Danette Lake thought surgery would relieve the pain in her knees.
The arthritis pain began as a dull ache in her early 40s, brought on largely by the pressure of unwanted weight. Lake managed to lose 200 pounds through dieting and exercise, but the pain in her knees persisted.
A sexual assault two years ago left Lake with physical and psychological trauma. She damaged her knees while fighting off her attacker, who had broken into her home. Although she managed to escape, her knees never recovered. At times, the sharp pain drove her to the emergency room. Lake’s job, which involved loading luggage onto airplanes, often left her in misery.
“I thought the knee replacement was going to be a cure,” said Lake, now 52 and living in rural Iowa. “I got all excited, thinking, ‘Finally, the pain is going to end and I will have some quality of life.'”
But one year after surgery on her right knee, Lake said she’s still suffering.
“I’m in constant pain, 24/7,” said Lake, who is too disabled to work. “There are times when I can’t even sleep.”
Most knee replacements are considered successful, and the procedure is known for being safe and cost-effective. Rates of the surgery doubled from 1999 to 2008, with 3.5 million procedures a year expected by 2030.
But Lake’s ordeal illustrates the surgery’s risks and limitations. Doctors are increasingly concerned that the procedure is overused and that its benefits have been oversold.
Research suggests that up to one-third of those who have knees replaced continue to experience chronic pain, while 1 in 5 are dissatisfied with the results. A 2017 study published in the BMJ found that knee replacement had “minimal effects on quality of life,” especially for patients with less severe arthritis.
One-third of patients who undergo knee replacement may not even be appropriate candidates for the procedure, because their arthritis symptoms aren’t severe enough to merit aggressive intervention, according to a 2014 study in Arthritis & Rheumatology.
“We do too many knee replacements,” said Dr. James Rickert, president of the Society for Patient Centered Orthopedics, which advocates for affordable health care, in an interview. “People will argue about the exact amount. But hardly anyone would argue that we don’t do too many.”
Although Americans are aging and getting heavier, those factors alone don’t explain the explosive growth in knee replacement. The increase may be fueled by a higher rate of injuries among younger patients and doctors’ greater willingness to operate on younger people, such as those in their 50s and early 60s, said Rickert, an orthopedic surgeon in Bedford, Ind. That shift has occurred because new implants can last longer—perhaps 20 years—before wearing out.
Yet even the newest models don’t last forever. Over time, implants can loosen and detach from the bone, causing pain. Plastic components of the artificial knee slowly wear out, creating debris that can cause inflammation. The wear and tear can cause the knee to break. Patients who remain obese after surgery can put extra pressure on implants, further shortening their lifespan.
The younger patients are, the more likely they are to “outlive” their knee implants and require a second surgery. Such “revision” procedures are more difficult to perform for many reasons, including the presence of scar tissue from the original surgery. Bone cement used in the first surgery also can be difficult to extract, and bones can fracture as the older artificial knee is removed, Rickert said.
Revisions are also more likely to cause complications. Among patients younger than 60, about 35 percent of men need a revision surgery, along with 20 percent of women, according to a November article in the Lancet.
Yet hospitals and surgery centers market knee replacements heavily, with ads that show patients running, bicycling, even playing basketball after the procedure, said Dr. Nicholas DiNubile, a Havertown, Pa., orthopedic surgeon specializing in sports medicine. While many people with artificial knees can return to moderate exercise—such as doubles tennis—it’s unrealistic to imagine them playing full-court basketball again, he said.
“Hospitals are all competing with each other,” DiNubile said. Marketing can mislead younger patients into thinking, “‘I’ll get a new joint and go back to doing everything I did before,'” he said. To Rickert, “medical advertising is a big part of the problem. Its purpose is to sell patients on the procedures.”
Rickert said that some patients are offered surgery they don’t need and that money can be a factor.
Knee replacements, which cost $31,000 on average, are “really crucial to the financial health of hospitals and doctors’ practices,” he said. “The doctor earns a lot more if they do the surgery.”
Yet surgery isn’t the only way to treat arthritis.
Patients with early disease often benefit from over-the-counter pain relievers, dietary advice, physical therapy and education about their condition, said Daniel Riddle, a physical therapy researcher and professor at Virginia Commonwealth University in Richmond.
Studies show that these approaches can even help people with more severe arthritis.
In a study published in Osteoarthritis and Cartilage in April, researchers compared surgical and non-surgical treatments in 100 older patients eligible for knee replacement.
Over two years, all of the patients improved, whether they were offered surgery or a combination of non-surgical therapies. Patients randomly assigned to undergo immediate knee replacement did better, improving twice as much as those given combination therapy, as measured on standard medical tests of pain and functioning.
