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Researching Magic

Neurologica Blog - 5 hours 30 min ago

David Gorski and I have just published a paper in Trends in Molecular Medicine titled: Clinical trials of integrative medicine: testing whether magic works?

While we have published literally thousands of online articles discussing these issues here, at Science-Based Medicine, and other venues, it’s great to get an article in the peer-reviewed literature, which hopefully will spark more of a discussion in academic circles.

The full article is available online at the link above, but here’s a quick summary of the main points:

The question is – should we devote limited research resources to investigating CAM (complementary and alternative medicine) methods? Those resources include not only money, but researcher time, available patients, and space for reporting and discussion at conferences and in the published literature. CAM is actually a false category, in my opinion, used really as a marketing strategy and not a meaningful designation. It makes it difficult to answer this question, because we first have to operationally define CAM. (As an aside, “integrative” medicine is essentially the same as CAM, just a different marketing term.)

The real question is – how far down the scale of plausibility should we go in allocating research resources? Should it matter?

David and I argue that it does matter. The primary reason is that the probability of scoring a hit (finding a treatment that works) becomes lower and lower as the plausibility of the treatment decreases. Of course we now have to define “plausibility.” Plausibility essentially refers to our best estimate of how likely a treatment is to work based upon all existing scientific evidence and our current scientific understanding of how the universe works.

If a treatment requires a dramatic change in our understanding of a disease, and that understanding has a solid basis in scientific evidence, then the treatment can be deemed relatively implausible. As an example, the liberation procedure for multiple sclerosis is based upon they hypothesis that MS is caused by blockages in the veins that drain blood from the brain. However, decades of research point to MS being primarily an autoimmune disorder.

This does not imply that our current understanding is always correct. We are talking about probability. Are we making a sound investment with this research, or playing the lottery.

Even more implausible would be treatments that violate basic laws of physics. In order for homeopathy to be true not only does our understanding of health and disease need to be wrong, but major areas of chemistry and physics would also need to be wrong. This gives homeopathy a plausibility that approaches zero.

Researching unlikely treatments is problematic for reasons other than just a low probability of finding an effective treatment. Statistical analysis and reviews of the published medical literature (specifically the work of John Ioannidis) find that the less plausible a hypothesis is the more likely it is to generate false positive outcomes.

Preliminary research itself has a false positive bias, and when such exploratory studies are positive they provoke follow up research which is larger, more rigorous, and therefore consumes more research resources. It may take 10-20 years of pre-clinical and clinical research to properly sort out if a treatment hypothesis is valid. This problem is exacerbated and more wasteful the less plausible the original hypothesis.

Therefore, from  a purely scientific and statistical perspective, research into highly implausible treatments are very likely to waste vast amounts of research resources without finding effective treatments. In fact, this has been the exact experience of the National Center for Complementary and Alternative Medicine (NCCAM). Through them Americans have invested billions of dollars in researching implausible CAM therapies, with nothing to show for it.

There are also less tangible social reasons to be concerned about researching implausible therapies. Proponents of such therapies (which usually means people with a vested interested in selling them) often point to the very fact that a treatment is being studied to argue that it is therefore legitimate (why else would they study it?). Combine with this the tendency of preliminary studies to be false positive, and a completely bogus therapy may enjoy 20 years of false legitimacy before definitive trials show that it is completely useless.

Even worse, CAM does not occur in a vacuum. It is part of a culture that “uses science as a drunk uses a lamp post, for support rather than illumination.” They have a history of distorting the process of science to suit their needs, engaging in bait-and-switch tactics, and attempting to change the rules of science in order to make negative evidence seem favorable. CAM often goes hand-in-hand with an anti-scientific, unscientific, or pseudoscientific world view. It is difficult to quantify the overall negative effect this has on our society.

Conclusion

Researching highly implausible medical therapies is very unlikely to result in the addition of new treatments to our medical options. It is unlikely to actually help reduce human disease and suffering.

It is very likely, however, to waste research and medical resources, to exploit desperate patients, create false hope, and distort the process of science and medicine. It is feeding into a culture that wishes to reduce or eliminate the standard of care in medicine, and to empower anyone who wishes to hang a shingle to sell any nonsense they choose with hyped health claims. The only real net effect of CAM research is to offer a patina of legitimacy to nonsense in order to better exploit the public with snake oil.

Categories: Medicine

Tens of millions for CAM research — and it’s all on your dime

Science Based Medicine - 8 hours 38 sec ago

The Federal Funding Accountability and Transparency Act (FFATA) was signed on September 26, 2006. The intent is to empower every American with the ability to hold the government accountable for each spending decision. The end result is to reduce wasteful spending in the government. The FFATA legislation requires information on federal awards (federal financial assistance and expenditures) be made available to the public via a single, searchable website, which is www.USASpending.gov.

And what subject is more deserving of being held accountable by the American people than complementary/alternative/integrative medicine?  After all, in what other area of government spending does scientific implausibility – indeed, even scientific impossibility – offer no impediment to spending millions of taxpayer dollars in research funds? We’ve complained about NCCAM’s wasteful spending on pseudomedicine here on SBM several times: here, here, here and here, among others.  As you shall see, the problem doesn’t stop at that particular $2.5 billion.

I ask you: does NASA fund astrology research?  No. Does it give money to schools teaching astrology? No. Does the Department of Transportation fund studies of perpetual motion machines as an “alternative” engine for vehicles?  Not to my knowledge.  How about the Department of the Interior?  Do they give people money to look for woodland nymphs?  Don’t think so.

The beauty of www.USASpending.gov is that it allows us to hone in on exactly who the beneficiaries of this wasteful government largesse are and what are they are being compensated for, over a period of 2001 to 2014. (Imperfectly, however.  The website is somewhat creaky and it’s not always clear how they are getting their totals. Also, I’m using amounts from a search of the “prime awards” only. Your results may differ.) That’s how I know the federal government has not spent a single penny on perpetual motion machines or locating woodland nymphs.  I did find one study of “Art and Astrology in Renaissance Italy” that got $40,000 from the National Endowment of the Humanities.  Of course, the 1300s – 1500s is exactly where astrology should be, along with acupuncture and other pre-scientific concepts.

Acupuncture

Acupuncture, on the other hand, has received more government funding than astrology.  Much, much more.  A whopping $76,848,958 since 2001, in the form of contracts, grants and direct payments.   Small Business Association loans accounted for an additional $250,000, including $80,000 to the Eternal Health Wellness Acupuncture Center in San Jose, California, which claims to treat a wide variety of diseases and conditions, such as MS, macro [sic] degeneration, bipolar disorder and herpes, among many others.

The biggest beneficiary of acupuncture research funds has been Massachusetts General Hospital, which received $23,229,593 from NIH between 2009 and 2014 (we are just shy of finishing the 2014 fiscal year).  Many of those research dollars went into brain imaging studies of patients being treated with acupuncture, or who were thinking about being treated with acupuncture (“An fMRI study of expectancy on acupuncture treatment outcomes in knee OA”).  As Steve Novella and David Coloquhoun pointed out, looking at surrogate outcomes is inappropriate until it is shown that patients get a useful degree of relief, and that hasn’t happened yet. (You can see some of the fruits of your tax dollars being used to stick people with needles and look at their brains  here.)

The Department of Defense and Veterans Administration are also big fans of acupuncture research.  Although they can’t match NCCAM, they’ve spent close to $8 million on such unpromising research projects as that conducted by the New England School of Acupuncture for “Effectiveness of Acupuncture in the Treatment of Gulf War Illness.” The school, recipient of a little over $5.5 million, promotes such appalling quackery as this:

Pediatrics in general and neurodevelopmental pediatrics in particular are perfect opportunities to apply the principles and practices of Chinese Medicine to help children manifest their destiny. In this two-day workshop, Stephen Cowan MD, developmental pediatrician and author of Fire Child Water Child will offer an in-depth discussion of the physiological unfoldings in child development and the treatment approaches to common developmental dysfunctions that include: attention deficit disorder, emotional dysregulation, learning disabilities and autism.

To add insult to injury, the school has a white coat ceremony for students.  Yet another honored medical tradition corrupted by “alternative medicine.”

The Department of Defense paid $750,000 to the Samueli Institute for “Acupuncture for the Treatment of Trauma-Induced Spectrum Disorder: A Three-Arm Randomized Pilot Study.” (The results of a Samueli sponsored study of acupuncture for PTSD touted before a Congressional Committee last year still have not been reported, as far as I can tell.)

The Samueli Institute is led by Wayne Jonas. M.D., and promotes “integrative medicine” and various “alternative” therapies, such as acupuncture and guided imagery, an issue I addressed before on SBM.  All in all, the Institute has received over $31 million in taxpayer funds from the Department of Defense and over $43 million in taxpayer dollars altogether since 2003, although none in 2014. 

Dr. Jonas recently wrote an opinion piece in JAMA Internal Medicine in which he expressed concern over opioid use for pain in the military and called for a “better way.”  And how might we discover this “better way?” More research on integrative medicine.  I think we can see where this is headed.

Perhaps just as disturbing as the actual studies are the monies spent in spreading acupuncture throughout the military.  Last year, the Henry M. Jackson Foundation for the Advancement of Military Medicine Research got over $3 million for acupuncture training “across clinical settings.”  Joseph M. Helms, MD, PC, (a proponent of medical acupuncture) has received $1.3 million,  much of it for education and curriculum development

Chiropractic

The government has spent almost $120 million on chiropractic, including $4.4 million on Small Business Administration loans to chiropractic practices.  There are also direct student loans, but those show up as $0, a curious outcome considering the default rate on chiropractic student loans runs into the millions of dollars. (Again, it’s not clear how the government is reaching the totals given on the website.) The balance is in grants, contracts and direct payments.

One of the primary benefactors of government monies is Palmer Chiropractic College, which received $14 million from the NIH and the Department of HHS Health Resources and Services Administration, as well as the military. These monies have gone toward the establishment of, and research conducted by, the Palmer Research Center. We’ve mentioned the Center before, in its conduct of a study which didn’t seem to produce much of anything in the way of useful results. (See Orac’s dissection here.)  That didn’t stop another $7 million plus from going to the RAND Corporation, which will, with the help of the Research Center and the Samueli Institute, conduct an even larger study of standard medical care alone plus standard medical care and “chiropractic care.” One wonders why not just spinal manipulative therapy, not “chiropractic care?”  At least that would help isolate the variable that may produce an effect. Or why not medical care and physical therapy?

The study’s title reveals a curious mixture of subjects: “Assessment of Chiropractic Treatment for Low Back Pain, Military Readiness, and Smoking Cessation in Military Active Duty Personnel.”  Smoking cessation, by the way, will not be a part of standard medical care – only the chiropractors will get to do that.  Let’s just imagine what the results will be: patients who get the extra time and attention beyond standard medical care will do better and this study won’t tell us why, including whether it was simply the extra attention.

But the problems with giving Palmer College all this money go beyond the questionable utility of spending millions of dollars on this study.  Palmer is firmly rooted in the non-existent subluxation and its students are required to be proficient in its “detection” and “correction.” As befitting a school loyal to the subluxation, it teaches quack diagnostic and treatment methods like the NUCCA technique and the Atlas Orthogonal Technique.  And although the Palmer College website is suspiciously silent on immunizations, chiropractic opposition to vaccination is well-known and one doubts that students are taught objective, evidence-based guidelines for immunizations.

The Center has also participated in other sketchy government-funded research, including the TACT trial.  This year, a study was conducted on “Effect of Lumbar Hypo & Hypermobility on Sensory Responses to Spinal Manipulation.”  Let’s decode this title.  Hypo/hypermobility of the vertebrae is of legitimate concern to manual therapists, but to some chiropractors this hypo/hypermobility is an indication of the presence of a “subluxation.”  In other words, it appears Palmer researchers are continuing to look for evidence that the elusive subluxation actually exists.

Why do I think this is a reasonable suspicion?  One, as discussed, Palmer College is loyal to the subluxation as a viable “theory” and teaches the concept and its clinical application to students.  Two, although the page was removed after I mentioned it in a post last year, as of July, 2013, the Center was telling the public that one of its three areas of research was “mechanisms of care, which encompass normative data, spine lesions (e.g. vertebral subluxation complex) and spinal manipulation/adjustment.”

Contrast the school’s credulous acceptance of a pseudo-scientific concept with the Palmer Research Center director’s taking the American Heart Association/American Stroke Association “to task” over their warning that stroke may be associated with cervical manipulation.  Here’s what Christine Goertz, DC, PhD, had to say about that:

“The facts are that VADs are very, very rare events, and there’s absolutely no research that shows a cause-and-effect relationship between chiropractic care and stroke,” said Dr. Goertz. “Doctors need to be careful about how they counsel patients based on misleading statements, like this one from the American Heart Association.” 

(Note the euphemistic “chiropractic care” used as a substitute for neck manipulation.)

In sum, looking for evidence of the non-existent chiropractic subluxation is perfectly reasonable, but we need research “that shows a cause-and-effect relationship between chiropractic care and stroke” to conclude that stroke may be associated with cervical manipulation.

Naturopathy, etc.

Compared to acupuncture and chiropractic, naturopathy has received a paltry $6 million since 2003, and the amount has dwindled to a less than $400,000 this year.  The majority of that was spent at naturopathic schools to teach naturopaths how to do research and most of it went to the National College of Natural Medicine, with a small portion going to Bastyr.  Educating naturopaths in research seems like a fool’s errand, since the evidence indicates they care little about evidence-based practice.  (See also: here, here and here, among others.)

A small amount of naturopathic funding went to actual research, including “Carpal Tunnel Syndrome and Static Magnetic Field Therapy.”  There was also a small (n=40) prospective study of adjunctive naturopathic care for Type 2 diabetes, in which patients got up to 8 visits to a naturopath in addition to medical care, but any positive results could not be attributed to anything the naturopaths did.  (This seems to be a recurring theme in CAM practitioner research: giving CAM an advantage in comparing it to standard medical care by providing extras to the CAM care group.)

Homeopathy got about $230,000 in government funding (including a study titled “Polysomnography in Homeopathic Remedy Effects” at the University of Arizona) although no money’s been spent since 2008.  Reiki, on the other hand, has gotten almost a million dollars, including over $400,000 paid by the Department of Defense to a “Reiki Master” in El Paso, Texas.

Why are we doing this?

As has been pointed out before, the government should not be funding research of pseudomedicine and quackery because it doesn’t appear to affect CAM practices. Why bother? It is also a terrible waste of resources.  How many other worthy projects went wanting due to lack of available funding?

But the spending has another deleterious effect.  It perpetuates institutions that have little respect for science.  It helps businesses get started that promote quackery.  Even where their operations are not directly affected by government largesse, this money allows those institutions to burnish their images with the presumed respectability of, for example, NIH research funding. It also builds infrastructure and allows the hiring of staff. I doubt there would be a Palmer Research Center without government funding.  According to its 2011 tax return, over half of the Samueli Institute’s annual expenses of about $12.5 million came from the government.  Dr. Jonas’s salary from this and a related organization were reported at just over $500,000.

Gosh, what we wouldn’t give for a measly half a million dollars to promote science-based medicine?

Addendum:  I had no idea when I wrote this post that a pointed and well-deserved critique of complementary/alternative/integrative medicine research would appear practically simultaneously  in the journal Trends in Molecular Medicine, written by SBM’s own David Gorski and Steve Novella.  Be sure to read the post below for more information and a link to this excellent article. 

 

Categories: Medicine, Skepticism

Clinical trials of integrative medicine: testing whether magic works?

Science Based Medicine - 13 hours 59 min ago

I just thought that I’d take the editor’s (and, speaking for Steve, the founder’s) prerogative to promote our own efforts. Regular readers of SBM are familiar with our message with respect to randomized clinical trials of highly implausible “complementary and alternative medicine” treatments, such as homeopathy or reiki. Well, believe it or not, Steve and I managed to get a commentary published in a very good journal in which we present the SBM viewpoint with respect to these trials. Even better, at least for now, you can read it too, because it doesn’t appear to be behind a paywall. (I’m at home as I write this, and I can read the whole thing on my wifi, no VPN needed.)

The article is entitled Clinical trials of integrative medicine: testing whether magic works? There’s also been a fair amount of news coverage on the article, and I’ve been frantically doing interviews over the last couple of days, including:

There are likely to be at least a couple more, given the interviews I’ve done; that is, unless editors reject the ideas.

In any case, Steve and I are interested in your comments. Trends in Molecular Medicine is good in that it published our article and it’s a pretty high impact review journal, but it doesn’t have a section for comments. So consider this your section for comments on our article.

Categories: Medicine, Skepticism

Vitamin K Refusal – The New Anti-Vax

Science Based Medicine - Wed, 08/20/2014 - 08:09

Variations of the vitamin K molecule.

A small but increasing number of parents are refusing vitamin K injections for their newborns, an intervention recommended since 1961. This is yet another example of the difference between a science-based and philosophy-based approach to medicine. Science has given us the tool of knowledge, and in medicine that knowledge can have very practical applications.

The term “vitamin” was coined in 1912 by the Polish biochemist Kazimierz Funk. A vitamin is an organic nutrient that an organism requires in small amounts but cannot synthesize in adequate amounts and therefore must obtain from the diet. Knowledge of specific vitamins, their food source, and their biochemical activity in the body, has allowed medical scientists to cure many serious nutritional diseases, such as scurvy, rickets, and blindness.

The Vitamin K family are derivatives of 2-methyl-1,4-naphthoquinone, a fat-soluble molecule. It is a cofactor necessary for the formation of factors that function in blood clotting and in bone formation. The primary effect of vitamin K deficiency is therefore bleeding. Infants are at risk for vitamin K deficiency because this molecule does not cross the placenta well. Infants are therefore born relatively deficient in vitamin K. Further, breast milk contains little vitamin K (regardless of the mother’s diet) so infants are at risk for vitamin K deficiency until they start eating solid food at around 6 months (see Clay Jones’ post on the topic here).

The standard of care for many decades has been to give all newborns a vitamin K intramuscular injection. This contains enough of the vitamin to cover them for 6 months until they start getting enough vitamin K in their diet.

Without supplementation, there is an incidence of vitamin K deficiency bleeding (VKDB) in the first week of life of 0.25-1.7%. There is also a late VKDB that is more severe but has a lower incidence of 4.4-7.2 per 100,000 live births. Bleeding most commonly occurs in the brain, and when severe it can be devastating and even fatal.

A single injection of vitamin K at birth significantly reduces the risk of VKDB. In fact, it virtually eliminates the risk. Recent studies looking at infants who have VKDB show that most or all of them did not receive vitamin K prophylaxis. This is a simple, safe, and effective preventive measure, essentially just giving a vitamin to newborns, that prevents a common and potentially devastating outcome. Why would anyone refuse such a clear homerun intervention?

As you might suspect – ideology can trump science and reason. A study published this week in Pediatrics by Sahni et. al. found that 0.3% of those in the study refused neonatal vitamin K. Those who did refuse were 14.6 times more likely to also have refused all recommended vaccines up to age 15 months. They were also 4.9 times more likely to have a planned home birth, and 3.6 times more likely to have delivered at a birth center. A New Zealand survey also published this year found that 100% of medical staff, but only 55% of midwives, agreed that all newborns should receive vitamin K.

One way to interpret this data is that there is a pattern of distrust of the medical establishment or distrust of science in general, and reliance upon so-called “alternative” approaches to birth and childcare. In other words, this is a result of ideology trumping science. As a result, there is an increasing incidence of early and late bleeding in infants.

The numbers of refusals are still low, but are rising fast, clustering in certain centers and hospitals. A recent Tennessee study found that in one hospital the refusal rate was as high as 3.7%. They also found that:

Of 102 vitamin K refusers surveyed, 47 (46%) responded; 31/47 (66%) identified bleeding as a risk of refusing prophylaxis. The leading reasons for refusal were desire for a natural birthing process (43%) and believing prophylaxis was unnecessary (43%). Hepatitis B vaccine and erythromycin eye ointment were also refused by 65% of respondents.

In other words, an irrational adherence to the naturalistic fallacy was largely to blame. This was possible combined with misinformation, but I have to wonder if the bleeding risk excuse was simply a post-hoc justification and not the true reason for refusal. Further, we see that those who refuse vitamin K also refuse other recommended interventions, including erythromycin eye ointment used to prevent blindness.

Conclusion

In my opinion, what we are seeing here are the downstream effects of the “alternative medicine” philosophy and world-view. Promoters of CAM often instill a general distrust in science and the institution of medicine. They promote dubious treatments with the notion that “natural” (even though poorly defined) is somehow inherently superior, and therefore interventions that seem technological are to be feared.

They have been unfortunately successful in marketing their philosophy. As a result there are parents who refuse for their newborn children safe and effective interventions supported by solid scientific evidence.

Categories: Medicine, Skepticism

The Reid Technique of Investigation

Neurologica Blog - Tue, 08/19/2014 - 08:33

If you like crime dramas, you have probably seen this countless times. The officer interrogating a suspect chums up to them, says they understand, and then offers them a face-saving version of guilt to which they can confess. It’s compelling drama.

What is being depicted is known as the Reid Technique, developed by John Reid in the 1950s. This technique remains popular, but is also highly controversial.

A recent study, however, claims 100% accuracy using the Reid technique to detect deception in 33 interviews. That is very impressive, but raises some red flags. The study also claims 97.8% accuracy is a second trial of experts interrogating suspects, and 93.6% accuracy when students viewed tapes of the interrogations in order to determine guilt.

The primary reason I don’t find the results compelling is that the psychological study may not be a good analog of real-life situations. The suspects were students who were participating in a fake psychological study and were cajoled into cheating by a confederate in order to obtain a monetary reward that was part of the fake study. The interviews were also fairly brief, 3-17 minutes.

It seems that this setup would minimize both false-positive and false-negative results. The students are hardly hardened criminals, and the setup is artificial. This might lower barriers to giving away guilt. Also, one of the criticisms of the Reid Technique is that it can pressure suspects into false confession, but those pressures were not present in the study.

The essence of the Reid technique is to interrogate the suspect with the presumption that they are guilty. The goal is to make them feel socially comfortable with confession – so the goal is to obtain a confession. Part of the technique is to offer the suspect a choice between two scenarios, one much worse than the other, but both involving guilt. If they admit to the lesser narrative, they are still admitting their guilt. The technique is deliberately manipulative, and is based on the assumption that an innocent person cannot be manipulated into confessing a crime they didn’t commit.

The primary criticism of the technique is that it can pressure people into false confessions. Interrogations can sometimes last for hours, and suspects might feel as if the only way to end the interrogation is to confess. They might naively believe that if they did not commit the crime the system will eventually find them innocent despite their confession. Therefore they confess as a way out of their current predicament.

The further problem here is that confessions tend to trump all other aspects of the case. Even hard evidence can be interpreted in order to be consistent with the confession, which people find very compelling.

In fact, Reid’s most famous case, and the one that established his fame, was later found to be in error - the 1955 case of Darrel Parker, who was convicted of killing his wife based upon a confession obtained by Reid himself, although Parker always maintained his innocence. Years later Wesley Peery, a career criminal, confessed to killing Parker’s wife. Parker was just recently fully exonerated of his guilt.

Critics of the Reid technique also point out that its main assumption, that guilty people will act anxious, is simply not true. Scientific research over the years has found little relationship between acting anxious and actual guilt. Some people can lie without anxiety, and others will be very anxious because of the accusation, even if they are innocent. This is the same reason that polygraphs are not reliable.

As with any test, it comes down to sensitivity and specificity. What is the probability of detecting someone who is guilty vs the probability of a false positive – believing someone who is innocent to be guilty? In a justice system based on the presumption of innocence, it is generally accepted that the primary goal is to minimize false positives, even if that means tolerating some false negatives.

The Reid technique, however, is the opposite. It seems to favor minimizing false negatives while tolerating some false positives.

