Normal Limits

"Chance is the very guide of life"

"In practical medicine the facts are far too few for them to enter into the calculus of probabilities... in applied medicine we are always concerned with the individual" -- S. D. Poisson

November 30, 2005

GAO - Medicaid: States� Payments for Outpatient Prescription Drugs

A Government Accountability Office report to Congressman Edward Whitfield, the vice chair of the House Subcommittee on Oversight and Investigations of the Committee on Energy and Commerce. This report was initiated to investigate the rising costs of Medicare to cover outpatient mediations.


Five states were studied: Mississippi, Montana, Pennsylvania, South Carolina,
and Utah.

For each drug covered, each state�s payment per unit was calculated as first taking
the lowest of:

  • The state�s estimate of drug acquisition cost

  • The pharmacy�s usual and customary charge

  • The federal upper limit (FUL, if available. The CMS is required by Federal regulations to set specific FULs for drugs that are provided by at least three suppliers.)

  • The state's maximum allowable cost (MAC, if available. Analogous to the FUL but set by individual states. As of December 2003, 38 states had established MACs for certain drugs at rates below the corresponding FUL or for drugs for which CMS had not set an FUL.)

...and dividing this minimum by the number of units dispensed to yield each state's payment per unit.

Note that dispensing fees are not included.

Each state's payment per unit (PPU) is compared against each of the 3 estimated market prices defined as:


Overall, minimal variation existed among the five states� payments for most drugs.

  • The five states� payments for 189 brand-name drugs varied less than 7 percent on average

  • The five states� payments for the 5 generic drugs we reviewed varied 30 percent on average.

The GAO found that Medicare in all 5 states pay higher prices than each of the 3 market prices:
On average, each state�s payments for brand-name drugs exceeded each market-based price by 10 percent or more. Additionally, states� average payments for brand-name drugs were 12 percent higher than AMP, 36 percent higher than Best Price, and 73 percent higher than FSS Price, on average.

The Centers for Medicare and Medicaid Services was given a chance to respond to the GAO:
CMS stated that this report makes it clear that the current payment rules result in overpayments for drugs and emphasizes the need for reform. CMS commented that payments should be determined using accurate acquisition cost data, which it said requires congressional action.

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ABC News - Baby Coach Teaches Newborns to Sleep All Night

Accompanying video clip.

The first few weeks with a newborn are all a blur, as "Good Morning America Weekend Edition" co-anchor Kate Snow can tell you. Her baby, Abby, is 11 weeks old.

Suzy Giordano, whose book, "Twelve Hours' Sleep by Twelve Weeks Old: A Step-by-Step Plan for Baby Sleep Success," will be out in January, teaches babies how to sleep through the night.

After Giordano leaves, she coaches Snow and Breault by e-mail for weeks. It's a time-consuming effort, but the payoff has been huge. At 11 weeks, Abby sleeps 10 hours every night.

"By the time she's 12 weeks of age, three months, she will be able to sleep 12 hours straight," said Giordano, who has been coaching new parents � mostly professionals in their 30s and 40s in the Washington, D.C., area, where she's based � for 13 years.

According to the Amazon Editorial Review,
Suzy Giordano is the mother of five children, the youngest being fraternal twin boys. Also known as the Baby Coach, Suzy has worked with hundreds of Washington, D.C. area families as a baby sleep specialist for the past ten years.

This is her website.

From a WaPo Article on Suzy Giordano back in 6/2005, by Jennifer Frey,

Suzy is Suzy Giordano, aka "the baby coach," a petite, Brazilian-born woman who is an underground legend in the Washington area for her ability to teach newborn babies how to achieve that parenting nirvana: sleeping through the night.

Interestingly in the WaPo article it is "Good Morning America"'s senior correspondent Claire Shipman and her husband Time magazine correspondent Jay Carney who need help with their baby,
[They] have a 4 1/2 -week-old baby and a 3 1/2 -year-old toddler. They celebrate five-hour sleep nights, they're not so sure where they left things -- maybe it's somewhere over there in the kitchen? -- and they don't know when they'll next have time for each other, let alone themselves.

But they have Suzy.

I have not read the book so I won't comment on the Baby Coach's methods. Since I'm such a fan of baby sleep methods, I'll be reviewing Ms. Girodano's book when it comes out in Jan 2006.

We note that like the Baby Coach, Dr. Harvey Karp is also moving towards a service-oriented approach. He has been touring the U.S. and Canada to promote his new certification program, which will train THB Educators, analogous to Lactation Consultants and childbirth Educators.

From Dr. Karp's FAQ,
Especially since a lot of Happy Baby is counterintuitive - the worry it will spoil baby, parents think it is a fad, baby may resist the swaddle, shush seems too loud, swinging, colic, parents needing to know when to suspect problem and when to call MD, etc.

Apparently this program is doing pretty well, with hundreds of participants already.

I welcome this trend. From discussions with pediatricians and non-pediatricians I meet during rotations, it appears that Dr. Karp's methods are quite conceptually appealing to medical professionals. And certainty it seems many people who have tried it find it immensely helpful.