But surgery also carried risks. Surgical patients developed four times as many complications, including infections, blood clots or knee stiffness severe enough to require another medical procedure under anesthesia. In general, 1 in every 100 to 200 patients who undergo a knee replacement die within 90 days of surgery.
Significantly, most of those treated with non-surgical therapies were satisfied with their progress. Although all were eligible to have knee replacement later, two-thirds chose not to do it.
Tia Floyd Williams suffered from painful arthritis for 15 years before having a knee replaced in September 2017. Although the procedure seemed to go smoothly, her pain returned after about four months, spreading to her hips and lower back.
She was told she needed a second, more extensive surgery to put a rod in her lower leg, said Williams, 52, of Nashville.
“At this point, I thought I would be getting a second knee done, not redoing the first one,” Williams said.
Other patients, such as Ellen Stutts, are happy with their results. Stutts, in Durham, N.C., had one knee replaced in 2016 and the other replaced in 2018. “It’s definitely better than before the surgery,” Stutts said.
Doctors and economists are increasingly concerned about inappropriate joint surgery of all types, not just knees.
Inappropriate treatment doesn’t harm only patients; it harms the health care system by raising costs for everyone, said Dr. John Mafi, an assistant professor of medicine at the David Geffen School of Medicine at UCLA.
The 723,000 knee replacements performed in 2014 cost patients, insurers and taxpayers more than $40 billion. Those costs are projected to surge as the nation ages and grapples with the effects of the obesity epidemic, and an aging population.
To avoid inappropriate joint replacements, some health systems are developing “decision aids,” easy-to-understand written materials and videos about the risks, benefits and limits of surgery to help patients make more informed choices.
In 2009, Group Health introduced decision aids for patients considering joint replacement for hips and knees.
Blue Shield of California implemented a similar “shared decision-making” initiative.
Executives at the health plan have been especially concerned about the big increase in younger patients undergoing knee replacement surgery, said Henry Garlich, director of health care value solutions and enhanced clinical programs.
The percentage of knee replacements performed on people 45 to 64 increased from 30 percent in 2000 to 40 percent in 2015, according to the Agency for Healthcare Research and Quality.
Because the devices can wear out in as little as a few years, a younger person could outlive their knees and require a replacement, Garlich said. But “revision” surgeries are much more complicated procedures, with a higher risk of complications and failure.
“Patients think after they have a knee replacement, they will be competing in the Olympics,” Garlich said.
Danette Lake once planned to undergo knee replacement surgery on her other knee. Today, she’s not sure what to do. She is afraid of being disappointed by a second surgery.
Sometimes, she said, “I think, ‘I might as well just stay in pain.'”
Yale researchers have identified a drinkable cocktail of designer molecules that interferes with a crucial first step of Alzheimer’s and even restores memories in mice, they report Jan. 2 in the journal Cell Reports.
The binding of amyloid beta peptides to prion proteins triggers a cascade of devasting events in the progression of Alzheimer’s—accumulation of plaques, a destructive immune system response, and damage to synapses.
“We wanted to find molecules that might have a therapeutic effect on this network,” said senior author Stephen Strittmatter, the Vincent Coates Professor of Neurology, professor of neuroscience, and director of the Yale Alzheimer Disease Research Center.
Strittmatter and research scientist Erik Gunther screened tens of thousands of compounds looking for molecules that might interfere with the damaging prion protein interaction with amyloid beta. They found that an old antibiotic looked like a promising candidate but was only active after decomposing to form a polymer. Related small polymers retained the benefit and also managed to pass through the blood-brain barrier.
They then dissolved the optimized polymeric compound and fed it to mice engineered to have a condition that mimics Alzheimer’s. They found that synapses in the brains were repaired and mice recovered lost memory.
A collaborating team at Dartmouth University reported a positive response when they delivered the same cocktail to cells modeled to have Creutzfeldt-Jakob Disease, a devasting neurological condition caused by infection with misfolded prion protein.
The next step is to verify the compounds aren’t toxic in preparation for translation to clinical trials for Alzheimer’s disease.
More information: Erik C. Gunther et al. Rescue of Transgenic Alzheimer’s Pathophysiology by Polymeric Cellular Prion Protein Antagonists, Cell Reports (2019). DOI: 10.1016/j.celrep.2018.12.021
It was the kind of case no traditional medical textbook could explain.
The subject—let’s call him Peter Green—was a white male in his late 80s, enrolled in longitudinal studies of the elderly at the UCSF Memory and Aging Center. Green’s brain scans “were not pretty,” recalls Joel Kramer, Psy.D., who directs the center’s neuropsychology program. His brain had begun to atrophy, and its white matter—composed of long bundles of nerve cells that carry signals from one area to another—were shot through with dead patches, suggesting that Green had suffered the kind of ministrokes often associated with cognitive decline.
