One of my goals as a science communicator with a focus on healthcare is to increase the general understanding of how to think about clinical interventions. Just take a look at the many health-related videos on TikTok or other social media platform, contradicting standard medical advice. Many are based on false information, but they also almost uniformly do not think about public health measures or medical decisions properly. This disconnect between how experts think of intervention and how the public may perceive them was massively on display during the recent COVID pandemic.

Here is the quick primer. Think of interventions based upon their risk vs benefit. You cannot only consider risk, and you have to consider the risk vs benefit of all options, including doing nothing. On the diagnostic end, it is better to consider the predictive value of information, not just whether it is a sign or symptom. In the realm of public health there are more considerations, not just the risk vs benefit at the individual and the population level. Because we have limited resources, and often there are competing valid options, we also like to look at the return on investment (ROI) of interventions. A recent study does that for the COVID-19 vaccines – how much public and private money was spent for their development, manufacture, and distribution and what were the health and economic benefits?

The bottom line is that the COVID-19 vaccination programs had a massive ROI, they had a positive cost-benefit and cost effectiveness (in addition to a positive benefit to risk ratio). But the details are interesting, so let’s dive in.

There are many ways to slice and dice such data, and many ways to estimate the cost benefits of preventing illness. So the authors provided as much information as possible, without just choosing one analysis. I am going to present the data from the bottom up – from the most conservative estimates to the most complete estimates. First, the estimated cost of all stages of the vaccine programs (including the first year of delivery) was $79.4 billion worldwide. That is a high price tag, but what did we get in return? The most straightforward type of cost benefit from a healthcare intervention is avoided future healthcare costs. The authors estimated this by using estimates of hospitalizations avoided and the average cost of hospitalization in each country. That amounted to $222 billion. So based on that maximally conservative estimate the vaccine programs were very cost-effective.  Continue Reading »

Christina Applegate, an American actress, has been an outspoken advocate for patients with multiple sclerosis (MS) since her own diagnosis. She has been open about her “MS journey” in hopes that it will help others facing the same challenge. Recently, however, her journey took an unexpected turn – she apparently does not have MS. She reported on her recent podcast that her doctors informed her the diagnosis of MS made in 2021 is not correct. She lamented that now she is “back to square one”, without a specific diagnosis.

However, this does not invalidate her MS journey in my opinion. This is a very common aspect of that journey for many patients, up to 20% of which will turn out not to have MS even after an MS diagnosis. This is a great learning experience and there are several lessons worth pointing out. The first of which is that the fact that her diagnosis has changed does not mean that her neurologists did anything wrong or substandard. That seems to be everyone’s first reaction – a “misdiagnosis” means someone screwed up. This is not true, for very informative reasons.

A couple of background points before I push on. First, I recently retired from a 30 year career as a clinical neurologist. I was not an MS specialist, but I obvious know a lot about MS as a neurologist and was involved in the care of many MS patients. But MS diagnosis and treatment is extremely complex and should be done by an MS specialist, which we had in our clinic. Second, I have no inside knowledge of Applegate’s case, so I am basing my comments on publicly available information. Besides, most of my observations her are based on MS and clinical principles generally, not specifically her case. But it will put the news reporting into a useful perspective.

So how could Applegate have been diagnosed with MS when it turns out she does not have MS without this being a mistake? Diagnoses in medicine come in many different forms, and are based on different kinds of information. There are diseases, which generally result from a specific pathological process. There are also syndromes and disorders which may simply be a common clustering of clinical signs and symptoms. We use labels (diagnoses) for clinical entities that seem to exist in different patients, so that we can communicate about them, research them, and develop a body of knowledge about their natural history, diagnosis, and treatment. Some of these entities may be fairly iron-clad, based on objective definable pathology that can be documented unambiguously. At the other end of the spectrum are diagnoses that are simply symptoms that may have a typical demographic pattern and natural history, but without any known specific cause. There is also everything in between. There are also different types of data we can use – symptoms, signs on exam, blood tests, biopsy results, imaging studies, electrodiagnostic studies, response to treatment, and time course.

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A recent study represents a confluence of technological advances that is pretty interesting. The specific problem being addressed – chemotherapy for bladder cancer – is very promising, but the technology itself can potential have many applications.

