Bench to Bedside

June/July 2016

Three Ways to Connect With Youth to Improve HIV Testing and Care


Too often, when Nadia Dowshen, MD, is in a patient exam room explaining to a teen living with HIV how antiretroviral therapy can keep the virus from destroying his immune system, he is looking at his cell phone and not fully paying attention. Could a random text message truly be more important than her lifesaving message? It was during one of these distracted clinical encounters that a novel pop-up message went off in her head.

“I thought, if they’re on these phones all the time, then we need to figure out how to use them, along with texting and social media, in order to help them improve their health,” said Dr. Dowshen, a pediatrician and adolescent medicine specialist who serves as director of Adolescent HIV Services in the Craig-Dalsimer Division of Adolescent Medicine at The Children’s Hospital of Philadelphia. She also is a faculty member at PolicyLab at CHOP and an assistant professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania.

A major advantage of using mobile health (mHealth) technologies to engage HIV positive youth, Dr. Dowshen said, is it that healthcare providers can deliver interventions in the real times and places where they need support as they go about their daily lives. mHealth approaches also can help to overcome some of the isolation and stigma often experienced by HIV positive youth.

In Philadelphia, about 2,000 people under age 30 are living with HIV, and they make up the highest percentage of those newly diagnosed; however, only one-third to one-half are as likely to be linked and retained in care as adults living with HIV. Also among youth, outcomes across the HIV care continuum — the series of steps from HIV diagnosis, to being engaged with medical care, to achieving effective virus suppression by consistently using HIV medications — are significantly worse than they are for adults.

Dr. Dowshen helped to launch an innovative research collaboration with CHOP’s Adolescent HIV Initiative and Philadelphia FIGHT Community Health Centers with support from the Health Resources and Services Administration to implement a comprehensive social media intervention to reach youth under 30 across the HIV care continuum in the city. Philadelphia FIGHT provides HIV primary care to low income members of the community, along with research, consumer education, advocacy, social services, and outreach to people living with HIV and those who are at high risk.

“We see these mHealth interventions as an extension of our clinics and staff who support these youth and establish strong relationships with them over time,” Dr. Dowshen said.

Dr. Dowshen is a co-principal investigator of the project, called Positively Connected for Health (PC4H), along with Helen Koenig, MD, MPH, an infectious diseases specialist who provides HIV specialty and primary care at the Jonathan Lax Treatment Center of Philadelphia FIGHT and a clinical assistant professor in the division of Infectious Diseases at the Hospital of the University of Pennsylvania. With their combined expertise, they aim to demonstrate that PC4H will be successful at helping youth to know their HIV status, assisting HIV-positive youth to gain access to care, and ultimately improving their health outcomes by increasing their adherence to therapy and reducing their viral load.

Under the PC4H umbrella, the research team will offer a series of three distinct yet integrated approaches developed by CHOP and FIGHT: the iknowUshould2 platform, the Treat YourSelf mobile application (app), and APPlify Your Health.

iknowUshould2 Platform

The Adolescent HIV Initiative produced this web-based social media platform about two years ago with CHOP’s public relations and marketing department to encourage youth to participate in testing for sexually transmitted infections (STI) and to know their HIV status. The design of the website and corresponding social media campaign was based on input from youth in the community and focuses on dispelling myths or fears youth may have about getting tested. The website was formatted for phone and tablet users, with Facebook, Twitter, Instagram, and YouTube all made accessible through the website homepage.

Currently, includes pages on ‘‘What R STDs?,’’ ‘‘STD Testing is Easy,’’ ‘‘Y Care about STDs?,’’ ‘‘Who Should UTalk To?,’’ and a page “Where To Get Tested’’ with a locator to identify free, confidential HIV and STI testing based on zip code in the Philadelphia area. The research team plans to update the iknowUshould2 platform, including adding more information about pre-exposure prophylaxis, which is another important HIV prevention modality to go along with HIV testing.

Treat YourSelf Mobile Application

Dr. Dowshen also relied on insights from her HIV-positive patients as she created this new mobile app with the goal of increasing adherence to HIV therapy, increasing retention in care, and reducing viral load. The app includes personalized, tailored time and location-based support.

“One of the things I noticed would happen often is youth would come in for a visit and say, ‘Everything was going great with my medicine, until two months ago when I lost my housing, or I started having issues with substance abuse.’ And I would ask, ‘Why didn’t you call me?’ This app will allow us to identify problems with adherence in real time so that we can intervene with personal support when it’s needed most,” Dr. Dowshen said.

For example, the app has an algorithm to detect when a youth has not indicated for several days in a row that he has taken his medication. The youth will receive a text message saying, “Hey, what’s going on? Do you want to call your support person or healthcare provider?” If a few more days go by and the youth still has not responded, the app has a feature that when enabled will automatically notify the youth’s support person and healthcare provider so that they can reach out to him and get things back on track.

“It is based on a theory of supportive accountability, which is the idea that these technological interventions are only as good as the person behind them that you trust and are accountable to,” Dr. Dowshen said.

