I cram for TAM, and, combined with other commitments, not the least of which is that it is finally sunny and warm in Portland, after a year that has resembled All the Summer in a Day,  which leads to a relatively short post.  There are just so many hours in a day and if possible those days need to be spent in the sun.

In my first year in practice I was sitting on a nursing station writing a note when a patient started howling in pain.  Further investigation revealed that the patient had a chronic, open surgical wound and the (old) surgeon had ordered sugar poured into the wound as part of wound care.  The cafeteria mistakenly sent up salt, and a metaphor became reality.  It did pique my interest in both sugar and honey for wound care,  an area where you have to be careful not to fall prey to all the errors in CAM thinking: a reliance on anecdotes, using suboptimal studies as evidence, mistaking a gobbet of basic science as a meaningful clinical application, and not realizing the warping effect of confirmation bias.

That being said, I have suggested honey and sugar for years for patients, and many patients with prior refractory wounds had healing.  And what are the three most dangerous words in medicine?  In my experience.  I have recommended honey less in the era of the wound vac, but there are not an insignificant number of people with insufficient financial resources who cannot afford even simple wound care supplies. Many  of the ointments, creams and special bandages for wound care costs too much.  Patients also like honey as it is natural (people do love to fall for the naturalistic fallacy) and inexpensive, and I always tell patients that the data is iffy, but not stupid.

Wound  itself is mostly a combination of tradition and hype.  One doc learned from his attending who learned from their attending, in a line that stretches back to the first barber-surgeon.  I was told as a medical student, never put in a wound what you wouldn’t put in your eye, which seemed to be a good guiding principle, although it is expensive to pack a wound with soft contact lenses.  New products, often combinations of old treatments, come out monthly with flashy brochures and little good data.

“There is a lack of large, high-quality published RCTs evaluating debridement per se, or comparing different methods of debridement for surgical wounds, to guide clinical decision-making. ”

So I rely on basic principals. Keep the wound clean, keep the new tissue from drying out, remove the dead meat, and keep the bacteria at bay, and do not let your pet lick it are more or less guiding rules in wound care.  That, and no matter what you do, most people will heal.  My rule remains: take credit for success, blame nursing when things go wrong.  That’s ‘humor’ for the sarcasm impaired.

What is the rationale for sugar and honey for wounds and burns?

Basic Biologic Plausibility

The first is mechanism of action is primarily mechanical.  The high osmolality of sugar and honey prevents bacterial overgrowth.  Food can be preserved in sugar (jam is a good example) so the honey and sugar can prevent or decrease bacterial colonization of wounds.  Honey has a low pH and contains hydrogen peroxide, both of which are antibacterial, but I doubt clinical relevance of the latter.  And there may be bee and flower constituents that aid in antibacterial properties, although again I wonder about clinical relevance. Also, sugar and honey do not damage new tissues and when the honey is washed off, it painlessly removes the dead tissues with it, so it is good for debridement.

Honey, and to make sure you can charge a premium amount call it medical grade honey, can kill bacteria and decrease skin colonization.  Avoid raw honey, as it can contain C. botulinum and has been the source of botulism in children.  I don’t expect it would be of much use on facial wrinkles

At least from a basic science perspective, honey and sugar have mechanical, perhaps biochemical, and certainly financial, reasons it could be beneficial in wound care.

Clinical trials

So how are the clinical trials? There are lots of poor quality studies.  Almost 400 references if you are in the mood for cherry picking.  The preponderance of the poor quality studies points to benefit.

For burns?

“Available evidence indicates markedly greater efficacy of honey compared with alternative dressing treatments for superficial or partial thickness burns, although the limitations of the studies included in the meta-analysis restrict the clinical application of these findings.”

and

“Honey may improve healing times in mild to moderate superficial and partial thickness burns compared with some conventional dressings”

For Wounds?

From the ever helpful  and potentially flawed Cochrane reviews:

Honey dressings as an adjuvant to compression do not significantly increase leg ulcer healing at 12 weeks. There is insufficient evidence to guide clinical practice in other areas.

and as they note

The poor quality of most of the trial reports means the results should be interpreted with caution.”

So be it.  I have read many of the 400 references over the years, and the sense is that honey is of some value in wound care.

There is even less information of granulated sugar, where it looks encouraging and has been used to treat mediastinitis , diabetic foot ulcers and sloughing wounds.

Of course, honey is not the end all and bee all of treating soft tissue infections. Depending on the process, surgery and antibiotics will do far more to resolve the infection and promote healing, espcially for acute and/or acutely infected wounds. Relying on only natural products has lead to one death in a complimentary practitioner who treated himself with honey:

“a minor injury became infected with gangrene, the judge was told. He died, aged 52, in April 2007. Instead (of standard care)  he used honey and magnesium sulphate.”’

The doctor who treats themself has a fool for a patient and an idiot for a doctor.

So in the end, do I recommend honey and sugar?  Yes.  The literature is interesting and I give patients a long  list of caveats.  It is maybe sort of probably useful in patients with chronic wounds who cannot afford other interventions.  In my experience it always works.  Back to TAM.

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Last week I described electrodermal testing. I’m sure many readers thought, “There oughta be a law against that.” Well, there are laws. Unfortunately, having laws and enforcing them are two different things.

Some of these devices are not approved at all. Most have received 501(k) approval from the FDA as biofeedback devices so similar to previous devices that they do not require new approval — for biofeedback. It is illegal to use the devices for anything other than biofeedback. The FDA has prohibited their sale or importation for unapproved purposes like electrodermal testing; it has sent warnings to companies, raided clinics, and confiscated machines. States have prosecuted users for practicing medicine without a license. Medical boards have chastised licensed providers. The Quackwatch website lists these regulatory actions but points out that there has been no systematic effort to drive these devices from the marketplace.

