TGN1412

It was apparently the medicine itself, not a contaminant that caused the horrific reactions to TGN1412:

A preliminary investigation of a UK trial in which six healthy volunteers became critically ill said this was probably due to effects of the drug in humans not predicted by animal studies. But the report stopped short of questioning how the study was carried out.

The investigation into the phase I trial of the monoclonal antibody TGN1412, carried out by the Medicines and Healthcare Products Regulatory Agency (MHRA), the body that approves clinical trials in England, said the trial was run according to the agreed protocol, using the correct dose. It also found no evidence of a manufacturing problem or contamination of the product given to the trial volunteers.

One problem with animal testing for monoclonal antibodies against human proteins is that they are likely to be much more potent in humans than animals since they are specifically engineered for high affinity for a human protein and may have little or no binding to the homologous animal protein. This is unlike more classic small molecules which are likely to have similar potencies in animals and humans.

Living longer

Death rates in the United Stares are plummeting, according to the National Center for Health Statistics; and the discrepancy between the races is closing. Looking at the figure, I'd estimate an 8-10% reduction in age-adjusted death rates since 2000. I blame George Bush.

Seriously, I'm glad I didn't write an article like this one, suggesting that mortality rates were likely to increase due to the increase in obesity.

UPDATE: missed link fixed, thanks to Flea

Medical professionals and the death penalty

Atul Gawande has a very thoughtful piece about the involvement of doctors and nurses in carrying out death sentences. I can't really do it justice here, but it is well written and describes pretty graphically how the process can go wrong:

Gas chambers proved no better: asphyxiation from cyanide gas,which prevents cells from using oxygen by inactivating cytochrome oxidase, took even longer than death by hanging, and the public revolted at the vision of suffocating prisoners fighting for air and then seizing as the hypoxia worsened. In Arizona, in 1992, for example, the asphyxiation of triple murderer Donald Harding took 11 minutes, and the sight was so horrifying that reporters began crying, the attorney general vomited, and the prison warden announced he would resign if forced to conduct another such execution.

And the full text is free, so read it all. Most fascinating are his interviews with 4 doctors and a nurse who have participated in executions. Most are furtive, unwilling to be identified, but the final doc is not what you'd expect:

Dr. D is a 45-year-old emergency physician. He is also a volunteer medical director for a shelter for abused children. He works to reduce homelessness. He opposes the death penalty because he regards it as inhumane, immoral, and pointless. And he has participated in six executions so far.

Dr D, who is actually Dr. Carlo Musso, argues that a death sentence is like state-imposed terminal cancer. The doctor needs to keep the patient from suffering unnecessarily, whateve the cause of death.

As Gawande notes, there are problems with this position, not least of which is that doctors involved in executions remain anonymous in a way oncologists and pain specialists don't. But Gawande's view, that execution should be legal, but medical professionals not involved, and if that makes it humane, then it should be unconstitutional and illegal is more than a little convoluted. Gawande also makes much of the American Medical Association's code of ethics which prohibits almost all participation by physicians in executions. But the AMA is, in my view, nothing more than a lobbying organization for physicians. I don't belong to it and don't feel in any way bound by it's views. For example, the AMA code of ethics contains the following pearl:

Ethical medical practice thrives best under free market conditions when prospective patients have adequate information and opportunity to choose freely between and among competing physicians and alternate systems of medical care.

which would shock many of my colleagues who advocate for a single-payer system. And while I disagree with them, I wouldn't accuse them of being "unethical" for advocating for their beliefs, whatever the AMA code of ethics say. More powerfully, of course, right and wrong are not determined by majority vote, as I've discussed before and Gawande also notes.

My own feelings are, alas, muddled. I weakly support the death penalty as the only fitting punishment for some crimes. But I also wonder if all the negative aspects of executions (and let's be honest, that is what they are; "capital punishment" is just a euphamism), are worth it. Personally, I don't have problems with medical professionals participating in executions, if society has determined that they should occur.

My first thought is that I would participate in an execution, but if I actually faced that possibility I'd have to consider the issues more deeply. It seems a bit inconsistent to be pro-execution, but not want to be involved yourself.

Life is good

I am sitting on my patio, enjoying a glass of Pinot Noir and the great view. The weather is nearly perfect (I could use a long-sleeve T-shirt instead of my short-sleeve one along with shorts, but a fleece would be too cold) and the mosquitos haven't arrived yet (for the year), and blogging via wireless.

I live in an urban area with fairly large single family homes situated on a hill side and I am picking up 3 separate wireless connections (of course I'm using my own, which is password protected).