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November 29, 2005

In the Pipeline - Ghrelin and Obestatin

Dr. Derek Lowe remarks on 11/11/2005 Science article Obestatin, a Peptide Encoded by the Ghrelin Gene, Opposes Ghrelin's Effects on Food Intake by Jian V. Zhang et al from Prof Aaron Hsueh's lab at Stanford. As Dr. Derek explains, this paper found that the same peptide product which gets cleaved into ghrelin--the famous appetite inducing peptide hormone--has been found to also give rise to obestatin, which does just the opposite and "suppressed food intake, inhibited jejunal contraction, and decreased body-weight gain". Dr. Derek says,

So now we know more about the regulation of appetite than we used to, although researchers in that field probably thought it was complicated enough already, thanks very much. What I find particularly interesting about this discovery is how these two opposing hormones are cut from the same larger protein. That means that they both come from the same gene, you know. Which shows you just how far a pure genome-driven approach to drug discovery will get you: not far enough.

IMHO, this may also demonstrate how far it does take us and all the new opportunities available to us in this post-genomics era.

We note that obestatin would not have been identified without cross-species sequence analysis of the pro-peptide giving rise to ghrelin. As shown in thie figure from the online supplement:

It is upon observing peptide sequence conservation and peptide hormone cleavage signals that Prof Hsueh's lab started the investigations ultimately discovering obestatin. We note that they actually developed an in-house algorithm for this purpose (Avsian-Kretchmer O and Hsueh AJ 2004 in Molecular Endocrinology).

For fun we look at the POMC gene, which like the ghrelin/obestatin precursor is also cleaved into a number of peptide hormones. We use my favorite genome browser Ensembl. The human POMC is on chromosome 2:

We align the POMC transcript with those from the dog, rat, and mouse, and find that they match up pretty well:

A quick peek at the finer details of the alignment, down at the base pair level, shows:

Note that in the first row, corresponding to the human POMC sequence, a base G is highlighted in green. This means that there is a SNP at this location. Clicking on the green part allows us to link to the NCBI dbSNP page explaining this genetic polymorphism. At this point even the existence of the SNP is as yet unvalidated. But if I were a medical researcher studying any of the peptide hormones generated from POMC, I'd be looking into the biochemical implecations of this SNP.

Of course this has been a very cursory look which didn't really yield any useful information. But I hope it demonstrated that genomics can efficiently target and fine-tune wet laboratory investigations.

All Ensembl results can be further explored by following this link.

Ensembl.org is heavily based on web services and is a good example of Science 2.0.

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Widowhood and Mental Illness

During rotations I have taken care of a couple of elderly widows and widowers. Suffice to say that they are quite a unique group of patients to take care of. So some research is warranted...

In the U.S., 60% of women between ages 75 to 84 are widowed (Merck Manual of Geriatrics). With their longer life expectancy, the majority of women seem destined to share the common experience of widowhood. But the loss of a spouse is an intensely personal experience�after all, the spouse is the most physically and emotionally intimate companion in life. Across age groups and cultures, the death of a spouse is consistently rated as the most stressful life event (Holmes and Rahe 1967). So traumatic is the experience that many new widows fit the diagnosis of PTSD (Zisook et al 1998). But the mental illness the widow is most at risk of, unsurprisingly, is depression.

The spouse is arguably the most important person in one�s social network. The disappearance of the spouse, then, represents a fundamental perturbation on the network. Feelings of isolation and loneliness are common. She must adapt to the loss by re-structuring her social network, substituting roles played by her husband and compensating for her unmet social needs. This substitution may take any of 3 forms:

  • Formation of new social ties

  • Rekindling of dormant ties

  • Intensification of existing ties

In a fascinating cohort study, Zettel and Rook (2004) conducted serial interviews on 322 older women, ages 60 to 85, widowed for 3 to 30 months, over the course of a year. Among some of their findings were the surprising observations that

  1. Widows whose social network included more rekindled ties or more intensified ties developed significantly more depressive symptoms over the course of a year.

  2. Widows whose social network included more new social ties developed significantly higher loneliness ratings over a year.

Unexpected as these findings may be at first glance, they authors present a number of plausible explanations. Most importantly, I think these associations may be useful clinically.

Of course, this was an observational study that measured profound emotional responses with structured interviews. But we could hardly do any better.

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November 28, 2005

(The Official) NCBI Toolbar

Via Alberto

Much like the Google Toolbar and the Yahoo Toolbar, now there's NCBI Toolbar! There's a search box and you can designate the database to search in. Here is an example of a PubMed search:

Note that search terms can be highlighted, just like Google Toolbar. You can search in the Genes DB:

Here is a Flash-based demo.

Ok, while not revolutionary, this is certainly an encouraging sign. I have always been impressed by how technology-friendly NCBI is and how open they are about sharing their data. Another feature I find very useful for getting updates on topics of interest is the PubMed RSS feed:

I'm still getting updates on new articles about acetaminophen toxicity, a RSS feed I set up when when I was taking care of a 16yo girl during pediatrics rotation.

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November 27, 2005

Paul Krugman - "Age of Anxiety"

NYT's Paul Krugman,
Mr. [Peter] Drucker wrote "The Age of Discontinuity" in the late 1960's, a time when most people assumed that the big corporations of the day, companies like General Motors and U.S. Steel, would dominate the economy for the foreseeable future.

New technologies would usher in an era of "turbulence"... corporations can't provide their workers with economic security if the companies' own future is highly insecure.

This, according to Prof Krugman, is an Age of Anxiety. He goes on to relate this to the burden of health insurance on companies and the need for a single-payer national health insurance in the U.S. By framing the financial difficulties of old-time American corporations this way, perhaps Prof Krugman can make the idea of national health insurance palatable to economic conservatives.

