Grand Rounds 5.36 at See First

This week’s edition of Grand Rounds is up at See First.

You can see the posts here.

Evan Falchuck (@efalchuk on Twitter) thinks nothing of it. [1] no theme, {2] accept any (appropriate) post and [3] allow people to submit a few hrs before publishing the Round!!!
I bet he got my post last. Great job.

Next week’s “June Is Busting Out All Over” edition will be at HealthBlawg of David Harlow.You can already see the announcement here. No theme again. Hurray!

CMV-infection, plaques and high blood pressure

A recent experimental study shows that a common virus that hides (becomes latent) after infection can trigger high blood pressure, a leading cause of cardiovascular disease.

The virus is cytomegalovirus (CMV). It belongs to the herpesviruses, hence it’s alternative name Human Herpesvirus 5 (HHV-5). The herpesviruses have in common that they can become latent (dormant) for a long while. Herpes simplex virus-1 (HSV-1) and varizella zoster virus usually hide in nerves (neurons) and can cause cold sores and shingles respectively after reactivation.

Cytomegalovirus (CMV) can be transmitted by sputum and other bodily fluids. After infection, it stays within the host, hiding primarily in certain white blood cells serving as a reservoir for reactivation.

The study by Cheng et al, consisted of an experimental mouse study and in vitro experiments, using mouse CMV (MCMV) and human CMV (HCMV)

1. In the in vivo experiment, 4 groups of mice -of 12 animals each- were treated as follows:
   • M: Mice in group 1 were infected by MCMV and fed a regular diet.
   • V: Mice in group 2 were mock-infected and fed a regular diet (control group).
   • V-HD: Mice in group 3 were infected by MCMV and fed a high cholesterol diet.
   • HD: mock-infected and fed a high cholesterol diet (control group).
     
2. After 6 weeks the blood pressure, measured in the carotid artery, was significantly enhanced in mice that were infected by the MCMV compared to mock-infected controls. Thus the blood pressure was significantly higher in V versus M and in V-HD versus HD mice. This was both true for the systolic and the diastolic blood pressure (see Fig).
3. Atherosclerotic plaque formation in mouse aortas was only observed in V-HD mice (MCMV infection and high cholesterol diet together). 3 out of 12 mice showed plaques against 0 out of 12 mice in the other groups.
4. The serumlevels of all 3 pro-inflammatory cytokines tested, IL-6, TNF-α and MCP-1, were higher in the mice infected with MCMV (V-HD and V) than in the mock-infected groups fed with either diet.
5. CMV infection induced renin and Ang II expression (in vitro cq in vivo). Renin is a rate limiting protein of Renin-Ang-II system and Ang II is the peptide that causes the blood vessels to constrict, thereby enhancing blood pressure.
6. The renin production was only enhanced in kidney-cells containing CMV-particles.
7. In mice infected with CMV, Ang II was also increased in serum and in artery tissues.
8. MCMV RNA and DNA were present in blood vessels post infection. Mice produced the latency-related CMV transcriptional product I-E1.
9. Next, in vitro experiments were carried out with human cells. Infection of human blood vessel endothelial cells with HCMV induced renin expression in a-dose dependent manner, without lysis of the cells (non-lytic infection). This means that viral gene expression takes place in the absence of a viral cytopathic effect. Only replicating forms of HCMV could induce renin.

Conclusion of the Authors:

“In summary, CMV infection alone caused a significant increase of arterial blood pressure. Enhanced expression of pro-inflammatory cytokines, renin and Ang II underlies the pathogenic mechanism of an active CMV infection to increase blood pressure and aggravate atherosclerosis. Thus, control of CMV infection to restrict development of hypertension and atherosclerosis may provide a new strategy to prevent cardiovascular diseases associated with HCMV infection.”

Review
The present article provides interesting new insights into various mechanisms whereby CMV could ultimately cause cardiovascular disease. Many different assays were performed, both with mouse CMV in vivo and in vitro and with human CMV in vitro.

It should be noted however, that several of the reported findings are not new. CVM DNA and RNA have long been identified in atherosclerotic plaques. CMV and other herpesviruses were known to induce IL-6 and other pro-inflammatory interleukines. And a relation between CMV-infection and cardiovascular disease has been established in the past.

The main new findings are (1) that CVM-infection can raise blood pressure and (2) the demonstration of possible mechanisms involved in the increase of blood pressure: induction of renin and angiotensin by infection of endothelial and renal cells (rather than induction of plaques?) and induction of cytokines. Importantly, the cytokine-enhancing effects were restricted to CMV-infected cells only.

Although the findings are very suggestive of a causal relationship, it remains to be proven whether hypertension via enhanced extrarenal production of renin and angiotensin is the causal factor of CMV-associated cardiovascular disease in the normal human situation. Some statements are not underpinned by the current data. See for instance the blue marked text in the author’s conclusion.

Arterial wall depicting major inflammatory features common to CMV infection and atherosclerosis. - K. Froberg

The current prevailing hypothesis is that atherogenesis is an inflammatory response to acute or chronic endothelial injury. Possible causes for this endothelial injury include free radicals, modified LDL, hypertension, diabetes mellitus and smoking [4,5]. More recently CMV and other infections have been added to the list of risk factors. It is generally thought that the formation of plaques concurrent with the enhanced induction of cytokines can contribute to atherosclerosis and vascular disease, after many years of chronic, active inflammation of the arterial wall.

In the present model, atherosclerosis was only observed in 3 out of 12 HD-V mice. This indicates that atherosclerosis is not involved in the increase of blood pressure. Instead, the present study shows, that CMV might contribute to cardiovascular disease via an effect on blood pressure, presumably mediated through an enhanced expression of renin and Ang II.

