Late night on Friday so straight to bed to try to catch up on sleep so this might cover a couple of days or so.Friday was our Statue of Liberty day. We had prebooked tickets so that we could do the whole thing that is walk up the Statue to the Crown. They only allow apparently 240 people a day to walk up to the crown and they told us yesterday that 2011 had been completely booked out by June
Thursday 6th October SwimmingRiver Village
When I eventually woke up this morning we went for a swim at the local country club where Sarah is a member of. We spend a good hour or 2 swimming around while taking turns looking after Hannah and Micah.We had buns and yummy salad fillings for lunch then we spent the next few hours mucking around home. I attempted to Skype Mum but the connection kept cutting out so that didn39t end up happenin
Finding my groove again
Namaskar I keep waiting for this feeling of excitement and wonder to overcome me the way it did when I first came to India but I am beginning to realize that it probably won39t happen everything here is familiar from needing to haggle with rickshaw drivers and fruitsellers to the taste of curried okra and naan bread. It39s a great feeling absolutely but not one where I am hyper over
Auf dem Weg zum Everest
Tibetische FahrkuensteMarco schreibtHeute haben wir uns mit dem Landcruiser auf den Weg nach Gyantse und dann weiter nach Shigatse gemacht. Bevor wir von den Highlights dieser Fahrt berichten werden kommen wir aber zu einem anderen Thema den tibetischen Fahrkuensten. Auf der tibetischen Strasse laeuft naemlich einiges anders als wir das bei uns gewohnt sind. So ist zum Beispiel bei uns das woh
Timtams and tea
So fuzzy head has cleared and silver linings to the cloud have been found1. Leicester Tigers get their players back sooner rather than later and it looks like we need them.2. I can go to the remaining games without the gut wrenching worry sad I knowNow packed for the epic 2nd leg of our journey and we will be down to 2 as John Hanlon otherwise known as Friar Tuck or Father Jack is flying bac
UnBelizeable Caye Caulker
Caye CaulkerWeh I deh No I havent turned off the auto spell check but as we arrived in Belize Spanish was no longer required just as we were getting the hang of it.. and English was back although with a bit of a twist namely Creole. So we left Mexico by getting our familiar ADO bus so Spanish dubbed movies and air con were again on the agenda until finally arriving at Chetumal
The last leg of our travels Sacramento to Vancouver
San francisco While in San Fran we walked to Pier 59 enjoyed the atmosphere watched street performers and indulged in good seafood. There is an arcade full of all the old machines so using up our quarters we got our fortunes told arm wrestled to test our strength. There was one that was a scene from a crack den designed to put children off drugs. We walked up multiple steps to see the Colbert
Settling into Vancouver
Lucille flew home to surprise her family for a 3 week visit so I explored Vancouver on my own for a bit... I started by organising all the practical things I needed to do got a bank account cell phone Insurance number so I could work and printed my cv ready for action. This is where I decided to give myself one last fun trip before job hunting really begun. So I signed up to a one night tour to
San Ignacio and the ATM Cave
So our time was up in Caye Caulker and it was time to head off to mainland Belize. San Ignacio was to be our next stop and it was right across the country in West Belize near the border of Guatemala. So we got up early for the boat to Belize City and from there we needed to pick up the bus all the way to San Ignacio. Upon arrival in Belize City we took a 510 minute taxi ride to the bus st
Summer Dream in Italy
It is summer vacation time. It is the highly coveted leisure time of a teacher and often the main highlight of living abroad. Daily life in a foreign country can wear on you although exotic it can be draining. I am fortunate enough to be able to meet my parents half way in Rome Italy for what will be a vacation of a lifetime.As the plane leaps off the ground into a sky portal the sound tell
The Prostrate Placebo
I seem to be writing a lot about the urinary tract this month. Just coincidence, I assure you. As I slide into old age, medical issues that were once only of cursory interest for a young whippersnapper have increasing potential to be directly applicable to grumpy old geezers. Like benign prostatic hypertrophy (BPH). I am heading into an age where I may have to start paying attention to my prostate (not prostrate, as it is so often pronounced, although an infection of the former certainly can make you the latter), so articles that in former days I would have ignored, I read. JAMA this month has what should be the nail in the coffin of saw palmetto, demonstrating that the herb has no efficacy in the treatment of symptoms of BPH: Effect of increasing doses of saw palmetto extract on lower urinary tract symptoms: a randomized trial.
It demonstrated that compared to placebo, saw palmetto did nothing. There have been multiple studies in the past with the more or less the usual arc of clinical studies of CAM products: better designed trials showing decreasing efficacy, until excellent studies show no effect. There is the usual meta analysis or two, where all the suboptimal studies are lumped together, the authors bemoan the quality of the data, and proceed to draw conclusions from the garbage anyway. GIGO.
The NEJM study from 2006 demonstrated that saw palmetto was no better than placebo but it was suggested that perhaps the dose of saw palmetto was not high enough or that the patients were not treated long enough to demonstrate an effect, and the JAMA study hoped to remedy that defect.There is, as is often the case, no good reason to suspect that saw palmetto would benefit or harm the prostate. Like many herbal preparations, it had widespread uses back in the day, when I had an onion tied to my belt, which was the style at the time. You couldn’t get white onions, because of the war. The only thing you could get was those big yellow ones.., but I digress:
“It is also an expectorant, and controls irritation of mucous tissues. It has proved useful in irritative cough, chronic bronchial coughs, whooping-cough, laryngitis, acute and chronic, acute catarrh, asthma, tubercular laryngitis, and in the cough of phthisis pulmonalis. Upon the digestive organs it acts kindly, improving the appetite, digestion, and assimilation. However, its most pronounced effects appear to be those exerted upon the urino-genital tracts of both male and female, and upon all the organs concerned in reproduction. It is said to enlarge wasted organs, as the breasts, ovaries, and testicles, while the paradoxical claim is also made that it reduces hypertrophy of the prostate. Possibly this may be explained by claiming that it tends toward the production of a normal condition, reducing parts when unhealthily enlarged, and increasing them when atrophied.”
At the turn of century Edwin M Hale, MD and homeopath, wrote a treatise on the topic, extolling its benefits on the prostate and other organs. You will be happy to know that if you have testicular atrophy from being an old masturbator, saw palmetto will help. For no good reason I can find, it became popular only for BPH. As best I can determine from the internet, there was a natural medicine fad in the early 1900’s, and saw palmetto became part of the fad. No clinical trials were responsible for the use. And, like acupuncture and homeopathy, there are many explanations for an efficacy that does not exist.
The JAMA study followed 369 men for 72 weeks. They received placebo or saw palmetto twice a day, and at weeks 24 and 48 the dose of each was increased.
They were followed for subjective complaints with the AUASI score, which is a 7 question self administered questionnaire:
Well validated as a tool for BPH symptoms, it relies overmuch on memory and is subject to wishful thinking on the part of the test taker. I doubt I could ever accurately remember my urinary patterns over the prior month without writing it down.
There were also objective endpoints like peak urine flow, PSA levels, and post void residual. Makes me wonder again what they want done when the radio advertisement says ‘Void were prohibited by law.’ Would saw palmetto make that easier? When it came to the subjective measurements, there was a slight, and similar, improvements in both groups. Objective, anatomic and physiologic endpoints were not affected. No surprise. So much for the powerful placebo.
Adverse effects were the same in both groups, with the only significant difference that the saw palmetto group had more physical injury and trauma. Was this the dreaded nocebo effect, or the random badness that occurs as a result of life? Probably the latter.
Based on the JAMA and NEJM trials, it is reasonable to conclude that saw palmetto has no efficacy in the treatment of symptoms due to BPH.
More interesting is what this article says about the so called placebo effect. This is yet another article that demonstrates that for hard endpoints, altering abnormal physiology or anatomy, placebo does nothing. I bet if we did brain scans of these patients they would show changes when the patient took the medications, and to that I would yawn. Do anything to anyone, give a placebo, tickle their feet, there will be changes in the brain. And while in some studies, increasing placebo amounts and frequency leads to increasing effects, in this study an increase in placebo dose led to no improvement in subjective outcomes.