The individual in the Age of Anxiety

These are really interesting times. As Thomas Friedman puts it,
When I was growing up, my parents used to say to me, "Tom, finish your dinner. People in China and India are starving." Today I tell my girls, "Finish your homework. People in China and India are starving for your jobs."

In The World Is Flat, Friedman proposes that there are 4 kinds of "untouchables" in this new flat world.

  • Special, e.g. Michael Jordan, Bill Gates

  • Specialized, e.g. vascular surgeons

  • Anchored, e.g. the local barber

  • Adaptable

Adaptability refers to the ability to learn how to learn.
As parts of your work becomes commoditized and fungible, or turned into vanilla [ice cream], adaptable people will always learn how to make some other part of the sundae... "because job churn will come faster, because innovation will come faster"

I don't think we in health care will be immune to this era of global transformation. We do live in interesting times.

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On Divorce

Media reports

"More Options to Answer 'What About the Kids?'" by NYT's Mireya Navarro, 11/27/2005,
The shift to more equitable custody arrangements over the last decades, a reflection of the changing role of fathers, has propelled many couples into more contentious divorce proceedings, as they fight over equal time with their children, some divorce lawyers say. Yet the resulting financial and emotional toll of protracted litigation is at the same time creating a powerful incentive for many separating couples to look for ways to agree.

The OurFamilyWizard.com web site is mentioned. This is basically a secure community site encompassing otherwise common tools such as group calendars, message boards, file storage space, etc, but specifically designed for divorced families. This web site received a lot of media coverage some years ago.

"The things that are difficult to discuss - who gets the kids when, who owes who money - that's handled electronically" ... "The kids don't have to listen to talk about all that. Our conversations are focused on the kids. They're about the school conference or Christmas."

Navarro talks about the "bird-nesting" custody arrangement, in which the family's original residence is kept while the 2 parents take turns live in with the kids.
The couple keep most of their belongings and receive mail at their old address. They switch off stays under certain rules: each will leave the house tidy, each is responsible for his or her own groceries, and neither will bring dates. Mr. Bowerman said the arrangement "makes it more difficult" for both parents "because you don't get closure."

But he added, "Right now I see it as the best thing for the kids."

San Francisco Chronicle's Adair Lara writes on bird-nesting,

By all reports, birdnesting requires so much tact and respect that onlookers wonder why, if they can pull this off, don't they stay married?

The kids are grateful... But when she visits friends, and sees their parents, Marie said, she missed not having two parents at home... Many experts worry that birdnesting kids will fantasize about their parents getting back together. "Parents need to remind their kids that's not in the future," said lawyer Sutton.

Pediatricians of children of divorce

One interesting thing of note in the OurFamilyWizard.com service is a tool to keep track of the children's medical records, in particular vaccination records. The American Academy of Pediatrics Task Force on Medical Informatics has a policy statement "Special Requirements for Electronic Medical Record Systems in Pediatrics". Specifically in the context of taking care of children of divorce,

  • Data representation: growth data, parent identifiers.

  • Data processing: pediatric dosage calculation (e.g. Dr. Jeremy Adler's Pocket-Doc) incorporated into computerized physician order entry; immunization records with decision support (e.g. how to make up for missed shots); automatically generate customized reports (e.g. shcool sports physicals, documents for family court)

  • System design: distinction between biological parents vs legal guardians; ability to represent adopted children; links to other family members; links to registries (e.g. newborn screening, immunization)

Most recent statistics on divorce in America

Finally, some statistics. The popular number that many like to quote is that "50% of all marriages end in divorce". However, this estimate is generated cross-sectionally. That is, (I believe), it looks at the number of divorces within a year and divides it by the number of marriages taking place that year. However, while it is by construction a ratio, it is not a proportion, since it is really studying 2 different populations. More nuanced analyses are performed by demographers and we summarize some results here.

Based on Cycle 5 of the National Survey of Family Growth (NSFG), collected in 1995, the CDC published a report in 2002 titled Cohabitation, Marriage, Divorce, and Remarriage in the United States. By dividing marriages by the time period in which they start, i.e. marriage cohorts, it found that for marriages starting in the 70s and 80s, the chance of divorce within 10 years is about 30%.

Now, broken down by duration of marrige, we note that the chance of divorce is almost constant, at an annual rate of about 4% per year. This cannot hold true of course, or else all marriages will end in 25 years. But we see no leveling in this graph.

There are some interesting findings on cohabitation. The chance of a cohabitation breaking up also appears to be constant, at about 6% per year.

... the chance of a cohabitation advancing into marriage yet again appears more or less constant, at about 7% per year.


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November 26, 2005

Science - Assistance of Microbial Glycolipid Antigen Processing by CD1e (de la Salle, Mariotti, Angenieux et al 2005)

Over view

Cell surface antigens CD1 A through E are expressed by professional antigen-presenting cells (APCs) for the presentation of non-peptide antigens to T cells. That is, they serve analogous functions as the MHC genes but are specialized in capturing and presenting a whole different class of antigens.

The MHC molecules are a large family of proteins. Each is different in its specificicity of antigen-capture, and most are highly polymorphic between individuals (hence matching of MHC, a.k.a. HLA, genotypes are performed prior to organ transplantation).