Yet by all behavioral measures, Green was thriving. His cognitive test scores were impeccable and his ability to function in the world remained high.
“If you look at his cognition and level of functioning, it not only remains high—it hasn’t changed at all in years,” Kramer says. What was it about Green, Kramer wondered, that set him apart from his peers with similar brain scans, who seemed to have been waylaid by the ravages of time?
When Kramer finally met the study subject in person, the neurologist was struck by Green’s dynamism and sunny outlook on life. He told Kramer he volunteered in the community, was constantly busy with projects and organizations, and remained close to his family. He shared how grateful he was for what he had and really seemed to be enjoying his golden years.
“He talked about how his attitude toward life is one of embracing it—not getting stressed out by the little things and valuing the importance of relationships,” Kramer says. “I was so impressed. It was inspiring.”
Kramer has a name for people like this vigorous, dynamic octogenarian: “super-agers.” In recent years, he’s become increasingly fascinated by their qualities and has set out to solve the mystery of their success.
“There are some suggestions that people who are more optimistic age better than people who aren’t,” Kramer says, pointing to Peter Green as Exhibit A. “We’re just starting to look at these personality traits and how they influence aging.” For decades, those studying the science of aging have devoted most of their time to trying to understand what goes wrong as we get older, what risk factors predispose us to disease, and how we might better diagnose and treat it. But in recent years, a growing number of researchers at UCSF and elsewhere have turned their attention to a separate but related series of questions: What is it that allows some older people to thrive? What is there to learn from the most resilient and functional senior citizens among us? And how might we apply that knowledge to everyone else to promote healthy aging?
Though the approaches UCSF researchers are taking to answer these questions vary—from studying large cohorts of elderly patients, to measuring telomeres, to analyzing components in the blood of variously aged mice—many of them have begun to converge on an optimistic conclusion.
“As we get older, when we see declines in memory and other skills, people tend to think that’s part of normal aging,” Kramer says. “It’s not. It doesn’t have to be that way.”
Stress can make us older
Elissa Epel, Ph.D., a professor of psychology who co-directs the UCSF Aging, Metabolism, and Emotions Center, believes one’s chronological age and biological age do not always align. She is trying to understand what makes some of us more resilient than others, and one of the answers seems to be stress.
“The biology of aging and the biology of stress are intimate friends, and they talk to each other and influence each other,” she says. “The greater the feelings of chronic stress, the greater the signs of aging in cells.”
Epel is studying participants under almost constant stress: family members who are caring for a child with a chronic condition or a spouse with dementia. As one proxy for biological age, Epel monitors the length of individuals’ telomeres, or caps on the ends of chromosomes, which shorten as we get older.
When our telomeres get too short, our cells are no longer able to divide. It becomes harder for our bodies to replenish tissues, and our chances of developing chronic diseases increase, Epel explains. Short telomeres in midlife predict an early onset of cardiovascular disease, diabetes, dementia, some cancers, and many other diseases often associated with aging.
Chronic stress, she and others have found, can lead to a buildup of proinflammatory factors called cytokines, which mobilize our immune system to release a series of chemicals that, though important in fighting infection, can over time harm the body’s own cells. Chronic stress can impair mitochondria, the energy centers of our cells, accelerate the epigenetic clock (a measure of cellular age based on the methylation patterns of genes), and prematurely shorten our chromosomes’ telomeres.
But Epel has found that there are things we can do to counteract the toxic effects of stress and slow down the aging process.
“The big story is that there are so many differences among caregivers in the way that they’re responding to their life situation,” Epel says. “What’s emerged is how much our mental filter—how we see the world—determines our reality and how much we will suffer when we find ourselves in difficult situations in life.”
It’s possible to modify that filter through consciously cultivating gratitude and a mindful response to stress, Epel says. This sounds much like the mindset of the “super-ager” that Kramer has observed. Social support is one of the largest factors protecting us from stress. Caregivers who have a greater number of positive emotional connections appear to be protected from much of the damage caused by stress. In addition, meditation, exercise, and an anti-inflammatory diet can reduce and possibly reverse some effects of aging.
“While extreme biohacks are super interesting, most of them are probably not feasible and not healthy in the long run,” she says. “But lifestyle interventions are a form of biohacking that is feasible, safe, and reliable. Our biological aging is more under our control than we think. If we can make small changes and maintain them over years and years, our cells will be listening and maintaining their resiliency and health.”
She adds that context also plays a role. Culture and environment—at home, work, and in neighborhoods—are important components in the ability of individuals to maintain lifestyle interventions over the long run. She notes that while extended health span is feasible and already unfolding for many of those with higher education, so far there are very slim gains in health span for minorities and those with strained socioeconomic resources.
