Tuesday, January 05, 2010

#PLoSOne paper keywords revealing: (#Penis #Microbiome #Circumcision #HIV); press release misleading


UPDATE - READ COMMENTS - LEAD AUTHOR HAS GOTTEN PRESS RELEASE CHANGED

A new paper just showed up on PLoS One and it has some serious potential to be important The paper (PLoS ONE: The Effects of Circumcision on the Penis Microbiome) reports on analyses that show differences in the microbiota (which they call the microbiome - basically what bacterial species were present) in men before and after circumcision. And they found some significant differences. It is a nice study of a relatively poorly examined subject - the bacteria found on the penis w/ and w/o circumcision. This is a particularly important topic in light of other studies that have shown that circumcision may provide some protection against HIV infection.

In summary here is what they did - take samples from men before and after circumcision. Isolate DNA. Run PCR amplification reactions to amplify variable regions of rRNA genes from these samples. Then conduct 454 sequencing of these amplified products. And then analyze the sequences to look at the types and #s of different kinds of bacteria.

What they found is basically summarized in their last paragraph
"This study is the first molecular assessment of the bacterial diversity in the male genital mucosa. The observed decrease in anaerobic bacteria after circumcision may be related to the elimination of anoxic microenvironments under the foreskin. Detection of these anaerobic genera in other human infectious and inflammatory pathologies suggests that they may mediate genital mucosal inflammation or co-infections in the uncircumcised state. Hence, the decrease in these anaerobic bacteria after circumcision may complement the loss of the foreskin inner mucosa to reduce the number of activated Langerhans cells near the genital mucosal surface and possibly the risk of HIV acquisition in circumcised men."
And this all sounds interesting and the work seems solid. I note that some friends / colleagues of mine were involved in this including Jacques Ravel who used to be at TIGR and now is at U MD and Paul Kiem who is associated with TGen in Arizona. For anyone interested in HIV, the human microbiome, circumcision, etc, it is probably worth looking at.

However, the press release I just saw from TGen really ticked me off. The title alone did me in "Study suggests why circumcised men are less likely to become infected with HIV". Sure the study did suggest a possible explanation for why circumcised men are less likely to get HIV infections - the paper was justifiably VERY cautious about this inference. They basically state that there are some correlations worth following up.

The press release goes on to say "The study ... could lead to new non-surgical HIV preventative strategies for the estimated 70 percent of men worldwide (more than 2 billion) who, because of religious or cultural beliefs, or logistic or financial barriers, are not likely to become circumcised." Well sure, I guess you could say that. I think they are iplying you could change the microbiome somehow and therefore protect from HIV but that implies (1) that there really is a causal relationship between the microbial differences in HIV protection and (2) that one could change the microbiome easily, which is a big big stretch given how little we know right now.

Anyway - the science seems fine and not over-reaching. But the press release is annoying and misleading. Shocking I know. But this one got to me.

UPDATE - SEE COMMENTS HERE AND IN FRIENDFEED. LEAD AUTHOR GOT PRESS RELEASE CHANGED.




ResearchBlogging.org

Price, L., Liu, C., Johnson, K., Aziz, M., Lau, M., Bowers, J., Ravel, J., Keim, P., Serwadda, D., Wawer, M., & Gray, R. (2010). The Effects of Circumcision on the Penis Microbiome PLoS ONE, 5 (1) DOI: 10.1371/journal.pone.0008422

19 comments:

  1. I think the press release is pretty horrible. Saying things like "could lead to new non-surgical HIV preventative strategies for the estimated 70 percent of men worldwide (more than 2 billion) who, because of religious or cultural beliefs, or logistic or financial barriers, are not likely to become circumcised." implies that circumcision is a good preventative strategy which I don't think it is given strategies with a far higher success rate such as putting on a condom. The idea of chopping off body parts for a small reduction in the chance of getting a disease that already has a fairly low prevalence is ludicrous.

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  2. I appreciate your positive comments on the science and your criticisms of the press release. I spent a lot of time with the PR folks making sure that the press release contents were accurate, but missed the fact that the title had been changed from "uncovering the impacts of circumcision" (Apparently, printing the title in bold at the top of the page was not enough to make me notice). As stated in the paper, my co-authors and I hypothesize that changes in the penis microbiota could be part of the biological mechanisms that link circumcision with reduced HIV risk; however, as stated in the paper, such changes — if related to risk — likely work in concert with other physiological changes (e.g., keratinization of the inner foreskin).

