Bench to Bedside

December 2014

Affordable Care Act Leaves Many Children Without Benefits


An article published in the December issue of Health Affairs is the first comprehensive analysis to investigate the Affordable Care Act’s (ACA) Essential Health Benefit (EHB) as it relates to children. The study found the EHB has resulted in a state-by-state patchwork of coverage for children and adolescents that has significant exclusions, particularly for children with developmental disabilities and other special needs.

Previous studies have compared the EHB standard more broadly to the Children’s Health Insurance Program (CHIP), but this analysis presents the most detailed evidence regarding the types of exclusionary practices that limit the effectiveness of coverage for children insured through health plans sold in the individual and small group markets. The analysis was conducted by researchers from PolicyLab at The Children’s Hospital of Philadelphia; Children’s National Health System in Washington, DC; Johns Hopkins Bayview Medical Center; and the Milken Institute School of Public Health at the George Washington University.

“The Affordable Care Act offers great promise for kids, but we are concerned that its intended benefits are not fully realized for children,” said the study’s lead author, Aimee M. Grace, MD, MPH, a pediatrician and fellow at Children’s National Health System. “We sought to understand which pediatric services are covered, and which ones are excluded, by health insurance plans in the health insurance Marketplaces. Since there is currently no national pediatric benefit standard, our analysis compared benchmark plans at the state-by-state level.”

“Pediatric services” is one of ten benefit classes required by the ACA that must be covered in all health insurance plans sold in the individual and small-group health insurance Marketplaces.  However, other than oral health and vision care, neither the ACA nor the regulations for implementing it define “pediatric services”.

Additionally, while the ACA gave the U.S. Department of Health and Human Services (HHS) Secretary the ability to define a pediatric benefit standard at the national level, HHS chose instead a state-by-state benchmark plan approach akin to CHIP, which affords greater discretion to both states and payers.

Administered by HHS, by giving states matching funds for insurance CHIP “provides low-cost health coverage to children in families that earn too much money to qualify for Medicaid,” according to As of 2013, there were roughly eight million children enrolled in CHIP nationwide, with more than 200,000 in New Jersey and 250,000 in Pennsylvania.

In the Health Affairs study, the researchers found that the state-by-state approach has led to great variation among states regarding coverage of pediatric services. For example, 25 states specifically cover treatments for congenital defects, and 24 specifically include coverage for both autism spectrum disorder (at least in part) and hearing aids.

There is also great variation among states regarding exclusion of certain pediatric services. For example, 13 states specifically exclude services for children with learning disabilities, and 10 states exclude speech therapy for developmental delays, stuttering, or both.

Stitching the Patchwork

According to the study’s senior author Sara Rosenbaum, JD, of George Washington University, “This benefit patchwork means significant state-to-state variation in what will be covered for children with special needs.”

The analysis suggests four potential policy steps:

  1. Pediatric treatment limits and exclusions, particularly exclusions based on mental retardation, mental disability, or other developmental conditions, should be barred.
  2. The concept of “medical necessity” should be incorporated into the defined pediatric benefit. Medical necessity should include not only the clinical utility and appropriateness of a covered service, but also whether the service is appropriate in the pediatric developmental health context.
  3. The essential health benefits standard for pediatric services should be revised to address both covered services, particularly for children with special needs, and actuarial value (the percentage that the average person can expect the plan to cover). The authors suggest keeping with the current CHIP practice of an actuarial value of 90 percent for qualified health plans sold in the Marketplaces, to reduce the burden of high deductibles, coinsurance, and other forms of cost sharing for families with children.
  4. The use of CHIP plans as a benchmark plan for pediatric services should be permitted.

HHS made a commitment to review its “benchmark plan” approach for the 2016 plan year. At this time, HHS could define a pediatric benefit standard at the national level. Establishing a benefit standard has important implications for the eight million children who currently receive their health insurance coverage through CHIP, whose funding has not been extended beyond 2015.

If this funding were not extended, many of these children would enter the Marketplaces for their insurance coverage. For these children, as well as the children already covered by plans in the Marketplaces, the appropriateness of the essential health benefits standard for children is one of the most important issues in child health policy today.

“With Congressional debate expected about whether to extend funding for CHIP beyond fiscal year 2015, how well the pediatric services element of the essential health benefits standard addresses the needs of children will be an important factor to consider,” said PolicyLab’s Kathleen Noonan, JD.