Another integral part of the app is that all youth who are using the app are connected to each other anonymously, and it gives them the opportunity to create a network of social support. Unfortunately, due to the stigma surrounding HIV, many youth who are living with the disease are not comfortable disclosing their concerns to others or coming to group support type interventions. The app allows users to choose an avatar and try different gaming functions, such as joining teams who can earn points for good adherence and other positive behaviors. In addition to some healthy competition, the app offers a chat function to send encouraging messages to each other.

APPlify Your Health

Philadelphia FIGHT developed this digital health literacy intervention which uses mobile pop-up labs that provide youth-centric small group workshops and sample mobile devices to introduce the iknowUshould2 platform and the Treat YourSelf app, and to ensure that these tools are used effectively. A series of workshops will focus on HIV-negative or status unknown youth. An instructor will show participants how to join the iknowUshould2 campaign, explore the reliable online HIV testing tools it features, and then invite them to participate in rapid HIV testing at the end of the session.

Anyone who tests positive will be linked to resources at CHOP and FIGHT and encouraged to attend another APPlify Your Health workshop that focuses on using the Treat YourSelf app, customizing the app for their preferences, and discussing other key concepts of digital health literacy. Through the APPlify Your Health workshops, the research team aims to enroll 125 high-risk HIV status unknown youth into the iknowUshould2 campaign intervention and 125 HIV-positive youth into the Treat YourSelf app intervention.

Meeting Young People Where They’re At

At the end of the four-year project period, Dr. Dowshen and the research team expect to determine the feasibility, acceptability, and efficacy of iknowUshould2, Treat YourSelf, and APPlify your Health. If successful, they hope that these three coordinated social media methods could be replicated and implemented as an intervention on a larger scale to support youth throughout the U.S. who are at risk for HIV or living with HIV. It would be a new paradigm to keep up with “mobile” teens and guide them at key times along the HIV care continuum.

“You’re actually carrying on an intervention every day at every moment,” Dr. Dowshen said. “At CHOP’s Adolescent HIV Initiative, we have a wonderful multidisciplinary team who all work together to help youth achieve their goals across the HIV care continuum, but the clinic’s hours may not be when our patients need us the most. mHealth allows us to intervene in real time and get them real human contact with a provider who they trust.”

Dr. Dowshen is also co-chair of a new mHealth Research Affinity Group launched within CHOP’s Research Institute. Read more about how it provides a forum for researchers to meet and collaborate about new ways to explore the ever-expanding array of technologies being used for mHealth.

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Wake Up to This Novel Data Collection Tool for Pediatric Sleep Research


One of the rites of passage into parenthood are those first few bleary-eyed months when soothing an infant to sleep seems like an impossible dream. All the lullabies, rocking, feeding, swaddling — hour after hour, night after night — can be exhausting. Many parents find themselves desperate at 2 a.m., wondering if they will ever find a golden pillow at the end of their sleepless nights.

Sleep problems are highly prevalent in infants and toddlers, occurring in approximately 20 to 30 percent of young children, according to Jodi A. Mindell, PhD, a psychologist in the department of Child and Adolescent Psychiatry and Behavioral Sciences and the division of Pulmonary Medicine, as well as the associate director of the Sleep Center at The Children’s Hospital of Philadelphia. Using an online tool as an innovative form of data collection, Dr. Mindell conducted a study to evaluate the sleep patterns of young children between birth and 35 months. Her findings about their bedtimes, wake times, night-time sleep duration, nap sleep duration, and sleep consolidation may offer groggy parents a glimmer of reassurance.

“This is real-world data that we collected on a night-to-night basis,” Dr. Mindell said. “It gives us a beautiful way of visualizing what infant sleep looks like in the U.S.”

Dr. Mindell and her study team collected data from the digital sleep diary function within a free publicly available iPhone/iPad app for sleep in young children. Overall, the study analyzed 156,989 sleep log sessions involving 841 children over a 19-month period, and the results appeared in the Journal of Sleep Research.

Narrowing down all that data was the biggest challenge for the study team, Dr. Mindell said, but the advantage is that these emerging technologies gave them a wide geographical reach. They also allowed for direct data capture, which increased accuracy because the researchers did not need to rely on parents’ recollections and verbal reporting.

While every baby is different, Dr. Mindell said a clearer image of how sleep patterns develop in the first few years began to emerge. For example, the results suggest that nighttime sleep becomes more predictable at an earlier age than daytime sleep. Between five and six months sleep patterns start to develop more clearly, with the majority of babies sleeping for longer durations, on average about 10 ½ hours. It isn’t until babies are eight months old that the duration and time of day of naps became more consistent, with most babies taking two naps a day of about 1 ½ hours each.

“The take-home message is that parents need to hang in there for those first three or four months because then you’re going to start to see some better predictability,” Dr. Mindell said.

Also, the study showed that while there was a wide variation of bedtimes, morning wake times were consistent for babies of all ages, with most starting their days around 7:15 a.m. This finding reinforces that differences in bedtimes are important, Dr. Mindell pointed out. For every hour that bedtimes were later, infants’ total sleep duration decreased by almost 30 minutes.

“The later your baby goes to bed, the less sleep he or she is going to get,” Dr. Mindell said. “Because morning wake times had very little variability, sleep duration is really driven by bedtime.”

