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

December 15, 2005

Paul Krugman - "Drugs, Devices and Doctors"

Paul Krugman's column explains Vioxx, Merck, and Cleveland Clinic, in terms of the inter-dependent network of pharma, academic research centers, and doctors as they now are.

Above all, the line between medical researcher and medical entrepreneur has been blurred... Usually, [Marcia Angell] says, "both academic researchers and their institutions own equity" in these companies, giving them a strong incentive to make the big drug companies happy.

The point is that the whiff of corruption in our medical system isn't emanating from a few bad apples. The whole system of incentives encourages doctors and researchers to serve the interests of the medical industry.

The good news is that things don't have to be that way. Economic trends gave rise to the medical-industrial complex, but only because those trends interacted with bad policies, which can be fixed.

Prof Krugman will propose some policy changes in future columns.

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Two blackeyes for biomedical research

As 2005 comes to a close, we first find that Merck had fudged its data on the Vioxx NEJM article.

Now it appears that Prof Hwang Woo-suk of Seoul National University had fudged his data too in his Science article on the creation of new stem cell cell lines.

BBC reports:
At least nine of 11 stem cell colonies used in a landmark research paper by Dr Hwang Woo-suk were faked, said Roh Sung-il, who collaborated on the paper.

Dr Hwang wants the US journal Science to withdraw his paper on stem cell cloning, Mr Roh said.

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The Crab Nebula across the millennia

Composite of Hubble pics of the Crab Nebula by NASA

The Crab Nebula is a six-light-year-wide expanding remnant of a star's supernova explosion. This composite image was assembled from 24 individual exposures taken with the NASA Hubble Space Telescope�s Wide Field and Planetary Camera 2 in October 1999, January 2000, and December 2000. It is one of the largest images taken by Hubble and is the highest resolution image ever made of the entire Crab Nebula.

So here is in fact a snapshot of the nebula as human civilization passes a major milestone. It's an anniversary of sort for the nebula as well, as the Crab Nebula was first observed, with the naked eye, just about a millenium ago in year 1054. From the Messier Catalog:


The supernova was noted on July 4, 1054 A.D. by Chinese astronomers as a new or "guest star," and was about four times brighter than Venus, or about mag -6. According to the records, it was visible in daylight for 23 days, and 653 days to the naked eye in the night sky. It was probably also recorded by Anasazi Indian artists (in present-day Arizona and New Mexico), as findings in Navaho Canyon and White Mesa (both Arizona) as well as in the Chaco Canyon National Park (New Mexico) indicate.



Prof Zhi Cheng Xiao at the Institute of Molecular and Cell Biology and Prof Gavin Dawe et al at the Stem Cell Research Center of the National University of Singapore They showed that stem cells from the fetus in the womb find their way into the maternal brain, where they differentiate into cells of the nervous system and *may* become a part of the mom's thought process. Fascinating stuff.


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via Wiki:
In Polynesian mythology (specifically the Maori of New Zealand), the Matariki ("small eyes") are the seven gods of the Pleiades, deities of agriculture and patron deities of navigators.

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Merck lied

Editorial released online by the New England Journal of Medicine, on the paper published in year 2000 by Bombardier et al on Merck's Rofecoxib. The editorial is penned by editors Gregory D. Curfman, M.D., Stephen Morrissey, Ph.D., and Jeffrey M. Drazen, M.D.:
a memorandum... obtained by subpoena in the Vioxx litigation and made available to the Journal, [showed] that at least two of the authors knew about the three additional myocardial infarctions at least two weeks before the authors submitted the first of two revisions and 4 1/2 months before publication of the article.

We determined from a computer diskette that some of these data were deleted from the VIGOR manuscript two days before it was initially submitted to the Journal on May 18, 2000.

NEJM re-ran the main anlysis and found:



Dr. Curfman, as quoted in the NY Times article by Alex Brenson:
"They did not disclose all they knew," [Dr. Gregory D. Curfman, the journal's executive editor] said. "There were serious negative consequences for the public health as a result of that."

As we can see clearly from these numbers that the exclusion of these 3 cases of myocardial infarction does not change the main conclusion!

The culprits

The authors of the original study implicated are Claire Bombardier, M.D, and Alise Reicin, Merck's Vice President of Clinical Research.

The fall of Merck

The history of Merck is reviweed here. Merck famously commercialized morphine for medical use and with Pfizer was one of the first companies to mass produce penicillin.

