’t think I could talk them into paying me enough to self-fund disability insurance. But I do think I can talk them into viewing small donor support as funding medically-imposed downtime that shouldn’t funge with grants. So however much they’d reduce funding to someone capable of full-time work, I should suffer less than that. 

This is only true to a point: at (wild-ass guess) $200k/year off my blog I expect grantmakers (assuming there are any relevant to me) to cease funding anything unless it has significant expenses or can’t be published, and I wouldn’t disagree with that choice. 

It’s also only true for back-support and patreon. I expect Manifund-type funding to funge pretty directly, although there’s something matching-like in that the more money I make elsewhere, the more comfortable I feel accepting unaligned grant money. 

[I showed this section to one of those grantmakers and he said it “Seems pretty reasonable”, which I interpret as he’s not committing to any particular detail but nothing is so wrong it’s easy to correct]

Low-urgency

I view my health as a giant ball of debt. The payments are steep and will eventually overwhelm my savings, but not today, and not in the next year either. There is time for the king to die, the horse to die, or the horse to learn to talk. I’m asking now because I feel far more comfortable asking for modest payment for value provided than crying for a large bailout after it becomes an emergency. But I don’t want to trick anyone into thinking my situation is desperate before it becomes so.

I mentioned that this experience left me with a burning desire to own my house. I should clarify that the mold problem was (probably) in my furniture, not the walls, and is (probably) fixed now, so I don’t need to move in the immediate future. However I am very tired of moving and landlords and environmental toxin roulette. I dream of living in a place that, should I discover mold, or the heating system is untenable, or the paint chips off when you breathe on the wall, I will have the power to fix it. I’m also so tired of moving.

Why I want this blog to stay free

  1. I meant it when I said having a readership is a gift and paywalling posts changes that relationship in ways I don’t like
  2. I prefer a world when goods with zero sharing cost are freely shared. Mandatory monetization destroys the value from people who would have benefited from a post a little but not enough to justify the price, or for whom a particular post would be immensely valuable but there’s no way to know that ahead of time.
  3. This goes double for goods intended to help vulnerable people, such as those with health issues. 
  4. There’s no good way to price blog posts with such range in value. What I really want is a fraction of my shapley value in improving your life, but you that’s impossible to calculate even in retrospect. 
  5. I prefer a world where people read a wide variety of things, instead of Substack World where people pay noticeable money to read their 5 favorites and only their 5 favorites. 

Conclusion

If you decide to contribute to this blog, thank you. It means a lot to me both symbolically and materially.

If you’re one of my 28 existing patrons, double thanks to you for contributing back when the option was hard to find. I look forward to seeing some of you in the new discord and live calls. 

Humming is not a free $100 bill

Last month I posted about humming as a cheap and convenient way to flood your nose with nitric oxide (NO), a known antiviral. Alas, the economists were right, and the benefits were much smaller than I estimated.

The post contained one obvious error and one complication. Both were caught by Thomas Kwa, for which he has my gratitude. When he initially pointed out the error I awarded him a $50 bounty; now that the implications are confirmed I’ve upped that to $250. In two weeks an additional $750 will go to either him or to whoever provides new evidence that causes me to retract my retraction.

Humming produces much less nitric oxide than Enovid

I found the dosage of NO in Enovid in a trial registration. Unfortunately I misread the dose-  what I original read as  “0.11ppm NO/hour” was in fact “0.11ppm NO*hour”. I spent a while puzzling out what this meant, with the help of Thomas Kwa, some guy on twitter, and chatGPT (the first time it’s been genuinely useful to me). My new interpretation is that this means “actual concentration upon application*1 hour/time at that concentration”. Since NO is a transient molecule, this means my guess for the amount of NO in Enovid was off by 2-3 orders of magnitude.

My estimates for the amount of NO released by humming may also be too high. I used this paper’s numbers for baseline NO concentration. However the paper I used to estimate the increase gave its own baseline number, which was an order of magnitude lower than the first paper.

This wasn’t intentional cherrypicking- I’d seen “15-20x increase in concentration” cited widely and often without sources. I searched for and spotchecked that one source but mostly to look at the experimental design. When I was ready to do math I used its increase but separately looked up the baseline concentration, and found the paper I cited.