Let’s start with the problem, delivering chemotherapy to bladder tumors. The trick with chemotherapy is to create the highest levels of toxicity possible for cancer cells while limiting the toxicity for healthy cells. There are several ways to achieve this, with the primary method being finding drugs that are inherently more toxic tumor cells than non-tumor cells. The classic feature that has been targeted is the fact that tumor cells are rapidly reproducing and have a high metabolic rate, so drugs that target such cells are used. This still has an effect on healthy cells, especially those that rapidly reproduce, like hair cells, which is why many chemotherapies cause hair loss. Essentially we push the toxicity of these drugs to the limit of tolerability, to kill the cancer cells as much as possible.

Another strategy is to get these drugs to the tumor in higher concentrations than the rest of the body. You can accomplish this by intralesional injecting (injecting chemotherapy directly into a tumor), by injecting into the body compartment that contains the cancer, or by directing the chemotherapy specifically to the cancer using advanced techniques (such as lipid nanoparticles). For some types of bladder cancer the strategy has been to fill the bladder with chemotherapy and keep it in there for as long as tolerated. This works to some extent, increasing the dose of chemotherapy to the tumor while limiting systemic effects. However, there is limited penetration of the drug into the tumor because of the nature of the bladder lining.

The researchers therefore developed a hybrid algae robot to delivery chemotherapy for bladder cancer. They started with the silica shell of a diatom algae, specifically Coscinodiscus granii. The shell is called a frustule, which you can think of as a tiny glass wiffle ball. They chose G. granii because it has a multilayered porous shell with different sized pores, including a network of nanopores. They cleaned it of all the living algae parts so just the frustule was left. Essentially they are using the algae as nanofactories, mass producing these finely structured rigid shells that are also biodegradable. Nature so far is much better at creating things at the nanoscale than our technology. They then coated the frustules with magnetite and filled them with a chemotherapeutic drug, doxorubicin.

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Understanding, at a deep level, the differences between legitimate science and pseudoscience is increasingly critical in our modern world. Science, in my opinion, is perhaps the most powerful tool humans have collectively developed for understanding the universe in which we find ourselves. (I would clarify that it is complementary with philosophy which is important to ensure that we are thinking clearly, rigorously, and consistently.) Pseudoscience pretends to be scientific but is essentially doing it wrong. There are many underlying reasons for the existence of pseudoscience – it is sometimes just poor quality science due to poor training or sloppy technique, it may result from a motivation to achieve a desired result rather than letting the empirical chips fall where they may, researchers may not appreciate their own biases, or it may be part of a dedicated campaign motivated by profit, politics, ideology, religion, culture, or just wishful thinking.

I spend a lot of time studying and writing about certain classic pseudosciences because I think they are especially instructive, and acupuncture is definitely on the short list.  I just wrote about it last week, specifically about a gullible article in the NYT which has bought into the pro-acupuncture propaganda. That piece resulted in lots of feedback, some of which doubled-down or extended the pseudoscientific arguments often made for acupuncture, so I wanted to reply to some of those and further clarify my position.

One common feature of pseudoscience is the use of vague or fluctuating definitions. Science requires unambiguous definitions, which is why it so often relies on technical jargon which evolves to be incredibly precise. This is one of the things I love about science, and why I think everyone should study it to some degree, at least enough to become functionally scientifically literate. Science forces you to think clearly, precisely, and consistently. If we take a seemingly simple question, for example, such as “does acupuncture work”, we first have to operationally define “acupuncture” and also “work”. You also have to include – work for what? I am usually careful to do so when addressing this question.

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Dozens of people have e-mailed me about a recent article in the New York Times Magazine on the interstitium. The reason is not because of the interstitium itself, but because it is being used to retcon an alleged explanation for acupuncture.  The discussion of the interstitium itself is fine, but then the author veered off into gratuitous pseudoscience.

The interstitium was proposed in 2018 based on a study showing that the interstitial connective tissue spaces around organs and other tissues in the body are not separate spaces but all appear to be connected. Essentially the authors propose this is a body-wide fluid filled space in the body through which fluids flow and communicate. This adds to the other fluid systems in the body, such as the lymphatic system (which drains excess fluid from tissues), the circulatory system (which distributes oxygen and nutrients and carries away waste), and the spinal fluid system (which is inside and surrounds the central nervous system). Later studies have supported the evidence for one continuous interstitial space.

Of course, the more we know about how the body works the better we will be able to understand disease processes and design treatments. Cancer cells, for example might spread through the interstitium, resulting in distant metastasis.

