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Autism, Neuroscience, Pediatrics, Research, Stanford News

Finding of reduced brain flexibility adds to Stanford research on how the autistic brain is organized

Finding of reduced brain flexibility adds to Stanford research on how the autistic brain is organized

A Stanford brain-imaging study has just shown that the brains of children with autism are less able to switch from rest to taking on a new task than the brains of typically developing children.

According to the study, which appears this week in the scientific journal Cerebral Cortex, instead of changing to accommodate a job, connectivity in key brain networks of autistic children looks similar to connectivity in the resting brain. The degree of inflexibility was linked to the intensity of children’s autism symptoms: those with less flexibility had more severe restrictive and repetitive behaviors, one of the hallmarks of the developmental disorder.

From our press release on the research:

“We wanted to test the idea that a flexible brain is necessary for flexible behaviors,” said Lucina Uddin, PhD, a lead author of the study. “What we found was that across a set of brain connections known to be important for switching between different tasks, children with autism showed reduced ‘brain flexibility’ compared with typically developing peers.” Uddin, who is now an assistant professor of psychology at the University of Miami, was a postdoctoral scholar at Stanford when the research was conducted.

“The fact that we can tie this neurophysiological brain-state inflexibility to behavioral inflexibility is an important finding because it gives us clues about what kinds of processes go awry in autism,” said Vinod Menon, PhD, the Rachel L. and Walter F. Nichols, MD, professor of psychiatry and behavioral sciences at Stanford and the senior author of the study.

The study is the first to examine unusual patterns of connectivity in the brains of children with autism while they are performing tasks; Menon’s team has previously published research on connectivity between different regions of the autistic brain at rest. Some regions of the autistic brain are over-connected to each other, that work has shown, and the degree of over-connection is linked to children’s social deficits, perhaps in part because it interferes with their ability to derive pleasure from human voices. Menon’s lab has also explored how differences in the organization of the autistic brain may contribute to better math performance in some people with autism.

“We’re making progress in identifying a brain basis of autism, and we’re starting to get traction in pinpointing systems and signaling mechanisms that are not functioning properly,” Menon told me. “This is giving us a better handle both in thinking about treatment and in looking at change or plasticity in the brain.”

Previously: Greater hyperconnectivity in the autistic brain contributes to greater social deficits, Unusual brain organization found in autistic kids who best peers at math and Stanford study reveals why human voices are less rewarding for kids with autism

Genetics, In the News, Pediatrics, Research

New Yorker story highlights NGLY1 research

New Yorker story highlights NGLY1 research

PackardGirl260x190The new issue of the New Yorker, out today, includes a fascinating medical story with a notable Stanford connection. As we’ve described before, a team of scientists from institutions around the world reported earlier this year on their discovery of a new genetic disease, NGLY1 deficiency. Stanford’s Gregory Enns, MB, ChB, was co-lead author of the paper describing the new finding, and one of his patients, Grace Wilsey, was among the small group of children in whom the disease first was identified. Grace’s inability to make tears when she cries was a key clue in unlocking the mystery of the disease.

But, as the New Yorker piece (subscription required) explains in detail, there’s much more to the story than that. In particular, it tells how the families of patients – especially Grace’s parents, Matt and Kristen Wilsey, and Matt and Cristina Might, who are the parents of index patient Bertrand Might – successfully encouraged researchers at different institutions to collaborate with each other in a way that advanced the discovery with exceptional speed. This was counter to the usual practice in science, the story explains. Typically, scientists avoid sharing data with competitors, even if doing so would advance the research:

If a team hunting for a new disease were to find a second case with the help of researchers from a competing lab, it could claim to have “solved” a new disease. But it would also have to share credit with competitors who may have done nothing more than grant access to existing data. When I asked [Duke University geneticist and NGLY1 deficiency co-discoverer Vandana] Shashi if she could imagine a scenario that would result in one research team’s publishing a paper with data from a different research group working on a similar project, she said, “Not that I can think of.”

