Cars, cars, cars

Posting will be a bit sporadic until Monday as we drove down to DC with the family for a few days of vacation over the kids spring break.

Posting was sporadic the last few days due to blogger.

I went running in Rock Creek Park today which is nice, but would be really beautiful if there wasn't a heavily used four lane road running down the middle (at least the part I ran from Adams Morgan down to the Potomac). Why is it that planners can't resist opening up parks, etc to cars.

Just from my experience Chicago would be much better if they hadn't built a highway down the lakefront, same with Boston and the Charles. In NYC, both Prospect and Central Parks would be better if they closed the roads, and same to a lesser degree with Schenley Park in Pittsburgh. I'm sure there are other good examples, too.

Of course, I've never regularly driven to work or school.

Doctor e-shopping

What I think is interesting about this story is how much control of her health care the patient took.

The woman has a stroke and is diagnosed with moyamoya (the Japanese word for "puff of smoke"), a rare disorder where blood vessels in the brain become blocked.

She found one bit of encouragement: a Web site, www.moyamoya.com, created by a patient, described an operation for the disease, a type of bypass in the skull that could improve circulation to the brain and prevent further strokes. The site included a link to Dr. Gary Steinberg, the head of neurosurgery at Stanford University Medical Center. Dr. Steinberg, who has operated on more than 130 people with the disease, is one of the few surgeons in the United States who have treated more than a handful of patients with moyamoya.

Mrs. Young e-mailed him. After studying her records and ordering more tests to map the blood vessels in her head, he recommended two operations, one on each side of her skull, a week apart. Her health insurer balked at first, insisting that she be treated in Missouri, but ultimately agreed that no brain surgeon there had Dr. Steinberg's expertise in moyamoya. By late February, Mrs. Young was on her way to Stanford.

This kind of thing, emailing the expert in your disease is going to become increasingly common. Some of it will be doctors e-mailing other doctors, but if we drop the ball patients will do it themselves.

More economics of medicine

This article nicely illustrates the dilemma facing the U.S. health care system.

In the two weeks since Genentech's expensive new drug Avastin was found to help the sickest lung cancer patients live a few months longer than expected, investors have pumped nearly $17 billion into the company.

But what's good for the patients, the company and its investors is also heavily stressing the ailing U.S. health care system, raising uncomfortable questions about the cost of end-of-life care.

"We are spending huge sums of money on treatments that are offering only modest benefits," says Dr. Richard Deyo, a University of Washington professor who recently wrote a book on the subject.

Of course if you are the one who gets a few extra months of life, it probably seems like a good deal to you. I don't have answers, but clearly from a societal standpoint, these drugs don't make a lot of sense.

More HOTHEAD

Reader Scott Kern, who knows a lot more than me about this area and has given it a lot of thought, sends this critique of the HOTHEAD reversion, crazy RNA memory paper in nature, I blogged about previously:

As a cancer geneticist who spends a lot of time trying to expunge mutation artifacts from our genetic studies, I'm appalled at the sloppy presentation of the arabidopsis reversions in Nature. No supplemental data, a methods section shorter than the Abstract, near absence of methodologic details in the text, etc.

In the first paragraph of the second page, did they really use allele-specific PCR to "clearly" show a conclusion? In other words, they purchased the chosen sequence by mail, then found the same sequence when the mail-order oligos were used in an artifact-prone method? All withoutshowing any controls for the specificity of the allele-specific method or for how the results might be potentially affected by small sample size (which by reducing the number of DNA templates, increases the influence of PCR-introduced errors).

In figure 1a, what was the restriction site used? Did it occur naturally in the sequence (I don't see it in the figure showing the sequences), or was it artifactually introduced during PCR? Why does the top allele in Figure 1A appear so much brighter than the restriction-cut allele just below it -are the alleles not in molar equivalence? If this is a two-allele system,molar equivalence would seem to be required.

In the Southern blot, what was the probe?

What were the primer sequences used for the assays ?

If the altered sequences were found by one method, could they be confirmed by finding them with use of another method having non-overlapping artifactual tendencies? I note that they didn't use phage lifts or allele-specific ligation to quantitate the allelic ratio of the revertant alleles, as had been done 15 years earlier to provide the necessary controls for the study that showed infrequent mutant genes in stool samples of colorectal cancer patients.

Why no negative controls - such as non-embryoid parts of the hth/hth and> HTH/HTH plants whose DNA had been isolated in minute amounts similar to the technique used for the seeds?

Why no primary data from gene sequencing in any of the figures? Did Nature refuse to publish the primary data even in supplemental form?

Do we really think that 38% of samples had gene reversion (table 2)? That would be a higher rate of gene conversion in trans than any other recombination system, including yeast.

Why no coded samples? When the infrequent gene mutations in pancreatic ductal lesions and in stool samples of pancreatic cancer patients werefound 10 years ago, the samples were tested blindly. Wouldn't everyone would do this or some similar form of investigator blinding? And why not do the studies in a lab that had never previously seen studies of the HTH gene? This has been done when other authors wanted to quantitate gene mutation prevalence rates in cancer patients.

I suppose Nature will once again call in the Amazing Randi to investigate the authors, just like they did with their water memory paper in 1988.

I don't claim to know whether the data in this paper are valid, but certainly the methods are not presented in adequate detail nor in adequate confirmatory depth to judge. Until then, discussing this paper is a waste of time.

I'll agree with Scott and say as I did last time that before you publish a paper in Nature that calls into question much of how we think about genetics, you need to have more than suggestive data; you need to have things nailed down airtight with all the data and controls everyone would want.

Grand Rounds XXVII

is up here and let's just say it is scandalous.

Carnival of Errors

Orac, of Respectful Insolence, summarizes some of the more misguided statements in recent history, by prominent prognosticators. My personal fav:

There is not the slightest indication that nuclear energy will ever be obtainable. It would mean that the atom would have to be shattered at will. -- Albert Einstein, 1932

Ugggh.

Now that is constipation.

More details here.

Outrageous

That is how I'd describe pharmacists who refuse to fill prescriptions that don't conform to their personal moral beliefs, at least those that don't make alternative arrangements.

Some pharmacists across the country are refusing to fill prescriptions for birth control and morning-after pills, saying that dispensing the medications violates their personal moral or religious beliefs.

Maybe they should consider a new line of work.

When I was a fellow, I used to moonlight covering a pediatric practice and one Saturday I got a call from a teenager (I don't remember the exact age, but it was at least 18) asking for the morning after pill since a condom had broken. As a supporter of this form of contraception (and it is contraception) I called it in, warning her to be more
careful in the future. I thought about what I'd do if I was opposed, but decided I'd really have to give up this moonlighting shift (or make alternative arrangements) since there was no particular reason patients should have to be inconvenienced by my personal religious beliefs. I feel the same way about other health care workers

If a doctor is personally opposed to abortion, he or she has no duty to perform them, but then he or she needs to find a job that doesn't require performing them. He or she can't very well take a job at Planned Parenthood and then object to doing his/her job. And if you take care of women in a specialty where they might become pregant, you have to be willing to refer to someone who will perform abortions.

I don't see it as being any different for pharmacists. If they won't fill prescriptions for OCPs they should start special pharmacies which clearly state which medicines they will and won't fill. If enough fundamentalist wackos want to go to those pharmacies, fine for them, but the average person deserves to have their prescriptions filled in any pharmacy that doesn't clearly and publically proclaim that there are certain prescriptions they won't fill.

I have little patience with the idea of "transferring" the prescription either. If it is a big pharmacy and they always make sure to work with another pharmacist who will fill those prescriptions that is no big deal, but I don't see why customers should have to schlepp all over town because somebody doesn't want to do his or her job.

This quote, I can hardly even comment on:

Brauer, of Pharmacists for Life, defends the right of pharmacists not only to decline to fill prescriptions themselves but also to refuse to refer customers elsewhere or transfer prescriptions.

"That's like saying, 'I don't kill people myself but let me tell you about the guy down the street who does.' What's that saying? 'I will not off your husband, but I know a buddy who will?' It's the same thing," said Brauer, who now works at hospital pharmacy.

Comparing morning after contraception, must less OCPs (Oral contraceptive pills is medical argot for birth control pills) to murder is way, way over-the-top. Morning after contraception probably works primarily by preventing implantation of the fertilized ovum (aka embryo) in the uterus. Guess what? The majority of fertilized embryos don't implant anyway. I haven't seen a lot of "funerals" for embryos that didn't implant or much medical research devoted to decreasing all these tragic deaths (ed: be careful what you wish for).