More real world data to suggest that there are no real placebo effects.
Of course, I have bias. I have spent 30 years in acute care hospitals. My patients have derangements of anatomy and physiology that, if not corrected or at least ameliorated, lead to death or permanent morbidity. Placebo isn’t going to cure endocarditis, stop a gastric ulcer bleed, or reverse a stroke. And even if the patient feels better from the therapeutic relationship, if the anatomic/pathophysiologic abnormalities continue unabated, the patient is toast.
I am not even certain it can be said that placebos cure gastric ulcers. There is little on the natural history of ulcers in the flexible endoscopy age. The only reference I could find suggests that patients who have ulcers found with x-ray screening (not a reliable way to diagnose ulcers and probably under-represented the incidence) and who are not treated had a 24% cure rate at 6 months and a 29% relapse rate at 24 months. Most of the placebo trials followed patients around 4 weeks and had a higher cure rate in the placebo wing than seen in the natural history report, but the two are not directly comparable. Given the propensity of untreated ulcers to come and go and the unreliability of symptoms for diagnosis, unless there was a study that had a treatment, a placebo, and a no intervention arm, I do not think it is reasonable to conclude that placebos ‘cure’ ulcers. Especially given the NEJM review that suggested that placebo is usually no more effective than a no treatment/waiting arm.
Perhaps it is me. I do have some intellectual blind spots, like the anthropic principal. Every time I come across it in a cosmology book, I think that it is inane. I lack the imagination, or perhaps I am not stoned enough, to recognize its significance. So too with the placebo effect.
Placebo effects are probably more like quantum mechanics. The single slit experiment gives key insights into the fundamental nature of reality, but in the macroscopic world of day to day life my electrons move about just fine to heat my house and run my computer. No need to worry about probability functions, I can throw potatoes at a slit all day and never see a interference pattern. So too with the placebo effect. Most of the practical effect is lost in the noise of the complexity of illness, especially in the acute care hospital where I spend most of my time.
As Harriet quotes Dr. Benedetti
the take-home message for clinicians, for physicians, for all health professionals is that their words, behaviors, attitudes are very important, and move a lot of molecules in the patient’s brain. So, what they say, what they do in routine clinical practice is very, very important, because the brain of the patient changes sometimes… there is a reduction in anxiety; but we know that there is a real change…in the patient’s brain which is due to… the ‘ritual of the therapeutic act.’
I do not disagree with that. I consciously try to accentuate just those interactions with every patient, because I know my job as a physician is more than ‘Me find bug, Me kill bug. Me go home’. But I do not think it is important for modifying any disease process I am involved with. Grooming each other has salubrious effects in monkeys, and as best I can tell, the placebo is no more than evolutionarily advanced nit picking.
Large swaths of the world rely on native healers and the only tool in their armamentarium is the “ritual of the therapeutic act.” And across the world and throughout time, people have suffered and died in droves. You may argue that is not a fair comparison, people suffered from poor hygiene, no vaccines, malnutrition and no health infrastructure. But the US has a group whose health care is only placebo, relying entirely on the ritual of the therapeutic act, and despite being surrounded by the benefits of western societal infrastructure, they die faster and younger: Christian Scientists.
At the end of the day, the practice of medicine is practical endeavor. I am a builder, not an architect. I have to try to make my patients better objectively and subjectively, and the placebo is a tool that has little utility in my toolbox. When my prostate grows to the size of a tennis ball, I am going to go looking for a therapy that will shrink it, not fool me into thinking I can write my name in the snow a little better.
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Legislative Alchemy III: Acupuncture
Acupuncture is typically depicted as sticking needles at various points on the body prescribed (inconsistently, it turns out) by charts indicating purported “meridians” through which “qi” flows in the human, or animal , body. However, from one of the many SBM posts on acupuncture , this one by Dr. Novella , we in fact know that:
the consensus of the best clinical studies on acupuncture show that there is no specific effect of sticking needles into acupuncture points. Choosing random points works just as well, as does poking the skin with toothpicks rather than penetrating the skin with a needle to elicit the alleged “de qi”. The most parsimonious interpretation of the evidence is that the needles (i.e. acupuncture itself) are superfluous — any perceived benefit comes from the therapeutic interaction. This has been directly studied, and the evidence suggests that the way to maximize the subjective effects from the ritual of acupuncture is to enhance the interaction with the practitioner, and has nothing to do with the acupuncture itself. Acupuncture is a clear example of selling a specific procedure based entirely on non-specific effects from the therapeutic interaction — a good bedside manner and some hopeful encouragement.”
Unfortunately, those who draft state legislation do not read SBM. They should. If they did, they wouldn’t be enacting acupuncture practice acts. But they do.
Through the magic of legislative alchemy, acupuncture or, in some cases, “oriental medicine,” is a licensed health care profession in 43 states. Like naturopaths, acupuncturists attempted to expand their geographic range in 2011 and, like chiropractors as well, tried to broaden their scope of practice to include methods and treatments far from their original tradition, wherever that may lie.
Kansas does not become the 44th state
Kansas does not license acupuncturists as a separate “healing art,”although, by statute, both naturopaths and veterinarians can employ acupuncture in their practices. In 2011, the “acupuncture and oriental medicine practice act” was introduced in the state Senate but never made it out of the Public Health and Welfare Committee.
Although it failed, it is worth reviewing for those unfamiliar with acupuncture practice acts as it demonstrates the startlingly broad scope of practice typically granted acupuncturists and “oriental medicine” practitioners by state law. It is as well a perfect example of legislative alchemy in its incorporation of sheer nonsense.
As with recent attempts by chiropractors to sound less chiropractic , acupuncturists are apparently trying to camouflage the more psuedoscientific- sounding concepts by re-casting them in what we might call faux biomedical language. Thus, nowhere in the Kansas legislation will you find any reference to “qi” or “meridians.” No, here acupuncture is
a form of health care that is based on a theory of energetic physiology that describes and explains the interrelationship of bodily organs or functions with an associated acupuncture point or combination of points that are stimulated in order to restore the normal function of the bodily organ or function.”
Thus, the “practice of acupuncture” is
the use of needles or of oriental medicine therapies for the purpose of normalizing energetic physiological functions including pain control and for the promotion, maintenance and restoration of health.”
“Qi” and “meridian” are out. “Energetic physiological functions” are in. And needles are not the only way to “normalize” these “energetic physiological functions.” Not by a long shot.
Acupuncturists would also have at their disposal “oriental medicine therapies.” And what exactly is “oriental medicine?” According to this proposed legislation, “oriental medicine”
means the distinct system of health care that uses health techniques of oriental medicine, both traditional and modern, to diagnose, evaluate, examine, manage and treat for the prevention, cure or correction of disease, illness, injury, pain or other physical or mental condition by controlling and regulating the flow and balance of energy, form and function to restore, promote and maintain health.”
So, “oriental medicine” is health care that uses “oriental medicine.” Got it? I suppose the fact that it must achieve its purpose by “controlling and regulating the flow and balance of energy, form and function” is somewhat of an explanation. I do not know, for there is no clue in the proposed statutory language, whether said “regulating the flow and balance of energy” etc. is the same thing as “normalizing energetic physiological functions.” Whatever that means.
In this vein of “daffy definitions,” we also learn that:
- “biofeedback device” is “an instrument that is used to detect and amplify internal physiological processes and mental functioning.”
- “herbal and animal-based substances” includes substances of “animal, vegetable or mineral origin.”(emphasis added) (I suppose the draftsman of this legislation missed that day in biology, or missed biology altogether.)
- “Nutritional supplement means a nutritional substance, including a concentrate or extract of such a substance.” (That’s it — the entire definition.)