In addition to giving parents the ability to track their young children’s sleep, the mobile app has an “Ask the Expert” section that also yielded valuable research insights into parents’ primary sleep concerns. In a previous study published in the journal Behavioral Sleep Medicine, Dr. Mindell and her research team analyzed 1,287 questions that were submitted across a 10-month period. The researchers revealed that parents’ top three pediatric sleep worries centered on the themes of night wakings, sleep schedule, and bedtime problems. For example, a common question was, “My 3-month-old will not sleep on her own. What can I do? As soon as I take her out of my arms, she wakes up and cries until picked up.” Dr. Mindell, who responds to the Ask the Expert questions, receives an influx of such questions before she arrives to her office each morning.

“About 35 percent of the questions come in overnight, which demonstrates that parents need access to information at all hours of the day, not just when their pediatrician’s office is open,” said Dr. Mindell, who typically replies in about two days. “That is how the app helps.”

She developed the app almost four years ago in conjunction with Avi Sadeh, a professor at Tel Aviv University’s School of Psychological Sciences and Johnson & Johnson Consumer Companies, to give parents easy access to empirically based pediatric sleep information and strategies. In addition to Ask the Experts, another popular feature of the app is its downloadable lullabies.

From the very beginning of the app’s conceptualization, the app’s creators included a research component. When parents download the app, they must agree to be research participants, and so far about 300,000 people have done so. Each time a user answers the apps’ series of questions in order to generate a customized sleep analysis and receive personalized recommendations, it builds the database that is available for researchers to analyze. In the future, they plan to insert particular research questions into these questionnaires that they’d like to explore. The app recently launched globally, and Dr. Mindell is excited to be able to start collecting data to compare infant sleep patterns from throughout the world to the researchers’ U.S. findings.

“Mobile technology is a unique way to do sleep research and to collect data across the globe and include dramatically larger groups that we can then look at very closely,” Dr. Mindell said. “You lose some specificity, but what you get is an incredibly large snapshot of sleep.”

Dr. Mindell also is a professor of psychology and director of Graduate Psychology in the department of Psychology at Saint Joseph’s University.

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Ready to Be a Healthy Adult Survivor of Childhood Cancer? Text Y/N


The needle sticks, body scans, chemo infusions, radiation, and looming fears are all behind you. The ordeal of childhood cancer has ended, and you are a survivor. Now what?

Time to grow up healthy. But that process is more complicated for survivors than for most children. Life after cancer entails some unique health needs that each survivor should attend to throughout their lives, which may include medical and/or psychosocial late effects of cancer treatment. New research getting underway at The Children’s Hospital of Philadelphia is helping find the best ways that mobile health (mHealth) technology can help pediatric cancer survivors manage their transition to adulthood and adult medical care while staying healthy.

An Online Survivorship Care Plan for Pediatric Cancer

One part of the research team’s innovation is a fresh digital approach to survivorship care planning for pediatric cancer, spearheaded by Dava Szalda, MD, MSHP, a pediatric oncologist at CHOP who also sees patients through their transition to adult care as an internist at the Hospital of the University of Pennsylvania (HUP).

Dr. Szalda wanted to ensure that childhood cancer survivors everywhere, not just in the practices at CHOP and HUP, could enter adulthood prepared to go through life aware of their individual needs. She described this approach as “heightened primary care,” which considers routine adolescent and young adult healthcare in combination with the unique exposures and medical needs of survivors.

In many practices, pediatric and adult patients leave cancer care with written recommendations on paper that they can take with them to future primary care appointments. Such survivorship care plans summarize a cancer survivor’s disease, treatments, and potential long-term risks and screening needs. In pediatrics, many oncologists follow pediatric survivorship care guidelines developed by the multi-institution Children’s Oncology Group to build a survivorship care plan for patients. Although access to survivorship care planning is growing, it is not universal or consistent across all practices.

When she set out to make pediatric cancer survivorship care plans more widely available, Dr. Szalda found inspiration close to home when she met Christine Hill-Kayser, MD, a radiation oncologist at CHOP and assistant professor of radiation oncology at HUP, who is editor-in-chief of the cancer education website OncoLink at Penn’s Abramson Cancer Center, and of the site’s cancer survivorship care planning tool, OncoLife.

OncoLife, a free, self-service online tool for adult survivors of adult cancers to develop a survivorship care plan, had been created in 2007 as one of the first ever online survivorship care plans and one of the most comprehensive. It had a number of distinct advantages.

“Patients and providers can both take advantage of this great resource, and patients anywhere in the world can utilize the tool,” said Dr. Szalda, who is also an instructor in the division of Oncology at the Perelman School of Medicine at the University of Pennsylvania. She added that this tool is available to survivors who may have completed cancer treatment years ago, when fewer doctors were thinking about survivorship care.

Dr. Szalda, Dr. Hill-Kayser, and several collaborators teamed up to adapt the online survivorship care plan for pediatric cancer survivors. Their team took information from the OncoLink planning tool and incorporated evidence-based guidelines for health risks and follow-up care for pediatric cancers. They conducted feasibility testing with adult survivors of pediatric leukemia and lymphoma, and the results showed that the care plan was feasible within this pilot group. The findings recently appeared in the Journal of Adolescent and Young Adult Oncology.