This would be funny

if hundreds of kids weren't dying:

Accusations by Islamic preachers that vaccines are part of an American anti-Islamic plot are threatening efforts to combat a measles epidemic that has killed hundreds of Nigerian children, health workers say....

In 2003, Islamic clerics claimed the United States was using polio vaccine to sterilize Muslims or contaminate them with the AIDS virus. They ordered a boycott in messages disseminated from mosques, in radio broadcasts and by door-to-door campaigning.

The U.S. Embassy called the claims "absolutely ridiculous."

Glad the AP gave U.S. officials a chance to respond.

Occasionally, I see anti-vaccine parents in my clinic. Since this belief, usually, doesn't directly affect the problem they are seeing me about, I tread lightly.

One thing that always amazes me is their shock, sometimes to the point of disbelief, when I confirm I've had my own kids immunized.

Look folks, immunizations are not some giant scam where us mean doctors are giving your kids shots just for kicks with the side benefit of injecting some toxic chemicals into their bodies. They are life saving. We believe in them; really.

Early to bed, Early to rise

makes my wife very cranky. I like to sleep in, but try to force myself to get up early to work-out, since it is easiest to fit in before everyone else gets up. It also ensures that I get it in, no matter how hectic my day gets or whatever comes up.

I notice how much easier it is to get up early in the summer, when it is at least getting light, than in the winter when I can easily run an hour and it still be dark out when I finish.

This NY Times article finds people exaggerate both how early they get up and how little they sleep:

In a study in which subjects claimed they could get by on just five hours' sleep, he said, researchers found the subjects were sneaking in long naps and sleeping in on weekends to make up for lost z's.

I think this is one of those things, like how strong they like coffee or how many hours a week they work, that people always round up.

I remember how early we'd have to get up during my surgery rotation as an MS-III (3rd year med student) and can't imagine how anyone keeps that up.

When families want to keep patients alive

It used to be that families fought doctors to withdraw care, not anymore

Now, doctors and ethicists say that when hospitals and families clash, conflicts often pit families who want to continue life support and aggressive medical care against doctors who believe it is time to stop

This is more common than you think. There are whole hospitals dedicated to care of patients on ventilators. Of course, some patients have intact cognitive function, but can't breathe due to neuromuscular disorders like ALS or spinal cord injuries, but some are just kept alive because the family doesn't want to let go.

In my limited experience, with some time and discussion the family usually comes to recognize the futility of further care and agrees to withdraw support.

While I agree with the sentiment, I think this statement is a bit over the top:

In Boston, doctors considered it so inhumane to keep alive Barbara Howe, a 79-year-old woman with Lou Gehrig's disease, that the chairman of the ethics committee wrote in June 2003, "this is Massachusetts General Hospital, not Auschwitz."

Good News on Avian Flu Vaccine

An avian flu vaccine is moving into clinical trials:

An experimental avian flu vaccine will soon be injected into healthy volunteers to determine whether it is potent enough to thwart infection with an often deadly strain circulating in Asia

Effectiveness will likely be measured by looking for antibodies against the specific hemagluttinin (H) and neuraminidase (N) contained in the vaccine. Generating those antibodies would presumably protect against infection or at least lessen severity. The vaccine would then hopefully move into field tests in Vietnam among those at risk of exposure.

Note that protection doesn't have to be absolute. So called memory responses (in which the immune system hs encountered something before) are generally much more rapid and robust than those to primary (previously unencountered) stimuli. So, someone whose gotten tis vaccine could potentially still get infected, but would hopefully mount a swift and vigorous response to infection, clearing it quickly with minimal symptoms (i.e. maybe like getting the regular flu or a cold)

Obesity and Life Span

Last week's New England Journal of Medicine contained a "Special Report" that rising obesity will eventually lead to reduced lifespan (unfortunately only available to subscribers; I think it's near criminal that NEJM publishes this kind of deliberately provocative article about and then doesn't make it available to the public):

Obesity could shorten the average lifespan of an entire generation — today's children — by two to five years, according to a controversial new life-expectancy analysis.

as USA Today put it, or

Obesity has been shown to have a substantial negative effect on longevity, reducing the length of life of people who are severely obese by an estimated 5 to 20 years

Will this happen? I can't be sure, but the arguments presented are remarkably weak. Basically, the authors argue that obesity is such a problem that it will overwhelm progress in other areas of health care and lead to declining life-expectancy.

Obesity has been shown to have a substantial negative effect on longevity, reducing the length of life of people who are severely obese by an estimated 5 to 20 years

So far so good. Everyone agrees obesity is bad. I'm sure almost everyone would agree that worsening obesity is likely to be a drag on life expectancy. The striking rise in diabetes, which primarily affects the overweight and inactive (this is type 2 or Adult onset Diabetes, not type 1 which usually starts young) is noted

From 1979 to 1999, rates of death from diabetes increased annually by an average of 2.8 percent for males and 1.8 percent for females. In 1990, diabetes decreased life expectancy by 0.22 year for males and 0.31 year for females, 40 but the negative effect of diabetes on life expectancy has grown rapidly since then. However, the negative effect of diabetes on the life expectancy of the population could now be several times as great as it was in 1990.

Terrifying, huh. It is until you think about why more people are dying of diabetes. The main one is they aren't dying of anything else. Advancements in treatment of cancer and, especially, treatment and PREVENTION of cardiovascular disease have mean a lot less people are dying of those. Hell, you've got to die of something. The decreasing mortality from heart disease is particularly notable because obesity is a risk for developing cardiovascular disease, as is diabetes

But that is not all. There is a lot more badness coming:

There are other realistic threats to increases in life expectancy. From 1980 to 1992 in the United States, the age-adjusted rate of death from infectious diseases rose by 39 percent, an increase fueled mostly by the AIDS epidemic;

but that's not all:

Other forces that could attenuate the rise in life expectancyinclude pollution, lack of regular exercise, ineffective blood-pressure screening, tobacco use, and stress.

If AIDS and obesity don't get you, ineffective blood-pressure screening will. With all this bad news, I'm almost surprised life-expectancy isn't falling already. But it isn't, is it? And in that observation lies the fatal flaw in the studies' reasoning.

Guess what? People are getting fatter, but they've been getting fatter for a while now. AIDS has been around for a while, etc. All these factors are already factored in when actuaries make projections about future life expectancy. As Samuel Preston put it in an accompanying editorial, that would be devastating if it weren't so darn nice:

The effect of an increase in the prevalence and severity of obesity on the longevity of U.S. citizens is already embedded in extrapolated forecasts made in recent periods. In fact, these forecasts implicitly assume that the severity of obesity will continue to worsen, and the prevalence will rise, since it is the rate of change in the determinants of mortality, rather than the level, that drives projected changes in life expectancy.

So, obesity is getting worse, but many other things are getting better and there is no reason to think obesity will suddenly overwhelm all the positive developments, like better treatements for AIDS, cancer, diabetes, etc. Of course, there is also the very real possibility that effective treatments for obesity itself will come about. Whether via lifestyle changes or a pill that increases metabolism, this is a real possibility.

Never underestimate the possibility for medicial progress. 8 years ago, someone I know well was in the hospital with Pneumocystis pneumonia, a CD4 count in the double digits and HIV throughout his body. Today he works, takes medicines and lives his life. Think about that.

Could an avian flu epidemic decimate the world. Maybe, but I doubt it. Anti-viral medicines are already being stockpiled in rich countries, work on a vaccine is progressing and the experience with SARS gives public health officials crucial experience in containing outbreaks of infectious disease. AIDS has been a drag on life expectancy, but hasn't caused it to go down (at least in the US, Africa is a different story)

Lost in the alarmism, is the point that obesity is a large and growing (sorry) problem for the health of Americans. I agree with this. It deserves money and attention, as do avian flu, cancer, heart disease, etc. It is a drag on life expectancy, but it is hardly the only factor.

Sky Running

Good article in todays NYTimes about races up and down mountains. These articles always seemed so surprise how pleasant ultrarunners are:

So there was blood and sweat atop the massive peak, but no tears. In fact, many runners were inexplicably cheerful; to the uninitiated, they called to mind Eric Idle's happy-go-lucky crucifixion victim in "Monty Python's Life of Brian." The first few runners, inured to the highs and lows of such long events, had little reaction to ending the long climb and beginning 20 miles of downhill back to town. But the middle-of-the-pack runners - those focused on finishing, as opposed to winning, many of them exhibiting an endorphin-fueled giddiness - bantered and chuckled with race staffers.