With regard to the statistical analysis, I wonder why each virus-treated group was only compared to its mock-infected control (using the Student’s t-test)? Why weren’t all groups compared to each other, using another statistical test? Is this because another approach would have rendered most differences insignificant? The differences between groups are consistent but not very large and the standard deviations are quite overlapping. (Thus significance might be lost when more rigid test are used)

It would for instance be interesting to know the relative contribution of the fatty diet to the rise in blood pressure, or the risk in the 4 groups relative to each other.
We all have CMV (well about 70-90%), but just few of us get high blood pressure (at young age). So likely other factors come into play, that may enhance the detrimental effects of CMV or vice versa. Therefore, it would for instance be interesting to know, to which extent high fat consumption would contribute to high blood pressure as well. Is the suggested order as we see it real: V alone giving slight elevation of blood pressure, HD alone giving more elevation and VHD giving the highest rise? (2×2 table).

The study has some fascinating results, but it is too soon to think about antiviral treatment as the authors and media [3] suggest. Nor is it necessary to worry the public by stating that: “You can find out if you have been infected with CMV by requesting a blood test from your GP”, as the daily mail does. This is useless, because CMV is omnipresent.(one might only see if teh

It hardly seems to be justified to suggest that everybody should be treated with antivirals. And what about the other viruses or bacteria that may play a role? Furthermore, lifestyle and other (immunological) parameters may be more important ànd lifestyle changes may be easier to implement.

Update: Tuesday 2009-05-26: 17.30 pm.

HATTIP: @microbytes (Twitter)

Figure: Kent Froberg from the University of Minesota (med.umn.edu)

References

1. Cheng, J., Ke, Q., Jin, Z., Wang, H., Kocher, O., Morgan, J., Zhang, J., & Crumpacker, C. (2009). Cytomegalovirus Infection Causes an Increase of Arterial Blood Pressure PLoS Pathogens, 5 (5) DOI: 10.1371/journal.ppat.1000427
2. http://www.sciencedaily.com/releases/2009/05/090514221915.htm
3. http://www.dailymail.co.uk/health/article-1186876/Heart-disease-isnt-catching-Oh-yes-scientists-warn.html
4. Many reviews from Cathrien A. Bruggeman and colleagues, like this review in a Book.
5. Kent Froberg from the University of Minesota (med.umn.edu)

Human Herpesvirus 5 (HHV-5)

Martin Bril: the Author, his Death and his Cancer

Martin Bril is dead.

No “news“, it happened a month ago: April 22.

Martin Bril was a well known Dutch writer, poet and columnist – and the man who invented “skirt day”.

He loved live -and love- in all it’s simplicity. He needed few words to describe the essence of things or as he would say: “The surface is deep enough”. But you know, it is looking at one drop of water and understanding the ocean. …

Other expressions: “Good is better than bad” and “You’ve people that bang the guitar really hard for hours, but I rather hear J.J. Cale. Always finished within 4 minutes, but the music stays with you.”

I liked his stories/columns most of the time, they often made me smile.

It is always sad when somebody dies young (Martin was 49), whether a “celebrity” or not. Especially when he leaves two young children and a wife.

I didn’t expect it and it really hit me. Why? I knew he had had cancer, but I thought it had gone. So did he a few years ago. I found a video-interview with him in 2007, where he said: “soon I will be declared “cured” – but then you will see it will return the other day.” In another interview I read: You never “beat cancer”, that’s Lance Armstrong-language. Cancer goes away or it stays. It often stays.

I always thought he had colon cancer, but it was esophageal cancer. That’s the trouble with Dutch:

• esophagus = slokdarm,
• jejunum, ileum = dunne darm
• colon = dikke darm.

Notice they all have “darm” in them. Mostly colon cancer is called “darmkanker” (or “dikke darmkanker”), and because esophagus is called slokdarm, slokdarmkanker is mistaken for darmkanker, which is quite another disease with other prospects.

Stupid, journalists keep on using the wrong name. Not that it matters a lot now, but still.

More “incorrect” was the fact that I first saw the announcement of his death in a newsletter from dokterdokter.nl (below). It is an online medical information site for patients. I have been getting their newsletter for years now, because -for one thing or another- I’m unsuccessful in unsubscribing to it. Dokterdokter.nl is typically a website that gives very general information, mostly leading to the advise “to check your doctor first”.

What struck me (besides the fact that I was taken by his death) was that his death was presented as Medical News, next to an enormous “oral sex” headline and the headline “what happens if you die?”. As if it was a tabloid. The message (he died the day before):

Martin Bril finally succumbed to esophageal cancer at the age of 49. Esophageal cancer has a bad prognosis. Why?
(if you click: )

“Martin Bril, the well known author …, died of esophageal cancer at the age of 49. He was a real hedonist. Cigarettes and alcohol were part of his life. Many years he had fought cancer, but Wednesday April 22 he lost his fight. Few people really completely recover from this illness.”

(….) Generally, the disease has to do with your lifestyle. In Western Countries, smoking and excessive alcohol consumption are the most important causes of esophageal cancer.

And then it continues summarizing the brochure of the Dutch Cancer Society (KWF- kankerbestrijding)

Whereas most medical sites (including the Dutch Cancer Society, from which all the information was taken) just neutrally say that the cause is unknown, but that alcohol and smoking are known risk factors for esophageal cancer, -and even more so in combination- dokterdokter puts a direct link between Martin’s lifestyle and his death, as if it was his own fault. Maybe it was, but at that moment I didn’t want to know. It didn’t matter. I found it disrespectful, tasteless. I’m quite interested in health and medicine and mechanisms, but the reason of his death -at this moment- was less important than his death itself.

As a matter of fact, Martin stopped using liquor and cocaine in 1997 after given an ultimatum by his wife (“you have two young kids!”) and after attending a trial of a drug baron (Johan V., de Hakkelaar) (to write about). He also wanted to quit smoking. I don’t know whether he succeeded, but he helped STIVORO (“for a smokeless future”) with their campaign (2002) by writing a beautiful column and making a video about (the difficulty of) quitting smoking. “I stopped smoking, because I didn’t like it anymore. Moreover, my kids didn’t want me to die because of smoking……..”

