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Podcast Transcript - August 21, 2007

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Hello, and welcome to this week’s Annals of Internal Medicine audio summary for our August 21, 2007 issue. I’m Michael Berkwits, Deputy Editor at Annals.

We have perfect end-of-summer reading for you this week, with articles on selenium supplementation and risk for type 2 diabetes; the lifespan of systematic reviews; the epidemiology of hospital-acquired group A streptococcal infections in Ontario; and a systematic review of implantable cardioverter defibrillators in adults with left ventricular systolic dysfunction.

I’ll also be talking to the author of this issue’s “On Being A Doctor,” about what it’s like to be an American physician treating wounded soldiers and Iraqi insurgents in Baghdad.

But first, an in-depth summary of this week’s articles.

Our lead article this week is about the risk for type 2 diabetes with selenium supplementation. Listeners who heard the summary of this article and my interview with the senior author of the accompanying editorial when they were released online in early July can go directly to the next segment by advancing to the 13:00 minute marker of this podcast.

Selenium is trace mineral that is found in the soil. It becomes incorporated into the food supply, and is a cofactor for enzymes, many of which have antioxidant functions. Since chronic disease and cancer have been linked to oxidative stress, both clinical researchers and the public have been interested in the use of antioxidant supplements as a way to prevent chronic disease and cancer.

This week’s article is a secondary analysis of the Nutritional Prevention of Cancer, or NPC trial. The trial, which randomized patients to selenium or placebo supplements, showed that selenium had no detectable effect on the recurrence of non-melanoma skin cancer in patients with initially treated non-melanoma skin cancer.

In this week’s report, lead author Dr. Saverio Stranges from the State University of New York in Buffalo and the Clinical Science Research Institute of Warwick Medical School in the United Kingdom, used the NPC trial data to determine if selenium supplementation is associated with a reduced risk of type 2 diabetes.

Prior animal and population studies have suggested that antioxidant supplements might improve fasting glucose levels and protect against diabetes. However, Dr. Stranges and his colleagues detected an increased absolute and relative risk for diabetes in patients randomized to take selenium supplements who were followed for a mean 7 to 8 year period. The effect was clear for patients of all ages, for men and women, for smokers and non-smokers, and for patients of all body mass index except those with the highest values of BMI. And, the risk was greatest among patients with higher baseline selenium levels, suggesting a dose-response relationship.

The authors conclude that, based on these data, selenium supplements do not protect against type 2 diabetes, and they even appear to increase the risk. The authors point out that trial participants were nearly all white and tended to be older, so the findings might not apply to younger age groups or other races or ethnicities. They acknowledge that the original trial was not designed to assess risk for diabetes, so this secondary analysis is not really a substitute for a study specifically designed to ask the question.

Nevertheless, Annals editors thought that these findings seemed a pretty clear signal from a strong study design that selenium supplements, which are often taken by healthy people without disease to prevent future disease, might actually cause, rather than prevent, chronic disease. Interestingly, in 2006 the same authors of this week’s report published the findings of a nearly identical analysis using the same trial data that showed that selenium had no effect on the risk of cardiovascular disease. The reason for the discrepancy between the diabetes and cardiovascular findings are unknown. However, the mean 7-8 year follow up period was similar in the two analyses, and that may have been sufficient time for trial participants to develop diabetes but not enough time for patients to develop cardiovascular disease, and for researchers to detect the effect. So studies with longer term follow up might also be of interest.

With us today to discuss these findings is Dr. Eliseo Guallar. Dr. Guallar is an associate professor of Epidemiology and Medicine at the Johns Hopkins University Bloomberg School of Public Health. He is the author of several papers on the safety and efficacy of dietary supplements, and is the senior author of an editorial published alongside this week’s article, entitled “Selenium and Diabetes: More Bad News for Supplements.”

Q: Dr. Guallar, thank you for joining us.

A: Thank you for having me.

Q: What role does selenium play in human health and disease?