The team continues to refine the prototype version of the pediatric online survivorship care plan by adding more cancer types and treatments. They are also assessing how well the plan aids survivors in improving knowledge about the care they need. Ultimately, after further testing and validation, Dr. Szalda expects to make the pediatric care plan publicly available to adult survivors of childhood cancer anywhere, at any age.

Beginning this summer, the team is also taking the tool to a new level by studying how another newer technology can help adolescent and young adult cancer survivors integrate their care plan into their daily lives.

Mobile Health Tool to Aid Survivor Self Management

The new study, called AYA STEPS, combines the online survivorship care plan for pediatric cancer survivors with a mobile app-based self-management system, and is funded by the Centers for Disease Control and Prevention. Dr. Hill-Kayser is principal investigator, with Dr. Szalda and another collaborator from the pediatric online care planning work, Lisa Schwartz, PhD, as co-investigators.

Dr. Schwartz, a psychologist in CHOP’s Cancer Center and assistant professor at Penn, had already developed a tool that would suit this new mHealth goal. In a project called THRIVE, she oversaw development and feasibility and acceptability testing of a two-way texting intervention for adolescent and young adult cancer survivors. THRIVE was initially part of a Department of Pediatrics Chair’s Initiative at CHOP, and it helped lay the groundwork for establishing the mHealth Research Affinity Group at CHOP which Dr. Schwartz now co-chairs. Now working with a new vendor to customize an existing smartphone app for an updated version of THRIVE in the new study, Dr. Schwartz is eager to apply what she learned from the feasibility testing.

The combination of the mHealth intervention with the online survivorship care planning tools could bring the best of both worlds for adolescent and young adult survivors. The new study will be a randomized controlled trial in which all participants complete the online survivorship care plan. Half of participants will also download the health management mobile app, which will contain a copy of their care plan along with other health promotion and education resources. Participants in the group using the app will also have two-way text messages focused on specific health concerns and questions they endorse. Their experiences can be further personalized based on their responses to the program’s text messages.

“The text messages are quite rich,” Dr. Schwartz said. “Some are quizzes, such as a question with a checklist so they can respond and say which item they want to check off. Depending on their answer, they might get different subsequent messages. We can text them a video or a link to other resources, as well.”

The team will measure how well each group of participants follows the recommendations of their survivorship care plans, using measures such as health behaviors, personal behavioral health and functional outcomes, and participants’ attendance to medical appointments that are necessary for their continued care.

“Adolescent and young adult cancer survivors are transitioning in many more ways than most adult survivors,” Dr. Hill-Kayser said. “At the same time they are transitioning from cancer patients to survivors, from kids to adults, from being managed by their parents to managing themselves, and, in many cases, going through emotional maturations that might have been delayed by active cancer treatment. It makes sense that they may need a different communication approach.”

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What’s in it for Me? Behavioral Economics to Improve Teens’ Glycemic Control


When young patients with type 1 diabetes reach adolescence and young adulthood, they tend to “fall off the cliff” and don’t take their medications or visit their healthcare providers on a consistent basis. This can send their glycemic control into a spiral leading toward short- and long-term medical complications. A collaborative pilot research project by investigators at The Children’s Hospital of Philadelphia and the University of Pennsylvania is taking a unique approach to steady this patient population’s adherence to recommended care practices.

“We’re applying a behavioral economic incentive technique called loss aversion to see if it motivates young people to improve their glycemic control by getting them to check their blood glucose levels more frequently and respond to their blood glucose levels in ways that are appropriate,” said co-principal investigator of the study Charlene Wong, MD, MSHP, a health services researcher and adolescent medicine fellow at CHOP and Penn.

Here’s how the concept of loss aversion fits into the study design, as Dr. Wong explained: Study participants have goals to check their blood glucose four times a day using a wireless glucometer and to take action when needed to keep their levels in a certain range, such as by administering correction doses of insulin. These goals are based on recommendations from the American Diabetes Association and CHOP’s division of Endocrinology and Diabetes. At the beginning of the month, each participant is given $60 in an electronic account. Each day that a participant is not adherent to the goals, he loses two dollars from the account. An automated daily text message or email sends the participant a reminder of where the account balance stands.

“We think that loss aversion could be a particularly strong incentive among youth because it is concrete,” Dr. Wong said. “They realize that this is money that they’re giving me, and I’m losing it by not doing the things that I’m expected to do as part of my routine care.”

In the fall, the study team began recruiting patients who were receiving care from CHOP’s Diabetes Center for Children, and they enrolled 90 participants ages 14 to 20; half were included in the intervention arm that lasted for three months. A second phase of the study will continue for another three months, except the intervention group will no longer receive the financial incentives.

The researchers check the participants’ hemoglobin A1C, which is a lab measure of glycemic control, at the start of the study, after three months, and at the end of six months to make comparisons. They also will conduct exit interviews to get participants’ perspectives on whether or not they found the study’s incentive design beneficial.

“The goal of using the incentives is to help participants identify ways to build in daily glucose monitoring practices into their usual routines of daily life,” Dr. Wong said. “And then, even after the incentives go away, our hope is that the study participants will be able to maintain the good habits that they’ve established.”

