Tag Archives: Paracelsus

Eliquis, over-prescribed but better than Coumadin.

Eliquis (apixaban) is blood thinner shown to prevent stroke with fewer side effects than Warfarin (Coumadin). Aspirin does the same, but not as effectively for people over 75. My problem with eliquis is that it’s over-prescribed. The studies favoring it over aspirin found benefits for those over 75, and for those with A-Fib. And even in this cohort the advantage over aspirin is small or non-existent because eliquis has far more serious side effects; hemorrhage, or internal bleeding.

Statistically, the AVERROES study (Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in AF Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment) found that apixaban is substantially better than aspirin at preventing stroke in atrial fibrillation patients, but worse at preventing heart attack.

Taking 50 mg of Eliquis twice a day, reduces the risk of stroke in people with A-Fib by more than 50% and reduces the rate of heart attack by about 15%. By comparison, taking 1/2 tablet of aspirin, 178 mg, reduces the risk of stroke by 17% and of heart attack by 42%. The benefits were higher in the elderly, those over 75, and non existent in those with A-Fib under 75, see here, and figure. Despite this, doctors prescribe Eliquis over aspirin, even to those without A-Fib and those under 75. I suspect the reason is advertising by the drug companies, as I’ve claimed earlier with Atenolol.

The major deadly side-effect is hemorrhage, brain hemorrhage and GI (stomach) hemorrhage. Here apixaban is far worse than with aspirin (but better than Warfarin). The net result is that in the AVERROES random-double blind study there was no difference in all-cause mortality between apixaban and aspirin for those with A-fib who were under 75, see here. Or here.

To reduce your chance of GI hemorrhage with Eliquis, it is a very good idea to take a stomach proton pump drug like Pantoprazole. If you have A-Fib, the combination of Eliquis and pantoprazole seems better than aspirin alone, even for those under 75. If you have no A-Fib and are under 75, I see no benefit to Eliquis, especially if you find you have headaches, stomach aches, back pain, or other signs of internal bleeding, you might switch to aspirin or choose a reduced dose.

A Japanese study found that half the normal dose of Eliquis, was approximately as effective as the full dose, 50 mg twice a day. I was prescribed Eliquis, full dose twice a day, but I’m under 70 and I have no A-Fib since my ablation.

Life expectancy has dropped in the US to undeveloped world levels. Biden blames COVID and racism. I think it’s too much drugs, and too few opportunities.

I’m struck by the fact that US life expectancy is uncommonly low, lower than in most developed countries. Lower too than in many semi-developed countries, and our life expectancy is decreasing while other countries are not seeing the same. It dropped by about 3 years over the last 2 years as shown. I wonder why the US has suffered more than other countries, and suspect we are over-prescribed. Too much of a good thing, typically isn’t good.

Robert Buxbaum, September 16, 2022. As a side issue, low dose aspirin may forestall Alzheimers and other dementias. See current article here. Also another study here.

The Scientific Method isn’t the method of scientists

A linchpin of middle school and high-school education is teaching ‘the scientific method.’ This is the method, students are led to believe, that scientists use to determine Truths, facts, and laws of nature. Scientists, students are told, start with a hypothesis of how things work or should work, they then devise a set of predictions based on deductive reasoning from these hypotheses, and perform some critical experiments to test the hypothesis and determine if it is true (experimentum crucis in Latin). Sorry to say, this is a path to error, and not the method that scientists use. The real method involves a few more steps, and follows a different order and path. It instead follows the path that Sherlock Holmes uses to crack a case.

The actual method of Holmes, and of science, is to avoid beginning with a hypothesis. Isaac Newton claimed: “I never make hypotheses” Instead as best we can tell, Newton, like most scientists, first gathered as much experimental evidence on a subject as possible before trying to concoct any explanation. As Holmes says (Study in Scarlet): “It is a capital mistake to theorize before you have all the evidence. It biases the judgment.”

It is a capital mistake to theorize before one has data. Insensibly one begins to twist facts to suit theories, instead of theories to suit facts (Holmes, Scandal in Bohemia).

Holmes barely tolerates those who hypothesize before they have all the data: “It is a capital mistake to theorize before one has data. Insensibly one begins to twist facts to suit theories, instead of theories to suit facts.” (Scandal in Bohemia).

