So Much | So Fast

I now have to stop talking about poop GI matters for a while since Adam is going to give the impression that I have an obsession of some sort with the stuff.

Instead of spending time in the laboratory tonight (for which I’m feeling tremendously guilty), I ambled down to my favorite moviehouse, the Coolidge Corner Theatre, for their latest Science on Screen feature, the terrific So Much | So Fast. This is a remarkable documentary about Stephen Heywood, a man diagnosed with amyotrophic lateral sclerosis in December of 1998, and his family’s remarkable journey.

The film was notable on a number of levels. First, woven in and out of the story was the juxtaposition between Stephen Heywood’s physical deterioration, which one saw progressing over the course of the movie, and his infant son’s development. There were multiple scenes of Stephen at varying stages of the disease, entirely fixated on his child testing out new motor skills. As a physician, especially a pediatrician, it was really a privilege to see these images on the screen. I don’t think that I fully appreciated the profound loss suffered by Stephen Haywood, and by extension, any patient with ALS, until I was able to see it in the context of the motor development of a child. We take for granted the normal development and functioning of our nervous system. During residency I memorized the developmental milestones, their anticipated times of onset, the normal ranges, and the differential diagnoses for delays. But there is something very affecting about seeing it in parallel to the devolution of an individual, and even moreso when that individual is that child’s father. I could only imagine what was in Stephen Haywood’s mind as he watched his child gain the skills that he was now losing.

The movie was also remarkable for the other main theme: the mission undertaken by Stephen’s brother Jamie, to accelerate the search for a cure. Without getting into too much detail, Jamie Haywood built a research group over the course of the past 8 years, and in doing so chose to do so according to an entirely different set of principles than those typically followed by the scientific “establishment”. Where as the paradigm of scientific research in this country has been to let clinical discoveries bubble up from investigator-initiated basic science research, Jamie Haywood chose to attack the problem of ALS with a “top down” approach: apply as many drugs as possible to a mouse model of ALS and use whatever works on patients. As scientists we would call this “empiric therapy” – the application of treatment without understanding the underlying mechanism. There are many, many pitfalls to this approach if you look at it from the point-of-view of a scientist. However, there are probably just as many pitfalls to the conventional approach if you look at it from the point-of-view of a patient with a progressive, fatal disease.

After the film I had a chance to talk to Jamie Haywood for a little while. He was a little different from the way he appeared in the movie. Some of the desparation that came across in the movie has been replaced with what appeared to me to be a broader understanding of the size of the problem. That being said, I think that he is willing to call out science for its flaws and shortcomings (e.g., lack of adequate funding, duplicative research, inadequate publishing of ‘negative’ results, the propriatary nature of modern science vis a vis patents, competition for credit, grants and publication, corporatization of research, etc.). But more than just being a gadfly or naysayer, he has the energy and initiative to bring people from outside of science together to find creative approaches. One of the things that we spoke briefly about was a “Science 2.0” akin to the “Web 2.0″. In addition to the “regular” bottom-up science, why not capitalize of the remarkable technologic infrastructure that we have in place to draw important data out of what is going on out there.

For example, if you’re a pediatric patient with, say, acute lymphoblastic leukemia (ALL), depending on where you are you may get treated according to a Children’s Oncology Group protocol, a BFM (Berlin-Frankfurt-Munster) group protocol, at St. Jude’s protocol, or a Dana-Farber Cancer Institute/ALL Consortium protocol. You’ll get some cocktail of many of the same drugs, but on a different schedule, with different doses at different times. Which one is the best (in terms of outcome) with the fewest side effects? One way to find out would be to do a randomized trial with hundreds (or more) patients, dividing them between each of the four regimens. You’d need to have large enough groups to account for differences in patient populations, and you’d need to run the trials for a long time to figure out which had the best outcomes. You’d need to score all of the side effects for all of the patients in the same way. You’d need the cooperation of dozens, if not hundreds, of investigators. It’d be a long, expensive trial.

