bmartin: August 2010 Archives

Released yesterday, the FDA's inspection report of facilities at Wright Company and Quality Egg, ground zero for the recent egg-borne salmonella outbreak, is either an outing of a filthy outlier in the business of mass agriculture or a revelation of the filthy business of mass agriculture. How much chicken shit is acceptable in and around hen houses is virtually unknowable for the 99% of Americans who don't farm. But 4-to-8-feet piles seem excessive.

According to the FDA, the laying facilities in north-central Iowa, managed by Austin "Jack" DeCoster's son, Peter, were plagued with the following:

• Massive and escalating amounts of chicken excrement.

Inspectors reported that "outside access to the manure pits...had been pushed out by the weight of the manure, leaving open access to wildlife or domesticated animals." Manure, aka "dark liquid," was also observed to be seeping through the concrete foundation of the outside of the laying houses. Uncaged birds were seen using the piled-up manure to access laying areas.

• Standing water near manure pits.
• Live rodents, namely mice, who evidently had free access into and out of the laying houses.
• And lots and lots of flies and maggots. "The live flies were on and around egg belts, feed, shell eggs and walkways in different sections of each egg laying area," the inspectors wrote. "In addition, live and dead maggots too numerous to count were observed on the manure pit floor..."

Most important, perhaps, was the fact that the FDA found evidence of Salmonella enteritidis in multiple locations, including in manure and chicken feed.

The FDA's inspection took place from August 12 to August 30, longer than 2 weeks. Given the duration of the inspection (and the possibility that facility managers knew that the FDA was coming), it seems that officers at Wright County and Quality Egg actually had the opportunity to clean up their facilities. If so, the conditions of these businesses may have been, in reality, considerably worse.

At the heart of Cedillo v. US DHHS was the claim that thimerosal-containing vaccines damaged Michelle Cedillo's immune system, which then allowed attenuated measles virus in the MMR vaccine to injure her brain, thereby causing autism. It's a convoluted (and medically illogical) argument, but one that was ostensibly supported, at least in part, by data from a questionable Dublin-based laboratory, Unigenetics.

In the original 2009 decision against the petitioner in the Omnibus Autism Proceeding,* Special Master George Hastings found the detection of vaccine-derived measles virus by Unigenetics in an intestinal sample from Cedillo "not reliable." The decision was based partly on expert testimony from Stephen Bustin, PhD, a UK-based molecular biologist who, as part of UK vaccine litigation, had obtained access to the Unigenetics laboratory and some of its relevant data. On the basis of a number of procedural flaws at Unigenetics, Bustin testified both in the UK and US courts that the company's work was plagued with potentially contaminating errors. Bustin also suggested that results from Unigenetics might even be fraudulent, after reviewing some of the laboratory's altered notebooks.

Access to documents from Unigenetics, on which Bustin based his expert opinion, was the crux of a recent appeal by Cedillo's parents to the US Court of Appeals for the Federal Circuit. This appeal was denied Friday, August 27th. And while the appeal court ruled that Special Master Hastings "erred in permitting the government to introduce the expert reports and testimony of Dr. Bustin because the government did not make available the underlying Unigenetics documents upon which Dr. Bustin relied," the court also noted that Hastings had given the petitioners virtually every opportunity to obtain this information from the UK court themselves, which they apparently did not try to do. (It should be noted that the government argued against the reliability of Unigenetics with other expert testimony. It is presumed on this basis that the Special Master's error was not a reversible one.)

In 2007, the government, in its case preparation, successfully petitioned the UK court to release the Bustin reports, but it did not request the laboratory notebooks or other data on which Bustin relied. The appellate decision further describes the background facts, 

The government explained at oral argument that UK counsel informed them that an application to the UK court requesting "everything" from the UK litigation would be denied as overbroad, and as a result, they needed to narrow their request to the most essential items. The government therefore subsequently "honed down" their request to cover solely the three reports, two of which were filed by Dr. Bustin, that they eventually obtained.

The upshot: Cedillo v. US DHHS has been put to bed.

In a coda to this case, it can be said that life, outside the courtroom, moves relatively quickly and in curious directions. Unigenetics dissolved as a company 5 years ago, although its former director, pathologist John O'Leary, is evidently still working in Dublin at Trinity College. In 2008, O'Leary, in an apparent effort to regain academic credibility, was coauthor of a multi-institutional study ("Lack of association between measles virus vaccine and autism with enteropathy: a case-control study" in PLoS One) that essentially negated the results produced by his own company for Cedillo.

