Tuesday, September 22, 2020

Fauci and Galileo

On April 12, 1633, the chief inquisitor appointed by Pope Urban VIII began the inquisition of physicist and astronomer Galileo Galilei. Galileo was ordered to turn himself in to the Holy Office to begin trial for holding the belief that the Earth revolves around the sun, which was deemed heretical by the Catholic Church. The Church had decided that the idea that the sun moved around the earth was an absolute fact of scripture that could not be disputed, even though scientists had known for centuries that the Earth was not the center of the universe. On June 22, 1633, the Church handed down the following order: “We pronounce, judge, and declare, that you, the said Galileo… have rendered yourself vehemently suspected by this Holy Office of heresy, that is, of having believed and held the doctrine (which is false and contrary to the Holy and Divine Scriptures) that the sun is the center of the world, and that it does not move from east to west, and that the earth does move, and is not the center of the world.” Galileo agreed not to teach the heresy anymore and spent the rest of his life under house arrest. It took more than 300 years for the Church to admit that Galileo was right and to clear his name of heresy.

Almost 400 years later, are we any better? Any smarter? Or is science still subservient to faith?

Science should be a powerful and positive force in society; it shapes the present, and it can guide our future. Politicians and policy makers should rely on validated research at critical moments of crises and emergencies to help guide their actions. Instead, what we have seen since the start of the Covid-19 crisis is shockingly close to Galileo’s treatment by the Catholic Church of the 17th Century.

By late February, many scientists were predicting hundreds of thousands of American deaths if strong measures were not taken but they were drowned out by Trump’s insistence that the virus would “disappear” mysteriously. The mainstream media deserves condemnation by reporting the fantasies of politicians as having equal weight to the opinions of epidemiologists. Highly opinionated politicians had their rhetoric amplified by social media. Wearing a mask to slow the spread of the virus has become a political stance instead of a scientifically proven way to protect others (and ourselves).

More recently, we have had the spectacle of CDC guidance about testing people exposed to the virus but without symptoms removed (and later restored) because Trump did not want numbers to look bad. This was done despite overwhelming evidence that asymptomatic carriers were a major source of spread. Guidance on how to safely open schools was redacted and edited to push for more school openings regardless of health consequences. The FDA gave “emergency use” approval of hydroxychloroquine to treat Covid-19 based largely on rantings by Trump and Peter Navarro, an economist by training, who insisted he knew more about the science than medical scientists. This was, again, removed when studies showed the drug did no good and might do harm.

The latest blurring of science and faith came when the CDC posted information about respiratory spread of the coronavirus, only to remove the post a day later – clearly because the information in the post did not gibe with large indoor rallies or rapid reopening of all businesses.

Case reporting was taken away from the CDC so that the numbers could be massaged to look better. Most recently we have had Alex Azar, the Secretary of HEW, insisting that he alone could sign off on any new rules, regardless of the opinions of the career scientists who were much more qualified to do this.

Anthony Fauci, America’s most esteemed virologist, who refused to kowtow to every Trump pronouncement, has been subjected to harassment and character assassination by Trump and by his right-wing media enablers.

Science does not have all the answers. Some decisions are inherently political. A 55 MPH national speed limit would probably cut deaths and would cut some greenhouse gases, but it would be widely flouted and may not be politically acceptable. Similarly, a total economic shutdown might be estimated to potentially save X deaths over the rest of the year but might be economically intolerable. What should happen is that politicians take advice from scientists, weigh the competing factors, and decide what is best for the country.

What, alas, is happening is that politicians ignore scientists and make decisions based on what they think will help them be re-elected. Vote for science. The life you save may be your own.

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Saturday, September 12, 2020

Coronavirus vaccines: ready for prime time?

When will we have a vaccine? Can life get back to normal when we have a vaccine? Questions like this have been in the news almost daily. The underlying questions of most interest to the public can be expressed as “when will a safe and effective vaccine be available to me and my family?” and “will the availability of a vaccine allow normal life to resume?”

