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Research, Science

Nature tracks 100 most-cited scientific papers

Nature tracks 100 most-cited scientific papers

Bound journals on shelves Flickr Taber Andrew BainAfter a researcher painstakingly collects the data, analyzes it, sweats over the manuscript that describes the findings, and finds a journal to publish it, a study that likely took years to conduct finally appears in public. Other researchers will read it and maybe get ideas for further research, and eventually cite the original article when publishing new findings.

The number of citations a paper receives is a way  – though imperfect – of keeping track of its influence in any given scientific field. And so, Nature recently compiled a list of the most-cited papers of all those cataloged in Thomas Reuters’ Web of Science since 1900. The journal ran some nifty graphs related to the list, including a yearly breakdown of the number of citations for each paper.

The top paper, by biochemist Oliver Lowry, MD, PhD, garnered more than 300,000 citations since its publication in 1951. The last one on the list had just a little more than 12,000 citations. Many famous discoveries such as Watson and Crick’s description of DNA’s double helix aren’t on the list, probably because those revolutionary findings quickly become well-known enough and authors didn’t consider citing the work necessary.

The story includes a mention of the work of a Stanford faculty member:

Number 41 on the list is a description of how to apply statistics to phylogenies. In 1984, evolutionary biologist Joe Felsenstein of the University of Washington in Seattle adapted a statistical tool known as the bootstrap to infer the accuracy of different parts of an evolutionary tree. The bootstrap involves resampling data from a set many times over, then using the variation in the resulting estimates to determine the confidence for individual branches. Although the paper was slow to amass citations, it rapidly grew in popularity in the 1990s and 2000s as molecular biologists recognized the need to attach such intervals to their predictions.

Felsenstein says that the concept of the bootstrap, devised in 1979 by Bradley Efron, a statistician at Stanford University in California, was much more fundamental than his work. But applying the method to a biological problem means it is cited by a much larger pool of researchers. His high citation count is also a consequence of how busy he was at the time, he says: he crammed everything into one paper rather than publishing multiple papers on the topic, which might have diluted the number of citations each one received. “I was unable to go off and write four more papers on the same thing,” he says. “I was too swamped to do that, not too principled.”

The article concludes with a description of some of the highlights in the fields of biological techniques, bioinformatics, phylogenetics, statistics, density fuctional theory and crystallography. It’s a nice look at some seminal findings that you won’t likely find in textbooks.

Previously: The benefits and costs for scientists of communicating with the public, Scientists preferentially cite successful studies, new research shows and A new era in scientific discourse? PubMed gets comments
Photo by Taber Andrew Bain

Events, Health Costs, Health Policy, In the News, Medicine and Society, Stanford News

Experts discuss high costs of health-care – and what it will take to change the system

Experts discuss high costs of health-care - and what it will take to change the system

4386861133_5e79734a6f_zNew York Times reporter Elisabeth Rosenthal, MD, visited Stanford this week for a Health Policy Forum, “Can we put a price on good health? Controlling the cost of health care,” with Stanford health-policy researcher Doug Owens, MD.

Those who attended looking for answers, easy fixes, or a master villain were out of luck. Instead, attendees gained insight into a convoluted system that all agree is broken, yet no one has the total power, or know-how, to fix. Here’s Rosenthal:

The issues and the problems are so diffuse… There’s the tendency to be very reductionist – ‘Oh, it’s the hospital, it’s the insurance companies, it’s pharma’… We’re all so codependent and it’s all so intertwined.

Finances dictate what we do and the incentives are so powerful. The message to patients is that we’re responsible too.

So that complimentary coffee you might get in a hospital lobby? Not actually free, Rosenthal said. She knows: While reporting for the well-known series “Paying Till It Hurts” she has talked to scores of patients and doctors and insurance representatives and policy-makers.

The main problems with the American health-care system are cost, quality and access, Owens said. The Affordable Care Act improved access, yet did little to lower costs or improve quality, he said.

And costs will continue to escalate if all the players remain most responsive to economic pressures, Rosenthal said. “Physicians feel like their income is being squeezed. Hospitals are better prepared to push back, and hospitals and physicians are looking to recoup some of that lost income in other ways. What’s lost in that very real tug of war is that patients are held hostage in the middle. That’s what’s distressing,” she said.

