God Does Not Play Dice. Should Doctors?
This is a talk that was given for Consilium Scientific today May 18 at the invitation of Leeza Osipenko. Consilium are doing more than anyone to raise questions about the quality of the evidence we have in medicine – in particular around controlled trials. They have had some fabulous contributions in recent months – all of which can be acess on their website. This Lecture by me came with a Question and Answer session that had its cut and thrust moment.
As usual with these lectures Bill James and I also recorded If God Doesn’t Play Dice, Should Doctors in a version that I think works very well.
The talk appeals to ideas that can best be found in the work of Sander Greenland – see Here – which has the memorable phrase – First Do no Harm to Knowledge. Adapted here to Do not bring Poison out of a Good.
Einstein
Einstein famously said that God does not play dice – with the universe. In France, in 1654, gambling with dice gave rise to probability theory, which led to what we now call medical statistics. 75 years ago doctors recruited medical statistics in the form of Randomized Controlled Trials (RCTs) to give them confidence when they Roll the Dice on the Drugs they give us.
How confident should we be?
Slide 2: Fifty years after the first RCT, Don Schell, a tough oilman from Wyoming, was put on Paroxetine for a minor sleep problem. Forty-eight hours later he shot his wife, his daughter and grand-daughter and then himself. His surviving son-in-law took a lawsuit against GlaxoSmithKline (GSK) – Tobin v SmithKline.
In the Tobin case, Ian Hudson, Chief Safety Officer of GSK was asked – Can SSRIs cause suicide. He says GSK practice EBM which means they base their views on randomized controlled trials (RCTs) – which use probability to find the truth.
A jury of 12 people, with no background in healthcare, dismissed Hudson’s EBM in favor of Evident Based Medicine. Their diagnosis was it was obvious paroxetine caused this and GSK were guilty of negligence.
Hudson’s view, however, remains ensconced at the top of Britain’s drugs regulator, of which he was later the Chief Executive Officer – as well as top of FDA, EMA, and other regulators.
Slide 3: Hudson’s views originate 70 years earlier in the work of a strange man – Ronnie Fisher. Here you see Fisher smoking a pipe. He dismissed the later link between smoking and lung cancer. Evidence was not Fisher’s strong point.
Fisher was not a doctor and never ran an RCT. Controlled trials and randomization were there before him but his book the Design of Experiments turbocharged them.
Fisher was trying to characterize expert knowledge. Experts know the right answer – like parachutes work. If we set up two groups, one with parachutes and the other not, we would expect those wearing parachutes to live and those not to die.
Chance was really the only thing that could get in the way of the expert being right – perhaps a strong wind lands a person in a snow covered tree. Chance could be assigned a statistically significant value. If 1 in 20 of those without parachutes lived, we wouldn’t say the expert didn’t know what he was talking about.
There might be other trivial things – someone with webbed feet might behave differently when falling, and randomization can control for any trivial unknown unknowns like this. Somehow Fisher’s book transformed randomization into something semi-mystical – that would help us overcome ignorance – but randomization can’t control for ignorance.
Slide 4: Fisher’s expert is a Robin Hood who 19 times out of 20 can split a prior arrow lodged in the Bull. Expertise is precise, accurate and Real World.
Slide 5: The RCTs done to license drugs, especially antidepressants, look like this rather than like Robin Hood. A mismatch on this scale indicates we are not dealing with expertise.
Slide 6: Tony Hill ran the first medical RCT in 1947 giving streptomycin for tuberculosis. Hill later showed smoking caused lung cancer. He had no time for Fisher. He knew doctors were not experts. His trial was not a demonstration of expertise. He used randomization as a method of fair allocation – not to manage mystical confounders.
Hill’s RCT found out less about streptomycin than a prior non-randomized trial in the Mayo Clinic, which showed it can cause deafness and tolerance develops rapidly.
Slide 7: In a 1965 lecture, Hill took stock of RCTs. He mentions that it is interesting that the people most heavily promoting RCTs are pharmaceutical companies.
He didn’t think trials had to be randomized. He thought double-blinds could get in the way of doctors evaluating a drug. He believed in Evident Based rather than Evidence Based Medicine.
Hill said we needed RCTs in 1950 to work out if anything worked. By 1960, we had lots of drugs that worked, none discovered by RCTs, and the need was to find out which drug worked best. This is not something RCTs can do – there is no such thing as a best drug.
He also said that RCTs produce average effects, which are not much good for telling a doctor what to do for the patient in front of them.
Here in this quote he is saying RCTs can help evaluate one thing a drug does which means they are not a good way to evaluate a drug overall. All RCTs generate ignorance but we can bring good out of this harm if we remember that. Hill never saw RCTs replacing clinical judgement.
Slide 8: This 1960 RCT run by Louis Lasagna makes Hill’s point. Thalidomide has therapeutic efficacy as a sleeping pill but this trial missed the SSRI-like sexual dysfunction, suicidality, agitation, nausea and peripheral neuropathy it causes.
Two years later, Lasagna was responsible for incorporating RCTs into the 1962 FDA Act – in order to minimize the chance of another thalidomide. By doing this, he was, more than anyone else, the man who got us using RCTs. The mechanism he put in place to stop thalidomide happening again was one it sailed through.
Other regulations aim at safety – whether for planes, cars, food or investment, bu the 1962 regulations uniquely stressed efficacy and in so doing badly compromised safety.
Slide 9: The 1950s gave us better antihypertensives, hypoglycemics, antibiotics and psychotropic drugs than we have ever had – all without RCT input.
Imipramine, the first antidepressant, is much stronger than SSRIs. It can treat melancholia –SSRIs can’t. Melancholia comes with an 80-fold increased risk of suicide.