How much better was the reaction of STIVORO to the death of Martin, saying “we have lost a talented author” and thanking him for his input. Just a short notice and ending with the column Martin had written for them: “Did you ever tried to quit smoking?…I did”.

——————

Bij Nederlanders hoef ik Martin Bril nauwelijks te introduceren. Dat ik hier over hem schrijf heeft vooral te maken met het stukje dat ik in de nieuwsbrief van Dokterdokter.nl las. In feite was het dit bericht, waardoor ik wist dat hij gestorven was. Voor mij een schok. Ik lees de Volkskrant niet meer, dus het was mij ontgaan dat het slecht met hem ging. Het is ook een jonge vent, jonger dan ik, met twee dochters, net als ik. Zo kom het altijd nog een beetje dichterbij. En hij kon mooi schrijven. “De oppervlakte was diep genoeg,” zo zei hij, maar het was bij hem net of je in een druppel de hele oceaan kon zien.

Voor het eerst zag ik trouwens dat hij slokdarmkanker had. De meeste journalisten spraken van darmdanker, waar men in de regel toch dikkedarmkanker mee bedoelt. Slokdarmkanker is een heel andere ziekte, met een heel andere prognose. Vreemd dat het meerendeel van de journalisten het toch steeds over darmkanker heeft

Maar dit terzijde. Ik vond het vreemd, dat het bericht als een “nieuwsaankondiging” stond naast de kop “orale sex” en “hoe voelt het als je dood gaat”. Misschien had Martin er wel om kunnen lachen, maar ik vond het bizar. Het verhaal zelf vond ik ook nogal ongepast.

Wat stond er?

De ziekte slokdarmkanker werd schrijver Martin Bril op zijn 49e fataal. Het is een ziekte met slechte vooruitzichten, mede omdat het vaak laat wordt ontdekt.

“Schrijver Martin Bril, bekend van boeken als De kleine keizer en Arbeidsvitaminen en van zijn columns in de Volkskrant, is op 49-jarige leeftijd aan slokdarmkanker overleden. Hij was een echte levensgenieter, sigaretten en alcohol waren een vast onderdeel van zijn leven. Al vele jaren streed hij tegen kanker, maar woensdag 22 april was zijn strijd gestreden. Maar weinig mensen weten volledig te herstellen van deze ziekte.”De ziekte heeft meestal te maken met de leefstijl van mensen. Roken en overmatig alcoholgebruik zijn in Westerse landen de belangrijkste oorzaken voor het ontstaan van slokdarmkanker.

Andere bronnen -ook de KWF-brochure, waar dit stuk aan ontleend is, schrijven steevast dat de oorzaak niet bekend is, maar dat roken en alcohol (vooral in combinatie) de belangrijke risicofactoren zijn. Mogelijk is zijn leefwijze inderdaad de belangrijkste reden geweest dat hij slokdarmkanker heeft gekregen. Nou en? Is het nodig om dit zo op te schrijven? Een dag na zijn dood? Ik vond het nogal oneerbiedig. Misschien dacht men bij dokterdokter.nl dat het schrikeffect mensen zou weerhouden om veel te roken en te drinken, want “kijk, daar krijg je slokdarmkanker van!!” Behalve dat dokterdokter niet bepaald het juiste publiek (de “zelfkanters” en “hedonisten”) zal bereiken, zal zo’n actie sowieso weinig zoden aan de dijk zetten. Dan was Martin’s bijdrage aan de Stivoro campagne “stoppen met roken” (2002/2003) waarschijnlijk veel effectiever. Hij schreef een column voor ze en werkte mee aan een video.

Martin zei: “Ik stopte met roken omdat ik er geen zin meer in had. Bovendien; mijn kinderen vonden dat ik er niet dood aan moest gaan”. Eerder, na een ultimatum van zijn vrouw en het bijwonen van een zitting tegen de drugsbaron de Hakkelaar, was hij al gestopt met alcohol en coke.

Zo anders was ook de reactie van Stivoro. Niets vingertje wijzen: “zie je wel!”, maar dit:

“Samen met de rest van Nederland treurt STIVORO om het heengaan van een bijzonder mens en groot schrijver: Martin Bril

STIVORO heeft Martin leren kennen toen hij zich enthousiast inzette voor onze ‘Stoppen met roken’ campagne van 2002/2003. Hij was toen bereid zijn persoonlijkheid en zijn schrijftalent voor deze campagne in te zetten.

Wij zijn dankbaar dat we met hem hebben mogen samenwerken. We wensen zijn familie en andere dierbaren heel veel sterkte toe.

Hij schreef voor ons de volgende column:

“Bent u wel eens gestopt met roken?
Ik wel……..”

Photo Credit (CC):

• Martin Bril Close Up : http://www.flickr.com/photos/roel1943/309048020/
• Man reading a book of Martin Bril: http://www.flickr.com/photos/wijkerslooth/3492121752/
• Rokjesdag (Skirt Day):http://www.flickr.com/photos/pforret/73554771/

Grand Rounds 5.35 at Healthcare Technology News

Grand Rounds is up at Healthcare Technology News. This edition of Grand Rounds, the Best of the Medical Blogosphere, focuses on Health Care Reform.

The Grand Round begins with a stunning quote of type 1 diabetic blogger Kerri Sparling that really hits the mark with her post at Six Until Me:

“Why, Insurance Company, are you so against proactive care? Why do I need to pay more for a brace or a shot or an extra visit when you’re more content paying for a several thousand dollar surgery instead? Not enough bang for your buck? Why do you fight me tooth and nail against coverage for a continuous glucose monitoring device?* Is my life not worth the investment to keep my legs on instead of paying 100% to amputate them in a few decades? I know I’m expensive as a chronic disease patient, but I’m healthier than 85% of the people I know. I eat well, I exercise regularly, and I am on top of my disease. Yet you deny me life insurance, you won’t let me purchase a private health insurance policy, and you would rather see me on an operating table than taking up a doctor’s time in an office visit. (And it’s not like I’m taking up more than 5 – 7 minutes of a doctor’s time, because that’s about all we get, on average. Pathetic.)”