And in an op-ed written by the study’s authors, they reiterate that continued “funding for CHIP is essential in the near-term because, despite the reforms introduced by the ACA, the private insurance market is still not ready for prime time.”

“These are all issues that the Administration could tackle since the terms of the ACA are broad and well within the Secretary’s authority,” the study’s authors note in their op-ed. “If the Administration does not address these issues, they should be front and center for Congress, which has a long history of successful bipartisan action on children’s health. The goal should not be simply to extend CHIP, but additionally to make the modifications needed so that the broader private insurance market works well for children and families.”

To read more, see the study abstract.

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Benefits Persist in T Cell Therapy for Children with Relapsed Leukemia


Acute lymphoblastic leukemia (ALL) is the most common form of childhood cancer and the most common childhood leukemia. Some patients with ALL have a highly aggressive form of the disease, one that causes either the cancer to recur or is resistant from the start to standard treatment.

An innovative cell therapy for this stubborn form of ALL continues to show highly promising results in children treated in a pilot clinical trial. Study leader Stephan A. Grupp, MD, PhD, a pediatric oncologist at The Children’s Hospital of Philadelphia and a professor of Pediatrics at the Perelman School of Medicine of the University of Pennsylvania, described outcomes and follow-up results of this study for pediatric patients with ALL at the annual meeting of the American Society of Hematology (ASH) in San Francisco.

Dr. Grupp, first author Shannon Maude, MD, PhD, a pediatric oncologist at CHOP and assistant professor of Pediatrics at UPenn, and colleagues reported that of the 39 children treated, 36 (92 percent) had complete responses one month after treatment. Of those 36 patients, 25 (69 percent) remained in remission at a median follow-up of 6 months after treatment. There were 10 relapses among the 36 patients with complete responses; 5 of the relapsed patients died.

The treatment is a personalized cell therapy program that reprograms a patient’s immune system and offers the potential of long-term success. At the heart of the therapy are bioengineered “hunter” T cells called CTL019 cells.

A relatively new approach in cancer treatment, this type of immunotherapy modifies T cells, the workhorses of the body’s immune system, to attack B cells, other immune cells that become cancerous in specific leukemias such as ALL. The CTL019 cells function as cancer hunters, killing the leukemia cells that normally evade regular T cell surveillance.

Researchers first extract a patient’s own T cells. They then use bioengineering techniques to reprogram each patient’s T cells into chimeric antigen receptor cells — the CTL019 cells — custom-designed to bind to a protein called CD19 that exists only on the surface of B cells. After being returned to the patient’s body, the CTL019 cells proliferate and then eliminate B cells. Moreover, they persist in the circulation, helping to guard against the cancer’s recurrence.

As the CTL019 cells potently attack leukemia cells, they also stimulate an unwanted, toxic immune response called cytokine release syndrome in patients. The care team successfully counteracted these side effects with an immunomodulating drug that had never been used for that purpose before, an approach which now has been adopted widely by cell therapy groups. In addition, because the CTL019 therapy eliminates healthy B cells along with cancerous B cells, patients must receive infusions of immunoglobin to perform the immune function provided by normal B cells.

“As we continue to follow children in this study, we see exciting results for patients who have exhausted their other treatment options,” said Dr. Grupp, who is an ongoing collaborator with colleagues at Penn Medicine, led by Carl H. June, MD, who offer this personalized cell therapy as a treatment for adult patients with other types of cancer.

The first child to undergo this therapy, 9-year-old Emily Whitehead, remains cancer-free since her T cell treatment in April 2012, and continues to enjoy normal childhood activities like going to school and playing with her dog, Lucy. Emily has appeared prominently in news stories since her doctors announced dramatic findings during the December 2012 ASH meeting.

“Our results show that these engineered ‘hunter’ cells greatly expand in patients, producing very high complete response rates that then persist in patients, potentially allowing for long-term disease control,” said Dr. Grupp. “Our next step is to conduct a Phase II, multi-site trial to assess safety and efficacy in multiple centers, which is now underway.”

This past July, the U.S. Food and Drug Administration designated the CTL019 approach as a Breakthrough Therapy, helping to expedite its progress into broader clinical trials. In August 2012, Novartis acquired exclusive rights from Penn to CTL019. Several authors from Novartis are co-authors of the abstracts presented by Dr. Grupp and others at the ASH meeting.

