Thursday, October 29, 2020

Virtual visits

One of the myriad ways that Covid-19 has changed our lives is the explosion in “telemedicine.” As hospitals, clinics and doctors’ offices shut down for non-critical illness visits, many shifted quickly to the use of “virtual” visits: visits done by connecting patients to their doctors and nurses via computer. While this has been done on a small scale for several years, most insurance plans had limited coverage for virtual visits, a major stumbling block to having them widely used in a revenue-driven fee for service environment. Medicare and most commercial insurers rapidly offered to cover these visits as the pandemic unfolded, and their use expanded 100-fold during the spring and summer.

Somewhat to their surprise, most patients found virtual visits to be satisfactory. It is obvious that for mental health visits, just as much can be done via remote communication as in person. Neither psychiatrists nor other mental health professionals normally do anything other than talk or listen. For other types of care, a virtual visit can be less than ideal. A good quality smart phone can allow the doctor to see a rash, but not to listen to the heart and lungs or feel an abdomen. As I noted in a prior post, the large majority of the information needed to make a diagnosis comes from a patient’s history – and this is done as well virtually as in person.

Advantages that have turned many patients into supporters of virtual visits include convenience and cost. Rarely does a patient with a 10 AM visit get seen at 10 – and cooling your heels in a waiting room is not high on most of our lists of favorite things to do. In-person visits also involve driving and parking (or taking public transportation), which add considerable time and often expense to the visit.

Doctors who were skeptics have widely come to accept this type of visit as well – having a patient seen conveniently and comfortably makes for a happier patient.

Are virtual visits for everyone? Almost certainly not. Specialties in which most of the data can be conveyed verbally will certainly continue to do this type of visit much more than those requiring high touch. A follow-up visit for diabetes revolves around reviewing test results and symptoms and is an easy one to do virtually. A visit for congestive heart failure requires much more physical examination and would be much harder to conduct via teleconferencing.

Another problem is access. Recent surveys found that 13% of the population, some 42 million people, do not have high speed internet access. Beyond that, many people do not have the technical skills to feel comfortable doing virtual visits, and these people are predominantly elderly and/or from minority communities that are already underserved. 25-30% of Medicare recipients and people with household incomes below $30,000/year lack both smart phones and high-speed Internet. An alternative for these people is the good old-fashioned telephone. This loses the ability to see facial expressions and other visual clues, but still allows for two-way communication “in real time,” which email does not provide.

Clearly virtual visits, no matter how high-tech, cannot (and should not) replace all in-person visits. Along with the inability to do more than a rudimentary physical exam, at a virtual visit one cannot give vaccinations or do procedures. Lab tests may be needed and require an in-person visit somewhere.

Our forced conversion to virtual visits in these uncertain times has, however, shown us that this is often a valuable addition to the medical care armamentarium. I think it is here to stay.


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Saturday, October 17, 2020

Public health: what is it? Why should I care about it?

Clinical medicine is very much a one-on-one interaction. A doctor will sit with a patient to make a diagnosis and/or discuss treatment. A nurse will sit with a patient with newly diagnosed diabetes and teach them how to manage their insulin. Even very complex medical interactions such as major surgery may involve multiple professionals but only one patient. Very rarely in clinical medicine is the health of the broad community considered. Public health comes at health problems from the opposite perspective: the health of populations: local, national or world-wide.

John Snow, M.D. (1813--1858), a legendary figure in epidemiology, provided one of the earliest examples of using epidemiologic methods to identify risk for disease and recommend preventive action. Snow had an interest in cholera and supported the unpopular theory that cholera was transmitted by water rather than through “miasma” (i.e., bad air).

On August 31, 1854, London experienced a recurrent epidemic of cholera; Snow suspected water from the Broad Street pump as the source of disease. To test his theory, Snow reviewed death records of area residents who died from cholera and interviewed household members, documenting that most deceased persons had lived near and had drunk water from the pump. Snow presented his findings to community leaders, and the pump handle was removed on September 8, 1854. Removal of the handle prevented additional cholera deaths, supporting Snow's theory that cholera was a waterborne, contagious disease. This became a model for modern epidemiology.

Because communities, rather than individuals, benefit from public health, it must be taxpayer-supported, and this is its Achilles heel. Whether you believe, as I do, that medical care is a basic human right, or that it is just another service that people should be prepared to pay for, needed medical services are usually provided and charged for. Those without or with poor insurance may be bankrupted, but they usually get the services they need. As a taxpayer-funded activity, public health must compete with myriad other demands for public funds, and since its successes are usually invisible, it does not have the same constituent pressure that do police, fire or public works.

At the local level, public health staff work to make sure restaurants are serving sanitary food; unless you have suffered from a food-borne illness caught at a restaurant, the need for this surveillance is probably not high on your radar. The very success of disease prevention makes it less visible. At the national and international level, public health agencies should protect us from major disease outbreaks such a Covid-19, or at least limit the damage. Again, since pandemics are thankfully rare events, it is easy for governments to cut the funding of public health agencies without much pushback from the citizenry.

A huge problem at the national level is the conflict between politics and science. We saw this early on in China, when Wuhan authorities tried to hide the emergence of the novel coronavirus. We saw it in spades in the United States when the warnings of the lead scientists at the renowned CDC (Communicable Disease Center) were ignored by Trump and his administration because their advice to slow down economic activity did not fit with his desire for a booming economy. We saw it in the wholesale rewriting of various CDC guidelines when they did not fit the narrative that Trump wanted to present.

The United States should have been among the countries best prepared to deal with Covid-19: our hospitals are first rate, our financial resources are more than adequate, and we have the world’s leading agency in dealing with disease outbreaks. We did not have adequate stockpiles of things like ventilators and personal protective equipment, because carrying rarely used inventory was bad for a hospital’s “bottom line,” and because other needs for public funds were given higher priority. What we also lacked, and still lack, is public trust in the government, a factor made worse by the actions of Trump and his enablers.