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  3. Thanks Lance for commenting. For this particular paper, I can see this could get out of control quickly in terms of the press coverage. See for example the Science Daily blurb which changed the title to "Why Circumcised Men Are Less Likely to Become Infected With HIV: Changes in Bacteria Within Penis Microbiome". I know press releases are sometimes hard to do right, but when one is working on something as important as HIV infection - it is even more important to be very careful. Maybe you can get them to change the title in Eureka Alert, etc before this gets worse ... Oh, and, as I said in the blog, nice work.

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  4. I've asked our PR group to change the Eureka Alert title ASAP.

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  5. Jonathan, thanks again for your comments!

    New press release title: Circumcision associated with significant changes in bacteria

    (we left the word penis out of the title so it doesn't get filtered as spam)

    http://www.eurekalert.org/pub_releases/2010-01/ttgr-ssw010510.php

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  6. Great Lance - glad they changed it so quickly --

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  7. This comment has been removed by the author.

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  8. Could you even imagine the growth in Mohel businesses if the statement turns out to be true?

    :-)

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  9. Does nobody think it's kind of biased to be conducting studies centered around legitimizing an ancient religious rite?

    It might sound noble to be wanting to look for "a better HIV prevention method," but if so, why the focus on circumcision?

    Think about this for a minute.

    Are there any "studies" being done in the FEMALE microbiome and "the effect of female circumcision" on it?

    What would we do with studies from African doctors who on the front want to "reduce HIV transmission," through female circumcision?

    Would these "studies" even be taken seriously, or would they be thrown out?

    Let's look at the backgrounds of the doctors who are conducting these studies. How many are long-standing circumcision advocates who have failed to make an association between circumcision and other diseases? How many are Jewish?

    Are these people REALLY interested in "HIV reduction," or are they interested in circumcision evangelization? Case in point: look how early the authors are already wishing to circumcise the remaining 70% of the male population accross the globe. Countries where there isn't even an HIV crisis.

    Is there not a conflict of interest here?

    I think it's about time we outlawed all of these circumcision "studies." They're not looking for a solution to a problem, they're looking for problems to legitimize their pre-determined "solution."

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  10. "I think they are iplying you could change the microbiome somehow and therefore protect from HIV but that implies (1) that there really is a causal relationship between the microbial differences in HIV protection and (2) that one could change the microbiome easily, which is a big big stretch given how little we know right now."

    When someone begins to prove somethnig by assuming what they are trying to prove, in argument terms, isn't this called "begging the question?" (AKA: "pepito principii?")

    In essence, aren't the very studies currently being used by the WHO to endorse circumcision as legitimate HIV prevention strategy guilty of this fallacy?

    The entire set of studies are based on the hunch that somehow HIV transmission is facilitated through the foreskin; a hunch that has yet to be proven, and which is being assumed yet again in this PLoSONE paper.

    The culprit that has been blamed all along as the "prime port of entry of HIV" are the Langerhans cells found in the foreskin. But is anyone familiar with the DeWitte study, which observes that the Langerhans cells actually help FIGHT HIV?

    http://www.circumcisionandhiv.com/files/de_Witte_2007.pdf

    The following study takes a look at "HIV-1 Interactions and Infection in Adult Male Foreskin Explants"

    http://retroconference.org/2009/PDFs/502.pdf

    It was found that: ""Equal depths of viral penetration were observed in inner and outer foreskin...

    We have visualized HIV-1 particles breaching epidermal barriers and penetrating into both inner and outer foreskin...

    In both inner and outer foreskin (n=10), there was a significant presence of Langerhans Cells at depths where penetrating viral particles were also seen."

    Outer foreskin is just shaft skin (men are not born with dotted lines marking where the shaft ends and the foreskin begins.

    It sounds like the whole of the African "studies" were based on pure bunk.

    It was an assumption then, and it sounds like pro-circumcision scientists want to run with it even now.

    I'm glad someone else has taken notice...

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  11. One more thing.

    This will be the last, I promise.

    I wonder if anyone at the WHO, or anyone at all actually, has taken notice of the fine print in the African "studies" being used to fuel the current circumcision/HIV hype.