Then there is the goal of science. It is not the goal of science to confirm some theory, model, or hypothesis; every theory probably has some limited area where it’s true. The goal for any real-life scientific investigation is the desire to explain something specific and out of the ordinary, or do something cool. Similarly, with Sherlock Holmes, the start of the investigation is the arrival of a client with a specific, unusual need – one that seems a bit outside of the normal routine. Similarly, the scientist wants to do something: build a bigger bridge, understand global warming, or how DNA directs genetics; make better gunpowder, cure a disease, or Rule the World (mad scientists favor this). Once there is a fixed goal, it is the goal that should direct the next steps: it directs the collection of data, and focuses the mind on the wide variety of types of solution. As Holmes says: , “it’s wise to make one’s self aware of the potential existence of multiple hypotheses, so that one eventually may choose one that fits most or all of the facts as they become known.” It’s only when there is no goal, that any path will do

In gathering experimental data (evidence), most scientists spend months in the less-fashionable sections of the library, looking at the experimental methods and observations of others, generally from many countries, collecting any scrap that seems reasonably related to the goal at hand. I used 3 x5″ cards to catalog this data and the references. From many books and articles, one extracts enough diversity of data to be able to look for patterns and to begin to apply inductive logic. “The little things are infinitely the most important” (Case of Identity). You have to look for patterns in the data you collect. Holmes does not explain how he looks for patterns, but this skill is innate in most people to a greater or lesser extent. A nice set approach to inductive logic is called the Baconian Method, it would be nice to see schools teach it. If the author is still alive, a scientist will try to contact him or her to clarify things. In every SH mystery, Holmes does the same and is always rewarded. There is always some key fact or observation that this turns up: key information unknown to the original client.

Based on the facts collected one begins to create the framework for a variety of mathematical models: mathematics is always involved, but these models should be pretty flexible. Often the result is a tree of related, mathematical models, each highlighting some different issue, process, or problem. One then may begin to prune the tree, trying to fit the known data (facts and numbers collected), into a mathematical picture of relevant parts of this tree. There usually won’t be quite enough for a full picture, but a fair amount of progress can usually be had with the application of statistics, calculus, physics, and chemistry. These are the key skills one learns in college, but usually the high-schooler and middle schooler has not learned them very well at all. If they’ve learned math and physics, they’ve not learned it in a way to apply it to something new, quite yet (it helps to read the accounts of real scientists here — e.g. The Double Helix by J. Watson).

Usually one tries to do some experiments at this stage. Homes might visit a ship or test a poison, and a scientist might go off to his, equally-smelly laboratory. The experiments done there are rarely experimenti crucae where one can say they’ve determined the truth of a single hypothesis. Rather one wants to eliminated some hypotheses and collect data to be used to evaluate others. An answer generally requires that you have both a numerical expectation and that you’ve eliminated all reasonable explanations but one. As Holmes says often, e.g. Sign of the four, “when you have excluded the impossible, whatever remains, however improbable, must be the truth”. The middle part of a scientific investigation generally involves these practical experiments to prune the tree of possibilities and determine the coefficients of relevant terms in the mathematical model: the weight or capacity of a bridge of a certain design, the likely effect of CO2 on global temperature, the dose response of a drug, or the temperature and burn rate of different gunpowder mixes. Though not mentioned by Holmes, it is critically important in science to aim for observations that have numbers attached.

The destruction of false aspects and models is a very important part of any study. Francis Bacon calls this act destruction of idols of the mind, and it includes many parts: destroying commonly held presuppositions, avoiding personal preferences, avoiding the tendency to see a closer relationship than can be justified, etc.

In science, one eliminates the impossible through the use of numbers and math, generally based on your laboratory observations. When you attempt to the numbers associated with our observations to the various possible models some will take the data well, some poorly; and some twill not fit the data at all. Apply the deductive reasoning that is taught in schools: logical, Boolean, step by step; if some aspect of a model does not fit, it is likely the model is wrong. If we have shown that all men are mortal, and we are comfortable that Socrates is a man, then it is far better to conclude that Socrates is mortal than to conclude that all men but Socrates is mortal (Occam’s razor). This is the sort of reasoning that computers are really good at (better than humans, actually). It all rests on the inductive pattern searches similarities and differences — that we started with, and very often we find we are missing a piece, e.g. we still need to determine that all men are indeed mortal, or that Socrates is a man. It’s back to the lab; this is why PhDs often take 5-6 years, and not the 3-4 that one hopes for at the start.

More often than not we find we have a theory or two (or three), but not quite all the pieces in place to get to our goal (whatever that was), but at least there’s a clearer path, and often more than one. Since science is goal oriented, we’re likely to find a more efficient than we fist thought. E.g. instead of proving that all men are mortal, show it to be true of Greek men, that is for all two-legged, fairly hairless beings who speak Greek. All we must show is that few Greeks live beyond 130 years, and that Socrates is one of them.