David Goldstein [another Duke geneticist who collaborated with Shashi] added, “It’s not an overstatement to say that there are inherent conflicts of interest at work.” Daniel MacArthur, a genetics researcher at Massachusetts General Hospital, is even more blunt. “It’s an enormous deal,” he told me. “And it’s a big criticism of all of us, but it’s a criticism we all need to hear. The current academic publication system does patients an enormous disservice.”

Fortunately for patients like Grace and Bertrand, and for the doctors who want to help them, the culture is shifting. One marker of the shift is the NIH’s announcement earlier this month that it will be expanding its Undiagnosed Diseases Program to a network of seven sites across the country (including Stanford) and building in a requirement that all seven centers share data with each other.

Another is that researchers are realizing that families like the Wilseys and Mights will continue to make an impact. In fact, the Wilsey family has recently launched the Grace Wilsey Foundation to raise awareness about NGLY1 deficiency and promote investigation of possible treatments for the disease.

As Shashi puts it at the conclusion of the New Yorker story:

“Gone are the days when we could just say, ‘We’re a cloistered community of researchers, and we alone know how to do this.’”

Previously: NIH network designed to diagnose, develop possible treatments for rare, unidentified diseases and Crying without tears unlocks the mystery of a new genetic disease
Photo of Grace Wilsey courtesy of Lucile Packard Children’s Hospital Stanford

Chronic Disease, Research, Science, Stanford News, Technology

Stanford team develops nanotech-based microchip to diagnose Type 1 diabetes

Stanford team develops nanotech-based microchip to diagnose Type 1 diabetes

Dr. Brian Feldman?s M.D. hold a computer chip that he develop that will benefit diabetic patients at the Stanford School of Medicine,  on Thursday, July 4, 2014.  ( Norbert von der Groeben/ Stanford School of Medicine )

Years ago, when patients showed up at the doctor with excessive thirst, frequent urination and unexplained weight loss – in other words, the classic symptoms of diabetes mellitus – diagnosing them was usually just a matter of checking for high blood sugar. Yes, they needed to be treated for the correct form of the disease, but the two main types were found in different populations. So, in most cases, no lab test was needed to figure out whether someone had Type 1 or Type 2 diabetes; demographic factors were enough to make the distinction.

Of late, there’s been much more cross-over between the two groups. To treat patients correctly, it’s important to diagnose the right form of diabetes, but there’s a problem: The only test that does so is expensive, cumbersome and available only in hospitals.

So it’s great news that Stanford scientists are developing a new Type 1 diabetes test, described in a paper published online this week in Nature Medicine. The new nanotechnology-based microchip, which researcher Brian Feldman, MD, PhD, holds in the photo above, tests patients’ blood for the auto-antibodies that cause Type 1 diabetes. The new test is cheap, portable, and uses much less blood than the older diagnostic test. Unlike the old test, it requires no radioactive reagents and is simple enough to use in low-tech settings.

The test uses a nanotech enhancement (specifically, nano-sized islands of gold; hence the golden glow of the chip that Feldman is holding) to help detect auto-antibodies. In addition to diagnosing new patients, this technology will also enable better research into how Type 1 diabetes develops, as our press release explains:

…[P]eople who are at risk of developing Type 1 diabetes, such patients’ close relatives, also may benefit from the test because it will allow doctors to quickly and cheaply track their auto-antibody levels before they show symptoms. Because it is so inexpensive, the test may also allow the first broad screening for diabetes auto-antibodies in the population at large.

“The auto-antibodies truly are a crystal ball,” Feldman said. “Even if you don’t have [Type 1] diabetes yet, if you have one auto-antibody linked to diabetes in your blood, you are at significant risk; with multiple auto-antibodies, it’s more than 90 percent risk.”

Feldman’s team has started a biotech company to further develop the test and is seeking FDA approval for the new method. In addition, Stanford University and the researchers have filed a patent for the new technique.

Previously: A simple blood test may unearth the earliest signs of heart transplant rejection, Stanford microbiologist’s secret sauce for disease detection and One family’s story on caring for their children with type 1 diabetes
Photo by Norbert von der Groeben

Patient Care, Research, Stanford News

New study shows standardization makes hospital hand-offs safer

New study shows standardization makes hospital hand-offs safer

A study published online this week in Pediatrics offers encouraging results from a large-scale effort to tackle a persistent safety problem in hospitals. The study is the first scientific investigation of a multi-hospital project to improve patient hand-offs, the times when a patient’s care is being transferred from one person to another.