There is an alternate technique that appears to be gaining popularity called “PEACE” (Preparation and Planning, Engage and Explain, Account, Closure and Evaluate). This technique is currently used in England, Newfoundland, Wales, Denmark and New Zealand.

The technique involves questioning the suspect but not trying to manipulate them or obtain a confession. Rather, it is based on the premise that lying is a larger cognitive load then telling the truth. If you keep circling back asking for more and more details, eventually the house of cards will collapse.

One article likens the Reid Technique to Starsky and Hutch, and the PEACE technique to Columbo – “Sorry, I hate to bother you, I just have one more question…”

It also seems to me that the PEACE technique is more analytical, while the Reid technique is more intuitive. With the PEACE technique the interrogator is looking for internal consistency and consistency with corroborating facts. The Reid Technique, on the other hand, relies upon picking up anxious cues and questionable assumptions about human psychology. Intuition is more susceptible to confirmation bias and other biases. The analytical approach is also subject to bias, but at least there is an ultimate appeal to objective facts.

In any case, the stakes are fairly high and therefore it is essential that researchers continue to evaluate different interrogation techniques.

Categories: Medicine

Pass the Salt (But Not That Pink Himalayan Stuff)

Science Based Medicine - Tue, 08/19/2014 - 03:00


Humans, like many other animals, crave the taste of salt. Animals frequent salt licks, humans have traded salt for equal weights of gold, and the word “salary” comes from the Roman soldier’s allowance for purchasing salt. Salt appears in our language in idioms like “worth its salt” and “salt of the earth.” Shakespeare’s play King Lear is a variant of a folktale where a daughter tells her father she loves him as much as meat loves salt. In a murder mystery I read years ago, a character listed the four food groups as sweet, salty, sticky, and chocolate.

It’s no fair: everything that tastes good turns out to be bad for us. We love the taste of salt, but dietary guidelines tell us we should all limit our sodium intake to less than 2.3 grams (2300 mg) a day to avoid high blood pressure and death from cardiovascular disease. And those who are over 51, African American, or who have high blood pressure, chronic kidney disease or diabetes should limit their intake even further, to 1500mg a day or less. (Note: the salt molecule consists of an atom of sodium and an atom of chloride; 40% of the weight is sodium, so 1500 mg of sodium equals 3750 mg of salt, roughly ¾ of a teaspoon. Over 75% of our salt is already in the food, not added from the salt shaker.) In 2010, the American Heart Association lowered its recommendations to 1500 mg a day for everyone. We thought that was good advice, but new evidence has muddied the waters.

In the latest issue of The New England Journal of Medicine, three new studies about the role of salt in cardiovascular disease were published. Instead of providing clear answers, they raise more questions. In a cute NEJM QuickTake cartoon video they summarize the findings of the studies. If you’d rather spend three minutes watching cartoons than reading my explanation, feel free.

Background

High blood pressure is a known risk factor for heart attacks and strokes. Numerous studies have shown a correlation between salt intake and blood pressure, but the correlation between salt intake and cardiovascular outcomes like stroke and death has not been so clearly established. The large INTERSALT study found a modest association between higher levels of sodium intake and higher blood pressure. Some systematic reviews of the literature have confirmed that association, others have not. A 2013 review in the British Medical Journal found that lower sodium intake was correlated not only with a lower risk of hypertension but also with a lower risk of stroke and fatal coronary heart disease. Prospective cohort studies have shown inconsistent associations between sodium intake and cardiac risk. Larger studies were needed to settle the issue.

First study: Association of Urinary Sodium and Potassium Excretion with Blood Pressure, by Mente et al.
Subjects: 102,216 adults from 18 countries. Method: single fasting urine levels of sodium and potassium were used to estimate 24-hour excretion, providing an indirect estimate of dietary intake. Findings: the association of sodium with BP was greatest in hypertensives, the elderly, and those who had the highest intakes of salt. It was greatest in those ingesting over 6 grams of sodium a day, modest in those ingesting 3-5 grams, and not significant in those ingesting less than 3 grams a day. They found an inverse relationship for potassium: higher levels of potassium were associated with lower blood pressures.

Second study: Urinary Sodium and Potassium Excretion, Mortality, and Cardiovascular Events, by O-Donnell et al.
Subjects: 101,945 adults from 17 countries. Method: as in the first study, single fasting urine tests were used to estimate 24-hour urinary sodium and potassium excretion; those estimates were compared to a composite outcome of death and major cardiovascular events. Findings: mean sodium excretion was 4.93 g. Compared to a reference range of 4.00-5.99 g a day, the odds ratio for death and cardiovascular events was 1.15 for high sodium excretion (over 7 g a day) but was even greater at 1.27 for a low sodium excretion (below 3 g). Higher potassium excretion was associated with decreased risk.

Third study: Global Sodium Consumption and Death from Cardiovascular Causes, by Mozaffarian et al.
The authors reviewed 205 studies on sodium consumption from 66 countries. Estimated mean global consumption was 3.95 grams a day, with regional means varying from 2.18 to 5.51. Daily sodium intake >6 grams a day was associated with increased risk of mortality and cardiovascular events. Surprisingly, so was intake of <3 grams. The lowest risk was in the 3-6 gram range. They used a computer model to estimate that 1.65 million deaths a year could be attributed to a sodium intake of greater than 2 grams a day. That’s about 10% of all cardiovascular deaths. The rate ranged from 4 deaths per million adults per year in Kenya to 1,967 per million in Georgia.

Discussion

We knew too much sodium was risky, but these studies raise concerns that too little sodium might be even worse. As the accompanying editorial points out,

They call into question the feasibility and usefulness of reducing dietary sodium as a population-based strategy for reducing blood pressure…the alternative approach of recommending high-quality diets rich in potassium might achieve greater health benefits, including blood-pressure reduction, than aggressive sodium reduction.

It may not be the potassium itself; diets rich in potassium are also rich in a lot of other healthy nutrients from fruits and vegetables.

These studies were large and well designed. They gathered an immense amount of data, looked at a variety of associations, and did their best to rule out possible confounding factors. But epidemiologic studies like these are imperfect by nature. The authors themselves pointed out several limitations of their studies, including the indirect way they measured sodium and potassium excretion.

What did we learn?

None of this really sheds any light on what we should do as individuals. Should we continue asking “pass the salt?” Should we abstain from adding salt at the table? Should we read labels and monitor the total amount of salt in our diet? Should we aim for 3-5 g a day?

These studies found associations, but they couldn’t determine causes, and they did not even attempt to measure what would happen if people changed the amount of sodium and potassium in their diets. If anything, they suggest that existing guidelines for salt restriction for the general population may be too extreme. They also suggest that “moderation in all things” and “eat your vegetables” are still good advice.

Bonus question: What kind of salt should we use?

A related question is whether some kinds of salt are healthier than others. Sea salt, table salt, kosher salt, flavored salt, fleur de sel, Hiwa Kai, Black Hawaiian Sea Salt, Kala Namak, “organic salt,” and Pink Himalayan Sea Salt are all basically the same chemical, sodium chloride. Only the trace amounts of other substances vary. Table salt is fortified with iodine and is a highly effective way to prevent iodine deficiency and goiter. Gourmet cooks swear by the taste differences of different salt varieties. Pink Himalayan sea salt was introduced to me by an e-mail correspondent who questioned the claim that it contained “84 trace minerals that promote health and well being.” I questioned it too, so I did a little research.

Mike Adams, the infamous Health Ranger, explains that Himalayan Pink Crystal Salt contains the full complement of minerals and trace elements “just like Mother Earth intended.” It is an unrefined, unprocessed raw salt mined by hand from salt caves that formed 250 million years ago as ocean salt settled into geologic pockets. It is stone-ground, which apparently doesn’t count as “processing.” Table salt is bad stuff, you see, since it was processed to remove all the good stuff and then they had to replace the iodine because people who ate it started to get goiters. Oh, and incidentally he sells the good stuff on his website and even offers a discount.

I found a website that reports the results of a spectral analysis. I think this is where the claim comes from. Even if this analysis is accurate, it is meaningless for health and if anything is worrisome. The amount of minerals in it is too minuscule to make any difference, and we already get plenty of the same trace minerals from other elements of the diet. They claim that two double-blind studies were done, but no such studies are listed in PubMed. There is NO evidence published in peer-reviewed journals that replacing white salt with pink salt makes a shred of difference or leads to any improvement in health.

If you read down the list of minerals, you will notice that it includes a number of radioactive substances like radium, uranium, and polonium. It also includes substances that act as poisons, like thallium. I wouldn’t be worried, since the amounts are so small; but if anyone believes the trace amounts of “good” minerals in Himalayan sea salt are good for you, why would they not believe the trace amounts of poisons and radioactive substances are bad for you?

The claim that pink Himalayan salt contains 84 trace minerals may be true, but the claim that it “promotes health and wellness” is false until proven otherwise by legitimate clinical studies. While waiting for evidence, I’d just as soon my salt didn’t contain uranium.

Categories: Medicine, Skepticism

Planned Obsolescence and Attribution Fallacy

Neurologica Blog - Mon, 08/18/2014 - 08:28

There are multiple threads to this story, all revolving around how we make sense of the data before us. Regular readers will likely not be surprised to hear that we tend to labor under a host of cognitive biases that lead us from an accurate interpretation.

This story starts with big data – a loose term referring to the access to massive amounts of data made possible by the internet, search engines, and social media. Google, for example, can track search terms in real time and look for trends. Tracking search terms related to the flu, for example turns out to be an accurate predictor of flu outbreaks.

Recently, Harvard University PhD student Laura Trucco searched through Google Trends and found that searches for “iPhone slow” tend to peak just before Apple is set to release a new model of iPhone. This lead to speculation that perhaps Apple is deliberately gimping older models of the iPhone in order to motivate users into upgrading.

The first question we have to ask is this – is the trend real? When mining large sets of data for correlations or trends, it’s easy to get fooled. By chance alone, there will be statistical anomalies. The probability of finding such anomalies increases the more open the search. So if you are looking for “any correlation” you are likely to find them.

In this case the search seemed fairly focused and the trend consistent, so it is reasonable to tentatively assume the trend is real. In order to confirm it, however, we would need to take a look at a fresh data set, hopefully prospectively. If the trend replicates, that would be convincing confirmation.

Assuming it’s real, the deeper question is, what does it mean? There are at least two possible interpretations. One is that iPhone users perceive their existing iPhones to be slow, even though they aren’t. The second is that existing iPhones do become slower just prior to a new release. These are not mutually exclusive. Some other cultural phenomenon may also be at work, but let’s stick with these two.

This is where another cognitive bias kicks in – the fundamental attribution error. This is the tendency to assume that the actions of other people are driven by internal factors, while we are happy to excuse our own behavior based upon external factors. If you trip walking down the sidewalk, you are clumsy. If I trip, it’s because there was a crack in the sidewalk.

Related to this is Hanlon’s Razor – “Never attribute to malice that which is adequately explained by stupidity.” The reason such an adage is necessary is to counter the tendency to assume that the harmful actions of others are due to deliberate malice, when there may be other explanations. Hanlon offers stupidity as a likely alternate, but I would generalize the rule  - there may be other internal factors, or unknown external factors.

So – if the iPhone performance becomes slow prior to a new release, there is a tendency to assume that Apple is doing this deliberately, as part of planned obsolescence, to motivate users to upgrade.

The notion of planned obsolescence is a complex one. To quickly summarize, it’s the belief that companies deliberately gimp their products so that they will not last long and will have to be replaced. Similarly, they may hold back on innovations so that they can be released later.

It is impossible to make too many sweeping statements about this, as there are many thousands of companies in various markets and industries and it’s likely the full spectrum of behavior can be seen. What is interesting is the tendency to assume deliberate planned obsolescence in specific cases, when many other factors are likely at work.

Just to give some basic examples: using cheaper materials may be cost effective, genuine improvement may make older designs obsolete, and there is no reason to engineer a product to last longer than is usefulness.

At the same time, companies use style and fashion to motivate customers to upgrade, or they may add features that are not genuinely useful, or they may abandon support for older models.

Bottom line – there is a certain amount of truth to the notion of planned obsolescence, but the full story is much more complex. Cynically assuming deliberate obsolescence in an individual case is therefore not always going to be accurate.

I therefore wanted to know, in the case of iPhones, is the slowness of older models real, and if so, what’s the cause?

On the latest episode of the SGU I interviewed Rene Ritchie, who is an Apple product expert. You can listen to the interview for the full discussion, but here’s the quick version:

Apple is the one company where hardware and software are connected. Other smartphone products have phones made by several companies and the operating system by another. This means that, before the release of a new hardware version of the iPhone, Apple does release a new operating system designed to handle all the new features. The new operating system is optimized for the new model, and older models may therefore run slower . 

In addition, new operating systems often add new features. In fact, customers will complain if they don’t get the new features on their older phones, thinking that this is deliberate obsolescence. New features will often slow down overall operation.

In addition, some of the perception may be illusory. Users pay more attention to the performance of their phone when a new model is announced. Finally, as any computer user will know, operating systems tend to slow down over time as new apps are added and the system gets a little clogged.

The real story is that Apple is dealing with a number of variables – compatibility, adding features, making genuine improvements, and the overall satisfaction of their customers. They also have to deal with competition – gimp their phones and users may decide to buy an Android instead. Having a reasonable life-expectancy is part of the value of their brand, and they wouldn’t necessarily tarnish this by deliberately pissing off users.

Therefore, even if Apple execs were making cold greedy decisions in their board rooms, this would not necessarily lead to the decision to deliberately make older iPhones slower. There are many other factors – yet our minds tend to go directly for deliberate manipulation (internal vs external factors).

Conclusion

The lesson from this one case is that, it is generally good to assume that any similar situation is likely more complex than it may at first appear. People, institutions, companies, and governments are complex, with a host of internal and external motivations and constraining factors, perhaps a complex history, and sometimes quirky factors you never would consider.

Therefore, don’t leap to conclusions. Step back and question the immediate assumptions you want to make, which usually will involve the notion that deliberate malice or manipulation is at work.

Taken to its extreme, this cognitive bias leads toward conspiracy theories. That’s why I say – we all have a little conspiracy theorist inside. The difference between an average person and a hardcore conspiracy theorist is generally one of degree.

Categories: Medicine

“Atavistic oncology” revisited: Dr. Frank Arguello responds

Science Based Medicine - Mon, 08/18/2014 - 03:16

The following post will be of a type that I like to refer to as “taking care of business.” That’s not to say that it won’t be, as my posts usually are, informative and entertaining, but it does say that I’m doing it instead of what I had originally had in mind because something came up. That something is a rather unhappy e-mail from the doctor whom I wrote three weeks ago. It’s just an indication that, although it’s a great thing that this blog is becoming more and more prominent, it’s also a two-edged sword. People actually notice it when I (or other SBM bloggers) criticize them for quackery. We see this in how Dr. Edward Tobinick has launched what I (and many others) consider to be a frivolous lawsuit against SBM founder Steve Novella over a post from 2013 clearly designed to silence criticism. It’s legal thuggery, pure and simple. That’s the bad end of the spectrum. I’ve been at the receiving end of similar retaliation that could have just as bad an impact on me personally as far as my career goes when antivaccine activists tried to get me fired from my job four years ago.

The more common (and far less agita-inducing) end of the spectrum consists of e-mails or letters of complaint. Sometimes they come from eminent radiologists who don’t like my criticism of their attacks on mammography studies. (Actually, truth be told, it is rarely eminent radiologists—or eminent physicians and scholars—who complain.) More commonly, it’s practitioners who object to how their treatments have been described. This time around, it’s a man named Dr. Frank Arguello, whose “atavistic chemotherapy” I described as quackery in one of my typical long posts that also explained why. Last week, I received this e-mail from Dr. Arguello:

Dear Dr. Gorski,

I was recently referred to the online comments you wrote against my efforts to help people with cancer: Comments

I am 100% sure this approach will change the practice of oncology in the world. It will be a historical work, and you and your comments online, even if removed, will live in infamy. We had been previously informed that you contacted the Saskatchewan College of Physicians and Surgeons in an effort to stop me. Failed!
I believe your actions online are a disservice to the community, particularly with your most recent comments about the science of atavistic oncology, not because you criticize questionable therapies around, but because you do not provide nor make any efforts to improve our current devastating results with conventional therapies.

I am starting to believe what is said about you, that you are a paid magnate from the pharmaceutical industry. You must be, because my clinical cases (not testimonials as you call them) are so compelling, that your actions can only be explained as coming from a person who does not understand clinical oncology and/or has an agenda to perpetuate our devastating oncological practices.

If you are not a paid magnate from the pharmaceutical industry, and you are genuinely interested in the science and treatment of cancer, are truly interested in helping people with cancer, and do not want to live forever in infamy, I challenge you to:

(1) Publish this letter next to your posting online and accept my public challenge posted on my website. I have a new patient from Hamilton, Ontario with disseminated melanoma. All medical records and CT-scan images are available from Prince Margaret Hospital in Toronto from as recently as last week. He had an inter-consultation with the Chair of the Melanoma Center at the Massachusetts General Hospital, Dr. Donald Lawrence, and we have his written opinion about that case.

You will not be responsible for expenses as stated in the original challenge on my website. But you will need to comply with all the public and medical scrutiny of the patient, treatment and results over time to be made known publically. I am meeting in Los Cabos with the patient this Saturday, August 16, 2014 to begin treatment. I could discuss this public challenge with him.

If you are in fact a paid agent from the pharmaceutical industry, or just a shameful character and enemy of science and medical progress, I propose the following:

(2) Put a link on the page of your comments, so that people can have a genuine scientific rebuttal to your comments. I would write and post this rebuttal online for this specific purpose.

I would like to clarify that my clinic was opened in Los Cabos in 2013, not 2002. You did not see publications from 2002, because I was working in medicine, but outside academia. Among other things, I was creating with my brothers a state-of-the-art, seven-floor high and now successful private Institute of Sciences and Genomic Medicine in Torreon, Mexico.
(http://www.institutodeciencia.com/gallery/gallery.htm)

Our institute has been visited by many important scientists, most recently by Dr. Kary Mullis, the Nobel Prize winner in chemistry in 1993 for his invention of the polymerase chain reaction (PCR), a process which is hailed as one of the monumental scientific techniques of the twentieth century. (http://www.institutodeciencia.com/aboutus.htm)

Thank you for your kind consideration of my proposal.
Respectfully,

Dr. Frank Arguello

P.S. I have recently compiled a number of articles from the early 1900s and late 1800s on survival times of patients with a variety of cancers. It appears that people live less now with our therapies (chemotherapy and radiation), when compared to untreated disease. Attached is a letter I just sent to an oncologist who contacted me several weeks ago to see if I could treat a patient with esophageal cancer. I rejected the case because it was terminal. In that recent letter, I question our practices, as I did with Dr. Lawrence, whom I mentioned above. I am planning to write an article regarding that, and if interested I could send you a draft prior to submission.

There was an attachment that led to a letter in PDF format from Dr. Arguello to Dr. Was Mansoor, a Consultant in Medical Oncology at the Christie Hospital in Manchester, England. I am not going to provide a direct link to the PDF because it mentions a patient’s name. I will, however, quote the letter dated August 11, expunging any patient-identifiable information:

Dear Dr. Mansoor,

I was contacted by XRX on July N, 2014, to let me know that her brother RXR had died. She mentioned that he died peacefully, but she still felt it was a bitter end to a valiant 18-month fight against the pain and his esophageal cancer. Unquestionably, it was an admirable effort from him as a cancer patient, and you as his oncologist.

In recent years, I have become concerned that patients “fights” against cancer are unfair, and destined to fail, because they are fighting with the wrong weapons. It is a fight where the outcome is already known before the “fight” starts, whether the patient maintains a positive attitude or not. The actual number of deaths due to a given cancer type can be predicted, even years in advance, regardless of our efforts. This trend will continue year after year if we do not change our way of thinking and our oncological practices. Obviously, all cancers are curable, and they have been curable for centuries, if removed completely with surgery before cancer cells have escaped to distant organs. The problem is for those patients in which cancer has escaped curability with surgery. Are we really treating and benefiting those patients with our current treatment approaches?

I have been studying the survival time of people with cancer who were never treated with our modern approaches of chemotherapy and radiation, not even surgery. Since it is extremely rare to find, today, cancer patients not exposed to some form of treatment, I collected papers from the 1800s and the first decades of the 1900s discussing survival time of untreated cancer patients. In the case of esophageal cancer, I found an article which reports the median survival time of 74 untreated patients with esophageal cancer seen at Middlesex Hospital, London, England, between 1883 and 1922. It reports an overall median survival time of 14.7 months (19.4 months for females and 12.1 months for males – with a range of months to several years) (Reference-1924). These are patients who did not receive any form of surgical treatment (medical treatments obviously did not exist at that time other than opium).

In a recent, 2014, study in the Netherlands involving 127 patients with inoperable or irresectable esophageal cancers, patients were divided into two groups – one group received chemotherapy and radiation and the other group radiation alone. The median survival time was 14 and 9 months, respectively (Reference-2014). There could be better survival times reported in the medical literature, but I selected this study because it is a large population of patients with inoperable esophageal cancers, and it emphases to toxicity inflicted in these patients with these forms of therapy.

Obviously, a treatment is of benefit only if it increases for a reasonable period of time the anticipated survival time without that treatment. In theory, we should be doing far better today in 2014 than 100 years ago, because aside from chemotherapy and radiation, we have potent antibiotics, blood transfusions, parenteral feeding, gastrostomies, stents, intensive care units, etc., which did not exist in the late 1800s and early 1900s. But this does not appear to be the case.

I am writing to you because I recently sent an e-mail to Dr. Donald Lawrence at the Massachusetts General Hospital (e-mail attached) with similar shocking findings with respect to our modern treatment for cutaneous and uveal melanomas (attached). I would like to extend the same invitation to you to reconsider what you are doing, what you could do, and invite you to help me to change our current oncological practices by taking my “Public Challenge” posted on my website. Although offered for breast cancer, we will take the challenge treating advanced esophageal cancer.

Respectfully,

Frank Arguello, MD
Atavistic Oncology Clinic
www.AtavisticChemotherapy.com
Former Assistant Professor of Oncology,
and Pediatrics, Hematology and Oncology,
University of Rochester School of Medicine and Dentistry. Rochester, New York USA.
Former Senior Scientist, Division of Cancer Treatment & Diagnosis, National Cancer Institute, National Institutes of Health.
Frederick, Maryland USA.

Dr. Gorski responds

I don’t know about you, but I find it quite odd that Dr. Arguello refers to himself on his official letters not by simply listing himself as the founder and director of the Atavistic Oncology Clinic, his current position, but by listing his previous positions, the most recent of which (his position at the NCI) he left 14 years ago. This is a signature, not a CV! Of course, the reason Dr. Arguello does this is obvious. It’s to assert to the world that he was once a real scientist and real oncologist, rather than an atavistic oncologist. How many people will mentally ignore the word “former” or even remember it? My immediate reaction upon seeing this was great amusement, and I’m sure that anyone who’s held an academic medical position will be similarly amused upon reading this.

Be that as it may, let’s take a look at the substance, such as it is, of the complaint. First, of all, I never contacted the Saskatchewan College of Physicians and Surgeons in an effort to stop Dr. Arguello. Perhaps someone else did, someone who was concerned about the spread of cancer quackery in Saskatchewan, but I assure Dr. Arguello that I did not. He can believe me or not. I don’t care, because, if someone really did try to stop him in Saskatchewan, I completely approve.

Next up, Dr. Arguello accuses me of not making any effort to improve existing therapies for cancer. This is, of course, utterly ridiculous, given that I have spent the last 15 years on the faculty of two different NCI-designated comprehensive cancer centers, where I’ve been funded at different times by private foundations, the NIH, and the Department of Defense to study ways to improve the treatment of breast cancer. Before that, I did laboratory research in what was then the cutting edge field of tumor angiogenesis. In addition, these days I also serve as one of the directors of a state-wide quality improvement initiative for breast cancer treatment. So it’s demonstrably wrong—and easily so!—to claim that I don’t do anything to improve cancer care with my career.