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Clinical Trials, Health Policy, NIH, Women's Health

A look at NIH’s new rules for gender balance in biomedical studies

A look at NIH’s new rules for gender balance in biomedical studies

In May, Francis Collins, MD, PhD, director of the National Institutes of Health, co-authored a Comment piece in Nature, outlining new requirements for biomedical researchers that made balancing the sex of animals and cell lines in studies much more important than they have been in the past. The first changes were set to be implemented this month. But, as Scientific American reported earlier this week,  the NIH isn’t likely to implement the changes as quickly as previously thought:

Funding rules, however, have yet to change, with only one week left in the month. Instead, the agency is gathering comments from researchers about which research areas need sex balance the most and the challenges scientists face in including male and female subjects in their studies. Officials have set aside $10.1 million in grants for scientists who want to add animals of the opposite sex to their existing experiments. The NIH is also making videos and online tutorials to teach scientists who are new to studying both sexes how to design such studies. Meanwhile, [Janine A. Clayton, director of the NIH’s Office of Research on Women’s Health] “can’t say” when new funding rules will take effect. “Details about the policy and implementation plans will roll out during the next year,” she says.

Scientists rely heavily on male animals, rarely using females, and the changes would require some drastic changes for researchers seeking funds from NIH. More from Scientific American:

Once in place and codified, the requirement would be a major shift for the nation’s biomedical labs, many of which study mostly or exclusively male animals. One estimate found that pharmacology studies include five times as many male animals as female ones, while neuroscience studies are skewed 5.5:1 male-to-female.

Scientists assumed biology findings that held in males would apply just as well to females, but a growing body of research has discovered this is not always true. Female and male mice’s bodies make different amounts of many proteins, for example. Men and women have differing risks for many health conditions that are not obviously sex-based, including anxiety, depression, hypertension and strokes. Yet those diseases are still predominantly studied in male animals. Scientists who study sex differences think the mismatch might be the reason women suffer more side effects than men do from drugs approved by the U.S. Food and Drug Administration. Pharmaceuticals that researchers test mainly on male animals may work better for men than for women.

When the NIH does begin to implement these changes, the first steps will be training staff and grantees on what these changes mean for experimental design. And it should be noted that this isn’t the first time that NIH has encouraged sex balance. In 2013, its Office of Research on Women’s Health started a program of supplemental grants for currently funded researchers to add enough animals for gender-balanced study results.

Previously: Why it’s critical to study the impact of gender differences on diseases and treatments, Large federal analysis: Hormone therapy shouldn’t be used for chronic-disease prevention and A call to advance research on women’s health issues
Photo by Mycroyance

Cancer, Research, Science, Stanford News, Surgery, Technology

New molecular imaging could improve bladder-cancer detection

New molecular imaging could improve bladder-cancer detection

Joseph LiaoThey say a picture is worth a thousand words. For bladder-cancer surgeons, an image can be worth many lives.

That’s because a crucial method for detecting bladder cancer is to produce images that allow surgeons to identify abnormal-looking tissue, a method called cystoscopy. In a study published yesterday in Science Translational Medicine, Stanford researchers developed a new way to image the bladder that they say could detect bladder cancer with more accuracy and sensitivity than the standard methods. As described in our press release:

 The researchers identified a protein known as CD47 as a molecular imaging target to distinguish bladder cancer from benign tissues. In the future, this technique could improve bladder cancer detection, guide more precise cancer surgery and reduce unnecessary biopsies, therefore increasing cancer patients’ quality of life.

Identifying cancerous tumors can be challenging — some bladder cancer treatments cause inflammation, which looks very similar to abnormal, cancerous tissue. The only way to know for sure is to perform a biopsy, which can be stressful for the patient. As co-senior author Joseph Liao, MD, explained:

 Our motivation is to improve optical diagnosis of bladder cancer that can better differentiate cancer from non-cancer, which is exceedingly challenging at times. Molecular imaging offers the possibility of real-time cancer detection at the molecular level during diagnostic cystoscopy and tumor resection.

