vitamin D

Article

vitamin D is a recurring brand in the Astral Codex Ten archive, appearing 2 times across 2 issues between November 17, 2021 and November 25, 2021. The archive places it in contexts such as “vitamin D or azithromycin cured COVID this effectively”; “Big trial on Vitamin D for depression finds null result”. It most often appears alongside ACE-2 receptor, ACSH, Ahmed et al.

Metadata

• Category: Brands
• Mention count: 2
• Issue count: 2
• First seen: November 17, 2021
• Last seen: November 25, 2021

Appears In

• Ivermectin: Much More Than You Wanted To Know
• Links For November

Related Pages

• • ACE-2 receptor (1 shared issues)
• • ACSH (1 shared issues)
• • Ahmed et al (1 shared issues)
• • Aleksandar Vucic (1 shared issues)
• • Alexandros Marinos (1 shared issues)
• • America (1 shared issues)
• • Aref (1 shared issues)
• • Aref et al (1 shared issues)
• • Argentina (1 shared issues)
• • Ariely study (1 shared issues)
• • aspirin (1 shared issues)
• • Australia (1 shared issues)

External Links

• • http://benjaminrosshoffman.com/d-is-for-covid
• • http://web.archive.org/web/20221104130431/https://stevekirsch.substack.com/p/1m-bet-rules
• • http://web.archive.org/web/20221129133112/https://blog.rootclaim.com/rootclaim-accepts-500000-challenge-on-covid-vaccine-safety-efficacy/
• • http://web.archive.org/web/20221224061743/https://www.skirsch.com/covid/SaarWilf.pdf
• • https://abc7news.com/post/graffiti-in-san-francisco-tagging-vandalism-street/13801629/
• • https://archive.ph/pY4gF#selection-663.103-683.190
• • https://astralcodexten.substack.com/p/covidvitamin-d-much-more-than-you
• • https://blog.rootclaim.com/treating-covid-19-with-vitamin-d-100000-challenge/
• • https://jamanetwork.com/journals/jama/fullarticle/2768978
• • https://liorpachter.wordpress.com/2020/11/17/mathematical-analysis-of-mathematical-analysis-of-a-vitamin-d-covid-19-trial/
• • https://pubmed.ncbi.nlm.nih.gov/29126319/
• • https://slatestarcodex.com/2014/01/25/beware-mass-produced-medical-recommendations/

Source Context

Recovered passages from the original issue text. When the raw archive preserved outbound links inside the source passage, they are listed directly under the quote.