The CD1 genes are rather different. They are much less polymorphic between individuals and each molecule (CD1a through CD1e) binds a diverse set of antigens. Several crystal structures of CD1-antigen binding have been solved. The CD1 genes have been found to contain deeply buried hydrophobic surfaces to bind lipid antigens while exposing carbohydrate- and peptide-moieties for interaction with T-cell receptors. An example of phophotidylinosiol in the CD1b pocket is shown here.

The CD1 genes show differences in structure and function (reviewed by Moody et al 2005, ibid):

  • The antigen-binding grooves in CD1a function as a 'molecular ruler' that binds lipids with a defined alkyl chain length.

  • CD1b proteins can bind antigens with a lipid component of variable length. Similiar to the ability of MHC II to bind peptides longer than its binding groove, CD1b lets long antigens to protrude through portals to the outside of the antigen groove.

de la Salle, Mariotti, Angenieux et al 2005

This article in Science showed that
mycobacterial antigens hexamannosylated phosphatidyl-myo-inositols (PIM6) stimulate CD1b-restricted T cells only after partial digestion of the oligomannose moiety by lysosomal a-mannosidase and that soluble CD1e is required for this processing.

Polymorphisms in the CD1 gene gamily

Coming back to the point about the CD1 genes being functionally non-polymorphic. As summarized by Profs Manfred Brigl and Michael B. Brenner in Annual Reviews of Immunology, the few polymorphisms that have been found so far are either silent, amino acid changes outside the antigen-binding groove, or have and no detectable differences in expression or antibody reactivity. The exceptions are two CD1e alleles, CD1E*01 andCD1E*02, which did affect antigen-binding, but so far no association has been found between carrying these alleles and susceptibility to mycobacterial infections.

In general, it is much more difficult to make negative inferences in science(e.g., no crows are white) than it is to make positive ones (e.g., lots of crows are black). we check the dbSNP database of single-nucleotide polymorphisms and find that there are 10 SNPs in CD1e, many of which are validated. I will not be surprised if one day an association is found linking some of these polymorphisms with autoimmune diseases or diseases of chronic inflammation.

SNPs in the human CD1e gene, based on NCBI Map Viewer

Role in the immune system: immunity against Mycobacteria


CD1 gene family: role in disease


Lipid antigens and the delivery of dietary lipids: a convergence

In an Oct Nature article, researchers from Prof Michael B. Brenner's lab found that the immune system uses apolipoproteins to deliver lipid antigens to CD1. That is,
Apolipoprotein E mediates the presentation of serum-borne lipid antigens and can be secreted by APCs as a mechanism to survey the local environment to capture antigens or to transfer microbial lipids from infected cells to bystander APCs. Thus, the immune system has co-opted a component of lipid metabolism to develop immunological responses to lipid antigens

By Peter van den Elzen from article in Focus

From Focus, the news magazine for Harvard Longwood Campus,
"This may change the way we look at activation of T cells in asthma,� said Dale Umetsu of Children�s Hospital Boston, whose work has implicated lipid-reactive T cells in asthma and allergy in both mice and humans.

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Harbin, China, 2005 vs Valdez, Alaska, 1989

The supertanker Exxon Mobil Valdez spilled between 11 million and 35 million gallons of crude oil. Take the middle value of 23 million gallons, assuming the density of crude oil to be 915 kg/m^3, this comes out to 915 * 42,000 = 38,430,000 kg of crude oil, or 38,430 tonnes. The Harbin benzene spill was 100 tonnes according to the BBC, which is 100,000 kg of benzene, less than 0.3% the Valdez spill by weight. Benzene is a lot more toxic however, and according to the BBC, this amount of benzene is "equivalent of 10 tanker-loads of lethal substances", all into the Songhua river. Tracing the BBC's reasoning, we note that 10 PANAMAX class tanker can carry up to 790,000 metric tons, hence the Harbin disaster spill is like a 20-super-tanker pile-up!. Ouch! I hope my math is wrong.

From the Wikipedia:
On March 23, 1989, the oil tanker Exxon Valdez departed from the Valdez oil terminal in Valdez, Alaska (on its 28th voyage), heading south through Prince William Sound, with a full load of oil. Captain Joseph Hazelwood radioed to the Coast Guard station that he would be changing course in order to avoid some growlers, small icebergs which had drifted into the sound from the Columbia Glacier... the vessel was not turning sharply enough and at 12:04 a.m. on March 24, the vessel hit Bligh Reef.

Hopefully the investigations into this disaster will yield a report as detailed and precise, to hold the responsible individuals accountable.

The Songhua River, just upstream of Harbin, China (to the right)

What about the people of Harbin?
In the NYT article The Half-Life of Anxiety on 7/10/2005 by Benedict Carey,
In studies of Alaskan communities that were affected by the oil spill from the tanker Exxon Valdez in 1989, and of towns dealing with water contamination in New Jersey and New York, sociologists have found what they call social corrosion. Sustained anxiety breaks down social groups and leads to an increase in mental health problems and potentially to economic downturn, said Lee Clarke, a sociology professor at Rutgers University and author of the forthcoming book, ''Worst Cases,'' an analysis of responses to disaster.