Putting numerical values on the mathematical relationship is a critical step in all science, as is the use of models — mathematical and otherwise. The path to measure the life expectancy of Greeks will generally involve looking at a sample population. A scientist calls this a model. He will analyze this model using statistical model of average and standard deviation and will derive his or her conclusions from there. It is only now that you have a hypothesis, but it’s still based on a model. In health experiments the model is typically a sample of animals (experiments on people are often illegal and take too long). For bridge experiments one uses small wood or metal models; and for chemical experiments, one uses small samples. Numbers and ratios are the key to making these models relevant in the real world. A hypothesis of this sort, backed by numbers is publishable, and is as far as you can go when dealing with the past (e.g. why Germany lost WW2, or why the dinosaurs died off) but the gold-standard of science is predictability.  Thus, while we a confident that Socrates is definitely mortal, we’re not 100% certain that global warming is real — in fact, it seems to have stopped though CO2 levels are rising. To be 100% sure you’re right about global warming we have to make predictions, e.g. that the temperature will have risen 7 degrees in the last 14 years (it has not), or Al Gore’s prediction that the sea will rise 8 meters by 2106 (this seems unlikely at the current time). This is not to blame the scientists whose predictions don’t pan out, “We balance probabilities and choose the most likely. It is the scientific use of the imagination” (Hound of the Baskervilles)The hope is that everything matches; but sometimes we must look for an alternative; that’s happened rarely in my research, but it’s happened.

You are now at the conclusion of the scientific process. In fiction, this is where the criminal is led away in chains (or not, as with “The Woman,” “The Adventure of the Yellow Face,” or of “The Blue Carbuncle” where Holmes lets the criminal free — “It’s Christmas”). For most research the conclusion includes writing a good research paper “Nothing clears up a case so much as stating it to another person”(Memoirs). For a PhD, this is followed by the search for a good job. For a commercial researcher, it’s a new product or product improvement. For the mad scientist, that conclusion is the goal: taking over the world and enslaving the population (or not; typically the scientist is thwarted by some detail!). But for the professor or professional research scientist, the goal is never quite reached; it’s a stepping stone to a grant application to do further work, and from there to tenure. In the case of the Socrates mortality work, the scientist might ask for money to go from country to country, measuring life-spans to demonstrate that all philosophers are mortal. This isn’t as pointless and self-serving as it seems, Follow-up work is easier than the first work since you’ve already got half of it done, and you sometimes find something interesting, e.g. about diet and life-span, or diseases, etc. I did some 70 papers when I was a professor, some on diet and lifespan.

One should avoid making some horrible bad logical conclusion at the end, by the way. It always seems to happen that the mad scientist is thwarted at the end; the greatest criminal masterminds are tripped by some last-minute flaw. Similarly the scientist must not make that last-mistep. “One should always look for a possible alternative, and provide against it” (Adventure of Black Peter). Just because you’ve demonstrated that  iodine kills germs, and you know that germs cause disease, please don’t conclude that drinking iodine will cure your disease. That’s the sort of science mistakes that were common in the middle ages, and show up far too often today. In the last steps, as in the first, follow the inductive and quantitative methods of Paracelsus to the end: look for numbers, (not a Holmes quote) check how quantity and location affects things. In the case of antiseptics, Paracelsus noticed that only external cleaning helped and that the help was dose sensitive.

As an example in the 20th century, don’t just conclude that, because bullets kill, removing the bullets is a good idea. It is likely that the trauma and infection of removing the bullet is what killed Lincoln, Garfield, and McKinley. Theodore Roosevelt was shot too, but decided to leave his bullet where it was, noticing that many shot animals and soldiers lived for years with bullets in them; and Roosevelt lived for 8 more years. Don’t make these last-minute missteps: though it’s logical to think that removing guns will reduce crime, the evidence does not support that. Don’t let a leap of bad deduction at the end ruin a line of good science. “A few flies make the ointment rancid,” said Solomon. Here’s how to do statistics on data that’s taken randomly.

Dr. Robert E. Buxbaum, scientist and Holmes fan wrote this, Sept 2, 2013. My thanks to Lou Manzione, a friend from college and grad school, who suggested I reread all of Holmes early in my PhD work, and to Wikiquote, a wonderful site where I found the Holmes quotes; the Solomon quote I knew, and the others I made up.