DHHS = Department of Health and Human Services; MMR = measles-mumps-rubella.

* Which was affirmed by Judge Thomas Wheeler in the US Court of Federal Claims.

Winter's Bone

(2010): An unusual KBF recommendation, solely because the movie is still in theaters. Winner of this year's Sundance Grand Jury Prize, Winter's Bone, based on the novel of the same name, is the story of a poverty-level teenager in the Ozarks, who searches for her meth-producing, bail-jumping father, while sustaining a fragile, nuclear family.

Inevitable comparisons are to be made with the superior Frozen River of 2008 (another Sundance winner), which was carried with greater skill by a truly exceptional (and considerably more mature) leading actress (Melissa Leo). But Winter's Bone is still worth the price of theater admission, even if one is to endure the likely distraction of popcorn munchers. In fact, consider your crude company part of the Sensorama experience.

In addition to Jennifer Lawrence in the lead role (who's probably getting more adulation than she deserves for her performance), Winter's Bone features veteran supporting actor John Hawkes of "Deadwood" fame and a nearly unrecognizable Sheryl Lee (Laura Palmer of "Twin Peaks") in a very bit part.

Two looming factors are set to ring the death knell for the small medical practice: 1) the sustainable growth rate formula; and 2) the Patient Protection and Affordable Care Act.

The former, set to kick in in December after numerous Congressional stays,* now dictates a 20-something percent drop in Medicare reimbursement to physicians. That alone could put the kibosh on many small physician practices that don't have the financial reserve to withstand such a precipitous drop in revenue. And while the Obama administration supports a financially responsible (if one exists) repeal of the SGR formula, Congress is unlikely to act. Repeal of the 12-year-old legislation would be viewed as an untenable increase in spending. Consequently Congress has repeatedly suspended the formula, while keeping the law "on the books" to avoid a monstrous increase in the already monstrous deficit. 

Whether Congress will suspend the SGR formula yet again is a mystery, albeit a short-term one. General opinion appears to be swinging in the direction of allowing the legislated cuts to begin. In fact, Medicare's trustees recently issued a rosy financial report on the program's Part B service, which assumed the SGR-defined cut.

The second impending factor for small-practice physicians, PPACA, heavily promotes the consolidation of healthcare providers into large groups to withstand the number of legislated reforms, including investment in information technology. In fact, buried in an opinion/cheerleading piece for PPACA, newly published in the Annals of Internal Medicine, is the following forecast from White House health-policy advisors.

These reforms will unleash forces that favor integration across the continuum of care. Some organizing function will need to be developed to track quality measures, account for and manage shared financial incentives, and oversee care coordination. Consequently, the health care system will evolve into 1 of 2 forms: organized around hospitals or organized around physician groups. These coordinating functions, to the extent that they currently exist, traditionally have been managed by hospitals or health plans. Only hospitals or health plans can afford to make the necessary investments in information technology and management skills.

But the advisors spin not-so-different alternatives: 

This is not inevitable. As physicians organize themselves into increasing larger groups—patient-centered medical home practices and accountable care organizations—they are, out of necessity, investing in information technology tools that are becoming both cheaper and more capable and investing in the acquisition or development of management skills that could provide these organizing functions efficiently for physicians groups.

They then make a promise or threat, depending on your viewpoint:

Physicians who embrace these changes and opportunities are likely to deliver the greatest benefits to their patients, the health system, and themselves. Physician practices that accept the challenge will be rewarded in the future payment system.

It's a spoonful of PPACA medicine that not everyone's willing to swallow, however. Over at Medscape, reporter Robert Lowes found several physicians and/or health-policy leaders who argue against the seemingly inevitable vertical integration of healthcare. For some, like Dennis Smith, former Medicaid director under George W., the push is an "example of big government meddling," Lowes reported. Lowes also obtained a nice quote from Smith: "If a physician's only choice is to join a large corporation, we're going down the wrong path." There are plenty of physicians still around who remember not-particularly-happy experiences with large HMO-led practices in the 80s and 90s. 

* Five or 6 in the last year; I've lost count.

Still from Black Narcissus trailer. Here Kathleen Byron (in a sinful red dress) plays the role of PPACA, and Deborah Kerr (in a nun's habit) is the physician in a small medical practice.