Of course, quality improvement through clinical trials and the mundane but necessary (and grueling) task of encouraging adherence to evidence-based guidelines is not what Dr. Arguello apparently considers to be “improving” cancer care. I’m just not going about it in the way that he approves of. He thinks I should be supporting him. What he doesn’t realize is that I would support him if he could provide evidence that his treatment works significantly better than the current standard of care. That’s the problem. He hasn’t provided such evidence and still doesn’t. Even worse, as I discussed last time, it’s not even clear what exactly he is giving his patients. He doesn’t tell them. He doesn’t provide detailed protocols. He’s so afraid that someone will steal his allegedly revolutionary idea that he doesn’t even tell his patients what they’re getting, except vaguely, unless there is a problem.

So instead Dr. Arguello resorts to the oldest form of ad hominem argument in the quack book of strategies: The “pharma shill” gambit. I must admit, I chuckled when he referred to me as a “paid magnate from the pharmaceutical industry.” Normally, I wouldn’t make fun of a comment like that coming from someone who is not a native English speaker, but Dr. Arguello lived and worked in the US from 1987 to 2000 and writes reasonably well, if his letters are any indication. Thirteen years in the US ought to have been enough for him to learn the meaning of the word “magnate,” namely someone who has great power and wealth in a particular business or industry. Even if I were a “pharma shill,” I would most definitely not be a pharma magnate (I don’t even run my own company!), and if I really were a pharma magnate does Dr. Arguello honestly think that I’d bother with the likes of him? (Besides, personally, I prefer the term “shill” or “minion.”)

Ignoring the ad hominem, let’s move on to the two “challenges” Dr. Arguello makes. The first part of his challenge is easy. He wants me to publish his letter? I publish his letter! Part one done! I’ll even make sure there’s a link to this in the previous post, and in my response to Dr. Arguello I pointed out that no one is stopping him from diving into the comment section to make his case that I’m a nefarious pharma shill/minion/magnate out to destroy his great new discovery because it will bankrupt the pharmaceutical industry of which I am a magnate. I repeat that offer here. I promise, as editor, that his posts will be approved; that is, unless they become quite abusive. I will also e-mail him a link to this response.

The second part of his challenge is not so easy for a number of reasons, not the least of which are ethical. First, patient challenges like this are not how science is done. To me, they’re unethical as hell, even if the patient gives permission. There’s also the rather major issue of patient confidentiality. I know HIPAA, the patient confidentiality laws in the US, but I don’t know what the equivalent to such laws is in Canada and Mexico. Regardless of what they are, following a patient like this that I’m not taking care of and who is not herself placing her scans and medical records in a publicly accessible repository (as Stanislaw Burzynski patients that I blog about do) makes me very uncomfortable—skeevy, even. So, no. I can’t do that.

I realize that Dr. Arguello thinks he’s making it easier for me by altering his original challenge that is on his website by not requiring me or my cancer center to pay for all patient expenses, but it’s a smokescreen. In this case, it’s one of his patients from Canada. In his original challenge, he expects the doctor (and institution) accepting the challenge to do all the work and bear all the expenses. This would be human subjects research, even if it’s only a single patient, because the treatment is very much nonstandard, even if a lot of what Dr. Arguello proposes is to use existing drugs off-label. Come to think of it, if I were a pharma magnate who happened to own a company that made some of the drugs or vaccines that Dr. Arguello uses for his “atavistic chemotherapy,” I might want to fund him, because if he really did have a treatment so much more effective than standard of care using my drugs off label, well, the profit potential would be fantastic! In any case, no institutional review board (IRB) worth its salt would approve a single patient experimental protocol using a drug protocol in which the drug identities, exact dosing and schedule, and duration of therapy aren’t spelled out in exquisite detail, and I know my IRB wouldn’t approve such a single patient study. Nor should it!

Of course, single case “challenges” are not in general particularly informative, especially for cancers like melanoma, which, as Dr. Arguello should know, can have variable courses, even when diagnosed as stage IV. Indeed, as Dr. Arguello should know, it is unclear whether the dominant driving force in melanoma long-term survivors is the host immune response against the tumor, inherent indolent disease biology, or response to therapy. So, even if the new patient Dr. Arguello patient were to be fortunate enough to turn out to be one of these long term survivors, it would not constitute compelling evidence that his treatment works. Those of us who’ve taken care of melanoma patients (as I have, albeit in relatively small numbers) or had a partner who takes care of a lot of melanoma patients (as I have) has seen outliers, patients with stage IV melanoma who have survived far longer than expected. The same is true of breast cancer (which, not coincidentally, was the main cancer in Dr. Arguello’s challenge before he made this one to me). That’s why we do clinical trials. A successful clinical trial would impress me far more than a single patient with a type of tumor that can produce long term survivor “outliers,” even in stage IV patients, as breast cancer and melanoma can. Dr. Arguello even seems to acknowledge that, as he turned down a case of esophageal cancer because it was “terminal.” Well, so is stage IV melanoma. Why does he accept stage IV melanoma and breast cancer cases and not esophageal cancer?

Now, I’ll take my lumps for getting one thing wrong. Dr. Arguello didn’t found his current clinic until 2013, and I will correct that in my original post. He does, however, have his El Instituto de Ciencia y Medicina Genómica (Institute of Sciences and Genomic Medicine) and his practice, founded in 2002. A perusal of the website using my rudimentary knowledge of Spanish plus Google Translate reveals that this is a “Mexico-British biotechnology company dedicated to scientific research in the field of gene and cell therapy. We also provide a diverse range of molecular and clinical laboratory analysis to other laboratories and hospitals around the country , as well as doctors and public in general.” Interestingly, I note that this company has contact with Kary Mullis, the Nobel Laureate who is best known for having in essence invented the modern day version of the polymerase chain reaction (PCR). One wonders what he thinks of atavistic chemotherapy. Or maybe one doesn’t. Mullis, as anyone who’s taken time to look into his history knows, has serious crank tendencies, not the least of which is HIV/AIDS denialism, a belief in astrology, anthropogenic climate change denialism, astral planes, and a belief in alien abduction. If I were Dr. Arguello, I don’t know that I’d be so anxious to advertise a connection with Kary Mullis, at least not if what I wanted was scientific respectability. In any case, what Dr. Arguello’s company appears to offer are molecular analyses for various purposes, including paternity, infectious diseases, genetic diseases, as well as cryopreservation of umbilical cord stem cells and of semen.

Of course, if I am a pharma magnate, Dr. Arguello wants me to “Put a link on the page of your comments, so that people can have a genuine scientific rebuttal to your comments. I would write and post this rebuttal online for this specific purpose.” As I’ve pointed out, though, there’s nothing stopping him from posting a comment after the original article, and there will be nothing stopping him from posting a comment and refuting me to his heart’s content after this post.

His final point rests on a publication from 1924 in which, or so he alleges, that the survival for esophageal cancer was actually better 100 years ago than it is now. To this end, he cites a paper from 1924 and compares it with a paper from 2014. Arguello notes that the median survival reported in 1924 was 19.4 months for females and 12.4 months for males. He then compares this to a series from 2014 examining patients with inoperable esophageal cancer, for whom median survival was 14 months with chemoradiation and 9 months for radiation alone. Does anyone see the problem with this comparison? I did, immediately.

First of all, the way esophageal cancer was diagnosed 100 years ago was very different than the way it is diagnosed now. During the time period when these cases were accumulated, endoscopy wasn’t routinely used. There weren’t even barium swallows These days, flexible endoscopes, with biopsy attachments are used to diagnose lesions of the esophagus. It’s also not a valid comparison to try to compare esophageal cancer in 2014 with 1924 and earlier, particularly cancer from 2014 that is inoperable. After all, what constituted “inoperable” 100 years ago was very different than what constitutes “inoperable” today. It’s a huge difference. Modern surgical technique allows us to remove tumors that no surgeon could have removed 100 years ago without killing the patient. Also, likely mixed in with the 1924 case series are benign tumors such as leiomyomas and tumors of less aggressiveness, given that there is no mention that there was verification by pathology in the paper. Finally, today cancer survival is calculated from time of diagnosis, not time of onset of symptoms. That means from the time that a biopsy is taken and cancer is demonstrated. I notice in the paper that “the natural duration of the disease in each case has been taken as that period which elapsed between the date of reputed onset as determined from the patient’s history and the date of death.” That alone could easily add several months—or even a year or more—to the survival times observed compared to now.

Round two and conclusion

After I responded to Dr. Arguello, he wrote back with a lengthy response. Given that it’s pretty much just repeating the same things again, I won’t be doing a blow-by-blow, but for completeness’ sake I will included it as an addendum to this post. What I will address are a couple of issues.

First, I note the same excuses we’ve heard from time immemorial that dubious practitioners trot out whenever they are challenged over why they don’t do clinical trials. After all, even Stanislaw Burzynski has done clinical trials! Dr. Arguello has done none, but he sure has a lot of excuses! Excuses aside, it is completely unethical to be administering this “atavistic chemotherapy” to patients under anything other than the auspices of a properly designed clinical trial with IRB approval (or approval from the equivalent ethics board in another country, if the trial is done elsewhere). It is even more unethical to charge patients for such a treatment outside of a clinical trial; there’s no excuse for that. I do find it interesting, however, that the Cancer Treatment Centers of American might consider such trials. All I can say is: When it comes to getting IRB approval, good luck with that. You’ll need it. Well, that, and, given the history of CTCA, I can’t think of a more “appropriate” partner for such scientifically questionable endeavor.

Finally, there’s his accusation that I did not read his book (which I didn’t, it’s true) and that I didn’t review the recent literature on cancer atavism. I didn’t need to read his book because (1) if what’s in his book is anything like what’s on his website then I know more than enough to know how wrong it is and (2) I know it’s wrong because I did review the recent literature on atavism for my last post, including the article by Davies and Lineweaver in Physical Biology entitled Cancer tumors as Metazoa 1.0: tapping genes of ancient ancestors. Indeed, I specifically cited that paper and discussed it in my post, along with several others. That Dr. Arguello didn’t notice (or ignored) that fact does not speak well of his observational powers. If Dr. Arguello wants to send me a copy of his book (preferably as an e-book readable on my iPad), I might just read it. Otherwise, I’m not paying for it. In fact, I learned there’s a new article fresh off the press making the same arguments. I might very well have to analyze that one too.

The bottom line is simple. The atavastic hypothesis of cancer, either as described by Lineweaver and Davies or by Dr. Arguello, is not a compelling hypothesis. It’s based on a misunderstanding of evolution and, as I discussed in detail last time, makes no good testable predictions about cancer and cancer treatment that are distinct from approaches that we are already taking in cancer research. Meanwhile, anecdotes demonstrate little or nothing, but it would appear that that’s all we’re going to get from Dr. Arguello. Note in that passage above that, Instead of publishing his results in a peer-reviewed journal, Dr. Arguello is basically declaring himself above it all (“I am not their peer”) and telling us that he will just publish another book. Guess what? I don’t care. It won’t impress me. If Dr. Arguello wants to prove he’s really on to something, the path forward is simple, but not easy: Do the work. Do the science, and do the clinical trials. Until then, don’t charge patients for an unproven treatment based on a dubious hypothesis.

And, as I have repeated before, Dr. Arguello is more than welcome to dive into the comments and demonstrate how mistake I am—if he can.

ADDENDUM:

The following is the text of the second e-mail that Dr. Arguello sent:

Dear Dr. Gorski:

I will numerate my comments, because each is a subject in itself:

(1) The Paid Magnate Agent. I was not aware of your existence until I was contacted by the Saskatchewan College of Physicians and Surgeons (SCPS). That is when I learned about online accusations made against you that you were a paid magnate from the pharmaceutical industry. Whether you are or not, it is totally irrelevant to me. You do not represent any organization dedicated to enforcing those types of rules, much less in another country. I personally condemn all forms of alternative treatments for cancer, in Tijuana or Germany, and I am starting to question all forms of conventional therapies (other than surgery) as well, but to be involved at a personal level and taking actions against the work of others by contacting agencies goes too far, and into malicious behavior, in my opinion.

(2) Questionable Fairness. Also, it is quite disturbing that you ignored the compelling evidences in my partial gallery of clinical cases on the website, which depict local recurrences of breast cancers after surgery and “prophylactic” chemotherapy and radiation; or progressions of cancers in conventional chemotherapy; or multiple metastases in the lungs, brain, liver, etc. disappearing following atavistic chemotherapy and immunotherapy. Most of them are cancer patients that were previously abandoned by their oncologists and hospitals in Canada, USA or Mexico. So, it would appear that you do not know or understand the evolution of patients in similar circumstances (the names of the hospitals involved, relevant pathological studies, etc., are described in each case). This is in fact a noble and unprecedented work in the history of cancer.

Could you show me any sequences of photos or radiological images of similar cancers (solid tumors) disappearing over time with any other therapy, after failing conventional chemotherapy and radiation? You could not even show me similar responses achieved in chemotherapy-naïve patients with any form of conventional chemotherapy. Radiation can do that but as a localized effect on individual tumors, not in a systemic fashion.

Our conventional therapies (except surgery) do not work for the vast majority of cancer patients. All common cancers are lethal today in 2014, just as it has been for centuries, if they escape curability with surgery. In this country alone, 1,605 men, women and children die every single day from cancer. Cancer is also the leading disease-related cause of death in children and adolescents between the ages of 1 and 19 in the USA. The mortality in cancer is increasing at an alarming rate, and I have started to believe that part of that is due to our conventional chemotherapies and radiation which trigger a non-return path to death in cancer patients because it generates resistant and aggressive cancers.

(3) Questionable Fairness #2. You say that “Because we at SBM always strive for accuracy, I will correct the date your clinic opened when I get a chance.” There are many inaccuracies in your comments. Hence my interest in a formal rebuttal, NOT a comment as you suggest, but a side by side discussion so that others may make their own judgments.

As is, it is a one-sided biased view of an important new approach in cancer. You did not provide any references to back up your statements as I do in my website. Your comments are totally your personal biased view of things, which is a completely unfair and improper way to discuss a scientific matter of the magnitude we are talking of here.

You did not even read my book, nor review recent literature on this topic after the publication of my book (see below). The science is there for you to review:

Article #1 Cancer: a de-repression of a default survival program common to all cells?: a life-history perspective on the nature of cancer (2012)

Article #2 Cancer tumors as Metazoa 1.0: tapping genes of ancient Ancestors (2011)

(4) Why I Do Not Publish Your Clinical Trials. I would love to and I will publish these findings, of course. However, you need to take into consideration the following. I started to evaluate this therapy around September 2011 in Mexico basically as a “Proof-of-Concept Study,” which was approved by the Ethical Board of the School of Medicine and State University Hospital of Torreon, Mexico. The treatment has been evolving and improving with time, to the point that I felt confident of its effectiveness and superiority to any conventional approach by 2013. Still, the numbers of patients is small and the therapy is still changing.

In 2013 I contacted the Cancer Treatment Centers of America (CTCA), the NCI and the Georgia School of Medicine in Augusta (places where I had connections) to consider formal clinical trials. What do you think the response was? I must say, however, that a Dr. Niu from the CTCA in Arizona agreed to run a clinical trial for breast cancer patients. They have more than 10 trials going on, so it will take time.

Also note that I have patent applications filed for “new use” of existing medicines and “new formulations” of existing medicines to protect the credit of my work. Again, I would love to share all the information now, if a large institution agrees to do the work, compensate me for my patents, and put me in a leading position to continue with this work. I hate to keep traveling to Los Cabos.

But what type of review should I anticipate from peer-review journals when I am not their peer? I will publish under my terms. I am working on a large publication in the form of a book. This way, others can practice this new oncology and generate proof in their own practice. Count on it.

(5) “…what you propose strikes me as dubious, at best, from an ethical standpoint, even if the patient gives permission. More importantly, single case “challenges” are not in general particularly informative, especially for cancers like melanoma, which, as you know, can have variable courses, even when diagnosed as stage IV.”

I know two stage IV melanoma patients who have had their disease for years. I am well aware of them (10% of melanomas behave in that way). I do not believe it is the immune system, but the nature of those cancers. Otherwise people could experience fever or signs of inflammation in or around the tumors. Despite our insistence, the immune system cannot recognize cancer cells as foreign or antigenic organisms, unless a reason exists for that. Cancer cells, despite being destructive and independent beings, are not foreign to the body. Immune attacks against cancer cells may be mounted against cancer cells, not for being cancer cells as such, but rather because they may express antigens which can be recognized as foreign to the body. These are malignancies in which a virus is known or believed to be involved–some forms of leukemias, Burkitt and Hodgkin lymphomas, or when the cancer cells are antigenic to the host for the nature of the tissue involved. For example, the testicular seminoma and the gestational choriocarcinoma are highly antigenic tissues to the host. Seminal cells appear after birth and therefore aren’t recognized as one’s own during intrauterine development. In gestational choriocarcinoma, the cells are in part foreign (father’s antigens).

Curiously, the only malignancies curable today with conventional chemotherapy and radiation are those mentioned above (no more, no less). HOWEVER, non-testicular (ectopic) seminomas and non-gestational (ectopic) choriocarcinomas, as those arising from in the brain, lung, ovary/teratocarcinomas, etc., are not curable with those therapies (does this ring a bell?).

The old oncology sees groups of patients in clinical trials. This is a failure on their part. It also tries to fit cancer into our concepts of pathology and treatment. Cancer is unique and it does not fit in our criteria of pathology. Cancer is a cellular process and a biological being. Its nature fits perfectly in the criteria postulated by Robert Koch (Koch’s postulates) – it is an agent that is isolable, can be expanded in the lab, and when re-inoculated in a healthy individual the disease is generated. See also contagious cancers.

The new science of Atavistic Oncology recognizes and, it is my experience too, that EACH CANCER IS UNIQUE with respect to its ability to overcome treatments/cytotoxic drugs (note emphasis). In the same way that nature provides diversity among individuals to protect them from foreign cells (bacteria, protozoa and fungi), prevent them from perpetuating genetic defects, etc., that diversity is also reflected in the malignant form of those cells. This new atavistic oncology will eliminate not only our conventional cytotoxic drugs and radiation which are not anticancer agents, but cell poisons, but it will also eliminate the old-fashioned approach of prospective clinical trials and the current treatments of radiation and anticancer drugs. What drugs and combinations have proven helpful in individual cases and in what type of malignancies? Those will serve as a guide to determine prospective treatments on an individual basis. Treatment will be similar to severe bacterial, fungal and protozoa infections, and will consist of trial and error until THAT particular patient starts to respond.

The patient I mentioned to you yesterday is a 52-year-old from Hamilton, ON. He has had a very rapid progression in less than a year, from local recurrence on October 2013 soon after removal of the primary, to multiple surgeries which have disfigured his face (just as with Alice mentioned below), to now having multiple metastases in the lungs, liver and spleen (based on CT-scans). I am afraid they are also in the brain and bone if evaluated with an MRI and a bone scan/bone biopsy, respectively. In the last three months, from the CT-scan in March 2014 to the CT-scan of August 2014, the number and size of metastases doubled. Now there are two, possibly three large metastases in the liver, 20 or so in the lungs and two in the spleen. This is under Dacarbazine.

What ethical matters are you concerned about? The patient is going to die if he continues on conventional treatments. The ethical thing to do here is to abandon our current practices that are ineffective. One person with melanoma dies in the USA every 57 minutes under conventional chemotherapy/immunotherapy.

Please note that I have two other melanoma patients with rapidly progressive melanomas: Barbara without any therapy offered in BC, Canada because of large brain metastases and given three months of life–That was seven months ago and going (the case you conveniently ignored in the gallery. But those images are never seen with our conventional therapies), and Alice who exhausted all treatments offered in Toronto (Dacarbazine, Ipilimumab which destroyed her pituitary gland, IL-2 therapy). That was more than a year ago (also in the gallery).

Which ethical and privacy issues are you concerned about if we have written consent to cover all aspects related to treatment using off-label practices of FDA approved drugs?

Whether you accept the challenge or not, the patient needs to try to save or prolong his life. Treating them in the correct way (atavistic chemotherapy and immunotherapy) is the ethical thing to do here.

I have tried to cover all your concerns now because my trip to Los Cabos is tomorrow. I hope you are a serious person interested in reconsidering our devastating and totally useless oncological practices in benefit of our fellow humans. Please post either of my two e-mails to you on your site, so that you do not deprive people from the opportunity to be treated correctly. Accept my challenge and then, and only then, you can give whatever advice you want to people. Again, your preemptive attacks are totally improper and unjustified. Just because we can write things on the internet, does not mean we are free to speak our minds. Not on this important, potentially life-saving matter.

Respectfully,

Frank

Categories: Medicine, Skepticism

The false dichotomies of CAM and “integrative medicine”

Science Based Medicine - Sun, 08/17/2014 - 11:00

A lot of medical specialties have throwaway newspapers/magazines that are supported by advertising and somehow mysteriously managed to show up for free in the mailboxes of their practitioners. In my case, I’ve found myself on the subscription list for such papers about oncology, but, given that I trained as a general surgeon. I’m Board-certified as a general surgeon. When I have to recertify in about three years, it will be as a general surgeon, which was really fun to try to do last time after having specialized as a breast cancer surgeon and will likely be even more fun next time, when I will be 10 years further out from my general surgery and surgical oncology training. In any case, that must be why, no matter where I end up working, sooner or later I end up receiving General Surgery News (GSN).

As throwaway professional newspapers go, GSN is not bad. However, occasionally it publishes op-ed articles that make me scratch my head or even tick me off with their obtuseness. Lately, apparently, it’s started some blogs. The one in particular that is the center of attention for this post is by Victoria Stern and called The Scope and is billed as “exploring the lesser known sides of surgery.” Of course, it’s a bit odd that some of the first posts on this blog are about work hour restrictions and whether they leave new surgeons unprepared to practice surgery, the debate over breast screening, and what it takes to train expert surgeons, none of which are exactly “lesser known sides of surgery.” Work hour restrictions, in particular, have been discussed in surgery journals, at conferences, and among surgeons ad nauseam, particularly whether we are training a generation of surgeons unable to deal with the rigors of practicing surgery in the real world.

What caught my attention, though was a post from yesterday entitled The Myth of Alternative Care, Growth of Complex Care. Reading the title gave me a sinking feeling because whenever anyone mentions “complex care” in the context of alternative medicine, “complementary and alternative medicine” (CAM), “integrative medicine,” or whatever you want to call it, I know that a heapin’ helping of tropes and positive spin on pseudoscience is likely to be on its way. The reason, of course, is that CAM advocates love to argue that patient care is so complex that conventional medicine can’t adequately address it and needs some “help” from CAM. The article doesn’t “disappoint.”

Basically, Stern frames the post thusly. Alternative medicine is “bad.” No argument there. However, CAM is a different beast altogether. She starts with the standard CAM talking point that increasingly “patients are looking for answers outside of conventional medicine.” (Where have I heard that one before? Oh, yes. In pretty much every article and post spouting CAM apologia that I’ve ever read.) She then cites a 2006 study that has been blogged about before by someone near and dear to many SBM readers about the use of alternative medicine to treat breast cancer that pointed out the less than optimal (to put it kindly!) outcomes that result from such practices. She then quotes my good buddy and SBM fearless founder and leader Steve Novella, such that it becomes rapidly obvious that the post is set up to contrast “integrative medicine” with that nasty cancer quackery such that CAM/IM is a good thing:

“Alternative medicine is harmful,” said Steven Novella, MD, a neurologist and assistant professor at Yale University School of Medicine who is executive editor of the blog Science-Based Medicine. “If such alternatives were evidence-based at all, they would be considered medicine, not alternative medicine, and would be adopted into mainstream care.”

Complementary therapies, however, are a different ballgame altogether. Unlike alternative therapies, complementary interventions are not touted as cancer treatments. As the name implies, complementary modalities, such as vitamins and herbal supplements, massage, acupuncture, are meant to accompany mainstream care. The idea is to treat the entire patient, not just the disease.

