A step toward letting medical devices communicate

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Plug and play: Two pulse oximeters, which measure blood oxygen levels, are linked with hardware that uses data from either device to control an intravenous drug device (not shown).
Credit: CIMIT

 

MIT Technology Review, September 24, 2009, by David Talbot  —  In a key practical step toward the long-sought goal of linking different hospital devices together to better manage patients and their care, a Boston research group has come up with a software platform for sharing information among gadgets ranging from blood-pressure cuffs to heart-lung machines.

“The vision of fully interoperable medical devices has been around for at least a quarter-century, but lack of adequate standards and lack of manufacturers’ desire to foster such integration has left us in a kind of Dark Ages,” says Peter Szolovits, an MIT computer scientist in the Harvard/MIT Division of Health Sciences and Technology, who was not involved with developing the new standards. He adds that they are “a critical component of making health-care information technology smarter, safer, and more efficient.”

When doctors disconnect a heart-lung machine after finishing heart surgery, they need to turn on the ventilator quickly, or the patient will suffer brain damage. Right now, however, there is no way for the heart-lung machine to sense whether the ventilator was switched on correctly and keep running if it wasn’t. Even the most high-technology medical devices used in hospitals don’t “talk” to each other in the way that, say, your PC “talks” to your printer.

The new standards for the Integrated Clinical Environment (ICE)–written by a research group convened by the Center for Integration of Medicine and Innovative Technology (CIMIT), a hospital/academic consortium in Boston–consist of a set of high-level design principles. Among other things, the standard says that an ICE must include a device analogous to a jet airliner’s “black box” that collects data. This black box will initially prove that integrating different systems can be safe enough to win regulatory approval. But in everyday practice, it will also be crucial to troubleshooting and improving interoperability. The standard also says that there must be only one overarching algorithm that interprets data from all connected machines to avoid conflicting instructions or warnings; and that if one piece fails, the failure must not be able to spread to other parts of the system.

“This is about building a comprehensive platform, like the Web, that allows the global community to innovate and build cool things on top of it that improve patient safety,” says Julian Goldman, director of CIMIT’s Medical Device Interoperability Program, who led the group that developed the standards, which will be published this fall by the standards body ASTM International.

“Any technologically sophisticated person would assume that if you are receiving a potent intravenous medication in a hospital, and at the same time your blood pressure is being measured by an automated cuff every 15 minutes, that we have a way to [automatically] stop that medication infusion if it causes your blood pressure starts to fall or rise rapidly,” says Goldman, who is also an anesthesiologist at Massachusetts General Hospital and medical director of Partners HealthCare Biomedical Engineering, “but it’s impossible to do that today.”

This lack of interoperability can lead to serious errors. It also means that clinicians waste time chasing false alarms set off by individual gadgets. For example, today’s telemetry monitors track heart rhythms, while other gadgets monitor heart rate and levels of blood oxygen. Sudden changes in activity and movement can cause sudden heart-rhythm fluctuations, triggering urgent warnings. But such alarms could be eliminated if an integrated system also checked heart rate and oxygen levels; if these were unchanged, no heart-attack warning would be necessary.

David Osborn, manager of international standards at Philips Healthcare, says that while the new standards will help, “the document put together so far is a high-level framework. The devil is in the details, and the details haven’t been written yet.” However, he adds, “harm is occurring to patients more often than we’d like to admit, and this can be a step toward a solution, if we can get beyond the framework.”

Szolovits says that the eventual goal is an integrated clinical environment, in which all devices are interconnected, in plug-and-play fashion, for better management. Currently, devices made by different manufacturers operate on their own, and, in general, they cannot communicate with one another. Several medical associations, including the American Medical Association, have called for interoperability.

“Even at leading modern hospitals, I have seen pulmonary technicians run around the foot of a patient’s bed to transfer ventilator settings from a device on one side of the bed to a computer system on the other,” says Szolovits. “Not only is such a process laughable to watch, but it increases the risk of errors, corrupts data, and possibly even puts patients at risk.”

