bmartin: August 2009 Archives

Last Thursday the Accreditation Council for Continuing Medical Education (ACCME)—the organization that accredits other organizations to provide certified CME in the United States—released detailed data on 729 providers. In an e-mailed press release, the ACCME's Chief Executive, Murray Kopelow, stated that these data were being made public in an effort to "increase the system's transparency and accountability."

Among the accredited providers, 124 (17%) received the designation of "Accreditation with Commendation" from the ACCME; 16 received commendation under the more stringent 2006 criteria, which is intended to foster providers' participation in "institutional or system-wide initiatives" to improve the quality of healthcare (whatever that entails exactly).

An examination of the ACCME's stats, which can be downloaded from the organization's web site, identifies all accredited organizations by name and their relevant data. The 16 commended providers include 8 academic institutions, 4 medical societies, 1 medical center (Memorial Sloan-Kettering), 1 government medical institute (the FAA's Civil Aerospace Medical Institute), 1 professional-liability insurance company (Norcal Mutual), and 1 medical-education communications company, or MECC (Discovery). According to the ACCME's data, only 21% of all providers have been reviewed under the 2006 criteria.

A total of 33 providers (4.5%) are on "probation." The designation means that providers may continue to offer certified CME, but they are also required to show their plans to improve areas of noncompliance within a specified time. Contrary to popular expectations, MECCs are not disproportionately represented among the CME providers on probation. Among the warned providers that were assessed under the 2006 ACCME criteria (n = 15), there are 4 academic institutions, 4 MECCs, 3 medical societies, 3 hospitals, and 1 physician group. The 18 providers on probation that were not assessed under the 2006 criteria include 16 medical societies, 1 MECC, and 1 community-based organization.

Among all accredited providers, 81% reported receiving commercial (ie, pharmaceutical) support; 66% received income from advertising and exhibits. Of those 124 commended providers, only 14 (11%) did not receive commercial support; 4 of the 14, however, did report advertising and exhibits income.

The latest WHO update for infection with the novel H1N1 virus indicates more than 209,438 cases of disease globally and at least 2185 deaths, for a crude mortality rate of 1%. However, this mortality rate is likely an overestimate of the actual H1N1-related mortality rate. Pitfalls in calculating the death rate (or the case-fatality ratio) during the H1N1 pandemic are discussed here.

Out of the Past (1947): Classic, classic, CLASSIC noir. Right up there with Double Indemnity. Cigarette smoke will be coming out of your speakers.

Does Robert Mitchum, as an ex-"detective," deserve redemption, or he is consigned to a damned life with a very bad girl? Nice scenes are created, in particular, between Mitchum and Kirk Douglas (in his second film), who plays Mitchum's off-and-on mob employer.

Better-than-average commentary is also provided on the DVD by noir expert James Ursini.

N.B. 1984's Against All Odds was the flop remake.

Children are considerably more vulnerable to infection with the novel H1N1 virus than adults, according to epidemiologic data from the Chicago Department of Public Health. Results of the surveillance of laboratory-confirmed cases of H1N1 infection were published in the latest issue of the CDC's MMWR.

Data from April 24 to July 25 indicate the following overall attack and hospitalization rates (per 100,000) by age group within the city's 77 communities.

Age Group, years	Hospitalization Rate (n = 205)	Overall Attack Rate (N = 1557)
0-4	25	113
5-14	11	147
15-29	4	48
30-59	5	25
≥60	4	10

Consequently the overall attack rate among children aged 5-14 years is more than 14 times that among adults aged 60 years or older. Hospitalization rates are also considerably higher among the younger pediatric populations. These data support current guidelines for preferentially vaccinating younger age groups against the novel H1N1 virus.

Reasons for the higher attack and hospitalization rates among children may be related to the existence of partial (ie, cross-reactive) immunity to the novel H1N1 virus among the elderly and/or higher virus-transmission/contact rates among children.

Overall attack and hospitalization rates are also higher among minority ethnic groups, for unclear reasons; although the relatively higher prevalence of underlying conditions, like asthma or diabetes, in minority ethnic groups may explain their increased vulnerability to H1N1 infection.

