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Changing Your Mind

Why is my mind so clean and pure?  Because I am always changing it.
In medical school the old saying is that half of everything you learn will not be true in 10 years, the problem being they do not tell which half.
In medicine, the approach is, one hopes, that data leads to an opinion.  You have to be careful not to let opinion guide how you evaluate the data.  It is difficult to do, and I tell myself that my ego is not invested my interpretation of the data. I am not wrong, I am giving the best interpretation I can at the time. For years  I yammered on about how it made no sense to give a beta-lactam and a quinolone for sepsis until a retrospective study suggested benefit of the combination.  Bummer. Now when I talk to the housestaff about sepsis, I have to add a caveat about combination therapy.  It is why my motto is, only half jokingly,  ”Frequently in error, never in doubt”.
At what point do you start to change you mind?  Alter your message as a teacher?  Have new behavior?  Medicine is not all or nothing, black and white.  Changes are incremental, and opinions change slowly, especially if results of a new study contradict commonly held conclusions from prior investigations.
Nevertheless, I am in the process of changing my mind, and it hurts.  I feel like Mr. Gumby. (http://www.youtube.com/watch? v=IIlKiRPSNGA)
It is rare that there is one study that changes everything; medicine is not an Apple product.  Occasionally that there is a landmark  study that alters practice in such a dramatic way that there is a before and after.  As I write this I cannot think of a recent example in infectious diseases, but I am sure there is one.  The problem is that once practice changes, it seems as we have always done it that way.
For me, three is the magic number.  One study that goes against received wisdom warrants an ‘interesting, but give me more.”
Two studies, especially if using different methodologies with the same results gives and ‘well, two is interesting, but I can argue against it.”  However, with two studies the seed of doubt is planted, waiting to be watered with the water of further confirmation.  Yeah. Bad metaphor.
Three studies with different methodologies independently confirming new concepts?  Then I say, “I change my mind. My brain hurts.”
There are now three studies concerning the issue of efficacy of the flu vaccine in the elderly.  You might remember my discussion of the Atlantic article several months ago. In that entry I discussed two articles  that suggested the flu vaccine may be less effective in the elderly than the studies demonstrated. http://www.sciencebasedmedicine.org/?p=2495
The argument was that the elderly who received the influenza vaccine were healthier at baseline than those that didn’t receive the vaccine and the deaths during flu season was not due to the protection from the vaccine, but due to the fact that healthier people are less likely to die when they get ill. In part this was demonstrated by showing decreased deaths in vaccinated populations when influenza was not circulating.  If insomnia is a problem, you can go back and read my post.   To quote my favorite author, me, I said
“One, it is an outlier, and outliers need confirmation. The preponderance of all the literature suggests that influenza vaccine prevents disease and death. If you do not get flu, you cannot die from flu or flu related illnesses. When outliers are published, people read them, think, “huh, that’s interesting”, but there is going to have to be more than one contradictory study to change my practice. But if “study after study” shows mortality benefit, and one study does not, it is food for thought, but not necessarily the basis of changing practice. The results, above all, needs to be repeated by others… In medicine we tend to be conservative about changing practice unless there is a preponderance of data to suggest a change is reasonable. Except, of course, if our big pharma overlords take us to a good streak house.”
Now we have a third article, “Evidence of Bias in Studies of Influenza Vaccine Effectiveness in Elderly Patients” from the Journal of Infectious Diseases.
In the study they examined the records of the elderly in the Kaiser Health System, their vaccination records, and their risk of death.  And the results were interesting.
“The percentage of the population that was vaccinated varied with age. After age 65, influenza vaccination increased until age 78 in women and age 81 in men, then decreased with increasing age. Vaccination coverage also varied in a curvilinear fashion with risk score, increasing with risk score to a risk score percentile of ∼80%, then decreasing. In addition, as the predicted probability of death increased, vaccination coverage increased. Vaccination coverage was highest among members with a probability of death of 3%–7.5%. Those with a predicted probability of death in the coming year of 17.5% had a de- creasing likelihood of influenza vaccination”