Countries such as Taiwan, Korea and Canada, all of which have performed much better than did we, had credible spokespeople, a consistent message, and a public inclined to listen. We thus find ourselves with 4% of the world’s population but 25% of the world’s Covid-19 cases and are among the top 10 in per capita deaths. Covid-19 will eventually be tamed, through some combination of vaccines, better treatments and eventual “herd immunity.” Unfortunately, the next pandemic is almost certainly brewing in some animal species, ready to make the jump to humans. NOW is the time to ensure that we do better next time. Public health must be adequately funded, and scientists must be allowed to have a leading voice (though not the only voice) in making public health policy.


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Wednesday, September 30, 2020

The Physical Exam: The next dodo?

Most experts who have looked at the relative value of the medical history, the physical examination and the findings of laboratory tests and imaging studies have come to the same broad conclusion. The medical history is by far the most important contributor to an accurate diagnosis; some 60 to 80% of the time, the history alone leads to the correct diagnosis. The physical exam generally contributes 12-20% of the needed information and laboratory/imaging results 10-20%. Both the physical exam and test results do increase practitioners’ confidence level that their diagnosis is correct.

You would thus expect that physicians would spend a lot of time taking a careful history and devote roughly equal time to doing a comprehensive physical exam and ordering and reviewing lab tests.

Alas, over the last few years my observations while accompanying friends and family members to medical appointments has been just the opposite. History taking is brief and appears to be largely devoted to “checking off” items such as smoking history and medications that are needed to complete the electronic chart. When patients start to tell their stories, the doctor typically interrupts in less than a minute.

As to the physical exam, it is charitable to call most I have witnessed cursory. Well-defined problems do not need a complete physical exam; if you are complaining of a sore throat, the doctor generally needs only check the inside of your mouth and your neck. Less well-defined problems such as weight loss or fatigue may need a classic head-to-toe exam. Even seemingly localized problems may need more than the obvious. Could your sore throat be mono? If so, checking for an enlarged spleen may be very useful.

You would expect hospital admission, reserved for the sickest patients, to require a thorough physical exam, as it was “in the old days.” What seems to pass for a complete physical these days seems to be listening to the heart and lungs and quickly feeling the upper abdomen. Rarely if ever do admitting doctors check the head and neck, and almost never is a breast or rectal exam done.

Instead the focus is on testing: “routine” blood work that gives little information and advanced imaging. The head echocardiography technician at a hospital where I worked once joked to me that the main reason residents ordered echocardiograms was that “the patient has a heart.” When ordered to follow up on a suspected diagnosis, imaging can be very useful; when ordered in a shotgun manner, it is equally likely to produce confusion and misinformation.

Patients, too, place more faith in CT scans and MRIs than in a good “H+P” (history and physical). That faith can be misplaced. Take back pain as a good example. Most people over 40 and almost everyone over 60 will have some abnormality when imaging is done of the spine. This includes people who have never had a backache in their life. All-too-often I have seen patients with muscular or arthritic back pain taken to surgery to fix an abnormality seen on a CT scan, and of course they were not benefitted in the least. A good H+P should strongly suggest the likelihood of a surgically curable source of back pain, and imaging can then confirm it, but the surgeon “who will not see me without a CT scan” is practicing poor quality medicine.

Worried about too much X-ray exposure? A recent study found that if you go to the Emergency Department with pain in your left lower abdomen, a simple combination of findings (absence of vomiting, presence of a fever and tenderness when the doctor presses on your abdomen that is only found in the lower left portion) makes a diagnosis of diverticulitis so accurately that a CT scan is not needed unless the doctor is worried about complications.

Let us not let the clinical exam, and in particular the physical, follow the dodo into extinction. Good history-taking skills and physical exam skills must be taught, and their use rewarded. We will see better results and lower costs.

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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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Monday, July 27, 2020

Sick while black: an unhealthy combination

The Covid-19 crisis has highlighted many of the failings of the U.S. healthcare system, including the racial disparities that have always been present. If you have followed the news, you are aware that African Americans and Hispanic Americans have suffered more from Covid-19 than their white fellow citizens. In Chicago, where blacks make up 30% of the population, they make up 50% of Covid-19 cases and nearly 70% of the deaths. Similar statistics are found throughout the country. Part of the reason that blacks have suffered disproportionately is due to social and economic factors: blacks are more likely to live in crowded housing, which increases disease spread; they are more likely to depend on crowded public transportation, where “social distancing” is difficult or impossible; they are more likely to work in low-paid occupations considered essential which cannot be done from home. African Americans also suffer more from the diseases that increase the odds of dying from Covid-19: hypertension, diabetes, obesity and cardiovascular disease.

What you may not realize, however, is that the ravages of Covid-19 are just the icing on the cake of racial disparities. Pregnancy-related deaths, a marker of how well a country’s health care system works, is much higher in the United States than in comparable wealthy countries, even among white women, but is strikingly higher in black women. In countries such as Japan, Australia, France, Germany and Denmark, the number of maternal deaths per 100,000 births ranges from 5 to 8. In the U.S. it is 17 among all women, but in non-Hispanic black women it is 40.8!

Black Americans with cancer, lymphomas and leukemias die sooner than white Americans with the same diseases. Those with lower socioeconomic status, who are disproportionally black, have much more premature coronary disease and die younger of heart disease. Even when they receive “high tech” interventions such as coronary stents, black Americans had higher risk for major cardiovascular events in the years that followed. Black adolescents got fewer flu shots than did white and Hispanic teens.

Hispanic and black Americans are less likely to have a primary care physician, make fewer doctor visits and are less likely to get outpatient mental health care than white Americans. The Affordable Care Act (AKA “Obamacare”) increased access to health insurance for the overall population but benefitted white much more than black Americans. The largest number of Americans get their health insurance from their employers, but small employers are much less likely to offer insurance than large ones, and many blacks work in hazardous low-paying jobs with companies that do not offer many benefits.