Now there’s a total waste of a perfectly good Steve Novella quote.

Yes, there’s the granddaddy of CAM/IM tropes right there, the claim, either direct or implied, that CAM/IM, contrary to “conventional” science- and evidence-based medicine treats the “whole patient” (in this case the “entire patient”) and “not just the disease. This argument is, as I like to say, a pile of fetid dingo’s kidneys, because the implication is that you can’t treat the “entire” patient without embracing quackery such as acupuncture. A good primary care doctor using science-based medicine is a wholistic doctor who treats the “entire patient.” The same is true of a good oncologist practicing science-based oncology or a good surgeon practicing science-based surgery. The false dichotomy is plain: Either embrace the quackery that is CAM, or you are not treating the “whole” patient. Yes, it irritates the crap out of me, because I see it so much, and so few physicians directly question the assumption at the heart of a passage like the one above.

Let’s just put it this way. Whenever a CAM apologist says that she doesn’t practice that awful, nasty alternative medicine (which is quackery) and doesn’t recommend using it instead of conventional therapy, I respond, “That’s nice,” because that’s all it deserves. No one should be recommending foregoing effective science-based treatment in favor of magic and fairy dust. That is a bare minimum that we expect of physicians. However, when in the same paragraph (sometimes in the same sentence) I see advocates saying that it’s perfectly acceptable to add unproven therapies as an adjunct to conventional medicine (the “complementary” in CAM) or “integrating” them with science-based medicine, my teeth start to grind involuntarily. Bad reasoning has that effect on me. Think about it. A lot of the “respectable” CAM in integrative medicine derives from the very same pseudoscientific and prescientific ideas that are behind the quackery.

I like to use the idea of “energy healing” like reiki to illustrate the point. As I’ve written so many times before, reiki is finding its way more and more into academic medical centers as a “respectable” bit of integrative medicine. The key precept of reiki, as you will recall, is that reiki masters claim to be able to channel “healing energy” from what they call the “universal source.” Now, to drive the point home, let me suggest that you substitute the word “God” for “universal source.” See what I mean? Reiki is faith healing that substitutes Eastern mysticism for Christian beliefs. So, if faith healing is bad used alone, why is it suddenly “good” and “treating the whole patient” when used with standard treatment. The only reason I can think of is that at least the patient is getting standard treatment. That’s not enough. We shouldn’t be recommending the addition of ineffective treatments based on magical thinking to conventional treatment. Whether practitioners realize or admit it or not, acupuncture is based on similar prescientific ideas, given that qi (life energy) is supposed to be flowing through “meridians” (never mind that no anatomic structure has yet been discovered that corresponds to acupuncture meridians) and the needles are supposed to be “unblocking” or “redirecting” its flow for therapeutic effect. The same concept fits into chiropractic, as well, where removing subluxations is supposed to remove impediments to the action of “innate intelligence” healing the body. The list goes on and on and on of how vitalism is at the root of so many CAM treatments that are being “integrated” into medicine.

Unfortunately, Stern also incorporates another trope into her post:

In his surgical practice, Bruce Ramshaw, MD, FACS, chairman of the Halifax Health General Surgery Residency Program and co-director of the Advanced Hernia Solutions, Daytona Beach, Fla., takes a similar patient-centered approach to care. Dr. Ramshaw and his team, which includes a patient care manager, do not just treat hernias, they also try to understand their patients—what they really go through in their day-to-day lives as well as their fears and concerns about their health—offer potential solutions to diminish issues or anxieties, and involve family members in the process for added support.

In hernia repair and in medicine in general, there is no perfect way to treat each patient, said Dr. Ramshaw, but he hopes to come closer to an optimal treatment paradigm by applying this patient-focused approach to care. “Our goal is to form genuine relationships with patients,” Dr. Ramshaw said. (Read more about Dr. Ramshaw’s thoughts in his opinion piece, Love: Its Real Effect On Patient Care).

This kind of complex care that looks at the patient as a whole is becoming increasingly important not only for enhancing patients’ overall health, ensuring that they stay away from dangerous interventions and helping patients measure their expectations, but also as a way to create a true bond between physician and patient, an element of care that has been waning over the years. Although compassion and empathy won’t treat a person’s ailments, these traits can only help improve patient care and ultimately patient health.

Actually, there is little objectionable in Dr. Ramshaw’s article itself, other than its tendency towards a bit of “Patch Adams” sentimentality (although I note that he has written other things for GSN that I thought about blogging about before regarding “complexity theory” in medicine). So what is the problem? It’s not so much with Dr. Ramshaw as with what Stern does with his statements and articles. I think you can see it. Notice how CAM/IM is being conflated, without evidence, with measures that not only “treat the patient as a whole” but serve as a way to create a “true bond” between physician and patient. This is another massive false dichotomy. It is not necessary to embrace quackery to form a “true bond” between doctor and patient. Indeed, recommending treatments without good evidence behind them strikes me as potentially major impediment to forming such a “true bond,” at least if the patient ever finds out how thin the evidence base is for these treatments. In addition, what does it tell physicians practicing science-based medicine who can and do form “true bonds” with their patients without selling them fairy dust to tell them that such fairy dust is necessary to help them form such “bonds”?

Stern promises that her next blog will explore the “pros and cons of integrative medicine.” I can hardly wait.

Categories: Medicine, Skepticism

A balanced look at gluten sensitivity

Science Based Medicine - Sat, 08/16/2014 - 03:00

Even though it doesn’t appear on any calendar, May 2014 will go down in history as “gluten sensitivity month.” After RealClearScience picked up on a 2013 paper that brought into question the existence of non-celiac gluten sensitivity (NCGS), news sites were obliged to post their own analysis of the article, and the blogosphere was alight with pro- and anti-gluten posts. One of the authors of the paper in question, Dr. Peter Gibson of Monash University, was even mentioned on the People magazine website, which gives him the distinction of being the only researcher to be published alongside the Kardashians.


Photo from flickr user surlygirl used under a CC licence.

The Monash paper,1 which was previously discussed on SBM, suggested that it might be the fructans in wheat and not gluten that is responsible for symptoms in IBS sufferers who feel better on a gluten-free diet. Fructans belong to a group of short-chain carbohydrates known as FODMAPs that are readily fermented by bacteria in the intestine. If fructans were really to blame for wheat-induced gastrointestinal symptoms, this would be good news for IBS sufferers currently on a gluten-free diet — for some, a diet low in FODMAPs would be less restrictive than one without gluten, making it less prone to nutritional deficiencies.

As it stands, the existence of NCGS has neither been proven nor disproven by anyone. But gluten sensitivity sits at the intersection of several dilemmas in medicine today and, unlike how it’s betrayed in the media, is hardly an all-or-nothing affair. Proving it wrong will not instantly heal the people who have prescribed themselves a gluten-free diet. Proving it wrong will not produce a cure for IBS, a shorter time to a celiac diagnosis, or the correct way to handle potential celiac disease. Neither will proving it right. In the eyes of one gluten avoider, “Modern medicine is really good at crisis intervention…[but] they don’t do well with chronic issues”.2

With these issues in mind, it’s time to move past the media debates and fad dieters and take a balanced look at NCGS. This overview will use four recent articles by the Monash group1, 3, 4, 5 as a framework to uncover some of the factors contributing to the gluten sensitivity phenomenon. Even though it has been gone over many times, a discussion of the FODMAPs study is still in order — in fact, essential — to appreciate the central importance of the elimination diet in diagnosing a food sensitivity. Along the way, we’ll get an idea of who the gluten sensitive might be, how successful gluten-free diets really are, and how challenging it is to pursue a celiac diagnosis.

Some definitions

To refresh, here are some of the key ideas discussed:

  • Gluten: A protein found in relatively large amounts in wheat, but also found in other grains.
  • Celiac disease: A genetically-linked autoimmune disorder caused by the small intestine reacting to gluten. Causes pain, altered bowel movements and malnutrition.
  • Irritable bowel syndrome: A diagnosis made purely on the basis of symptoms (bloating, pain and either diarrhea, constipation, or both), with no known current cause.
  • Elimination diet: A diet which removes specific foods or classes of foods from the diet in an effort to identify the trigger to an allergic reaction or symptom(s).
A food sensitivity is born

In 2011, an international panel of experts defined NCGS as “a non-allergic and non-autoimmune condition in which the consumption of gluten can lead to symptoms similar to those seen in celiac disease”.6 Non-intestinal symptoms can include behavioral changes, bone or joint pain, muscle cramps, leg numbness, weight loss, and chronic fatigue.7 But this is only a working definition, and there is still a lot of uncertainty as to what NCGS actually represents, even for its proponents.

So far, NCGS appears to be a heterogeneous phenomenon, with at least three different and potentially-overlapping subtypes6, 8:

  • A type reminiscent of celiac disease — a family history of celiac disease or the celiac HLA genes but no increase in intestinal permeability and no auto-immune response.
  • A type reminiscent of irritable bowel syndrome — intestinal motility issues but a greater frequency non-intestinal symptoms.
  • A type reminiscent of food allergies — prior history of allergy or concurrent food sensitivities and some immunological markers for celiac disease, but no activation of mucosal basophils by gliadin.

Multiple subtypes imply multiple mechanisms, and this too needs to be ironed out for NCGS. Sapone et al.9 described NCGS as “an inflammatory condition mostly supported by innate immune mechanisms,” which differentiates it from celiac disease and wheat allergy, and in vitro evidence suggests that other poorly-digested wheat proteins known as amylase-trypsin inhibitors might trigger the innate immune response.6 Changes in intestinal microbiota may also play a role in NCGS.10 And, of course, the fructans have their own special magic.

The backstory

When NCGS was officially created by consensus, things weren’t proceeding according to the normal order. Celiac researchers, mainly centered at the University of Maryland, were pretty convinced that they had seen non-celiac patients whose symptoms had improved on a gluten-free diet. They searched for a set of biomarkers that would shed light on these cases, but found nothing consistent except for the absence of two celiac hallmarks — an autoimmune response and increased intestinal permeability.6, 8

From a food sensitivity perspective, however, searching for biomarkers is putting the cart before the horse. Food sensitivities, like cow’s milk protein intolerance or certain food additive intolerances, are only recognized after they have been demonstrated in studies using a double-blind, placebo-controlled food challenge (DBPCFC). The DBPCFC works regardless of the mechanism behind the reaction, so it can be used before any biomarkers have been identified.

Back in 2011, only one study had been completed on gluten sensitivity using a DBPCFC,3 and this first bit of positive evidence came from the Monash group. The study looked at a small group of IBS sufferers who identified themselves as gluten sensitive and who tested negative for celiac disease. They could only enter the study if their symptoms — abdominal pain, bloating, gas, constipation, diarrhea, or tiredness — were currently well controlled by a gluten-free diet.

Most DBPCFC studies use a crossover design, but the first Monash study randomly divided the participants into test and control groups. All participants continued on their usual gluten-free diet during the course of the study and were challenged with either gluten-free or gluten-containing low-FODMAP bread and muffins. The gluten group experienced greater gastrointestinal symptoms and tiredness compared to the control group, so it looked like gluten could induce GI symptoms on its own.

Shortly thereafter, a group at the University of Palermo11 used a DBPCFC to see whether any of their IBS patients were affected by wheat. In the end, they reclassified 30% of the 920 patients as suffering from wheat sensitivity. Notice I said wheat sensitivity — this study used capsules of wheat flour as the challenge instead of gluten. It also differed from the Monash study in that it included a stricter elimination diet before and during the challenges, not just relying on participants to maintain their own gluten-free diets.

The elimination diet — or the baseline diet — just may be the most important part of a DBPCFC. It puts everyone on a level playing field, stabilizing symptoms and doing away with any effects that might carry over from the participants’ normal diets. An elimination diet excludes the food under investigation and, if the study is thorough, all other foods or food additives that might produce a reaction. If symptoms don’t improve by the end of the elimination diet, then the study is on the wrong track.

The Palermo researchers were looking at a broader set of food sensitivities than just wheat. Gluten-free participants were asked to resume a normal diet for 2-4 weeks before beginning the elimination diet, which excluded wheat plus cow’s milk, eggs, tomato, and chocolate — foods known to aggravate IBS — and any other triggers identified by the participants. A challenge was considered positive if symptoms returned after having disappeared during the elimination diet. Of those testing positive for wheat sensitivity, the majority were also positive for cow’s milk protein intolerance when challenged separately; half were also sensitive to eggs and tomato.

Since many different foods are commonly, although not universally, reported to trigger or worsen IBS symptoms, the Palermo study didn’t go far enough to determine whether NCGS (or wheat sensitivity) is really its own entity outside of IBS or to explain the possible overlap between the two conditions. On the other hand, the Monash results were significant because gluten alone seemed to have caused an adverse reaction in IBS sufferers. But this result needed to be replicated under stricter conditions, so 2013 brought a new paper from the Monash group1 on a second gluten trial.

FODMAPs-gate

In IBS, the enteric (intestinal) nervous system is easily overstimulated, leading to abnormal contractions and an exaggerated perception of pain. Food triggers IBS symptoms by stimulating the enteric nervous system directly through various chemical receptors or indirectly by pressure.12 FODMAPs — which include fructans, galactans, polyols, fructose, and lactose — lead to more pressure in the intestine than other foods because they are poorly absorbed, rapidly fermented, and osmotically active.13 In other words, they cause gas and loose stools. The low-FODMAP diet, developed in 2008 by the same group at Monash University that we have been discussing, is the first comprehensive diet plan shown to reduce symptoms in the majority of IBS sufferers.14

Before the low-FODMAP diet, avoiding single foods like wheat or milk wasn’t always effective in treating IBS14; eliminating more than one carbohydrate type, like fructans and fructose, seems to have an additive effect that controls IBS symptoms better.15 That said, not everyone with IBS is sensitive to all of the FODMAPs, and the diet is highly customizable. The effectiveness of the low-FODMAP diet means that any diet study involving IBS sufferers must control for the effects of high-FODMAP foods.

The second DBCPFC study from the Monash group — the one that has received all the media attention — was a randomized crossover trial using stricter diets and stricter testing to make sure that participants did not have latent celiac disease. In this trial, meals were provided and additional snacks were logged. Here they ran two experiments — one where the elimination diet excluded high-FODMAP foods and the other where the elimination diet excluded high-FODMAP foods, dairy, and known triggers of pharmacological food intolerance reactions.

In the first arm of the study, participants were given challenge foods containing gluten, gluten plus whey, and pure whey, each separated by a washout period. Overall, symptoms improved during the low-FODMAP elimination diet but worsened for each of the challenges. Individually, though, only 3 out of 37 showed a significant response attributable to gluten when all challenges were considered.

In the second arm, 22 people from the first group were rechallenged with foods that contained gluten, whey, or no additional protein. This phase, which was meant to verify the results of the first using an even stricter elimination diet, could not reproduce any of the previous reactions. For example, only 2 out of 22 responded to gluten in the second arm, and these were not the same people who responded to gluten in the first.

One blogger took issue with the fact that many of the participants reacted to whey: “If some of the ‘placebo’ and low-gluten patients were, in fact, sensitive to whey, then that would invalidate the results of the study.” But that’s not true. The point to remember is that most people did not react to the same challenge food twice, and only one person consistently reacted to whey. Furthermore, it isn’t a catastrophe in a study like this if someone reacts to the placebo — this can happen for many reasons, including just having a bad day. What matters is how the reaction to the real challenge compares to the placebo reaction; if it is significantly greater, then the challenge is positive.

What did the researchers conclude? Considering both arms of the study and the immunological testing that also took place, no evidence of gluten-specific effects were found in patients on a low-FODMAP diet. They did not conclude that gluten sensitivity does not exist, only that “gluten may not be a specific trigger of functional gut symptoms once dietary FODMAPs are reduced.” That, however, does not settle the debate over gluten sensitivity. What the two Monash trials have shown us is the correct elimination diet to be used when looking for NCGS.

Gluten free with symptoms

The story doesn’t end there, though. From the Monash work we also learned that a good number of gluten-free dieters continue with the diet even though their symptoms do not completely resolve. This came out in two ways. To be included in the two Monash studies, participants needed to have well-controlled symptoms on a gluten-free diet. For the second study, for example, 147 volunteers were screened using several questions, one being, “Do you currently feel in control of your symptoms?”4 To this, 22% answered “no,” 3% answered “sometimes,” 16% answered “mostly,” and 59% answered “yes.” Then, when participants rated their symptoms at the beginning of the study, 11 of 37 were under significant distress, and 22% of the group significantly improved while on the low-FODMAP elimination diet.1

It is tempting to think that the people who did see complete improvement on their own gluten-free diet were not really sensitive to gluten in the first place, but we don’t have the data to support this — only 58% of the larger group believed that they were strictly gluten free, and it is not clear how many of the gluten ‘cheaters’ still had symptoms. As the researchers pointed out, we also do not know how the symptomatic group felt before they began avoiding gluten — perhaps they had actually improved quite a bit on a gluten-free diet, but just not completely. Another explanation is that FODMAPs were really to blame for their symptoms, and avoiding only wheat wasn’t enough to provide complete relief.

It isn’t surprising that a person could be mistaken about having gluten sensitivity. According to someone like Dr. Oz, gluten sensitivity can be diagnosed by avoiding gluten for a while — say two weeks or a month — and then trying some to see what happens. But avoiding a staple food like wheat amounts to a major change of eating habits, and it is likely that wheat will not be the only food that is eliminated. For those who aren’t accustomed to performing experiments on themselves, these diet instructions don’t explain that any and all foods excluded during an elimination diet must be excluded for the entire diet and then used as a challenge later on. On top of this, placebo challenges really are necessary, and one round of challenges may not be enough — when symptoms are subjective or when a strong nocebo effect is expected, the active and placebo challenges should be randomized and repeated three times.6, 7

Oddly, many participants from the second Monash study opted to continue their gluten-free diet after the study ended because the diet made them “feel” better.5 This intrigued the researchers, so they invited the participants back for a third study to find out whether gluten was affecting their mental state.5 This trial proceeded along the same lines as the second, and mental state was assessed using the Spielberger State Trait Personality Inventory. Gluten still had no impact on gastrointestinal symptoms, but it did induce feelings of depression. This is a very interesting result because it could explain the lure of the gluten-free diet; however, researchers are still a long way off from uncovering a definite link between gluten and depression, transient or otherwise.

The missing celiacs and other sufferers

The final bit of information from the Monash researchers comes from the 147 people who applied to participate in their gluten studies.4 Of these, 44% had initiated their gluten-free diet themselves; the rest were following the advice of an alternative health professional (21%), dietitian (19%), or general practitioner (16%). In the surveys that followed, the researchers determined that two-thirds had not adequately excluded celiac disease, meaning that 15% had not been tested at all for celiac disease and that 29% of those who had undergone duodenal biopsies did not consume enough gluten beforehand for the results to be valid [see 18]. This includes half of the tests initiated by general practitioners.

Considering that one in 56 people with symptoms will have celiac disease,19 it is important to know why people feel confident diagnosing themselves with gluten sensitivity without first ruling out the more serious problem. Even if they do maintain a strict gluten-free diet for their entire lives, without a formal diagnosis, these people with possible celiac miss out on follow-up care, accommodations by schools and employers, and tax breaks or food subsidies in many countries. The truth is, many have pursued a celiac diagnosis or wish that they could have pursued one. The decision to go it alone is not taken lightly — consider these situations pulled from stories posted online:

  1. They met the serologic for celiac disease but had a negative biopsy.
  2. Their doctor won’t test them even though they have asked.
  3. Their doctor says that they cannot have celiac disease because they are overweight.
  4. Their doctor told them that they are too old to have celiac disease.
  5. They were not told to or told not to do a gluten challenge before the endoscopy.
  6. Their doctor ordered a colonoscopy to check for celiac disease.
  7. They already believe that they have celiac disease because of their symptoms and family history.
  8. An alternative practitioner told them that they have celiac disease because their reaction to gluten is severe.
  9. They are already gluten free and don’t want to “get glutened” again in order to be tested.
  10. Having a celiac diagnosis won’t affect their commitment to a gluten-free diet.
  11. They believe that the Cyrex test is more thorough than conventional celiac testing from a doctor.
  12. They believe that celiac disease is only a minor part of the spectrum of gluten-related disorders.
  13. They are worried that their health and life insurance premiums will increase.
  14. They don’t want a preexisting condition on their the health insurance records.
  15. They do not have enough money for an endoscopy.
  16. Their health insurance wouldn’t pay for an endoscopy.

Regardless of what we might think about these reasons, they paint the picture of a larger problem. Roughly 80% of celiac cases go undiagnosed,20, 1 a situation that The Lancet has described as a “public health farce”21 in light of the millions of healthy people who choose to be gluten free. Undiagnosed celiac disease can lead to osteoporosis, anemia, infertility, certain intestinal cancers, other autoimmune disorders, and an increased risk of mortality, although the latter is still under debate.3, 4 Still, the average time to receive a celiac diagnosis has been around 11 years.22

Right now we don’t know how many people with self-diagnosed gluten sensitivity actually have celiac disease, but the Monash data tells us that this is a significant concern. Efforts are being made to cut down the time it takes for a celiac diagnosis, but progress is slow.22 Increasing celiac awareness among physicians is part myth busting and part reeducation, and in the absence of mass screening, doctors must be able to spot non-GI or “atypical” symptoms and associated conditions that suggest the presence of the disease.23 At the same time, the protocol for diagnosing celiac disease is being reexamined24 — in Europe, the duodenal biopsy, currently regarded as the gold standard for celiac diagnosis, can be omitted in certain circumstances.25

We also don’t know how often potential celiac disease is actually mislabeled as gluten sensitivity. Potential celiac disease describes cases where serologic and genetic markers for celiac disease are positive but the biopsy is negative.22 There is no consensus on whether to treat potential celiac disease, nor, for that matter, whether it is a real problem or just a false-positive result.5,9 Some evidence suggests that a gluten-free diet is beneficial,26 while another report describes patients whose symptoms spontaneously improved even though they continued to eat gluten.27 Until the issues surrounding celiac and potential celiac disease have been resolved, non-celiac gluten sensitivity — or at least one of its subtypes — cannot be clearly defined.

Where do we go from here?

In a large Australian survey from 2013, roughly 7% of respondents had diagnosed themselves with gluten sensitivity.28 The gluten free fad is just as popular in Australia as it is in the US,1, 2 so this figure might also estimate the prevalence of gluten sensitivity here, even though a 2009 estimate was much lower at 0.55%.29

Who might be in the 7%? Some with IBS, some with a botched celiac diagnosis, some with potential celiac disease, some who are intolerant to foods that they inadvertently eliminated because of their new diet, some who get only a psychological benefit from avoiding gluten, some whose symptoms continue despite their best efforts, some who really are hypochondriacs, and perhaps some with NCGS as its own entity. It doesn’t even matter whether non-celiac gluten sensitivity exists — these people will remain.

But it’s going to be a while until gluten sensitivity is understood. According to Dr. Alessio Fasano, director of the Center for Celiac Research at the Massachusetts General Hospital, NCGS stands where celiac disease stood 40 years ago.8 Even so, all we need are a few good DBPCFC trials to answer the basic question as to whether gluten sensitivity exists. This may be easier said than done, however, as the Monash group found such a strong nocebo effect in their trials that they now believe that future research should involve IBS sufferers who have not tried a gluten-free diet before.30

In the meantime, more people will suspect that they are sensitive to gluten, and if they are not to be lost to self-diagnosis or alternative medicine, the medical community must be able to lead them through the process of sorting out their suspicions. The Monash researchers have suggested an interim pathway for diagnosing gluten sensitivity, which includes:4

  1. The adequate exclusion of celiac disease.
  2. The exclusion of other dietary triggers, like FODMAPs or other foods suspected by the individual.
  3. A gluten-free diet, if symptoms did not resolve or improve in Step 2.
  4. Blinded gluten challenges, if symptoms did improve in Step 3.
  5. Rechallenges with gluten to establish their gluten threshold.