I just asked google again and got an even higher estimate of baseline nasal concentration, so seems like there is a great deal of disagreement here.

If this were the only error I’d spend the time to get a more accurate estimate. But it looks like even the highest estimate will be a fraction of Enovid’s dose, so it’s not worth the energy to track down.

Using the new values, you’d need 28 minutes of humming to recreate the amount of NO in Enovid (spreadsheet here). That wouldn’t be so bad spread out over 4-6 hours, except that multiple breaths of humming in a row face diminishing returns, with recovery to baseline taking 3 minutes. It is possible to achieve this in 6 hours, but only just. And while it’s not consequential enough to bother to look it up, I think some of the papers applied Enovid more often than that.

This leaves humming in search of a use case. People who care a lot about respiratory illnesses are better off using Enovid or another nasal spray. People who don’t care very much are never going to carefully pace their humming; and the amount of humming they might do won’t be very effective. The only use case I see is people who care a lot and are pushed into a high risk situation without notice, or who want a feeling of of Doing Something even if it is not doing very much at all.

Reasons to not write off humming entirely

The math above assumes the effect is linear with the amount of NO released, regardless of application time. My guess is that frequent lower doses are more effective than the same amount as a one off. Probably not one effective enough to give humming a good non-emergency use case though.

Another possibility is that Enovid has more nitric oxide than necessary and most of it is wasted. But again, it would have to be a lot moreto make this viable.

Conclusions

Humming hasn’t been disproven as an anti-viral intervention, but the primary reason I believed it worked has been destroyed. I will be observing a six week period of mourning for both my hope in humming and generally feeling dumb.

The fact that I merely feel kind of dumb, instead of pricing out swords with which to commit seppuku, is thanks to the little angel that sits on my shoulder while I write. It constantly asks “how will you feel about this sentence if you turn out to be wrong?” and demands edits until the answer is either “a manageable amount of unhappy” or “That’s not going to come up”. This post thoroughly tested her work and found it exemplary, so she will be spending the next six weeks partying in Vegas.

[RETRACTED] Do you believe in hundred dollar bills lying on the ground? Consider humming

Introduction

[Reminder: I am an internet weirdo with no medical credentials]

A few months ago, I published some crude estimates of the power of nitric oxide nasal spray to hasten recovery from illness, and speculated about what it could do prophylactically. While working on that piece a nice man on Twitter alerted me to the fact that humming produces lots of nasal nitric oxide. This post is my very crude model of what kind of anti-viral gains we could expect from humming.

ETA 6/6: I made a major error in this post and its numbers are incorrect. The new numbers show that matching Enovid’s nitric oxide content, or even getting close enough for a meaningful effect, takes way more humming than anyone is going to do.

I’ve encoded my model at Guesstimate. The results are pretty favorable (average estimated impact of 66% reduction in severity of illness), but extremely sensitive to my made-up numbers. Efficacy estimates go from ~0 to ~95%, depending on how you feel about publication bias, what percent of Enovid’s impact can be credited to nitric oxide, and humming’s relative effect. Given how made up speculative some of these numbers are, I strongly encourage you to make up  speculate some numbers of your own and test them out in the guesstimate model.

If you want to know how nitric oxide reduces disease, check out my original post.

Math

Estimating the impact of Enovid 

I originally estimated the (unadjusted) efficacy of nitric oxide nasal sprays after diagnosis at 90% overall reduction in illness, killing ~50% of viral particles per application. Enovid has three mechanisms of action. Of the papers I looked at in that post, one mentioned two of the three (including nitric oxide) a second mechanism but not the third, and the other only mentioned nitric oxide. So how much of theat estimated efficacy is due to nitric oxide alone? I don’t know, so I put a term in the guesstimate with a very wide range. I set the lower bound to ⅓ (one of three mechanisms) to 1 (if all effect was due to NO). 

There’s also the question of how accurate the studies I read are. There are only two, they’re fairly small, and they’re both funded by Enovid’s manufacturer. One might reasonably guess that their numbers are an overestimate. I put another fudge factor in for publication bias, ranging from 0.01 (spray is useless) to 1 (published estimate is accurate).