According to NY Times:

Merck now faces more than 6,000 lawsuits from people who say they or their family members suffered heart attacks and strokes as a result of taking Vioxx, and tens of thousands more lawsuits are expected.

Despite Merck's recent victories in court, it looks more and more likely that Merck will be brought down by its COXII inhibitor.

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December 12, 2005

Pregnancy and diseases

Fascinating summary in JAMA on pregnancy and the associated medically relevant physiological changes, by Profs Risto Kaaja of Helsinki University Hospital and Ian Greer of University of Glasgow.

In order to optimize the delivery of nutrients and oxygen to the fetus, the removal of fetal waste, the preparation for labor, and the peaceful co-existence of fetal tissue within the body, a variety of coordinated physiological changes occur during pregnancy:

These perturbations--traumatic as they already are for the healthy mom--represent an even more severe challange to those with diseases or those with otherwise-hidden propensities towards developing diseases.

For instance, during pregnancy the mom's immune system, in order to develope tolerance to the fetus, shifts towards a TH2-dominant state. Correspondingly, TH1-dominant diseases such as rheumatoid arthritis (RA), multiple sclerosis (MS), and thyroiditis all improve during pregnancy. In constrast, systemic lupus erythematosis (SLE), a TH2-dominant disease, tends to deteriorate.

Other diseases of the endocrine and the cardiovascular systems are also perturbed by the pregnant state:

Based on these findings, Profs Kaaja and Greer, both obstetricians, recommend screening protocols to be performed peri-partum to screen for these diseases.

We note also recent work with stem cells have found neurons of fetal origin to be present in the maternal brain, such that in parts of the maternal brain a portion of the mom's nervous system is contributed by their children! (it's important to note that it's not clear these neurons of fetal origin participate in the maternal brain or are just idle bystanders. See also Parasitic Hairworm Charms Grasshopper Into Taking It for a Swim)

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December 08, 2005

Outbreak of Clostridium difficile diarrhea associated with fluoroquinolone use

A New England Journal of Medicine editorial by Drs. John Bartlett and Trish Perl on these 2 papers:

and the CDC report.

Diarrhea secondary to Clostridium difficile colitis is in hospital in-patients characterized clinically by watery diarrhea, abdominal cramps, and white blood cell counts elevated in the 50,000s. Such dramatically high WBC counts are rare, in fact, except in cases of leukemia, and are useful in clinical diagnosis. The typical laboratory diagnosis is done by detection of the C. diff toxins. The assay is in fact based on cross-reactivity between antiserum to Clostridium sordelli against Clostridum difficile cytotoxin (a.k.a. Toxin B) in tissue culture. (Notes on Medical Microbiology by Yifan Douglas Yang, Morag C Timbury, A Christine McCartney, Bishan Thakker). Interestingly, this lab test will not identify this epidemic strain (? more details coming).

In the 1970s, clindamycin was associated with C diff diarrhea. In the 1980s it was cephalosporins. Now it is the use of fluoroquinolones.

Pathogenicity of the new C diff strain

As Warny et al described in the Lancet, this new strain of C diff associated with fluoroquinolone use in hospital in-patients is unique in its rate of toxin production. With mutations in its tcdC locus, it seems to have evolved the ability to produce vastly larger amounts of toxins A and B. In addition, whereas other strains of C diff produce only minimal amounts of toxin while they are busy growing and dividing (i.e. the log phase), the new outbreak strain produces toxins A and B even during this time.

We note that the genome of Clostridium difficile is still being sequenced by the Sanger Institute.

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December 07, 2005

Applying public health measures to HIV infection

Dr. Thomas R. Frieden, the Commissioner of the New York City Department of Health and Mental Hygiene, et al in the New England Journal of Medicine.

25 years into the epidemic, progress is stalled. The number of deaths among people with AIDS has not declined since 1998, and the number of newly diagnosed cases is rising slightly... Late diagnosis of infection is common... Notification of the partners of infected persons is rare.

...given the availability of drugs that can effectively treat HIV infection and progress on antidiscrimination initiatives, perhaps society is ready to adopt traditional disease-control principles and proven interventions that can identify infected persons, interrupt transmission, ensure treatment and case management, and monitor infection and control efforts throughout the population.