They then looked at mortality when flu was not circulating.
“A change in the pattern of vaccination had a striking effect on mortality. For members > 75 years old who had been receiving influenza vaccinations in previous years, not receiving a seasonal influenza vaccination was strongly associated with mortality in the months ahead (Table 1). A person who had received an influenza vaccination every year in the previous 5 years had a more than double probability of death outside the influenza season if he or she missed a vaccination in the current year, compared with a person who was vaccinated as usual (odds ratio, 2.17; P < .001). On the other hand, if a person did not receive any seasonal influenza vaccination in the previous 5 years, then receipt of a vaccination in the current year was associated with a greater probability of death. “
If they had a history of flu vaccine for five years and missed it, the probability of death went up.
If they did not have a flu vaccine for five years and got one, the probability of death went up.
They suggest in the first case, the patients may have had an increase in their co-morbidities and as a result did not get the vaccine and died of underlying diseases. Their increased risk of death was from accumulating prior illnesses.
In the second case, people who were healthy and did not seek care subsequently developed diseases that lead them to a doctor who advised the vaccine.  Their increase risk of death was due to new illnesses.
Either way, the uptake of the flu vaccine is more complicated than I had suspected and makes interpretation of efficacy of the vaccine in prior studies harder to evaluate.  The table shows an unexpected relationship between age, risk of death and use of the flu vaccine.
table here
They say in the discussion
“We showed that, despite strong efforts to increase vaccination among the elderly population, vaccination is relatively low in the oldest and sickest portions of the population. Persons 65 years old with a 17.5% chance of death in the upcoming year are less likely to receive the influenza vaccine. Because persons who are most likely to die are less likely to receive the vaccine, vaccination appears to be associated with a much lower chance of dying; thus, the “effectiveness” of the vaccine is in great part due to the selection of healthier individuals for vaccination, rather than due to true effectiveness of the vaccine. Previous studies have argued that worsening health is associated with increasing vaccination. We found this to be a curvilinear relationship, in which increasing illness means increasing vaccination, up to a point, and then, as people come closer to the end of life, there is a decrease in vaccination coverage.”
They do not say the vaccine is not effective, but they suggest that there is a bias that may make the vaccine appear more effective in the elderly than it really is.  Reality is often more complex than one would think at the beginning.
After three studies I am reasonably convinced that efficacy of the flu vaccine in the elderly is potentially not as well understood as I had thought.
So do I think the flu vaccine is no longer useful in the elderly?  No.  I still think it is a reasonable intervention but it may not have the efficacy I would like.  But I have always known that, for a variety of reasons, the flu vaccine is not a great vaccine. But it is better than no vaccine. There are, as discussed in the earlier post on the vaccine, many lines of evidence to show that the flu vaccine has benefit; at issue is the degree of the benefit.  Perhaps what is needed is a better vaccine with adjuvants or multiple injections to get a better result in the elderly, who respond poorly to the vaccine.  Or perhaps it will be better to focus on increasing vaccination in those who care for or have contact with the elderly.  But when I talk to my patients and residents, when I get to part about flu vaccine efficacy, I will be a little more nuanced, use more qualifiers. I will tell them that the vaccine is like seat belts.  It does not prevent all death and injury, but if you had a choice, would you not choose to use seat belts?
In the end the data has to change the way I think about medicine, not matter how much it hurts.
Compare and contrast that with the anti-vaxers who have the belief that vaccines cause autism.  They look for data to support the pre-existing belief and ignore contrary data.  Opinion does not follow from data.