A: Selenium is needed for proper functioning of the antioxidant system, for proper functioning of the thyroid system and the immune system. Selenium is an essential micronutrient meaning that it’s a compound that we need in very small quantities for our normal physiology. And selenium is incorporated into a variety of about between 25 and 30 selenoproteins with a variety of physiological functions. Probably the most important one and the best studied is called glutathione peroxidase, which is one of the key antioxidant enzymes in our body.

Q: Are there states of selenium deficiency that listeners need to know about?

A: There are states of selenium deficiency happening in areas with low selenium content in the soil in rural China, resulting in cardiomyopathy. But selenium deficiency is really not a concern in the U.S. The content of selenium in the U.S diet is high enough so that these problems with deficiency are never seen in practice.

Q: Why do selenium supplements have such a high consumer profile?

A: Selenium supplements are considered antioxidant supplements and it belongs to a group of heterogeneous chemical substances that are supposed to reduce oxidative stress and to help our antioxidant defenses. These supplements include vitamin E, beta carotene, vitamin C and selenium. And for many years they have had a very high profile and they have been marketed for prevention of chronic diseases such as cardiovascular disease or cancer. This was based on experiments that showed that these supplements could reduce the level of oxidative stress in vitro and in experimental animals and also in the studies showing that people with higher levels of these compounds in their blood or in their serum had lower risk of cardiovascular disease, cancer and other chronic diseases.

So the epidemiological research was very promising but then investigators started doing randomized controlled trials. The results of these trials have been very, very disappointing. For many of these antioxidant compounds they have shown that people taking high doses of antioxidants might actually be increasing their risk of different diseases or they might be increasing their mortality. This is I think now quite well established for beta carotene and nobody should be taking beta carotene supplements, and there also is well founded concerns that the same thing might be happening for vitamin E. Vitamin C has still been well less studied and there are several trials going on. One key difference between vitamin C and other antioxidants is that vitamin C is excreted from the body much more quickly than vitamin E or beta carotene and it’s probably not as toxic as selenium. Above a certain level of vitamin C whatever excess we take we basically excrete it through the urine right away. So one advantage we can say of vitamin C is that it is much less likely to be toxic just because we excrete it out. On the other hand this means that probably high doses of vitamin C are also less likely to be efficacious in perfecting against any type of disease.

Q: Why was there reason to think that selenium might prevent diabetes?

A: The main reason is that selenium is a component through selenocysteine of glutathione peroxidase, and under conditions of oxidative stress cells that produce insulin might not work as well and there might be also a situation of increased insulin resistance. So the idea was that if we maximize the action of antioxidant compounds insulin might be produced better and might work better. There is also some experimental evidence that some selenium compounds might have an insulinomimetic action but this applies only to some specific compounds of high doses. But still there was the hope that they could work in humans. What the paper by Stranges and colleagues show is that selenium does not reduce the risk of diabetes it actually might be increasing the risk of diabetes. And again we don’t have a very good explanation for it. This is just a population based study so we cannot look at the mechanisms here but it’s possible that some antioxidant compounds at higher doses become pro-oxidant and it’s also possible that selenium might be having other toxic effects.

Q: This week’s article references some ongoing clinical trials that use selenium. What are the implications of these findings for those ongoing trials?

A: So there are at least two major trials in the U.S. testing the efficacy of selenium as a compound that might prevent prostate cancer. These trials are very large, they are ongoing and we will not know the findings still for several years. One obvious consequence is that investigators in these trials could use data from the trials or could modify their protocols to see if the findings of Stranges and colleagues hold up also in those trials. Now if they hold up and if the hypothesis of the trials also turn out to be true, which means that selenium might both cause diabetes and might prevent let’s say prostate cancer, then people would have to balance the risk of diabetes versus the potential benefit of prostate cancer prevention. But I think that the main message here is that the supplements are not just compounds that can only have beneficial consequences. They can induce harmful effects and the public needs to be aware of that. With respect to the benefits the trials that are ongoing are very important, and we should wait until they are completed to know if selenium has any proven benefit.