Ethnic Group	Hospitalization Rate (n = 205)	Overall Attack Rate (N = 1557)
Black, non-Hispanic	9	29
White, non-Hispanic	2	11
Hispanic	8	36
Asian/Pacific Islander	8	37

Among those hospitalized, 40 (19.5%) were admitted to an intensive-care unit; 9 (4%) required mechanical ventilation. The rates of preexisting asthma and diabetes in hospitalized patients were 21% and 7%, respectively. Also notable is the fact that 14 (7%) hospitalized patients were pregnant. Among those surviving patients with admission and discharge data (n = 97), the median hospital stay was 2 days (range, 1-11 days).

As of August 24, there were 7 H1N1-related deaths in Chicago (crude mortality rate, 0.45%); all were associated with respiratory compromise.

1. 20-year-old pregnant woman
2. 54-year-old women with acute myeloid leukemia
3. 22-year-old man receiving long-term hemodialysis
4. 32-year-old obese* man with asthma
5. 52-year-old man with lymphoma
6. 26-year-old woman with no reported chronic health conditions
7. 47-year-old woman with no reported chronic health conditions

The CDC editors note that the true hospitalization rate and, particularly, the attack rate associated with the novel H1N1 virus in Chicago might be overestimated, because the number of confirmed cases is underestimated. To alleviate laboratory workloads, H1N1 testing was discouraged for outpatients by the city's Department of Public Health after April 30th.

The most common clinical symptoms among affected Chicagoans are fever (73%), cough (68%), sore throat (29%), and dyspnea (15%).

* Another recent MMWR report from the Michigan Department of Community Health suggests that obese and extremely obese patients may be particularly vulnerable to complications associated with novel H1N1 infection.

Although the crude mortality rate for infection with the novel H1N1 virus has been supplied at this blog (by using raw data from the World Health Organization), there are a number of pitfalls when calculating this value during an epidemic/pandemic. The drawbacks of using the simple equation for the mortality rate—that is, dividing the number of known deaths (the numerator) by the number of known cases (the denominator)*—are outlined in a recent (if somewhat mathematically challenging) article in the BMJ.

Briefly, however, the UK authors highlight 2 general sources of potential error: 1) difficulties with case ascertainment; and 2) inevitable delays between infection onset, death, and subsequent reporting.

Case Ascertainment

Particularly as the pandemic advances (for example, in the hot zones of Mexico and the United States), there is the likelihood of underrecognizing (or simply ignoring) mild cases of infection. Consequently the denominator is underestimated, and the mortality rate is overestimated.

But deaths due to H1N1 may also be unrecognized. For instance, some vascular deaths may not be recognized as caused by influenza. Also, at least in developing areas, hospital surveillance may be poor. Consequently the numerator and the mortality rate are underestimated.

The authors' solution (at least for the underrecognition of cases) is to use closely monitored hospitalization data from the early part of the pandemic and in-hospital mortality data later in the pandemic (when total case ascertainment becomes difficult). The overall mortality rate (or really, the case-fatality ratio) is the hospitalization ratio X the fatality ratio among hospitalized cases.

Of course, this calculation requires sufficient sample sizes. For instance, to obtain 95% confidence intervals for a case-fatality ratio ranging from 0.5 to 1.5, you would need ~1100 cases and ~200 hospitalizations. An important assumption with this solution, the authors stress, is that the hospitalization ratio and the in-hospital death ratio remain constant over the course of the pandemic; but guidelines for the hospitalization of H1N1 cases, in particular, may change as the pandemic advances.

Nevertheless, by using numbers from the CDC, the H1N1 case-fatality ratio can be estimated according to the authors' equation. There were 43,771 confirmed or probable cases of novel H1N1 infection in the United States from April 15 to July 24,** resulting in 5011 hospitalizations. Therefore the hospitalization ratio for this time period was 0.114. As of August 20, there have been 522 deaths among 7982 hospitalizations, for an in-hospital death ratio of 0.65 0.065. The case-fatality ratio in the United States is therefore 0.114 X 0.65 0.065, or 0.0075 (and the mortality rate is 0.75%).

Inevitable Delays

The case-fatality ratio may also be underestimated when there is a delay between the onset of infection and knowledge of the final outcome of the case. This effect, the authors note, is known statistically as censoring—which subsides after the pandemic peaks.