Under the proposed statute, the “practice of acupuncture includes, but is not limited to:”
dietary and nutritional counseling “based on traditional [but not "modern", apparently] Chinese medical principles”
recommendation, administration or dispensing of food, vitamins, minerals, enzymes, homeopathic preparations, amino acids or nutritional supplements (see above for definition).
So, homeopathy, supplements, diet, amino acids, vitamins, minerals, enzymes and biofeedback devices were all to become part of acupuncture practice under the new law. Apparently what acupuncturists, like chiropractors, really want to be is naturopaths.
Expanding scope of practice
Acupuncturists in Connecticut, where they are already licensed, were successful in expanding their practice by convincing the legislature to abandon any control over what they do as long as their practices are “consistent with accepted standards within the acupuncture and Oriental medicine profession.”
This was accomplished in a single section of a 98-section public health bill governing such diverse topics as regulation of day care, treatment of STDs, recording of vital statistics, and needle exchange programs. The term “sneaking it in” comes to mind.
Connecticut had already modernized, if you will, acupuncture by eschewing the old-fashioned terms “qi” and “meridians” for “the theory of physiological interrelationship of body organs with an associated point or combination of points for diseases, disorders and dysfunctions of the body.” The new practice act, however, abandons that definition for “modulation and restoration of normal function in and between the body’s energetic and organ systems and biomechanical, metabolic and circulation functions using stimulation of selected points.” Whether this is a new “theory” or simply a restatement of the old “theory” is not disclosed.
In any event, Connecticut acupuncturists are no longer limited to “needles, heat, pressure or electrical stimulation” of said points. Now any “method” is ok as long as it complies with the aforementioned “standards” of the “acupuncture and Oriental medicine profession.”
Also added as means for achieving “promotion and maintenance [as opposed to “modulation and restoration”] of normal function in the body’s energetic and organ system and biochemical, metabolic and circulation functions” are “Oriental dietary principles,” including (of course!) “supplements” and “other practices . . . consistent with the recognized standards of the . . . profession and accepted by the National Certification Commission for Acupuncture and Oriental Medicine.”
Acupuncturists can now also perform “assessment of body function, development of a comprehensive treatment plan and evaluation of treatment outcomes according to acupuncture and Oriental medicine theory.”
Putting it all together, the Connecticut acupuncturist will now be able to assess the body’s energetic system, treat the energetic system with any method consistent with professional standards, and know when the energetic system is modulated/restored/promoted/maintained through assessment of treatment outcomes. An amazing achievement considering that no research has ever demonstrated that this “energetic system” exists or what its properties might be.
The acupuncturist as naturopath
In addition to their try for licensing in Kansas, and success at expanding their scope of practice in Connecticut, acupuncturists attempted to become naturopaths in other states where they are already licensed. To date, success has eluded them.
In Ohio, a bill would have added a new type of practice — “Oriental Medicine” — separate from acupuncture, while at the same time increasing the scope of practice for acupuncturists. Acupuncturists would be allowed to use “supplemental techniques” including “the use of traditional and modern oriental therapeutics [the scope of which are not defined], counseling [including] the provision of information regarding lifestyle modifications and the therapeutic use of foods and supplements including homeopathics, gladulars, vitamins, and minerals.”
“Oriental medicine” practice, on the other hand, is defined as “a form of health care in which acupuncture is performed with or without the use of herbal therapy” which is not the same as “supplemental techniques” (see above). Once again demonstrating that one does not need to have taken biology to draft licensed health care provider legislation, “herbal therapy” is defined as “the use of herbs, vitamins, minerals, organ extracts, homeopathics or physiological materials for energetic or physiologic therapy.”
New York Senate and Assembly bills would expand “the profession of acupuncture” to allow “recommendation of traditional remedies and supplements including, but not limited to, the recommendation of diet, herbs and natural products, and their preparation in accordance with traditional and modern practices of modern East Asian or Oriental (Chinese, Korean or Japanese) medical theory.” What! No homeopathy?
Acupuncture for drug addiction
In Massachusetts, a bill would expand the scope of acupuncture practice to treat drug addiction via “Acupuncture Injection Therapy” defined as “the injection of herbs, homeopathic, and other nutritional supplements in the form of sterile substances into acupuncture points by means of hypodermic needles but not intravenous therapy.” The purpose of this is to “help prevent addiction to prescription drugs and prevent and reduce drug abuse; to promote, maintain, and restore health; for pain management and palliative care; and for acupuncture anesthesia.” This is so obviously dangerous that snark escapes me. The bill has not passed, although the Massachusetts legislature has not adjourned for the year.
“Acupuncture Injection Therapy” is not the only way acupuncture is used to treat substance abuse. In Colorado, licensed acupuncturists already use “five point NADA auricular acupuncture” which, as a bill summary explains, “is acupuncture done on the ear that is often used to treat substance abuse, mental health and behavioral health disorders.” “NADA” is the “National Acupuncture Detoxification Association.”
Apparently, other health care providers want to get in on the act, so proposed legislation would allow chiropractors, physicians, physician assistants, nurses, mental health professionals, and psychiatric technicians to perform this “five point NADA auricular acupuncture” but only if, as further explained in the summary, “they have successfully completed the proper training.” This bill actually made it to the Colorado House floor, where it failed to pass.
New Mexico
Faithful SBM readers will be wondering by now, “what about New Mexico, the state where anyone can practice medicine?” And they won’t be disappointed. There was, of course, a bill introduced in New Mexico to expand the acupuncturists’ scope of practice.
In New Mexico, as you might guess, acupuncturists already have limited prescriptive authority. Too limited, in their opinion.
First, they attempted to eliminate the requirement that prescription of “devices” be limited to those “necessary in the practice of oriental medicine.” As for drugs and their mode of administration, acupuncturists already had a formulary in the current practice act, but apparently didn’t like it. So, as did the New Mexico chiropractors, they tried to change it. It would have specifically included the following, although whether the acupuncturists could already prescribe and administer some of these under the current statute is unclear: subcutaneous and intramuscular epinephrine, injectable vitamin B-12, intradermal and subcutaneous injection of homeopathics, dextrose, minerals, sarapin and vitamins, and IV administration of water-soluble vitamins and minerals.
While, under the current statute, acupuncturists can prescribe “bioidentical hormones” they would be able to prescribe under the proposed expansion “topical estradiol, estriol, progesterone, testosterone and desiccated thyroid,” but only if the acupuncturist had “a signed collaborative practice agreement” with an M.D. or D.O. Thus, as with chiropractors and naturopaths who want to prescribe real drugs, adult supervision would be required. The bill died in committee. Even New Mexico has its standards.
Sticking needles in healthy people
As noted in the Introduction, research discloses that it doesn’t matter where you stick the needle in acupuncture. A bill introduced in the Oregon legislature was refreshingly honest about that fact. The bill, which died in committee, would have changed the statutory definition of acupuncture, currently “an Oriental health care practice used to promote health and to treat neurological, organic or functional disorders by the stimulation of specific points on the surface of the body by the insertion of needles.” “Oriental” would have been removed, as would have “specific points,” which simply became “points in and on the body.” In other words: stick it anywhere, it’s all the same.
As also noted, acupuncture doesn’t work. This makes it perfect for treating someone who isn’t sick, as a Pennsylvania bill — most certainly unintentionally — acknowledged. Under Pennsylvania law, acupuncturists can treat “a person’s condition” without the condition being diagnosed by a physician, dentist or podiatrist for 60 days. After that time, the treatment may continue only if the person “obtained a diagnosis of the treated condition” by a physician, dentist or podiatrist. A proposed amendment to this law would make these limitations inapplicable “if a person does not present any symptoms of a condition.”
It’s really the ideal “CAM” legislation — ineffective treatments for people who are not ill — and it may become state law. Both the House and Senate versions of this bill have made it to the floor of the Pennsylvania legislature, which meets year-round.
Conclusion
As I’ve said before, no person should be subjected to scientifically implausible diagnostic methods and treatments. States should be working to eliminate such practices, not giving out licenses to perpetuate them.