The most representative statement of their approach is on the 14 studies website where they say  ”“We gave this study our highest score because it appears to actually show that MMR contributes to higher autism rates.”
The key phrase in the whole site. Data that supports their position is good, data that does not is bad. What makes a study good is not its methodology or its rigor, or its reproducibility, or its biologic plausibility,  but if it supports vaccines casing autism.
Dr. Wakefield, as has been noted over the last week, had his MMR/autism paper withdrawn from Lancet not for bad science, but for dishonest science.  In medicine you can be wrong, but you cannot lie.  If the results of medical papers were shown to be fabrications, such as the papers of Scott S. Reuben, no one the medical field would defend the results.  Dr. Reuben, as you may remember http://www.sciencebasedmedicine.org/?p=408, was found to have fabricated multiple studies on the treatment of pain.  Nowhere can I find web sites defending his faked research.  No suggestions it was due to a conspiracy of big pharma to hide the truth. No assertions that he is still a physician of great renown.   He lied and is consigned to ignominy.   Physicians who used his papers as a basis of practice no longer do so, or so I would hope.
The response to Dr. Reuban is in striking contrast to the defense of Dr Wakefield, where bad research combined with unethical behavior, results in reactions like this
“It is our most sincere belief that Dr. Wakefield and parents of children with autism around the world are being subjected to a remarkable media campaign engineered by vaccine manufacturers reporting on the retraction of a paper published in The Lancet in 1998 by Dr. Wakefield and his colleagues.
The retraction from The Lancet was a response to a ruling from England’s General Medical Council, a kangaroo court where public health officials in the pocket of vaccine makers served as judge and jury. Dr. Wakefield strenuously denies all the findings of the GMC and plans a vigorous appeal.”
Opinions did not change when the Wakefield paper was demonstrated to be not just wrong but false, the researcher’s behavior unethical, and the study could not be reproduced using similar methodologies (http://www.plosone.org/article/info:doi%2F10.1371%2Fjournal.pone.0003140).  Instead, the defense of Dr. Wakefield became, well, like a Jim Carrey shtick. The Mask defends retracted autism research. Fire Marshall Bill on the medical literature.  Jenny and Jim’s defense does make more sense read as comic performance art.  Andy Kaufmann would have been proud.
I wonder if the more grounded in fiction an opinion is, the harder it is to change, the more difficult it is to admit error.  I have to admit I cannot wrap my head around the ability of people to deny reality.  It is the old Groucho line come to life, “Who are you going to believe, science or your lying eyes?”
So I will, I hope, keep changing my mind as new information come in.  It is what separates real health care providers from acupuncturists and homeopaths and naturopaths and anti-vaxers.  It is what some truly great minds admit to doing (http://www.edge.org/q2008/q08_index.html).  As one deeper thinker and better writer (http://www.emersoncentral.com/selfreliance.htm) than I said, kind of,
“The other terror that scares us from self-trust is our consistency; a reverence for our past act or word, because the eyes of others have no other data for computing our orbit than our past acts, and we are loath to disappoint them.
But why should you keep your head over your shoulder? Why drag about this corpse of your memory, lest you contradict somewhat you have stated in this or that public place? Suppose you should contradict yourself; what then? It seems to be a rule of wisdom never to rely on your memory alone, scarcely even in acts of pure memory, but to bring the past for judgment into the thousand-eyed present, and live ever in a new day. In your metaphysics you have denied personality to the Deity: yet when the devout motions of the soul come, yield to them heart and life, though they should clothe God with shape and color. Leave your theory, as Joseph his coat in the hand of the harlot, and flee.
A foolish consistency is the hobgoblin of little minds, adored by little statesmen and philosophers and divines and anti-vaxers. With consistency a great soul has simply nothing to do. He may as well concern himself with his shadow on the wall. Speak what you think now in hard words, and to-morrow speak what to-morrow thinks in hard words again, though it contradict every thing you said to-day. — ‘Ah, so you shall be sure to be misunderstood.’ — Is it so bad, then, to be misunderstood?”