I mananged to take my kids to Buildabear for their Easter treat, get a lot of work done in the garden, do our laundry for the week as well as a load of dishes and work-out, which isn't too bad for one day. Our taxes are done and I'm getting a pretty big refund which is poor planning, but better than having to write a big check. Adrianne is cooking pork-chops for dinner. I may be old, slow and broken-down, but I'm enjoying these few minutes!

I'm also trying to send good vibes to my friend Ollie, who must be about halfway throught the McNaughton 100 mile race right about now

Happy Easter, Passover, or just a happy spring (I guess it is fall "down under") weekend to all Dr. Andy readers.

UPDATE:

Cool HIV fact

that I learned from the item immediately preceeding this one.

How fast does HIV mutate?

The global sequence diversity of influenza, another variable RNA virus, during a pandemic is lower than the diversity of viruses observed within a single HIV-infected individual

So there is more variability between the HIV viruses in a single infected person than among all the different influenza viruses circulating all over the world. That's fast.

Quote from this review of HIV; original article here.

Experiment of nature

Some experiments you just have to be in the right place at the right time. Such is the case in this study in which 2 identical twins got infected with the same strain of HIV at the same time by sharing needles. They routinely shared needles with each other, but shared only once with someone else and both contracted HIV from that incident.

Because the twin brothers share the same immune system genes, including the MHC genes which are responsible for presenting peptides from infectious agents to the all-important T-cells, they should have very similar initial responses to infection.

It is known that HIV mutates rapidly, allowing it to stay one step ahead of the immune response (from commentary accompanying article):

Recent longitudinal studies of early HIV infection have shown that strain-specific neutralizing antibodies are elicited in response to the virus. When these antibodies reach a critical threshold (a matter of weeks), a resistant virus emerges. Eventually, a neutralizing antibody response to this virus develops and a new resistant virus emerges. Apparently, the virus always stays one step ahead of the evolving neutralizing antibody response.

The twin brothers, who were followed for 3 years, until one died of an overdose, had remarkably similar immune responses to the virus. And the pattern of viral mutations was similar as well, suggesting that the interacton of virus and immune system over time may be more predictable that previously thought. This might aid development of an effective vaccine.

Incredibily, a similar pair of twins were the subject of a report in the Journal of Virology published in December. This pair were infected by a single blood donor while babies. They followed a remarkably similar clinical course, developing symptoms of HIV infection at age 7, progressing to severe disease at 17 and then improving with initiation of HAART (highly active anti-retroviral therapy). By that point however, their immune responses to the virus had diverged signficantly. The cytotoxic T cells response had more differences than commonalities.

Since both sets of twins were infected by the same virus at the same time this suggests that the initial interaction of virus and immune system is predictable (as the first set of twins had very similar responses) but diverge over time, probably just by chance. This suggests any effort to target immunity based on knowledge of viral and host immune factors needs to happend soon after infection.

Moderate drinking

may not actually be good for you.

It has generally been accepted that moderate drinking was good for you, based on the fact that epidemiological studies demonstrated decreased death rates for those who drank some alcohol compared to those who abstained. The benefit is seen largely in decreased rates of cardiovascular disease; this finding has biologic plausability as alcohol consumption raises levels of HDL, the so-called good cholesterol.

The exact definitions of moderate drinking and the minimum amount of alcohol needed to gain this protection haven't been 100% clear. 2-3 drinks/day would be the upper limit of "moderate" and some studies have suggested even a drink or two per week confers the observed benefit, although this is controversial.

A new meta-analysis of these studies suggests most have a serious flaw: they incorrectly group those who have quit drinking alcohol in with those who never partook. Because people quite for reasons including illness, aging and the need to take medicines which interact with alcohol, this may lead to bias. Specifically, buy grouping sick or old patients into the group of abstainers it may incorrectly show a benefit to alcohol consumption.

I don't have access to the new article, which was published in the journal Addiction Research and Treatment, so what I now is from this BMJ new item, which isn't free full text:

The researchers, from the University of California at San Francisco and the University of British Columbia, said that most of the 54 prospective studies were flawed as they included as abstainers people who had reduced or stopped drinking, which people often do because of ageing or ill health. Abstainers thus seemed to be less healthy than light drinkers and had a higher risk of death.

After considering 57 variables the researchers found just seven of the studies to be free of error and to include long term abstainers. Analysis of these studies showed no reduction in mortality among moderate drinkers in comparison with abstainers. Only studies containing the "abstainer error" showed protection against death with moderate drinking

So I guess my wine consumption may not be good for my health after-all and the reticence of doctors to encourage alcohol consumption by their patients may have been well-advised. At least the methodologically sound studies didn't show any harm from moderate drinking.

