Neuroscience leaders discuss innovations and their successes, and the need for much more work to be done

Two of CHOC’s leading pediatric neurosurgeons recently shared their insights on how innovation is helping to close the gap between clinical needs and the availability of pediatric devices, but how there is much more work to be done to get critically ill kids the treatments they need.

The webinar, “From Clinical Insight to Commercialization: Innovations That Can Transform Pediatric Healthcare,” featured Dr. Suresh N. Magge, CHOC CS Neurosurgery Division Chief, and co-director of CHOC’s Neuroscience Institute, and Dr. Michael G. Muhonen, the institute’s previous co-director.

Hosting the “OC LIFe (Lifesciences Innovators Forum)” on April 28, 2021 was Dr. Terence Sanger, a physician, engineer, and computational neuroscientist and vice president, chief scientific officer at CHOC, and vice chair of research for pediatrics at the UCI School of Medicine.

“As innovators, we should never be satisfied,” said Dr. Sanger, who specializes in movement disorders and who helped pioneer deep brain stimulation, which has yielded positive outcomes. “An innovative and collaborative approach is required so that pediatric patients can have access to the fit-for-purpose devices they need.”

Brain tumor treatments

Drs. Magge and Muhonen took turns discussing new neurosurgical technologies and opportunities for interventions.

Dr. Magge focused on new technology that has been used to treat brain tumors, which are a different breed compared to adult brain tumors. More often, Dr. Magge said, pediatric brain tumors are of a lower grade and can be treated.

“Many kids have gone on to live good lives thanks to innovation, research, and applying the technologies we have,” Dr. Magge said.

In one example, he detailed how microsurgical techniques have greatly aided in the removal of a craniopharyngioma, a benign tumor that usually arises in the base of the brain near the pituitary gland that can be dangerous or life threatening if not treated.

“If you can get the tumor out,” Dr. Magge said, “you can cure the patient. But it’s challenging because it’s in a deep part of the brain.” 

During the procedure, the neurosurgeon must locate some of the natural divides of the brain and separate them out to get to the tumor. Microsurgery allows the neurosurgeon to work between very narrow areas.

With a technology known as surgical navigation, neurosurgeons can pinpoint exactly where they are in the brain and get to very specific areas. Another technology is a powerful microscope that magnifies small areas of the brain. In addition, ultrasound and MRI within the operating room can tell you in surgery if there is any tumor left. 

“This is all thanks to innovation and technology that we are incorporating in surgery,” Dr. Magge said.

Dr. Magge then discussed medulloblastomas, one of the most common types of tumors neurosurgeons see in kids. Such large tumors grow in the lower back part of the brain — the cerebellum, which is involved in muscle coordination, balance, and movement.

Thirty years ago, Dr. Magge said, kids with medulloblastomas received high doses of radiation that left a lot of them with severe cognitive and hormonal deficits.

The treatment for medulloblastomas had evolved so that less radiation is used in the treatment. In addition, in the last decade, researchers have discovered that these tumors differ significantly based on their genetic makeup.

“These tumors have multiple genetic subtypes, and we can target them genetically with different types of treatments,” Dr. Magge explained.

He said innovation also has led to advances in the treatment of diffuse intrinsic pontine gliomas (DIGP), highly aggressive and difficult-to-treat brain tumors that grow in an area of the brainstem that controls many of the body’s most vital functions such as breathing, blood pressure, and heart rate.

The prognosis for DIPGs remains very poor because they are considered non-resectable tumors – ones that cannot be removed with surgery. Life expectancy is eight to 12 months after diagnosis.

“This is one of the toughest diagnoses we have to give to families because of the lack of good treatment options,” Dr. Magge said.

For years, biopsies were ruled out because they could cause significant side effects, and neurosurgeons saw no point in performing them since there were no treatments. Without biopsies, the tumor tissue could not be studied in a lab for potentially effective treatments. 

Technology has changed this is the last 10 years, Dr. Magge said, thanks to stereotactically guided needles that allow neurosurgeons to perform DIPG biopsies safely.

“We at CHOC and other pediatric hospitals have shown we can do this safely with minimum morbidity,” said Dr. Magge, who has participated in a large clinical trial regarding DIPG biopsies.

“With this technology, we can get tissue and genetically sequence these tumors and find out if there are certain mutations that are particularly amenable to certain treatments,” Dr. Magge said of this precision-medicine approach. 