In an RCT of imipramine versus placebo in melancholia, we would expect the red dots showing suicide attempts to be less on imipramine even though it can cause suicide because it treats this high risk condition. This RCT would look like evidence imipramine cannot cause suicide.
Imipramine was launched in 1958. At a meeting in 1959, experts noted that while it was a wonderful treatment it made some people suicidal. Stop the drug and the suicidality clears. Re-introduce it and suicidality comes back. This was Evident Based Medicine.
Slide 10: In the mild depression trials that brought the SSRIs to market – we see an increase of suicidal events compared to placebo in people at little or no risk of suicide.
Slide 11: Used as a comparator in these trials imipramine now too causes suicides.
The diametrically opposite RCT outcomes for imipramine stem from the fact these are Treatment Trials not Drug Trials. If the condition and treatment produce superficially similar effects, RCTs can confound us. This is true for most medical conditions and their treatments.
If you want to see what a drug does – you should do a Drug Trial.
Slide 12: Here is what a Drug Trial looks like. In healthy volunteer studies in the 1980s, companies found SSRIs made volunteers suicidal, dependent and sexually dysfunctional. These Drug Trials enabled companies to engineer Treatment Trials to hide these problems.
Slide 13: There are more dead bodies on SSRIs than on placebo in trials, yet the RCTs show the drugs work. This is because working is measured on a surrogate outcome. For antidepressants it’s the Hamilton Scale for Depression. Fifteen years after its creation, Max Hamilton commented that this scale standardizes clinical interviews which can be good and bad.
Slide 14: In trials, the Hamilton scale has suicide, appetite, sleep, anxiety and sex items on all of which the illness or the drug may produce effects. If Leeza is in an RCT and I ask her if she has been suicidal in the last week, if she says yes she tried to kill herself, I would score a 4. But if I figured this was caused by the drug I would score a Zero.
But trials eliminate judgement. Introduce judgement and one knows what the results mean. Trials have become just the opposite to what Tony Hill intended.
Slide 15: In addition to randomization, Fisher put Statistical Significance on the map. By 1980 every leading medical statistician was saying we need to get rid of statistical significance in favor of Confidence Intervals.
This image is from the James Webb telescope. Confidence Intervals were introduced by Gauss in 1810 to solve a telescope problem. Because of measurement error, telescopes often failed to establish if there was one or two stars in a location. As measurement errors should distribute normally, confidence intervals could help distinguish individual stars.
Slide 16: Confidence intervals rushed into therapeutics in the mid-1980s. Leading medical statisticians argued they were more appropriate than significance testing. They are more appropriate for measurement error but is this what we have in Treatment Trials?
Slide 17: Confidence intervals allow us to estimate the size of an effect and the precision with which it is known. The details on the likelihood of the Red Drug killing you here are more precise than for the Yellow Drug. The best estimate of the lethality of the Yellow Drug however is greater. The standard view is that if we increase the size of the Yellow Drug Trial, we will have greater precision and know better what the risks are. This is wrong, as you will see.
If you are forced to take one of these drugs, as things stand now, Ian Hudson, and FDA will say the only dangerous drug here is the Red One. This is because more than 95% of the data, more than 19 out of 20 data points, lie to the right of the line through 1.0. This is exactly what medical statisticians say is wrong.
I would take the Red drug, because these confidence intervals are not managing measurement error and we don’t know what they mean when they are not representing measurement error.
Slide 18: In 1991, facing claims Prozac caused suicide, Lilly analysed their RCTs and spun the Confidence Intervals here as evidence Prozac does not cause suicide. This is Ian Hudson thinking – there is no problem as nothing is statistically significant.
Sander Greenland and leading medical statisticians say you need to view these as compatibility intervals rather than confidence intervals. All these curves show a compatibility with Prozac causing suicide and the consistent excess of suicidal events in all groups points strongly to a problem.
The bigger point is that for 100 years statisticians have been telling us we cannot assume that statistical data bears any relationship to the real world – we have to establish it.
Slide 19: Here is a representation of suicidal events from the trials bringing Prozac, Seroxat and Zoloft to market around 1990. Note the events under screening. There is a 2 week washout period before a trial starts where people are taken off prior drugs before being randomized. This phase of a trial is dangerous – people are in withdrawal and may become suicidal.
Slide 20: When submitting the data to FDA, the companies moved events as you see here – arguing people in the run in phase were on nothing which is equivalent to being on placebo. There were other maneuvers at the end of the trials as ou see here.
Even with these maneuvers, there was an excess of suicidal events on SSRIs but the 95% confidence interval was no longer to the right of 1.0. Why do this? Because regulators and companies need a Stop-Go mechanism and statistical significance provides this. But doctors don’t need an external Stop-Go mechanism to replace their clinical judgement, so why do we go along with this?
Slide 21: Nobody noticed these maneuvers in 1990, but 10 years later in a crisis about children becoming suicidal on SSRIs, questions were asked. GSK and Pfizer responded:
‘GSK did not intentionally submit any erroneous or misleading information to FDA. The suicide data submitted to FDA explicitly identified when events occurred during the placebo run-in period. FDA had all this information right from the beginning.’
“Pfizer’s 1990 report to FDA plainly shows … that 3 placebo attempts as having occurred during single blind placebo phases… FDA has neither criticized these data or the report as inappropriate, nor required additional analyses”.
These maneuvers breach FDA regulations, which FDA staff noted. Senior FDA honchoes ignored this and even put their name to articles that embraced these illegitimate figures to argue placebo controlled RCTs were not unethical, as those on placebo were not at any greater risk than those on treatment.
