Randomized controlled clinical trials and the Human Genome Project

by George Lundberg, MD
First, relevant disclosures: I work half-time as editor-at-large at MedPage Today in Little Falls, N.J., and I work half-time as editor-in-chief of Cancer Commons from CollabRx in Palo Alto.
Many of you know that I was the editor at JAMA for 17 years and at Medscape for 10 years. You also know that I have been a strong advocate for evidence-based medicine (EBM) for decades and have trumpeted the large randomized controlled clinical trial as the “gold standard” for EBM.
That was in good faith and was the best that we could do for populations with diseases that we believed were reasonably homogeneous. Of course, clinical trial results are reported as medians and ranges, and there are often discordant results amongst clinical trials and thus the need for meta-analyses to work out the differences. And there are always those pesky outliers and what to do with them.
And then came the human genome project, and I thought when we understood the genes, medical science would become a lot simpler.
How wrong I was.
We now know that heterogeneity may be the rule and not the outlier; that it may make no sense to lump patients with diseases that are heterogeneous by genetic mutations and metabolic molecular pathways into groups for large clinical trials.
The great poet Alexander Pope said that “the proper study of mankind is man.” Okay, I’ll admit that is sexist language, man should be “human.” But I say that “the proper study of me is me.” And further, if I were to get a cancer, the proper study of my cancer would be my cancer, a clinical trial with an N of 1, me.
George Lundberg is a MedPage Today Editor-at-Large and former editor of the Journal of the American Medical Association.
Originally published in MedPage Today. Visit MedPageToday.com for more genetics news.

Breathe properly at night and learn to sleep better

by Steven Y. Park, MD

Every time you see a depiction of someone sleeping on TV or in the movies, you’ll see the person sleeping on his or her back, and oftentimes, snoring.

The lay public, doctors, and even alternative and complementary practitioners naturally assume that you’re able to breathe properly at night. This couldn’t be further from the truth.

Evolutionary biologists and comparative anatomists have stated that speech and language development was ultimately detrimental to humans. The voice box, by descending underneath the tongue, unprotected the airway. The human upper airway serves three functions: breathing, speech, and swallowing. Overdevelopment of speech can be detrimental to breathing and swallowing.

There are clearly significant benefits to complex speech and language development, but the downside is that humans have so many breathing and swallowing problems that most other animals don’t have. In fact, only humans regularly choke and die.

We compensated for this situation until about a century ago when we began to eat more processed, soft foods. Dr. Weston Price, in his nutritional classic, Nutrition and Physical Degeneration, described significant dental crowding and narrowed jaws when indigenous cultures moved away from eating naturally off the land, mountains or oceans, to highly processed foods and refined sugars. This phenomenon occurred across all cultures in all continents.

As a result of dental crowding, the tongue takes up relatively too much space. Many modern humans literally can’t sleep on their backs, since due to gravity, the tongue and voice box can obstruct breathing, especially when in deeper levels of sleep when muscle relaxation occurs. Most people with this anatomy naturally prefer to sleep on their sides or stomachs. The problem is that even if you sleep on your side, obstructions and arousals can still occur.

Because of our upper airway anatomy, by definition, all humans stop breathing once in a while. For example, if you’re completely “normal” and you suffer from a head cold with a stuffy nose, you’ll probably toss and turn at night. One major reason for poor sleep is because you’ll stop breathing more often. A congested nose creates vacuum forces downstream in the throat that causes your tongue to fall back more often. This process is confirmed by the fact that in a study, sleep apnea was documented though sleep studies when healthy college students had their noses plugged.

If you stop breathing at night, even for a few seconds, a vacuum effect is created, which suctions up your normal stomach juices into your throat. This can cause the all-too-common symptoms of laryngopharyngeal reflux disease, with associated throat pain, throat clearing, post-nasal drip, chronic cough, hoarseness, difficulty swallowing, tightness, lump sensation, or burning. In most cases you won’t feel any stomach discomfort whatsoever.