Why is my mind so clean and pure?  Because I am always changing it.

In medical school the old saying is that half of everything you learn will not be true in 10 years, the problem being they do not tell which half.

In medicine, the approach is, one hopes, that data leads to an opinion.  You have to be careful not to let opinion guide how you evaluate the data.  It is difficult to do, and I tell myself that my ego is not invested my interpretation of the data. I am not wrong, I am giving the best interpretation I can at the time. For years  I yammered on about how it made no sense to give a beta-lactam and a quinolone for sepsis until a retrospective study suggested benefit of the combination.  Bummer. Now when I talk to the housestaff about sepsis, I have to add a caveat about combination therapy.  It is why my motto is, only half jokingly,  ”Frequently in error, never in doubt”.

At what point do you start to change you mind?  Alter your message as a teacher?  Have new behavior?  Medicine is not all or nothing, black and white.  Changes are incremental, and opinions change slowly, especially if results of a new study contradict commonly held conclusions from prior investigations.

Nevertheless, I am in the process of changing my mind, and it hurts.  I feel like Mr. Gumby.

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Posted in: Clinical Trials, Science and Medicine, Vaccines

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CardioFuel—another magic pill

I get a lot of email asking me about various alternative therapies and supplements. A recurring theme on this blog has been the hyperbolic claims of alternative practitioners and supplement makers, and while I can’t answer every email, I can at least address some of them in the blog. Supplements are often marketed using unsupported health claims to which is appended the Quack Miranda Warning, essentially allowing the makers to say that the pill will have such and such a benefit, while simultaneously denying any responsibility for the claim.  Since the FDA isn’t examining these claims, it’s worth while to ask our own questions.

The latest email concerned a product called CardioFuel. Let’s take a closer look at this stuff.

According to the distributor:

CardioFuel is the most profound energy producing supplement on the market today! It does something like no other can: Increase energy at the most basic metabolic level, by increasing ATP (the biochemical energy unit of transfer) production. More ATP means more energy reserves to overcome chronic disease, beat the competition, and handle the everyday stressors of today’s fast paced world!

So to be taken seriously, there should be evidence that this product: 1) increases ATP, 2) increases “energy reserves”, and 3) helps overcome chronic disease and “the competition”. First, it is not possible to directly measure ATP in a human being under normal clinical conditions, so any claims about this must be an inference from markers of ATP metabolism, or a guess. We’ll see what the literature says about this below. Second, we need an operational definition of “energy reserves”. Does this mean fat stores? Glycogen stores? These things are measurable to an extent.  Finally, we can do a literature search to see if CardioFuel or an acceptable analog has been tested for its effect on relevant outcomes.

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Posted in: Science and Medicine

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Science by press release

Last week I wrote about a study that purported to show that antidepressants have no effect in mild to moderate depression. A careful reading of the paper shows that the authors dramatically overstated their findings, particularly in their public statements to the media. The study has another implication beyond the misleading claims about antidepressants. It is an object lesson in an ongoing and disturbing phenomenon in mainstream journalism, the wholesale reprinting of press releases of scientific papers instead of reading and analyzing the papers themselves.

Pick up any newspaper or magazine and you can read about the latest scientific breakthroughs in cancer, Alzheimer’s or heart disease. Just keep in mind that what you are reading is probably a commercial message direct from the authors, not an accurate representation of the paper itself. Medical journalists are supposed to interpret the findings of recent medical publications and present them to the general public in ways that they can understand. They are supposed to provide context for the discovery, explaining what it might mean for disease treatment or cure. Yet, they rarely do. Instead, they simply copy the press release.

Most people are unaware that scientists issue press releases about their work and they are certainly unaware that medical journalists often copy them word for word. Instead of presenting an accurate representation of medical research, medical journalists have become complicit in transmitting inaccurate or deceptive “puff pieces” designed to hype the supposed discovery and hide any deficiencies in the research.

Imagine if a journalist reviewing the newest Ford cross-over vehicle didn’t bother to drive the car, but simply copied the Ford brochure word for word. Could you rely on the journalist’s evaluation? Of course not. Yet that is precisely what medical journalists are doing each and every day.
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Posted in: Science and Medicine, Science and the Media

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Checklists and Culture in Medicine

Surgeon and journalist, Atul Gawande, is getting quite a bit of deserved press and blog attention for his new book, The Checklist Manifesto: How to Get Things Right. The premise of his book is simple – checklists are an effective way to reduce error. But behind that simple message are some powerful ideas with significant implications for the culture of medicine.

One of the biggest ideas is that medicine has culture – a way of doing things and thinking about problems that subconsciously pervades the practice of medicine. This idea is not new to Gawande, but he puts it to powerful practice.

The Humble Checklist

Gawande tells not only the story of the checklist but of his personal experience designing and implementing a surgery checklist as part of a WHO project to reduce morbidity and mortality from surgery. He borrowed the idea from other industries, like aviation, that use checklists to operate complex machinery without forgetting to perform each little, but vitally important, step.

