US vs. EU scienctific productivity

From a study in the BMJ:

The research productivity of the first 15 countries to join the EU, adjusted for population, was lower (76%) than that of the US—and even lower (66%) when the 10 newest EU countries were included in the analysis.

This is based just on number of papers, so a crappy paper in a crappy, put PubMed indexed, journal counts the same one in Nature, but I suspect the US would do even better if quality were included.

One interesting, but hard, extension of this research would be to see what percentage of papers published in the US have either first or senior authors who are not US-native, and for the first author group, what percentage are not US permanent residents or citizens. I suspect that a lot of US scientific output is by immigrants, either temporary or permanent, some form the EU, but other from Asia and elsewhere.

Tragic story

The pediatrician accused of killing her mother told police she first tried to suffocate the woman, then made her a milkshake laced with an anti-anxiety drug before strangling her.

Depressed daughter wants to kill herself, but decides she wants to take her mother with her. Manages to kill her mom, but can't go through with killing herself (a bit more background here)

Apparently the woman, now charged with murder, was a pediatrics resident here at Children's of Pittsburgh, but she finished right when I came and I don't have any inside information about her. I feel for the remaining kids.

Life span and infectious disease

Sorry if this image is hard to read, I had trouble converting from the .pdf file.
This is a view of life-span over time, showing almost no change from the paleolithic era until the mid-19th century (this data is apparently based on data from skeleltons at excavated sites but some assumptions needed to be made about survival in early childhood since very few skeletons of young children were found). The article it comes from notes that only about 1/3 made it to age 40 in the UK even at the end of the 19th century, indicating just how far we've come in the last 100 years. And the reason is infectious; very few people in the paleolitic era died of cancer or heart disease.

The article points out just how ineffective the human immune system is. As a clinical immunologist in the 21st century, it is easy for me to see how well it works aided by vaccines, hygeine and powerful antibiotics availabe at any pharmacy. In fact, until recently most deaths were caused by infections.

This perspective also helps explain the complexity of the human immune system and the amount of "energy" (from both an organismal and genetic/evolutionary perspective) devoted to immunity. Because that is what killed people:

In mid–19th century England, 60% of deaths were due to infectious diseases and this proportion was even higher in previous centuries, especially during epidemics

So the human (and, in general) mammalian immune system is complex and costly, but not very effective. So why do we have it? As brilliantly discussed in this (different) article, the answer is because we need it. Kids with SCID (severe combined immune deficiency, what used to be called the bubble-boy disease) die in infancy of infections that don't bother those with intact immune systems.

As the commentary notes, our immune systems can never hope to absolutely protect against infection, as bacteria may have 100,000 generations for each of ours. There ability to evolve quickly is much greater than ours. One idea is that by allowing generation of diversity many times within each organism (i.e. harnessing natural selection in lymphocytes by recombination of T cell receptor and antibodies) we are able to keep up. But the existence of complex, long-lived invertebrates like squids indicates it isn't simply our complexity or life-span that generated the need for such a complex immune system.

So what is the answer? Probably that a better immune system creates a selective advantage in comparison to other humans. In each generation, those individuals who avoid death of disability due to infection are the ones most likely to reproduce.

By selecting for evermore-devious parasites, the immune system is the cause of its own necessity

As our immune systems improve so do the ability of microbes to resist or outwit them:

The proposal here is that contrary to widely held views of practicing immunologists, the immune system is not evolutionarily selected to prevent infection in an absolute sense. Rather, it is selected to make one individual slightly more resistant or at least different than others of the same or related species. The adversary of any individual is not really the world of parasites, they are truly undefeatable, it is his or her neighbor. A zebra doesn't have to outrun the lion, just the slowest member of the herd.

Another way of looking at this is that acquired immunity was not a final solution to the problem of parasitism. There is no final solution. As novel as the acquired immune was, for rapidly multiplying agents, it was just another hurdle. It may have driven parasites to invent new strategies for fitness, but it did not convey invincibility or anything like it. To say the combination of innate and acquired immunity is the optimal defense is a misunderstanding of the evolutionary landscape. I don't believe there is an optimal defense. I don't believe there is a conceivable immune system that could not be obviated once the barriers to infection have been breached. For all animals and their parasites, generation upon generation, it has been evolutionary thrust and parry, until today as it was a million years ago and as it will be a million years hence, each and every species is literally plagued by parasitic microbial agents and viruses.