As a clinical approach, this moves us away from thinking about gluten sensitivity in all or nothing terms and addresses the issues one person at a time.

The author

Laurie Laforest, PhD is a former materials scientist turned computer programmer turned food intolerance mom. She blogs at foodconnections.org to clear up misconceptions on the nature, the prevalence, and the diagnosis of food intolerance.

References
  1. Biesiekierski JR, Peters SL, Newnham ED, Rosella O, Muir JG, Gibson PR. No Effects of Gluten in Patients With Self-Reported Non-Celiac Gluten Sensitivity After Dietary Reduction of Fermentable, Poorly Absorbed, Short-Chain Carbohydrates. Gastroenterology. 2013 Aug;145(2):320–328.e3. PMID 23648697
  2. Moore LR. “But we’re not hypochondriacs”: The changing shape of gluten-free dieting and the contested illness experience. Social Science & Medicine. 2014 Mar;105:76–83. PMID 24509047
  3. Biesiekierski JR, Newnham ED, Irving PM, Barrett JS, Haines M, Doecke JD, et al. Gluten causes gastrointestinal symptoms in subjects without celiac disease: a double-blind randomized placebo-controlled trial. Am J Gastroenterol. 2011 Mar;106(3):508–514. PMID 21224837
  4. Biesiekierski JR, Newnham ED, Shepherd SJ, Muir JG, Gibson PR. Characterization of Adults With a Self-Diagnosis of Nonceliac Gluten Sensitivity. Nutrition in Clinical Practice [Internet]. 2014 Apr 16 [cited 2014 Apr 26]; Available from: http://ncp.sagepub.com/cgi/doi/10.1177/0884533614529163. PMID 24740495
  5. Peters SL, Biesiekierski JR, Yelland GW, Muir JG, Gibson PR. Randomised clinical trial: gluten may cause depression in subjects with non-coeliac gluten sensitivity – an exploratory clinical study. Alimentary Pharmacology & Therapeutics. 2014 May;39(10):1104–12. PMID 24689456
  6. Mansueto P, Seidita A, D’Alcamo A, Carroccio A. Non-Celiac Gluten Sensitivity: Literature Review. Journal of the American College of Nutrition. 2014 Feb;33(1):39–54. PMID 24533607
  7. Sapone A, Bai JC, Ciacci C, Dolinsek J, Green PH, Hadjivassiliou M, et al. Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC medicine. 2012;10(1):13. PMID 22313950
  8. Catassi C, Bai J, Bonaz B, Bouma G, Calabrò A, Carroccio A, et al. Non-Celiac Gluten Sensitivity: The New Frontier of Gluten Related Disorders. Nutrients. 2013 Sep 26;5(10):3839–53. PMID 24077239
  9. Sapone A, Lammers KM, Casolaro V, Cammarota M, Giuliano MT, De Rosa M, et al. Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity. BMC Med. 2011 Mar 9;9:23. PMID 21392369
  10. Carroccio A, Mansueto P, D’Alcamo A, Iacono G. Non-Celiac Wheat Sensitivity as an Allergic Condition: Personal Experience and Narrative Review. The American Journal of Gastroenterology. 2013;108(12):1845–52. PMID 24169272
  11. Carroccio A, Mansueto P, Iacono G, Soresi M, D’Alcamo A, Cavataio F, et al. Non-celiac wheat sensitivity diagnosed by double-blind placebo-controlled challenge: exploring a new clinical entity. The American Journal of Gastroenterology. 2012 Dec;107(12):1898–1906; quiz 1907. PMID 22825366
  12. Gibson PR, Shepherd SJ. Food choice as a key management strategy for functional gastrointestinal symptoms. The American Journal of Gastroenterology. 2012 May;107(5):657–666; quiz 667. PMID 22488077
  13. Gibson PR, Shepherd SJ. Evidence-based dietary management of functional gastrointestinal symptoms: The FODMAP approach. J Gastroenterol Hepatol. 2010 Feb;25(2):252–8. PMID 20136989
  14. Halmos EP, Power VA, Shepherd SJ, Gibson PR, Muir JG. A Diet Low in FODMAPs Reduces Symptoms of Irritable Bowel Syndrome. Gastroenterology. 2014 Jan;146(1):67–75.e5. PMID 24076059
  15. Shepherd S, Gibson P. The Complete Low-FODMAP Diet: A Revolutionary Plan for Managing IBS and Other Digestive Disorders. Workman Publishing; 2013. 290 p. ISBN 9781615190805
  16. Gellerstedt M, Bengtsson U, Niggemann B. Methodological issues in the diagnostic work-up of food allergy: a real challenge. Journal of Investigational Allergology and Clinical Immunology. 2007;17(6):350. PMID 18088015
  17. Bindslev-Jensen C. Standardization of double-blind, placebo-controlled food challenges. Allergy. 2001;56(s67):75–7. PMID 11298015
  18. The number of those improperly tested for celiac disease could actually be a little lower than 29% since the researchers judged the adequacy of the prerequisite gluten challenge against the current Australian guidelines (at least four weeks of 16 g of gluten per day), and this duration and amount may be higher than necessary:
    Leffler D, Schuppan D, Pallav K, Najarian R, Goldsmith JD, Hansen J, et al. Kinetics of the histological, serological and symptomatic responses to gluten challenge in adults with coeliac disease. Gut. 2013 Jul 1;62(7):996–1004. PMID 22619366
  19. Fasano A, Berti I, Gerarduzzi T, Not T, Colletti RB, Drago S, et al. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study. Arch Intern Med. 2003 Feb 10;163(3):286–92. PMID 12578508
  20. Rubio-Tapia A, Ludvigsson JF, Brantner TL, Murray JA, Everhart JE. The prevalence of celiac disease in the United States. The American Journal of Gastroenterology. 2012 Oct;107(10):1538–1544; quiz 1537, 1545. PMID 22850429
  21. Gluten-free diets: vital or vogue? The Lancet. 2012;380(9843):704. PMID 22920739
  22. Catassi C, Fasano A. Is this really celiac disease? Pitfalls in diagnosis. Current Gastroenterology Reports. 2008;10(5):466–72. PMID 18799121
  23. Collin P. Should adults be screened for celiac disease? What are the benefits and harms of screening? Gastroenterology. 2005 Apr;128(4):S104–S108. PMID 15825117
  24. Caio G, Volta U. Coeliac disease: changing diagnostic criteria? Gastroenterology and Hepatology from bed to bench [Internet]. 2012 [cited 2014 Jun 4];5(3). Available from: http://journals.sbmu.ac.ir/ghfbb/index.php/ghfbb/article/viewFile/274/227. PMID 24834212
  25. Husby S, Koletzko S, Korponay-Szabo IR, Mearin ML, Phillips A, Shamir R, et al. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. Journal of Pediatric Gastroenterology and Nutrition. 2012;54(1):136–60. PMID 22197856
  26. Kurppa K, Collin P, Viljamaa M, Haimila K, Saavalainen P, Partanen J, et al. Diagnosing Mild Enteropathy Celiac Disease: A Randomized, Controlled Clinical Study. Gastroenterology. 2009 Mar;136(3):816–23. PMID 19111551
  27. Biagi F, Trotta L, Alfano C, Balduzzi D, Staffieri V, Bianchi PI, et al. Prevalence and natural history of potential celiac disease in adult patients. Scandinavian Journal of Gastroenterology. 2013 May;48(5):537–42. PMID 23506211
  28. Golley S, Corsini N, Topping D, Morell M, Mohr P. Motivations for avoiding wheat consumption in Australia: results from a population survey. Public Health Nutrition. 2014 Apr 17;1–10. PMID 24739252
  29. DiGiacomo DV, Tennyson CA, Green PH, Demmer RT. Prevalence of gluten-free diet adherence among individuals without celiac disease in the USA: results from the Continuous National Health and Nutrition Examination Survey 2009–2010. Scandinavian Journal of Gastroenterology. 2013 Aug;48(8):921–5. PMID 23834276
  30. Biesiekierski JR, Muir JG, Gibson PR. Is Gluten a Cause of Gastrointestinal Symptoms in People Without Celiac Disease? Current Allergy and Asthma Reports. 2013 Dec;13(6):631–8. PMID 24026574
Categories: Medicine, Skepticism

Bad Reporting About Epigenetics

Neurologica Blog - Fri, 08/15/2014 - 12:20

Brad Crouch should be fired. At the very least he should never write a science news article again (well, maybe after remedial education and appropriate penance). At first I thought perhaps he was a general or fluff journalist taken off the dog show beat and asked to cover a science news item, but his byline for The Advertiser (an Australian news outlet) says he is a “medical reporter.” That’s frightening.

I read a lot of bad science news reporting, but rarely does a reporter so thoroughly misrepresent the actual science news – unless there is an obvious ideological agenda, but as far as I can tell this is just pure incompetence.

He is reporting on a review article on epigenetics recently published in Science. The two articles have very little in common, and it’s difficult to see how Crouch arrived at his story other than just making shit up. He begins:

LANDMARK Adelaide research showing that sperm and eggs appear to carry genetic memories of events well before conception, may force a rethink of the evolutionary theories of Charles Darwin, scientists say.

First, the paper is not research, let alone “landmark” research. It is a review article. It’s not even a systematic review or a meta-analysis, which a reporter might be forgiven for calling a “study” – it’s just a discussion of the topic of epigenetics.

What is especially interesting is that the words “evolutionary theory,” “Darwin,” and “Lamarck,” appear nowhere in the review, despite the fact these are the focus of Crouch’s reporting. Further, the word “epigenetics” appears nowhere in Crouch’s reporting, despite the fact that this is the focus of the review article.

Here is what the review actually says:

Transgenerational epigenetic effects interact with conditions at conception to program the developmental trajectory of the embryo and fetus, ultimately affecting the lifetime health of the child. These insights compel us to revise generally held notions to accommodate the prospect that biological parenting commences well before birth, even prior to conception.

Essentially, epigenetics are tweaks to the expression of genes in response to environmental factors. If a mother is, for example, living in times where there is good access to food, epigenetic factors will adapt her children to the current abundance. If she is living in lean times, they will we more adapted to food scarcity.

One biochemical mechanism of epigenetic factors that has been discovered is methylization of base pairs. This does not affect the sequence of genes, but it can affect their expression.

While epigenetics is stil fairly new, and the details are being worked out, so far the experiments show that it is a short term (1 or a few generations) tweak for adaptation to immediate conditions. It does not have any real impact on Darwinian evolution. It certainly does not indicate that the inheritance of acquired characteristics (often referred to as Lamarckism, even though this notion did not originate with Lamarck, was not unique to Lamarck, and was abandoned by Lamarck later in his career) will now replace Darwinian evolution.

I am not even sure I buy the much more limited conclusion of the review that healthful lifestyles are transmitted to children. This seems like an awful lot of extrapolation from limited research. It is plausible and consistent with existing research that being obese or overeating during pregnancy may cause and epigenetic signal of abundance, leading to children with a greater tendency to put on weight. What is not clear is if this is clinically relevant in humans. I also would not generalize this to “healthful lifestyle.”

Crouch goes way beyond overcalling epigenetics, and takes a left-turn into bizarro world:

It paves the way for a review of the work of French biologist Jean-Baptiste Lamarck, whose theory that an organism can pass to its offspring characteristics acquired during its lifetime was largely ignored after Darwin’s publication of On The Origin of Species in the mid-1800s, that work defining evolution as a process of incidental, random mutation between generations.

Wrong. It’s not Lamarck’s theory, but worse still epigenetics has absolutely nothing to do with the mechanisms of evolutionary change. Crouch does then pivot to the actual subject of the review, the effect of parental habits on the child. He quotes one of the authors, Sarah Robertson:

“People used to think that it didn’t matter because a child represented a new beginning, with a fresh start.

“The reality is, we can now say with great certainty the child doesn’t quite start from scratch. They already carry over a legacy of factors from their parents’ experiences that can shape development in the foetus and after birth.

“There is now biological evidence that memories of experiences in adults can be transferred through egg and sperm for the lifetime prospects of the child.

“If evolution has developed something like this it can give a child an edge to survive. This will rewrite long held views, that experiences can actually be transferred to offspring.”

You will notice that Robertson never says anything to support either the notion that epigenetics calls Darwinian evolution into question, nor the hyped interpretation that lifestyle transfers to children. Everything she says is compatible with a conservative interpretation of epigenetics. Crouch, however, uses them as if they support his ridiculous interpretation.

This is unfortunately common in bad science journalism. The reporter has their story in mind, usually some hyped interpretation not supported by the actual research they are reporting, or some tiny footnote they will exagerate as if it’s the main finding of the study. They then interview experts, not to find out what is really going on or to put the story into perspective, but to mine for quotes they can plug into their pre-existing narrative.

Then he does it again:

Prof Robertson stressed that genes remain the blueprint for a new baby, but said the work of both Darwin and Lamarck may need to be reconsidered.

“The genes are the blueprint and that won’t change,” Prof Robertson said. “But this is at another level, it is the decoration of the gene, the icing on the cake if you like, a gift to offspring that gives them another layer of information about survival.”

She says nothing about Darwin and Lamarck, just like the review says nothing abuot Darwin and Lamarck. Her statements that he uses to support his interpretation, in fact contradict it. Epigenetics is another level of information, which does not change the basic fact that genes are the “blueprints.’

As an aside, I do not like the “blueprint’ metaphor for genes. It’s misleading. Genes are not a blueprint. There is no representation of the final product in the genes. Genes, rather, are more of a recipe, a set of instructions that, if followed, result in the final organism. Yes this is nitpicking, but metaphors in science communication should strive to be conceptually accurate.

He finishes with the lifestyle theme again:

“Lifestyle changes by potential parents and improvements in the right direction, especially in the months leading up to conception, could have a lasting, positive benefit for the future of their child,” Prof Robertson said.

This, at least, is the proper focus of the paper. Here Crouch failed also. He never mentioned epigenetics, never gave this central concept to the review article any background, and he did not appear to interview other scientists to see if this one scientist, discussing her own paper, was in the mainstream or not.

Conclusion

Crouch’s reporting of this review article on epigenetics was an utter disaster. He displays everything that is wrong with bad science journalism.

Epigenetics is also not a new concept, as one might think from reading Crouch’s article. It is still relatively young, scientifically speaking, and there is likely scant public awareness of epigenetics. Reporting on this review was a good opportunity to introduce readers to the concept of epigenetics and to put it into some historical and scientific perspective.

Anyone reading Crouch’s piece who was not already familiar with evolutionary theory and epigentic would have come away without gaining any real insight, but rather completely misinformed.

My own take on epigenetics is that this is an interesting layer of complexity to the function of genes that allows for short term adjustments to current environmental conditions. Epigenetics have no significant impact on evolutionary theory, however.

Also, the concept that genes themselves are not destiny, but rather genetic expression interacts with the environment is nothing new. The term “epigenetics” was coined in 1939, and the modern sense of the word (mechanisms that affect the expression of genes) dates back to the mid 1970s.

Here’s Crouch’s headline: “Darwin’s theory of evolution challenged by University of Adelaide genetic memory research, published in journal Science.” (I know reporters don’t usually write their own headlines, but this is fairly based on Crouch’s reporting.)

Here’s the real headline: “Local scientists write a review article on the decades-old concept of epigenetics.”

Categories: Medicine

Separating Fact from Fiction in Pediatric Medicine: Nocturnal Enuresis

Science Based Medicine - Fri, 08/15/2014 - 08:00

There is no role of chiropractic in treating childhood bedwetting

In pediatrics, very few things are completely black and white. This is an aspect of conventional medicine in general that tends to separate the approach of science-based practitioners from that of proponents of the many forms of irregular medicine commonly discussed on SBM. They appear to experience no shame in claiming absolute certainty while doling out all manner of implausible remedies for ailments ranging from the well established to the fictional.

While we do face questions from patients and their caregivers regarding largely invented diagnoses in pediatrics, with chronic Lyme disease and non-celiac gluten sensitivity being just two of many increasingly encountered concerns, my experience has been that alternative medical providers tend to focus their efforts on the same real problems that pediatricians and family practitioners deal with on a daily basis. And I don’t believe that it is mere coincidence that these conditions are largely self-limited in nature, a fact often not shared. Parental and patient buy-in is often more easily obtained with certainty rather than nuance.

Chiropractors, for example, seem to pride themselves on their ability to cure ear infections. Of course in greater than 80% of children with acute ear infections, symptoms will resolve without any intervention whatsoever. This is why the AAP has been trying for years to decrease the rates of antibiotic prescriptions for ear infections, unfortunately with little in the way of success thus far. And when the infections don’t resolve on their own, there is no good evidence that anything a chiropractor has to offer can help. The same can be said for their claims regarding colic and gastroesophageal reflux, which I’ve written about before.

Another condition frequently mentioned by chiropractors as being particularly in their wheelhouse is nighttime bedwetting, the medical term for this being nocturnal enuresis. Rarely have I seen a chiropractic website with a section on the benefits for children not mention their success in curing bedwetting. Fred Clary, DC even claims on his website to be able to cure bedwetting in the newborn baby. And to think I’ve just been ignoring the problem as a newborn hospitalist. Is it because the thought of a newborn infant gaining continence is absurd, or am I just a shill for Big Pampers?

With nocturnal enuresis, as with all of pediatric healthcare, there is science-based approach that takes a variety of factors into account. In fact, bedwetting is an excellent example of the success that comes with considering the biology, psychology and social environment of a patient. You could even call it a holistic approach if that weren’t such a loaded description. I prefer biopsychosocial.

In keeping with my usual pattern, before I delve into the the idiocy of the chiropractic conceptualization of bedwetting and its approach to treatment, please allow me to present a science-based understanding:

What is nocturnal enuresis?

Incontinence is essentially universal in infants and toddlers, particularly while asleep for long periods of time. Nobody, with perhaps the exception of Fred Clary, expects a 2-year-old, let alone an infant, to consistently make it through a substantial period of sleep without voiding urine. Most readers, especially those with kids or who have worked with younger children, realize that there is a normal range of a few years during which kids will usually acquire the ability to stay dry through the night. What many readers may not realize is how common it is for kids to take longer than expected. In general, we consider children over the age of 5 years who continue to have intermittent episodes of nighttime incontinence as having the diagnosis of nocturnal enuresis (NE).

As many as 10-15 out of every 100 6-year-old children are unable to hold urine in the bladder for long periods of sleep. As these children age, the numbers tend to decrease with roughly an additional 15 per 100 achieving nighttime continence all on their own each year. When all is said and done, 1%-2% of adults continue to have occasional bedwetting. These older kids, and the few adults, who are unable to ever completely maintain overnight continence for a period of at least 6 months without assistance, and who otherwise are healthy, have primary monosymptomatic nocturnal enuresis (PMNE).

When kids have nocturnal enuresis in the setting of additional conditions, such as urinary tract infections, urine incontinence while awake, anatomical abnormalities, or neurologic bladder dysfunction, they are diagnosed with nonmonosymptomatic nocturnal enuresis (NMNE). Children who are able to go 6 months without wetting the bed, and without any of the treatment approaches I’ll be discussing, who then have a recurrence have secondary nocturnal enuresis. Accuracy of the diagnosis is important when deciding on a treatment plan and for prognostic implications.

When is nocturnal enuresis a problem?

When nighttime incontinence becomes a problem really depends on the individual child and his unique social environment, in particular the expectations of the caregivers. If the parents aren’t worried about their healthy 6-year-old wetting the bed occasionally, and the kid is oblivious, then starting any kind of treatment plan would likely not be worth the trouble. And it may even backfire. Simple reassurance and expectant management usually will suffice.

Some families may only be interested in an approach that will allow for continence on a short-term basis, such as for a Summer camp or a slumber party, while still allowing nature to take its course for the most part. Unfortunately, not all parents take such a laid back response to NE. It is common for children to develop feelings of guilt, and to be be repeatedly punished for something they have no control over. The potential for physical abuse is a very real concern, especially when parents begin to blame or resent the child.

In general, NE is a problem and requires a comprehensive treatment approach when the family unit asks for help, not just the caregivers. For the child, the desire to achieve continence typically becomes urgent once wetting the bed begins to limit his or her ability to interact socially. And it is important to strike while the iron is hot, so to speak, in order to then prevent untoward psychological repercussions. It is actually critical to the success of any management approach, however, that the child is bothered by the NE enough to demonstrate their readiness to assume responsibility for their own treatment.

Why does primary monosymptomatic nocturnal enuresis happen?

The development of mature bladder function, and the ability to maintain continence while asleep, relies upon the coordination of the autonomic (involuntary) and somatic (voluntary) nervous systems within the spinal cord and brain. Ultimately, we are able to store urine in a relaxed bladder until we consciously decide to urinate. During urination, the muscles in the bladder wall squeeze and the pressure at the bladder outlet decreases to allow urine to exit the bladder via the urethra.

Initially we have no conscious control over this process. As the infant bladder fills, it will eventually begin to contract in order to empty. As we age, awareness of having a full bladder begins to develop followed by the ability to purposefully hold off contraction of the bladder wall muscles. As more time passes, the ability to time bladder contraction with relaxation of the bladder outlet comes online. Thus continence while awake comes first, followed ultimately by the ability to make it through a long sleep period at around age 5 years, give or take a year, for the majority of children.

There are many factors that can contribute to the development of PMNE, which again occurs in otherwise healthy kids and makes up the vast majority of nocturnal enuresis cases. At the core, however, is the absent or inconsistent arousal from sleep in response to the need to urinate, and children are often described by caregivers as especially deep sleepers. Delayed maturation of bladder function likely plays some role, which might explain why it tends to resolve over time even without intervention. But PMNE likely will still occur in many children despite normal bladder function if the limits of their ability to hold urine overnight are pushed to the breaking point and they simply don’t wake up in time.

A smaller than average capacity to hold urine while asleep as well as excessive urine production can exacerbate this problem. This can occur when a child drinks a large amount of fluid right before bed, or if there is a relative insensitivity or underproduction of antidiuretic hormone (vasopressin), a chemical in the body which helps to regulate water retention in the kidneys. It is thought that ADH secretion is normally increased overnight following a circadian pattern and that this pattern is developmental, perhaps explaining why some children simply grow out of PMNE.

There is a large genetic component to PMNE as well. When one identical twin has delayed continence, there is a 68% chance that the other twin will as well,  while the concordance with non-identical twins is still significant at 36%. Three of every four children born to parents with a history of PMNE will also have delayed continence, while the risk is 50% when just one parent was affected. 

Naturally, when a child presents with concerns of bedwetting at an older than typical age, it can’t be assumed to be a primary and largely self-limiting condition such as PMNE. It is extremely important to consider and rule out, with a thorough history and physical exam usually being all that is necessary, more worrisome potential causes. A number of serious medical conditions can present with bedwetting, such as seizures and diabetes, as well as anatomical abnormalities involving the spinal cord.

Even simple constipation, although not as serious as a tethered spinal cord or spina bifida, can cause bedwetting in an older child. There are many more examples of pathological causes of NE, some of which are not intuitively linked to bedwetting such as pinworms, obstructive sleep apnea and psychologic comorbidities. I’ll spare you the full differential breakdown. I hope that it is abundantly clear how inappropriate it is for inadequately trained alternative medicine practitioners to consider themselves experts on this topic.

Science-based treatment of primary monosymptomatic nocturnal enuresis

As I mentioned earlier, our understanding PMNE is biopsychosocial in nature. The approach to treatment also takes into account the psychosocial aspects of the condition as well as the biology. In fact, lifestyle changes, sometimes aided by some nifty technology, are first line treatments. With few exceptions, such as a pressing need to achieve continence quickly in order to preserve declining psychosocial functioning, pharmaceutical interventions take a backseat to lifestyle modifications.