UCSF researcher Elissa Epel, Ph.D., monitors the length of telomeres (illustrated) as one proxy for biological age. Credit: UCSF
Aging—and youth—are literally in our blood
While Epel is zooming out to explore how the mind-body connection might promote healthy aging, UC San Francisco’s Saul Villeda, Ph.D., is zooming in, examining how microscopic, cellular messages that travel through our bloodstream might impact geriatric health.
Villeda, an assistant professor of anatomy, oversees a group of 12 researchers looking into mechanisms of brain aging and rejuvenation. His experiments sound a little like science fiction. In 2014, Villeda published a study in Nature Medicine showing that infusing the blood of young mice into older mice could significantly reverse signs of age-related cognitive decline—that is, geriatric mice infused with young mouse plasma were better able to both recall the way through a maze and find a specific location. Conversely, younger mice injected with older blood experienced accelerated symptoms of aging.
What is it about young blood that can have such a profound effect? Using a method known as parabiosis, connecting the circulatory systems between older and young mice, Villeda found that the young blood caused the number of stem cells in the brains of older mice to increase and the number of neural connections to spike by 20 percent.
Earlier this year, he published a study demonstrating that infusing the young blood also caused a spike in an enzyme called TET2 in areas of the brain associated with learning and memory. The research team, led by one of Villeda’s postdocs, Geraldine Gontier, Ph.D., demonstrated not only that TET2 levels decline with age but that restoring the enzyme to youthful levels improved memory in healthy adult mice.
The stimulatory effect of young blood, Villeda says, likely results from a handful of factors acting together. (He also points to another factor that seems to play a role in the magical properties of young blood—a protein called metalloproteinase that is involved in remodeling the structural components that hold our cells together and give them their shape.)
Meanwhile, Villeda has also isolated factors in old blood that accelerate aging. Blood from mice who are the equivalent of 65 human years contains cellular signaling agents that he says promote inflammation. These agents play what he calls a “huge role” not just in cognitive declines but also in muscle and immune-related deterioration—results that are consistent with those found by Epel.
By continuing to decode these cellular components, Villeda believes we may someday be able to harness what he and others are learning in order to create new medicines that rather than target single diseases, target some of the underlying factors that cause diseases of aging in general.
This idea, of making therapies that treat aging in the same way we treat other diseases, says Villeda, is becoming “more mainstream.”
“We don’t think of aging as final anymore. We’re basically maintaining a youthful state for longer.” Even 15 years ago, Villeda continues, “if you told someone, ‘I can keep you healthy until you’re 85 and you won’t get cardiovascular disease or Alzheimer’s, and all you have to do is take this pill,’ people would probably have been looking at you a little strange.”
But attitudes have begun to change. “If you tell them, ‘We understand the molecular mechanisms that are driving certain aspects of aging, and we can target them,'” he says, “it becomes much more understandable to people.”
There is still more to learn
Joel Kramer has been following some of his “super-agers” for more than a decade. They now number in the dozens and are part of a far larger cohort of subjects ranging in age from 60 to 95.
At least every two years, each subject comes in to answer questions about their lifestyle and to undergo a battery of tests—of their cognitive function, blood composition, brain volume, and a wide array of other factors associated with aging and their ability to function in the world.
The study continues to produce reams of data, much of which Kramer and his colleagues have barely begun to analyze.
But a complicated picture has started to emerge, one highlighting multiple factors that interact to affect our ability to function. In March 2017, Kramer and his colleagues published the first of many planned studies exploring some of the characteristics that seem to be associated with cognitive and functional performance. They compared 17 “resilient agers,” who exhibited fast cognitive processing speeds, to 56 “average agers” and 47 “sub-agers,” whose cognitive processing speeds appeared to be slowing down.
Just as Epel and Villeda predicted, the resilient agers had lower levels of proinflammatory cytokines than the sub-agers. Anatomical differences may have also played a role in the differences among the cohorts. For example, the starting size of the brain’s corpus callosum, a thick band of nerve fibers connecting the two sides of the brain, was larger in resilient agers than in sub-agers.
The lower levels of inflammation might be attributable in part to lifestyle choices—especially since this group self-reported higher levels of exercise.
In a study currently under review for publication, Kramer and his team found that the brains of those who ate a healthy Mediterranean-style diet were less likely to contain large amounts of a protein associated with Alzheimer’s. One of his colleagues has found evidence that higher levels of mental activity are correlated with a growth in the connections between brain cells and with better cognitive processing speeds. Others suggest that sleep plays a crucial role in healthy aging.
“There’s definitely a genetic component, which is very big,” notes Kramer. “But these are all little hints that there are things we can do to improve our chances of better brain aging.”