If you are interested, I strongly recommend reading the entire second article. It is well worth it.

Good medical care is expensive

THE first report for 13 years on the cost of treating asthma in Australia indicates spending on the disease has doubled. But according to the National Asthma Council, that is a good thing.

"We expected this would happen," CEO Kristine Whorlow said. "We are managing asthma better, so we are taking more medications – the only way to control asthma is with medications."

I blame Advair!

Seriously, while there are other approaches to asthma than just medicines (exercise, weight loss for obesity, environmental controls) I have no doubt with the conclusion: better asthma control is expensive.

For example, I follow an asthmatic man who has severe growth supression (< 5 ft tall) and has had necrosis of both hips due to dependence on oral corticosteroids for most of his childhood and adolescence . Now, with potent inhaled corticosteroids (ICS), ICS/long-acting beta agonist combinations like Advair and Omalizumab, we can manage almost everyone without such severe complications. And more good (but expensive) treatments are on the way.

Doctors gettng dumber?

It appears so, at least in the UK

This study (free PDF avaialble), summarized in this news article, shows declining performance on the MRCP(UK). It sounds like this is something like Step III of the US national boards, taken after 18 months of residency (or its equivalent):

The examination can be taken eighteen months after graduation, and a high proportion of UK graduates take it at the earliest possible time, when they typically have five or six years of undergraduate education, a year of PRHO posts, and six months of SHO training.

But only about 1/3 of grads take it, raising the possibility that the drop in scores is related to the population taking the test. The authors show some data that this is not the full explanation, but can't exclude it completely as an explanation.

I've never been completely convinced that these type of exams are that useful. No doctor practices in an environment where he can't look something up or ask for help. I'd rather have a doctor who knew a bit less, but also knew his limitations, than one who knew more but didn't know when to get help

Tangled bank XXXIII

is here. It is a science/biology carnival with many fascinating posts from fascinating blogs.

Bad medicine

Two reports in the NEJM cast doubt on just how well the market works in U.S. healthcare.

In the first (free full text!) the popularity of nesiritide, a treatment of heart failure is questioned:

How can a drug that is associated with higher rates of both renal dysfunction and death than placebo — and that costs 50 times as much as standard therapies and for which there are no meaningful data on relevant clinical end points — be given to more than 600,000 patients and be promoted throughout the United States for serial outpatient use, an indication not listed on the label?

The answer, unfortunately is a marketing campaign combined with a strategy that make provision of the drug financially advantageous for the doctor's who prescribe it:

an aggressive marketing campaign by the manufacturer, Scios, which is encouraging physicians to start their own "infusion centers" for whose services they can bill Medicare as if they were providing chemotherapy

In the second, we learn how Guidant, maker of implantable defibrillators, failed to warn physicians and patients when it learned that one of its products was prone to short-circuiting, leaving patients unprotected and leading to unnecessary deaths. While the risk was arguably small, the company seems to have covered up the data for finanacial reasons:

Guidant, the second-largest manufacturer of implantable defibrillators, had identified the electrical flaws in the Prizm 2 DR in February 2002 and had made manufacturing changes, on April 16 and November 13 of that year, in an effort to prevent this rare but unpredictable and catastrophic type of failure. To date, there have been no reports of failures of such devices built after the April 2002 change. Guidant, however, continued to sell devices that had been manufactured before that change was made and issued no public statements about the problem or the corrections. The company’s first announcement came on May 23, 2005 — more than three years after Guidant had become aware of the problem and hours before the New York Times published an article about Oukrop’s death.

The problem in health care is too often the incentives are in the wrong place. Nesiritide is lucrative for physicians who prescribe it and the company that makes it, but at best an unnecessary expense for the system as a whole (and a danger to patients in the worst case). While society benefits from the knowledge that some of Guidant's products are defective, Guidant (who has the information) doesn't and is actually hurt by it's disclosure.

Grand Rounds XXXXIV

is here

As usual I'm one of the only doctors actually working ;->

A very cool museum

I'm not much for guy stuff: cars, fireworks and chainsaws hold no particular interest to me.

But the National Air and Space Museum is awesome. We visited the site on the mall in D.C. in April and then finished the job with a visit to the site at Dulles airport yesterday (we are in northern Virginia for a mini-high school reunion for the wife). The Dulles site is an enormous hanger and includes a control tower, a space shuttle, and a Concorde, as well as tons and tons of other cool planes, gliders, and helicopters. Highly recommended.