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Regeneration is one of the futuristic tropes of science-fiction, because it is both incredibly powerful and not theoretically impossible. Imagine the ability to regrow a lost limb, or simply to replace a diseased or worn out limb. There are about a million limb amputations worldwide every year, so it is a very common medical problem. What if we could regenerate organs? This would be a game-changer for medicine.

There are several approaches to addressing missing limbs or failing organs. One is the cyborg approach – make a mechanical version to replace the biological one. We are making progress here, with brain machine interfaces, mechanical hearts, and other advances. Or you could transplant the body part from another person, or even an animal that has been genetically modified to be compatible. You can also regrow the missing or failing body part from the intended recipient’s own tissues and then transplant that. Or you could inject stem cells programed to regrow the needed part inside the recipient. All of these options are active research programs, have shown some incredible promise, but are also years or even decades away, especially in their mature form.

Let’s now add one more technology to the list – genetic therapy that triggers natural regeneration, meaning from the person’s own tissue. This has long been a target of potential therapy, inspired by the fact that there are many animals that can already naturally do this. Most extreme is the axolotl (a type of salamander that for some reason has become very population with the young generation), which can regenerate just about any of its body parts. They form a blastoma of pluripotent stem cells at the site of injury that can quickly regrow into a missing limb, heart, spinal cord, parts of the brain, etc. in weeks. There are also zebrafish, which can regrow their tail fins. Mice can also regrow missing digits, which is important because they are mammals showing that regeneration can happen even within the mammal clade. You don’t have to be a salamander.

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This is a tiny ray of light in what has been a gloomy year for science-based federal health policy. Recently U.S. District Court Judge Brian Murphy in Boston ruled that the actions of RFK Jr. as HHS Secretary to fire the entire Advisory Committee on Immunization Practices (ACIP) did not follow procedure and is therefore not valid. Further, he concluded that the new ACIP, packed with anti-vaxxers, made capricious and arbitrary decisions that did not follow established science-based procedure. His ruling is a preliminary injunction that has delayed meetings of the ACIP and stays the revised vaccine schedule. The ruling is in a case brought by a coalition of medical professional societies, including the American Academy of Pediatrics. They are celebrating the ruling as “a momentous step toward restoring science-based vaccine policymaking.”

There are a few layers to this story. The first is RFK Jr. himself and what he has been doing as HHS secretary. I have not written much about him here, because posts about him and other Trump health appointees have dominated the SBM blog over the last year. This has been an “extinction level event” for rational federal health policy, and we have documented it and analyzed it every step of the way. David Gorski has done a great job specifically documenting what RFK Jr. has done to vaccines in the US in his series – “RFK Jr. is definitely coming for your vaccines”, in which he just published part 8. He did a great job not only documenting all of RFK Jr’s harmful actions but actually predicting them. Essentially, RFK is systematically using every lever at his disposal to dismantle the vaccine infrastructure in the US to reduce vaccines as much as possible. Given his actions he clearly straight-up lied to the confirmation committee when he said he was not anti-vaccine and would not take away American’s vaccines.

We, of course, recognized exactly what RFK Jr was doing during the hearings, because we have been following his nonsense for 30 years. He said, for example, “If we want uptake of vaccines, we need a trustworthy government,” Kennedy said. “That’s what I want to restore to the American people and the vaccine program. I want people to know that if the government says something, it’s true.” He then promised “gold standard science”. I would argue he has done the exact opposite. But what this statement is is classic denialism. Just claim you want to review the science, that everything is open to examination, and you just want the highest standards of science. These principles are great, but they can be used as a weapon, not just a tool. You can deny well-established scientific conclusions by arbitrarily claiming we need yet higher standards. Also, claiming you want to “restore” faith in the vaccine program assumes there is currently a lack of faith, which is rich coming from the person who has done the most to undermine that faith with pseudoscience and false claims. That is another denialist strategy – make a well-established science seem controversial, then argue that because it’s controversial we need to reexamine it and call it into question.

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The news is abuzz with talk of a potential universal respiratory vaccine. It’s definitely interesting research, but may not be what you think. In this case, the reporting has been quite good on the whole, but the headlines can be misleading if you are not deeply steeped in the complexities of mammalian immunity. Let me start with the biggest caveat – this is a mouse study. This is therefore encouraging pre-clinical research, but we are still years away from translating this into an actual vaccine. Also, most interventions that are encouraging at the animal stage don’t make it through human testing. So don’t expect any revolution based on this treatment anytime soon. Having said that – there is great potential here.