Much recent research analyzes mass disasters in terms of bioterrism, e.g., Facing the Possibility of Bioterrorism by Bill Durodi� in Current Opinion in Biotechnology:
In his [2004 book Therapy Culture: Cultivating Vulnerability in an Uncertain Age], Furedi explores the roots of a growing sense of social and individual vulnerability in what he coins 'therapeutic culture'. By increasingly framing problems through the prism of their emotions, people are actively incited to feel powerless and ill. Accordingly, �the spirit of stoicismand sacrifice�, along with �a sense of common purpose,unity or a commitment to fight� are now rarely in evidence. A powerful consequence of this, along with distorted perceptions and an increase in reported rates of depression, is provided by the phenomenon of mass psychogenic (or sociogenic) illness, numerous instances of which became evident in the aftermath of the anthrax attacks.

While the concept of "therapeutic culture" sounds reasonable and intriguing, it may be oversold here and takes on too much of a Theory of Everything tinge. I do like the basic idea though.

On an individual level,

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Science - Hematotoxicity in Workers Exposed to Low Levels of Benzene (Lan et al 2004)

A landmark study on benzene toxicity by a collaboration between the U.S. National Cancer Institute and the Chinese Center for Disease Control, Lan et al 2004 was an observational study comparing hematological changes in workers exposed to varying amounts of benzene vapor.

  1. It demonstrated statistically significant hematological disturbances even for exposure less than 1 ppm, the current U.S. occupational standard.

  2. It found benzene exposure to assocaited with decreases in hematopoetic stem cells in the blood, in a dose-dependent manner.

Here is Table 1 with just the comparison of CBCPD and flow cytometry results between the control group and the less than 1 ppm group. The other 2 exposed groups are 1 to 10 ppm (110 subjects) and greater than 10 ppm (31 subjects).

Here is Figure 1 comparing the amount of hematopoietic stem and progenitor cells in the circulation between subjects with 0, less than 10 ppm, and greater than 10 ppm of benzene exposure. As explained in the online supplement:
Colonies arising from the most primitive, early progenitor cells are called colony-forming-unit�granulocyte, erythroid, macrophage, megakaryocyte (CFU-GEMM) because the progenitors can give rise to any of these mature cells. Colonies derived from more committed progenitor cells that give rise to reticulocytes and erythrocytes are called burst-forming unit�erythroid (BFU-E), whereas those that give rise to granulocytes and macrophages are called colony-forming unit�granulocyte-macrophage (CFU-GM).

Notes on methods:
  • Levels of exposure were measured repeatedly for up to 16 months before hematological measures

  • Benzene and toluene air levels were estimated by "the arithmetic mean of an average of two measurements per subject collected during the month prior to phlebotomy" (online supplement)

Notes on stats:

  • Population heterogeneity examined with random effects model

  • Tests for trends (e.g., trends in changes in WBC count with respect to leveel of benzene exposure) were adjusted by the subject of the covariates { smoking, EtOH, recent infections, and BMI } that is significant (model selection method unclear? not detailed in online supplement either). Level of toluene exposure is also put in the model for continuous covariates since toluene competitively inhibits benzene metabolism.

  • Repeated measures adjusted with generalized estimating equation models

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NYT - The Deadly Shot

NYT Editorial on the problem of neede re-use in poor countries leading to HIV and Hepatitis C infections.

As third-world health problems go, this one seems solvable. Single-use syringes, whose plungers break or are blocked after first use, cost about 6 cents apiece.

The biggest problem is that many poor countries are injection-crazy... patients demand injections because they think the medicine is stronger, and health care workers like to give them because they can charge more.

The Safe Injection Global Network, backed partly by the World Health Organization, is trying to help countries develop educational programs for health care workers and doctors.

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November 24, 2005

Paul Krugman - "Bad for the Country"

NYT's Paul Krugman has been commenting on the need for a National Health Insurance in the U.S. He attributes GM's planned termination of 30,000 jobs to the disproportional cost of healthcare that American companies have to spend to cover health insurance for their employees.
... commentary [on G.M.'s troubles] from some conservatives has an unmistakable tone of satisfaction, a sense that uppity workers who joined a union and made demands are getting what they deserve.

We shouldn't be so complacent.

... If the United States had national health insurance, G.M. would be in much better shape than it is.

I need to make a clarification here... On a previous post on Prof Krugman's column A Private Obsession, I said,
One day, many generations from now, when all medical records become electronic, when every senior is well-informed of the risks and benefits of every medication for every disease that they may develop with known probability, the wisdom of the market will triumph. Oh yes it will.

Some have asked me if I said that in jest. First let me say that I know nothing about theories of economics other than what I learned from a political economics course I took in undergrad--about 8 years ago. Hence I don't know where to find reputable sources for support. What follows is all IMHO...

The market economy is known to arrive at efficient equilibriums without intervention. Since interventions are known in some cases to prevent the market economy from reaching that equilibrium, it is argued that the market should be left alone. Laissez-faire.

However while there is much talk on this nirvana of equilibrium, little attention is paid to the kinetics of market economy. That is, given a system of market economy, assuming that such equilibrium exists, how much time will it take to reach this (presumed) nirvana?

Certainly the fact that we have observed successful cases of market economy suggests the kinetics may be reasonable--within a human lifetime--at least in these isolated cases. The economic theorists in us wish to generalize these observations into a Grand Theory of Market Economy. But we cannot. We do not have the data to make this inference. In fact, the empiricists in us make the observation that millions of Americans are left uninsured. These empircists in us may have no health insurance themselves.