Ivermectin: Much More Than You Wanted To Know

November 17, 2021 · Original source

Click to expand. # is how many people were in the smallest relevant group (eg if there were 20 people in placebo and 10 in ivermectin, it was 10). Dose is ivermectin dose x number of days. Tested w/ is what drugs were given alongside ivermectin; compare is what drugs were in the “placebo” group (I excluded some very common things like paracetamol). %-PCR7 is what percent of patients had a negative PCR test (indicating recovery) after 7 days (though if 7 wasn’t available, I accepted anything from 6-12); the (I) and (P) are ivermectin and placebo groups. R is the ratio - green if statistically significant, red otherwise. DaysPCR is how many days it took to get a negative PCR test. Days to -sym are how many days it took symptoms to resolve. -outc is some serious negative outcome in the study, either clinical worsening, hospitalization, or death. I was inconsistent which one I chose, trying to pick whichever I thought struck a balance between high sample size and severity. Since this was almost never significant, I made it blue if it favored ivermectin and orange if it favored placebo (which it never did; there is no orange). Lowest p is the lowest p-value in the study for one of the headline results. 1o+ is whether the primary outcome was positive or not. I made this very quickly and unprincipledly and I am sure there are a lot of errors; please forgive me. Of studies that included any of the endpoints I recorded, ivermectin had a statistically significant effect on the endpoint 13 times, and failed to reach significance 8 times. Of studies that named a specific primary endpoint, 9 found ivermectin affected it significantly, and 12 found it didn’t. But that’s still pretty good. And “doesn’t affect to a statistically significant degree” doesn’t mean it doesn’t work. It might just mean your study is too small for a real and important effect to achieve statistical significance. That’s why people do meta-analyses to combine studies. And the ivmmeta people say they did that and it was really impressive. All of this is still basically what things would look like if ivermectin worked. But of course we can’t give every study one vote. We’ve got to actually look at these and see which ones are good and which ones are bad. So, God help us, let’s go over all thirty of the ivermectin studies in this top panel of ivmmeta.com. (if you get bored of this, scroll down to the section called “The Analysis”) The Studies Elgazzar et al: This one isn’t on the table above, but we can’t start talking about the others until we get it out of the way. 600 Egyptian patients were randomized into six groups, including three that got ivermectin. The ivermectin groups did substantially better: for example, 2 vs. 20 deaths in ivermectin group 3 vs. non-ivermectin group 4. There were various other equally impressive outcomes. Unfortunately, it’s all false. Some epidemiologists and reporters were able to obtain the raw data (it was password-protected, but the password was “1234”), and it was pretty bizarre. Some patients appeared to have died before the trial started; others were arranged in groups of four such that it seemed like the authors had just copy-pasted the same four patients again and again. Probably either the study never happened, or at least the data were heavily edited afterwards. You can read more here. A lot of the apparent benefit of ivermectin in meta-analyses disappeared after taking out this paper (though remember, this isn’t even on the table at the top of the post, so it doesn’t directly affect that). Since the Elgazzar debacle, a group of researchers including Gideon Meyerowitz-Katz, Kyle Sheldrake, James Heathers, Nick Brown, Jack Lawrence, etc, have been trying to double-check as many other ivermectin studies as possible. At least three others - Samaha, Carvallo, and Niaee - have similar problems and have been retracted. Those studies were all removed before I screenshotted the table above, and they’re not on there. But everybody is pretty paranoid right now and looking for fraud a lot harder than they might be in normal situations. Moving on: Chowdury et al: Bangladeshi RCT. 60 patients in Group A got low-dose ivermectin plus the antibiotic doxycycline, 56 in Group B got hydroxychloroquine (another weird COVID treatment which most scientists think doesn’t work) plus the antibiotic azithromycin. No declared primary outcome. Ivermectin group got to negative PCR a little faster than the other (5.9 vs. 7 days) but it wasn’t statistically significant (p = 0.2). A couple of other non-statistically-significant things happened too. 2 controls were hospitalized, 0 ivermectin patients were. This is a boring study that got boring results, so nobody has felt the need to assassinate it, but if they did, it would probably focus on both groups getting various medications besides ivermectin. None of these other medications are believed to work, so I don’t really care about this, but you could tell a story where actually doxycycline works great at addressing associated bacterial pneumonias, or where HCQ causes lots of side effects and that makes the ivermectin group look good in comparison, or whatever. Espitia-Hernandez et al: Mexican trial which is probably not an RCT - all it says is that “patients were voluntarily allocated”. 28 ended up taking a cocktail of low-dose ivermectin, vitamin D, and azithromycin; 7 were controls. On day ten, everyone (!) in the experimental group was PCR negative; everyone (!) in the control group was still positive. Also, symptoms in the experimental group lasted an average of three days; in the control group, more like 10. These results make ivermectin look amazingly super-good, probably better than any other drug for any other disease, except maybe stuff like vitamins for treatment of vitamin deficiency. Any issues? We don’t know how patients were allocated, but they discuss patient characteristics and they don’t look different enough to produce this big an effect size. The experimental group got a lot of things other than ivermectin, but I would be equally surprised if vitamin D or azithromycin cured COVID this effectively. It deviated from its preregistration in basically every way possible, but you shouldn’t be able to get “every experimental patient tested negative when zero control patients did” by garden-of-forking-paths alone! But this has to be false, right? Even the other pro-ivermectin studies don’t show effects nearly this big. In all other studies combined, ivermectin patients took an average of 8 days to recover; in Espitia-Hernandez, they took 3. Also, it’s pretty weird that the entire control group had positive PCRs on day 10 - in most other studies, a majority of people had negative PCRs by day 7 or so, regardless of whether they were control or placebo. Everything about this is so shoddy that I can easily believe something went wrong here. I don’t have a great understanding of this one but I don’t trust it at all. Luckily it is small and non-randomized so it will be easy to ignore going forward. I’m not saying this is related, but I’m not saying it *isn’t* related either. Carvallo et al: This one has all the disadvantages of Espitia-Hernandez, plus it’s completely unreadable. It’s hard to figure out how many patients there were, whether it was an RCT or not, etc. It looks like maybe there were 42 experimentals and 14 controls, and the controls were about 10x more likely to die than the experimentals. Seems pretty bad. On the other hand, another Carvallo paper was retracted because of fraud: apparently the hospital where the study supposedly took place said it never happened there. I can’t tell if this is a different version of that study, a pilot study for that study, or a different study by the same guy. Anyway, it’s too confusing to interpret, shows implausible results, and is by a known fraudster, so I feel okay about ignoring this one. Mahmud et al: RCT from Bangladesh. 200 patients received ivermectin plus doxycycline, 200 received placebo. Everything was written up very nicely in real English, by people who were clearly not on 34 lbs of meth at the time. They designated a primary outcome, “number of days required for clinical recovery”, and found a statistically significant difference at p < 0.001: Okay, fine, they misspelled “recovery” once. But they spelled it right the other time! That puts it in the top 50% for ivermectin papers! The fraud-hunters have examined this paper closely and are unable to find any signs of fraud. @PubPeer on the Mahmud trial of ivermectin in covid patients.\n\nI have now reviewed the individual patient data master sheet.\n\nI did not find any irregularities and the summary data matches the published data.\n\n","username":"K_Sheldrick","name":"Kyle Sheldrick","profile_image_url":"","date":"Sat Jul 17 11:06:25 +0000 2021","photos":[],"quoted_tweet":{},"reply_count":0,"retweet_count":2,"like_count":12,"impression_count":0,"expanded_url":{"url":"https://pubpeer.com/publications/E1D65711EF28D14517731BEACB89C8#2","title":"PubPeer - Ivermectin in combination with doxycycline for treating COVI...","description":"There are comments on PubPeer for publication: Ivermectin in combination with doxycycline for treating COVID-19 symptoms: a randomized trial (2021)","domain":"pubpeer.com"},"video_url":null,"belowTheFold":true}" data-component-name="Twitter2ToDOM"> I think this paper is legitimate and that its findings need to be seriously considered. Serious consideration doesn’t always meant they’re true - sometimes if we have strong evidence otherwise we can dismiss things without understanding why. And there’s always the chance it was a fluke, right? Can something have a p-value less than 0.001 and still be a fluke? Szenta Fonseca et al: This is a chart review from Brazil. Researchers looked at various people who had been treated for COVID in an insurance company database, saw whether they got ivermectin or not, and saw whether the people who got it did better or worse. About a hundred people got it, and a few hundred others didn’t. The people who got it did not do any better than anyone else, and you’ll notice this is one of the rare red boxes on the table above. But we shouldn’t take this study seriously. Nobody took any effort to avoid selection bias, so it’s very possible that sicker people were given more medication (including ivermectin), which unfairly handicaps the ivermectin group. Also, it’s hard to tell from the paper who was on how much of what, and the discussion of ivermectin seems like kind of an afterthought after discussing lots of other meds in much more depth. This is another one I feel comfortable ignoring. Cadegiani et al: A crazy person decided to put his patients on every weird medication he could think of, and 585 subjects ended up on a combination of ivermectin, hydroxychloroquine, azithromycin, and nitazoxanide, with dutasteride and spironolactone "optionally offered" and vitamin D, vitamin C, zinc, apixaban, rivaraxoban, enoxaparin, and glucocorticoids "added according to clinical judgment". There was no control group, but the author helpfully designated some random patients in his area as a sort-of-control, and then synthetically generated a second control group based on “a precise estimative based on a thorough and structured review of articles indexed in PubMed and MEDLINE and statements by official government agencies and specific medical societies”. Patients in the experimental group were twice as likely to recover (p < 0.0001), had negative PCR after 14 vs. 21 days, and had 0 vs. 27 hospitalizations. Speaking of low p-values, some people did fraud-detection tests on another of Cadegiani’s COVID-19 studies and got values like p < 8.24E-11 in favor of it being fraudulent. And, uh, he’s also studied whether ultra-high-dose antiandrogens treated COVID, and found that they did, cutting mortality by 92% . But the trial is under suspicion, with a BMJ article calling it “[the worst] violations of medical ethics and human rights in Brazil’s history” and “an ethical cesspit of violations”. [update 2022: this section originally contained more accusations against Cadegiani. Alexandros Marinos does a deeper dive with information not available at the time I wrote this, and finds some of them were overstated or false by implication] Anyway, let’s not base anything important on the results of this study, mmkay? A defiant Flavio Cadegiani. Imagine a guy who looks like this telling you to take ultra-high-dose antiandrogens. Ahmed et al: And we’re back in Bangladesh. 72 hospital patients were randomized to one of three arms: ivermectin only, ivermectin + doxycycline, and placebo. Primary endpoint was time to negative PCR, which was 9.7 days for ivermectin only and 12.7 days for placebo (p = 0.03). Other endpoints including duration of hospitalization (9.6 days ivermectin vs. 9.7 days placebo, not significant). This looks pretty good for ivermectin and does not have any signs of fraud or methodological problems. If I wanted to pick at it anyway, I would point out that the ivermectin + doxycycline group didn’t really differ from placebo, and that if you average out both ivermectin groups (with and without doxycycline) it looks like the difference would not be significant. I had previously committed to considering only ivermectin alone in trials that had multiple ivermectin groups, so I’m not going to do this. I can’t find any evidence this trial was preregistered so I don’t know whether they waited to see what would come out positive and then made that their primary endpoint, but virological clearance is a pretty normal primary endpoint and this isn’t that suspicious. It’s impossible to find any useful commentary on this study because Elgazzar (the guy who ran the most famous fraudulent ivermectin study) had the first name Ahmed, everyone is talking about Elgazzar all the time, and this overwhelms Google whenever I try to search for Ahmed et al. For now I’ll just keep this as a mildly positive and mildly plausible virological clearance result, in the context of no effect on hospitalization length or most symptoms. Chaccour et al: 24 patients in Spain were randomized to receive either medium-dose ivermectin or placebo. The primary outcome was percent of patients with negative PCR at day 7; secondary outcomes were viral load and symptoms. The primary endpoint ended up being kind of a wash - everyone still PCR positive by day 7 so it was impossible to compare groups. Ivermectin trended toward lower viral load but never reached significance. Weirdly, ivermectin did seem to help symptoms, but only anosmia and cough towards the end (p = 0.03), which you would usually think of as lingering post-COVID problems. The paper says: Given these findings, consideration could be given to alternative mechanisms of action different from a direct antiviral effect. One alternative explanation might be a positive allosteric modulation of the nicotinic acetylcholine receptor caused by ivermectin and leading to a downregulation of the ACE-2 receptor and viral entry into the cells of the respiratory epithelium and olfactory bulb. Another mechanism through which ivermectin might influence the reversal of anosmia is by inhibiting the activation of pro-inflammatory pathways in the olfactory epithelium. Inflammation of the olfactory mucosa is thought to play a key role in the development of anosmia in SARS-CoV-2 infection This seems kind of hedge-y. If you’re wondering where things went from there, Dr. Chaccour is now a passionate anti-ivermectin activist: @Finneganporter in @BusinessInsider \n\nThe roots of #ivermectin mania: How South America incubated a fake-medicine craze that took the US by storm\n\n","username":"carlos_chaccour","name":"Dr. Carlos Chaccour ??????","profile_image_url":"","date":"Sun Nov 07 18:40:28 +0000 2021","photos":[],"quoted_tweet":{},"reply_count":0,"retweet_count":2,"like_count":9,"impression_count":0,"expanded_url":{"url":"https://www.businessinsider.in/international/news/the-roots-of-ivermectin-mania-how-south-america-incubated-a-fake-medicine-craze-that-took-the-us-by-storm/articleshow/87554081.cms","image":"https://bucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com/public/images/88d08e70-c9e2-46d4-a5df-96807b6c3a13_2000x1000.jpeg","title":"The roots of ivermectin mania: How South America incubated a fake-medicine craze that took the US by storm","description":"The popularity of unproven anti-parasitic drug ivermectin as a COVID-19 treatment is surging. Its use has roots in South America, where it was hyped by populist","domain":"businessinsider.in"},"video_url":null,"belowTheFold":true}" data-component-name="Twitter2ToDOM"> So I guess he must think of this trial as basically negative, although realistically it’s 24 people and we shouldn’t put too much weight on it either way. Ghauri et al: Pakistan, 95 patients. Nonrandom; the study compared patients who happened to be given ivermectin (along with hydroxychloroquine and azithromycin) vs. patients who were just given the latter two drugs. There’s some evidence this produced systematic differences between the two groups - for example, patients in the control group were 3x more likely to have had diarrhea (this makes sense; diarrhea is a potential ivermectin side effect, so you probably wouldn’t give it to people already struggling with this problem). Also, the control group was twice as likely to be getting corticosteroids, maybe a marker for illness severity. Primary outcome was what percent of both groups had a fever: on day 7 it was 21% of ivermectin patients vs. 65% of controls, p < 0.001. No other outcomes were reported. I don’t hate this study, but I think the nonrandom assignment (and observed systematic differences) is a pretty fatal flaw. I can’t find anyone else talking about this one. At least no one seems to be saying anything bad. Babaloba et al: Be warned: if I have to refer to this one in real-life conversation, I will expand out the “et al” and call it “Babalola & Alakoloko”, because that’s really fun to say. This was a Nigerian RCT comparing 21 patients on low-dose ivermectin, 21 patients on high-dose ivermectin, and 20 patients on a combination of lopinavir and ritonavir, a combination antiviral which later studies found not to work for COVID and which might as well be considered a placebo. Primary outcome, as usual, was days until a negative PCR test. High dose ivermectin was 4.65 days, low dose was 6 days, control was 9.15, p = 0.035. Figure 2 is apparently a photograph of the computer screen where they did this calculation. Gideon Meyerowitz-Katz, part of the team that detects fraud in ivermectin papers, is not a fan of this one: He doesn’t say there what means, but elsewhere he tweets this figure: It’s always a bad sign when your study features in an image with “NUMEROUS IMPOSSIBLE NUMBERS” in red at the top. I think his point is that if you have 21 people, it’s impossible to have 50% of them have headache, because that would be 10.5. If 10 people have a headache, it would be 47.6%; if 11, 52%. So something is clearly wrong here. Seems like a relatively minor mistake, and Meyerowitz-Katz stops short of calling fraud, but it’s not a good look. I’m going to be slightly uncomfortable with this study without rejecting it entirely, and move on. Ravakirti et al: Here we’re in Eastern India - not exactly Bangladesh again, but a stone’s throw away from it. In this RCT patients were randomized into an ivermectin group (57) and a placebo group (58). Primary outcome was negative PCR on day 6, because doing it on day 7 like everyone else would be too easy. As with several other groups, this was a bad move; too few people had it to make a good comparison; it was 13% of intervention vs. 18% of placebo, p = 0.3. Secondary outcomes were also pretty boring, except for the most important: 4 people in the placebo group died, compared to 0 in ivermectin (p = 0.045). On the one hand, this is one outcome of many, reaching the barest significance threshold. Another fluke? Still, there are no real problems with this study, and nobody has anything to say against it. Let’s add this one to the scale as another very small and noisy piece of real evidence in ivermectin’s favor. Bukhari et al: Now we’re in Pakistan. 50 patients were randomized to low-dose ivermectin, another 50 got standard of care including vitamin D. There was no placebo, but primary outcome was number of days to reach negative PCR, which it seems hard for placebo to affect much, so I don’t care. 5 controls and 9 ivermectin patients left the hospital against medical advice and could not be followed up, which is bad but not necessarily study-ruining. They never measured their supposed primary outcome of “days to reach negative PCR” directly, but they did measure how many people had negative PCR on various days, and ivermectin had a clear advantage - for example, on day 7, it was 37/50 for IVR and only 20/50 for control. Even if we assume all the lost-to-followup patients had maximally bad-for-the-hypothesis results, that’s still a positive finding. Nobody else has much to say about this one, certainly no accusations that they’ve found anything suspicious. Keep. Mohan et al: India. RCT. 40 patients got low-dose ivermectin, 40 high-dose ivermectin, and 45 placebo. Primary outcomes were time to negative PCR, and viral load on day 5. In the results, they seem to have reinterpreted “time to negative PCR” as the subtly different “percent with negative PCR on some specific day”. High-dose ivermectin did best (47.5% negative on day 5) and placebo worst (31% negative), but it was insignificant (p = 0.3). There was no difference in viral load. All groups took about the same amount of time for symptoms to resolve. More placebo patients had failed to recover by the end of the study (6) than ivermectin patients (2), but this didn’t reach statistical significance (p = 0.4). Overall a well-done, boring, negative study, although ivermectin proponents will correctly point out that, like basically every other study we have looked at, the trend was in favor of ivermectin and this could potentially end up looking impressive in a meta-analysis. Biber et al: This is an RCT from Israel. 47 patients got ivermectin and 42 placebo. Primary endpoint was viral load on day 6. I am having trouble finding out what happened with this; as far as I can tell it was a negative result and they buried it in favor of more interesting things. In a "multivariable logistic regression model, the adjusted odds ratio of negative SARS-CoV-2 RT-PCR negative test" favored ivermectin over placebo (p = 0.03 for day 6, p = 0.01 for day 8), but this seems like the kind of thing you do when your primary outcome is boring and you’re angry. Gideon Meyerowitz-Katz is not a fan: He notes that the study excluded people with high viral load, but the preregistration didn’t say they would do that. Looking more closely, he finds they did that because, if you included these people, the study got no positive results. So probably they did the study, found no positive results, re-ran it with various subsets of patients until they did get a positive result, and then claimed to have “excluded” patients who weren’t in the subset that worked. I’m going to toss this one. Elalfy et al: What even is this? Where am I? As best I can tell, this is some kind of Egyptian trial. It might or might not be an RCT; it says stuff like “Patients were self-allocated to the treatment groups; the first 3 days of the week for the intervention arm while the other 3 days for symptomatic treatment”. Were they self-allocated in the sense that they got to choose? Doesn’t that mean it’s not random? Aren’t there seven days in a week? These are among the many questions that Elalfy et al do not answer for us. The control group (which they seem to think can also be called “the white group”) took zinc, paracetamol, and maybe azithromycin. The intervention group took zinc, nitazoxanide, ribavirin, and ivermectin. There were very large demographic differences between the groups of the sort which make the study unusable, which they mention and then ignore. From there, they follow this normal and totally comprehensible flowchart: There is no primary outcome assigned, but viral clearance rates on day seven were 58% in the yellow group compared to 0% in the white group, which I guess is a strong positive result. This table… …looks very impressive, in terms of the experimental group doing better than the control, except that they don’t specify whether it was before the trial or after it, and at least one online commentator thinks it might have been before, in which case it’s only impressive how thoroughly they failed to randomize their groups. Overall I don’t feel bad throwing this study out. I hope it one day succeeds in returning to its home planet. Lopez-Medina et al: Colombian RCT. 200 patients took ivermectin, another 200 took placebo. They originally worried the placebo might taste different than real ivermectin, then solved this by replacing it with a different placebo, which is a pretty high level of conscientiousness. Primary outcome was originally percent of patients whose symptoms worsened by two points, as rated on a complicated symptom scale when a researcher asked them over the phone. Halfway through the study, they realized nobody was worsening that much, so they changed the primary outcome to time until symptoms got better, as measured by the scale. In the ivermectin group, symptoms improved that much after 10 days; in the placebo group, after 12, p = 0.53. By the end of the study, symptoms had improved in 82% of ivermectin users and 79% of controls, also insignificant. 4 patients in the ivermectin group needed to be hospitalized compared to 6 in the placebo group, again insignificant. This study is bigger than most of the other RCTs, and more polished in terms of how many spelling errors, photographs of computer screens, etc, it contains. It was published in JAMA, one of the most prestigious US medical journals, as opposed to the crappy nth-tier journals most of the others have been in. When people say things like “sure, a lot of small studies show good results for ivermectin, but the bigger and more professional trials don’t”, this is one of the two big professional trials they’re talking about. Ivermectin proponents make some good arguments against it. In order to get as big as it did, Lopez-Medina had to compromise on rigor. Its outcome is how people self-score their symptoms on a hokey scale in a phone interview, instead of viral load or PCR results or anything like that. Still, this is basically what we want, right? In the end, we want people to feel better and less sick, not to get good scores on PCR tests. Also, it changed its primary outcome halfway through; isn’t that bad? I think maybe not; the reason we want a preregistered primary outcome is so that you don’t change halfway through to whatever outcome shows the results you want. The researchers in this study did a good job explaining why they changed their outcome, the change makes sense, and their original outcome would also have shown ivermectin not working (albeit less accurately and effectively). I don’t know of any evidence that they knew (or suspected) final results when switching to this new outcome, and it seems like the most reasonable new outcome to switch to. Finally, their original placebo tasted different from ivermectin (though they switched halfway through). This is one of the few studies where I actually care about placebo, because people are self-rating their symptoms. But realistically most of these people don’t know what ivermectin is supposed to taste like. Also, they did a re-analysis and found there was no difference between the people who got the old placebo and the new one. I’m making a big deal of this because ivmmeta.com - the really impressive meta-analysis site I’ve been going off of - puts a special warning letter underneath their discussion of this study, urging us not to trust it. They don’t do this for any of the other ones we’ve addressed so far - not the one by the guy whose other studies were all frauds, not the one where 50% of 21 people had headaches, not the unrandomized one where the groups were completely different before the experiment started, not even the one by the guy accused of crimes against humanity. Only this one. This makes me a lot less charitable to ivmmeta than I would otherwise be; I think it’s hard to choose this particular warning letter strategy out of well-intentioned commitment to truth. They just really don’t like this big study that shows ivermectin doesn’t work. Also, the warning itself irritates me, and includes paragraphs like: RCTs have a fundamental bias against finding an effect for interventions that are widely available — patients that believe they need treatment are more likely to decline participation and take the intervention [Yeh], i.e., RCTs are more likely to enroll low-risk participants that do not need treatment to recover (this does not apply to the typical pharmaceutical trial of a new drug that is otherwise unavailable). This trial was run in a community where ivermectin was available OTC and very widely known and used. Nobody else worries about this, and there are a million biases that non-randomized studies have that would be super-relevant when discussing those, but somehow when they’re pro-ivermectin the site forgets to be this thorough. I think a better pro-ivermectin response to this study is to point out that all the trends support ivermectin. Symptoms took 10 days to resolve in the ivermectin group vs. 12 in placebo; 4 ivermectin patients were hospitalized vs. 6 placebo patients, etc. Just say that this was an unusually noisy trial because of the self-report methodology, and you’re confident that these small differences will add up to significance when you put them into a meta-analysis. Roy et al: We’re back in East India, and back to non-randomized trials. 56 patients were retrospectively examined; some had been given ivermectin + doxycycline, others hydroxychloroquine, other azithromycin, and others symptomatic treatment only. We don’t get any meaningful information about how this worked, but we are told that they did not differ in “clinical well-being reporting onset timing”. Whatever. Chahla et al: The first of many Argentine trials. 110 patients received medium-dose ivermectin; 144 were kept as a control (no placebo). This was “cluster randomized”, which means they randomize different health centers to either give the experimental drug or not. This is worse than regular randomization, because there could be differences between these health centers (eg one might have better doctors who otherwise give better treatment, one might be in the poor part of town and have sicker patients, etc). They checked to see if there were any differences between the groups, and it sure looks like there were (the experimental group had twice as many obese people as the controls), but as per them, these differences were not statistically significant. Note that if this did make a difference, it would presumably make ivermectin look worse, not better. The primary outcome was given as “increase discharge from outpatient care with COVID-19 mild disease”. This favored the treatment; only 2/110 patients in the ivermectin group failed to be discharged, compared to 20 patients in the control group. But, uh, these were at different medical centers. Can’t different medical centers just have different discharge policies? One discharges you as soon as you seem to be getting better, the other waits to really make sure? This is an utterly crap endpoint to do a cluster randomized controlled trial on. If you’re going to do cRCT, which is never a great idea, you should be using some extremely objective endpoint that doctors and clinic administrators can’t possibly affect, like viral load according to some third-party laboratory, using the same third-party laboratory for both clinics. This is such a bad idea that I can’t help worrying I’m missing or misunderstanding something. If not, this is dumb and bad and should be ignored. Mourya et al: We’re back in India. This is a nonrandomized study comparing 50 patients given ivermectin to 50 patients given hydroxychloroquine. No primary outcome was named, but they focus on PCR negativity. Only 6% of patients in the hydroxychloroquine group were negative, compared to 90% of patients in the ivermectin group! On what day did they do the test? Uh, kind of random, and they admit that “in [the hydroxychloroquine group], mean time difference from the date of initiation of treatment and second test was significantly longer (7.24±2.75 days) as compared to 5.22±1.21 days in [the ivermectin group] (p=0.021).” Since they assessed these groups at different times, we shouldn’t draw any conclusions from them getting different results. Except that as far as I can tell this should handicap ivermectin, making it especially impressive that it did better. But also, the ivermectin group was made mostly of people who had been asymptomatic at the beginning (70%), and the hydroxychloroquine group had almost no asymptomatic cases (8%) . They were giving the ivermectin to healthy people and the hydroxychloroquine to sick people! They admit deep in the discussion that this “may be a confounding factor”. So basically they got totally different groups of people, tested them at totally different times, and the two sets of test results differed. So what? So this is why normal people do RCTs instead of whatever the heck this is, that’s what. Loue et al: …this one isn’t going to be an RCT either. Loue tells a story about a cluster of COVID cases at the French nursing home where he works. He asked people if they wanted to try ivermectin; 10 did and 15 didn’t. 1 ivermectin patient died, compared to 5 non-ivermectin patients. The non-ivermectin group looked a bit sicker than the ivermectin group in the inevitable Table 1, though it’s hard to tell. One interesting possible confounder (not mentioned, but I’m imagining it) is that demented patients probably couldn’t consent to ivermectin and ended up in the control group. This is another case of “I’m not going to trust anything that isn’t an RCT”. Merino et al: Another (sigh) non-RCT. Mexico City tried a public health program where if you called a hotline and said you had COVID, they sent you an emergency kit with various useful supplies. One of those supplies was ivermectin tablets. 18,074 people got the kit (and presumably some appreciable fraction took the ivermectin, though there’s no way to prove that). Their control group is people from before they started giving out the kits, people from after they stopped giving out the kits, and people who didn’t want the kits. There are differences in who got COVID early in the epidemic vs. later, and in people who did opt for medical kits vs. didn’t. To correct these, the researchers tried to adjust for confounders, something which - as I keep trying to hammer home again and again - never works. They found that using the kit led to a 75% or so reduction in hospitalization, though they were unable to separate out the ivermectin from the other things in the kit (paracetamol and aspirin), or from the placebo effect of having a kit and feeling like you had already gotten some treatment (if I understand right, the decision to go to the hospital was left entirely to the patient). I think this study is a moderate point in favor of giving people kits in order to prevent hospital overcrowding, but I’m not willing to accept that it tells us much about ivermectin in particular. Faisal et al: This one was published in The Professional Medical Journal (mispelled as “Profesional Medical Journal” in its URL), so you know it’s going to be good! It describes itself as “a cross-sectional study”, but later says it “randomized patients into two groups”, which would make it an RCT - I think they might just be using the term “cross-sectional” different from the standard American usage. A hospital in Pakistan got 50 patients on ivermectin + azithromycin, and another 50 on azithromycin alone. Primary outcome was not mentioned, and the data were presented confusingly, but a typical result is that only 4% of the ivermectin group had symptoms lasting more than 10 days, whereas 16% of the control group did, p < 0.01. They do a really weird thing where they compare how long it took symptoms to resolve between IVM and control groups within each bin. That is, if I’m understanding correctly, they ask “of the people who took between 3-5 days for symptoms to resolve, did they resolve faster for IVM or control?”. This is an utterly bizarre analysis to perform, although it doesn’t affect the fact that their other results still seem to favor ivermectin. Maybe I’m confused about what’s going on here. I’ve mostly been letting people off easy on no placebo, but I as far as I can tell (not very far) this paper seems to be going off whether patients reported continuing to have symptoms to the hospital doing the study, and I think that is potentially susceptible to placebo effects. Additionally, there’s no preregistration, and even though they talk a lot about doing PCR tests they don’t present the results. This is by no means the worst study here but I still think it’s pretty low quality and I don’t trust it. Aref et al: This one is published in the International Journal Of Nanomedicine, even though I’m pretty sure that isn’t a real thing. In this case the “nanomedicine” is a new nasal spray version of ivermectin which is so confusing I cannot for the life of me figure out what dose they are giving these patients. This Egyptian study gives 57 patients intranasal ivermectin plus hydroxychloroquine, azithromycin, oseltamavir, and some vitamins; another 57 patients get all that stuff except the ivermectin. Primary outcome is not stated, but they look at various symptoms, all of which look better in the ivermectin group: 95% of ivermectin patients got negative PCRs at some time point, compared to 75% of controls, p = 0.004. I am pretty suspicious of this study, not least because it comes from Egypt which has an awful reputation for fake studies, and it returns extreme results that I wouldn’t expect even if ivermectin was actually a wonder drug. But I cannot find any particular thing wrong with it, nor did anyone else I looked at, so I will grudgingly let it stand. Krolewiecki et al: Another Argentine study. This one is a real RCT. 30 patients received ivermectin, 15 were the control group (no placebo, again). Primary outcome was difference in viral load on day 5. The trend favored ivermectin but it was not statistically significant, although they were able to make it statistically significant if they looked at a subset of higher-IVM-plasma-concentration patients. They did not find any difference in clinical outcomes. A pro-ivermectin person could point out that in the subgroup with the highest ivermectin concentrations, the drug seemed to work. A skeptic could point out that this is exactly the kind of subgroup slicing that you are not supposed to do without pre-registering it, which I don’t think this team did. I agree with the skeptic. Vallejos et al: Another Argentine study. It’s big (250 people in each arm). It’s an RCT. It tries to define a primary outcome (“Primary outcome: the trial ended when the last patient who was included achieved the end of study visit”), but that’s not what “primary outcome” means, and they don’t offer an alternative. Other outcomes: no difference in PCR on days 3 or 12. Hospitalization is nonsignificantly better in the ivermectin group (14 vs. 21, p = 0.2), but death is nonsigificantly better in the placebo group (3 vs. 4, p = 0.7). This isn’t even the kind of nonsignificant that might contribute to an exciting meta-analysis later. This is just a pure null result. I cannot find any problem with this study, and neither can anyone else I checked. This is the biggest RCT we’ve seen so far, so we should take it seriously. TOGETHER Trial: Speaking of big RCTs… This one hasn’t been published yet. There’s a video of a talk about it, but I am not going to watch it, because it is a video, so I am getting information secondhand from eg here. Apparently, it compares 677 people (!) randomized to ivermectin to 678 people randomized to placebo. 86 ivermectin patients ended up in the hospital compared to 95 placebo patients, p-value not significant. This was a really big professional trial done by bigshot researchers from a major Canadian university, and the medical establishment is taking it much more seriously than any of these others. When it comes out, it will probably get published in a top journal. When discussing Lopez-Medina, I wrote: When people say things like “sure, a lot of small studies show good results for ivermectin, but the bigger and more professional trials don’t”, this is one of the two big professional trials they’re talking about. This is the other one. Not coincidentally, it’s also the other trial that ivmmeta.com has a warning letter underneath telling you to disregard. Their main concern is that instead of truly randomizing patients to ivermectin vs. placebo, they did a time-dependent randomization that meant during some weeks more patients were getting one or the other. This is a problem because the trial takes place in Brazil, where different variants were more common at different times. Here’s their image: On the one hand, I have immense contempt for ivmmeta for letting all those other awful studies pass and then pulling out all the stops to try to nitpick this one. I have no idea if their proposed randomization failure really happened. And no doubt the reason they’re even able to investigate this is that this study is really careful and transparent - most of them don’t tell you anything about their randomization method. I would be shocked if other studies don’t have all these problems and worse. On the other hand, the point isn’t to be fair, it’s to be right. And this is a potential confounder. Not a huge one. But a potential one. I guess all we can do is try to bound the damage. Even if the confounding is 100% real and bad, there’s no way to make this study consistent with the crazy super-pro-ivermectin results of studies like Espitia-Hernandez and Aref. And even if we deny any confounding, we see the same slight pro-ivermectin trend - 86 hospitalizations vs. 95 - that we’ve seen in so many other studies. Nothing is going to make me believe that this isn’t in the top 33% of studies we’ve been looking at, so let’s add it as grist for the meta-analysis (though maybe not quite as much grist as its vast size indicates) and move on, angrily. Buonfrate et al: An Italian RCT. Patients were randomized into low-dose ivermectin (32), placebo (29), or high-dose ivermectin (32). Primary outcome was viral load on day 7. There was no significant difference (average of 2 in ivermectin groups, 2.2 in placebo group). They admit that they failed to reach the planned sample size, but did a calculation to show that even if they had, the trial could not have returned a positive result. Clinically, an average of 2 patients were hospitalized in each of the ivermectin arms, compared to 0 in the placebo arm - which bucks our previously-very-constant pro-ivermectin trend. Mayer et al: Not an RCT. Patients in an Argentine province were offered the opportunity to try ivermectin; 3266 said yes and become the experimental group, 17966 said no and became the control group. There were many obvious differences between the groups, but they all seemed to handicap ivermectin. There was a nonsignificant trend toward less hospitalization and significantly less mortality (1.5% vs. 2.1%, p = 0.03). While looking into this study, I learned the term “immortal time bias”. This means a period in between selection for the study and the beginning of study recording where patient outcomes are not counted. I think the problem here is that if you signed up for the system on Day X, and if you got sick before they could give you ivermectin, you were in the control group. See this Twitter thread, I have not confirmed everything he says. This only hardens my resolve to stay away from non-RCTs. Borody et al: Our last paper! …is it a paper? I can’t find it published anywhere. It mostly seems to be on news sites. Doesn’t look peer-reviewed. And it starts with “Note that views expressed in this opinion article are the writer’s personal views”. Whatever. 600 Australians were treated with ivermectin, doxycycline, and zinc. The article compares this to an “equivalent control group” made of “contemporary infected subjects in Australia obtained from published Covid Tracking Data”; this is not how you control group, @#!% you. Then it gets excited about the fact that most patients had better symptoms at the end of the ten-day study period than the beginning (untreated COVID resolves in about ten days). Why are these people wasting my time with this? Let’s move on. The Analysis If we remove all fraudulent and methodologically unsound studies from the table above, we end up with this: Gideon Meyerowitz-Katz, who investigated many of the studies above for fraud, tried a similar exercise. I learned about his halfway through, couldn’t help seeing it briefly, but tried to avoid remembering it or using it when generating mine (also, I did take the result of his fraud investigations into account), so they should be considered not quite independent efforts. His looks like this: He nixed Chowdhury, Babaloba, Ghauri, Faisal, and Aref, but kept Szenta Fonseca, Biber (?), and Mayer. There was correlation of 0.45, which I guess is okay. I asked him about his decision-making, and he listed a combination of serious statistical errors and small red flags adding up. I was pretty uncomfortable with most of these studies myself, so I will err on the side of severity, and remove all studies that either I or Meyerowitz-Katz disliked. We end up with the following short list: We’ve gone from 29 studies to 11, getting rid of 18 along the way. For the record, we eliminated 2/19 for fraud, 1/19 for severe preregistration violations, 10 for methodological problems, and 6 because Meyerowitz-Katz was suspicious of them. …but honestly this table still looks pretty good for ivermectin, doesn’t it? Still lots of big green boxes. Meyerowitz-Katz accuses ivmmeta of cherry-picking what statistic to use for their forest plot. That is, if a study measures ten outcomes, they sometimes take the most pro-ivermectin outcome. Ivmmeta.com counters that they used a consistent and reasonable (if complicated) process for choosing their outcome of focus, that being: If studies report multiple kinds of effects then the most serious outcome is used in calculations for that study. For example, if effects for mortality and cases are both reported, the effect for mortality is used, this may be different to the effect that a study focused on. If symptomatic results are reported at multiple times, we used the latest time, for example if mortality results are provided at 14 days and 28 days, the results at 28 days are used. Mortality alone is preferred over combined outcomes. Outcomes with zero events in both arms were not used (the next most serious outcome is used — no studies were excluded). For example, in low-risk populations with no mortality, a reduction in mortality with treatment is not possible, however a reduction in hospitalization, for example, is still valuable. Clinical outcome is considered more important than PCR testing status. When basically all patients recover in both treatment and control groups, preference for viral clearance and recovery is given to results mid-recovery where available (after most or all patients have recovered there is no room for an effective treatment to do better). If only individual symptom data is available, the most serious symptom has priority, for example difficulty breathing or low SpO2 is more important than cough. I’m having trouble judging this, partly because Meyerowitz-Katz says ivmmeta has corrected some earlier mistakes, and partly because there really is some reasonable debate over how to judge studies with lots of complicated endpoints. By this point I had completely forgotten what ivmmeta did, so I independently coded all 11 remaining studies following something in between my best understanding of their procedure and what I considered common sense. The only exception was that when the most severe outcome was measured in something other than patients (ie average number of virus copies per patient), I defaulted to one that was measured in patients instead, to keep everything with the same denominator. My results mostly matched ivmmeta’s, with one or two exceptions that I think are within the scope of argument or related to my minor deviations from their protocol. Placebo vs. ivermectin groups sometimes differed in size, which I’ve adjusted for and rounded off. Probably I’m forgetting some reason I can’t just do simple summary statistics to this, but whatever. It is p = 0.15, not significant. This is maybe unfair, because there aren’t a lot of deaths in the sample, so by focusing on death rather than more common outcomes we’re pointlessly throwing away sample size. What happens if I unprincipledly pick whatever I think the most reasonable outcome to use from each study is? I’ve chosen “most reasonable” as a balance between “is the most severe” and “has a lot of data points”: Now it’s p = 0.04, seemingly significant, but I had to make some unprincipled decisions to get there. I don’t think I specifically replaced negative findings with positive ones, but I can’t prove that even to myself, let alone to you. [UPDATE 5/31/22: A reader writes in to tell me that the t-test I used above is overly simplistic. A Dersimonian-Laird test is more appropriate for meta-analysis, and would have given 0.03 and 0.005 on the first and second analysis, where I got 0.15 and 0.04. This significantly strengthens the apparent benefit of ivermectin from ‘debatable’ to ‘clear’. I discuss some reasons below why I am not convinced by this apparent benefit.] (how come I’m finding a bunch of things on the edge of significance, but the original ivmmeta site found a lot of extremely significant things? Because they combined ratios, such that “one death in placebo, zero in ivermectin” looked like a nigh-infinite benefit for ivermectin, whereas I’m combining raw numbers. Possibly my way is statistically illegitimate for some reason, but I’m just trying to get a rough estimate of how convinced to be) So we are stuck somewhere between “nonsignificant trend in favor” and “maybe-significant trend in favor, after throwing out some best practices”. This is normally where I would compare my results to those of other meta-analyses made by real professionals. But when I look at them, they all include studies later found to be fake, like Elgazzar, and unsurprisingly come up with wildly positive conclusions. There are about six in this category. One of them later revised their results to exclude Elgazzar and still found strong efficacy for ivermectin, but they still included Niaee and some other dubious studies. The only meta-analysis that doesn’t make these mistakes is Popp (a Cochrane review), which is from before Elgazzar was found to be fraudulent, but coincidentally excludes it for other reasons. It also excludes a lot of good studies like Mahmud and Ravakirti because they give patients other things like HCQ and azithromycin - I chose to include them, because I don’t think they either work or have especially bad side effects, so they’re basically placebo - but Cochrane is always harsh like this. They end up with a point estimate where ivermectin cuts mortality by 40% - but say the confidence intervals are too wide to draw any conclusion. I think this basically agrees with my analyses above - the trends really are in ivermectin’s favor, but once you eliminate all the questionable studies there are too few studies left to have enough statistical power to reach significance. Except that everyone is still focusing on deaths and hospitalizations just because they’re flashy. Mahmud et al, which everyone agrees is a great study, found that ivermectin decreased days until clinical recovery, p = 0.003? So what do you do? This is one of the toughest questions in medicine. It comes up again and again. You have some drug. You read some studies. Again and again, more people are surviving (or avoiding complications) when they get the drug. It’s a pattern strong enough to common-sensically notice. But there isn’t an undeniable, unbreachable fortress of evidence. The drug is really safe and doesn’t have a lot of side effects. So do you give it to your patients? Do you take it yourself? Here this question is especially tough, because, uh, if you say anything in favor of ivermectin you will be cast out of civilization and thrown into the circle of social hell reserved for Klan members and 1/6 insurrectionists. All the health officials in the world will shout “horse dewormer!” at you and compare you to Josef Mengele. But good doctors aren’t supposed to care about such things. Your only goal is to save your patient. Nothing else matters. I am telling you that Mahmud et al is a good study and it got p = 0.003 in favor of ivermectin. You can take the blue pill, and stay a decent respectable member of society. Or you can take the horse dewormer pill, and see where you end up. In a second, I’ll tell you my answer. But you won’t always have me to answer questions like this, and it might be morally edifying to observe your thought process in situations like this. So take a second, and meet me on the other side of the next section heading. … … … … … The Synthesis Hopefully you learned something interesting about yourself there. But my answer is: worms! As several doctors and researchers have pointed out (h/t especially Avi Bitterman and David Boulware), the most impressive studies come from places that are teeming with worms. Mahmud from Bangladesh, Ravakirti from East India, Lopez-Medina from Colombia, etc. Here’s the prevalence of roundworm infections by country (source). But alongside roundworms, there are threadworms, hookworms, blood flukes, liver flukes, nematodes, trematodes, all sorts of worms. Add them all up and somewhere between half and a quarter of people in the developing world have at least one parasitic worm in their body. Being full of worms may impact your ability to fight coronavirus. Gluchowska et al write: Helminth [ie worm] infections are among the most common infectious diseases. Bradbury et al. highlight the possible negative interactions between helminth infection and COVID-19 severity in helminth-endemic regions and note that alterations in the gut microbiome associated with helminth infection appear to have systemic immunomodulatory effects. It has also been proposed that helminth co-infection may increase the morbidity and mortality of COVID-19, because the immune system cannot efficiently respond to the virus; in addition, vaccines will be less effective for these patients, but treatment and prevention of helminth infections might reduce the negative effect of COVID-19. During millennia of parasite-host coevolution helminths evolved mechanisms suppressing the host immune responses, which may mitigate vaccine efficacy and increase severity of other infectious diseases. Treatment of worm infections might reduce the negative effect of COVID-19! And ivermectin is a deworming drug! You can see where this is going… The most relevant species of worm here is the roundworm Strongyloides stercoralis. Among the commonest treatments for COVID-19 is corticosteroids, a type of immunosuppresant drug. The types of immune responses it suppresses do more harm than good in coronavirus, so turning them off limits collateral damage and makes patients better on net. But these are also the types of immune responses that control Strongyloides. If you turn them off even very briefly, the worms multiply out of control, you get what’s called “Strongyloides hyperinfection”, and pretty often you die. According to the WHO: The current COVID-19 pandemic serves to highlight the risk of using systemic corticosteroids and, to a lesser extent, other immunosuppressive therapy, in populations with significant risk of underlying strongyloidiasis. Cases of strongyloidiasis hyperinfection in the setting of corticosteroid use as COVID-19 therapy have been described and draw attention to the necessity of addressing the risk of iatrogenic strongyloidiasis hyperinfection syndrome in infected individuals prior to corticosteroid administration. Although this has gained importance in the midst of a pandemic where corticosteroids are one of few therapies shown to improve mortality, its relevance is much broader given that corticosteroids and other immunosuppressive therapies have become increasingly common in treatment of chronic diseases (e.g. asthma or certain rheumatologic conditions). So you need to “address the risk” of strongyloides infection during COVID treatment in roundworm-endemic areas. And how might you address this, WHO? Treatment of chronic strongyloidiasis with ivermectin 200 µg/kg per day orally x 1-2 days is considered safe with potential contraindications including possible Loa loa infection (endemic in West and Central Africa), pregnancy, and weight <15kg. Given ivermectin’s safety profile, the United States has utilized presumptive treatment with ivermectin for strongyloidiasis in refugees resettling from endemic areas, and both Canada and the European Centre for Disease Prevention and Control have issued guidance on presumptive treatment to avoid hyperinfection in at risk populations. Screening and treatment, or where not available, addition of ivermectin to mass drug administration programs should be studied and considered. This is serious and common enough that, if you’re not going to screen for it, it might be worth “add[ing] ivermectin to mass drug administration programs” in affected areas! Dr. Avi Bitterman carries the hypothesis to the finish line: First two images are with all relevant studies; second two are a sensitivity analysis that removes some of the most dubious. The good ivermectin trials in areas with low Strongyloides prevalence, like Vallejos in Argentina, are mostly negative. The good ivermectin trials in areas with high Strongyloides prevalence, like Mahmud in Bangladesh, are mostly positive. Worms can’t explain the viral positivity outcomes (ie PCR), but Dr. Bitterman suggests that once you remove low quality trials and worm-related results, the rest looks like simple publication bias: This is still just a possibility. Maybe I’m over-focusing too hard on a couple positive results and this will all turn out to be nothing. Or who knows, maybe ivermectin does work against COVID a little - although it would have to be very little, fading to not at all in temperate worm-free countries. But this theory feels right to me. It feels right to me because it’s the most troll-ish possible solution. Everybody was wrong! The people who called it a miracle drug against COVID were wrong. The people who dismissed all the studies because they F@#king Love Science were wrong. Ivmmeta.com was wrong. Gideon Meyerowitz-Katz was…well, he was right, actually, I got the worm-related meta-analysis graphic above from his Twitter timeline. Still, an excellent troll. Also, the best part is that I ignorantly asked, in my description of Mahmud et al above: And it was! It was a fluke! A literal, physical, fluke! For my whole life, God has been placing terrible puns in my path to irritate me, and this would be the worst one ever! So it has to be true! The Scientific Takeaway About ten years ago, when the replication crisis started, we learned a certain set of tools for examining studies. Check for selection bias. Distrust “adjusting for confounders”. Check for p-hacking and forking paths. Make teams preregister their analyses. Do forest plots to find publication bias. Stop accepting p-values of 0.049. Wait for replications. Trust reviews and meta-analyses, instead of individual small studies. These were good tools. Having them was infinitely better than not having them. But even in 2014, I was writing about how many bad studies seemed to slip through the cracks even when we pushed this toolbox to its limits. We needed new tools. I think the methods that Meyerowitz-Katz, Sheldrake, Heathers, Brown, Lawrence and others brought to the limelight this year are some of the new tools we were waiting for. Part of this new toolset is to check for fraud. About 10 - 15% of the seemingly-good studies on ivermectin ended up extremely suspicious for fraud. Elgazzar, Carvallo, Niaee, Cadegiani, Samaha. There are ways to check for this even when you don’t have the raw data. Like: The Carlisle-Stouffer-Fisher method: Check some large group of comparisons, usually the Table 1 of an RCT where they compare the demographic characteristics of the control and experimental groups, for reasonable p-values. Real data will have p-values all over the map; one in every ten comparisons will have a p-value of 0.1 or less. Fakers seem bad at this and usually give everything a nice safe p-value like 0.8 or 0.9.