Which brings me to “The Cure,” anti-sCAM legislation I’ll be proposing in a future post. Stay tuned.
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Statistical Errors in Mainstream Journals
While we frequently on SBM target the worst abuses of science in medicine, it’s important to recognize that doing rigorous science is complex and mainstream scientists often fall short of the ideal. In fact, one of the advantages of exploring pseudoscience in medicine is developing a sensitive detector for errors in logic, method, and analysis. Many of the errors we point out in so-called “alternative” medicine also crop up elsewhere in medicine – although usually to a much less degree.
It is not uncommon, for example, for a paper to fail to adjust for multiple analysis – if you compare many variables you have to take that into consideration when doing the statistical analysis otherwise the probability of a chance correlation will be increased.
I discussed just yesterday on NeuroLogica the misapplication of meta-analysis – in this case to the question of whether or not CCSVI correlates with multiple sclerosis. I find this very common in the literature, essentially a failure to appreciate the limits of this particular analysis tool.
Another example comes recently from the journal Nature Neuroscience (an article I learned about from Ben Goldacre over at the Bad Science blog). Erroneous analyses of interactions in neuroscience: a problem of significance investigates the frequency of a subtle but important statistical error in high profile neuroscience journals.
The authors, Sander Nieuwenhuis, Birte U Forstmann, and Eric-Jan Wagenmakers, report:
We reviewed 513 behavioral, systems and cognitive neuroscience articles in five top-ranking journals (Science, Nature, Nature Neuroscience, Neuron and The Journal of Neuroscience) and found that 78 used the correct procedure and 79 used the incorrect procedure. An additional analysis suggests that incorrect analyses of interactions are even more common in cellular and molecular neuroscience.
The incorrect procedure is this – looking at the effects of an intervention to see if they are statistically significant when compared to a no-intervention group (whether it is rats, cells, or people). Then comparing a placebo intervention to the no-intervention group to see if it has a statistically significant effect. Then comparing the results. This seems superficially legitimate, but it isn’t.
For example, if the intervention produces a barely statistically significant effect, and the placebo produces a barely not statistically significant effect, the authors might still conclude that the intervention is statistically significantly superior to placebo. However, the proper comparison is to directly compare the differences to see if the difference of difference is itself statistically significant (which it likely won’t be in this example).
This is standard procedure, for example, in placebo-controlled medical trials – the treatment group is compared to the placebo group. But what more than half of the researchers were doing in the articles reviewed is to compare both groups to a no-intervention group but not comparing them to each other. This has the effect of creating the illusion of a statistically significant difference where none exists, or to create a false positive type of error (erroneously rejecting the null hypothesis).
The frequency of this error is huge, and there is no reason to believe that it is unique to neuroscience research or more common in neuroscience than in other areas of research.
I find this article to be very important, and I thought it deserved more play than it seems to be getting. Keeping to the highest standards of scientific rigor is critical in biomedical research. The authors do an important service in pointing out this error, and researchers, editors, and peer reviewers should take note. This should, in fact, be part of a check list that journal editors employ to ensure that submitted research uses legitimate methods. (And yes, this is a deliberate reference to The Checklist Manifesto – a powerful method for minimizing error.)
I would also point out that one of the authors on this article, Eric-Jan Wagenmakers, was the lead author on an interesting paper analyzing the psi research of Daryl Bem. (You can also listen to a very interesting interview I did with Wagenmakers on my podcast here.) To me this is an example of how it pays for mainstream scientists to pay attention to fringe science – not because the subject of the research itself is plausible or interesting, but because they often provide excellent examples of pathological science. Examining pathological science is a great way to learn what makes legitimate science legitimate, and also gives one a greater ability to detect logical and statistical errors in mainstream science.
What the Nieuwenhuis et.al. paper shows is that more scientists should be availing themselves of the learning opportunity afforded by analyzing pseudoscience.
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The wrong way to “open up” clinical trials
Science-based medicine rests on twin pillars that are utterly essential to the development of treatments that are safe and efficacious. Both of these pillars depend on science, but in different ways. The first of these is, of course, the basic science that provides the hypotheses to test about the mechanisms behind the diseases and malfunctions that plague the human body. This basic science suggests ways of either correcting or alleviating these malfunctions in order to alleviate symptoms and prevent morbidity and mortality and how to improve health to increase quality and quantity of life. Another critical aspect of basic science is that it also provides scientists with an estimate of the plausibility of various proposed interventions, treatments and cures designed to treat disease and improve health. For example, if a proposed remedy relies upon ideas that do not jibe with some of the most well-established laws in science, such as homeopathy, the concepts behind which violate multiple laws of physics and chemistry, it’s a very safe bet that that particular treatment will not work and that we should test something else. Of course, the raison d’être of this blog derives from the unfortunate fact that in today’s medicine this is not the case and we are wasting incredible amounts of time, money, and lost opportunities in order to pursue the scientific equivalent of fairy dust as though it represented a promising breakthrough that will save medicine, even though much of it is based on prescientific thinking and mysticism. Examples include homeopathy, reiki, therapeutic touch, acupuncture, and much of traditional Chinese medicine and Ayurveda, all of which have managed to attach themselves to medical academia like kudzu.
Of course, basic science alone is not enough. Humans are incredibly complex organisms, and what we consider to be an adequate understanding of disease won’t always result in an efficacious treatment, no matter how good the science is. Note that this is not the same thing as saying that utter implausibility from a scientific basis (as is the case with homeopathy) doesn’t mean a treatment won’t work. When a proposed treatment relies on claiming “memory” for water that doesn’t exist or postulates the existence of a “life energy” that no scientific instrument can detect and the ability to manipulate that life energy that no scientist can prove, it’s a pretty safe bet that that treatment is a pair of fetid dingo’s kidneys. Outside of these sorts of cases, though, clinical trials and epidemiological studies are the second pillar of science-based medicine, in particular clinical trials, which is where the “rubber hits the road,” so to speak. In clinical trials, we take observations from the laboratory that have led to treatments and test them in humans. The idea is to test for both safety and efficacy and then to begin to figure out which patients are most likely to benefit from the new treatment.
Over the last 50 or 60 years, for all its flaws (and what system devised by humans doesn’t have flaws?) it’s been a highly effective system. When it works well, physicians take observations from the clinic, go to the laboratory, where basic scientists and physicians try to figure out what’s going on to explain a particular observation and then develop an intervention, after which that intervention, be it a drug, procedure, or other treatment, is taken back to the clinic to test. In practice, this process can be very messy, as biases such as publication bias, selection bias, and other confounding factors can at times mislead. Money can corrupt the process as well, given that clinical trials are the final common pathway to the approval of new drugs by the Food and Drug Administration and the hundreds of millions of dollars it costs pharmaceutical companies to bring a single drug from bench to final phase III clinical trials in the hopes of recouping that investment and making large profits besides. Despite all that, no one has as yet been able to propose a better process.
That’s not to say that periodically there aren’t proposals to radically reinvent the clinical trials process. Certainly, I can sympathize to a point; being involved in clinical trials myself, I understand how even a relatively small clinical trial involves an enormous amount of time, money, and regulatory hurdles to jump over. I’ve never personally run a large phase III trial (although I hope to some day); so I can only know what that would be like from my interactions with colleagues who have. In any case, it’s the onerous nature of the current clinical trial system that has led to a recent editorial published in Science by Andrew Grove, former Chief Executive Officer of Intel Corporation and a patient advocate at the University of California, San Francisco, entitled, appropriately enough, Rethinking Clinical Trials. From the article, it’s obvious that Groves is not a scientist, but that doesn’t mean he isn’t worth listening to—to a point. Unfortunately, his proposed solution is unlikely to work, even though he does have a grasp of the problem:
The biomedical industry spends over $50 billion per year on research and development and produces some 20 new drugs. One reason for this disappointing output is the byzantine U.S. clinical trial system that requires large numbers of patients. Half of all trials are delayed, 80 to 90% of them because of a shortage of trial participants. Patient limitations also cause large and unpredicted expenses to pharmaceutical and biotech companies as they are forced to tread water. As the industry moves toward biologics and personalized medicine, this limitation will become even greater. A breakthrough in regulation is needed to create a system that does more with fewer patients.