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Oral, Intravenous Antibiotics Equally Effective at Treating Bone Infection


The Children’s Hospital of Philadelphia’s (CHOP) Ron Keren, MD, MPH, was the first author of a study published recently in JAMA Pediatrics that showed treating osteomyelitis with oral antibiotics did not result in more treatment failures than treatment with intravenous antibiotics. As a result, the researchers — all part of the Pediatric Research in Inpatient Settings Network (PRIS) — suggest physicians reconsider using intravenous antibiotics to treat this condition because of that treatment method’s complications.

A serious infection of the bone, osteomyelitis affects approximately 1 in 5000 children per year. Osteomyelitis can require multi-week regimens of antibiotics, often given intravenously, and in some cases the condition can lead to surgery to remove dead bone tissue.

In 2012 Dr. Keren and colleagues received an award from the Patient-Centered Outcomes Research Institute (PCORI) to lead a study of serious bacterial infections that require hospitalization and then a long course of antibiotics. In collaboration with researchers from PRIS-affiliated institutions and the Children’s Hospital Association (CHA), Dr. Keren has been studying whether children with infections that require prolonged antibiotic therapy experience similar outcomes when taking antibiotics orally as when receiving antibiotics intravenously.

Specifically, Dr. Keren and colleagues have been comparing oral antibiotics to those delivered via a peripherally inserted central catheter, or PICC line. Because they tap directly into the circulatory system, PICC lines deliver the maximum concentration of the medicine, and are preferred by many clinicians for long-term treatment of severe infections. However, PICC lines often require sedation for insertion, require regular maintenance, and can clot, break, or become dislodged. In addition, any bacteria that are introduced into a PICC line can go directly to the heart and be pumped throughout the body.

Oral antibiotics, on the other hand, are much easier for patients to take and caregivers to manage. However, to achieve the same efficacy as IV medications oral antibiotics must have high “bioavailability” — that is, the amount of medicine absorbed into the blood through the digestive tract needs to be high.  By definition, all antibiotics administered through PICC lines have 100 percent bioavailability, but only some oral antibiotics have high bioavailability.

Retrospective Study of Osteomyelitis Treatment and Outcomes

In the JAMA Pediatrics study, Dr. Keren and colleagues — including Samir S. Shah, MD, MSCE, from Cincinnati Children’s Hospital; the University of Utah Health Care’s Rajendu Srivastava, MD, MPH; Shawn Rangel, MD, MSCE, from Boston Children’s Hospital, and Matthew Hall, PhD from CHA — coordinated a retrospective review of medical records of children who were hospitalized between January 1, 2009 and December 31, 2012 across 36 children’s hospitals.

After excluding for a number of criteria, the final study cohort included 2060 children, split almost evenly (1005 oral, 1055 PICC) between those who were discharged to receive antibiotics via a PICC line vs. the oral route. The children were prescribed antibiotics for a mean of 32 days in the oral group and 27 days in the PICC group.

The investigators found that treatment failure rates were similar across the PICC and oral groups, at 4 and 5 percent, respectively. Adverse drug reactions were similarly low, at less than 4 percent in both groups. But the research group found that of children who received PICC lines, 15 percent developed a PICC-related complication, such as a blood stream infection, clot, or dislodgement that required a visit to an emergency department, rehospitalization, or both.

“PICC complications such as blood clots and blood stream infections are quite serious. We can avoid such complications by using oral antibiotics,” said Dr. Shah, a hospitalist and infectious diseases specialist.

Overall, the researchers showed children prescribed oral antibiotics did not have higher rates of treatment failure than did their peers who received antibiotics via a PICC line.  However, the frequency of complications related to PICC lines “means that children treated via the PICC route had a higher risk (by 14 percentage points) for adverse events compared with their propensity-matched peers who received antibiotics via the oral route,” the investigators note. The researchers said it is important to note that isolation of methicillin-resistant Staphylococcus aureus (MRSA) did not modify the benefit of oral antibiotics and that physicians should feel comfortable using oral antibiotics even when MRSA is the cause.

“Once a bone infection improves after a few days of intravenous antibiotics, children can be transitioned to oral antibiotics and have excellent outcomes, without the hassles and potential complications of PICC therapy,” Dr. Keren said.