Vaccine availability will not fail for lack of trying! Vaccine development is usually a back-page issue, and not a high priority to the pharmaceutical industry because profits from sale of vaccines lag well behind those of most pharmaceutical products. With the world’s attention so focused, we now have 38 vaccines against Covid-19 in clinical trials in humans and another 90+ that are in animal trials.

If you are a regular reader of these posts, you know that I consider vaccines to be the most important public health development in medical history. Prevention is always better than treatment, and vaccines have saved many millions of lives over the 225 years since Jenner’s first experiment.
What may be confusing to many is the different approaches that different researchers and companies are taking to making vaccines. Traditionally, vaccination has taken one of two forms: give people a mild illness that is close enough to a serious one that they build up their immunity to the serious one – Jenner’s approach in 1796 – or inject people with killed virus or virus particles that also lead to an immune response without getting sick – the standard approach with influenza vaccines. A major problem with the latter approach is that it is very slow, growing virus in egg cultures before destroying the virus and using it to make vaccines.

Current vaccination research is much more “cutting edge.” Genetic engineering techniques are being used; “viral vectors” are being tested: putting bits of Covid-19 RNA into harmless adenoviruses which infect human cells and produce an antibody response; getting various Covid proteins, including the spike protein, into such vectors. The many approaches taken reflect our inability to know which is most likely to work (as well as companies’ need to have their own unique product!).

As to the “when,” the issue is not developing a candidate but proving that it is both effective and safe. An effective vaccine not only results in recipients developing antibodies, which is easy to measure, but prevents disease in exposed individuals, which is much harder. There is still much we do not know about the body’s response to Covid-19; a clear worry is that people can get repeated colds, many of which are caused by other coronaviruses, so it is not clear that exposure always results in immunity. In my practice, I observed that first or second year teachers seemed to be sick all winter, but that veteran teachers rarely got colds. Perhaps we need repeated exposures to coronaviruses before our immune system can fight them off?

While vaccines in general are very safe (please don’t get me started on the “anti-vax” movement!), vaccines developed and deployed too quickly have been problematic. This can reflect poor manufacturing practices: in the 1950’s a polio vaccine manufactured by Cutter Labs intended to contain inactivated polio virus mistakenly had some batches with live virus.

In the late 1990’s the FDA halted use of a vaccine against rotavirus, a potentially fatal diarrheal illness of children, when it appeared to cause bowel obstruction, and it was eight years before a safe rotavirus vaccine was approved. The complication was rare, and so was only found after the vaccine was in widespread use.

Rushing a vaccine into use is a serious risk. Faced with predictions of a swine flu pandemic in 1976, President Ford launched a huge effort to develop and distribute a vaccine against swine flu, but the flu was less serious than predicted and some 450 people who got the vaccine developed a rare form of paralysis.

How do you develop and test a vaccine to be sure it is both effective and safe? You do not cut corners!

The first step is testing in laboratories, first in cells and then in animals. Initial human testing, Phase 1, is done in small numbers of healthy volunteers to be sure the vaccine results in an immune response and does not have obvious safety issues. In larger, Phase 2 trials, the vaccine is given to hundreds of people, generally including both children, young adults and the elderly, to see if it acts differently in different groups and to watch for obvious safety issues. If these small samples do not raise any concerns, the vaccine moves into Phase 3, in which thousands of volunteers are given either the vaccine or a placebo. These trials must show that many fewer people receiving the vaccine get sick than do those given placebo. They are also watched carefully for any less common side effects that did not appear in the early phase trials.

Only when the results of Phase 3 trials show that a vaccine is both effective and safe should it be approved. The vaccines developed in China and Russia that were rushed into production without results of Phase 3 trials may have serious risks and/or may not work.

My big worry is that a beleaguered FDA, which we have already seen respond to political pressure and approve hydroxychloroquine for Covid-19 only to later rescind that approval, will bow to political pressure and approve a coronavirus vaccine before Phase 3 trials have been completed. Hopefully the manufacturers, wary of lawsuits, will be the regulating force that our regulators should be.

A truly effective and safe Covid-19 vaccine is badly needed and will be welcomed, but “warp speed” is better left to the ships of Star Trek than to public health.

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Monday, September 7, 2020

What is the truth about marijuana?