Theoretical generalizations are always be trumped by empirical observations.

Comments welcome.

In the same column, Prof Krugman comments on trade deficit:
The trade deficit isn't sustainable... we'll have to reorient our economy back toward producing things ... pulling a lot of workers back into manufacturing. So the rapid downsizing of manufacturing since 2000 - of which G.M.'s job cuts are a symptom - amounts to dismantling a sector we'll just have to rebuild a few years from now.

How much of that rebuilding will be in Michigan?

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AP - Toxic slick flows into major Chinese city

According to the Medical Management Guidelines (MMGs) for benzene published by ASTDR.CDC, benzene is only slightly soluble in water and floats on the water surface. Ingestion of benzene can cause both acute benzene toxicity--CNS depression, light-headedness, headache, euphoria, respiratory depression, apnea, coma, and death--and
a burning sensation of the oral mucous membranes, esophagus, and stomach may occur after ingestion. Nausea, vomiting, and abdominal pain may also result from oral ingestion.

ASTDR's online case study on benzene toxicity, designed for PCPs (CME credits!).

Out of curiosity I queried ToxMap for industrial sources of benzene around Ann Arbor--not surprisingly there's a cluster of 4 sources in Wayne County.

According to Toxics Release Inventory, these 4 sources are:

  1. MARATHON OIL CO (EPA #48174RMLSR28000): 445 lb/year

  2. EQ RESOURCE RECOVERY INC (EPA #48174MCHGN36345): 250 lb/year

  3. FORD MOTOR CO TRUCK PLANT (EPA #48184FRDMT38303): 132 lb/year

  4. FORD MOTOR CO WAYNE ASSEMBLY (EPA #48184FRDMT37625): 60 lb/year

[update: BBC reports that the leak was 100 tonnes, "equivalent of 10 tanker-loads of toxic chemicals." 10 tonnes is about 220,000 lb, or about 250 times the environmental release of benzene in Wayne County, MI per year.]

People in China do not enjoy this kind of government oversight...
Protests have erupted in rural areas throughout China over complaints that pollution is ruining water supplies and damaging crops. Protesters often accuse officials of failing to enforce environmental rules either in exchange for bribes or for fear of hurting local business.
�This is the tip of the iceberg,� said Elizabeth Economy, director of Asia Studies at the Council on Foreign Relations in New York and author of the 2004 book �The River Runs Black: The Environmental Challenge to China�s Future.� �We�ve seen over the past six months or so a number of factory-related protests ... because factories don�t live up to or don�t enforce China�s own environmental regulations and laws,� she said. �So if, in fact, this is a case of that happening, then this is part of a much broader, systemic problem.�

Dr. Elizabeth Economy, a Wolverine, is Director for Asia Studies at Council for Foreign Relations.
China's environmental crisis is evident everywhere. The country's air quality is among the worst in the world: According to the World Bank, 16 of the world's 20 most polluted cities are on the mainland, and acid rain affects one-third of China's agricultural land. The country is already one-quarter desert, and that desert is advancing at a rate of 1,300 square miles per year.
The most serious environmental challenge, however, is providing clean water to the Chinese people: 60 million people have difficulty getting enough water to meet their daily needs and 10 times that many drink contaminated water on a daily basis.

A recent study published in Science found that benzene may have adverse health risks even at levels below currently accepted safety standards. Review pending.

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AP - South Korean cloning pioneer apologizes

�I am very sorry that I have to tell the public words that are too shameful and horrible,� Hwang said, appearing downcast and solemn before a packed news conference. �I should be here reporting the successful results of our research, but I�m sorry instead to have to apologize.�

�Ethics and science are the two wheels that drive the civilization of mankind,� Hwang said. �Scientific research should be conducted within the boundaries of ethics but in reality, there were some cases in which the ethics regulations backing (quickly developing) science had not been in place.�

�The responsibility for all disputes and controversy lies on me,� Hwang said. �I will not make any excuse.�

Professor (Woo-suk Hwang), a national hero and a de facto celebrity in South Korea, will resign as head of the World Stem Cell Hub �to atone to the public.�

Extensive coverage at the official blog of the American Journal of Bioethics, including a very interesting unsigned comment
A comment from Korea... Through a series of media interviews and lectures, Prof Hwang has been strongly advocating that the development of stem cell therapy is just around the corner and it would save hundreds of thousands of lives.

Despite [the revelations] ... a considerable number of Korean citizens think that that's not an important issue at all. Because .... for them, Prof Hwang's research "IS" a cure for incurable diseases ... for them, his research "IS" a solution for the Korean economy. These people think that the societal debates about complex bioethical issues are unnecessary, if not harmful to the patients and the Korean economy.

It was also reported, via JoonAng Daily, that Professor Hwang's supporters have started a "I love Hwang Woo-suk" website, on which numerous women have already pledged to donate their eggs for stem cell reearch.

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November 23, 2005

Book: Mommy Knows Worst: Highlights from the Golden Age of Bad Parenting Advice.

(via Samantha Critchell of Chicago Sun-Times)
Review of James Lilek's Mommy Knows Worst : Highlights from the Golden Age of Bad Parenting Advice. Medical recommendations from the 40's and 50s included "advice from the Chicago Board of Health in the 1920s to give children sunbaths -- and then cod oil baths."

