| | Welcome to this video and a particular welcome back to Professor Colleen Aldous. |
| | Professor, thank you for coming back. |
| | It's always a pleasure to check. |
| | Really, I do enjoy it. |
| | So do I. I love it. |
| | Now, I've been checking on you. |
| | You're a professor at the University of KwaZulu-Natal, South Africa, and you are involved in checking and supervising all forms of medical research. |
| | For example, mentorship of research in surgery, paediatrics, general medicine, psychology, human genetics, research, policy change and epidemiology. |
| | Apart from that, I think the rest is a little bit boring, but that covers just about the entire field. |
| | And what we want to look at today is this paper that you've just published very recently that we see on the screen now. |
| | Critical appraisal of multi-drug therapy in the ambulatory management of patients with COVID-19 and hypoxemia. |
| | Now, just as an introduction, you're going to be using the Bradford Hill criteria, which are just fantastic. |
| | I think we should be using these way more than we are. |
| | It's just not talked about anything like enough. |
| | And I just did a little bit of a sketch last night. |
| | Bradford Hill criteria are deciding what factors, when they're correlated, could be causally related. |
| | And this goes back to 1965 with Austin Bradford Hill, the famous British epidemiologist working with Richard Doll. |
| | And using these criteria, they worked out for the first time that smoking causes lung cancer. |
| | That asbestos causes mesothelioma. |
| | They both discovered that. |
| | And before that, people didn't know. |
| | I remember when I was a boy, my dad saw an upper teacher, me to saw asbestos. |
| | I mean, it's just unbelievable. |
| | And the criteria have been used more recently to look at vitamin D in cancer, molds and infant pulmonary hemorrhage, alcohol and cardiovascular disease, sugar and sweetened components in drinks and obesity, and the effect of neonicotinoids, pesticides on honeybee prevalence. |
| | So all sorts of things coming out there. |
| | But tell us what first drew your interest to the ivermectin story. |
| | And then how did you decide to use the Bradford Hill criteria to adjudicate its efficacy? |
| | Well, I was first drawn into the ivermectin story in late 2020, when our South African pharmaceutical agency, Sopra, put out a notice to say nobody's allowed to use ivermectin and that it could kill you. |
| | And at that point, I realized that something just did not add up. |
| | Because although I did not know the drug very well at the time, the one thing I knew about it is it has just about no side effects. |
| | And whatever side effects it has, even at extraordinarily high doses, are transient. |
| | So I thought something was up. |
| | And then I got involved in looking at the evidence for ivermectin. |
| | And I immediately started collecting a library of evidence. |
| | Everything that was published from 2020 onwards on ivermectin and COVID, I consumed. |
| | And I created that real paper that we spoke about last time. |
| | It actually shows the lie of the land of all the research. |
| | So it has the totality of evidence. |
| | It also tells you, you know, how much evidence is laboratory evidence, how much is clinical evidence, and how much is positive and how much is negative. |
| | But still, people were carrying on with this whole thing about a randomized control trial. |
| | They were parroting the same phrase. |
| | It's almost like somebody in some big Western country said, we need a large, well-designed, randomized control study. |
| | And that sentence, as I've just said, it was parroted everywhere. |
| | In our country, they were saying, unless we have a large, randomized, well-designed, controlled trial study, we're not going to even look at ivermectin. |
| | And we actually sent off a paper showing the initial findings. |
| | We did a mini-analysis to our local journal. |
| | And they wrote back saying, they are not going to print anything on ivermectin unless it is a large, randomized control trial. |
| | And, of course, Santoshi Omoro's institution in Japan actually offered to host such a trial, but no one stopped up the $10 or $20 million that was required for such a trial. |
| | Surprise, surprise. |
| | Yes. |
| | I think that Professor Omura even asked Merck if they would sponsor it, and they said no. |
| | But they also had, at that time, they had a vaccine that they were going to put out to trial. |
| | It didn't see the light of day, but they also had interests to look after. |
| | And then what sort of got you convinced that ivermectin is efficacious in, let's say, for example, acute presentation of COVID-19? |
| | Well, I started working with Martin Gill and Jackie Stone. |
| | And they were sending me evidence all the time, showing me what was happening in their clinics. |
| | And it was a very interesting story. |
| | Jackie Stone was from Zimbabwe, and Martin Gill was in South Africa. |
| | And ivermectin was not clear for use in either country until much later. |
| | In South Africa, it was cleared for use on a Section 21, I think. |
| | But what happened on, and they said it was the 8th of August 2020, is they met and had a conversation. |
| | And up until that point, Jackie had been using silver in her patients and had said the silver was improving their breathing. |
| | But she had to keep on at it. |
| | She had to keep nebulizing the patients. |
| | Martin had said he wasn't losing patients while he had ivermectin going if the patients got him early. |
| | So the two of them decided together that they were going to use both silver and ivermectin. |
| | And both of them said on that day their death stopped. |
| | So using those two things together certainly had an impact. |
| | And I could not but believe this was happening because they were giving me this information all the time. |
| | I was part of the ivermectin interest group. |
| | Other doctors were telling me what was happening in hospitals. |
| | Some doctors had ivermectin in their pockets and were handing out tablets out of their pockets to patients. |
| | Highly illegal. |
| | If it was ever caught, they'd be in big trouble. |
| | But that is where it was at the time. |
| | And I felt it was my duty as a scientist to support them and to show them that this is really working. |
| | As much as people were saying ivermectin is not doing anything for anybody, it was. |
| | And I felt it was my duty as a scientist not to abdicate my responsibility and to support those clinicians. |
| | So basically, I think we should probably just pause at this point to remember Dr. Jackie Stone, who sadly left this world on the 3rd of October 2024 after a very, very, very difficult time. |
| | So sadly no longer with us. |
| | But we don't use silver in this country. |
| | So basically in England that I've never seen. |