Going forward, Dr. Keren and his PRIS colleagues plan to continue their comparison of antibiotic delivery methods, looking at oral and PICC-line antibiotic treatment of complicated pneumonia and appendicitis. To read more about Dr. Keren et al.’s overall antibiotics project, see the PRIS page about it. For more information about this study, see JAMA Pediatrics.

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Study Questions Packing Children’s Lunches


To pack a lunch or not to pack a lunch: that is every parent’s question. A study recently published in JAMA Pediatrics may supply some answers to the age-old question of what to do about your children’s lunch.

Baylor College of Medicine’s Karen Weber Cullen, DrPH, RD, and the Houston Department of Health and Human Service’s Michelle Caruso, MPH, RD, examined the nutritional value of lunches brought from home versus National School Lunch Program (NSLP) guidelines. They found, on average, that lunches brought from home often contained more sodium and fewer servings of vegetables, fruits, and whole grains than NLSP guidelines specify.

And in an editorial that accompanied Drs. Cullen and Weber’s study, The Children’s Hospital of Philadelphia’s Virginia A. Stallings, MD, says NSLP guidelines — which were passed by Congress in 2011, and emphasize vegetables, fruits, and a variety of healthful foods — have “the potential to fundamentally change the diet quality and food variety of school-aged children.”

A program of the U.S. Department of Agriculture (USDA), the NLSP has been adopted by more than 100,000 schools and as of 2012 provided “nutritionally balanced, low-cost or free lunches to more than 31 million children each day,” according to the USDA website. Its nutritional requirements include increased portions of grains, vegetables, and fruits, and age-appropriate calorie limits ensure children receive the proper amount of nutrition and don’t overeat.

A Professor of Pediatrics at The Children’s Hospital of Philadelphia and the University of Pennsylvania’s Perelman School of Medicine, Dr. Stallings is a leading clinical nutrition and growth specialist. Last year, she launched an investigation that measure the degree to which patients with cystic fibrosis (CF) taking the drug ivacaftor experience improvements in nutritional status and growth. She has also led recent studies of vitamin D in HIV/AIDS and energy expenditure following surgery to correct congenital heart disease.

In Dr. Stalling’s JAMA Pediatrics editorial, she points out that lunches brought from home are not addressed by federal guidelines and “the general assumption is that home-prepared lunch will be as healthful as school lunch and possibly better.” However, Drs. Cullen and Weber’s investigation shows that may not be the case.

Focusing on one Houston school district, from October to December 2011, Drs. Cullen and Weber’s team observed 242 elementary students and 95 intermediate students brought their lunch from home. They found, compared to NLSP guidelines, lunches from home “contained a significantly greater amount of sodium,” fewer vegetables, and less liquid milk. In addition, about “90 percent of lunches from home contained desserts, snack chips, and sweetened beverages, which are not permitted in reimbursable school meals,” the researchers note.

“Because of the problem of childhood obesity, much attention has been given to the school food environment and the NLSP,” Drs. Cullen and Weber write in their JAMA Pediatrics study. “However, it is apparent that a large component of the school food environment — foods brought from home — has not been thoroughly investigated and could be a contributing factor to child overweight status.”

For her part, Dr. Stallings notes future studies “are needed to encourage families who choose to provide lunch from home to prepare meals that are similar to the NLSP diet patterns and the health promotion goals. Little contemporary information is available about families and students who choose not to participate in the school lunch and may result in less healthful lunch alternatives or skipping lunch.”

To learn more about healthy eating and nutrition for children, see Children’s Hospital’s page on school-aged child nutrition.

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Genetic Clues Found in Food Allergy Eosinophilic Esophagitis


Scientists have identified four new genes associated with the severe food allergy eosinophilic esophagitis (EoE). Because the genes appear to have roles in other allergic diseases and in inflammation, the findings may point toward potential new treatments for EoE.

“This research adds to the evidence that genetic factors play key roles in EoE, and broadens our knowledge of biological networks that may offer attractive targets for therapy,” said study leader Hakon Hakonarson, MD, PhD, director of The Children’s Hospital of Philadelphia’s Center for Applied Genomics.

The study team — which included researchers from CHOP, the University of Pennsylvania, and Rady Children’s Hospital-San Diego — published the study recently in Nature Communications. The research builds on a 2010 study by Dr. Hakonarson and colleagues that identified TSLP as the first major gene associated with EoE. Children’s Hospital’s Patrick M.A. Sleiman, PhD, also of the Center for Applied Genomics, was the first author of the study, and performed the data analysis.

