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Behavioral Science, Chronic Disease, Mental Health, Neuroscience, Research, Stanford News

Can Alzheimer’s damage to the brain be repaired?

Can Alzheimer's damage to the brain be repaired?

repair jobIn my recent Stanford Medicine article about Alzheimer’s research, called “Rethinking Alzheimer’s,” I chronicled a variety of new approaches by Stanford scientists to nipping Alzheimer’s in the bud by discovering what’s gone wrong at the molecular level long before more obvious symptoms of the disorder emerge.

But Stanford neuroscientist Frank Longo, MD, PhD, a practicing clinician as well as a researcher, has another concern. In my article, I quoted him as saying:

Even if we could stop new Alzheimer’s cases in their tracks, there will always be patients walking in who already have severe symptoms. And I don’t think they should be forgotten.

A study by Longo and his colleagues, which just went into print in the Journal of Alzheimer’s Disease, addresses this concern. Longo has pioneered the development of small-molecule drugs that might be able to restore nerve cells frayed by conditions such as Alzheimer’s.

Nerve cells in distress can often be saved from going down the tubes if they get the right medicine. Fortunately, the brain (like many other organs in the body) makes a number of its own medicines, including ones called growth factors. Unfortunately, these growth factors are so huge that they won’t easily cross the blood-brain barrier. So, the medical/scientific establishment can’t simply synthesize them, stick them into an artery in a patient’s arm and let them migrate to the site of brain injury or degeneration and repair the damage. Plus, growth factors can affect damaged nerve cells in multiple ways, and not always benign ones.

The Longo group’s study showed that – in mice, at least -  a growth-factor-mimicking small-molecule drug (at the moment, alluded to merely by the unromantic alphanumeric LM11A-31) could counteract a number of key Alzheimer degenerative mechanisms, notably the loss of all-important contacts (called synapses) via which nerve cells transmit signals to one another.

Synapses are the soldier joints that wire together the brain’s nerve circuitry. In response to our experience, synapses are constantly springing forth, enlarging and strengthening, diminishing and weakening, and disappearing.They are crucial to memory, thought, learning and daydreaming, not to mention emotion and, for that matter, motion. So their massive loss — which in the case of Alzheimer’s disease is a defining feature – is devastating.

In addition to repairing nerve-cells, the compound also appeared to exert a calming effect on angry astrocytes and  microglia, two additional kinds of cells in the brain that, when angered, can produce inflammation and tissue damage in that organ. Perhaps most promising of all, LM11A-31 appeared to help the mice remember where things are and what nasty things to avoid.

Previously: Stanford’s brightest lights reveal new insights into early underpinnings of Alzheimer’s, Stanford neuroscientist discusses the coming dementia epidemic and Drug found effective in two mouse models of Huntington’s disease
Photo by Bruce Turner

Cancer, Research, Stanford News, Surgery, Women's Health

Breast cancer patients are getting more bilateral mastectomies – but not any survival benefit

Breast cancer patients are getting more bilateral mastectomies - but not any survival benefit

woman looking out window2The most common cancer diagnosis you or a woman you love is likely to receive is early stage breast cancer, probably after detection by mammogram. One would think that given the regularity with which it’s diagnosed, treatment options for early stage breast cancer would be streamlined. Unfortunately, this isn’t the case.  There’s a staggeringly large menu of potential surgeries and treatments from which a patient and her doctor must choose, each with their own risks and benefits. Not including all of the different hormone blocking and chemotherapies, patients must pick one of three surgeries, shown here in order of escalating invasiveness and risk of complication:

  • Breast-conserving surgery (removal of the tumor only), followed by radiation
  • Single mastectomy (removal of the entire affected breast and any affected lymph nodes)
  • Bilateral mastectomy (the above plus the the unaffected breast)

One also would assume that the medical evidence base providing the benefits to the risk/benefit equations for each surgery would be large and up-to-date. Surprisingly, it is not. The randomized trials comparing lumpectomy and single mastectomy were conducted 30 years ago, and they showed similar risks of death. There has not been (and probably will never be) a randomized trial comparing bilateral mastectomy to one of the less invasive choices for healthy women. Angelina Jolie and other women positive for the breast cancer genes (BRCA1 and BRCA2) are in a different situation. For these women, clinical studies have observed a survival benefit after prophylactic mastectomy. For the 99 percent of women without mutations in these or other high-risk genes, existing trial data do not speak to current trends.