What can we do? As the richest major country in the world, we cannot allow any of our citizens to starve or to not have a roof over their heads or die from treatable illnesses. Whether through adopting universal health care, expanding Medicaid or providing a public option for those without employer-based insurance, we must guarantee that everyone has access to basic healthcare.

Since much of an individual’s (and a nation’s) health depends on social factors rather than traditional healthcare, we should strive to see that everyone, white, Hispanic and black, has a living wage and affordable housing and access to healthy foods. New mothers would be less likely to have health issues if the U.S. joined most of the western democracies to mandate paid maternity leave.

We can do better and we must do better. Covid-19 will eventually be behind us, but the health disparities that have been made worse by this pandemic will remain unless we take this opportunity to create a better country for all.

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Thursday, July 16, 2020

It's only natural

It is hard these days to shop for anything, whether at the supermarket, the pharmacy or the beauty shop, without seeing products touted as being “natural.” The term is used even more often than its frequent companion, “organic.” Over the past decade, while total food sales have risen 2%, sales of “natural” food have risen 12% and “organic” foods 15%. Clearly these words sell products, but is it always a good idea to buy a natural product over others? What does “natural” really mean?

When a food is using the USDA-approved label of organic, this does have some specificity. By law, products labelled organic must be grown with no genetically modified ingredients, no irradiation, no antibiotics, no synthetic feeds or pesticides, no hormones and no chemical fertilizers. The contents of a package must be over 95% organic to carry the label. (Note that in many parts of the world, “night soil” is used as fertilizer, and while this is organic, I would prefer not to eat food fertilized with the contents of an outhouse.)

There is no legal definition of “natural.” One is reminded of the line from Lewis Carroll’s book Through the Looking Glass, when Humpty Dumpty says to Alice: “When I use a word, it means just what I choose it to mean—neither more nor less.”

Perhaps because of the lack of a defined meaning, you will see “natural” used on supplements, food products, cosmetics and just about anything else you can buy. Unfortunately, many clearly natural products are dangerous. After all, botulinum toxin is a natural substance, found in nature with no human intervention, but it will paralyze and kill you when ingested. (In micro-doses, botulinum toxin is safely used as Botox.) Many natural products found in marketed “supplements” have dangerous potential. These would include cesium chloride and aconite (heart rhythm problems), lobelia (seizures), kava kava and celandine (liver failure) and germanium (kidney damage). If you are taking a “supplement,” look for these ingredients and toss the tablets if any of these products are in them.

“Natural skin care” has become a multi-billion-dollar market, carving out 25% of the $5.6 billion spent in 2018 on skin care products. “Clean beauty” evangelists such as Gwyneth Paltrow have ignited fear in consumers about using many products such as sulfates, parabens and propylene glycol, not on the basis of facts but by using scary statements such as “do you want antifreeze in your moisturizer?” Dermatologists have pointed out that many of the “natural” products touted are more likely to cause allergic reactions than the products they are replacing. [See JAMA Dermatology, December 2019.] A widely used web site from the Environmental Working Group touts safe skin products, but in many cases gets a percentage of sales from products it deems safe, an obvious conflict of interest.

So, when shopping, remember that just as beauty is in the eye of the beholder, natural is in the claims of the seller, and don’t pay up for something unless there is a good reason to do so.

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Monday, June 22, 2020

Lowering cholesterol? How, why?

This post was suggested by a reader, who had read enough about the coronavirus, and it is a topic that merits attention. Cardiovascular disease remains by far the number one killer in the developed world and is rapidly rising to that spot in the developing world as well, and our ability to prevent heart attacks is in large part related to lowering cholesterol.

The first point to note is that cholesterol is not arsenic – cholesterol is part of normal cells, and no one dies of cholesterol. It has, however, been known for many decades that an elevated level of cholesterol, along with high blood pressure and smoking, increases the risk of developing coronary disease. Norwegian researchers in 1939 described families with abnormally high levels of blood cholesterol and premature heart attacks. This led, beginning in the 1950s, to attempts to lower cholesterol with diet and medication. Most of the medications which were then available, which included nicotinic acid, fibrates and cholestyramine, were not very effective and/or were difficult for people to take for any time, and their use did not reduce the risk of heart attack by a large amount.

A breakthrough in cardiology occurred with the development of the class of drugs technically known as HMG-CoA reductase inhibitors and widely known as “statins.” The first in this class, lovastatin, was discovered in 1978 and first tested in humans in 1980. Multiple similar drugs followed, and we now have seven on the American market. They vary in potency, but all work in a very similar way. The first major trial of using a statin to prevent CV death was conducted in the west of Scotland, among men at high risk of heart attack. Participants were enrolled between 1989 and 1991 and the results of the trial were published in 1995. Those taking the active drug, which in this trial was pravastatin, had about 31% fewer heart attacks, and there was about a 9% reduction in total mortality (from 38.6% to 34.7%) over an extended 20-year follow-up. Multiple later trials, done in lower risk patients, all showed similar results: fewer heart attacks and a trend to lower overall deaths in statin-treated groups.

I do not own stock in any healthcare companies, so have no conflict of interest in stating that the statins as a class are one of the best medicines in our armamentarium. Most are now available generically and are dirt-cheap in the big picture of pharmaceutical products; they are well-tolerated by most people; and have very few bad side effects. There was a flurry of concern a few years back about them contributing to dementia, but this has been disproven by many large studies. They do seem to slightly hasten the onset of diabetes in people prone to it, but the benefit far outweighs the risk.

There is one fly in the ointment: many people develop muscle aches from taking a statin. Only a tiny number have muscle damage (which can be measured with a blood test), and in my opinion if you fall in that tiny number you should never take any statin, but 5-10% complain of muscle aching that goes away when you stop the drug. In some cases, taking a different statin can be done without the problem recurring, but some get the same reaction to every statin they try. What options are available if you are in this group?