Only recently recognized as a distinct condition, eosinophilic esophagitis has been rapidly increasing in prevalence over the past 20 years. Its hallmark is inflammation and painful swelling in the esophagus, along with high levels of immune cells called eosinophils. It can affect people of any age, but is more common among young men who have a history of other allergic diseases such as asthma and eczema.

EoE is often first discovered in children with feeding difficulties and failure to thrive. Because children with EoE are often allergic to many foods, they may be placed on a highly restricted diet containing no large food proteins, to allow time for their symptoms to resolve. Physicians then perform tests to determine which foods a child can or cannot eat.

In the current research, the investigators performed a genome-wide association study (GWAS), first in a discovery cohort of 603 EoE patients compared to 3,637 control subjects, then in a replication cohort of 333 patients versus 675 controls. All the subjects were of European ancestry. The study team identified four novel loci significantly associated with EoE. Two of them, STAT6 and c11orf30, previously were found in association with both allergies and autoimmune diseases. Two other gene loci, ANKRD27 and CAPN14, were specific to EoE.

CAPN14 may be of particular interest, said co-author Jonathan Spergel, MD, PhD, a pediatric allergist-immunologist at CHOP. The gene appears to be expressed only in the esophagus. “A recent study in a mouse model for asthma showed that a drug that inhibits a related protein reduces inflammation and improves airway functioning in animals,” he said.

While a similar drug might relieve esophageal inflammation in children with EoE, he added, “However, the finding of four genes indicates that a single drug might not work for all patients with EoE, and we may need a tailored approach to treatment, based on patients’ genetic profiles.”

Dr. Spergel was a co-author with Dr. Hakonarson on the 2010 study that identified the first EoE-associated gene. He directs CHOP’s Center for Pediatric Eosinophilic Disorders, one of the nation’s premier programs for such diseases. The CHOP center recently joined a new NIH-funded network, the Consortium of Eosinophilic Gastrointestinal Disease Researchers, which brings together leading centers in the field.

To learn more about eosinophilic esophagitis, see Children’s Hospital’s website.

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Researchers Study Factors That May Complicate Concussion Recovery


Recognition and diagnosis of concussions have exploded over the past decade, mainly due to increased media attention on how professional sports teams deal with these serious injuries. Nearly 173,000 children and adolescents are seen in emergency departments annually for sports- and recreation-related traumatic brain injuries (TBI), including concussions, according to the Centers for Disease Control and Prevention.

“Concussions have become a hot button issue across the country,” said Daniel J. Corwin, MD, of the Division of Emergency Medicine at CHOP. “We have become much more aware and adept at concussion diagnosis and management.”

As the number of children treated for concussions continues to increase, the evidence-based program Minds Matter developed by concussion experts at The Children’s Hospital of Philadelphia has expanded to clinicians in the emergency room and primary care practices. A concussion is a mild TBI caused by a blow or jolt to the head or body that causes the brain to shake. The injury disrupts how well the brain’s cells function and work together, and it can cause multiple symptoms, including headaches and dizziness, sleep problems, confusion, and irritability. Some symptoms are obvious and immediate, while others are more subtle and may not show up for several days.

A subset of patients may experience a more complicated recovery that can last for months. In a retrospective study published in the December issue of the Journal of Pediatrics, Dr. Corwin and colleagues investigated a broad group of characteristics that may help clinicians to identify which patients are most at risk for prolonged recovery.

“We suspect that there is something about these children that may predispose them to having poorer outcomes from concussion and longer recovery times,” Dr. Corwin said. “It is possible that even if a child has mild symptoms, they may have a longer recovery time if they have one of the pre-existing conditions or the specific types of clinical presentations that we studied.”

The study team hypothesized that patients with pre-existing mood disturbances or learning disabilities, dizziness as an initial symptom, abnormal findings upon vestibular examination, a history of prior concussion, and younger age would be associated with a more complicated recovery from concussions. They analyzed data collected via an electronic medical record query from patients aged 5 to 18 with concussion who were referred to CHOP’s sports medicine clinic.

The investigators examined several recovery outcomes, including how long on average it took for patients to be symptom-free (64 days), how long until they were fully cleared to return to learning without any academic accommodations (35 days), and how long until they were fully cleared for all activities, including sports (76 days). Overall, the study reported recovery times that were longer than the healing times estimated in previous studies among the general pediatric population (14 to 28 days).