Even after accounting for [numerous factors], we found no evidence of lower mortality for women who had bilateral mastectomy in comparison to breast-conserving surgery

The complexity of choosing a breast cancer surgery – and how evidence should play into that choice – has been a hot topic in the last two months, after the publication of a large study calculating (based on predictive models) that bilateral mastectomy ultimately provides little to no improvement  in life expectancy as compared to a single mastectomy. Soon thereafter, on the New York Times’ opinion page, journalist Peggy Orenstein discussed the emotional reasons why women remove their remaining healthy breast, but firmly labeled bilateral mastectomy as  the wrong approach to breast cancer, saying, “It’s hard to imagine… that someone with a basal cell carcinoma on one ear would needlessly remove the other one ‘just in case’ or for the sake of ‘symmetry’.” Other journalists shared why they chose bilateral mastectomy knowing that it wouldn’t necessarily save their life.

To improve the evidence regarding outcomes after the three surgery types, our team at the Stanford Cancer Institute and the Cancer Prevention Institute of California used one of the largest cancer databases available: the cancer registry for the entire state of California. We tracked all 189,734 women diagnosed with stages 0-III breast cancer from 1998-2011 to learn which surgeries they were undergoing for breast cancer treatment and how long they survived afterwards.  These are all women who should have been eligible for breast conserving surgery with radiation. Our results were published today in the Journal of the American Medical Association today and have already received media attention.

We found that bilateral mastectomy for early stage breast cancer increased from 2 percent in 1988 to more than 12 percent in 2011.  The rate of increase was fastest among women younger than age 40 at diagnosis, among whom over one-third of those diagnosed in 2011 had a bilateral mastectomy. Bilateral mastectomy was more often chosen by non-Hispanic white women, those with private insurance, and those who received care at a National Cancer Institute-designated cancer center; while unilateral mastectomy was more often chosen by non-white women and those with public/Medicaid insurance. Even after accounting for characteristics of the women themselves, their tumor types, and their hospitals, we found no evidence of lower mortality for women who had bilateral mastectomy in comparison to breast-conserving surgery. Surprisingly, we found that women who underwent unilateral mastectomy had higher mortality than those who had the other two surgery types. We concluded that despite the growing popularity of bilateral mastectomy, it likely does not provide a better outcome than a less invasive procedure.

These data and the public response to them underscore the need for more updated and more personalized information regarding outcomes after common surgeries. Ideally, these would be accessible real-time by patients and their doctors in easily-understood formats.

Christina A. Clarke, PhD, is a Research Scientist and Scientific Communications Advisor for the Cancer Prevention Institute of California, and a member of the Stanford Cancer Institute.

Previously: At Stanford event, cancer advocate Susan Love talks about “a future with no breast cancer”, Exploring the reasons behind choosing a double mastectomy and Researchers unsure why some breast cancer patients choose double mastectomies
Photo by Alex

Nutrition, Obesity, Research, Stanford News

When it comes to weight loss, maintaining a diet is more important than diet type

When it comes to weight loss, maintaining a diet is more important than diet type

bathroom_scaleSelecting a weight-loss plan can be tricky. Everywhere you look, media reports bombard you with stories about how Jennifer Hudson lost 80 pounds by joining Weight Watchers, Sharon Osbourne shed 23 pounds on the Atkins diet, and other A-listers slimmed down on the Zone Diet. And then there’s that close friend who dropped three dress sizes after following the South Beach Diet. How do you determine which dieting plan is the most effective?

To answer this question, Edward Mills, PhD, a visiting associate professor at Stanford, and colleagues completed a network meta-analysis of 48 randomized trials of brand-name diets, which included a total of more than 7,200 overweight or obese adults. In addition to those mentioned above, researchers also evaluated six other diets: Ornish, Vulumetrics, Jenny Craig, Rosemary Conley, Biggest Loser and Nutrisystem. The diets were divided into three categories —  low-carb, low-fat and moderate macronutrient.