The authors' solution is to divide the number of deaths by the number of cases in which the outcome is known; however, this solution may be problematic when there is a relatively long delay between symptom onset and death, as is typical in cases of influenza.

Their second proposed solution is an estimator, which contains a big, fat sigma (a sigma!), to calculate the case-fatality ratio on a particular day. The estimator also requires knowledge of the time from symptom onset to death to approximate the expected number of deaths on the particular day in question.

The estimator is reproduced here for statisticians, epidemiologists, and the otherwise fanatical. Knock yer-selves out (and feel free to post yer calculation).

* And multiplying by 100 to obtain a percentage.

** On July 24, counts of confirmed or probable cases were discontinued.

Senator Ted Kennedy succumbed approximately 15 months after his diagnosis of glioblastoma multiforme. In June of 2008, Kennedy underwent neurosurgery at Duke, followed by unspecified chemotherapy (probably temozolomide [Temodar; Schering-Plough]) and radiation therapy at MGH. Kennedy's survival was about 4 months longer than his expected median survival.

Fault the New York Times for what you will, but the paper consistently prints top-notch obituaries. Kennedy's is no exception (although there's been plenty of time to draft it).

Photo: Biographical Directory of the United States Congress.

Addendum: Highly irreverent, but funny bit from The Onion, America's Finest News Source.

Today the Centers for Disease Control and Prevention (CDC) released its recommendations for the use of the vaccine against the novel H1N1 (swine flu) virus. Because the initial supply of vaccine may not meet the universal demand, the CDC has identified the following 5 target groups for preferred vaccination on the basis of their risk of infection and disease-related complications:

1. pregnant women;
2. persons who live with or provide care for infants younger than 6 months of age;
3. healthcare and emergency medical services personnel;
4. individuals from 6 months to 24 years of age; and
5. individuals 25-64 years of age who have medical conditions (eg, asthma, hypertension, diabetes, HIV) that increase the risk of influenza-related complications.

This population, in total, is estimated to include 159 million Americans, although the estimate does not account for overlap among subgroups (eg, a physician-parent with a young infant). The CDC advises that vaccination of these subgroups should begin as soon as vaccine is available.

The CDC has also identified sub(sub)groups of candidates, should the vaccine supply not meet the targeted demand:

1. pregnant women;
2. persons who live with or provide care for infants younger than 6 months of age;
3. healthcare and emergency medical services personnel who have direct contact with patients or infectious material;
4. children from 6 months to 4 years of age; and
5. children and adolescents 5-18 years of age who have medical conditions that increase the risk of influenza-related complications.

Licensed vaccines, which are expected to be available in the United States by mid-October, are necessary because the vaccines for seasonal influenza are not likely to provide adequate protection against the novel H1N1 virus.

Picnic at Hanging Rock (1975): An early film by Australian director Peter Weir (Witness, Master and Commander); based on the novel of the same name (which was falsely believed to be based on a true story). Three popular students and their teacher go missing during an otherwise idyllic school outing on St. Valentine's Day in the year 1900. The cryptic solution has something to do with a wrinkle in the time-space continuum—which Weir alludes to, but never fully divulges, in his portrait of the dreamlike event and its traumatic aftermath.

As of today, the World Health Organization reports 1799 deaths due to the novel H1N1 swine-flu virus among a global total of more than 182,166 cases. By using these numbers, the overall mortality rate is 0.98% (although the actual rate is somewhat lower). The death rate as of August 6th was 0.82%. Again most of the deaths (~87%) have occurred in the Americas.

According to yesterday's WSJ, stock analysts are speculating that Abbott's extended-release niacin (Niaspan) outperformed ezetimibe (Zetia; Merck/Schering-Plough) in a phase 4 head-to-head atherosclerosis study that was terminated early in June. The NIH clinical-trials web site indicates that an independent steering committee stopped the trial on the basis of results from a prespecified, blinded interim analysis and adds that the study was not stopped because of safety concerns.

