the Natural Condition

The Public Library of Science seems, to my nerdy eye, to be the ‘open source’ repository of the publishing community. Last week, PLoS Medicine hosted an article that provided a fascinating, and chilling, look into the mind of a ‘drug rep.’ Drug reps are the suave pawns of the pharmaceutical companies who market the newest therapeutic agents. They meet with physicians, prepared with a convincing heap of data supporting their products, and most importantly, armed with a smile and a checkbook. Drug reps often treat physicians to fine dinners that create a convenient forum to discuss family life and, should it come up, cycloxyprxanimibidodizole, or whatever the drug of the week is.

In the article, the authors discuss some of the thought processes of the reps. The main ‘informant’ is a former drug representative for the pharmaceutical company Eli Lilly. If you read anything from the original piece, make sure to peruse Table 1, “Tactics for Manipulating Physicians.” The table describes various ways to market a product based on the type of physician, from the “high-prescribers” to the “acquiescent docs” to the “aloof and skeptical.” The article covers many common practices in the field, such as clever script tracking schemes and the value of giving out samples. While the article is professional and rigorous in its evaluation, it also offers several personal quotes from the front lines of the business:

While it’s the doctors’ job to treat patients and not to justify their actions, it’s my job to constantly sway the doctors. It’s a job I’m paid and trained to do. Doctors are neither trained nor paid to negotiate. Most of the time they don’t even realize that’s what they’re doing…

and

During training, I was told, when you’re out to dinner with a doctor, ‘The physician is eating with a friend. You are eating with a client.’

Even I, a lowly research assistant (but future physician!), was once chatted up by a smooth-talking, curiously-pretty-for-her-age drug rep. I happen to work in a cubicle next to a fellowship program director, who in turn organizes the lives of the actual doctors in the fellowship program, who, finally, are the young, clinical minds who wield the malleable prescription pads. She was, naturally, of an exceptionally amiable nature, but I found the true aim of her banter to be quite obvious: get in good with the right people and, indirectly, the favors and face-time will come. A wry smile came across my face as I thought to myself, “I don’t even know the names of the fellows … you’re wasting your time, miss.”

Despite my obvious skepticism, from an economical perspective, I believe these salespeople are probably integral parts to the progress of modern medicine. When all is said and done, the main thing that drives innovation — and I speak in generalities — is the bottom line. Pharmaceutical companies are firms that sell a product, who are accountable to shareholders. The only way they can attract the brightest minds to develop the breakthrough drugs is by competitive compensation, which stems from a great market share. This is not to say that pharmaceutical companies are purely money-making machines; they probably rely on high volume products (Viagra) to subsidize research efforts for meds that are cost sinks because of either low disease prevalence, or an inability to pay among the afflicted population (poverty). In any case, foolish beneficence on the part of the drug company would be bad for everyone. Drug companies need to sell their products or else no one gets better, and physicians happen to be the retailers — or, at least, the gatekeepers.

So long as the drug reps are not presenting falsified or incomplete information, then schmoozing a doc to prescribe your pill seems just business as usual. I, however, will remain “aloof and skeptical” as long as I can.

References:
(1) Following the Script: How Drug Reps Make Friends and Influence Doctors. Fugh-Berman A, Ahari S. PLoS Medicine Vol. 4, No. 4, e150 doi:10.1371/journal.pmed.0040150

An important study was released in Nature today that described alarming findings concerning Diet Coke. Researchers discovered that drinking as little as 9 cans of Diet Coke each day can induce hyper-metastatic hyperplasia of the lateral incisors: tooth cancer. Even more disturbing than the fact that this common American beverage causes cancer is the speed of its onset. Certain subjects in their phase IV, double-blind, covariate-adapted, randomized, placebo-controlled trial reported symptoms within seconds of consumption, and many subjects regrettably succumbed to the disease after only a few hours.

The sweetener aspartame is the suspected cause of the tooth cancer, although researchers are continuing to investigate the dubious additive dihydrogen oxide as a possible agent. This rigorous, NIH study found conclusive evidence that aspartame causes cancer in rats. Although the source is yet to be verified in a phase V randomized, controlled trial, scientists have preemptively decided to name the Diet Coke illness “Sweetener-Induced Dental Syndrome,” or “SIDS” for short (although the Samui International Diving School contests their use of the acronym).