For their work, the researchers looked for a target that would distinguish cancer cells from benign cells and found it in CD47, a protein on a cell’s surface that cancer cells produce in higher quantities than normal cells. In previous work, co-senior author Irving Weissman, MD, developed a CD47 antibody that binds to the cancer cell’s surface and blocks the signal. They hypothesized it would be a good imaging target. More from our release:

 To test their hypothesis, the researchers added a fluorescent molecule to an antibody that binds to CD47. The modified antibodies were then introduced into intact bladders, which had been surgically removed from patients with invasive bladder cancer. Because they bladders were kept in good condition, the study’s imaging methods mirrored the way an urologist might use with a real patient.

After 30 minutes, they rinsed the bladder, so only the antibodies that bound to the CD47 protein remained. When they shine the tumor was exposed to with fluorescent light, the cancer cells “lit up” whereas normal or inflamed cells did not.

“Our goal through better imaging is to deliver a higher- quality cancer surgery and better cancer outcomes,” Liao told me. “I am very excited about the potential to translate our findings to the clinics in the near future.”

Previously: Healing hands: My experience being treated for bladder cancer, Drug may prevent bladder cancer progression, say Stanford researchers, Cellular culprit identified for invasive bladder cancer, according to Stanford study and Mathematical technique used to identify bladder cancer marker
Photo of Liao by Norbert von der Groeben

Autoimmune Disease, Behavioral Science, Immunology, Pediatrics, Research

What happens when the immune system attacks the brain? Stanford doctors investigate

What happens when the immune system attacks the brain? Stanford doctors investigate

SM PANS image - smallerThe first time he flew into a psychotic rage, Paul Michael Nelson was only 7 years old. He stabbed at a door in his family’s home with a knife, tore at blankets with his teeth, spoke in gibberish. His very worried parents, Paul and Mary Nelson, rushed him to their local emergency room, where the medical staff thought that perhaps the little boy had simply had a bad temper tantrum.

But his rages got worse. Over the weeks and months that followed the first March 2009 emergency room visit, as Paul Michael cycled in and out of psychiatric hospitals, his parents and doctors struggled to understand what was wrong. Finally, they came to a surprising conclusion: Paul Michael had an autoimmune disease. His immune system appeared to be attacking his brain.

As strange as the case seems, the Nelsons are far from alone. As I describe in a recent story for Stanford Medicine magazine, Paul Michael was the first of more than 70 children who have been evaluated at a new clinic at Lucile Packard Children’s Hospital Stanford for pediatric acute-onset neuropsychiatric syndrome, a disease (or, more likely, a group of diseases) that doctors are still working to define. The suddenness and severity of the syndrome are frightening. Healthy children abruptly begin to show psychiatric symptoms that can include severe obsessive-compulsive behavior; anorexia; intense separation anxiety at the thought of being away from a parent; deterioration in their school work, and many other problems. From my story:

“In some ways, it’s like having your kid suddenly become an Alzheimer’s patient, or like having your child revert back to being a toddler,” says Jennifer Frankovich, MD, clinical assistant professor of pediatric rheumatology at the School of Medicine and one of the clinic’s founders.

“We can’t say how many kids with psychiatric symptoms have an underlying immune or inflammatory component to their disorder, but given the burgeoning research indicating that inflammation drives mood disorders and other psychiatric problems, it’s likely to be a large subset of children and even adults diagnosed with psychiatric illnesses,” says Kiki Chang, MD, professor of psychiatry and behavioral sciences.

To shed light on the disease, Frankovich and Chang are working with scientists from around the world on defining the parameters of the illness and launching urgently-needed research. In a special issue of the Journal of Child and Adolescent Psychopharmacology that published online this month, the researchers lay out several aspects of the problem. The Stanford experts are co-authors of a scientific article describing how doctors should evaluate children with the disease, known by its acronym, PANS. Other researchers have written about disordered eating in PANS and given a detailed description of the disease phenotype.

Recognition and treatment of the disease are still an uphill battle, but the growth of research efforts is a hopeful step. As Frankovich says at the conclusion of the Stanford Medicine story, “We cannot give up on this. There are so many of these cases out there.”