The principal investigators are otherwise mum, advising that the trial results will be presented in mid-November at the Scientific Sessions of the American Heart Association. But the logical conclusion is that one drug significantly outperformed the other; stock analysts are placing their bets on Niaspan, possibly because the study is cosponsored by Abbott.*

The randomized, open-label, 2-center study, abbreviated ARBITER 6-HALTS, was designed to compare the effects of raising the HDL level (with Niaspan) with those of lowering the LDL level (with Zetia) at 14 months. The primary endpoint, as in the notorious ENHANCE study, was the mean change in the intima-media thickness of the common carotid artery (CIMT). (Presumably all enrollees received statin therapy; so Niaspan and Zetia were add-on medications.)

It's important to note that the NCEP ATP III guidelines stress the lowering of the LDL level as the primary target of cholesterol-altering therapy. Therefore Abbott has a vested interest (and an uphill battle) in showing that raising the HDL level with Niaspan is just as good as, or possibly better than, lowering the LDL level with Zetia. In a previous, placebo-controlled study, ARBITER 2 (N = 167), Niaspan reduced the rate of CIMT progression when added to statin therapy in high-risk patients who did not have insulin resistance; however, the drug did not appear to alter the risk of cardiovascular events at 1 year.

Unlike ARBITER 6-HALTS, ARBITER 2 was placebo controlled, and study drugs were assigned in a double-blind fashion. A drawback of both trials is the fact that the primary endpoint, the mean change in CIMT, is merely a surrogate marker for clinical cardiovascular outcomes.

ARBITER 6-HALTS = ARterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6 - HDL and LDL Treatment Strategies in Atherosclerosis; ENHANCE = Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression; HDL = high-density lipoprotein; LDL = low-density lipoprotein; NCEP ATP III = Third Adult Treatment Panel of the National Cholesterol Education Program.

* The other cosponsor is the Walter Reed Army Medical Center.

Sweeping the web with lightening speed, unlike the glacial pace of a classical zombie!

News of the newly available, When Zombies Attack!: Mathematical Modelling of an Outbreak of Zombie Infection, by 4 Canadian mathematicians. Their mothers, despite the authors' statistically probable dateless existences,* must be so proud. The web server for the University of Ottawa math department is inundated, just like the Winchester pub in Shaun of the Dead!

For the mathematically unsophisticated, the bulk of the paper is a blur of italicized English or Greek letters and a few arabic numbers, organized by the obligatory parens, brackets, and braces. The occasional chart and what look like electrical diagrams (really model flow diagrams) make the paper unreadable to the ignorant. At least, until the amusing Discussion section.

Making a half-hearted nod to similarities between a zombie attack and an of-this-world biologic pandemic, the authors conclude, "An outbreak of zombies infecting humans is likely to be disastrous, unless extremely aggressive tactics are employed against the undead." Eradicating the zombies, which requires removing the head or destroying the brain, is not predicted by their formulas—unless attacks are "sufficiently frequent" and with "increasing force."

The best possible scenario is humans coexisting with zombies in some kind of equilibrium. The 2 big problems with zombie-ism are that a) there is no immunity and b) the dead can always rise. Also, if the zombie attack is prolonged, the authors predict that zombies will completely eradicate humans; ongoing human births and deaths will provide the zombies with a limitless supply of infectees. (But this doomsday scenario begs the question: What happens when the world is populated solely by zombies?)

The authors propose that their mathematical models may be applied practically to cases of "allegiance to political parties" (heh-heh, way to slide one in) or infectious diseases with a dormant phase.

* Okay, I really have no idea. The authors could be totally cool operators, with children (ie, zombie noshes) peppering the globe.

Zombies from Night of the Living Dead from Wikipedia.

Addendum: The "?" after the anchor author's name (Robert J. Smith?) is evidently not a typo.

The situation: You plan to launch a novel drug in a therapeutic area, but your sales force has no experience in that therapeutic area. So how do you train your sales force before the drug launch?

Novartis's solution: Obtain approval to market a well-known drug in that therapeutic area before you launch your novel drug.

So...

Today the FDA announced the approval of Novartis's copycat version of Betaseron (Bayer Schering), or subcutaneous interferon beta-1b, for relapsing-remitting multiple sclerosis (RRMS). Novartis's right to market an identical interferon beta-1b product, trade named Extavia, comes by way of an intricate manufacturing deal with Bayer Schering that began 2 years ago.