In general, the goals of PMNE intervention don’t include achieving immediate and permanent continence as quickly as possible. In order to reduce the risk of frustration, the focus is on incremental improvement. And treatment shouldn’t even be initiated until the child as well as the caregivers demonstrates readiness. The child must be responsible for his treatment and understand that the process can be lengthy. The parents must be supportive and aware of the need to avoid blaming the child or incorporating punishment into the treatment regimen.

Lifestyle modifications can, and probably always should, include the limiting of fluid intake in the hour before bedtime, keeping in mind that hydration status takes precedence over bedwetting. Establishing a pattern is rarely easy with children, but a consistent bedtime routine, including an appropriate amount of total nightly sleep, can help reduce bedwetting by preventing excessive fatigue. Keeping a calendar for documenting dry versus wet nights, along with other details such as number of nightly episodes and new symptoms can also be very helpful.

Appropriate means of motivating a child to actively take part in achieving continence overnight can involve the use of reward systems, such as sticker or star charts. When a child makes it through a night without wetting the bed, or meets some other agreed upon goal, he or she can place a sticker or star on the chart. Once requirements have been met, such as a certain number of consecutive dry nights, the child is rewarded. Passive interventions such as this are often tried for several weeks or longer if more urgent continence is not needed.

The use of bedwetting alarms or pharmaceutical intervention, particularly in older children with increasing social concerns or negative psychological sequelae, can be extremely effective. And medication is the only way to achieve immediate continence when desired, although NE may return as soon as the drug is discontinued. Alarms work via a moisture detector typically positioned in the child’s underwear, and can be audible or vibratory. Initially, the alarm simply wakes the child up once he has already begun to wet the bed. Over time, the child is conditioned to wake up prior to actually voiding, or to suppress urination without waking. They work well but are limited to older kids with a strong will to achieve continence, and who will wake up to the alarm. They are not ideal in situations where continence is needed quickly or only for intermittent short periods.

The drug most commonly used to prevent bedwetting is desmopressin, a synthetic version of the antidiuretic hormone naturally secreted by the brain. This is the hormone that is believed to deficient, or less active because of receptor insensitivity, in some children with PMNE. It works by binding specific receptors in the collecting ducts in our kidneys, increasing the reabsorption of water back into the blood and decreasing urine output. This effect is rapid in onset, and the drug is often successful on the first night of use.

It is not risk free, although complications are pretty rare. The most significant potential adverse effect can occur in the setting of a child drinking a large amount of fluid prior to taking the medication. The combination of increased intake and decreased urine output can lead to dilution of the blood and a potentially dangerous drop in the serum sodium level. This dilutional hyponatremia can, in rare instances, cause changes in mental status, seizures, coma and even death. This outcome was more common with intranasal administration of the drug, which is no longer recommended in children with bedwetting.

Medical interventions, whether simple education and reassurance, lifestyle modifications, or pharmaceutical agents, are highly successful. But they aren’t perfect by any means. PMNE is a condition which takes time to resolve. And, as stated previously, it will eventually resolve completely on its own in time in roughly 98% of children.

For a more detailed discussion of the evaluation and treatment of PMNE, here are the 2010 recommendations of the International Children’s Continence Society, which is the worst name for a superhero team ever, just beating out the International League Against Epilepsy. I do admire their work however.

What is the chiropractic approach to noctural enuresis?

Now that you know the science-based medical understanding of why nocturnal enuresis occurs, and our approach to treatment, let’s take a look through the looking glass at how this condition is conceptualized by the chiropractic community. As expected, their take runs the gamut from the utterly devoid of rational thought to the only slightly nutty, with many chiropractic websites getting a number of things right. Many, for example, explain how NE is not the child’s fault and that punishment can be counterproductive.

One common theme I discovered on my journey was the blaming of bedwetting on an immature “phrenic reflex” and subsequent development of elevated levels of carbon dioxide in the blood, with one chiropractor going so far as to claim that “The typical bed wetting child sleeps in a high state of carbon dioxide intoxication.” Their explanation goes like this: infants are incontinent because an elevated carbon dioxide level fails to stimulate the phrenic reflex, which causes diaphragmatic contraction and increased respiratory activity which in turn lowers carbon dioxide levels. Carbon dioxide acts as a smooth muscle (muscle we don’t control consciously, like the bladder wall) relaxant, so high levels cause relaxation of the smooth muscle in the bladder outlet and undesired nocturnal urination. (1)(2)(3)(4)(thousands more)

And what is to blame for this supposed delayed maturity of the “phrenic reflex?” After a brief mention of the possibility of a genetic contribution, which is of course true but not in the way they are claiming, the bulk of their discussions focus on, you guessed it, the subluxation. This fictional cause of all ailments is behind the poor functioning of the phrenic nerves. Something, something, something nerve interference of the 3rd, 4th and 5th cervical spinal nerves which innervate the diaphragms by way of the phrenic nerves, one for each of the left and right hemidiaphragm. Many chiropractic websites also claim that subluxations involving lower thoracic, lumbar and sacral spinal nerves directly lead to incontinence.

It may sound compelling, but it’s all complete baloney. First off, their version of the “phrenic reflex” is a fiction. In newborns, there is a little known reflex known as the intercostal-phrenic reflex which actually inhibits breathing when the rib cage is distorted. It has absolutely nothing to do with levels of carbon dioxide in the blood and it doesn’t increase respiration.

Speaking of carbon dioxide, rising levels do tend to increase the respiratory drive, but by stimulating chemoreceptors in the aorta, carotid arteries and brainstem rather than by a “phrenic reflex.” The increase in breathing keeps the levels in check in healthy individuals. If a young infant were to fail to respond to this signal to increase the respiratory drive, as sometimes happens for reasons poorly understood, they die. This is actually one of the proposed mechanisms of Sudden Infant Death Syndrome (SIDS).

Hypercapnia, the abnormal persistent elevation of carbon dioxide in the blood, can cause acidosis and a number of symptoms including but not limited to difficulty breathing, headache, altered mental status, cardiac arrhythmias, seizures, coma and death. It does not cause isolated bedwetting. In fact, if elevated levels of carbon dioxide in the blood caused relaxation of bladder smooth muscle it would cause urinary retention rather than incontinence. Urination requires contraction of the bladder wall, not just relaxation of the bladder outlet. Medications that relax smooth muscle in the bladder are actually often used to treat incontinence related to overactive bladder syndrome.

Finally, if both phrenic nerves, which again contain contributions from the 3rd, 4th and 5th cervical spinal nerves, were not functioning properly a child would have paralyzed diaphragms (C, 3, 4, 5, keeps the diaphragm alive!) and severe respiratory problems if not an inability to breath at all. This actually happens sometimes during vaginal deliveries when significant lateral force on the head and neck is required to deliver a large baby that has become stuck at the shoulders. This can stretch the cervical spinal nerves to the point of injury or even complete transection, causing diaphragmatic paralysis as well as other unfortunate injuries.

Despite hours of reading chiropractic claims regarding bedwetting, I failed to find any legitimate discussion of the potentially serious causes of nocturnal enuresis. Parents could likely search hundreds of chiropractic websites without coming across any mention of red flags for conditions that would need evaluation and treatment by a real physician or surgeon. These are the people that want to work as primary care providers to children.

In addition to chiropractic, a wide variety of alternative medical treatments have been used to treat nocturnal enuresis in children. The folks at Cochrane reviewed the available evidence in 2011, and didn’t have anything positive to say in their conclusion:

“There was weak evidence to support the use of hypnosis, psychotherapy, acupuncture, chiropractic and medicinal herbs but it was provided in each case by single small trials, some of dubious methodological rigour. Robust randomised trials are required with efficacy, cost-effectiveness and adverse effects clearly reported.”

That’s about as negative as Cochrane gets, but I disagree with any calls for more research. This pattern of weak evidence is typical of modalities that work via the many placebo effects when investigated  as a treatment for a largely self-resolving condition. Let’s think of an activity off the top of our heads. How about knitting? Knitting by a caregiver in the same room as a sleeping child. Wait. Knitting in a different country while simply thinking of the little bedwetter. I am confident that intercessory knitting would be found to have weakly positive benefits for children with PMNE if studied by proponents. Some kind of an alternative sewing circle perhaps.

Here is a nice breakdown of two of the frequently cited, but painfully weak, studies cited by chiropractors to support their claims of success treating nocturnal enuresis.

Conclusion

Bedwetting is a common pediatric complaint with a multifactorial etiology. It is usually benign and almost always improves over time, with 98% of children with primary monosymptomatic nocturnal enuresis eventually becoming fully continent. Interventions exist which can involve simple reassurance and education, bedwetting alarms, or pharmaceutical agents. They all have solid evidence of success and relatively few risks.

Anytime a child continues to wet the bed past the typical age of roughly 6 years, and whenever a continent child has a recurrence of nocturnal enuresis, it is vital to rule out a number of potentially serious problems. When practitioners of chiropractic, or any field inadequately trained in pediatric healthcare, believe that they are capable of assuming the role of primary care provider for children, there is a very real risk of delayed diagnosis of one of these conditions. One need look no further than the information available for caregivers online to see that chiropractic education is vastly inferior to practitioners of science-based medicine.

Categories: Medicine, Skepticism

An App To Monitor Parkinson’s Disease

Neurologica Blog - Thu, 08/14/2014 - 08:25

In 2000 Michael J. Fox began a non-profit organization to support research into Parkinson’s Disease (PD). This was shortly after he was diagnosed with the disease. Since then Fox has been the model celebrity spokesperson and advocate. (He doesn’t kibitz, he just raises awareness and supports the science.)

Now his foundation, together with Intel, have developed a wearable device and accompanying app that can monitor the symptoms of PD in real time 24 hours a day. This is an interesting application of technology, and something that we are beginning to see more, and will likely increase in future.

PD is a neurodegenerative disease affecting a part of the brain called the substantia nigra. Neurons in that structure produce and release dopamine. These neurons are part of a circuit (the extrapyramidal system) that essentially monitors and adjusts the sensitivity or gain of the motor system. It’s a sensitive feedback loop that keeps our movement smooth. If the gain is turned up too high then we would constantly be moving and writhing. If it’s turned down too low, then we start to freeze. People with PD have the gain turned down too low.

The symptoms of PD are stiffness, decreased movement, tremors, and difficulty walking and maintaining posture. The new device is worn like a watch, and it can monitor movements with 300 data points per second. This generates about a gigabyte of data per day, which can be uploaded to a database using a smartphone app.

This massive amount of information can potentially be very useful to researchers. They will be able to map fluctuations in the control of PD symptoms throughout the day. This could be used in drug trials to record the effect of PD medication. It can be used to mine for environmental factors that affect symptoms, such as sleep, eating, and time of day.

While we have some clues, we essentially don’t know what causes PD and we don’t know how to cure it. Treatment is therefore mainly symptomatic. It’s a delicate system, and it becomes increasingly difficult to obtain good control of symptoms as the disease progresses.

Therefore, in advanced PD, making small tweaks or improvements to the treatment regimen can have a significant impact on the quality of life of PD patients.

I also love the idea of continuous real-time ambulatory monitoring of medical parameters. One of the frustrations of practicing medicine is that we often have incomplete and subjective information about what is happening with patients. We spot check things like blood pressure, laboratory values, neurological function, whatever, and otherwise rely on patient report to document how they have been doing.

There are specific tests that involve monitoring a parameter for 24 hours or so, like a Holter monitor which is essentially a 24 hour EKG.

Portable electronics and smartphones, however, open up the possibility of gathering massive amounts of objective data over long periods of time, data that can then be analyzed by computer to look for trends and anomalies.

If used correctly, this type of data can provide very useful feedback with which to adjust treatments. It can also be used diagnostically.

There is a potential downside, however. It’s easy to be overly impressed with data, and to read significance into noise. I predict that as such systems come into legitimate use, they will also be abused by marginal or fringe practitioners. Small and insignificant fluctuations will be used to give bogus diagnoses, or to demonstrate response to bogus treatments. Large sets of data like this are ripe for mining data, confirmation bias, and creating the illusion of legitimate science.

Conclusion

This new device developed by Michael J. Foxes charity and Intel looks very promising and I would predict that it will find its uses in the management of PD patients.

The technology also is part of a trend toward real time monitoring of medical parameters generating massive amounts of data. This is an exciting development, as there are many opportunities that clever researchers can exploit.

Big data comes with a caution, however, as it is also ripe for exploitation by the pseudoscientific or unscrupulous.

Categories: Medicine

Naturopathy vs. Science: Prenatal Vitamins

Science Based Medicine - Thu, 08/14/2014 - 08:00

 

This is another in the naturopathy versus science series, where a naturopath’s medical advice is assessed against the scientific evidence. Today’s topic is brought to you by Toronto naturopath Shawna Darou, who recently published her evaluation of prenatal vitamins.

Vitamin supplementation is unnecessary for the vast majority of people. You wouldn’t know this walking through a drug store, where you’ll usually find an entire aisle packed with supplements. Alternative health providers like naturopaths tend to be strong supporters of supplementation, but this advice seems to be based mainly on the belief that “vitamins are magic”, rather than good science.  Because the best  evidence hasn’t found a strong evidence base for supplements. We definitely need vitamins in our diet to live. But that’s where we should be getting those vitamins – from our food, instead of from pills. If you eat a reasonable and balanced diet, vitamin supplementation won’t offer meaningful health benefits. In the absence of any deficiency, vitamin supplements seem to be useless at best and harmful at worst.

That doesn’t mean vitamins are always useless or unnecessary. They can also have important medical uses. Vitamin deficiencies can occur, and sometimes the consequences can be significant. Pregnancy is one example. Pregnant women may not obtain adequate amounts of nutrients like folate in their diet. Deficiencies are linked to major birth abnormalities: neural tube defects. It is well established that folic acid supplementation around the time of conception, and continued through pregnancy, can significantly reduce the risk of neural tube defects, and may reduce the risk of some other abnormalities as well. There are now widespread recommendations for folic acid supplementation in pregnancy. Because many pregnancies are unplanned, public health strategies have included fortifying food with folic acid, and this approach also seems to reduce birth defects in populations.

Folate is not only the only deficiency possible in pregnancy. Pregnant women have higher requirements for calcium and iron. There’s also the need to ensure adequate amounts of vitamins A, the B’s, C, D, E and zinc. While these needs can potentially be met through diet, some  guidelines recommend a multivitamin (and not just folic acid) because of the consequences of a deficiency and a lack of any real risks. And supplementation works. The most common maternal multivitamin (at least here in Canada) is Materna though there are many competitors, and lots of generics. Costs can be as low as $4-8 per month. Prenatal vitamins all contain 0.4mg-1mg of folic acid – it’s the most essential ingredient. Most contain slightly higher amounts of calcium and iron, along with modest amounts of other vitamins. That helps diets meet nutritional requirements requirements, reduces risks of birth defects, and is a practice aligned with the best evidence.

Choosing a prenatal vitamin is normally a fairly straightforward matter: pick one, and take it daily, starting from when you begin to contemplate having a baby. I could find no guidelines that have established one brand of prenatal vitamin as superior, though some may be better tolerated than others.  I usually suggest Materna (as it’s been used in clinical trials) but it’s expensive, so if cost in an issue, a store brand product should be fine.  (In Canada a prescription-only vitamin called PregVit is also popular.) With the exception the occasional reports of nausea and vomiting, most women have no problems finding a product they can tolerate and also afford. Beyond the basic prenatal vitamin brands, you’ll find other brands that are advertised as being superior for you and your baby’s growth.  That’s why I read a recent blog post from a naturopath with interest, as she listed her preferred prenatal vitamins, and why.

What do naturopaths think of prenatal vitamins?

I first learned about naturopathy when I was a retail pharmacist in Toronto – Toronto has one of a handful of naturopathy schools in North America, so it’s not uncommon to meet patients that consult them. I spent some of my time in that pharmacy helping patients source strange supplements, which sometimes cost hundreds of dollars per month. It was good for that pharmacy’s sales, but I was curious how naturopaths could always find conditions like food “intolerance”, pH “imbalances”, adrenal “fatigue”, and hormone “depletion” in their patients. I’d never heard of these conditions, and there was nothing in the medical literature that established they were real. It seemed the likelihood of being diagnosed a condition like “candida overgrowth” was highly correlated with visiting a naturopath, as nearly every client was taking purgatives and avoiding bread, believing they were fighting some sort of a whole-body colonization of yeast that was both widespread in their body yet not detectable by medical science. The treatment, of course, was more supplements, sometimes combined with different forms of “detox” kits and some homeopathy.

Naturopaths consider themselves to be primary care providers comparable to medical doctors. Toronto naturopath Shawna Darou’s bio notes she “graduated from the Canadian College of Naturopathic Medicine (www.ccnm.edu ) at the top of her class and was the recipient of the prestigious Governor’s Medal of Excellence”,  so presumably she’s an example of the advice you’d get from a typical Toronto naturopath. Her services advertised include women’s health and prenatal care, so I’d expect her to know what she’s talking about if she’s going to make recommendations about nutrition in pregnancy. There is a well-established evidence base to rely on, alongside dozens of guidelines and advice from groups like the Cochrane  Collaboration.

The Naturopath’s Advice

Darou opens her post:

Choosing prenatal vitamins can be complicated, as the world of supplements is difficult to navigate. The two most popular prenatal vitamins are “Materna” and “Preg vit”, but I would like to show you why professional brands of supplements are far superior in both nutrient levels, and absorption. My current favourite prenatal vitamin is NFH brand “Prenatal SAP”, as they have integrated the most current research into their prenatal vitamin formula. Other great brands are Thorne Research, Douglas laboratories and Pure Encapsulations.

Perhaps not surprisingly, Darou’s website sells NFH Prenatal SAP. The same company also sells products to fight candida overgrowth and adrenal fatigue (both common naturopath-diagnosed conditions), which sends a signal about the credibility of the company, since candida overgrowth (as defined by naturopaths) and adrenal fatigue are both fake diseases.

Darou says she had four criteria for her selection:

  1. Nutrient levels – how much of each individual vitamin and mineral is in a daily dose?
  2. Absorbability of nutrients – are the vitamins and minerals found in their most absorbable form?
  3. Form of folate – folic acid or methylated folate? This is essential if you carry a defect in the MTHFR gene.
  4. Fillers and other additives. It’s amazing what you find when you read the fine print!

Darou has designed her own chart that compares between the different brands.

Nutrient Levels

Not surprisingly, more is better to Darou:

In a careful comparison between seven prenatal vitamins, I found that there is an enormous difference in the amount of basic nutrients, with the biggest discrepancy in B-vitamin levels. For example, vitamin B-5 levels range from 5 mg per day in PregVit to 100 mg per day in NFH’s Prenatal SAP. Overall, the professional lines (Pure Encapsulations, Douglas labs, Thorne Research and NFH) contained significantly higher levels of essential nutrients.

The most important nutrient in a prenatal vitamin is folic acid. Optimal levels of the others are not known, as there’s no evidence to suggest that additional amounts of the other B-vitamins or other ingredients offers any benefits at improving perinatal health. They’re unlikely to be harmful, however.

Absorbability

Darou criticizes three ingredients in multivitamins as being “cheap” (and presumably, inferior):

Calcium carbonate vs. Calcium Citrate: Darou prefers the citrate version, stating it is “more easily broken down and absorbed’. When given as single supplements, calcium citrate may cause less stomach upset than the carbonate version, but at the expense of larger tablets (citrate versions contain less elemental calcium). However, the amounts in multivitamins are all low, and when prenatal vitamins are taken with food, the choice of carbonate or citrate should not result in any meaningful differences.

Oxide forms of minerals vs. citrate forms (magnesium, zinc, copper): Darou states the oxide versions of minerals “have lower absorption, and can be irritating to the digestive tract, while the citrate forms have much better absorbability.” Even if correct, it doesn’t mean no absorbtion or that there are clinically meaningful differences. Again, this is a trivial difference without any meaningful impact on perinatal health.

Vitamin B12: cyanocobalamin vs. methylcobalamin: Darou states:

Cyanocobalamin is a synthetic form of vitamin B12 that does not exist in nature. When absorbed, it releases a cyanide molecule which is toxic and must be processed by the body. It is added to most multivitamins as it is significantly cheaper than the higher absorbed, more bioavailable form called methylcobalamin. All of the naturopathic lines of prenatal vitamins contain methylcobalamin.

Note the naturalistic fallacy – cyanocobalamin is not only unnatural, it releases cyanide! Vitamin B12 is a group of related compounds containing cobalt as the central ion. Cyanocobalamin is a version of B12 with a cyanide group.  Darou doesn’t mention the fact that the amount of cyanide released from cyanocobalamin is insignificant to the body (and besides, cyanide is natural). She also doesn’t mention that cyanocobalamin is the version of B12 that is the most studied. There’s no published evidence that shows methylcobalamin is superior to cyanocobalamin as a prenatal supplement. B12 is widely believed to be some sort of energy panacea, but the science doesn’t support this claim. In your prenatal supplement, there’s no evidence demonstrating cyanocobalamin is inferior.

Folic Acid or Folinic Acid?

Darou says:

…up to 65% of women contain a defect in an enzyme called MTHFR which is essential in the absorption of folate. What this means is that ‘folic acid’, found in most prenatal vitamins may not be absorbed well for many women. I highly recommend folate supplements in the ‘methylated’ version which bypasses this step of absorption. Folate in the form of 5-MTHF (5-methyl tetra hydrofolate) is best.

The MTHFR deficiency has no effect on folic acid absorption (contrary to what Darou says) but rather its metabolism. Daroun recommends 5-methyl tetra hydrofolate, more commonly known as folinic acid. While there is some preliminary evidence suggesting that MTHFR deficiency in the mother may increase the risk of NTDs, there isn’t any published evidence suggesting folinic acid is superior to folic acid to prevent neural tube defects.  All of the large trials establishing the benefits of folate supplementation have used folic acid, so folic acid remains the preferred, evidence-based version of folate that should be used for the prevention of neural tube defects.

Tablet Fillers and other Additives: Not a bug, but a feature

Darou doesn’t like other ingredients in her supplements:

It is shocking to find the fillers and additives found in pharmacy brands of prenatal vitamins. For example Materna contains: BHT, corn starch, FD&C red #40, gelatin, lactose, mineral oil, polysorbate 80, sodium lauryl sulfate, soybean oil, titanium dioxide among others! Note that there are three key allergens here (corn, soy and lactose), and several toxic chemicals! PregVit vitamins are even worse in the fillers, containing ammonium hydroxide, D&C Red #27, FD&C Blue #1, FD&C Blue #2, FD&C Red #40, FD&C Yellow #6, PEG 3350, polyvinyl alcohol, propylene glycol, shellac glaze, sodium lauryl sulfate, talc and titanium dioxide!!

These ingredients are included in pharmaceuticals and vitamin supplements for one reason: to ensure the finished product is of high quality. A high quality product has a long shelf life, doesn’t smell bad, has consistent ingredient quality, is easy to swallow and then dissolves quickly and thoroughly, with the ingredients being absorbed quickly.  A tablet manufactured without any excipients would likely disintegrate in the bottle or in a worst case scenario, fail to dissolve at all. Excipients are not harmful and actually improve the quality of the product, rather than weaken it. She doesn’t seem to understand that “the dose make the poison” and the amounts in any product are deliberately there to ensure the final product is of high quality. There are no harms, real or expected, from the excipients in supplements.

Conclusion

Darou paints a negative picture of conventional multivitamins using weak, and sometimes erroneous arguments, while subtly promoting a product and brand of vitamin that she happens to sells on her website. If you want a textbook example of a conflict of interest in health, here it is. Her recommendations are largely consistent with what I’ve seen from naturopaths before – limited scientific literacy that is filtered through a belief system, generating advice that can sometimes be reasonable but more often than not is inconsistent with the best medical evidence. Women that need nutritional advice would be better advised to speak with health professionals that practice according to scientific standards, such as registered dieticians. You’ll be more likely to get reliable and most importantly, unbiased advice. The stakes are too high in pregnancy to rely on the advice of alternative medicine providers.