Because it was a retrospective study, many of the differences that the researchers identified in association with specific patient characteristics did not reach statistical significance, but their findings could spark more in-depth studies of these predisposing factors. For example, the investigators found that patients with a history of anxiety and depression had prolonged recovery time and worse school outcomes.

“They may have underlying abnormalities that make their brain a little more sensitive to a given impact,” Dr. Corwin suggested as a hypothesis for future exploration.

He also anticipates that the study’s findings will prompt more research into how assessment of vestibular deficits could be incorporated into concussion exams to help with prognosis, which already is the standard for care for CHOP’s sports medicine specialists but is not done universally. The vestibular system includes parts of the inner ear and brain that help control balance and eye movements.

One element of the assessment tests near-point convergence, which determines how difficult it is for patients to see an object clearly as it moves closer. In the current study, patients who demonstrated abnormal near-point convergence ended up having prolonged symptoms and poorer school outcomes.

“Usually, an object becomes blurry at about 6 cm,” Dr. Corwin said. “We found that for some patients, an object was blurry at 10 cm to 20 cm, which can make schoolwork quite difficult.”

The study team also considered concussion patients who had difficulty looking horizontally and vertically back and forth rapidly, as they do in a classroom when taking notes. Patients with initial oculomotor abnormalities on physical examination also had prolonged symptoms and poorer school performance.

“Perhaps if these vestibular deficits are present at the initial exam, they could be markers that a concussion injury may cause more severe dysfunction,” Dr. Corwin said, adding that this is an area where researchers could help to provide future data.

Other factors that the study team associated with patients who took longer for their symptoms to resolve included those who reported dizziness or loss of consciousness at the time of injury, at least two prior concussions, and younger age, especially those 12 and under.

Future research also is needed to see how clinicians’ recommendations for physical rest and early cognitive rest — which restricts patients’ exposure to activities that may stress the brain and worsen symptoms, such as sports, schoolwork, computers, texting, or video games — could affect patient outcomes in these high risk groups.

“It can often be challenging to have patients cognitively rest,” Dr. Corwin said. “As clinicians are counseling families and following up with these patients, they can be aware of which children are at increased risk for prolonged recovery and worse outcomes, and hopefully better prepare them and set expectations from the beginning that will encourage them to rest more effectively.”

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Transparent Microelectrodes Allow for Dynamic Imaging to Study Epilepsy


The brain is the body’s control center, and it relies on an intricate circuitry of thousands of neurons that communicate with each other through electrical and chemical signals. An electroencephalogram (EEG), which is a recording of brain activity using small button electrodes, helps neuroscience researchers to better understand the cellular mechanisms involved with brain disorders, such how epileptic seizures occur.

One of the most common disorders of the nervous system, epilepsy affects 2.7 million Americans of all ages, races, and ethnic background. A seizure takes place when spontaneous high-frequency bursting of neural networks appears that temporarily interrupts normal electrical brain function.

Neuroscience researcher Hajime Takano, PhD, who works in Douglas Coulter, PhD’s, epilepsy research laboratory, is especially interested in which specific neurons could be inciting the neural network. But pinpointing those neurons’ locations and plotting the intensity of their activity in real time has been problematic because traditional metal electrodes cause interference when used in conjunction with sophisticated, multicellular calcium imaging techniques that investigators couple with high-speed microscopes to see and record when neurons are firing.

Dr. Takano, who is also a research assistant professor in the Neurology Department in the Perelman School of Medicine at the University of Pennsylvania, collaborated with other Penn researchers from the School of Engineering to test a new type of transparent, flexible microelectrode they developed that could solve this problem. It is made of the strongest material known to man: graphene, a two-dimensional form of carbon only one atom thick. Because it is see-through, the graphene microelectrode allows for simultaneous optical imaging and electrophysiological recordings of neural circuits.

“The idea of applying this technology to basic neuroscience for brain recording is something new and very exciting,” said Dr. Takano, who also has an engineering background.

In a study published in Nature Communications, Dr. Takano, senior author Brian Litt, PhD, Penn Engineering postdoc Duygu Kuzum, and colleagues described how they were able to use the graphene microelectrode technology in combination with calcium imaging involving confocal and two-photon microscopy to observe seizure-like activity that they induced in neural tissue from rats. The investigators were able to obtain both high spatial and temporal resolution, which is the ability to discriminate between two points in space and time.