Groves does have a point in that the clinical trial system in this country has indeed become quite expensive and unwieldy. He’s also correct that the evolution towards “personalized medicine” will exacerbate the problem. The reason is that, as we check more and more biomarkers or genetic markers to guide therapy, we will decrease the number of patients falling into each category requiring a certain drug, in essence, slicing and dicing the patient population into ever smaller slivers, each of whose treatment will be different. Sorting all this out will be quite difficult. Unfortunately, Groves approaches the problem from the wrong perspective in that it’s clear he has little feeling for how science should be applied to medicine, as will become clear by his analogy:
The current clinical trial system in the United States is more than 50 years old. Its architecture was conceived when electronic manipulation of data was limited, slow, and expensive. Since then, network and connectivity costs have declined ten thousand–fold, data storage costs over a million-fold, and computation costs by an even larger factor. Today, complex and powerful applications like electronic commerce are deployed on a large scale. Amazon.com is a good example. A large database of customers and products form the kernel of its operation. A customer’s characteristics (like buying history and preferences) are observed and stored. Customers can be grouped and the buying behavior of any individual or group can be compared with corresponding behavior of others. Amazon can also track how a group or an individual responds to an outside action (such as advertising).
Yes, you heard that right. Groves thinks that doing science is enough like cataloging customer orders, preferences, and history the way Amazon.com does. So what’s his suggestion? In essence, Groves is proposing what is commonly known a “pragmatic trial” but on megadoses of steroids, all using computers to figure out what’s going on:
We might conceptualize an “e-trial” system along similar lines. Drug safety would continue to be ensured by the U.S. Food and Drug Administration. While safety-focused Phase I trials would continue under their jurisdiction, establishing efficacy would no longer be under their purview. Once safety is proven, patients could access the medicine in question through qualified physicians. Patients’ responses to a drug would be stored in a database, along with their medical histories. Patient identity would be protected by biometric identifiers, and the database would be open to qualified medical researchers as a “commons.” The response of any patient or group of patients to a drug or treatment would be tracked and compared to those of others in the database who were treated in a different manner or not at all. These comparisons would provide insights into the factors that determine real-life efficacy: how individuals or subgroups respond to the drug. This would liberate drugs from the tyranny of the averages that characterize trial information today. The technology would facilitate such comparisons at incredible speeds and could quickly highlight negative results. As the patient population in the database grows and time passes, analysis of the data would also provide the information needed to conduct postmarketing studies and comparative effectiveness research.
I found out about Andy Groves’ article from Derek Lowe, who didn’t think that much of it but didn’t dismiss it altogether. I tend to agree, although I suspect I’ll end up being a little bit harder on it than Derek is. And it’s not an altogether crazy idea. It’s not even necessarily that bad an idea, except that Groves clearly doesn’t understand clinical trials, and you have to understand clinical trials before you can apply technology to it. For example, Groves seems to labor under the delusion that phase I trials prove safety of a new medication. That is a gross misunderstanding of the purpose of the phase I trial. Yes, checking for safety is part of what a phase I trial does, but a phase I trial doesn’t “prove safety.” What a phase I trial does is to rule out any really major side effects or toxicities that are common (remember, phase I trials usually only have around 20 to 100 participants, too small a number to catch uncommon adverse events), study pharmacokinetics (how the drug level varies with dose and how it’s metabolized), and establish both a maximal tolerated dose and a dosing interval. This last purpose is usually achieved using a technique as dose escalation Often phase I trials are performed using healthy volunteers, although in my specialty (cancer) that’s rarely the case. In any case, a better way of describing the purpose of a phase I was summed up by Freedman, “[T]he reason for conducting the trial is to discover the point at which a compound is too poisonous to administer.” That’s exactly what I meant by “maximal tolerated dose.”
Yes, that is the purpose of a phase I “first in humans” clinical trial. It’s absolutely necessary, too.
Here’s the problem with Groves’ idea. What he is basically proposing is to do, in essence, a whole bunch of “N of 1″ trials, each patient being a clinical trial in and of himself or herself. Then, through the magic of computer technology, he seems to be suggesting that we take all these “N of 1″ trials and try to do a meta-analysis of them. Here, we have a case where more does not necessarily mean better. What will result are data that are ridiculously heterogeneous—possibly unanalyzably so. As Derek Lowe points out, one of the most difficult aspects of clinical trial design is to standardize the treatment, to make sure that patients across multiple clinical trial sites are actually being treated and followed in the same way. Under Groves’ concept, heterogeneity is a feature, not a bug. However, it is not this aspect that bothers me so much about this proposal. Rather, it’s Groves’ dismissive comment about “liberating” clinical trials from the “tyranny of averages.” As if averages are a bad thing! That “tyranny of averages” is what makes sure that the patients being enrolled in a clinical trial are comparable to each other. Without relatively strict inclusion criteria in early phase II trials, the most likely thing that would happen if Groves’ proposal were adopted is that any signal would be drowned out by all the noise due to the heterogeneity of the patients and the data derived from each “N of 1″ trial.
Perhaps the biggest practical problem with Groves’ idea is how patients will be selected for therapies. Notice how Groves says that “once safety is proven, patients could access the medicine in question through qualified physicians.” There’s another problem with this concept other than the lack of recognition of the fact that phase I trials don’t “prove safety,” and that’s the issue of who decides which patients will take the drug, and basically it appears to me that what Groves is proposing is that any physician can take any drug that has passed phase I testing and offer it to any patient. As much as Groves prattles on about “real world” efficacy, this is a real world recipe for disaster. First, phase I trials do not demonstrate efficacy; they only evaluate safety and toxicity. Consequently, it is difficult (for me, at least) to imagine how physicians could ethically administer drugs whose efficacy has not been demonstrated or, more importantly, how they could know for which patients these new drugs would be appropriate. (Short answer: They can’t.”) It’s difficult enough to maintain clinical equipoise.
Indeed, one huge unspokean (and unsupported) assumption is that allowing unfettered access to experimental drugs that have passed phase I trials would help more people than it would hurt. In actuality, because phase I trials only identify acute toxicities and do not identify adverse reactions that occur with longer use, physicians administering these drugs would be flying almost blind. The potential for harm is enormous, particularly when it is powerful chemotherapeutic agents that are being given. It is far more likely that widespread use of unapproved substances would harm far more patients than it would help. Indeed, at the level of the individual patient, trying such drugs is more likely to harm than help. If there’s one thing worse than dying of cancer, it’s making one’s last days shorter and more miserable with toxicities from unapproved drugs or, even worse still, paying big bucks to do so.
Yet, somehow Groves seems not to have considered this possibility.
Perhaps the most problematic aspect of Groves’ entire proposal, though, is the very reason why we do clinical trials, namely to answer the question, “Does the drug work?” In a system such as that proposed by Groves, how, exactly, would we figure out whether a drug works or not? What would be the endpoint? What result would tell us that the drug is doing what it is intended to do? For example, in the case of cancer chemotherapy drugs, the purpose of the drug is to prolong survival. Figuring out if a new drug did that is difficult enough in the current system of clinical trials. Indeed, we already know from the example of Avastin in breast cancer that teasing out whether an improvement in disease-free survival translates into an improvement in overall survival. Under Groves’ proposal, it would be well nigh impossible. Groves seems to be arguing that, if we just keep track of enough variables and possible confounding factors, everything will shake out due to the wonder of modern computerized “e-commerce”-style tracking applied to patients. Maybe that’s possible. Maybe (and more likely) such a system will result in an uninterpretable mass of data from which extracting meaningful correlations will be at best problematic, at worst impossible. Even if it does work, then what is the endpoint of a clinical trial? When can investigators declare that they’ve accrued enough patients.