How much nitric oxide does Enovid release?

This RCT registration uses a nitric oxide nasal spray (and mentions no other mechanisms). They don’t give a brand name but it’s funded by the company that produces Enovid. In this study, each application delivers 0.56 mL of nitric oxide releasing solution (NORS) (this is the same dose you get from commercial Enovid), which delivers “0.11ppm [NO]*hrs”. 

There’s a few things that confusing phrase could mean:

  • The solution keeps producing 0.11ppm NO for several hours (very unlikely). 
  • The application produces 0.88ppm NO almost immediately (0.11*8, where 8 hours is the inter-application interval), which quickly reacts to form some other molecule. This is my guess, and what I’ll use going forward. It won’t turn out to matter much. 
  • Some weirder thing. ETA 5/25: Thomas Kwa points out that the registration says “0.11ppm*hrs” not “0.11ppm/hr”. I’m on a tight deadline for another project so haven’t been able to look into this; it definitely seems like my interpretation is wrong, but I’m not sure his is right. I’ve reached out to some biology friends for help.

How much nitric oxide does humming move into the nose?

Here we have much more solid numbers. NO concentration is easy to measure. Individuals vary of course, but on average humming increases NO concentration in the nose by 15x-20x. Given baseline levels of (on average) 0.14ppm in women and 0.18ppm in men, this works out to a 1.96-3.42 ppm increase. More than twice what Enovid manages.

The dominant model is that the new NO in the nose is borrowed from the sinuses rather than being newly generated. Even if this is true I don’t think it matters; sinus concentrations are 100x higher than the nose’s and replenish quickly. 

Estimating the impact of humming

As far as I can find, there are no published studies on  humming as an antimicrobial intervention. There is lots of circumstantial evidence from nasal vs. mouth breathing, but no slam dunks. So I’m left to make up numbers for my Guesstimate:

  • Paper-reported decline in illness due to spray (0.9) 
  • Proportion of effect due to NO (0.33 to 1)
  • Adjustment for publication bias (.01 to 1)
  • Adjustment for using prophylactically rather than after diagnosis (0.75 to 2.5) (set this to 1 if you want to consider post-diagnosis use)
  • Bonus to humming due to higher NO levels and more frequent application (1 to 5) 
  • I capped the results so they couldn’t suggest that the effect size was less than 0  or greater than 1, and then applied the nasal-infection discount. 
  • Proportion of infections starting in the nose (because infections in the throat should see no effect from humming) (0.9 to 1) (set this to 1 if you believe the spray effect estimate already includes this effect)

From that I get an estimate of effect of 0 to 0.98, with an average of 0.67. This is of course incredibly sensitive to assumptions I pulled out of my ass. If you prefer numbers from your own ass, you can enter them into my model here. For comparison, microcovid.org estimates that masks have an efficacy against of 33% (for thick, snug cloth masks) to 87% (well-sealed n95s). 

How to hum

Here is what I’ve advised my elderly parents, and will use myself once I find a way to keep it from activating the painful nerve damage in my jaw:

  • This really is normal humming, just be sure to exhale entirely through your nose.
    • If you google “how to hum” you will mostly get results on singing exercises, which I think are suboptimal. This very annoying video has decent instructions on how to hum with your lips sealed. 
    • Higher pitch (where the vibration lives more in the nose and less in the throat) should be more effective, but making it easy to do is probably more important.
    • You only need to do one breath per session, after that you face diminishing returns.
  • Once per hour is probably overkill, but it’s also easy to remember. Alternately, pick a trigger like entering a room or opening Twitter.
    • A beta reader asked if it was worth waking up in the middle of the night to hum. I’m still not a doctor, but my immediate reaction was “Jesus Christ no”. Sleep is so important, and once per hour is a number I made up for convenience. However if you happen to wake up in the middle of the night, I expect that’s an especially valuable time to hum.
  • The less time between exposure and humming, the better. Since you can’t always know when you’ve been exposed, this suggests humming during and after every high risk event, or making it an everyday habit if you find it cheap.
  • How long after? For Enovid I made up a plan to use it for one full day after the last high risk period, which my very crude math estimates gives your body an extra day to ramp up your immune system. 