Former Duke med classmate Chuck Murry, co-director of U Washington's Institute for Stem Cell and Regenerative Medicine, was featured last night in an NBC Nightly News piece on embryonic cell research (video here). Veteran science reporter Robert Bazell said that what Murry has done, converting embryonic cells to beating cardiac tissue, is "remarkable."

But Murry's work and others' like it are now threatened by Monday's decision from a federal judge, Royce C. Lamberth, which blocks President Obama's 2009 order to expand funding for embryonic cell research. Lamberth ruled that the executive order conflicts with a legislated ban on using federal funds to destroy embryos (first contained in the Dickey-Wicker Amendment to the Balanced Budget Downpayment Act of 1996).

According to NIH director Francis Collins, by way of USA Today, the effects of Lamberth's ruling are chilling. A total of 167 grants, representing $149 million, will be frozen in the very near future. However, another 131 awarded grants, which are already "out the door," will not be affected until they're up for renewal next year.

Yesterday the US Department of Justice announced that it will appeal Lamberth's ruling. A profile of the judge, a Reagan appointee, is provided by the Washington Post.

The NYT and the WSJ are also, predictably, all over the story. According to the NYT, a Clinton* administration lawyer tried to circumvent the Dickey-Wicker Amendment in 1999, by arguing that federal money could support research on stem cell colonies, or lines, that had already been produced with private funding. (The idea being: use private funds to destroy the embryonic cell as it differentiates; then use federal funding to support research on the created stem-cell line.) The Bush administration adopted the lawyer's argument "with severe restrictions," and Obama attempted to lift the Bush restrictions last year. 

* BTW, Clinton signed the Balanced Budget Downpayment Act of 1996 with the Dickey-Wicker Amendment. 

P.S. Go Chuck.

The FDA advises that a combination drug for Parkinson disease may increase the risk of cardiovascular events—like MI, stroke, or CV death. The drug, containing carbidopa, levodopa, and entacapone and marketed by Novartis as Stalevo, is the focus of a 15-trial meta-analysis conducted by the agency to further determine the associated CV risks of the drug, when compared with the foundational treatment of carbidopa/levodopa (aka Sinemet) alone.

Entacapone, a peripheral inhibitor of the enzyme COMT, is also sold separately by Novartis as Comtan.* The drug is intended to smooth out the fluctuating clinical responses or dyskinesias associated with Sinemet treatment. (For a comprehensive 2009 review of entacapone, go here). Entacapone's sole competitor is tolcapone (Tasmar; Valeant), the use of which is limited by significant hepatotoxicity.

The FDA's retrospective review is prompted by data from the STRIDE-PD trial (published in July), which showed an increased number of heart attacks with Stalevo. During the 134-week study, there were 7 MIs and 1 CV death in 373 Stalevo-treated patients and none in 372 Sinemet-treated patients. The FDA's meta-analysis revealed 27 CV events with Stalevo and 10 with Sinemet, for a relative risk of 2.46. But removal of the STRIDE-PD data reduced the relative risk to 1.67. Most of the trials (11) included in the meta-analysis were briefer than 6 months, which makes a solid assessment of CV risk difficult. Other confounding factors include the fact that the baseline CV risk in PD patients is relatively increased, primarily owing to age.

An elevated risk of CV events with entacapone is counterintuitive, at least from a biochemical perspective. Inhibition of COMT reduces, at least in theory, homocysteine synthesis. High homocysteine levels have been suggested to raise the risk of atherosclerosis, although the American Heart Association has not yet labeled homocysteinemia as an official risk factor for heart disease.

The STRIDE-PD data also prompted the FDA to evaluate the risk of prostate cancer in men given entacapone (rates, 3.7% vs 0.9% with Sinemet). (Why COMT inhibition would increase the risk of prostate cancer is also a mystery.) 

The FDA estimates that 154,000 patients have received Stalevo since its approval in June 2003 (through October 2009).

COMT = catechol-O-methyl transferase, which degrades catecholamine neurotransmitters like dopamine; CV = cardiovascular; STRIDE-PD = Stalevo Reduction in Dyskinesia Evaluation-Parkinson's Disease.

* The drug, by itself, has no antiparkinsonian effect. It is intended to prolong the half-life of levodopa by inhibiting the peripheral action of the dopamine-degrading enzyme COMT.

Image of 1886 drawing of PD patient by neurologist Sir William Richard Gowers from Wikimedia Commons.