To understand how this new approach works, let’s review some basics of immunity. (Note – the immune system is incredibly complex, and I can only give a very superficial summary here, but enough to understand what’s going on.) Mammalian immune systems have two basic components, innate immunity and adaptive immunity. The adaptive immune system is probably what most people think about when they think about the immune system and vaccines. Adaptive immunity targets and recognizes specific antigens (such as proteins) on pathogens like viruses, bacteria, or fungi. Antibodies attach to these antigens, flagging them to be targeted by immune cells like macrophages which then eat them. The macrophages in turn display the antibody-flagged antigens on their surface, triggering a greater and more specific reaction to those specific antigens. Adaptive immunity is considered slow (it takes days to ramp up), specific (it targets specific antigens on specific pathogens) and durable (it has memory, and will react more quickly and robustly to the same pathogen in the future).

By contrast, the innate immune system is fast, non-specific, and short-lived with no memory. The innate immune system consists of physical barriers, like skin and mucosa, and immune cells that target pathogens based on broad patterns that are not learned but are innate (hence the name). There are Toll-like receptors (TLRs – the name Toll comes from the German for “fantastic”, allegedly said by a researcher upon discovery). The Toll gene was first discovered in fruit flies and then similar genes were later discovered in mammals, hence “Toll-like”. TLRs detect pathogen-associated molecular patterns (PAMPs), which are highly conserved features of types of pathogens. In other words –  a TLR might recognize a snippet of RNA as a pattern typical of RNA viruses, or proteins that tend to occur on pathogenic bacteria. “That looks like an RNA virus, so let’s attack it.”

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A new study reinforces the evidence for the safety and efficacy of the mRNA COVID-19 vaccines. That’s the TLDR, but let’s dive into the details.

Medical evidence is always rolled out in stages. First there is what we would consider preclinical evidence, or basic science. This could be initial uncontrolled clinical observations, or mechanistic animal or in vitro research. At some point we have sufficient evidence to generate a hypothesis that a specific treatment could be effective in treating a specific disease, enough to progress to human research. For FDA qualifying research, there are four specific phases. Phase I trials look at the safety of the intervention in usually healthy controls, while also answering basic questions and mechanism and effects. If there are no safety red-flags then the research progressed to a phase II trial, which look for preliminary evidence of efficacy, and further safety data. Again, if that data continues to look encouraging we can progress to a phase III trial, which is a larger and more rigorous trial designed to be definitive. Usually the FDA requires several phase III trials to grant approval of a drug for a specific indication. Then, once on the market there is phase IV trials, which look at data from more widespread use to confirm safety and effectiveness in the real world.

Looked at another way, we do research in the lab, then on dozens of people, then score to hundreds of people, then hundreds to thousands of people, and then finally on thousands to millions of people. Each step of the way we gain the ability to detect less and less common side effects in a broader set of people. Further, the types of evidence are designed to be complementary. Phase III trials, for example, are rigorously experimental, with highly defined populations with randomization to control as many variables as possible. Phase IV trials, on the other hand, are generally observational, designed to look at very large numbers of people in an uncontrolled setting – to determine how safe and effective the treatment is in real-world conditions.

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Yesterday, Trump and RFK Jr had a press conference which some are characterizing as the absolutely worst firehose of medical misinformation coming from the White House in American history. I think that is fair. This was the presser we knew was coming, and many of us were dreading. It was worse than I anticipated.

I suspect much of this stems from RFKs previous promise that in six months he would find the cause of autism so that we can start eliminating these exposures – six months is September. This was an absurd claim given that there has been and continues to be extensive international research into autism for decades, and absolutely no reason to suspect any major breakthrough in those six months. Those of us following RFK’s career knew what he meant – he believes he already knows the causes, that they are environmental (hence “exposures”) and include vaccines.

So Kennedy had to gin up some big autism announcement this month, and there is always plenty of preliminary or inconclusive research going on that you can cherry pick to support some preexisting narrative. It was basically leaked that his target was going to be an alleged link between Tylenol (acetaminophen) use in pregnancy and autism. This gave us an opportunity to pre-debunk this claim, which many did. Just read my linked article in SBM to review the evidence – bottom line, there is no established cause and effect and two really good reasons to doubt one exists: lack of a dose response curve, and when you control for genetics, any association vanishes.

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