Other than alcohol, marijuana (cannabis) is the most commonly used drug in the United States. Some 39 million Americans, 12% of the population, use marijuana at least occasionally. While clearly more commonly used by adolescents and young adults, in 2018 4% of adults over 65 admitted to using it within the prior 30 days.

In the United States, the use and possession of marijuana is illegal under federal law for any purpose, by way of the Controlled Substances Act of 1970. Under the CSA, cannabis is classified as a “Schedule I” substance, right up there with heroin and methamphetamine, determined to have a high potential for abuse and no accepted medical use – thereby prohibiting even medical use of the drug. At the state level, however, policies regarding the use of cannabis vary greatly, and in many states conflict significantly with federal law. As of 2020, medical use of marijuana is legal in 33 states and the District of Columbia, and recreational use is legal in 11 more states.

What are the benefits of marijuana? What are the harms? To a large degree, we simply do not know. Marijuana is not a single substance; the plant contains at least 500 chemical substances. The best known and studied are cannabidiol (CBD) which I wrote on recently and delta-9-tetrahydrocannabinol (THC). It is THC that has the CNS (brain) effects. Because of the federal classification of cannabis, much less research has been done than should be, and much of what you read is low quality. Many of the reputed benefits and harms arise from studying people who admit or deny use. Since use was until recently a criminal offense, self-reporting is likely to be unreliable. There is also the confounding factor of whether people who do or do not use marijuana are otherwise the same. Many of the studies claiming adverse effects on intellect are of this variety and not necessarily valid.

Another confounding factor is that the THC content of marijuana, at least that seized by the DEA, the federal Drug Enforcement Agency, has been going steadily and dramatically higher. In 1995, the average concentration of THC in seized products was 4%; in 2014 it was 12% - this is not the pot of the 1960’s!

The human brain has cannabinoid receptors, which mediate the psychoactive effects of cannabis. There are other receptors in immune cells and other tissues that may be more targeted by CBD. Acutely, the effect of THC is the “high:” euphoria, relaxation, altered sensations – and also: decreased processing speed, attention and reality testing. “Tolerance” develops quickly as the receptors are down regulated, so that daily use results in much less response.

Proven benefits of THC are limited. It has some benefit in preventing chemotherapy-related nausea and improves the appetite in many people with wasting disease such as AIDS. While it has been “approved” for pain relief in states where medical marijuana is legal, its benefits beyond those of prescription and OTC pain relievers are modest.

The headlines were dominated in August by a statement from the American Heart Association which stated that cannabis had no cardiovascular benefits but did have adverse CV effects, including arrhythmias and heart attacks. Critics noted that most of the adverse effects were anecdotes and case reports.

Inhaled marijuana products can have the same adverse effects as smoking any product. Before Covid-19, when vaping-relating lung disease was our biggest public health concern, it appeared that vaping cannabis products was particularly dangerous.

Bottom line? Cannabis is not a miracle drug. It is probably no worse than alcohol. (I have never heard of an angry belligerent pot user.) It can clearly impair your ability to safely drive or operate machinery. If you feel it helps your migraine or other painful condition, use it, but use it cautiously, as it is habit-forming.

Until we know more about its effects on the developing brain, I would actively discourage use by adolescents, as I do for alcohol.

More quality scientific study is needed and would be encouraged by moving cannabis out of Schedule I by the DEA.

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Thursday, August 27, 2020

Lies, damn lies and statistics

This was going to be a post about THC, but the recent dust-up over the FDA’s emergency approval of convalescent plasma to treat Covid-19 has encouraged me to deal with this subject as a more pressing topic. We are going to discuss the use of statistics in medicine. While I know that sounds dull, trust me, it is important to all of us, not just to doctors.

Picture this. 100 people come to my clinic complaining of fever and a cough. All hundred test positive for Covid-19. I give all of them a secret potion made with ground up dried newt, sunflower seeds and some CBD. A month later, 95 have recovered completely, 3 are still in hospital but recovering and two have died. I call a press conference and announce that my remedy has a 98% cure rate and should be widely used.