Gird yer loins, Austin "Jack" DeCoster. You're about to receive uncompromising media and Congressional attention. And the metaphoric (and partially ironic) tarring and feathering may long be overdue, if archived news stories are any indication.

The growing recall of Salmonella-tainted eggs is focusing widespread attention on DeCoster (photos here and here), who is the owner of Wright County Egg in Galt, Iowa, and Quality Egg, a supplier of chicks and feed to Hillendale Farms in New Hampton, Iowa. On August 13, Wright County recalled 380 million eggs that it had shipped since May 19. Hillandale recalled 170 million eggs on Friday, according to USA Today.

The FDA says that the Wright County eggs had been distributed to "food wholesalers, distribution centers and food service companies in California, Illinois, Missouri, Colorado, Nebraska, Minnesota, Wisconsin and Iowa." These companies distribute eggs nationwide. The recalled eggs were packaged under the brand names of Lucerne, Albertson, Mountain Dairy, Ralph’s, Boomsma’s, Sunshine, Hillandale, Trafficanda, Farm Fresh, Shoreland, Lund, Dutch Farms  and Kemps. [Writer's note: Because Lucerne consistently provides the least expensive dairy products in Chicago-area Dominick's stores, I've always been skeptical of their origin. BTW, Lucerne's cheese is absolutely tasteless.]

DeCoster, who also has a history in hog farming, is reportedly no stranger to alleged health, safety, or labor violations, which date back to at least the mid-1990s.

Reports USA Today,

• In 1997, DeCoster Egg Farms of Turner, Maine, agreed to pay $2 million to settle health and safety citations. Employment conditions at DeCoster's farm were publicly denounced by Labor secretaries Robert Reich (he called them "dangerous and oppressive") and Alexis Herman (who said they were "simply atrocious"). See the NYT's "In Maine, Egg Empire Is Under Fire."
• In 2000, Iowa (as in the state of) called DeCoster a "habitual violator" of environmental regulations. One infraction: allowing hog manure to run off into waterways. DeCoster was prohibited from building new farms. See a 2000 statement from the Iowa Attorney General.
• In 2002, DeCoster paid more than $1.5 million in a settlement with the EEOC regarding sexual harassment claims (including rape) from Mexican women who worked at Wright County.

Other violations, including those of animal mistreatment, are reported by the Washington Post and detailed by Mercy for Animals here and here. DeCoster's heavy use of battery cages to house chickens has been linked to the spread of Salmonella on egg farms.

More than 1000 Americans have been sickened by Salmonella-tainted eggs in the current recall, according to the latest news reports, and the obligatory litigation is in the works. This may be one case in which it is reasonable to root for personal-injury attorneys. 

Night Train to Munich (1940): A rakish UK operative (Rex Harrison) goes undercover in Germany to rescue a kidnapped Czech scientist and his daughter from the Nazi regime. Paul Henreid, aka Paul von Hernried, plays a duplicitous Axis bad guy two years before his iconic role as a WW2 resistance leader in Casablanca. Directed by Carol Reed.

An international group of researchers has unlocked another door to understanding the cause of facioscapulohumeral muscular dystrophy (FSHD), the third most common muscular dystrophy.* Reporting electronically in Science, Lemmers and colleagues add to the long-known genetics of the autosomal dominant disease.

In 1992, it was discovered that the molecular defect in FSHD localizes to the distal portion of the long arm of chromosome 4 (specifically 4q35), in which a dormant repetitive element, D4Z4, is truncated. Only individuals with 1-10 D4Z4 repeats can acquire FSHD (normal individuals have 11-100 repeats). It was further learned that the number of D4Z4 repeats in people with FSHD correlates inversely with the age of onset and disease severity; however, it was also observed that clinical manifestations among family members with the same deletion can differ. (For a free review of FSHD and its genetics, circa 2008, go here.)

The Science authors showed that, somehow, the truncated D4T4 area in FSHD patients changes the chromosomal configuration, which allows for the transcription of an internal homeobox gene, DUX4. But FSHD patients also carry specific single nucleotide polymorphisms (SNPs) distal to the D4Z4 region that encode for a transcript-stablizing poly-A tail. Therefore, in people with FSHD, the transcribed DUX4 gene, which might otherwise be chewed up, is stabilized by being polyadenylated.

What the product of the polyadenylated DUX4 transcript is and what it does remain to be discovered.