The following video shows one man, Rick Astley, shortly before his untimely demise. Mr. Astley had imbibed only 10 cans of Diet Coke in one hour, but he quickly became symptomatic for SIDS. His convulsions in the video demonstrate the relentless cruelty of the disease. The song is a requiem for his ambivalent love of Diet Coke. “Never gonna give you up, never gonna let you down…” were Mr. Astley’s dying words.

Well I think that will suffice for this April Fool’s Day. See, isn’t medicine fun?!

Being overweight is bad for your health, right? With all the talk of the American obesity epidemic and the consequent rise in diabetes and associated ailments, combined with the fact that cardiovascular disease is known to be the leading killer in America and is exacerbated by lack of exercise, most people assume that excess poundage will lead to a shortened life span. While the information I am about to divulge is not new, I would like to summarize the findings of a 2005 study that, very shockingly, discovered a decrease in the death rate for “overweight” persons.

In 2005, JAMA published an article by Flagel et al. of the National Center for Health Statistics (a division of the CDC) and the National Cancer Institute entitled “Excess Deaths Associated With Underweight, Overweight, and Obesity.” The authors sought to answer broad questions about the impact of weight (BMI) on mortality. They used 3 of the National Health and Nutrition Examination Surveys (NHANES), which comprise data on over 35,000 people dating as far back as 1971. They grouped patients into 4 categories of interest, with one control, all based on BMI. They used the national standards for BMI classification:

1. <18.5 : Underweight
2. 18.5 - <25 : Normal (control)
3. 25 - <30 : Overweight
4. 30 - <35 : Obese
5. ≥35 : Morbidly Obese

When performing their analyses, each group was controlled for known confounding factors to mortality, such as smoking. The table below outlines their findings for relative risk of death by age group and BMI. A RR<1 means that a population is at less of a risk for dying than the Normal-weight group, RR>1 means they do worse.

^{Relative risk of death by age group and BMI. Image courtesy of JAMA.}

What we see in this table is that both the Obese and Underweight cohorts have substantially higher relative risks than Normal-weight individuals, and more markedly so in younger age groups. The big, and unanticipated, anomaly is the Overweight cohort, which exhibited a relative risk <1 in every case. Flagel et al. then used these relative risks, in conjunction with US prevalence data on BMI, to yield estimations of excess deaths due to weight … or, for the Overweight category, lives saved.

^{Annual excess death estimates by cohort, paneled by BMI category. Image courtesy of JAMA.}

If that last line about ‘lives saved’ for being overweight chaffed you: it chaffed me, too, so let’s dig deeper. While I am not a statistician, I did read their Methods thoroughly, but still do not quite understand how they reached their estimates for excess death, which incorporate the relative risks. One seemingly important point about the relative risks for the Overweight group (above table) is that, while each estimate fell below 1, the 95% confidence intervals for every Overweight RR overlapped 1. Because a relative risk of 1 never fell outside of their confidence band for an alpha of .05 for any age group, how could they reach the conclusion that there is always a negative number of excess deaths (positive number of lives saved), “–86 094 deaths; 95% CI, –161 223 to –10 966″¹? They say that the uncertainty of the relative risk is propagated in the excess death estimate, but as I just outlined, the result does not seem coherent.

Their findings are, nonetheless, suggestive that having an ‘Overweight’ BMI may confer additional years of life, although “bias may also result from failure to control for unknown confounders that are associated with body weight and mortality,”¹ as the authors indicate. I should mention that nowhere in the paper do the authors esteem their finding of a decreased relative risk for ‘overweight’ BMIs. In a way, they elegantly dismiss that peculiar result, stating simply that “Overweight was not associated with excess mortality.”¹

In any case, the more important fact to glean from this discussion is that any large deviation from a normal BMI is associated with increased mortality. In response to the Flagel study, Thomas Hoerher, PhD wrote, “although mortality is an important measure of the burden of a disease, it is not the only one. Obesity also has significant impacts on morbidity, health care costs, and quality of life.”² Obesity is not healthy, and 112,000 excess death per year is a serious matter.