Do you accept my claim? I hope not! As Groucho Marx said when asked “How’s your wife:” “compared to what?” If you have followed this evolving story, the death rate among people with Covid-19 who have symptoms is estimated to be somewhere between 1 and 2%, with a huge variation dependent on age and ethnicity. Young Caucasians have a death rate well under 1% while octogenarians have a mortality well over 10%. Thus, to make any sense about my claimed “cure,” you must first ask for a breakdown of the ages and ethnicities of those I treated. If they were all white college students, chances are my remedy killed rather than cured. If they were all elderly Blacks, there may be something that warrants further study. Finally, no matter what the demographic breakdown, the most important question of all, is how my remedy compared to other available treatments.

This brings up the idea of the controlled clinical trial. There is a well-known aphorism in science: the plural of anecdote is not data. Medicine is full of “accepted” treatments that were proven worthless, and the fact that a patient improved after a treatment does not always mean they recovered because of the treatment. They may have recovered despite the treatment, which actually made some patients worse, or would have recovered with no treatment.

The current gold standard in deciding whether one treatment is better than another is the controlled trial. A large group of patients are randomly given treatment A or B; neither the patients nor the doctors know which they are given. After an appropriate amount of time, the pre-specified outcome is compared between the two groups. The outcome chosen is crucial: ideally, it is both important and clear. I always look first at death rate – whether one is alive is obviously important, and it is also very clear; you don’t need a committee to decide if a patient is alive (as you do in many reported outcomes).

When the trial is reported, the researchers will describe the difference and will usually indicate whether it is “statistically significant,” using a P value. This is simply the odds that the outcome was due to a real difference between the treatments or simply by chance. If you flip a coin and it comes up heads three times in a row, this does not mean the coin is unbalanced. Every time you flip a balanced coin, there is a 50% chance it will be heads, so getting heads three times in a row is not surprising. If you get heads 20 times in a row, you should be suspicious that there is something unusual about the coin. Hence, when a study reports a difference, they indicate the likelihood the account was due to chance. A “P less than .05” simply means that there is less than a 5% chance the difference was due to chance. Note that this is not a guarantee the results were valid.

Also important, and particularly relevant to Covid treatments these days, is whether the results are presented as relative or absolute differences. Drugs companies, not surprisingly, tend to emphasize relative differences, which are usually larger. Let’s say that 40% of patients with a very nasty disease are dead in year without treatment, while with treatment A, 25% die and with treatment B, 22% die. The honest way of presenting this would be to say that 3 out 100 more patients lived with B than A. A marketer would rather say that the death rate was reduced by 12% (22 compared to 25).

The Mayo Covid study had several issues limiting its value for making life-and-death decisions. Most important, the study was observational, not controlled. There was no group given an alternative (or only supportive care). No attempt was made to select who got serum with different amounts of antibody. They followed a large group of patients who were given plasma and compared those who received transfusions within three days of the diagnosis with those transfused four or more days after. They also compared those who received higher, medium or lower amounts of antibody in the plasma they happened to receive.

My focus was on the death rate at 30 days (a “hard” end-point – good). Those transfused earlier had a 21.6% death rate; those who got the plasma later had a 26.7% death rate. Thus, the absolute difference was 5% - possibly important if verified by better studies, but not the “35% reduced death rate” put out to the media. The latter figure came from comparing death rates at 7 days between those who received very high dose of antibodies (8.9%) and those who received very low levels (13.7%), a difference that was less at 30 days. There was no way to prove the groups were the same.

Does convalescent plasma help patients with severe Covid-19 survive? I think the only honest conclusion one can reach is “Maybe.” It is biologically plausible. The observations reported are consistent with a possible benefit, but better designed trials are clearly needed before this can be considered of proven benefit.

What I do know is that the FDA, which is supposed to be our defense against allowing ineffective and/or dangerous medications to be marketed, has increasingly made decisions based on political pressure rather than science.

This goes hand in hand with the Trump administration’s directive to the CDC to change its testing guidelines to discourage testing of asymptomatic Covid contacts, a decision that is opposed by almost every expert in the field. Fewer tests may lead to fewer reported cases but will lead to wider spread and more deaths.