Excuses, Excuses

One electrodermal testing website admits that what it is doing is illegal and tries to fight back with this specious disclaimer:

It is important to understand that the laws in the USA forbid me from being able to treat, diagnose, cure or prevent disease. The AMA has a patent on those words and only a licensed medical doctor can do that.  And although it is legal for a licensed medical doctor to violate the Hippocratic oath and prescribe toxic drugs that cause harm and sometimes even kill patients, it is illegal for me to claim you can be cured using natural, nontoxic remedies, even though thousands of people can testify how they have been healed using natural remedies.

These machines are being used to practice medicine without a license, but they think they can get around the law by offering a disclaimer and by espousing the fiction that they are not diagnosing or treating diseases but only detecting energy imbalances and advising patients about how to restore balance.

Here are some typical protestations:

• I can only find imbalances that may be causing problems. It would be up to a medical doctor to determine if what I am finding IS the cause.
• I wouldn’t call EAV biofeedback “treatment”. You don’t treat anything with EAV. Creating a vial of treated water for a client to take may help balance their energy. Balancing energy is not medical treatment. It is perfectly legal to own one for home usage.
• And the reason all these people are spending money on this equipment is what??? Would they continue to invest in something that is “bogus”?
• EAV is not anything like the medical tests that we are used to. It works by quantum physics not biology.
• Yes, there are a bunch of enforcement actions. I assume that what is listed is about the entire list. Do you also want to list the claims made against regular M.D.s?
• Something that shows up energetically does not necessarily mean that it is a physical condition!
• We are only just now getting the scientific ability to test these [homeopathic] remedies by quantum physics.

In the training videos I mentioned in my previous article, the demonstrator answers questions from the audience that reveal more about the way they operate:

Q: I’m not a doctor. I have to send patients to an MD for IV infusions. What do you say when the doctor questions how you determined the patient needs it?

A: Tell him you determined it by electrodermal testing, similar to muscle testing [applied kinesiology] and ask him if what he does is any better. At least we have some monitoring device.

Q: One remedy you recommended is acid, but she has an acid problem.

A: That seems contradictory but we need it for her circulation, and the body can sort out what it needs.

Q: Is the circulation due to blockage in her superior vena cava?

A: No.

Q: Should she stop other medications or products?

A: Bring in the products and put them on the test tray. Medicine is a legal issue, so we can only show her what it does to her pancreas, we can’t tell her to stop using it. You might be liable if you told them to go off their meds.

Q: Will other medications interfere with our treatment?

A: Our treatment will not be as effective if they stay on their meds. Cancer treatments like chemo and radiation will usually interfere with our efforts.  If the patient needs to stay on medication, we can give more products to balance out the effect of prescription meds on liver and to reduce med side effects.

Q: [Something about] cancer showed up on the readings. Does that mean she has cancer?

A: I don’t think she has cancer, but if she doesn’t correct the problems in her body, I can guarantee you down the road she will have problems like that. Cancer loves miasms, acidosis, poor circulation, emotional issues, and immune dysfunction. She’s got ‘em all. It’s just a matter of time. You can’t tell a person they have cancer — just that that matches the picture. Biopsy is needed for medical diagnosis. You can treat it before it gets to the biopsiable stage.

Q: What if the patient says “Every time I come in you give me something different.”

A: Well duh, do you want to be on the same thing all your life if it’s not working? If it’s fixed, why keep taking it? The body prioritizes all the time, so what it needs today will not be what it needs tomorrow.

Regulatory Actions

The FDA, state attorney generals, professional licensing boards, and foreign regulatory agencies have all taken action to stop electrodermal testers.  Details of many of these cases can be found on Quackwatch.

An examination of 3 cases from my own state, Washington, highlights some of the problems with regulation.

The Ames Case

A licensed physician was using a LISTEN device to diagnose allergies. The findings of fact are interesting:

• After he used the LISTEN machine, he wrapped the probe in tissue paper and had the patient hold the probe with tissue paper wrapped around it. When the patient asked why, he answered that he has done this so long, that he could do what the machine could do, and that he did not need the machine anymore.
• He used the machine not only to diagnose, but to treat allergies.
• He also used applied kinesiology, a phoney muscle testing procedure.
• He used dubious hair and urine tests to determine that the patient had a mineral imbalance, and told him he needed treatment for metal poisoning.
• He used what sounds like a chiropractic “activator” device on acupressure points.
• He prescribed the Metabolic Type Diet, a diet with no scientific justification.

The Washington State Department of Health Medical Quality Assurance Commission suspended his license for 5 years. Only they didn’t, because the suspension was stayed as long as he (a) stops using the device, (b) undergoes quarterly practice reviews, and (c) pays a $5,000 fine. The MQAC’s decision was appealed but the state Supreme Court upheld the decision, saying that Ames had “led patients to believe that LISTEN could diagnose and treat allergies, when in fact it could do neither.”  Note that the board and the courts only considered his use of the device and did not even address any of his other questionable practices or his basic competence to practice medicine.

The Trasker Case

Joyce Trasker was convicted of practicing medicine and veterinary medicine without a license. She used the Orion and the Asyra devices to determine a patient’s “energy signature” and to prescribe homeopathic remedies. She offered testing on saliva and blood samples sent to her by mail. Eventually she began taking these samples and the machine onto an Indian reservation to do the testing, claiming that the State had no jurisdiction there. She claimed she was not practicing medicine. She even claimed that the right to free speech protected what she was doing. Her case went all the way to the state Supreme Court. She was ordered to cease and desist and to pay a fine of $10,000.

No problem: she simply moved a short distance across the state line to Idaho where she is still offering the same electrodermal testing for $295 per test. You can mail in saliva samples, even from Washington State: her website says “Washington may not prohibit its residents from patronizing an Oregon or Idaho business.” She is also involved in a long term campaign for the freedom to choose safe unregulated health care.

A Dropped Complaint

A few years ago I found a website for a local clinic offering electrodermal testing. After I filed a complaint with the medical board, all references to electrodermal testing mysteriously vanished from the website. The doctor and his lawyers threatened the medical board with legal action if they tried to act on the complaint. The complaint was dropped.

Confusing Terminology

The variety of devices and the many variants of terminology make it difficult to identify the magnitude of the problem. These devices are illegal and cannot be sold or imported, but they are still available. On E-bay I found 6 Biomeridian systems for sale. They seem to be going for around $5000 compared to an original price of $12,000 to $17,000.