Remember how I referred to Groves’ proposal as being in essence replacing the current clinical trial system with that of “pragmatic trials”? We’ve been very critical here at SBM of the use and abuse of pragmatic trials by proponents of quackademic medicine. In fact, more than anything else, what Groves is proposing comes across to me as a high tech version of the very same pragmatic trials that acupuncturists are agitating for. There are no controls, which means that placebo responses will go uncorrected for. There are a plethora of variables and potential confounding factors, which would also be unaccounted for.
Don’t get me wrong. I’m not dismissing Groves’ idea; I’m merely pointing out that he has an incredibly simplistic view of how clinical trials operate and what evidence must be obtained before it’s reasonable to conclude that a new treatment “works” for a particular illness. Basically, spurred on by his own personal battles with prostate cancer and Parkinson’s disease, he has had a late life conversion to patient advocate. There’s nothing wrong with that and much to be admired, but unfortunately Groves seems to think that his knowledge of the computer and semiconductor industry is easily transferable to the pharmaceutical industry. It’s not for nothing that four years ago Derek Lowe also referred to Groves as Rich, Famous, Smart, and Wrong. Groves expresses frustration at the slow pace of research into Parkinson’s disease and other diseases. Fair enough. If I had a relentless degenerative neurological condition that would slowly rob me of my ability to function (and, in particular, to do surgery and write), I’d be frustrated too. Unfortunately, he doesn’t seem to understand that medicine is not the semiconductor industry. There’s a reason why we haven’t cured cancer yet, for example. It’s damned hard, and biomedical research does not lend itself easily to the sort of deadline-driven mentality that Groves had as CEO of Intel.
Derek Lowe put it well:
Mr. Grove, here’s the short form: medical research is different than semiconductor research. It’s harder. Ever seen one of those huge blow-ups of a chip’s architecture? It’s awe-inspiring, the amount of detail that’s crammed into such a small space. And guess what — it’s nothing, it’s the instructions on the back of a shampoo bottle compared to the complexity of a living system.
That’s partly because we didn’t build them. Making the things from the ground up is a real advantage when it comes to understanding them, but we started studying life after it had a few billion years head start. What’s more, Intel chips are (presumably) actively designed to be comprehensible and efficient, whereas living systems — sorry, Intelligent Design people — have been glued together by relentless random tinkering. Mr. Grove, you can print out the technical specs for your chips. We don’t have them for cells.
And believe me, there are a lot more different types of cells than there are chips. Think of the untold number of different bacteria, all mutating and evolving while you look at them. Move on to all the so-called simple organisms, your roundworms and fruit flies, which have occupied generations of scientists and still not given up their biggest and most important mysteries. Keep on until you hit the lower mammals, the rats and mice that we run our efficacy and tox models in. Notice how many different kinds there are, and reflect on how much we really know about how they differ from each other and from us. Now you’re ready for human patients, in all their huge, insane variety. Genetically we’re a mighty hodgepodge, and when you add environment to that it’s a wonder that any drug works at all.
It is, indeed.
None of this is to imply that we can’t improve our clinical trials system. As has been pointed out, it’s hugely expensive and inefficient, and these problems are getting worse with the evolution of drug treatment towards “personalized medicine.” We are going to have to figure out ways to make clinical trials smaller and more targeted. We are also going to have to find ways to extract every last bit of information and benefit out of every last clinical trials subject. An approach such as what Groves proposes might well contribute to achieving that aim, particularly when coupled with new trial designs that emphasize the incorporation of biomarkers for drug response. Contrary to Andy Groves’ claims, however, there is no way his sort of approach will ever replace well-designed clinical trials.
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Artificial Sweeteners: Is Aspartame Safe?
Note: This was originally published as a “SkepDoc” column in Skeptic magazine under the title “Aspartame: Safe Sweetener or Perilous Poison?” and is reprinted here with the kind permission of Michael Shermer. There are other artificial sweeteners not specifically addressed here, but as far as I know there are no convincing health concerns about any of them, just this same kind of hype and fearmongering based on animal studies and speculation with no validation from human clinical studies.
Aspartame is a low calorie sugar substitute marketed under brand names like Equal and Nutrasweet. It is a combination of two amino acids: L-aspartic acid and L-phenylalanine. It is available as individual packets for adding to foods and it is a component of many diet soft drinks and other reduced-calorie foods. Depending on who you listen to, it is either a safe aid to weight loss and diabetes control or it is evil incarnate, a deadly poison that is devastating the health of consumers.
A reader sent me an ad from his local newspaper that recommended using stevia instead of aspartame and made these startling claims about aspartame:
- It is derived from the excrement of genetically modified E. coli bacteria
- Upon ingestion, it breaks down into aspartic acid, phenylalanine, methanol, formaldehyde, and formic acid.
- It accounts for over 75% of the adverse reactions to food additives reported to the FDA each year including seizures, migraines, dizzinesss, nausea, muscle spasms, weight gain, depression, fatigue, irritability, heart palpitations, breathing difficulties, anxiety, tinnitus, schizophrenia and death.
Let’s look at those claims one by one.
- In some markets, aspartame manufacture takes advantage of modern genetic laboratory processes. A plasmid introduces genes into E. coli bacteria; the genes are incorporated into the bacterial DNA and they increase production of enzymes that enhance the production of phenylalanine. The bacteria produce more phenylalanine, serving as little living factories. The phenylalanine these workhorses produce for us is exactly the same as phenylalanine from any other source. It is disingenuous and inflammatory to characterize it as “derived from excrement.” Genetic processes like this are widely used today. One stunning example is Humulin. Diabetics used to develop allergic reactions to the beef and pork antigens in insulin derived from cows and pigs because it was slightly different from human insulin and contained impurities. Scientists found a way to put human insulin genes into E. coli bacteria and put them to work producing true, pure human insulin. This was such a great advantage to diabetics that animal insulins are no longer even available.
- Some of the things we ingest are directly absorbed and utilized unchanged, like water. But most of what we ingest is metabolized. Aspartame is metabolized. It does indeed break down into aspartic acid, phenylalanine, and methanol. Aspartic acid and phenylalanine are amino acids that we need to survive. Methanol is produced in small amounts by the metabolism of many foods; it is harmless in small amounts. A cup of tomato juice produces six times as much methanol as a cup of diet soda. Methanol is completely metabolized via formaldehyde to formic acid; no formaldehyde remains. Lastly, the formic acid is broken down into water and carbon dioxide. Human studies show that formic acid is eliminated faster than it is formed after ingestion of aspartic acid. So yes, those compounds appear, but so what? We get much larger amounts of the same compounds from our food, and they don’t hurt us.
- I searched for documentation of that claim, and I couldn’t find the 75% figure anywhere. What I did find was that FD&C dyes (not aspartame) are the food additives most frequently associated with adverse reactions. Anyway, a list of reported adverse reactions is meaningless by itself. People can report any symptom they noticed after using aspartame, but they can be fooled by the post hoc ergo propter hoc fallacy: just because a symptom occurred after ingesting aspartame, that doesn’t prove aspartame caused the symptom. Controlled studies are needed to determine if the symptom occurred more often in people using aspartame than in people not using it. Many such studies have been done and have not shown a correlation of aspartame use with any of those symptoms.
Internet Hoax
So the ad amounts to scare tactics based on false and distorted information. Actually, this ad is pretty mild compared to some of the alarmist misinformation circulating on the Internet. There we are told that there is a widespread epidemic of aspartame poisoning, causing headaches, seizures, Alzheimer’s, cancer, diabetes, blindness, multiple sclerosis, birth defects, even Gulf War Syndrome. We are told that “If you…suffer from fibromyalgia symptoms, spasms, shooting pains, numbness in your legs, cramps, vertigo, dizziness, headaches, tinnitus, joint pain, depression, anxiety attacks, slurred speech, blurred vision, or memory loss-you probably have ASPARTAME DISEASE!” We are expected to believe the lie that “When they remove brain tumors, they have found high levels of aspartame in them.”