“These are small steps along the path,” he added. “We have by no means found all the answers. We have so much farther to go, but I think we’re on the right track.” 

Closing the gap

Dr. Muhonen recalled one of the first patients he saw when he came to Orange County in 1995: a young girl with severe spasms in her legs. She couldn’t walk without assistance.

“We had to do something innovative,” Dr. Muhonen said.

He had injected baclofen, a muscle relaxer and antispasmodic agent, into the spinal column of an adult the year before, but never in a child. After receiving approval to do so, he implanted a device that allowed long-term injection of baclofen in the girl’s spinal cord. Six months later, she was able to walk and even run on her own.

In another example of innovation, Dr. Muhonen worked for five years on helping to develop a wireless sensor to measure pressure in the brain. The FDA approved the device for adults, but has yet to for children.

Most companies get medical devices approved for adults because it’s easier, because there’s a larger patient population, and there’s more money to be made. 

“The bulk of challenges associated with developing and accelerating pediatric medical devices is market-driven,” Dr. Muhonen said. “We want children to get the best possible care available, but the relative market size is small compared to adults, which is one reason some device makers avoid it.”

One of Dr. Muhonen’s chief interests is treating hydrocephalus, the buildup of fluid in the ventricles deep within the brain.

Innovation in this area has been a long time coming, he said, since the invention in the early 1950s of a shunt that drained fluid from the brain into the abdominal cavity. Many problems can occur with the shunt, such as spontaneously twisting up into a knot due to a child’s movement or calcifying and breaking apart after being in the body for a long time. Kids who received a shunt typically face more than 10 surgeries, Dr. Muhonen said.

“The holy grail for pediatric neurosurgeons is, can we create a ‘smart shunt?’” Dr. Muhonen said.

An ideal shunt, he said, could be programmed to drain a specific amount of water and measure pressure.

Dr. Muhonen said a derivative from cone snails is inspiring research into a new generation of painkillers for adults, but has yet to be approved for testing on kids.

Impediments to innovation

Dr. Sanger asked Drs. Magge and Muhonen about impediments to pediatric innovation. Ethically, he posited, shouldn’t new devices and other innovations be tested in adults first? 

“I don’t think there are any easy answers to this,” Dr. Magge said. “It’s difficult. You don’t just do a biopsy on a tumor that might help kids in the future. If you perform surgery on a child, there has to be some potential benefit to that child.”

Dr. Muhonen said children are the most vulnerable of society and thus are the worthiest of innovations in healthcare. 

Dr. Magge said he and others at CHOC have been looking at ways to inject dyes to paint brain tumors to more easily distinguish them from healthy brain tissue.

“Sometimes the tumor is obvious, sometimes it’s more challenging,” he said.  While dye injections have been used in adults, it is less commonly used in children.

Dr. Sanger mentioned “big effect sizes” resulting from innovation in pediatric medicine. 

“We’re used to the idea of statistical research involving a lot of patients,” he said. “But this is a different type of research. You take someone who has never walked before and now they’re running. You take someone who is going to die of a brain tumor and now they’re not. These are very big effect sizes.” 

“There are good reasons for the regulations we have,” Dr. Magge said. “That being said, that doesn’t mean we can’t innovate. And there are mechanisms for us to do that, and to do it safely.

“Our first motto is, ‘Do no harm,’” Dr. Magge continued. “I always tell residents to do the right thing and treat each patient as if they were your own child. Doing the right thing means asking the right questions. ‘How can we do this better?’ You can always learn from everything you do. At the end of every procedure, you critique it. You’re constantly learning. That’s what I always encourage.” 

Dr. Sanger closed the session by noting that clinical evidence should ideally be reflective of the spectrum of pediatric patients and the developmental differences that can impact the use and effectiveness of medical devices.

“This is a collaborative effort,” he added. “CHOC is working closely with the FDA’s new System of Hospitals for Innovation in Pediatrics – Medical Devices (SHIP-MD) Program, our academic partners, industry, entrepreneurs and the investor community to close the gaps. Also, we are now practicing medicine in a world immersed with data. Advances in computing and health information technology have given rise to new sources and types of biomedical data. Clinicians know real-world data will continue to emerge as a source of clinical evidence.”