Anaerobic or non-aerobic?

From an amusing, if a bit snarky, NYTimes magazine article on professional mini-golfers (I kid you not)

Maybe the name of the sport is the problem. If it were simply called ''putting,'' the idea of a pro circuit might not seem any more hilarious than it does for pool or bowling or any other nearly anaerobic sport played for money.

I don't think he really means anaerobic, which in this sense means of such intensity that the bodies oxygen extraction and utilization process can't keep up, what he means is non-aerobic. Sprinting and weight lifting are anaerobic, golf and bowling are not.

Tangentially, if your sport aspires to the level of respect that pool and bowling get, you are in bad shape.

Bad medical writing

From the abstract of a review of immunosuppression for pancreas transplants:

There is also evidence-based information to support the combination of tacrolimus and mycophenolate mophetil as the preferred maintenance immunosuppressive in simultaneous pancreas—kidney transplantation.

What additional information is communicated by "evidence-based information" as opposed to just "evidence?"

Low birth weight and subsequent impairment

This is no surprise to anyone who has spent signficant time in a NICU:

Our results reveal that ELBW children have extremely high ratesof chronic conditions compared with NBW children. These conditionsinclude asthma, cerebral palsy, and visual disability, as well as poorer cognitive ability, academic achievement, motor skills, and social adaptive functioning. These differences are evident even in ELBW children who do not have major neurosensory impairments and manifest in a higher overall frequency of functional limitations and need for compensatory aids and services above those routinely required by children in general.

ELBW = extremely low birth weight = less than 1 kg = less than 2.2 lbs and
NBW = normal weight = greater than 2.5kg = greater than 5.5 lbs
so these kids are really small. But as the article points out

In the United States in 2002, there were 22 845 live births with a birth weight of 500 to 999 g, of whom approximately 70% survived.

Meaning about 15,500 kids a year survive at this size. No offense to anyone, but humans simply aren't designed to be born this prematurely. Tremendous advances have been made in keeping extremely premature babies alive, but therapies to decrease disability (nitric oxide, nutrition, supplements, gentler ventilation) have not had much success.

The NYTimes article about the study is here.

Living with half a brain

I don't think you need to be a radiologist to appreciate this isn't a normal head CT.

But this CT is of a nearly normal 36 year old man:

The parents noticed some clumsiness in early childhood. Right-sided hemiparesis and an equinus deformity at the ankle were diagnosed, with surgical treatment at the age of 18 years. During childhood, the patient received physical therapy. Additional sensorimotor and language development during childhood was not restricted. At the age of 28 years, the patient experienced his only general seizure. The rest of his medical history was unremarkable. Our patient was and is not receiving any medication. Intellect and language were unimpaired; the patient could complete school and is now working in a security department. He reported some disabilities concerning fine motor control of his affected right hand in tasks of daily living but had no other complaints.

So basically this guy was born with half his brain missing and he has some right sided weakness and difficulty with fine motor tasks using his right hand.

Truly amazing. As the authors note the human brain is remarkably plastic when damage occurs early. Remeber that the left side of the brain is usually dominant for speech and language, yet he has no impairment.

Coffee and type 2 diabetes

This meta-analysis finds that increased coffee consumption is associated with a lower risk of type 2 diabetes. Remember that meta-analysis is just going back and combining multiple smaller studies into one big one to improve statistical power and that type 2 diabetes is the kind that tends to affect the old, the obese and the inactive. Risk was reduced about 1/3 for the highest coffee consumers (>6 or 7 cups per day, which seems like a lot), and 1/4 for those drinking a bit less.

I have heard it said that "meta-analysis is to analysis as metaphysics is to physics" which probably overstates the case, but meta-analysis does have some problems. In addition, these kind of studies can only show correlation, not causation.

Most of the studies aggregated into the meta-analysis corrected for factors like age, sex and obesity (you could imagine that the obese drink less coffee because they are too lazy to get up and get it), so the authors hypothesize a direct effect of some component of coffee (apparently not caffeine itself since decaf gives a similar benefit) on the insulin/glucose metabolism machinery.

I also learned from reading this that drinking filtered coffee decreases LDL (the bad cholesterol) compared to drinking pot-boiled coffee. Apparently the switch from pot-boiled to filtered in Finland is thought to have signficantly decreased the incidence of coronary artery disease.