Footnotes/Further Reading:
(1) Excess Deaths Associated With Underweight, Overweight, and Obesity. JAMA. 2005.
(2) Controversies in Obesity Mortality: A Tale of Two Studies. RTI-UNC Center of Excellence in Health Promotion Economics. 2006.
(3) CDC Downscales Mortality Risk From Obesity, USA. MedicalNewsToday.com. 2005.

One need not search far to palpate a growing dissatisfaction among physicians about the current state of the practice of medicine. Complaints include longer hours, waning compensation, the hassle of insurance providers, direct-to-consumer drug advertisement, skyrocketing malpractice premiums due to growing fears of injury litigation, and a general disintegration of the prestige and respect long given to the title “MD.” While all these claims are valid, a vociferous elite in the published medical community dwell ad nauseum on the shortcomings of modern practice, while often neglecting the timeless virtues of the physician. Medical Economics recently published an opinion piece by a pediatrician who claims that the he has not, in fact, been overcome with the disenchantment that reverberates in the commentary of many practitioners. “Hard to believe, but it’s been almost 20 years, and I still feel the same way,” writes Dr. Lawrence Rifkin. “Being a doctor can be a hassle. But it’s still a joy and a privilege.”¹

Although Dr. Rifkin’s essay is a mere 700 words long, he uses the term “wonder” five times.² The word has many applications, but “wonder” may be most aptly ascribed to the sentiment of aspiring doctors. Medical students and prospective medical students gaze upon the field with a starry-eyed perspective; we mean to do good, and to make humanity healthier. And good for us. For, just as the crabby, nostalgic docs warned Dr. Rifkin 20 years ago, our opinions will likely change. But I say, you have to set out at level 10 on the “wonder” scale in order to accommodate the proposed drop to a disillusioned level 4. Were students to enter medicine already jaded, they might fall off the charts altogether and find themselves practicing, well … plastics.³ But Dr. Rifkin says that his sense of wonder has not left him. It is “reawakened by stepping back and taking a second or two now and again to look at the big picture.”¹ His point of view is thoroughly refreshing and encouraging to the newest generation of medical students entering a cynical world.

When I pause and really think about what our profession has accomplished, the sense of wonder rushes in. Since the mid-1800s, life expectancy in much of the world has doubled. It’s as if modern medicine and public health have given each of us a second lifetime. Who among us doesn’t have a relative who was saved by modern science—heart bypass surgery, perhaps, breast cancer treatment, or a C-section? My role may be small, but it still feels good to be a part of such a positive change.¹

I hope to thrive off the wonder of being part of a positive change for as long as I can when I officially begin my medical career this summer. And regardless of what truth may lie beneath the seemingly glossy finish, I am sure that cynical diatribes accomplish very little to affect real change, whether in the practice of medicine, or in any profession. But optimism … now there’s a start.

Footnotes:
(1) Still a privilege to be a doctor. Medical Economics. 2008.
(2) Forgive the literary deconstruction of this piece. My undergraduate training involved a good deal of textual analysis, and I cannot help but to count words and to distill meaning where meaning may not actually exist. Nonetheless, I do believe that an author may pen words that arise from a deeper part of their consciousness of which they may not even be aware; the repetition of “wonder” is then seen as an inadvertent, and important, theme.
(3) This comment is, admittedly, a cheap shot. My apologies to the plastic surgeons out there who really do correct horrible disfigurement, such as lifting those dreaded wrinkles that come from the unnatural process of “aging.”

DNA, and its oxidized counterpart, RNA, are the fundamental molecules of all living organisms. The fascinating thing about life is that, elementally, it is almost all identical; the same 6 elements (carbon, hydrogen, nitrogen, oxygen, phosphorous, and sulfur — CHNOPS) comprise over 99% of the weight of living matter. Indeed, the only reason that a lizard is a lizard and a human, a human is due to the different instruction set coded into DNA. James Watson and Francis Crick, two young molecular biologists at the time, published their seminal findings on the structure of DNA in the journal Nature in 1953. The piece was entitled, “A structure for deoxyribose nucleic acid.” The article was a mere 3 pages long, but it was undoubtedly one of the most significant scientific advances of the 20th century, as it would change the way we understood how living creatures procreate and differentiate, at both the cellular and organismal levels.