Unlike in physics, in medicine the different roles played by theorists and empiricists are not clear-cut. Here, tthe empiricists in us draw statistical conclusions from studies, but it is the theorists in us that make the scientific inferences and generalizations. IMHO it's best to tame these theorists in us, lest we lost the public's credibility.

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The Doctor's Office - Quality Rankings Can Work, For Patients and Doctors

WSJ's Dr. Benjamin Brewer, a private practice doctor, shares his practice's report card,
The research is conducted through the Practice Partner Research Network, a joint effort whose participants include a medical software company and the Medical University of South Carolina, which designs and conducts the research. The university studies data from my electronic medical record on about 75-80 quality indicators ... compared with data from about 100 practices across 37 states.

We've been participating for the last six months and the process is still relatively new to us. This week I received my first big "report card."

Here's Dr. Brewer's report card

Since it is expected that practices with higher scores will attract more patients,
To balance supply and demand, the price for the services of top-performing physicians would have to go up in response to the good ratings -- but so far insurers and the government don't seem to want to pay the price when it comes to primary care.

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WSJ - In a Stroke Patient, Doctor Sees Power of Brain to Recover

WSJ Page One news item today by Thomas Burton talks about a movement by some in Neurointensive Care to use scientifically reasonable (but still incompletely unproven) methods to treat comatose stroke patients. These are patients that according to current standards of practice are deemed incurable. Some like Dr. Stephan Mayer, Director of Columbia University's Critical Care Neurology, disagree.
They say many of the studies underlying the earlier consensus are out of date, and they believe newer treatments such as one designed to cool the brain may help stroke patients in comas. "Doctors are telling people there's no hope when, in fact, there is," says Dr. Mayer.

Dr. Justin A. Zivin at UCSD Stroke Center, who was instrumental in the development of tPA stroke therapy, responds:
"It would be extraordinarily helpful if they had evidence," he says. "Have they proven that these therapies are better than nothing? I'm not saying it won't ultimately be proven." Dr. Zivin says this is one reason many hospitals have yet to embrace the idea of a separate neurocritical care unit.

Dr. Mayer:
"We have to push the envelope and do things that at least are well-grounded in the scientific evidence that is available."

One such still-experimental treatment is "brain cooling", which we note is also being tested at UCSD's Stroke Center.

The Oxford Vascular Study published in this week's The Lancet found that, at least in the UK, the clinical burden of stroke has surpassed that of heart disease.

In men, the incidence of stroke is comparable to coronary artery disease (CAD), while in women the risk of stroke is significantly higher than the risk of CAD:

The risk of non-fatal (but potentially debilitating) stroke is also much higher than that of non-fatal (likewise debilitating) CAD:

As WSJ notes,
Aggressive treatment of stroke victims can have a serious downside. If a patient is kept alive for a few extra weeks in an intensive-care unit only to die at the end, the cost may be tens of thousands of dollars with no benefit. The American Stroke Association estimates that the annual U.S. cost of stroke care is $35 billion.

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NYT - Deaths After Abortion Pill to Be Studied by Officials

Gardiner Harris of NYT:

  • Ms. Patterson died [on Sept. 17, 2003] seven days after taking Mifeprex. She lived in Livermore, Calif.

  • On Dec. 29, 2003, Vivian Tran, 22, of Costa Mesa, Calif., died six days after taking Mifeprex.

  • On Jan. 14, 2004, Chanelle Bryant, 22, of Pasadena, Calif., died six days after taking Mifeprex.

  • And on May 24, 2005, Oriane Shevin, 34, of Los Angeles died five days after taking Mifeprex.

In each case, Clostridium sordellii infected the women's uteruses, flourished and then entered their bloodstreams. The bacterium can cause nausea, vomiting, diarrhea and weakness but may not induce fever ... antibiotics [treatments after the onset of infection] are often ineffective ...

No similar deaths have been reported in Europe, where Mifeprex is widely used. But in the United States, most physicians give Mifeprex and an accompanying drug, misoprostol, in a regimen that involves inserting misoprostol vaginally.

Combing through the stacks of UM's Taubman Library Google Book Search on Clostridium sordelli reveals:

  • Postpartum episiotomy infection beneath the deep facsia leads to myonecrosis. Clostridium perfringens accounts for most cases, but Clostridium sordelli has also been implicated. These cases were unique in presenting with "massive malignant vulvar edema thought to be caused by toxin production and results in death from cardiovascular collapse" (Clinical Maternal-Fetal Medicine by Hung N Winn, John C Hobbins)

  • Clostridium sordelli has also been reported in pleuropulmonary infections after penetrating chest trauma. Of the 39 cases of such infections due Clostridium reported from 1935 to 1993, 2 cases (5%) were attributed to Clostridium sordelli. (Community-Acquired Pneumonia by Thomas J Marrie)

  • It has been implicated in neonatal omphalitis (infection of the umbilical stump) in deliveries outside traditional medical facilities and in cultures where cow dung is applied to the umbilical stump postpartum. (The 5-minute Pediatric Consult, Edited by M. William Schwartz)

Interestingly, antiserum to Clostridium sordelli cross-reacts and neutralizes Clostridum difficile cytotoxin (a.k.a. Toxin B) in tissue culture. This forms a component of the laboratory diagnosis of intestinal C. diff overgrowth in patients on antibiotics. (Notes on Medical Microbiology by Yifan Douglas Yang, Morag C Timbury, A Christine McCartney, Bishan Thakker)

That little literature search was completed within 20 minutes. Unlike regular Googling, the reliability of these sources are not in doubt. The importance of Google Book Search in Science 2.0 cannot be denied.