Medical Emergency Teams

This is such a good idea, I wish I had thought of it:

Much of the chaotic, terrifying and often unsuccessful drama of treating cardiac arrest in the hospital can be avoided, and the number of unexpected hospital deaths can be reduced by 30 percent, if a team of specially trained doctors and nurses steps in before the heart has stopped, as soon as the patient takes a turn for the worse.

That's the concept behind medical emergency teams, or MET

If you've never worked in a hospital, it might seem obvious that when a patient isn't doing well, he gets immediate attention, but too often that isn't the case. A patient starts doing poorly, so the nurse pages the intern. He is busy (covering 8 or 10 patients of his own, plus maybe 20 or 30 more if the other interns on the team have gone home) so it takes a while to make it to see the patient. Then he tries some (minor) intervention, hoping he won't have to bother the more senior resident and thereby admit he can't handle things himself. Another 30 to 60 minutes later he calls the resident, who is busy with an admission and takes 1/2 hour to get there. If everything goes well, the resident realizes the seriousness of the situation, starts appropriate interventions and calls the ICU, who sends another resident, or maybe fellow to try and block the transfer (ICUs are always full). If the patient is really sick, the ICU eventually agrees to take the patient, but it takes an hour to clear a bed, get nursing report, etc.

So 3 or 4 hours later at best, the patient makes it to the ICU where he starts getting the care he needs, but those 3 or 4 hours might be the difference between life and death (or between a minor setback and a major complication). With METs, the nurse can directly summon senior physician and nursing backup and manpower to intervene early in the process.

Shameless self promotion

They mispelled my name, but you can see me interviewed, briefly (like about 2 seconds- ed) here
then click on the story on allergy proofing your home (may not work with all browsers)

Immigrating docs and nurses

The BMJ and Lancet have had a flurry of articles about the migration of health care workers migrating from the developing to the developed world. Apparently, this is rampant (no surprise to anyone in health care in the US) and leads to a substantial hardship in areas like sub-Saharan Africa where there are inadquate numbers of medical professionals.

The situation is compounded by the fact that countries like the U.K. and U.S. depend on immigration as they don't train enough docs and nurses.

As the spouse of an immigrant (from the Philippines) who has a number of physicians in-laws I can certainly understand the appeal of living and working in the US, described in this letter:

While working in your own country you were used to fashioning a chest drain from a discarded drip set; you had to buy the catheter for that patient because otherwise he or she could not go to theatre; and you had to buy drugs on occasions when your salary hardly lasted a week.

Then, given the opportunity to either study or work in the West, you start to enjoy your work, although you work longer hours. You can get a chest x ray film within an hour, and you don't have to worry about your salary running out before the end of the month. You start to re-evaluate your life. You look at the priorities of the society you left behind—often it is not so poor that it cannot afford these things, but greed, corruption, and a total lack of political will has stopped any form of growth in health care. Even senior doctors are oblivious to what the world is about, and you despair.

I think his point about the difficulty and frustration working in a corrupt society is particularly well taken.

I don't have any brillant insights. My libertarian instincts say we shouldn't prevent people immigrating as they wish and that the market will work out the best solution, but in this case that solution is pretty clearly with a lot of foreign born and educated RNs and MDs practicing for high salaries in the US while the poor in the developing world lack care.

Trauma surgeon

A moving piece (unfortunately, no free full text) in JAMA from a Zsolt Stockinger, a Naval trauma surgeon in Iraq, capturing the essence of being a physician

I knew in my heart before he arrived that if he wasn’t dead, he soon would be, the odds were so much against him. But 99.1% mortality is not certain death. When our soldiers and Marines face the bombs and the bullets, they need to know that we will do everything we can to save them. We need to know it. And next time, we will see that soldier who is the one percent.

Women physicians earnings

are the subject of this study (apparently full text not on-line, how 90s is that?) in the Journal of Human Resources, reported here in the BMJ (where quotes are from)

Married women doctors in the United States earn 11% less than men and unmarried women without children . . . . They earn another 14% less if they have one child and 22% less if they have more than one child. . . .

The report says that women doctors are less likely to be married than men (80% of women and 89% of men). If they are married, women doctors are twice as likely to have a working spouse (94%) than their male counterparts (46%) and more than twice as likely to be married to another doctor (40% of women and 14% of men).