| | So basically what they were doing is they were using, they were getting patients in and patients were hypoxemic, that their blood levels of oxygen were low with COVID. |
| | Okay, it was a minority of patients that were getting the low oxygen levels, but it was life-threatening in a minority of patients. |
| | And as good clinicians, when confronted with a new disease, they tried things that were locally available. |
| | They tried to save the lives of their patients. |
| | And I think Jackie did succeed in that, didn't you? |
| | This paper you've done, Colleen, is basically three studies, isn't it? |
| | Yes, it is. |
| | But maybe just outline what those three studies are now that maybe that you considered for your Bradford Hill paper. |
| | Okay, just before I do that, I want to draw to the attention of anybody who reads these articles. |
| | And just to mention, this is part two of a two-part series, and I'll refer to part one later. |
| | But they are both dedicated to the memory of Jackie because Jackie trained a whole lot of doctors in Zimbabwe who all used this healing protocol and saved a lot of lives. |
| | So the three studies that we looked at, we have referred to before in the stone paper. |
| | We have previously written up the data in Zimbabwe. |
| | So Jackie had 30-odd patients that we wrote up that were all hypoxemic. |
| | And we wrote up how quickly their blood oxygen levels shot up. |
| | And it was literally a miraculous shooting up. |
| | And in that paper, we compared her results with two others, and we didn't know these people at the time. |
| | We compared her results to Sabine Hazan, who did a similar study in Malibu and in the state, and to Dr. Babalola, who also looked at the study in Nigeria, I think it was. |
| | It was, yeah. |
| | So those, yeah, there were three ivermectin protocols. |
| | So in this diagram that you have on the screen, Yep, yep. |
| | The gray bottom line is a trial that did not use ivermectin at all. |
| | So all the studies, the patients at day zero, all started off with the same reading on that zero line. |
| | The people who did not... |
| | So the y-axis is what? |
| | Mean change in oxygen saturation percentage from... From day zero. |
| | Yeah. |
| | Yeah, yeah. |
| | Oh, so, okay. |
| | So that's the percent... |
| | The numbers are the percentage of change in oxygen saturations. |
| | Yeah. |
| | Yeah. |
| | So thyroid study shows that the blood oxygen continues to drop. |
| | But the Babalola, Hazan, and Stone et al. |
| | studies all show an immediate increase in the SpO2. |
| | Yeah, which is the oxygen... That's the way you would measure the oxygen with a peripheral oxygen saturation probe on your finger. |
| | Yeah. |
| | So immediately, your patients start to feel better because now they can breathe. |
| | So you've started the healing process. |
| | Yeah. |
| | And if you have a look, it's instant. |
| | And what this graph also shows is that Sabine, Hazan, and Jackie Stone both used aggressive ivermectin regimens. |
| | And they used doxycycline. |
| | They used vitamins as well. |
| | The silver was used by Jackie. |
| | But they had a higher dose. |
| | Dr. Babalola used a lower dose. |
| | But you can still see there was an increase. |
| | Well, very, very much so. |
| | Yeah. |
| | It's clear blue water between the gray line and the blue line, isn't there? |
| | Absolutely. |
| | So the only difference that there was... And later on, you'll see that Thyru and Babalola's studies are compared, and they are able to show a benefit for mortality. |
| | So clearly, ivermectin was the only difference. |
| | And ivermectin has got the patients breathing again. |
| | And once you've got your patient breathing again, treating everything else in the long term is doable. |
| | They're not going to die because they can't breathe anymore. |
| | And we've got a significant improvement here after really just hours, haven't we? |
| | Because, I mean, dramatic improvement after 24 hours. |
| | Yeah. |
| | That line is going up steep. |
| | So the oxygen saturations are going to have increased from two, three hours after taking the ivermectin. |
| | It is very rapid. |
| | And we know why. |
| | We're going to get to that a bit later. |
| | But we do know that once the ivermectin gets into the system, it starts withdrawing the spike protein of the microclots that have been caused with the red blood cells. |
| | So now the oxygen is free to get to the rest of the body. |
| | We're not going to have those problems in the alveoli where people can't breathe. |
| | So people were actually just suffocating if you left them. |
| | If you look at the thyroid, if you've got a really sick patient, they would suffocate to death. |
| | And I believe in Jackie's situation, there was literally no oxygen available. |
| | Yeah. |
| | So it's not as if this could be accused of an ethical violation in that you were withholding oxygen from patients. |
| | But it simply wasn't available. |
| | Remember, we had all those pictures at the time of people frantically riding around on motorbikes and things, trying to buy oxygen cylinders for their relatives because there was simply no oxygen available in parts of the African situation. |
| | In Zimbabwe, I think she told me, if I remember correctly, they created one hospital for COVID at the beginning when the lockdown started. |
| | And that was the only oxygen tank for the whole of Harare, which is the capital of Zimbabwe. |
| | So the majority of patients that came to see Jackie and other doctors were hypoxemic with no option at that point of going anywhere else. |
| | And with Sabine, too, those patients were not included in trials. |
| | They were not able to get to a facility where there was oxygen. |
| | So she treated them at home. |
| | And the irony, of course, is that a lot of these patients did better than the patients who were admitted to intensive care units in Canada, Australia, United Kingdom, not so much Australia, but Canada, the United Kingdom, United States, because when patients went on to ventilators, not many got off. |
| | Yeah. |
| | Just like a kiss of death. |
| | Very, very high mortality after ventilation. |
| | Yeah. |
| | Now, I think we should probably go through some of the stages in this paper methodically, Colleen, if that's OK. |
| | So what we have here, we clearly have an association between ivermectin and increased oxygen saturation. |
| | And of course, anyone who's done research 101 will say, of course, correlation is not causality, which it isn't. |
| | But correlation can often be causality. |
| | Things that are causally related are, of course, going to be correlated. |
| | Things that are correlated may or may not be causally related. |
| | So how do we decide which is which? |
| | And this is where the Bradford Hill criteria come in, going all the way back to the early 1960s and the amazing work done that no one knew about, smoking causing lung cancer. |
