July 2008 Archives

While the effects of anti-amyloid agents in Alzheimer's disease (AD) have been less than overwhelming (see here and here, for example), a phase 2 study presented at the recent International Conference on Alzheimer's Disease suggests that going after tangle-related tau protein may be more fruitful.

A formulation of methylene blue—yeah, the Wright's stain agent—produced a significant 5.5-point difference (vs placebo) on the ADAS-cog at 24 weeks in patients with moderate AD. The proprietary drug, trade name "rember" (ugh), was assessed in an initial double-blind, randomized, placebo-controlled, dose-ranging study in mild-to-moderate AD (N = 321), followed by a blinded, extension phase. Pooled data after 19 months revealed a significant 6.8-point difference on the ADAS-cog in patients with either mild or moderate AD. Statistically significant cognitive changes at both time points were observed with the dosage of 60 mg tid, versus initial placebo treatment.

Rember was evidently well tolerated in the phase 2 trial, except for a high incidence of diarrhea, which may depend on the drug's intestinal absorption. Reports indicate that the efficacy and tolerability of a 100-mg dose may have been compromised because of formulation problems.

Rember is an investigational agent of TauRx Therapeutics and inhibits in-vitro tau aggregation, the foundation of AD's neurofibrillary tangles. The clinical study was headed and presented by Claude M. Wischik, MBChB, of the University of Aberdeen, who also happens to be founder and executive chairman of TauRx.

A large phase 3 trial of rember in AD is planned but awaits FDA approval.

Primary sources: Medpage Today; AP via Yahoo.

As if you need another reason to bang your head against a wall on Wall Street.

After phase 2 data of bapineuzumab in Alzheimier's disease (AD) were released on June 17, shares of Elan and Wyeth climbed 10.6% and 4.8%, respectively. However, after the same data were presented yesterday at the International Conference on Alzheimer's Disease (ICAD) in Chicago, the share prices dropped 19.6% and 11.2%, respectively. So what were the differences between the June press release and the meeting presentation? Not a heck of a lot.

 

Both presentations provided information about the missed primary endpoint in the trial, a change in cognition or disability at 18 months (although the primary outcome was buried in the second paragraph of the June press release). Both provided information about the post-hoc assessment of subgroup data—namely, that ApoE4 noncarriers performed statistically better on the ADAS-cog at 18 months (mean score difference: 5 points, bapinueuzumab vs placebo). And both reported a risk of vasogenic brain edema with the agent, especially in ApoE4 carriers.

In June, analysts talked up the bapineuzumab phase 2 study, despite the missed primary endpoint, and the companies' prospects. Yesterday, not so much. Nevertheless, Elan and Wyeth are apparently moving forward with phase 3 investigation of the amyloid buster in AD.

Women who live into their 90s are significantly more likely to be demented than similarly aged men, according to a report in this week's issue of Neurology. The finding supports data from previous studies, in which the prevalence of dementia among centenarians was higher among surviving women.

By using in-person examination data and telephone and informant questionnaires, US investigators assessed the all-cause dementia rate among participants in the so-called 90+ Study (N = 911). Among women, the overall dementia rate was 45% (95% CI: 41.5, 49.0), versus 28% (95% CI: 21.7, 34.2) among men. Moreover, the dementia rate in women doubled every 5 years after the age of 90 (Figure). Dementia in women, but not men, correlated inversely with education. From a glass-half-full perspective, dementia was not universal in women 100 years of age or older (61%).

In an accompanying editorial, David Hogan, MD, cites limitations of the study including differing methods used for the diagnosis of dementia; the characteristics of the study population (white, relatively well educated, upper middle class); insufficient pathologic data; a high lost-to-study rate (21%); and a low absolute number of dementia cases among men 95 years of age or older (n = 23). However, Hogan supports the overall conclusion and suggests that the lack of an age-associated increase in dementia among very old men may be due to their shortened survival with the condition.

A confirmed case of the uncommon LaCrosse encephalitis was reported recently in northern Virginia—a notable story (at least for the local news source), because the disease "typically occurs" further south in the state. The Virginia report and yesterday's news of several cases of West Nile disease in Los Angeles provide an opportunity to review here the mosquito-transmitted encephalitides that occur in the not-always-good-old summertime.

Causing about 70 cases of encephalitis per year in the United States, the LaCrosse virus belongs to the Bunyaviridae family of negative-stranded RNA viruses. The main transmission cycle is between small vertebrate hosts, like squirrels or chipmunks, and the treehole mosquito. LaCrosse encephalitis in humans occurs mainly in Appalachia and the Midwest (the disease was first recognized in 1963 in La Crosse, WI). Although most cases of infection are asymptomatic, the latency from mosquito bite to symptoms (either a flu-like illness or, less commonly, frank encephalitis) ranges from 5 to 15 days. Those who are especially susceptible to disease in endemic areas are persons engaged in outdoor activities and children younger than 16 years of age. The fatality rate, however, is less than 1%.

Both the West Nile and St. Louis viruses belong to the family Flaviviridae, genus Flavivirus—positive-stranded RNA viruses. The transmission cycle for these viruses, like that for most arboviruses, is between wild birds and mosquitoes. In 2003, there were more than 9800 cases of documented West Nile encephalitis in the United States, and the average annual number of cases of St. Louis encephalitis is approximately 110. West Nile encephalitis has spread rapidly throughout the United States, since its recognition in New York in 1999. St. Louis encephalitis occurs most often in the central and eastern parts of the country. The latency from bite to symptoms for both infections ranges from 3 to 15 days; although, the overwhelming majority of infected persons remain asymptomatic. For the less-than-1% of those who do develop encephalitis, the fatality rate is 50% for West Nile (2002-2003 data) and 5%-30% for St. Louis disease. Older individuals are particularly vulnerable.

The Eastern and Western Equine Encephalitis viruses belong to the family Togaviridae, genus Alphavirus— positive single-stranded RNA viruses. The main transmission cycle for these viruses is also between wild birds and mosquitoes, and, as the name implies, horses are common "dead-end" hosts. Infection with the Eastern Equine Encephalitis virus (EEEV) is most common in the eastern part of the United States, with the largest number of encephalitis cases in Florida, Georgia, Massachusetts, and New Jersey. Infection with the Western Equine Encephalitis virus (WEEV) is most prevalent in the plains regions. The average annual number of EEEV and WEEV encephalitis cases in the United States is 5 and 15, respectively. Like persons infected other arboviruses, those with EEEV and WEEV are mostly likely to remain asymptomatic. Symptoms, if manifest, occur approximately 3-10 days after a bite from a transmitting mosquito. Persons older than 50 years of age or younger than 15 years are at greatest risk for developing severe infection with either virus; although, the fatality rate with EEEV (33%) among symptomatic persons is much higher than that with WEEV (3%).

The most common and reportedly efficient way to diagnose infection with these viruses is to assay for neutralizing IgM antibodies in either serum or CSF. Care is purely supportive for symptomatic individuals. There are no vaccines to prevent human disease; although vaccines to prevent EEEV and WEEV in horses are evidently available.

Primary source: CDC

Photo of Culex quinquefasciatus, known to transmit St. Louis encephalitis virus, from Galveston County Mosquito Control.

The longstanding answer to inactivity in the city kid is now an official, judged sport in NYC schools, writes the AP.

A video segment of the 2006 Double Dutch Holiday Classic at the Apollo Theater: The Harlem crowd reacts with lovable honesty to a Japan team's Best in Show win.

Reportedly one of Dustin Hoffman's favorites, Straight Time (1978) also features newbies Gary Busey (before he went absolutely meshuga), Kathy Bates, and Theresa Russell, along with M. Emmet Walsh. Rock on, casting director Dianne Crittenden.

Hoffman, playing lifelong con and current parolee Max Dembo, tries to make it—as the film title indicates—legitimately.

In honor of the upcoming Olympics and prompted by recent (alleged) doping incidents, here are the substances prohibited by the World Anti-Doping Agency (WADA). The list indicates that world-class athletes and trainers are highly enterprising in their search for (and cover-up of) that little extra edge.