* Affecting 1 in 20,000.

One part of a much-publicized 3-part Innogenetics assay appears to predict dementia in Parkinson disease. According to an early-release, prospective, cohort study (N = 45) from U Penn, low and declining levels of beta amyloid 1-42 in spinal fluid are associated with cognitive impairment in the disorder. There is no association, however, between dementia and CSF levels of total tau, phosphorylated tau, or any tau-to-beta-amyloid ratios. In fact, adding any tau measurement to the mix actually diminishes the predictive value of the beta-amyloid measure in PD patients.

During the 1-3-year PD study, baseline beta amyloid 1-42 levels of less than 192 pg/mL, which are considered diagnostic for Alzheimer disease, significantly increased the risk of dementia. On the basis of their data, the authors concluded that a PD patient with a low CSF beta-amyloid level would "progress from essentially normal cognition to a level consistent with [PD-associated dementia] within a 2-year period of follow-up." CSF beta-amyloid levels also correlated with apolipoprotein E ε4 carrier status among the small number of PD patients (15) who carried the AD risk factor.

Last week, the full 3-part Innogenetics assay (which measures CSF levels of beta amyloid 1-24, total tau, and phosphorylated tau) was promoted to predict AD in people with mild cognitive impairment (see Alzheimer Assay Deserves Qualified Embrace). In this study, there was a distinctive pattern change as MCI progressed to mild AD and then to advanced disease: CSF beta amyloid levels fell while tau levels rose. The former event appears to be true in PD patients who develop dementia. Lower levels of CSF beta amyloid reflect the underlying amyloid pathology of the dementing aspect of the disease and may be due to the sequestration of beta amyloid into developing amyloid plaques. At least that's the speculation.

The Penn authors concluded that the CSF level of beta amyloid 1-42 "may provide clinically useful prognostic information, particularly if combined with other risk factors for cognitive impairment in PD." Dementia may occur in the disorder in up to 80% of patients.

A Belgian company, Innogenetics was acquired by Solvay Pharmaceuticals in 2008 and is listed on Euronext Brussels (ticker, INNX)

Image of 1886 drawing of PD patient by neurologist Sir William Richard Gowers from Wikimedia Commons.

Eli Lilly announced today that it is pulling the plug on semagacestat, a gamma secretase inhibitor in phase 3 development for Alzheimer disease. Preliminary results from 2 large, ongoing, multinational phase 3 trials* showed that AD patients taking semagacestat actually performed worse on measures on cognition and activities of daily living than placebo-treated patients. Semagacestat treatment was also associated with a relatively increased risk of skin cancer (although the company's press release did not indicate what kind of skin cancer).

Lilly says it is still moving forward with its phase 3 clinical trials of another anti-beta-amyloid compound in AD: solanezumab, a monoclonal antibody. The drug works differently than semagacestat, an inhibitor of the enzyme (gamma secretase) that produces beta amyloid. The company also assures everyone that it will publish the results of its semagacestat trials.

By my estimation, Lilly is/was the frontrunner in clinical AD trials. Late-phase study of another anti-amyloid mAb, Pfizer/JNJ's bapineuzumab, has been complicated by underwhelming efficacy results and vasogenic brain edema.

* IDENTITY and IDENTITY-2.

Photograph of atrophied brain from person with AD: National Institute on Alcohol Abuse and Alcoholism.

Last week's report

of a beta-lactam-resistant superbug in the United Kingdom,* which was likely imported from India, highlights the infectious risks associated with medical tourism, according to an accompanying editorial. The growing trend of traveling to get medical care in non-Western countries—particularly for procedures not covered by insurance (eg, gastric bypass)—is expected to grow in India at an annual rate of 30%, says a 2009 news report. By 2015, medical tourism in India will be a 95-billion-rupee or $2-billion industry (if I'm calculating correctly).

At least one Indian doctor is accusing the report's corresponding author, who happens to be from the UK, of fear mongering and racism (despite the fact that multiple nationalities are represented by the listed investigators).

* Specifically Klebsiella pneumoniae and E. coli containing New Delhi metallo-beta-lactamase 1.

Scanning electron micrograph of E. coli bacterium from CDC/Janice Haney Carr.