After a few more examples of the Patient and Consumer Perspective on why we do need reform, this edition continues with:

• Providers, Prevention and Self-Management
• Meaningful Use and Enabling Technology
• Dollars and Sense
• What’s Working Elsewhere?

Please read the whole edition here

Next Grand Round will be hosted by See First, Insights into the uncertain world of Healthcare.

————————-

* I saw the same problem mentioned on a Dutch Blog “Diabetesblog“, where the story was told of a patient who has hypo-unawareness: she can’t feel when her blood glucose is low. Therefore she suffers many complications of diabetes, i.e she has poor sight and has recently fainted in front of the children. The only thing which she feels would work is the (FDA approved) continuous glucose monitoring device (CGMS). The problem is that the her insurer won’t cover CGMS, as it’s efficacy has yet to be proved.

Coincidentally I’m gathering the evidence on “the effectiveness of the CGMS in the management of type I diabetes” for a Cochrane Protocol (not approved yet). However, it will take some time for the authors to finish the review after the protocol has been approved.

See the full Story on Diabetesblog (in Dutch) here

Some excerpts:

Sinds een jaar of vijf draagt ze daarom een insulinepomp die continue een klein beetje insuline afgeeft. ‘Maar dat zegt natuurlijk niks over mijn bloedsuikergehalte op dat moment’, zegt Judith. Meer baat zou de Losserse volgens haar internist hebben bij een continue glucosemeter met implanteerbare sensor, een apparaat dat is overgewaaid uit de Verenigde Staten. De sensor meet 24 uur per dag de bloedsuikerspiegel en geeft een waarschuwingssignaal als de waarde te laag dreigt te worden.

Het probleem is echter dat de zorgverzekeraar van Judith, Menzis, het apparaat – kosten: 40 à 50 euro per stuk; één exemplaar gaat maximaal drie dagen mee – niet wil vergoeden, ook niet nadat de internist van Judith daarop heeft aangedrongen. Te duur, oordeelt Menzis. En bovendien, zo motiveert een woordvoerder het standpunt van de zorgverzekeraar, ‘heeft het College voor zorgverzekeringen (CVZ) onlangs besloten de sensor niet te vergoeden’.

Ook een tweede verzoek dat de arts onlangs indiende heeft niets opgeleverd. Volgens de woordvoerder van Menzis is de zorgverzekeraar zelfs strafbaar als het apparaatje vergoed zou worden, omdat het onvoldoende getest zou zijn. Onzin, zegt Getkate. ‘Niet voor niets heeft de Diabetesvereniging Nederland een positief advies gegeven. Er zijn bovendien andere zorgverzekeraars die het al wèl vergoeden.’

En dus ligt de Losserse in de clinch met haar zorgverzekeraar. Wat haar nog het meeste steekt is ‘dat Menzis eigenlijk op de stoel van de arts gaat zitten’…..

Web 2.0 and Health Care Reform: Two Dutch Examples (1)

The theme for the next Grand Round hosted by Healthcare Technology News is Healthcare Reform.

“We’ll be publishing a wide range of articles, from those that share anecdotes about why we need to improve the health care system, to examples of innovations and care that are working well, through to the policy recommendations that we need.”

Although I easily could give some anecdotal examples from the past about “failures or shortcomings” in Healthcare, I prefer to give some positive examples of how a web 2.0 approach can bring patients and doctors together. There are numerous examples of successful application of web 2.0 tools by patients to find and share information and to improve the management of their disease. There are also many healthcare people who use web 2.0 tools to write down their experiences (blogs, social media), to get their information (RSS) and to put information on the web (wiki’s) for patients or colleagues. There are hospitals that are actively engaged in social media and that facilitate patients to use these tools to gather information, but I’ve seldom seen a real web 2.0 based patient-doctor collaboration…. till recently…. close to home in Nijmegen at the Zorg 2.0 (Health 2.0) event, organized by Lucien Engelen (twitter: zorg20; and on linkedin). In fact, the whole meeting was a success with lots of interesting lectures (i.e. from Bertalan Mesko of Scienceroll and Maarten Lens Fitzgerald of Maarten’s Journey.) and workshops.

All podcasts of the Zorg 2.0 event can be seen here

Two presentations were given by two professors on patient centered care in the so called award winning initiative MijnZorgNet (MyCareNet): Bas Bloem and Jan Kremer.

I will discuss their two presentations in separate posts.

This post will summarize the presentation of Bas Bloem, neurologist from the UMC St Radboud Ziekenhuis Nijmegen and initiator of the Parkinson Center.

Bas Bloem began with his “take home message” (with which I couldn’t agree more):

Health 2.0 is not “the world of gadgets”, but a new way of thinking in healthcare:

1. the patient becomes centric, care becomes collaborative: the patient is not passive, he is “equal” to the healthcare provider. It isn’t “he asks, we provide”, but the patient definitively has a voice (and choice) in his own healthcare.
2. coherent and transparent healthcare.
3. expertise (few experts, but with very specialized knowledge).

He set up a program for Parkinson care delivery networks, first in the surroundings of Nijmegen and later throughout the Netherlands. Although his talk is about Parkinson, it can be seen as a model for all kinds of complex diseases.

Bas is an idealist. He believes most healtcare people choose their job to really help people. Doctors choose to care. Only the system doesn’t help them to realize this.

To change this, a paradigm shift is needed. Healthcare needs to be centered round the patient:

1. The patient has the right to see the best specialist -in a structured way; the assessment of the patient is “CENTRAL”, in an intramural setting, i.e. by a neurologist. In the present example, people from the first line can easily contact the specialists or plan an appointment in their agenda. In this way the patient is helped promptly and he notices the good cooperation between the two lines.
2. Daily healthcare is close to home, only performed by a handful of specialists (i.e. physiotherapists) specially trained to treat Parkinson patients. This is called the ParkinsonNet. Patients rather have someone with expertise who is within a 20 minutes distance, than a less experienced person round the corner.
3. There is optimal communication between the “two layers”.
4. The patient plays an active role.