Prohibited in and out of competition

1. Exogenous and endogenous anabolic androgenic steroids (AAS): A perennial favorite. Olympic athletes from East Germany, especially female swimmers, were systematically doped with AAS from 1965 to 1989, as were the obviously acned, female swimmers from China in the 1990s. According to sports medicine expert Ken Fitch, MD, AAS was the most frequently detected category of banned substances in athletes who participated in the last 2 Summer Olympics. Canadian sprinter Ben Johnson famously lost his gold medal from the 1988 games owing to the post-race detection of anabolic steroids. And last year, American medalist Marion Jones admitted to anabolic steroid use in preparation for the 2000 Olympics in Sydney. The use of designer AAS, which may evade current detection methods, has emerged as a particular problem during the last few years, writes Fitch.
2. Other anabolic agents: The β2 adrenergic agonist clenbuterol was allegedly detected in urine samples this month from US swimmer Jessica Hardy. Selective androgen-receptor modulators, investigational agents for the treatment of osteoporosis and muscle atrophy, are new to the WADA list as of this year. Tibolone is a postmenopausal hormone replacement therapy (HRT) with estrogenic, progestogenic, and androgenic properties. Also banned are the cattle-feed steroids zeranol and zilpaterol.
3. Other hormones and related substances: Doping with erythropoiesis-stimulating agents (ESAs) is notorious in endurance sports, like cycling and long-distance running. Also widely abused, human growth hormone (hGH) is reportedly taken frequently with AAS by doping athletes. However, a reliable test for distinguishing exogenous from endogenous hGH has been elusive, according to the literature, and physiologic levels of hGH can vary widely within and among individuals. Other banned endocrinologic agents include insulin-like growth factors, the new-to-me mechano growth factors (MGFs), gonadotrophins (luteinizing hormone, human chorionic gonadotropin* [in men only]), insulins, and corticotrophins.
4. β2 agonists: For example, clenbuterol. The use of inhaled anti-asthmatic drugs, like formoterol, salbutamol, salmeterol, and terbutaline, requires an Abbreviated Therapeutic Use Exemption.
5. Hormone antagonists and modulators: Here's disturbing enterprise. Athletes use agents indicated for hormone-receptor-positive breast cancer, like aromatase inhibitors (eg, anastrozole) or selective estrogen-receptor modulators (eg, tamoxifen), to produce an indirect androgenic effect. Also new to the WADA list this year are inhibitors of myostatin, an endogenous factor that limits the growth of muscle tissue.
6. Diuretics and masking agents: The general idea is either pee out the banned substance or dilute it. An example of a masking agent is epitestosterone, which is used to normalize the testosterone-to-epitestosterone ratio during traditional testing. According to Wikipedia, US runner Mary Decker failed a T/E ratio test in 1996. Other banned substances in this category, besides traditional diuretics, are probenecid, α-reductase inhibitors, and plasma expanders (eg, albumin).
7. Blood and blood substitutes
8. Gene doping: Circulating now is news of a German TV report that warns of gene doping (eg, stem cell therapy) offered in China.

Prohibited in competition

1. Stimulants: For example, amphetamine, ephedrine.
2. Narcotics
3. Cannabinoids: Not even in snowboarding, dude.
4. Nontopical glucocorticoids: Although intra-articular and similar local injections require an Abbreviated Therapeutic Use Exemption.

Prohibited in particular sports

1. Alcohol: With regard to the Olympics, alcohol levels greater than 0.10 g/L are prohibited in archery (ouch), karate (huh?), and shooting sports (bigger ouch).
2. β-blockers: The use of β-blockers is prohibited in archery (in and out of competition), bobsledding (but not luging?), curling (aw, somebody cares), gymnastics, shooting sports, skiing, snowboarding, and wrestling.

* Yes, the pregnancy hormone.

Photo: Qian Hong, winner of the 100-m butterfly at the 1992 Barcelona Olympics and possessor of killer triceps.

Contrary to reported statements made by WADA president John Fahey to the Australian Broadcasting Corp., Roche now clarifies to Bloomberg that the company did not plant a molecule in Mircera to aid detection of the drug in athletes. The drug was evidently identified in cyclist Riccardo Ricco because "WADA received the molecule well in advance and was able to develop ways to detect it, including through the current EPO detection method," commented the agency.

In an online statement, Roche writes that it provided samples of Mircera, which is functionally and structurally different from endogenous erythropoietin and all other erythropoiesis-stimulating agents, and assay reagents to WADA to ensure that the agency could conduct reliable testing.

Unfortunately it remains unclear whether Fahey misspoke to (or was misinterpreted by) the Australian news source or WADA is backtracking for reasons of trade secrecy.

WADA = World Anti-Doping Agency.

Update: Expect a whole lot more doping news in the near future. NBC's Olympics web site reports that US swimmer Jessica Hardy, 21, tested positive for the banned β2 adrenergic agonist clenbuterol. Tests for the substance on 2 samples from July 4 were both positive, but samples from July 1 and July 6 were negative, reveals the web site. According to Wikipedia, the half-life of clenbuterol is approximately 37 hours.

With the media fixation on the cholesterol-lowering combo Vytorin (ezetimibe/simvastatin)—namely, the negative results of the ENHANCE study and the SEAS trial—it's easy to forget that statins alone have their drawbacks. Case in point is the well-known risk of myopathy with the drug class, which is reported to occur approximately once per 10,000 patients who take lower-dose therapy.

This incidence rate may seem inconsequential, until you remember that about 13 million Americans take statins—some at high dosages and with drugs that can inhibit statin metabolism (thereby increasing the risk of drug-associated myopathy).

In this week's issue of the NEJM, UK investigators report a "single strong association" of simvastatin-related myopathy* with the presence of the rs436657 single-nucleotide polymorphism (SNP) on the gene SLCO1B1 (chromosome 12). The SLCO1B1 gene encodes for an organic anion-transporting polypeptide that has been shown to regulate the hepatic uptake of statins—suggesting that the SNP dictates a class effect for the risk of myopathy. The odds ratio for myopathy was 16.9 (95% CI: 4.7, 61.1) in individuals homozygous for the C (cytosine) allele, versus individuals homozygous for the T (thymidine) allele.

Genetic data were collected and analyzed from 85 subjects who developed myopathy while taking simvastatin 80 mg/d in the Study of the Effectiveness of Additional Reduction in Cholesterol and Homocysteine (SEARCH) (N = 12,064) and compared with data from 90 subjects who did not develop myopathy while taking high-dose simvastatin. The SNP association with myopathy in SEARCH was corroborated by data from the Heart Protection Study of simvastatin 40 mg/d; although the relative risk with a C allele was less robust in this lower-dose study.

Other relative risks for baseline patient characteristics from SEARCH reveal a markedly elevated risk of simvastatin-associated myopathy with the concomitant use of amiodarone.

Characteristic	Relative Risk of Definite or Incipient Myopathy During First Year (95% CI)
Age ≥65 vs <65 y	2.3 (1.3, 4.1)
Female vs male	1.6 (0.9, 3.0)
GFR <60 vs ≥60 mL/min/1.73 m2	2.4 (1.3, 4.3)
Creatinine  ≥85 vs <85 µmol/L	2.5 (1.4, 4.6)
Amiodarone use vs no use	8.8 (4.2, 18.4)
Calcium antagonist use vs no use	2.7 (1.6, 4.5)
DM vs no DM	1.2 (0.6, 2.7)

The authors conclude that genotyping of SLCO1B1 polymorphisms may enable safer statin treatment, and Yusuke Nakamura, MD, PhD, advises in an accompanying editorial that SLCO1B1 variants must be tested for an association with a more severe myopathic event, statin-induced rhabomyolosis, as soon as possible.

* Reversible.

Italian cyclist and Tour de France competitor Riccardo Ricco was caught doping with Roche's new erythropoiesis-stimulating agent (ESA) Mircera, according to numerous news reports today. An official of the World Anti-Doping Agency (WADA) reported to Bloomberg that use of the drug—a long-acting, pegylated version of epoetin beta—was made detectable because of an implanted, traceable molecule within the product. A brief scan of relevant, online FDA documents suggests that the implanted molecule is a trade secret of Roche.