Sixty six per cent of women doctors and 79% of men doctors had children, and on average the women had fewer children than men.

Women also tend to seek specialties and jobs with fewer demands on time and more opportunity to balance career and family.

This is all consonant with my experience. I'd also point out that the study group was US physicians under 40, so the rates of marriage and child-bearing will probably go up.

I think it is unfortunate that women (and men) who want a balance of work and family (or outside life in general) are effectively excluded from certain specialties (e.g. general surgery). Maybe with the 80 hour work week requirement this will change.

The study concludes that differences are the results of married physicians and those with children choosing to work less rather than outright discrimination, but the BMJ article (I don't have access to full text either) doesn't say how they came to that conclusion; perhaps just based on the decreased hours working.

I do think that medicine remains an attractive career for women (and men) who want to work less than full time or more. It is easy for, say, a pediatrician to work half time, while an academic or investment banker has much less chance for reduced hours but similar work.

Stem cells

A summary of where we stand in the U.S. with stem cell research and information on the guidelines issued jointly by the Institute of Medicine and National Research Council in this NEJM article.

Nothing too new if you are up on the issues, but a good summary. I didn't realize that the new guidelines prohibit payment to women donation oocytes (women who donate for fertility purposes are routinely paid.).

Long acting beta agonists and the FDA

According to this story, the FDA is considering taking long-acting beta agonists (LABAs) off the market because of a single study that showed increase risk of death in asthmatics who added one of them, salmeterol (marketed alone as Serevent and in combination with fluticasone, an inhaled steroid as Advair) increased asthma deaths. The increase was almost entirely among black patients and the majority of deaths occurred in those not taking inhaled steroids, which is contrary to current practice.

The second member of this class on the market, fomoterol (Foradil) has not been implicated in increasing deaths, but some worry that the increase deaths may be a "class effect" occurring with all LABAs.

Albuterol is a short-acting beta agonist and works by relaxing the airway smooth muscle and thereby improving air movement to and from the lungs (bronchodilation). LABAs have a similar effect but last longer (12+ hours) allowing patients with relatively bad asthma ongoing symptoms relief. They also seem to decrease severe exacerbations, but whether this is via their effect on smooth muscle or other, possibly anti-inflammatory actions, is not clear. Inhaled corticosteroids (ICS) such as fluticasone are the workhorse of asthma control and act by decreasing inflammation in the airway.

I think pulling Advair would be a huge mistake. It is a very effective medicine and greatly improves asthma control and quality of life in many pateints with asthma. In addition, because it combines an inhaled steroid and LABA it ensures that patients taking LABA are also taking ICS, which is a always a worry. The Glaxosmithkline reps (makers of Advair) claim there post-marketing data are reassuring re: deaths from patients on Advair, but it is probably a good idea to get that data in the public domain.

As an asthma specialist, I'd be happy to see Serevent (salmeterol alone) off the market as I don't think it has a role in asthma therapy, although it may be useful in treating COPD (chronic obstructive pulmonary disease). A combination of budesonide (another inhaled steroid) and fomoterol is in clincal trials and I think should be approved soon (both medicines are approved individually and the combination is bound to be safer since it forces patients to take their ICS).

Bacteriophages

Bacteriophages are viruse that infect bacteria. They are now being studied as possible treatment for bacterial infections, particularly those that are resistant to antibiotics.

Apparently these bacterial viruses looked like a promising antimicrobial treatement 100 years ago, but enthusiasm died out with the discovery of penicillin. As we face increasing problems with drug resistance, the idea of phage based therapies is making a comeback, according to an article in the June 25th Lancet.

For whatever reason, phage research continued in Georgia (the country that was formerly part of the Soviet Union, not the US state) and the Eliava Institute in Tbilisi is still at the center of this strategy.

From the article it sounds like the field is still in its infancy. Instead of having pure strains of different bacteriophages for different infections, the researchers at Eliava get mixtures of different phages from sewage (that won’t play well in direct to consumer marketing), which is bad for a number of reasons, not least of which such gamishes will be impossible to get regulatory approval for.

In addition there appears to be a lack of well-controlled trials of bacteriophage therapy

“There are too many evangelists and too little data and it’s still being hyped”, says Ian Molineux, a microbiologist at the University of Texas who specializes in bacteriophages and host–parasite interactions. “There have never really been any proper controlled experiments.” Much of the positive spin on phage therapy is little more than hyperbole, he says.