If these systems do use some kind of frequency analyzer to capture EMF and then use a frequency generator to re-introduce that same signal back into the human body for “testing”, now they have produced what the FDA considers a radiation emitting device and not a galvanic skin response meter. The QXCI, EPFX, or SCIO falls into that category. The FDA banned importation of this device after an embarrassing exposé by investigative reporters in The Seattle Times featuring patients who died because they relied on the device to treat cancer.

What Can We Do?

In his exposé, Quackwatch’s Stephen Barrett says:

The devices described in this article are used to diagnose nonexistent health problems, select inappropriate treatment, and defraud insurance companies. The practitioners who use them are either delusional, dishonest, or both. These devices should be confiscated and the practitioners who use them should be prosecuted. If you encounter any such device, please report it to the state attorney general, any relevant licensing board, the FDA, the FTC, the FBI, the Better Business Bureau, and any insurance company to which the practitioner submits claims that involve use of the device.

I echo his plea. There is an online directory of practitioners that could be helpful in identifying some of the offenders, but there are undoubtedly many more who are avoiding publicity for fear of legal consequences. We have the tools to stop most of these offenders, but first we need to identify the offenders and then we need to actually use the tools.

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The hypothesis that vaccines cause autism has been about as thoroughly falsified through research as any health hypothesis can be. Even if, by bending over backward into a back-breaking contortionist pose to be “open-minded”, some people will concede that there’s still a bit of room for reasonable doubt about whether there is no link between vaccines and autism in “susceptible” populations, there is no room for reasonable doubt left over whether vaccines caused the so-called “autism-epidemic” of the last two decades. They did not. Similarly, the mercury-containing preservative thimerosal, which used to be in several childhood vaccines until the end of 2001, when thimerosal was removed from all but some flu vaccines, has been about as cleared of being a cause of autism as it is possible for a substance to be. Basically, if thimerosal-containing vaccines were a cause of autism, we would have expected to see a decrease in autism prevalence beginning three to five years after the removal of thimerosal. Epidemiological studies have failed to find such a decline and have also failed to find evidence of correlation. I realize that anti-vaccine activists argue that there are still trace amounts of thimerosal in some vaccines, but, even so, thimerosal exposure in children fell almost overnight to levels lower than the 1980s, which was before the beginning of the “autism epidemic.” At the very least, one would expect autism rates to fall back to 1980s levels if thimerosal in vaccines were a driving force behind this “epidemic.” They haven’t. Quite the contrary, they’ve continued to climb.

So why does the manufactroversy that vaccines cause autism persist? There is no longer a scientific controversy; by and large, the question has been asked and answered. Vaccines do not cause autism, as far as we can detect. True, it’s impossible to completely prove a negative hypothesis, but if there is any way that vaccines do cause autism, it’s at a level below the ability of large epidemiological studies with tens or even hundreds of thousands of children to detect. Yet the fear persists.

One reason is that it’s very hard to eradicate a false belief, once entrenched. I’ve discussed many times how difficult it is to change people’s minds, as motivated reasoning leads them to seek confirming evidence and discount all else. Disconfirming evidence can even lead people to harden their beliefs even more. In particular, the hardcore anti-vaccine activists who persist in spreading the vaccine-autism myth have an interest and motivation in this mythology at least as potent as the interest pharmaceutical companies have in defending vaccines—more so, arguably, given the emotional attachment people have for their children. After all, all pharmaceutical companies are interested in, according to this mythology, is profit. If a parent, correctly or incorrectly, somehow comes to believe that something or someone has hurt his or her child, it is among the most potent motivations known to do something about it.

Another reason is that the concept has become entrenched in our culture—or at least parts of our culture—to the point where it appears regularly in the media, thus reinforcing the idea among those who don’t pay attention to the issue or those who do but haven’t decided if they believe that vaccines cause autism that maybe there is something to fear. Maybe there is still a controversy. A perfect example appeared in The Baltimore Sun over the weekend entitled We don’t know enough about childhood vaccines and subtitled Researcher asks: Are 36 doses of vaccine by age 2 too much, too little, or just right? I contend that the editors of The Baltimore Sun, by publishing this anti-vaccine propaganda, which would have been at home on the websites of the anti-vaccine blog Age of Autism or on the website of anti-vaccine groups SafeMinds, Generation Rescue, the International Medical Council on Vaccination or the National Vaccine Information Center (NVIC). Examining this article, written by Margaret Dunkle, described as a “senior research scientist at the Department of Health Policy at George Washington University and director of the Early Identification and Intervention Collaborative for Los Angeles County” and as having “a family member who is vaccine-injured,” is what I would consider a “teachable moment” in analyzing the tactics of the anti-vaccine movement.

Anti-vaccine propaganda in a major newspaper

Dunkle’s article begins rather oddly. At least, it could easily strike someone as odd if he isn’t familiar with the rhetorical techniques and bad science favored by propagandists like Dunkle:

The topics of vaccines and vaccine safety spark emotional outbursts at scientific meetings and family dinner tables alike. But many of these debates are remarkably fact-free. Surprisingly few people — not just concerned parents but also doctors, policy makers and even immunization experts — can answer this seemingly simple question: How many immunizations does the federal government recommend for every child during the first two years of life?

The answer is important because most states, including Maryland, faithfully follow the recommendations of the federal Centers for Disease Control and Prevention, codifying CDC guidelines into requirements for children to enroll in school, kindergarten, preschool and child care.