It’s also been shown that H. pylori and even pepsin can be found in middle ear, sinus and lung fluid washings. Notice that many “colds” usually begin with a scratchy, sore throat and then it travels up into the nose, or down into the lungs. This can aggravate or cause the classic bronchitis, ear and sinus “infections” that’s too commonly treated with oral antibiotics.

All humans have some degree of partial to total obstruction and arousals while sleeping. Only the the end extreme of this spectrum is called obstructive sleep apnea. Even if you don’t officially have obstructive sleep apnea, you can still have breathing problems during sleep that can be exacerbated by any form of temporary inflammation (colds, allergies, reflux), or weight gain due to anatomic narrowing.

Chronic upper respiratory symptoms that linger after a simple cold can be explained by this sleep-breathing paradigm. If you suffer from recurrent or lingering colds, can’t sleep on your back, and feel tired, no matter how long you sleep, perhaps it’s your inability to breathe properly at night that could be contributing to your problem.

Steven Y. Park is Clinical Assistant Professor of Otolaryngology at the New York Eye & Ear Infirmary, and author of the book, Sleep, Interrupted: A Physician Reveals The #1 Reason Why So Many Of Us Are Sick And Tired.

Things that make me grumpy

by Grumpy, M.D.

Dave showed up at my office last week with neck pain, worsening weakness in his arms and legs, and changes in his bladder control. All signs pointed to something gone bad in his neck.

His internist had already thought of this, because he'd ordered the appropriate MRI's. And they'd all been read as normal, leaving me without a cause.

Here is where the problem began. EVERYTHING about Dave's exam and story pointed to something serious in his neck. But the tests were normal...

There are A LOT of MRI places out there. Some of them have good quality machines, while others haven't updated their machines, or software, in a long time. In addition to this, some places use specially trained neuro-radiologists to read MRI's, while others use general radiologists. So there's a different quality of reader, too.

This isn't meant as a slap against general radiologists. As a general neurologist, I don't claim to be exceptionally good at various subdivisions of my field, either. No one is good at everything, and recognizing our limitations is part of the job.

As a result, Annie and I have a short list of MRI places I use, where I trust both the equipment and radiologists.

But your average internist doesn't usually know the difference, as they're too busy with the insanity of a general medical practice. Most of the time the decision is made by a scheduling person, based on the patient's insurance, when the next available opening is, and maybe even what place brought them lunch. And, Dave, unfortunately, had his studies done at Shitty MRI, Inc.

So I called Shitty MRI, Inc., and asked for the films, which came the next day. The image quality was terrible, and Dave moved during the study. From what I could see, the films were unreadable.

But I'm not much of a radiologist, let alone a neuro-radiologist. So I dragged the films to someone I trust. She agreed. They were unreadable and worthless.

Now, it might have been a tolerable situation if the reading doctor had dictated something about the films being useless, and recommended they be repeated with sedation, or on a different machine, or whatever. But instead he dictated them as normal.

So I needed another MRI, done on a decent machine, with sedation, and read by a neuro-radiologist. Easier said than done.

I ordered the study. His insurance denied it, on the grounds that he just had an MRI last week, and so they wouldn't pay for another.

I appealed it, and personally called their physician-reviewer. I told him the patient had something serious going wrong in his neck. I told him the previous films were worthless. I even offered to send him the films to look at himself.

He told me that I'd have to live with them, and it wasn't his fault that the ordering doctor had chosen that facility.

(For those of you who believe there aren't bureaucrats between you and your doctor, the above is how it's been in the U.S. for the last 15 years).

So I was stuck. And Dave was getting worse. What could I do?

I had only one option.

I admitted Dave to the hospital. It was a gamble. Once I had him in I could do whatever tests I wanted, but if I were wrong, it would be a nightmare to justify the admit to his insurance.

While I was working at my desk, Dave was rolling into the hospital's MRI. Within an hour the neuro-radiologist called me. Dave had a HUGE herniated disk in his neck, crushing his spinal cord. I called a neurosurgeon immediately, and 2 hours later Dave was having the disk, and it's threat of landing him in a wheelchair, taken out.