The study team is using an innovative web-based platform called Way to Health, which was created by Penn’s Center for Health Incentives and Behavioral Economics at the Leonard Davis Institute (LDI CHIBE), to conduct the study. The platform automates many of the research functions necessary to perform these sorts of behavioral economic randomized controlled trials using devices such as wireless activity trackers and other mobile health applications to test ways of improving health behaviors. The wireless glucometers automatically upload study participants’ glucose readings to the Way to Health platform study site, so the researchers know whether or not they’re adhering to their daily glucose monitoring goals.

In addition, the pilot study aims to build the foundation for future work with adolescents and young adults using behavioral economic principles and Way to Health. The study team will gather feedback on how youth friendly the Way to Health platform is perceived to be and if the study participants have any recommendations to increase its appeal to young users.

“Part of doing this pilot study is to see how these techniques work with youth populations,” Dr. Wong said. “If it’s successful, we would anticipate doing larger trials with young patients with type 1 diabetes and expanding our research to apply these same techniques into other disease categories with populations of adolescents and young adults.”

The study team is currently collecting data on the 90 participants who are enrolled and expect to analyze and report on results by the end of the year. Dr. Wong’s co-principal investigator is Mitesh Patel, MD, MBA, assistant professor of Medicine and Health Care Management at the Perelman School of Medicine and The Wharton School at Penn, and an LDI CHIBE faculty member. They also are collaborating with Carol Ford, MD, chief of the Craig-Dalsimer Division of Adolescent Medicine at CHOP; Steve Willi, MD, director of the Diabetes Center for Children at CHOP; Kathryn Murphy, RN, PhD, associate director of the Diabetes Center; and Victoria Miller, PhD, director of research for Adolescent Medicine. This project was supported in part by the Institute for Translational Medicine and Therapeutics of the Perelman School of Medicine at Penn.

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Microbiome Study of Inflammatory Bowel Disease Will Give the Gut a Holiday


Lindsey Albenberg, DO, wants to give her patients’ guts a vacation.

Dr. Albenberg, a pediatric gastroenterologist at The Children’s Hospital of Philadelphia, is launching a new study of Crohn’s disease that gives the digestive tract a “holiday” by temporarily wiping out the bacteria and fungi that populate it. A growing weight of evidence suggests that this population of microbes, known as the gut microbiome, plays an important role in triggering the body’s excessive and painful immune response in this and other forms of inflammatory bowel disease (IBD).

“It’s a very bacterially mediated disease,” said Dr. Albenberg, who is also an assistant professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania. The most common treatments for IBD involve antibiotics and drugs that suppress inflammation and the immune system, but only some patients respond to these treatments. Many patients continue to have painful and unpleasant symptoms, ranging from abdominal pain to diarrhea and blood in the stool.

A clue to this new approach comes from the fact that some patients experience temporary relief after undergoing ileostomy, a surgical procedure that diverts digestive products before they reach the colon. The process starves bacteria and other microbes, leading Dr. Albenberg and her collaborators to hypothesize that dramatically reducing the colon’s population of microbes could offer some patients a similar benefit without the undesirable procedure.

She was recently awarded a pilot grant from the Broad Program at the Crohn’s and Colitis Foundation of America to begin this new HOLIDAY study. The study will enroll 20 adults at Penn and 20 children at CHOP, all of whom have Crohn’s disease that does not respond to the best available medications. Participants will empty their digestive tracts’ contents in a process similar to preparing for a colonoscopy, then take a combination of antimicrobial drugs intended to drastically reduce the population of microbes in the gut.

Dr. Albenberg and her colleagues will monitor patients’ clinical symptoms during treatment and after for six months using a validated disease activity score; measures of inflammation including biomarker proteins in blood and feces; and microbiome measures of the bacterial and fungal load, bacterial and fungal composition, and metabolites produced by the gut microbes. They hope to correlate changes in both bacterial and fungal load and bacterial and fungal composition with the outcome measures. The focus on fungi in this study is a rare but emerging focus among microbiome studies.

“We published a paper about a year ago that showed differences in the fungal microbiota in children with IBD at CHOP, as compared to healthy controls,” Dr. Albenberg said. “There were significant differences in the composition of gut fungi. So this is now a question: Should we be treating IBD patients with antifungal medications?”

HOLIDAY study participants will be randomized so that half take an antifungal drug in addition to the multiple antibiotic drugs taken by all study participants.

Dr. Albenberg noted that this small study is exploratory but could provide a wealth of information about the role of the microbiome in Crohn’s disease, as well as about the process of repopulating microbes after treatment. Because the disease is so heterogeneous, she does not expect all patients to respond to this treatment, but she believes that some might.

“I think ultimately this could be a stepping stone to many other projects,” she said. “Even if it doesn’t work for everyone, we’ll learn a lot about the microbiome in people with IBD who are refractory to the best medications that we have out there. If it works, then I think that it opens up the door for novel treatment methods with antimicrobial medications.”

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‘Y’ Could Help Answer ‘How’ for Autism Spectrum Disorder in the Brain


The Y chromosome could help point the way to new answers about the neural mechanisms of autism spectrum disorder (ASD). Studies underway at The Children’s Hospital of Philadelphia are seeking possible structural and functional differences in the brain associated with having an extra copy of this male sex chromosome, a condition known as 47,XYY syndrome. Typically, human males have one X and one Y sex chromosome, while the remaining 22 pairs of chromosomes do not vary by sex.