Inline links: Elgazzar et al:, here, Chowdury et al, Espitia-Hernandez et al:, deviated from its preregistration, https://substackcdn.com/image/fetch/$s_!nJOk!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2Fda0f378f-c7e9-446c-909b-b870b062fd39_589x444.png, Carvallo et al:, another Carvallo paper was retracted, Mahmud et al:, https://substackcdn.com/image/fetch/$s_!ST60!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F1ff4783b-1473-4413-9230-8b15a5549208_500x469.gif, Szenta Fonseca et al:, Cadegiani et al:, a BMJ article, a deeper dive, https://substackcdn.com/image/fetch/$s_!ARca!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F7fe429e5-dba6-4b59-b46f-a2345b6acaf4_1080x720.jpeg, Ahmed et al:, Chaccour et al:, Ghauri et al:, Babaloba et al:, https://substackcdn.com/image/fetch/$s_!f598!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F0238280a-236e-47f5-9db6-7c35c07c5fc2_520x393.jpeg, https://substackcdn.com/image/fetch/$s_!SRpb!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2Fb5271fbd-b82a-4e34-9787-8b3aa6e8d2f6_595x522.png, https://substackcdn.com/image/fetch/$s_!cKHm!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2Ff9be5d50-858b-4c3a-bef7-a312df762eda_638x549.png, Ravakirti et al:, Bukhari et al:, Mohan et al:, Biber et al:, the preregistration, Elalfy et al:, https://substackcdn.com/image/fetch/$s_!B_IH!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F4d3559ee-a058-44cc-9b38-09b78a0f5035_1352x1070.png, https://substackcdn.com/image/fetch/$s_!9mI_!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2Fbffceed7-c84a-45c1-abfe-1fb2706dc383_483x674.png, Lopez-Medina et al:, Roy et al:, Chahla et al:, Mourya et al:, Loue et al:, Table 1, Merino et al:, never works, Faisal et al:, Aref et al:, https://substackcdn.com/image/fetch/$s_!-FoK!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2Ff6de79b6-091b-4c13-b7be-715c9bb194a7_986x810.jpeg, Krolewiecki et al:, Vallejos et al:, TOGETHER Trial:, here, https://substackcdn.com/image/fetch/$s_!7X0m!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F1f65fd44-58b9-4489-a934-02a5a7330499_706x768.png, Buonfrate et al:, Mayer et al:, immortal time bias, this Twitter thread, Borody et al:, https://substackcdn.com/image/fetch/$s_!Wpjs!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F2d8a451b-b1fc-44e5-ae67-b1506e491762_914x657.png, https://substackcdn.com/image/fetch/$s_!DOjA!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F17d5827a-38da-4a99-beb3-c3018df5c633_920x604.png, https://substackcdn.com/image/fetch/$s_!GX1n!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2Fc692fec8-a450-4579-b337-c72bec060970_912x298.png, https://substackcdn.com/image/fetch/$s_!YcH4!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2Ff36db98e-e653-44da-906c-20312b1689a3_468x205.png, https://substackcdn.com/image/fetch/$s_!jbcL!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2Fd189a844-daf2-4199-bb2e-830d4fc64415_468x206.png, later revised their results to exclude Elgazzar, Popp, https://substackcdn.com/image/fetch/$s_!2B6r!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F505c5ac4-3fe8-47a4-8505-dab80601b44d_416x198.png, Avi Bitterman, David Boulware, https://substackcdn.com/image/fetch/$s_!JWWh!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2Fac9e4f34-f9cc-40f2-9d83-da4e7178fad7_772x330.png, source, Gluchowska et al, the WHO, carries, https://substackcdn.com/image/fetch/$s_!xExE!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F5da21781-249c-4e59-b616-9f23d83cc044_2048x1184.jpeg, https://substackcdn.com/image/fetch/$s_!4SMr!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2Fdcd6e4b2-37f7-4602-93d5-2581c3b27a60_700x432.png, https://substackcdn.com/image/fetch/$s_!-6n2!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F7fd6e8f4-093e-4e02-bce7-363615146c9c_2228x1346.jpeg, https://substackcdn.com/image/fetch/$s_!CPZs!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2Fb0425847-198a-4bd3-a63b-149f15d147ba_700x432.png, https://substackcdn.com/image/fetch/$s_!H3rK!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F9972491b-25b0-4c06-8aca-86fce102ae63_666x147.png, even in 2014, The Carlisle-Stouffer-Fisher method