But what if you had a computer infrastructure in place for all patients on acute lymphoblastic leukemia therapy. A system that was open to the oncologists and the patients and their families. What if you put in all of the data. You’d enter the patient’s demographics, disease characteristics, treatment regimen, drug doses, schedule, the physician’s assessment of side effects, etc. On the patient side you’d have the patient or parent enter their assessment (timing, severity) of side effects. You’d collect other data: how many missed days of school, assessment of mood, appetite, mouth sores, hair loss, infections, missed doses of medication. Anything that you can think of, as long as you’d make it quantitative. As a result you’d have this large array of leukemia data, not dissimilar to the array data that you get from whole-genome cDNA arrays, or SNP arrays. The task then would be to mine the data. Much like gene chip data, you’d be able to mine it in innumerable ways. You’d find subsets of patients who, for example, got through their therapy without much nausea and vomiting. You could then go back and see how those patients did in terms of outcome. You could find out what cocktails of anti-nausea drugs they took and see if that was different than a group of patients with an average amount of nausea and vomiting, or those with the worst nausea and vomiting. Once we have the ability to quickly and cheaply run gene chips on patients and their disease you could correlate outcome or side effects with different patient or disease genotypes. Ultimately we could end up with a remarkable new “meta science” which would pool all disease data and genomic data, allowing sophisticated multi-dimensional views to replace the traditional two-dimensional Kaplan-Meyer curves (probability of survival versus time).

This seems awfully pie-in-the-sky, but in talking with Jamie Haywood, I was struck by the fact that he “gets it”. And while the part of me that is trained as a traditional scientist is skeptical when he takes on traditional clinical trials and peer-review, I appreciate the fact that he is trying to make us, as a community, take an honest look at the system by which we define scientific reality.

For more information about this movie, you can visit the film’s website here. There’s a preview of the movie available here. Jamie’s organization is the ALS Therapy Development Foundation. Their research page is well worth a look.

Tragically, Jamie’s brother Stephen died on November 27th in a tragic accident, in which is home ventilator became disconnected. The alarm was not heard and as a result he died from anoxia. Despite the fact that ALS is a progressive disease, patients can be maintained on a ventilator for many years. It was clear from the movie that Stephen’s life was cut short of what he wanted.

I would encourage anyone who reads this to try to see this movie, if not now, then when it becomes available on DVD. It is a remarkable and touching story of a man and his family. It is also a story about questioning the status quo. It is a story about the cost of pursuing a goal without limits. And ultimately, it is one man’s story about what is important in life.

[Nota bene: An excellent review from the New England Journal of Medicine can be found here.]

Hey, Boston … wash your hands!

Sometimes I take it for granted that I occupy a part of the world in which there are more Purell dispensers than people.

In fact, at times I wonder if I’ve developed some odd transdermal addiction. I find myself seeing out this glorious gelled delight in settings other than the lab or the hospital. After walking through grocery stores, filling the tank at the gas station, or before sitting down to dinner in a restaurant, I crave that faintly perfumed peace-of-mind.

Suffice it to say, as a result I rarely get sick. In fact, for the third time in a year, I’ve played doctor to Mrs. Blog, MD, who has contracted several nasty colds. She says that it is because I’ve been around so many sick children that I’ve become sufficiently immune. I say it’s because of my fastidious hand hygiene.

Whatever the case may be, I feel confident that I’ll not be affected by the current wave of viral gastroenteritis. I started to see cases of it several weeks ago at the hospital where I moonlight. Today, according to the Boston Globe, it appears to be a full-fledged outbreak, enough to warrant the attention of the Centers for Disease Control and, of course, a story in the paper. It appears that there have been over 3700 gastro-related ED visits in Boston in the past 6 weeks, as well as a surge (pun intended) of visits on Christmas Day.