“This seems like an interesting way of probing the neural correlates of the Y chromosome,” said study co-leader Timothy Roberts, PhD, vice chair of research in Radiology at CHOP and a professor of Radiology at the Perelman School of Medicine at the University of Pennsylvania.

Boys with 47,XYY syndrome generally are physically healthy, but they are sometimes larger in physical size, and are more likely to experience delays in learning and physical development, as well as various behavioral problems. And, Dr. Roberts’ collaborator and study co-leader Judith Ross, MD, a professor at Thomas Jefferson University, has observed one other important difference: Boys with this condition are far more likely than the general population to meet diagnostic criteria for ASD, at a rate of about one in four, compared to one in 68.

“Once we were aware of that, we started thinking of XYY as a human genetic model of autism,” Dr. Roberts said. He added that it was a particularly attractive genetic model because boys are overall four times more likely to be diagnosed with ASD than girls, which could imply a role for genes on the Y chromosome as a contributor to many other cases of ASD. And studies comparing the presence vs. absence of an extra Y chromosome between boys with and without 47,XYY syndrome would introduce fewer variables than comparing the presence of a Y chromosome in boys to the presence of a second X chromosome in girls.

The National Institute of Mental Health of the National Institutes of Health recently awarded Dr. Roberts and Dr. Ross a new grant to examine neural measures of boys with 47,XYY syndrome, focusing on structural and functional markers in the brain that have been identified as differing between children on the autism spectrum and typically developing children. They are using magnetic resonance imaging and magnetoencephalography to measure these biomarkers.

By pairing this newly funded study group with related research already underway with funding from the Department of Defense (DoD), the team will address larger questions and perform more complex comparisons to better understand the neural differences associated with meeting ASD diagnostic criteria and those associated with the Y chromosome, in various combinations.

Participants in the DoD-funded arm of the study include three age-matched groups: boys with 47,XYY syndrome, boys who do not have 47,XYY syndrome but are on the autism spectrum, and typically developing boys.

The first question the researchers want to address is whether ASD looks the same or different in the brain, depending on whether boys have one Y chromosome or two. If ASD is more homogeneous in the 47,XYY population, then any signature neural features in this population could point to new findings about the genetic contribution of the Y chromosome to neural structure or function.

Another critical question: If an extra Y chromosome increases the likelihood of ASD compared to the general population, why does it only raise that chance to one in four? Dr. Roberts and Dr. Ross are interested in finding any neural differences in the three out of four boys with 47,XYY syndrome who do not meet ASD diagnostic criteria. Those differences might provide insight into mechanisms of ASD or into pathways to target for interventions.

“It’s likely that through this work we will find something helpful to families and boys with XYY,” Dr. Roberts said. “I hope some mechanistic findings will be generalizable to the broader ASD population. And I hope even more that we’ll identify something protective or compensatory in the nonsymptomatic boys with XYY that can then be generalized to help the ASD population at large.”

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Study Aims to Match Injured Children to Hospitals Best Equipped for Their Care


The first responder has a critical decision to make as she loads a severely injured child into an ambulance. Take the child to the nearest hospital emergency department (ED) to be seen and stabilized as soon as possible, or go another three miles farther to a hospital with specialized trauma care facilities? Or 20 minutes farther still to a specialized children’s hospital?

Little evidence exists to help her make the tradeoff between expediting care and the facility’s capabilities to manage a critically injured child. A team of researchers from The Children’s Hospital of Philadelphia, Thomas Jefferson University, and the University of Pennsylvania, is working to change that and build a useful knowledge base that can shape policy and guidelines in order to improve the outcomes of injured children in the U.S.

“One way we can optimize their outcomes is by improving the matching of the child’s needs to the care they can receive at the hospital,” said Scott Lorch, MD, MSCE, a neonatologist and director of the Center for Perinatal and Pediatric Health Disparities at CHOP, and an associate professor of Pediatrics at the Perelman School of Medicine at Penn. Dr. Lorch is co-principal investigator of the new four-year project, which is funded with a grant from the Agency for Healthcare Research and Quality.

U.S. hospitals’ trauma care capabilities vary widely — from community EDs with no trauma or pediatric specialty designation, to designated trauma centers for adults that may lack specialized personnel and equipment for pediatrics, to trauma centers with pediatric capabilities, and specialty designated children’s trauma centers including children’s hospitals — and even within each type of facility, the specific capabilities and strengths can vary. The study team will conduct a national survey of these EDs and trauma centers to fill in the largely unknown landscape of what structures and processes of care are available to pediatric trauma patients at each facility. Structures, for example, include staffing level, types of available specialists, ED capacity, and pediatric-specific equipment, while processes include round-the-clock availability of various pediatric and adult specialists, protocols for events such as triage and transfer, and the department’s research and education activities.

The team next aims to build on that new knowledge of what structures and care processes exist in the pediatric trauma system, to answer a far more complex question of which ones deliver the best outcomes for children with injuries of various types and levels of severity.

“More severely injured patients tend to be taken to more specialized centers, so it is hard to compare facilities — and even harder to determine which structures and practices are most likely to improve outcomes,” said Brendan Carr, MD, associate professor of Emergency Medicine and associate dean at Thomas Jefferson University, who is co-principal investigator of the study with Dr. Lorch.

