By now most people have heard that AstraZeneca, a UK pharmaceutical, working with Oxford University, are one of the major companies developing a vaccine for SARS-CoV-2, and also that they have had to pause their Phase 3 clinical trial because a subject came down with an inflammatory disorder. Let’s put this into some important context.

The basic facts are that the AstraZeneca vaccine did very well in Phase 1 and 2 preliminary trials. These are smaller trials mostly about safety, with the Phase 2 trial including some preliminary (usually open label) efficacy data. These trials are basically used to determine if it is safe and worth it to proceed to a huge Phase 3 trial. The Phase 3 trial includes 30,000 subjects. When you increase the number of subjects by orders of magnitude then you are likely to pick up increasingly rare side effects. That is one of the main points of this staged approach to research. Then, of course, a drug or vaccine might be marketed to millions of people, and still more rare side effects will crop up. There is simply no way to avoid this – it’s math. That is why so-called Phase 4 trials follow reported side effects after market.

But also, when you are studying 30,000 subjects all the things that normally happen to people will happen at the background frequency. Some of them will get sick during the trial by chance alone, having nothing to do with the study drug or vaccine. So every potential adverse effect is tracked, determined if it is biologically likely that it is related to the experimental treatment, and then statistically analyzed to see if it is above the background rate.

In this case one subject developed transverse myelitis, which is inflammation in one segment of the spinal cord. This will cause weakness and numbness at that level and below, therefore usually affecting the legs. The background incidence of transverse myelitis is about 1.3-4.6 cases per million people per year (this does not include people known to have an autoimmune disease like MS that causes transverse myelitis). If we take 4 cases per million per year, that translates to 0.033 cases per 33,000 subjects over three months. That is the probability that one of the subjects in that trial would have randomly developed transverse myelitis. That may seem really unlikely, but actually you have to consider the probability of a subject developing any disease, not just transverse myelitis. When you add it all up it’s actually pretty likely that one or several people in the trial would randomly develop a disease not related to the vaccine. In fact, this is the second person in this particular trial to develop a serious potential adverse event resulting in a pause of the trial.

Continue Reading »

A new review of the published literature regarding the ketogenic diet and intermittent fasting has, from my perspective, entirely predictable results. By this I mean they are consistent with previous dieting research and there are no surprises. They are also consistent with one of the major themes of this blog – you cannot get away from fundamental realities by making cosmetic changes. You cannot change the laws of physics or the nature of biology. This often translates to the fact that, as a general rule, there are rarely easy or simple answers to complex problems.

When it comes to dieting, researchers generally focus on several basic outcomes – weight maintenance, heart health, and glucose metabolism. You can also look at overall health outcomes, such as the risk of death over time. In terms of weight, there is only one factor that seems to matter – calories in vs calories out. This is the unavoidable reality, and there does not seem to be a way to game the system to significantly alter this equation. Proponents of special diets will argue that varying the proportion of macronutrients (fat, protein, and sugars) can affect metabolism. Some ironically argue that their recommended macronutrient balance will make metabolism “more efficient”. This is not necessarily a good thing when it comes to weight, however. Efficiency could mean getting more use out of fewer calories. If you want to waste energy (i.e. fat) you want to be inefficient.

But the bottom line of decades of research is that any effect of diets that vary macronutrient ratios on metabolism seem to have an insignificant effect on weight. You simply cannot get away from the massive factor of calories in vs calories out by slightly tweaking metabolism.

What does this current review show? Exactly that. First they find, as with most prior research, that the two diets do result in short-term weight loss. Pretty much all diets do. However, they also found that long term research (meaning up to 12 months) show that any short term advantage is lost and not sustainable. Since the goal of weight management is long term control, a short term reversible and small advantage does not contribute to this goal. It may, in fact, backfire. It is a distraction from effective long term behavioral changes. And some studies show that the rebound weight gain is greater. The review also concludes that any short term weight loss may be due to simply reducing calories, not any metabolic change. That is still the overall conclusion of the totality of dieting research – that any observed weight loss is due to reduced calories and not some other factor.

Continue Reading »

This is the big question facing many countries, but especially the US – how do we reopen schools while still in the middle of a pandemic? This is a serious dilemma. The American Academy of Pediatrics urges that, especially younger children, have the opportunity for in-person learning.  This is important not only for their education but their socialization and development.

The other important variable here, however, is how susceptible are children to SARS-CoV-2 and the COVID-19 infection it causes? Early experience showed that children are less susceptible to getting the illness and when they are infected are less likely to have serious disease. This partly informed the AAP’s recommendation. However – more recent data is casting doubt on the notion that children can safely return to school.

The most comprehensive review of the data so far, just published, shows that children are asymptomatic carriers of the virus, and have high viral loads, which means they can be very contagious. Further, when they do get symptoms they are likely to be more like cold symptoms, with a fever and runny nose, which in adults makes it less likely they have COVID-19. These two factors mean that children have been widely underdiagnosed. Most testing programs are focusing on symptomatic individuals, and children get missed by such efforts.