Bob le Flambeur (1956): Another notable film of the disaffected criminal subculture from Jean-Pierre Melville, director of the similarly themed Le Cercle Rouge and Classe Tous Risque. When Bob, an inveterate gambler, suffers an extended streak of bad luck, he recruits a small group of friends to crack open a casino safe. But in the immediate buildup to the heist, Bob gets sidetracked by his addiction...with ironic results. French actor Roger Duchesne, as Bob, carries the film with perfect platinum coolness.

Therapeutic doses of lithium carbonate are no more effective than subtherapeutic doses in amyotrophic lateral sclerosis (ALS), according to a newly published, multicenter Italian study. The randomized, dose-finding trial, the findings of which are available today in an e-pub version of Neurology, is the second trial to demonstrate no benefit of the compound in ALS.

A total of 171 patients with probable or definite mild-moderate ALS received either therapeutic (blood levels, 0.4-0.8 mEq/L) or subtherapeutic (blood levels, 0.2-0.4 mEq/L) doses of lithium in single-blind fashion.* In the 15-month study, there was no difference between treatment groups in the rate of the composite primary endpoint, tracheostomy-free survival or "severe" loss of autonomy. (At about 1 year, the rate of the primary endpoint was approximately 60% in both treatment groups, by my read of the provided Kaplan-Meier graph.) The rates of secondary endpoints were also not significantly different between therapeutic and subtherapeutic lithium. In addition, a post-hoc analysis of the primary endpoint, which excluded patients who were not taking riluzole (the only FDA-approved treatment for ALS), showed no treatment-related differences.

A high percentage of patients, nearly 70%, discontinued the study because of adverse events (n = 32), perceived lack of efficacy (n = 32), or poor adherence (n = 4); however, there were no significant differences between the treatment groups in rates of study discontinuation. In each treatment group, 25 discontinuing patients reached the primary endpoint, and another 15 patients completed the 15-month study.

The negative outcomes in this limited Italian study support findings from a recently reported, placebo-controlled North American study (N = 84). Both studies were conducted on the basis of the positive results of Fornai et al, who advertised in 2008 the benefits of lithium in an ALS mouse model and a pilot trial of 84 ALS patients. Last year, Gill et al reported that they were unable to reproduce the positive effect of lithium in the mouse model.

* Evaluating physicians were blinded to treatment.

A pattern of 3 markers in CSF—beta amyloid 1-42, phosphorylated tau, and total tau—appears to strongly predict Alzheimer disease in people with mild cognitive impairment (MCI), according to a newly published and highly publicized study from the US Alzheimer's Disease Neuroimaging Initiative. But the study findings, which can be found in the Archives of Neurology (subscription required), do not necessarily mean that the CSF assay should be incorporated immediately into clinical care—despite the fact that 1) the authors are lobbying hard for the test to be included in the diagnostic criteria for AD and 2) an accompany editorial urges clinical use of the CSF assay with the wince-inducing title, "Sharpen That Needle."

The "AD signature" of low beta amyloid 1-42 and elevated tau levels was found in 90% of AD patients (n = 102), 72% of MCI patients (n = 72), and 36% of cognitively normal subjects (n = 114). Consequently the sensitivity of the test is 90% (the rate of positivity in AD patients), and the specificity is 64% (the percentage of cognitively normal subjects who don't show the AD CSF pattern [ie, 100% - 36%]).

Among a subset of 68 people with autopsy-confirmed AD, 64 (94%) showed the AD CSF pattern, which correlates well with the 90% sensitivity measure in clinically diagnosed AD patients (via the MMSE). In another subset of 57 patients with MCI who developed AD during 5-year follow-up, all exhibited the AD CSF pattern for a sensitivity of 100%.

Rather than view a positive CSF assay in cognitively normal people as a failing of the test (ie, it has limited use in normal subjects), the authors conclude that these people are at risk of AD. This conclusion may well be true, but it seems that further study is warranted before such a bold statement can be made. The authors did find an "enrichment" of the apolipoprotein E ε4 allele, a recognized genetic risk factor for AD, in this population, but the finding was not uniform.

At least ABCNews, unlike many other news sources, found medical commentators who advise against the whole-hearted embrace of this assay. Cliff Saper, who is one of the most level-headed neurologists I've ever met, said there is no reason to perform the test until there is a successful treatment for AD. "This test shows up positive in presymptomatic individuals, and Alzheimer's disease is a common disorder," Saper was quoted. "The main value would be to detect [Alzheimer's disease] in atypical cases." For what it's worth, I agree.