Hormesis, Sunshine and Radioactivity

It is often the case that something is good for you in small amounts, but bad in large amounts. As expressed by Paracelsus, an early 16th century doctor, “There is no difference between a poison and a cure: everything depends on dose.”

Aereolis Bombastus von Hoenheim (Paracelcus)

Phillipus Aureolus Theophrastus Bombastus von Hoenheim (Dr. Paracelsus).

Some obvious examples involve foods: an apple a day may keep the doctor away. Fifteen will cause deep physical problems. Alcohol, something bad in high doses, and once banned in the US, tends to promote longevity and health when consumed in moderation, 1/2-2 glasses per day. This is called “hormesis”, where the dose vs benefit curve looks like an upside down U. While it may not apply to all foods, poisons, and insults, a view called “mitridatism,” it has been shown to apply to exercise, chocolate, coffee and (most recently) sunlight.

Up until recently, the advice was to avoid direct sun because of the risk of cancer. More recent studies show that the benefits of small amounts of sunlight outweigh the risks. Health is improved by lowering blood pressure and exciting the immune system, perhaps through release of nitric oxide. At low doses, these benefits far outweigh the small chance of skin cancer. Here’s a New York Times article reviewing the health benefits of 2-6 cups of coffee per day.

A hotly debated issue is whether radiation too has a hormetic dose range. In a previous post, I noted that thyroid cancer rates down-wind of the Chernobyl disaster are lower than in the US as a whole. I thought this was a curious statistical fluke, but apparently it is not. According to a review by The Harvard Medical School, apparent health improvements have been seen among the cleanup workers at Chernobyl, and among those exposed to low levels of radiation from the atomic bombs dropped on Hiroshima and Nagasaki. The health   improvements relative to the general population could be a fluke, but after a while several flukes become a pattern.

Among the comments on my post, came this link to this scholarly summary article of several studies showing that long-term exposure to nuclear radiation below 1 Sv appears to be beneficial. One study involved an incident where a highly radioactive, Co-60 source was accidentally melted into a batch of steel that was subsequently used in the construction of apartments in Taiwan. The mistake was not discovered for over a decade, and by then the tenants had received between 0.4 and 6 Sv (far more than US law would allow). On average, they were healthier than the norm and had significantly lower cancer death rates. Supporting this is the finding, in the US, that lung cancer death rates are 35% lower in the states with the highest average radon radiation levels (Colorado, North Dakota, and Iowa) than in those with the lowest levels (Delaware, Louisiana, and California). Note: SHORT-TERM exposure to 1 Sv is NOT good for you; it will give radiation sickness, and short-term exposure to 4.5 Sv is the 50% death level

Most people in the irradiated Taiwan apartments got .2 Sv/year or less, but the same health benefit has also been shown for people living on radioactive sites in China and India where the levels were as high as .6 Sv/year (normal US background radiation is .0024 Sv/year). Similarly, virtually all animal and plant studies show that radiation appears to improve life expectancy and fecundity (fruit production, number of offspring) at dose rates as high as 1 Sv/month.

I’m not recommending 1 Sv/month for healthy people, it’s a cancer treatment dose, and will make healthy people feel sick. A possible reason it works for plants and some animals is that the radiation may kill proto- cancer, harmful bacteria, and viruses — organisms that lack the repair mechanisms of larger, more sophisticated organisms. Alternately, it could kill non-productive, benign growths allowing the more-healthy growths to do their thing. This explanation is similar to that for the benefits farmers produce by pinching off unwanted leaves and pruning unwanted branches.

It is not conclusive radiation improved human health in any of these studies. It is possible that exposed people happened to choose healthier life-styles than non-exposed people, choosing to smoke less, do more exercise, or eat fewer cheeseburgers (that, more-or-less, was my original explanation). Or it may be purely psychological: people who think they have only a few years to live, live healthier. Then again, it’s possible that radiation is healthy in small doses and maybe cheeseburgers and cigarettes are too?! Here’s a scene from “Sleeper” a 1973, science fiction, comedy movie where Woody Allan, asleep for 200 years, finds that deep fat, chocolate, and cigarettes are the best things for your health. You may not want a cigarette or a radium necklace quite yet, but based on these studies, I’m inclined to reconsider the risk/ benefit balance in favor of nuclear power.

Note: my company, REB Research makes (among other things), hydrogen getters (used to reduce the risks of radioactive waste transportation) and hydrogen separation filters (useful for cleanup of tritium from radioactive water, for fusion reactors, and to reduce the likelihood of explosions in nuclear facilities.

by Dr. Robert E. Buxbaum June 9, 2013