In June, Danish investigators indicated that the detection of older, shorter-acting ESAs, namely recombinant human erythropoietin (rHuEpo), in urine by WADA laboratories is highly unreliable. The official WADA method is to distinguish endogenous Epo from rHuEpo on the basis of molecular charge, a technique that has been criticized for generating a high number of false positives and negatives.

To assess the reliability of current rHuEpo testing by WADA labs, the Danish investigators injected 8 healthy, nonathlete, male university students with rHuEpo, by using a boosting (5000 IU qod x 14 d) and maintenance (q weekly x 2 weeks) program. Urine samples were submitted to 2 different WADA labs for testing, with the following results.

Phase	Laboratory A	Laboratory B
Boosting	All positive	None positive
Maintenance	6/16 positive; 2 suspect	5 suspect
Posttreatment	2/24 positive; 3 suspect	None positive

The investigators also found little correlation between suspect or positive results from the 2 WADA labs and suggest that the "only strategy which provides a possible chance for obtaining a positive urine Epo test" is to perform out-of-competition testing at more than 1 WADA lab during the suspect rHuEpo boosting period. Alternatively they suggest that efforts should be focused on reliable detection, such as that evidently facilitated by Roche for Mircera.

Photo: iStockPhoto

This may be merely an example of water seeking its own level, but World Wrestling Entertainment and Jenny McCarthy will be getting together next month on prime-time network TV* to support Generation Rescue, an organization which promotes the unfounded (and dangerous) idea that "toxins" in vaccines produce autism and other neuropsychiatric disorders in children.

I suspect between choreographed body slams, there will be no discussion of the hazards of anabolic steroids.

* NBC, to be exact.

The fact can never be emphasized sufficiently: The results of retrospective, observational studies do not necessarily predict the outcomes of prospective trials.

Case in point is the missed primary endpoint in the prospective, placebo-controlled SEAS trial, in which the combination of ezetimibe and simvastatin (Vytorin; Schering-Plough/Merck) failed to reduce major cardiovascular events associated with aortic valve or atherosclerotic disease. These results follow those of 2 double-blind, placebo-controlled studies of atorvastatin (Lipitor; Pfizer) in aortic stenosis (AS) (see here and here), which also showed that the cholesterol-lowering drug did not alter AS progression.

The proposal that statins may alter the course of AS isn't a bad one, given the association between hypercholesterolemia, coronary artery disease, and atheroma. And in fact, several retrospective, observational studies showed that statin therapy delayed AS progression, as measured by hemodynamics and valvular calcification. But the idea, clearly, has not been realized to date in prospective evaluations.*

Two other interesting results of the SEAS trial, according to the press release, are 1) a significant reduction of the secondary endpoint of atherosclerotic events (nonfatal MI, CABG, PCI, hospitalization for unstable angina, nonhemorrhagic stroke, and cardiovascular death); and 2) a significant and unexplained increase in the incidence of cancer (9.9% vs 7.0%; P = .02).

The former result may portend a positive outcome in IMPROVE-IT, a comparison of ezetimibe/simvastatin with simvastatin alone to reduce the primary composite endpoint of major coronary events, stroke, or cardiovascular death. As far as a potential cancer risk is concerned, an independent analysis of the data from IMPROVE-IT and another ezetimibe/simvastatin study, SHARP, revealed that the overall risk of cancer is not increased with the drug.

IMPROVE-IT: Improved Reduction of Outcomes: Vytorin Efficacy International Trial; PCI = percutaneous coronary intervention; SEAS = Simvastatin and Ezetimibe in Aortic Stensosis; SHARP = Study of Heart and Renal Protection.

* A prospective study of rosuvastatin in AS is ongoing. Results are expected at the end of the year.

Update: Over at the Disease Management Care Blog, Jaan Sidorov considers the blogger-fomented Vytorin-cancer scare and says, more or less, "Drink your juice, Shelby."

Immunization with synthetic amyloid beta (AN1792; Elan) clears amyloid plaques in brain but is not associated with improved cognition or survival in the long term, according to a small UK study of patients with Alzheimer's disease (AD). Results of the placebo-controlled trial, funded by the Alzheimer's Research Trust, were published in this month's issue of The Lancet.

A total of 80 patients with probable mild-to-moderate AD received either randomly assigned AN1792 (50 or 225 ug) with adjuvant (n = 64) or adjuvant alone (n = 16).* Postmortem examination of 8 actively treated AD patients revealed a significantly lower Aβ load than that in nonimmunized controls.^† However, the investigators noted considerable variation of the Aβ load and the extent of plaque removal among immunized cases.

There was no relationship between the dose of AN1792 and Aβ load or postmortem plaque removal, but the mean antibody response during treatment showed a nonsignificant correlation with Aβ load. Seven of the 8 patients, including those who demonstrated "virtually complete plaque removal," exhibited severe end-stage dementia, and there were no survival or cognitive differences between the immunized and placebo-treated groups.

A phase 2a study of AN1792 was halted when 6% of patients developed meningoencephalitis. The study did not show relative cognitive improvement at 1 year with immunization, despite the presence of high levels of Aβ antibodies. In June, Elan and Wyeth announced favorable results with the anti-Aβ monoclonal antibody bapineuzumab in mild-moderate AD, despite the fact that the primary endpoint in the phase 2 trial was not met.

* In a protocol extension, patients received either AN1792 (n = 51) or adjuvant alone (n = 13) in a modified formulation to increase Aβ solubility.

† Because no patients in the placebo-treated group underwent postmortem examination, histologic findings in an age-matched, nonimmunized control group of patients with AD were used for comparison.

Image of wild-type amyloid precursor protein (left) and amyloid fibril (right) by David S. Goodsell from Wikimedia Commons.

A wonderful girl's movie: I Know Where I'm Going! (1945) with Wendy Hiller. Any heroine whose lifetime mantra is the movie title is bound to be sidetracked on the way to her wedding in the Hebrides. Enjoy the lilt of the occasional, impenetrable Gaelic and look for a brief appearance by 12-year-old Petula Clark.

Poster image from Wikipedia and reproduced under fair use law.

Not exactly a US public health menace, but the rise of Balamuthia mandrillis encephalitis is something worth watching. The latest issue of the MMWR provides information on 10 cases identified between 1999 and 2007 by the California Encephalitis Project. Since the recognition of balamuthiasis in 1989 (in a pregnant mandrill baboon at the San Diego Zoo), 150 human cases have been identified worldwide.

What is Balamuthia mandrillis?
A free-living amoeba in soil.

How is disease transmitted?
Airborne cysts are inhaled, or skin lesions are directly contaminated.

Who or what is affected?
Immunocompetent or immunocompromised humans, nonhuman primates, horses, dogs, and sheep. People with occupational or recreational exposure to soil (agriculture, construction, dirt biking) may be especially vulnerable.

What are disease symptoms?
Those consistent with other forms of encephalitis—eg, fever, encephalopathy, cranial nerve palsies, seizures.

What does the CSF look like?
Markedly elevated protein (>100 mg/dL); elevated WBC with a predominance of lympocytes; normal or low glucose.

What does brain MRI look like?
Typically abnormal. In the California cases, multiple ring-enhancing lesions, white matter lesions, hypointense lesions, or hydrocephalus were noted.

How is disease definitively diagnosed?
Indirect immunofluorescence staining of formalin-fixed tissue—eg, brain. PCR testing for Balamuthia DNA in CSF or brain tissue has been used; although, the specificity and sensitivity of PCR testing for Balamuthia are unknown, as are the specificity and sensitivity of serologic testing.

Where are reference laboratories? 
At the CDC (gsv1@cdc.gov) and the California Department of Public Health (shilpa.gavile@cdph.ca.gov).

What is the treatment?
Three surviving patients in the United States received pentamidine isethionate, fluconazole, flucytosine, sulfadiazine, and a macrolide antibiotic (azithromycin or clarthromycin).

What is the survival rate?
In the California cases, approximately 10%.

Who or what is Balamuth?
Balamuthia co-discoverer Govinda S. Visvesvara, PhD, of the CDC, writes by e-mail that the organism was named after his major advisor, William Balamuth (1914-1981), Professor of Zoology at UC Berkeley. How's that for homage?

Photomicrograph of Balamuthia mandrillis trophozoites in brain tissue from the CDC.