The first step is to decide with your doctor if you truly need to have your cholesterol lowered. While statins seem to have a similar relative reduction in heart attack risk in all groups, there is a difference between relative and absolute risk. Let’s say that taking a moderate dose of a statin reduces your risk of having a heart attack in the next 10 years by 25%. If that risk is 40%, then reducing it by 25% means you have reduced your odds by 10%. If that risk is 4%, reducing it by 25% means your actual benefit is a 1% risk reduction – perhaps not worth it in your mind. There are on-line risk calculators that will help you calculate your personal risk.

If you feel that lowering your cholesterol is important and cannot take a statin, there are several choices available, but NONE of them has been studied for risk reduction when taken alone – all have been shown to lower your risk of heart attack when added to a maximally-tolerated dose of a statin.

Ezetimibe (Zetia) inhibits absorption of cholesterol from the intestine and reduces cholesterol by about 18% (compared to 25-60% reduction with a statin). There are two new injectable drugs, called PCSK9 inhibitors, that are very potent, but are extremely expensive and require self-injection every 2-4 weeks. Unless you have a very high risk, your health insurance company is likely to balk at paying for these. The newest entry is bempedoic acid (Nexletol), which also lowers cholesterol by about 18%, and it has also only been tested as an add-on.

Finally, do not forget lifestyle changes: a better diet, weight loss, moderate aerobic exercise. If you are a smoker, quitting will do more to reduce your heart attack risk than any pill.

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Saturday, June 6, 2020

Health care: black and white

The Covid-19 pandemic has brought into sharp relief the failings of the U.S. health care system to give adequate priority to public health: our woeful performance in testing, contact tracing and availability of personal protective equipment. It has also highlighted the marked social disparities in how we deliver health care.

Across the United States, the death rate from Covid-19 per 100,000 among non-Hispanic whites is 22.7, among Asian-Americans 24.3, among Hispanics 24.9 and among African Americans 54.6. The strikingly higher death rate reflects many factors. Blacks are more likely to live in crowded housing, making “social distancing” more difficult; they are more likely to have to depend on crowded public transportation; they have a higher incidence of such medical conditions as hypertension and diabetes that increase mortality; and they are more likely to work in such “essential” jobs as meat packing, nursing homes and home health care and grocery stores, and less likely to be able to work from home.

The racial disparity in health care exposed by the pandemic is not new. Overall deaths per 100,000 in the U.S. in 2018 were 725 for non-Hispanic whites and 852 for African Americans. The maternal death rate in this country has been (or should have been) an embarrassment for a long time. While the death rate per 100,000 live births in most of the western world ranges from 5 to 8 and has been falling, in the U.S, during the decade 2007-2016, it rose from 15 to 17. Here too there was a marked racial disparity. The maternal death rate among white women averaged 12.7/100,000 in the most recent figures, while it was 40.8 among black women. Poverty alone is not the explanation; among women with at least a college degree, the maternal death rate of black mothers was 5.2 times that of whites.

Too often, minority populations live in the least safe housing, are less likely to have health insurance and have less access to health care.

As detailed in Prescription for Bankruptcy, some 80% of a nation’s health, as measured by factors such as our life expectancy at birth, is determined by social factors rather than the traditional health care delivery system. To lead healthy lives, people need safe housing, access to healthy food, green spaces, educational opportunity, social support and, most important of all, a living wage.

Whether through development of a vaccine or the gradual development of effective treatment and herd immunity, the pandemic will end. The racial disparity in health and health care will not unless we make a conscious decision to make societal change.

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Tuesday, June 2, 2020

What do Covid-19 tests tell us?

To understand what various tests for Covid-19 mean, you must first accept one important fact: medical tests are not perfect. Even the most accurate tests we have at our disposal may say that someone has a disease when they do not (a “false positive”) or that they do not have the disease when they do (“false negative”). All tests must be interpreted together with the clinical findings and the likelihood of someone having the disease in question.

Let’s look at how Covid-19 is diagnosed. The “gold standard” is detection of the virus’ RNA in specimens from the respiratory tract of a sick person. These tests go by the highfalutin label of “reverse transcriptase-polymerase chain reaction” or RT-PCR, and this describes a technique by which the presence of viral RNA is measured and quantified. This technique can be used on any specimen, but the earliest and still most common specimen has been a swab taken from the very back of the nasal passage. It has also been used on sputum (spit), throat culture, stool samples and even semen.

In most people who develop symptoms of Covid-19, viral RNA becomes detectable in the nasopharyngeal swab as early as day 1 of symptoms and in over 98% within the first week. Detection falls off after week 3, though positive tests have been reported as late as six weeks after symptoms begin. Tests for Covid-19 RNA in the stool and semen have also been found positive long after patients recover. It appears that late tests often do NOT indicate that the person is still contagious, and that they may simply be shedding decayed viral remnants.

The RT-PCR is highly accurate when positive. False negative tests do occur because of technical problems: the specimen may have not been taken properly or not transported properly to the lab, or there may have been a problem with the way the test was conducted.

The other type of test about which you will read is the antibody test. When we are exposed to an infectious agent (or a vaccine), our immune system gears up to fight it off by producing proteins called antibodies that both directly fight the infectious agent and call in various cells to do the same. It takes time for antibodies to be produced, so they are unlikely to be found very early in an illness. In the case of Covid-19, some antibodies have been found as early as 4 days into symptoms, but it is generally in week 2 or 3 that they are reliably found. First to appear are a group called IgM antibodies, that fall off by week 6, while IgG antibodies appear slightly later but persist, for months or years.

Antibodies are commonly measured in blood samples and provide proof of prior exposure to an infectious agent. In many, but not all, cases, presence of antibodies indicates at least some immunity to the agent against which they are targeted. The degree to which the presence of antibodies means immunity to the disease varies a lot. If you have measles antibodies, you are safe, but that is less true for whooping cough or for the coronaviruses that cause the common cold. We simply do not yet know if antibodies against Covid-19 will protect one from re-infection. It is clearly premature to use these tests to offer “immune passports.”