The irony of someone like Dunkle referring to debates over vaccines being “fact-free” is left for the amusement of the reader. Consider the old adage that everyone is entitled to his or her opinions but no one is entitled to his or her own facts. In the case of determining the number of vaccines that the Centers for Disease Control and Prevention recommends for children before age two, the anti-vaccine movement is a master at counting vaccines in such a manner as to make the CDC-recommended vaccine schedule appear to contain as large and scary a number of vaccines as possible. It does this by counting multivalent vaccines, such as the measles-mumps-rubella vaccine (MMR), as individual components, thus multiplying one dose or shot into three vaccines. If you count it up the right way, you can get a total of 36 vaccines, a number and anti-vaccine talking point that appears to date back to a full page ad run in USA Today by Generation Rescue three years ago:

Notice a number of fallacies all rolled up into one big poster-sized ad: “Too many too soon”; the “toxin” gambit; and confusing correlation with causation. Around the same time, Jenny McCarthy started showing up on Larry King Live! using this particular talking point. Prometheus once pointed out that he couldn’t find a way to come up with a total of 36 and thought that Generation Rescue screwed up. Be that as it may, Dunkle continues:

The critical number is how many doses of vaccine a child receives. Why? If a vaccine is strong enough to confer immunity against a disease, it is important enough to count separately.

No, the critical number is not how many doses of a vaccine a child receives. It is the number of antigens to which a child is exposed, and the number of antigens to which children are exposed is much lower than it was 25 years ago as whole cell-derived vaccines have been replaced with acellular vaccines, whatever the “true” number of vaccines as counted by Dunkle is. That’s what really matters.

Going back to find up that old chestnut of an ad on Archive.org, it occurred to me that Dunkle is a bit behind the times. Since that ad ran over three years ago, anti-vaccine groups have managed to find ways to inflate the seeming number of vaccines even higher than 36, such as 48. I tried to find the link, but I’ve even seen a blog post where the blogger was trying to claim that babies get over 60 vaccines before age two. Dunkle needs to get with the program. On the other hand, the number 36 appears to be the “official” talking point number used by most anti-vaccine groups since around 2008; so I’m not surprised that she chose it. I’m also not surprised that she’s bought into the “too many too soon” mantra that groups like Generation Rescue began promoting—surprise, surprise!—about three years ago, when Jenny McCarthy and her then-boyfriend Jim Carrey led a “march on Washington”-style rally under the banner of “Green Our Vaccines” to protest the vaccine schedule.

So where is Dunkle going with all this? Easy. She uses her complaint about the “36 vaccines” or “36 shots” as a prelude to citing a paper that claims to have found that there is a correlation between vaccine uptake and the prevalence of autism spectrum disorders:

A new Journal of Toxicology and Environmental Health study reports that the higher the proportion of infants and toddlers receiving recommended vaccines, the higher the state’s rate of children diagnosed with autism or speech-language problems just a few years later. This analysis is sure to rekindle the debate about vaccine safety.

Not really. It takes solid evidence and a quality scientific paper analyzed well to rekindle a debate. The paper to which Dunkle refers is anything but. Actually, it’s a truly execrable bit of data-mining by Gayle DeLong published earlier this year and entitled A Positive Association found between Autism Prevalence and Childhood Vaccination uptake across the U.S. Population. Prometheus and Sullivan have already had a go at this wretched bit of autism “science,” but I’ll comment as well, given that Dunkle used the paper as ammunition in her op-ed piece, that other anti-vaccine activists point to it as “proof” that “too many too soon” is a valid concern, and that DeLong’s paper has not yet been discussed here on SBM. In this case, better a month or two late than never, I say.

How bad can an epidemiology paper be?

Dunkle is actually a bit late promoting this study, as it’s been floating around the anti-vaccine blog underground for well over a month now. One thing that is very apparent from the article and DeLong’s analysis: DeLong is not a scientist. A quick perusal of almighty Google reveals that she is, rather, a faculty member in the Department of Economics and Finance in the Zicklin School of Business, Baruch College/City University of New York. As always, the fact that DeLong is clearly not a scientist doesn’t necessarily mean that she is wrong. Rather, her poor study design, clear lack of some very basic background knowledge about her study subject, and biased presentation are far more likely to indicate that she is wrong. Even so, somehow DeLong managed to get her manuscript accepted to the Journal of Toxicology and Environmental Health, a journal I only vaguely remember having heard of.

I can’t resist pointing out a bit of misinformation right in the abstract. For example, the reason for the rapid rise of autism in the U.S. is not, as DeLong characterizes it, really much of a “mystery.” It’s very likely the result of diagnostic substitution in the wake of the broadening of the diagnostic criteria for autism and autism spectrum disorders that occurred in the early to mid-1990s, as Paul Shattuck has shown and Steve Novella has discussed. Yes, there may have been a genuine increase in autism prevalence over the last 20 years (although even that is debatable), but, if such an increase has occurred, it appears to be so small that it’s not even clear that there was one.

DeLong carries on this sort of misinformation right in the text. Here’s one thing you should know about reading scientific papers. The introduction is where the authors try to “frame” the issue that led them to do the research and the hypothesis that derives from that issue in the most favorable way possible. To the knowledgeable reader or reviewer, a botched up introduction section that misrepresents the scientific consensus and the issues is almost always a sure sign that the science that follows will either (1) not support the authors’ hypothesis; (2) be of such poor quality that it doesn’t really support or refute any hypothesis at all; or even (3) cast doubt upon the authors’ hypothesis, even though the authors spin it otherwise. In this paper, for instance, DeLong argues that there “are several reasons why vaccines may trigger autism,” after which she lists a veritable laundry list of long-discredited anti-vaccine notions, bringing up (naturally!) old anti-vaccine bogeymen like mercury and aluminum. Nowhere is it mentioned that DeLong’s view is not the scientific consensus. Only one side is presented, the anti-vaccine side.

Another way you can recognize a bad introduction to a research paper is by the quality of the research that is cited. In DeLong’s case, the research cited is awful indeed, with citations to papers by SafeMinds and Age of Autism stalwart Mark Blaxill, the anti-vaccine father-son tag team of Mark and David Geier (otherwise known as the doctor with a suspended license and his son busted for practicing medicine without a license), Russell Blaylock (who counts HIV/AIDS denialism, antivax, and many other forms of pseudoscience as part of his repertoire), and Laura Hewitson, whose “monkey business” research was also published in the very same journal in which DeLong’s study appears. There’s more, but these are just some of the examples, perhaps the most egregious of which is a reference by anti-vaccine homeopath James Compton Burnett writing in 1884.