The diet that a person can maintain for the long term, or for as long as possible, is the most effective weight-loss plan

Overall, the study showed that if people stuck to their diets (no matter the type) they lost weight, but ultimately the “weight-loss differences between individual diets were minimal and largely unimportant,” according to Mills. The study authors concluded that the diet that a person can maintain for the long term, or for as long as possible, is the most effective weight-loss plan. They also found that exercise and behavioral support can enhanced weight loss.

Interested to know more about the research, I reached out to Mills, who explained how the evidence failed to support recommending a specific diet and discussed the potential of being able to combine diets to achieve lasting weight loss without having to maintain strict eating habits.

Why did you and your colleagues complete a comparison study of popular diets?

There is a massive weight-loss industry that promotes different diets that are marketed in different ways. Some diets are promoted as being more medical, such as the Ornish diet, while others target people according to lifestyle, for example the South Beach diet. With all the promotion of different diets occurring and people discussing what they believe works or does not work, we wanted to examine whether the clinical trial evidence demonstrated superiority of any particular diet, a strategy we are calling “evidence-based dieting.”

In the study, individuals on a low-carb and low-fat diet lost the most weight (8 kg over six months), compared to those who were not on any diet. Why are these diets not considered to be the most effective of those studied?

These diets do appear to offer the largest weight-loss benefits, but the difference between the different diets was so small that other issues begin to be more important. We looked at the diets using two different analyses. First, we grouped diets according to their type of diet, called a class, and then examined whether the individual diet resulted in different outcomes. Although we found differences according to the classes of diets, these were not really observed when we examined the individual diets. So at this point, we can’t recommend any particular diet over another. But those that are low carb or low fat are preferable.

What did you find most surprising about the study results?

What is most surprising about the results is that the individual diet a person chooses doesn’t seem to be the most important aspect of dieting, instead maintaining a diet is. Some people have a lot of difficulty adhering to a diet because they find the particular diet too difficult to maintain, such as avoiding carbs if they’re trying the Atkin’s diet. It appears that if all diets offer more or less the same benefits, then people should be able to switch between diets when they need to. This approach may be really helpful in adhering to dieting in general.

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Research, Surgery, Technology

Replicating the sensitivity of human touch in robots

Replicating the sensitivity of human touch in robots

A piece published today in the New York Times examines the importance of replicating the sensitivity of human touch in designing the next generation of robots. Noting that the Stanford Artificial Intelligence Laboratory designed the first robotic arm in the 1960s, reporter John Markoff offers a look at ongoing research around campus, and elsewhere, involving robotics:

Consider Dr. Nikolas Blevins, a head and neck surgeon at Stanford Health Care who routinely performs ear operations requiring that he shave away bone deftly enough to leave an inner surface as thin as the membrane in an eggshell.

Dr. Blevins is collaborating with the roboticists J. Kenneth Salisbury andSonny Chan on designing software that will make it possible to rehearse these operations before performing them. The program blends X-ray andmagnetic resonance imaging data to create a vivid three-dimensional model of the inner ear, allowing the surgeon to practice drilling away bone, to take a visual tour of the patient’s skull and to virtually “feel” subtle differences in cartilage, bone and soft tissue. Yet no matter how thorough or refined, the software provides only the roughest approximation of Dr. Blevins’s sensitive touch.

“Being able to do virtual surgery, you really need to have haptics,” he said, referring to the technology that makes it possible to mimic the sensations of touch in a computer simulation.

Markoff goes on to discuss advances in haptics, “a science that is playing an increasing role in connecting the computing world to humans.”

Previously: Stanford surgeon uses robot to increase precision, reduce complications of head and neck procedures, CyberKnife: From promising technique to proven tumor treatment and Stanford researchers develop flexible electronic skin

Mental Health, Nutrition, Obesity, Research, Women's Health

Stressed? You could be burning fewer calories

Stressed? You could be burning fewer calories

cupcakesBad news, ladies: Findings (subscription required) recently published in Biological Psychiatry show that women who consumed comfort food while feeling stressed burned fewer calories than their zen-like counterparts.

In the study, Ohio State University researchers quizzed a group of women about what was causing stress in their lives before they ate a caloric meal consisting of eggs, turkey sausage, biscuits and gravy. Scientific American reports:

Turns out that the most stressed women had higher levels of insulin. Which slows down metabolism and causes the body to store fat. And that fat, if not burned off, accumulates in the body.

The women who had reported feeling stressed or depressed in the day before eating the meal burned 104 fewer calories during the seven hours following the meal than women who felt more mellow.

