NYT, 02/23/09 — Researchers have engineered antibodies that attack a part of the influenza virus that is shared by many strains.

Flu Vaccines go after the spikes on flu viruses, preventing them from penetrating human cells and injecting viral RNA. But there are 16 types of spikes, and the shapes mutate constantly. So flu vaccines have to be reformulated each year.


New Antibodies go after the neck of the spike, which apparently does not mutate. Once clamped, the neck can still penetrate a cell, but it cannot inject RNA. Mice tested with the antibodies were protected from H5N1 flu in 80 percent of cases.
Source: Nature Structural & Molecular Biology

ScienceDaily.com — The brains of individuals with major depressive disorder appear to react more strongly when anticipating pain and also display altered functioning of the neural network that modifies pain sensitivity, according to a new report.

“Chronic pain and depression are common and often overlapping syndromes,” the authors write as background information in the article. Recurring or chronic pain occurs in more than 75 percent of patients with depression, and between 30 percent and 60 percent of patients with chronic pain report symptoms of depression “Understanding the neurobiological basis of this relationship is important because the presence of comorbid pain contributes significantly to poorer outcomes and increased cost of treatment in major depressive disorder.”

Irina A. Strigo, Ph.D., of the University of California San Diego, La Jolla, and colleagues studied 15 young adults with major depressive disorder (average age 24.5) who were not taking medication and 15 individuals who were the same age (average 24.3 years) and had the same education level but did not have depression. Patients with depression completed a questionnaire that evaluated their tendencies to magnify, ruminate over or feel helpless in the face of pain. All participants underwent functional magnetic resonance imaging (fMRI) while their arms were exposed to a thermal device heated to painful levels (an average of 46.4 degrees to 46.9 degrees Celsius, or about 115 degrees to 116 degrees Fahrenheit) and also to non-painful temperatures. Visual cues (a green shape for non-painful warmth and a red shape for painful warmth) were presented before the heat was applied.

Compared with the controls, patients with depression showed increased activation in certain areas of their brain—including the right amygdala—during the anticipation of painful stimuli. They also displayed increased activation in the right amygdala and decreased activation in other areas, including those responsible for pain modulation (adjusting sensitivity to pain), during the painful experience.

To examine whether the activation of the amygdala was associated with passive coping styles, the researchers compared the percentage change in the activations of the amygdala with the helplessness, rumination and ramification reported by the participants with depression. “Significant positive correlations were observed in the major depressive disorder group between greater helplessness scores and greater activity in the right amygdala during the anticipation of pain,” the authors write.

“The anticipatory brain response may indicate hypervigilance to impending threat, which may lead to increased helplessness and maladaptative modulation during the experience of heat pain,” the authors write. “This mechanism could in part explain the high comorbidity of pain and depression when these conditions become chronic.”

“Future studies that directly examine whether maladaptive response to pain in major depressive disorder is due to emotional allodynia [a pain response to a non-painful stimulus], maladaptive control responses, lack of resilience and/or ineffectual recruitment of positive energy resources will further our understanding of pain-depression comorbidity,” they conclude.

This study was supported by Barrow Neurological Foundation, grants from the National Institute of Mental Health, the National Association for Research in Schizophrenia and Depression and the University of California San Diego Center of Excellence for Stress and Mental Health.

Journal reference:

1. Irina A. Strigo, PhD; Alan N. Simmons, PhD; Scott C. Matthews, MD; Arthur D. (Bud) Craig, PhD; Martin P. Paulus, MD. Association of Major Depressive Disorder With Altered Functional Brain Response During Anticipation and Processing of Heat Pain. Arch Gen Psychiatry, 2008;65(11):1275-1284

Adapted from materials provided by JAMA and Archives Journals.


The Conflict Of Reward In Depression

Stanford University Psychology Department — In Love and Death, Woody Allen wrote: “To love is to suffer…To be happy is to love. To be happy, then, is to suffer.” The paradoxical merging of happiness and suffering can be a feature of depression. A new study of regional brain activity using functional magnetic resonance imaging may help further our understanding of how happiness and suffering are related in depression.