Previously: Stanford Medicine magazine traverses the immune system and My descent into madness – a conversation with author Susannah Cahalan
Illustration by Jeffrey Decoster

Biomed Bites, Cancer, Dermatology, Genetics, Research, Videos

Spotting broken DNA – in the DNA fix-it shop

Spotting broken DNA - in the DNA fix-it shop

It’s Thursday. And here’s this week’s Biomed Bites, a weekly feature that highlights some of Stanford’s most innovative research and introduces Scope readers to innovators in a variety of disciplines.

Neon green streaks across the screen. The phrases “End mismatched ligation” and “Repair of DNA double-strand breaks” flash at me. Did I stumble across an online, genetic fix-it shop? Sort of -  in that Stanford biochemist Gilbert Chu, MD, PhD, studies broken DNA and has a website to match.

Chu describes his research in the video above: “We started out in the lab trying to understand and recognize DNA that’s been damaged by ultraviolet radiation, which causes skin cancer. This led to the discovery of a protein that turned out to be missing in patients with a very rare disease called xeroderma pigmentosum.”

XP afflicts about 1 in 1,000,000 people in the United States. Without the protein Chu mentioned, mutations and damage accumulates in sufferers DNA, causes cancers and extreme sensitivity to the sun.

Chu’s team has also developed methods that allow other researchers to examine the expression of genes across an entire genome and to determine which cancer patients might be harmed by treatment with ionizing radiation.

“The reason I got interested in this research is that as a member of the Department of Medicine, I am an oncologist and I’m very interested in trying to help cancer patients,” Chu said.

Learn more about Stanford Medicine’s Biomedical Innovation Initiative and about other faculty leaders who are driving forward biomedical innovation here.

Previously: Skin cancer linked to UV-caused mutation in new oncogene, say Stanford researchers, Radiation therapy may attact circulating cancer cells, according to new Stanford study and How ultraviolet radiation changes the protective functions of human skin

Global Health, Infectious Disease, Stanford News

Stanford physician shares his story of treating Ebola patients in Liberia

Stanford physician shares his story of treating Ebola patients in Liberia

P1030655For a month, emergency physician Colin Bucks, MD, found himself in the remote, dense jungle of northeast Liberia in the heat of the battle against Ebola. A clinical assistant professor of surgery at Stanford, Bucks was a volunteer with the International Medical Corps at a new tent-like unit hastily built to accept the continuing stream of Ebola patients in the hard-hit West African country.

The facility, a series of low, tin-roofed, concrete buildings, were primitive in design but had very effective methods for controlling infection, including spigots everywhere that dispensed virus-killing doses of chlorine and protective gear for covering the body head to toe. Aside from providing basic care, such as fluid and electrolyte replacement, Bucks said much of his time was spent comforting patients, who were physically isolated from family members because of the threat of infection.

P1030673“In this setting (in West Africa), there is an additional barrier because you have one physical degree of separation, as your head, your hands, your face are completely covered. But that doesn’t preclude the same level of connection to the patient and the same sense of responsibility and care,” said Bucks, who left Liberia Oct. 22 and is now isolated at his home in Redwood City, Calif. “There may be a higher percentage of sad cases because Ebola has a high-case fatality rate, so there is an added burden there. But there is a similarity to working a tough case in rural Liberia to working a tough case in a U.S. critical care unit.”

He said the unit received patients from a nearby hospital, as well as those brought in by makeshift ambulances that might travel as much as eight hours to retrieve ailing victims. “We would get these reports everyday from the ambulance – we have four cases and three flat tires. The roads would be blocked with trees. They would have to drive through dense jungles. The ambulance stories were by far the most riveting.”

Colin Trish PPEBucks said the caregivers at the unit, which included 125 Liberians, were able to save just under half the patients who came in, with each survivor serving as an important ambassador to the community.

“The public health message was blanketing the country, but there was still a lot of fear and misunderstanding,” he said. “People are scared to come to the hospital. People are scared to undergo treatment. It helped every time we had patients discharged as cured.”

Bucks, who is now following recommendations and Stanford requirements to remain in isolation for 21 days, says there is a desperate need for other U.S. volunteers like himself to help contain the spread of the virus. “There needs to be a rational policy that facilitates health-care workers going to and from the U.S. Policy should help this – not impede this. But you need an organized response on West Africa. Otherwise we will be fighting a much bigger battle in the U.S. and around the globe.”