If eating high-calorie comfort food to alleviate stress becomes habitual, the result could be an average weight gain of 11 pounds per year.

So next time you’re feeling overwhelmed and exhausted, you might want to reconsider reaching for a cupcake.

Previously: Learning tools for mindful eating, Mindful eating tips for the desk-bound and Want to curb junk food cravings? Get more sleep
Photo by Class V

Autoimmune Disease, Chronic Disease, Health and Fitness, Research, Technology

Video game accessory may help multiple sclerosis patients reduce falls, boost brain connections

Wii_balance_boardNintendo’s Wii Balance Board has helped get people off the couch and moving as they play aerobic video games like Super Hula Hoop or Dance Dance Revolution. Now a study published this week in Radiology shows that the video game console’s balance board may help reduce multiple sclerosis (MS) patients’ risk of falls by rewiring their brains.

In a small study, researchers used an MRI technique called diffusion tensor imaging to analyze changes in the brain of MS patients that used the Wii Balance Board while playing video games for 30-40 minutes a day five days a week.

According to a recent Forbes post:

MRI scans in the MS patients in the study demonstrated significant growth of nerve tracts which are integral in movement as well as balance. It turns out that the changes seen on MRI correlated with improvements in balance as measured by an assessment technique called posturography.

These brain changes in MS patients are likely a manifestation of neural plasticity, or the ability of the brain to adapt and form new connections throughout life, said lead author Luca Prosperini, M.D., Ph.D., from Sapienza University in Rome, Italy.

”The most important finding in this study is that a task-oriented and repetitive training aimed at managing a specific symptom is highly effective and induces brain plasticity.”

“More specifically, the improvements promoted by the Wii balance board can reduce the risk of accidental falls in patients with MS, thereby reducing the risk of fall-related comorbidities like trauma and fractures,”

 added Prosperini.

Researchers cautioned that the improvements in balance did not persist after patients stopped playing the video games, suggesting that patients will need to continue their training in order benefit from the intervention.

Previously: Study analyzes video game-related injuries and Comparing the Wii Fit board to a clinical force platform
Photo by Joachim S. Müller

Applied Biotechnology, Parenting, Pediatrics, Research, Sleep, Stanford News, Technology

Biodesign fellows take on night terrors in children

Biodesign fellows take on night terrors in children

baby on bed

Standing in the Clark Center’s grand courtyard, gazing upward at scientists ascending an outdoor staircase and traversing the exterior corridors on the top two floors, one senses that big ideas take shape here. But how?

Prototyping, say Andy Rink, MD, and Varun Boriah, MS, who spent the last year as Biodesign fellows. Part of Stanford’s Bio-X community, the Biodesign Program trains researchers, clinicians and engineers to be medical-technology innovators during its year-long fellowship. Fellows learn the Biodesign Process, which could be likened to design thinking for health care. On teams of two or four, the fellows identify a substantial health-care need and generate ideas to solve it using medical-device innovation.

Though most Biodesign projects take root after fellows complete a “clinical immersion” shadowing health-care workers in a hospital to observe problems, Rink found his inspiration when visiting family and waking up to a 3-year-old relative’s screams from recurring night terrors. The problem was not so much that it affected the child – pediatricians may advise that children will likely outgrow the condition – but that it affected the parents, Rink saw.  The parent’s lost sleep and anxiety over their child’s well being had huge effects on their quality of life. (In some cases, these are so severe that Xanax and Valium may be prescribed to the children as a last-ditch effort.) What if a treatment could be found that involved no medication and no parental intervention, offering everyone a solid night’s sleep?

The physician and engineer are working with School of Medicine sleep researchers Christian Guilleminault, MD, professor of psychiatry and behavioral sciences, and Shannon Sullivan, MD, clinical assistant professor of psychiatry and behavioral sciences, on a clinical method to treat night terrors in children. In a first-floor room of the Clark Center, they’re protoyping an under-mattress device that senses how deeply a child is sleeping and is able to prevent the nightly episodes from occurring, creating a healthier sleep cycle for the children.  This relieves the parent’s anxiety, and helps the entire family sleep better.