Do college premeds really need a second semester of organic chemistry? That's the question asked and answered by Jules Dienstag, MD, in this week's issue of the NEJM. Dienstag argues that the longstanding premed requirements of 1 year of biology, 2 years of chemistry (including 1 year of organic chemistry), and 1 year of physics "fail to...prepare students for tackling the sciences fundamental to medicine at the advanced molecular level." He continues, "We should expect a higher standard from students who wish to pursue medicine in an era in which genomics and informatics will revolutionize biomedical science and health care."

Dienstag argues for premed science requirements that are more relevant to today's medicine, as opposed to teaching the principles of 19th-century chemistry (as my orgo professor mused more than 20 years ago) to budding doctors. Instead of a second round of orgo,* go right into introductory biochem, he proposes—introducing molecular reactions that are actually relevant to bodily function and the manifestation of disease.

Dienstag also urges the integration of traditionally compartmentalized disciplines, like physiology, anatomy, and genetics, to foster a holistic approach to health and disease. And he rightly emphasizes a foundation in writing and communications skills. On this subject, I would stress a full semester of basic grammar and style (even if it's a bloody review), perhaps focusing on medical and scientific communications. Having been on the receiving end of medical manuscripts, I've noted these skills to be embarrassingly poor in too many established, academically based physicians.

* Not once do I recall the benefit in medical practice of knowing the Grignard reaction, and I was one of those freaks who liked organic chemistry.

Image of formation of Grignard reagent from Wikipedia.

Daniel Carlat argued yesterday that Pfizer withdrew its direct commercial support of MECC-sponsored CME because MECCs―unlike other CME-producing organizations―receive most of their income from industry-funded CME. The argument is that, because MECCs are so dependent on industry for their existence, they are more likely to bias their CME to curry favor and foster continued business with the industry grantor. 

However, this explanation ignores the fact that pharma income of other CME-producing organizations, like medical societies, is not inconsequential, despite what Dr. Carlat alleges. For instance, by examining the ACCME's 2006 Annual Report (the same report that Dr. Carlat references), it is apparent that the collective, net commercial income (total commercial support – total expense) for nonprofit organizations (eg, a physician membership organization) was actually higher than that for publishing/education companies in 2006: $247,782,325 vs $210,811,540. And the average net income per nonprofit organization (n = 267) was not that far behind the net income per publishing/education company (n = 154): $928,024 vs $1,368,906.

Organization Type	2006 Net Income	Average Net Income per Organization
Government or military (n = 16)	-935,343	-58,459
Hospital/health care delivery system (n = 93)	-287,209	-3088
Insurance company/ managed care company (n = 14)	-4,308,420	-307,744
Nonprofit, other (n = 34)	26,122,848	768,319
Nonprofit (eg, MD organization) (n = 267)	247,782,325	928,024
Not classified (n = 29)	12,946,920	446,446
Publishing/education company (n = 154)	210,811,540	1,368,906
School of medicine (n = 122)	71,740,237	588,035

So while Dr. Carlat argues that loss of pharma CME income for a big-budget academic medical center would "cause barely a hiccup," this is not likely the case for a medical society operating on much smaller revenues. For instance, the 2006 expenses of the American Academy of Neurology, the flagship organization of practicing neurologists, totaled approximately $3.5 million.

Pfizer's move to cut off MECCs, I would argue, is primarily (if not solely) based on the perception of bias in MECC-generated CME, not actual bias.* Otherwise, according to Dr. Carlat's argument, Pfizer would have considered cutting off direct CME grants to medical societies as well―a questionable PR move.

ACCME = Accreditation Council for Continuing Medical Education; MECC = medical education communications company.

* And if bias did exist in Pfizer-funded CME, it's only because Pfizer expected (even demanded) bias. 

Esmin Green, whose June 19 death in the waiting room of Brooklyn's Kings County Hospital psych ward was caught on videotape, died of pulmonary embolism. The medical examiner's conclusion was reported by the New York Daily News last weekend. According to the paper, Green may have been sitting for 20 hours, after receiving a "mild sedative," while waiting for psychiatric admission to the facility.

Although it is not known how long Green may have experienced deep vein thrombosis, the source of her embolism, earlier medical attention may have alerted physicians to its presence, resulting in appropriate medical intervention. The paper reports that, because Green's death is being classified as due to natural causes, there will be no homicide charges.

As many a blog is reporting this morning (eg, WSJ Health Blog), the Massachusetts House will vote today on a proposed pharma-code bill for the state. The vote follows yesterday's honing of the proposed legislation, which led to the removal of 1) a ban on gifts and meals to physicians; 2) the reporting of physician payments for consulting and speaking, and 3) a $5000 fine per violation. The Massachusetts Senate had unanimously passed a previous version of the bill that had included the removed items.

According to the Boston Globe, the bill will require that pharma adopt a marketing code of conduct, like the one PhRMA unveiled last week, which eliminates drug-branded tchotchkes, other noneducational gifts, and anything more than pizza or sandwiches during working hours.

Unlike the PhRMA code, however, the Massachusetts bill bans pharma's purchase and use of drug-prescribing information. New Hampshire's attempt to limit the use of these data by drug companies was judged last year to be an unconstitutional violation of commercial free speech. The AMA currently offers an opt-out program to physicians, which contractually obligates pharma from sharing their prescribing information with reps.

July 17 update: The Massachusetts House unanimously approved the watered-down bill, according to today's Boston Globe. But the House voted to delay the effective date of the part of the bill that bars the purchase by pharma of prescription info (to November 2009), while New Hampshire wrestles with the issue of commercial free speech. The differences between the bill passed in the Senate and the bill passed in the House will probably be reconciled before the end of the month, the paper writes.

The use of rofecoxib (Vioxx; Merck) or valdecoxib (Bextra; Pfizer), but not celecoxib (Celebrex; Pfizer), increased the risk of stroke in a retrospective study of Medicaid enrollees. Results of the study, which are consistent with several, previous observational studies, were published in this month's issue of Stroke.

Investigators at Vanderbilt examined the incidence of ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage among 336,906 noninstitutionalized enrollees, aged 50-84 years, in the Tennessee Medicaid program (TennCare) from 1999 through 2004 and the use of commonly prescribed NSAIDs, including the coxibs rofecoxib, valdecoxib, and celecoxib. The adjusted* hazard ratios (HRs) for stroke among all NSAID users and among new NSAID users (to reduce bias) are shown (reference = nonusers).

Exposure	All NSAID Users (n = 94,456)	New NSAID Users
	Adjusted HR (95% CI)
Celecoxib	1.04 (0.87, 1.23)	1.12 (0.83, 1.52)
Rofecoxib	1.28 (1.06, 1.53)	1.46 (1.08, 1.98)
Valdecoxib	1.41 (1.04, 1.91)	1.39 (0.74, 2.59)
Naproxen	0.94 (0.80, 1.11)	1.02 (0.73, 1.42)
Ibuprofen	0.88 (0.73, 1.06)	1.26 (0.87, 1.81)
Diclofenac	0.94 (0.59, 1.49)	0.31 (0.04, 2.18)
Indomethacin	1.20 (0.85, 1.69)	1.29 (0.53, 3.09)
Other NSAID	1.04 (0.87, 1.23)	1.23 (0.84, 1.78)
Former NSAID	1.02 (0.94, 1.10)	1.02 (0.95, 1.10)
Former rofecoxib	1.16 (0.96, 1.39)	…
Former valdecoxib	1.17 (0.83, 1.66)	…

Hospitalization for stroke was most common among users of low-dose rofecoxib or valdecoxib. Most strokes were identified as ischemic, and the risk of hemorrhagic stroke (intracerebral and subarachnoid hemorrhages) did not differ significantly by NSAID exposure.

The investigators found that all enrollees in the TennCare program were at high risk for vascular disease, and one quarter had "serious" cardiovascular disease before entering the program. More than 60% were taking one or more antihypertensive agents at baseline. A higher percentage of coxib users had been diagnosed with atrial fibrillation and took anticoagulants or platelet inhibitors. However, aspirin use and smoking-related conditions did not differ appreciably between NSAID users and nonusers in the cohort.