A new blood test could improve cancer-screening compliance

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Tissue test: Healthy colon tissue (shown top), with surface cells dyed green and internal stromal cells dyed red. In cancerous colon tissue (bottom), the tissue structure is broken down, and surface and internal cells are mixed together. Credit: OncoMethylome Sciences 

MIT Technology Review, September 23, 2009, by Michael Day  —  A blood test designed to enable simple screening for colon cancer has been hailed by experts as a major advance. The test detects cancer due to a chemical change called methylation that occurs disproportionately in two key genes in colorectal tumor cells.

Since more people should be willing to have a simple blood test, the screening method could help identify those patients who need a more invasive, more diagnostically rigorous colonoscopy.

The U.S. death toll from the condition is around 50,000 a year. The American Cancer Society recommends that men over the age of 50 have about one colonoscopy every 10 years, and that those at a higher risk be screened earlier and more often. Yet until now, only invasive colonoscopies and stool tests have been available and compliance by those deemed in need of screening is disappointingly low, at less than 50 percent. Screening programs have been shown to cut deaths by allowing more victims to receive earlier, curative treatment so a simpler test could save lives by encouraging more people to get screened.

The developers of the new test, OncoMethylome Sciences, based in Liège, Belgium, say their method, which relies on one three-milliliter sample of blood, has the potential to boost compliance rates and conserve precious health service resources.

The test identifies the presence of methylated SYNE1 and FOXE1 genes, which mark out colorectal cancer cells. The researchers compared test results from 686 healthy control patients with 193 patients already diagnosed with the disease. The test was able to detect colorectal cancer in 77 percent of those subjects with the disease, according to data presented at the Congress of the European Cancer Organization in Berlin, Germany, on Monday. It correctly identified healthy, noncancerous patients in 91 percent of cases.

“This test has potential to provide a better balance of performance, cost-effectiveness, and patient compliance than other options currently available for colorectal cancer screening,” says Joost Louwagie, vice president of product development at OncoMethylome.

Louwagie hopes that with further testing and refinements the test will become more sensitive and provide fewer false-positive results. But he says that even a 77 percent sensitivity would be “very useful” if it were applied to the large numbers of people who decide not to have screening using more-intrusive methods. He stresses, however, that colonoscopies remain the gold standard for diagnosing the disease.

Ernst Kuipers, head of the colorectal screening program and a professor of medicine at Erasmus University Medical Center in Rotterdam, praises the results. “This is an excellent new method, technically very well done,” he says. “It represents a major advance on what we have now.”

Kuipers says the 77 percent accuracy in detecting cancer-containing samples is “a good result.” In comparison, the fecal-immunological screening method that he has been researching is around 60 percent accurate. He notes, however, that the specificity of the blood test–its ability to correctly identify healthy patients–will need to improve. “In practice, everyone over 55 would be screened, perhaps every two years,” he says. “That’s millions of people. So, if you had more than 5 percent false-positive rates, the number of follow-up colonoscopies you’d need to do would become too great.”

Kuipers says that the specificity of the test needs to be at least 95 percent for it to be used in colorectal screening and that a large-scale evaluation will be vital.

With this in mind, Louwagie and colleagues are enrolling people in a prospective colorectal screening study at several German colonoscopy centers. “We plan to complete enrollment of 7,000 people by the end of 2009,” he says.

The trials should also shed more light on how effective the test is at detecting the very earliest stages of colorectal cancer. Such a gene test will not be able to spot precancerous polyps. But it could be particularly effective if it can detect stage-one and stage-two colorectal cancers, which are almost always curable with surgery.

A new paper by Kuipers, due to appear in Journal of the National Cancer Institute, will provide new evidence that colorectal screening can ultimately save health services money, he says. But he believes that the most important measure will be a reduction in the number of colon cancer deaths. Kuipers notes that older, repeat-stool type testing, which was considered ineffective and not very sensitive, has been shown to have cut colorectal cancer deaths by 15 percent. He says that a reasonably sensitive and simple test with higher compliance levels could prevent many more colon cancer deaths.