The Presenting Sponsor of the webinar, “From Clinical Insight to Commercialization: Innovations That Can Transform Pediatric Healthcare,”  was Biocom California, which connects life science organizations to each other so they can collaborate and work smarter together. The CHOC Research Institute co-sponsored the hour-plus session.

The webinar was presented in partnership with SBDC @ UCI Beall Applied Innovation, a resource for any high-technology, high-growth, scalable venture from the community or the UCI ecosystem that needs help with business planning, business development and funding-readiness.

Learn more about CHOC’s Neuroscience Institute.

New app helps build daily routines for kids with autism spectrum disorder

A couple of years ago, Adam Gold, CHOC’s chief technology officer, started thinking about what kind of app could help parents of kids with autism – or kids with other cognitive challenges, for that matter.

Gold has a nephew who has autism spectrum disorder (ASD), and his wife, Lisa, is a special education teacher. 

Now, Gold’s creation, an app he calls uTine (a play off the word “routine”), is on the verge of being tested on patients at the Thompson Autism Center (TAC), with a pilot version set to be ready by July 2021.

“The idea was to develop an app for children with autism and other cognitive challenges that they could use to help them get into routines or complete daily tasks,” says Gold, who will detail the app at CHOC Innovation Day on June 25.

Adam Gold, chief technology officer at CHOC

Casey Clay, PhD, director of the Behavior Program at the TAC, will pilot the app with patients and their parents.  

“Kids on the autism disorder spectrum like predictability of events, and this app will provide them with visual reminders of their next activity or task,” Clay says.

“What’s interesting about this app,” he adds, “is there’s a rich literature base in the field of behavior analysis and a lot of research on the effects of picture activity schedules, or visual activity schedules to help kids follow a schedule or get through an activity.”

CHOC Innovation Day — “A celebration of innovation at CHOC — will be held Friday, June 25, from 1-3 p.m. The online session, held in honor of the late Dr. Nick Anas for his contributions to innovation and medical intelligence, is open to all CHOC physicians and associates.

The virtual event will feature remarks by CHOC CEO Kim Cripe and Dr. Anthony Chang and also will showcase groundbreaking artificial intelligence and virtual reality projects, innovation by nurses, and much more.

On May 20, Gold previewed the uTine app during Pediatric Innovation Start-up Demo Day, an online forum hosted by The Innovation Lab in Newport Beach.

Gold worked with the Innovation Lab, a for-profit organization owned by non-profit healthcare systems, in developing uTine.

“I’m excited about it for a couple of reasons,” says Suzy Engwall, national director at The Innovation Lab. “First, the incidence of autism continues to grow. Kids with autism grow up to be adults with autism, and many who are on the spectrum never learn some of the basic life skills they need to have in order to take care of themselves every day.

“Second, as those with ASD get older, they ‘age out’ of many services, and if they don’t have family members who can take care of them, they will often end up in institutions or other places that they really shouldn’t be in, instead of living on their own because they haven’t learned all of the necessary life skills to do so.

“It’s really important to start as young as we can to teach these life skills in a fun and memorable way. We’ve really got to help those of the autism spectrum become as self-sufficient as possible.”

Suzy is working on the uTine app along with Innovation Lab colleagues Matt Keller, client engagement executive; Ganesh Laxminarayan, executive director, Health IT; Hesham (Sam) Mahdawi, technical project manager; and Durai Ashok, senior solutions architect.

How the app works

The app, which helps kids complete routine tasks such as brushing their teeth, putting on their shoes, and eating lunch, is easy to use with a simple design starring several cartoon animals, including a dog, a cat and a porcupine.

A parent signs up and creates a profile for his or her child, including name, age and personal preferences.

The parent can then start creating “uTines” with step-by-step instructions on how to complete a task. 

Using their own phone or their parent’s phone, the child captures each attempted or completed task by snapping a picture. The parent receives a notification and reviews the picture. The parent then can reward the child for completing a task – such as 15 minutes of TV time, 10 minutes on YouTube, one hour of playing with the dog – whatever the child likes to do.

When they reward their child, a parent can click on a pre-written message to send, such as, “You’re on fire today!”

Gold says he’s working on creating a public library parents can use for very simple uTines so they don’t have to create them themselves.

A key feature of the app is that parents can invite members of the child’s care team into the experience – a doctor, a nurse, a teacher, a psychologist. They, in turn, can gain insights into how the child is doing and chat back on forth securely with the parent.