Both rofecoxib and valdecoxib were withdrawn from the market (September 2004 and April 2005, respectively) owing to drug-related cardiovascular adverse effects. Celecoxib remains on the market, despite reports of increased cardiovascular risk with high dosages. The TennCare study, however, showed no significantly increased risk of stroke with the use of celecoxib.

Because NSAIDs have both antithrombotic activity (inhibition of platelet thromboxane) and prothrombotic activity (inhibition of prostacylin), the balance of these activities or the relative potency of coxibs may determine cardiovascular risk, write the authors. Other possible mechanisms include the elevation of blood pressure and the promotion of atherosclerosis.

* For age, race, sex, calendar year, residence, enrollment category, rheumatologic disease, aspirin use, smoke-related illness, outpatient visits, ED visits, hospital admissions, unique no. prescription drugs, adjusted vascular risk score, and the use of anticonvulsants, antimicrobials, bronchodilators, estrogens, and psychotropic drugs.

Photo: iStockPhoto

Teva Pharmaceuticals, the maker of Copaxone (glatiramer acetate) and an aggressive peddler of generic drugs, is being investigated by Israel's Minister of Health for the company's study of Copaxone in patients with amytrophic lateral sclerosis (ALS). The investigation stems from claims made by Teva's co-licensing partner, ProNeuron, which alleges that Teva deliberately sabotaged the clinical study of Copaxone in neurodegenerative diseases to protect its exclusive interest in the drug.

Copaxone is currently approved by the US FDA for reducing relapses in relapsing-remitting multiple sclerosis (MS). North American and European sales of the drug during the first quarter of this year approached $2 billion, according to news sources.

The co-licensing back story is gleaned largely from a December 2007 story in Haaretz and a recent report in the Globes. (However, the linear story of the 2 companies, especially beginning around 2006, is not as transparent as it could be.)

1986: Yeda, which commercializes intellectual property from Israel's Weizmann Institute, and Teva enter into a licensing agreement, which allows Teva to develop glatiramer acetate (copolymer-1) for the treatment of MS.

1996: On the basis of preclinical glaucoma studies, Yeda gives biotech startup ProNeuron a license to develop glatiramer acetate for the treatment of neurodegenerative diseases.

December 1996: The US FDA approves Copaxone 20 mg SQ daily for the reduction of relapses in relapsing-remitting MS.

1996 and later: ProNeuron conducts preclinical trials, which show that "vaccination" with glatiramer acetate is effective in certain neurodegenerative conditions, like a Huntington's disease model or in cases of optic nerve degeneration due to glaucoma (eg, Kipnis J et al. Proc Natl Acad Sci U S A. 2000;97:7446-7451). However, glatiramer acetate is not effective and, in fact, shows adverse effects in an animal model of ALS. On the basis of the collective preclinical results, Teva shows interest in ProNeuron.

2003: Teva, ProNeuron, and Yeda sign agreements, giving Teva a secondary license to develop and commercialize glatiramer acetate for the treatment of neurodegenerative diseases. Teva and ProNeuron set up a joint venture, in which Teva comes to own approximately 13% of the company. Drug-development milestones and ProNeuron's royalties are established.

2005: A secondary co-licensing agreement between Teva and ProNeuron (according to ProNeuron) ensures that clinical trials with glatiramer acetate in neurodegenerative diseases will begin no later than October 2006. The agreement stipulates that Teva can delay clinical development by 1 year, if it pays ProNeuron $5 million. The agreement also stipulates that, after clinical development begins, ProNeuron loses the right to terminate the agreement, if the agreement is breached by Teva. [Blogger's note: Not sure why ProNeuron would agree to this last condition.]

February 2006: According to ProNeuron, Teva negotiates to delay clinical study by a year, owing to the mixed results of the preclinical trials. However, a few days later, Teva indicates that it will begin clinical development of daily glatiramer acetate in ALS, despite the negative preclinical trial results and the fact that the glatiramer dose used in the preclinical model was not comparable to daily administration of the drug.

April 2006: Investigators at Columbia University report the results from a 6-month, prospective, randomized phase 2 study, partially funded by Teva, in which patients with ALS received randomly assigned glatiramer acetate 20 mg SQ daily or biweekly. According to the article, 30 patients were enrolled between June and September 2004 (which would predate the secondary licensing agreement between Teva and ProNeuron). The authors conclude that the tolerability of the drug and the "sufficiently meaningful" immune responses support ongoing study, despite the fact that one patient showed unusual neurodegenerative changes at autopsy.

June 2006: An international, 1-year phase 2 study of glatiramer acetate 40 mg SQ daily is begun. The study is sponsored by Teva and is to be conducted in Belgium, France, Germany, Israel, Italy, and the United Kingdom.

December 2006: An e-pub study from Johns Hopkins shows that vaccination with Teva's investigational compound, TV-5010 (which is a high-molecular-weight version of glatiramer acetate) does not alter disease onset or survival in 3 different rodent models of ALS.

December 2007: Final data are to be collected from Teva's phase 2 study of high-dose glatiramer acetate in ALS. ProNeuron asks the Tel Aviv District Court to terminate its 2003 and 2005 agreements with Teva and requests to retain its exclusive rights to develop glatiramer acetate in neurodegerative diseases. ProNeuron claims that Teva hastily conducted its ALS clinical study, knowing that the investigation was likely to fail on the basis of the negative preclinical results.

Early 2008. The Israeli Ministry of Health begins investigating the conduct of the Health Ministry, which approved Teva's ALS trial, and the Tel Aviv Sourasky Medical Center (Ichilov Hospital), where part of the trial was conducted. The investigation reveals that the Ministry of Health did not receive all of the necessary information before approving the trial—specifically the negative preclinical trial results in the ALS animal model.

March 2008: Teva announces negative results from the phase 2 trial of high-dose glatiramer acetate in ALS.

July 2008: The Israeli Ministry of Health appoints a special committee to study Teva's conduct in the clinical investigation of glatiramer acetate in ALS. On a somewhat related note, Teva reports that it will file a lawsuit against Momenta/Sandoz for patent infringement, given the filing by Momenta/Sandoz of an abbreviated NDA that requests certification of generic Copaxone.

HT: Pharmalot

Big man Laird Cregar is The Lodger (1944), a weird and weirdly sympathetic Victorian boarder, who may or may not be Jack the Ripper. The film's merits rest largely on Cregar's layered performance, along with the dramatic black-and-white photography of Lucien Ballard and the set design of a perpetually foggy London town.

Poster image from Wikipedia and reproduced under fair use law.

So far this year, 127 Americans have contracted measles (rubeola), say Federal health officials, creating the largest measles outbreak in the United States since 1997. The current outbreak is believed to be the result of unvaccinated Americans acquiring the viral disease during overseas travel.

States with measles cases now include Arizona, Arkansas, California, Georgia, Hawaii, Illinois, Louisiana, Michigan, Missouri, New York, New Mexico, Pennsylvania, Virginia, Wisconsin, and Washington. The disease has also been reported in Washington, DC. Measles was acquired in Belgium, China, Germany, India, Israel, Italy, Pakistan, the Philippines, Russia, and Switzerland, according to the CDC.

The lack of vaccination among some American children is due to the increasing use of personal or religious exemptions by parents, owing to their unsubstantiated fears of the risk of autism. Reuters reports that, last month, measles was declared endemic in England for the first time since the mid-1990s, because parents declined vaccinations for their children.

Photo of child with measles rash from the CDC.

In a moment of righteous perspective, an FDA advisory panel voted yesterday against adding a so-called black box to the labels of 11 anticonvulsive agents,* warning of suicide risks. According to the WSJ, the vote breakdown was 14 against, 4 in favor, and 3 abstaining. Other news sources report that the panel vote was segregated by profession, with clinicians voting against the black box and statisticians in favor. The panel was, however, receptive to sending a pamphlet-type medication guide to physicians, detailing the small risk of suicide associated with anticonvulsant use.

The advisory panel was convened to assess the FDA's meta-analysis of 199 placebo-controlled studies of patients with epilepsy, selected psychiatric illnesses, or pain conditions. In its analysis, the FDA found that there were 4 (0.009%) suicides in drug-treated patients and none in placebo-treated individuals. Suicidal behavior or ideation was reported in 0.37% of patients who received an anticonvulsant and in 0.22% of those who received placebo. While the risk of suicidality was almost 70% higher with anticonvulsant treatment, the absolute risk remained small at 0.15%. Despite voting against a black-box warning, yesterday's panel did confirm the FDA's findings.