Think about it, having reached the top of the mountain, these runners are almost certain to finish, an accomplishment of some merit, according to the article. Wouldn't you be giddy.

As to why ultrarunners do this kind of race, I tell people, if you have to ask, you wouldn't understand. The first time I heard about Western States, I knew someday, somehow I'd have to run that race. Unfortunately, I feel the same way about Badwater.

As a general rule, whatever one person can do, someone else will want to do something even more insane.

Transmission of infectious diseases during commercial air travel

is the subject of a review in last week's Lancet (only available to subscribers, ref: Lancet 365:989).

Overall, it is reassuring, with few documented cases of infection and less airborne transmission than one might expect. The airflow they describe is mostly top to bottom, which limits spread among passengers

data suggest that risk of disease transmission to othersymptom-free passengers within the aircraft cabin is associated with sitting within two rows of a contagious passenger for a flight time of more than 8 h

Unfortunately there are exceptions and SARS seems to be one of them.

Overall it seems the biggest public health risk is moving infected people rapidly from place to place rather than infections acquired while travelling.

One cool thing most people probably don't know is that there are sporadic cases of malaria around airports in non-endemic areas (like the US) transmitted by mosquitoes who hitch a ride on international flights and then take up residence. Luckily, this hasn't led to establishment of endemic infection anywhere (yet).

Jurassic Park at hand?

Maybe, as according to this NY Times article, "soft tissues" from a 70 Million year old dinosaur have been found in Montana. I am skeptical they'll get any meaningful amount of DNA, but with PCR you don't need much...

"Informed" Consent

The Anonymous Clerk notes use of high pressure to obtain "informed" consent of electroconvulsive therapy for depression (which is actually safe and effective. They need to get the convulsive out of the title, maybe rename it, global electric stimulation therapy or something).

This reminds me of a time in residency when a patient needed the attending to obtain informed consent from a family for some study. The attending's response was

Sure, I'll obtain informed consent. But let me know which kind. If you want the "this is an innovatiive, exciting new therapy that could change the way we view this disease; if it were my child I'd definitely do it" I'll get that. On the other hand if you want "this is an experimental treatemnt whose safety is unknown. It seems kind of risky, given there are other, well-studied alternatives, but if you want to expose your child to that risk because it might be slightly better, that is your right" kind of consent, I can get that too.

Realistically, patients come to doctors because they are experts in the field. If they new about all the risks, benefits, alternatives, etc. they wouldn't need us.

Malpractice reform works

or so says this American Medical News article

Physicians aren't ready to celebrate just yet, but tort reform efforts are showing signs of positive effects in Texas, West Virginia and Ohio -- states that enacted legislation in 2003.

From lower liability insurance premiums -- or less dramatic premium increases -- to more insurers entering the market, doctors are starting to see at least some of the results they hoped for when they pushed for change in their respective states.

Too Weird

While all anyone can talk about is Terry Schiavo, who is, after all, just a single person without much cognitive function left, a letter in this week's Nature (confusingly, short articles in this most prestigous of scientific journals are called letters) challenges much of what we know of genetics.

As I briefly summarized yesterday, plant genetecists at Purdue have observed unusual reversions of a mutant gene to the wild-type sequence in the plant Arabidopsis. They study a gene called HOTHEAD, that causes unusual fusion of flower petals when mutated. They observed that a substantial fraction of offspring of parents with normal flowers and were puzzled. Sequencing showed that in each case the gene was identical to the "normal" sequence. They did a pretty good job of ruling out contamination of there stocks or pollenation by wild-type plants by doing experiments like looking at embryos or cross-breeding different strains.

Then they tried to exclude the possibility that another DNA sequence in the genome was acting as a "template" to restore the correct information. This kind of process would be unusual and interesting, but probably not revolutionary. In this they did a less good job, in my opinion.

They noted the sequence alwasy went back to the parental, and cite, but don't show, more data showing sequences can be recovered several generations later. They note that other related genes have other sequence differences that aren't found in the reverted gene, but don't do a search of the Arabidopsis genome to exclude a stretch of matching DNA outside a known gene, despite the fact that the Arabidopsis genome is sequenced.

They hand-wave a bit about RNA storage of genetic data, but there are several problems with this.

First, they don't attempt to document wild-type RNA sequences. This would be pretty straightforward using RT-PCR (first RNA is reverse transcribed into single-stranded DNA and then amplified by PCR). Interpretation of data MIGHT be hard because only a few percentage of RNAs would carry it and PCR enzymes are error prone, but I think you have to try.

Second, this would imply a complex genetic apparatus of which we have remained blissfully unaware despite all our knowledge of cell biology, having sequenced the genome of multiple organisms, etc. Just think of all the genes that would be needed to store copies of RNA (which would have to be passed on in pollen), activate some sort of DNA repair enzymes that use RNA as a template only under certain conditions of stress, make the repairs, etc. How many generations is RNA retained and when is it replaced. Recall that RNA is far less stable than DNA and therefore more prone to damage.

Additionally, I'd be a lot more confident in their data with a few more controls. One good one they didn't do was to make plants with genes that were slightly altered via silent polymorphisms. Would those then be altered back in HOTHEAD deficient plants? What if they were introduced into a strain with slightly different sequences. Would those be reverted too. This would be a lot of work (I know n0thing of the details of plant work, I purposely ignored those sections druing grad school), but before you publish a paper challenging the basis of genetics you have got to have your I's dotted and T's crossed

Overally, I'm a skeptic. I suspect they have a gene conversion going on and just haven't recognized the template yet.

"Toxic Dust" = Credulous reporter

Would it be that hard for the press to clearly distinguish between real science presented in a peer-reviewed journal and a "report" produced by advocacy organizations?

These kinds of "news" stories, where pseudoscience put out by advocacy groups via unquestioning reporters drives me crazy. This "report" is put out by several organizations whose sole purpose is to try to remove various chemicals from use, others have goals like "eco tax" and "dematerialized economy." These may or may not be admirable, but a reporter should have the sense to be a bit less credulous in acting like the "report" is some sort of peer reviewed publication.

The report which is impressively professional, is just a scare document. It carefully reviews all the bad things linked to each outcome and all the serious diseases that may or may not be related to them. It gives levels of various chemicals in dust samples, but doesn't give any idea what those levels mean. In a brief moment of almost honesty, they authors write:

The degree to which these trends can be linked to hazardous chemicals exposure is not the main issue. The real question is why should we take chances?

If the effects of these chemicals is not the main issue why are you writing this report?

To his or her credit, the reporter does identify the sponsors as "environmental groups" but looking at some of their websites, I don't think that goes far enough. These are pure advocacy groups. At least chemical industry representative is given some space to defend the industry.

Googling on the authors I find a Greenpeace employee (Pat Costner), a "consumer advocate" (Beverly Thorpe) and a "project director" (Alexandra McPherson). Not a graduate degree among them.

As a kicker, check out this article from 9 months ago. The same groups released and almost identical report about "toxic dust," this times from reporters.

Maybe these toxic chemicals are harming us, but this report does zilch to address the issue. Instead it is designed to scare people, with the help of incompetent reporters.

Or maybe not

Two headlines above the same AP story on genetically modified foods:


Genetically Modified Foods Eaten Regularly (Excite)

Americans clueless about gene-altered foods (MSNBC)

I realize the two headlines aren't contradictory and, in fact, both are accurate, if not complete. I'd be interested to know the funding of the "Grocery Manufacturers of America." It sounds like a group representing processed food makers, but it is hard to know.

FWIW, I think GM food is safe and the process just speeds up what farmers and plant breeders have done for thousands of years. As an allergist, I am a bit worried about poorly labelled GM food leading to reactions in people who don't realize a food contains something they are allergic too.

More Schiavo

There is lots of hot air on both sides of this issue. I would particularly recommend DB's Rants, Kausfiles, and Charles Krauthammer's commentary today.

To me, the case for pulling the tube is increasingly shaky.

1. "Rule of Law" arguments carry no weight for me. I believe doing what is right is most important If the law leads to a morally wrong answer, the law should be changed. If it takes an emergency act of Congress, then that is what should be done.

If an alleged killer were about to be wrongly executed, and the state government and courts refused to intervene to right the injustice, would it be wrong for Congress to pass an emergency law to stop the execution?