    The following can be found in a summary of the study:

    "Inclusion criteria:
    ...
    Consenting to avoid sexual contact (except with condom protection) during the 6 weeks following the medicalized circumcision"

    http://clinicaltrials.gov/show/NCT00122525

    The following was disseminated to the circumcised, but not the uncircumcised control group:

    "When you are circumcised you will be asked to have no sexual contact in the 6 weeks after surgery. To have sexual contact before your skin of your penis is completely healed, could lead to infection if your partner is infected with a sexually transmitted disease. It could also be painful and lead to bleeding. If you desire to have sexual contact in the 6 weeks after surgery, despite our recommendation, it is absolutely essential that your (sic) use a condom."

    http://medicine.plosjournals.org/archive/1549-1676/2/11/supinfo/10.1371_journal.pmed.0020298.st003.pdf

    Not to mention, the studies were ended early.

    It was condoms and education that yielded the results in the studies, but the credit was given to circumcision.

    Does nobody think this is a problem at all???

    Whatever your views on circumcision may be, I hope readers out there can find the integrity in their hearts to call BS on this campaign to endorse circumcision as legitimate HIV policy.

    These are the "studies" that the CDC and AAP want to base any future "recommendation" for circumcision on.

    Either they really are that blind or they're smoking crack.

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  12. Joseph - the circumcision/HIV work is my area of expertise. However, I note that I think the connection was made by retrospective studies that noticed a possible reduced rate of HIV in people who were circumcised on their own. And that is what I think led to all the clinical trials and other work. Thus I believe people did not go in looking to justify circumcision in this case. I do accept that there are those out there who are looking for justifications of circumcision, but I do not think that applies in any obvious way to the HIV protection studies.

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  13. The epidemiology study that link circumcision to reduce risk of HIV transmission was previously published and the data is strong. See this paper:

    Gray RH, Kigozi G, Serwadda D, Makumbi F, Watya S, et al. (2007) Male circumcision for HIV prevention in men in rakai, uganda: A randomised trial. Lancet 369(9562): 657–666.

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  14. Farhat and Joseph,

    A few comments:

    I understand that there are radicals on both sides of the circumcision issue; however, none of my colleagues are radical proponents of male circumcision. My colleagues and I have one common goal: reducing HIV transmission (not necessarily by circumcision).

    Male and female circumcisions are not equivalent. To say so, one would have to be disingenuous or ignorant to the details of these procedures.

    There is good evidence that langerhans cells can play protective or detrimental roles depending on whether or not they are activated. Certain bacteria present on the penis could activate langerhans cells—this is certainly worth investigating.

    Randomized control trials are the most robust tools for evaluating clinical interventions. All three randomized control trials conducted so far indicate that male circumcision reduces the risk for HIV acquisition in men. If given the choice between HIV and circumcision, I would certainly choose the later.

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  15. That's certainly an interesting paper that "makes sense" theoretically given the physiology.

    Lance B:

    I have taken offense to how the 3 African RCTs were used (or rather, misused). I won't go into how I feel the limitations of the studies (at least, the 2 that I read all the way through) may have negatively impacted the significance of the studies, or how people insist on reporting the relative risk (of 50-60%) instead of the absolute risk reduction (of closer to 2-3%), but let's assume the studies were ironclad valid.

    They still aren't necessarily generalizable to places outside of Africa. Nations like the US, Europe, Asia, etc are vastly different in so many ways from Africa. For any country outside of Africa to start crafting policy based on the results of these 3 RCTs is dangerous, particularly if the results haven't been (and they haven't been) replicated in other countries (or continents, rather).

    Also, it's one thing to offer circumcision as an intervention to an adult at high risk of contracting HIV. It's quite another to state policy to have it done in infancy, where the child has no choice in the matter and is not at risk for contracting HIV (for at least 15-18 years, in which time there may be a better treatment/prevention method).

    It's a controversial operation, it's an emotive one, and it's not always done (perhaps rarely so) for logical/medical reasons. So it should be policy to wait until a person is an adult so that he can decide for himself, after given all the risks, (possible) benefits, etc.

    I choose the 3rd option you didn't mention - condoms.

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  16. Aek, Thanks for your thoughtful comments. I don't disagree that these are important considerations.

    Does anyone want to talk about the penis microbiome?

    Otherwise, I suggest that we switch the conversation to abortion.

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  18. Unfortunately HIV/AIDS is still a killer in many parts of the world and statements about possible causes / cures of HIV/AIDS require very careful consideration. I agree that this paper presents some decent microbial ecology and I appreciate the fact that the authors fixed that press release.
    Nevertheless, I am baffled by the fact that a possible causality with HIV is presented as THE main conclusion of this study (See Abstract).
    I also wonder what the authors really mean with “pro-inflammatory anaerobes”.
    I think an equally plausible hypothesis would be that the anaerobes have antagonistic (probiotic) properties analogous to lactobacilli in the vaginal flora.

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