Okay, fine, they misspelled “recovery” once. But they spelled it right the other time! That puts it in the top 50% for ivermectin papers! The fraud-hunters have examined this paper closely and are unable to find any signs of fraud. @PubPeer on the Mahmud trial of ivermectin in covid patients.\n\nI have now reviewed the individual patient data master sheet.\n\nI did not find any irregularities and the summary data matches the published data.\n\n","username":"K_Sheldrick","name":"Kyle Sheldrick","profile_image_url":"","date":"Sat Jul 17 11:06:25 +0000 2021","photos":[],"quoted_tweet":{},"reply_count":0,"retweet_count":2,"like_count":12,"impression_count":0,"expanded_url":{"url":"https://pubpeer.com/publications/E1D65711EF28D14517731BEACB89C8#2","title":"PubPeer - Ivermectin in combination with doxycycline for treating COVI...","description":"There are comments on PubPeer for publication: Ivermectin in combination with doxycycline for treating COVID-19 symptoms: a randomized trial (2021)","domain":"pubpeer.com"},"video_url":null,"belowTheFold":true}" data-component-name="Twitter2ToDOM"> I think this paper is legitimate and that its findings need to be seriously considered. Serious consideration doesn’t always meant they’re true - sometimes if we have strong evidence otherwise we can dismiss things without understanding why. And there’s always the chance it was a fluke, right? Can something have a p-value less than 0.001 and still be a fluke? Szenta Fonseca et al: This is a chart review from Brazil. Researchers looked at various people who had been treated for COVID in an insurance company database, saw whether they got ivermectin or not, and saw whether the people who got it did better or worse. About a hundred people got it, and a few hundred others didn’t. The people who got it did not do any better than anyone else, and you’ll notice this is one of the rare red boxes on the table above. But we shouldn’t take this study seriously. Nobody took any effort to avoid selection bias, so it’s very possible that sicker people were given more medication (including ivermectin), which unfairly handicaps the ivermectin group. Also, it’s hard to tell from the paper who was on how much of what, and the discussion of ivermectin seems like kind of an afterthought after discussing lots of other meds in much more depth. This is another one I feel comfortable ignoring. Cadegiani et al: A crazy person decided to put his patients on every weird medication he could think of, and 585 subjects ended up on a combination of ivermectin, hydroxychloroquine, azithromycin, and nitazoxanide, with dutasteride and spironolactone "optionally offered" and vitamin D, vitamin C, zinc, apixaban, rivaraxoban, enoxaparin, and glucocorticoids "added according to clinical judgment". There was no control group, but the author helpfully designated some random patients in his area as a sort-of-control, and then synthetically generated a second control group based on “a precise estimative based on a thorough and structured review of articles indexed in PubMed and MEDLINE and statements by official government agencies and specific medical societies”. Patients in the experimental group were twice as likely to recover (p < 0.0001), had negative PCR after 14 vs. 21 days, and had 0 vs. 27 hospitalizations. Speaking of low p-values, some people did fraud-detection tests on another of Cadegiani’s COVID-19 studies and got values like p < 8.24E-11 in favor of it being fraudulent. And, uh, he’s also studied whether ultra-high-dose antiandrogens treated COVID, and found that they did, cutting mortality by 92% . But the trial is under suspicion, with a BMJ article calling it “[the worst] violations of medical ethics and human rights in Brazil’s history” and “an ethical cesspit of violations”. [update 2022: this section originally contained more accusations against Cadegiani. Alexandros Marinos does a deeper dive with information not available at the time I wrote this, and finds some of them were overstated or false by implication] Anyway, let’s not base anything important on the results of this study, mmkay? A defiant Flavio Cadegiani. Imagine a guy who looks like this telling you to take ultra-high-dose antiandrogens. Ahmed et al: And we’re back in Bangladesh. 72 hospital patients were randomized to one of three arms: ivermectin only, ivermectin + doxycycline, and placebo. Primary endpoint was time to negative PCR, which was 9.7 days for ivermectin only and 12.7 days for placebo (p = 0.03). Other endpoints including duration of hospitalization (9.6 days ivermectin vs. 9.7 days placebo, not significant). This looks pretty good for ivermectin and does not have any signs of fraud or methodological problems. If I wanted to pick at it anyway, I would point out that the ivermectin + doxycycline group didn’t really differ from placebo, and that if you average out both ivermectin groups (with and without doxycycline) it looks like the difference would not be significant. I had previously committed to considering only ivermectin alone in trials that had multiple ivermectin groups, so I’m not going to do this. I can’t find any evidence this trial was preregistered so I don’t know whether they waited to see what would come out positive and then made that their primary endpoint, but virological clearance is a pretty normal primary endpoint and this isn’t that suspicious. It’s impossible to find any useful commentary on this study because Elgazzar (the guy who ran the most famous fraudulent ivermectin study) had the first name Ahmed, everyone is talking about Elgazzar all the time, and this overwhelms Google whenever I try to search for Ahmed et al. For now I’ll just keep this as a mildly positive and mildly plausible virological clearance result, in the context of no effect on hospitalization length or most symptoms. Chaccour et al: 24 patients in Spain were randomized to receive either medium-dose ivermectin or placebo. The primary outcome was percent of patients with negative PCR at day 7; secondary outcomes were viral load and symptoms. The primary endpoint ended up being kind of a wash - everyone still PCR positive by day 7 so it was impossible to compare groups. Ivermectin trended toward lower viral load but never reached significance. Weirdly, ivermectin did seem to help symptoms, but only anosmia and cough towards the end (p = 0.03), which you would usually think of as lingering post-COVID problems. The paper says: Given these findings, consideration could be given to alternative mechanisms of action different from a direct antiviral effect. One alternative explanation might be a positive allosteric modulation of the nicotinic acetylcholine receptor caused by ivermectin and leading to a downregulation of the ACE-2 receptor and viral entry into the cells of the respiratory epithelium and olfactory bulb. Another mechanism through which ivermectin might influence the reversal of anosmia is by inhibiting the activation of pro-inflammatory pathways in the olfactory epithelium. Inflammation of the olfactory mucosa is thought to play a key role in the development of anosmia in SARS-CoV-2 infection This seems kind of hedge-y. If you’re wondering where things went from there, Dr. Chaccour is now a passionate anti-ivermectin activist: @Finneganporter in @BusinessInsider \n\nThe roots of #ivermectin mania: How South America incubated a fake-medicine craze that took the US by storm\n\n","username":"carlos_chaccour","name":"Dr. Carlos Chaccour ??????","profile_image_url":"","date":"Sun Nov 07 18:40:28 +0000 2021","photos":[],"quoted_tweet":{},"reply_count":0,"retweet_count":2,"like_count":9,"impression_count":0,"expanded_url":{"url":"https://www.businessinsider.in/international/news/the-roots-of-ivermectin-mania-how-south-america-incubated-a-fake-medicine-craze-that-took-the-us-by-storm/articleshow/87554081.cms","image":"https://bucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com/public/images/88d08e70-c9e2-46d4-a5df-96807b6c3a13_2000x1000.jpeg","title":"The roots of ivermectin mania: How South America incubated a fake-medicine craze that took the US by storm","description":"The popularity of unproven anti-parasitic drug ivermectin as a COVID-19 treatment is surging. Its use has roots in South America, where it was hyped by populist","domain":"businessinsider.in"},"video_url":null,"belowTheFold":true}" data-component-name="Twitter2ToDOM"> So I guess he must think of this trial as basically negative, although realistically it’s 24 people and we shouldn’t put too much weight on it either way. Ghauri et al: Pakistan, 95 patients. Nonrandom; the study compared patients who happened to be given ivermectin (along with hydroxychloroquine and azithromycin) vs. patients who were just given the latter two drugs. There’s some evidence this produced systematic differences between the two groups - for example, patients in the control group were 3x more likely to have had diarrhea (this makes sense; diarrhea is a potential ivermectin side effect, so you probably wouldn’t give it to people already struggling with this problem). Also, the control group was twice as likely to be getting corticosteroids, maybe a marker for illness severity. Primary outcome was what percent of both groups had a fever: on day 7 it was 21% of ivermectin patients vs. 65% of controls, p < 0.001. No other outcomes were reported. I don’t hate this study, but I think the nonrandom assignment (and observed systematic differences) is a pretty fatal flaw. I can’t find anyone else talking about this one. At least no one seems to be saying anything bad. Babaloba et al: Be warned: if I have to refer to this one in real-life conversation, I will expand out the “et al” and call it “Babalola & Alakoloko”, because that’s really fun to say. This was a Nigerian RCT comparing 21 patients on low-dose ivermectin, 21 patients on high-dose ivermectin, and 20 patients on a combination of lopinavir and ritonavir, a combination antiviral which later studies found not to work for COVID and which might as well be considered a placebo. Primary outcome, as usual, was days until a negative PCR test. High dose ivermectin was 4.65 days, low dose was 6 days, control was 9.15, p = 0.035. Figure 2 is apparently a photograph of the computer screen where they did this calculation. Gideon Meyerowitz-Katz, part of the team that detects fraud in ivermectin papers, is not a fan of this one: He doesn’t say there what means, but elsewhere he tweets this figure: It’s always a bad sign when your study features in an image with “NUMEROUS IMPOSSIBLE NUMBERS” in red at the top. I think his point is that if you have 21 people, it’s impossible to have 50% of them have headache, because that would be 10.5. If 10 people have a headache, it would be 47.6%; if 11, 52%. So something is clearly wrong here. Seems like a relatively minor mistake, and Meyerowitz-Katz stops short of calling fraud, but it’s not a good look. I’m going to be slightly uncomfortable with this study without rejecting it entirely, and move on. Ravakirti et al: Here we’re in Eastern India - not exactly Bangladesh again, but a stone’s throw away from it. In this RCT patients were randomized into an ivermectin group (57) and a placebo group (58). Primary outcome was negative PCR on day 6, because doing it on day 7 like everyone else would be too easy. As with several other groups, this was a bad move; too few people had it to make a good comparison; it was 13% of intervention vs. 18% of placebo, p = 0.3. Secondary outcomes were also pretty boring, except for the most important: 4 people in the placebo group died, compared to 0 in ivermectin (p = 0.045). On the one hand, this is one outcome of many, reaching the barest significance threshold. Another fluke? Still, there are no real problems with this study, and nobody has anything to say against it. Let’s add this one to the scale as another very small and noisy piece of real evidence in ivermectin’s favor. Bukhari et al: Now we’re in Pakistan. 50 patients were randomized to low-dose ivermectin, another 50 got standard of care including vitamin D. There was no placebo, but primary outcome was number of days to reach negative PCR, which it seems hard for placebo to affect much, so I don’t care. 5 controls and 9 ivermectin patients left the hospital against medical advice and could not be followed up, which is bad but not necessarily study-ruining. They never measured their supposed primary outcome of “days to reach negative PCR” directly, but they did measure how many people had negative PCR on various days, and ivermectin had a clear advantage - for example, on day 7, it was 37/50 for IVR and only 20/50 for control. Even if we assume all the lost-to-followup patients had maximally bad-for-the-hypothesis results, that’s still a positive finding. Nobody else has much to say about this one, certainly no accusations that they’ve found anything suspicious. Keep. Mohan et al: India. RCT. 40 patients got low-dose ivermectin, 40 high-dose ivermectin, and 45 placebo. Primary outcomes were time to negative PCR, and viral load on day 5. In the results, they seem to have reinterpreted “time to negative PCR” as the subtly different “percent with negative PCR on some specific day”. High-dose ivermectin did best (47.5% negative on day 5) and placebo worst (31% negative), but it was insignificant (p = 0.3). There was no difference in viral load. All groups took about the same amount of time for symptoms to resolve. More placebo patients had failed to recover by the end of the study (6) than ivermectin patients (2), but this didn’t reach statistical significance (p = 0.4). Overall a well-done, boring, negative study, although ivermectin proponents will correctly point out that, like basically every other study we have looked at, the trend was in favor of ivermectin and this could potentially end up looking impressive in a meta-analysis. Biber et al: This is an RCT from Israel. 47 patients got ivermectin and 42 placebo. Primary endpoint was viral load on day 6. I am having trouble finding out what happened with this; as far as I can tell it was a negative result and they buried it in favor of more interesting things. In a "multivariable logistic regression model, the adjusted odds ratio of negative SARS-CoV-2 RT-PCR negative test" favored ivermectin over placebo (p = 0.03 for day 6, p = 0.01 for day 8), but this seems like the kind of thing you do when your primary outcome is boring and you’re angry. Gideon Meyerowitz-Katz is not a fan: He notes that the study excluded people with high viral load, but the preregistration didn’t say they would do that. Looking more closely, he finds they did that because, if you included these people, the study got no positive results. So probably they did the study, found no positive results, re-ran it with various subsets of patients until they did get a positive result, and then claimed to have “excluded” patients who weren’t in the subset that worked. I’m going to toss this one. Elalfy et al: What even is this? Where am I? As best I can tell, this is some kind of Egyptian trial. It might or might not be an RCT; it says stuff like “Patients were self-allocated to the treatment groups; the first 3 days of the week for the intervention arm while the other 3 days for symptomatic treatment”. Were they self-allocated in the sense that they got to choose? Doesn’t that mean it’s not random? Aren’t there seven days in a week? These are among the many questions that Elalfy et al do not answer for us. The control group (which they seem to think can also be called “the white group”) took zinc, paracetamol, and maybe azithromycin. The intervention group took zinc, nitazoxanide, ribavirin, and ivermectin. There were very large demographic differences between the groups of the sort which make the study unusable, which they mention and then ignore. From there, they follow this normal and totally comprehensible flowchart: There is no primary outcome assigned, but viral clearance rates on day seven were 58% in the yellow group compared to 0% in the white group, which I guess is a strong positive result. This table… …looks very impressive, in terms of the experimental group doing better than the control, except that they don’t specify whether it was before the trial or after it, and at least one online commentator thinks it might have been before, in which case it’s only impressive how thoroughly they failed to randomize their groups. Overall I don’t feel bad throwing this study out. I hope it one day succeeds in returning to its home planet. Lopez-Medina et al: Colombian RCT. 200 patients took ivermectin, another 200 took placebo. They originally worried the placebo might taste different than real ivermectin, then solved this by replacing it with a different placebo, which is a pretty high level of conscientiousness. Primary outcome was originally percent of patients whose symptoms worsened by two points, as rated on a complicated symptom scale when a researcher asked them over the phone. Halfway through the study, they realized nobody was worsening that much, so they changed the primary outcome to time until symptoms got better, as measured by the scale. In the ivermectin group, symptoms improved that much after 10 days; in the placebo group, after 12, p = 0.53. By the end of the study, symptoms had improved in 82% of ivermectin users and 79% of controls, also insignificant. 4 patients in the ivermectin group needed to be hospitalized compared to 6 in the placebo group, again insignificant. This study is bigger than most of the other RCTs, and more polished in terms of how many spelling errors, photographs of computer screens, etc, it contains. It was published in JAMA, one of the most prestigious US medical journals, as opposed to the crappy nth-tier journals most of the others have been in. When people say things like “sure, a lot of small studies show good results for ivermectin, but the bigger and more professional trials don’t”, this is one of the two big professional trials they’re talking about. Ivermectin proponents make some good arguments against it. In order to get as big as it did, Lopez-Medina had to compromise on rigor. Its outcome is how people self-score their symptoms on a hokey scale in a phone interview, instead of viral load or PCR results or anything like that. Still, this is basically what we want, right? In the end, we want people to feel better and less sick, not to get good scores on PCR tests. Also, it changed its primary outcome halfway through; isn’t that bad? I think maybe not; the reason we want a preregistered primary outcome is so that you don’t change halfway through to whatever outcome shows the results you want. The researchers in this study did a good job explaining why they changed their outcome, the change makes sense, and their original outcome would also have shown ivermectin not working (albeit less accurately and effectively). I don’t know of any evidence that they knew (or suspected) final results when switching to this new outcome, and it seems like the most reasonable new outcome to switch to. Finally, their original placebo tasted different from ivermectin (though they switched halfway through). This is one of the few studies where I actually care about placebo, because people are self-rating their symptoms. But realistically most of these people don’t know what ivermectin is supposed to taste like. Also, they did a re-analysis and found there was no difference between the people who got the old placebo and the new one. I’m making a big deal of this because ivmmeta.com - the really impressive meta-analysis site I’ve been going off of - puts a special warning letter underneath their discussion of this study, urging us not to trust it. They don’t do this for any of the other ones we’ve addressed so far - not the one by the guy whose other studies were all frauds, not the one where 50% of 21 people had headaches, not the unrandomized one where the groups were completely different before the experiment started, not even the one by the guy accused of crimes against humanity. Only this one. This makes me a lot less charitable to ivmmeta than I would otherwise be; I think it’s hard to choose this particular warning letter strategy out of well-intentioned commitment to truth. They just really don’t like this big study that shows ivermectin doesn’t work. Also, the warning itself irritates me, and includes paragraphs like: RCTs have a fundamental bias against finding an effect for interventions that are widely available — patients that believe they need treatment are more likely to decline participation and take the intervention [Yeh], i.e., RCTs are more likely to enroll low-risk participants that do not need treatment to recover (this does not apply to the typical pharmaceutical trial of a new drug that is otherwise unavailable). This trial was run in a community where ivermectin was available OTC and very widely known and used. Nobody else worries about this, and there are a million biases that non-randomized studies have that would be super-relevant when discussing those, but somehow when they’re pro-ivermectin the site forgets to be this thorough. I think a better pro-ivermectin response to this study is to point out that all the trends support ivermectin. Symptoms took 10 days to resolve in the ivermectin group vs. 12 in placebo; 4 ivermectin patients were hospitalized vs. 6 placebo patients, etc. Just say that this was an unusually noisy trial because of the self-report methodology, and you’re confident that these small differences will add up to significance when you put them into a meta-analysis. Roy et al: We’re back in East India, and back to non-randomized trials. 56 patients were retrospectively examined; some had been given ivermectin + doxycycline, others hydroxychloroquine, other azithromycin, and others symptomatic treatment only. We don’t get any meaningful information about how this worked, but we are told that they did not differ in “clinical well-being reporting onset timing”. Whatever. Chahla et al: The first of many Argentine trials. 110 patients received medium-dose ivermectin; 144 were kept as a control (no placebo). This was “cluster randomized”, which means they randomize different health centers to either give the experimental drug or not. This is worse than regular randomization, because there could be differences between these health centers (eg one might have better doctors who otherwise give better treatment, one might be in the poor part of town and have sicker patients, etc). They checked to see if there were any differences between the groups, and it sure looks like there were (the experimental group had twice as many obese people as the controls), but as per them, these differences were not statistically significant. Note that if this did make a difference, it would presumably make ivermectin look worse, not better. The primary outcome was given as “increase discharge from outpatient care with COVID-19 mild disease”. This favored the treatment; only 2/110 patients in the ivermectin group failed to be discharged, compared to 20 patients in the control group. But, uh, these were at different medical centers. Can’t different medical centers just have different discharge policies? One discharges you as soon as you seem to be getting better, the other waits to really make sure? This is an utterly crap endpoint to do a cluster randomized controlled trial on. If you’re going to do cRCT, which is never a great idea, you should be using some extremely objective endpoint that doctors and clinic administrators can’t possibly affect, like viral load according to some third-party laboratory, using the same third-party laboratory for both clinics. This is such a bad idea that I can’t help worrying I’m missing or misunderstanding something. If not, this is dumb and bad and should be ignored. Mourya et al: We’re back in India. This is a nonrandomized study comparing 50 patients given ivermectin to 50 patients given hydroxychloroquine. No primary outcome was named, but they focus on PCR negativity. Only 6% of patients in the hydroxychloroquine group were negative, compared to 90% of patients in the ivermectin group! On what day did they do the test? Uh, kind of random, and they admit that “in [the hydroxychloroquine group], mean time difference from the date of initiation of treatment and second test was significantly longer (7.24±2.75 days) as compared to 5.22±1.21 days in [the ivermectin group] (p=0.021).” Since they assessed these groups at different times, we shouldn’t draw any conclusions from them getting different results. Except that as far as I can tell this should handicap ivermectin, making it especially impressive that it did better. But also, the ivermectin group was made mostly of people who had been asymptomatic at the beginning (70%), and the hydroxychloroquine group had almost no asymptomatic cases (8%) . They were giving the ivermectin to healthy people and the hydroxychloroquine to sick people! They admit deep in the discussion that this “may be a confounding factor”. So basically they got totally different groups of people, tested them at totally different times, and the two sets of test results differed. So what? So this is why normal people do RCTs instead of whatever the heck this is, that’s what. Loue et al: …this one isn’t going to be an RCT either. Loue tells a story about a cluster of COVID cases at the French nursing home where he works. He asked people if they wanted to try ivermectin; 10 did and 15 didn’t. 1 ivermectin patient died, compared to 5 non-ivermectin patients. The non-ivermectin group looked a bit sicker than the ivermectin group in the inevitable Table 1, though it’s hard to tell. One interesting possible confounder (not mentioned, but I’m imagining it) is that demented patients probably couldn’t consent to ivermectin and ended up in the control group. This is another case of “I’m not going to trust anything that isn’t an RCT”. Merino et al: Another (sigh) non-RCT. Mexico City tried a public health program where if you called a hotline and said you had COVID, they sent you an emergency kit with various useful supplies. One of those supplies was ivermectin tablets. 18,074 people got the kit (and presumably some appreciable fraction took the ivermectin, though there’s no way to prove that). Their control group is people from before they started giving out the kits, people from after they stopped giving out the kits, and people who didn’t want the kits. There are differences in who got COVID early in the epidemic vs. later, and in people who did opt for medical kits vs. didn’t. To correct these, the researchers tried to adjust for confounders, something which - as I keep trying to hammer home again and again - never works. They found that using the kit led to a 75% or so reduction in hospitalization, though they were unable to separate out the ivermectin from the other things in the kit (paracetamol and aspirin), or from the placebo effect of having a kit and feeling like you had already gotten some treatment (if I understand right, the decision to go to the hospital was left entirely to the patient). I think this study is a moderate point in favor of giving people kits in order to prevent hospital overcrowding, but I’m not willing to accept that it tells us much about ivermectin in particular. Faisal et al: This one was published in The Professional Medical Journal (mispelled as “Profesional Medical Journal” in its URL), so you know it’s going to be good! It describes itself as “a cross-sectional study”, but later says it “randomized patients into two groups”, which would make it an RCT - I think they might just be using the term “cross-sectional” different from the standard American usage. A hospital in Pakistan got 50 patients on ivermectin + azithromycin, and another 50 on azithromycin alone. Primary outcome was not mentioned, and the data were presented confusingly, but a typical result is that only 4% of the ivermectin group had symptoms lasting more than 10 days, whereas 16% of the control group did, p < 0.01. They do a really weird thing where they compare how long it took symptoms to resolve between IVM and control groups within each bin. That is, if I’m understanding correctly, they ask “of the people who took between 3-5 days for symptoms to resolve, did they resolve faster for IVM or control?”. This is an utterly bizarre analysis to perform, although it doesn’t affect the fact that their other results still seem to favor ivermectin. Maybe I’m confused about what’s going on here. I’ve mostly been letting people off easy on no placebo, but I as far as I can tell (not very far) this paper seems to be going off whether patients reported continuing to have symptoms to the hospital doing the study, and I think that is potentially susceptible to placebo effects. Additionally, there’s no preregistration, and even though they talk a lot about doing PCR tests they don’t present the results. This is by no means the worst study here but I still think it’s pretty low quality and I don’t trust it. Aref et al: This one is published in the International Journal Of Nanomedicine, even though I’m pretty sure that isn’t a real thing. In this case the “nanomedicine” is a new nasal spray version of ivermectin which is so confusing I cannot for the life of me figure out what dose they are giving these patients. This Egyptian study gives 57 patients intranasal ivermectin plus hydroxychloroquine, azithromycin, oseltamavir, and some vitamins; another 57 patients get all that stuff except the ivermectin. Primary outcome is not stated, but they look at various symptoms, all of which look better in the ivermectin group: 95% of ivermectin patients got negative PCRs at some time point, compared to 75% of controls, p = 0.004. I am pretty suspicious of this study, not least because it comes from Egypt which has an awful reputation for fake studies, and it returns extreme results that I wouldn’t expect even if ivermectin was actually a wonder drug. But I cannot find any particular thing wrong with it, nor did anyone else I looked at, so I will grudgingly let it stand. Krolewiecki et al: Another Argentine study. This one is a real RCT. 30 patients received ivermectin, 15 were the control group (no placebo, again). Primary outcome was difference in viral load on day 5. The trend favored ivermectin but it was not statistically significant, although they were able to make it statistically significant if they looked at a subset of higher-IVM-plasma-concentration patients. They did not find any difference in clinical outcomes. A pro-ivermectin person could point out that in the subgroup with the highest ivermectin concentrations, the drug seemed to work. A skeptic could point out that this is exactly the kind of subgroup slicing that you are not supposed to do without pre-registering it, which I don’t think this team did. I agree with the skeptic. Vallejos et al: Another Argentine study. It’s big (250 people in each arm). It’s an RCT. It tries to define a primary outcome (“Primary outcome: the trial ended when the last patient who was included achieved the end of study visit”), but that’s not what “primary outcome” means, and they don’t offer an alternative. Other outcomes: no difference in PCR on days 3 or 12. Hospitalization is nonsignificantly better in the ivermectin group (14 vs. 21, p = 0.2), but death is nonsigificantly better in the placebo group (3 vs. 4, p = 0.7). This isn’t even the kind of nonsignificant that might contribute to an exciting meta-analysis later. This is just a pure null result. I cannot find any problem with this study, and neither can anyone else I checked. This is the biggest RCT we’ve seen so far, so we should take it seriously. TOGETHER Trial: Speaking of big RCTs… This one hasn’t been published yet. There’s a video of a talk about it, but I am not going to watch it, because it is a video, so I am getting information secondhand from eg here. Apparently, it compares 677 people (!) randomized to ivermectin to 678 people randomized to placebo. 86 ivermectin patients ended up in the hospital compared to 95 placebo patients, p-value not significant. This was a really big professional trial done by bigshot researchers from a major Canadian university, and the medical establishment is taking it much more seriously than any of these others. When it comes out, it will probably get published in a top journal. When discussing Lopez-Medina, I wrote: When people say things like “sure, a lot of small studies show good results for ivermectin, but the bigger and more professional trials don’t”, this is one of the two big professional trials they’re talking about. This is the other one. Not coincidentally, it’s also the other trial that ivmmeta.com has a warning letter underneath telling you to disregard. Their main concern is that instead of truly randomizing patients to ivermectin vs. placebo, they did a time-dependent randomization that meant during some weeks more patients were getting one or the other. This is a problem because the trial takes place in Brazil, where different variants were more common at different times. Here’s their image: On the one hand, I have immense contempt for ivmmeta for letting all those other awful studies pass and then pulling out all the stops to try to nitpick this one. I have no idea if their proposed randomization failure really happened. And no doubt the reason they’re even able to investigate this is that this study is really careful and transparent - most of them don’t tell you anything about their randomization method. I would be shocked if other studies don’t have all these problems and worse. On the other hand, the point isn’t to be fair, it’s to be right. And this is a potential confounder. Not a huge one. But a potential one. I guess all we can do is try to bound the damage. Even if the confounding is 100% real and bad, there’s no way to make this study consistent with the crazy super-pro-ivermectin results of studies like Espitia-Hernandez and Aref. And even if we deny any confounding, we see the same slight pro-ivermectin trend - 86 hospitalizations vs. 95 - that we’ve seen in so many other studies. Nothing is going to make me believe that this isn’t in the top 33% of studies we’ve been looking at, so let’s add it as grist for the meta-analysis (though maybe not quite as much grist as its vast size indicates) and move on, angrily. Buonfrate et al: An Italian RCT. Patients were randomized into low-dose ivermectin (32), placebo (29), or high-dose ivermectin (32). Primary outcome was viral load on day 7. There was no significant difference (average of 2 in ivermectin groups, 2.2 in placebo group). They admit that they failed to reach the planned sample size, but did a calculation to show that even if they had, the trial could not have returned a positive result. Clinically, an average of 2 patients were hospitalized in each of the ivermectin arms, compared to 0 in the placebo arm - which bucks our previously-very-constant pro-ivermectin trend. Mayer et al: Not an RCT. Patients in an Argentine province were offered the opportunity to try ivermectin; 3266 said yes and become the experimental group, 17966 said no and became the control group. There were many obvious differences between the groups, but they all seemed to handicap ivermectin. There was a nonsignificant trend toward less hospitalization and significantly less mortality (1.5% vs. 2.1%, p = 0.03). While looking into this study, I learned the term “immortal time bias”. This means a period in between selection for the study and the beginning of study recording where patient outcomes are not counted. I think the problem here is that if you signed up for the system on Day X, and if you got sick before they could give you ivermectin, you were in the control group. See this Twitter thread, I have not confirmed everything he says. This only hardens my resolve to stay away from non-RCTs. Borody et al: Our last paper! …is it a paper? I can’t find it published anywhere. It mostly seems to be on news sites. Doesn’t look peer-reviewed. And it starts with “Note that views expressed in this opinion article are the writer’s personal views”. Whatever. 600 Australians were treated with ivermectin, doxycycline, and zinc. The article compares this to an “equivalent control group” made of “contemporary infected subjects in Australia obtained from published Covid Tracking Data”; this is not how you control group, @#!% you. Then it gets excited about the fact that most patients had better symptoms at the end of the ten-day study period than the beginning (untreated COVID resolves in about ten days). Why are these people wasting my time with this? Let’s move on. The Analysis If we remove all fraudulent and methodologically unsound studies from the table above, we end up with this: Gideon Meyerowitz-Katz, who investigated many of the studies above for fraud, tried a similar exercise. I learned about his halfway through, couldn’t help seeing it briefly, but tried to avoid remembering it or using it when generating mine (also, I did take the result of his fraud investigations into account), so they should be considered not quite independent efforts. His looks like this: He nixed Chowdhury, Babaloba, Ghauri, Faisal, and Aref, but kept Szenta Fonseca, Biber (?), and Mayer. There was correlation of 0.45, which I guess is okay. I asked him about his decision-making, and he listed a combination of serious statistical errors and small red flags adding up. I was pretty uncomfortable with most of these studies myself, so I will err on the side of severity, and remove all studies that either I or Meyerowitz-Katz disliked. We end up with the following short list: We’ve gone from 29 studies to 11, getting rid of 18 along the way. For the record, we eliminated 2/19 for fraud, 1/19 for severe preregistration violations, 10 for methodological problems, and 6 because Meyerowitz-Katz was suspicious of them. …but honestly this table still looks pretty good for ivermectin, doesn’t it? Still lots of big green boxes. Meyerowitz-Katz accuses ivmmeta of cherry-picking what statistic to use for their forest plot. That is, if a study measures ten outcomes, they sometimes take the most pro-ivermectin outcome. Ivmmeta.com counters that they used a consistent and reasonable (if complicated) process for choosing their outcome of focus, that being: If studies report multiple kinds of effects then the most serious outcome is used in calculations for that study. For example, if effects for mortality and cases are both reported, the effect for mortality is used, this may be different to the effect that a study focused on. If symptomatic results are reported at multiple times, we used the latest time, for example if mortality results are provided at 14 days and 28 days, the results at 28 days are used. Mortality alone is preferred over combined outcomes. Outcomes with zero events in both arms were not used (the next most serious outcome is used — no studies were excluded). For example, in low-risk populations with no mortality, a reduction in mortality with treatment is not possible, however a reduction in hospitalization, for example, is still valuable. Clinical outcome is considered more important than PCR testing status. When basically all patients recover in both treatment and control groups, preference for viral clearance and recovery is given to results mid-recovery where available (after most or all patients have recovered there is no room for an effective treatment to do better). If only individual symptom data is available, the most serious symptom has priority, for example difficulty breathing or low SpO2 is more important than cough. I’m having trouble judging this, partly because Meyerowitz-Katz says ivmmeta has corrected some earlier mistakes, and partly because there really is some reasonable debate over how to judge studies with lots of complicated endpoints. By this point I had completely forgotten what ivmmeta did, so I independently coded all 11 remaining studies following something in between my best understanding of their procedure and what I considered common sense. The only exception was that when the most severe outcome was measured in something other than patients (ie average number of virus copies per patient), I defaulted to one that was measured in patients instead, to keep everything with the same denominator. My results mostly matched ivmmeta’s, with one or two exceptions that I think are within the scope of argument or related to my minor deviations from their protocol. Placebo vs. ivermectin groups sometimes differed in size, which I’ve adjusted for and rounded off. Probably I’m forgetting some reason I can’t just do simple summary statistics to this, but whatever. It is p = 0.15, not significant. This is maybe unfair, because there aren’t a lot of deaths in the sample, so by focusing on death rather than more common outcomes we’re pointlessly throwing away sample size. What happens if I unprincipledly pick whatever I think the most reasonable outcome to use from each study is? I’ve chosen “most reasonable” as a balance between “is the most severe” and “has a lot of data points”: Now it’s p = 0.04, seemingly significant, but I had to make some unprincipled decisions to get there. I don’t think I specifically replaced negative findings with positive ones, but I can’t prove that even to myself, let alone to you. [UPDATE 5/31/22: A reader writes in to tell me that the t-test I used above is overly simplistic. A Dersimonian-Laird test is more appropriate for meta-analysis, and would have given 0.03 and 0.005 on the first and second analysis, where I got 0.15 and 0.04. This significantly strengthens the apparent benefit of ivermectin from ‘debatable’ to ‘clear’. I discuss some reasons below why I am not convinced by this apparent benefit.] (how come I’m finding a bunch of things on the edge of significance, but the original ivmmeta site found a lot of extremely significant things? Because they combined ratios, such that “one death in placebo, zero in ivermectin” looked like a nigh-infinite benefit for ivermectin, whereas I’m combining raw numbers. Possibly my way is statistically illegitimate for some reason, but I’m just trying to get a rough estimate of how convinced to be) So we are stuck somewhere between “nonsignificant trend in favor” and “maybe-significant trend in favor, after throwing out some best practices”. This is normally where I would compare my results to those of other meta-analyses made by real professionals. But when I look at them, they all include studies later found to be fake, like Elgazzar, and unsurprisingly come up with wildly positive conclusions. There are about six in this category. One of them later revised their results to exclude Elgazzar and still found strong efficacy for ivermectin, but they still included Niaee and some other dubious studies. The only meta-analysis that doesn’t make these mistakes is Popp (a Cochrane review), which is from before Elgazzar was found to be fraudulent, but coincidentally excludes it for other reasons. It also excludes a lot of good studies like Mahmud and Ravakirti because they give patients other things like HCQ and azithromycin - I chose to include them, because I don’t think they either work or have especially bad side effects, so they’re basically placebo - but Cochrane is always harsh like this. They end up with a point estimate where ivermectin cuts mortality by 40% - but say the confidence intervals are too wide to draw any conclusion. I think this basically agrees with my analyses above - the trends really are in ivermectin’s favor, but once you eliminate all the questionable studies there are too few studies left to have enough statistical power to reach significance. Except that everyone is still focusing on deaths and hospitalizations just because they’re flashy. Mahmud et al, which everyone agrees is a great study, found that ivermectin decreased days until clinical recovery, p = 0.003? So what do you do? This is one of the toughest questions in medicine. It comes up again and again. You have some drug. You read some studies. Again and again, more people are surviving (or avoiding complications) when they get the drug. It’s a pattern strong enough to common-sensically notice. But there isn’t an undeniable, unbreachable fortress of evidence. The drug is really safe and doesn’t have a lot of side effects. So do you give it to your patients? Do you take it yourself? Here this question is especially tough, because, uh, if you say anything in favor of ivermectin you will be cast out of civilization and thrown into the circle of social hell reserved for Klan members and 1/6 insurrectionists. All the health officials in the world will shout “horse dewormer!” at you and compare you to Josef Mengele. But good doctors aren’t supposed to care about such things. Your only goal is to save your patient. Nothing else matters. I am telling you that Mahmud et al is a good study and it got p = 0.003 in favor of ivermectin. You can take the blue pill, and stay a decent respectable member of society. Or you can take the horse dewormer pill, and see where you end up. In a second, I’ll tell you my answer. But you won’t always have me to answer questions like this, and it might be morally edifying to observe your thought process in situations like this. So take a second, and meet me on the other side of the next section heading. … … … … … The Synthesis Hopefully you learned something interesting about yourself there. But my answer is: worms! As several doctors and researchers have pointed out (h/t especially Avi Bitterman and David Boulware), the most impressive studies come from places that are teeming with worms. Mahmud from Bangladesh, Ravakirti from East India, Lopez-Medina from Colombia, etc. Here’s the prevalence of roundworm infections by country (source). But alongside roundworms, there are threadworms, hookworms, blood flukes, liver flukes, nematodes, trematodes, all sorts of worms. Add them all up and somewhere between half and a quarter of people in the developing world have at least one parasitic worm in their body. Being full of worms may impact your ability to fight coronavirus. Gluchowska et al write: Helminth [ie worm] infections are among the most common infectious diseases. Bradbury et al. highlight the possible negative interactions between helminth infection and COVID-19 severity in helminth-endemic regions and note that alterations in the gut microbiome associated with helminth infection appear to have systemic immunomodulatory effects. It has also been proposed that helminth co-infection may increase the morbidity and mortality of COVID-19, because the immune system cannot efficiently respond to the virus; in addition, vaccines will be less effective for these patients, but treatment and prevention of helminth infections might reduce the negative effect of COVID-19. During millennia of parasite-host coevolution helminths evolved mechanisms suppressing the host immune responses, which may mitigate vaccine efficacy and increase severity of other infectious diseases. Treatment of worm infections might reduce the negative effect of COVID-19! And ivermectin is a deworming drug! You can see where this is going… The most relevant species of worm here is the roundworm Strongyloides stercoralis. Among the commonest treatments for COVID-19 is corticosteroids, a type of immunosuppresant drug. The types of immune responses it suppresses do more harm than good in coronavirus, so turning them off limits collateral damage and makes patients better on net. But these are also the types of immune responses that control Strongyloides. If you turn them off even very briefly, the worms multiply out of control, you get what’s called “Strongyloides hyperinfection”, and pretty often you die. According to the WHO: The current COVID-19 pandemic serves to highlight the risk of using systemic corticosteroids and, to a lesser extent, other immunosuppressive therapy, in populations with significant risk of underlying strongyloidiasis. Cases of strongyloidiasis hyperinfection in the setting of corticosteroid use as COVID-19 therapy have been described and draw attention to the necessity of addressing the risk of iatrogenic strongyloidiasis hyperinfection syndrome in infected individuals prior to corticosteroid administration. Although this has gained importance in the midst of a pandemic where corticosteroids are one of few therapies shown to improve mortality, its relevance is much broader given that corticosteroids and other immunosuppressive therapies have become increasingly common in treatment of chronic diseases (e.g. asthma or certain rheumatologic conditions). So you need to “address the risk” of strongyloides infection during COVID treatment in roundworm-endemic areas. And how might you address this, WHO? Treatment of chronic strongyloidiasis with ivermectin 200 µg/kg per day orally x 1-2 days is considered safe with potential contraindications including possible Loa loa infection (endemic in West and Central Africa), pregnancy, and weight <15kg. Given ivermectin’s safety profile, the United States has utilized presumptive treatment with ivermectin for strongyloidiasis in refugees resettling from endemic areas, and both Canada and the European Centre for Disease Prevention and Control have issued guidance on presumptive treatment to avoid hyperinfection in at risk populations. Screening and treatment, or where not available, addition of ivermectin to mass drug administration programs should be studied and considered. This is serious and common enough that, if you’re not going to screen for it, it might be worth “add[ing] ivermectin to mass drug administration programs” in affected areas! Dr. Avi Bitterman carries the hypothesis to the finish line: First two images are with all relevant studies; second two are a sensitivity analysis that removes some of the most dubious. The good ivermectin trials in areas with low Strongyloides prevalence, like Vallejos in Argentina, are mostly negative. The good ivermectin trials in areas with high Strongyloides prevalence, like Mahmud in Bangladesh, are mostly positive. Worms can’t explain the viral positivity outcomes (ie PCR), but Dr. Bitterman suggests that once you remove low quality trials and worm-related results, the rest looks like simple publication bias: This is still just a possibility. Maybe I’m over-focusing too hard on a couple positive results and this will all turn out to be nothing. Or who knows, maybe ivermectin does work against COVID a little - although it would have to be very little, fading to not at all in temperate worm-free countries. But this theory feels right to me. It feels right to me because it’s the most troll-ish possible solution. Everybody was wrong! The people who called it a miracle drug against COVID were wrong. The people who dismissed all the studies because they F@#king Love Science were wrong. Ivmmeta.com was wrong. Gideon Meyerowitz-Katz was…well, he was right, actually, I got the worm-related meta-analysis graphic above from his Twitter timeline. Still, an excellent troll. Also, the best part is that I ignorantly asked, in my description of Mahmud et al above: And it was! It was a fluke! A literal, physical, fluke! For my whole life, God has been placing terrible puns in my path to irritate me, and this would be the worst one ever! So it has to be true! The Scientific Takeaway About ten years ago, when the replication crisis started, we learned a certain set of tools for examining studies. Check for selection bias. Distrust “adjusting for confounders”. Check for p-hacking and forking paths. Make teams preregister their analyses. Do forest plots to find publication bias. Stop accepting p-values of 0.049. Wait for replications. Trust reviews and meta-analyses, instead of individual small studies. These were good tools. Having them was infinitely better than not having them. But even in 2014, I was writing about how many bad studies seemed to slip through the cracks even when we pushed this toolbox to its limits. We needed new tools. I think the methods that Meyerowitz-Katz, Sheldrake, Heathers, Brown, Lawrence and others brought to the limelight this year are some of the new tools we were waiting for. Part of this new toolset is to check for fraud. About 10 - 15% of the seemingly-good studies on ivermectin ended up extremely suspicious for fraud. Elgazzar, Carvallo, Niaee, Cadegiani, Samaha. There are ways to check for this even when you don’t have the raw data. Like: The Carlisle-Stouffer-Fisher method: Check some large group of comparisons, usually the Table 1 of an RCT where they compare the demographic characteristics of the control and experimental groups, for reasonable p-values. Real data will have p-values all over the map; one in every ten comparisons will have a p-value of 0.1 or less. Fakers seem bad at this and usually give everything a nice safe p-value like 0.8 or 0.9.