Faculty and students from more than 40 departments across Stanford’s campus, including the schools of medicine, business, law, engineering and humanities and sciences, play a role in Biodesign, as do experts from outside the university. Fellows work closely with the Institute of Design at Stanford, attending – and then teaching – the school’s d.bootcamp. They also have access to the d.school’s facilities and consult regularly with their faculty. Some of the d.school’s methods – focusing on big problems, encouraging radical collaboration, prototyping early and user-testing before focusing on functionality – guide the trajectory of Biodesign projects.

Physicians who are Biodesign fellows often work outside their specialty, and engineers bring a mix of academic and industry experience to the design table. While faculty mentors may simply provide advice to fellows, Guilleminault and Sullivan have become invested in the course of the research as lead investigators on the study. For their involvement, they were both honored with the Biodesign Specialty Team Mentorship Award.

Fellow Boriah noted that medical-device innovation is moving from products like catheters to systems such as health IT, mobile health and software. A former CEO and co-founder of a wearable patient blood-diagnostics device, he said the Biodesign program has provided valuable “access to clinical reality.” Rink, a surgical resident at Northwestern University, said that as a fellow, he’s been “exposed to a side you don’t see in a hospital.”

The researchers are currently recruiting participants ages 2-12 for their study. Rink and Boriah are also working with the Stanford-supported StartX to see their project into the next stage of development.

Previously: Sleep, baby, sleep: Infants’ sleep difficulties could signal future problemsStudying pediatric sleep disorders an “integral part” of the future of sleep medicine and At Med School 101, teens learn that it’s “so cool to be a doctor” 
Photo by MissMayoi

Behavioral Science, In the News, Research

Does non-conformity fuel creativity?

Does non-conformity fuel creativity?

IMG_8143When you think about it, visionaries and inventors like Steve Jobs and Steve Wozniak became as well-known for bucking the system and creating controversy as they were for Apple computers. And Galileo Galielei, who was pivotal in the development of modern astronomy, spent the last years of his life under house arrest for his divergent scientific views.

Historically, innovation and acceptance have not gone hand in hand. A recent article in Psychology Today looks at three studies that theorize about the idea that social rejection, for people who have an independent self image, may fuel creativity.

From the piece:

Across three studies, Sharon Kim, Lynne Vincent, and Jack Goncalo explicitly rejected participants by telling them they were not selected to be in a group. In another condition, they told participants they would join the group after completing some tasks. After either being rejected or accepted, participants were then given 7 minutes to complete a measure of creativity called the Remote Associations Test (RAT), in which they were asked to find a word that connects three seemingly unrelated words (e.g., fish, mine, and rush; see answer at the end)…

…The results suggest that rejection may not merely be a result of the unconventionality of creative people but that the actual experience of rejection may promote creativity. What’s more, the effects depend on a person’s self-concept. For those who are highly invested in belonging to a group by affirming their feelings of independence, rejection may constrain them. But for those scoring sky high in a need for uniqueness, the negative consequences of rejection on creativity may be mitigated and even reversed.

All of these results suggest that rejection may not merely be a result of the unconventionality of creative people but that the actual experience of rejection may promote creativity. What’s more, the effects depend on a person’s self-concept. For those who are highly invested in belonging to a group by affirming their feelings of independence, rejection may constrain them. But for those scoring sky high in a need for uniqueness, the negative consequences of rejection on creativity may be mitigated and even reversed.

While rejection and isolation aren’t pleasant, and are actually things many of us actively avoid, it seems there could be great benefit in becoming aware of how we respond to these things. Do we let them define us or use them to our advantage to stimulate growth and self-esteem?

Previously: To get your creative juices flowing, start movingMedicine X symposium focuses on how patients, providers and entrepreneurs can ignite innovation and Stanford Medicine X partners with IDEO to create design challenge
Photo By: Lloyd Dangle

Big data, Evolution, Genetics, In the News, Research, Science, Stanford News

Flies, worms and humans – and the modENCODE Project

Flies, worms and humans - and the modENCODE Project

It’s a big day in comparative biology. Researchers around the country, including Stanford geneticist Michael Snyder, PhD, are publishing the results of a massive collaboration meant to suss out the genomic similarities (and differences) among model organisms like the fruit fly and the laboratory roundworm. A package of four papers, which describe how these organisms control how, when and where they express certain genes to generate the cell types necessary for complex life, appears today in Nature.

