Recently in Epidemiology Category
According to early-release 2009 data from the CDC.
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 |
|
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.
While some news sources are claiming that the results from WHO's large INTERPHONE study (yet another study assessing the risk of brain tumors with cell-phone use) are "inconclusive," a review of the published article, in the International Journal of Epidemiology, generally reveals otherwise. (A press release for the article can also be found here.)
Among dozens of case-control analyses in the study, many of which involved small numbers, few demonstrated an increased odds of meningioma or glioma. Moreover, in the vast majority of cases, the odds of these brain tumors were actually lower with cell-phone use.* On the basis of their results, the authors concluded that there is no increased risk of meningioma among cell-phone users.
When considering glioma, however, the odds were increased among users whose cumulative call time exceeded 1639 hours (OR, 1.40; CI: 1.03, 1.89), regardless of how long they had been using cell phones (1-4 years, 5-9 years, or 10+ years).** The highest cumulative call time was also associated with an increased odds of glioma in the temporal lobe (OR, 1.87; CI: 1.09, 3.22) and on the same side as typical cell-phone use (OR, 1.96; CI: 1.22, 3.16). "Still, the evidence for an increased risk of glioma among the highest users was inconclusive," the authors wrote, citing several possible sources of study biases, including selection bias. (Unfortunately several news sources evidently grabbed the word "inconclusive" for their provocative ledes.)
The INTERPHONE study was a multinational study, involving 16 centers in 13 countries (Australia, Canada, Denmark, Finland, France, Germany, Israel, Italy, Japan, New Zealand, Norway, Sweden, and the United Kingdom). Between 2000 and 2004, data were collected from people aged 30-59 years, given that these individuals were likely to have a history of significant cell-phone use. The data were compared with information from matched control populations (who, evidently, didn't use cell phones...ever...! [Addendum "Oops," see below for a clarification of the control pop). The main analyses included 2409 meningioma cases (2662 matched controls) and 2708 glioma cases (2972 matched controls).
The rationale for studying a possible link between cell-phone use and brain-tumor risk is based on the proposal that low-level exposure to radiofrequency (RF) magnetic fields from cell phones increases the risk of brain tumors that absorb this energy. While cell-phone use has increased dramatically since the time of the study, any risks associated with increased cell-phone use are probably mitigated by lower RF emissions, on average, from newer phones and the prevalent use of texting and hands-free devices (which keeps the RF-emitting cell phone away from the head).
* Use of hands-free devices was excluded.
** However, the confidence interval for the 1-4-year odds ratio was very wide.
Addendum 10/20/37: The reference or control group, defined as "never regular users," included those people with meningioma (32% of cases) or glioma (26%) who never had more than 1 call per week, on average, for 56 months. Never users (11% of meningioma cases and 9% of glioma cases) were, in fact, never users.
Yesterday Orac provided another blog-based review of this study, citing the "inconclusive" moniker as accurate. I disagree, given the overall results of the study (and the extent to which any negative study can ever be called conclusive). The only hedge is provided by the high-end cell-phone users for glioma. But even Orac writes, "There was no compelling evidence of an association between cell phone use and either of these cancers."
Orac also poo-poos the RF rationale for assessing a link between cell-phone use and brain cancer, at least on the basis of DNA breakage. This appears to be an important point to stress (despite the fact that the study was conducted in the first place!).
The INTERPHONE study authors write,
"Much biological research has been done in recent years on possible biological effects of RF fields. This work covers in vitro and in vivo exposure, alone and in combination with other physical or chemical agents, and has found no evidence that RF fields are carcinogenic in laboratory rodents or cause DNA damage in cells in culture. Possible effects of RF fields on other biological endpoints are still being explored."
The authors cite a white paper from the European Commission, "Health Effects of Exposure to EMF," which summarizes,
"It is concluded from three independent lines of evidence (epidemiological, animal and in vitro studies) that exposure to RF fields is unlikely to lead to an increase in cancer in humans. However, as the widespread duration of exposure of humans to RF fields from mobile phones is shorter than the induction time of some cancers, further studies are required to identify whether considerably longer-term (well beyond ten years) human exposure to such phones might pose some cancer risk."