Inline links: Szenta Fonseca et al:, Cadegiani et al:, a BMJ article, a deeper dive, https://substackcdn.com/image/fetch/$s_!ARca!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F7fe429e5-dba6-4b59-b46f-a2345b6acaf4_1080x720.jpeg, Ahmed et al:, Chaccour et al:, Ghauri et al:, Babaloba et al:, https://substackcdn.com/image/fetch/$s_!f598!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F0238280a-236e-47f5-9db6-7c35c07c5fc2_520x393.jpeg, https://substackcdn.com/image/fetch/$s_!SRpb!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2Fb5271fbd-b82a-4e34-9787-8b3aa6e8d2f6_595x522.png, https://substackcdn.com/image/fetch/$s_!cKHm!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2Ff9be5d50-858b-4c3a-bef7-a312df762eda_638x549.png, Ravakirti et al:, Bukhari et al:, Mohan et al:, Biber et al:, the preregistration, Elalfy et al:, https://substackcdn.com/image/fetch/$s_!B_IH!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F4d3559ee-a058-44cc-9b38-09b78a0f5035_1352x1070.png, https://substackcdn.com/image/fetch/$s_!9mI_!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2Fbffceed7-c84a-45c1-abfe-1fb2706dc383_483x674.png, Lopez-Medina et al:, Roy et al:, Chahla et al:, Mourya et al:, Loue et al:, Table 1, Merino et al:, never works, Faisal et al:, Aref et al:, https://substackcdn.com/image/fetch/$s_!-FoK!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2Ff6de79b6-091b-4c13-b7be-715c9bb194a7_986x810.jpeg, Krolewiecki et al:, Vallejos et al:, TOGETHER Trial:, here, https://substackcdn.com/image/fetch/$s_!7X0m!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F1f65fd44-58b9-4489-a934-02a5a7330499_706x768.png, Buonfrate et al:, Mayer et al:, immortal time bias, this Twitter thread, Borody et al:, https://substackcdn.com/image/fetch/$s_!Wpjs!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F2d8a451b-b1fc-44e5-ae67-b1506e491762_914x657.png, https://substackcdn.com/image/fetch/$s_!DOjA!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F17d5827a-38da-4a99-beb3-c3018df5c633_920x604.png, https://substackcdn.com/image/fetch/$s_!GX1n!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2Fc692fec8-a450-4579-b337-c72bec060970_912x298.png, https://substackcdn.com/image/fetch/$s_!YcH4!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2Ff36db98e-e653-44da-906c-20312b1689a3_468x205.png, https://substackcdn.com/image/fetch/$s_!jbcL!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2Fd189a844-daf2-4199-bb2e-830d4fc64415_468x206.png, later revised their results to exclude Elgazzar, Popp, https://substackcdn.com/image/fetch/$s_!2B6r!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F505c5ac4-3fe8-47a4-8505-dab80601b44d_416x198.png, Avi Bitterman, David Boulware, https://substackcdn.com/image/fetch/$s_!JWWh!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2Fac9e4f34-f9cc-40f2-9d83-da4e7178fad7_772x330.png, source, Gluchowska et al, the WHO, carries, https://substackcdn.com/image/fetch/$s_!xExE!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F5da21781-249c-4e59-b616-9f23d83cc044_2048x1184.jpeg, https://substackcdn.com/image/fetch/$s_!4SMr!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2Fdcd6e4b2-37f7-4602-93d5-2581c3b27a60_700x432.png, https://substackcdn.com/image/fetch/$s_!-6n2!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F7fd6e8f4-093e-4e02-bce7-363615146c9c_2228x1346.jpeg, https://substackcdn.com/image/fetch/$s_!CPZs!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2Fb0425847-198a-4bd3-a63b-149f15d147ba_700x432.png, https://substackcdn.com/image/fetch/$s_!H3rK!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F9972491b-25b0-4c06-8aca-86fce102ae63_666x147.png, even in 2014, The Carlisle-Stouffer-Fisher method