Q: And finally how would you advise the otherwise healthy patient taking an over-the-counter multivitamin that might contain selenium?

A: Well this is going to depend on the amount of selenium in the multivitamin. Typically the amount of selenium is not very high. But this also opens the big question which is “What are the effects of multivitamins on our health?” There are not too many large randomized controlled clinical trials testing the effects of multivitamins. So as long as people don’t take too many pills, probably the amount of selenium they are taking in the multivitamin mineral supplement is not too high. But at the same time, I think a good question that people have to start asking is “What are the benefits of those multivitamin supplements?” And I think one important message is that none of the supplements including selenium or vitamin E or beta carotene or multivitamin supplements has convincingly shown in any study that they prevent cardiovascular disease or cancer, which is one of the reasons why many people take these supplements.

Q: Dr. Guallar thank you for joining us

A: Thank you for having me.

That was Dr. Eliseo Guallar of Johns Hopkins University, discussing the findings of this week’s lead article on selenium supplements and the risk for type 2 diabetes.

Our CME article this week is a systematic review of implantable cardioverter defibrillators, or ICDs, in adults with left ventricular dysfunction. Clinical trials have established the role of ICDs for the secondary prevention of sudden cardiac death in patients with diminished left ventricular ejection fractions. In this week’s review, senior author Finlay McAlister and his colleagues at the Evidence-Based Practice Center at the University of Alberta in Edmonton, Alberta, Canada, searched the literature for evidence about the role of ICDs in the primary prevention of cardiac events, and for evidence of ICD effectiveness and safety in real-world clinical settings outside of controlled clinical trials.

The paper has 3 main findings.

First, ICDs reduced the relative risk for death by 20% for adults with an LVEF less than or equal to 35% who had predominantly NYHA class 2 and 3 symptoms, whether or not they had a history of hemodynamically significant ventricular arrhythmias. The devices were as effective when used for primary prevention in these patients as they were when used for secondary prevention, but data were inconclusive about the benefits of the devices in patients with NYHA class 1 and 4 symptoms.

Second, ICDs were at least as if not more effective at reducing all-cause mortality when looked at in observational studies compared to clinical trials, but the authors acknowledge that the findings may be attributable to clinicians in real world settings selecting healthier patients for ICD insertion who are less likely to die of non-cardiac causes.

Third, ICD implantation was relatively safe, with perioperative deaths occurring in only 1.2% of patients. However, complications, including device malfunction and lead problems, occurred at a rate of 1-2 per 100 patient years, AND the devices of 2/3 to ¾ of patients in the observational studies never discharged, while inappropriate shocks were very common.

Despite the limitations of their review, including the absence of patient-level data that would have allowed the authors to explore which patient subgroups get more or less benefit from an ICD, and the absence of data on long-term outcomes, the authors emphasize that the findings point to a real benefit of ICDs in patients with LV dysfunction. But, they claim, the findings also underscore the need for a prospective registry of device implantation that can provide real world estimates of benefits and risks, and they point to the urgent need to develop risk stratification tools to identify patients who are most likely to benefit from the devices, given the apparent frequent mismatch between patients and shocks in real world settings.

Subscribers to Annals can receive CME credits by answering 2 quiz questions about this article at cme.annals.org. Just click the “My CME” link, to register or sign in.

Other articles in this week’s issue include a survival analysis of systematic reviews, demonstrating that new evidence that might justify updating of the review had already appeared within 1 year for 15% of the reviews, implying that users should check for new evidence that could alter review findings whenever a systematic review is more than a year old and that authors should update their reviews at least annually; and a study of 20 hospital outbreaks of invasive group A streptococcal infection in Ontario in the 1990s, demonstrating that contrary to the conventional wisdom that nosocomial group A strep infections usually occur post-surgically or postpartum, most of the outbreaks involved at least 1 non-surgical, non-obstetric infection, and that the outbreak started with admission of a patient with community-acquired necrotizing fasciitis or draining soft-tissue infection to the ICU in 25% of cases, implying that prevention of hospital outbreaks will require prompt isolation of patients with necrotizing fasciitis at admission.