Inactivated vaccine was more efficacious than live-attenuated vaccine in healthy adults 

Two types of seasonal influenza vaccines are currently licensed: an inactivated formulation, injected intramuscularly, and a live-attenuated formulation, administered by intranasal spray. Now, results from a double-blind trial conducted in Michigan during the 2007-2008 influenza season (and supported in part by the inactivated vaccine’s maker) shed light on the comparative efficacy of these preparations in healthy adults. During that season, influenza A (H3N2) viruses predominated, with a slight antigenic drift from the vaccine strain.

A total of 1952 healthy adults aged 18 to 49 were randomly assigned to receive inactivated vaccine or matching intramuscular placebo, or live vaccine or matching nasal-spray placebo, in a 5:1 vaccine:placebo ratio. Throat-swab specimens were collected from individuals who developed influenza symptoms; culture, PCR, or both were used to confirm the diagnosis.

During the study period, 119 participants (6%) had laboratory-confirmed influenza; 91% of these cases involved influenza A. Efficacy was 68% for the inactivated vaccine and 36% for the live-attenuated preparation, compared with placebo. The inactivated vaccine was 50% more efficacious than the live-attenuated one.

Comment: Interestingly, these results in healthy adults are opposite those seen in young children. The authors speculate that the live-attenuated viruses may be unable to infect some adults because of these individuals’ past exposure to similar strains. Of note, efficacy against influenza B could not be assessed because the circulating influenza B viruses were not included in the vaccine.

Lynn L. Estes, PharmD

Published in Journal Watch Infectious Diseases September 23, 2009

Citation(s):

Monto AS et al. Comparative efficacy of inactivated and live attenuated influenza vaccines. N Engl J Med 2009 Sep 24; 361:1260.

Research News from the Howard Hughes Medical Institute

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Howard Hughes Medical Institute, September 24, 2009, by Joseph W. Thornton PhD  —  New research demonstrates that in evolution, proteins can’t go home again –

at least not by their original route. Scientists have long debated whether

natural selection could loop back on itself, allowing an organism to revert to

its ancestral form. Now, by analyzing the molecular evolution of a hormone

receptor found in virtually all vertebrates – the glucocorticoid receptor (GR)

– Howard Hughes Medical Institute researchers have concluded that protein

evolution is irreversible.

 

Joseph W. Thornton, a Howard Hughes Medical Institute (HHMI) early

career scientist at the University of Oregon who led the study, says the results

suggest that evolution acts as an “epistatic ratchet” – meaning the molecular

tinkering that leads to new features in an organism turns, like all ratchets, in

only one direction.  “Our work. . . implies that the biology we have today is just one

of many possible rolls of the evolutionary dice.”

 

– Joseph W. Thornton

Thornton and his colleagues, Jamie Bridgham of the University of Oregon

and Eric Ortlund of Emory University, published their study in the September

24, 2009, issue of the journal Nature.

 

The human GR makes us exquisitely sensitive to the steroid hormone

cortisol, which regulates our response to long-term stress, including changes

in metabolism, immune defenses, and even aspects of memory formation in

the brain.

 

GR is the sister gene of a very similar hormone receptor, the

mineralocorticoid receptor (MR), which responds to different hormones to

regulate salt levels in the body, controlling blood pressure and cardiovascular

health. GR and MR genes are duplicates of a single ancestral gene that last

existed more than 450 million years ago in an ancient vertebrate. The ancient

protein encoded by that gene (AncCR, for ancestral corticoid receptor) was a

less discriminating molecule than the modern GR, says Thornton, and could

be activated by both cortisol and mineralocorticoids.