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Monday, August 24, 2020

CBD: salve or snake oil?

Cannabidiol (CBD) products are everywhere, in products ranging from bath salts to dog treats, and touted as remedies for just about every ailment. What are they? Do they do any good? Are they safe?

Cannabis sativa, better known as marijuana, is an annual flowering plant that contains over 100 identified compounds. The best known is tetrahydrocannabinol, or THC, which is responsible for the psychoactive effects of marijuana, the euphoria or “high.” Another well-known component is CBD. Unlike THC, CBD does not make users high, but is promoted to reduce pain, ease anxiety and give better sleep.

Commercial use of CBD has exploded, on-line and through herbal and health-food sales outlets. Sales through these sources in 2018 totaled $52.7 million, over triple the amount sold in 2017, and replaced turmeric as the top-selling product of these companies.

What do we know about its benefits? There is an FDA-approved drug (Epidiole) used to treat two rare seizure disorders in children. Every other promoted use has scant evidence behind it. While there have been hundreds of papers published about CBD, most studies have been small and usually without good research design. Moreover, a study published earlier this year in The Annals of Internal Medicine found that a large majority of the authors of articles promoting CBD use had close ties to the CBD industry, raising obvious questions about conflict of interest.

Is CBD safe? A huge problem is the lack of oversight of what you are getting, since CBD is sold as a “supplement” rather than a medication, thus removing FDA regulation. CannaSafe, a California cannabis testing lab, recently analyzed 20 popular CBD products and found that only three of the twenty contained what their labels claimed. Eight contained less than 20% of the amount of CBD on the label, and two contained none. Some of the products were found to contain high levels of poisonous solvents.

CBD can interfere with the way your body deals with many prescription drugs, so if you are using it and are on any medication, be sure to tell your doctor. It can also adversely affect the liver, even when not tainted.

If you want to use one of these products, be sure they are EPA-certified Organic, as this will lessen the chances of chemical contamination. You might also want to get products from Europe, where they are much more closely regulated.

Does CBD do any good? It is unclear at this time, but probably not. The limited studies done to date by legitimate researchers relate in part to the DEA's insistence that marijuana is a "class I" substance, putting it up there with heroin and methamphetamine, even though alcohol would probably be a better analogy. Some very preliminary studies needed to be expanded.

Is CBD safe? Possibly, given the comments above, but caveat emptor.

Next time, let’s look at THC.

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Sunday, August 16, 2020

How to avoid the bite

While lions and tigers and bears (Oh my!) may be fearsome predators, humankind is at much more risk from critters at the other end of the size scale: mosquitos and ticks! World-wide, malaria, carried by anopheles mosquitos, caused 228,000,000 cases and 405,000 deaths in 2018. While malaria has been largely banished in North America, mosquitos also carry the viruses causing Eastern Equine Encephalitis, Zika, West Nile, Dengue and chikungunya: diseases that are serious and often fatal.

Ticks carry Lyme disease, Babesiosis and Rocky Mountain spotted fever among others. Since many of these illnesses have no treatment, prevention is key. Prevention means not getting bitten by mosquitos and ticks. Is this possible? Yes, by using a combination of simple measures: avoidance and deterrence.

Mosquitos tend to be most active feeding between dusk and dawn, so when mosquito-borne illnesses are around, it is wisest to avoid being outdoors at that time. Barbecues at noon are lower risk; barbecues at 7 PM much higher, so have the friends over in the afternoon, not the evening. Drain any pools of free-standing water (where mosquitos breed) – and do not forget such mosquito havens as gutters. Be sure your screens are in good repair and fit snugly. If you use window air conditioners, be sure to seal around them.

Clothing can be protective: do not walk barefoot through the grass, where ticks are lurking and ready to latch on. Wear long pants and long-sleeve shirts when mosquitos are around.

Finally: use effective repellants. The news media recently carried banner stories about a new “natural” insect repellant, nootkatone, found in minute quantities in grapefruit skin and Alaska yellow cedar trees. You had to read the small print to learn that while it has been approved, it will not be commercially available until 2022. Until then, several effective products are widely available.