Worries about a rise in Guillain-Barre syndrome during the 2009 H1N1 vaccination campaign were unfounded. Only 35 cases of the acute autoimmune neuropathy were reported to the CDC or the FDA's voluntary reporting system, VAERS, at the end of last year, say researchers at the ongoing annual meeting of the American Academy of Neurology in Toronto.
The 2009 H1N1 (or swine flu) vaccination campaign began in earnest in mid-October of last year, and approximately 100 million vaccinations were administered in the United States. Consequently the rate of GBS associated with vaccination was 3.5 per 10 million. All but 1 case occurred within 6 months of vaccination; 23 cases occurred within 2 weeks of inoculation. The annual background rate of GBS is about 1-4 cases per 100,000. (The 2009 H1N1 vaccine protects against GBS, anyone?)
Original worries about a vaccine-associated increase in GBS stemmed from the observed rise in the condition during the 1976 swine-flu vaccination program.
VAERS = Vaccine Adverse Event Reporting System.
As just about everyone knows by now, the Special Masters of the US Court of Federal Claims handed down their decisions on Friday, which deny a causative link between the vaccine preservative thimerosal and autism in 3 test cases.
Among the many opinions rendered in the decisions from the Special Masters (see here, here, and here) are discussions of the autism studies published by Mark and David Geier—whose work has been criticized sharply and at length at this blog and in my 2009 letter to the Journal of the Neurological Sciences.
The court's Special Master George Hastings, for instance, writes in his decision re King v Secretary of Health and Human Services:
[M]ost of the epidemiologic studies that have addressed the thimerosal/autism causation issue have failed to find any association between thimerosal-containing vaccines and autism, but there have been certain exceptions. Those exceptions were studies published by the research team of Dr. Mark Geier and his son David Geier[*]...To be sure, the petitioners in this case have not cited or relied upon those Geier studies in their post-hearing briefs, because, as I will discuss below...the petitioners argue that all of the epidemiologic studies done to date are irrelevant to the petitioners' causation theory in this case. However, since I find that the epidemiologic studies are of relevance, I have found it reasonable to examine those Geier studies, to see if they afford any significant counterweight to the many contrary studies...
After careful consideration, I conclude that the Geiers' studies cannot be given any weight. A number of those studies were considered by the Institute of Medicine (IOM) committee that fully studied the entire thimerosal/autism causation issue in 2004. That committee concluded that the studies were so flawed as to be "uninterpretable," and that the studies contributed nothing meaningful ("noncontributory") concerning the causation issue...The committee noted that the studies were based on databases that themselves had "significant limitations"...and that the studies had "serious methodological problems"...or "serious methodological limitations"...The committee added that the Geiers' articles describing their analytical methods were "not transparent" and omitted "important details," so that it was impossible to evaluate the studies...Other specific deficiencies in the studies were also discussed, including the fact that the Geiers incorrectly used several epidemiologic terms and measures.
In addition, Dr. Fombonne [respondent's expert] agreed with the IOM's criticisms of the Geier studies, and testified that the Geier studies in general failed to use accepted epidemiologic methods...Dr. Rutter [respondent's expert] was critical of the Geier studies as well...Further, petitioners' own expert witness concerning epidemiology, Dr. Greenland, agreed with the criticisms of the Geier articles, acknowledging that those studies are "deficient in methodology"...And none of the expert witnesses for the petitioners vouched for the reliability of the Geier studies.
I have reviewed the published Geier studies discussed in the 2004 IOM report, and I agree with the analysis of those studies set forth in that IOM report. Further, I have reviewed the additional studies published by the Geiers since the 2004 IOM report, and find that those studies suffer from the same type of flaws as the earlier Geier studies. That view includes a study published in 2008 by the Geiers, along with Young as the third author. Two of respondent's experts, Drs. Fombonne and Rutter, testified that that 2008 study was again deeply flawed, and those experts provided a number of specific examples of deficiencies in the study...And, again, none of the petitioners' experts testified in support of that 2008 Young, Geier, and Geier study.