| | Quite incredible looking back on it now. |
| | But I don't want to jump the gun. |
| | I want to go through your stages in your paper just one at a time and thinking about the criteria as applied to the specific case of the ivermectin and oxygen saturations. |
| | So the first one in your paper is temporality. |
| | What does that mean and what did you find? |
| | Well, temporality would mean how does it work over time? |
| | And I've made some notes to get a chance to you. |
| | Please do. |
| | Yeah. |
| | So clearly we have been able to show that ivermectin would satisfy temporality because you see this jump. |
| | In the same time, with those two particularly aggressive regimens, both in the same time push up the blood oxygenation. |
| | So that's temporality. |
| | The effect is following the cause. |
| | Absolutely. |
| | They're in the right order. |
| | Yeah. |
| | Exactly. |
| | So I just also want to mention to you that the Bradford Hill criteria of 1965 included nine criteria. |
| | Yeah. |
| | And like a lot of people who like rules to think, they created a tick box system. |
| | Yeah. |
| | And so, which is not what Bradford Hill intended. |
| | What Bradford Hill intended was to look at arguments from all these different angles and come up with what he called an inference to best explanation. |
| | Yeah. |
| | Yeah. |
| | And also, in the 1960s, if you cast your mind back, there weren't many RCTs around. |
| | You can't remember the 60s, Colleen. |
| | I was born then. |
| | Yeah. |
| | Yeah. |
| | But there weren't any randomized controls. |
| | So people were trying to make sense of how can we infer an explanation. |
| | And so to modernize these, a lot of people have criticized Bradford Hill. |
| | Howick and his group in 2009 took those criteria and have modernized them a bit. |
| | So they do include randomized control trials, which were not included in the beginning. |
| | So they do fit here. |
| | But temporality is common across both of them. |
| | And that is, we actually do see these things happening in completely different experiments. |
| | Well, they're not experiments, in completely different studies. |
| | Clinical situations. |
| | Yeah. |
| | At the time that the data was being collected, Hazan, Stone, Babalola didn't know each other. |
| | Hmm. |
| | We all got together a bit later and we've now become friends internationally. |
| | But that shows your temporality. |
| | It definitely did work. |
| | And we showed this particular graph in the Zimbabwe paper, the Stone paper, that we discussed a good few years ago now. |
| | Hmm. |
| | And of course... |
| | So we were able to... |
| | Sorry? |
| | Sorry. |
| | No, go ahead, Cluyn. |
| | Sorry. |
| | Scientifically, one of the tenets of good science is to be able to have repeatability. |
| | Yep. |
| | And these three studies actually show that. |
| | Hmm. |
| | They had slightly different approaches, but they all showed that it was with ivermectin that you could improve blood saturation. |
| | And it's not just these three studies. |
| | I mean, I talked to Dr. Pierre Corey. |
| | Yeah. |
| | Way, way back in... |
| | I can't remember. |
| | I think it was 2020, actually. |
| | He'd done a deputation before, I can't remember if it was Congress or Senate, on steroids, and that was accepted. |
| | And he did another one on ivermectin, and that was not accepted. |
| | And it had 10 million views on YouTube in about a couple of days, and then it was taken down. |
| | So it's doctors around the world who, if you like, were flying by the seat of the pants in 2020, just looking for ways to suit their sick patients. |
| | I found ivermectin worked, but this war on ivermectin seemed to crop up. |
| | Almost, a cynic might say, in a coordinated way around the world. |
| | I find it... |
| | The cynical side of me, just to address that, is we now post-COVID. |
| | Yeah. |
| | And people are acknowledging it was a lab leak. |
| | There is just no other explanation. |
| | The debate is basically over, isn't it? |
| | Yeah. |
| | And people like you and I who mentioned this in, what, 2022 when we first met? |
| | Yeah, I think in 2021 I was getting pretty suspicious about it. |
| | Yeah. |
| | Yeah. |
| | I mean, we were saying it very quietly because we said it out loud and we were accused of being cooked. |
| | Yeah, yeah. |
| | And whenever I did say it out loud, I was shouted down. |
| | So the lab leak theory is out there. |
| | Yeah. |
| | I think we also started talking about serious adverse events with the vaccine a few years ago. |
| | And again, we were doing it very quietly. |
| | I very subtly left a position of power I was in because I felt very uncomfortable. |
| | And I didn't want to be truthful about it because I'd have been told that I was a kook. |
| | But now people are accepting, yes, we've got serious adverse events. |
| | But what has not reached the trusted news initiative, which includes lots of newspapers and television stations around the world, is the fact that we had very good drugs that were repurposed that worked. |
| | And they were squashed. |
| | And they were squashed because other companies wanted to try out the new thing. |
| | Or again, a cynic might say they wanted to make some money. |
| | Who could possibly know? |
| | Oh, well, people like you and I, money isn't important. |
| | Well, it sounds like you're going to pay for your groceries. |
| | But yeah, I'm sure we could both make a heck of a lot more money than we do. |
| | Right. |
| | Let's move on to the I know you could. |
| | You're an internationally renowned professor. |
| | You could certainly make a lot more than you do. |
| | No, you are. |
| | People don't realize professors are remarkably senior. |
| | Well, it is the most senior academic grade, isn't it? |
| | You know, it's not. |
| | I was never a professor. |
| | I was no, I never got past senior lecturer. |
| | I was just a minion. |
| | Professors were kind of up there to me. |
| | But it doesn't mean we are internationally renowned. |
| | No, but you happen to be. |
| | I know we did a couple of gigs together in Sydney. |
| | So yeah, at least we're known to some extent in Australia. |
| | Yeah. |
| | Now, next criteria, the strength of association. |
| | This is kind of a size, an effect size, isn't it? |
| | What were you thinking about the strength of association? |
| | So for strength of association, you have to start looking at maths. |
| | Oh, it's a bit tricky. |
| | And so the reason for the two part series is part one is establishing that strength of association. |
| | And that's where Elefterios is an absolute genius when it comes to looking at a problem and coming up with a mathematical solution to it. |
| | So I first met Elefterios, who's the first author on both of these papers, when he approached Dr. Zelenko several years ago now, when Dr. Zelenko was putting out his protocol where he got very good results in New York with hydroxychloroquine. |