How is this organized?

1. When the patient is referred to the neurologist, he first has to fill in a screening list and has to prioritize 5-10 health problems, which he/she would like to discuss when visiting the Day Center. So one patient may want to see a sexologist, a dietitian and a physiotherapist and an other a rehabilitation physician, gerontologist and a neurologist.
2. Doctors and patients sit round a table, each in the same position (no hierarchy).
3. Consumer reviews are shown (anonymously) on the Internet. This makes healthcare transparent. When scores are bad some action should be taken to improve it.

How is this achieved?

1. Selection of experts who get education (via e learning etc), on basis of geographic distribution. Patients have to travel a bit more, healthcare is canalized,
2. All healthcare workers work according a multidisciplinary guideline. Patients were active co-producers of the guideline.
3. Implementation (see above)
4. Yellowpages (paper and digital version) have been made of healtcare providers, enabling patients to choose.
5. Indicators are developed, patients are invited to give feedback and to grade the healthcare (providers). If someone performs bad, (gets the red card) he/she may ultimately be taken out of the network.

The experiment of patient empowerment in Parkinson’s Disease management has grown from very small (region Nijmegen) to almost national. The blank region (see Figure) is not included to be able to assess the effectiveness of this system compared to the traditional approach.

The next step is the creation of a virtual community. This is certainly important and not out of reach for the elderly. A transmural electronic health record is available (Parkinson dossier) both for the patient and the healthcare worker.

Slides (Dutch): http://www.slideshare.net/lucienengelen/bloem-zorg-20-maart-2009
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more about “4. Zorg20 Event Spring 2009 | Keynote…“, posted with vodpod

See http://www.vimeo.com/4271353

* Since the video stuck half way, I may have missed part of the presentation.

One Third of the Clinical Cancer Studies Report Conflict of Interest

While many of us just recovered from the news that Elsevier was paid to produce fake Journals to promote pharmaceutical products, another news item has appeared about “conflicts of interests in scientific publications”

This news is based on a new journal article from researchers from the University of Michigan’s Comprehensive Cancer Center in Ann Arbor, published in an early online edition of Cancer [1]

As mentioned in my previous post about the Elsevier “Fake Journals”, pharma-sponsored trials rarely produce results that are unfavorable to the companies’ products [e.g. see 3 for an overview, and many papers of Lisa Bero]. Concerned by these findings, the main medical journals now require researchers to disclose their potential conflicts of interest (COI).

The present study [1] analyzes the frequency of self-reported conflicts of interest (COI), source of study funding, and (their relationship with) other characteristics in original clinical cancer research (thus no reviews or basic research) published in 8 medical Journals in 2006. The 8 journals are high-impact clinical journals, 5 are oncology journals (Journal of Clinical Oncology, the Journal of the National Cancer Institute, Lancet Oncology,Clinical Cancer Research, Cancer) and 3 are core general medical journals (New England Journal of Medicine,JAMA, the Journal of the American Medical Association, Lancet).

In these medical journals 1534 original oncology studies were found. Twenty-nine percent of the oncology articles reported COI: 17% declared industrial funding and the remaining 12% of the studies had authors who were an employee of industry at the time of publication, or were funded by industry.

The study was thoroughly done: 2 students independently coded the articles and 2 other coders, blinded for the initial coding, assessed all randomized trials (within those 1543 papers) for the outcomes. They graded the authors’ subjective interpretations as positive (in favor of the intervention), neutral, or negative (in favor of the control arm). Overall survival was assessed quantitatively.

The main results:

• Conflicts of interest varied by discipline (P<.001). Studies that had a corresponding author from a medical oncology department or division were most likely to have conflicts (45%), and studies from diagnostic radiology were least likely to have conflicts (4%)
• Likewise the cancer type mattered, especially with regard to likelihood of industrial funding (P = .001). Studies on the male reproductive system and lung cancers scored highest and studies on neurological cancers scored lowest as to the likelihood of funding. (however there is some contradiction because gynecologic departments have a high score and gynecologic cancers have a relatively low score, conf. figures 1 and 2)
• Continental origin was also an important variable (P<.001). COI were observed in 33% of the North American studies, 27% of the European studies, 5% of the Asian studies, and 40% of the studies from other locations.
• COI was most likely in articles with male first and senior authors (P<.001).
• Industry funded studies were more likely to focus on treatment (P<.001), and less on epidemiology, prevention, risk factors for incidence, screening, or diagnostic methods.
• The randomized trials (n=124) that assessed survival were more likely to report positive survival outcomes when a COI was present (P=.04). (see below)

The paper has received a lot of media attention, initiated by the press release of the University of Michigan Health System itself. The data however are less shocking then they may seem. The main finding is that “conflicts of interest characterize a substantial minority of the clinically oriented cancer research published in high-impact medical journals”. This and the characteristics of the papers with COI (see above) add to earlier papers that report on the occurrence of COI in published articles, including papers in the field of clinical oncology.”

Some outcomes are not very surprising, such as that pharmaceutical industries and funding will be most involved in intervention studies in medical oncology studies (not so much in radiology or diagnostics).

In itself, COI does not mean that the results cannot be trusted or that they are plain wrong. Credibility could be questioned if only positive results are published or if the results are represented more positive then they really are.

Indeed, Jagsi et al show that “randomized trials with a COI were more likely to report positive survival outcomes (P=.04)”. However, the likelihood that the author interpretation was positive or more positive than the objective effect on overall survival wasn’t influenced by COI. And differences in industrial funding didn’t influence any of the blinded outcomes assessed. Also in this study, the non-neutral findings are emphasized.