Neurons and their processes are small, with a spatial extent measured in micrometers. In contrast, the circuits within which neurons function may extend millimeters to a centimeter or more. The new microelectrode allows for dynamic imaging that can provide valuable information on individual cells, while at the same time probing the regions that they may span.

“By monitoring a seizure with the transparent electrodes and imaging individual neurons at the same time, we can try to pinpoint where a seizure started,” Dr. Takano said. “If there are repeated seizures, we can see if the seizure-initiating cell is always the same or not. And if there is an initiating cell, what is different about it?”

At the Society for Neuroscience’s Annual Meeting, held recently in Washington, D.C., Dr. Takano presented a poster describing how the study team used the graphene electrodes to record high-frequency bursting activity. The response from attendees was overwhelmingly positive, Dr. Takano said.

In the future, Dr. Takano plans to use the graphene electrodes in conjunction with other advanced imaging approaches to provide new insights into the functions of neural circuits during seizures. For example, they will allow him to use chloride imaging to explore factors that control the level of electrical activation in cellular regions.

Development of the transparent microelectrode technology involved a multidisciplinary effort from Penn’s new Center for NeuroEngineering and Therapeutics, Penn’s departments of Neuroscience, Pediatrics, and Materials Science, and the Division of Neurology at CHOP.

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CHOP Expert Contributes to Resident Hour, Colon Cancer Studies


The Children’s Hospital of Philadelphia’s Jeffrey H. Silber, MD, PhD, contributed to two recent studies that span the research spectrum. The first, published in The Journal of the American Medical Association (JAMA), investigated changes to the number of hours medical residents can work. The second investigation, of which Dr. Silber was the lead author and which appeared in the Annals of Internal Medicine, was a study of racial disparities in colon cancer survival.

In the JAMA study, Dr. Silber and colleagues found resident duty hour reforms did not result in significantly higher 30-day readmission or mortality rates. And with the Annals of Internal Medicine investigation, the researchers showed racial disparities in colon cancer survival did not decrease over a 14-year period, from 1991 to 2005.

A pediatrician and healthcare economist, since 1997 Dr. Silber has directed CHOP’s Center for Outcomes Research. He has published extensively on the use of multivariate matching in healthcare, and has applied this approach to outcomes research in both pediatric and adult medicine and surgery, disparities research, and cancer research. Dr. Silber is a professor of Pediatrics, Anesthesiology and Critical Care at the University of Pennsylvania Perelman School of Medicine and professor of Health Care Management at The Wharton School.

With the JAMA study, the researchers sought to determine whether 2011 reforms to the number of hours residents could work had affected patient mortality and readmissions. Implemented by the Accreditation Council for Graduate Medical Education (ACGME), the reforms maintained the 2003 maximum of 80 hours a week but reduced residents’ work limit from 30 to 16 consecutive hours for first-year residents, and to 24 hours for more experienced residents.

The investigators performed an observational study of Medicare patient admissions data from July 1, 2009 to June 30, 2012, comprising some 2,790,356 patients with 6,384,273 admissions across 3104 hospitals, and examined a number of medical conditions (such as congestive heart failure and diabetes) and surgical categories. They found “no significant positive or negative associations of duty-hour reforms” with 30-day all-location mortality or 30-day all-cause readmissions.

“There has been a lot of speculation about the effect of the 2011 ACGME duty hour reforms on patient outcomes, so we looked at death and readmission rates at the national level,” said the study’s lead author, the University of Pennsylvania’s Mitesh S. Patel, MD, MBA, MS.

“Some hoped that by shortening intern shifts from 30 hours to 16 hours, less fatigued residents would lead to less medical errors and improved patient outcomes. Yet, others were concerned that shorter shifts would increase patient handoffs and leave less time for education, thereby negatively affecting patient outcomes,” said Dr. Patel. “These results show that in the first year of the reforms, neither was true.”

Presentation to Blame for Colon Cancer Survival Disparities

The Annals of Internal Medicine study, meanwhile, examined racial disparities in colon cancer survival rates.

Dr. Silber has previously investigated racial disparities in cancer survival. In August of 2013 he published a study in JAMA that showed differences in how breast cancer patients present at diagnosis are more responsible for racial disparities in 5-year survival than treatment differences.