Are there downsides?

Everything with a real effect has downsides.  I’m struggling to come up with ones that won’t be immediately obvious, like vibrating a broken nose or annoying your spouse, but I’ve been surprised before.

One possible source of downsides is that the nitric oxide was more valuable in the sinuses than the nose. This doesn’t worry me much because sinus levels are 100x nasal levels, and judging from the exhalation experiments sinus levels completely recover in 3 minutes. 

The barest scraps of other evidence

This (tiny) study found that Bhramari Pranayama (which includes humming) reduced sinusitis more than conventional treatment. But the same size of 30 (per group) and lack of a no-treatment group makes this hard to take seriously.

There appeared to be a plethora of literature that nasal breathers had fewer respiratory infections than mouth breathers. I wouldn’t find this convincing even every study showed a strong effect (because it’s over such a long time period and impossible to track causality), so I didn’t bother to investigate. 

Some dude may or may not have eliminated his chronic rhinosinusitis (inflammation of nose and sinuses) that may or may not have had an infectious component by humming, which may or may not have worked by increasing nasal nitric oxide. He used a very different protocol that to my eye looks more likely to work via sheer vibration than by nitric oxide, especially because a lot of his problem was located in the sinuses.

Reasons to disbelieve

  1. If my model is correct, humming is the equivalent of finding a paper sack full of hundred dollar bills on the ground. Both the boost from humming and the immune function of NO have been known for decades; medical research would have to be really inadequate to produce so little data on this. 
  2. All of the data on the impact of nasal nitric oxide is on covid; maybe NO is less effective on other viruses.
  3. If nasal nitric oxide is so great, why did evolution give us the nasal NO concentration it did?
    1. I love me a good evolution-based argument, but I think they’re at their weakest for contagious diseases. Relative to the ancestral environment we have a much easier time finding calories to fuel our immune system and diseases with which to keep it busy, so we should expect our immune systems to be underpowered. 
  4. If humming has any effect outside the nose, it has got to be tiny. 

Conclusion

Hourly nasal humming might be as effective as masks at reducing respiratory infections. The biggest reasons to disbelieve are the paucity of data, and skepticism that society would miss something this beneficial. If you’re the kind of person who looks at an apparent hundred dollar bill on the ground and gets excited, humming seems like an unusually good thing to try. But if the pursuit of loose bills feels burdensome or doomed, I think you should respect your instincts.

I have an idea for how to generate more data on humming and respiratory illnesses, but it requires a large conference in winter. If you’re running a conference with 500+ nerds, in your local winter, with a majority of attendees coming from locations in local winter, I’d love to chat. You can reach me at elizabeth@acesounderglass.com.

Betadine oral rinses for covid and other viral infections

Before we get started, this is your quarterly reminder that I have no medical credentials and my highest academic credential is a BA in a different part of biology (with a double major in computer science). In a world with a functional medical system no one would listen to me. 

Tl;dr povidone iodine probably reduces viral load when used in the mouth or nose, with corresponding decreases in symptoms and infectivity. The effect size could be as high as 90% for prophylactic use (and as low as 0% when used in late illness), but is probably much smaller. There is a long tail of side-effects. No study I read reported side effects at clinically significant levels, but I don’t think they looked hard enough. There are other gargle formulas that may have similar benefits without the risk of side effects, which are in my queue to research.

Benefits

Math

One paper found a 90% decrease in salivary viral load after mouthwash use (which probably overestimates the effect). Another found a 90% reduction in bad outcomes, with treatment (in mouth, nose, and eyes) starting soon after diagnosis. I suspect both of these are overestimates but 1. 90% reduction is a fantastic upper bound to have 2. Neither of these looked at prophylactic use. A third study found a significant reduction in viral DNA after usage, but did not quantify that by viral load or outcomes. 

I feel like if povidone iodine was actually that good we’d have heard about it before. OTOH mouthwash formulations are barely available in the US, and most of these studies were in Asia, so maybe it went to fixation there years ago and the west is just catching up. 