On the other hand, authors had to rely on the information given, i.e. not all conflicts of interests may have been reported. Another issue is that not all known COIs are disclosed to the public (i.e. medicalnewstoday)

The following conclusion of the lead author Reshma Jagsi seems most relevant:[2]

“Given the frequency we observed for conflicts of interest and the fact that conflicts were associated with study outcomes, I would suggest that merely disclosing conflicts is probably not enough. It’s becoming increasingly clear that we need to look more at how we can disentangle cancer research from industries”

References

1. Jagsi, R., Sheets, N., Jankovic, A., Motomura, A., Amarnath, S., & Ubel, P. (2009). Frequency, nature, effects, and correlates of conflicts of interest in published clinical cancer research Cancer DOI: 10.1002/cncr.24315
2. University of Michigan Health System (2009, May 13). 29 Percent Of Cancer Studies Report Conflict Of Interest. ScienceDaily. Retrieved May 14, 2009, from http://www.sciencedaily.com­ /releases/2009/05/090511090846.htm
3. Smith R. Medical Journals Are an Extension of the Marketing Arm of Pharmaceutical Companies. PLoS Med. 2005 May; 2(5): e138. Published online 2005 May 17. doi: 10.1371/journal.pmed.0020138.

You may also want to read:

• Merck’s Ghostwriters, Haunted Papers and Fake Elsevier Journals

Hattip: @sciencebase, Reinout Rietveld (via NRC-next)

LOCA Congress for Interns – LOCA co-assistenten congres

Last Sunday I was an invited speaker at a national congress for interns, the LOCA congress. LOCA stands for “Landelijk Overleg Co-Assistenten”.

This congress has been initiated to facilitate the contact between interns of all Dutch universities and to cover in depth subjects that usually don’t get much attention.

The LOCA congress offered a diverse program, varying from “minimal invasive and maximal effective surgery”, “memory training” and “a dirty mind is a joy forever”. You can see the program here (Saturday; Sunday).

The previous event I gave a Search Workshop, this time the subject was “Medicine 2.0″.

I didn’t realize in advance that this wasn’t a convenient day. First it was Mother’s day. My children weren’t pleased that I wouldn’t be around. Furthermore I had to prepare an Evidence Based Searching day the following Monday and several other workshops that week. Still, Sunday morning we spent together in the garden eating home made smoothies and muffins that my eldest daughter L made, with on them in colors: “Mama blog”, “L X M”, “Laika twitter”, “Success”,  etcetera, which illustrates how they see me now.

Despite  that I had 40 min. instead of the expected 60 min., and just about half of the workshop subscribers (it was a very sunny day) showed up, I found it a pleasant workshop. Mostly because the audience was very interested and interactive. Within those 40 minutes, however, I could only touch upon some aspects, giving most emphasis to the web 2.0 tools which can be used in daily practice by medical professionals to find information (social networking sites, RSS also in Pubmed, personalized home pages, blogs and wiki’s)

40 minutes is short and I promised the interns to provide them with some information afterwards.

I’m too busy at the moment with my regular job, but I expect that the promised information will be available within 1-2 weeks at:

• This blog
• Slideshare
• A wiki created for this occasion: http://medicine20.wetpaint.com/

But I won’t withhold a series of tweets (Twitter messages)  specifically directed to the interns of this workshop. You can view the tweets labeled with #MOVIR, here at Visibletweets. They have been tweeted by doctors, a patient, a nurse and a physiotherapist. Please see them all, the first tweets are shown last.

Grand Rounds 5.34 at the Health Observatory Blog

Grand Round is up at Health Observatory Blog.

Kudos to the bloggers Ivor Kovic and Ileana Lulic, for this blogcarnival on “Diversity”, which they introduced as follows:

We want to demonstrate how rich, colorful, multidimensional and diverse the health/medical blogosphere truly is. So please send us your dearest posts, the ones that genuinely reflect your style and personality, no matter the subject.

They quite succeeded in making a grand round with great diversity. I like the style. It gives a good introduction to the posts, without being too lengthy or too short (X wrote a post Y on Z). You can read the the present edition here.

Health Observatory Blog is part of the website Health Blogs Observatory, started with the aim to conduct annual surveys of health bloggers and their blogs to gain better insights into the state of health blogging.

It is possible to submit your blog to their directory to gain better exposure and participate in their future research.
I surely plan to do that, increasing the number of Dutch blogs included from 2 to 3.

Next Round will be hosted by Healthcare Technology News.

Merck’s Ghostwriters, Haunted Papers and Fake Elsevier Journals

What is the purpose of publications? (…) The purpose of data is to support, directly or indirectly, the marketing of our product.” [1, 2]

It is well known that studies with significant positive results are easier to find than those with ‘negative’ results. This so called publication bias can arise from the tendency to submit or accept manuscripts that have a positive rather than a negative or neutral result. It can also be the consequence of deliberately overemphasizing positive results or even worse: the results can be “embellished”, (partly) faked or negative results can be “hidden“

In fact, pharma-sponsored trials rarely produce results that are unfavorable to the companies’ products [3, 4, 5]. For instance, none of the published 56 trials of  NSAIDs in arthritis identified by Rochon et al in 1994 [3] had outcomes that were unfavorable to the company that sponsored the trials. Another study showed that studies funded by a company were four times more likely to have results favorable to the company than studies funded from other sources [1, 4]

Ghostwriters, who write articles that are officially credited to another person, are part of the tactics. Ghostwriters may be hired by companies to write articles for medical journals that appear under the names of scientists who didn’t substantially contribute to the paper. In extreme cases pharmaceutical companies and their agents control or shape multiple steps in the research, analysis, writing, and publication of articles. This so called ghost management can be outsourced to MECC’s, medical education and communication companies.