Dr. Carr has studied trauma care systems in adults and children and run into these challenges in comparing different types of facilities. The current collaboration began when he and other colleagues in trauma and emergency care at Penn and CHOP took notice of research Dr. Lorch had done that applied a novel approach to a similar challenge in neonatology.

Women with high-risk pregnancies whose babies are likely to need immediate care in the neonatal intensive care unit (NICU) have to make a choice about their hospital for delivery similar to the choice facing an emergency medical technician transporting an injured child. In both cases, the closest hospital might ordinarily be a compelling option, but a more specialized, better-equipped, or better-staffed center could lead to better outcomes for the child.

Even after adjusting for the fact that the more specialized NICUs tend to treat a higher proportion of the most severely ill infants, earlier research did not initially bear out the idea that babies had better outcomes there. Dr. Lorch then applied a statistical method from economics called an instrumental variables approach that better controlled for differences in the patient population. He found that mortality was as much as 50 to 60 percent lower when severely ill infants received care at better-equipped and better-staffed NICUs.

“The Instrumental Variable approach is an important tool that we believe will help us to build a better system,” Dr. Carr said, of the team’s plan to adapt this method to understanding and improving pediatric trauma care.

The team will correlate structures and processes of trauma care to children’s outcomes using population-based data from ED and inpatient hospital records in 13 states. The primary outcomes they will measure include mortality, prolonged hospital stay and complications, and other care utilization factors.

“We want to look at a variety of injury types and a variety of variables to try to understand, are there different patients who may benefit more from coming to the most specialized centers?” Dr. Lorch said. “And we need to sort out what practices can be exported to centers that aren’t focused on children in order to improve outcomes.”

Additional collaborators on the team are CHOP pediatric emergency medicine physician and Penn Assistant Professor Sage Myers, MD, MSCE; Michael Nance, MD, director of the Pediatric Trauma Program at CHOP and professor of Surgery at Penn; and M. Kit Delgado, MD, MS, an assistant professor of Emergency Medicine and Epidemiology at Penn.

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Time to Strengthen Parent-Pediatrician Conversations About Autism Care


“The times I have asked about treatment, I am kind of met with a blank stare,” one parent reported of the experience of discussing therapy for their child’s autism spectrum disorder (ASD) with the pediatrician.

This parent’s experience is likely not unique, according to a recent qualitative study led by researchers at The Children’s Hospital of Philadelphia.

When a young child receives a diagnosis of ASD, his or her parents can find themselves facing a wide array of therapeutic choices and services from medical providers, educational settings, complementary and alternative sources, and friends and family, that all claim to help their child with some aspect of behavior, learning, or physical health. The number and variety of options can be dizzying. Especially for a condition that is as varied and individual in its presentation as ASD, the best choices for each child can be unclear.

The new study, led by Susan E. Levy, MD, MPH, a developmental and behavioral pediatrician in the Center for Autism Research and the Division of Developmental and Behavioral Pediatrics at CHOP, suggests that pediatricians and families may miss opportunities to work together to sort through those choices and find each family the most appropriate treatments and supports, through a process called shared decision-making (SDM). Based on these findings, the researchers encourage pediatricians and parents to do more to seek out available resources about ASD and treatments and be open to discussing them as a team.

A major roadblock to weighing and making treatment decisions together, according to parents and pediatricians interviewed in the study, is that the conversations that could involve SDM only rarely occur. Many parents reported that they did not discuss the choice of any treatment options with their pediatricians.

“We really don’t involve the pediatrician,” one parent said. “Those kinds of decisions are made between our family and the actual hands-on therapists that [our child] has now.”

The study involved in-person or telephone interviews of 20 pediatricians and 20 parents of young children with a diagnosis of ASD, ages 2 to 5 years. All participating clinicians were from the CHOP pediatric network, equally drawn from urban and suburban settings. The findings were published online in Academic Pediatrics.

Dr. Levy’s initial goal in conducting these surveys was to gain insight into what factors are successful in supporting SDM. However, the overall lack of communication about ASD treatment choices meant too little SDM occurred in this group to determine what factors support it. SDM has been studied over recent decades as a method for improving provider-patient communication and partnership, with improvements seen in satisfaction, adherence, and health outcomes.

Still, the major themes that emerged from the interviews point to important gaps that could become opportunities to improve care. In addition to the lack of treatment discussions, another major thematic finding was that both parents and physicians reported knowledge gaps about ASD treatments and community resources, and they described ambiguity about the pediatrician’s role in ASD care.

“I was a little surprised that pediatricians didn’t feel they had the knowledge, and also that they didn’t feel it was within their scope of practice to be advising families about treatments, other than to provide referrals to outside specialists or services,” said Dr. Levy, who is also a professor of Pediatrics at the Perelman School of Medicine and a member of the Center for Public Health Initiatives at the University of Pennsylvania.

In addition, the research team found that the use of complementary and alternative medicine (CAM) treatments created conflict between pediatricians and parents — a finding supported by prior research by Dr. Levy and others. According to national and international surveys, less than 50 percent of pediatricians and family practice doctors routinely ask about CAM use.