Support free speech

and don't buy from Borders

When I got up to the counter the dreadlocked hippie asked, "If I found everything I was looking for?" I explained that I had not and asked where I could find a copy of the magazine “Free Inquiry”. He was confused I explained why it wasn’t there his manager started hovering behind him he explained that I must be mistaken I assured him I was not. Then I said, “I won’t be purchasing these books today because your company has decided not support free speech.”

Hat tip Ace of Spades. Note I don't necessarily agree with other views expressed in the linked vignette.

Bingo odds

My kid's school PTA had a bingo event to raise money Friday night. I volunteered to call numbers. In my first game, I went 16 numbers without getting an I (for bingo novices, there are 75 letters, divided into 5 letter groups; 1-15 ar B, 16-30 are I, etc.) So I wondered what the odds of that are.

Mathematically inclined readers may want to pause here to work this out for themselves, if they haven't already figured it out.

You might think the odds would be (60/75)^n where n is the number of balls drawn. This would be correct if balls were replaced during the game, but once a ball is drawn it is out for the remainder of the game.

So the odds are (60/75)(59/74)...depending on how many numbers are drawn.

This can be expressed using the factorial function where 5!=5x4x3x2x1 as

odds = (60!/(60-n)!)/(75!/(75-n)!). Plugging in 16 (or setting up a spreadsheet so you can see how the odds change with varying n) I get about a 1.75% chance, which is unusual but not exactly shocking; even at 20 draws you have a >0.5% or 1 in 200 chance of this happening (and this doesn't take into account that there are 5 groupings of numbers)

I also calculated the odds while replacing balls and at lower numbers it doesn't change the odds as much as I'd have guessed: 2.8% and 1.15% at 16 and 20 draws, respectively.

More info on this kind of problem here. Nerdy readers may wish to work out the problem of what the odds of completely filling there bingo cards (24 spaces+free space) for a given number of draws.

One funny note. My second game calling "four corners" I mistakenly called out the I, N, G numbers not realizing those were of no use. I was quickly reprimanded by a grandmother looking type who obviously had a lot more bingo experience than I.

UPDATE: fixed formulas (removing errant 1- at start) per Ollies comments. Note to self: you know math professor is regular reader; proofread future math posts closely

Updates

I've updated my blogroll with a few more medical blogs as well as the blogs of some friends. I try to stay out of politics but both Blueollie and Freerangeathlete are primarily political but from very different perspectives, with a bit of running (or in Ollie's case walking) thrown in. Tom and Ollie are ultrarunning friends. Check out Jason's Photography Space for amazing pictures photographs. Jason is also an MD, a former colleague, but focuses on other interests in his blogging. Funny how that works.

I find it interesting that my relatively small blogroll now contains 2 female general surgeons, a female urologist and a male pediatrician. Given the respective dominance of males in surgery and females in peds, this is surprising. I'll speculate that bloggers are less conventional types, more willing to go against convention.

I don't mean to keep my blogroll "exclusive" but am always finding something else to do rather than update it. So if you feel "left out" just email me and I'll put you on with my next update (which could be a while)

Absolute versus relative poverty

You often hear how well off the poor are in the US:

Overall, the typical American defined as poor by the government has a car, air conditioning, a refrigerator, a stove, a clothes washer and dryer, and a microwave. He has two color televisions, cable or satellite TV reception, a VCR or DVD player, and a stereo.

Yet this absolute affluence (in the face of relative poverty) doesn't seem to translate into health and well-being. According to a recent commentary in JAMA (no free full text) by Michael Marmot:

blacks in the United States have about 4 times the income of men in Costa Rica or Cuba, but about 9 years’ shorter life expectancy.

The article goes on to demonstrate that simple explanations such as poor diet or sedentary life style don't explain the entire discrepency and that a health effect of status (as opposed to income) exists in every society studied and at every level of status. For example

In egalitarian Sweden, Erikson showed that individuals with a PhD have lower mortality than those with a master’s degree, who have lower mortality than those with a bachelor’s degree, and so on down the educational hierarchy. “Greater poverty,” or material deprivation, is not a helpful answer to the question of why someone with a master’s degree should have higher mortality than someone with a PhD.

While omnipresent, the status effect is more pronounced in some societies (e.g. the United States) than others (Sweden). Marmot proposes some reasons (stress, social participation) but there doesn't seem to be much data backing those up.

Here's a research idea for an enterprising epidemiologist. There seems to be a trend toward US citizens retiring in Mexico, where the cost-of-living is lower. My hypothesis is that the higher social status middle income US retirees in Mexico enjoy should lead to better health and longer lives compared to similar retirees who remain in the US despite similar or decreaseds access to quality medical care in Mexico. Call it status arbitrage.

The Shangri-la diet

I blogged about this when it was featured in the Freakonomics section of the NYTimes magazine (that column can be found here). Now, Seth Roberts, a professor of psychology, has a book coming out about his unusual diet.