All the above approaches, -and more- are said to have been used by Merck to sell their Vioxx (rofecoxib) pills, the blockbusting painkiller, that could cause heart attacks and strokes [6]. Merck knew, but didn’t disclose (all) these adverse effects*. Later it appeared that many Vioxx- manuscripts were prepared by sponsor employees (ghost writers), but attributed to academic investigators who did not always disclose industry financial support. Distancing himself from one such article, first author Jeffrey Lisse said in an interview that:

“Merck designed the trial, paid for the trial, ran the trial…Merck came to me after the study was completed and said, ‘We want your help to work on the paper.’ The initial paper was written at Merck, and then it was sent to me for editing” [NY-times -[2005].

And although Merck has “voluntarily” withdrawn Vioxx from the market in 2004 and has agreed to pay billions to settle lawsuits in the US, the Vioxx-ghost keeps hunting Merck (and us).

In a few weeks 3 news-items have crossed my eyes.

A. The Guardian ( May 4) mentioned that Merck refused to compensate hundreds of Britons who have suffered serious cardiovascular  problems while on Vioxx.  Ministers apparently backed down from supporting these people after lobbying by the company.

B. May 1st NewsInferno com reported that Merck was accused of hiring a ghostwriter for a Circulation paper (2001) to minimize issues linked to Vioxx’s safety, while the well known cardiologist Dr. Marvin Konstam agreed to act as lead author. This was revealed by Prof. Jelinek during an Australian lawsuit against Merck.

C. The above news story was covered by Australian Newspapers including “the Australian“. In its article on the lawsuit, the Australian also devotes one sentence to a fake Elsevier/Merck journal. It says:

“The drug company also allegedly produced an entire journal — called The Australasian Journal of Bone and Joint Medicine — and passed it off as an independent peer review publication.”

It is this sentence that has caused a tsunami, starting with the Scientist, via blog.bioethics.net to  many other blogs of researchers, publishers, librarians and to newspapers. “Everybody” was alarmed.

What were the allegations? Are they all true? Who is to blame? Merck or Elsevier? Most importantly: is it an isolated incidence, something completely new and what is its impact?

Points addressed by the Scientist (mainly based on interviews, i.e. with George Jelinek)

1. Australasian Journal of Bone and Joint Medicine, is published by Exerpta Medica, a division of Elsevier
2. This Journal is not indexed in the MEDLINE database and has no website.
3. It had the looks of a peer-reviewed medical journal, but contained only reprinted or summarized articles
4. Most of the articles presented data favorable to the Merck products Fosamax (for osteoporosis) and Vioxx.
5. So called “review” articles only cited one or two references. Even a meta-analysis contained 2 references, one of which referring to a real meta-analysis.
6. The articles are “simply a summary of already published articles”
7. There are several ads for Fosamax and Vioxx.
8. It is unclear who wrote the editorials
9. One member of the editorial board, Peter Brooks said that he didn’t ever get manuscripts to review while on the board. Neither was he paid for his role.
10. There is no disclosure of company sponsorship.
11. Merck paid an undisclosed sum to Elsevier to produce several volumes (confirmed by Elsevier).

According to a statement of Merck (see pdf on their website):

“The Australasian Journal of Bone and Joint Medicine (..) was published by the medical publishing company Elsevier. Merck Sharp & Dohme Australia understood that Elsevier envisaged the complimentary publication would draw on the vast resources of Elsevier, publishers of many leading peer-reviewed journals including Lancet, Bone, Joint Bone Spine and others, to deliver novel and timely full-text articles and abstracts to physicians.”

In the same PDF Merck states that “ghostwriting” allegations concerning the 2001 Circulation paper about VIOXX [item B] are false and that professor Jelinek has witdrawn his accusation under cross examination. According to Merck, the lead author Dr. Marvin Konstam, was in fact very much involved in the study. Indeed, according to the Heartwire, Konstam maintained he acted properly. He  takes full responsibility for everything he has published.

Elsevier acknowledged the concern that the journal didn’t have the appropriate disclosures,” and although they said they had no plans in looking further into the matter, Elsevier disclosed today that in total 6 such fake Australasian Journals were produced (see Scientist).

Now what? An isolated blunder by staff of the Australian Branche of Elsevier who published a fake peer review while Elsevier headquartes and Merck were totally unaware?

First, although I don’t want to triviliaze the affair, obviously this Journal does not pretend to be a peer reviewed paper (i.e. see this pdf, obtained by the Scientist). Any doctor who even considers it to be a peer reviewed paper must have very little experience with critically reading of peer reviewed papers. It is clear from the start that all articles are just copied from other (Elsevier) Journals, the citations are given, articles are classed to type (in black boxes at the tope) and the so called meta-analyses just describes another meta-analysis, which is cited.

The editorial board is called “Honorary”. The advertorials and the repeated mentioning of Merck drugs makes it immediately clear that this Journal is just a so-called throwaway. True, it should have been disclosed at the front page and the Journal’s name and lay-out might suggest otherwise at first glance. And to me as a librarian it is particularly strange that there was an annual subscription for institutions of $250. Throw-aways are usually for free. Furthermore it is not included in Science Direct nor the usual bibliographic databases.

As a matter of fact, this Journal is what you would expect from an “Excerpta Medica Journal”: an excerpt of various articles. At least that’s what the name suggests and that’s what I remember from the old fashioned Excerpta Medica abstract journals I browsed as a post-doc.

But it is remarkable that “the reliable and authorative” Elsevier, publisher of journals like the Lancet, lends itself to a biased publication of articles that only serve as promotional material? Surely this is an exception?

Well, whereas Elsevier itself has dismayed the Lancet by sponsoring one of the largest military exhibitions in the world (CMAJ 2007), its medical and health sciences division Excerpta medica is clearly a separate business. On the Elsevier website 41 titles of Excerpta Medica are listed, but none of the Australian Excerpta clones. Here it says that:

Every journal contains bibliographic references and abstracts summarizing original articles from primary research and clinical journals. The records are carefully selected from 4,000 journals from 70 countries around the world, which makes the Excerpta Medica Abstract Journals very comprehensive.