FDA and companies liaised closely over the suicide crisis in 1990. Criminally? Perhaps. I prefer the idea of strategic ignorance.
There is a crisis in knowledge production here. This is not something you can expect FDA to take a lead on – they are bureaucrats. Doctors should be the people creating medical knowledge but they went missing in action around 1990, leaving companies able to create the appearances of knowledge.
Slide 22: Following the suicide in children crisis, FDA wanted the data from adult trials and wanted companies not to make the same maneuvers they had made before. GSK submitted these data, which you see point to a problem for paroxetine
The sacred mantra of RCTs is randomization controls for all possible confounders in all possible universes. The ability of randomization to introduce confounders into clinical trials is about to come to GSK’s rescue.
Slide 23: GSK also did 2 trials in Intermittent Brief Depressive Disorder (IBDD) patients who have regular suicide attempts. Paroxetine didn’t do well – one trial was stopped it was doing so poorly. Why do these trials?
Slide 24: When you add these figures together suddenly paroxetine protects against suicide. First you need to know IBDD patients could be admitted to MDD trials – we have no way to distinguish them. Some patients become IBDD by virtue of a poor response to an SSRI. What happens if IBDD patients are in an MDD trial is the same as if you add the groups of trials together as we did here.
This scenario happens every time a medical condition is heterogenous – as diabetes, dementia, parkinson’s disease, breast cancer, back pain, hypertension and most conditions are. In these cases, randomization will hide effects good and bad – and enable us to use a problem a drug causes to hide a problem a drug causes.
Slide 25: Graphically the Red Drug here is the MDD curve alone – more than 95% of the data are to the right of the 1.0 line. The traditional wisdom is that adding some more events to the Red Drug trials should give us a more precise version of the same estimate.
Adding less than 3% more in this case, we have shifted the curve to the opposite side of the 1.0 line. It’s a more precise confidence interval but this precision speaks to our ignorance rather than to better knowledge. Medical statistics books don’t hint at this possibility.
We can add 40 suicidal events to the paroxetine IBDD arm before GSK would have to admit Paroxetine causes a problem – on the basis that the results are now statistically significant.
Confidence intervals do not help us work out what is going on here. Nor do they help in heterogenous drug responses. If we clone a David who is sedated by a Red Drug and an Ian Hudson who is stimulated by it, the best estimate of the Red Drug’s effect will lie on the 1.0 line, apparently showing this drug has no effect on sleep. A method to distinguish between one and two stars should not produce an answer that there are no stars. Algorithmic judgements cannot substitute for a human judgement.
Slide 26: Here is another image from James Webb. Confidence intervals were a step on the way to revealing the individuality of stars. From genetics to astronomy, science reveals individuality except in medicine where statistical approaches as applied operate against individuality.
We are legitimately bound to be as objective as we can. Because of our fetish with numbers, we think that using Chance to control Bias is going make us objective and so we allow mindless algorithms to replace clinical judgement. Clinical medicine, like law, and the first 300 years of science, however, used Bias to Control Chance.
Slide 27: In the early 1980s, the idea that RCTs were the scientific and sophisticated way to demonstrate adverse effects was creeping in – as you see here. Lasagna, the man responsible for us doing RCTs took issue with this and said this is only true if by sophisticated you mean adulterated – to sophisticate wine means to adulterate it.
Evident Based Medicine is how to establish adverse events and a great example turned up a few years later.
Slide 28: In 1990 Martin Teicher and 2 colleagues claimed fluoxetine made 6 people suicidal. Following traditional clinical approaches for determining causality, exposure to the drug, dechallenge, rechallenge, listening to the patient, this article nailed beyond doubt that fluoxetine made some people suicidal.
Roughly twenty other groups reported similar findings over the next year including me. This was Evident Based Medicine showing Prozac could cause suicide.
Slide 29: Lilly responded with this article in the BMJ claiming an analysis of their RCTs showed no evidence Prozac made people suicidal. The cases reported, they said were sad but anecdotal – and the plural of anecdote is not data. Depression was the problem not fluoxetine. Clinical trials are the science of cause and effect. The challenge to all of us was whether we were going to believe the science or the anecdotes.
This was a knowledge creation moment that likely had input from all companies and perhaps FDA. This article created Evidence Based Medicine and just as with RCTs 30 years earlier, the people exhorting doctors to practice EBM today are Pharma companies.
In fact, the original phrase is the plural of anecdotes is data – otherwise Google wouldn’t work.
The idea the disease is responsible for suicide attempts and suicides in healthy volunteers is hard to believe but companies can wheel out experts to say just that.
My key point is Evident Based Medicine is the science – the Lilly data is an artefact. My challenge to you is which are you going to believe the Science or the Artefact?
Lilly claimed Prozac didn’t cause suicide even though the excess of suicidal events on it in this paper was compatible with the fact it does.
You’ve seen all companies cooked the books. When uncooked this excess was statistically significant.
But that’s not the real problem. An incompatability between an Evident Based Medicine and Evidence Based Medicine can help us move science forward. If Prozac was as effective as Imipramine grappling with the incompatibility outlined earlier would have increased our expertise.
Lilly, however, were not in the business of embracing discrepancies. Their argument was a religious one – a dogmatic one. They demanded we ignore the Evident.
The Evidence Based Medicine movement has refused to call out the ghostwriting of the company trial literature and the lack of access to company trial data. More to the point, they have not taken issue with this egregious breach of scientific methodology.
Therapeutics involves bringing good out of the use of a poison. Volunteering for clinical trials was a risky good we undertook to benefit our family, friends and countrymen. Companies have been bringing a poison out of this good.