| | I think it was still in Trump's first term. |
| | Yeah. |
| | And that is what Trump was saying, we're going to use hydroxychloroquine. |
| | Well, he took it himself for a period of time. |
| | Yeah. |
| | And Elefterios then wrote up a method where you could compare multi-drug treatments to be able to come up with a mathematical evidence that this is truth. |
| | Yeah. |
| | As opposed to doing a single drug randomized control trial. |
| | Because let's face it, when you're in a pandemic, you've got sick people in front of you. |
| | You're not going to get away with just one drug, with a monotherapy. |
| | I mean, every single illness is treated with a cocktail because there are lots of different aspects of the disease that need to be treated. |
| | So Elefterios had written this paper with Dr. Zelenko showing mathematically that you can compare multi-drug treatment protocols. |
| | And so what he did for our paper in part one is he looked at the three studies, the Hazan, Stone and Babalola papers, and used ordinary maths to show that it's almost impossible that the results for our two criteria were mortality or admission to hospital. |
| | So it's just about impossible that it wasn't ivermectin that caused people to not go to hospital and not to die. |
| | So the strength of association is worked out in paper one. |
| | And that's a mathematical paper that I'm very proud to have my name on. |
| | It is written by a professor of mathematics. |
| | So it is pretty comprehensive. |
| | And it's been downloaded. |
| | Luckily, part one has been downloaded a lot of times. |
| | So I'm thinking a lot of people are beginning to see that we can use other kinds of maths. |
| | It doesn't have to be a randomized controlled trial with a p-value. |
| | And we'll get to the p-value a bit later. |
| | So what he was able to show mathematically is that we have got a strength of association here. |
| | It's definitely ivermectin that prevented these patients from serious hospitalization or from dying. |
| | So we have that factor satisfied now. |
| | Well, I've got two ticks so far. |
| | Yeah. |
| | Yeah. |
| | So he explains this as it's not causation. |
| | It's inference to best explanation. |
| | Yeah. |
| | By saying, for example, you go to the movies and you eat popcorn at the movies. |
| | And you come out of the movies at the end and somebody hits you over the head with a baseball bat. |
| | And you end up in the A&E. |
| | So what is the likely cause of your injury? |
| | Is it the popcorn that popped so much that you fell on the ground? |
| | Is it the movie? |
| | Or is it the baseball bat? |
| | And you can make a decision that it's a baseball bat probably because you've seen previous baseball bat injuries. |
| | You've not seen any injuries like that resulting from popcorn, etc. |
| | So that is what we're looking for. |
| | Yeah. |
| | It's not saying it's a perfect causation, but it's the best explanation. |
| | It's using scientific and human logic. |
| | It's almost like an Occam's razor sort of thing, isn't it? |
| | Yes. |
| | It's exactly that. |
| | Yeah. |
| | Good. |
| | Now, the next thing in your paper is biological gradient. |
| | What is a biological gradient? |
| | Well, if you have a look at this diagram that you've got here. |
| | Oh, this one. |
| | This one. |
| | Yeah. |
| | Yeah. |
| | Sabine and Jackie used a lot of ivermectin. |
| | They used high doses of ivermectin. |
| | And Fabalola used a lower dose for less time. |
| | So you can actually see less ivermectin, slower progress. |
| | Big bolus of ivermectin, quick progress. |
| | Interesting. |
| | And that would be your biological gradient. |
| | Interesting and very sad anecdote is I know of a patient, an elderly woman who was hospitalized. |
| | And her family managed to find three ivermectin tablets for her that they smuggled in. |
| | And she was, after her first one, she was able to breathe. |
| | After the second one, she felt fantastic. |
| | After the third one, she said she's now ready. |
| | She's feeling great. |
| | But they kept her in hospital because she was pretty advanced. |
| | She was still in a cytokine storm. |
| | Yeah. |
| | And she just 12 milligram tablets of ivermectin. |
| | Yeah. |
| | Yeah. |
| | Yeah. |
| | But it was at a period where people still didn't know about dosages. |
| | They were still scared of liver issues. |
| | And so she couldn't get any more ivermectin. |
| | And she just dived and died. |
| | So that to me also shows it's anecdotal. |
| | It will never be written up because there'd be too much trouble around it. |
| | But to me, that also is a biological gradient. |
| | You withdraw treatment and the patient dies. |
| | Well, and it fits in with the temporality as well, doesn't it? |
| | Yeah. |
| | She took the ivermectin. |
| | She felt better. |
| | She stopped the ivermectin while the infection was still raging. |
| | And yeah. |
| | Yeah. |
| | Yeah. |
| | It's a very sad, very sad story. |
| | Right. |
| | Mechanistic evidence. |
| | What is that? |
| | Yeah. |
| | This is a lot of fun because in the ivermectin wheel, we could show a lot of laboratory studies. |
| | So there is a lot of mechanistic evidence that ivermectin has got various different mechanisms of action. |
| | Yeah. |
| | And these are published. |
| | So if we move on to that diagram on therapeutic response. |
| | Yeah. |
| | It's plot. |
| | The word is plausible, isn't it? |
| | There's plausibility here. |
| | Yeah. |
| | Yes. |
| | It's not like giving something silly or homeopathic preparation. |
| | There's actually a way that this could work. |
| | Yeah. |
| | So if you have a look at the progression of the disease. |
| | Yeah. |
| | Now this diagram comes from McGonagall et al. |
| | Originally there is this viral infection and then it proliferates. |
| | Yep. |
| | And if it's not treated early, this is why people like Jackie were pushing for early treatment. |
| | Yeah. |
| | That would have prevented going into that cytokine storm. |
| | Mm-hmm. |
| | If the cytokine storm is not controlled, then also while you've got the cytokine storm going, you've got this thrombosis going on. |
| | And ultimately that leads to death because you've got these microclots that are whizzing around the body, causing all sorts of organ damage and end up with death if your body's not able to fight that. |
| | And of course, particularly in the capillaries in the lungs because they're some of the smallest capillaries in the body. |
| | Yes. |
| | So anything that's going to- They're so small that only single red blood cells can get through them. |
| | Yeah. |
| | In fact, it's even more than that. |
| | They have to squeeze down to get through. |
| | So, you know, the red cells about seven micrometers in diameter and they actually squeeze down to about half that to get through. |
| | You can actually see them deforming to get through the pulmonary capillaries. |