Gold says he hopes the app gains traction for children with any condition or kids in general who have a hard time establishing routines.

“This app builds on a rich body of evidence-based research, so it’s very likely to succeed,” adds Clay. “This is all about pushing evidence-based research further so we at CHOC can help parents who have kids with autism and other conditions.”

Register here for CHOC Innovation Day.

Learn more about the Thompson Autism Center at CHOC.

As COVID-19 wanes, CHOC’s medical epidemiologist, Dr. Jasjit Singh, recalls 2016 dental clinic outbreak

As the grip of the COVID-19 pandemic continues to weaken, Dr. Jasjit Singh, CHOC’s medical epidemiologist and medical director of infection prevention and control, recalls a ghost of outbreaks past.

Nearly five years ago, a mysterious outbreak of oral infections that eventually was traced to a clinic in Anaheim alarmed parents and dominated the local news.

The health crisis spurred Dr. Singh and a multidisciplinary team at CHOC, working with several community partners, to search for answers – and to provide optimal care for the patients, whose median age was 6.

Over 100 children were admitted to CHOC for evaluation, of whom 70 were confirmed cases, hospitalized for an average of more than a week.

Some suffered permanent tooth loss – as many as six teeth.

The culprit: a Mycobacterial abscessus infection that was detected after each child underwent a pulpotomy procedure, or “baby root canal,” to remove or treat an infected tooth at the Anaheim clinic between Jan. 1 and Sept. 6, 2016.

The outbreak turned out to be the largest ever of invasive Mycobacterial abscessus infections associated with a dental practice. The commonly occurring M. abscessus bacteria is found in water, dust, and soil, but it’s an uncommon cause of healthcare-associated infection.

Between July and September 2016, three patients were admitted to CHOC with atypical infections. All had some combination of facial cellulitis, dental abscess, and/or cervical adenitis that had been present for weeks.

“We had our first child present with what appeared to be a really unusual infection,” Dr. Singh recalls. “Our first thought was, ‘What’s wrong with this child’s immune system?’

“When the second child came in, one of my very astute colleagues, Dr. Negar Ashouri, ascertained that the child had been treated at the same dental clinic. She alerted the OC Health Care Agency immediately, who soon found unexplained symptoms brewing in other kids.” 

A mobilized effort

The California Department of Public Health, the Centers for Disease Control and Prevention, and the Dental Board of California worked with the OC Health Care Agency (OCHCA) to investigate the infections.

The team at CHOC helped OCHCA with the epidemiologic and diagnostic probe. Of 1,081 at-risk patients, 71 case patients (22 confirmed; 49 probable) were identified.

Here at CHOC, 27 of the most severely affected children were treated with a complex regimen of antibiotics, including clofazimine, marking the largest number of children to ever receive that medication outside of treatment for leprosy.

Details of the work of Dr. Singh and many others recently was published by Oxford University Press on behalf of the Infectious Disease Society of America.

Publication of the paper, “Invasive Mycobacterium abscessus Outbreak at a Pediatric Dental Clinic,” was delayed a year and a half by the COVID-19 pandemic, Dr. Singh says.

The infections were caused by untreated municipal water the Anaheim clinic was using for drilling and irrigation during pulpotomy procedures. Because pulpotomies are not considered surgical procedure, sterile water is not required.

A change in state water standards

The work of Dr. Singh and an army of others led to a change in water standards for pediatric dental procedures in California.

In September 2018, the governor signed into law a bill that specified as unprofessional conduct the use of water that is not sterile or that does not contain recognized disinfecting or antibacterial properties when performing dental procedures on exposed dental pulp.

Dr. Singh is hopeful that the publication of the paper, whose listed authors include 11 CHOC physicians and three officials with the OC Health Care Agency, will lead to similar laws being enacted in other states.

As the paper puts it, “The authors believe the measure adopted in California for the use of sterile water for all pulpotomies is an appropriate standard which we would like to see embraced by the American Dental Association and state dental boards around the country.”

Dr. Singh credits the multi-disciplinary team for caring for the patients. The team included specialists in infectious disease, oral surgeons, ENT doctors, radiologists, dentists, pharmacists, and staff members of Providence Speech and Hearing, among others.

“These were normal, healthy children that were affected,” Dr. Singh says. “The multi-disciplinary coordination was a huge part of the success of this story. Still, many of the patients who lost permanent teeth will need dental rehabilitation in the future. It was a very difficult period for these families.