We also have a case series from the NIH of 100 adult patients with nephropathic cystinosis. Now that’s a pretty obscure disease, but this is an interesting report that links cell biology with phenotype and treatment. Nephropathic cystinosis is an autosomal recessive storage disease caused by defective transport of cystine out of lysozomes. Kids with the disease used to die of renal failure, but advances in renal replacement therapy have transformed the disease into one of adults. So this week’s article details the clinical features, including thyroid gland fibrosis with hypothyroidism; hypogonadism in men; myopathy affecting swallowing and respiratory function; and pancreatic dysfunction; and it highlights the importance of early treatment with oral cysteamine. The drug converts cystine with an “i” into cysteine with an “e-i,” bypassing the defective lysozome transporter, and it prevents or delays the onset of many of the disease manifestations, especially in patients on who take the drugs over years.

We also have an update from the International Committee of Medical Journal Editors about new expectations and standards among the ICMJE journals for registering clinical trials, and we have an Update in Perioperative Medicine, the third of 10 Updates appearing this year based on presentations given at the American College of Physicians annual Internal Medicine 2007 session held last April in San Diego.

Finally, our On Being A Doctor piece this week is entitled “Treating the Enemy,” by Dean Winslow. It’s a striking first-hand account of Dr. Winslow’s experiences as a physician examining U.S. casualties and treating wounded and sick Iraqi insurgent detainees in Baghdad in 2006. Dr. Winslow is a flight surgeon in the Air Force National Guard Reserves and, in his civilian life, is the Medical Director and Chief of the Division of AIDS Medicine at Santa Clara Valley Medical Center in Santa Clara, CA, and a Clinical Professor of Medicine in the Division of Infectious Diseases and Geographic Medicine at Stanford University. I caught up with him to ask him about his experiences in the Air Force, about medical care in Baghdad, and about the Iraq war in general.

Q: Dr. Winslow, thank you for joining me

A: Thanks for asking me to participate.

Q: You did several tours of duty in Iraq and Afghanistan between 2003 and 2006.

A: That’s correct. I think as you know that really we were in a state of low level war ever since the first Gulf War, so I deployed three different times as a flight surgeon during the 90’s with my flying unit, to certainly Turkey and then we flew combat air patrols over northern Iraq, then of course with 9/11 and the invasion of Afghanistan, we’ve been very high operations tempo both in Afghanistan and Iraq, so since 9/11 I’ve been deployed once to actually Uzbekistan, where we flew missions in and out of and all around Afghanistan and then three different times to Iraq.

Q: Did you notice any changes over that time?

A: Well I think certainly going back to the war in Iraq, all of us were much more optimistic about the situation immediately following the fall of Baghdad in April-May 2003, whereas even by the time that I redeployed to Iraq in the fall of 2003 the insurgency was pretty well established, and I think that many of us realized that very likely our country was in for a much longer haul than any of us really initially had anticipated.

Q: And why did you go back to Baghdad in 2006?

A: The bottom line is that the US military needs doctors, and no matter what my personal feelings are about the war, the fact is that we have kids the age of my own biologic children that are in harm’s way, and when I was asked to return and serve, primarily working as an emergency room doctor in this latest deployment, I felt that it was the right thing to do.

Q: Did you ask to be stationed in Baghdad, or did you have choice of where in the country you wanted to be?