It’s always a bad sign when your study features in an image with “NUMEROUS IMPOSSIBLE NUMBERS” in red at the top. I think his point is that if you have 21 people, it’s impossible to have 50% of them have headache, because that would be 10.5. If 10 people have a headache, it would be 47.6%; if 11, 52%. So something is clearly wrong here. Seems like a relatively minor mistake, and Meyerowitz-Katz stops short of calling fraud, but it’s not a good look. I’m going to be slightly uncomfortable with this study without rejecting it entirely, and move on. Ravakirti et al: Here we’re in Eastern India - not exactly Bangladesh again, but a stone’s throw away from it. In this RCT patients were randomized into an ivermectin group (57) and a placebo group (58). Primary outcome was negative PCR on day 6, because doing it on day 7 like everyone else would be too easy. As with several other groups, this was a bad move; too few people had it to make a good comparison; it was 13% of intervention vs. 18% of placebo, p = 0.3. Secondary outcomes were also pretty boring, except for the most important: 4 people in the placebo group died, compared to 0 in ivermectin (p = 0.045). On the one hand, this is one outcome of many, reaching the barest significance threshold. Another fluke? Still, there are no real problems with this study, and nobody has anything to say against it. Let’s add this one to the scale as another very small and noisy piece of real evidence in ivermectin’s favor. Bukhari et al: Now we’re in Pakistan. 50 patients were randomized to low-dose ivermectin, another 50 got standard of care including vitamin D. There was no placebo, but primary outcome was number of days to reach negative PCR, which it seems hard for placebo to affect much, so I don’t care. 5 controls and 9 ivermectin patients left the hospital against medical advice and could not be followed up, which is bad but not necessarily study-ruining. They never measured their supposed primary outcome of “days to reach negative PCR” directly, but they did measure how many people had negative PCR on various days, and ivermectin had a clear advantage - for example, on day 7, it was 37/50 for IVR and only 20/50 for control. Even if we assume all the lost-to-followup patients had maximally bad-for-the-hypothesis results, that’s still a positive finding. Nobody else has much to say about this one, certainly no accusations that they’ve found anything suspicious. Keep. Mohan et al: India. RCT. 40 patients got low-dose ivermectin, 40 high-dose ivermectin, and 45 placebo. Primary outcomes were time to negative PCR, and viral load on day 5. In the results, they seem to have reinterpreted “time to negative PCR” as the subtly different “percent with negative PCR on some specific day”. High-dose ivermectin did best (47.5% negative on day 5) and placebo worst (31% negative), but it was insignificant (p = 0.3). There was no difference in viral load. All groups took about the same amount of time for symptoms to resolve. More placebo patients had failed to recover by the end of the study (6) than ivermectin patients (2), but this didn’t reach statistical significance (p = 0.4). Overall a well-done, boring, negative study, although ivermectin proponents will correctly point out that, like basically every other study we have looked at, the trend was in favor of ivermectin and this could potentially end up looking impressive in a meta-analysis. Biber et al: This is an RCT from Israel. 47 patients got ivermectin and 42 placebo. Primary endpoint was viral load on day 6. I am having trouble finding out what happened with this; as far as I can tell it was a negative result and they buried it in favor of more interesting things. In a "multivariable logistic regression model, the adjusted odds ratio of negative SARS-CoV-2 RT-PCR negative test" favored ivermectin over placebo (p = 0.03 for day 6, p = 0.01 for day 8), but this seems like the kind of thing you do when your primary outcome is boring and you’re angry. Gideon Meyerowitz-Katz is not a fan: He notes that the study excluded people with high viral load, but the preregistration didn’t say they would do that. Looking more closely, he finds they did that because, if you included these people, the study got no positive results. So probably they did the study, found no positive results, re-ran it with various subsets of patients until they did get a positive result, and then claimed to have “excluded” patients who weren’t in the subset that worked. I’m going to toss this one. Elalfy et al: What even is this? Where am I? As best I can tell, this is some kind of Egyptian trial. It might or might not be an RCT; it says stuff like “Patients were self-allocated to the treatment groups; the first 3 days of the week for the intervention arm while the other 3 days for symptomatic treatment”. Were they self-allocated in the sense that they got to choose? Doesn’t that mean it’s not random? Aren’t there seven days in a week? These are among the many questions that Elalfy et al do not answer for us. The control group (which they seem to think can also be called “the white group”) took zinc, paracetamol, and maybe azithromycin. The intervention group took zinc, nitazoxanide, ribavirin, and ivermectin. There were very large demographic differences between the groups of the sort which make the study unusable, which they mention and then ignore. From there, they follow this normal and totally comprehensible flowchart: There is no primary outcome assigned, but viral clearance rates on day seven were 58% in the yellow group compared to 0% in the white group, which I guess is a strong positive result. This table… …looks very impressive, in terms of the experimental group doing better than the control, except that they don’t specify whether it was before the trial or after it, and at least one online commentator thinks it might have been before, in which case it’s only impressive how thoroughly they failed to randomize their groups. Overall I don’t feel bad throwing this study out. I hope it one day succeeds in returning to its home planet. Lopez-Medina et al: Colombian RCT. 200 patients took ivermectin, another 200 took placebo. They originally worried the placebo might taste different than real ivermectin, then solved this by replacing it with a different placebo, which is a pretty high level of conscientiousness. Primary outcome was originally percent of patients whose symptoms worsened by two points, as rated on a complicated symptom scale when a researcher asked them over the phone. Halfway through the study, they realized nobody was worsening that much, so they changed the primary outcome to time until symptoms got better, as measured by the scale. In the ivermectin group, symptoms improved that much after 10 days; in the placebo group, after 12, p = 0.53. By the end of the study, symptoms had improved in 82% of ivermectin users and 79% of controls, also insignificant. 4 patients in the ivermectin group needed to be hospitalized compared to 6 in the placebo group, again insignificant. This study is bigger than most of the other RCTs, and more polished in terms of how many spelling errors, photographs of computer screens, etc, it contains. It was published in JAMA, one of the most prestigious US medical journals, as opposed to the crappy nth-tier journals most of the others have been in. When people say things like “sure, a lot of small studies show good results for ivermectin, but the bigger and more professional trials don’t”, this is one of the two big professional trials they’re talking about. Ivermectin proponents make some good arguments against it. In order to get as big as it did, Lopez-Medina had to compromise on rigor. Its outcome is how people self-score their symptoms on a hokey scale in a phone interview, instead of viral load or PCR results or anything like that. Still, this is basically what we want, right? In the end, we want people to feel better and less sick, not to get good scores on PCR tests. Also, it changed its primary outcome halfway through; isn’t that bad? I think maybe not; the reason we want a preregistered primary outcome is so that you don’t change halfway through to whatever outcome shows the results you want. The researchers in this study did a good job explaining why they changed their outcome, the change makes sense, and their original outcome would also have shown ivermectin not working (albeit less accurately and effectively). I don’t know of any evidence that they knew (or suspected) final results when switching to this new outcome, and it seems like the most reasonable new outcome to switch to. Finally, their original placebo tasted different from ivermectin (though they switched halfway through). This is one of the few studies where I actually care about placebo, because people are self-rating their symptoms. But realistically most of these people don’t know what ivermectin is supposed to taste like. Also, they did a re-analysis and found there was no difference between the people who got the old placebo and the new one. I’m making a big deal of this because ivmmeta.com - the really impressive meta-analysis site I’ve been going off of - puts a special warning letter underneath their discussion of this study, urging us not to trust it. They don’t do this for any of the other ones we’ve addressed so far - not the one by the guy whose other studies were all frauds, not the one where 50% of 21 people had headaches, not the unrandomized one where the groups were completely different before the experiment started, not even the one by the guy accused of crimes against humanity. Only this one. This makes me a lot less charitable to ivmmeta than I would otherwise be; I think it’s hard to choose this particular warning letter strategy out of well-intentioned commitment to truth. They just really don’t like this big study that shows ivermectin doesn’t work. Also, the warning itself irritates me, and includes paragraphs like: RCTs have a fundamental bias against finding an effect for interventions that are widely available — patients that believe they need treatment are more likely to decline participation and take the intervention [Yeh], i.e., RCTs are more likely to enroll low-risk participants that do not need treatment to recover (this does not apply to the typical pharmaceutical trial of a new drug that is otherwise unavailable). This trial was run in a community where ivermectin was available OTC and very widely known and used. Nobody else worries about this, and there are a million biases that non-randomized studies have that would be super-relevant when discussing those, but somehow when they’re pro-ivermectin the site forgets to be this thorough. I think a better pro-ivermectin response to this study is to point out that all the trends support ivermectin. Symptoms took 10 days to resolve in the ivermectin group vs. 12 in placebo; 4 ivermectin patients were hospitalized vs. 6 placebo patients, etc. Just say that this was an unusually noisy trial because of the self-report methodology, and you’re confident that these small differences will add up to significance when you put them into a meta-analysis. Roy et al: We’re back in East India, and back to non-randomized trials. 56 patients were retrospectively examined; some had been given ivermectin + doxycycline, others hydroxychloroquine, other azithromycin, and others symptomatic treatment only. We don’t get any meaningful information about how this worked, but we are told that they did not differ in “clinical well-being reporting onset timing”. Whatever. Chahla et al: The first of many Argentine trials. 110 patients received medium-dose ivermectin; 144 were kept as a control (no placebo). This was “cluster randomized”, which means they randomize different health centers to either give the experimental drug or not. This is worse than regular randomization, because there could be differences between these health centers (eg one might have better doctors who otherwise give better treatment, one might be in the poor part of town and have sicker patients, etc). They checked to see if there were any differences between the groups, and it sure looks like there were (the experimental group had twice as many obese people as the controls), but as per them, these differences were not statistically significant. Note that if this did make a difference, it would presumably make ivermectin look worse, not better. The primary outcome was given as “increase discharge from outpatient care with COVID-19 mild disease”. This favored the treatment; only 2/110 patients in the ivermectin group failed to be discharged, compared to 20 patients in the control group. But, uh, these were at different medical centers. Can’t different medical centers just have different discharge policies? One discharges you as soon as you seem to be getting better, the other waits to really make sure? This is an utterly crap endpoint to do a cluster randomized controlled trial on. If you’re going to do cRCT, which is never a great idea, you should be using some extremely objective endpoint that doctors and clinic administrators can’t possibly affect, like viral load according to some third-party laboratory, using the same third-party laboratory for both clinics. This is such a bad idea that I can’t help worrying I’m missing or misunderstanding something. If not, this is dumb and bad and should be ignored. Mourya et al: We’re back in India. This is a nonrandomized study comparing 50 patients given ivermectin to 50 patients given hydroxychloroquine. No primary outcome was named, but they focus on PCR negativity. Only 6% of patients in the hydroxychloroquine group were negative, compared to 90% of patients in the ivermectin group! On what day did they do the test? Uh, kind of random, and they admit that “in [the hydroxychloroquine group], mean time difference from the date of initiation of treatment and second test was significantly longer (7.24±2.75 days) as compared to 5.22±1.21 days in [the ivermectin group] (p=0.021).” Since they assessed these groups at different times, we shouldn’t draw any conclusions from them getting different results. Except that as far as I can tell this should handicap ivermectin, making it especially impressive that it did better. But also, the ivermectin group was made mostly of people who had been asymptomatic at the beginning (70%), and the hydroxychloroquine group had almost no asymptomatic cases (8%) . They were giving the ivermectin to healthy people and the hydroxychloroquine to sick people! They admit deep in the discussion that this “may be a confounding factor”. So basically they got totally different groups of people, tested them at totally different times, and the two sets of test results differed. So what? So this is why normal people do RCTs instead of whatever the heck this is, that’s what. Loue et al: …this one isn’t going to be an RCT either. Loue tells a story about a cluster of COVID cases at the French nursing home where he works. He asked people if they wanted to try ivermectin; 10 did and 15 didn’t. 1 ivermectin patient died, compared to 5 non-ivermectin patients. The non-ivermectin group looked a bit sicker than the ivermectin group in the inevitable Table 1, though it’s hard to tell. One interesting possible confounder (not mentioned, but I’m imagining it) is that demented patients probably couldn’t consent to ivermectin and ended up in the control group. This is another case of “I’m not going to trust anything that isn’t an RCT”. Merino et al: Another (sigh) non-RCT. Mexico City tried a public health program where if you called a hotline and said you had COVID, they sent you an emergency kit with various useful supplies. One of those supplies was ivermectin tablets. 18,074 people got the kit (and presumably some appreciable fraction took the ivermectin, though there’s no way to prove that). Their control group is people from before they started giving out the kits, people from after they stopped giving out the kits, and people who didn’t want the kits. There are differences in who got COVID early in the epidemic vs. later, and in people who did opt for medical kits vs. didn’t. To correct these, the researchers tried to adjust for confounders, something which - as I keep trying to hammer home again and again - never works. They found that using the kit led to a 75% or so reduction in hospitalization, though they were unable to separate out the ivermectin from the other things in the kit (paracetamol and aspirin), or from the placebo effect of having a kit and feeling like you had already gotten some treatment (if I understand right, the decision to go to the hospital was left entirely to the patient). I think this study is a moderate point in favor of giving people kits in order to prevent hospital overcrowding, but I’m not willing to accept that it tells us much about ivermectin in particular. Faisal et al: This one was published in The Professional Medical Journal (mispelled as “Profesional Medical Journal” in its URL), so you know it’s going to be good! It describes itself as “a cross-sectional study”, but later says it “randomized patients into two groups”, which would make it an RCT - I think they might just be using the term “cross-sectional” different from the standard American usage. A hospital in Pakistan got 50 patients on ivermectin + azithromycin, and another 50 on azithromycin alone. Primary outcome was not mentioned, and the data were presented confusingly, but a typical result is that only 4% of the ivermectin group had symptoms lasting more than 10 days, whereas 16% of the control group did, p < 0.01. They do a really weird thing where they compare how long it took symptoms to resolve between IVM and control groups within each bin. That is, if I’m understanding correctly, they ask “of the people who took between 3-5 days for symptoms to resolve, did they resolve faster for IVM or control?”. This is an utterly bizarre analysis to perform, although it doesn’t affect the fact that their other results still seem to favor ivermectin. Maybe I’m confused about what’s going on here. I’ve mostly been letting people off easy on no placebo, but I as far as I can tell (not very far) this paper seems to be going off whether patients reported continuing to have symptoms to the hospital doing the study, and I think that is potentially susceptible to placebo effects. Additionally, there’s no preregistration, and even though they talk a lot about doing PCR tests they don’t present the results. This is by no means the worst study here but I still think it’s pretty low quality and I don’t trust it. Aref et al: This one is published in the International Journal Of Nanomedicine, even though I’m pretty sure that isn’t a real thing. In this case the “nanomedicine” is a new nasal spray version of ivermectin which is so confusing I cannot for the life of me figure out what dose they are giving these patients. This Egyptian study gives 57 patients intranasal ivermectin plus hydroxychloroquine, azithromycin, oseltamavir, and some vitamins; another 57 patients get all that stuff except the ivermectin. Primary outcome is not stated, but they look at various symptoms, all of which look better in the ivermectin group: 95% of ivermectin patients got negative PCRs at some time point, compared to 75% of controls, p = 0.004. I am pretty suspicious of this study, not least because it comes from Egypt which has an awful reputation for fake studies, and it returns extreme results that I wouldn’t expect even if ivermectin was actually a wonder drug. But I cannot find any particular thing wrong with it, nor did anyone else I looked at, so I will grudgingly let it stand. Krolewiecki et al: Another Argentine study. This one is a real RCT. 30 patients received ivermectin, 15 were the control group (no placebo, again). Primary outcome was difference in viral load on day 5. The trend favored ivermectin but it was not statistically significant, although they were able to make it statistically significant if they looked at a subset of higher-IVM-plasma-concentration patients. They did not find any difference in clinical outcomes. A pro-ivermectin person could point out that in the subgroup with the highest ivermectin concentrations, the drug seemed to work. A skeptic could point out that this is exactly the kind of subgroup slicing that you are not supposed to do without pre-registering it, which I don’t think this team did. I agree with the skeptic. Vallejos et al: Another Argentine study. It’s big (250 people in each arm). It’s an RCT. It tries to define a primary outcome (“Primary outcome: the trial ended when the last patient who was included achieved the end of study visit”), but that’s not what “primary outcome” means, and they don’t offer an alternative. Other outcomes: no difference in PCR on days 3 or 12. Hospitalization is nonsignificantly better in the ivermectin group (14 vs. 21, p = 0.2), but death is nonsigificantly better in the placebo group (3 vs. 4, p = 0.7). This isn’t even the kind of nonsignificant that might contribute to an exciting meta-analysis later. This is just a pure null result. I cannot find any problem with this study, and neither can anyone else I checked. This is the biggest RCT we’ve seen so far, so we should take it seriously. TOGETHER Trial: Speaking of big RCTs… This one hasn’t been published yet. There’s a video of a talk about it, but I am not going to watch it, because it is a video, so I am getting information secondhand from eg here. Apparently, it compares 677 people (!) randomized to ivermectin to 678 people randomized to placebo. 86 ivermectin patients ended up in the hospital compared to 95 placebo patients, p-value not significant. This was a really big professional trial done by bigshot researchers from a major Canadian university, and the medical establishment is taking it much more seriously than any of these others. When it comes out, it will probably get published in a top journal. When discussing Lopez-Medina, I wrote: When people say things like “sure, a lot of small studies show good results for ivermectin, but the bigger and more professional trials don’t”, this is one of the two big professional trials they’re talking about. This is the other one. Not coincidentally, it’s also the other trial that ivmmeta.com has a warning letter underneath telling you to disregard. Their main concern is that instead of truly randomizing patients to ivermectin vs. placebo, they did a time-dependent randomization that meant during some weeks more patients were getting one or the other. This is a problem because the trial takes place in Brazil, where different variants were more common at different times. Here’s their image: On the one hand, I have immense contempt for ivmmeta for letting all those other awful studies pass and then pulling out all the stops to try to nitpick this one. I have no idea if their proposed randomization failure really happened. And no doubt the reason they’re even able to investigate this is that this study is really careful and transparent - most of them don’t tell you anything about their randomization method. I would be shocked if other studies don’t have all these problems and worse. On the other hand, the point isn’t to be fair, it’s to be right. And this is a potential confounder. Not a huge one. But a potential one. I guess all we can do is try to bound the damage. Even if the confounding is 100% real and bad, there’s no way to make this study consistent with the crazy super-pro-ivermectin results of studies like Espitia-Hernandez and Aref. And even if we deny any confounding, we see the same slight pro-ivermectin trend - 86 hospitalizations vs. 95 - that we’ve seen in so many other studies. Nothing is going to make me believe that this isn’t in the top 33% of studies we’ve been looking at, so let’s add it as grist for the meta-analysis (though maybe not quite as much grist as its vast size indicates) and move on, angrily. Buonfrate et al: An Italian RCT. Patients were randomized into low-dose ivermectin (32), placebo (29), or high-dose ivermectin (32). Primary outcome was viral load on day 7. There was no significant difference (average of 2 in ivermectin groups, 2.2 in placebo group). They admit that they failed to reach the planned sample size, but did a calculation to show that even if they had, the trial could not have returned a positive result. Clinically, an average of 2 patients were hospitalized in each of the ivermectin arms, compared to 0 in the placebo arm - which bucks our previously-very-constant pro-ivermectin trend. Mayer et al: Not an RCT. Patients in an Argentine province were offered the opportunity to try ivermectin; 3266 said yes and become the experimental group, 17966 said no and became the control group. There were many obvious differences between the groups, but they all seemed to handicap ivermectin. There was a nonsignificant trend toward less hospitalization and significantly less mortality (1.5% vs. 2.1%, p = 0.03). While looking into this study, I learned the term “immortal time bias”. This means a period in between selection for the study and the beginning of study recording where patient outcomes are not counted. I think the problem here is that if you signed up for the system on Day X, and if you got sick before they could give you ivermectin, you were in the control group. See this Twitter thread, I have not confirmed everything he says. This only hardens my resolve to stay away from non-RCTs. Borody et al: Our last paper! …is it a paper? I can’t find it published anywhere. It mostly seems to be on news sites. Doesn’t look peer-reviewed. And it starts with “Note that views expressed in this opinion article are the writer’s personal views”. Whatever. 600 Australians were treated with ivermectin, doxycycline, and zinc. The article compares this to an “equivalent control group” made of “contemporary infected subjects in Australia obtained from published Covid Tracking Data”; this is not how you control group, @#!% you. Then it gets excited about the fact that most patients had better symptoms at the end of the ten-day study period than the beginning (untreated COVID resolves in about ten days). Why are these people wasting my time with this? Let’s move on. The Analysis If we remove all fraudulent and methodologically unsound studies from the table above, we end up with this: Gideon Meyerowitz-Katz, who investigated many of the studies above for fraud, tried a similar exercise. I learned about his halfway through, couldn’t help seeing it briefly, but tried to avoid remembering it or using it when generating mine (also, I did take the result of his fraud investigations into account), so they should be considered not quite independent efforts. His looks like this: He nixed Chowdhury, Babaloba, Ghauri, Faisal, and Aref, but kept Szenta Fonseca, Biber (?), and Mayer. There was correlation of 0.45, which I guess is okay. I asked him about his decision-making, and he listed a combination of serious statistical errors and small red flags adding up. I was pretty uncomfortable with most of these studies myself, so I will err on the side of severity, and remove all studies that either I or Meyerowitz-Katz disliked. We end up with the following short list: We’ve gone from 29 studies to 11, getting rid of 18 along the way. For the record, we eliminated 2/19 for fraud, 1/19 for severe preregistration violations, 10 for methodological problems, and 6 because Meyerowitz-Katz was suspicious of them. …but honestly this table still looks pretty good for ivermectin, doesn’t it? Still lots of big green boxes. Meyerowitz-Katz accuses ivmmeta of cherry-picking what statistic to use for their forest plot. That is, if a study measures ten outcomes, they sometimes take the most pro-ivermectin outcome. Ivmmeta.com counters that they used a consistent and reasonable (if complicated) process for choosing their outcome of focus, that being: If studies report multiple kinds of effects then the most serious outcome is used in calculations for that study. For example, if effects for mortality and cases are both reported, the effect for mortality is used, this may be different to the effect that a study focused on. If symptomatic results are reported at multiple times, we used the latest time, for example if mortality results are provided at 14 days and 28 days, the results at 28 days are used. Mortality alone is preferred over combined outcomes. Outcomes with zero events in both arms were not used (the next most serious outcome is used — no studies were excluded). For example, in low-risk populations with no mortality, a reduction in mortality with treatment is not possible, however a reduction in hospitalization, for example, is still valuable. Clinical outcome is considered more important than PCR testing status. When basically all patients recover in both treatment and control groups, preference for viral clearance and recovery is given to results mid-recovery where available (after most or all patients have recovered there is no room for an effective treatment to do better). If only individual symptom data is available, the most serious symptom has priority, for example difficulty breathing or low SpO2 is more important than cough. I’m having trouble judging this, partly because Meyerowitz-Katz says ivmmeta has corrected some earlier mistakes, and partly because there really is some reasonable debate over how to judge studies with lots of complicated endpoints. By this point I had completely forgotten what ivmmeta did, so I independently coded all 11 remaining studies following something in between my best understanding of their procedure and what I considered common sense. The only exception was that when the most severe outcome was measured in something other than patients (ie average number of virus copies per patient), I defaulted to one that was measured in patients instead, to keep everything with the same denominator. My results mostly matched ivmmeta’s, with one or two exceptions that I think are within the scope of argument or related to my minor deviations from their protocol. Placebo vs. ivermectin groups sometimes differed in size, which I’ve adjusted for and rounded off. Probably I’m forgetting some reason I can’t just do simple summary statistics to this, but whatever. It is p = 0.15, not significant. This is maybe unfair, because there aren’t a lot of deaths in the sample, so by focusing on death rather than more common outcomes we’re pointlessly throwing away sample size. What happens if I unprincipledly pick whatever I think the most reasonable outcome to use from each study is? I’ve chosen “most reasonable” as a balance between “is the most severe” and “has a lot of data points”: Now it’s p = 0.04, seemingly significant, but I had to make some unprincipled decisions to get there. I don’t think I specifically replaced negative findings with positive ones, but I can’t prove that even to myself, let alone to you. [UPDATE 5/31/22: A reader writes in to tell me that the t-test I used above is overly simplistic. A Dersimonian-Laird test is more appropriate for meta-analysis, and would have given 0.03 and 0.005 on the first and second analysis, where I got 0.15 and 0.04. This significantly strengthens the apparent benefit of ivermectin from ‘debatable’ to ‘clear’. I discuss some reasons below why I am not convinced by this apparent benefit.] (how come I’m finding a bunch of things on the edge of significance, but the original ivmmeta site found a lot of extremely significant things? Because they combined ratios, such that “one death in placebo, zero in ivermectin” looked like a nigh-infinite benefit for ivermectin, whereas I’m combining raw numbers. Possibly my way is statistically illegitimate for some reason, but I’m just trying to get a rough estimate of how convinced to be) So we are stuck somewhere between “nonsignificant trend in favor” and “maybe-significant trend in favor, after throwing out some best practices”. This is normally where I would compare my results to those of other meta-analyses made by real professionals. But when I look at them, they all include studies later found to be fake, like Elgazzar, and unsurprisingly come up with wildly positive conclusions. There are about six in this category. One of them later revised their results to exclude Elgazzar and still found strong efficacy for ivermectin, but they still included Niaee and some other dubious studies. The only meta-analysis that doesn’t make these mistakes is Popp (a Cochrane review), which is from before Elgazzar was found to be fraudulent, but coincidentally excludes it for other reasons. It also excludes a lot of good studies like Mahmud and Ravakirti because they give patients other things like HCQ and azithromycin - I chose to include them, because I don’t think they either work or have especially bad side effects, so they’re basically placebo - but Cochrane is always harsh like this. They end up with a point estimate where ivermectin cuts mortality by 40% - but say the confidence intervals are too wide to draw any conclusion. I think this basically agrees with my analyses above - the trends really are in ivermectin’s favor, but once you eliminate all the questionable studies there are too few studies left to have enough statistical power to reach significance. Except that everyone is still focusing on deaths and hospitalizations just because they’re flashy. Mahmud et al, which everyone agrees is a great study, found that ivermectin decreased days until clinical recovery, p = 0.003? So what do you do? This is one of the toughest questions in medicine. It comes up again and again. You have some drug. You read some studies. Again and again, more people are surviving (or avoiding complications) when they get the drug. It’s a pattern strong enough to common-sensically notice. But there isn’t an undeniable, unbreachable fortress of evidence. The drug is really safe and doesn’t have a lot of side effects. So do you give it to your patients? Do you take it yourself? Here this question is especially tough, because, uh, if you say anything in favor of ivermectin you will be cast out of civilization and thrown into the circle of social hell reserved for Klan members and 1/6 insurrectionists. All the health officials in the world will shout “horse dewormer!” at you and compare you to Josef Mengele. But good doctors aren’t supposed to care about such things. Your only goal is to save your patient. Nothing else matters. I am telling you that Mahmud et al is a good study and it got p = 0.003 in favor of ivermectin. You can take the blue pill, and stay a decent respectable member of society. Or you can take the horse dewormer pill, and see where you end up. In a second, I’ll tell you my answer. But you won’t always have me to answer questions like this, and it might be morally edifying to observe your thought process in situations like this. So take a second, and meet me on the other side of the next section heading. … … … … … The Synthesis Hopefully you learned something interesting about yourself there. But my answer is: worms! As several doctors and researchers have pointed out (h/t especially Avi Bitterman and David Boulware), the most impressive studies come from places that are teeming with worms. Mahmud from Bangladesh, Ravakirti from East India, Lopez-Medina from Colombia, etc. Here’s the prevalence of roundworm infections by country (source). But alongside roundworms, there are threadworms, hookworms, blood flukes, liver flukes, nematodes, trematodes, all sorts of worms. Add them all up and somewhere between half and a quarter of people in the developing world have at least one parasitic worm in their body. Being full of worms may impact your ability to fight coronavirus. Gluchowska et al write: Helminth [ie worm] infections are among the most common infectious diseases. Bradbury et al. highlight the possible negative interactions between helminth infection and COVID-19 severity in helminth-endemic regions and note that alterations in the gut microbiome associated with helminth infection appear to have systemic immunomodulatory effects. It has also been proposed that helminth co-infection may increase the morbidity and mortality of COVID-19, because the immune system cannot efficiently respond to the virus; in addition, vaccines will be less effective for these patients, but treatment and prevention of helminth infections might reduce the negative effect of COVID-19. During millennia of parasite-host coevolution helminths evolved mechanisms suppressing the host immune responses, which may mitigate vaccine efficacy and increase severity of other infectious diseases. Treatment of worm infections might reduce the negative effect of COVID-19! And ivermectin is a deworming drug! You can see where this is going… The most relevant species of worm here is the roundworm Strongyloides stercoralis. Among the commonest treatments for COVID-19 is corticosteroids, a type of immunosuppresant drug. The types of immune responses it suppresses do more harm than good in coronavirus, so turning them off limits collateral damage and makes patients better on net. But these are also the types of immune responses that control Strongyloides. If you turn them off even very briefly, the worms multiply out of control, you get what’s called “Strongyloides hyperinfection”, and pretty often you die. According to the WHO: The current COVID-19 pandemic serves to highlight the risk of using systemic corticosteroids and, to a lesser extent, other immunosuppressive therapy, in populations with significant risk of underlying strongyloidiasis. Cases of strongyloidiasis hyperinfection in the setting of corticosteroid use as COVID-19 therapy have been described and draw attention to the necessity of addressing the risk of iatrogenic strongyloidiasis hyperinfection syndrome in infected individuals prior to corticosteroid administration. Although this has gained importance in the midst of a pandemic where corticosteroids are one of few therapies shown to improve mortality, its relevance is much broader given that corticosteroids and other immunosuppressive therapies have become increasingly common in treatment of chronic diseases (e.g. asthma or certain rheumatologic conditions). So you need to “address the risk” of strongyloides infection during COVID treatment in roundworm-endemic areas. And how might you address this, WHO? Treatment of chronic strongyloidiasis with ivermectin 200 µg/kg per day orally x 1-2 days is considered safe with potential contraindications including possible Loa loa infection (endemic in West and Central Africa), pregnancy, and weight <15kg. Given ivermectin’s safety profile, the United States has utilized presumptive treatment with ivermectin for strongyloidiasis in refugees resettling from endemic areas, and both Canada and the European Centre for Disease Prevention and Control have issued guidance on presumptive treatment to avoid hyperinfection in at risk populations. Screening and treatment, or where not available, addition of ivermectin to mass drug administration programs should be studied and considered. This is serious and common enough that, if you’re not going to screen for it, it might be worth “add[ing] ivermectin to mass drug administration programs” in affected areas! Dr. Avi Bitterman carries the hypothesis to the finish line: First two images are with all relevant studies; second two are a sensitivity analysis that removes some of the most dubious. The good ivermectin trials in areas with low Strongyloides prevalence, like Vallejos in Argentina, are mostly negative. The good ivermectin trials in areas with high Strongyloides prevalence, like Mahmud in Bangladesh, are mostly positive. Worms can’t explain the viral positivity outcomes (ie PCR), but Dr. Bitterman suggests that once you remove low quality trials and worm-related results, the rest looks like simple publication bias: This is still just a possibility. Maybe I’m over-focusing too hard on a couple positive results and this will all turn out to be nothing. Or who knows, maybe ivermectin does work against COVID a little - although it would have to be very little, fading to not at all in temperate worm-free countries. But this theory feels right to me. It feels right to me because it’s the most troll-ish possible solution. Everybody was wrong! The people who called it a miracle drug against COVID were wrong. The people who dismissed all the studies because they F@#king Love Science were wrong. Ivmmeta.com was wrong. Gideon Meyerowitz-Katz was…well, he was right, actually, I got the worm-related meta-analysis graphic above from his Twitter timeline. Still, an excellent troll. Also, the best part is that I ignorantly asked, in my description of Mahmud et al above: And it was! It was a fluke! A literal, physical, fluke! For my whole life, God has been placing terrible puns in my path to irritate me, and this would be the worst one ever! So it has to be true! The Scientific Takeaway About ten years ago, when the replication crisis started, we learned a certain set of tools for examining studies. Check for selection bias. Distrust “adjusting for confounders”. Check for p-hacking and forking paths. Make teams preregister their analyses. Do forest plots to find publication bias. Stop accepting p-values of 0.049. Wait for replications. Trust reviews and meta-analyses, instead of individual small studies. These were good tools. Having them was infinitely better than not having them. But even in 2014, I was writing about how many bad studies seemed to slip through the cracks even when we pushed this toolbox to its limits. We needed new tools. I think the methods that Meyerowitz-Katz, Sheldrake, Heathers, Brown, Lawrence and others brought to the limelight this year are some of the new tools we were waiting for. Part of this new toolset is to check for fraud. About 10 - 15% of the seemingly-good studies on ivermectin ended up extremely suspicious for fraud. Elgazzar, Carvallo, Niaee, Cadegiani, Samaha. There are ways to check for this even when you don’t have the raw data. Like: The Carlisle-Stouffer-Fisher method: Check some large group of comparisons, usually the Table 1 of an RCT where they compare the demographic characteristics of the control and experimental groups, for reasonable p-values. Real data will have p-values all over the map; one in every ten comparisons will have a p-value of 0.1 or less. Fakers seem bad at this and usually give everything a nice safe p-value like 0.8 or 0.9.