When hand-offs go wrong, the doctors and nurses taking over a patient’s care may not understand the individual’s diagnosis or current problems. They might not know which tests have been completed or which medication doses have already been given. These types of errors can, at best, waste everyone’s time, and, at worst, harm patients.

Fortunately, these latest findings demonstrate how hospitals can cut back dramatically on such problems. The one-year study of 23 pediatric hospitals across the country found a significant drop in hand-off related care failures when the process was standardized. Researchers examined both shift changes and patient transfers from one hospital department to another. The rate of hand-off related care failures went from slightly over 25 percent at baseline to about 8 percent by the end of the study. (Researchers didn’t measure actual harm to patients, but rather communication failures that could have resulted in harm had they gone unnoticed.)

“Surprisingly, this manuscript was amongst the first of its kind to actually show a decrease hand-off-related care failures,” senior author Paul Sharek, MD, medical director of quality management and chief clinical patient safety officer at Lucile Packard Children’s Hospital Stanford, said in an e-mail.

How did they improve so dramatically? By defining every element of the hand-off, including the interactions’ intent, content, process and team leadership. At the end of the study, the researchers identified several elements of good hand-offs, including the need for active participation by both sending and receiving teams; a defined opportunity for the receiving team to ask questions; a script of all the important hand-off elements; and a summary of basic issues and next steps for each patient. Overall, caregivers were satisfied with the new process, suggesting they’d buy into it for the long run.

“Given the increasing recognition of the risk of hand-offs in health care, these findings reassure us that large-scale improvements in hand-0ff safety can be achieved rapidly,” the researchers write.

Previously: Less burnout, better safety culture in hospitals with hands-on executives, new study shows, How efforts to mine electronic health records influence clinical care and Automated safety checklists prevent hospital-acquired infections, Stanford team finds

Immunology, In the News, Infectious Disease, Parenting, Pediatrics, Public Health

Side effects of childhood vaccines are extremely rare, new study finds

Side effects of childhood vaccines are extremely rare, new study finds

Pneumococcus-vaccineAs you may have heard about elsewhere, a new paper published today on the safety of childhood vaccines provides reassurance for parents and pediatricians that side effects from vaccination are rare and mostly transient. The paper, a meta-analysis appearing in Pediatrics, updates a 2011 Institute of Medicine report on childhood vaccine safety. It analyzed the results of 67 safety studies of vaccines used in the United States for children aged 6 and younger.

“There are no surprises here; vaccines are being shown over and over again to be quite safe,” said Cornelia Dekker, MD, medical director of the vaccine program at Lucile Packard Children’s Hospital Stanford, who chatted with me about the study earlier today. “The safety record for our U.S.-licensed vaccines is excellent. There are a few vaccines for which they document that there are indeed adverse events, but the frequency is quite rare, and in almost all cases they are very easy to manage and self-limited.”

A Pediatrics commentary (.pdf) accompanying the new study puts the value of immunization in context:

Modeling of vaccine impact demonstrates that routine childhood immunizations in the 2009 US birth cohort would prevent ~42,000 deaths and 20 million cases of disease and save $13.5 billion in direct health care costs and $68.8 billion in societal costs.

The commentary goes on to contrast the risks of vaccines with the potential complications of vaccine-preventable diseases:

The adverse events identified by the authors were rare and in most cases would be expected to resolve completely after the adverse event. This contrasts starkly with the natural infections that vaccines are designed to prevent, which may reduce the quality of life through permanent morbidities, such as blindness, deafness, developmental delay, epilepsy, or paralysis and may also result in death.

The study found evidence against suspected links between vaccines and several acute and chronic diseases. For instance, the researchers found high-quality evidence that several different vaccines are not linked to childhood leukemia and that the measles, mumps and rubella (MMR) vaccine is not linked to autism. The DTaP vaccine is not linked to diabetes mellitus, and the Hepatitis B vaccine is not connected to multiple sclerosis, according to moderate-quality evidence.