From our release:

The research is an extension of the ENCODE, or Encyclopedia of DNA Elements, project that was initiated in 2003. As part of the large collaborative project, which was sponsored by the National Human Genome Research Institute, researchers published more than 4 million regulatory elements found within the human genome in 2012. Known as binding sites, these regions of DNA serve as landing pads for proteins and other molecules known as regulatory factors that control when and how genes are used to make proteins.

The new effort, known as modENCODE, brings a similar analysis to key model organisms like the fly and the worm. Snyder is the senior author of two of the papers published today describing some aspects of the modENCODE project, which has led to the publication, or upcoming publication, of more than 20 papers in a variety of journals. The Nature papers, and the modENCODE project, are summarized in a News and Views article in the journal (subscription required to access all papers).

As Snyder said in our release, “We’re trying to understand the basic principles that govern how genes are turned on and off. The worm and the fly have been the premier model organisms in biology for decades, and have provided the foundation for much of what we’ve learned about human biology. If we can learn how the rules of gene expression evolved over time, we can apply that knowledge to better understand human biology and disease.”

The researchers found that, although the broad strokes of gene regulation are shared among species, there are also significant differences. These differences may help explain why humans walk, flies fly and worms slither, for example:

The wealth of data from the modENCODE project will fuel research projects for decades to come, according to Snyder.

“We now have one of the most complete pictures ever generated of the regulatory regions and factors in several genomes,” said Snyder. “This knowledge will be invaluable to researchers in the field.”

Previously: Scientists announce the completion of the ENCODE project, a massive genome encyclopedia

Pain, Research, Stanford News

New painkiller could tackle pain, without risk of addiction

New painkiller could tackle pain, without risk of addiction

painkillersThose suffering from chronic pain, take note: A new pain-reliever may soon be on the scene that lacks the “high” of opioids and the cardiac-risk of non-steroidal anti-inflammatory (NSAIDs) drugs such as aspirin. The compound reduced inflammatory pain in mice, according to research by a team of Stanford scientists led by Daria Mochly-Rosen, PhD, a professor of chemical and systems biology.

Mochly-Rosen discovered the compound, called Alda-1, more than five years ago while searching for the reason moderate alcohol use can decrease the severity of heart attacks. She found an enzyme, called aldehyde dehydrogenase 2, that breaks down a family of alcohol byproducts, called aldehydes. Aldehydes also cause pain in mice and Alda-1 relieves the pain, Mochly-Rosen said.

“I’m not a pain expert,” Mochly-Rosen says in our release on the Science Translational Medicine paper. “We hit this enzyme for a completely different reason. Hopefully this will help people who have pain.”

Alda-1 — coincidentally, Alda is also the name of Mochly-Rosen’s 87-year-old mother — works by knocking aldehyde dehydrogenase 2 into high gear. Say goodbye to the aldehydes, and goodbye to the pain.

Mochly-Rosen’s discovery of the link between pain and Alda-1 is a big deal for many reasons, including the suffering of thousands addicted to opioids such as Oxycontin. It’s also particularly meaningful for the millions in the Han Chinese ethnic group who suffer from alcohol flush.  They have a mutation in aldehyde hydrogenate 2, which makes it uncomfortable to drink alcohol and causes sufferers to turn red.

The inflammation is caused by the build-up of aldehydes, which are byproducts of alcohol. Alcohol-flush syndrome, as it’s sometimes called, has been recognized for decades.

The researchers created a mouse with a mutation akin to the enzyme mutation in humans. When they injected aldehydes into the mice, the mice with the mutation felt more pain than the other mice. And Alda-1 also relieved their pain.

Dribbles of evidence suggest some Asians are more sensitive to pain. Now, Mochly-Rosen and her team plan to investigate if the susceptibility stems from the enzyme mutation.

Becky Bach is a former park ranger who now spends her time writing, exploring, or practicing yoga. She’s currently a science writing intern in the medical school’s Office of Communication & Public Affairs.

Previously: Another big step toward building a better aspirin tablet, Blocking addiction risks of morphine without reducing its pain-killing effects, Patients’ genetics may play a role in determining side effects of commonly prescribed painkillers, and Stanford’s Sean Mackey discusses recent advances in pain research and treatment
Photo by Michelle Tribe/Wikimedia Commons

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