*The 11 drugs are carbamazepine (Carbatrol; Shire); felbamate (Felbatol; Meda); gabapentin (Neurontin; Pfizer), lamotrigine (Lamictal; GSK); levetiracetam (Keppra; UCB); oxcarbazepine (Trileptal; Novartis); pregabaline (Lyrica; Pfizer); tiagabine (Gabitril; Cephalon); topiramate (Topamax; Ortho-McNeil); valproate (Depakote; Abbott); and zonisamide (Zonegran; Eisai).

...But close.

Today, the AMA issued a formal apology for its longstanding history of discrimination against African-American physicians. According to an AP story,

The apology comes more than 40 years after AMA delegates denounced policies at state and local medical societies dating to the 1800s that barred blacks. For decades, AMA delegates resisted efforts to get them to speak out forcefully against discrimination or to condemn the smaller medical groups that historically have had a big role in shaping AMA policy.

The AMA's apology is evidently intended to foster greater minority representation among physicians. African Americans currently represent approximately 13% of the US population but less than 3% of the nation's 1 million doctors or medical students.

You want a Viagra-branded ballpoint pen? On January 1, 2009, you'll have to go to eBay, instead of your Pfizer rep.

That's when PhRMA's updated code on industry's interactions with healthcare professionals—which is now banning non-educational gifts like pens, mugs, notepads, and (alas) stress balls—will go into effect.* Drug reps may continue to provide "modest" educational items (costing less than $100) to physicians, like medical textbooks or patient-education anatomical models. But other items, like stethoscopes, pedometers, and DVD players, are not acceptable—even if used for patient education or to promote healthy behavior. The updated code outlines other acceptable interactions in a number of contexts.

Rep visits: Reps may continue to present educational, scientific information to healthcare professionals during their work day, including mealtimes, and reps may provide "occasional, modest" meals like sandwiches or pizza to healthcare attendees. However, these visits are limited to the office or hospital, and no spouses or guests are allowed to attend. The PhRMA code also emphasizes no scavenger-like "dining and dashing."

CME: Drug companies should separate their CME grant-making functions from their sales and marketing departments (a move that most, if not all, companies have already undertaken within the last few years). Funding companies should not advise or guide the content or faculty selection for the CME program, even if asked by the CME provider. Healthcare professionals who attend industry-funded CME should not be reimbursed for their travel, lodging, or other personal expenses. That means no parking validation; so don't even ask.

Consultant/advisory relationships: The nature of these relationships should be specified in a written contract, and compensation may be made for the services of the consultant/advisor and related travel, lodging, and out-of-pocket expenses. However, meetings should not occur at resort locations (although, these venues may cost no more than non-resort locations). Also, any healthcare professional who is a member of a committee that sets formularies or develops clinical guidelines should disclose his industry relationship to the committee. This disclosure should extend for 2 years beyond the end of the industry relationship.

Speaker programs: It is important to note that the FDA holds companies accountable for the presentations of physician speakers, meaning that these speakers must be trained and must adhere to a company's medical-regulatory-approved slides and content. Therefore, the distinction between speaker programs and CME programs should be made clear to all involved. (This distinction really can't be emphasized enough.) Also, like consultant/advisory meetings, speaker events should not be held at resort locations, and any healthcare professional who is a member of a committee that sets formularies or develops clinical guidelines should disclose his industry relationship to the committee. Again, this disclosure should extend for 2 years beyond the end of the industry relationship. 

Product samples: Products samples for patient use are okay to distribute to healthcare professionals in accordance with the Prescription Drug Marketing Act.

Prescriber data: These data should not identify patient users, and companies must respect the confidential nature of the data. Companies should designate an internal contact person to handle data-use inquiries and appropriate disciplinary actions. Companies should also respect the request of any healthcare professional who asks that his/her data not be made available to company reps.  

Last, PhRMA indicates that companies completing an annual certification announcing their commitment to the updated code will be noted at the PhRMA web site.

If you're already anticipating swag withdrawal or a substantial uptick in swag value, type "drug rep" in the eBay search box.

* According to the Promotional Products Association International, the business of promotional products was a $19.4-billion industry in 2007. PPAI data indicate that pharmaceutical/chemical companies accounted for approximately 13% of this industry last year. 

It's an unfortunate and open secret that nurses, most of whom are women, bear the brunt of on-the-job verbal and physical abuse―the latter either threatened or real. The source can be mentally compromised patients, as described in yesterday's NYT article ("Nurses Step Up Efforts to Protect Against Attacks"); but I've also seen senior physicians (typically male) exploit the entrenched hierarchy in medicine by intimidating all sorts of subordinate healthcare staff with their vitriolic tantrums.

Having left clinical medicine several years ago and any OR experience even further behind me, I can only hope that the abuse I witnessed in male-dominated specialities of yore remains a vaguely amusing memory. Okay, I'm talking specifically about the collective behavior of the 100% male Duke Surgery Department of the 1980s under the leadership of David C. Sabiston, Jr, MD, in which quaking, incredulous medical students (without naming names) witnessed an attending surgeon throw a resected organ at a flabbergasted scrub nurse or fling instruments with such force that they become fragmented, ricocheting missles.

Let's hope that behavior no longer remains a model of abuse for physicians in training. Okay?

Photo: iStockPhoto

Update: On point and on cue, the Joint Commission released an alert today requiring that all accredited hospitals create a code of conduct that defines acceptable and unacceptable behaviors and...establish a formal process for managing unacceptable behavior," beginning January 1, 2009.

HT for update: WSJ Health Blog 

The utility of measuring carotid intima-media thickness (CIMT) in studies of cholesterol-lowering medications may be dubious, given the recent, unexpected results of Pfizer's atorvastatin (Lipitor) in the CASHMERE trial. According to a recent Dow Jones Newswire report, market analyst Robert Hazlett discovered the negative results of the placebo-controlled trial at clinicalstudyresults.org and issued a report last week, which questioned the usefulness of CIMT for assessing the efficacy of cholesterol-lowering drugs.

In the 12-month, multicenter study of nearly 400 postmenopausal women,* the change in mean CIMT (the primary endpoint) with atorvastatin 80 mg/d (2.9%) was not significantly different from that with placebo (2.5%). However, secondary endpoints, as expected, showed statistically significant reductions in total cholesterol, LDL cholesterol, and triglyceride levels with atorvastatin. Lipitor was initially FDA approved in 1996 for hypercholesterolemia and indicated in 2004 to reduce the risk of clinical cardiac events and stroke.

The negative CIMT data in CASHMERE, by extension, may justify the continued use of the combination of simvastatin/ezetimibe (Vytorin; Schering-Plough/Merck), despite the widely publicized, negative CIMT results from the ENHANCE trial. (However, there are currently no data demonstrating a risk reduction of cardiac events with Vytorin use. These endpoints are being assessed in the ongoing IMPROVE-IT study). The Dow Jones report suggests that both CASHMERE and ENHANCE may have failed to show changes in CIMT thickness with treatment, because of the relatively low burden of arterial disease in enrollees at baseline. Tabulated below are the baseline mean CIMT data from both studies, which can be compared with the mean maximum CIMT measurements (from 12 carotid sites) in the METEOR trial of rosuvastatin (Crestor; AstraZeneca) in "low-risk" individuals. The METEOR trial did show a statistically significant, placebo-controlled effect of rosuvastatin on CIMT over 2 years.

Trial	Baseline CIMT, mm (SD)
	Placebo	Active Drug
CASHMERE	0.699 (0.12)	0.682 (0.10)
ENHANCE	0.70 (0.13)	0.69 (0.64)
METEOR	1.15 (0.19)	1.17 (0.20)

In the extensive coverage of the ENHANCE trial, Schering-Plough and others alternatively suggested that a substantial percentage of the CIMT measurements in the study were either biologically implausible or missing―thereby calling into question the study's final, negative results.