| | So if we look at this diagram here, there's evidence that ivermectin can prevent viral proliferation. |
| | It's a zinc ionophore and if it allows zinc into the cells, it's going to prevent the proliferation. |
| | It has an anti-inflammatory impact in the cytokine storm. |
| | Yeah. |
| | And then there was this very elegant experiment done on the thrombosis. |
| | So Boschie and his group took petri dishes and infected them with the various COVIDs. |
| | And if the- with blood- so he put blood in the petri dish and then infected them and he got this microthrombotic effect. |
| | He then put ivermectin and other drugs, I think were also in it, but ivermectin into all these plates and that resolved. |
| | If he- if there was ivermectin on the tray and the blood was then added and then the virus, there was no microglutination. |
| | So they showed that ivermectin prevented that microglutination. |
| | And how David Scheim has explained that is that these spike proteins are free in the- in the blood system. |
| | And they- they- they are attracted to the red blood cells. |
| | So the blood- red blood cells start looking like they've got Velcro around the weed from spike proteins. |
| | And so they start- They're gumming up the sticky spike protein. |
| | Yeah. |
| | So they start sticking to each other. |
| | And when they stick to each other, they make these microclots. |
| | Yeah. |
| | Which means when they've got a microclot, it's going to block up your blood vessels. |
| | Yeah. |
| | So your red blood cells are no longer able to get oxygen to the rest of your system. |
| | So not only are your clots causing havoc in the rest of your blood- in the rest of your body- you've got these clots in your- in your lungs that can't get oxygen, can't release their carbon dioxide and get their oxygen. |
| | Ivermectin comes along and it competes for those spike proteins. |
| | And- and it resolves. |
| | It takes those spike proteins off the red blood cells. |
| | And that explains why the patient feels better. |
| | So they've got these clots- We'd call it a competitive inhibition, wouldn't we? |
| | Yes. |
| | So the ivermectin is competing with the red cells to bind the spike protein. |
| | And it does it very effectively. |
| | Yeah. |
| | The ivermectin has got a higher affinity for the spike protein than the red blood cells. |
| | So the spike protein binds to the ivermectin, not the red blood cells, meaning that the red blood cells are free to become individual cells again and perfuse the pulmonary capillaries. |
| | It makes perfect sense. |
| | As does the anti-inflammatory. |
| | Yeah. |
| | Let us just digress for a moment here. |
| | Hmm. |
| | So now we know, and we knew quite a while ago, that it's the spike protein that is gluing the red blood cells together. |
| | Yep. |
| | So you and I are tasked with creating a vaccine. |
| | Are we going to sit down and design a vaccine that makes your body create lots more spike protein? |
| | Let me think. |
| | Maybe we should leave a thing. |
| | Let me think about that one just a minute. |
| | No, the answer isn't. |
| | I mean, how could they have got it so wrong? |
| | Let's design a vaccine. |
| | Yeah. |
| | That causes the body to produce the most toxic part of the virus. |
| | It just doesn't make any sense. |
| | Given they do, they probably didn't know that. |
| | But then as soon as the evidence was coming through, they should have. |
| | Coronavirus have been around for a while. |
| | I mean, you know, there's lots of other proteins in the virus that they could have, lots of other epitopes they could have attacked. |
| | Yeah. |
| | It really is quite bizarre. |
| | But the other mechanism I like there is the zinc iron a force. |
| | So what's happening there is zinc when zinc is inside the cell. |
| | So viruses, of course, are what we call obligate intracellular parasites. |
| | They get into the cell. |
| | They're working inside the cell. |
| | They're replicating inside the individual cell. |
| | But zinc can kill viruses or zinc is antiviral. |
| | So if we can get more zinc from the outside into the cell, it's going to have an anti viral effect. |
| | And we know that ivermectin will open up the doors. |
| | What we call the zinc iron O4s. |
| | So a four is a channel. |
| | An ion is the zinc. |
| | It gets into the cell. |
| | It mediates the zinc through this phospholipid bilayer cell membrane, which is normally impervious to. |
| | Gets it into the cell and the zinc does its stuff and gets it gets gets gets rid of the virus. |
| | I mean, all these mechanisms just make perfect physiological pharmacodynamic sense. |
| | They sound really quite plausible. |
| | Exactly. |
| | So if we had early treatment for everybody, then we wouldn't have got to have to need the cytokine storm issue. |
| | Yeah. |
| | And I think I think that's the key thing. |
| | The key thing here is these antiviral treatments need to be given early to stop the viral count going up, causing the complications. |
| | If the viral load can be controlled at an early stage and basically the whole disease is aborted, it's terminated. |
| | Well, that explains why prophylaxis worked in those countries that had ivermectin prophylaxis. |
| | That's explained. |
| | This diagram also explains why high doses of ivermectin in the thrombotic phase are important, because that by the time the patients are not able to breathe, they have they have got to the thrombosis phase. |
| | Yeah. |
| | So low doses of ivermectin right in the beginning to prevent progression of disease or disease at all. |
| | Is ideal. |
| | Yeah. |
| | And higher disease, higher doses later to zap those clots. |
| | Get those red red blood cells freed up. |
| | Get the oxygen through. |
| | Break the clots in the alveoli, etc. |
| | So the earlier in the evolution of the disease that you give the ivermectin, the lower doses will be efficacious. |
| | I would think so. |
| | In later states. |
| | I haven't come across many, many of those trials, but the fact that we had prophylaxis trials, that indicates that to me. |
| | Yeah. |
| | But but to break up the if you are in the thrombotic stage, you'll need much higher doses of ivermectin to be. |
| | Yeah. |
| | And that's what. |
| | Yeah. |
| | Sabine Hazan and Jackie Stone showed that. |
| | Yeah. |
| | In the two studies we've used. |
| | Yeah. |
| | Yeah. |
| | Yeah. |
| | Okay. |
| | So I've ticked mechanistic evidence and biological plausibility. |
| | Is there any other components to look at under mechanistic evidence or is that the basics of that done? |
| | I think we've gone the coherence is looking at the fact that we can show the BOSCHI study. |
| | Yeah. |
| | How the in the. |
| | And we really wanted to do an experiment where we could look at the blood flow through the fingers of patients. |
| | And have a look at how it changed with ivermectin. |