 

Thornton can speak so authoritatively about this ancient protein because he

has it in his lab’s freezer. His research group “resurrected” the AncCR by

combining computational analysis of gene sequences with biochemical

methods for synthesizing DNA and expressing proteins. First, Thornton

determined the sequence of the ancestral gene by analyzing the receptor

sequences of hundreds of modern vertebrates using a bioinformatics method

called maximum likelihood phylogenetic analysis. Working his way back

down the gene’s family tree, he identified the signature genetic changes

where intermediary forms of the receptor branched off and followed the most

likely conserved genetic sequence all the way back to the earliest common

ancestor.

 

With the probable AncCR sequence in hand, Thornton’s research group

synthesized the gene from scratch and expressed the ancient protein in cells

grown in the laboratory. They then used cutting-edge techniques to

characterize the structure and function of the receptor — tearing it apart and

rearranging it to see how it folds into a functional protein and what hormones

regulate its activity.

 

Once he knew that the GR’s ancestor responded to a wide range of hormones,

Thornton wanted to determine precisely how and when the modern protein’s

unique sensitivity to cortisol evolved. Moving up the phylogenic tree from

the duplication that produced the GR lineage, his group resurrected additional

ancestral receptors. They identified the very last one that functioned like

AncCR and the first one to work like a modern GR. Thornton calls those

ancient receptors AncGR1 and AncGR2. AncGR1 existed about 450 million

years ago in the ancestor of all jawed vertebrates. “That’s the last common

ancestor of you and a shark,” Thornton says. AncGR2 represents the GR

about 40 million years later in the ancestor of all vertebrates with bones —

“the last common ancestor of you and a salmon,” he says.

 

Thornton found his “epistatic ratchet’ in that 40-million-year gap. His first

step was to identify the mutations that caused AncGR2 to evolve its new

function during that interval. He found that seven historical amino acid

changes, when introduced into AncGR1 by DNA engineering, were sufficient

to recapitulate the evolution of cortisol specificity. His group also determined

the order in which the seven mutations had to have occurred to make the

receptor more sensitive to cortisol, while preserving the function of

intermediate forms of the receptor.

 

But when the team’s experiments began to go backward in evolutionary time,

they hit an unexpected evolutionary brick wall. When Bridgham, a research

scientist in Thornton’s laboratory, manipulated AncGR2 to reverse the seven

key mutations, she could not recreate a receptor with the more general

function of AncGR1. Surprisingly, the ancestral states at these mutation sites

had become lethal, yielding a non-functional protein that would not respond

to any hormones. Changing the order of reversed mutations led nowhere,

which led Thornton to the concept of the epistatic ratchet. “During evolution,

the conditions that facilitated the evolution of past states are destroyed as new

states are realized,” he explained.

 

To determine why evolution had become irreversible, Thornton looked to the

other mutations that had occurred between AncGR1 and AncGR2. Ortlund,

his collaborator, determined the atomic structures of the resurrected proteins

using X-ray crystallography. By comparing the two structures, Thornton’s

group identified five additional mutations in AncGR2 which would cause

clashes between atoms, destabilizing the protein and making it unable to

function properly, if the rest of the structure were returned to its ancestral

state. And indeed, once these five mutations were set back to their ancestral

states, the protein could then tolerate reversal of the seven key mutations,

yielding a protein with the ancestor’s broad sensitivity. When introduced into

AncGR1 in the forward direction, however, the five “restrictive” mutations

had virtually no impact on the protein’s function.

 

Based on these experiments, protein evolution seems irreversible, says

Thornton. Although the five restrictive mutations must be reversed before the

seven key mutations, reversing those five alone either destroys the receptor’s

function or has no effect, depending on the order in which they are

introduced. Backward evolution would therefore require at least five initial

steps that natural selection would be powerless to drive. Instead, Thornton

says, selection would have to drive the protein to some adaptive state

different from its past.

 

As an organism moves forward in evolutionary time and adapts to new

opportunities or threats, a host of random genetic mutations cause subtle

changes to the structures of its proteins. Some of these rearrangements, like

those Thornton studied, are “restrictive” in blocking the path back to older

states, while others are “permissive,” opening up paths to new functions that

were previously inaccessible. The process is incremental, mutation after

mutation, but cumulative in that once a new organism “works,” the restrictive

mutations can’t be undone without crashing the chain. The evolutionary

bridge back to earlier states gets burned.