So I’m going to call this 9-45% reduction in illness timeXintensity when used after symptom onset. Before onset ought to be higher, my wild ass guess is up to 90%. 

One reason I think earlier use is better is that, at least with covid, most of the real damage happens when the virus reaches the lungs. If iodine gargles can form a firewall that prevents an upper respiratory infection from becoming a lower respiratory infection, you’ve prevented most (although not all) of the worst outcomes.

Papers

I livetweeted every paper I read, collected here. I don’t want to brag, but those tweets were very popular among ladies with large boobs and 10 numbers in their twitter handles. So if that’s your type you should definitely check out those threads. Everyone else will probably find them tedious, so I’m going to summarize the most relevant papers here.

Estimating salivary carriage of severe acute respiratory syndrome coronavirus 2 in nonsymptomatic people and efficacy of mouthrinse in reducing viral load: A randomized controlled trial

This study had participants rinse their mouth with one of four mouthwashes, and compared the pre-mouthwash salivary viral load with the viral load 15 and 45 minutes later. The overall effect was very strong: 3 of the washes had a 90% total reduction, and the loser of the bunch still had a 70% reduction (error bars fairly large). 

Note that despite the title, they only gave mouthwashes to participants with symptoms.

My guess is this is an overestimate of impact, because I expect an oral rinse to have a larger effect on saliva than on cellular levels. I wish they’d tested 4-6 hours later, after the virus had had some time to regrow.

Effect of 1% Povidone Iodine Mouthwash/Gargle, Nasal and Eye Drop in COVID-19 patient 

On one hand, this paper features significant ESL issues, missing data, terrible presentation of other data, and was published in a no-name journal. On the other hand, it had one of the best study designs and 30x the number of participants of other studies. I’d love to discard this paper but there aren’t better options.

We see an almost 90% reduction in testing positive on the third day. I suspect that overstates the results because it lowers salivary or nasal fluid viral load more than cellular load, so let’s look at outcomes:

90% reduction in hospitalization, 85% reduction in oxygen use, and  88% reduction in death. 

I was skeptical of these numbers at first, especially because they only tell you the total number of an age/sex group in the study, and the number of people in a demographic group with a bad outcome. Their percentages also don’t work out properly, making it hard to see the real impact. 

Luckily almost everyone in the control group was still PCR positive on day 3, which is almost like having a participant count. The number of control participants still sick on day 3 is indeed about half of every demographic. This doesn’t rule out trickier stuff like putting people at the higher end of their age band in the control group, but it’s a good deal better than that one paper where the youngest person in the control group was a year younger than the oldest person in the treatment group. 

The short-term effect of different chlorhexidine forms versus povidone iodine mouth rinse in minimizing the oral SARS-CoV-2 viral load: An open label randomized controlled clinical trial study

I originally ignored this paper, because it only reported Ct values and not outcomes or viral load.* However the previous two papers are from the same author and have shockingly concordant results, and I wanted a second opinion. 

[*Ct value = how often you have to run the PCR machine on a sample to get over a particular threshold. This corresponds to viral load but the relationship is complicated and variable. A higher Ct value means lower viral load]

The most important finding is that Ct went up by 3.3 (S genes) and 4.4 (E genes). 

N=12 so I’m not thrilled with this study, but pickings are slim. 

Side Effects, Or: Should I just gargle iodine all the time then?

Barring very specific circumstances, I wouldn’t. There are several issues that give me pause about long term continuous use.

Hyperthyroidism

Povidone iodine skin washes can cause hyperthyroidism in infants. Among adults, many studies found increases in Thyroid Stimulating Hormone (an indicator of issues but not itself terrible), but not T3 or T4 (directly casual to outcomes). These studies tend to be small and in some cases used the wrong statistical test that missed a long tail clearly visible in their plots, so I assume there exist people for whom this creates a clinically significant effect, especially after prolonged use.

I didn’t include this paper when calculating health benefits, because its control group was too different from its treatment group. But it’s still potentially useful for tracking side effects (although at n=12, it’s still pretty limited). It found a 50% increase in TSH after a week of treatment, but no change in T3 or T4. TSH returned to normal within 12 days of ceasing treatment. That’s not worrisome for healthy people on its own, but could easily reach worrisome with longer use or a vulnerable patient. 