In summary, I conclude that all of the Geier epidemiologic studies are not reliable, and cannot be accorded any weight.
In a lengthy footnote from the decision handed down in the case of Mead v Secretary of HHS, Special Master Patricia Campbell-Smith writes,
Although the studies conducted by Dr. Mark Geier and his son purport to find an association between thimerosal-containing vaccines and autism, their studies have been criticized consistently by various reviewers, including petitioners' own expert epidemiologist, as methodologically deficient...(Dr. Rutter [characterized] the 2008 Young study—that was conducted in part by Dr. Geier and his son...as a poorly designed study for the following reasons: (1) the researchers used a "strange" study design that is both a cohort study [a controlled study] and a time-trend analysis of the available database information [an ecological study] and (2) the researchers included emotional disturbance as one of the neurodevelopmental disorders observed following exposure to thimerosal-containing vaccines even though emotional disorders are not included in any of the official psychiatric classifications systems for neurodevelopmental disorders). The undersigned has reviewed carefully the presented studies conducted by the Geiers and has considered the criticisms leveled against the Geiers' studies. Persuaded that the studies are flawed methodologically in critical respects, the undersigned, without addressing the studies in extensive detail here, declines to accord any evidentiary weight to the studies. The undersigned notes that other researchers have been unable to verify the validity of the Geiers' statistical analysis on a number of occasions and a number of courts have expressed concerns about the reliability of their work.
Campbell-Smith goes on to cite 8 court cases in which the Geiers' work was called, among other things, "unintelligible," or in which Dr. Geier's testimony was described as "not reliable."
In her decision for the third test case, Special Master Denise Vowell affords special attention to the Young, Geier, and Geier study of 2008—which was specifically pulled apart at this blog and by Epi Wonk.
The only studies demonstrating a relationship between TCVs [thimerosal-containing vaccines] and ASD [autism spectrum disorder] are those in which Dr. and Mr. Geier appear as co-authors, including the Young study published in May, 2008, and funded by the OAP PSC [Omnibus Autism Proceeding Petitioners' Steering Committee]...Because petitioners’ own expert commented that the Geier studies were not reliable as evidence... and they were thus not addressed by respondent’s experts, I do not discuss the earlier Geier studies any further. In view of the numerous criticisms of the earlier Geier studies and petitioners' own expert’s dismissal of them, I have placed no reliance on them.
The Young study was an ecological analysis using the VSD database...Doctor Greenland [petitioners' expert] did not comment on this study during his testimony, as the article was introduced after his appearance and excusal. The study found an increased risk of ASD, based on increasing exposure to TCVs. Doctor Fombonne offered several criticisms of this study. In a critique common to many of the studies performed by Dr. and Mr. Geier, Dr. Fombonne commented that the Young article did not provide the data that would allow others to verify the calculations performed.
Doctor Fombonne reproduced one chart from the article...Using the chart, he explained that the birth cohorts used in the study did not all contain the same number of individuals, with most representing 40,000 children...One birth cohort, that of children born in 1990, contains only 2,000 children...When this "outlier" is removed, the purported statistical relationship between ASD and TCVs during the first four years of the sample disappears.
Doctor Fombonne was also highly critical of the authors' addition of invented numbers to the 1995 and 1996 data from the VSD...If the adjustments are removed, there is no correlation at all between the increase in thimerosal exposure and increase in autism cases per 10,000...Doctor Fombonne commented: "It’s dishonest to impute like 45 new cases which are just invented to top up the prevalence in a way which is supportive of their hypothesis. It’s clear that these investigators have a clear track record to do with the data that supports their hypothesis. And I’ve seen that in their previous papers."
Doctor Rutter offered similar criticisms of the Young study...calling it "a poor study for several different reasons"...It began with a cohort design, but ended up being analyzed as a time trend study. That required the authors to make adjustments to the first and last cohorts. Doctor Rutter described this as "putting together chalk and cheese in the hope of gazpacho soup coming out"...The "analytic design and strategy was not a satisfactory one."