| | But we drew up that study when Omicron came out. |
| | So there were no longer patients going to a hospital. |
| | So we couldn't do the study. |
| | Yeah. |
| | But that would have. |
| | That would have been something really good to show with the coherence as well. |
| | Did you just unpack that coherence idea a bit, Colleen? |
| | I mean, I mean, what do we really mean? |
| | What did Bradford Hill mean by coherence? |
| | Well, I think coherence comes more in. |
| | Let me just find my notes. |
| | I mean, basically, it's is there consistency between epidemiological findings and laboratory findings and clinical findings? |
| | It's it's how internal internal validity really, isn't it? |
| | So we've got consistency at viral proliferation level with Cayley's study, that very first one that came out in April 2020. |
| | Yeah. |
| | From Australia. |
| | So there's that study that showed when she put out all her petri dishes with COVID and treated all of them with different repurposed drugs, ivermectin just killed the COVID. |
| | Yeah. |
| | So there's that lab study that looks at that mechanism. |
| | And then the thrombosis study was that study with that Boschi et al did. |
| | But we've got coherence between we've got coherence between communities that use divermectin, individual bench science on the plausibility mechanisms tied in with the clinical effects that people like Jackie Stone were seeing. |
| | So we've got coherence between these three lines of evidence, what you might call the biochemical bench evidence, the bedside evidence, clinical evidence, and then the whole community level of evidence. |
| | We've got we've got coherence between these three epistemological ways of analyzing the problem, really. |
| | So again, and that is where the wheel would come in, because in one picture of the wheel, you could actually see the coherence. |
| | You can see how much is being done in the lab, how much has been done clinically. |
| | And the wheel did show a lot was done in observational trials. |
| | And it was mostly positive, showing that ivermectin was working. |
| | A lot was done in the labs, also showing that how they could explain why it was working in the clinic. |
| | There just weren't many randomized control trials, because who does a randomized control trial within two to three months of a pandemic being announced? |
| | It's just not feasible. |
| | And I think it's inappropriate for randomized control trials to be called for, especially with a single therapeutic in a pandemic situation. |
| | We're not automatons. |
| | We are looking at human beings. |
| | Yeah. |
| | I mean, to do a randomized control trial there, not only was it never going to happen because there's no money in it. |
| | Also, had it happened for a drug with the efficacy of ivermectin, it would have been completely unethical to have a placebo group. |
| | Well, that is exactly what Tess Laurie said. |
| | Yeah, because they would simply have died. |
| | If Jackie had divided her patients into ivermectin group and placebo group, then, well, it would be unconscionable for a clinician to do that. |
| | Exactly. |
| | Yeah. |
| | Especially with the evidence that there was already. |
| | Yeah. |
| | And that is why I believe we should be looking at Bradford Hill, not a randomized control trial, but a look at every single angle. |
| | Absolutely. |
| | But there were some trials and we can get onto them next. |
| | Yeah. |
| | That brings us onto parallel evidence, doesn't it, Colleen? |
| | Yeah. |
| | What is it? |
| | So the parallel evidence, we have only focused on the parallel evidence in our paper on the trials, on the randomized control trials that were done, that started coming out well after the pandemic had found its feet. |
| | But what does parallel evidence mean? |
| | What is the concept of parallel evidence? |
| | Well, you're seeing a whole lot of different kinds of evidence coming out at the same time. |
| | From different geographical locations. |
| | Absolutely. |
| | Yeah. |
| | So this is worldwide. |
| | Yeah. |
| | Yeah. |
| | So we've seen from South America, from Asia, Australia. |
| | India. |
| | Exactly. |
| | The United States. |
| | Canada, Canada, with the McMaster study, they managed the Brazil study. |
| | So what we're looking at is if we can see that we can justify its mechanism of action and tell ourselves through theory how it's working, through research theory how it's working, what other evidence is coming up to support that? |
| | Mm-hmm. |
| | And so we limited ourselves. |
| | And this is where a wheel would be very useful if people are going to start thinking about monitoring drugs better in the future. |
| | And we separated the studies into those that showed positive results and those that showed negative results. |
| | Mm-hmm. |
| | And it's very clear what the differences are. |
| | The one main difference is those with negative results got published in top journals. |
| | And the trusted news initiative would put out articles like the final nail in the coffin of ivermectin or final proof ivermectin doesn't work. |
| | Well, it must be true if it's in a large scale international randomized international journal of great repute. |
| | It must be true. |
| | That's what we used to think. |
| | This is part of the disillusionment of what we've learned, isn't it? |
| | That these can no longer be taken as gospel. |
| | I have learned more in the last five years of my career than I did in the first ten. |
| | Yeah. |
| | And it's not textbook stuff. |
| | No. |
| | Yeah. |
| | So negative results, very prestigious journals, very readily published, very readily distributed. |
| | by mainstream media, fact checkers and trusted news initiatives, whatever that means. |
| | Negative results tended to be in what? |
| | Smaller journals? |
| | Maybe just tweeted a few times? |
| | If we could get them into any journal at all. |
| | And if they hadn't been withdrawn after years, because they might be telling inconvenient truths, maybe? |
| | Yeah. |
| | Yeah. |
| | So, you know. |
| | For example, this paper we're talking about now, how easy was it to get published? |
| | It bounced off so many desks of editors. |
| | It did not even get to review. |
| | We, I think it's been ready for over a year. |
| | We got very little review to improve it ourselves. |
| | How can a paper of this obvious quality not be sent for peer review? |
| | As soon as they read the, we kept the word ivermectin out of the title. |
| | But as soon as you see the abstract, the word ivermectin pitches up. |
| | So, yeah. |
| | So eventually it's published in the Japanese Journal of Antibiotics. |
| | And it really is an indictment, isn't it? |
| | Of a lot of our sophisticated in brackets, Western countries that we haven't published things, but. |
| | No interesting stuff coming out of Korea, interesting work coming out of Japan. |