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Yes, Jacqueline: EBM ought to be Synonymous with SBM

“Ridiculing RCTs and EBM”

Last week Val Jones posted a short piece on her BetterHealth blog in which she expressed her appreciation for a well-known spoof that had appeared in the British Medical Journal (BMJ) in 2003:

Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials

Dr. Val included the spoof’s abstract in her post linked above. The parachute article was intended to be humorous, and it was. It was a satire, of course. Its point was to call attention to excesses associated with the Evidence-Based Medicine (EBM) movement, especially the claim that in the absence of randomized, controlled trials (RCTs), it is not possible to comment upon the safety or efficacy of a treatment—other than to declare the treatment unproven.

A thoughtful blogger who goes by the pseudonym Laika Spoetnik took issue both with Val’s short post and with the parachute article itself, in a post entitled #NotSoFunny – Ridiculing RCTs and EBM.

Laika, whose real name is Jacqueline, identifies herself as a PhD biologist whose “work is split 75%-25% between two jobs: one as a clinical librarian in the Medical Library and one as a Trial Search Coordinator (TSC) for the Dutch Cochrane Centre.” In her post she recalled an experience that would make anyone’s blood boil:

I remember it well. As a young researcher I presented my findings in one of my first talks, at the end of which the chair killed my work with a remark that made the whole room of scientists laugh, but was really beside the point…

This was not my only encounter with scientists who try to win the debate by making fun of a theory, a finding or …people. But it is not only the witty scientist who is to *blame*, it is also the uncritical audience that just swallows it.

I have similar feelings with some journal articles or blog posts that try to ridicule EBM – or any other theory or approach. Funny, perhaps, but often misunderstood and misused by “the audience”.

Jacqueline had this to say about the parachute article:

I found the article only mildly amusing. It is so unrealistic, that it becomes absurd. Not that I don’t enjoy absurdities at times, but absurdities should not assume a life of their own.  In this way it doesn’t evoke a true discussion, but only worsens the prejudice some people already have.

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Posted in: Clinical Trials, Medical Academia, Medical Ethics, Science and Medicine

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Study shows antidepressants useless for mild to moderate depression? Not exactly.

As Harriet Hall has written (http://www.sciencebasedmedicine.org/?p=353), psychiatry bashing is a popular media sport. There seems to be a bias against treatment of psychiatric disabilities, and a common claim is that antidepressants are no better than placebo. The New York Times illustrated both the perpetuation of the myth that antidepressants are ineffective, and the increasing and disturbing tendency of major media organizations to confuse the wholesale acceptance of medical press releases with medical journalism.

In Popular Drugs May Help Only Severe Depression The New York Times credulously publicized the findings of a recent study that claimed to show that antidepressants are ineffective in treating mild and moderate depression. Yes, that’s what the study showed, but the study itself is so limited, so fraught with problems, and the conclusions are so misleading that the article is a terrible disservice.

Before we consider what the study showed, let’s think about what kind of evidence we’d need to conclude that antidepressants don’t work.

First, although there are different types of antidepressants, the term used colloquially refers to antidepressants of a specific type, SSRI’s or selective serotonin reuptake inhibitors. There are other, older types of antidepressants that are rarely used today because of their unpleasant side effects. Hence any study that claims to show that “antidepressants” are ineffective, must look at SSRIs.

Second, there are literally thousands of studies of SSRIs, and it would be helpful to aggregate the results. Aggregating results can be done in a type of paper known as metaanalysis. Metaanlysis adds the results of multiple similar studies to find trends that might not be apparent in individual small studies. But a metaanlysis is subject to several important limitations that must always be considered. The most important limitation is that the authors of the metaanalysis choose the papers to be included. Bias can be introduced by examining only papers that have a desired outcome; that can be accomplished by restricting the inclusion criteria in arbitrary ways.