2. Michael Schiavo is looking worse and worse. As James Taranto points out, he has clearly not fulfilled the typical role of a spouse, openly living with and having two children with another women. I think this is justified, but raises question about his motivations and right to act with authority of a spouse.

I would still want the tube out if it was me, but am increasingly uneasy that this is the correct decision in this case.

Tangled Bank

Tangled Bank is a blog carnival about medicine and science with a strong dash of evolution. The 24th edition is now here.

It also features my first contribution, about evolution of the immune system. Enjoy.

"It's Just Weird"

I'll say. Apparently, plants have a reservoir of genetic material, from which they can correct mutations in their DNA.

In a discovery that has flabbergasted geneticists, researchers have shown that plants can overwrite the genetic code they inherit from their parents, and revert to that of their grandparents.

I didn't believe it either, but it sounds like it may be true (I don't have access to the full article here at home, I'll read it when I go to work and update later).

The researchers, at Purdue, were studying Arabidopsis, the most commonly used organism in plant genetics. Having identified a gene, HOTHEAD, that caused abnormal fusion of flower petals, they noticed that about 10% of offspring of HOTHEAD flowersdeficienct plants had normal flowers. They went back and showed that the gene sequences had reverted to normal.

One obvious possibility would be contamination, but presumably they were very careful about that. Excluding that, the gene correction implies a normal template somewhere in the organism. They couldn't find a DNA copy, so they speculate that there is an RNA reservoir somewhere in the cell. This seems plausible, but presumably you could check for such a copy by doing RT-PCR (basically using an enzyme that converts RNA to DNA and then amplifying via PCR) on a mutant plant. Some fraction of the amplified RNA should code for the correct gene.

One thing I'll be interested to see is how much of the gene is corrected and how well the "RNA copy" matches the original DNA.

This would be an incredible finding, if verified. Think of all the questions it raises. Where is the "gene reservoir" kept? How is RNA deposited in it? When is it activated?

I'll count myself as skeptical, but open minded

Hypomanic?

This article discusses the fact that being a bit manic may not be a bad thing.

The article is okay, but raises a point many people forget: many traits that are harmful when taken to extremes are helpful in moderation. If you check to make sure you locked your door 200 times in the morning that is pathalogic, but I'm glad my accountant rechecks my tax returns for mistakes (actually I use Turbotax). A little bit of obsession is good (BTW obsessions are thoughts and compulsions are actions).

As one of my psychiatry professors put it in med school "if you hear voices and they tell you which stocks to buy and you become a content billionaire, you aren't schizophenic. You may be a prophet but you aren't schizophrenic."

UPDATE: it's hard to imagine what would be beneficial about a mild form of this disorder:

But an obsessive desire for a limb amputation - one that drives people to cut off healthy arms and legs - tests the tolerance of even the most open-minded.

Maybe keeping your nails well trimmed

Body integrity identity disorder has led people to injure themselves with guns or chain saws in desperate efforts to force surgical amputations.

Grand Rounds XXVI

is up here Enjoy. I am (still) blogging from San Antonio, which is a great place to attend a convention. The convention center is just steps from lots of hotels and restaurants which were busy even on a Monday night. Nice weather as well. I'm heading back tonight

More Computerized Order Entry

Cedars-Sinai's attempt to institute computerized order entry was an umitigated disaster:

an array of problems that grew into a full-blown staff rebellion in the fall of 2002 and forced Cedars-Sinai to shelve its $34 million computer system after three months.

This sounds a bit like a "what not to do" primer.

I have no firsthand knowledge, but Cedar-Sinai's reputation is a hospital of the stars with lots of well known (i.e. big egoed) private attendings. This has to be the group least willing to adapt to any sort of technological innovation.

Taking the whole hospital live all at once with an untested system also proved to be, predictably, a disaster. Any complex system will have multiple bugs, like those detailed in the article. By starting small you can work those out as you go, but when you do it all at once, you risk a revolt, which is what they got.

I remain optimistic about the potential of computers to improve care and prevent mistakes

Inhaled Corticosteroids in Asthma

This is nothing new, but data continue to accumulate showing inhaled corticosteroids prevent asthma exacerbations, even in very young kids.

Asthma is a disease of inflammation in the lungs, and the inflammation is there all the time, even when patients aren't having symptoms. Regular use of inhaled corticosteroids (note these steroids are distinct from the anabolic steroids apparently used by most Major League Baseball players) decreases this inflammation and prevents serious asthma attacks. I children, these attacks are often caused by viral infections.

One of the challenges of being an asthma doctor is convincing parents and patients that medicine is necessary every day, even when kids don't have symptoms. You'd be surprised how many parents don't want to believe their child has a chronic illness, even after multiple hospitalizations and even ICU stays.

Interestingly, use of anti-inflammatories like inhaled steroids don't cure the disease, they just decrease morbidity. A number of large trials have showed that once inhaled steroids are discontinued, patients quickly go back to being just like untreated patients.

Evolution of Adaptive Immune Response

How did the adaptive immune system evolve? By adaptive I mean the ability to respond to specific antigens. Plants and invertebrates lack this capacity. They have generalized defenses including cells called phagocytes that can engulf invading microorganisms and small proteints (peptides) that can kill a variety of bacteria, but they don't generate an immune response that specifically recognzies a given microbe.

All vertebrates from the level of the jawed fish on up have the ability to mix and match immune genes to create a near infinite number of receptors, which should be capable of recognizing just about any protein (or other appropriately sized molecule).

How did such an ability suddenly appear?

Two RAG (recombination activating gene) genes are key in cutting the DNA so that it can then be spliced together to form new genes. These are expressed only in B and T cells which use recombination to generate antibodies (aka immunoglobulins) and T cell receptors (TCRs), the two components of the adaptive immune response.

It has been known for some time that the RAG genes have unusual features.They lack introns, stretches of DNA which don't code for the final protein, but are rather cut out at the RNA stage. This suggests they entered the genome late in evolution. They share several other features that suggest they may have evolved from transposons.

Transposons are pieces of DNA that can move around within and between cells. I think of them as the lowest level on which natural selection can operate (one might argue that prions operate on an even less complex level). A minimal transposon has two essential features: repeated DNA sequences at each end and a gene encoding transposase, an enzymes which recognizes the repeated DNA sequences and can cut out the transposase. Of course many can be more complex.

RAG genes recognize repeated sequences that flank the component sequences of antibodies and TCRs.

The transposons (aka jumping genes made famous by Barbara McClintock) hop around, inserting and leaving DNA, often when they sense stress in the cell (obviously I am leaving a lot out her) and can have effects on genes which they insert near.

One mystery is that RAG genes cleave DNA by a method different from that used by other transposases. This mystery is now solved as a transposase encoded by a transposon called Hermes which is found in the housefly uses an identical mechanism to cleave DNA (Zhou Nature 432:995). I won't go into the details, but to my mind this resolves beyond any reasonable doubt that RAG genes evolved from a transposase.

More later on an equally fascinating (ed equally fascinating? I'll be sure to caffeinate beforehand) topic: the immune system of lampreys, which of course are non-jawed fish.

Index of Suspicion

9 year old with fever. 9? Why do you bring a 9 year old to the Emergency Department with a cold? A 9 month old maybe, but 11 hours into a 15 hour moonlighting shift, I had no patientce for a 9 year old. Since I had finished residency and could see patients independently, I was working "non-acute," a small offshoot of the main ED where those judged not in need of significant intervention were seen. All day it had been a steady stream of upper respiratory infections for which I could offer nothing but symptomatic care with the occasional strep throat.

I went in to see my patient, who had been waiting several hours already. They were Haitian immigrants, son's English better than mom's. I went through the standard questions: fever was 101.5, not dangerously high, he complained of mouth pain but was able to eat and drink, a sibling was also ill at home. For some reason this was the 3rd time she had sought medical attention for him, convinced something was wrong.

I started through my quick exam. He was well hydrated, but had ulcers on his gums, unusual but not unheard of. His throat looked fine his lungs were clear. I put my stethoscope to his chest quickly, just to be complete. He had a murmur, a LOUD murmur, and was tachycardic. Hmm, I thought, that's unusual, given he didn't look dehydrated.

Between mom's conviction something was wrong, the oral ulcers and the murmur, something struck me as not quite right. I figured 90% chance he was fine, just a kid with a virus, but decided to check a CBC (complete blood count) and electrolytes just to make sure. I drew the blood and sent it off to the lab, then went back to all the viral infections and strep throats who were waiting.