Previously: How to keep safe while operating on Ebola patients, Experience from the trenches in the first Ebola outbreak, Ebola: A look at what happened and what can be done and Dr. Paul Farmer: We should be saving Ebola patients
Photos courtesy of Colin Bucks

Cancer, In the News, Nutrition, Patient Care, Surgery

“Prehab” routines before cancer surgery help patients bounce back faster

Surgery_flickr_thinkpanamaIf you’ve ever had surgery, especially an orthopedic one, you’ve probably had rehabilitation therapy. In recent years, orthopedic surgery plans have begun to include a period of “prehabilitation” exercise to help prepare patients for their procedure. Now, researchers have demonstrated that a pre-surgery work-out routine combined with some dietary changes may be able to help cancer patients regain their baseline strength levels sooner. A story on NPR’s Shots blog described the recent study:

Researchers from McGill University in Montreal studied 77 patients scheduled for colorectal cancer surgery. A kinesiologist gave the patients aerobic exercises and strength training to do at home. A registered dietitian gave them nutritional counseling and prescribed a whey supplement to make up any protein deficits, and a psychologist provided anxiety-reducing relaxation exercises.

Half of the patients were told to start the program before surgery – an average of about 25 days before – and to continue afterward for eight weeks. The other group was told to start right after surgery.

Not surprisingly, the group assigned to prehabilitation did better on a presurgery test that measured how far they could walk in 6 minutes. And it paid off.

Two months after surgery, the prehabilitation group walked an average of 23.7 meters farther than when they started the study. Rehab-only patients walked an average of 21.8 meters less than when they started. (A change of 20 meters is considered clinically significant.) And a greater proportion of the prehabilitation group was back to baseline exercise capacity by then.

Because of the methology the researchers used, it’s not clear how the diet or the exercise prescribed in the pre-surgery regimen affected the outcome. Previous studies that looked at exercise-only regimens did not show post-surgery improvements. A larger study with a more varied pool of patients is likely needed for definitive answers.

Previously: Wellness after cancer: Stanford opens clinic to address survivors’ needs and A call for rehab services for cancer survivors
Photo by thinkpanama

Genetics, Pediatrics, Research, Science, Stanford News

Move over CRISPR, there’s a new editor in town: Stanford-devised approach cures hemphilia in mice

Move over CRISPR, there's a new editor in town: Stanford-devised approach cures hemphilia in mice

A lot of attention has been paid lately to the idea of genome editing. This technique allows researchers to precisely modify an animal’s DNA to replace one version of a gene with another, or to add a working copy for a mutated gene. An approach called CRISPR/Cas9 in particular has garnered interest with its ease of use, ability to modify multiple genes, and relatively quick turnaround time when making specific strains of laboratory animals like mice for study.

Now pediatrician and geneticist Mark Kay, MD, PhD, has published  in Nature a new way to conduct genome editing that could give CRISPR a run for its money because it could be both safer and longer-lasting than other methods. As described in our press release:

The approach differs from that of other hailed techniques because it doesn’t require the co-delivery of an enzyme called an endonuclease to clip the recipient’s DNA at specific locations. It also doesn’t rely on the co-insertion of genetic “on” switches called promoters to activate the new gene’s expression.

Inclusion of endonucleases and promoters run the risk of a gamut of adverse effects in the recipient, from cancers if the promoter turns on the wrong gene in the genome to an unwanted immune response geared toward the foreign proteins. The researchers in Kay’s lab, including postdoctoral scholar and study lead author Adi Barzel, PhD, found a way around their use, and showed that it worked to enable mice with hemophilia to produce a missing blood clotting factor:

The technique devised by the researchers uses neither nucleases to cut the DNA nor a promoter to drive expression of the clotting factor gene. Instead, the researchers hitch the expression of the new gene to that of a highly expressed gene in the liver called albumin. The albumin gene makes the albumin protein, which is the most abundant protein in blood. It helps to regulate blood volume and to allow molecules that don’t easily dissolve in water to be transported in the blood.

The researchers used a modified version of a virus commonly used in gene therapy called adeno-associated virus, or AAV. In the modified version, called a viral vector, all viral genes are removed and only the therapeutic genes remain. They also relied on a biological phenomenon known as homologous recombination to insert the clotting factor gene near the albumin gene. By using a special DNA linker between the genes, the researchers were able to ensure that the clotting factor protein was made hand-in-hand with the highly expressed albumin protein.