The current outbreak appears to be due to a member of the norovirus family. Noroviruses (genus Norovirus, family Caliciviridae) are a group of related, single-stranded RNA, nonenveloped viruses that cause acute gastroenteritis in humans. Norovirus was recently approved as the official genus name for the group of viruses provisionally described as “Norwalk-like viruses” (NLV). The prototype of this family, Norwalk virus, was named for the town of Norwalk, Ohio where, in November 1968, an outbreak of acute gastroenteritis occurred among children at an elementary school. In 1972, immune electron microscopy on saved stool samples identified the virus, which was called subsequently called Norwalk virus. Those of you who, like me, enjoy the history of medical discovery, might be interested in reading a terrific historical perspective paper by Albert Kapikian, who identified Norwalk virus (note: links to .pdf file).

Norwalk virus received a lot of press several years ago when it caused several outbreaks of diarrhea on cruise ships. These outbreaks were so bad that several ships had to return to port, emptied of their passengers, and then cleaned from (ahem) stem to stern. It appears that noroviruses are making quite a … um … splash, this year. Wikipedia has a very detailed list of outbreaks for 2006. I counted 12 major outbreaks in December alone.

Of course, as a pediatrician, whenever I think viral gastro, I usually think of rotavirus, but the timing of this outbreak makes rotavirus an unlikely suspect. Rotavirus is also a fascinating bug, first isolated by electron microscopy from cow diarrhea, and was subsequently identified in humans by electron microscopy of bowel biopsy samples. My hat is off (and my mask is on) for the scientists who wrote that paper. What is so interesting about rotavirus is that it follows a regular spatial and temporal pattern. Rotavirus season typically begins in the late fall (November) with the greatest number of cases in the southwestern United States. As the year progresses, the disease marches northeast, arriving in our neck of the woods by April:

 

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You can track the ebb and flow of rotavirus through the CDC’s National Respiratory and Enteric Viruses Surveillance System:

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As you can see, the rotavirus peak is just starting to form. Incidentally, it also looks like we’re finally hitting the peak for this year’s RSV (respiratory syncytial virus) season:

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In any case, my point was not necessarily to give a full lecture on the epidemiology of these common ailments. Rather, it was to impress the need for meticulous, regular and damn-near universal handwashing. It’s not hard to do. There are videos available on-line for those who really need help. When you consider that, at least for rotavirus, there are 10^12 viral particles (colony-forming units) in each millileter of liquid poop (that’s 30,000,000,000,000 infectious particles in each ounce of poop for those not SI-inclined), you have to realize that it is hard to keep all of those viruses coralled. They’re inclined to stick to hands, and then to other flat surfaces. Shake hands with someone shedding virus, or who has a child at home who is sick, or touch a doorknob after someone else wasn’t so good about handwashing, and presto! You’re primed to infect yourself as soon as you put hand to mouth.

So please, please, please … for yourself, for your kids, for those like me fielding admissions from the pediatric ED in the middle of the night, for the Fleas who have to take phone calls in the middle of the night, and for the interns who have to trudge down from their call rooms to the ED to admit you … please wash your hands (or at least stock up on the good stuff).

Kill Your Television.

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I don’t watch much television (as a matter of fact, one of my favorite gadgets that I’ve acquired is the TV-B-Gone (it’s a great way to make a hospital room quiet on rounds). It’s not that I don’t like television. I do. It’s mindless relaxation that is semi-informative, occasionally funny, and once-in-a-while, entertaining. I will admit to having been captivated by Homicide: Life on the Streets, Twin Peaks, M*A*S*H, and most recently by Lost.

I never liked, with the exception of M*A*S*H, and perhaps St. Elsewhere, medical television shows. Medicine is exciting and dramatic, but most shows like ER and House pack more psychodrama, trauma, and tension into an hour than I’ll get in my worst month. There is also the medical “unreality” of these shows that was first documented in a terrific article in the New England Journal of Medicine entitled, Cardiopulmonary Resuscitation on Television – Miracles and Misinformation. This paper looked at the shows ER, Chicago Hope, and Rescue 911 and compared the outcomes from CPR on the show versus data from real life. Their discussion (which you can read in its entirety here [note: .pdf file]) was not exactly a surprise:

“Patients have few sources from which to learn about illness and death. Acute illness – and, in particular, terminal illness – is for many people no longer part of everyday life. Therefore, images in the media strongly shape the public’s beliefs about medicine, illness, and death. The portrayal of CPR and death on three popular television programs is misleading in a number of ways.