A: The Air Force actually runs several what are called EMEDS hospitals in Iraq, stands for Expeditionary Medical Support. So basically this is the modular surgical hospital that the Air Force can deploy on fairly short notice and then modify as necessary or augment to provide more sustained and more comprehenseive medical operations. We have one up in Kirkuk; the large Air Force theatre hospital in Balad, which is about 50 miles north of Baghdad; we have the EMEDS in Baghdad; and then I believe we still have an EMEDS at Talil airbase which is near the village of Nasariya, which is about halfway between Baghdad and Basra in the South.

Q: Were you able to make it out of the hospital compound and into the city?

A: You know, not to any great extent. My contact in terms of downtown Baghdad proper was very, very limited. However, the US Army Civil Affairs Brigade, Baghdad, had recently started a free clinic where many of the both Army and Air Force doctors stationed in and around Baghdad would volunteer. This hospital was located just outside the wire of our base west of Baghdad, and this afforded us the opportunity to see primarily indigent Iraqi civilians when we were off duty. And it was a very, very rewarding, very satisfying experience for, I think, for all of us that participated.

Q: And did you get any sense of either the political or the civilian situation in the city by treating those patients to the extent that you volunteered there?

A: Well you get a little bit of a sense of it, but I think the biggest thing that helps give you a sense of the mood in the civilian population is talking with the Iraqi civilians that were working as contractors with the Coalition forces. This includes several individuals who actually had been lawyers prior to the war, several women working as translators who had been schoolteachers in Iraq, and these were all very educated, articulate people with whom it was just fascinating to talk. One time a lovely, lovely man named Salah Adin shared with me that his brother had been killed by “terrorists,” as he refers to them, just a few days before. Another occasion, one of the female translators came in, was obviously very upset, and shared with me that her cousin had actually been killed a day or two before in what essentially sounded like a carjacking. One of things that perhaps is downplayed with all of the news about sectarian violence and political violence, etc. that is taking place in Iraq is the fact that there’s actually a lot of common criminal activity taking place. One of the things that Saddam did just prior to the invasion was that he essentially released all of the hardened criminals from his prison system just prior to the war beginning. So much of the violence that’s going on is, you know, simple violent crime, and even kidnapping for money. That’s one of the reasons that many of the Iraqi doctors have fled the country, is that they’re prime targets for these kidnappers.

Q: And did you get the sense that the people who were working with you in the hospital compound were putting themselves at risk by allying themselves with the Americans?

A: Oh there’s no question. And I still keep in touch with a few of these individuals by e-mail. I think everyone in America appropriately recognizes the bravery of our own soldiers, sailors, marines, airmen, etc. that are stationed in Southwest Asia. But one of the things that I think is very much underappreciated is the fact that there are still thousands of Iraqis who despite all odds believe that potentially their country has a future as secular democracy and so again these individuals who still live in Baghdad and drive every day to the base to work to try to help create a better situation are definitely putting not only themselves but their families at risk. But when you’re working as a doctor in a military unit your perspective often changes day to day or even hour to hour. And certainly, one day, when one would be talking to these very brave Iraqis who despite all odds, you know, were still optimistic about the future of their country you would start to say, well, this is probably all good, and it’s worthwhile, and it’s worth the sacrifice that these young Americans largely are making with their blood and with their lives. And then when you would see a particular bad trauma case, or a number of soldiers let’s say killed by an IED, one goes back to the feeling of being a father, and the grief that one feels when you imagine that these are your own children. Then one potentially questions whether the sacrifice is worth it. But you’re over there, and you’re serving your county, and I was very, very proud of what I saw my colleagues doing, not only on the medical side, but the way that all of the soldiers that I interacted with, I think really, when they went over to Iraq, wanted to make a difference, and wanted to know that they were making the world a better place potentially by their service there. So I left overall with a great sense of pride in my fellow American service members.

Q: You write in the piece about treating insurgents. Why were Iraqi insurgents brought to you in a US medical compound for care?