He pointed to Table 3 as a striking example of the poor design...Table 3 compares "neurodevelopmental disorders" to several control disorders, measuring the difference in rates of the disorder developing in the cohorts that received 100 micrograms more mercury. The table shows higher rate ratios for autism, ASD, ADD/ADHD, developmental or learning disorders, disturbance of emotions, and tics...Doctor Rutter called this table an example of demonstrating a statistical effect without showing a causal effect...If the neuroinflammation hypothesis is correct, it is difficult to explain how neuroinflammation causes tics or disturbance of emotions. The study reported TCV effects across a very broad range of unconnected disorders having different ages of onset, different genetic factors, and different disease courses...The broad range of effects in these diverse disorders caused Dr. Rutter to be "immediately skeptical as to what [the study] shows."
He also questioned why "disturbance of emotions" was listed in the category of neurodevelopmental disorders, noting that anyone knowledgeable about the field of neurodevelopmental disorders would not have categorized it as one, and would have placed it with the control disorders...To prove their hypothesis that increased mercury exposure causes increases in neurodevelopmental disorders but not control disorders, the authors have to demonstrate that mercury is associated with increased rates of one but not the other. If "disturbance of emotions" was properly placed with the list of control disorders, it would undercut the authors' hypothesis. Their comparison between the two groups is therefore invalid.
Vowell also comments on a reanalysis of the Young et al data by Young herself, who found no association between birth year (which was purported to be associated with exposure to TCVs) and ASD when the imputed cases were removed.
Doctor Young’s subsequently-filed letter indicated that she reanalyzed the data to respond to Dr. Fombonne's criticisms. After she removed the 1990 birth cohort (the one containing only 2,000 cases) and the notional cases for 1995 and 1996, the results for autism, ASD, and unspecified developmental disorders lost statistical significance...She nevertheless defended the use of the 1990 birth cohort and her adjustments to the numbers for 1995 and 1996.
Vowell also dismisses the study of Young et al on the basis of its funding source.
For the reasons indicated in the criticisms proffered by Drs. Fombonne and Rutter, I have accorded the Young study little weight. An additional reason for viewing this study as unreliable is the conflict of interest generated by the PSC’s funding of the study. In its opinion on remand in Daubert, the Ninth Circuit considered whether the matters an expert proposed to testify about flowed from research conducted independently of involvement in the litigation in question, noting that this factor provides objective proof that the research was conducted for scientific purposes.
Yet, despite these unequivocal, disparaging opinions on the work of Geier and Geier, they continue to find sympathetic medical publishers. Their latest article (pdf here) can be found in the Journal of Toxicology and Environmental Health, Part A, which has now published the Geiers' work on 5 occasions.
In their latest article, the Geiers (along with Janet Kern of the Genetic Consultants of Dallas) again try to link the excretion of some urinary porphyrins (their dubious pet marker for mercury toxicity) with ASD severity. The study is very similar to their previously published work in the JNS, and one wonders if there isn't substantial overlap in the study subjects (26 vs 28 children).
Despite the suspicion, the tabulated presentation of the Geiers' urinary porphyrin data in JNS (nanomoles per gram of creatinine) makes it virtually impossible to compare these numbers with their urinary porphyrin values in the latest article (which are presented in "normalized" uP levels). Similar objections can be raised of their graphed data, primarily because of differences in the presentations of the x-axes.
N.B.--The Geier studies reviewed by Special Master Hastings included the following:
The Alzheimer's Association has a new report on the large and growing effect of Alzheimer disease and other dementias on Americans. Here's the distillation:
- AD is the most common cause of dementia, affecting 5.3 million Americans (1.7% of the current US population). The vast majority (96%) of those affected are older than 64 years of age.
- Dementia affects women preferentially because they live longer, on average, than men. (Advancing age is the biggest risk factor for AD.)
- In 2006, AD was the 7th leading cause of death among all Americans. In those older than 64 years of age, AD was the 5th most likely cause of death.