I do not know much about applied epidemiology myself, but this is how Dr. Frieden breaks it down:

  1. Case finding and surveillance:

    • Named reporting of all found with a reportable condition (e.g., Salmonella infections and Reye's syndrome). This is now true for patients found to be HIV positive in Michigan.

    • Availability of routine testing in health care settings. Dr. Frieden states that this is often not available.

    • Notification and testing of partners

  2. Interruption of transmission: promotion of condom use, perinatal veritcal transmission prevention, blood product screening, development of vaccine.

  3. Systematic treatment and case management:

    • Case management of the infected individual and his/her contacts, with the case managers accountable for patient outcome. In Ann Arbor, the non-profit HIV/AIDS Resource Center (HARC) provides this service.

    • Linkage of social services to medical care compliance

  4. Population-based monitoring:

    • Contact of treating physician by public health agencies if patient shows inadequate response. This is generally not done for HIV/AIDS.

    • Monitoring viral resistance. Not done outside of research studies.

Support World AIDS Day

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December 06, 2005

Washington Post on the (inadequate) use of fistula for hemodialysis

According to the The National Kidney Foundation�s Kidney Disease Outcomes Quality Initiative (K/DOQI) Clinical Practice Guidelines for
Vascular Access, published in year 2000, Guideline 3:

The wrist [arteriovenous] fistula is the first choice of access type because of the following advantages:

  1. It is simple to create.

  2. It preserves more proximal vessels for future access placement.

  3. It has few complications. Specifically, the incidence of vascular steal is low, and in mature fistulae, thrombosis and infection rates are low.

Yet Gilbert M. Gaul of WaPo notes:
Today, fewer than four in 10 dialysis patients nationwide have a fistula, despite overwhelming evidence that they are safer, cheaper and more effective than grafts and catheters.

...fistula rates remain stubbornly low in the United States, and vary dramatically by geography.

Medicare, which picks up most of the $15 billion annual tab for dialysis treatment, pays surgeons more for grafts and catheters than fistulas -- in effect, rewarding inferior care. That's because its reimbursement system is based on the time and resources needed to do a procedure, not on the outcome.

In 2003, it cost Medicare an average of $52,751 to care for a patient with a fistula, compared with $61,929 for those using a graft and $69,893 for those on a catheter, federal data show.

Patients with grafts and catheters also have a 20 to 70 percent greater chance of dying in the first year of treatment, according to CMS.

From the Rayner et al 2004 paper in the American Journal of Kidney Diseases, "Vascular access results from the Dialysis Outcomes and Practice Patterns Study (DOPPS): performance against Kidney Disease Outcomes Quality Initiative (K/DOQI) Clinical Practice Guidelines", we see that:

The U.S. ranks in the very bottom for fistula use in chronic hemodialysis. The DOPPS studies have produced some very interesting results. Among others, it has shown that American patients on hemodialysis have much higher mortality than those in other countries. I'm not certain if this is due to differences in patient characteristics or medical care, but it has been suggested the difference may be related to the much faster, much higher-flow hemodialysis preferred by patients and dialysis centers alike.

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December 05, 2005

Nicholas Kristof on "The Hubris of the Humanities"

In this column, the worldly and profound Nicholas Kristof begins with the intelligent design debate and comments on the American culture's disdain of science as it is, "a profound illiteracy about science and math as a whole".

A larger problem is the arrogance of the liberal arts, the cultural snootiness of, of ... well, of people like me - and probably you.

... In the U.S. and most of the Western world, it's considered barbaric in educated circles to be unfamiliar with Plato or Monet or Dickens, but quite natural to be oblivious of quarks and chi-squares.

Such great thinkers of the Western tradition as Aristotle insisted that women have fewer teeth than men. As Bertrand Russell said, "although he was twice married, it never occurred to him to verify this statement by examining his wives' mouths."

While I'm a fan of Aristotle's On Rhetoric--as I am a bigger fan of Kant's metaphysics--parts of their works have quite limited applicabilities today. As historical works of smart men and women before our time, they demonstrate both the power and the limits of reason, how deeply the mind can make sense of the world and how simply it can fall short.


...don't pin too much faith on the civilizing influence of a liberal education... similar arguments were used in past centuries to assert that all a student needed was Greek, Latin and familiarity with the Bible - or, in [Ming Dynasty] China, to argue that all the elites needed were the Confucian classics.