Dave did fine.

But the case is still pretty damn scary when you think about what might have been

Death by OSHA

by noreply@blogger.com (911DOC)

In clinic the other day there was a rapid shuffling of feet to my door and a very young medical assistant said, "Doc, the safety people are here... do you know what to do if someone falls in the clinic?"

"My dear child," I intoned, "I certainly hope so at this point in my career... You see, even though the book answer is to start with the ABCs we can skip those if the patient is yelling..."

"No, no!... The safety people are here."

"Safety people? Are they going to ask me what to do?"

"Yes, unless your door is closed."

(Closing door)... "I've gotta know... It's killing me... What's the answer?"

"You pull a form double-ought XYZ from the red binder in the nurse manager's office and fill it out."

I kept the door closed.

More Radiographic Signs

by erdoc85@gmail.com (erdoc85)

We have previously covered the "Throckmorton Sign", but I do not recall an example of this radiographic sign.

This young lady presented today with shortness of breath and displayed an impressive radiographic example of the "Dimmersome-Bigguns" sign.

(No, Frank....I didn't get her phone number for you).

The ER v SomeGuy

by Ten out of Ten

Timeless advice: don’t run with scissors, don’t swim after eating, don’t drunkenly stagger out of a pawn shop and onto an interstate feeder road.  Especially if it lands you squarely in the crosshairs of a barreling tow truck.
To the driver who had glanced down at his radio, it was as if he had materialized out of thin air.  The story almost ended here, someguy to share the same fate as the flattened critters on the truck’s grille.  Only in retrospect was it clear that he was far too mean to die so easily.  Instead, the driver instinctively smashed the brake and yanked on the wheel, the front end seemingly just whistling by, but the side mirror smacking him flush on the shoulder, spinning him around, then the passing rear bumper catching him just below the knee.
Undeterred, someguy got up and resumed his staggering, although this time minus a chunk of his leg.  Police and EMS quickly arrived on scene, and someguy wanted no part of an ER evaluation but he was in no position to refuse, being drunk and high and whatever else, and so our paths crossed.
I examined him, cautiously, unsettled by his lability: he was laughing hysterically one minute, sobbing the next, then vicious the next.  The exam was about as revealing as a nun-of-the-month calendar — all I took away from it was that this guy was hit by a freaking tow truck and needed to be CAT scanned from head to pelvis.
But then the blood pressure cuff started inflating, and it was as if the cuff had become white-hot too.  Someguy, in an impressive burst of insanity, sat bolt upright, screamed, ripped off the cuff, ripped off his neck brace, ripped off his gown, and ripped out his IV, splattering drops of blood across the wall.
Clearly he needed to be restrained, for his safety and ours.  We did the usual thing, one person for each extremity, and I took my place at the head of the bed to keep his neck bones immobilized.  He fought the leather restraints, thrashing dangerously, so I slipped my fingers under his jaw and applied upward pressure, a move that typically elicits submission.  Not this time though, it was as if he was impervious to pain.  And then, suddenly, he managed to wrench an arm free and pow/pow punched me twice in the face.
I felt no pain, it didn’t hurt until later.  Instead shock and a primal rage that spread internally like a reservoir through a crumbling dam pleading and empowering me to retaliate but I didn’t, fortunately, I just grimly dug deeper into his jaw until finally that arm like the rest of him was tied up.
I went back to reassess a few minutes later, composed, since I am scary good at setting aside emotions to deal with the task at hand.  The nurse stood by with the haldol and ativan as I explained to someguy how important it was to get the scans, that he could have life threatening injuries for all I knew.  He looked at me wild-eyed and said as crudely as you can imagine that he’d never allow it to happen.  Immediately, I saw in my mind’s eye an image of the CT scanner, with the tech and nurses struggling to hold him down, and then returning to reality I looked at the nurse and asked her to put the haldol and ativan away.
Enough was enough.  I decided to sedate him far deeper, to a level that would require intubation and mechanical ventilation.  Reflecting on the decision while getting things ready I found myself more apprehensive than usual: there is always risk involved in taking over someone’s airway and here I didn’t have a “hard” indication like being unable to adequately breathe or clear secretions.  But here we were an hour and a half into his ER visit and I had yet to even be able to assess if he had any sort of internal injury, not to mention he was consuming the majority of resources available in the ER, so that he was compromising not just his care but the rest of the patients as well.
We gave him the intubating meds and his oxygen levels almost immediately plummeted.  Normally they’ll hold steady for 3-5 minutes or so, but his metabolic rate was ramped up so crazy high from all the stuff he was on that his body was chewing through oxygen like crop-deprived locusts through a field.  I hastily stuck the laryngoscope in his mouth and his vocal cords politely dropped into view.  ”Gimme that tube” I said, quickly easing it down his throat, the monitor voicing approval with some happier-pitched beeping.  Finally, blissfully, his care became routine, he went quietly through the scanner, and in fact he did have some internal injuries that were treated without incident.
Sometimes alcohol turns people into a-holes, and sometimes a-holes just happen to be drunk; this guy went on to reveal himself as the latter.  Not that it matters.  No matter how base, or irresponsible, or dangerous you might be I’m stuck with you.  How I feel about being the nation’s safety net is a whole other post, for this one it is suffice to say that holding the rope at times can literally leave a mark