Stanford University researchers recruited both depressed and non-depressed volunteers to undergo brain scans, via functional magnetic resonance imaging (fMRI), while they participated in an activity where they won and lost money. Dr. Brian Knutson, first author on this article, explains their findings: “When they anticipated winning money, both depressed and nondepressed individuals showed neural activation in the nucleus accumbens, a region implicated in the anticipation of reward. Only the depressed participants, however, additionally showed increased activation in the anterior cingulate, a region of the brain that has been implicated in conflict.”

John H. Krystal, M.D., Editor of Biological Psychiatry and affiliated with both Yale University School of Medicine and the VA Connecticut Healthcare System, notes that this finding indicates that “this complex mixture of findings suggests that depression is not simply the absence of reward, but rather a contamination of neural processing of rewards with features of neural processing of punishments.” Dr. Knutson agrees, commenting that “these findings are consistent with formulations that depression involves difficulties in the processing of positive information, and suggest more specifically that depressed people actually experience conflict when they are faced with the likelihood of receiving a reward.”

Dr. Krystal concludes that “one intriguing potential implication of this work is that some forms of depression may be experienced, not as the absence of pleasure, but as the ubiquitous presence of emotional pain, disappointment, or frustration.” Dr. Knutson and his colleagues are currently examining whether this increased experience of conflict when anticipating reward hinders recovery from depression.

The article is “Neural Responses to Monetary Incentives in Major Depression” by Brian Knutson, Jamil P. Bhanji, Rebecca E. Cooney, Lauren Y. Atlas and Ian H. Gotlib. The authors are affiliated with the Department of Psychology at Stanford University in Stanford, California. The article appears in Biological Psychiatry, Volume 63, Issue 7 (April 1, 2008), published by Elsevier.

The New York Times, February 10, 2009, by Nicholas Bakalar — Lengthy television viewing in adolescence may raise the risk for depression in young adulthood, according to a new report.

The study, published in the February issue of The Archives of General Psychiatry, found a rising risk of depressive symptoms with increasing hours spent watching television.

There was no association of depression with exposure to computer games, videocassettes or radio.

Researchers used data from a larger analysis of 4,142 adolescents who were not depressed at the start of the study. After seven years of follow-up, more than 7 percent had symptoms of depression.

But while about 6 percent of those who watched less than three hours a day were depressed, more than 17 percent of those who watched more than nine hours a day had depressive symptoms.

The association was stronger in boys than in girls, and it held after adjusting for age, race, socioeconomic status and educational level.

“We really don’t know what it was specifically about TV exposure that was associated with depression, whether it was a particular kind of programming or some contextual factor such as watching alone or with other people,” said Dr. Brian Primack, the lead author and an assistant professor of medicine at the University of Pittsburgh.

“Therefore, I would be uneasy to make any blanket recommendations based on this one study.”

The New York Times, February 20, 2009, by Roni Caryn Rabin — One of the largest clinical trials to compare stent therapy with traditional heart bypass surgery in patients with severe heart disease has found that those receiving stents were not at higher risk for having a heart attack or dying and were less likely to suffer strokes.

But patients receiving stents were more likely to need some sort of additional treatment, the study found.

Although the study’s authors concluded that coronary artery bypass graft surgery, or C.A.B.G., remains the gold standard treatment for patients with severe coronary artery disease, the new report paints a complex and nuanced picture of the pros and cons of each therapy. Stenting, the insertion of tiny metal “scaffolds” designed to keep arteries open, may be a good option for some patients with severe disease who have traditionally been referred to bypass surgery, the authors said.

The study was published online Tuesday in The New England Journal of Medicine.

“This gives patients more information about the choices they have as they make their own decisions about what therapy they would like to be treated with,” said Dr. David R. Holmes, professor of medicine at the Mayo Graduate School of Medicine and one author of the multicenter study.

“In the past, we really only had data saying that C.A.B.G. was really the only thing that could be done,” he added. “Now we know patients can be offered stenting.”

The data also provide additional details about the advantages and disadvantages of each approach, Dr. Holmes said. The study is one of the largest international multicenter controlled trials to randomly assign patients to either bypass surgery or percutaneous coronary intervention with a drug-eluting stent, which is coated with a compound designed to prevent blood clots from forming.