Increasingly, we face public policy issues - avian flu, stem cells - that require some knowledge of scientific methods, yet the present Congress contains 218 lawyers, and just 12 doctors and 3 biologists. In terms of the skills we need for the 21st century, we're Shakespeare-quoting Philistines.

Mr. Kristof quotes work by Jon Miller, the Director of the Center for Biomedical Communications at Northwestern University showing that "in 34 countries, says Turkey is the only one with less support for evolution than the U.S." Couldn't find the original source, so can't comment on the methodology.

I did find this report at National Science Foundation on public understanding of science and tech from 2004:

More Americans now agree with the theory of evolution. The 2001 NSF survey marked the first time that more than half (53 percent) of Americans answered "true" in response to the statement "human beings, as we know them today, developed from earlier species of animals." (In Europe, 69 percent responded "true.")

The data sources of this report:

Other interesting findings from this report:

While belief in pseudoscience is still common--60 percent of surveyed Americans said they believe in extrasensory perception, and 41 percent thought that astrology is at least somewhat scientific., only a small subset (10 percent) of the American population admit no interest in science and technology issues. It's not clear however if this interest is in science and tech in themselves or if it includes antagonism.

As seen on the figure on the right, Americans get most of their information about science and tech from TV (top pie). But when they have specific science & tech questions, they overwhelmingly turn tot he internet (bottom pie).

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Diagnostic Clinical Trial: Phased evaluation of medical diagnostic technologies

From the Statistics in Medicine special issue on the 25th Annual Conference of the International Society for Clinical Biostatistics, Prof Margaret S. Pepe from University of Washington Dept of Biostatistics and Fred Hutchinson Cancer Research Center's article "Evaluating technologies for classification and prediction in medicine".

To begin with, Prof Pepe points to the CONSORT statement, which in essence gives guidelines for the design, analysis, and reporting of randomized clinical trials of therapeutics. She notes the Standards for Reporting of Diagnostic Accuracy (STARD) initiative which has arisen to specify analogous guidelines for medical diagnostics.

Prof Pepe proposes that the structured investigation of therapeutics into the canonical 4 phases can also be adapted for the investigation of medical diagnostics.

Prof Pepe proposes a 5-phase approach. For each phase she identifies the major objective and the best study design to achieve these goals.

  1. Preclinical exploratory: to identify promising directions by convenience sample case-control studies

  2. Clinical assay and validation: to determine if a lcinical assay detects established disease by population-based case-control studies

  3. Retrospective screening: to determin if the biomarker detects disease before if becomes clinical, and to define a "screen positive" rule, by nested case-control studies

  4. Prospective screening: to determine the extent and characteristics of disease detected by the test and to identify the false referral rate, by cross-sectional studies

  5. Cancer control: to aseess the impact of screening on reducing the burden of disease on the population, by--ideally--randomizaed trial

Prof Pepe also identifies a number of interesting statistical issues that apply distinctly to medical diagnostics. Will review.

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December 04, 2005

DNA microarray for speciation of clinical fungal pathogen isolates

From the Journal of Clinical Microbiology, Leinberger et al uses microarray technology to rapidly speciate human fungal pathogens.

Susceptibility testing is already quite unreliable for bacteria, and it is even less useful for fungal infections. In fact antifungal agent choice is mostly based on the speciation of the fungus. Yet speciation is typically performed by examining the shape of the fungus and performing biochemical tests on fungal colonies. This requires a relatively large number of fungi, which will needs a couple of days to grow. This process is of course the rate-limiting step of clinical decision making in treating fungal infections.

Using DNA microarray technology, Leinberger et al produced a spot array chip containing unique sequences of rRNAs from 12 common pathogenic fungi. These were validated against 21 speciated clinical isolates. They found that the microarray chip was able to rapidly (within about 4 hours) and accurately speciate 12 of the most common fungal pathogens in the genus Candida and Aspergillus.

This clinical applications of DNA microarray technology is particularly clinically relevant, as critically ill and immunocompromised patients can be infected by multiple fungal species. Rapid and targeted antifungal selection should help clinicians better balance the treatment of infections against the often serious adverse effects of antifungals.

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Tom Cruise buys an ultrasound machine for home use

The American College of Radiology (ACR)'s press release regarding Mr. Cruise:

...ultrasound should not be considered completely innocuous. Laboratory studies have shown that diagnostic levels of ultrasound can produce physical effects in tissue, such as mechanical vibrations and rise in temperature, particularly when used for a prolonged period of time.