Inline links: Ravakirti et al:, Bukhari et al:, Mohan et al:, Biber et al:, the preregistration, Elalfy et al:, https://substackcdn.com/image/fetch/$s_!B_IH!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F4d3559ee-a058-44cc-9b38-09b78a0f5035_1352x1070.png, https://substackcdn.com/image/fetch/$s_!9mI_!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2Fbffceed7-c84a-45c1-abfe-1fb2706dc383_483x674.png, Lopez-Medina et al:, Roy et al:, Chahla et al:, Mourya et al:, Loue et al:, Table 1, Merino et al:, never works, Faisal et al:, Aref et al:, https://substackcdn.com/image/fetch/$s_!-FoK!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2Ff6de79b6-091b-4c13-b7be-715c9bb194a7_986x810.jpeg, Krolewiecki et al:, Vallejos et al:, TOGETHER Trial:, here, https://substackcdn.com/image/fetch/$s_!7X0m!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F1f65fd44-58b9-4489-a934-02a5a7330499_706x768.png, Buonfrate et al:, Mayer et al:, immortal time bias, this Twitter thread, Borody et al:, https://substackcdn.com/image/fetch/$s_!Wpjs!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F2d8a451b-b1fc-44e5-ae67-b1506e491762_914x657.png, https://substackcdn.com/image/fetch/$s_!DOjA!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F17d5827a-38da-4a99-beb3-c3018df5c633_920x604.png, https://substackcdn.com/image/fetch/$s_!GX1n!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2Fc692fec8-a450-4579-b337-c72bec060970_912x298.png, https://substackcdn.com/image/fetch/$s_!YcH4!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2Ff36db98e-e653-44da-906c-20312b1689a3_468x205.png, https://substackcdn.com/image/fetch/$s_!jbcL!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2Fd189a844-daf2-4199-bb2e-830d4fc64415_468x206.png, later revised their results to exclude Elgazzar, Popp, https://substackcdn.com/image/fetch/$s_!2B6r!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F505c5ac4-3fe8-47a4-8505-dab80601b44d_416x198.png, Avi Bitterman, David Boulware, https://substackcdn.com/image/fetch/$s_!JWWh!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2Fac9e4f34-f9cc-40f2-9d83-da4e7178fad7_772x330.png, source, Gluchowska et al, the WHO, carries, https://substackcdn.com/image/fetch/$s_!xExE!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F5da21781-249c-4e59-b616-9f23d83cc044_2048x1184.jpeg, https://substackcdn.com/image/fetch/$s_!4SMr!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2Fdcd6e4b2-37f7-4602-93d5-2581c3b27a60_700x432.png, https://substackcdn.com/image/fetch/$s_!-6n2!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F7fd6e8f4-093e-4e02-bce7-363615146c9c_2228x1346.jpeg, https://substackcdn.com/image/fetch/$s_!CPZs!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2Fb0425847-198a-4bd3-a63b-149f15d147ba_700x432.png, https://substackcdn.com/image/fetch/$s_!H3rK!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F9972491b-25b0-4c06-8aca-86fce102ae63_666x147.png, even in 2014, The Carlisle-Stouffer-Fisher method