CASHMERE = Carotid Atorvastatin Study in Hyperlipidemic Postmenopausal Women: A Randomised Evaluation of Atorvastatin Versus Placebo; ENHANCE = Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression; IMPROVE-IT: Improved Reduction of Outcomes: Vytorin Efficacy International Trial; METEOR = Measuring Effects on Intima-Media Thickness: An Evaluation of Rosuvastatin.

* Belgium, 12 centers; France, 54 centers; The Netherlands, 3 centers. Fasting LDL, 130-190 mg/dL; triglyceride level, ≤4 g/L. Dropout rate: atorvastatin, 32.8%; placebo, 22.3%.

HT: Pharmalot

Just about every physician has known another physician who has committed suicide. And the medical community's reaction to the physician who kills himself—at least from personal experience—is like that to any suicide: devastation, self-reproach, anger, resignation. But doctors, who deal with depression, stress, and death on a regular basis, may be particularly likely to view a colleague's self-induced death as a statistical inevitability—perhaps even as a "particularly brutal form of social Darwinism," as Scott Anderson puts it in his excellent piece, "The Urge to End It All," in yesterday's NYT Magazine.

However, Anderson indicates that our sense of futility about suicide prevention, either generally or among highly stressed medical professionals, may be a function of our misguided concentration on the "why" of suicide, instead of the "how." He suggests that we should, perhaps, focus on reducing the means to committing suicide to reduce its incidence.

The idea, Anderson points out, is supported by the phenomenon of the "British coal-gas story," in which England's suicide rate dropped by approximately one third after the nation converted from coal-derived gas to cleaner, natural gas for domestic heat and stove fuel. With the conversion, people could no longer kill themselves by carbon monoxide asphyxiation from their unlit ovens. And most important, their means of suicide wasn't supplanted by some other method. Anderson explains,

At least a partial answer is that many of those Britons who asphyxiated themselves did so impulsively. In a moment of deep despair or rage or sadness, they turned to what was easy and quick and deadly—“the execution chamber in everyone’s kitchen,” as one psychologist described it—and that instrument allowed little time for second thoughts. Remove it, and the process slowed down; it allowed time for the dark passion to pass.

Anderson indicates that the same conclusion can be made by examining impulsive suicides from bridge jumps. Even a small maneuver, like raising a fence barrier a few feet on a preferred "suicide bridge" can be enough to thwart the act. And what's really curious is that most would-be suicides don't have backup methods for killing themselves. So if you obstruct one way of committing suicide, you typically prevent the suicide.

But what about physicians who commit suicide? In a 2004 meta-analysis, Schernhammer and Colditz reported that the suicide rate is approximately 40% higher among male physicians and nearly 130% higher among female physicians* than the general population. Are physicians, therefore, more successful at committing suicide, because they choose less "impulsive" and more reliable ways to commit suicide? The general conclusion is yes, but that doesn't mean that physician suicides cannot be prevented by obstructing preferred methods for committing the act.

According to a 2000 study of suicide methods among physicians in England and Wales (and I had a devil of a time finding data specific to US physicians), the overwhelming preferred method for committing suicide among doctors is, not surprisingly, drug poisoning. And the most preferred death-inducing drug is a barbiturate; although one half of anesthesiologists choose to kill themselves with an anesthetic agent.

Suicide Method	Doctors, % (n = 272)	General Population, % (n = 59,096)
Poisoning—drugs	57.0	26.6
Hanging, strangulation, suffocation	13.2	22.7
Gas, including CO	9.9	21.5
Cutting, piercing	5.9	1.9
Firearms, explosives	4.4	3.8
Drowning	3.7	7.8
Poisoning—other	1.5	1.5
Jumping	0.7	4.7
Other/unspecified means	3.7	9.4

Drug	Percentage
Barbiturates	21.5
Gas, including CO	15.8
Analgesics	13.5
Opiates	12.3
Antidepressants	9.6
Anesthetic agents	8.8
Minor tranquilizers	8.8
Major tranquilizers	3.5
Insulin	3.1
Other prescribed drugs	7.0
Chemicals	1.7
Recreational drugs	0.9
Unknown	8.3

Those who study physician suicide conclude that doctors' suicide rates are higher because they have relatively easy access to medications and possess knowledge of their use. The conclusion is supported by data from the 1970s, which showed that suicide rates increased in Australia after a law facilitated access to barbiturates. 

So the proposal here is that, although a physician's hoarding of prescription medications may be difficult to gauge, it is certainly possible to more closely monitor self-prescribed controlled substances, like barbiturates or opiates, which may be intended for abuse or, ultimately, suicide.

* Publication bias may explain the substantially higher relative risk of suicide among female physicians.

What else? Yankee Doodle Dandy starring New York boy, James Cagney, with songs by (who else?) George M. Cohan (along with Rodgers and Hart [see below]). The backstage story of the theatrical Cohan family, told in flashback by George M. to FDR, is directed by one of the great, immigrant, studio-contract directors, Michael Curtiz (The Adventures of Robin Hood, Mildred Pierce, Casablanca).

When we finally see Cagney's Cohan play FDR in "Off the Record," the President not only walks, he dances:

When I was courting Eleanor, I told her Uncle Teddy,
I wouldn't run for President, unless the job was steady.
Don't print it. Strictly off the record.

In the current housing market, a seller's serotonin levels may determine just how likely a buyer's low offer will be accepted. Serotonin depletion and the acceptance of unfair offers were recently explored on a smaller scale by researchers at the University of Cambridge and UCLA by using the so-called Ultimatum Game—a game which uncomfortably resembles today's property transactions.

The investigators examined the responses of 20 healthy volunteers, who underwent a double-blind, placebo-controlled depletion of tryptophan,* the amino-acid precursor of serotonin. After the procedure, participants were offered 1 of 3 ways to split a sum of money with another player: fair (45% of stake); unfair (30%); or most unfair (20%).

The investigators found that respondents were significantly more likely to reject "most unfair" offers after tryptophan depletion than after placebo treatment (F = 7.551; P = .013). However, the rejection rates of fair or unfair offers were not significantly affected by tryptophan depletion. On the basis of related assessments, the researchers concluded that the higher rejection of "most unfair" offers with tryptophan depletion could not be attributed to other factors, like changes in mood.

* Acute (5-hour) tryptophan depletion results from the ingestion of a tryptophan-free amino-acid drink (see Young SN et al. Psychopharmacology (Berl). 1985;87:173-177).

Photo: iStockPhoto

In an unprecedented move, Pfizer is immediately cutting off all CME grants given directly to medical education communications companies (MECCs), according to today's press release from the company. However, Pfizer will honor existing grant committments and will continue to provide financial support for physician-directed CME to healthcare facilities and medical societies.

The move unfairly implies that MECCs, unlike other ACCME-accredited organizations, have specifically undermined the credibility of pharma-supported CME; although Pfizer does nothing more than make the implication. Joseph Feczko, Pfizer's Chief Medical Officer, is quoted: "We understand that even the appearance of conflicts in CME is damaging and we are determined to take actions that are in the best interests of patients and physicians." It is presumed that academic centers or medical societies, unlike like MECCs, confer a desirable credibility to CME.

According to the Dow Jones Newswires, Pfizer spent approximately $80 million last year on CME, with less than half given directly to for-profit MECCs. It is unknown if other pharma companies will follow Pfizer's lead; but if MECCs are to survive the current and impending climate of ill will toward pharma-supported CME, they will need to partner up with academic CME offices or medical societies in jointly sponsored CME projects. In this event, MECCs will no longer need independent accreditation from the ACCME, which at last count accredited 155 MECCs.*

HT: WSJ Health Blog

* Not counting initial or reaccreditation ACCME fees, the loss of annual fees from these 155 accredited MECCs would amount to a yearly loss of at least $310,000 for the ACCME.

Update: On a Pfizer-related note, Derek Lowe at In the Pipeline hears rumors of autumn layoffs at Groton.

By now, pretty much everyone has seen the June 19 videotape of Esmin Green, 49, dying on the waiting room floor of Brooklyn's Kings County psychiatric facility, aka G Building, while others―including security guards―saw the prostrate woman and did nothing. Until it was too late.