The evidence does connect a few vaccines to side effects. For instance, the MMR, pneumococcal conjugate 13 and influenza vaccines are linked to small risks of febrile seizures, with the risk of such seizures increasing slightly if the PCV-13 and flu vaccines are given together.

“A febrile seizure can be quite alarming, but fortunately it does not have long-lasting consequences for child,” Dekker said, noting that the risk of such seizures from vaccines is around a dozen per 100,000 doses of vaccine administered.

The rotavirus vaccine is linked to risk of intussusception, an intestinal problem that can also occur with rotavirus infection itself. But the benefits of rotavirus vaccination “clearly outweigh the small additional risk,” Dekker said.

The study confirmed earlier research showing that some vaccines, including MMR and varicella, cause problems for immunocompromised children, such as kids who have HIV or who have received organ transplants. Since they can’t safely receive vaccines, this group of children relies on the herd immunity of their community to protect them.

“It’s not as if the parents of immunocompromised kids have a choice about whether to vaccinate,” Dekker told me. “They have to depend on others to keep immunization levels high, and that starts breaking down when more people hold back from having their healthy kids fully immunized.”

Dekker hopes the new findings will encourage more parents to have their healthy kids fully vaccinated.

Previously: Measles is disappearing from the Western hemisphere, Measles are on the rise; now’s the time to vaccinate, says infectious-disease expert and Tips for parents on back-to-school vaccinations
Photo by Gates Foundation

Global Health, In the News, Pediatrics, Public Safety, Sexual Health, Women's Health

Stanford research shows rape prevention program helps Kenyan girls “find the power to say no”

Stanford research shows rape prevention program helps Kenyan girls "find the power to say no"

The San Francisco Chronicle has a great story today about a collaborative project that is reducing rape and sexual assault of impoverished girls in Kenya.

The story highlights the combined efforts of activists Jake Sinclair, MD, and his wife, Lee Paiva Sinclair, who founded nonprofit No Means No Worldwide to provide empowerment training to Kenayn girls, and the Stanford team that has been analyzing the results of their efforts. As we’ve described before, this work is a great example of the academic chops of Stanford experts’ being combined with on-the-ground activism to make a difference for an urgent real-world problem.

As the article explains:

The girls and hundreds of others like them have participated in a rape-prevention workshop created by Jake Sinclair and Lee Paiva, a San Francisco doctor and his artist wife who have been working in Kenya for 14 years.

Their program is working, and that’s not just according to the dozen or so testimonials online, the couple said. Two studies out of Stanford – one published in April this year, one the year before – have found that girls who have gone through the couples’ classes experience fewer sexual assaults after the workshops.

More telling, perhaps: More than half of the girls report using some tool they learned from the classes to protect themselves, from kicking a man in the groin to yelling at someone to stop.

“It’s great to see the girls just find their voice, to find the power to say ‘no,’ ” Sinclair said. “It’s so enlightening. You can see it in their eyes, that something’s changed.”

Stanford research scholar Clea Sarnquist, DrPH, who has played an important role in the project, adds:

“A lot of these girls are using voice and verbal skills first,” Sarnquist said. “That’s one of the key things, is teaching the girls that they have the right to protect themselves – that they have domain over their own bodies, and they have the right to speak up for their own self interest.”

The whole story is definitely worth a read.

Previously: Empowerment training prevents rape of Kenyan girls and Self-defense training reduces rapes in Kenya

Big data, Obesity, Pregnancy, Public Health, Women's Health

Maternal obesity linked to earliest premature births, says Stanford study

Maternal obesity linked to earliest premature births, says Stanford study

preemiefeetExpectant mothers who are obese before they become pregnant are at increased risk of delivering a very premature baby, according to a new study of nearly 1,000,000 California births.

The study, which appears in the July issue of Paediatric and Perinatal Epidemiology, is part of a major research effort by the March of Dimes Prematurity Research Center at Stanford University School of Medicine to understand why 450,000 U.S. babies are being born too early each year. Figuring out what causes preterm birth is the first step in understanding how to prevent it, but in many cases, physicians have no idea why a pregnant woman went into labor early.

The new study focused on preterm deliveries of unknown cause, starting from a database of nearly every California birth between January 2007 and December 2009 to examine singleton pregnancies where the mother did not have any illnesses known to be associated with prematurity.