Slide 30: The usual histories of science start with the foundation of The Royal Society in 1660, which famously said Science would deal with matters that could be Settled by Data. Participants could be Xtian, Hindu, Jew, Muslim, or Atheist, but they were called on to leave these badges at the door and come to a consensus about the best way to explain the experimental outcome in front of them.
The histories of science emphasize the word Data. Settled is a more important word. Statistics played no part in this science. The experiments were events that didn’t need statistical descriptions. Science does not replace judgment calls with a statistical artefact – this only began 33 years ago.
Slide 31: This history overlooks an event in 1618, when Walter Raleigh was executed – for being too close to the French and Spanish. Raleigh was convicted on the basis of things said about him by people who did not come into court to be cross-examined.
The legal system recognized an injustice and introduced Rules of Evidence. Hearsay could not be used as evidence. Jurors – a group of 12 people, Xtians, Hindus, Muslims, Atheists and Jews, can only base a verdict on material put in front of them that can be examined and cross-examined. The process of forcing 12 people with very different biases to come to a Verdict about what is in front of them is the essence of science.
Verdicts and diagnoses are provisional, which might appear to contrast with the objectivity of science, but scientific views are similarly provisional. Scientists attempt to overturn verdicts with new data.
Let’s say I gave Leeza fluoxetine 33 years ago and she became suicidal. I could examine and cross-examine her, run labs and scans, raise the dose, stop the drug, add an antidote, have a case conference with all of you able to ask questions to see if we could explain this in any other way. She is the data, the apparatus in which the experiment is taking place.
If Leeza and I and you conclude fluoxetine made her suicidal and report this to MHRA or FDA, the first thing FDA will do is to remove her name. No-one can now examine or cross-examine her and come to a scientific view about whether there is a link or not. Her injury has been made Hearsay – misinformation.
If you are later injured in the same way and see tens of thousands of reports of suicidality on SSRIs on FDA’s adverse event reporting system, you cannot bring this into court because no-one can be brought into court. It’s Hearsay not Evidence.
Company RCTs are equally hearsay and should not be let into Court as evidence. Accessing the data means accessing people – like Leeza or me – and we cannot do that with subjects in company trials, who often don’t exist. Company articles are ghostwritten and the authors, who have seen none of the patients, cannot speak to what happened either.
In contrast, if Leeza and I report her case in a Medical Journal as a Case Report, with our names on it, this is evidence and we can both be brought into Court.
Slide 32: In 1997, you have Lasagna here echoing Tony Hill 30 years earlier saying:
In contrast to my role in the 1950s which was trying to convince people to do controlled trials, now I find myself telling people that it’s not the only way to truth.
Evidence Based Medicine has become synonymous with RCTs even though such trials invariably fail to tell the physician what he or she wants to know which is, which drug is best for Mr Jones or Ms Smith – not what happens to a non-existent average person.
Slide 33: RCTs have created a scenario where drugs have benefits and no problems. This is leading to polypharmacy noted as an issue around 2000.
As of 2016, over 40% of over 45s in the US were on 3 or more drugs every day of the year. Over 40% of over 65s on 5 or more drugs every day of the week. US life expectancy has been falling dramatically – this is all pre-Covid.
Reducing medication burdens can increase life expectancy, reduce hospitalizations, and improve quality of life.
Slide 34: But reducing a medication burden is not easy – as this image from the movie The Hurt Locker illustrates. Many of these drugs explode on attempting to withdraw them. Deprescribing is the primary medical task of our age. No RCT will ever help with this. The best evidence will lie in clinical experience of tackling similar situations. Being able to talk to clinical colleagues will help but the key scientific partner is the patient – who brings clues from missing doses of some of these drugs, and a sense of what the drugs are doing that can only be accessed through them. The patient is the apparatus in which the experiment is taking place and each patient and their response to drugs is unique.
Slide 35: We began with Einstein. Ein Stein means one stone – one shape. Up till now, we have had no mathematics that might counter the averaging we get from misapplied medical statistics. Now we have.
Mathematics is more about shapes than numbers and earlier this year a New Shape was discovered, the first aperiodic or truly individual shape – that means it cannot be incorporated into other shapes or averages. This may offer us a template for a new robustly individual mathematics – and perhaps a better template for clinical practice than rolling dice has been – or should I say the rigged gambling we have had up to this.
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Playing the Dice…
“On-Off”
“cut and thrust moment.” …
https://www.youtube.com/watch?v=Jby3xtEVm0g
DC’s Improbable Science
Truth, falsehood and evidence: investigations of dubious and dishonest science
https://web.archive.org/web/20130302072440/http://www.dcscience.net/
This is very sad, because I have great reason to like the drug industry. I’ve benefitted from several of their products myself. But the industry is in trouble. Many of its products provide only marginal benefits. Furthermore, some of the things that seemed to be useful, like SSRI antidepressants, have turned out to be next to useless once hidden trials were revealed (4).
The MHRA’s learning module on SSRIs doesn’t seem to have caught up with this yet.
Sadly, the reaction of industry has been to resort to dishonesty, to hide unfavourable data and to increase yet more what it spends on marketing. Between 2009 and 2012, fines of at least 10 billion dollars (5) have been imposed on some of the most eminent companies. They include Lilly, Pfizer, AstraZeneca, Merck, Abbott and GlaxoSmithKline (GSK). The biggest fine of all ($3 bn, in July 2012) went to a British company, GSK. This succession of large fines seems to be regarded by the companies as mere marketing expenses.
All these fines were levied in the USA. Where, one might ask, are the regulators in the UK?
Why have there been no fines here? Why, indeed, are some of the senior managers of these companies not in jail? Why has the BPS remained silent about the prostitution of its subject?