The review also concludes that a small percentage of children can get a late-stage complication of COVID-19, even if the illness is mild or asymptomatic – their immune reaction several weeks after infection can cause serious illness, including heart disease. This is one of the serious features of this illness, the immune system’s response can sometimes be severe, causing much more damage than the infection itself.

Continue Reading »

There are many “holy grails” in medicine (as in every field) – a treatment or drug that has optimal properties. These are often elusive for a couple of reasons. First, often technology requires a suite of simultaneous traits in order to be useful. Lacking any one is a potential deal-killer. Second, desired traits may be inherently mutually exclusive, or at least very difficult to reconcile. One such holy grail in medicine we have taken a big step towards is a treatment that thins the blood to reduce the risk of abnormal blood clotting (thrombosis) without impairing normal clotting and increasing the risk of bleeding.

A recent article in Nature Communications details a preliminary study of just such a treatment, although it is not yet quite ready for prime-time.

Blood-thinning is a useful treatment for several reasons. Blood clots cause many strokes and heart attacks, which are among the highest killers. They also can form on artificial implants, such as mechanical heart valves and artificial lungs (temporary bridging treatment for patients awaiting lung transplant). Essentially any artificial surface that comes in contact with blood in the body can serve as a trigger for thrombosis.

But, of course, we need our blood to clot, or otherwise we would bleed. Therefore treatments to inhibit blood clotting to reduce the risk of stroke or heart attack have always been a delicate balancing act – thinning the blood just enough to reduce risk while minimizing the increased risk of bleeding. You always get one with the other, however, and optimal treatment is a matter of finding the optimal trade-off. If we could, however, reduce thrombosis without increasing bleeding risk, that would be ideal. But it seems that the two things go hand-in-hand, so how is this possible even in theory?

Continue Reading »

The evidence for this has been building over the last few years, and we are now at the point where it is reasonable to act on the evidence. Replacing wood, plastic, and stainless steel surfaces in hospitals with those either made of copper or embedded with copper significantly reduces bacteria and viruses (microbial burden, or MB) on those surfaces.

I am always suspicious of claims of ancient uses of healing methods, because there were many ancient cultures and collectively they pretty much did everything as a healing remedy. So the fact that we can cherry pick examples of some ancient society using copper to treat infections is not that impressive. They also used it for things for which it has no effect. But having said that, it was in fact used in wounds and to treat diseases in several ancient cultures. And copper does legitimately reduce the chance of infection.

It does this by leaching electrons from bacteria, which causes a charge to build up inside the cell which ultimately leads to free radical formation and cell death. Many studies have now shown that the microbial burden on copper surfaces is reduced by >80% compared to traditional surfaces. When used on frequently touched surfaces in hospitals, this can significantly reduce the amount of bacteria hanging around. Another study showed that the total reduction in bacteria from a copper alloy surface was 99.9% (compared to baseline, not to control surfaces). In controlled studies, copper surfaces work as advertised – they kill bacteria and viruses.

Continue Reading »

The Alaska Supreme Court just reaffirmed a very important legal and ethical principle – declaring that prayer is not a replacement for medicine. While this may seem obvious to many, this is a critical legal decision. It will probably not have the downstream effect that it should, but it does highlight a vital reality.

The case involves Rachel “O”, who has been taking care of her mother, Tiffany “O”. Rachel states that because she graduated from a ministry school she is qualified to treat her mother solely with prayer, including her mother’s epilepsy, and emergency treatment. The essence of the ruling is this:

“If Tiffany required immediate medical attention, the results could be fatal,” the court concluded. “For this reason, while religious liberty is a fundamental right under the Alaska Constitution, the state’s actions in this case are justified by a compelling interest.”

Generally, when the Constitution or other laws establish that people have certain rights, the state cannot infringe upon those rights, unless the state has a “compelling interest” that is deemed by the courts to be greater than the infringement on individual rights. This is a balancing act, and can sometimes lead to controversial decisions. Eminent domain is an example – we have a right to property and the state cannot seize our property, unless they have a compelling public interest in eminent domain (they need to build a highway through your property). This is meant to balance public interest with individual interest. This became highly controversial because of the Kelo vs New London case, in which the Supreme Court expanded eminent domain to include the state’s interest in maximizing its taxation.

Continue Reading »

One of the challenges of dealing with the COVID-19 pandemic, both on an individual patient level and public health level, is that this is a novel virus. We don’t yet have a lot of experience with it or clinical data about how it behaves, what it is capable of doing, and how the immune system deals with it. We are learning fast, but there is still much we don’t know, especially, of course, about long term effects.