Photo from flickr user Thomas van Ardenne used under a CC licence.

Categories: Medicine, Skepticism

A Statement on Cervical Manipulation and Dissections

Science Based Medicine - Wed, 08/13/2014 - 08:10

The American Heart Association and the American Stroke Association recently published in the journal, Stroke, a thorough analysis of the evidence for an association between cervical manipulative therapy (CMT) and both vertebral artery dissection (VAD) and internal carotid artery dissection (ICAD). The full article is online: Cervical Arterial Dissections and Association With Cervical Manipulative Therapy: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association.

For background, an arterial dissection is essentially a tear in the inner lining of the artery. This tear disrupts the normal regular streams of blood flow, and also platelets will gather at the site of injury. This can result in a blood clot at the site of the dissection. This blood clot can block flow through the artery, or it can break off and lodge downstream, blocking flow at that point. Dissections, therefore, can result in a stroke (a lack of blood flow to a portion of the brain causing damage).

There are four arteries in the neck that bring blood from the heart to the brain, two carotid arteries in the front, and two vertebral arteries in the back. A dissection in one or more of these arteries is associated with 2% of all strokes, but with 8-25% of strokes in patients <45 years old. This is mostly because strokes associated with processes like atherosclerosis are much less common in the younger population.

Arterial dissections are classified as either spontaneous or traumatic. Trauma can be either severe, such as whiplash injury from a car accident, or subtle, such as yoga, or simply turning one’s neck to look behind them.

There is an ongoing controversy as to the relationship between CMT and cervical dissection, either ICAD or VAD. Chiropractors, who are one of the main practitioners of CMT, have generally denied a causal connection, while neurologists have been more cautious.

As the reviewers point out, it is now clear, based on several studies, that there is an association between CMT and cervical dissection. What is not clear is if the CMT is causing the cervical dissection. They write:

In summary, a few case-control studies suggest that CMT is associated with CD. These studies did not specifically distinguish whether the CMT included a thrust maneuver or not; the former is typically used with chiropractic manipulation. In the absence of prospective cohort or randomized studies, the current best available evidence suggests that CD, especially VAD, may be of a low incidence but could be a serious complication of CMT. Although these studies suggest an association, it is very difficult to determine causation because patients with VAD commonly present with neck pain, which may not be diagnosed prior to any CMT.

There is on study in particular, the Cassidy study, that is often cited as the evidence that the correlation between dissection and CMT is not causal. Specifically, they found that patient are just as likely to visit a medical practitioner as a chiropractor in the weeks prior to a stroke. Therefore, they authors argue, patients go to the doctor for the neck pain, rather than CMT causing the neck pain through dissection.

While the review was otherwise thorough, I was disappointed in their treatment of the Cassidy study. Our own Mark Crislip did a much better job, pointing out that the many flaws in the Cassidy study. Specifically, they included older strokes and a longer time frame, both resulting in a statistical dilution of cases where CMT might have caused VAD. When you look only at stroke patients <45 and withing 24 hours of having CMT, there is a clear association – about a 5 fold increased in risk of VAD.

Other information discussed in the review is also illuminating. For example, the ratio of ICAD to VAD in spontaneous dissection is 2:1, but following CMT the ratio is 3:1 in favor of VAD. This can have two interpretations – either CMT causes some VAD, or that patients with VAD are more likely to seek treatment for neck pain than patients with ICAD. Both conditions result in neck pain, but VAD is more posterior so it is not entirely implausible that this difference in symptoms is partly responsible for the increased association between VAD and CMT.

They also discuss possible mechanism. There is no question that CMT stretches the vertebral artery, although in most cases probably not enough to cause dissection. This makes sense, as VAD is a rare complication of CMT (even if we assume that 100% of the association results from CMT causing VAD). In the rare cases of VAD associated with CMT, this may result from aggressive CMT, or from the particular of the patient’s anatomy.

Conclusion:

The authors of the new review conclude:

Clinical reports suggest that mechanical forces play a role in a considerable number of CDs, and population controlled studies have found an association of unclear etiology between CMT and VAD stroke in young patients. Although the incidence of CD in CMT patients is probably low, and causality difficult to prove, practitioners should both strongly consider the possibility of CD and inform patients of the statistical association between CD and CMT, prior to performing manipulation of the cervical spine.

This is a typically conservative conclusion, and it’s difficult to fault the authors for being so. I do think they are understating the probability of a causal relationship, however, probably because they were overly influenced by the Cassidy study, which they should not have been given its fatal flaws.

That aside, we can state clearly that, although rare, VAD is associated with CMT. There is a very plausible mechanism for injury, and it is clearly known that even mild trauma can cause VAD. Further, there are numerous case reports of young healthy patients developing symptoms of VAD, including stroke, shortly after their CMT, sometimes immediately.

It is true that none of this proves a causal connection, because we can’t do randomized trials (although prospective trials would be helpful). But this is true in the same way that we can’t prove smoking causes lung cancer, we only have association. When we have a clear association with multiples lines of evidence suggesting the most likely causal explanation, and that explanation points to a medical risk, then I think it is reasonable to act on that risk. We recommend that patients do not smoke. We should also recommend that they do not have CMT, especially high manipulation and forceful manipulation.

Medicine is a game of risk vs benefit, and so considering the risk is not enough. What is the benefit of CMT for the specific conditions it is used to treat? The evidence for the benefit of CMT is less than the evidence that it causes VAD. A Cochrane review of CMT for neck pain and headache concluded:

Done alone, manipulation and/or mobilization were not beneficial; when compared to one another, neither was superior.

So CMT does not work, but perhaps may have some benefit when added to medical management, and even then it is no better than the gentler mobilization. Therefore, since CMT (if it works at all) is not superior to mobilization, and may involve a rare but serious risk of VAD and stroke, it seems to me it is unethical to perform CMT for neck pain or headache rather than mobilization.

It can further be noted that, even if chiropractors are correct in saying that most people with VAD and CMT presented with an existing VAD causing neck pain, that still does not justify CMT. In such a case (someone with a VAD and neck pain) the neck should not be manipulated at all because such manipulation could very plausibly provoke a stroke. Cases of suspected VAD need emergent medical evaluation and treatment.

The current review is further evidence that CMT should be eliminated as a medical procedure.

Categories: Medicine, Skepticism

Tocco’s Anti-vaccine Narrative

Neurologica Blog - Tue, 08/12/2014 - 08:35

Part of the scientific approach to knowledge is to integrate information at various levels. It’s important to get the tiny facts correct, but you also have to put those facts into progressively broader and deeper frameworks. Theories are informed by facts which in turn make sense only in the context of the theory.

I try to take this approach with topics on this blog, by not only spending time addressing specific facts but also trying to see the big picture. For example, Mary Tocco, who is an anti-vaccine activist, was recently given space for a guest column on Michigan Live. I will go through and deconstruct her specific claims, but it’s also helpful to view her article in the broader social context.

Tocco is part of Michigan Opposing Mandatory Vaccination, or MOM (how can you not love “mom”). In her article she writes:

“The authors labeled Michigan Opposing Mandatory Vaccines an anti-vaccine group. Our organization is about protecting parental right to choose whether or not to use vaccines as a method of health care for themselves and their children.”

From this one paragraph we can see many of the threads currently weaving through culture. The big picture is that there is an ideological struggle going on between those who take a science-based worldview and believe that rational regulations should be based on the best science available, and those who wish to promote some other agenda that is not science-based.

Those on the anti-science side of the equation all use similar tactics, which I suspect they learn from each other (partly because there tends to be overlap in anti-scientific groups). One such tactic is to frame the debate as being about rights and freedom, rather than about the science. Therefore we see anti-vaccine groups presenting themselves as being pro-vaccine choice. Promoters of alternative medicine try to erode consumer protections by being for “health care freedom.” Anti-GMO activists present themselves as simply favoring consumer information through mandatory labeling.

It’s better to be for freedom than against science. But make no mistake – these groups only want the freedom to be anti-science.

It also strikes me that these groups typically also promote a narrative that pits parents (moms), children (because we have to think about the children) and consumers generally against corporate greed or government malfeasance. When you scratch the surface, however, they are often promoting one industry over another.

Anti-GMO activists often have a vested interest in promoting the organic food industry. Anti-vaxxers have a huge overlap with those promoting “alternative health.” They are selling something, often a product that is scientifically dubious. From a maximally cynical (but I think justifiable) point of view, the anti-vaccine movement, “natural” health movement, health care freedom movement, and anti-GMO movement are all largely about promoting one industry over a competitor using deceptive marketing. Unfortunately, these tend to be effective marketing campaigns because they target human emotions. They often trade on fear, for example.

Mary Tocco, for example, appears to make her living as a natural health consultant. Regardless, her specific claims are all tired anti-vaccine tropes that have long been debunked. This raises another common theme – anti-science groups are not genuinely engaged with the science or their critics. They have propaganda points that they endlessly repeat, whether or not they are true, and long after they have been completely destroyed in public discourse.

She writes:

We have protected the rights of parents in Michigan since defeating a bill back in September 1995 that would have eliminated the philosophical exemption to vaccinations and are a voice for thousands of parents who support transparent information about the known safety risks of vaccines. MOM encourages informed vaccine decisions and do not tell people how to decide or whether or not to vaccinate.

Philosophical exemption simply means anyone can simply choose not to vaccinate their children and still place them in public school. Keep in mind, vaccines are only mandatory in the US in that children need them to enter public school. Parents can always opt out and either homeschool or send their kids to private school that doesn’t require vaccination.

No one disagrees with medical exemptions from vaccines. Religious exemptions are controversial, and I won’t delve into that topic here. The real issue is, if states allow for any non-medical exemption, how difficult is it to obtain? Philosophical exemptions are all about lowering the bar and making it easy.

Saying that the group “support transparent information about the known safety risks of vaccines,” implies that this is an issue. If you want transparent scientific information about vaccine risks, ask your doctor, or go to the CDC website.  Look up any vaccine and they will list all the known side effects and their incidence right there.

Anti-vaccine groups pay lip service to informed decisions and transparency, but actually they are promoting misinformation and so are actually working against informed consent. They are muddying the waters with nonsense, cherry picking, distortion of facts, and outright lies.

She writes:

The authors claim that Michigan’s unvaccinated rates are a health risk. I have not seen any studies proving that those who are unvaccinated or lacking in all of their vaccines have shown a reduction in health.

Then you have not been looking. I reviewed the literature here. What published studies show is that vaccinated children are different from unvaccinated children in one way – they have fewer vaccine-preventable diseases. That is what vaccines are supposed to do. There are also countless studies looking at individual vaccines, showing that they reduce the risk of contracting the disease they are meant to prevent.

She goes on:

It is a fact that when a child recovers from these infectious illness, they obtain life-long immunity as a benefit.

This is a distortion. Not all infections produce life-long immunity. Length of immunity varies. The same is true for vaccination – length of immunity varies. Researchers track how long the immunity from vaccines last, and schedule booster shots accordingly.

Sometimes immunity from surviving the disease lasts longer than the vaccine, because the length and intensity of exposure to antigens is greater, but at what cost? Vaccine-preventable infections are not all benign. Many can cause serious permanent harm or even death. If nothing else, who wants to be miserably sick for weeks. The whole point of vaccine is to trigger immunity without the disease. If you take a risk vs benefit approach, the benefit of vaccines vastly outweighs the risk, perhaps by more than any other medical intervention.

She digs in:

The science “is not settled” on vaccine safety or efficacy.

This is a lie. The science is absolutely settled. Vaccines are safe and effective. “Safe” does not mean zero risk – life does not come with zero risk, ever. It means they are relatively safe, and that benefit outweighs risk.

As evidence to support her misinformation she writes:

The United States Vaccine Court has settled over 85 cases where children are injured with neurological injuries from vaccines since 2000.

This is another distortion. The vaccine court does not determine if vaccines caused the reported injuries. They only determine if compensation is appropriate, based on their rules which are designed to favor the claimant. They err way on the side of compensating sick children, and they don’t force them to prove cause and effect. This is, therefore, not a good line of evidence that vaccines cause harm.

And of course, no one denies that rare (on the order of magnitude of one in a million) cases of vaccine serious side effects do occur.

If Tocco is going to site the vaccine court, however, then she should note that the court did make a ruling on the association of vaccines and autism, hearing the best cases the anti-vaccine crowd had to offer, and rejected their claims. 

She continues:

As I travel the country speaking with parents, the #1 concern is vaccine ingredients. Many are not meant to eat and yet we inject them via vaccination!

This is naked fearmongering with the “toxin gambit.” David Gorski has deconstructed this myth many times. 

Conclusion

Tocco’s article is a Gish Gallop of fearmongering, misdirection, and misinformation. As you can see, many sentences require full articles to deconstruct.

She is not, in my opinion, being an honest broker of science-based information. She is selling a narrative, one that is crafted to resonate with common fears and concerns of most people. She is marketing an anti-scientific alternative health ideology, one that is highly profitable and is threatened by accurate scientific information.

The anti-vaccine movement cannot win in the arena of science. In fact, they have already lost. So they are desperately trying to change the venue by framing the narrative as one about freedom, choice, and transparency. Ironically they are doing this with misinformation that detracts from transparency and freedom of choice.

Categories: Medicine

Antibiotics vs. the Microbiome

Science Based Medicine - Tue, 08/12/2014 - 03:00

In 1850, one in four American babies died before their first birthday, and people of all ages died of bacterial infections that could have been successfully treated today with antibiotics. Unfortunately, treatments that have effects usually have side effects, and we are seeing problems due to the overuse of antibiotics. They are given to people with viral infections for which they are useless and to food animals to improve their growth. As a result, antibiotic-resistant organisms are evolving and the development of new antibiotics is not keeping up with the threat. This is common knowledge, but we’re starting to realize that there may be other problems with antibiotics even when they are used correctly to save lives.

The rates of obesity, diabetes, asthma, food allergies, hay fever, eczema, inflammatory bowel disease, celiac disease, acid reflux disease, and esophageal cancer are all on the rise. Martin Blaser, MD, director of the Human Microbiome Program at NYU, thinks antibiotics may be to blame, either as a causal or a contributing factor. In his book Missing Microbes: How the Overuse of Antibiotics Is Fueling Our Modern Plagues,  he describes some of the fascinating research he and others have been doing to elucidate the role of the more than 100 trillion microbes that live on and in each of us, and the possibility that antibiotics may have a causal role in several of the so-called diseases of civilization.

H. pylori

I learned a new word from the book: amphibiosis, the condition in which two life-forms create relationships that are either symbiotic or parasitic, depending on context.  You have probably heard of Helicobacter pylori, the bacteria that earned Dr. Barry Marshall and Dr. Robin Warren a Nobel Prize in 2005 for finding it in the stomach and discovering its connection to gastritis, ulcers, and stomach cancers. We think of it as a pathologic organism that we should eliminate with antibiotics. Dr. Blaser argues that along with the harms it causes, it protects its hosts from a number of diseases.

That may sound like a crazy idea, but he provides a lot of surprising supporting evidence, as well as insights from evolutionary theory. Genetic studies have shown that humans have carried H. pylori for 100,000 years. We can trace human migration patterns with different strains: pure East Asian strains can be found deep in the Amazon jungles while European strains predominate in South American coastal cities. Until recently it colonized virtually all children early in life; today, only 6% of American children harbor it. Nearly all adults in Africa, Asia and Latin American carry the bacteria, but only half of adults in Australia do. The reason for its declining prevalence can be explained in one word: transmission. Sanitation is better, families are smaller so kids are less likely to pick it up from siblings, and antibiotics destroy bacteria.

We are just beginning to appreciate the importance of the microbiome, the mixture of microbes that help keep us healthy. Babies get their first dose of microbes as they pass through the birth canal. Babies born by C-section are not colonized by their mother’s vaginal lactobacilli, and their microbiome only gradually comes to resemble that of vaginally born babies over the next several months. We don’t know how much this matters, but it’s certainly worth thinking about. The C-section rate varies geographically from 4% in some parts of Sweden to 80% in Rome.

H. pylori stimulates a profusion of lymphocytes and macrophages in the stomach. This is diagnosed as gastritis, but Blaser argues that maybe we should think of it as a normal immune response that attacks some pathogens and improves the ecology of the stomach for friendly microbes. The increase in T-cells is protective against diseases like asthma, especially early in life.

Carriers of H.pylori are 6 times as likely to develop stomach cancer as non-carriers, and carrying the cagA-positive strain doubles the risk.

Non-carriers have higher levels of stomach acid, have more heartburn, and are 8 times as likely to develop gastroesophageal reflux disease (GERD).

Carriers are 30-40% less likely to have asthma and are less likely to have hay fever and skin allergies.

H. pylori affects the regulation of the hormones ghrelin and leptin. Farm animals are given antibiotics because they promote growth. Subtherapeutic antibiotic treatment (STAT) alters bacterial diversity, converts indigestible food in the intestine to useable calories, and increases body fat; and the effect is synergistic with a high-fat diet. Transferring the STAT microbiome to germ-free mice makes them fat. Studies in mice have shown that even brief exposures to antibiotics early in life can contribute to lifelong obesity. Children who got antibiotics in the first 6 months of life were fatter. And C-section births were associated with childhood obesity.

Antibiotics and C-sections

There is evidence that antibiotics early in life and C-sections increase the incidence and progression of diabetes. Patients who recently developed celiac disease are 40% more likely to have been prescribed antibiotics in the preceding months. Children who develop inflammatory bowel disease (IBD) are 84% more likely to have received antibiotics. Victims of salmonella infections were more than 5 times as likely to have taken antibiotics in the previous month. Blaser speculates that antibiotic use might also be a contributory factor in conditions as diverse as nut allergies and autism.

Babies in the US routinely get antibiotics on the first day of life to prevent devastating gonorrheal eye infections, but the risk is low today. In Sweden, they are not treated, and there is no effect on the rate of infection. Perhaps we should reconsider.

Blaser says our microbiome evolved for good reasons and tampering with it is potentially dangerous. He is enthusiastic about the prospects of increasing our understanding of all those critters that live inside us, but he recognizes the limits of our current knowledge. He is skeptical of claims for probiotics and prebiotics, but he does support more rational antibiotic use and efforts like the Antibiotics Are Not Automatic campaign that has reduced the prescriptions of antibiotics by 26% in France.

Conclusion

Blaser’s book is well-written, explains the science clearly for the average reader, and includes fascinating stories and facts. This is exciting stuff! I wish I could be alive 100 years from now to see how research into the microbiome will change the practice of medicine.

Categories: Medicine, Skepticism

Another Carrington Event Inevitable

Neurologica Blog - Mon, 08/11/2014 - 08:03

On September 1, 1859, a massive solar flare struck the Earth, resulting in beautiful auroras but also inducing currents in telegraph wires causing them to spark and start fires. Hours earlier amateur astronomer Richard Carrington was observing the sun and noticed large sunspots giving off a brief bright flare. In 1859 the telegraph was about the only electric infrastructure we had. What if a Carrington-type event struck today?

Solar flares result from the complex magnetic fields of the sun. Gas in the sun is so hot the electrons are stripped from the hydrogen, resulting in a plasma. Since plasma is therefore made from ions, it carries and electric charge, and when electric charges move they generate a magnetic field. Magnetic fields further induce electric current.

Sometimes the magnetic fields near the surface of the sun interact in such a way that they give off an explosion of energy, called a solar flare. There is also something called a coronal mass ejection, in which a bubble of hot gas erupts from the sun’s corona in a fashion similar to a solar flare. CMEs and solar flares often occur together, but not always, and their causal relationship is not clear.

Solar flares and CMEs cause a pulse of energy in the solar winds. Charged particle racing from the sun, if they were aimed in our direction, would strike the Earth about 17 hours after the visible solar flare, so we would have some warning. The charged particles would interact with the Earth’s magnetic field, causing aurora.

More importantly, the magnetic fields induced by the ions striking the earth would induce powerful currents in any conductive material. Any electronic device that was not shielded would be fried, it’s components damaged or even melted.

Think about what this would mean for our civilization. Every computer would be gone. Our satellites would be destroyed also. The power grid would go down. Communications would be gone.

Essentially we would be plunged into a pre-electrical age. I was recently asked what would happen to jets in the sky. Their electronics would be fried also, knocking them out of the air. Of course, there would be sufficient warning to ground all aircraft.

Modern cars with their electronics would also not function. We would all be trapped, without communication, transport, or electricity. The damage would be so extensive it could take many months to restore basic services. Damage would be in the trillions of dollars. It’s hard to imagine there would be massive loss of life and suffering as a result.

What are the chances of a Carrington event hitting. One published estimate is that there is a 12% chance of a similar event occurring in a 10 year span (at least between 2012 and 2022, this varies with the solar cycle). We’re not talking about the possibility of an asteroid striking something in the next 100,000 years – there is very likely to be such as event in the next 100 years.

In fact, a CME of the size of the Carrington event occurred just in 2012. Luckily, it missed the Earth.

So what should we do about it? First we need to have a reliable early warning system. Sun activity monitors are necessary to guarantee we see the solar flare, and then immediate distribute the warning throughout the world.

But of course we need to have some way to respond to the warning. Grounding aircraft and stopping any activity that would be dangerous if equipment stopped functioning is a start. What we really need to do, however, is shield critical electronic infrastructure against strong external magnetic fields.

This is possible. The military also does this, as nuclear explosions release an electromagnetic pulse with similar effects. We would need to shield our satellites against solar flares, and they need the ability to turn away from the sun and quickly fold their solar panels (if they have them) and close up any exposed electronics. We would also need to shield the power grid and build in safety shut offs.

Consumer electronics are another matter. I’m not sure how much I would pay for a shielded computer, but I might buy a shielded hard drive to back up my data. Would you pay a few hundred dollars extra to have your car’s electronics shielded from an EMP or Carrington size solar flare? That would be an interesting upgrade.

The cost of protecting our electronic infrastructure from a Carrington event would be billions of dollars, but the cost of a Carrington event would be orders of magnitude greater.

I suspect that any attempt to predict what would happen would such an event occur is an underestimate. It’s difficult to trace the sequence of progressive collapse that would happen to civilization. Further, it’s actually likely that this might occur.

This is definitely an investment in prevention that seems worth the probable expense.

Categories: Medicine

Medical marijuana as the new herbalism, part 2: Cannabis does not cure cancer

Science Based Medicine - Mon, 08/11/2014 - 03:02

About a month ago, I finally wrote the post I had been promising to write for months before about medical marijuana. At the time, I also promised that there would be follow up posts. Like Dug the Dog seeing a squirrel, I kept running into other topics that kept me from revisiting the topic. However, over the couple of weeks, the New York Times gave me just the little nudge I needed to come back and revisit the topic, first by openly advocating the legalization of marijuana, then by vastly overstating the potential medical benefits of pot (compare the NYT coverage with my post from a month ago), and finally this weekend by running a story lamenting the federal law that makes research into medical marijuana difficult in this country.

I stated my position on marijuana last time, which is that marijuana should be at least decriminalized or, preferably, legalized, taxed, and regulated, just like tobacco and alcohol. I also likened the cult of medical marijuana to the “new herbalism,” because it (1) vastly inflates the potential of medicinal uses of marijuana and (2) ascribes near mystical powers to smoking or making extracts out of marijuana, rather than identifying and isolating constituents of the plant that might have medicinal value. All of this is very much like herbalism in alternative medicine. Indeed, promoting laws legalizing medicinal marijuana is such an obvious ploy to open the door to full legalization that some advocates don’t even bother to disingenuously deny it any more. Given that I tend to support legalization, as a physician this sort of deception irritates me. It also has consequences, particularly when overblown claims are made for what cannabis can do. Perhaps the best example of this is the claim that cannabis cures cancer, which pops up all over the Internet in memes such as the one in the image above.