Tissue damage could leave you worse off?

There is a long history of aggressive use of topical antimicrobial treatments leaving users worse off due to long term tissue irritation. This is why proper wound treatment changes every decade. That same study looked at this and found no increase in cellular irritation in the throat after six months of use. It’s possible they didn’t look hard enough, or they didn’t have sufficient sample size to catch the effect. It’s also possible the species that invented ghost peppers for fun has a throat surface built to handle irritation and iodine is too weak to hurt us

Oral microbiome damage could leave you worse off?

No one studied this at all, but it looks to me like an obvious failure point. I already use oral probiotics, but if I didn’t I would add them in while using iodine.

How to use

0.5% povidone iodine is sold under the brand name Betadine. You can also buy more concentrated povidone iodine and dilute it yourself. You might be tempted to use a higher concentration, but: 1. Remember the long tail of side-effects. 2. There’s some weird evidence that higher concentrations are less effective. I didn’t dig into this very weird claim but you probably should if you plan to try it. 

The Betadine bottle recommends gargling 10ml for 30s, 4x/day. The short term studies used 4-6x/day. Spacing that out is nontrivial attention tax, so when I was sick I just put the bottle on my bathroom sink and used it every time I used the bathroom. This probably comes out to more than 6x/day (especially when I’m sick and chugging fluids), but I also didn’t use a full 10ml and rarely made it to a full 30s, so hopefully it balanced out. 

More Data Needed

The state of existing knowledge around iodine gargles is poor. This is especially frustrating because I don’t think it should be that challenging to gather more. I’m toying with a plan to fix this, but will publish separately since it’s not specific to iodine. 

For financial support I would like to thank my Patreon supports and Lightspeed grants.

Nitric oxide for covid and other viral infections

Epistemic status: I spent about 5 hours looking into this, and the next day developed covid myself.  I did a bit more research plus all of the writing while sick. So in addition to my normal warning that I have no medical credentials, you should keep in mind that this knowledge may be cursed. 

ETA 4-30-24: In this post I used “nitric oxide spray” and “enovid” as synonyms. I’ve since learned this is incorrect, NO is one of several mechanisms Enovid uses. The other mechanisms weren’t mentioned in the papers I cite so it’s possible these are accurate for NO alone.

Introduction

Nitric Oxide Nasal Spray, sold under the brand name Enovid, is a reactive compound that kills viruses (and I suspect taxes your nasal tissue). It has recently been tested and marketed for treatment of covid. The protocol I found in papers was 2 sprays per nostril every 2-3 hours, after you develop symptoms. Enovid’s instructional pamphlets say twice per day, also after you get sick. This seems a little late to me.

I suspect the real power of NONS lies in use before you develop symptoms, ideally as close to exposure as possible. This is difficult because you don’t know when you would have gotten sick, and I suspect there are costs to indefinite use. I initially thought (and told people, as a tentative guess) that one round of 4 total sprays after a high risk event was a good trade off. After doing the math for this post, that intervention seems much less helpful to me, and picking the right length of post-exposure prophylaxis depends on equations for which we lack good numbers. I pulled some numbers out of my ass for this post, but you should not trust them. 

My guess is NONS is minimally useful once covid has reached the throat, unless you combine it with a separate disinfectant of the throat. I hope to write up a report on one such disinfectant soon, although TBH it’s not looking good. 

NONS can lead to false negatives on any test based on a nasal swab, because it breaks the relationship between nasal viral load and overall load.

How does it work?

First, nitric oxide is highly reactive, which makes it destructive to anything organic. Virions are fragile to this kind of direct attack, and certain immune cells will produce nitric oxide to kill bacteria, viruses, and your own diseased cells.

First-and-a-half, nitric oxide may alter the pH of your nose, and this effect may last well past the death of the original NO molecules. This was an aside in one paper, and I haven’t followed up on it. 

Second, nitric oxide is a signaling molecule within your body, probably including but definitely not limited to the immune system. I assume the immune system uses it as a signal because it serving a functional purposes. For the rest of body the selling point appears be that it crosses membranes easily but dies quickly, making it useful when the body wants the signal to fade quickly. Viagra works by indirectly increasing your body’s synthesis of nitric oxide. 