All this misinformation has been identified as a hoax, an urban legend, by various sources including Time.com, Snopes.com and About.com. Much of it hinges on a widely disseminated e-mail by a “Nancy Markle” who was accused of plagiarizing it from Betty Martini. Martini is the founder of Mission Possible World Health International, which is “committed to removing the deadly chemical aspartame from our food.” She is also anti-vaccine, anti-fluoride, anti-MSG, a conspiracy theorist, and thinks she was cured of breast cancer by an herbal formula.
Her website consists of misinformation, testimonials, and hysterical rants. She implores readers: YOUR personal horror story needed NOW!. She is associated with a number of others notorious for circulating unreliable information, including the infamous Joseph Mercola.
There’s even a book, Sweet Poison, by Janet Hull, creator of the Aspartame Detox Program.
Scientific Studies
Aspartame has been found to be safe for human consumption by the regulatory agencies of more than ninety countries worldwide, with FDA officials describing aspartame as “one of the most thoroughly tested and studied food additives the agency has ever approved” and its safety as “clear cut.”
When the European Commission’s Scientific Committee on Food evaluated aspartame, they found over 500 papers on aspartame published between 1988 and 2001. It has been studied in animals, in various human populations including infants, children, women, obese adults, diabetics, and lactating women. Numerous studies have ruled out any association with headaches, seizures, behavior, cognition, mood, allergic reactions, and other conditions. It has been evaluated far more extensively than any other food additive.
When new rat studies by the Ramazzini Foundation in Italy appeared to show an association with tumors, the European Food Safety Authority examined Ramazzini’s raw data and found errors that made them discredit the studies. Their updated opinion based on all the data available in 2009 said there was no indication of any genotoxic or carcinogenic potential of aspartame and that there was no reason to revise their previously established ADI (Acceptable Daily Intake) for aspartame of 40 mg/kg/day. Studies have shown that actual consumption is well below that limit.
People who are absolutely convinced they get adverse effects from aspartame have been proven wrong. For instance, the New England Journal of Medicine published a study of people who reported having headaches repeatedly after consuming aspartame. When they knew what they were consuming, 100% of them had headaches. In a double blind crossover trial, when they didn’t know what they were getting, 35% had headaches after aspartame, and 45% had headaches after placebo.
Is Stevia Safer?
Stevia comes from a plant, and the Guaraní Indians of South America have been using it to sweeten their yerba mate for centuries. The “natural fallacy” and the “ancient wisdom fallacy” sway many consumers, but for those of us who are critical thinkers, who want to avoid logical fallacies and look at the scientific evidence, what does science tell us? Is stevia preferable to aspartame? We really don’t know. Concerns have been raised about possible adverse effects such as cancer and birth defects. Stevia is banned in most European countries and in Singapore and Hong Kong because their regulatory agencies felt that there was insufficient toxicological evidence to demonstrate its safety. The US banned its import in 1991 as a food additive, but the 1994 Diet Supplement Health and Education Act (DSHEA) legalized its sale as a dietary supplement. Most of the safety concerns have been dismissed, but so have the concerns about aspartame. Arguably, the concerns about stevia are more valid than those about aspartame, because there is less evidence refuting them.
The plant extract is refined using ethanol, methanol, crystallization and separation technologies to separate the various glycoside molecules. The Coca-Cola Company sells it as Truvia. Pepsi sells it as PureVia. It is a product of major corporations and is prepared in a laboratory using “toxic” chemicals like methanol. For some reason that doesn’t bother those who are promoting stevia as a natural product.
What about HFCS?
High fructose corn syrup (HFCS) is also being demonized. “High” fructose isn’t really so high. HFCS is 55% fructose. Sucrose (table sugar) is 50% fructose and 50% glucose. Honey is 50% fructose. Apples have 57% fructose; pears have 64%. Fructose has been blamed for obesity, diabetes, heart disease and a wide variety of other illnesses, but the evidence is inconclusive. Avoiding fructose would mean avoiding all sources of fructose, not just HFCS. Avoiding fruit is probably not healthy. An International Life Sciences Institute (ILSI) Expert Panel concluded that “there is no basis for recommending increases or decreases in [fructose] use in the general food supply or in special dietary use products.” HFCS is 25% sweeter than sucrose, so you can use less of it and get fewer calories. Limiting total calorie intake is healthy, and both HFCS and aspartame can contribute to that goal.
Is Aspartame Safe?
Yes! For everyone except people who have the genetic disorder phenylketonuria (PKU). They must avoid aspartame because they can’t process phenylalanine and accumulated high levels of phenylalanine can damage their brains. Science has adequately demonstrated that aspartame is safe for everyone else.
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Global Expansion: On to Amsterdam
Over the course of about a month, you were able to follow the build-out progress of SoftLayer’s Singapore data center facility. Todd book-ended his coverage of the process with an early look on September 2 and the official “LIVE” announcement on October 3, and given the fantastic response from customers to those updates, we’re going to keep them going from Amsterdam.
If you follow SoftLayer on Twitter or keep an eye on our Flickr account, the last time you saw the Amsterdam facility, it looked pretty empty. You might assume that with all the attention on Singapore, Amsterdam wasn’t getting much attention, but you’d be wrong … Folks have been working non-stop in Europe as well, and the facility looks beautiful:
It’s pretty obvious with the racks you see pictured that our go-live team has been on the ground and working hard in the new facility. We shipped loads of gear across a different ocean to get it to Amsterdam, but things will probably look pretty familiar.
When Singapore went live on Monday, customers were ecstatic. We’ve already provisioned a few hundred servers in the new facility, and the chorus of users anxious about our European expansion has gotten louder as a result. As you can see, Amsterdam is coming along nicely, so you’ll have a SoftLayer server in Amsterdam before you know it.
SoftLayer’s growth internationally has been fueled by customer demand, so while we’re working on Amsterdam, we’d love to hear where you’d like to see us next. Leave a comment with the country/region you think could best benefit from a local SoftLayer facility … And if you agree with any of the ideas, be sure to post your agreement as well so we get an even clearer picture of customer demand.
More to come!
On the Passing of a Giant
In March of 2000, Apple was set to launch the first version of Mac OS X. At the time, I was working for a company called Macromedia (creators of Flash, subsequently purchased by Adobe) on a professional illustration program called FreeHand. Part of the Mac OS X transition was a system that reimplemented the programming interfaces from Mac OS 9 on the operating system kernel of Mac OS X. That system was called Carbon and was key to the strategy that let Mac OS 9 application transition to the Mac OS X platform. We had worked very hard with Apple and FreeHand was one of the first applications to run under the new system. I was invited to demo FreeHand running on Mac OS X at the Mac OS X launch event.
The launch was held on the Apple Campus in the “Town Hall,” the same venue that recently hosted the launch of iOS 5 and the iPhone 4s. Members of The Press were across the hallway in an adjacent room while those of us who were going to present were reviewing our parts, being fitted with microphones, and anxiously milling about. At one point an Apple employee stuck her head into the room and announced that Steve Jobs would be arriving in a few minutes. Most people took the announcement in stride and continued about their business.
At some point in this process, two of the representatives from Apple’s Developer Relations team that I had been working with seated themselves about halfway up the auditorium; they were innocently waiting for the event to start.
When Steve walked into the room, he did so through a side door that was just to the left of my seat. I was standing in front of the seat, and Steve came to stop right in front of me. The moment he walked into the room, all conversation died out. The entire room held it’s breath for a few heart beats while Steve stretched and commented aloud about being “ready to do this thing.”
As the conversations around the room came back on-line, Steve turned to me, pointed at the Developer Relations folk halfway up the auditorium and forcefully asked “Who are those people?” Naturally I fumbled to find a reply and was explaining that they worked for Developer Relations. Thankfully the VP of Developer Relations was nearby. He tapped Steve on the shoulder and told him “Those are my people, Steve.” I often tell folks at that point that “The Eye of Sauron turned” as Steve went off to review his presentation.