But reports of inhumane psychiatric care at Kings County Hospital (dubbed "Killer County" by online wags) are nothing new. A search of the NYT archives reveals that repeated and gross deficiencies in treatment existed there at least as far back as the 1960s. On a least 2 occasions, the facility lost its accreditation status, according to the paper. The remarkably dubious history of the public facility, culminating in Green's death, suggests that blame could go as high up as possible, arguably to city hall.

Last year, the Mental Hygiene Legal Service (MHLS) and the NY Civil Liberties Union, on behalf of patients, filed suit against the NYC Health and Hospital Corporation (HHC) and others, alleging that the Kings County facility is a "chamber of filth, decay, indifference, and danger where individuals...are subjected to overcrowded and squalid conditions often accompanied by physical abuse and punitive injections of mind-altering drugs." The plaintiffs cite lack of basic sanitation and laundry services, inadequate food, no wheelchair accessibility, vermin infestation, and neglect alternating with verbal or physical abuse from healthcare staff and security personnel.

The HHC, the largest city hospital and healthcare system in the United States, comprises more than a dozen hospitals, including Kings County, in the city's 5 boroughs. The HHC Chairperson, Charlynn Goins, along with HHC President and CEO, Alan D. Aviles, are named defendants in the lawsuit. Goins and Aviles, both lawyers, were appointed to their positions by Mayor Bloomberg in 2004 and 2005, respectively. Yesterday, Aviles provided a written statement to news sources on the death of Green: "We are shocked and distressed by this situation. It is clear that some of our employees failed to act based on our compassionate standards of care."

The suit also names the following defendants, at least 2 of whom are longstanding employees of Kings County:

• Jean G. Leon, RN, Executive Director, Kings County Hospital: Leon, a native of Trinidad, has evidently held her position for at least 13 years (see 2005's "10 years of inspired leadership"). A PR-type video on YouTube featuring Leon was posted April 2008.
• Kathie T. Rones, MD, MPH, Medical Director, Kings County Hospital: Rones, a 1980 graduate of the Brown University School of Medicine and a board-certified internist, has held her position since 1996. She received a tribute for her services from the NY House of Representatives on April 3, 2006.
• David K. Dailey, MD, Chief of Psychiatry, Kings County Hospital: According to the NY State Department of Health, Dailey is a 1981 graduate of the Loyola University Chicago, Stritch School of Medicine and has been licensed in the state since 1998.
• Joseph A. Charlot, MD, Comprehensive Psychiatric Emergency Program, Kings County Hospital: Charlot received his medical degree in 1968 from the State University of Haiti and has had a NY medical license since 1979.
• Ellen B. Tabor, MD, Medical Director, Adult Psychiatric Inpatient Services, Kings County Hospital: Tabor is a 1983 graduate of the Rush University School of Medicine in Chicago. She has held a NY medical license since 1990.
• Jacqueline Purser, Captain, Hospital Police
• Oswald David (or David Oswald), Assistant Director of Nursing/Product Line Manager, Comprehensive Psychiatric Emergency Program, Kings County Hospital
• Elsa P. Bush, Associate Executive Director of Nursing, Kings County Hospital

According to today's NYT, the hospital fired the director of psychiatry, the doctor on duty, and the director of security at Kings County on June 20, the day after Green died.  It is not clear if the "director of psychiatry" refers to Dailey, Charlot, Tabor, or someone else. According to Esmin Green's medical records, provided by the NYCLU, a "Dr. Estes" was on duty at the time of her death. Two nurses and one security guard were also "suspended pending union-mandated hearings."

The NY Daily News provides earlier coverage and more background on Esmin Green and Kings County:

June 27 "Shocking death on Kings County Hospital psych ward stirs reform call"

June 22 "Video shows staff ignored patient later found dead"

June 21 "Patient dies waiting for bed at Kings County Hospital"

June 21 "Video shows Brooklyn hospital staff ignore patient later found dead"

May 17 "US Attorney probes claims of patient abuse at Brooklyn psych ward"

In addition to a Federal investigation of civil rights violations at Kings County, the latest reports indicate that criminal charges are being considered in the case of Green's death.

07/03/08 update: The NY Daily News reports that Pierre R. Arty, MD, the head of psychiatry at Kings County, was 1 of 6 people fired after Esmin Green's death. The others included Kenneth Jones, the hospital's director of security, and the 2 security guards (not 1, as previously reported) seen in the waiting-room videotape.

In its recently released Policy Announcements, the ACCME proposed that the commercial support of CME should only be allowed to continue in the setting of several changes. These proposed changes stipulated that educational needs and CME content should be specified by a "bona fide" organization that does not receive commercial support. Some (eg, Daniel Carlat) have suggested that these organizations may include those that draft core competencies (eg, the American Board of Psychiatry and Neurology) or, perhaps, practice guidelines. However, a responding question to that definition is Must the authors of these guidelines have no ties to industry? Which begs the follow-up, What is the extent of commercial ties among authors of practice guidelines?

This question is examined in the latest issue of Neurology, which reports potential conflicts of interest (COIs) among guideline authors for the American Academy of Neurology (AAN), the flagship organization of practicing neurologists.* The authors reported that, among 50 clinical-practice AAN guidelines examined, more than 90% had at least 1 author with a potential COI, and almost half of all authors had 3 or more COIs. The breakdown of the types of potential COIs is provided:

• Any, 77% (n = 272/351)
• Research, 45%
• Clinical practice, 42% (ie, practice of clinical procedure within last year)
• Personal income, 33% (eg, fees for consulting, speakers' bureaus, ad boards)
• Equity/stock options, 7%
• Expert testimony, 6%
• Fiduciary role, 3% (ie, officer, director, partner, or manager in company)
• Advocacy role, 2% (ie, payment for advocacy in nonprofit organization or government)
• Patent rights/royalties, 2%

The AAN's most recent Policy on Conflicts of Interest (June 2008) stipulates that COIs may be resolved or lessened by avoidance, withdrawal (either from the commercial relationship or the AAN responsibility), or disclosure. However, given the high rate of disclosed COIs among drafters of the AAN guidelines, it appears impractical and unrealistic to expect avoidance or withdrawal. To that point, the AAN currently indicates that "[d]isclosure is the appropriate remedy for mitigating most instances of [COI]."

Of note, two authors of the Neurology article (Holloway and Miyasaki) disclosed their own potential COIs with commercial entities.

* The AAN does not allow industry employees to participate in the guideline process or direct corporate sponsorship of the process; however, the AAN does accept corporate funding generally.

The World Health Organization (WHO) now recommends a line-probe assay (LiPA) for the rapid, 2-day detection of multidrug-resistant tuberculosis* (MDR-TB), according to yesterday's press release. LiPA (eg, GenoType MTBDRplus; Hain LifeScience) extracts and amplifies sputum-derived Mycobacterium tuberculosis DNA, which is then hybridized with oligonucleotide probes to detect genes conferring rifampin or isoniazid resistance (eg, rpoB, katG, inhA).

In a 2006 study, the sensitivity and specificity of a rifampin-resistance LiPA (INNO-LiPA.Rif; Innogenetics) or traditional 2-3-month culture were examined in 420 new or retreatment sputum specimens from Asia, Africa, Europe, or Latin America (Studies suggest that rifampin resistance is a reasonable indicator of MDR-TB, where the prevalence of disease is high.) The concordance between LiPA and culture for rifampin resistance was 99.6%.

Result	LiPA	Culture
Positive for M. tuberculosis DNA, %	92.6	74.3
Positive for rifampin-resistance DNA, %	30.6	30.8
Missed positive specimens	22	100

WHO estimates that only 2% of the world's MDR-TB cases are recognized and treated appropriately, and that the multimillion-dollar initiative to systematically implement LiPA testing in 16 countries will increase that percentage to 15% or higher by 2012. Designated countries will receive the tests and appropriate training through the Stop TB Partnership's Global Drug Facility. According to WHO, Lesotho is ready to implement the use of LiPA for rapid MDR-TB detection, and Ethiopia will be ready by the end of this calendar year.

Photomicrograph of M. tuberculosis in sputum smear stained with Ziehl-Neelson acid-fast stain. Courtesy of CDC/Ronald W. Smithwick.

* Defined as resistance to both rifampin and isoniazid.