The 1,800 patients were treated at 85 medical centers in the United States and in Europe, and all had severe, untreated, three-vessel disease or left main coronary artery disease. But the participants were mostly men, and they were tracked for just a year.

Patients were randomly assigned to undergo either C.A.B.G. or stenting, and then monitored for adverse events including deaths, strokes, heart attacks or repeat revascularization procedures.

Over all, the stent patients had a higher risk of adverse outcomes, with 17.8 percent suffering an adverse outcome, compared with 12.4 percent for C.A.B.G. patients.

The two groups had similar risks for deaths and heart attacks, but C.A.B.G. patients were more likely to have strokes, with 2.2 percent suffering a stroke compared with 0.6 percent of stent patients.

Stent patients were more likely to need repeat procedures, the researchers found. Some 13.5 percent needed repeat revascularization, compared with 5.9 percent of bypass patients.

C.A.B.G. was determined to be a better treatment over all, because the guidelines of the clinical trial called for evaluating the risk of all adverse events combined. But some experts questioned whether an increased risk for an additional procedure, associated with stenting, should carry the same weight as the increased risk of stroke, associated with C.A.B.G.

“Having another procedure is not optimal, but it’s a heck of a lot better than dying or having a stroke,” said Dr. L. David Hillis, chairman of the department of medicine at University of Texas Medical School in San Antonio, who co-wrote an editorial accompanying the study.

“What they’re telling us is that these procedures are similar in many respects,” he added. “For individual patients, one is often better than the other. For a patient who can have either one, there are pluses or minuses to each one.”

For about two-thirds of the patients, bypass surgery was preferable, a subsequent analysis found, while for about one-third of the patients, stenting was preferable, said Dr. Patrick W. Serruys, the principal investigator of the study and a professor of medicine at Erasmus University Medical Center in Rotterdam.

“For the most severe left main coronary artery and three-vessel disease,” he said, “surgery is probably most appropriate.”

The study was supported by Boston Scientific, which manufacturers drug-eluting stents.

Jeffrey Coolidge/Getty Images In the quest to cut spiraling health care costs, what happens to the doctor-patient bond?

The New York Times, Tara Parker-Pope –As the medical system struggles with spiraling costs, one solution is pay-for-performance. Instead of giving doctors flat fees, insurers pay doctors based on whether they have met quality goals — such as helping patients get their diabetes or blood sugar under control.

But inherent in pay-for-performance systems is a push to reduce costs. That, asks Dr. Pauline Chen, in her latest Doctor and Patient column, raises questions about how pay-for-performance will affect the doctor-patient relationship.

Dr. Chen recently spoke with a colleague about his new pay-for-performance contract.

“I do worry about how this will affect my relationship with patients,” she said. “If my patient comes in with a headache and wants a CAT scan, but I don’t order it because I think it’s not medically indicated, will that patient think I’m just trying to save money?”

Unfortunately, as Dr. Chen reports, very little has been done to explore the impact pay-for-performance can have on patient trust. What do you think of your doctor’s pay being tied to performance?


Are Insurance Companies Really Interested in Doctors’ & Their Patients’ Outcomes?

The New York Times, February 20, 2009, by Pauline W. Chen MD — During medical school, I learned about randomized clinical trials. Every experimental drug went through three types of clinical trials before approval. There were Phase I clinical trials which tested for toxicity and dosing. Phase II trials then examined optimal dosing and efficacy. Finally, Phase III trials compared the efficacy of the new drug with the current “gold standard” treatment.

I’m now learning that health care policy doesn’t always undergo the same kind of rigorous study.

I met up recently with a friend who is a primary care physician. His practice has just signed a contract with the state’s largest insurer that reimburses not according to the traditional fee-for-service, which pays doctors a set price for each visit, test or procedure they do, but according to a newer standard known as “pay-for-performance.” The insurance company will give his practice a budget for each patient; the doctors in the practice can earn more by cutting costs and by meeting certain quality goals, like controlling blood sugar or high blood pressure in patients.