As Kay, who is also a member of the Stanford Cancer Institute, the Stanford Child Health Research Institute and Stanford Bio X, explained, the integration of the clotting factor gene is key to the successful treatment (other clinical trials involving gene therapy for hemophilia rely on the expression of a free floating, unintegrated gene in the nucleus):

The real issue with AAV is that it’s unclear how long gene expression will last when the gene is not integrated into the genome. Infants and children, who would benefit most from treatment, are still growing, and an unintegrated gene could lose its effectiveness because it’s not copied from cell to cell. Furthermore, it’s not possible to re-administer the treatment because patients develop an immune response to AAV. But with integration we could get lifelong expression without fear of cancers or other DNA damage.

Previously: Gene “editing” could correct a host of genetic disorders, Policing the editor: Stanford scientists devise way to monitor CRISPR effectiveness and Both a doctor and a patient: Stanford physician talks about his hemophilia

Ask Stanford Med, Neuroscience, Surgery

A Stanford neurosurgeon discusses advances in treating brain tumors

A Stanford neurosurgeon discusses advances in treating brain tumors

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Last year, an estimated 70,000 people were diagnosed with a primary brain tumor, which originates and remains in the brain, and far more will develop metastatic brain tumors, those that begin as cancer elsewhere in the body and spread to the brain. Although physicians face a number of challenges in treating these tumors, the encouraging news is that advances in technology and new therapies are improving patient outcomes.

During a Stanford Health Library event on Thursday, Steven Chang, MD, director of the Stanford Neurogenetics Program and the Stanford Neuromolecular Innovation Program, will deliver an update on the latest in surgical and non-surgical treatments of brain tumors. (The lecture will also be webcasted for those unable to attend.) In anticipation of the talk, Chang answered some questions related to the topics he’ll be addressing.

Why has a greater understanding of genetics and the biology of tumors improved physicians’ understanding of how patients will respond to certain therapies?

Having a greater understanding of the genetics and biology of brain tumors helps neurosurgeons to tailor treatments for each patient. In essence, we are able to deliver personalized medicine if we understand which subsets of brain tumors respond to specific treatments. For example, we now understand that gliomas with certain genetic makers are more likely to respond to chemotherapy treatments. The presence or absence of these genetic markers will also help guide patients in determining which clinical trials it may be most appropriate for them to enroll in.

How have advances in brain-mapping technologies made a difference in treating low-grade gliomas, which are slow growing and often affect younger patients?

Low-grade gliomas don’t typically contrast enhance on brain MRI scans. Furthermore, low-grade gliomas are more likely than higher-grade gliomas to have appearances similar to normal brain tissue, with no obvious color or consistency distinction between tumor and normal brain. These factors make resection of low-grade gliomas potentially more complex than high-grade gliomas, which often have distinct appearances from normal brain tissue. Advances in brain-mapping technologies include both image guided navigation and electrophysiologic mapping. Image-guided navigation consists of the use of MR imaging to provide real-time guidance during tumor resections. High-speed computer workstations provide images that show neurosurgeons exactly where they are with respect to brain anatomy during tumor resections. Electrophysiologic mapping is the use of specific electrical simulations of the brain tissue to identify eloquent brain cortex. By mapping out these critical brain regions, the neurosurgeon can safely avoid them when performing tumor resection.

In what ways have improvements in imaging technology over the last decade changed the treatment approach for both surgical and non-surgical treatment of brain tumors?

Improvements in imaging technology over the last several years have provided valuable tools for neurosurgeons in the treatment of brain tumors. A significant advance in surgical treatment of brain tumors has been the development of intraoperative MRI scanners. This allows a surgeon to perform a tumor resection, and then, post resection, perform a set of MR imaging directly in the operating room. If this MR imaging shows residual tumor, the surgeon has an opportunity to perform a further resection prior to completing the surgical operation. Additional imaging advances include functional MR imaging. This provides a graphic representation of critical functions such as speech or motor function. This is useful in determining both whether a patient is inoperative candidate and in assessing risk of the surgical resection.

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