And why have the MHRA done so little to stop it?
https://web.archive.org/web/20130302072439/http://www.dcscience.net/?p=5821
“Stop-Go”
Slide 20
Even with these maneuvers, there was an excess of suicidal events on SSRIs but the 95% confidence interval was no longer to the right of 1.0. Why do this? Because regulators and companies need a Stop-Go mechanism and statistical significance provides this. But doctors don’t need an external Stop-Go mechanism to replace their clinical judgement, so why do we go along with this?
Slide 21
FDA and companies liaised closely over the suicide crisis in 1990. Criminally? Perhaps. I prefer the idea of strategic ignorance.
Doctors should be the people creating medical knowledge but they went missing in action around 1990, leaving companies able to create the appearances of knowledge.
Slide 34
the key scientific partner is the patient – who brings clues…
Shaping the Future?
David has introduced a new perhaps hopeful topic to me . Thank you
‘Mathematics is more about shapes than numbers and earlier this year a New Shape was discovered, the first aperiodic or truly individual shape – that means it cannot be incorporated into other shapes or averages. This may offer us a template for a new robustly individual mathematics – and perhaps a better template for clinical practice than rolling dice has been – or should I say the rigged gambling we have had up to this.’
I find this possibility intriguing (maybe Escher the artist – mathematical genius who was fascinated by shapes would have been too) But will progress be corrupted by the same disgusting scumbags which float around the contaminated pond of ‘scientific research’ , sacrificing millions, without conscience without pity? We can hope – maybe. .
Seems the possibility is somewhere on the horizon in another lifetime that good will come out of the new science. But whether the research being carried out will outlaw the stuff being pumped into bodies often without consent almost always without proper knowledge will alter the type of drugs produced or enable them and their harms to be avoided is another thing. ,
Let’s hope they get the maths right this time. Take the time to avoid others jumping on another theoretical bandwagon when charismatic, usually men so far, like the funny little creature sitting cross legged on a rock smoking a pipe, (hilarious) gather their followers and sycophants.
In Smithsonian Magazine
Introducing the Scutoid, Geometry’s Newest Shape
The scutoid allows skin cells to remain packed tightly together even over curved surfaces (Touch and the skin are often topics on Rxisk Blogs)
Jason Daley
July 30, 2018
Scutoid
This shape, dubbed the scutoid, had no name until researchers found it while modeling how skin cells pack together. University of Seville and Lehigh University
Most of us only need to master the classic shapes like circles, squares, triangles, and a handful of polygons to get along in this world. But that’s not all that’s out there—there are dozens of funky shapes that scientists, engineers and biologists have classified, including things like the hemihelix, discovered in 2014, which resembles a kinked Slinky. Now, biologists have found another new shape, dubbed the scutoid. It’s likely found in your armpits, up on your nose and all over your face, as it’s a shape your skin cells take as they bend.
Bruce Y. Lee at Forbes reports that the new shape, described in a paper in the journal Nature Communications, helps solve a long-standing conundrum about human skin. Millions upon millions of epithelial cells are packed together to create human skin, which is pretty good at being air- and watertight. On a totally flat surface, columns, prism, or cube-shaped cells could be squeezed close enough together to create such a strong barrier. But the human body has few, if any totally flat surfaces (apologies to Channing Tatum’s abs), meaning cubes and columns don’t work. And epithelial cells need to do some pretty extreme bending and curving during embryonic development too.
To solve the mystery, researchers in the U.S. and Europe collaborated on a computer model using a process called Voronoi diagramming to figure out just how epithelial cells are packed together. According to a press release, the best solution was a totally new shape the team dubbed a scutoid, since it resembles a top-down view of a beetle’s scutellum, part of its shell. The shape looks like a long five-sided prism with a diagonal face sliced off one end, giving that end six sides. That makes it possible to pack scutoids together with alternating five-sided and six-sided ends making up the surface, allowing the shapes to make curved surfaces without pulling apart. Don’t worry if it’s hard to envision—the team had trouble making sense of it too, until one of the scientists and his daughter modeled it using clay.
“During the [computer] modeling process, the results we saw were weird,” co-author Javier Buceta of Lehigh University says in the release. “Our model predicted that as the curvature of the tissue increases, columns and bottle-shapes were not the only shapes that cells […] developed. To our surprise, the additional shape didn’t even have a name in math! One does not normally have the opportunity to name a new shape.”
Jessica Boddy at Gizmodo reports that the team then found scutoid-like shapes in the epithelium of zebra fish and the salivary glands of fruit flies. While Sesame Street will probably not be singing a ditty about the scutoid anytime soon, the shape could have important uses in medicine. “For example, if you are looking to grow artificial organs, this discovery could help you build a scaffold to encourage this kind of cell packing, accurately mimicking nature’s way to efficiently develop tissues,” Buceta says in the release.
“We believe that this is a major breakthrough in many ways,” co-author Luis Escudero of the University of Seville tells Boddy. “We are convinced that there are more implications that we are trying to understand as we speak.”
and
Shame about the animal experiments
Maybe one day this could this benefit those who are being vaccinated and harmed
1
Math model predicts several useful new drug combinations that may help treat heart attacks
Reviewed by Emily Henderson, B.Sc.Jun 17 2022
The new model predicts several useful new drug combinations that may one day help treat heart attacks, according to researchers at The Ohio State University.
Treatment to restore blood flow to these blocked passages of the heart often includes surgery and drugs, or what’s known as reperfusion therapy. Nicolae Moise, lead author of the study and a postdoctoral researcher in biomedical engineering at Ohio State, said the study uses mathematical algorithms to assess the efficacy of the drugs used to combat the potentially lethal inflammation many patients experience in the aftermath of an attack.