Links For November

November 25, 2021 · Original source

Boris Johnson (left) is 5’9, so the guy in the middle must be gigantic. Who is he? Looks like it’s Milo Djukanovic, President of Montenegro, who’s 6’6 (198 cm). Is he the tallest world leader? It seems like he’s tied with his colleague across the border, Serbian president Aleksandar Vucic. Why are Balkan leaders so tall? As usual, the answer is “genetics”. This article says: It has been noted that men from Herzegovina are taller on average than men in other places—the average male height is just over six feet...Putting all the data together, researchers concluded that the most likely cause of larger-than-average height of Herzegovinian men is lifestyle during the Paleolithic—men hunted large animals such as mammoth for survival—such a diet, heavy in protein, combined with small population densities, would have provided ideal conditions for height selection, resulting in increasingly taller men who passed the trait down through their I-M170 chromosome to future generations. Some sources note that they manage to beat the Dutch despite the latter country’s much higher human development index. The Dutch are probably tall through a combination of nature and nurture; Balkan people are tall through nature alone. 7: Eliezer Yudkowsky doesn’t need more ego boosts, but an idea he had a couple of years ago - using strings of bright lights to provide a better and brighter experience for Seasonal Affective Disorder sufferers than regular light boxes - spread from him to the rationalist community to the wider world, and has finally gotten tested in a formal study (see Acknowledgments section). Results seem vaguely positive: "SAD symptoms of both groups improved similarly and considerably...exploratory analyses indicate that a higher illuminance is associated with a larger symptom improvement in the BROAD light therapy group" 8: Percent of people who choose woke options on polls very tentatively and preliminarily seems to be going down post-Trump (h/t Richard Hanania). 9: Twitter conspiracy theories 10: Did you know: all those reconstructions of “how classical art would have looked with the original paint” are probably inaccurate. There is no reason to think the Greeks and Romans used garish technicolor hues on their statues; what evidence we have suggest they were good at shading, and the statues were probably colored very tastefully. 11: Complaints about how Karl Friston uses the term “Markov blanket” 12: Trevor Klee on the claim that cyclosporine patients don’t get dementia. Apparently there was a big study where basically nobody on the immunosuppressant cyclosporine ever got dementia, and there are some theoretical reasons why cyclosporine might prevent neurodegeneration. But another study found people on cyclosporine got dementia at the usual rate. I think in a situation like this you should have a really high prior on “the people who got the crazy result bungled their study somehow”, but I’m interested in hearing what other people think. 13: Also from Trevor: a history of fluvoxamine treatment for COVID. 14: To tide you over until the next book review contest, here is awanderingmind’s review of The Conquest Of Bread. 15: Claims: cnbc.com/2021/11/05/sam…\nft.com/content/dcb75a… (better article, but paywalled)","username":"moskov","name":"Dustin Moskovitz","profile_image_url":"","date":"Fri Nov 05 15:49:46 +0000 2021","photos":[],"quoted_tweet":{},"reply_count":0,"retweet_count":184,"like_count":1188,"impression_count":0,"expanded_url":{"url":"https://www.ft.com/content/dcb75a56-ca23-439c-96db-56483979bf34","image":"https://bucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com/public/images/80a58c96-c72f-4301-b571-aa9384f132bd_2400x1350.jpeg","title":"Subscribe to read | Financial Times","description":"News, analysis and comment from the Financial Times, the worldʼs leading global business publication","domain":"ft.com"},"video_url":null,"belowTheFold":true}" data-component-name="Twitter2ToDOM"> 16: Big trial on Vitamin D for depression finds null result. Peter Attia tries to tear it apart here, but I am unconvinced, especially in the context of Vitamin D never working for any of the things people say it does besides the most boring aspects of bone health. 17: “California is actively considering the adoption of flawed and inequitable guidance on math curricula based on misleading data and inaccurate success metrics reported by San Francisco Unified School District (SFUSD)...Based on our review of the data, we found misleading, unsupported, and cherry-picked assertions of success for the new math program. We noted that overall test scores are down and enrollments in UC-approved advanced math classes have dropped as well.” It looks like San Francisco is trying the good old “lower standards, then when more kids meet the standards, claim your school reform plan worked” trick again. 18: A new study claims that self-reported “Long COVID” symptoms are more associated with believing you’ve had COVID than with actually having it (as measured by serologic testing), which sounds like pretty strong evidence that it’s psychsomatic. Expert reactions are mixed-to-negative, although the only one of these that doesn’t sound like excuse-making is Dr. Rossman’s about the unreliability of the tests. I haven’t confirmed test reliability stats but Philippe Lemoine also thinks this is a plausible confounder. 19: Noahpinion: What If Xi Jinping Just Isn’t That Competent? I appreciated this for making me think, and for underlining the extent of the difference between the Deng/Jiang/Hu era and what Xi’s doing. I especially appreciated this line, which I’d never thought about before: Xi presided over the end of China’s hypergrowth. To some extent this is not his fault. No country can grow at 10% forever, and there were many structural forces pushing downward on China’s numbers — the end of the demographic dividend, the exhaustion of rural surplus labor (the Lewis Turning Point), the saturation of export markets, and so on. But China is also slowing down earlier than South Korea, Taiwan, or Japan did in their day. China’s per capita GDP (at PPP) is still only about 1/3 that of a developed country, so if they stop catching up at about half of developed-country levels, that will not be a great showing. A big lesson of the past twenty years has been “actually liberal democracy isn’t necessary to reach developed-country status”, so it would be quite the twist if it turned out you needed liberal democracy to reach developed-country status. This gets pretty close to the great mystery of why some less-developed countries “catch up” and others don’t; whatever happens in China is going to be a really useful data point. 20: Variations on the fable of The Frog And The Scorpion. 21: You’ve probably heard about the University of Austin, the new project by a bunch of wokeness-critical academics to start a new university that won’t cancel people or force conformity (New York Post article, Politico article - these were the two least “you need to be super-outraged about this right now” articles I could find). Tyler Cowen and Larry Summers are involved; Steven Pinker was supposed to be but left for unclear reasons. My thoughts, in no particular order: Even forgetting the political aspect, attempts to start new universities are always welcome.

Inline links: Milo Djukanovic, Aleksandar Vucic, This article, in a formal study, Richard Hanania, Twitter conspiracy theories, There is no reason to think, Complaints about, cyclosporine patients don’t get dementia, a history of fluvoxamine treatment for COVID, The Conquest Of Bread, Vitamin D for depression, here, is trying, A new study, Expert reactions, Philippe Lemoine also thinks, What If Xi Jinping Just Isn’t That Competent?, Lewis Turning Point, slowing down earlier, per capita GDP (at PPP), the great mystery, Variations on the fable of The Frog And The Scorpion, New York Post article, Politico article

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