The researchers found a link between mom’s obesity and the earliest premature births, those that happen before 28 weeks, or about six months, of pregnancy. The obesity-prematurity connection was  stronger for first-time moms than for women having their second or later child. Maternal obesity was not linked with preterm deliveries that happen between 28 and 37 weeks of the 40-week gestation period.

From our press release about the research:

“Until now, people have been thinking about preterm birth as one condition, simply by defining it as any birth that happens at least three weeks early,” said Gary Shaw, DrPH, professor of pediatrics and the lead author of the new research. “But it’s not as simple as that. Preterm birth is not one construct; gestational age matters.”

The researchers plan to investigate which aspects of obesity might trigger very early labor. For example, Shaw said, the inflammatory state seen in the body in obesity might be a factor, though more work is needed to confirm this.

Previously: How Stanford researchers are working to understand the complexities of preterm birth, A look at the world’s smallest preterm babies and New research center aims to understand premature birth
Photo by Evelyn

Pediatrics, Stanford News, Transplants

How mentorship shaped a Stanford surgeon’s 30 years of liver transplants

How mentorship shaped a Stanford surgeon's 30 years of liver transplants

Carlos Esquivel - OR_560

This year, pediatric liver transplant surgeon Carlos Esquivel, MD, PhD, is celebrating the 30th anniversary of his first liver transplant and his long career as a innovator of transplantation for tiny, fragile babies. When I was researching a story to mark the milestone, I wondered what led Esquivel to perform his very first transplant back in 1984.

As my story describes, a high-powered mentor shaped Esquivel’s career:

Near the end of his surgical residency at UC Davis, [Esquivel] realized that his planned career in vascular surgery would not challenge him enough. He sought a fellowship with the University of Pittsburgh’s Thomas Starzl, MD, PhD, who had performed the first successful human liver transplants a few years before and was refining the difficult, esoteric procedure. Soon, Starzl guided Esquivel through a transplant on a man with acute liver failure who had come to the hospital in a deep coma. The operation went well. Two days later, the patient awoke.

“Once I saw that — somebody who was at death’s doorstep waking up — it was unbelievable,” Esquivel said. “I never looked back.”

The background to that first surgery, which didn’t make it into my story, is quite interesting. When Esquivel arrived in Pittsburgh, Starzl’s team was conducting 300 liver transplants per year, sometimes several in a day. Esquivel was one of 40 fellows vying to learn the procedure. Surgeons operated with crowds of these apprentices peering over their shoulders.

Liver transplant was tricky. Because the liver performs many unique functions, including filtering toxins and secreting essential proteins into the blood, the patients were very ill.

“They’re some of the sickest patients in the hospital,” Esquivel told me. “When the liver doesn’t work, the blood doesn’t clot.” During transplant, patients could lose significant amounts of blood.

Esquivel was fortunate: As he described it, Starzl quickly took a liking to him. Many fellows were in Pittsburgh for a long time without being allowed to operate, but just three months after Esquivel arrived, Starzl said “Carlos, you are going to do your first liver transplant.”

Esquivel’s first-time jitters were mild until he learned that his patient was also a surgeon, a young surgical resident who had contracted acute hepatitis through a needle-stick injury. The man’s liver was failing fast. He came to the hospital on a respirator, in a deep coma. Despite Esquivel’s anxiety the procedure went smoothly – so well that, when the patient woke up, he was hungry.

“Even still hooked up to the respirator, he was asking what there was for breakfast,” Esquivel said, adding the comment I quoted above about his amazement at seeing the awakening of someone who had been at death’s doorstep. With Starzl’s guidance, Esquivel went on to tackle the toughest liver transplants with aplomb, eventually saving the lives of many babies and young children whom other surgeons turned away.

Continue Reading »

Clinical Trials, Nutrition, Parenting, Pediatrics, Research, Women's Health

Stanford study investigates how to prevent moms from passing on eating disorders

Stanford study investigates how to prevent moms from passing on eating disorders

veggie-stirfryResearchers have known for some time that women who have previously had eating disorders face a special set of challenges when they begin feeding their own children: They may unintentionally pass on problematic eating behaviors to their kids.