“Biology and medicine are starting to become more mathematical,” Moise said. “There’s so much data that you need to start integrating it into some kind of framework.”
But this study chose to model how certain immune cells like myocytes, neutrophils and macrophages -; cells imperative to fighting infection and combating necrosis (toxic injury to the heart) -; react to four different immunomodulatory drugs over a period of one month. These drugs are designed to suppress the immune system so that it doesn’t cause as much damaging inflammation in parts of the heart that were damaged.
Bruce Hartpence et al., Intelligent and Converged Networks, 2021
A simple and easily implemented risk model to predict 1-year ischemic stroke and systemic embolism in Chinese patients with atrial fibrillation
Chao Jiang et al., Chinese Medical Journal, 2021
Mayo Clinic Healthcare, 2023
Their findings showed that certain combinations of these drug inhibitors were more efficient at reducing inflammation than others. “In medicine, math and equations can be used to describe these systems,” Moise said. “You just need to observe, and you’ll find rules and a coherent story between them.
“With the therapies that we’re investigating in our model, we can make the patient outcome better, even with the best available medical care,” he said.
Depending on their health beforehand, it can take a person anywhere from six to eight months to heal from a heart attack. The quality of care patients receive in those first few weeks could set the tone for how long their road to recovery will be.
Because Moise’s simulation is purely theoretical, it won’t lead to improved therapies anytime soon. More precise mouse data is needed before their work can become an asset to other scientists, but Moise said he does envision the model as a potential tool in the fight against the ravages of heart disease.
Heartsink – ‘Its going to be some years before we can actually integrate this kind of approach into actual clinical work. But what we’re doing is the first step towards that.”
Thank you for another powerful and compelling lecture, and for the skilful, detailed responses to questions. These lectures keep our hopes of improved prescription drug ADR awareness (amongst prescribers and patients) alive.
Kristina understands it. Kristina gets it. Kristina says it.
https://share.transistor.fm/s/81400fb3
Of ‘strategic significance’ to Dan
Dan Johnson
@DanJohnsonAB
#worldfamilydoctorday
Failure of duty to warn.
Killed by pseudoscience.
Primum non nocere means nothing now.
4:41 AM · May 20, 2023 from Lethbridge, Alberta
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The ‘Power’ of Prozac…
Can you tell me where the Q and A’s are please?
They should be at the end of the Consilium version of the talk
D
See Comment One
Do we have problems with, skipping ‘o’er the water’ … Robert Burns
O’ver the Water Tae Charlie – A fine poem
A FDA Bureaucrat speaks!
Here’s a little clip from the recent FDA pantomime examination of the safety/dangers of Pfizer’s RSV vaccine about to be unleashed onto unsuspecting American pregnant people.
https://youtu.be/NXVMILYvocM?t=22411
Dr Hana El Sahly has the measure of these guys (and Pfizer) and voted against the proposal that this vaccine is safe.
“first-ever”
Albert Bourla
@AlbertBourla
Thrilled that #VRBPAC has voted independently to recommend our maternal RSV vaccine candidate to
@US_FDA
. In the United States, ~500,000 to 600,000 cases of medically attended lower respiratory tract disease due to RSV occur annually in infants <12mo. This is an important step toward what could be the first-ever maternal immunization vaccine to help protect infants from birth through 6 months from this contagious respiratory illness. https://on.pfizer.com/3WiVgXV
https://www.pfizer.com/news/press-release/press-release-detail/fda-advisory-committee-votes-support-approval-pfizers
“The role of the VRBPAC is to provide recommendations to the FDA; however, these recommendations are not binding.”
“first-ever”…
Bourla’s dice are loaded.
Indeed, this vaccine will likely help protect infants from RSV from birth through 6 months.
Then they’ll get it worse when they are older.
https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(22)00371-6/fulltext
God Does Not Play Dice.
Louis appleby
@ProfLAppleby
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Brilliant novelist. #Money – its subtitle “A Suicide Note” – the novel that captured the greed & selfishness of the 80s. Uncompromising, opinionated – wonderful to see live. And for a time Prof of Creative Writing at @OfficialUoM (I like to think of him as a colleague).
louis appleby
@ProfLAppleby
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Beautiful day at South Stack on #Anglesey. A wildlife haven – puffins, porpoises, kittiwakes & guillemots. And hundreds of Manx shearwaters. Like a small albatross gliding just above sea. Incredible sight.
louis appleby
@ProfLAppleby
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Because severe anxiety is debilitating, with long-term consequences. Social anxiety can have serious impact on school/work & relationships. In young patients who die by suicide, anxiety is behind only depression & autism as diagnosis. Let’s not dismiss it & stigmatise it more.
Slide 29
“The idea the disease is responsible for suicide attempts and suicides in healthy volunteers is hard to believe but companies can wheel out experts to say just that.”
https://www.theguardian.com/society/2023/may/21/labour-vows-to-reverse-rise-in-suicides-in-england-and-wales-within-five-years-keir-starmer
‘Its a long way to Tipperary’ …
God Does Not Play Dice.
“Imagine if as much time and effort that went into reducing smoking went into suicide prevention.” – The Samaritans
louis appleby
@ProfLAppleby
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Full-throttle call of a Cetti’s warbler at Llyn Llywenan tonight & a more distant repeat. One of 7 types of warbler singing at the lake just now.
Francesco Cetti was an 18thC Sardinian mathematician.
louis appleby
@ProfLAppleby
Why do so many think suicide is rising? Not just political speech-writers but people I happen to meet. In last 20yrs we have had lowest rates since records began in 1861.
1. stigma – easier for families to talk about.