The other major problem with current Covid-19 antibody tests is that many of the tests now available are far from reliable. Many were rushed to market with limited testing and have a high number of both false positives and false negatives. Remember that Covid-19 is one of a group of coronaviruses, many of which cause the common cold, and a poorly designed antibody test may simply be detecting a prior exposure to one of these other viruses.

Bottom line: until we have more consistently reliable antibody tests, and until we know if the presence of antibodies is a reliable way to guarantee immunity to re-infection, I would not be in a hurry to get tested.

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Wednesday, May 27, 2020

Musings on masks

Let me start with the punch line and then work backwards.

You do not wear a face mask to protect yourself, though it may offer some modest protection. You wear one to protect your fellow human beings. Refusing to wear a mask does not indicate bravery and toughness but rather a lack of concern for others.

How does the coronavirus spread? It spreads almost entirely when viral particles are expelled from the respiratory tract of an infected person and inhaled by another person. Huge numbers of viral particles are spread when an infected person coughs or sneezes, large numbers when they sing or shout, and fewer but enough to spread with normal talking or even breathing.

Who can be a virus spreader? Alas, it is not only people who are obviously ill. There are still gaps in our knowledge, and it is hard to give exact numbers, but all experts agree, backed up by increasing data, that many people who harbor coronavirus and can spread it have minor or no symptoms. The most recent study I found, published in a British medical journal, found that 81% of passengers on a cruise ship who tested positive had no symptoms when they were tested. Moreover, even those who develop symptoms are most infectious just before symptoms develop. Lack of symptoms seems to be more common in women than men, and in younger adults. Roughly half the Covid-19 patients in China appeared to have been infected before the patient from whom they caught it knew they were sick.

How much do masks protect the wearer? Probably not a lot. Only N95 masks, which remain in short supply and are needed by healthcare workers, filter out most viral particles, which are very small and can pass through the fabric of cloth or disposable surgical masks. They do offer modest protection against moist droplets which carry viral particles from a sneeze or cough.

The masks do cut down on spread of the droplets generated by speaking, coughing or sneezing. The key point is not that masks do not block every virus particle, but that they filter out many. Every virus particle that does not escape into the air is a virus that will not be inhaled by others or fall on surfaces and perhaps be picked up on the hands of others.

Just as wearing a seat belt does not confer immortality if you get in a car accident, but does cut down on deaths, wearing a face mask will not prevent all spread of coronavirus but will reduce it. Wearing a mask is an easy, inexpensive and harmless way to show that you care about others.


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Friday, May 22, 2020

Surrogate or real?

The dictionary defines surrogate as “a person appointed to act for another,” and to the general public probably the most common use is in terms such as surrogate parent

In medicine, it is common to have surrogate decision-makers, such as the parents of a minor child, or the spouse or child of a person who is incapable of making their own decisions. Such surrogate decision makers have all-too-often been put in the difficult position during the COVID-19 pandemic of making dread decisions such as whether to have a loved one put on a ventilator. It is very common for an elderly patient to undergo intensive care when they have asked this not be done, and researchers have also found that many surrogates’ wishes are not followed by the medical staff. It is always best, and Covid-19 has just underlined this, for a older person (or a person of any age with serious medical problems) to be sure their wishes regarding the trade-off between possibly life-sustaining care and comfort be explicit, in writing, and discussed with family.

I want to focus, however, on another form of surrogate – the use of “surrogate end points” to approve a new drug.

The gold standard for proving that a new treatment works, or works better than an existing one, is the controlled clinical trial. A large group of patients are randomly given Drug X or Drug Y, or, if there is no existing useful treatment, Drug X or a placebo. They are then followed until a pre-specified outcome occurs and the results of the two groups compared. As regular readers of these posts know, I am much more impressed with a trial that uses death as the outcome being measured. For many of the events reported, the definition is often fuzzy. The research group frequently establishes a committee to “adjudicate” whether an event occurs. You do not need a committee to decide if a patient is alive or dead.

From a researcher’s perspective, the problem with using death as the outcome is that to establish that one treatment is better than another may take a large sample followed over a long time unless the disease is rapidly lethal. Large trials over a long time are costly to perform.

Enter the “surrogate.” The trial of a cancer drug may use “shrinking of the tumor by 50% on CT scan” or “reduction of a biomarker (blood test)” as the outcome studied. While these MAY correlate well with outcomes of more value to the patient, such as lifespan or quality of life, they may not. More and more cancer drugs are now being approved by the FDA based on surrogate outcomes. A recent study published in JAMA Internal Medicine found only a very weak correlation between these end points and overall survival. While a drug approved on this basis is supposed to have further tests done that do track overall survival, in a large percentage these studies are never done. Since these new drugs are often very expensive and have many major side-effects, it appears that patients are often exposed to potential harm with minimal potential meaningful benefit.

So, when the latest “wonder drug” is suggested, be sure to ask just HOW wonderful it really is. The reported results may be “statistically significant,” but are they clinically significant? Can anyone tell you this treatment will make you feel better or live longer, or will there just be a meaningless "surrogate" improvement?

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Thursday, April 30, 2020

A cure for COVID-19?

We are all desperate for a “cure” for the coronavirus illness, COVID-19. Since even the most optimistic accept that a vaccine is at least a year away (and that would be unprecedently fast), a drug that could offer a cure is the next great hope. On Wednesday, the press reported a statement by Dr. Anthony Fauci about the drug remdesivir from Gilead Science. The headlines touted “a cure,” a “game-changer,” and Gilead’s share price soared.