[… T]hese three television programs give a misleading impression about the kind of people most commonly given CPR. On television, children, teenagers, and young adults accounted for 65 percent of the patients given CPR. Of the total number of deaths on the programs, 83 percent were of nonelderly patients. In fact, cardiac arrest is much more common in the elderly than in children or young adults … CPR succeeded more frequently on television than in the real world as reflected in the medical literature. On all three shows combined, 75 percent of the patients were alive immediately after their cardiac arrests, and 67 percent appeared to survive in the long term. On Rescue 911, which focuses on the successes of emergency services, the survival rate after CPR was 100 percent. Of the patients on ER, 65 percent survived the initial arrest; three of these patients died before discharge from the hospital. On Chicago Hope, 64 percent of the patients given CPR initially survived cardiac arrest, and 36 percent survived to discharge.

[…] Rates of long-term survival after cardiac arrest as reported in the medical literature vary from 2 percent to 30 percent for arrests outside a hospital, and from 6.5 percent to 15 percent for arrests that take place inside a hospital. For average elderly patients, the rate of long-term survival after cardiac arrest outside a hospital is probably no better than 5 percent. For arrests due to trauma, the reported survival rates vary from 0 to 30 percent. Clearly, the rates on television are significantly higher than even the most favorable data reported in the literature.”

What the authors worry even more about, besides the factual misrepresentations, is the effect that this phenomena has on patient expectations, espcially when patients and their families are making decisions about whether or not to attempt resuscitative events:

“In a subtle way, the misrepresentation of CPR on television shows undermines trust in data and fosters trust in miracles. In the stories retold on Rescue 911, physicians often predict poor outcomes for patients, while family members voice their hope and, in the end, their joy in the “miracle” of their loved ones’ recovery. We acknowledge that this drama produces good television, as evidenced by the large viewing audiences. However, these exceptional cases may encourage the public to disregard the advice of physicians and hope that such a miracle will occur for them as well. Faith is central to our ability to maintain hope in difficult situations and often is an important adjunct to the therapy physicians offer. Belief in miracles, however, can lead to decisions that harm patients. The portrayal of miracles as relatively common events can undermine trust in doctors and data.

Misrepresentations of CPR on television may lead patients to generalize their impressions to CPR in real life. For example, an 85-year-old woman with metastatic breast cancer may believe that CPR can work as well in her situation as it does for the 23-year-old trauma victim on television. Physicians discussing decisions about the end of life with patients and families should be aware that the public has many sources of information about CPR, some of them misleading. To help patients and families make informed decisions, doctors should encourage patients to discuss their impressions of CPR and its chances of success. We should clarify misperceptions, provide actual data on outcomes, and address specifically the differences between CPR as seen on television and CPR as it is experienced by real patients.”

The differences between medicine in real life compared to medicine as portrayed in television is clearly an important topic, and I hope that in the 10 years since this paper was published, that both television writers, patients and physicians have learned from the authors astute conclusions.

Equally problematic, however, is another phenomena in which television has raised unrealistic expectations of physicians. This phenomena was the subject of an important study recently published in the British Medical Journal:

Phenotypic differences between male physicians, surgeons, and film stars: comparative study
The problem is clear: physicians on television look nothing like physicians in real life. Not to say that there aren’t very aesthetically pleasing physicians and nurses. Believe me, there are. But for the most part, physicians look like people who’d rather leaf through the latest New England Journal of Medicine than the latest GQ or Esquire.

Except for the surgeons.

I remember first noticing, while a third year medical student, that the surgeons always seemed to dress a little sharper, walk a little taller, and have the nicest manicured hands. That’s not to say that the internists and pediatricians were all slobs. But you were more likely to see a rumpled looking, balding man with a tweed jacket heading to medicine grand rounds then to the operating room. And I’ve never seen a pediatric tie on a surgeon. Never. Not even a pediatric surgeon.