And all of this maneuvering by Novartis is apparently in anticipation of its launch of fingolimod, a novel oral agent with positive phase 3 clinical data in RRMS. The new drug, also called FTY720, is in an approval horse race with oral cladribine (Merck Serono) for the same indication. Notably, in the United States, Merck Serono has been marketing its own version of interferon beta-1a (Rebif) for RRMS since 2002.

N.B. Novartis does have experience in the neurology market with existing products for Alzheimer disease, Parkinson disease, and epilepsy.

HT: WSJ Health Blog

The Friends of Eddie Coyle

(1973): Robert Mitchum is Coyle, a burnt-out arms dealer in Boston who tries to play snitch in exchange for a lighter upcoming sentence. But his friends (with finger quotes in full effect) may or may not be better at the ratting game. With Peter Boyle, Alex Rocco (Moe Greene in The Godfather), Richard Jordan, and Steven Keats. Directed by Peter Yates (Bullitt, Breaking Away).

Merely by example, old-schooler Mitchum could teach a thing or two about naturalistic acting to any method whippersnapper.

As of August 6th, the World Health Organization reports 1462 deaths due to the novel H1N1 swine-flu virus among a global total of 177,457 cases, for an overall mortality rate of 0.82%. The death rate as of July 31st, was 0.71%, which is up more than 60% from mid-June. Among the tabulated deaths, a steady 87% (1462) have occurred in the Americas.

The long-time head of the FDA's Center for Devices and Radiological Health (CDRH), Daniel Schultz, will resign. Schultz describes his impending resignation as the result of a "mutual agreement" with the new FDA chief, Margaret Hamburg, reports the AP. His announced departure from the center comes after months (if not years) of discontent among the center's scientists, 9 of whom alleged that the agency was "fundamentally broken" in recent letters to the House Energy and Commerce Committee and Obama's transition team. The scientists also reported that FDA managers "ordered, intimidated and coerced" the scientists to manipulate data during product reviews.

In response to the scientists' complaints, the FDA conducted its own internal investigations last year. The first was led by William McConagha, the FDA's Assistant Commissioner for Integrity and Accountability. A follow-up investigation was conducted by Schultz himself, who concluded that "FDA physicians and scientists need to 'move forward,'" according to the scientists' letters. They also alleged that Schultz allowed management reprisals against FDA device reviewers, including threats of job loss and "illegal and improper employee performance evaluations." 

Schultz, a medical doctor, is/was a career FDA officer who was appointed CDRH Director in 2004.

Photo of Daniel Schultz from the FDA.

This month's issue of Lancet Oncology provides a reasonably comprehensive and up-to-date review of progressive multifocal leukoencephalopathy (PML) in the context of monoclonal-antibody (mAb) therapy. The authors draw on data from Northwestern's Research on Adverse Drug Events and Reports (RADAR) project.

Perhaps most surprising is the total number of PML cases that have been reported to date with rituximab treatment—76. Although it's important to remember that the mAb has been on the market for more than 10 years, with greater than 1 million patient exposures (at least according to the drug's web site). By contrast, the latest incidence of PML with natalizumab treatment has been calculated at about 1.2 in 10,000.

A supplemented synopsis of PML with rituximab, natalizumab, or efalizumab therapy is provided here:

Rituximab (Rituxan; Genentech/Biogen IDEC): As of July 29, 2009, a total of 76 cases of PML have been reported in rituximab-treated patients. These cases include 69 oncology patients, 1 patient with autoimmune hemolytic anemia, 5 patients with autoimmune disorders (eg, SLE), and 1 patient whose primary condition is described as unknown. Median time to death is 2 months. Survival in patients with non-Hodgkin's lymphoma is higher in those who develop PML after hemoatopoietic stem-cell transplantation (eg, 38% vs 10%). Rituximab is proposed to increase the risk of PML by indirectly expanding the population of pre-B cells that harbor JC virus.

Natalizumab (Tysabri; Biogen IDEC/Elan): As of July 24, 2009, there have been a total of 11 PML cases in natalizumab-treated patients since the drug's relaunch in July 2006 (multiple sclerosis, 10; Crohn's disease, 1). The risk of PML with natalizumab appears to be increased by the concomitant use of interferon beta and extended monotherapy (eg, ~2 years). Natalizumab may cause PML by enhancing the migration of JC virus-infected CD34+ cells into the CNS.