Don’t believe me? Just Google “cannabis cures cancer” or “marijuana cures cancer.” To my relief, you’ll find the National Cancer Institute’s page on cannabis and cannabinoids, which, as I discussed last time, dwells more on whether cannabinoids are useful for pain relief, nausea, and cancer cachexia than on whether they can be used to treat cancer directly. However, you’ll also find pages like 20 Medical Studies That Prove Cannabis Can Cure Cancer, a Facebook page Cannabis Cures Cancers!, and articles like Rick Simpson’s Hemp Oil Medicine, which resembles a lot of articles for various alternative medicine and quackery in terms of providing lots of testimonials of cures for skin cancer, diabetic ulcers, and other skin diseases and conspiracy mongering but no hard evidence. Indeed, a commenter by the ‘nym of “Danman” showed up at another blog many of you are familiar with and proceeded to make hilariously bad arguments for the healing power of cannabis and how a post at that blog was a “prohibitionist hit piece,” even though it expressed the opinion that marijuana should be legalized over the course of over 150 comments. Meanwhile, others are recommending hash oil for gliomas with a near-religious fervor, touting the same sort of evidence that Stanislaw Burzynski uses to claim he can cure gliomas with antineoplastons.

So what is the story, really?

Cannabinoids versus cancer: Hype versus science

The first problem one encounters when examining the evidence concerning the effect of cannabinoids on cancer is that the vast majority of studies touted by advocates claiming that “cannabis cures cancer” are either in vitro or animal studies. In vitro and animal studies are what we in the biz call “preclinical data,” meaning data obtained before trying a treatment in the clinic. As the American Cancer Society put it:

More recently, scientists reported that THC and other cannabinoids such as CBD (cannabidiol) slow growth and/or cause death in certain types of cancer cells growing in laboratory dishes. Some animal studies also suggest certain cannabinoids may slow growth and reduce spread of some forms of cancer. However, these substances have not been tested in humans to find out if they can lower cancer risk. There is no available scientific evidence from controlled studies in humans that cannabinoids can cure or treat cancer.

This basically says it all, and it’s tempting to wind up this post right there, but, as Han Solo said after being urged to be quiet while taking out some storm troopers, “Hey, it’s me.” Besides, you, our SBM readers expect science in addition to my self-absorbed blather, as amusing as it might sometimes be. So you shall have it. As good a place as any to start is, as you might imagine, 20 Medical Studies That Prove Cannabis Can Cure Cancer. After all, I assume that Arjun Walia, the person who put this list together, wanted to provide the very best evidence that could be found, particularly given the emphasis that “this is a short list.” I perused the papers in the list and was—shall we say?—underwhelmed. I’ll divide my discussion into tumor types, the way the list does. First, you have to understand that CBD, one of the cannabinoids found in marijuana, is viewed as particularly promising because it does not produce the same psychotropic effects as Δ9-tetrahydrocannabinol (THC), making it a particularly attractive for developing treatments whose side effects don’t involve being stoned all the time.

Glioma. The first thing that jumped out at me is that one of these papers has nothing to do with cancer, specifically this study that suggested that cannabinoids could protect the brain against neurodegeneration in neonatal rats caused by the toxin ouabain (an Na+/K+-ATPase inhibitor). The vast majority of the other studies were in human cell lines, such as this one studying the effect of cannabidiol, a nonpsychoactive cannabinoid, on glioma cell lines. As a cancer researcher, I noted that the IC50 (the concentration that produces 50% of maximal inhibition, was 25 μM), which is a bit higher than we like for an anticancer compound. I was thus not particularly impressed, although in fairness subcutaneous injection of CBD was able to inhibit the growth of glioma xenografts implanted subcutaneously in athymic nude mice, although no dose-response was demonstrated, and a dose of 0.5 mg per mouse is a pretty generous dose (25 mg/kg for a typical 20 g mouse). So while there does appear to be antitumor effect against the glioma cell lines tested, it was, at best, modest. Certainly it wasn’t the sort that would knock my socks off as a cancer researcher. A different study, which combined THC and temozolomide, produced more impressive results, not for the THC, which produced at best modest antitumor effect, but for the combination, which looked a bit more promising. Of course, one also must note that this is not hash oil or smoked pot, but the purified THC component. That THC might be useful against glioma does not tell us that hemp oil or smoking the weed will be useful against glioma any more than the fact that digoxin works in congestive heart failure tells us that it would be a good idea to ingest foxglove leaves.

Skeptical Raptor puts it in perspective:

In one study, the researchers determined that it would take a concentration of cannabinoids of approximately 10 µmol/L to cause the death breast cancer cells in cell culture. This converts to around 3.14mg/L of THC. So, you’d have to assume that to kill any breast cancer cells, you’d need at least a blood level of 3.14 mg/L to achieve breast cancer cell death. So how close to that 3.14 mg/L can we get by just smoking a joint or two? According to research, smoking one joint will give you a blood level of THC of around 1.3-6.4 ng/mL serum, or about .00013-.00064 mg/L. In other words, to get an anti-cancer effect, you need to light up around 1000 joints per day.

The IC50 values in these studies were higher than 10 μM.

Finally, there was one human study in the list of glioma papers. Basically, this was a phase I trial testing a method of administering THC. This was also some strange science in that nine patients with recurrent glioma had their tumors resected, but a catheter was left in the cavity left behind after surgery, and then:

Each day an aliquot of the THC solution (100 mg ml−1 in ethanol) was dissolved in 30 ml of physiological saline solution supplemented with 0.5% (w v−1) human serum albumin, and the resulting solution was filtered and transferred to an opaque syringe. This process was performed at the Department of Pharmacy of the Hospital Universitario de Canarias. Owing to the high hydrophobicity of THC, we controlled by gas chromatography/mass spectrometry (see below) the actual concentration of THC in the final solution. The THC solution was administered to the patients for different times starting at days 3–6 after surgery at a rate of 0.3 ml min−1 with a syringe pump connected to the subcutaneous reservoir. In the case of Patients 1 and 2, who received THC for 30 and 26 days, respectively, biopsies were also taken after the THC-treatment period and various tumour-cell parameters were evaluated.

As you can see, this is very different from smoking marijuana or ingesting hash oil. It involves directly infusing THC solution at a high concentration directly into the brain cavity where the tumor had been, in the hope of killing off any remaining tumor cells surrounding the cavity. Let’s just put it this way. There’s a reason why direct intratumoral injection of any drug is generally frowned upon, and that’s because it’s invasive and rarely works. Moreover, no one generally bothers with intratumoral infusion of a drug unless it requires a very high concentration to work. Mean survival was 24 weeks, and two patients survived approximately a year. The authors try (rather like Stanislaw Burzynski, actually) to argue that this is better than would be expected based on other studies and controls, and to claim that some patients responded. I find no convincing evidence of this in the paper, and in a cohort of nine patients though, it’s pretty darned hard to conclude this. I agree with Harriet. There is nothing “earth shattering” about these results. The could be consistent with an antitumor effect, but they could just as easily be consistent with no effect. Worse, this was not simply ingesting, smoking, or being injected with cannabinoids. The study involved having catheters sticking out of the subjects’s heads and having THC infused directly into the brain.

Breast cancer. I’m a breast cancer surgeon; so I’m going to go out of order here. There are four breast cancer studies listed. The first study examines CBD activity against a mouse breast cancer cell line 4T1 (another cell line I’m quite familiar with, having used it in my lab and because it was a cell line developed by a now retired investigator whom I know), and the breast cancer cell line MDA-MB-231 (which I’m more familiar with than I’d like to be). Basically, the study showed a modest effect against these two cell lines in vitro and in mouse models using 1 mg/kg and 5 mg/kg CBD. The second study looked at five different cannabinoids and found that CBD was the most potent inhibitor of breast cancer cell growth in vitro (IC50 between 6.0 and 10.5 μM) and that CBD and “CBD-rich oil” could inhibit the growth of MDA-MB-231 tumor xenografts. In this study, the effects of THC on cancer cell growth were weak (IC50 between 14.2 and over 25 μM, depending on the cell line). The third study showed similar results for HER2/neu(+) tumor cell lines using THC and specific synthetic agonists (activators) of cannabinoid receptors CB1 and CB2 (Win55,212-2 and JWH-015, which activate CB1 and CB, respectively). except that THC was not as weak. The fourth study didn’t look at marijuana cannabinoids at all, but rather the endogenous cannabinoid anandamine, with similar results.

Lung cancer. The next set of three studies look at lung cancer. The first study used a cell line with which I’m quite familiar, A549 lung cancer cells, using both cell culture and mouse xenograft models. I must say that I was singularly unimpressed with the effect sizes, at least in the in vitro studies, which also required fairly high concentrations (15 μM) of THC. In a mouse tail vein injection model of lung metastases, 5 mg/kg of THC decreased metastases by 50%, which is not bad, and in a straightforward xenograft model resulted in a 50% growth delay of the tumors, which is also not bad. The next study found similar results testing CBD against lung cancer cell lines and tumor cells from a patient in cell culture and mouse models. The third study showed that stimulation of cannabinoid receptors (CB1 and CB2) with synthetic agonists, Win55,212-2 and JWH-015, which activate CB1 and CB2, respectively, inhibited the growth and invasion of A549 lung cancer cells in vitro and their growth and metastases in mouse models.

And so it goes. Nearly all of these studies look at purified cannabinoids, usually either THC or CBD, but sometimes the endogenous cannabinoid anandamine (which isn’t even in marijuana), as the breast cancer study above and this prostate cancer study. Some use synthetic agonists, such as the breast cancer and lung cancer studies above, or this study of mantle cell lymphoma that tested R(+)-methanandamide in addition to Win55,212-2, or this study of non-Hodgkin’s lymphoma, which also used R(+)-methanandamide. With the exception of the glioma study, all were preclinical studies looking at cell culture models and mouse models. One was a review article. One, as I pointed out above, had nothing to do with cancer, and I suspect the author included it to round up his list of studies to 20.

Unfortunately, it’s a highly intellectually dishonest list of studies if your goal is to provide evidence that “cannabis” (as in the plant or extracts from the plant) can cure cancer. Unfortunately, this is not the first time Arjun Walia has constructed such a list. Last year, Liz Ditz nailed him for constructing a similarly intellectually dishonest list of studies that “show vaccines cause autism.” Let’s just put it this way. In 2013, Walia was still citing some highly discredited studies, such as studies by Mark and David Geier.

The intellectual dishonest of representing this list of studies as evidence that cannabis cures cancer aside, it is a group of moderately interesting papers that suggest that purified cannabinoid receptor agonists can produce reasonable, albeit by no means spectacular, antitumor effects in preclinical models. As a whole, they suggest that some of these purified cannabinoid agonists, whether naturally occuring, such as THC, CBD, or synthetic, such as R(+)-methanandamide, or specific to CB1 or CB2, such as Win55,212-2 and JWH-015, might be worth investigating further. Again, we’re talking about pharmacology, isolating active substances and purifying or chemically modifying them to improve their activity and safety profile, not smoking weed or using hash oil. Cancer Research UK concludes:

But claims that this body of preclinical research is solid “proof” that cannabis or cannabinoids can cure cancer is highly misleading to patients and their families, and builds a false picture of the state of progress in this area.

It’s also noted that the best results in the lab have come from using using a combination of highly purified THC and CBD, but that there have also been positive results with synthetic cannabinoids, such as a molecule called JWH-133, just as I’ve described, through mechanisms that include:

  • Triggering cell death, through a mechanism called apoptosis
  • Stopping cells from dividing
  • Preventing new blood vessels from growing into tumors
  • Reducing the chances of cancer cells spreading through the body, by stopping cells from moving or invading neighbouring tissue
  • Speeding up the cell’s internal ‘waste disposal machine’ – a process known as autophagy – which can lead to cell death

Unfortunately, as good as that sounds, it’s not all good. There is also evidence that cannabinoids, under some circumstances, can stimulate cancer cell growth and possibly contribute to tumor progression. They can also have different effects depending on dose and the level of cannabinoid receptors on the tumor cells being treated. For instance, this study suggests that cannabinoids only induce apoptosis in cells that express low levels of receptors that couple to a signaling pathway called ERK1/2 but don’t induce apoptosis in cells that have high levels of receptors because they then couple through a survival pathway known as AKT. Interestingly, cannabinoids also seem able to induce cell death through pathways that don’t involve cannabinoid receptors. In other words, it’s complicated, because cancer is complicated, and cancer drugs tend to work only against certain cancers. If cannabinoids do have anticancer effects in humans, it will likely only be against certain cancers, most likely combined with existing chemotherapy and targeted drugs. We also know from the preclinical work that has been done that it will take purified THC and/or CBD and/or synthetic cannabinoid receptor agonists to produce even the modest effects observed thus far, effects that are too modest to expect cannabinoids to be any sort of cure for cancer on their own. Smoking weed or using hash oil just isn’t going to cut it.

But what about the anecdotes?

On that other blog that you all hopefully know and love, one of the commenters, Justin Kander, cited a case report that’s been going around social media as “proof” that cannabis cures cancer. This case report describes a 14-year-old girl, PK, who presented with symptoms of “weakness, shortness of breath and bruising when she was taken to the Hospital for Sick Children, Toronto, Canada, on the 10th March 2006.” She was diagnosed with acute lymphoblastic leukemia (ALL) and underwent standard chemotherapy for ALL for six months. Upon analysis, she was found to be positive for a mutation in the Philadelphia chromosome, which is found in 2-10% of pediatric ALL cases. Philadelphia chromosome-positive ALL tends to have a poorer prognosis than other ALL. PK underwent a bone marrow transplant but was noted to have blast cells six months after treatment and therefore underwent aggressive chemotherapy along with a tyrosine kinase inhibitor. After more recurrences and more treatment (such as radiation therapy to the brain for a presumed, but never completely documented, infiltration of the brain by leukemia, it was stated in the case report:

On the 4th February 2009, blood was noted in the patient’s stools and a blood cell count revealed the presence of blast cells. As a result, all treatment including the disatinib was suspended and the patient’s medical staff acknowledged failure in treating her cancer. It was charted by the patient’s hematologist/oncologist that the patient ‘suffers from terminal malignant disease. She has been treated to the limits of available therapy… no further active intervention will be undertaken’. She was placed in palliative home care and told to prepare for her disease to overwhelm her body and from which she would suffer a stroke within the next 2 months.

The family found articles on how cannabis supposedly cures cancer, and found their way to Rick Simpson, who has been featured in High Times as the man who can cure cancer with hemp oil, who provided her with hemp oil mixed with honey (because of the bitter taste and viscous nature of hemp oil). This was administered in daily doses. It is claimed in this case report that there was a strong correlation between increasing dose of the hemp oil and decreases in PK’s blast count (a measure of leukemia cells in the blood), but looking at Figures 1, 2, 3, and 4, I have a hard time seeing it. Figure 1 shows increasing doses of hemp oil from what was called the “chronic” strain. That’s the closest we see to decreasing blast counts correlating with hemp oil dose. By day 15, the chronic strain was gone, and PK started taking Hemp Oil #2 from an outside source. In actuality in Figure 2, we see the blast count increasing with increasing dose until day 27, when it starts falling. Figure #3 shows Hemp Oil #3 (Afghan/Thai strain) from days 44 to 49. Given that the blast count stayed the same one can’t say much about this. Then Hemp Oil #4 was tried from day 50 to day 67, and her blast counts started rising. Finally, Hemp Oil #5 was tried and PK’s blast count fell between days 69 and 78. During that time, PK suffered the psychotropic effects of the hemp oil, including euphoria, disoriented memory, and the like.

Unfortunately, PK developed gastrointestinal bleeding and bowel perforation with peritonitis on day 78 and passed away. So, basically, she lived two and a half months after being placed on hospice. The authors assert that a dose-response curve was achieved, but to my eye I really don’t see it, except perhaps at the beginning, nor do I really buy the claim that the bumps in blast counts correlate with using “lower potency” strains. They also assert because PK was treated for tumor lysis syndrome (a syndrome in which the waste products of tumor breakdown, often seen after intense chemotherapy in hematopoietic malignancies, injure organs such as the kidneys).
Unfortunately, even if a mild dose-response effect was observed that would not rule out spontaneous remission. Spontaneous remission is known to occur in ALL, although it is usually temporary, and spontaneous tumor lysis syndrome has been reported, although it is rare. In any case, one has to wonder whether the patient’s bone marrow was petering out near the end, something that is hard to determine because almost no laboratory values other than blast counts presented, except at the end, when she had a very low platelet count (8K; normal 150K to 450K), a low white blood cell count (1.4, normal 4.5-13.0), and severe anemia (hemoglobin 8.2; normal: 13 to 16). It wasn’t established how the diagnosis of tumor lysis syndrome was made other than that the patient had elevated urate levels. Indeed, the entire case report seemed to have been written with the belief that it was the hemp oil that accounted for the decrease in blasts. A lot of information has been left out about the patient’s clinical course. All we know is that, after being placed in hospice, she was fortunate to have her blast count fall, developed a central line infection, and was treated for tumor lysis syndrome. We can also infer that she was still having considerable issues with her gut because she was on total parenteral nutrition (being fed by vein) and had trouble when they started to try to feed her orally again.

It should also be remembered that, whether or not hemp oil was responsible for the decline in blasts (which is possible but not convincingly demonstrated by this ) or whether it was “burnout” of the bone marrow in the terminal phase of the disease or even spontaneous remission, the patient still died. She still developed GI bleeding and a GI perforation with peritonitis and died of it only 78 days after going on hospice. There’s no way of knowing whether hemp oil prolonged her life. Probably it did not, as a two to three month survival after going into hospice after being declared terminal for leukemia is well within what is expected. In other words, this case report is mighty thin gruel indeed.

Of course, the sad story of PK and the treatment of her terminal relapsed ALL with hemp oil is probably the cancer cure testimonial due to hemp oil that is the highest quality, and unfortunately its quality is not that high at all. The rest of the anecdotes I ran into tended to be about as convincing to someone familiar with cancer as nearly all the other alternative cancer cure testimonials I’ve found; i.e., not very. If you don’t believe me, take a look at this article, in which Rick Simpson claims his success rate for patients with terminal cancer is around 70% and says:

“The ones that can’t be saved are usually the ones who’ve had the most chemotherapy and radiation, or wait too long to start the treatment,” he says. “They have to be able to stay alive long enough for the oil to start to work.” In fact, most patients who undergo chemotherapy die from the treatment, not the disease.

No, it is not a “fact” that most patients who undergo chemotherapy die from the treatment, not the disease. It’s a lie. In any case, Rick Simpson is just like cancer quacks the world over, who have no firm evidence to back up their miraculous-sounding cure rates and excuse their failures by claiming that the treatment patients had before prevented the treatment from working. Quacks like Rick Simpson do those who think that cannabinoids have promise in treating cancer no favors.

Conclusions

There’s a lot of interesting research about the role of cannabinoid receptors in cancer and whether targeting them with cannabinoid agonists from marijuana or other natural sources, synthetic agonists, or endocannibinoids will be a useful tool to add to the armamentarium of anticancer therapies. From what we know now, it is quite clear that cannabis does not cure cancer, at least not by itself and certainly not ingested or smoked as marijuana or ingested or applied topically as hemp oil. Even in purified form, naturally derived or synthetic cannabinoid agonists show relatively modest antitumor activity in preclinical models, which means that they will have to be combined with existing chemotherapeutic regimens. If they do find their way into the routine clinical treatment of cancer, it will be through rigorous pharmacological studies and rigorous clinical trials, the latter of which, in particular, are painfully lacking. Indeed, if you search ClinicalTrials.gov, you’ll quickly find lots of trials of cannabinoids to treat cancer-related symptoms and side effects, but precious few to treat cancer itself. There’s this phase I trial of Dexanabinol in Patients With Advanced Solid Tumors, which has been open two years and is still accruing patients, as well as this one of Dexanabinol against brain cancers. It’s not a lot, and suggests that there is not much interest in even synthetic cannabinoids as a treatment for cancer. After all, there are so many other promising avenues that class of drugs that show the modest effects that the cannabinoids I’ve discussed do just don’t excite researchers that much.

In any event, the claims of advocates that “cannabis cures cancer” are nothing more than herbalism infused with the magical thinking of the naturalistic fallacy. Just because it’s “natural” does not make it better. In the case of cannabis for cancer, the only potentially promising way forward is to isolate the active components and figure out which of the hundreds of different cancers in which these components have activity against.

Finally, I have no objection to lobbying for the legalization of marijuana for recreational use. I would support such measures myself. However, trying to use hugely exaggerated claims of medicinal benefit as a back door path to legalization gets my skeptical antennae all a’twitchin’ about all the other claims made by advocates and provides ammunition for critics whose real goal is prohibition.

Categories: Medicine, Skepticism

IBM’s Brain on a Chip

Neurologica Blog - Fri, 08/08/2014 - 08:18

Well,  a small one, but it’s a start.

IBM announced that they have build a computer chip, dubbed TrueNorth, based on a neuronal architecture. The team published in Science:

Inspired by the brain’s structure, we have developed an efficient, scalable, and flexible non–von Neumann architecture that leverages contemporary silicon technology. To demonstrate, we built a 5.4-billion-transistor chip with 4096 neurosynaptic cores interconnected via an intrachip network that integrates 1 million programmable spiking neurons and 256 million configurable synapses. Chips can be tiled in two dimensions via an interchip communication interface, seamlessly scaling the architecture to a cortexlike sheet of arbitrary size. The architecture is well suited to many applications that use complex neural networks in real time, for example, multiobject detection and classification. With 400-pixel-by-240-pixel video input at 30 frames per second, the chip consumes 63 milliwatts.

Sounds pretty cool. I have written about brain-like computing previously (most recently here). Von-Neumann architecture refers to the traditional basic setup of modern computers, which were described in 1945 by (you guessed it) John von Neumann. This setup has three components: memory, communication, and processing. Information is binary, essentially ones and zeros.

The neuromorphic architecture combines these three elements into one. The neurons are the memory and the processing, and they communicate with each other, similar to a biological brain. Instead of binary code, the neurons spike with a certain frequency. When they send spikes to another neuron, they bring it closer to its threshold for spiking. This is very similar to how the brain functions.

The chip is 3cm across, a 64 x 64 grid of cores, with a total of 1 million neurons each with 256 connections. (The Stamford University neuromorphic board also has 1 million neurons, with billions of connections, in a board about the size of an iPad.)

TrueNorth is also claimed to be completely scalable, meaning that you can connect any number of these chips together to get larger and larger computers.

There are similar projects underway, such as the Stamford effort above. There is also SpiNNaker, which uses a similar massively parallel architecture but boasts flexible synapses, rather than hard-wired connections. Movidius takes another approach. Their chip is less flexible and is dedicated to video processing, but it is also more energy efficient.

We seem to be at a time when multiple teams are developing neuromorphic architectures for computers. Until now computers have mostly relied upon the 70 year old von Neumann design. The shift to a different architecture has potential advantages. The massive parallel processing has the potential for being faster, more efficient, adaptable, and scalable.

We appear to be in the phase of experimentation and competition (or adaptive radiation, in evolutionary terms). Think of personal computing in the early 1980s. It’s likely that either one or a very few designs will emerge as the victor, if any do. It does seem likely that some version of neuromorphic computing will be in our future, unless some other model leap frogs this technology.

It is still very much an open question also what the application of neuromorphic computing will be. There is a huge barrier to adoption of this computer design for the average personal computer – new software needs to be written from scratch. However, during the transition it is possible for someone to create an application that is a virtual environment in which traditional software can operate. Still, shifting over to a completely new architecture will have to have substantial advantages to be worth the bother.

It is more likely that neuromorphic computers will find their way into niche applications. There are some things that traditional computing does well – like much of what most people use their computers for. Other tasks, however, such a image recognition, is more efficiently performed by massively parallel architectures. Like the Movidius chip, we may increasingly see dedicated neuromorphic chips in devices, rather than powering our desktops.

And of course, we have to ask if such neuromorphic computing brings us any closer to AI. That’s a complex question. I will just say that I think it’s likely future AI will use architecture much more similar to current neuromorphic chips than traditional von Neumann chips.

Categories: Medicine
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