But I digress. Male physicians on television, for the large part, all tend to look, well, like television stars: tall, in-shape, square jaw, with a healthy glow. Think about it: Dr. Richard Kimball (The Fugative), Dr. Doug Ross (ER), that guy from Marcus Welby, a general practitioner, was a handsome devil. OK. Charles Emerson Winchester III wasn’t the most handsome figure on the small screen. But you get my point.

So here’s the problem: it appears that TV actors playing the parts of physicans look far better than the roles they play, raising unrealistic expectations of the true phenotype of physicians. Moreover, there appears to be a true phenotypic difference between the surgeons and internists. Could this possibly be true? The investigators write:

“The tallest and most handsome male [medical] students were more likely to go for surgery, and the shortest (and perhaps not so good looking) ones were more likely to become physicians (including doctors of internal medicine and its subspecialties). Now, after all these years we hypothesize that, on average, surgeons are taller and better looking than physicians. We conducted a comparative study to test this hypothesis.”

The authors of this cutting-edge research out of the University of Barcelona selected a random sampling of senior staff surgeons and internists, as well as external controls (Harrison Ford as Dr. Richard Kimble, George Clooney as Dr. Doug Ross, Patrick Dempsey as Dr. Derek Shepherd, and Hugh Laurie as Dr. Gregory House), and showed them to an independent group of eight female observers (3 doctors and 5 nurses). Each of the physicians, surgeons and control subjects were given a “good looking score”. The outliers were discarded and the six remaining scores were averaged (± standard deviations) and compared using a standard t test. or non-parametric (Mann-Whitney U) test.

The results: film stars (external controls) had significantly higher good looking scores than surgeons (5.96 versus 4.39, p=0.013) and physicians (5.96 versus 3.65, p=0.003). Surgeons had statistically significantly higher good looking scores than physicians (4.39 versus 3.65, p=0.010).

Moreover, the surgeons were taller (179.4 cm versus 176.2 cm, p=0.01), on average, than the internists. And to top it off the authors, “… noted a higher proportion of baldness (surrogate marker) among the internists.” Is there no justice for the humble internist!

Their discussion sheds remarkable insights into these findings:

“There are several potential explanations for the phenotypic changes between surgeons and physicians. Firstly, surgeons spend a lot of time in operating rooms, which are cleaner, cooler, and have a higher oxygen content than the average medical ward, where physicians spend most of their time. Furthermore, surgeons protect (but not always properly) their faces with surgical masks, a barrier to facial microtrauma, and perhaps an effective anti-ageing device (which deserves further testing). They often wear clog-type shoes, a confounding factor that adds 2-3 cm to their perceived height. The incidental finding that fewer surgeons are bald might be related to these environmental conditions and to the use of surgical caps.

In contrast, senior physicians are surrounded by fewer people in their habitat (the patient’s bedside and the office), and they therefore have less need to be easily identified or spotted by families and nurses in the middle of a swarm. Physicians tend to hang heavy stethoscopes around their necks, which bows their heads forward and reduces their perceived height. They also complain of a (clearly abnormal) need to endlessly update their knowledge in accordance with the current evidence based approach to medicine by reading and studying heaps of medical journals; this overload of information further grinds them down. Although a prospective study found that doctor’s white coats decrease in weight with increasing seniority, no significant difference was found between the mean weight of physicians’ coats and surgeons’ coats (1.4 v 1.5 kg).”

Well, it is clear that television still has a long way to go in accurately portraying medicine. I’ll be happy to continue using my TV as a place to pile my medical books and journals. Despite my techno-geek longings for a flat screen LCD, I have chosen to save the money for something more relevant (like a good bottle of wine, or a trip somewhere nice, or perhaps some eggs or cat litter). And while I grudgingly admit that the surgeons are a little taller, and the orthopaedic docs appear to be in better shape, I take solace in knowing that our jokes about them are much, much funnier than theirs about us.