30 minutes later a nurse from the acute side pulled me out of a room "the lab just called, Patient X has a hematocrit of 19 (just about 1/2 of normal), were you expecting that."

My heart sank, "What was the white count?" I asked.

"Not back yet, I'll let you know" she replied.

But I already knew the diagnosis. Sure enought 5 minutes later I got paged by the lab with the news: the white blood cell count was almost 100,000, more than 10 times normal and most were an immature form of cells called blasts that don't normally appear in peripheral blood.

He had leukemia

My remaining 3 hours flew by as I called the onc fellow who came in, at 10PM on a Sunday, to see the patient, broke the news to the patient and mother, put in IVs, drew a million labs and signed him out to the onc resident.

I got an e-mail the next day from the ED attending, congratulating me for picking this up and pointing out I could have saved the patients life (the leukemic cells packing his bone marrow crowd out everything els,e leaving him deficient in normal white blood cells, despite his high total number, and susceptible to overwhelming infection).

I wish I could say I was smart enough to have figured it all out in advance, that I knew what I was looking for. In retrospect, the ulcers were a sign of neutropenia, the murmur his heart beating harder and harder to keep up with the decreased number of red cells. But I can't, I wasn't that smart. I was just smart enough to realize something might not be right and look a bit harder.

A priori, I would have thought this experience would have reassured me about my clinical abilities. I had picked the needle (leukemia) out of the proverbial haystack (fundametally healthy kids with minor illnesses). Instead, it terrified me. How close I had come to reassuring the mom and sending the kid home. I became increasingly, painstakingly thorough with my histories and physicals, like being a 2nd year medical student all over again. Of course after a couple weeks that faded too and I was back to churning through patients

Follow up: He did well, achieving remission with standard doses of chemotherapy and was still doing in remission last time I checked.

The Schiavo Case

I've avoided discussng this case because I didn't have much to add. I'm not sure I do now but here goes.

This is a very difficult case. It is not black and white. Terry Schiavo has suffered massive brain injury and is in what is called, unfortunately, a persistent vegetative state (PVS) which is not to be confused with brain death which is the irreversible cessation of all brain activity. It is very unlikely, but probably not impossible that she will improve substantially.

If it were me, I'd want the feeding tube out and my loved ones to go on with their lives without me, but I don't think it is impossible that someone else might want to be kept alive for the 1 in a million (maybe) chance of improvement.

Of course nobody knows what Terry Schiavo wants and her husband, who is her legal guardian, and her parents differ. Mr. Schiavo thinks whe would want support removed, but her parents want her kept alive. That is what makes the case so difficult. If everyone agreed, whichever way, we'd probably never hear about the case.

I guess in the end, someone needs to decide for people who can't decide for themselves, and in this case the three people who can best decide, are irrevocably split. I do think that the Florida legislature and Congress getting involved is rididculous. This is one tragic case, not a national crisis

(Ed still don't have much to add, huh? no, no I don't). I would advise people to make sure they have a living will, so they decide what happens to them in cases like this.

UPDATE: these kinds of decisions are surprisingly common

How should airport WiFi be priced

I am blogging from a free WiFi hotspot at the San Antonio convention center. It isn't clear if it's is always available or hear just for our convention.

Anyway, Pittsburgh features free WiFi in its airport for everyone while in Dallas/Fort Worth, it is $10 for unlimited use for a day. Anecdotally, more people were using it in Pittsburgh.

I wonder what the best pricing scheme would be? Obviously, I love the free WiFi but no one makes any money giving it away. Plus it is not like a restaurant or coffee shop where you have much of a choice. I guess you could arrange travel to connect in an airport with free WiFi but few people would sacrafice a better fare or shorter flight just for that (it certainly hasn't helped Pittsburgh much).

$10 seems high to me, especially since by the time I took the ridiculous train, made it to my new gate and ate dinner, I only had 15 minutes until boarding. I admit I'm cheap but I bet they'd generate more revenue by selling it for $4 or $5 dollars an hour with a daily maximum of $10. I'm assuming that once you put the network in, the marginal cost of each additional user is low (mostly for processing payment).

While I enjoy the free access in Pittsburgh, it seems silly for taxpayers to provide a service that b enefits primarily the well-off.

I am aware there are some plans that allow you to pay a monthly fee and connect at various hotspots but don't know how comprehensive coverage is.

More Elidel and Cancer

Am I glad I'm not involved in this study.

The idea seemed good. Many kids with eczema go on to develop asthma. Since pimecrolimus (Eladil) was a completely safe steroid-free treatment for eczema, maybe regular use would prevent eczema patients from going on to get asthma.

Of course that was before we knew Eladil causes cancer. I wonder what they are going to do about the study? I'm surprised we haven't heard anything about this in the press, given how worried the parents must be.

I am writing this from the Pittsburgh airport (free WiFi) as I head to San Antonio for the American Academy of Allergy Asthma and Immunology meeting (AAAAI is the trade group for allergists).

At least they aren't autistic

Hundreds of children have died from an upsurge in measles cases in Nigeria, despite a series of local vaccination campaigns aimed at combating the disease, health authorities said Friday. At least 589 have died from measles so far this year

All from a disease that is easily prevented by vaccination. Of course this is the country that halted vaccination for polio, which is almost eliminated, because of concerns that it was a U.S. plot to sterilize Muslims (or infect them with HIV).

Methamphetamine

use triggers production of anti-methamphetamine antibodies.

Users therefore require larger and larger doses to obtain the same effect (at least in mice). This may explain some of the binge behavior associated with the drug.

I therefore suggest to all my patients to start anti-B cell therapy such as Rituxan before beginning meth use.

"Earlier use of prostate cancer vaccines urged by Hopkins scientists"

Shockingly, the researchers also called for more funding for their research.

This is a press release, not a news article, but still. Of course, whatever Researcher X is working on is incredibly interesting, underfunded and about to lead to a big breakthrough, according to Researcher X.

That said, I agree that cancer vaccines are likely to be most effective when used early, perhaps even before cancer develops.

The concept of cancer vaccination is straightforward, but proof of efficacy has been hard to come by. Just as exposing someone to antigens expressed by viruses or bacteria generates an immune response that can prevent infection, immunizing them with tumor antigens should lead to an immune response to the cancer. Harnessing the awesome power of the immune system (think about the toll of rheumatoid arthritis or multiple sclerosis if you think awesome is overkill) against cancer seems great. The problem is that cancers have already avoided the immune system. Or at least to the ones we see; it is likely that a lot of potential cancers are eliminated before they are clinically apparent, which is why medicines like Elidel and Protopic, which supress T cells, a key component of the immune system, may lead to increase risk of cancer

Growth of a cancer is basically evolution at work. Cells that grow faster have a selective advantage and so do those that can avoid immune surveillance. Cancerous cells seem to use a variety of mechanisms to avoid elimination by the immune system.

Unsurprisingly, new cancer therapies are generally tested on patients who have failed more standard therapies. This guarantees advanced tumors and poor prognosis. For some therapies this may be good as it may be easy to see benefit (see lung cancer drugs that extend life 2 months). However, for drugs that rely on the immune system it may be too late as tumors have become too large or cells too resistant to the immune system. The study above shows vaccination in a mouse model of prostate cancer is much more effective when done early.

Cautionary note: it is a lot easier to "cure" cancer in a mouse model than in wild-type humans, so many promising "cures" never make it through clinical trials

Bird Flu Vaccine

This may be more hype, than anything new, but it would seem that anything to decrease the time to producing an avian flu vaccine would be good

U.S. health officials have said it would take months to manufacture a vaccine against the H5N1 avian flu strain should it cause a human epidemic.

It would even seem to me we should be gearing up production now, after all isn't the idea to avoid an epidemic, rather than to react to one

Ancient Autism

Folktales from Europe describe children with autism, suggesting autism is not a new phenomena, according to this report in the Archives of Diseases of Childhood:

Fairytales from the British Isles, Germany, and Scandinavia include stories about changelings. They describe a child who exhibits remarkable and sudden changes in behaviour and/or appearance, explaining that supernatural folk steal normal children and replace them with one of their own, or some other substitute. The new child—the changeling—is characterised by unresponsiveness, resistance to physical affection, obstreperousness, inability to expressemotion, and unexplained crying and physical changes suchas rigidity and deformity. Some are unable to speak.