| | Where maybe the tentacles of control are somewhat less than this was published in the Japanese journal, which is good to see. |
| | Well, we were very honored to have had our paper accepted there. |
| | It's the same journal that Professor Yagesawa has published his literature reviews in with Professor Satoshi Amura, who was one of the recipients of the Nobel Prize for ivermectin. |
| | Yeah. |
| | So we took a chance. |
| | Yeah, we took a chance. |
| | We thought this is our last chance. |
| | Let's just try. |
| | I'm thinking that they don't take review articles. |
| | But when we sent it to them, I think they saw the scholarship that has gone into it. |
| | It took us a very long time to put this article together. |
| | Yeah. |
| | And they did send it out for review, and we got very good review that helped us improve the quality of the article. |
| | And it's now been published, and people like Professor Satoshi Amura will have read it. |
| | And I feel incredibly proud. |
| | I'd rather know that a Nobel Prize winner has read our work than have it in some big journal where it might get lost. |
| | But, of course, it doesn't mean it won't be that widely read amongst the medical and scientific communities in Western countries, because I'd never heard, to be quite honest, of the Japanese Journal of Antibiotics. |
| | It's not on my regular reading list. |
| | So it's going to fall between a lot of cracks, isn't it? |
| | Unfortunately, it will. |
| | And also, unfortunately, because we didn't put the word ivermectin into the title, so it's not searchable if people are looking for specific research on ivermectin. |
| | It might go to people looking for Bradford Hill criteria. |
| | And hopefully those researchers looking at evidence-based medicine will benefit. |
| | And also hypoxemia, maybe, if they're looking at that later. |
| | But basically it means that mass distribution is left to the odd eccentric YouTuber. |
| | Yes, indeed. |
| | Thank you very much. |
| | Which is, you know, the fact that this distribution falls to people like me, I just find that a tragic indictment of the whole, you know, of the whole. |
| | I'm just a strange bloke from England sitting in his back room, you know. |
| | And yet, you know, if the mainstream media is failing us, the alternative is to sit and do nothing and say nothing. |
| | It's yours, yours and my conscience wouldn't live well with that, I'm sure. |
| | Yeah, so, yeah, we mentioned the analogy and the similarity of the positive studies in the next, the best explanation. |
| | So you've come up with your own four criteria for pandemics. |
| | Well, I'd just like to go back to, if I might, John. |
| | Yeah, please. |
| | We've got some positive studies that we've expanded on. |
| | But we've also looked at how useful the negative studies are. |
| | So if you are a good scientist, you're going to look and see why the results differ. |
| | Yeah. |
| | And in most cases, the failed studies had very short regimens, like three days. |
| | And we're often given very late in after the onset of symptoms. |
| | Exactly. |
| | Low doses, very late or with low risk patients. |
| | So you're not going to see hospitalization anyway or mortality anyway. |
| | So there were many reasons why those particular negative studies are useful to be able to show us, yes, we need high doses at certain times in the disease. |
| | We need to look at a certain demographic of patients that's going to use these. |
| | A 16-year-old won't get sick from COVID, but a 60-year-old might get seriously sick. |
| | So a really good scientist is not going to say there were positive studies that were good and there were bad studies that were negative. |
| | Or the other way around, like the people who have got the negative studies who say anybody with a positive study was just anecdotal and they are kooks. |
| | So the usdryl might get some happen to be yeah yeah it might be something as simple as iodine gargling you know exactly that yeah it could be i mean it's bemusing we've got we've got studies from international prestigious centers which made in my view really quite simplistic errors of giving small doses four five six days after the onset of symptoms and then using that as evidence of non-efficacy i mean and the people that are doing these studies are not cognitively challenged people it makes you it really makes you wonder why the blatantly flipping obvious didn't jump up off the table and hit them in the face um it really is quite hard to explain the lack of analytical thinking and the poor design of a lot of these expensive trials um it's so we've gone into quite a lot of detail in the paper on why those failed but if i might share with you my favorite story go for it is there was one study that had intention to treat groups so intention to treat is that statistical number that your statistician said you must have in your study so you might have 600 600 participants 600 will be on placebo 600 will be on intervention if some of those people disappear after they start you then have what is called the per protocol number so it might be 550 yeah in the group so you then work out what actually happened in terms of the per protocol as well as to the intention to treat so in your intention to treat you say that there were 10 patients who died yep but you only end up with out of 600 only 300 are there so what these people do is they say okay out of 600 10 died so they get a small percentage but actually only 300 people were on the protocol so that's 10 out of 300 who died so i queried that with the author and the author told me he's not interested in answering answering my question because it's not the kind of question that should be asked so i said well okay i'll take that message to my colleagues and he said well also tell them that it's not a flat earth so well i mean you know people like people like people like you need to be patronized from time to time i suppose it's just incredible so the intention to treat is the good intentions as it were at the start of the trial oh let's get a thousand patients in you end up with 500 it's obviously going to halve the numbers that's going to double the the apparent effect and not to take account for that is just well it's almost like a breach of basic research methodology isn't it well i think it's unethical because when i worked out what what the rate would have been if it was worked on what i worked out in the paper it could have been per protocol there was a definite mortality benefit yeah yeah yeah yeah so so in other words it reverses the finding of the study exactly yeah yeah yeah there's not only that where people we scientists get um lose lose sight of what our science is for our science is to help people it's not to make sure that your university gets the next grant yeah we might lose our jobs because of that but medical ethics is patient first beneficence to the patient yeah there is one of those trials that came out as negative that showed that a p