The CSF assay currently appears to be most useful in the context of research—as an additional tool to reinforce the diagnosis of MCI or AD in clinical studies. Assay results may also inform the use of investigative therapies at different stages of cognitive decline. One of the most intriguing findings from the study is that there appears to be a distinctive pattern change as MCI progresses to mild AD and then to advanced disease: CSF beta amyloid levels fall while tau levels rise. Anti-beta-amyloid therapies like bapineuzumab, may provide relatively greater benefit in MCI or very early AD, while anti-tau therapies may have their place in more severe dementia. 

In the meantime, Innogenetics, which employs or employed several of the authors, provides the tripartite CSF assay (Inno-Bio AlzBio 3) for "research use only." Information on the cost of the assay, after several Google searches, remains elusive. 

CSF = cerebrospinal fluid.

Photograph of atrophied brain from person with AD: National Institute on Alcohol Abuse and Alcoholism.

In 1971, Pentagon insider Daniel Ellsberg leaked a top-secret study, aka the Pentagon Papers, to the press. The mammoth document demonstrated the high-level, systematic deceit of multiple administrations to escalate the war in Vietnam, and the press predictably gobbled it up. Ellsberg's treacherous act and its aftermath were chronicled on film in last year's Academy Award-nominated The Most Dangerous Man in America, which is now on DVD.

And while the documentary isn't particularly original in its execution or perspective on Ellsberg's derring-do, it does show (perhaps inadvertently) just how compromised a character must become before he can morph into a historic whistleblower. Think of the initially Koolaid-guzzling characters of Big Tobacco's Jeffrey Wigand and, to a lesser extent, ADM's Mark Whitacre, but on much more expansive stage in a much more explosive era, and you've got an idea of what Ellsberg was and is all about. The steeper the slide into moral ambiguity, the more dramatic the atonement and, god knows, the lengthier the proselytizing.

And if you want to see Defense Secretary Robert McNamara wrestle with his role in the Vietnam War, watch the life-sucking The Fog of War (2004).

The improved outlook for Medicare's solvency, which increased from 2017 to 2029, is due to PPACA, say Medicare's trustees* in their newly released summary report (the full report can be found here). The trustees essentially borrowed on the projected savings (or really anticipated cost-cutting measures) from legislated healthcare reform to extend the life of Medicare's Hospital Insurance Trust Fund specifically.

The life of Medicare's Part B service, which covers outpatient and prescriptions costs for seniors, was also extended. But the trustees' current projection on Part B assumes that the SGR-defined cut in Medicare reimbursement to physicians will kick in December 1, reports MedPage Today. The cut now stands at 23%. Congress has repeatedly voted to stall the cut but is yet to repeal the formula; to do so would add substantially to the deficit. (One healthcare expert recently predicted in the NEJM that Congress will never repeal the formula.)

The trustees' report, in some ways, is a veiled warning to those Republicans (and Republican states—lookin' at you, Missouri) who would attempt to mess legislatively with PPACA. You repeal PPACA, they might say to detractors, you doom Medicare (and Social Security) to an earlier death.

PPACA = Patient Protection and Affordable Care Act; SGR = sustainable growth rate.

* Timothy F. Geithner, Secretary of the Treasury; Kathleen Sebelius, Secretary of HHS; Hilda Solis, Secretary of Labor; and Michael J. Astrue, Commissioner of Social Security.

Yesterday Missouri voters, assumed to be mostly Republican, tried to nullify the federal mandate to purchase insurance or pay a tax penalty, as dictated by the Patient Protection and Affordable Care Act. But the approved state measure, known as Proposition C, is largely seen as an empty Republican nose-thumbing to the Obama presidency and PPACA.* By the time the insurance mandate goes into effect in 2014, courts will have already decided on the constitutionality of the federal law. And federal law usually trumps state law, when the challenge arises.

Voters in 2 other Republican-heavy states, Arizona and Oklahoma, will vote on similar paper tigers this year.

The NYT has a limited story. The St. Louis Post-Dispatch reports that Proposition C passed by a margin of 3 to 1 and that the Missouri Hospital Association attempted last-minute opposition.

* Pronounced fondly as puh-PACK-uh.

Seal of the state of Missouri from http://www.sos.mo.gov/symbols/default.asp, where it can be learned that the state fossil is the crinoid.

According to early-release 2009 data from the CDC.

Percentages indicate rates of obesity (self-reported data).

But try explaining that concept to a jury.