- Next year, the first baby boomers will turn 65. In 30 years, all of the estimated 70 million baby boomers will be older than 65. The Association estimates that there will be 1 million new cases of AD by the year 2050.
- People with AD and other types of dementia need a lot of health care, including long-term and hospice care. In 2010, care costs for people with dementia will reach $172 billion. Medicare costs for people with dementia are nearly 3 times higher than those for the nondemented elderly. Medicaid costs are nearly 9 times higher. (Blogger's note: I suspect this is the result of Medicaid-funded nursing home care.)
- Older African Americans and Hispanics are about 2 and 1.5 times more likely, respectively, to have AD and other types of dementia than older whites.* Reasons for the higher risk of AD among these minorities include a greater prevalence of known risk factors for dementia, like hypertension, diabetes, and lower education and income levels. (Ethnically dependent genetic risks have not been identified.) Despite the higher risk of dementia among African Americans and Hispanics, the diagnosis is more likely to be delayed in affected minority patients. Delays in diagnosis mean missed opportunities for treatment, which is more likely to be effective in the early stages of AD.
- Last year, nearly 11 million family members or other uncompensated persons provided 12.5 billion hours of care for people with dementia. Unpaid care was assessed at $144 billion, which is more than the US government (ie, Medicare and Medicaid) spends on people with dementia. Costs of giving care are also measured in emotional and physical stress, declining caregiver health, and lost employment-related productivity.
* This is the lead of today's press release from the Alzheimer's Association.
Photograph of atrophied brain from person with AD: National Institute on Alcohol Abuse and Alcoholism.
People with migraine—especially people who experience aura before headache—are known be at increased risk of ischemic stroke and cardiovascular disease. What isn't well known, however, is 1) whether these increased risks apply to people who have migraines without aura; and 2) whether migraine is an independent risk factor for vascular disease or merely a marker for well-known risk factors, like diabetes.
A new survey study of more than 11,000 people, the results of which are published online in the journal Neurology, essentially answers "yes" to these issues.
- People who experience migraine without aura have increased risks of heart attack and peripheral vascular disease—but, surprisingly, not stroke. These increased risks, however, are smaller than those for people who experience migraine with aura.
- All people who experience migraine (with or without aura) are more likely to have been diagnosed with diabetes, hypertension, or high cholesterol levels—all well-known vascular risk factors.
- But, on the basis of a multivariate analysis (including control for triptan use*), migraine also appears to be an independent risk factor for vascular disease.
The absolute rates of vascular events and vascular risk factors, discovered by the authors, are tabulated here:
|
|
Controls (Without Migraine) |
All Migraineurs |
Migraine With Aura |
Migraine Without Aura |
|
Heart attack, % |
1.9 |
4.1 |
5.5 |
3.4 |
|
Stroke, % |
1.3 |
2.0 |
3.8 |
1.1 |
|
Claudication, % |
0.9 |
2.6 |
4.2 |
1.8 |
|
Diabetes diagnosis, % |
9.4 |
12.6 |
13.8 |
12.0 |
|
Hypertension diagnosis, % |
27.8 |
33.1 |
35.7 |
31.9 |
|
High cholesterol level, % |
25.6 |
32.7 |
33.8 |
32.2 |
|
Smoking, % |
14.2 |
15.8 |
16.3 |
15.5 |
|
Mean Framingham risk score |
8.5 |
10.7 |
11.0 |
10.6 |
The mean Framingham risk scores for all 3 groups of migraineurs were significantly higher (P = .001) than the mean score for the surveyed control population.
The authors, who represent industry (Merck**) and academia (Albert Einstein, Brigham and Women's), stress that a history of migraine in patients should prompt a search for modifiable cardiovascular risk factors. They also postulate that migraine itself may predispose to vascular disease by compromising the function of vascular endothelium.
The question of whether triptan use or migraine prevention (eg, with beta blockers) alters the risk of vascular events is raised by Diener and Harrer in an accompanying editorial. They propose that the necessary length of a prospective study would be prohibitive (eg, >10 years). They also wonder whether the relatively low risks of vascular events in migraineurs would justify the effort and expense.