Then there’s the design of the study itself. First (and most egregious), there’s the issue of why DeLong combined speech or language impairments (SLIs) with autism diagnoses to do her analysis. DeLong appears to have used statistics that states are required to maintain under federal legislation, the Individuals with Disabilities Education Act (IDEA). Under IDEA, every school is required to provide data on children who have an Individual Education Plan (IEP), including the students’ primary classification. As Liz Ditz pointed out, IDEA classifications are not medical diagnoses. A child with a diagnosis of autism under IDEA may or may not actually have autism. Also, children with an IDEA classification of SLI are most commonly children with problems in fluency, articulation, or voice, not autism. Examples include apraxia and aphasias, voice disorders, stuttering, and language-based learning disabilities. It’s not for nothing that James Laidler characterized IDEA data as not being a reliable measure that can be used to track autism prevalence accurately.

Naturally, DeLong cites papers to justify lumping together SLIs and autism for purposes of her analysis. None of them support her hypothesis, and her citing them demonstrates that she does not have even a very basic understanding of her subject. For example, she confuses SLI (speech or language impairment) with SLI (specific language impairment). True, this nomenclature can be confusing, but if you’re going to write a scientific paper involving these topics, you need to know the language. DeLong clearly doesn’t know the language. At the very least, that this remained in her paper is a massive failure of peer review on the part of the journal, whose peer reviewers should have picked up on this. Finally, one of the three papers DeLong cited was apparently an error, but she later stated that she had meant to cite other papers, neither of which actually support her decision to lump SLIs together with autism either.

I’m left with the not-so-sneaking suspicion that the only reason that SLIs were lumped together with autism and ASDs for purposes of correlation with the percentage of children in each state receiving their full vaccine schedule is because the numbers somehow worked out the way that DeLong wanted them to. Otherwise, DeLong’s looking at mostly unrelated phenomena that have some degree of overlap. Certainly there appears to be no valid scientific or medical justification for combining the data from the IDEA classifications of SLI and autism.

Then there’s the methodology chosen for trying to find correlations, described here:

Children who are vaccinated at age 2 years may not develop autism until they are older. To determine the prevalence of autism for a specific cohort of children, the vaccination data from when the children were 2 years old is compared with autism prevalence when they are 8 years old. The relevant vaccination data for children who were 8 years old in 2001 are those from 1995, when the children were 2 years old. For children who turned 8 years old in 2002, the relevant vaccination data are from 1996, and so on. The earliest available data–vaccination data from 1995–were matched with autism prevalence up to 2007.

Besides DeLong’s having fallen for the ecological fallacy (group level comparisons rather than individual-level comparisons), she doesn’t provide much in the way of a good justification for why she chose ages 2 and 8 as their vaccine time point and prevalence time point. Then there’s the issue of confounders. DeLong tried to control for ethnicity, but in explicably she used the CDC’s National Immunization Survey rather than, say, U.S. Census data to derive ethnicity figures. Other potential confounders examined included family income, other disabilities, and the number of pediatricians in each state. Of course, states range in size from small to very large, and it can easily be argued that state level data are not “fine” enough to be used for this purpose. After all, many states are quite large, with huge differences in urbanicity. Think, for instance, California, with several large cities separated by huge swaths of rural and mountainous land. Or think Pennsylvania, which is in essence a 360 mile wide state with two very large cities, one east and one west, and several medium-sized cities clustered mostly in the east, all separated by miles upon miles of farm land or mountains. Urbanicity, as you might recall, can have a huge effect on the number of autism diagnoses, as I discussed three years ago. Naturally, DeLong made no attempt to control for urbanicity.

In other words, there’s no reason to put any real credence in DeLong’s study, especially given how small the observed effect appears to be. After reading this study, I was left wondering why on earth DeLong did it. After all, most of DeLong’s previous work appears to involve the study of banking, the FDIC, and financial risk taking. Why did she embarrass herself so by moving out of her specialty? After all, I would never think of trying to do a paper on economics or business and expect it to be accepted to peer-reviewed journal in the relevant academic discipline. As Dirty Harry Callahan once said, “A man’s got to know his limitations,” and I do, for the most part, know my limitations. DeLong apparently does not, and unfortunately Dunkle doesn’t recognize DeLong’s limitations, either.

Sprinkle in anti-vaccine fallacies, mix, and bring to simmer

Besides the invocation of yet another bad study, the rest of Dunkle’s article is a concise listing of a number of common anti-vaccine fallacies. There is, of course, repetition of the “too many too soon” mantra. Then, of course, there’s the “aluminum” gambit:

In addition to the number of doses, vaccine ingredients can be problematic, especially for susceptible subgroups. First are adjuvants, substances added to boost effectiveness and allow smaller doses of vaccine antigen to be used. The most common adjuvant is aluminum, which is found in vaccines for hepatitis and diphtheria-pertussis-tetanus.

There is no convincing evidence that aluminum adjuvants in vaccines are dangerous or cause autism as administered, and there is a lot of evidence that they are safe.

Dunkle follows this up with a combination of the “mercury” gambit and the “toxins” gambit:

Second are preservatives — such as thimerosal, which is 49.6 percent mercury. Thimerosal is still contained in many flu shots, although it was, except for trace amounts, removed from other child vaccines a decade ago. Many child vaccines (including those for diphtheria-pertussis-tetanus, HIB, and hepatitis) contain formaldehyde, which was just added to the government’s list of known human carcinogens.

The hypothesis that mercury in vaccines somehow causes autism or autism-spectrum disorders is a failed hypothesis.

Moreover, the attempt to scare mothers with claims of all sorts of nasty chemicals in vaccines is nothing more than a toxic myth. I once chastised Santa Monica pediatrician to the stars’ children (including Jenny McCarthy’s son Evan), Dr. Jay Gordon, for invoking the “formaldehyde” bogeyman. Formaldehyde is actually a normal byproduct of human metabolism, and a typical 5 kg two-month-old infant has about 1.1 mg of formaldehyde circulating in his blood, which is five times more than any vaccine contains. As for formaldehyde’s recent addition to the list of carcinogens by the National Toxicology Program, it should be noted that this is for higher exposures. As the National Toxicology Program itself points out on its fact sheet:

Studies of workers exposed to high levels of formaldehyde, such as industrial workers and embalmers, found that formaldehyde causes myeloid leukemia, and rare cancers including sinonasal and nasopharyngeal cancer.