Efalizumab (Raptiva; Genentech): Four cases of PML were reported with the use of efalizumab, a mAb that was indicated for the treatment of psoriasis. Consequently efalizumab was withdrawn from the US market on June 8, 2009.

Treatment of PML, which is due to the activation (or reactivation) of latent JC* virus in the CNS, has been chiefly informed by experience with PML in patients with AIDS. Therapy requires reconstitution of the immune system (and, in the case of mAb treatment, the discontinuation of the mAb). In patients with AIDS, HAART reduces the severity of PML, but its use in HIV-negative patients is unproven. Treatment with cytarabine is supported by case studies, say the authors. There is also 1 ongoing, international, company-sponsored study of the antimalarial drug mefloquine in PML; however, the outcomes do not include survival endpoints. 

AIDS = acquired immunodeficiency syndrome; CNS = central nervous system; HAART = highly active antiretroviral therapy; HIV = human immunodeficiency virus; SLE = systemic lupus erythematosus.

* JC = John Cunningham, a patient with PML (see Padgett BL et al. Lancet. 1971;1:1257-1260.).

Seven Israeli infants who were fed a thiamine-deficient soy-based formula remain moderately to severely neurologically impaired at 5 years. Long-term impairment includes various degrees of mental retardation and motor, brainstem, or basal-ganglia dysfunction. The grave outcomes for these children, who displayed severe epileptic seizures during infancy, are presented in the latest print issue of Neurology.

A total of 20 Israeli infants were "seriously" affected after being fed the kosher baby formula, Remedia Super Soya 1—which was produced in 2003 by Humana, a German company, and imported by Remedia, an Israeli company. Infants quickly developed the known symptoms of cardiomyopathy or neurologic dysfunction that are associated with wet and dry beriberi, respectively. At least 3 infants died. Tests of the formula revealed negligible amounts of thiamine.

In an accompanying editorial, child neurologist Marc Patterson reviews the effects of deficient thiamine, or vitamin B1, which cannot be synthesized or stored to any significant degree by humans. In addition to the long-described forms of beriberi, thiamine deficiency is also manifest in Wernicke encephalopathy and Korsakoff syndrome—amnestic conditions associated with inveterate alcoholism and diencephalic injury. Leigh disease, a metabolic pediatric encephalopathy associated with thiamine deficiency, is neuropathologically similar to Wernicke disease, minus the mammillary-body lesions. Infantile thiamine deficiency, itself, is very rare in developed nations and is seen primarily in infants who are breastfed by thiamine-deficient mothers. It has a better prognosis, however, than Leigh disease.

According to the Jerusalem Post, parents of the affected infants received substantial financial compensation from the formula manufacturer and the Israeli importer. The Israeli State Attorney's office is prosecuting 3 Remedia officials and 5 Health Ministry workers—including pediatrician Dorit Nitzan-Kaluski, the former head of the Food Service Division and coauthor of the 2005 report of the incident in Pediatrics.

Depicted chemical structure of thiamine from Wikipedia.

A twofer—for two entertaining, but seriously flawed, movies.

Ne le dis a personne (Tell No One) (2006): Francois Cluzot (who could easily pass for Dustin Hoffman's cuter, younger brother) is a pediatrician suspected of killing his wife. The truth of the matter, however, is impossibly complicated in this are-we-done-yet French blockbuster. I'll eat my hat if an American remake is not in the works.

Transsiberian (2008): If you can get past Woody Harrelson's caricature of a goofball American tourist and the preposterous climax, Transsiberian effectively conveys the intense discomfort of en-masse, international travel in very tight quarters. Especially effective are Emily Mortimer as Harrelson's rehabilitated wife; Eduardo Noriega as the hot, dangerous Spaniard; and Kate Mara as his young American girlfriend. Also Ben Kingsley offers one of his usual, engaging performances, this time as a Russian police detective.