2. More media coverage.
3. (Misplaced) fears about Covid?
louis appleby
@ProfLAppleby
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Misleading from @samaritans , wrongly implying no progress over 2 decades.
Suicide rates reached all-time low in 2007, almost as low in 2017.
Rates since 2018 have been inflated by lower standard of proof required at inquest – comparison with 20yrs ago is not like with like.
Samaritans
@samaritans
This
Suicide rates are as high now as they were 20 years ago, so any pledge to save lives is welcome. Smoking rates are at their lowest levels since records began. Imagine if as much time and effort that went into reducing smoking went into suicide prevention.
https://twitter.com/samaritans/status/1660607997524033537
“Like with Like”
The Birds and The Bees…
I read a paper by this person a while ago. Didn’t need to read much more after the first conclusion sentence.
“Suicide rates among patients subject to Community Treatment Orders in England, 2009-2018”
Conclusions
CTOs may be effective in reducing suicide risk. The relative benefits of CTOs and intensive aftercare may be time-dependent, with the benefit of a CTO being less before 12 months after discharge but greater thereafter. CTO utilisation requires a careful balancing of patient safety versus autonomy.
Last year I conversed with a person on a CTO paliperidone depo in the Netherlands – they feared for their life as many do. I had a daily blow by blow account of what this drug did to them and no quick way out after it’s been injected.
When did it start to be the case that doctors stopped listening to the patients re adverse events – and if people do not think it the case – it 100% happened to myself, and was it the drug companies who inured health workers in to this with the anecdotal training or are they just trying to save themselves or maybe both ?
So many facets to this question.
In the case of Stewart Dolin, his doctor, who was a family friend, was distraught. At the trial against GSK, his doctor said something along the lines of if only he had known the dangers of Paroxetine.
This would point to this doctor not feeling that GSK had given adequate warnings.
In the case of Stephen O’Neill, fully documented, his doctors seemed to make drug decisions without any evidence that they were following any sort of common prescribing sense and did not make any efforts to discuss their, as it turned out, disastrous reasoning’s.
These are two diametrically opposite points of view which throws out the questions as to how well pharmaceutical companies hid the dangers with fraudulent clinical trials and ghostwriters and how well this may have worked by keeping doctors in the dark.
What also has kept doctors in the dark, are organizations such as RCP and RCGP who really should know better by now, but are still nonchalant and apathetic.
It surely is the worst thing in the world to be put in a life-threatening situation by doctors who didn’t believe their patient. For the patient to then die, should be a matter for an inquiry.
It seems ludicrous to us that doctors are still in a state of denial. I think some of their reasoning comes from the fact that antidepressants are given for anxiety and depression, and a host of other problems, which points to, in their minds, an ‘unstable personality’, for want of a better expression, hence their justification for mucking about with changing dosages, adding more drugs and all in all making a complete mess of it. It’s a bit of a high faluting attitude, with nothing to back it up but is clearly disastrous for the patient. They can be reckless and naïve playing god with peoples lives.
Children of the Cure by David Healy; Prescription for Sorrow by Patrick D. Hahn, are good places to start.
Good question, Chris, I am sure others will have a go at it.
I certainly don’t think the world was prepared for the mass over-prescribing that has taken place, somewhat like the ‘Covid Vaccines’ taken the world by storm.
Thank you for that.
My situation was almost the same as Stephen O’Neil.
I’d love to see psych patients in A&E with anxiety/panic attacks if they were not on any drugs inducing the problem I’d just give them B6 p5p it would just be a matter of how much and the problem would stop within 2 to 3 hours for most. Mine went on for 10 years, near death many times and many other human rights abuses.
Roos of the Who
Rob Roos MEP Retweeted
Rob Roos MEP
@Rob_Roos
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MUST WATCH: The #WHO is pushing for a Global Pandemic Treaty. In minutes, I present you reasons why this would endanger our freedom and our democracy. Please share this video. And please e-mail it to your elected officials. We cannot allow this to happen:
https://twitter.com/Rob_Roos/status/1661400401885667329
https://twitter.com/Rob_Roos
“That’s a concern that’s been documented,” says Linsey McGoey, a professor of sociology at Essex University in the UK who wrote a book (“No Such Thing as a Free Gift: The Gates Foundation and the Price of Philanthropy”) on Gates and global public health. She thinks Gates has an ideological interest in seeing measurable results on a quick timescale, to show that “billionaire philanthropy” is working. “I think it’s because he has a personal interest in seeing results quick, because it helps to bolster his own reputation,” says McGoey.
Does Bill Gates have too much influence in the WHO?
https://www.swissinfo.ch/eng/politics/does-bill-gates-have-too-much-influence-in-the-who-/46570526
Some public health officials have disagreed with Gates’s priorities, but there is reluctance to criticise him for fear of losing support.
The Ruse of the Whose…
‘The plans represent a significant shift for the organisation, from a member-led advisory body to a health authority with powers of compulsion.’
Britain could be thrown into another lockdown in the future… by the World Health Organization! Fears over new pandemic powers being considered for all member states
The WHO could order governments to impose rules in future disease outbreaks
Tory MPs have called for a block on powers that would dictate UK health policy
By EMILY CRAIG SENIOR HEALTH REPORTER FOR MAILONLINE
UPDATED: 12:01, 26 May 2023
https://www.dailymail.co.uk/health/article-12127267/Britain-thrown-lockdown-future-World-Health-Organization.html
Britons may be plunged into lockdowns at the whim of the World Health Organization in future, MPs fear.
Sweeping powers being considered by the UN agency would force all member states — including Britain, the US and Australia — to comply with any rules enacted during pandemics.
Such measures could include ones that were deployed to thwart the spread of Covid, such as vaccine passports and border closures.