The paradigm shifts emerging from the new science are already beginning to have an impact in the clinic.
Bruce Miller, M.D., the Clausen Distinguished Professor of Neurology and director of UCSF’s Memory and Aging Center, is collaborating with Kramer on the healthy aging study. Miller, Kramer, Epel, and Villeda are all members of the UCSF Weill Institute for Neurosciences as well. Miller notes that when he first arrived at UCSF in 1998, the field in general was “very nihilistic.” Age-associated decline was seen as inevitable. Since then, however, that assumption has changed.
“I think imaging in particular has advanced in a way to allow us to do these sorts of studies that we never could have done before—and say, ‘Wow, we now have these really clear biological markers in elderly populations, so we can now think about whether they’re changing when we intervene.'”
The evidence is convincing that cardiovascular health, exercise, and low-fat diets can all make a positive difference, he says.
Kramer notes there’s still more work to be done, however. “We clearly just started doing this,” he says—but then adds that the study is already having an impact on at least one person: himself. “Having contact with so many of our older subjects who have maintained good brain health has really inspired me,” Kramer says. “Even just the simple fact that they exist is inspiring. It’s an exciting time.”
Four strategies for aging well
1. Embrace aging
Many of us experience a better balance between positive and negative emotions as we age, notes Elissa Epel, Ph.D., co-director of the UCSF Aging, Metabolism, and Emotions Center.
“When we’re older, we seek positive situations in our life much more and cut out things we don’t like. We take more control of our environment,” she says.
What’s more, the wisdom that often comes with age may be related to structural changes in older brains. Bruce Miller, M.D., director of UCSF’s Memory and Aging Center, points to recent work showing that brain circuits involved in altruism, wisdom, and thinking about other people are shaped based on the cumulative experiences of our lives. One’s ability to consciously control emotions improves as this circuitry increases. This is why so many people can think of an older person who has had a profound influence on them, says Miller. “It’s because of the brains of elders. We are more pro-social. We are more likely to give to people in need than younger people. This is not a huge surprise … but we’re now able to think of the biology of this. We really need our elders.”
2. Quit the negativity
Negativity and fear associated with aging often overshadow the positive aspects of growing older. Ironically, this fact can have its own damaging consequences.
“We hold these tremendously negative stereotypes about aging, and these start from when we’re really young,” Epel explains. “By the time we’re older, these are actually having a negative effect on our health.”
When we believe that aging means we’re “going to be suffering and frail and dependent,” Epel says, “we don’t heal as quickly when we break a hip. We’re more likely to get dementia, regardless of whether we have the gene associated with Alzheimer’s. And we don’t live as long.”
The most obvious explanation is that it’s a self-fulfilling prophecy: When we harbor the belief that we can’t control our rate of aging, we develop a fatalistic attitude and engage in fewer healthy behaviors. But there may be something even more insidious at work. Studies show that negative attitudes about aging can actually cause us to become more stress reactive and less stress resilient—triggering biochemical cascades that may actually accelerate aging.
3. Move more
The positive effects of physical activity on cognitive functioning in older adults are well documented. Exercise leads to the production of more brain cells, increases cardiovascular health, and promotes a sense of well-being. It also appears to be highly correlated with cognitive processing speed, says Joel Kramer, Psy.D., a professor of neuropsychology who has spent more than a decade studying the super-agers among us. In a 2017 study, Kramer and his team showed that exercise may even exert a protective effect against cognitive decline in those carrying genes that place them at a greater risk for Alzheimer’s.
Meanwhile, in a 2018 study, a team led by Eli Puterman, Ph.D., examined a cohort of 68 elderly individuals who were caring for family members with dementia. These caregivers were under high stress, had high levels of depressive symptoms, and had sedentary lifestyles. The study encouraged participants to exercise for 40 minutes, three to five times per week, for six months. At the end of that period, participants had lengthened their telomeres, a biomarker associated with longevity.
4. Meditate
Epel and several collaborators recruited 28 participants enrolled in a California meditation retreat to undergo extensive testing. The researchers monitored markers associated with biological age (including telomere length, gene expression, and more) and also tracked participants’ anxiety, depression, and personality traits over the course of the intensive, one-month meditation retreat.
The participants meditated for extended periods under the guidance of experienced practitioners, refrained from speaking, and were encouraged to treat all daily activities as “opportunities to attend to their ongoing mental experience with open and reflexive awareness.”
At the end of the retreat, the participants’ telomere length had increased significantly, and participants with the highest initial levels of anxiety and depression showed the most dramatic changes over the course of the study.