The FDA's statement in June 2005 warned:
those who subject individuals to ultrasound exposure using a diagnostic ultrasound device (a prescription device) without a physician's order may be in violation of State or local laws or regulations regarding use of a prescription medical device.

This may not be a purely technical violation, as MSNBC's Fran Kritz noted:

The FDA says that while prenatal sonograms are generally done at very low power levels, current machines, which range in price from $15,000 to $200,000, can produce sound wave intensities eight times higher than a decade ago and at that level, especially if used for prolonged periods, there could be a real risk to the developing fetus.

Mr. Cruise should note that there is a new Alberta, Canada law which will allow children to sue their mothers for injuries suffered in the womb.

(via Kevin, MD blog)

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Medical tourism amongst Asian countries and the Globalization of Medical Care

By Steve Mollman of WSJ:
Facing age 40, Paul Luciw decided an extensive health checkup was in order. His local hospital in Hong Kong said it would cost the equivalent of about $1,300.

He got a quote from Bangkok's Bumrungrad International hospital for about $300. So, with a few buddies who also wanted checkups, he made a mini-vacation out of it earlier this year.

The article gives figures quoted by Ruben Toral, marketing director at Bumrungrad International:

Health-care services in Thailand is

  • about 40 percent cheaper than in Singapore

  • about 75 percent cheaper than in Japan

Mr. Toral also says the number of foreign patients at his hospital jumped to more than 380,000 this year, from about 168,000 in 2000.

Quality Assurance in Globalization of Medicine

The Joint Commission International is a U.S.-based accreditor of health-care organizations around the world, which
extends [Joint Commission on Accreditation of Healthcare Organizations (JCAHO)]'s mission worldwide. Through international consultation, accreditation, publications and education, Joint Commission International helps to improve the quality of patient care in many nations. Joint Commission International has extensive international experience working with public and private health care organizations and local governments in more than 60 countries.

What this means for medical students

I personally do not see any significant force or event of sufficent strength and persistence--save an all-out WWIII as in Scorpion's Gate--to reverse this emerging trend. One could make the argument that for U.S. patients, the psychological and financial barriers are a bit higher, given the longer distance required for travel and the stronger baseline suspicion we harbor towards foreign science and technology. But at least within regions--specifically Asia and Europe where medical tourism has been observed by local media to have emerged--this trend will be irreversible. The main question then is how far will this go?

From a medical student's perspective, it does not seem unreasonable to go into a global medical practice. That is, since we have no established practice of yet, this trend is less disruptive than it is promising. As an example, for 6 months out of the year, my family and I could fly to an Asian country and practice, where given the lower local costs I charge lower prices and I live cheaper. Suppose I was a pulmonologist, then I could help deal with the COPD patient population to come given the massive cigarette consumption in Asian countries. For the other 6 months of the year, I could practice in the U.S. in an academic center where I can focus on taking care of American patients and learning the latest developments of my field. For more elective services, I might even be able to refer U.S. patients to my Asian practice.

Some pre-requisite:

  • Infrastructure: sufficient number of academic centers/practice groups need to be comfortable enough with accepting such international doctors.

  • Accreditation: it sure would be nice if medical licensure can become global. I don't see this happening anytime soon since this is the major mechanism for controlling the supply of doctors in the U.S.

  • Well my hypothetical wife and children will have to be able to accept this lifestyle. As far as education for children... I guess I'll just enroll them in MIT's Open CourseWare :)

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December 03, 2005

WHO Stops Hiring Smokers

Sam Cage via AP via WaPo:

"WHO has taken a very public lead in the fight against tobacco use," spokesman Iain Simpson said. "As a matter of principle, WHO does not want to recruit smokers."

WHO chief Lee Jong-wook wrote a letter to U.N. Secretary-General Kofi Annan asking him to consider whether all United Nations agencies and offices should be made smoke-free areas.

For example, the WHO job posting for an Epidemiologist in New Delhi has this at the bottom:

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NYT Editorial on "South Korea's Cloning Crisis"

Continued fall out of Dr. Hwang Woo Suk's use of his underlings' eggs for stem cell research.