Do we really have an “effective treatment” against coronavirus? No, not really. Here is what Dr. Fauci said in a much-hyped White House announcement: “The data shows that remdesivir has a clear-cut significant positive effect in diminishing the time to recovery . . . The mortality rate trended towards being better in the sense of less deaths in the remdesivir group – 8 percent versus 11 percent in the placebo group. It has not reached statistical significance, but the data needs to be further analyzed.” When a result is described as not having reached statistical significance, this means that the differences could be due to chance alone. Flipping a coin three times, you will not be shocked to get heads three times, and it does not mean the coin is rigged. Similarly, small differences in response to different treatments will often show up without meaning there is a real difference, but simply by chance.

As to the “positive effect” cited by Dr. Fauci, he was describing a reduction in the mean duration of hospitalization from 15 days to 11 days. That is good, but hardly “an effective treatment against coronavirus” or a “drug that can block the virus” as the headlines blared.

Dr. Fauci’s announcement was unusual because it was made before the results of the trial have been published or subjected to peer review. To his credit, Dr. Fauci described the results as “preliminary.” He also tried to tamp down expectations arising from his announcement by saying that the data was a “proof of concept” rather than an effective treatment, similar to early results of drugs against AIDS. That important qualification was missing from many headlines. We later heard from Dr. Fauci that he made the announcement because he “feared it would come out in leaks.” While perhaps understandable, hardly the best reason or way to present science.

Contrast the NIH-sponsored trial with the results of a trial done in China and published on-line on April 29 in The Lancet, a prestigious medical journal. These researchers randomly assigned 237 patients with severe COVID-19 (all with low oxygen levels and pneumonia seen on CT) to remdesivir or placebo, They found that remdesivir use was not associated with a difference in time to clinical improvement, though there was trend to faster improvement with the drug in patients who were started on treatment earlier. They also found that treated patients had more “serious” adverse effects. There was no difference in death rates between the two groups (and those who read these posts regularly know I focus on that - a number that is neither subjective nor able to be fudged).

Why the difference between these two studies? Probably because the effects were so small that it was similar to a coin flip, but perhaps because one or the other trial had flaws. Since the Chinese study was peer-reviewed, it has inherently more credibility. Whichever proves to be more correct, the drug may (or may not) be helpful but is hardly “a cure.”

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Saturday, April 18, 2020

The fox guarding the henhouse?

A tale of greed, bad science and poor decision-making by the FDA which is unfortunately not unique.

Pre-term birth, delivery before 37 weeks gestation, is a serious problem. It puts the baby at risk of disability or even death. Women who have had one “premie” are eager to do anything to avoid one in subsequent pregnancies, as are their doctors. The best estimates are that women who have had one premature delivery have a 30% risk of having one on a subsequent pregnancy.

Short of putting women on prolonged bedrest, there has been little available to reduce the rate of premature delivery. A “meta-analysis” of previously published studies done in 1990 suggested that while the hormone hydroxyprogesterone did not prevent miscarriage (for which it had been used), it appeared to protect against preterm birth. In 2003, a trial was conducted that claimed to show that injecting pregnant women weekly with hydroxyprogesterone in mid-pregnancy reduced the number of premature births. The treated group had 36% premature deliveries compared to 55% in the placebo group. There were many critics of the study, who pointed out that the placebo group had a much higher rate of premature birth than would have been expected, and those in the treated group had a similar but higher rate than expected if nothing were done. It was also pointed out that the pregnant uterus was “awash” in progesterone and so there was little biologic reason to expect the injections to do much.

Despite these reservations, many obstetricians began prescribing this treatment. Compounding pharmacies began making the injections and selling them for $15/shot. Enter stage right Adeza Biomedical, which used the 2003 trial to support their application for FDA approval of their branded hydroxyprogesterone for the prevention of premature birth. Many of the FDA’s own scientists pointed out the flaws of the trial, and when the branded product (Makena) was approved, it was with the stipulation that further trials be conducted. This trial, which enrolled over three times as many women, and reported results in March 2019, showed NO benefit from use of Makena.

The FDA convened another “expert panel” to decide if the drug should be kept on the market. The panel voted unanimously that the newer trial did not verify the benefit of Makena, and 13 to 3 that the combined evidence from the original and the newer trial did not provide evidence of any substantial benefit. When the vote came on whether to leave it on the market, the vote was much closer: 9 to 7 in favor of removing it from the market. The FDA decided to leave it on the market.

“Follow the money” has clarified many apparently confusing stories. While the product was sold for $15/shot by compounding pharmacies, Makena was marketed at an initial price of $1440/shot! As generics have entered the market, the list price has fallen, but is still $848/shot for a product that was profitable at $15. This obscene profit margin has allowed its current manufacturer, AMAG Pharmaceuticals, to generously support the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine, which supplied many of the expert panelists. Neither society has yet reflected the negative trial in their guidelines.

My take home is that all FDA panelists should be truly disinterested. Societies accepting money from drug manufacturers and researchers getting support from manufacturers should be automatically excluded from advisory panels.

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Sunday, April 12, 2020

The coronavirus chaos: who is to blame?

“WE'RE NUMBER ONE 1!” I guess that is supposed to be something to make Americans proud. However, on April 11 that meant the United States had passed Italy in registering the greatest number of reported deaths from COVID-19. Worldwide, there are now over 1.7 million confirmed cases and over 104,000 deaths. The United States, with a bit over 4% of the world’s population, had some 501,700 cases and 18,860 deaths.

IN THE RICHEST COUNTRY ON PLANET EARTH, the vice president is suggesting that doctors "recycle gowns" because hospitals don't have enough; states are sending ventilators to other states when this disease seems to recede because the medical devices are scarce; a fund meant to rescue small business is running out of money and Congress can't figure out how to fix it; the president said "we have the best" system for testing people for the coronavirus, even though other nations have tested a far higher percentage of their population; and a debate is raging among politicians about opening the economy, even though medical professionals say the disease is not yet controlled.