I asked my friend if he was happy about the new contract.

“I guess so,” he replied with some hesitation. “I’m not sure how else we are going to stop spiraling health care costs.” But then he added, “I do worry about how this will affect my relationship with patients. If my patient comes in with a headache and wants a CAT scan, but I don’t order it because I think it’s not medically indicated, will that patient think I’m just trying to save money?”

I thought about his concerns, and at first could not see any downside to linking quality to financial incentives. When doctors are working on a fee-for-service plan, there’s just not that much incentive for them to take time to promote healthy living or strong doctor-patient relationships; the payment system rewards for high turnover and pits doctors against the clock.

I knew that other industries, like business corporations and education, had successfully used pay-for-performance to improve quality. And health care quality, which is a secondary concern with fee-for-service incentives, could definitely use a boost. A 2003 New England Journal of Medicine study showed that only about half of patients received the standard, nationally recognized care for preventive health issues and acute and chronic conditions.

I felt, too, that my own area of training, liver transplantation, could benefit from linking financial incentives to quality, not quantity. A surgeon must, for example, weigh the relative importance of multiple, sometimes counterbalancing factors when deciding to accept a donor liver for a waiting patient. Will the donor liver be too big or too small for the patient? Is the donor liver cirrhotic or too fatty or too old? Is the recipient too sick to receive this particular organ or able to accept the risk of waiting for the next one?

These are vital questions, because they help liver transplant surgeons avoid some of the worst complications of transplantation — body-wide infections, bleeding so profuse that staff cannot change the bed sheets quickly enough, and a coma so deep that it can only end in death.

Yet every liver transplant surgeon has seen these devastating complications. And as multiple studies have shown, despite a surgeon’s best predictions, from 5 to 10 percent of all transplanted livers will not work for reasons that none of us know or understand.

Nonetheless, in a fee-for-service payment system that reimburses hospitals anywhere from $400,000 to $500,000 per liver transplant, it’s hard not to suspect less-than-savory intentions from any surgeon or hospital with high transplant numbers and consistently more complications than the accepted norms. Last fall, in a piece titled “Doing a Volume Business in Liver Transplants,” The Wall Street Journal reported on one such case involving a surgeon hired six years ago by the University of Pittsburgh Medical Center. Allegations against this surgeon and the medical center include using questionable donor livers in relatively healthy patients in order to increase the number of transplants performed.

I could not help but think that if the medical center’s reimbursement had been based on pay-for performance — and had been subject to the inherent quality checks and transparency of such a plan — perhaps fewer patients and families would have been so terribly affected for so long. And perhaps the disastrous repercussions on trust between potential liver transplant patients and their surgeons in the wake of this case would have been averted.

Still, I wondered how pay-for-performance might affect the doctor-patient relationship in daily interactions, as my primary care doctor friend mentioned. He is one of the best clinicians I know, a devoted patient advocate.

So I began searching for clinical trials on pay-for-performance plans. In this era of evidence-based medicine, I was certain I would find plenty of well-designed studies focusing on cost, quality and the doctor-patient relationship.

What I found was this: waves of new pay-for-performance payment plans across the country, a relatively modest number of articles on the subject and, most disturbingly, very few high quality studies on efficacy. Looking for a few good studies, it turned out, was like searching for a needle in a massive haystack of social experimentation.

But what an impressive haystack. Since early this decade, an ever-increasing number of employer groups and health plans have chosen to adopt pay-for-performance initiatives. For example, more than half of the private sector health maintenance organizations (H.M.O.’s) now have pay-for-performance programs. California adopted a voluntary pay-for-performance program in 2003 and now has the largest such program in the country, involving 225 participating physician organizations, some 35,000 physicians and over 6 million state residents. And in the Deficit Reduction Act of 2005, Congress mandated that the Center for Medicare and Medicaid Services adopt a pay-for-performance plan into Medicare.