As always, the dose makes the poison, and the tiny amount of formaldehyde in vaccines is not the same thing as the amount of formaldehyde that to which industrial workers are exposed in industries where formaldehyde is manufactured or used extensively or to which embalmers are exposed. If you peruse the scientific report issued by the National Toxicology Program, you’ll see that all the supporting studies involved rather large exposures, far more than any vaccine exposure. Dunkle’s citing formaldehyde as a carcinogen has about as much relevance to vaccine safety as the observation that people can drown in lakes does to discussions of the optimal amount of water people need to drink each day.

Unfortunately, either through advocacy, knowing an editor, or taking advantage of an editor’s desire to publish something interesting and controversial, anti-vaccine groups and activists manage to get articles like this one by Margaret Dunkle into major newspapers. Sometimes, it’s reporters themselves who fall for harmful pseudoscience like this. (Sharyl Attkisson, Steve Higgs, and Steve Wilson, I’m talking to you.) In either case, such articles and reporting represent massive failures of fact-checking, objectivity, and journalistic responsibility, and that’s exactly what The Baltimore Sun is guilty of by publishing Margaret Dunkle’s propaganda.

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So, you’re curious about herbal medicine. Is there any truth to this stuff?

Uncle Howie tells you that he read in the National Enquirer about an herb that has better antibacterial effects on cuts and scrapes than Neosporin ointment — never mind that Neosporin is composed of three different antibiotics that come originally from bacteria themselves.

So you set out on a quest to purchase some of this herb, known colloquially as goldenseal. When you go to your local Whole Hippie Dump-a-Load-of-Cash Emporium you find goldenseal alright, in about twenty different forms. On one side of the aisle are containers with loose, crushed up leaves and roots that look like medical marijuana. On a shelf, you find see-through capsules that seem to contain a powdered version of the herb. Down the aisle a bit you find boxes of blister-packs containing a proprietary extract of free-range goldenseal from the Appalachians harvested under moonlight by bare-breasted virgins. The same company also makes an ointment, allegedly procured the same way.

A scraggly young man with a rainbow-colored Whole Hippie tam comes by and says, “Dude, can I help you?” As you wave away the cloud of patchouli oil and three days of body odor, you ask him, “So, this goldenseal — which one should I buy?”

Hippie Boy looks both ways down the aisle and motions with his finger to come close.

“Dude, all this expensive stuff is just a ploy by The Man trying to make a buck with their fancy scientific words and processes. What you want is the whole herb, man — the stuff given to us by the sprites and spirits. Those capsules miss the point. Part of the magic is missing. You pay extra to get less.”

“But, dude,” you say. “I want to try the ointment, you know, for cuts and scrapes. How do I use this herb?”

The fine young man then explains how to make a poultice, an old-fashioned decoction of plant material that one wraps on a cut — sort of like collard greens.

This really seems like more trouble than it’s worth. You’re about a millisecond away from just heading down to the Done-Rite Drugs, Liquor, and Tobacco to buy a simple tube of Neosporin. But hey, it’s an experiment and you’re curious.

While you’re checking out from the health food store, a local scientist friend is in line at the next register, checking out your stash of goldenseal.

“You know, you should really go read Science-Based Medicine to get the straight dope on that stuff.”

And so, here you are. And I’m here for you.

[Note to readers: Apologies to my hippie friends. I love you all. No hippies were harmed in the drafting of this blogpost.]

Is there any scientific evidence to support a common herbalist claim that whole plant materials are “better” than semi-purified extracts or pure, individual chemicals made by the plant?

And I can tell you this — it depends.

But as long as the National Center for Complementary and Alternative Medicine (NCCAM) is in existence, this is the exactly the kind of work that should be supported by this arm of the US National Institutes of Health. In a recent paper to appear in the Journal of Natural Products, Dr. Nadja Cech and colleagues from the University of North Carolina at Greensboro, Dept. of Chemistry & Biochemistry, used traditional separation chemistry and cutting-edge analytical chemistry techniques to address this very question.

[Update: I neglected to note at the time of posting that Catherine M. Cooney wrote a nice article on this work at the online site for Chemical & Engineering News.]

The medicinal use of goldenseal (Hydrastis canadensis L. (Ranunculaceae)) dates back to Native Americans of the Cherokee and Iroquois tribes. Goldenseal was used externally for skin and eye infections and internally for relief from gastrointestinal symptoms. Today, goldenseal ranks among the 20 top-selling herbal products in the US.

In her group’s paper, Cech demonstrates the cooperative action in goldenseal between berberine, a weak, naturally-occurring antibacterial compound in the plant, and other chemicals that make the berberine more active. Even more fascinating is that these berberine-enhancing chemicals have no antibacterial activity on their own. In other words, these other chemicals potentiate the bacteria-killing effects of berberine. This potentiation is a form of synergy, a process where the combined action of two or more chemicals is greater than the sum of the parts.

(Disclosure: I have a NIH-funded collaboration with co-authors on Dr. Cech’s paper but not with her laboratory.)

Cech and her co-workers had already known that berberine killed Staphylococcus aureus bacteria at relatively high concentrations. Microbiologists use a term called, “minimum inhibitory concentration,” or MIC, to describe the minimum concentration of a drug required to kill a population of bacteria. But Cech had also observed that some parts of the goldenseal plant could increase the action of berberine.

To find out what these chemicals were, Cech’s lab purchased whole goldenseal plants, crushed them up in a series of alcohols and solvents, and separated out the constituents using a process called flash chromatography. Picture a tube filled with a specialized type of sand, silica gel. When you pour a gimmish on top of this column of separation material, some chemicals stick to it and flow through the bottom of the tube rather slowly while others wash past the silica quickly. Other chemicals bind somewhere in between, allowing this complex plant extract to be separated into smaller groups of chemicals.