Preliminary data from the CDC

indicate that rapid influenza diagnostic tests (RIDTs) for the novel influenza A (H1N1) virus are relatively insensitive—especially when viral titers are low in specimens from nasopharyngeal and oropharyngeal swabs. Therefore a negative RIDT for the novel H1N1 virus does not rule out the diagnosis of swine flu, particularly in the context of consistent clinical symptoms. The CDC recommends that, if laboratory confirmation is required, further testing should be performed by using the real-time reverse transcription-polymerase chain reaction (rRT-PCR) assay or viral culture.

The CDC determined the following sensitivities of 3 commercially available RIDTs by using respiratory specimens that were positive for the novel H1N1 virus with rRT-PCR. However, the CDC advises against discriminating among the 3 tests' sensitivities, because of the relatively low number of specimens analyzed.

Test	High Novel H1N1 Titer (n = 9)	Low Novel H1N1 Titer (n = 36)	All Novel H1N1 Specimens (n = 45)
BinaxNow Influenza A&B	89%	28%	40%
Directigen EZ Flu A+B	89%	38%*	49%
QuickVue Influenza A+B	100%	61%	69%

* n = 34.

The sensitivities of the RIDTs declined in proportion to declining titers of novel H1N1. Factors that affect influenza titers in specimens include the timing of specimen collection during illness, the age of the patient, the type of specimen collected, and the transportation and storage of the specimen.

The overall sensitivities of the RIDTs for seasonal H1N1 (n = 5) or seasonal H3N2 (n = 15) were observed to be 60%-80% and 80%-83%, respectively. (It is important to note that RIDTs do not distinguish among subtypes of influenza A virus.) The CDC advises that the results of RIDTs should be interpreted in the context of known circulating viral strains and provides this link for guidance.

N. B.—The sensitivity and specificity of the rRT-PCR assay, when compared with the reference standard of viral culture, are 99.3% and 92.3%, respectively.

08/13/09 update: RIDT data from the Naval Health Research Center indicate respective sensitivities of 51% for the detection of novel H1N1 (n = 39 patients), 63% for seasonal H1N1 (n = 19), and 31% for H3N2 (n = 19). Specificities for all influenza A virus types were 99%. Values are for the QuickVue Influenza A+B test; the reference standard is rRT-PCR. 

As of July 31st, the World Health Organization reports 1154 deaths due to the H1N1 virus among a global total of 162,380 cases, for an overall mortality rate of 0.71%. Consequently the H1N1 death rate has increased more than 60% after holding steady at about 0.44% since mid-June. The current H1N1 death rate also surpasses the death rate from early June (0.66%). Among the tabulated deaths, 87% (1008) have occurred in North and South America.

 

Your government at work.

Yesterday the FDA announced generic (or nonproprietary) name changes for 2 approved versions of injectable botulinum toxin.* Botox (Allergan), formerly botulinum toxin type A, is now onabotulinumtoxinA; and Myobloc (Solstice Neurosciences), formerly botulinum toxin type B, is now rimabotulinumtoxinB. The generic name for the most recently approved version, Dysport (Tercica), remains abobotulinumtoxinA. The names were changed to emphasize the different potencies of the products—the unit dosages of which are not interchangeable.

In the United States, nonproprietary names for drugs are assigned by the US Adopted Names (USAN) Council, a long-time collaboration among the American Medical Association, the US Pharmacopeial Convention, the American Pharmacists Association, and the FDA. The USAN Council works closely with the International Nonproprietary Names Programme of the World Health Organization to provide standardized and consistent drug names for worldwide use.

According to WHO, nonproprietary names "have to be distinctive in sound and spelling, and should not be liable to confusion with other names in common use"—an explanation which clarifies the unwieldy length of some generic drug names and their near unprounounceability. Pharmacologically related drugs should also share a common stem, which explains why all generic names for therapeutic monoclonal antibodies (mAbs) end with the -mab suffix (eg, rituximab, belimumab). For botulinum toxin products, the names are evidently distinguished by a short prefix (ie, ona-, rima-, and abo-) and the tail designator of "A" or "B," which denotes the toxin type.

Clearly pharmaceutical marketers take advantage of cumbersome generic names by assigning catchier and easier-to-pronounce trade names. For instance, who's going to say, "Hand me the syringe of onabotulinumtoxinA"?

* The FDA also announced that the labels of botulinum toxin drugs would now carry a boxed warning, describing the potential spread of the toxin and the attendant, possibly life-threatening effects.