A: The short answer to that is that insurgent or any type of prisoner of war becomes the responsibility of the captors under the law of armed conflict and the various Geneva Conventions that deal with this. So, basically once someone is in your custody, you become responsible for their care, and the level of care that the captor is responsible for providing has to be equivalent to that which would be provided to one of your own soldiers. Just from a practical standpoint, the detention facilities are also located out near the Baghdad international airport, so since our hospital provided the highest level of care certainly in that area, when a medical condition would require a level of care that was beyond what could be handled at one of the smaller clinics, let’s say at one of the detention facilities, that it was appropriate to transport the patient in to our facility.

Q: And you wrote that insurgents needing medical care were brought to you blindfolded, and that it was up to you to decide whether or not to remove the blindfold. Did you ever examine a blindfolded patient? Was that ever a question for you?

A: No, I always insisted that the blindfold be removed, and I think almost all of my colleagues did the same thing. You know, I think all of us as doctors and health care providers, we always try to see our patients as the human beings that they are and worthy of care, and certainly having a blindfold removed so someone can see your eyes, your body language, your facial expressions, etc., I think is really important to having a therapeutic alliance.

Q: And some of the insurgents were accused by US forces of storing and planting IEDs and of participating in ambushes of Coalition forces. So what was it like treating them?

A: As all of us get older we realize that things perhaps aren’t as black and white as they seem, and that much of life is a shade of gray, and where one looks at things from different perspectives. I think the bottom line though is that in many cases these really were very violent people, I won’t use the word bad, but these were certainly people who were not only capable but very likely had killed or wounded Coalition forces, so as an American and as someone who was called upon to treat individuals who had been very seriously wounded, it was somewhat of an ambivalent experience.

Q: Typically new trauma techniques are tested during wartime. Are we learning anything new as physicians and as a profession about caring for soldiers who are wounded in Iraq?

A: Certainly a lot of what we practice routinely now in the civilian world in terms of trauma management were things that we learned during the Vietnam War. Similarly with this war, one of the signature injuries are blast injuries related to improvised explosive devices. One of things is that the neurosurgeons are very, very quickly decompressing the brain, and actually removing a fairly large portion of the skull to allow better control of increased intracranial pressure. And then after things settle down and often after a second surgical procedure is done, that the skull or some type of an artificial device is inserted to reestablish continuity of the intracranial cavity.

Q: And how have your experiences in Iraq affected you personally?

A: I think one of things that my experiences serving in Iraq gave me was a greater appreciation for what we have in this country, not only the natural beauty, but the fact that, despite the problems we have in this country, that we are able to live in peace as a pluralistic society. At a personal level, it gave me an even greater appreciation for the presence and the love and support of my family and my colleagues, and most importantly, it gave me just a real sense of gratitude for all of the blessings that I have been given in my life.

Q: What are your responsibilities in the future? Do you plan to go back?

A: It’s unclear at this point. There’s a very good chance that I will be asked to return one more time before I retire. I think the future of the US military is in very good hands, and particularly military medicine. I was just very impressed with not only the competence but also the kindness and professionalism of the medical colleagues with whom I worked in Baghdad last year, not only the doctors, but also the nurses, medics, and x-ray technicians, etc. So I think our country should be rather proud of the people serving in both Iraq and Afghanistan.

Q: Dr. Winslow, thank you so much for talking to me.

A: Thank you Dr. Berkwits, it’s a real pleasure and an honor.

That was Dr. Dean Winslow, author of “Treating the Enemy,” a first hand account of his time as an emergency room physician in Baghdad in the summer of 2006.

Well that’s it for today. If you liked what you heard, of if you didn’t, tell us about it, at podcast@annals.org.

For full details of all of this week’s articles, please consult your print journal, or go to www.annals.org.

Technical support for this summary was provided by Andrew Langman, Neil Kohl, and Beth Jenkinson.

Special thanks to Kevin Stahl and all our friends at WHYY, public radio and television of Philadelphia, who helped produce this podcast.

Check back in 2 weeks for a complete summary of our regularly scheduled September 4, 2007 issue.

I’m Michael Berkwits, and thanks for listening.

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