But biotech companies have become interested, so these weaknesses may soon be remedied.

A final problem is that some bacteriophages (those that are lysogenic and can integrate their DNA into the bacteria’s) have been implicated in spreading genes for antibiotics resistance between different bacterial strains. Any bacteriophages approved for therapy would have to be incapable of this.

Overall I’d view phage therapy as promising and exciting, but unproven.

One important advantage of this approach is that medicine can harness the power of natural selection instead of fighting it. Whenever a new class of antibiotic is approved, a huge number of bacteria in patients treated with it are placed under selective pressure. Any existing resistance is quickly selected for and even if none existed before, random variation can quickly produce it. Genes responsible for this resistance can spread quickly under such powerful selection

With bacteriophages, if bacteria develop resistance to one strain of phage, variant strains which are still effective can be selected in the laboratory. One could even imagine this could be done on an individual patient basis in the (distant) future

The panacea of socialized medicine

Despite long waiting lists, staff shortages, and quality of care problems, most Canadians have continued to support the system because they believe access to care should be fair and equitable.

From an article in The Lancet, believe it or not. Apparently fair and equitable is more not as sc important as timely and high-quality.

UPDATE I screwed up my sarcastic final line an wrote "not as" when I meant "more." Thanks for commentors for pointing it out.

Small nuclear RNAs and cancer

The central dogma of molecular genetics is that DNA codes for RNA which codes for protein which does the work. Like many dogmas this one captures an essential truth, but is incomplete. It has become clear over the last 25 years or so that RNA can have functional roles beyond just coding for protein. For example, essential components of the ribosome, which translates RNA into protein are composed of RNA.

Now, a whole new class of RNAs has emerged:

During the past few years, molecular biologists have been stunned by the discovery of hundreds of genes that encode small RNA molecules1. These microRNAs (miRNAs) — 21 to 25 nucleotides in length — are negative regulators of gene expression. The mechanisms by which they work are similar in plants and animals, implying that they are involved in fundamental cellular processes.

These miRNAs bind to mRNAs (m is for messenger here) which encode proteins and prevent/decrease their translation, thereby decreasing the amount of protein produced. They can also target the mRNAs they bind for destruction, preventing production of any protein at all.

Now, three papers in the June 6th Nature (quote above from commentary by Meltzer) implicate these miRNAs in cancer. One paper shows that similar cancers express similar patterns of miRNAs and that the tissue of origin could generally be determined from miRNA expresison, even for very poorly differentiated tumors (those that don’t look much like any normal tissue). This was not true for expression of mRNAs encoding protein. This could actually be a practical approach to patients presenting with tumors so poorly differentiated that no one is sure what kind of cancer they are (a not so uncommon problem) and therefore how best to treat them. In addition, the first article showed that miRNAs are expressed at lower levels in tumors than in normal tissue

Another paper solves the mystery of why certain cancers, B cell lymphomas, often contain an extra copy of a piece of chromosome 13. It turns out this region encodes miRNAs that when overexpressed lead to faster cell growth (this is different than the first paper which showed in general decreased expression of miRNAs in cancer). Overexpression of these miRNAs in a mouse model of lymphoma hastened tumor development. Finally, a third paper demonstrates that c-myc, a gene known to be involved in a variety of cancers (i.e. an oncogene) affects expression of miRNAs including those identified in the second paper as important in lymphoma development.

Together the papers introduce a new level of complexity into the regulation of cell growth and division, and the perturbations in these processes that underlie cancer and remind us that things are always more complex than they first seem

"Camping" pictues

Here are Colin and Isabel "practicing" for our recent camping trip. Isabel now has her own sleeping bag

More Obesity

I took the kids camping this weekend (here) and a short hike (0.4 miles) from the campground was a beach.

I know retract any comments I've made previously about obesity not being a problem. Holy cow, almost every adult there was obese, many of them morbidly so.

I was amazed at how many people were so fat they couldn't, say, walk a mile. I've read that obesity is worse in rural areas and I believe it now. I guess in the city (even in Pittsburgh where it seems everyone drives everywhere) you have to walk some and thereby get some exercise. In rural areas, you don't have to walk at all.

The number of smokers was also disappointing, as were the beer guzzling Canadians at the next-door camp site.

More race and medicine

I've posted twice on BiDil, a combination drug for heart failure approved only for blacks. As I noted previously, there is controversy about whether it really is only effective for blacks, as the pivotal trial didn't include a non-black control group.