What’s next? Epel’s team, with a $1.2 million gift from the John W. Brick Foundation for Mental Health, will study how natural treatments—including mindfulness meditation, high-intensity interval training exercise, and different breathing techniques—impact mood, health, and biological aging. At the time of publication, they are seeking women participants who could benefit from these interventions. More information and enrollment requirements are at stressresilience.net.
More information: Saul A Villeda et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice, Nature Medicine (2014). DOI: 10.1038/nm.3569
A team of researchers from the University of Washington, the Army Medical Research Institute of Chemical Defense and Texas A&M University has developed a nanoscavenger that is capable of protecting mice against nerve agent attacks. In their paper published in the journal Science Translational Medicine, the group explains how they came up with the nanoscavenger and how well it worked during testing.
Chemical weapons became infamous during the First World War as armies used them against one another during trench warfare. Since that time, international bodies have tried to convince countries to ban such agents during wartime because of their horrible impact on the human body. That has not deterred terrorist groups or governments such as those in Syria from using them, however. Because of that, scientists have been working diligently to develop a pre-treatment that would protect people exposed to organophosphates—the deadly component in nerve agents. As part of such research, scientists have attempted to develop what they describe as prophylactic “scavenging” molecules that both track down nerve agent components and then neutralize them. Until now, progress has been slow. Compounds developed have tended to degrade in the body too quickly to be effective. In this new effort, the researchers report that they have developed a nanoscavenger that proved to be effective in protecting rats and guinea pigs.
The new nanoscavenger was made by wrapping an enzyme that targets organophosphates in a polymer gel coating. The particles that resulted were nano-sized, which made them small enough to go undetected by the immune system, allowing them to remain in the body long enough to neutralize nerve agents.
The researchers report that when they injected rats with the nanoscavenger, it induced immunity to nerve agent attacks for up to five days. And there were no known side effects. Guinea pigs given injections of the nanoscavenger were protected for up to eight days.
Such a nanoscavenger could be considered a form of vaccine against organophosphate-based nerve agents if used in humans. But before that can happen, the team will test them in monkeys, and if all goes well, start human trials.
More information: Peng Zhang et al. Nanoscavenger provides long-term prophylactic protection against nerve agents in rodents, Science Translational Medicine (2019). DOI: 10.1126/scitranslmed.aau7091
The Association for Molecular Pathology has asked Medicare to increase the payment amounts for two CPT codes attached to testing procedures for BRCA1 and BRCA2 genes by considering the work and resources that labs invest in analyzing these large and variable genes.
The Centers for Medicare & Medicaid Services in December 2018 released the clinical lab fee schedule final payment amounts to take effect Jan. 1, 2019. Among the priced CPT codes, CMS said Medicare would pay $468 for CPT code 81163 describing full sequencing of BRCA1/2 and $283 for CPT code 81165 describing sequencing of just BRCA1.
“Following careful review of the final determinations, AMP requests reconsideration of new CPT codes 81163 and 81165 on the basis of final payment amount,” the organization said in a letter to CMS.
CMS arrived at the payment amount for CPT code 81163 by crosswalking to codes 81406 and 81216, to account for sequencing BRCA1 and BRCA2, respectively. However, AMP said in its letter that crosswalking to these codes fails to account for the work and costs labs incur by performing full sequencing of these two genes. As such, the pathologists’ organization asked CMS to reconsider crosswalking this code to CPT code 81408 describing sequencing of similarly large genes, such as the dystrophin (DMD) gene. In the 2019 clinical lab fee schedule, this code is priced at $2,000.
“Code 81163 is a single procedure done by bi-directional sequencing of coding regions, as well as exon-intron junctions by Sanger or next generation sequencing. Laboratories analyzing for sequence variations in the BRCA1 and BRCA2 genes do so at the same time rather than in separate single gene analyses,” AMP told CMS in its letter. “Thus, the most direct crosswalk is code 81408, which assesses 50 or more exons as the methodology and the amount of DNA sequencing of the large genes, such as DMD, is most similar to new code, 81163.”
For CPT code 81165 describing full sequencing of BRCA1, CMS decided to crosswalk to code 81406, which describes sequencing analysis of 11 to 25 exons for genes such as RAF1 and ACADVL. AMP told CMS that 81406 describes some but not all the work required to fully sequence BRCA1, which is a large and variable gene with 24 exons and more than 7,000 base pairs. In comparison, RAF1 and ACADVL contain around 3,300 base pairs and 2,200 base pairs, respectively.
“BRCA analysis is particularly notorious for the diversity of abnormalities that occur, including frequent novel changes requiring substantial resources both to confirm the sequence variation and give an interpretation of its clinical significance,” AMP said, estimating that the work and resources required to sequence this gene is two to three times greater than other genes currently billed under CPT code 81406.