How well does it work?

Good question, and it depends a lot on how you use it.

My best guess is that a single application (2 sprays in each nostril) of Envoid ~halves the viral load in your nose. Covid doubles in 36 hours, so that’s how much extra time you’ve bought your immune system to ramp up defenses. If you follow the more aggressive protocols in the literature and apply that treatment 6 times per day, you wipe out 95% of covid in the nose. I will attempt to translate this an efficacy estimate in that mythical future, but in the meantime siderea has a write-up on why reducing viral load is valuable even if you can’t destroy it entirely

Sometimes you will see very impressive graphs for Enovid’s impact; these are inevitably looking at the results of nasal swabs. Since even in the best case scenario NONS doesn’t affect spread once an infection has reached the throat, this doesn’t feel very relevant to me. 

Sometimes you will see very unimpressive graphs, from the rare studies that looked at transmission or symptoms. These effects are so weak, in such small studies, that I consider them essentially a null result.

…Except that these studies all started treatment days after symptoms emerged. In one case it was a minimum of 4 days. Another said “0-3 days” after symptoms, but since it takes time to see a doctor and be recruited into a study I expect the average to be on the high end of that. Additionally, both studies showed a downward slope in infection in both treatment and control groups. This is a big deal because I expect the largest effect to come if NONS is used before exponential growth really takes off. If they’re seeing a decline in viral load in their control arm, they either administered treatment too late or their placebo isn’t. 

[I think this reasoning holds even if immune overreaction is part of the problems with long covid. Long covid is correlated with severity of initial infection.]

To figure the impact of prophylactic use, I’m going to have to get, uh, speculative. Before I do that, let me dig into exactly what the data says. 

Effect size on nasal viral load

This has very solid data: even under the unfavorable circumstances of a strong infection, a day of usage drops viral load by 90-95%

Paper 1 says 95% reduction in one day, 99% in two. They took samples from the nose and throat but don’t clarify which location that applies to. If I had the energy I’d be very angry about that right now. 

(Their placebo was a saline spray, which other people claim is an antimicrobial in its own right, so this may understate the effect)

Paper 2 finds an adjusted 93-98% decline after 1 day’s use of NONS. 

Effect on symptoms/transmission, as measured by poorly designed studies

Paper 1 did track time to cure, but with a 40% response rate on a sample size of 40 in the treatment arm I can’t bring myself to care.

Paper 2 reported a couple of metrics. One is “Time to cure (as defined by PCR results)” which is still worthless because it’s still using a nasal swab. Another is clinician-assessed improvement; this effect seemed real but not huge. 

They also checked for spread to close contacts, but not very well. Contacts had to take the initiative to get tested themselves, and AFAICT they didn’t establish if they were infected before or after treatment started.  You can try to factor that out by only looking at the last day of recorded data, but the difference appears to start on day 1 of treatment, when there absolutely shouldn’t be an effect. 

Other Diseases

NONS has been studied against other infections and I fully meant to look at that data. Now that I have actual covid I consider it kind of a race to get this post out before I’m too tired, so this will come later if at all.

My wild ass guess of impact

What does a single dose do? I did a very stupid model assuming six doses over 24 hours each having the same proportionate effect, and found that halving viral load with each application was a perfect match with the data. I expect the first dose of the day has a larger effect and each one is a little less effective until you sleep and the virus has some time to marshal forces, but barring better data I’m going to treat Enovid as rolling back one doubling. 

[I want to emphasize I didn’t massage this to make the math easier. I tried .9 in my naive spreadsheet knowing it wouldn’t work, and then tried 0.5 to find it perfectly matched the data]

If my covid infection starts in the nose and I take a full course of treatment immediately after exposure, <10% chance I get sick. But that’s unachievable without constant use, which I think is a bad idea (see below).

What if you’re infected, but only in your nose? It’s a 95% reduction per day. It’s anyone’s guess how much that reduces the chance of spread to your throat; I’d say 95% is the upper bound, and am very arbitrarily setting 50% as the lower bound for the first day (this time I am trying to make the math easier). But you’re also reducing the cumulative load; on day three (after two days of treatment), your viral load is 99% lower than it would otherwise be, before you take any new doses.