Contrast the U.S. with South Korea, an advanced economy of some 51.5 million, not nearly as wealthy as the U.S., nor blessed with the wealth of scientific and medical resources. Both South Korea and the U.S. reported their first COVID-19 cases on January 20. From that point, things dramatically diverged. If South Korea had cases and deaths in the same proportion of their population, they would have registered 79,635 cases and 2994 deaths. The actual numbers? 10,480 cases and 211 deaths! You cannot explain this away by different counting methods. South Korea has been much more aggressive in testing than the U.S., so we are much more likely to be undercounting than are the Koreans.

Who is to blame for the fiasco that is the U.S. response to COVID-19? There is blame enough for many, but the federal government bears the lion’s share.

China must take some share. When the first cases of the novel pneumonia appeared in Wuhan, the Chinese desire to save face and avoid scrutiny from Beijing led the political leaders of Hubei Province to downplay it and try to silence the messenger: Dr. Li Wenliang issued a warning about a strange new virus. Then the authorities summoned him for questioning. He was told to be silent. Dr. Li died of COVID-19, a true martyr. Precious weeks of preparation were lost.

Our health care system has in places responded with speed and cooperation, but in others has not covered itself with glory. We are all aware of the lack of personal protective equipment (PPE) that puts our doctors and nurses at risk. In several well-publicized cases, doctors and nurses who went public with their concerns or even started a GoFundMe campaign to obtain the needed gear were fired by their hospitals! Shades of Dr. Li. Not only does lack of PPE put front-line health care personnel at risk, it harms patients by making the physicians and nurses see them less often and/or transmit virus between patients. More and more physicians now work for venture capital firms. In NY, many of these responded to the COVID epidemic by cutting down the doctors’ shifts; after all, many of these patients are uninsured and not profitable. This epidemic has shown it is time to take direction of health care away from “the suits” and put it in the hands of those who understand patient care.

By far the biggest failure is the incompetence of the federal response. When word of the novel coronavirus spread, South Korea sprang into action with early mass testing, tracking and isolating all contacts of those infected. It started developing and stockpiling test kits in early January, as soon as Chinese scientists released the virus's genetic code and before a single Korean had been infected. The U.S. could have done the same. As far back as 2005, George Bush, having read a book about the 1918-1919 Spanish flu, tasked the CDC with gearing up to respond to pandemics. The Obama administration refined this during the Ebola crisis, and had a pandemic unit within the National Security Council. In 2018, as part of “reorganizing” the NSC, the pandemic unit was eliminated. While South Korea mobilized to prepare, and despite multiple warnings from within his administration, Trump insisted that “this is no worse than the flu,” and that “it will magically disappear by April.”

Shortages of supplies for our hospitals and health-care providers continue to plague our response to the novel coronavirus. As late as March 2, the administration was urging American businesses to take advantage of the booming market to export such supplies to other countries. If Trump had invoked the Defense Production Act earlier, he could have kept masks, ventilators, and PPEs at home. In February 2020, the value of U.S. mask exports to China was 1094% higher than the 2019 monthly average.

Even more disturbing are investigations into what is happening to the supplies hospitals and states are ordering. In the absence of federal masks, PPEs, ventilators, and so on, the president urged states to get what they needed themselves. They have bought supplies on the open market, only to have the federal government confiscate them. Federal supplies are being disproportionally distributed to states that vote Republican rather than states which most need them. It seems likely that at least some of the confusion is simply poor management, but the suggestion that leading administration officials are trying to create political capital out of this crisis seems in keeping with their usual patterns.

Testing, despite Trump’s claims, remains far behind that done in Korea, Singapore and other countries. Unproven therapies with potential for harm are being pushed by non-medical administration figures, from the President down. The Trump administration seems fixated on his image and the economy, public health be damned. This goes back to Trump’s insistence that a cruise ship with coronavirus-infected passengers not be allowed to dock in California lest U.S. numbers look worse and continues as he fixates on his TV ratings rather than competent management.

When we come out of this, let us resolve to do better. Let us resolve to have a President who believes in science rather than “his gut.” Let us resolve to have a President who puts the safety and health of the American people above his political future. Let us insist that our medical care system focus on patients before profits.

Prescription for Bankruptcy. Buy the book on Amazon


Friday, April 3, 2020

What's the latest on COVID-19?

As the evening newscasters are so fond of saying, “this is an evolving story, so stay tuned.” What you hear about the coronavirus seems to change almost daily, and if you are confused, that is because you should be! The traditional way medical research is reported is through publication in a “peer-reviewed” journal. The researchers submit their work and the editors send it to experts in the field for evaluation. These reviewers typically find minor (or major) flaws in the way the study was conducted or how the data are interpreted; their comments go to the researchers, who are expected to rewrite their paper in response. While this does generally result in better science, it is very time-consuming. In the current pandemic environment, many researchers are bypassing the established journal system to post their work on-line, and journal editors are often dramatically shortening the cycle. The good side is that research findings are communicated much more quickly; the bad is that much of what is spread reflects bad science that may not hold up.

That said, I wanted to share what we have learned in recent days, with the caveat that some of this is more conjecture than proof.

The first broad area is how the coronavirus is spread. The CDC believes that some 25% of people infected with the virus are asymptomatic, but still able to spread it to others. A short report published in the British Medical Journal on April 2 from China claims that as many as 78% of new infections detected by culture had no symptoms. Similar findings were reported from a small study in northern Italy. Another new piece of data says that while we are aware the virus is spread by coughing or sneezing, it may also be spread by normal breathing or talking. The bottom line: when you see new advice to wear a mask when out in public, realize that this is more to protect other people from you than to protect you from others.

How about the widely promulgated 6-foot rule? It is based on a Harvard study from the 1930’s. An MIT professor (not Trump’s uncle) claims this is not adequate, and that a vigorous sneeze may propel droplets over 20 feet. Dr. Fauci has no plans to change the CDC advise, but I think we can conclude that 6 feet is the minimum safe distance!