Each fraction of these chemicals were then tested in multiple combinations alone and together with pure berberine. The research team observed that some of these fractions could increase the antibacterial action of berberine by a factor of 16. This synergistic action was not due to berberine in the plant extract of other related antibacterial alkaloid compounds.

After repeating the separation and antibacterial assay several times, Cech used a molecular sizing technique called mass spectrometry to identify two compounds whose size had not been previously known to occur in goldenseal. The group then used nuclear magnetic resonance spectroscopy to determine the strengths of bonds between individual atoms in the chemicals.

This combination of techniques led to the identification of three flavonoid compounds responsible for this synergy. One of the goldenseal chemicals is called sideroxylin. The other compound turned out to be two isomers that share the same molecular size, 8-desmethyl-sideroxylin and 6-desmethyl-sideroxylin. But how do these chemicals work?

Staphylococcus aureus has a protein that pumps toxic compounds out of the cell. This pump called NorA considers the plant chemical berberine to be toxic to its survival. The siderloxylin compounds block the action of the NorA pump and allow berberine to accumulate in the S. aureus cells to cytotoxic levels. Cech demonstrated that in S. aureus cells lacking the NorA pump, these chemicals could no longer potentiate berberine’s antibacterial action.

Cech’s team then went back to the original plant material to investigate where these synergistic compounds were present. Interestingly, the sideroxylin compounds were up to 50-fold more concentrated in the leaves relative to the root and rhizomes. In contrast, berberine was 5-fold more prevalent in the roots. Cech writes,

The finding that goldenseal leaf extracts have higher levels of synergists while root extracts contain higher levels of alkaloids suggests the potential benefit of using a mixture of root and leaf material in the production of dietary supplements from goldenseal. Further studies would, however, be needed to evaluate the safety and efficacy of goldenseal leaf extracts in vivo.

Indeed, goldenseal still needs to be studied in living models of bacterial infections rather than on laboratory dishes containing an optimal growth medium. Nevertheless, the traditional use of goldenseal alone has caused the plant to be endangered due to overharvesting in the wild. The plants used for this study were instead cultivated in their native environment of hardwood forest understory. Cech’s work provides a strong argument for herbalists and herbal compounds to be more responsible in sourcing their products and use cultivated plants.

But the primary significance of this work is that substantiation of common claims for combined or synergistic action in herbal products requires intensive chemical and biological investigation by a multidisciplinary research team. In this one case of goldenseal, synergy does indeed exist. This synergy-directed fractionation research strategy should be applied to other natural products where similar cooperative activity is suspected.

Reference:

Junio HA, Sy-Cordero AA, Ettefagh KA, Burns JT, Micko KT, Graf TN, Richter SJ, Cannon RE, Oberlies NH, & Cech NB (2011). Synergy-Directed Fractionation of Botanical Medicines: A Case Study with Goldenseal (Hydrastis canadensis). Journal of Natural Products PMID: 21661731

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Few groups are more hazardous to public health than the anti-vaccine movement — because there’s a body count affiliated with their actions. When vaccination rates drop, communicable diseases re-emerge, and people suffer. While anti-vaccine sentiment will probably persist as long as vaccines are around, we’re fortunate that vaccination rates, on balance, remain very high. In 2009, U.S. vaccination rates for most childhood vaccines were over 90%. And less than 1% are completely unvaccinated. But do high vaccination rates mean that parents have confidence in the safety and effectiveness of vaccines? Most states and provinces maintain public health regulation that require documentation of vaccination status for school or day care admission. So vaccines may be seen as a requirement or obligation which may override lingering concerns. Do concerns remain? That’s what a recent survey undertook to explore.

I’ve blogged before on antivaccination sentiment, and its drivers.  It’s remarkable that viewing anti-vaccination material for even five to ten minutes can increase the perception of risk of vaccination, and decrease the perceived risk of omitting vaccines, leading to lowered vaccination intentions.  It tells me that as a health professional, I need to be ready to address vaccines concerns directly, honestly and completely. To do that, I need to be prepared for the common arguments and concerns about vaccinations. The SBM archives are a good resource, serving as a compilation for issues and topics of interest to its authors.

Allison Kennedy, an epidemiologist at the Centers for Disease Control (CDC) and other colleagues at the CDC used a consumer survey of parents to examine intentions, behaviors and concerns about vaccines. The survey also sought to understand common sources for vaccine information.This paper, Confidence about vaccines in the United States: Understanding Patient Perceptions, is unfortunately behind a paywall. So I’ll touch on the highlights of this survey, and what it means for those “in the trenches” of vaccine advocacy.

Kennedy’s analysis is data cut from a large survey on consumer behaviors and intent, the 2010 HealthStyles survey, which included 4,198 households. The analysis was limited only to households with children aged six or younger, shrinking the pool to 376 responses. It’s a small sample size, admittedly, so how representative these data are isn’t clear. In addition, the authors comment that one cannot infer causality: We don’t know if cited concerns preceded or followed vaccination actions.

Intentions

The majority of respondents (94%) intended to vaccinate their child with all recommended vaccines. Only 5% intended to partially vaccinate, and 2% (seven people) intended to leave their children completely unvaccinated. (Number don’t add to 100 because of rounding.) These number look good and seem consistent with the (U.S.) national vaccination goals. Reason to be reassured? Not quite.

Despite an overwhelming majority intending to vaccinate, only 23% reported no concerns about childhood vaccines.  The rest reported a number of concerns:

• 38% — painful to receive so many shots during one visit
• 36% — too many vaccines at once
• 34% — too many vaccines during first two years of life
• 32% — vaccines may cause fevers
• 30% — vaccines may cause learning disabilities, such as autism
• 26% — ingredients in vaccines are unsafe
• 17% — vaccines are not tested enough for safety
• 16% — vaccines may cause chronic disease
• 11% — vaccines are given to prevent diseases children are not likely to get
•  9% — my child will not be vaccinated on time because there’s not enough of some vaccines
•  8% — vaccines are given to prevent diseases that are not serious
• 23% — no concerns

This list should look pretty familiar. With the exception of concerns about shortages (which isn’t a negative against vaccines), this is a succinct summary of standard anti-vaccine arguments the contributors to this blog has addressed again and again.