* Recently the same authors (Bigal et al) reported that tripan use is lower in migraineurs with cardiovascular risks, "suggesting that doctors and/or patients fear using tripans in individuals at risk."
** Merck makes Maxalt (rizatriptan).
Depiction of classic fortification spectra of migraine aura, as depicted by Dr. Gowers in 1907.
Occupational exposure to the industrial solvent trichloroethylene increases the risk of Parkinson disease, according to researchers at the Parkinson's Institute and Clinical Center. The California-based, nonprofit organization released its study findings, which have not been presented at a scientific meeting or peer reviewed, on Sunday—apparently by way of press release. The data are scheduled to be presented at the annual meeting of the American Academy of Neurology in April.
According to sources picking up news of the study, data from 198 twin pairs in the World War II Veteran Twins Cohort Registry showed that the risk of PD in individuals with probable exposure to the solvent* was more than 5 times that of twins without probable exposure.** In a MedPage Today piece, an odds ratio (5.5) is reported, but no frequency rates of disease are provided. Also the 95% confidence interval for the odds ratio is very wide (1.02, 30)—indicating that the accuracy of the measured risk is uncertain.
Interest in trichloroethylene exposure as a risk factor in PD extends back to the early 90s, when it was reported by German investigators that a metabolite of the solvent is chemically similar to the neurotoxin MPTP. (The metabolite of MPTP, MPP+, has a predilection for the dopamine-producing neurons of the substantia nigra—the area of the brain that is primarily affected in PD. The MPTP story, itself, is fascinating and the subject of an excellent Nova episode, "The Case of the Frozen Addict," from 1986.)
In 2008, researchers at the University of Kentucky published their study of 30 industrial workers with PD or parkinsonism, who had long-term exposure to trichloroethylene. The study authors suggested that a worker's proximity to the solvent was related to his risk of the movement disorder. These findings were complemented by animal studies, which showed that oral intake of trichloroethylene for 6 weeks resulted in the degeneration of brain areas that are typically affected in PD.
* Presumed on the basis of occupation (eg, aircraft mechanic, electrician).
** The study of twins (and presumably, these are identical twins) largely eliminates any potentially confounding genetic risks of Parkinson disease.
Image of 1886 drawing of PD patient by neurologist Sir William Richard Gowers at Wikimedia Commons.
Pandemic influenza may "notably increase" the overall death rate for pregnant American women in 2009. The prediction is based on data from pregnant or postpartum women who died of infection with the 2009 H1N1 virus in California during a 4-month period. An assessment of flu-related hospitalizations and deaths in this population is available in the latest issue of the NEJM.
Investigators from the California Pandemic (H1N1) Working Group collected data from 239 pregnant, postpartum, or nonpregnant women of reproductive age who were hospitalized with or died of probable or confirmed* pandemic flu between April 23 and August 11, 2009. Most (~78%) acquired infection in June or July.
Underlying chronic conditions, specifically asthma, were observed in substantial percentages of all women and particularly nonpregnant women—confirming that pregnancy itself is a risk factor for severe infection with the 2009 H1N1 virus.
|
Patient Feature |
Pregnant |
Postpartum |
Not Pregnant |
P Value [b] |
|
Chronic illness, % |
34 |
25 |
60 |
<.001 |
|
Asthma, % |
16 |
0 |
28 |
.04 |
|
Nongestational diabetes, % |
2 |
0 |
15 |
.002 |
|
Immunosuppression, % [c] |
3 |
0 |
15 |
.006 |
|
Neurologic disorder, % |
1 |
12 |
10 |
.009 |
|
Hypertension, % |
5 |
12 |
17 |
.009 |
|
Gastrointestinal disease, % |
2 |
0 |
14 |
.006 |
a. Percentages based on pregnant women for whom data were available.
b. Pregnant women vs nonpregnant women.
c. Related to cancer or transplantation.