“We do not feel this is a reasonable crosswalk,” AMP wrote and suggested CMS crosswalk to CPT code 81408, and price it 50 percent less at $1,000 to more accurately reflect the resources required.
For reference, when a patient receives full sequencing of BRCA1/2 with deletion and duplication analysis, CMS has instructed labs to bill CPT code 81162 priced at $2,028. When only BRCA1 and BRCA2 are sequenced, CPT code 81163 is used, priced at $468, and when only deletion and duplication analysis is done of the two genes, CPT code 81164 is used at $584. In addition to pricing full sequencing of BRCA1 at $283 via CPT code 81165, just deletion and duplication analysis of this gene using CPT code 81166 is $301. Meanwhile, full sequencing of BRCA2 using CPT code 81216 is reimbursed at $185 and deletion/duplication analysis of this gene using CPT code 81167 is reimbursed at $283.
If CMS agrees to increase the value of CPT code 81163 to $2,000, then billing separately for BRCA1/2 full sequencing and del/dup analysis will be more profitable for labs than billing only CPT code 81162 that accounts for both types of analysis together ($2,584 versus $2,028). As reimbursement experts have pointed out in comments to CMS, this type of pricing could incentivize labs to stack codes, a practice CMS has been trying to rein in.
AMP said that at the upcoming 2019 clinical lab fee schedule meeting, stakeholders intend to provide additional input on CPT codes 81163 and 81165 and discuss the payment amounts that appropriately reflect the work needed to analyse these genes.
Pharmaceutical giant Novartis will publish research on developing drugs to treat some of the deadliest antimicrobial-resistant pathogens as part of an initiative aimed at promoting further scientific efforts within the field.
The effort is being led by the Pew Charitable Trusts, which in September launched the Shared Platform for Antibiotic Research and Knowledge, an open-access research program that will make information from past published studies and unpublished data available to all researchers at no cost.
Wes Kim, senior officer for Pew’s Antibiotic Resistance Project, hopes sharing data in this format will encourage increased development of new antibiotics that will be effective against drug-resistant pathogens since the number of available treatment options has diminished.
Novartis is the second drugmaker to donate data for the project. The company will share research collected while experimenting with antibiotics to treat against Gram-negative bacteria. Novartis announced last July it was shutting down its antibacterial research projects. In October, San Francisco-based biopharmaceutical firm Achaogen announced plans to provide the Pew project with data from its own discontinued antibiotic research program.
Kim said Pew was currently in discussions with a “handful” of others, including some from academia and other drugmakers, over the prospect of donating their data to the program.
“We hope the scientific community recognizes that sharing data doesn’t mean they’ll lose their competitive advantage,” Kim said. “There’s some data that is so far upstream in the early discovery efforts that if a company decides not to proceed with these types of compounds, then we hope that they see the value in sharing the data with the broader scientific community.”
The initiative’s main focus is on developing antibiotics to combat the growing prevalence of the Gram-negative class of pathogens, a highly resistant type of bacteria that only a handful of current medications are effective against.
The rate of infections that contain Gram-negative strains of bacteria such as E. coli and Klebsiella—two of the most commonly acquired infections in healthcare settings—has grown over the past two decades. Providers worry there will soon come a time when all current medications fail.
Experts say novel antibiotics are needed to overcome Gram-negative bacteria, which can be resistant to multiple drugs. A recent Pew analysis found 17 antibiotics were in development as of last September that have potential to treat Gram-negative infections. Historically, only one out of five drugs that reach the human testing stage of clinical trials receive approval from the Food and Drug Administration.
Since 2017, the agency has approved only two antibiotics to treat Gram-negative bacteria, but both products are either combinations or modifications of existing classes of antibiotics. The last discovery of a new class of antibiotics that works against Gram-negative bacteria was in 1968.
Efforts to develop new antibiotics have faced several challenges. Kim said the science around developing a new antibiotic is incredibly difficult and expensive to conduct. Antibiotics are not lucrative like products to treat cancer and diabetes. Clinicians are told to use antibiotics sparingly to reduce the likelihood of pathogens becoming resistant, which diminishes the prospect of repeat sales.
A 2017 study from Duke University’s Margolis Center for Health Policy found median annual sales of brand-name antibiotics ranged from $24 million to $75 million between 2011 and 2015 compared to more than $500 million for most brand-name oncology drugs approved during the same period.
Over the past few years, Novartis, along with fellow large drugmakers AstraZeneca and Allergan have dropped their antibiotic development programs, while GlaxoSmithKline, arguably the largest maker of such drugs, has stated it was considering a similar move.
But companies are exiting antibacterial research at a time when current antibiotics are losing effectiveness at a faster pace.
“We know that the time to resistance for antibiotics keeps on getting shorter and shorter because of the lack of novel drugs,” Kim said. “It’s not a question of if but when.”