The details of these myriad plans vary. Reimbursements and bonuses can be based on the work of, and thus are paid to, individual doctors, groups of doctors, or groups of providers who are part of a “medical home.” Some plans, such as HealthPartners in Minnesota, refuse to pay for so-called “never events,” rare and preventable complications like giving a mismatched blood transfusion, making a major medication error or operating on the wrong body part. Other plans transfer the responsibility for traditional insurance risks such as unknown genetics, unpredictable events or simply bad luck away from insurance companies and over to doctors. Still others, such as the Prometheus Payment model now being tested in four communities across the United States, attempt to make doctors responsible for only the risks they can control with high quality care by adjusting payments to reflect that risk alone.

But in this profusion of programs, I found it nearly impossible to find the kind of randomized control study I have come to trust when evaluating experimental drugs or even new devices or surgical therapy. And the few studies that have been published are only mixed or guardedly positive in their conclusions regarding pay-for-performance plans. Only one study has focused on cost-effectiveness.

Even more concerning, however, are the unintended consequences that some of these studies have uncovered. Some pay-for-performance plans have resulted in increased administrative costs. Certain physicians and hospitals have found ways to “work” the system, avoiding patients who require more costly care or who skew quality records and exaggerating the severity of patient status in order to document the kind of dramatic improvement that might result in a bonus.

And none of the studies focused on the effect of pay-for-performance on the relationship between patients and their doctors.

In other words, we are continuing to charge ahead with pay-for-performance plans without stopping to look at what we’ve already done. And what we’ve already done may or may not be as promising as we believe or would like to hope.

Wondering if I had missed something, I called Dr. Laura A. Petersen, lead author of the most recent review of studies on pay-for-performance plans and chief of the section of health services research at Baylor College of Medicine in Houston.

Dr. Petersen had had similar concerns when she began first began sifting through clinical studies for her review. “Pay-for-performance was being implemented everywhere, so I thought that there had to be a lot of evidence,” she told me. “But I was shocked. There was only this tiny group of studies. I called everyone I knew, contacted people around the country; but there just was really nothing. I found it fascinating that a widespread policy intervention like this could spread like wildfire on the basis of no evidence.”

She mentioned the appeal of the idea behind pay-for-performance as a possible reason. “We are having runaway costs because the incentive is for individual doctors to ramp up their volume to increase income,” she said. “Pay-for-performance is a really interesting policy intervention because it’s an attempt to switch to incentives based on quality rather than on volume and intensity of services. We want to be able to pay people for good quality.”

I asked Dr. Petersen about some of the unintended negative consequences, like the avoidance of certain patients and increased administrative costs. “I think the answer is to try to design pay-for-performance schemes where those negative consequences are minimized or accounted for,” she said. “And all the efforts of the current administration to implement electronic medical records have the potential to help with administrative costs and to make this more doable.”

I mentioned my primary care physician friend and his concerns. Did she know about the effects of pay-for-performance on the doctor-patient relationship? Could it pit one against the other?

“There’s potential for that if the programs aren’t designed well and if we don’t think through all the incentives properly,” she said. “But if we align incentives, if we change from being volume-driven to somehow paying for patients being satisfied, we can ameliorate the relationship. I hope that by getting off this volume treadmill, we will ultimately do more for the doctor-patient relationship.”

“Actually,” she then deadpanned, “it’s worse than a treadmill. It’s like one of those gerbil wheels.”

I asked Dr. Petersen about her current research. Last year with funding from the National Institutes of Health and the Veterans’ Administration, she started a 20-month study looking at pay-for-performance in 12 different Veterans’ Administration hospitals across the country. She and her co-investigators plan to examine the effects on primary care physicians, clinical staff, administrative staff, hospital leaders and patients. They hope to improve understanding of the relationships among incentives, costs, quality and the doctor-patient relationship.

“My passion is health care quality, improving and figuring out ways we can structure and get high quality,” Dr. Petersen said. “Even in the best hospitals, you find that things happen that shouldn’t. And it is not that people are bad or dumb, but that the system is not ensuring the best care. I’m interested in those enforcing functions that make it almost impossible to do the wrong thing.”

She added, “I am pretty optimistic right now. I think our current crisis of payment is going to stimulate action.”

And, it appears, the kind of long overdue research, that we need, in order to make the best choices as doctors and patients.