Best known is DEET (dimethyl-m-toluamide), available in lotions, sprays and wipes. While DEET products can contain from 5% to 99% of the active ingredient, at least 20% is recommended, and concentrations above 50% add little. DEET can cause skin irritation, but is generally very safe, and can be used on children and infants over 3 months.

An alternative product with similar efficacy is picaridin, available in concentrations of 5-20%. 10% is a good compromise and is safe for children.

A slightly less effective product is IR3535. Be careful to get a product that has 20% concentration; the 7.5% product has been found ineffective.

For those inclined to “natural” products, there is oil of lemon eucalyptus (whose products often use the word Botanicals in the name). It is somewhat more likely than the others to cause skin irritation and should not be used on children under 3.

Citronella oil-based products are less effective and are not recommended unless nothing else is available.

Finally, consider use of permethrin on clothing and footwear. It kills mosquitos and ticks on contact. You can spray it on not only clothing, but on tents, sleeping bags and mosquito nets. Permethrin-impregnated clothing is commercially available and remains active for several weeks, though multiple launderings.

While you may see wearables such as wrist bands with insect repellants, none of these are of much benefit.

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Sunday, August 2, 2020

Sunscreens: are they harmful?

Ah, summer. Beaches, swimming, sailing, outdoor parties, skin cancer.

Wonderful as it is to be outdoors in the sun, there is a potential price to pay. In addition to the visible sunshine and heat we get from the sun, we also get ultraviolet (UV) rays, that are damaging to our skin. There are at least three forms of UV light: A, B and C. All the UVC rays, with the shortest wavelength and which are the most damaging, are absorbed by earth’s ozone layer, as are many of the UVB rays, but most of the UVA and some of the UVB rays reach us. UVB rays on our skin have the valuable function of producing Vitamin D from precursors, so people who avoid all sun may need to take supplements to avoid becoming deficient in D.

UVA and B cause sunburns and are a major risk factor for melanoma and other skin cancers in fair-skinned populations. Some 60,000 people world-wide die of melanoma every year. Not surprisingly, Australia and New Zealand (with large majority Caucasian residents and a lot of outdoor activities) lead the world in melanoma cases per 100,000 people. Next in line are the Nordic countries – presumably because they are the fairest of the fair-skinned peoples. People of African and South Asian descent are much less susceptible to this risk. Melanin is the body’s protection against UV rays, and dark-skinned individuals have more melanin in their skin.

“Suntan lotions” with little UV protection may allow one to get a tan without as much risk of burning, but they offer almost no protection against skin cancer (nor the cosmetic effects of prolonged sun exposure: wrinkles and leathery skin years later).

Enter sunscreens. These come labelled with SPFs (skin protection factors). This number is an estimate of how much longer you can be in the sun without burning; if you would get a burn after 30 minutes in the sun, then a lotion with an SPF of 6 would let you be in the sun for 3 hours before you burned. Most dermatologists recommend using a lotion with an SPF of at least 30 to prevent skin cancer down the road.

One concern is whether habitual use of sunscreens might lead to Vitamin D deficiency, but this does not appear to happen based on recent research.

There has been a lot of press recently about another potential risk. Sunscreens may include organic and inorganic filters. Inorganic filters such as titanium dioxide and zinc oxide physically reflect UV rays away from the skin and are clearly safe. Organic filters, too many to list, absorb UV radiation and are the most widely used because they are colorless. Two trials conducted by the FDA found that “normal” application of sunscreens led to measurable levels of these compounds in the blood of people who used them. The FDA was careful to point out that this was not a reason to stop using them, but simply a call for more research.

If the news stories have you worried, what should you do? I would strongly recommend you not stop protecting your skin. There is no current evidence that the compounds have any harmful effects and any theoretical worries must be balanced against the known carcinogenic effects of the sun’s UV rays.

One obvious step is to use physical barriers: dark umbrellas block most of the UV rays, as does most clothing: denim, nylon and polyester (but less so cotton). If media reports have you worried about sunblock, use zinc or titanium-based products, which the FDA considers totally safe. If you consider those unsightly, use the organic-based products; their “hazards” are conjecture and their benefits proven.

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