Now a Stanford research team is studying how to help these moms. They are recruiting families with a child between the ages of 1 and 5 whose mother had anorexia nervosa, bulimia nervosa or binge-eating disorder in the past. In the 16-week study, the researchers will work with both the mother and her partner to build healthy family interactions around food.

From our announcement about the study:

“The data on feeding practices of mothers who have had eating disorders are very worrying,” said Shiri Sadeh-Sharvit, PhD, a visiting scholar at Stanford who is leading the new study. “These mothers are good parents who want only the best for their children, but they struggle with eating-disorder thinking. It’s something that comes and blurs their parenting.”

Prior research has shown that mealtime conflict is more common in families in which the mother has had an eating disorder. These mothers may overfeed or underfeed their children, though underfeeding is more predominant. They also have more difficulty recognizing hunger and fullness cues in themselves and their children, which makes it harder for them to help their kids learn to respond to these sensations. Children whose mothers have had eating disorders are more likely than other kids to be dissatisfied with their bodies and engage in emotional eating, binge eating or restrictive eating.

Sadeh-Sharvit is collaborating with James Lock, MD, PhD, who has a long track record of demonstrating the effectiveness of eating-disorder treatments that involve the patient’s family in the treatment process.

Local families who are interested in participating in the research can contact Sadeh-Sharvit at (650) 497-4949 or shiri_sade@yahoo.com for more information. Stanford’s Eating Disorders Research Program also maintains an online list of all of their eating-disorder studies that are currently seeking participants.

Previously: Promoting healthy eating and a positive body image on college campuses, A growing consensus for revamping anorexia nervosa treatment and Story highlights need to change the way we view and diagnose eating disorders in men
Photo by Indiana Public Media

Global Health, In the News, Orthopedics, Pediatrics, Stanford News

6-year-old Palestinian boy learning to walk after treatment at Lucile Packard Children’s Hospital Stanford

6-year-old Palestinian boy learning to walk after treatment at Lucile Packard Children's Hospital Stanford

Hadi_mom_and_Richard_Gee-small fileHadi Alkhadra is a small boy with a huge grin. He’s got reason to smile: After living for years with a severe congenital defect that made it challenging to stand and impossible to walk, the 6-year-old Palestinian boy is on his feet. Last fall, Hadi and his mother came around the world from the Tulkarem refugee camp in the West Bank, Palestine to Lucile Packard Children’s Hospital Stanford so that he could receive several months of orthopedic surgeries and physical therapy.

The treatments address Hadi’s arthrogryposis, a condition that is analogous to polio in utero. Before he was born, some of the motor centers on Hadi’s spinal cord were damaged, probably by a virus. Some of the muscles that are supposed to move his knees, ankles and feet do not work normally. As a result, before treatment, his feet pointed backward and his knees had very restricted motion, bending only a small amount in the wrong direction. From the hospital’s press release about his journey:

With assistance from the Palestine Children’s Relief Fund, Hadi and mom Shireen have traveled 7,500 miles to receive care from orthopaedic surgeon Lawrence Rinsky, MD, who has led Hadi’s successful surgeries at Lucile Packard Children’s Hospital Stanford. Though there is no complete cure, with the assistance of braces and our Rehabilitation Services team, Hadi is now able to wear shoes for the first time, stand with his feet flat, leave his new wheelchair and start walking.

A warm, outgoing and intelligent young man, Hadi has become a big fan of the 49ers, Chuck E. Cheese, and iPads since arriving in the Bay Area last fall. Now, he looks forward to seeing his sister, two brothers and dad when he returns home in late June. Though he will wear lower-leg braces for most activities, including walking, for at least a few years, Hadi will be able to attend school for the first time while planning his dream “to be a surgeon, just like Dr. Rinsky.”

Previously: How orthopedic surgery straightened out one man’s life, Custom-made exoskeleton helps young girl with muscle disease use her arms and Strong-arm tactic: Saving toddler’s limb from amputation
Photo of Hadi with his mother, Shireen, and his physical therapist, Richard Gee, courtesy of Lucile Packard Children’s Hospital Stanford.

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