FYI this was on my search results page

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November 21, 2005

NEJM - . . . And a Diagnostic Test Was Performed (Greenwald 2005)

A correspondence from Dr. Robert A. Greenwald, describing a recent case conference during which a patient with IPEX was diagnosed by a fellow in attendance using not her clinical acumen per se but Google.

Where does this lead us? Are we physicians no longer needed? ... Even worse, the Google diagnostician might be linked to an evidence-based medicine database, so a computer could e-mail the prescription to the e-druggist with no human involvement needed. The education of house staff is morphing into computer-search techniques. Surely this is a trend to watch.

Search Google Book Search (formerly Google Print) with "IPEX immunodeficiency"...

Do we even need medical libraries? From my laptop, I can access publication quality, full color, annotated dermatology pictures, and pathology slides (and the entire BluePrint review book series)! Indeed Google Book Search turned out quite useful the other day when we admitted a patient with a strange rash.

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November 20, 2005

Science 2.0 - Peer-reviewed publications

Robert Boynton gives us a cautionary tale of then-University of Chicago political science junior faculty Daniel Drezner. He was denied tenure because part of his academic output had been directed into the blogosphere.

The current antipathy toward blogging may have something to do with the fact that universities have no tools for judging blogs. And most people agree that blogs would need to be evaluated through some kind of peer-review mechanism if they are to be taken into account. "It is utterly absurd to propose giving someone credit for activity with no barriers to entry," [John Holbo, the Editor of The Valve] says.

So, how might a blog be peer-reviewed? The market provides a number of viable models. eBay, for one, has established an efficient rating system for buyers and sellers, based on the number and quality of transactions they execute. In a noncommercial medium, Slashdot uses a "Moderation and Meta Moderation System," in which moderators are awarded higher or lower "karma" according to how well they police the discussions on the site. (The "Meta Moderation System" judges the moderators' moderators.)

An even better model is Kuro5hin.org, which I think has successfully adapted the peer-review process to the Web. The manuscript submission process should sound familiar:
  1. The author contribue articles by formatting the manuscript (or "stories" in the world of Kuro5hin) with respect to a standard recommendation.

  2. The author submits the manuscript to the edit queue, along with plans for editing the manuscript

  3. A subset of Kuro5hin users are selected to be editors of this particular mansucript. They see a link to the manuscript in their Kuro5hin "moderation" pages. At this point, the text is not visible to the rest of the Kuro5hin community.

  4. Editorial commments are visible to the author, who can respond to the comments, make changes to the manuscript, and even rate the usefulness of each individual editorial comment

  5. Editors vote on acceptance of this manuscript

  6. Assume it is accepted, the manuscript becomes an article. Another subset of Kuro5hin users are select to vote on the placement of the article: on the Frontpage or in one of the Sections (e.g., Politics, Technology, Culture, etc).

  7. Now the entire Kuro5hin community can read the article and comment.

  8. Each reader can rate other readers' comments. The author can likewise respond to the questions and comments.

Possible improvements:

  • Allow editors to tack on metadata to the text. This seems a natural task for editors, who will be doing fact-checking as a part of the editing process.

  • Allow for multiple authors per manuscript for collaborative efforts.

  • Anonymous editorial process to encourage frank discussions.

  • Giving some structure to the comment system, making it easier to track questions that have been answered by the author and those that have not.

  • As noted by many, a credit system for rewarding editorial work and constructive comments.

John Holbo's post on this on The Valve.

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November 19, 2005

Science 2.0 - How To Guide to CiteULike

As the world flattens, people-to-people and machine-to-machine communication becomes standardized and efficient, how do we as scientists find new ways to plug into this new infrastructure and collaborate with each other in the 21st century?

An article at OpenWetWare talks about the emergence of Science 2.0. See the accompanying brainstorming Wiki for even more inspiring ideas.

Britannica Online-->Wikipedia
Science 1.0-->2.0

Some drawbacks of the current situation
  • There is only one main level of information dissemination: peer-reviewed, highly polished summaries of work in journals.

  • ...
  • Current publishing approaches do not encourage open feedback and reviews of work.

Pubmed --> Faculty of 1000 --> Cite-U-Like

What is CiteULike? Like del.icio.us, CiteULike is a social bookmarking service. But it is specifically tailored to academic discussions. Mechanisms are in place to automatically create records of journal articles, tag them, and discuss them with other users of CiteULike. Connotea is a similar service hosted by the Nature Publishing Group. But the CiteULike website is more responsive, its user interface more intuitive, and its comment system more amenable to public discussions.

I have created groups in CiteULike where we could review and discuss recent articles in evidence-based medicine and randomized clinical trials methodology.

To get started:

  1. Register at CiteULike

  2. Install the bookmarklet on this page appropriate for your machine. Make sure to bookmark it into a toolbar for easy 1-click access.

  3. Go to the PubMed page of the article you want to comment on, and click the bookmarklet button

  4. Tag this post, leave public or private notes, and even upload your PDF file for later access.

  5. Go to the CiteULike groups page to join discussion groups. If you'd like, join the groups Evidence-based-medicine, Randomized-clinical-trials-methodology, and/or Randomized-clinical-trials-review

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