Of course this describes autism pretty accurately. So it doesn't seem that autism is brought on by some aspect of modern society, but represent underlying biological predisposition.

Cuban health care

The wonder of socialized medicine, even in a poor country is documented photographically here
(via Babalublog via Captain's Quarters via Instapundit).

I don't necessarily think gleaming expensive modern equipment = good health care, particularly in a poor country, but these pictures are really disturbing (particularly the cockroach one). I also can't vouch for the authenticity of the pictures or the motivation of those that took them, but if real they are scary

Asthma Persistence

An article in this month's Chest (ed Chest? It's an real journal honest) shows that for many patients, asthma never really goes away.

Examining data from a longitudinal study in New Zealand, the study shows that about a 1/3 of patients who were thought to have outgrown their asthma at age 18 had some symptoms by the time they were 26. Fortunately, for most it was mild.

Patients who had asthma throughout childhood which persisted to age 18 were likely to have continued asthma, and it was more serious than in those patients in which it recurred.

Interestingly, about 10% of subjects who had never had asthma, developed it between age 18 and 26.

Grand Rounds XXV

is now posted at Respectful Insolence, in creative form no less.

Enjoy.

One blog

I won't be reading regularly (tip via Instapundit)

Bird Flu

Not that much new in this article, but a good summary of the good news/bad news aspect of there being a number of unrecognized infections

Good in that the fatality rate goes down. Bad in the number of infections (and therefore ease of human to human infection goes up.

Expandable ribs

are a godsend for patients with severe scoliosis, but like much medical technology they will likely raise overall medical costs by letting these kids live longer and longer.

During residency, I'd sometimes take care of kids, usually with cerebal palsy, multiple dystrophy, and/or other big problems who developed increasingly severe, impossible to treat (then at least) scoliosis and basically slowly smothered because they couldn't breathe. Many of the kids were cognitively normal which made it particularly sad.

Quality, not cost

is what medical reform should focus on, according to Harvard economist David Cutler:

Cutler's approach is radically different. He says that most health-care spending is actually good. Spending has been rising, he says, because it delivers positive, and measurable, economic value, and because it can do more things that Americans want. Therefore, Cutler says, we should focus on improving the quality of care rather than on reducing our consumption of it. Rather than pay less, he wants to pay more wisely -- to encourage health-care providers to do more of what they should and less of what is wasteful.

The lengthy article in yesterday's New York Times magazine spells out some of Cutler's work in this area and his prescriptions for improvement. He is obviously a smart guy, so read it all.

I think he is right that cost may not be as big a problem as we think. Sure we spend more than any other society ever has on health care (and more per capita than China spends on everything, as the article points out), but so what? Should we spend more on Ipods or lattes?
We are also the most affluent society ever and health is very important to people. Health care improvements do a lot of good, even if they don't save money.

I just read an article which looked at pneumococcal infections in Atlanta before and after introduction of Prevnar, an antipneumococcal vaccine which kids now get routinely. There was a >50% overall decrease in invasive pneumococcal infections with >80% decrease for kids >2 and >70% for kids 2-4. My calcualtion is that in the Atlanta area (~3.1 million population per article) this saved around 500 infectons per year. Given that 3.5% of infections were CSF, that is 17 or 18 cases of meningitis per year. As a father and a pediatrician, I would put a very, very high value of preventing a case of meningitis.

I agree with the article that quality improvement could be far more effective:

There is an aphorism for such behavior in the business world: ''You manage what you measure.'' If doctors measure how long it takes to deliver an EKG, then EKG's are delivered faster.

Currently, a lot of "quality improvement" is crap. Someone decides we have to measure patient pain better, so now everyone who comes to allergy clinic gets a questionairre to rate their (or their child's) pain on a scale of 1-10. Of course, most of our patients don't come for pain, so the sheet is a waste of eveyone's time and gets ignored by nurses and doctors and just adds to the pile of useless papers.

I don't think implementing better examples will be easy or that good programs are even intuitively obvious, but I think with focus people can come up with better ideas.

One big problem is the goals of health care researchers. Business executives and consultants want to cut costs and improve efficiency so they get more money. Health care researchers mostly want to do studies they can get published so they get promoted. Right now, not much health research focuses on actually improving things, becasue it is hard to do (also true in business) but also hard to publish. The Kaiser and General Motors initiatives are exceptions.

Finally I liked Cutler's emphasis on what is possible in the US. I think he is right that it would be almost impossible to go to single payer health care here because too many people are dead set against it. And rationing spending, discouraging innovation, decreasing access to specialists etc. just won't work in America, whatever one's view of their desirability.

So all in all I agree with a lot of Cutler's ideas. I do agree with the criticism that at some point we need to address how much we are spending on health care:

According to Henry Aaron of the Brookings Institution, ''We can't continue to provide all care for all people.''

Or as I'd put it, we can't give everyone the same level of health care that the richest part of our population is willing to pay for. Nonetheless we should try to get the most we can out of what we do spend.

Heart Stem Cells

Scientists can't replicate a finding that adult blood stem cells can differentiate into heart cells, but that hasn't stopped clinicians from forging ahead with experiments which seem to have a modest benefit, according to this article.

I would be very suspicious of findings that other labs can't replicate. I would be even more suspicious of small improvements seen in poorly controlled trails of a new therapy. A good control group would have to have non-stem cells injected (ideally) or at least a sham injection (just water with no cells) and it doesn't sound like that was done in these trials.

A small improvement like that described here, can sometimes be just from improved supportive care and or all the attention one gets as a trial participant.

Ont the other hand, at least these are real trials. Better than what is going on in Russia where beauty salons are injecting "stem cells."

Fat and fatter

Rural communities seem to have fatter kids than urban one:

More than a quarter of all fifth-graders in West Virginia are obese, where two-thirds of the population is rural. One in four public school children in Arkansas are obese

Two much time inside, not enough exercise, and bad diet. Yesterday I took my kids to see "Robots" in Omnimax (entertaining, but nothing special) and there was an enormously fat kid in front of us with his moderately fat father. The two of them ate a large popcorn, a cotton candy, two boxes of candy, and two large sugared sodas. No surpise there.

One good thing, I think, about living in a city is you walk more. I walk 15 minutes to and from work 4 days a week and my son walks the mile or so each way to school when the weather isn't too bad. Of course, the study notes high rates of obesity in very poor urban communities, which is suspect is it being too dangerous for kids to go out much

Medicine could really use an effective method for changing behavior.

The Ethicist

Today's NY Times feature "The Ethicist" has a letter from a scrupulous physician, Jon Morrow. Dr. Morrow responded to a call from help during a commercial airline flight and helped a sick passenger. He was offered a reward of frequent flier miles by the airline but declined. He wonders if it would be ethically okay to accept such a gift.

The columns author, Randy Cohen, responds that he should feel free to accept the gift, as it was given freely. I agree (which I often don't with Mr. Cohen), but I think his analysis leaves out one important point: the airline seeks no untoward secondary gain from giving the reward.

Consider a similar scenario. Dr. Morrow sees a patient and appropriately prescribes a course of expensive medication. Dr. Morrow acts of pure intention, prescribing what he believes to be the most appropriate treatment. Two days later, a drug rep from the pharmaceutical company who makes the expensive treatment calls to offer an expensive gift, say dinner for two at a fancy restaurant, as a "thanks" for prescribing the treatment. Can Dr. Morrow accept?

I think not. Doing so would call into question his motives and could be seen as a sort of bribe. The drug company is rewarding him not for doing the right thing, but to encourage use, appropriate or not, of its product. Also, the miles are a reward for an unusual (and otherwise uncomensated) action. Seeing a patient and prescribing a treatment are part of a docs expected duties, and so deserve no special reward.

I'm not a big fan of airlines

especially the legacy carriers, although I can hardly blame them for this:

Travelers, now ready to book trips for spring and summer, are increasingly complaining that the tight supply of free tickets on crowded planes means they cannot secure their first or second or even third choice of dates and destinations at the airlines' cheapest rates. Some are spending far more miles than they anticipated in a bid to evade complicated restrictions. Others must split up family groups and fly on different days, spoiling some of their holiday fun.

One can hardly expect them to give away flights when they can't make money. And I agree with something Gregg Easterbrook wrote, that we as consumers are to blame by choosing carriers based only on price and not be willing to spend even a few dollars more for better service or (importantly when you are 6'2" like me) more space.