The authors attempted to distill differences in concerns between parents that fully intended to vaccinate their children, and those that stated an intent to reduce or eliminate vaccines. As expected, everyone without concerns intended to fully vaccinate.  And as would be expected, there were more concerns among parents who intended to reduce or avoid recommended vaccines.  While there were some modest differences in the incidence of some specific concerns between the two groups, the sample size of the latter is too small to draw any meaningful observations.

Sources of Information

Fully 60% of parents sought out “some” or “a lot” of information on vaccine safety prior to any vaccination — not surprising given the movement for patients to become more involved as partners in care decisions.  Other people were cited as one of the three most important source of information, including health care professionals (85%), family members (46%) and friends (22%). The internet is a growing source of information, with 24% including it in their top three sources ( I discussed popular sites in a prior post) while traditional media, including television, newspapers, and magazines, are infrequent sources of information. Reassuringly, daytime television was a top information source for less than 1% of respondents, so Dr. Oz, no friend of science, may not have the influence on vaccination that his viewership might suggest.

Among professional organizations, the American Academy of Pediatrics and the Centers for Disease Control were also among the top sources of information. No SBM (yet).

Most respondents, when asked about their relationship with health professionals, gave generally good evaluations. Over half “strongly agreed” they trusted the advice of their health care professional, while 31% “somewhat agreed”.

Implications

We cannot be complacent when it comes to vaccination rates: Concerns about vaccine safety are prevalent in parents, even among those that intend to complete the vaccination schedule for their children. Clearly, anti-vaccination arguments are resonating, though thankfully they’re not translating into vaccine refusal in most parents. Given the dual importance of both the internet, and personal advice, on vaccine confidence, this survey reinforces the need to be aware of the shifting goalposts from the anti-vaccine movement, in order that we can be prepared to proactively discuss these concerns.  Moreover, non-professionals that are familiar with and can address typical anti-vaccine concerns should be able to have a meaningful impact on vaccine confidence.

This paper ultimately left me thinking about the complexity of understanding and addressing vaccine concerns. Parental concerns are far more nuanced than can be summed up in a single confidence parameter.  As advocates we need to do a better job of understanding the relationship between attitudes and behaviors, recognizing that simply having the facts available is just on component of maintaining confidence in vaccination.

Reference

Kennedy A, Lavail K, Nowak G, Basket M, & Landry S (2011). Confidence about vaccines in the United States: understanding parents’ perceptions. Health affairs (Project Hope), 30 (6), 1151-9 PMID: 21653969

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Any institution that is based upon science is also dependent upon the integrity of the scientific process, and must guard that integrity jealously. That is certainly one of the missions of Science-Based Medicine. A particular challenge is that medicine is a massively expensive enterprise, and growing in both absolute and relative terms. This means that there is a great deal of money at stake (to be potentially earned and spent) and this fact constantly threatens to distort the process of science that is supposed to underlie medicine.

In particular, wherever there are millions or billions of dollars to be made, the motivation to find clever and subtle ways to distort the scientific process is huge. We find such behavior among any industry that has a medical product or service to sell. A recent example of this behavior was recently published in the Archives of Internal Medicine – Study of Neurontin: Titrate to Effect, Profile of Safety (STEPS) Trial.

Krumholz et al. reviewed the documents resulting from Harden Manufacturing vs Pfizer and Franklin vs Warner-Lambert and concluded:

The STEPS trial was a seeding trial, used to promote gabapentin and increase prescribing among investigators, and marketing was extensively involved in its planning and implementation.

Seeding Trials

A seeding trial is a pharmaceutical industry term for a clinical trial whose true and stealthy purpose is not to do science but to expose the investigators to a drug. There  are often many comparable drugs that can be prescribed for the same indication, and manufacturers therefore want their brand to compete with the others. Also, many drugs are underprescribed and raising awareness among physicians and patients about a disease or condition and the availability of treatments will also serve to increase sales. There are perfectly legitimate ways to accomplish these goals — through honest advertising and medical education, for example.

A seeding trial is a dishonest way to promote a drug. The goal of the trial is to make the physicians who are the investigators in the trial more familiar with the company’s drug. This will demonstrably increase their use of the drug. Further, since “clinical leaders” at academic institutions are often chosen to be investigators, the hope is that they will spread their familiarity and use of the drug to their communities (hence the term “seeding” trial).

The authors of the study make note that marketing was involved in the planning and implementation of the STEPS trial. This is a no-no. Pharmaceutical companies have marketing divisions and research divisions, and they must never “cross the streams.” For example, in optimizing a trial as a seeding trial a company may choose many centers, each of which will recruit a few patients (the STEPS trial had 772 investigators). This maximizes the number of investigators, but is probably not optimal for doing good science.

This type of practice is unethical because it violates the trust of the subjects who enter the trial. As a society we have come to recognize that we have a great responsibility to human subjects of research. People offer themselves up to be experimented on with the understanding — the contract — that the research is legitimate, worthwhile, and every attempt is made to ensure that it is safe and that there is a reasonable probability of benefit. People who entered the STEPS trial did so with the understanding that the study would help improve the practice of medicine, while the real purpose was to promote a product.

The Archives paper gives ample evidence that the STEPS trial was not good science. It was uncontrolled and unblinded, with vague outcome measures. These concerns were even raised prior to implementing the trial. In short — it was bad science, probably because it was designed by marketers.

Conclusion

We can add seeding trials to the list of deceptive practices by industry that distort the science of medicine. This practice was known about prior to the Archives paper — but this is perhaps the best documented instance. I have also written before about companies ghostwriting scientific papers as another example of a deceptive marketing tool. These practices erode the institution of medicine. It seems that eternal vigilance is not only the price of freedom, but scientific integrity as well.

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