the mortality benefit had a p value or fisher's preference of 0.09 so because it wasn't 0.05 they put it into the no group and i've done a lot of thinking about this p value thing because it gets drummed into students that p value of 0.05 is a yes no yeah and even ronald fisher hated that idea ronald fisher was the person who came up with p equals 0.05 in i think it was 1926 oh really i didn't know almost 100 years ago so it's a centenary of people abusing his work yeah yeah so yeah just to provide some context he was a population geneticist in 1920 so he wasn't working with genes because genes had not been um had not been found we only found the shape of dna in 1953 and only in the 60s did we find the bases that actually give us the the genetic code so in the 1920s he was working on trace so he was working with very big numbers and was looking for precision and he when in his context 0.05 worked for him it's two standard deviations away from the mean and it fits with those tables and i don't know whether you did stats in the 80s or earlier than that but i was supposed to do stats in my first degree but i wasn't uh i did a few yes i was never very good at it we had those books that we had to go and look of when we were doing car speed tests i just had flow diagrams i just used to go through the flow diagrams and work out which it was i never fully understood it to be quite honest but uh but no no the 0.05 it's just completely essentially arbitrary isn't it i mean you know so some something could be um you know if something's as you say here 0.09 that means there's a nine percent chance that the result arose by chance but if the p-value was uh 0.04 there's a four percent chance the result arose by chance that result could still have arisen by chance it's just less probable yeah so what's happening in medical literature at the moment is if something is 0.049 or it'll be concluded if it's 0.051 it's up that's just so we're throwing that we're throwing the baby out at the bath water to to use an old idiom people are not using their brains they they so often abdicate their own thinking to rule rules the rule of the randomized control trial the rule of p equals 0.05 yeah but i think if people actually understood what that p-value meant and used it in the context of what they would do for their own family yeah would they not even consider something at 0.2 even at 0.2 maybe they're confuses if you said to me the p-value is 0.2 that means there's an 80 chance this is going to work for me exactly i'd bite your hand off a 80 chance of life yes please so for clinical reasoning i would propose that we use a p-value of 0.0 of 0.2 and start looking at how to refine it yeah if you're looking for a certain effect size in a new novel drug and you want it to be at 0.05 bully for you yeah but if i'm looking for something that's going to save my parents life during a pandemic like you said i'm going to bite your hand off for it yeah yeah yeah so it's people are abdicating their thinking to rules and they're not being very scientific about it yeah yeah so your your shortcut criteria here for the next pandemic we need something that's cheap and safe that's the key thing cheap readily available safety of course is vital uh maybe some people regulated regulatory bodies around the world should uh take note of this interventions should be safe if the hat fits put it on regulatory bodies around the world yeah yeah we should know that they're safe and not just assume they're safe because they've come from an international body i'm not convinced everything we're doing now is safe to put it mildly so cheap safe some plausible mechanism because we don't want voodoo mumbo jumbo there's got to be some reasonable plausible mechanism and preferably backed up by some evidence would be yeah would be nice and then as more information comes in go through all the bradford hill uh if people can do some randomized control trials so much the better but that's just the icing on the cake and uh you know we look around at other things that are happening now and um you know we need to work out ways to prevent them we need to work out ways to treat them and the current mechanisms that we have for developing new treatments in my view simply aren't making the grade it's not cutting the mustard it's not not getting there we need changes in philosophy i would have said well i think we need to to bring philosophy back so that people understand it yeah i think too many people are only following the philosophy of capitalist um and i'm not against capitalism but capitalist gain and not beneficence of page for patience absolutely yeah yeah yeah let's clarify my position i'm not a marxist and i don't think you are either people need me people need to make some money but as you say um human life and efficacy and uh morality has to come has to come first great i'll put the links to both of those papers clean as always um anything else just that that's an hour by the way you will unpack that really quite nicely um i'm just very grateful that you've given us the platform to let people see where this work is coming up from i really hope that people who are interested in evidence-based meds and start broadening their view and start standing up to this rctp equals 0.05 dogma we've got to get rid of this dogma absolutely absolutely thinking and not abdicate i thought that the next thing they're going to abdicate their thought to ai and that is that is scary while i love ai to help me do my work i i think the abdication of thought is is going to be a problem in fact i think you're shortly doing a lecture to to doctors on application of ai in medical research is that true yes i am next month i'm going to be giving a talk to students on ai in in medical research how you can use it to be more productive to help you read papers and how you should not be using it yeah well that after you've done that talk let's talk again that sounds really quite interesting you certainly can be part of the way ahead um now about about what we find is about 30 of people watch these videos all the way through so um if you made it all the way through you're a serious viewer thank you for sticking with us um and and for the people that do watch it all the way through i think we've covered some really important points and the papers of course are there free to download colleen i think yes they are yep really gets on my nerves when you got to pay for papers it's just outrageous um they're on the research gate as well um um free on research gate under under elifterios's name and my name yep and i certainly downloaded the pdfs without any difficulty and they are detailed but um the mathematical one of course i didn't follow it all but but yours is is really quite readable quite straightforward if you've got a few hours sit down read it you will make sense of it it's uh completely intelligible um but for now um um thank you thank you as always thank you john |