“If providers do not ask, they cannot discuss it,” Dr. Levy and colleagues wrote. They emphasized that pediatricians are in need of better resources and strategies to help them engage in productive discussions with parents about CAM treatments, including talking about potential dangers of some CAM treatments and about shared goals and parents’ views and values.

More broadly, based on their findings, the researchers suggest that as primary care pediatricians encounter more children with ASD in their practice, they may benefit from the use of tools available through the American Academy of Pediatrics (AAP), such as the Autism Toolkit and clinical practice guidelines. Such tools have helped support pediatricians in managing children with attention deficit hyperactivity disorder (ADHD) in primary care.

However, significant differences, such as more medication options that may be effective in treating core symptoms of ADHD than are available for ASD, could make the learning curve steeper for pediatricians getting familiar with ASD treatments, noted study co-author Alexander Fiks, MD, MSCE. Dr. Fiks, a pediatrician at CHOP’s PolicyLab and the Center for Pediatric Clinical Effectiveness and associate professor of Pediatrics at Penn, has investigated how to implement SDM approaches for children with special healthcare needs, including ADHD.

Additional resources the study team recommend include the CAR Autism Roadmap developed at CHOP for families and providers anywhere, resources linked from the CHOP autism pathway for screening and referral, and decision aid tools that physicians might use to frame conversations about treatment choices. Many of these resources were not yet available at the time the researchers surveyed pediatricians.

In addition, Dr. Levy said, a forthcoming clinical report from the AAP at the end of this year will offer pediatricians strategies on the use of SDM. Dr. Levy, a member of the AAP’s Council on Children with Disabilities and Autism Subcommittee, is a contributor to that report.

Reaching decisions together may not ever be easy, but Dr. Levy encourages both families and physicians to begin by trying to have the conversation.

“The hope is that we can get both sides open to having a discussion in the format that occurs in shared decision-making,” she said. “That’s not pushing one way or another, but an open discussion about different treatments that are out there and available, sharing thoughts, knowledge, and questions, and figuring out together how to reach the right solutions.”

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Scientists Reveal New Mechanism Adenovirus Uses to Sabotage Immune System


Adenovirus, a common human virus that usually affects the lungs and causes respiratory tract infections, is an old friend to virologists. They have long studied how this virus interacts with host cells to understand cellular processes and reveal key regulators of cellular functions. But even your closest friends may have hidden secrets, as scientists at The Children’s Hospital of Philadelphia revealed when they identified a surprising way that adenovirus works to subvert a host’s immune system and allow the infection to spread.

Daphne C. Avgousti, PhD, first author of the study that appeared in Nature and a postdoctoral fellow in the lab of Matthew Weitzman, PhD, a CHOP virologist, found a new mechanism by which a viral protein, called protein VII, sequesters an important danger signal, called HMGB1, that host cells use to alarm the immune system. When it is normally released as an “alarmin,” HMGB1 is like a scout that travels beyond the cell to recruit an inflammatory response during an infection or injury.

“What we’ve discovered is that this viral protein, which normally packages DNA, actually retains the danger signal,” said Dr. Weitzman, who also is an associate professor of Pathology, Pediatrics and Microbiology at the Perelman School of Medicine at the University of Pennsylvania. “It prevents these alarmins from getting out of the cell, which results in abrogation of the immune response. It was a completely unexpected role for this viral protein.”

Adenovirus uses protein VII to compact its genome within virus particles, similarly to how histone proteins condense a cell’s DNA into chromosomes, collectively called chromatin. Because protein VII resembles histones, the study group tested whether protein VII could manipulate cellular chromatin by mimicking histones and disrupting chromatin structure. They found that protein VII alters cellular chromatin in cell culture, in human lung tissue in the laboratory, and in mouse models.

Dr. Weitzman pointed out that a Nature paper, from back in 1977, was the first to describe how protein VII was histone-like. Another Nature paper published in 2002 described how HMBG1 is a potent mediator of inflammation when released. The latest paper ties these findings together and combines the fields of virology, immune signaling, and chromatin biology. Establishing these new connections within the context of a classic virus opens a new area of basic scientific research to determine the extent to which other viral proteins mimic histones.

“The implication is other viruses probably do something similar, but nobody had known to even look,” said Dr. Avgousti, who had the idea when she came to Dr. Weitzman’s lab three years ago to view protein VII through a new lens by applying the same research techniques and principles that are used to study histones.

The study team also plans to do more investigations to see how they could possibly exploit their findings about protein VII’s dual role in both viral and host DNA. For example, now that they understand how protein VII traps HMGB1 in the cell nucleus to suppress immune responses, they want to see if knowledge of this process could somehow benefit patients in other cases by leading to new ways to control unwanted inflammation in diseases such as cancer and severe infections such as sepsis.

Many experts contributed to this discovery of adenovirus’ novel immune evasion mechanism, including CHOP neonatology researcher G. Scott Worthen, MD, and biochemists Ben Black, PhD, and Benjamin Garcia, PhD, of Penn. The study team also relied on insights from their colleagues in virology, pulmonology, and proteomics.

“We had access to a large number of collaborators and were able to harness their knowledge for this project,” Dr. Weitzman said. “Penn-CHOP has a great community that is highly collaborative and really allows you to move into new areas.”

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