A letter in the 6/25 BMJ by Jonathan Kahn clues us in as to why the maker has been so eager NOT to resolve this issue (for example with another trial looking for efficacy in non-black patients).

NitroMed, the corporate sponsor of the BiDil trials, holds at least two patents to BiDil. One is not race specific and covers the use of BiDil in the general population. This patent expires in 2007. The other is race specific; it does not expire until 2020. NitroMed therefore has a vested interest in framing BiDil as a race specific drug —regardless of the limitations imposed by the actual evidence.

UPDATE: Kahn has a whole law review article about this, available in PDF form here, which seems to take as a premise that any race specific approach to medicine is wrong. It is a mix of medicine, statistics and social commentary which to me was not persuasive, but read it yourself if you are interested in the case against BiDil

Hemmorhagic fever viruses

The best summary of Marburg and Ebola and what happens during outbreaks is here. An outstanding article and accesible to anyone with a basic knowledge of biology

Early treatment of first seizure

A common dilemna for primary care physicians and neurologists is what to do with patients after their first seizure. Some will never have a never seizure, while others will progress to full-blown epilepsy. There is no sure way to tell the difference. There have been some theoretical reasons to suspect early treatment might prevent progression to epilepsy, but this speculation is largely based on animal data.

A study in a recent issue of Lancet (June 11th, Marson et al) suggests no such protective effect. More than 1400 patients with recent onset of seizures (most had 1 or 2 total) were randomized to an anti-seizure medication or no treatment (i.e. it was not placebo controlled).

As expected, early treatment with anti-seizure meds decreased the number of the seizures in the short term, but, perhaps suprisingly, had no effect on progression to chronic epilepsy, with about 2/3 of each group being seizure free for a prolonged period 5 years after randomization. As the accompanying editorial points out, however, avoiding seizures in the short-term is no small accomplishment as seizures can cause signficant harm if they occur while, say, driving.

Adhesion molecule blocker for ulcerative colitis

This report in the NEJM shows that treatment with an antibody designed to block T cell migration into the gut is effective in treating ulcerative colitis. The antibody block a molecule on lymphocytes (white blood cells) called alpha-4 beta-7 integrin (integrins are adhesion molecules that bind to other molecules, in this case allowing lymphocytes to home to the appropriate tissue; integrins consist of two chains an alpha chain and a beta and are named based on the identity of these chains. alpha-4 beta-7 is important for homing to the gut. Binding to this integrin and blocking its interaction with other adhesion molecules on the wall of blood vessels block the lymphocytes that are destined for the gut. Since UC is a disease of inflammation this presumably decreases inflammation and therefore disease

About 2/3 of patients with ulcerative colitis achieved remission, versus only 1/3 of controls. There were two possible downsides. First about 1/4 of patients treated with the antibody, cleverly named MLN02, made antibodies against it (that is antibodies to the antibodies), which prevented it from having full effect. Patients in this trial only got 2 doses, so this could be an increasing problem with longer use. Second there were 3 serious infections in the MLN02 groups (two doses were used) versus none in the placebo group. This didn’t reach statistical significance, but bears watching in larger trials.

Recall that natalizumab (tysrabi), an antibody against just the alpha-4 component (which is part of other integrins beside alpha-4 beta-7) apparently caused several cases of progressive multifocal leukoencephalopathy (PML), which is caused by an unusual virus. The idea being that preventing lymphocytes entering the brain allows the JC virus that causes PML to evade an effective immune reaction.

Natalizumab was also trialed for Crohn’s disease, which shares some similarities to UC, but caused a case of PML in a patient in that trial as well, although it apparently wasn’t recognized until later.

Because MLN02 is specific for the alpha-4 beta-7 pair, which is not involved in migration of white blood cells into the central nervous system (that is thought to be alpha-4 beta-1 integrin) it shouldn’t cause PML, but it bears watching.

Physician suicide

Physicians in the United States have a significantly higher suicide rate than the general population

The combined results of 25 studies suggest that the suicide rate among male doctors is 40 percent higher than that among men in general, whereas the rate among female doctors is 130 percent higher than that among women in general.

In the general populations, females are more likely to attempt suicide, but males are more likely to succeed since they generally choose more effective methods (e.g. shooting themselves in the head). A significant reason for the increase is that physicians, and female physicians in particular, are much more likely to be successful when they attempt suicide, probably because they have access to drugs and knowledge about how to use them more effectively.