Hiya Neighbor

by Ten out of Ten

The ambulance pulled up and two medics hopped out, which was unusual since I wasn’t at work.  From my kitchen window I had seen them drive past my house to the next door neighbor’s, a nice enough couple that I share a fence but little else with as they are more than twice my age.  I thought about going over to see if I could help, but other than being in the way I add nothing to a medic’s prehospital interventions, not to mention I was literally heading out the door for work and I figured I’d just see them there.

I saw him soon thereafter, and shook his hand, and told all his family the next time we get together let’s do it someplace besides the ER since that always lightens the mood with people you only kind of know.  As I started my assessment it soon became clear that he had something VERY BAD.  I ordered a series of tests to show the BAD and quantify how VERY, placing some calls to make sure they were done as soon as possible
A bystander might wonder how an ER can be so devoid of empathy, how we can be unaffected by and in fact make light of disease and suffering and death.  The reason is that it’s impersonal, that we interact with you but don’t know you, that the fact of the matter is unless something is particularly tragic some sort of an interpersonal connection is necessary to conjure up grief.  It’s the difference between reading an AP story of another soldier’s death, then watching a sit-down interview with his decimated wife and kids.
I’ve been cognizant of my emotional detachment for some time now, but never really appreciated its benefits until I worked without it.  I’ve taken care of friends and acquaintances before, but always for some relatively minor ailment.  But now here was my neighbor, and his VERY BAD findings.  No longer was I able to run the department expertly, only adequately, since I was spending far too much time perseverating on him.  He had a few different treatment options, his accompanying co-morbidities causing each choice to carry a substantial countering risk.  I second guessed myself far longer than I normally would, continually revisited and reupdated his family, and had a persistant underlying sense of unease and jitteriness — all because I had a small but legitimate fear that he would tip over some ill-defined physiologic precipice and die in front of me, his house becoming my permanent reminder of his family’s grief, my house turning into a monument of failure and shortcoming to his widow.
Finally he was gone from the ER, as stable as possible, and at least if something happened now I’d be off the hook for it.  As it was, he went on to make a full recovery.  He now credits me for saving his life, and while my emotional side is plenty willing to soak that up, my more insistant logical side knows his diagnosis couldn’t have been more obvious, that sometimes a patient’s fate is set, one way or the other, regardless of this or that treatment thrown at them, that as an ER doc it doesn’t feel like you’ve done anything extraordinary unless you, well, do something extraordinary — certainly not just see over some case that anyone, save for a complete hack, would be unable to bungle.
Still, I’m so glad you’re ok neighbor, for both you and for me.  Next time we get together let’s do it someplace besides the ER