Notable among pregnant women was a rapid clinical deterioration that looked qualitatively different from typical seasonal influenza. About 25% of pregnant women who required mechanical ventilation were intubated at the time of hospitalization, and several deliveries were made in intensive care units. ICU admission and death were about 4 times more likely in pregnant women who received antiviral treatment after 48 hours of symptom onset. Delay of antiviral treatment appeared to be associated with false-negative rapid-antigen test results.
During the 4-month period, the mortality ratio for pandemic flu in pregnant women was estimated at 4.3. Previous mortality ratios for all-cause death among pregnant women in California (2005) and in the United States (2006) were 19.3 and 13.3, respectively.
The authors urge pregnant women to be vaccinated against pandemic flu on the basis of their findings and preliminary vaccine-trial results.
RT-PCT = reverse-transcriptase polymerase chain reaction.
* Probable disease was defined as a positive result by real-time RT-PCR for influenza A that could not be subtyped H1 or H3. Confirmed disease was defined as a positive result by real-time RT-PCR that was specific of 2009 H1N1 influenza.
Depiction of H1N1 virus from Wikipedia.
About 16% of people with mild cognitive impairment (MCI) progress to Alzheimer disease during the course of a year, according to new data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Progression from MCI to AD, which correlated with baseline CSF levels of amyloid beta-42, occurred despite the prevalent use of available antidementia therapies (~50% of subjects).
ADNI investigators followed up more than 800 elderly subjects (mean age, ~75 years) with normal cognition, MCI, or AD. Baseline data were notable for remarkably high mean verbal IQ scores and education levels among all 3 groups and relatively high percentages of APOEε4 carriers among individuals with MCI or AD.
|
Baseline Feature |
Normal |
MCI |
AD |
P Value |
|
Mean education, y |
16 ± 2.9 |
15.7 ± 3.0 |
14.7 ± 3.1 |
<.001* |
|
Estimated mean premorbid verbal IQ |
120 |
116 |
114 |
— |
|
APOEε4 carriers, % |
26.6 |
53.3 |
66.1 |
<.001* |
|
Mean MMSE score |
29.1 ± 1.0 |
27.0 ± 1.8 |
23.3 ± 2.1 |
<.001** |
|
Mean ADAS-cog score |
6.2 ± 2.9 |
11.5 ± 4.4 |
18.6 ± 6.3 |
<.001** |
|
AChEI, % |
0 |
43.7 |
84.9 |
— |
|
Memantine, % |
0 |
10.8 |
47.4 |
— |
|
Combined therapy, % |
0 |
8.8 |
40.6 |
— |
|
Mean CSF Aβ-42 level, pg/mL |
206 ± 5 |
164 ± 4 |
143 ± 4 |
<.001** |
* Control vs MCI amd MCI vs AD.
** Control vs MCI; control vs AD; and MCI vs AD.
On the basis of a battery of cognitive and neuropsychological tests, the estimated rate of conversion from normal cognition to MCI was 1.4% during 12 months, and that from MCI to AD was 16.5%. Eight individuals with MCI reverted to normal cognition, and 2 subjects with AD reverted to MCI at 1 year.
Among individuals with MCI, scores on a range of assessments (eg, MMSE, ADAS-cog, clock drawing) could be used to predict progression to AD. Lower CSF levels of amyloid beta-42, which did (and are known to) correlate with higher ADAS-cog scores, were also associated with cognitive decline in normal people and those with MCI.
In July, the ADNI reported that structural abnormalities on MR images are more useful than known CSF biomarkers for discriminating among people with AD, amnestic MCI, or normal cognition, but that the use of MR imaging and CSF analysis is more diagnostically helpful than each measure individually.
AChEI = acetylcholinesterase inhbitor; ADAS-cog = Alzheimer's Disease Assessment Scale, Cognitive Subscale; APOE = apolipoprotein E; CSF = cerebrospinal fluid; MMSE = Mini-Mental State Examination; MR = magnetic resonance.
Photograph: Atrophied brain of person with AD from National Institute on Alcohol Abuse and Alcoholism.