While the paper dealt uniquely with proposing a structure for the molecule, Watson and Crick subtlety hint at the obvious magnitude of their discovery in one of the concluding paragraphs:

It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.

The “pairing” they refer to is the central dogma of the nitrogenous base hydrogen-bonding preferences: adenine bonds to thymine, and guanine to cytosine. Within that simple code of A-T|C-G arise the instructions for the arrangement of every organ, tissue, cell and molecule in complex lifeforms, similar to the way computers use a binary of 1s and 0s to perform exceedingly complex tasks. Watson and Crick had peered into the biological foundation of life, and the rest is history. I highly encourage you to read their original article.

Cancer. The very word evokes an uneasiness in our health-obsessed culture … and, unfortunately, for good reason: malignant neoplasms (cancers) are responsible for more than 1 in every 5 deaths in the United States.¹

First, a little background on cancer (skip to next paragraph for the news). Cancer is basically the proliferation of cells that shouldn’t proliferate. However, a ‘malignant’ neoplasm is additionally defined by proliferating cells that invade the surrounding tissue, causing an indistinct margin between normal cells and the neoplasm. Malignant tumors are contrasted by their benign counterparts, called ‘in situ’ tumors. In situ literally means ‘in place,’ and indicates a well-behaved neoplasm that sticks to itself. In situ tumors can, however, be precursors to malignant behavior. Malignant cancer cells, in addition to encroaching on the immediate surrounding tissue, may enter the blood vessels and lymphatics of the tissue and travel to other parts of the body like the liver, lungs and bone, where they will implant and seed a new colony of cancer cells (however, the colony is made up of the same tissue type as the primary tumor). This event is named metastasis.

The diagram on the right illustrates the accepted progression of healthy cells into cancer. A most interesting aspect to the process is that, while we understand how cancer cells arise — inactivation of tumor suppressor genes, DNA repair mechanisms going haywire, etc. — there is little consensus on why they arise. Many scientists believe that genetic mutations occur at random in some tumor cells, which then father a line of more “rare variant clones,”² leading to observable metastases. Everyone agrees that genetic mutation is the root, but the reason for the genetic mutation is the subject of much debate and extensive research.

Fortunately, new findings help to shed a little light on possible sources of the genetic anomalies. This week’s Nature journal hosted an article that identifies the nuclear protein SATB1, a genomic organizer, as one likely cause of the upregulation of oncogenes and the downregulation of tumor suppressor genes in breast carcinoma. Likely, as in P<0.0001 for prognostic ability, likely.

[The SATB1 protein works] by recruiting chromatin remodelling/modifying enzymes and transcription factors13, 14 to genomic DNA, which it tethers via specialized DNA sequences highly potentiated for unpairing (base unpairing regions, or BURs). … In breast cancer cells, we find that once SATB1 is expressed, it coordinates expression of a large number of genes to induce metastasis.²

The SATB1 protein affects the regulation of over 1000 genes, making it a major player in the pathway to metastatic disease. The researchers also discovered that removing SATB1, “not only reverses metastatic phenotypes but also inhibits tumour growth”² in aggressive breast cancers. The study comprised tests for the presence of SATB1 in human breast carcinoma, among other in vivo trials in mice and in vitro assays.

This discovery is novel because most cancer therapies attempt to combat the disease by minimizing the proliferation of the cancer cells. If a drug were made that targets the SATB1 protein for destruction, it could prevent the cells from developing into cancer at all. Of course, those are BIG “ifs,” and the next obvious question is, what leads to expression of SATB1? And down the carcinogenic rabbit hole we will continue.³

References:
(1) Final Draft of National Vital Statistics Report for 2004. CDC. 2007.
(2) SATB1 reprogrammes gene expression to promote breast tumour growth and metastasis. Nature. 2008.
(3) The proverbial ‘rabbit hole’ is not, itself, a carcinogen; that wouldn’t make any sense. It was just a metaphor for the limitless depth of cancer understanding that we will pursue for the sake of saving lives. Ok, you know what, just forget I mentioned the rabbit hole.