In the current study, Dr. Silber and colleagues — including Wharton’s Paul R. Rosenbaum, PhD; and Penn Medicine’s Bruce J. Giantonio, MD — examined Survey, Epidemiology, and End Results (SEER) Medicare data from 1991 to 2005 across 16 sites to determine the extent to which colon cancer disparities result from presentation at diagnosis or treatment.

One of the most common forms of cancer, colon and rectal cancer account for approximately 10 percent of new cancer cases each year worldwide. According to the National Cancer Institute (NCI), five-year survival rates for colon and rectal cancer vary widely depending on how early it is detected. Based on data from 2004 to 2010, 89.8 percent of patients with localized cancer survived five years after being diagnosed, while only 12.9 percent of patients with distant or metastasized cancer survived five years. And during 2014 the NCI estimates 2014 there will be approximately 50,000 deaths from colon and rectal cancer.

Using SEER data, Dr. Silber and colleagues matched 7,677 black patients aged 65 and older with three groups of 7,677 white patients aged 65 and older — who were followed until 2009 — to investigate the roles of demographics, presentation, and treatment in survival. Finding a “persistent disparity,” the researchers’ data showed a 9.9 percent difference in five-year survival between black and white patients when matched for demographics. When matched for presentation the disparity was 4.9 percent, and when matched for treatment it was 4.3 percent.

“In conclusion, more of the racial disparity in colon cancer survival is explained by differences in health at diagnosis (both the state of the cancer and comorbid conditions) than by differences in subsequent treatment,” the authors write. “Our study suggests that the most effective route to reducing the racial survival disparity is to find ways to reduce the disparity in presentation, so fewer black patients present with advanced disease.”

To read more about the JAMA study, see Penn Medicine’s press release. And for more information about the Annals of Internal Medicine paper, see the journal.

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Lessons Learned From OB Unit Closures: Planning, Communication Needed


Hospital staff of obstetric (OB) units are dedicated to ensuring that an infant’s birth is a moment of wonder and joy, but after a series of hospitals in Philadelphia began closing their maternity programs, the OB units that remained open were strained by surges in patient volume, low workforce morale, and lack of care continuity, according to a new study led by researchers at The Children’s Hospital of Philadelphia.

From 1997 to 2012, 13 out of 19 hospital maternity units shut down within the city. The researchers conducted semistructured interviews with 23 obstetric department chairs, leaders of private obstetric groups, obstetricians, nurses, nurse managers, and midwives at 11 hospitals that continued their maternity units. Based on their responses, the researchers learned that better transition planning is needed to help reduce stress on the health systems’ staff and avoid fragmented care for mothers and babies.

“While the degree of obstetric unit closures was larger in Philadelphia than in any other metropolitan area, analyzing the situation may provide useful lessons for other areas as hospital consolidations, closures, and mergers have accelerated since the enactment of the Affordable Care Act,” said study leader Scott A. Lorch, MD, MSCE, a neonatologist and researcher in the Center for Outcomes Research at CHOP.

Dramatic surges in delivery volume were the greatest challenge, according to study participants. Maternity units averaged a 58 percent increase in volume, resulting in frequent overcrowding, understaffing, and lower staff morale. Moreover, the overall patient mix shifted toward poorer patients who were more likely to receive late or no prenatal care.

Prior to the closures, patients often received prenatal care at the same hospital where they gave birth. As the maternity units shut down, the patients had to choose another birthing hospital. Their prenatal health information did not always follow them to the new hospital. “One clear message from this study is that women need help from their healthcare system in obtaining better continuity of care throughout their pregnancies,” Dr. Lorch said.

Overall, the study participants identified two main areas for improvement: better communication among hospitals before closures occurred, and the development of regional solutions to exchange health information and coordinate prenatal care with care at delivery.

“Because hospitals compete with each other for patients, local health departments may need to exercise foresight and planning, identifying hospital units at risk for closing,” Dr. Lorch said. “Easing the transition when obstetric units close should improve the experience of both patients and caregivers.”

Dr. Lorch and colleagues published their research in the December 2014 issue of Health Affairs and spoke Dec. 8 at a forum sponsored by the journal at the National Press Club in Washington. Co-authors included Ashley Martin, MPH, and Richa Randa, MPH, both from the Center for Outcomes Research at CHOP; and Sindhu K. Srinivas, MD, MSCE, and David Grande, MD, both from Penn Medicine. The study was funded by the Agency for Healthcare Research and Quality, part of the National Institutes of Health.

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