I have had an American credit card for almost 20 years and fly them as much as I can (doctors don't fly that much). Now I have a pile of miles I am having trouble using and am thinking I should probably switch to an Amazon or cash-back card.

In retrospect, the airlines were creating huge liabilities during the heydey of giving away mileage and with them in complete control of the programs, it is not surprising they've acted to devalue miles.

Winter, Winter go away

Winter in Pittsburgh is just handing on and on and on. This is our first winter in Pittsburgh, but I know the Midwest and Northeast are still in mid-winter mode.

I had to shovel maybe 8 or 10 times December to February and now I've had to shovel almost that much in March alone. We haven't had any big snows, but it seems every day we get an inch or so. Our driveway is on the basement level so we need to shovel in order to get out. At least I can walk to work.

Ugh.

The case against therapuetic cloning

is effectively laid out by Dr. Charels Krauthammer in his Washington Post column today (free registration required, probably available elsewhere). Unlike President Bush, Krauthammer does not oppose embryonic stem cell research using embryos left-over from attempts at in vitro fertilization.

He draws his distinction based on the purpose for which the embryo was created. Extant embryos were created with the purpose of creating a baby and are therefore okay for research. Therapeutic cloning would use embryos created solely for the purpose of research (initially) and treatment (later) and Krauthammer finds that unacceptable:

But I deplore the step that proponents of such research are already demanding: research cloning, i.e., creating special embryos entirely for the purpose of using them for their parts.

The distinction comes down to the reason the embryo was created. Many distinctions in medical ethics come down to intent (e.g. is the morphine given to to end life or to relieve pain with the foreknowledge that it will stop breathing and end life?) and I am often skeptical.

Why, exactly, is it okay to experiment on human embryos and use them for parts if they were initially created as part of IVF (in vitro fertilization) and discarded as opposed to being created specifically for the purpose of curing disease and relieving suffering?

Aren't the "thousands of frozen and/or discarded embryos left over from work by in vitro fertilization clinics" troublesome to Krauthammer. Shouldn't we be a bit more careful about discarding human life and a bit more careful about how much we create?

I see the distinction, but to me either way you are doing research on what is, arguably, a human life. I see the potential benefits of such research as outweighing the downsides of creating and destroying life at such an early stage (the majority of "natural" embryos at this stage don't make it to birth), however the embryos. Krauthammer also doesn't address the fact that embryos created for therapeutic cloning may not be capable of ever progressing to humans (due to details of the process used to create them) than "left-over" embyros in fertility clinics. Some experts think technical obstacles to reproductive cloning may be insurmountable.

I've written much more here, here and here, and responded to what I consider less persuasive arguments against stem cell research here

Incredible

This just boggles the mind:

an elaborate insurance scheme in which thousands of patients from 40 states had been transported to California to undergo unnecessary surgical and diagnostic procedures for which doctors filed more than $1 billion of fraudulent insurance claims

Apparently, patients were paid $200-2000 each and got a series of procedures, typically colonoscopy, upper GI endoscopy and some sort of procedure to treat sweaty palms, perhaps ligating a nerve?

First of all, who would undergo all this stuff for that kind of money and what made the doctors think they would get awasy with this? I mean they had to figure eventually they'd get caught.

It was just 21 doctors according to the article, meaning they'd have to generate charges of almost $50 million/doctor, which seems high. Maybe by spreading it out among patients from different states they figured no individual insurer would catch on how high their volume was. Of course, I would think an insurer in, say Texas, would find it odd to be paying out a ton of money to doctors in California.

Yet another reason not to smoke

Maternal cigarette smoking during the third trimester, adjusted for the seven covariates, showed a negative association with offspring adult intelligence (P=0.0001). The mean difference between the no-smoking and the heaviest smoking category amounted to 0.41 standard deviation, corresponding to an IQ difference of 6.2 points

Researchers reviewed records from a Danish birth cohort with IQs obtained from testing when they were 18 as part of compulsory draft-board registration. The study is reported in the January issue of Paediatric and Perinatal Epidemiology (ed. Paediatric? It's a British journal. oh.)

The data is "old" with the kids being born in Denmark between 1959 and 1961.

Of course, these kind of studies can only show association, not causation. If low maternal intelligence is both heritable (either due to genetics or environment) and predicts maternal smoking (seems to) it could cause the association. The authors note that negative effects of smoking during pregnancy were not widely appreciated in Denmark at that time (ed if your IQ was 6.2 points higher you would have used "deleterious!" Shut up). About half the women smoked, and even quote a contemporary references endorsing smoking during pregnancy as a remedy for constipation.

The high cost of health care

Stories like this are just going to get more frequent.

The number of medical interventions that save money is small. The number that improve duration or quality of life is high.

Somehow as a society we are going to have to make decisions about how much we are willing to spend, if everyone should have the same access to all the healthcare that the rich will pay for, and, if so, how we will pay for it.

Right now, things are barely holding together. I am all for market solutions, but when you read stuff like this

Families can face a cruel choice: Keep working and go into debt or bankruptcy, or quit a job or get a divorce to cut income to the level that qualifies for Medicaid, the federal-state insurance program for the poor and disabled.

you know that the market isn't working very well.

Progress on Brain Cancer

Three studies in the NEJM this week show some tentative steps forward in treating brain tumors, in both adults and kids. One showed adding the chemotherapuetic agent temezolomide to radiation prolonged survival, the first study to definitively show this. A second study identified a genetic marker for patients likely to benefit from this medicine

The final study suggested surgery + chemotherapy for a type of brain tumors in children was as effective as surgery + radiation (based on historical controls) but the kids treated with chemotherapy had much less cognitive impairment (radiation is bad for the developing brain).

These are devastating illnesses that either kill or leave disabled many who suffer from them, so any progress is welcome.

Cancer in the brain is different from elsewhere in the body in that it can be very hard to remove the tumor even if it hasn't metastasized (spread). Elsewhere, if the cancer can be caught early, it can be removed and cured if it hasn't spread. But in the brain it is often impossible to remove all the tumor without doing serious damage

Complement, Macular Degeneration Linked

Three new studies have linked a single nucleotide polymorphism is a complement protein, Factor H, to an increased risk of macular degeneration. Macular degeneration is the most common cause of vision loss in the elderly. All 3 studies appear were published online in the journal Science.

In the Texas study, 31.4 percent of the people with the disease had two copies of the variant gene, and 21.5 percent had no copies. In the control group without the disease, 13.7 percent had two copies of the variant and 42.6 percent had no copies. The rest, nearly half of both groups, had one copy of the variant.

So obvioulsy there must be other factors at work as well

Complement is a very basic, ancestral part of the immune response. It serves to mark invading organisms for uptake by specialized cells called phagocytes. It exists as far back as echinoderms, which include star fish and sea urchins. Basically, some complement proteins bind to "foreign cells" and activate either uptake by phagocytes or lysis of the cells. Factor H is expressed on the surface of host cells and downregulates the complement response. One can imagine that less active versions of Factor H could increase complement mediated damage to host tissues, such as the eye.

Other complement linked diseases include susceptibility to gram negative bacterial infections, particularly meningococcus, paroxysmal nocturnal hemoglobinuria and hereditary angioedema. In addition complement plays a big role in many autoimmune diseases such as lupus and dermatomyositis.

Knowing that complement is involved should lead to new avenues of treatment, presumably starting with inhibition of the complement system.

Elidel, Protopic, and Cancer

This story is starting to hit the mainstream press.

I wouldn't wan't to be holding stock in Fujisawa chemical (or Novartis) right now.

Isn't it suprising how long it took? The letter went out to physicians 2/24, according to the articles and I posted on it on 2/25 (ed- it is always about you isn't it?) in what was my 3rd day of blogging. I found about it because I'm always on top of things because a parent faxed it to our clinic.

Don't news organization employ doctors or people to look at the FDA website occasionally?

I don't think the risk is actually that high (there were 5 million prescriptions and 13 cases of cancer, although it is a passive reporting system so the true incidence is probably higher) but this is the death of these medications. Given that steroid creams have modest side effects and work as well or better, who is going to keep using these?

I know I'm not recommending them anymore.

UPDATE: there were articles in the mainstream media about the FDA looking at safety in early February, but I didn't see anything about the FDA warning until today.

More Stem Cells

Doesn't look like embryonic stem cell opponents are backing down:

Catholic Bishop Donald Wuerl of Pittsburgh has issued a pastoral letter saying that it is wrong to kill human embryos for their stem cells, and that research on adult stem cells has more medical promise.