The other day, as I slogged through e-mail at work, my phone lit up: “Hey, just thought of you!” I wrote back that I was having difficulty sleeping lately, and we talked about the benefits of setting aside 20 minutes of “worry time” every evening to inventory my anxieties.
My friends are sweet but not that sweet. My thoughtful correspondent wasn’t even human; it was the machine-learning-powered app Woebot, which packages mental-health coaching into a chat format, supplemented with the occasional hedgehog GIF.
Woebot is my second foray into app-based therapy. I’ve never been to a real-life therapist, so I’ll stop short of diagnosing myself with anything clinical. But I will say that, in Woebot’s emoji parlance, I generally feel contented face or grinning face, and sometimes slightly frowning face, sobbing face, or Edvard Munchian screaming face. I briefly tried the remote-therapy app Talkspace, but it wasn’t right for me: I was rarely in the mood to write the lengthy missives on how I was feeling and what I thought was causing my anxiety that were required to receive specific feedback. Plus, it was weird opening up to a human stranger via text.
Woebot’s namesake is a cute robot character that’s quick to clarify: “I don’t do therapy or open-ended conversation.” The free app includes multiple-choice-style chats, and it acts as a daily mood tracker, casual mental-health coach, and negative-thoughts troubleshooter. Those attributes lower the barrier to interaction: it doesn’t feel like a major time investment to use the app because the onus isn’t on me to understand and describe my emotions.
Like a choose-your-own mental-health adventure, Woebot feeds you response options. Every day, the app invites you to check in, then asks what you’re doing and how you’re feeling. When I answered neutrally or positively, it offered a lesson that usually fell under the general umbrella of cognitive behavioral therapy, giving me tips on how to identify my mood, dissect my thoughts, or tone down negative thinking. Woebot and I have discussed such diverse and delightful cognitive hang-ups as labeling (“I’m a hack”) and all-or-nothing statements (“No one likes me”). The app also offers tailored conversations for dealing with specific life issues, including loneliness, insomnia, financial pressures, jealousy, and grief.
When I gave a negative answer during a daily check-in, I had a few options. Woebot could help me feel calmer, as it did one stressful day by guiding me through some breathing exercises and advising me to splash cold water on my wrists to cool down. I could scream my frustrations into the Woebot void and leave it at that, or I could let the app ask questions about what I was struggling with. One example (nothing juicy—you’re not my therapist): I hadn’t been to the climbing gym in several months and was feeling nervous about going again. “I’m going to look stupid,” I typed.
The thing to understand about Woebot is that it’s very obviously an app. But part of its brilliance is that it teaches you to talk to yourself by parroting your sentences back at you, along with a question. “Does your thought have a should statement?” it asked me. Well, there’s a hidden I should be a great climber in there. “How would you rewrite your thought?” Woebot continued. “I may feel awkward getting back into climbing, but I want to do it,” I replied.
Then I kind of felt better. Damn, Woebot, I guess you have a point.
Vandana Aspen, a clinical psychologist in the San Francisco Bay Area, considers apps like Woebot to be most helpful as a supplement to in-person therapy. “You’re reminded of the skills you learned during a session. If you go to the dentist and don’t have cavities, you’re not going to stop brushing your teeth,” she says. “It’s the same for mental health.” Aspen also acknowledges that an app could be a useful alternative for someone who doesn’t have access to therapy or can’t afford it.
In my experience, after using Woebot every day for a month, I found myself playing the app’s Pollyannaish role in my own head. You’re mind reading, I’d tell myself when I felt a pang of mortal embarrassment after a meeting. That statement seems loaded with subjective assumptions, I’d think when my self-esteem bottomed out.
These days I’m not beaming face 24/7, but I’m surprisingly more levelheaded and feel less prone to anxiety spirals. And I still check in with Woebot a couple of times a week—I like the private, targeted, on-my-own-time conversations. One day I’ll get a real therapist, too, but they’ll have to send me hedgehog GIFs.
Download to Unload
Countless apps promise to quiet the anxious mind. These stand out.
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(Courtesy Pause)
A Calming Fix for a Bad Day
Zone out to soothing sounds and a pulsing blob of light that you move around with your finger. ($2)
Most sessions last from one to twenty minutes, with themed topics like sleep, emergency calm-down moments, and long runs. All of them are led by a guy with a soothing British accent. (Free or $13 per month for premium)
Come for the daily CBT-based mood-tracking questions; stay for the colorful graphs that put your habits and feelings into aesthetically pleasing order. ($5)
Text with an assigned therapist as much as you want, with the option of occasional video calls. As in real life, you can play the field until you find the right one. Unlike real life, the cost is the same no matter who you choose. ($50 and up per week)