Member states would also have to use 5 per cent of health budgets on preparing for another pandemic if controversial proposals are given the go ahead.
World Health Organization (WHO) bosses are whittling down the suggested amendments, before a vote next spring decides whether they will come into force.
Six Tory MPs have now written to the Foreign Office, demanding it block any new powers that could see the WHO dictate policy and budgets in the UK.
Ex-Cabinet minister Esther McVey warned the powers would see the organisation, described as China’s puppet by critics, move from a ‘member-led advisory body to a health authority with powers of compulsion’.
The powers are being considered as part of an update to the WHO International Health Regulations (IHR) 2005, which sets out obligations for its 194 member states to prepare for and respond to outbreaks and other public health risks.
More than 300 amendments to the IHR have been proposed by member states after the Covid pandemic showed it ‘needs to be improved’, the WHO said.
In parallel, the agency is also working on a pandemic preparedness treaty.
WHO chiefs say both instruments will make the world safer from health threats, with another crisis feared to be lurking around the corner.
But among the 308 suggested changes are proposals to create a ‘legally binding’ response to public health emergencies.
This amendment, suggested by African nations, states that the current wording of the IHR — that countries ‘should’ respond to health risks — is ‘weak’.
If given the green light, the move could see the WHO decide on how nations respond to outbreaks, such as imposing vaccine passports, quarantine rules and restrictions on movement.
At a four-day meeting last month, the WHO discussed a third of the proposed amendments while being ‘mindful’ of each nation’s ‘equity, sovereignty and solidarity’.
The IHR working group is set to meet again in July, October and December and will agree on an amendments package to present to the World Health Assembly (WHA) in May next year, where a majority vote among member states decides whether they should be adopted.
The updated IHR would then come into force within a year for all member states, unless a country files a rejection.
And a meeting about the ‘complimentary’ pandemic treaty will take place in July, which sets out that all nations are expected to devote no less than 5 per cent of their budget to improve their pandemic preparedness.
However, a letter from Tory MPs, led by Ms McVey, calls for a vote in the Commons on the draft before it is signed.
The letter, seen by The Telegraph, states that there is ‘growing concern’ about both the IHR and the treaty.
Ms McVey said: ‘The plans represent a significant shift for the organisation, from a member-led advisory body to a health authority with powers of compulsion.
‘This is particularly worrying when you consider the WHO’s poor track record on providing consistent, clear and scientifically sound advice for managing international disease outbreaks.’
The WHO repeatedly came under fire during the pandemic for its stalwart defence of China.
This included parroting Beijing’s dismissal that the virus could have leaked from the Wuhan Institute of Virology.
In the earliest days of the outbreak, WHO director Dr Tedros Adhanom Ghebreyesus even went as far as to praise Beijing’s ‘commitment to transparency’ which he called ‘beyond words’.
At around the same time, China’s Communist Party began censoring public information about the spread of the virus and its potential origins, at one point suggesting that US troops could have been the initial carriers.
Ms McVey’s letter was co-signed by Tory MPs Sir John Redwood, David Davis, Philip Davies, Sir Christopher Chope and Danny Kruger, The Telegraph reported.
Andrew Mitchell, a Foreign Office minister and MP for Sutton Coldfield, told the newspaper that he would support a WHO treaty that speeds up sharing data on pathogens that could trigger an outbreak so that nations can ‘respond quickly’.
‘We’re clear that we would never agree to anything that crosses our points of principle on sovereignty or prevents the UK from taking decisive action against future pandemics,’ he added.
A WHO spokesperson said: ‘Just as with negotiation on pandemic accord this is a process led by sovereign states and the WHO secretariat is facilitating the negotiations.
‘As with all international instruments, any amendments to IHR, if and when agreed by member states, would be determined by governments themselves, who would take any action while considering their own national laws and regulations.’
Prof Norman Fenton
@profnfenton
·
Vaxx injured @Nohj_85 provides an important dissection of the new BBC @mariannaspring initiative which looks like it will be about ‘proving’ that the vaxx injured are ‘conspiracy theorists’ and ‘spreaders of dangerous misinformation’.
Wow – WATCH ‘TIL THE END
From a Vaccine Injurred person’s perspective The @BBCNews ‘Disinformation & Social Correspondent’ @mariannaspring seems somewhat confused
So I thought I’d help her out by telling some of OUR experiences, debunking some of HER myths & say who she SHOULD actually be ‘investigating’ (can you guess)
Let’s see if I get a response or a straight block, shall we!
BRING THE NOISE!
https://twitter.com/Nohj_85/status/1662101120121028609
Safe and Effective – A Second Opinion
The documentary was removed from YouTube on 26th October 2022 under the pretext of alleged “medical misinformation”. At that time it had accumulated over 990,000 views and 7,000 comments.
Watch the film in 4K here and decide for yourself.
https://www.oraclefilms.com/safeandeffective
Robert F. Kennedy Jr Calls Out Pfizer’s Clinical Trial Data on National Television
https://twitter.com/TheChiefNerd/status/1662051461352632324
BBC Verify – A Second Opinion…
Robert F. Kennedy Jr
@RobertKennedyJr
No one is safe! Be afraid! Are we ready to outgrow this kind of messaging?
Matt Orfalea
@0rf
“NOBODY IS SAFE!” #COVID19
https://twitter.com/RobertKennedyJr/status/1662078835976798213
Thread
Robert F. Kennedy Jr
@RobertKennedyJr
Yeah, it’s not safe all right. It’s not safe for you to see the data. It’s not safe for you to have your own thoughts. It’s not safe for you to question authority. It’s not safe to criticize the oligarchs who are crushing your freedoms and taking your money. Not safe for them, anyway.