The clinical data, and they are imperfect to say the least, suggest that there may be an idiosyncratic link between Accutane use and depression or suicide. But studies (not case reports) do not collectively support a bona fide association between the drug and affective disorders in users.*

It turns out that the same may be true for any posited association between Accutane and inflammatory bowel disease (IBD)—despite the hundreds of personal-injury cases brought against Accutane's former maker, Roche, in mass-tort litigation.**

There are at least 3 compelling case reports (here, here, and here) suggesting that Accutane causes or exacerbates enteritis or colitis and that these flares remit and recur with withdrawal and reuse, respectively, of the drug. And the drug's PI warns against the occurrence of IBD with Accutane use. (The mechanism by which Accutane, a vitamin A analogue, might cause IBD is unknown.) But a recent, population-based study in Canada found no association between Accutane use and the development of IBD. The study, which was not funded by Roche, is evidently the first of its kind to examine any such association, outside of case reports.

By using the Manitoba Health databases, the Canadian authors identified a similar percentage of patients (age cutoff, <40 years) who used Accutane before or after their first diagnosis of IBD (see adapted Table). These data suggest no association, much less a causal link, between Accutane use and the development of IBD. Moreover, Accutane use among matched controls (for age, sex, and residence) without IBD was similar (1.1% and 0.9% for the before and after populations, respectively). And the mean time between the diagnosis of IBD and the last Accutane prescription was lengthy (1048 days or ~2.8 years), suggesting that any cause-effect relationship in the 25 "before" IBD cases is unlikely.

Accutane Use	Cases (%)	Matched Controls (%)	Odds Ratio (95% CI)
IBD
Before dx	25 (1.2)	213 (1.1)	1.16 (0.73, 1.77)
After dx	23 (1.2)	182 (0.9)	1.25 (0.77, 1.94)
None	1960 (97.6)	19,419 (98.0)
Crohn’s
Before dx	14 (1.3)	120 (1.1)	1.15 (0.61, 2.02)
After dx	14 (1.3)	115 (1.0)	1.21 (0.64, 2.12)
None	1090 (97.5)	10,801 (97.9)
Ulcerative colitis (UC)
Before dx	11 (1.2)	93 (1.1)	1.16 (0.56, 2.20)
After dx	9 (1.0)	67 (0.8)	1.33 (0.58, 2.69)
None	870 (97.8)	8618 (98.2)

A more recently published, case-control study from UNC largely confirmed the Canadian findings, but the US authors concluded a "strong" association between Accutane use and UC among 24 total cases of IBD (OR for ulcerative colitis = 4.36 [95% CI: 1.97, 9.66]). The risk of UC appeared to increase with Accutane dosage and duration of treatment among the small number of cases (only 0.3% of subjects in the total IBD population had been exposed to Accutane). The US authors concluded, "Although the absolute risk of developing UC after taking [Accutane] is likely quite small, clinicians prescribing [Accutane] as well as prospective patients should be aware of this possible association." 

* Whatever Emory psychiatrist Doug Bremner may say on YouTube in his not-particularly-sophisticated interpretation of his and others' data.

** One of these cases was brought by actor James Marshall of "Twin Peaks" and A Few Good Men fame. Marshall, who is reportedly corralling celebrity witnesses to argue his case, claims that Accutane caused his IBD, which in turn put the kibosh on what would have been a James Dean-like film career (without the violent, early death, presumably). See last week's Bloomberg story.

Photo of Roaccutane, aka Accutane, from Wikipedia.

08/06/10 addendum: Yesterday the New Jersey Superior Court Appellate Division repealed the $10.5 million verdict for the plaintiff in Kendall v Hoffman-La Roche. The appellate court ruled that the Roche was hobbled during trial by restrictions on the presentation of background data for the incidence of IBD. Kendall, who was treated several times with Accutane for nodular acne during adolescence and young adulthood, developed UC at the age of 15 years, which coincided with Accutane retreatment. However, her bowel condition was not uniformly exacerbated by further treatments with Accutane.

Kendall's case hinges on the argument that Roche failed to warn of the risk of IBD, and Roche's warnings are based on risk data known at the time of Kendall's Accutane treatments. Bloomberg covered the story; the appellate decision can be found here.

A similar appellate reversal was made in McCarrell v Hoffman LaRoche, and the retrial resulted in an even bigger verdict for the plaintiff. An appeal on this verdict is reportedly in the works.