As the NEJM Perspective the quote comes from points out, physicians with mental illnesses such as depression or substance abuse problems are probably reluctant to seek help for fear of jeopardizing their licensure, which is, of course, crazy.

More on obesity and lifespan

An amusing post from Different River about a study whose results show that among those who are overweight mortality is lowest among those who try to lose weight and fail. Trying to lose weight and suceeding or not even trying are associated with higher mortality.

Note that many of the confidence intervals overlap 1 and are therefore nonsignificant. I'd add to DR's explanations the possibility that some individuals who lost weight did so because of other health problems (e.g. cancer) which also increased mortality.

Most troubling to me was DR's suggesting this explanation:

Perhaps those who are losing weight on purpose are doing dangerous things to accomplish the loss. For example, not all diets are safe, even if they are successful. (Three doctors told me that if the only way I could lose weight was to use the Adkins diet, I was better off staying fat.) Also, some people may exercise beyond their body’s capabilities in an effort to lose weight

As an ultramarathoner who fasts one day a week to lose weight this hits a bit close to home

Asthma- getting worse or better recognition

I came across an interesting article in my reading (Carter et al, Annals of Allergy, June edition, not free online). Using a questionnaire the authors divided Seattle middle school students (about 2300 each time) into 3 groups: those with asthma symptoms in the last year who’d by diagnosed with asthma, those with asthma symptoms in the last year who did not carry the diagnosis of asthma, and those without symptoms (presumably there were few patients who had no symptoms but had been diagnosed with asthma).

The results? In 1995 about 3% of the population of kids were diagnosed with asthma and another 12% had undiagnosed asthma (symptoms w/o diagnosis). In contrast, in 2003, just over 6% of kids had asthma and an equal number had undiagnosed asthma.

So, at least based on this study, the total number of kids with asthma is steady to slightly decreased over the 8 years, but a much higher proportion of kids is being correctly diagnosed, albeit only about 50%, even now.

Straight, gay or lying?

According to this article, there are few if any, true male bisexual:

People who claim bisexuality, according to these critics, are usually homosexual, but are ambivalent about their homosexuality or simply closeted. "You're either gay, straight or lying," as some gay men have put it.

In the new study, a team of psychologists directly measured genital arousal patterns in response to images of men and women. The psychologists found that men who identified themselves as bisexual were in fact exclusively aroused by either one sex or the other, usually by other men.

I could see how, depending on the circumstances, a person who was primarily homosexual would try to feel desire toward women as well.

NIH AIDS

Great, the division of the NIH charged with fighting AIDS is too busy protecting a deputy director who like to harrass female subordinates and firing a whistleblower to actually, you know, make progress against HIV.

The report apparently criticizes the whistleblower

The report, however, also criticized Fishbein, citing some of his supervisors' statements that he did not take enough time to adapt to the "culture" of the AIDS division

Did it ever occur to them that this wasn't a "culture" worth adapting too?

Scary story

about an attempted robbery in an ED is here, by Dr. Tony.

I would have been tempted to use a paralytic. The downside would be they couldn't breathe without being intubated. Of course, I'm inclined to see that as an advantage.

More Elidel, Protopic and cancer

The American Academy of Allergy, Asthma and Immunology (AAAAI, usually called "quad-AI") has released it's expert panel report on the danger of topical immunomodulators and cancer here.

Not surprisingly, it says it is too early to draw conclusions and opposes the FDA decision to put a "Black box" warning on the producs, which are marketed as Elidel (pimecrolimus) and Protopic (tacrolimus). The report states out a pretty strong stance in favor of these medicines, stating they may even be used here, here and here.

iArticles?

The June 11th BMJ has an interesting letter suggesting journals should price articles for non-subscribers at $0.99 just like songs on iTunes.

The author, Nicholas Moore, points out that current prices ($10-$40/article where a yearly subscription is on the order of $80-$120) encourage illegal photocopying. At a reasonable price, many users would choose to download rather than be bothered to, say, go to the library. He correctly notes that total revenue to the journal would almost certainly increase (the one exception is if there are institutional users, say investment banks, who need offical copies and pay for them, but don’t subscribe to the journal, but that seems unlikely).

This might also be a good model for institutional licensing. Rather than a flat fee, institutions could pay by download.