This was my first encounter with Steve Jobs. I’ve had a couple more over the years, minor interactions that I have no doubt he would never have remembered. Still, I have been working on Apple products since I was very young. Over the years my specialization in the field of Apple development has allowed me to care for myself and my family. Apple’s products continue to be an important part of my life.
Shortly the official press event announcing Mac OS X, I was invited to the cafeteria at Apple, Caffe Macs, and heard Steve talk about how Mac OS X was going to change everything. Over 10 years later, and that operating system now powers not only the Macintosh computer, but the host of iOS devices as well. A decade away I’m now working at SoftLayer to bring some of that innovation, and excellence to our mobile products.
I am one of millions whose lives have been touched by Steve Jobs. I know that while he was here he seized life with an intensity that inspires many of us. I hope that where he has gone he will have time to relax, reflect, and rest for a time.
That is, I have no doubt, before he starts “One More Thing…”
Rest in Peace, Steve.
-Scott
Raising Funds and Awareness – American Heart
SoftLayer is having a contest between all departments to see who can raise the most money for the American Heart Association. Each department (some departments were combined depending on the amount of employees in the group) was asked to think of a fundraiser, event or just some way the team could raise money for a great cause. Whoever raises the most money wins the grand prize of bragging rights around the office.
The Teams
- Accounting/Finance
- Marketing/Strategy
- Administration/HR/Legal
- Networking
- CSA/Managed Services
- Sales
- CST
- SBT/Infrastructure/Implementation
- Executives (Officers and SVP’ s)
- Systems – Windows/Linux
- Facilities
- Technology
- Inventory
Most departments have done very well, but given my affiliation with the Marketing team, I want to talk about how amazingly we performed. The Marketing and Strategy team kicked off our fundraising efforts with a BBQ event that consisted of ribs, brisket and potato salad, an auction with some great prizes like Rangers tickets, Calloway Golf polo shirts and FC Dallas Tickets, and T-shirts for sale that read, “DEDICATED and we don’t just mean our servers” sponsored by SuperMicro:
And here are a few snapshots from the BBQ Event:
It’s pretty clear that 3 Bars BBQ is a pretty big draw in the SoftLayer office.
Needless to say this event was a great success! The Marketing team didn’t stop there, though. We had FOUR more auctions … And we pulled out the big guns (two 600GB SSD hard drives and two 16GB iPad 2s). In my biased opinion, the Marketing team worked the hardest for our donations with sweat and tears … mainly sweat – you know how hot it is outside in the middle of June in Texas.
To date, our team has raised a little over $7,500 in donations for the American Heart Association. You may say, “Wow that’s a lot of cash!” but one of the coolest ways we were able to raise so much money was that we didn’t need to take cash: we got a mobile credit card device so the “I don’t have cash on me” excuse was rendered useless! Yeah I know … we are the smartest team ALIVE! After a few events, every department asked us to use our device for their fundraising efforts.
I am so proud of all the work the Marketing and Strategy teams have put into this fundraiser, and I’m especially proud to be a part of an organization that goes to such lengths to help out a charity.
Go Team SoftLayer!
-Natalie 
Global Expansion: Singapore is LIVE!
I write this message while overlooking the International Business Park in Singapore. The desk I sit at faces east; the sun is now on the opposite side of the building and our new Singapore office is starting to cool off, but it’s eerily quiet here on the 6th floor.
Our new Singapore General Manager Michael Ong is in Dallas meeting the rest of the SoftLayer team, our new Server Build Technicians (SBTs) are on the data center floor assisting the Go Live Crew (GLC) and the inventory team is indexing and organizing of the mountains of gear we have in the Large Parts Room (LPR).
Thinking back just 30 days, we were getting early access to our two data center suites. Our four ocean containers were unloaded and waiting for us in the LPR, and the members of the GLC from Dallas, Houston, Seattle and Washington, D.C. had their steel toe boots on, hard hats in place and dragging a little from the 14 hour time change. The GLC has worked tirelessly to get this data center online.
Our success on the ground was far from a standalone feat, though. The steadfast support, backing and encouragement from everyone back home enabled our successful launch. Many departments and individuals spent tireless nights on the phone and on email helping us through issues. I can’t overstate the importance of their support and willingness to step up to get things done. Without their help, the data center certainly wouldn’t look like this:
Our first international data center and office are worth celebrating, but it’s important to realize that our work doesn’t stop today. It’s critical that we continue to support the Singapore office like we do our other offices and data centers around the U.S. We are depending on the local team to run the daily operations, and they’re depending on us to provide them with the necessary guidance to keep the gears in motion. This is not a fire and forget mission — we are now truly a global company.
While we sweep up the imaginary confetti from the floor in SNG01 (since we’d never let real confetti in the DC), we know that the GLC in Amsterdam is on the ground getting our first European facility ready. The ocean containers have been delivered and racks are being built. It’s time to get some rest and sleep fast … We’ve got another data center coming online soon.
To all our new Singaporean team members: Welcome to SoftLayer. We’re excited and proud to have you join our team. To everyone that supported us: Thank you again from the very bottom of our hearts. To our customers: Enjoy your new SoftLayer servers in Singapore. And to our competition: This is just the start.
3BFL.
An Introduction to Redis
I recently had the opportunity to get re-acquainted with Redis while evaluating solutions for a project on the Product Innovation team here at SoftLayer. I’d actually played with it a couple of times before, but this time it “clicked.” Or my brain broke. Either way, I see a lot of potential for Redis now.
No one product is a perfect fit for all of your data storage needs, of course. There are such fundamental tradeoffs to be made in designing storage architectures that you should be immediately suspicious of any product that claims to fit every need.
The best solutions tend to be products that actually embrace these tradeoffs. Redis, for instance, has sacrificed a small amount of data durability in exchange for being awesome.
What is it?
Redis is a key/value store, but describing it that way is sort of like calling a helicopter a “vehicle.” It’s a technically correct description, but it leaves out some important stuff.
You can think of it like a sophisticated older brother of Memcached. It presents a flat keyspace, and you can set those keys to string values. Another feature of Memcached is the ability to perform remote atomic operations, like “incr” and “append.” These are really handy, because you have the ability to modify remote data without fetching, and you have an assurance that you’re the only one performing that operation at that instant.
Redis takes this concept of remote commands on data and goes completely nuts with it. The database is aware of data structures like hashes, lists and sets in addition to simple string values. You can sort, union, intersect, slice and dice to your heart’s content without fetching any data. Redis is a data structure server. You can treat it like remote memory, and this has an awesome immediate benefit for a programmer: your code and brain are already optimized for these data types.
But it’s not just about making storage simpler. It’s fast, too. Crazy fast. If you make intelligent use of its data structures, it’s possible to serve a lot of traffic from relatively modest hardware. Redis 2.4 can easily handle ~50k list appends a second on my notebook. With batching, it can append 2 million items to a list on a remote host in about 1.28 seconds.
It allows the remote, atomic and performant manipulation of data structures. It took me a little while to realize exactly how useful that is.
What’s wrong with it?
Nothing. Move along.
OK, it’s a little short on durability. Redis uses memory as its primary store and periodically flushes to disk. A common configuration is to do so every second.
That sounds pretty reasonable. If a server goes down, you could lose a second of data. Keep in mind, however, how many operations Redis can perform in a second. If you’re in a high-volume environment, that could be a lot of data. It’s not for your financial transactions.
It also supports relatively limited availability options. Currently, it only supports master/slave replication. Clustering support is planned for an upcoming release. It’s looking pretty powerful, but it will take some real-world testing to know its performance impact.
These challenges should be taken into consideration, and it’s probably clear if you’re in a situation where the current tradeoffs aren’t a good fit.
In my experience, a lot of developers seriously overestimate the consequences of their application losing small amounts of data. Also consider whether or not the chance of losing a second (or less) of data genuinely represents a bigger threat to your application than any other compromises you might have made.
More Information
You can check out the slightly aging docs or browse the impressively simple source. There are probably already bindings for your language of choice as well.
-Tim