Briefly, Roberts used himself as a lab rat and tried a variety of diets to try and lose weight. He hypothesized that the body has a "setpoint" which is the weight it thinks it should way. If you weigh more than your setpoint, you will not feel hungry or want to eat much. If you weigh less, you'll obsess about food and tend to eat more. This concept has considerable empirical support and explains why while many dieters succesfully lose weight, so few can keep it off: will power or an unusual diet works for a while but it is very difficult to keep it up.

Based on his experience drinking unusual sugared sodas while on vacation, Roberts hypothesized that regular intake of a small numbers of calories with no flavor (or, it turns out, just sweetness) would reset the setpoint allowing him to lose weight. Depending on whether you believe the NYTimes article or the book he lost somewhere between 30 and 40 pounds over a period of 3 months, by taking in a few hundred calories as either extralight (and therefore almost flavorless) olive oil or water sweetened with fructose. Otherwise he ate what he wished, but he found he didn't have much an appetite.

He believes that other light oils like canola or table sugar (sucrose) in water work just as well. He cut down the number of calories taken in this way once he got thin enough and has managed to keep the weight off.

The extent of the empirical evidence is his weight loss and that some friends have also lost weight this way. No animal trials, no human trials, nothing. He does quote a few commentors on blogs who had initial succes with the diet after the Freakanomics feature. I'd have a lot more faith that this would work if there were more data. He quotes a bunch of animal research that has some relevance to his theory but no direct tests of this diet. (The Penguin site does note that "fformal clinical trials will soon be under way" whatever that means; the skeptic in me wonders if the trials aren't working so they are getting the book out before it becomes clear this method doesn't work for most people).

The theory underlying the diet, which seems to be that taking in bland calories signals scarcity while taking in lots of familiar, highly flavored foods signals abundance doesn't seem very intuitive to me; lab mice and rats along with many other animals stay thin on chow. In fact, in his extra credit chapter which gives other tips for losing weight is sometimes self-contradictory, simultaneously advocating eating a variety of unusually flavored foods and eating bland food like cottage cheese. He does rail against fast food as too many calories that taste the same everytime.

Besides the anecdotal nature of his success, the book feels as though it was thrown together in a hurry to capitalize on the media exposure he was getting (I think he also appeared on Good Morning America or elsewhere). It is 176 pages, but the information could have fit in half that number. Like the proverbial term paper, they seem to have used every trick to make it longer: small pages, big margins, etc.

Finally, Roberts seems to have an unusual relationship to food and eating. One of the benefits he sees in the diet is the time he saves. He currently eats only one small meal a day, and doesn't seem to miss the rest. I can remember a number of great meals I've eaten, but if Roberts has similar memories, he doesn't share them in the book.

I love food and I love eating. I'm pretty sure I'd abandon any diet where I only had appetite for one small meal a day, and I'd miss the pleasure of eating tasty food if I was so limited. I don't sense Roberts has even considered that. I suspect that even if people lose weight on this diet, they'll gain it back as they either grow tired of plain oil and sugar water or miss the experience of eating.

That said, it seems to work. I'm never shy about trying a preposterous new diet and I could always lose a few lbs. so I've given this one a shot for the last week. I haven't been regularly checking my weight, but the decreased appetitie is noticeable. I fill up on much less food than typically, although still much more than Roberts eats. I should note than I'm big, exercise a lot and usually eat quite a bit. Now I'd say that a reasonable portion is enough for me, but I still eat three good meals a day.

The drinking sugar water or oil isn't too bad, although to avoid establishing taste-calorie connections in your brain you have to not take in anything flavored (food, drink, even brushing your teeth seems to count) for an hour before or after, which means you have to plan a bit.

Of course, every diet works at the start. I'll keep Dr. Andy readers updated about how I'm able to keep this up overtime. You may remember I succesfully lost 15lbs by fasting one day a week. That diet works well but requires an enormous amount of willpower, going to be at night, having had no calories for 24 hours with a full refrigerator downstairs. If I ever decide to get really thin for a race, I may try combining the diets and fast a day a week except for some plain oil or sugar water.

FULL DISCLOSURE: The book is not out yet. Some publicist from Penguin emailed me to ask if I wanted a copy to review and I said yes. So I did get the book free, but I have no other financial interest. I suspect Dr. Roberts will soon be a wealthy man, whether or not his experience turns out to be generally applicable.

UPDATE: follow my weight loss here.

TGN1412 update

One of the two men left critically ill by a phase I trial of a new monoclonal antibody almost two weeks ago is improving, says the latest statement released by the hospital caring for him.

Which sounds like good news. Still no word on what exactly what went so horribly wrong