How harshly Dr. Hwang should be judged for such transgressions is a matter of dispute... But what really torpedoed Dr. Hwang was the cover-up: his repeated lies to the effect that his eggs were donated by unpaid volunteers. These misrepresentations led his most prominent American collaborator to sever ties because his trust had been shaken.

Actually I believe Dr. Hwang has only admitted to ignorance of these problems.

The key unresolved issue is whether lying about egg donations suggests that the Korean team may have lied about its scientific results... American collaborators and observers remain confident that the team's achievements were real. But science is an enterprise that relies heavily on trust. The Koreans should not be surprised if their next scientific breakthrough is greeted with extreme caution.

I'm afraid NYT is being a bit harsh here. Is one research group's actions to taint the scientific output of one Department? University? An entire Country?

While their personalities are apparently disparate, I like to compare Prof Hwang with our own Dr. Craig Venter. Both scientists of vision. Both ostracized for the source of their research raw material. (Recall the human genome sequenced by Celera/Applera was Venter's own)

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December 02, 2005

GAO - Geographic variations in pricing and spending of the Federal Employees Health Benefits Program (FEHBP)

Government Accountability Office's Health Care Director Bruce Steinwald testifies before the House's Subcommittee on Health, Committee on Ways and Means, titled "Differences in Health Care Prices Across Metropolitan Areas Linked to Competition and Other Factors".

What can this report tell us? According to the GAO, the prices that FEHBP preferred provider organizations (PPOs) negotiate with hospitals and physicians are comparable to those negotiated by PPOs working with private sector employers. And since prices for FEHBP PPO show great geographical variations--prices for hospital stays vary by more than 250 percent and that for physician services by about 100 percent across metropolitan areas, understanding the factors contributing to these price differences may shed some light on price differences ordinary consumers across the U.S. encounter.


Market competitiveness was defined as either:

  1. Hospital competition: a measure of concentration of hospital beds across all hospitals in the metro area.

  2. Payer bargaining power: measured as percentage of HMO capitation in the area.

Main results

  1. "Areas with the least competitive markets�that is, areas with a higher percentage of hospital beds concentrated in the two largest hospitals or hospital networks�had prices of hospital stays and physician services that were higher than areas with the most competitive markets."

  2. When other factors are controlled for, the associations between hospital competition and payer bargaining power with lower prices are decreased, but remain statistically significant. And much variation remained unexplained.

  3. In general, price (e.g., price per night of hospital stay) contributed to 1/3 of the geographic differences in spending per enrollee, whereas utilization (e.g., number of days of hospital stay) explained the other 2/3.

This report was not very detailed as far as its methodology. We also note that this testimony is not written with the usual and customary tone of neutrality that characterize other GAO reports I have read.

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December 01, 2005

SLIM, from NCBI comes a fantastic alternative PubMed search interface for clinicians!

A pre-print from BMC Medical Informatics and Decision Making 2005, "SLIM: an alternative Web interface for MEDLINE/PubMed searches - a preliminary study", by Michael Muin, Paul Fontelo, Fang Liu, and Michael Ackerman from NCBI.

You have to give SLIM a try at http://pmi.nlm.nih.gov/slide/.

Muin et al have have given the PubMed "Limits" search capability a complete makeover. Using Javascript and DHTML, they use an interface based on sliders for users to limit search by:

  1. Publication date: going back 1 year? 2 years? ... no need to laboriously type in dates

  2. Journal subset: from all journals to the 120 core clinical journals in the Abridged Index Medicus

  3. Age group

  4. Study design: from case reports to randomized clinical trials to systematic reviews

  5. Search mapping: e.g. text search in Title/Abstract, MeSH term search, etc

Preset values are available for common limits such as recent systematic reviews.

The search results can be displayed in the same page. Individual abstracts can be expanded/collapsed easily.

SLIM was written in PHP and developed on an Apache 2.0.52 server running PHP 4.3.10. The PHP scripts generate a HyperText Markup Language (HTML) and JavaScript search form. JavaScript provides most of the functionality of the search form and search results. Free and open source JavaScript codes were downloaded from the Internet for the slider controls.

Muin et al make use of widgets obtained from WebFx and Dynamic Drive.

Eighteen physicians from the US, Australia and the Philippines participated in the beta-testing phase of the application and provided performance and usability feedback through an online survey.

I love this interface!

As an example, here I search for "paroxetine" and "suicide" and limit my search to the core clinical journals and the age group to adolescents, like so:

The results are displayed as:


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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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