The home page of Excerpta Medica states that it is an “Elsevier Business”, a strategical medical communications agency, partnering with their clients in the pharmaceutical and biotech industries to educate the global health care community to enable them to make well informed decisions (copied from EBM definition of Sackett, hé?)

Under the heading “strategic planning” it is written that “Our relationship with Elsevier allows us access to editors and editorial boards who provide professional advice and deep opinion leader networks” ….(!!)

I’m not the first one noticing this.

In 2007 the same link was given by the PLOS-paper about ghost management[1], discussed above..

Here Excerpta is mentioned as an example of a MECC.

And not only in this paper. Both a Medscape[7] and a Perspectives in Biology and Medicine article[2] mention the role of Excerpta as a MECC. A citation from the latter:

Recovered documents show that the pharmaceutical company Wyeth hired the MECC Excerpta/Medica to produce several scientific papers on the dangers of obesity and on obesity treatment as part of their marketing strategy for Fen-Phen. Mundy documents that Wyeth paid between $15,000 to $20,000 for Excerpta to prepare each article, of which $1,500 would go to the “named author” as an honorarium. Some completed papers, simply listed as “author to be determined,” lacked a “named author,” while others had made their way in to print or were under review. One doctor, Dr. Richard Atkinson, was so pleased with the arrangement for “Therapeutic Effects of Dexfenfluramine: A Review” that he wrote a thank you note to Excerpta/Medica saying,“Let me congratulate you and your writer. . . . Perhaps I can get you to write all of my papers for me” (Mundy 2002, p. 164).

And Medscape:

What made Excerpta Medica such an inspired choice is that it is a branch of the academic publisher, Reed Elsevier Plc., which publishes many of the world’s most prestigious science journals. Excerpta Medica manages two journals itself: Clinical Therapeutics and Current Therapeutic Research. According to court documents, Excerpta Medica planned to submit most of the articles it produced to Elsevier journals. In the actual event, Excerpta managed to publish only two articles before Fen-Phen was withdrawn from the market in 1997. One appeared in Clinical Therapeutics, the other in the American Journal of Medicine (another Elsevier journal). In neither case did the authors of the articles disclose that they were paid by Excerpta Medica. So clean was the laundering operation, in fact, that many of the authors did not even realize that Wyeth was involved.

By the way Fen_Phen was not particularly effective, and was linked to valvular heart disease, leading to the death of hunderds of people. Even after withdrawal Wyeth spent $100 million on public relations to convince the public that the response had been overblown.

Hereby I do not want to suggest that Excerpta has played a similar role in the Vioxx case, but it does illustrate that Excerpta is a MECC with dangerous principles as it organized the ghostwriting for Wyatt elaborately, using its connections with Elsevier in a very nontransparent way.

I also don’t want to suggest that the followed procedure is unique for Excerpta. Several other MECC’s follow the same approach. For many other examples see the references below, especially [1, 2, 7]. It is really tarnishing. And worth a reading.

However, In my opinion we have to fear more from the strategic publication planning of the MECCs in authentic journals then the fake Australian Excerpta series. Firstly, because the known Journals are far more trustworthy and have far more impact than the throwaways. Secondly because the phenomenon of ghostwriting is widespread, also among “first class Journals”. A conservative benchmark for ghostwriting of papers published in biomedical journals is roughly 10%[2], but in particular cases the percentage may be much higher [1]. This has caused Richard Smith, former editor of the BMJ to sigh that “Medical Journals Are an Extension of the Marketing Arm of Pharmaceutical Companies.”

Anyway, I bet that my doctor did not describe Vioxx for my backache 10 years ago because he read “The Australasian Journal of Bone and Joint Medicine”. Rather he must directly or indirectly have learned from the results of the VIGOR trial published in the New England Journal of Medicine.

With respect to the citation I began with, it is not from Merck, but from Pfizer as an answer to the question: “What is the purpose of publications?” on the header on a Pfizer sales document (2000)

References

1. Sismondo, S. (2007). Ghost Management: How Much of the Medical Literature Is Shaped Behind the Scenes by the Pharmaceutical Industry? PLoS Medicine, 4 (9) DOI: 10.1371/journal.pmed.0040286
2. Moffatt, B., & Elliott, C. (2007). Ghost Marketing: Pharmaceutical Companies and Ghostwritten Journal Articles Perspectives in Biology and Medicine, 50 (1), 18-31 DOI: 10.1353/pbm.2007.0009
   The whole issue is dedicated to this topic: Perspectives_in_biology_and_medicine.
3. Rochon PA, Gurwitz JH, Simms RW, Fortin PR, Felson DT, et al. A study of manufacturer-supported trials of nonsteroidal anti-inflammatory drugs in the treatment of arthritis. Arch Intern Med. 1994;154:157–163. [PubMed]
4. Lexchin J, Bero LA, Djulbegovic B, Clark O. Pharmaceutical industry sponsorship and research outcome and quality. BMJ. 2003;326:1167–1170. [PubMed]
5. Smith R. Medical Journals Are an Extension of the Marketing Arm of Pharmaceutical Companies. PLoS Med. 2005 May; 2(5): e138. Published online 2005 May 17. doi: 10.1371/journal.pmed.0020138.
6. Ross JS, Hill KP, Egilman DS, Krumholz HM. Guest Authorship and Ghostwriting in Publications Related to Rofecoxib: A Case Study of Industry Documents From Rofecoxib Litigation JAMA. 2008;299(15):1800-1812.
7. http://www.medscape.com/viewarticle/492877

Photo Credits

Margaret Shear, Public Library of Science, see [6]

*Merck has never admitted that Vioxx could cause a cardiovascular risk, but the general idea is they just covered it up.

Grand Round 5.33

Grand Round is up at Ausmed Blog (or Nursing Handover).

It is the first time Nursing handover hosts the Grand Round and I’m glad there wasn’t a theme ànd all submissions were accepted.
You can read the compilation here.

Next week’s Grand Round will be hosted by Health Blogs Observatory.