Prevention would be ideal. A vaccine would be best but is a long time away. A peer-reviewed study published this week in EBioMedicine reported on a candidate vaccine that induced an immune response in rodents within two weeks. While encouraging, you must remember that vaccines, which are given to huge numbers of healthy people, must pass stringent tests of both efficacy AND safety before they are approved. Optimistically, we are at least a year away, and probably longer.

A tantalizing study came out this week that showed that the COVID-19 seemed to have less impact in countries that routinely used BCG vaccine, a vaccine to prevent tuberculosis, that is universally given to newborns in Japan and China. It was previously used in France and Spain, but was discontinued years ago, and was never adopted in Italy or the U.S. Several vaccines, including BCG, have been shown to produce non-specific improved immune response against microbes in general. The BCG vaccine is proven safe, and so might be a candidate for use.

Treatment recommendations for established COVID-19 disease rest on tiny studies and are almost certainly going to mislead as much as help.

A study from China looked at the anti-viral agents lopinavir and ritonavir, used for AIDS, and found they had no benefit in a study involving 199 moderately severe patients given the drug combination for two weeks. They are being further studied in larger trials sponsored by the World Health Organization.

How about Vitamin C? If you are a devotee of Internet searches, Linus Pauling’s old miracle cure for colds and many other illnesses will cure COVID-19 as well. Well, Vitamin C does NOT cure the common cold, nor is it likely to cure COVID-19. A trial is being done in China, but do not hold your breath.

Finally, what about the “Trump cure:” hydroxychloroquine (HCQ) with or without azithromax. It makes sense to look at hydroxychloroquine as a possible treatment, as it has been shown to have some anti-viral activity in the test tube, but to date the evidence for its benefit to patients is mixed at best. The early French study which I discussed in a prior post, which claimed 100% clearance of the virus in patients given HCQ and azithromax, was bad science and essentially useless to aid in medical decision-making. Two small clinical trials have shown conflicting results. A Chinese study looked at 62 patients, half given 5 days of 400 mg/day HCQ, and half supportive care, and found that treated patients recovered more quickly than those not given the medicine, and that four of those not given HCQ progressed to severe disease while none of the treated patients did. Sounds good? Unfortunately, another French group studied eleven patients using the HCQ/azithromax regimen and found no benefit, as did a second Chinese study of HCQ. Both drugs can cause serious heart rhythm disorders, and when given together may cause sudden death. The proper role for these drugs, singly or together, is in a proper clinical trial, with careful heart monitoring.

What you should do remains the same as it was last week. Stay away from others. Do not go out if you are sick. Cover your face when out. Wash your hands whenever you touch anything outside (or use hand sanitizer). Wash your hands after dealing with the mail or opening packages.


Prescription for Bankruptcy. Buy the book on Amazon

Thursday, March 26, 2020

"Cures" for COVID-19 - caveat emptor

Most of what I was taught about pharmacology in medical school many decades ago is long outmoded and useless, but one aphorism remains very relevant. “When the latest ‘miracle drug’ appears,” our professor said, “use it right away, because in a few months it will not work as well.” This sums up nicely the fallacy of using media accounts of “breakthroughs” as a guide to truth, or of listening to science-denying political figures as a source of medical advice.

I had an interesting experience many years ago when a long-time but infrequently seen patient was brought in by his wife because of failing memory. He was clearly in the beginning stage of Alzheimer’s disease. Aricept had just been brought to market as a treatment for this disease, so I prescribed it and saw him back a few weeks later and was astonished by his improvement. I was ready to pronounce this a “cure” for the disease. Unfortunately, this experience was never repeated in the dozens of subsequent patients to whom I gave the drug, and we now know that Aricept and similar medicines are not a cure but at best slow down the disease progression a bit. Why did my patient seem to benefit so much? His improvement may have been totally unrelated to the Aricept. Many things can worsen dementia, including infections and over-the-counter drugs such as Benadryl, and if I had prescribed green tea I would have seen the same improvement.

I tell this story because physicians now know that only carefully designed trials with adequate numbers of patients are reliable ways to find out if a medicine is truly effective and safe. Or, as I have heard said, the plural of anecdote is not data. The fact that my patient seemed to benefit did not prove that there was a cure for Alzheimer’s.

We are in a similar stage with the coronavirus and COVID-19. With no proven treatment available, we want to believe there is “cure” out there. The latest “cure” is the anti-malarial drugs chloroquine and hydroxychloroquine. The basis for these claims appears to be a single study done in France. Unfortunately for those who want a miracle, the study is a slim reed on which to base our hopes. The authors started with 36 patients, six with no symptoms but a positive swab, 22 with only upper respiratory symptoms and eight with probable pneumonia. Eight were admitted to the ICU and not followed, one left the hospital and was not followed, and they reported on only 20 patients. Moreover, they did not randomly split them into treated and untreated groups as is expected in clinical trials but used untreated patients from another center and patients who refused to be tested as their control group. The results showed that the 20 treated patients had less virus in their nasal secretions at the sixth day than the “controls.” While mildly encouraging, this is hardly a cure – and the patients studied were not the sickest, who really need effective medication.

A Chinese trial, done in a much more robust manner, tested a combination of two anti-viral drugs on more severely ill COVID-19 patients and found no benefit.

All drugs are potentially dangerous. Since Trump pronounced the anti-malarials a cure, at least three people have died from overdosing on chloroquine.

The World Health Organization is coordinating an international trial that will look at four different treatments for COVID-19: a new drug developed by Gilead for Ebola, the same anti-viral drugs found ineffective in the Chinese trial with and without interferon-Beta and chloroquine. These will be compared to each other and to “standard” care, which is support with IV fluids and respiratory support as needed. The same four treatments are also being studied by a European cooperative group headed by France.

Until the preliminary results of these trials are available, take any claims of “cure” with a grain of salt. Practice social distancing, keep up good general health habits and wash your hands.

Prescription for Bankruptcy. Buy the book on Amazon