Health Affairs released a report yesterday (March 10th) that outlined trends in American Emergency Department wait-times between 1997 and 2004. They considered three overlapping cases: all patients (18 and older), patients with ‘emergent’ conditions as indicated by triage staff (should be seen within 15 minutes), and patients with an eventual diagnosis of acute myocardial infarction — heart attack. On the whole, the median wait time to see an ED physician increased 36%. While wait times for ‘all patients’ and ‘emergent patients’ increased by about 40% per year (22 to 30 minutes, and 10 to 14 minutes, respectively), the change in the ‘AMI patient’ wait time dwarfed them both:

During the 7 years examined, the median wait time for patients eventually diagnosed with AMI increased by 150%, from 12 minutes in 1997 to 20 minutes in 2004. That is truly shocking news. Cardiogenic-shocking news, to be precise (pardon the pun).

In the decade from 1994 to 2004, total ED visits increased by about 18% (from 93 million to 110 million, annually). Emergency Department closures — as many as 12% during the decade — compounded the boom in visits. “Other likely contributors include inpatient bed shortages leading to bottlenecks in the ED; increasing uninsurance; population aging; shortages of staffing, space, and interpreters; and difficulties assuring non-ED follow-up care.” The sum of which totaled to a crucial deferral of care in the neediest patients. The authors of the paper raise the important point that staggering wait times, or even the misgiving of staggering wait times, will cause many prospective patients to avoid the ED altogether.¹

Wide-angle reports like this one demonstrate that all the ingenious, expensive, life-saving interventions are worthless if we do not first step back and survey the simple obstructions to keeping people healthy. We might do well to count something on this scale more often.

Reference:
(1) Waits To See An Emergency Department Physician: U.S. Trends And Predictors, 1997–2004. Health Affairs. 2008. [full text - restricted access] The full article contains many more interesting statistics about wait-time changes in sub-populations (race, gender, region, etc.).

Monosodium glutamate, often referred to as MSG, is a common flavor-enhancing additive in contemporary foods. The Japanese were the first to discover the compound’s unique flavorful property in 1908¹, but it did not reach American consumers until the middle of the 20th century, when the white powder was added en masse to (American) Chinese food. It is now ubiquitous in highly-processed cuisine, like ramen noodles, soup, and fast food.

One can isolate the chemical MSG from the fermentation of starches, molasses, sugar cane, or sugar beets. In solution, the Na+ ion will freely dissociate from the terminal carbonyl, rendering the functional substance glutamate. Glutamate is a non-essential amino acid, meaning that most humans need not obtain the compound exogenously; they can produce it themselves. As an amino acid, glutamate occurs naturally in protein-rich foods such as meats and dairy products, especially Parmesan cheese.² Moreover, although it is not an additive, glutamate is a common component of soy sauce and Worcestershire sauce, arising from the fermentation processes used in their production. Although food producers are required to specifically indicate if monosodium glutamate is an ingredient, free glutamate may also appear under the less-assuming titles of “hydrolyzed soy protein” and “autolyzed yeast.”
… (Read the rest of this article »)

Americans have long accepted the idea that caffeine acts as a diuretic, causing fluid excretion to exceed fluid retention. The New York Times: Health published an article yesterday (March 4th) that suggests otherwise, citing several studies conducted in the past few years. According to the report,

… research has not confirmed that notion. Most studies have found that in moderate amounts, caffeine has only mild diuretic effects — much like water. … Investigations comparing caffeine with water or placebo seldom found a statistical difference in urine volume

While a cup of coffee might be a fine way to start your morning, remember to consume a total of 2-3 liters of fluids each day to remain truly hydrated. Be well and drink up!

In my own investigation, I found these scholarly studies supporting this claim:
(1) Caffeine, Fluid-Electrolyte Balance, Temperature Regulation, and Exercise-Heat Tolerance. Exercise and Sport Sciences Reviews. 2007. [full article - limited access]
(2) Caffeine ingestion and fluid balance: a review. Journal of Human Nutrition and Dietetics. 2003.