Let’s look at the study, Antidepressant Drug Effects and Depression Severity. According to the abstract:
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The Lancet retracts Andrew Wakefield’s article

In 1998 Andrew Wakefield and 11 other co-authors published a study with the unremarkable title: Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Such a title would hardly grab a science journalist’s attention, but the small study sparked widespread hysteria about a possible connection between the mumps-measles-rubella (MMR) vaccine and autism spectrum disorder (ASD).

The study itself has not stood the test of time. The results could not be replicated by other labs. A decade of subsequent research has sufficiently cleared the MMR vaccine of any connection to ASD. The lab used to search for measles virus in the guts of the study subjects has been shown to have used flawed techniques, resulting in false positives (from the Autism Omnibus testimony, and here is a quick summary). There does not appear to be any association between autism and a GI disorder.

But it’s OK to be wrong in science. There is no expectation that every potential finding will turn out to be true – in fact it is expected that most new finding will eventually be found to be false. That’s the nature of investigating the unknown. No harm no foul.

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Success in the fight against childhood diarrhea

Rotavirus is the world’s most common cause of severe childhood diarrhea.  In the U.S. alone, rotavirus disease leads to around 70,000 hospitalizations, 3/4 million ER visits, and nearly half-a-million doctor office visits yearly.  But it rarely causes death.

The same is not true for the developing world.  Rotavirus disease is estimated to kill around a half-million children a year world wide.   Finding a way to mitigate this is an active public health concern, with the World Health Organization specifically recommending rotavirus vaccinations in areas where the virus has a significant public health impact.

Rotavirus causes a severe diarrheal illness. It is passed via a fecal-oral route, meaning that contaminated food, surfaces, and water can all be sources.   In developed countries like the US, rotavirus disease is unpleasant and inconvenient.  Since rotavirus spreads more readily in areas without access to clean water and medical care, it takes a greater toll in these areas, and children afflicted are at risk of death due to dehydration.  The US has seen a decline in rotavirus disease in the last few years, an effect that appears to be due to increased vaccination and a herd immunity effect.

Given the large number of pediatric rotavirus deaths in developing countries, the World Health Organization (WHO) has made vaccination a priority. Two articles in this week’s New England Journal of Medicine report on the progress of the fight against rotavirus.

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Reflexive doubt

Those of us who study, practice and write about medicine cherish the hope that explaining the science behind medicine (or the lack of science behind “alternative” treatments) will promote a better understanding of medicine. Certainly, I would not bother to write about medical topics if I did not believe that promoting science based medicine would lead to increased understanding of medical recommendations and decreased gullibility in regard to “alternative” remedies. Nonetheless, lack of scientific knowledge is not the only reason for the current popularity of “alternative health. Indeed, many advocates and purveyors of “alternative” health are impervious to the scientific evidence. What else might be going on?

Belief in “alternative” medicine is a complex social phenomenon. Like any complex social phenomenon, the explanation cannot be reduced to a simple answer. But I would argue that there is an important philosophical component, developed by and promoted by advocates of “alternative” health. That philosophical component is the rise of reflexive doubt. Simply put, among a significant segment of society, it has become a badge of honor to question authority.

As an obstetrician, I am most familiar with its expression among childbirth activists. They recognize that many people hold the common sense belief that modern obstetrical practice has made birth safer, and have worked ceaseless at undermining this common sense view. Craig Thompson, a professor of marketing, has examines this tactic in his paper What Happens to Health Risk Perceptions When Consumers Really Do Question Authority?:
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Evolution in Medicine

A recent series of article in the Proceedings of the National Academy of Sciences (PNAS) discusses the role of evolutionary biology in modern medicine. The authors collectively make a forceful point – medicine is an applied science. It is based upon a number of basic sciences, and one of those basic sciences is evolution.

The most obvious example is bacterial antibiotic resistance. Antibiotics place a selective pressure on a bacterial population, often resulting in the emergence of resistant strains. Understanding this “evolutionary arms race” between bacteria and antibiotics allows us to develop strategies for minimizing resistance.

But there are less obvious ways in which evolutionary principles apply to infectious diseases. It has been known for a long time that sickle-cell trait provides resistance to malaria (the blood cells are less hospitable to the P. falciparum protozoan parasite that is one cause of malaria). This explains the persistence of sickle cell disease in populations where malaria is endemic.

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