One burning question is – what are the prospects for developing natural herd immunity as the infection spreads throughout communities? Herd immunity (or community immunity) occurs when enough people in a population are resistant to infection due to having effective antibodies that the infection cannot easily spread. This is how epidemics or pandemics burn themselves out – eventually enough people have already been infected and are resistant that the virus cannot find receptive hosts and stops spreading. The percent of the population with resistance needed to achieve herd immunity varies with each type of infection, and can be as high as 90+%. Here are some of the unknowns with COVID-19.

Do people who get infected develop neutralizing antibodies with sufficient activity to resist reinfection?

How severe an illness is required to develop these antibodies? Is a mild or asymptomatic infection enough?

Do these antibodies prevent reinfection alone or do they also prevent passing the virus on to others, even if the host does not get sick themselves?

How long do these antibodies last?

Continue Reading »

As the pandemic goes into its 5th month in the US it’s important that we do not suffer from pandemic fatigue. As I wrote previously, this is a marathon, not a sprint. In the US all indications are that we are failing, miserably. As of right now the world has suffered 13.7 million cases of COVID-19 and 587,000 deaths. The US has had almost 3.5 million of those cases, and 137,000 deaths. These numbers are certainly underestimates. While most other industrialized nations are winding down their cases and safely returning to life as normal, cases continue to rise in the US and are spiking in some states.

The bright side of this story is the massive scientific effort to study this virus and understand how to prevent and treat it. The science has been steadily progressing, and it is now clear what we need to do to stop the pandemic. All that is required is political will. Here are some very recent studies that reinforce what we now know.

First – masks work. They really do.  They protect the wearer a little bit, and they protect other people a lot. This is because the virus is spread mostly in small droplets of fluid that are directly spread from one person to another. When you talk to someone, you are spraying them with these tiny droplets. When you wear a mask, this is mostly blocked. To add to the data that masks work, a recent study looked at infection rates among health care workers at MGB hospital. They found a dramatic decrease in infection rate once universal mask wearing was mandated.

The pushback against maskwearing seems particularly irrational. We are in the middle of a deadly pandemic. Wearing a mask is a small sacrifice that is a courtesy to those around you, mostly to minimize the chance that you infect them. Not wearing a mask is essentially a choice that your personal liberty is so important, you won’t bring yourself to take a small measure that will reduce the chance that you kill other people with your germs and perpetuate the broader pandemic.

Continue Reading »

The graph, by itself, tells much of the story. We are still in the first wave of COVID-19, but the US is seeing a second hump to that wave. We are having the highest number of new cases right now, five months into this pandemic. A few months ago we hoped that by July we would start to see the tail end of this first wave, while we anxiously await a possible second wave in the fall, but instead we are seeing a surge. What is happening?

It’s always challenging to clearly see what is going when we are still in the middle of this pandemic, and our information is always a couple of weeks behind reality. But infectious disease experts and epidemiologists are seeing some patterns and are all expressing the same concerns. First, part of what we are seeing is just the natural course of this pandemic. In the US it largely started in urban centers with airports. NY had multiple introductions of the virus from Europe, for example. For this reason they were hit early and hard, while rural America was largely unscathed.

But the wave has moved through those urban centers into the rest of the US. Part of the problem is that, if you look at pooled US data it looked in May and into June that the death toll was declining and new cases were also declining. This created the false impression that, as a country, we were seeing the end of the first wave and we could start opening up. Plus there were legitimate concerns about the effect on the economy of prolonged shutdown, and understandably people were getting lockdown fatigue. But the total US numbers did not tell the full story. In April, as total US numbers started to go down, if you just removed New York from the data the rest of the 49 states were still going up. New York City, which was hit very early, was distorting the data. In May and June all you had to do was remove NY, CT, NJ, and MA from the data, and the other 46 states were increasing. But the illusion that the first wave was winding down had its effect.

Continue Reading »

A study by Russian researcher purports to find that a treatment, Impaza, increases penis length during copulation in rats, while the water placebo group and sildenafil (Viagra) did not. The authors conclude: “This effect, together with an absence of motivational actions, suggests that Impaza may be the most valuable treatment for erectile dysfunction.” The study was originally published in the International Journal of Impotence Research, but was later retracted by the editors. The primary reason for the retraction is that the editors discovered that Impaza is a homeopathic product, something that was apparently missed on initial peer review.

This is definitely an editorial fail, but at least it was quickly corrected. To put the failure in context, however, Impaza was not presented as homeopathic, but rather as a “release-active antibody-based” drug. This is code in Russia, apparently, to disguise the homeopathic nature of certain products. It is not uncommon in pseudoscience for proponents to come up with scientific sounding euphemisms for their nonsense in order to hide from the negative association with charlatans and quacks.

Editors and reviewers, however, need to dig deep enough to uncover such pseudoscience. At the very least there was a lack of curiosity on the part of the editors, and insufficient vigilance against the intrusion of pseudoscience.

Continue Reading »