 

Thornton points out that his epistatic ratchet touches on the hotly debated

question of whether evolution is driven by contingency or by determination.

That is the granddaddy of all evolutionary arguments–was the evolution of

Homo sapiens an inevitable outcome or a happy accident?

 

Thornton believes that the epistatic ratchet concept he observed in

glucocorticoid receptor evolution supports the argument for contingency.

“Our work suggests that the outcomes of evolution depend crucially on

low-probability chance eventson where an evolutionary trajectory starts and

where it happens to wander along the way,” Thornton says. “It implies that

the biology we have today is just one of many possible rolls of the

evolutionary dice.”

 

Joseph W. Thornton, Ph.D, HHMI Early Career Scientist

 University of Oregon

by Mehmet Oz, MD and Michael Roizen, MD |

You can add color to your next dinner party by inviting the eccentric with the orange hair who lives two doors down. Or you can do it in a far quieter and healthier way: By bringing winter squash to the table. This golden-orange vegetable helps you live longer and better (even if it won’t offer to do the dishes). Here’s just part of its healthy resume:

It reduces the rate at which your arteries age. Varieties such as acorn and butternut are high in potassium, which is part of what makes your nerves and muscles contract when you want them to. It also helps regulate blood pressure, allowing your heart and kidneys to function properly. One cup of cubed squash contains almost 900 milligrams of this mineral, which gets you a long, tasty way toward the 3,000 milligrams a day we recommend.

It keeps your knees (and hips) moving. Winter squash is high in beta cryptoxanthin (you don’t have to spell it; just eat it) and vitamin C, two nutrients credited with helping save joints.

It helps control your appetite. Squash is low in calories (if you don’t douse it in butter and brown sugar, which you don’t need for great taste) and high in fiber, so you eat fewer calories and feel full longer.

Our favorite ways to get it on your plate:

  • Serve it as a side dish. Puree butternut squash with a bit of olive oil, lime juice, and nutmeg.
  • Add cubed or mashed squash to stews, casseroles, and stir-frys.
  • Cut it into the shape of french fries. Mix with a lot of garlic and a little olive oil and then roast in the oven.

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Michael F. Roizen, MD

Michael F. Roizen, MD, is cofounder of RealAge, chief wellness officer at the Cleveland Clinic, and chairman of the RealAge Scientific Advisory Board. Dr. Roizen’s first consumer book, RealAge: Are You as Young as You Can Be?, was a New York Times #1 best-seller and has been translated into more than 20 languages. He has also edited multiple medical journals and coauthored many other books. Most recently, he and Mehmet C. Oz, MD, teamed up to produce their best-selling YOU books, which include YOU: The Owner’s Manual, YOU: On a Diet, YOU: Staying Young, and YOU: Being Beautiful. In addition, Dr. Roizen hosts his own radio show and makes frequent TV appearances on everything from Good Morning America to PBS.

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Mehmet C. Oz, MD

Mehmet C. Oz, MD, is a member of the RealAge Scientific Advisory Board and vice chairman of cardiovascular services, Department of Surgery, Columbia University Medical Center. For several years, he has also been the health expert for The Oprah Winfrey Show. Beginning in the fall of 2009, he will host his own daily TV hour, The Dr. Oz Show. He has written more than 350 original publications, book chapters, abstracts, and books and has received several patents. In addition, he and Dr. Roizen have coauthored several New York Times #1 best-sellers, including YOU: The Owner’s Manual; YOU: On a Diet; YOU: Staying Young; and YOU: The Smart Patient, which he wrote on his own. Dr. Oz is the founder and chairman of HealthCorps, which is fighting to stem the crisis of child obesity.

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Lifting Fog
By Vicki France
09/23/09
Mt. Horeb, Wisconsin