I suspect the real killer app here is combining Enovid with a throat disinfectant, and am prioritizing a review of at least one throat disinfectant in a future post. 

Can I get this effect for free, without the painful stinging or logistical hassle of a nasal spray?

Maybe. Your nose already naturally produces nitric oxide, and you can increase this by 15x by humming. I haven’t been able to find the dosage of a single spray of Enovid to compare, but humming doesn’t sting so I assume it’s a lot less. On the other hand, you can hum more often than six times per day. On the third hand, I can’t tell if humming causes you to produce more NO or just release it faster, in which case chronic humming might deplete your stores. 

A quick search found multiple published articles suggesting this, but none actually studying it. The cynic in me says this is because there’s no money in it, but this study would take pennies to run and be so high impact if it worked that I suspect this is less promising than it seems. 

Update 2024-10-01: No.

Thank you to Michael Tontchev on twitter for pointing me towards humming.

Should I just use this all the time?

I don’t regularly use Envoid, despite having a shit immune system. The history of treatments like this is that long term use causes more problems than it solves. They dry out mucous membranes, or kill your own immune cells. I think the rest of you should seriously consider developing a humming habit; alas I have nerve damage in my jaw that makes vibration painful so not an option for me. 

I do think there’s a case for prophylactic use during high risk situations like conferences or taking care of a sick loved one. 

Where can I buy Enovid?

Amazon has it, but at $100/bottle it’s quite expensive. You can get it from other websites for half the price but longer shipping times; my friend used israelpharm.com and confirms he got his shipment. 

Inositol Non-Results

Three months ago I suggested people consider inositol for treating combined vague mood issues and vague stomach issues. I knew a few people who’d really benefited from it, and when one talked about it on his popular Twitter account several more people popped up thanking him for the suggestion, because it fixed their lives too. But those reports didn’t come with a denominator, which made it hard to estimate the success rate; I was hoping mentioning it on my blog and doing a formal follow-up to capture the non-responders would give a more accurate number.

Unfortunately, I didn’t get enough people to do anything useful. I received 7 responses, of which 3 didn’t have digestive issues and thus weren’t really the target. The low response rate might be a consequence of giving the wrong link in the original follow-up post, or maybe it just wasn’t that interesting. I’m reporting the results anyway out of a sense of civic virtue. 

Of those 4 remaining responses:

  • 2 rated it exactly 5 out of 10 (neutral)
  • 1 rated it as 6, which was not strong enough for them to try it a third time.
  • 1 rated it as 3- not bad enough that they spontaneously noticed a problem, but they did detailed mood tracking and the linear regression was clearly bad. 

That response rate isn’t really low enough to prove anything except that anything with a real effect can hurt you, and the value of detailed data. So for now we just have David’s estimate that 5% of people he inspired to take inositol benefited from it. 

Follow-up survey: inositol

Two months ago I wrote about inositol as a treatment that occasionally works for anxiety and depression, especially when the user also has weird digestive issues (not medical advice, I am not a doctor). If that inspired you to try inositol I would love if you would fill out this 5-7 question survey about your experience. This follow-up data helps other people considering inositol, and is broadly helpful to me in figuring out what luck based medicine looks like. 

And to the four people who already filled this out: gold star for epistemic virtue. 

The survey doesn’t allow for a lot of detail, which I know is painful for some people (it’s me. I’m people). If you would like to share more, feel free to write up as much as you’d like in a comment here, or share a link detailing your experience.

Elsewhere in luck based medicine: it was a dude in my survey, but I met a few more people who really love the Apollo Neuro. They are all the kind of people who already know what “somatically aware” or “embodiment” mean, so this is some support for my theory that that’s a prerequisite. It’s still an open question if you need that background for the Neuro to be beneficial, to notice it’s beneficial, or to stick with it long enough that it has time to be beneficial. 

The Apollo app has gotten even worse since last time I wrote. Every time I open it it bugs me to enable notifications, a permission it absolutely does not need.