I don't agree with the second part of his argument. Actually I don't agree with either part. see the first part as a moral judgement that reasonable people will disagree on. I see the second part as intellectually dishonest.

"According to the most recent research, adult stem cells have produced 140 successful treatments for 56 diseases," wrote Wuerl, who has become a point man for the U.S. bishops on bio-medical ethics.

Really? The only treatment I can think of from stem cells (adult or embryonic) is stem cell transplant, which is a pretty rudimentary use of stem cells. Here is a quote from an excellent review I noted in my earlier posts on this subject

However, the word "promise" must be underscored — to date, no cures have been realized, no disease mechanisms have been uncovered, and no new drugs have been developed

It seems that pastoral letters aren't footnoted (or available online), so if anyone can provide backing for this claim I'd appreciate it.

More Bird Flu

Two good posts on Avian Flu here and here. The first one has nice pictures

This is scary, but maybe not as scary as some people think.

First, the 1918-1919 pandemic was beyond category, even as pandemics go, a sort of pandemic among pandemics.

Second, in 1918 medical care was rudimentary at best. There were no intensive care units and no ventilatiors. It would be a decade before Fleming discovered penicillin and another decade before it was put into use. No we have all kinds of supportive care that might keep people alive until their immune system can fight back, not to mention an increasing arsenal of antiviral meds. And I think, under pressure, a vaccine could be produced pretty quickly, although it might not be 100% effective. Steps toward preparing for large-scale virus production are a huge step in the right direction

Of course all these things are available mostly in developed countries.

No doubt this could be scary, but I think it's very unlikely you'll see deaths in the 100s of 1000s in the U.S. or Europe.

Of course, what do I know, I thought SARS was going to be a global catastrophe.

Blame Canada

Most of the lead, cadmium and other heavy metals pollution sampled from Lake Roosevelt, the reservoir behind the Grand Coulee Dam, came from a smelter in Trail, British Columbia, according to a new report from the U.S. Geological Survey.

It will be interesting to see how Canada responds. Of course, not everyone in the U.S. want the Canadian company implicated to pony up:

Last summer, Paul Cellucci, the U.S. ambassador to Canada, told the EPA that he opposed a Superfund cleanup for Lake Roosevelt due to concerns about the precedent it could set. Some U.S. mining and electric companies fear Canada would then have grounds to complain about air and water pollution from their operations.

I knew there had to be a downside.

Does computerized order entry increase medication errors?

You might think so reading this article about 2 studies and an editorial in this months JAMA (Journal of the American Medical Association; these probably require subscription access).

The first interviewed house staff (interns and residents) at a teaching hospital about possible errors facilitated by the CPOE (computerized physician order entry) system in use there (which apparently has ~60% market share) and identified "22" ways in which the system could lead to errors.

It is crucial to note that no objective data on actual medication errors or harm to patient was collected and there was no control group. They just asked house staff about potential problems and then went back to ask how often they'd observed specific problems. More troubling, there is no control group of house staff who used non-computerized error entry, so no way of knowing if the many benefits of CPOE (no mistakes due to illegible handwriting, less delay in orders reaching pharmacy, computerized checking of dosage and allergies, etc) outweigh the problems identified. Such studies of CPOE have been done an result in an up to 80% decrease in medication errors.

I don't see this study as very informative. Any doc who has used a computerized order entry system knows they are far from ideal, but previous studies clearly show that CPOE does reduce medication error.

The one big advantage of CPOE is that they can be iteratively improved. In that sense, identifying sources of error is helpful in that the programs can be modified to improve or fix the problems.

A second study, systemically reviewed decision support software which, ideally, helps clinicians make decisions about diagnosis and treatment, and found they were overall disappointing. Not surprisingly, results were better when studies were conducted by the same individuals who designed the systems. Unlike CPOE, such decision support systems are not in wide use.

In general, I think decision support systems try to do too much. I think they would be most useful in suggesting alternative diagnosis for unusual or atypical patients, not in mananging more straightforward patients, which doctors are pretty good at already (ed really? At least we thing we are!).

The editorial is, to my mind, unnecessarily pessimistic about the role of technology in medical care. It brings up some good points, such as that new IT projects are usually initiated by some combination of non-care providers and senior faculty who don't have any sense of how most work is actually carried out and imposed on the actual care providers (e.g. nurses and house staff) without much input from the end users.

It unfortunately drifts into socio-babble:

Clinical work, especially in hospitals, is fundamentally interpretative,
interruptive, multitasking, collaborative, distributed, opportunistic, and
reactive.1, 13, 20, 24-25
In contrast, CPOE systems and decision support systems are based on a different
model of work: one that is objective, rationalized, linear, normative, localized
(in the clinician’s mind), solitary, and single-minded

Well now that we have that straight!

I think medicine, like all industries, will make big strides as younger people more comfortable with technology come into the system. Some peculiar features of the way health care is structured (fragmentation, transient nature of house staff, lack of focus on quality improvement, poor measurement of quality)have delayed the commitment to use of information technology compared to other industries.

Well, off to do some interprative, interruptive, multitasking, collaborative, opportunistic, and reactive work.

Bird flu infection may be asymptomatic

At least 2 people in Vietnam were infected with avian flu but didn't get symptoms

This is good news in that maybe it won't make people as ill as was feared, but bad news in that it may be spreading more than is realized.

Interestingly, both asymptomatic individuals were elderly, which ties in with the observation in the 1918 pandemic that mortality was highest among young adults.

Grand Rounds 24

The 24th Grand Rounds is up. I particularily enjoyed the list of top ten things doctors hate to hear.

It is also the first Grand Rounds I submitted to, but hopefully not the last

"As Treatable as Erectile Dysfunction"

Drug companies are racing to find medicines that will help smokers quit with several in or getting ready for Phase III trials (generally the final trials before approval).

The drugs have different targets (Pfizer's varenicline blocks nicotine craving, Sanofli Aventis's rimonabant blocks the positive feedback smokers get when lighting up, and NicVax actually generates antibodies which block nicotine's action), so combinations might eventually be more efficacious than any one alone.

According to the article, a trial of varenicline showed quit rates of about 50%, versus 33% with buproprion (Zyban) which is currently on the market, apparently at 7 weeks. Of course, as many smokers can tell you, quitting is easy, it's staying away from cigarettes that is hard.

I hope one or more of these workout. Can you imagine how important an effective treatment for smoking would be? How many smokers do you know that wouldn't want to quit? It would be great for health, but a disaster for Social Security.

Bird Flu is coming

This is scary. Here is the basic scoop on the bird flu:

The "normal" flu virus varies a bit from year to year. That is why you need to get revaccinated year. The two main genes that vary are called hemagglutinin (H) and neuraminidase (N) which, not surprisingly, are exposed on the outside of the virus and therefore the immune system. You may see flu strains referred to as H1N5 or whatever to denote the strain based on hemagglutinin and neuraminidase sub-types.

If you can make antibodies that bind to these exposed portions of the virus they can block infection. To make these antibodies you either need to be vaccinated or previously exposed. Hemagglutinin and neuraminidase are under enormous selection pressure, so they mutate much faster than proteins on the inside of the virus, a nice example of natural selection at work,

Generally, the changes from year to year are small, so there is some level of residual protection at a population level.

Flu viruses also circulate among poultry and swine, but these viruses either can't infect humans or do so ineffectively. Because they are genetically different from the usual human viruses there is no history of previous exposure and so they are usually more deadly. But because they don't infect humans very well, they generally don't spread from person to person.

The big fear is that a person (or, interestingly, a pig) will be simultaneously infected with both the avian and the more typical flu viruses. This will allow the genetic materials of the two viruses to combine. This has the potential to generate a new virus has the deadly combination of ability to infect humans, but new antigenic determinants (H and N) on the outside which humans haven't encountered before and so aren't resistant against.

This leads to what is called a pandemic, where the new virus sweeps the world, killing millions.
The 1918 pandemic killed an estimated 20-40 million worldwide, more than WWI or the plague. Interestingly, mortality was highest among healthy young adults, unlike more typical years, when most death is among young children and the elderly. The reason for this, and whether it would be repeated in another pandemic is unknown (at least to me).

Preparations for a new pandemic are inadequate but people are starting to realize the need for them. The two most important things are to have the capacity to rapidly produce a vaccine in large quantities and to stockpile anti-viral drugs.

This could be really, really bad.