“We talked to national experts and really delved through whatever literature was out there,” Dr. Singh adds. “We all came together to get the kids and families through this with the least morbidity and the best long-term outcome possible.” 

Read about Dr. Jasjit Singh and Dr. Antonio Arrieta earning a global distinction for excellence.

Virtual Pediatric Lecture Series: High Blood Pressure in Children and Adolescents

CHOC’s virtual pediatric lecture series continues with “Pediatric Nephrology: High blood pressure in children and adolescents.”

This online discussion will be held Thursday, June 17 from 12:30 to 1:30 p.m. and is designed for general practitioners, family practitioners and other healthcare providers.

Dr. John D. Nguyen, pediatric nephrologist at CHOC, will discuss several topics, including:

  • Diagnostics and work up for pediatric hypertension
  • Identifying findings and history suggestive of secondary hypertension.
Dr. John D. Nguyen, pediatric nephrologist at CHOC

This virtual lecture is part of a series provided by CHOC that aims to bring the latest, most relevant news to community providers. You can register here.

CHOC is accredited by the California Medical Association (CMA) to provide continuing medical education for physicians and has designated this live activity for a maximum of one AMA PRA Category 1 Credit™. Continuing Medical Education is also acceptable for meeting RN continuing education requirements, as long as the course is Category 1, and has been taken within the appropriate time frames.

Please contact CHOC Business Development at 714-509-4291 or BDINFO@choc.org with any questions.

State-of-the-art CHOC Outpatient Heart Center now open

A new state-of-the-art clinical space on CHOC’s main Orange campus brings together multidisciplinary pediatric cardiology and cardiothoracic surgery outpatient services under one roof.

The 10,000-square-foot CHOC Outpatient Heart Center, which began seeing patients May 24, offers general and subspecialty pediatric cardiology, as well as cardiothoracic surgery outpatient services, multidisciplinary cardiology and cardiothoracic surgery services — including evaluation and management — and cardiodiagnostics to patients with congenital and acquired cardiac disease.

The new outpatient center is devoted to evaluating children as early as possible, engaging children with diagnoses, symptoms and behaviors that diminish their quality of life and life expectancy. The center creates a treatment plan for each patient, coordinating care and establishing a long-term support system for children with complex care needs.

With 23 clinical rooms for echocardiograms, stress testing and consultations, as well as rooms that can be used for exams or echocardiograms, the center establishes a single location for patients’ cardiology needs.

Sky and seascape imagery in a soothing color palette fill the serene environment of the CHOC Outpatient Heart Center. In the waiting area, patients can interact with a digital, touchless coloring display.

The Heart Center also features a physician reading room; a conference room; an exercise stress test room; a flex space; and family consultation/telehealth rooms.

Refer a patient to the CHOC Outpatient Heart Center.

Three-stage DBS results in better outcomes for secondary dystonia

Due to the complexity of secondary dystonia and the brain’s potentially unpredictable response, deep brain stimulation (DBS) has seldom been used in the treatment of this disorder. However, a CHOC neuroscientist has developed a breakthrough method of DBS to treat secondary dystonia in pediatric patients.

Dr. Terence Sanger, pediatric neurologist and chief scientific officer at CHOC, has pioneered a new surgical approach in DBS for pediatric secondary dystonia. Patients undergo three procedures rather than two, nullifying the need for patients to be awake during DBS surgery. Not only does this save children from the potentially traumatic experience of being awoken during brain surgery, it leads to significantly better outcomes in secondary dystonia treatment, with a current success rate between 85% and 90%.

Dr. Terence Sanger, pediatric neurologist and chief scientific officer at CHOC

Unlike patients receiving DBS for other disorders, where results can be observed during surgery, a child with secondary dystonia may have concerns with movements or actions that can’t be addressed on the operating table. For example, a child with secondary dystonia may have difficulty walking, but the physician cannot test DBS’ effectiveness by waking the child and asking him or her to walk.

To overcome this obstacle, Dr. Sanger and his team first insert test electrodes into the patient’s brain. The initial procedure is followed by a week of surveillance and testing. After selecting which electrodes are most effective at treating the patient’s symptoms, the team places permanent electrodes followed by a third procedure to implant the stimulator. The week between the placement of test electrodes and the placement of permanent electrodes allows Dr. Sanger and his team to observe which electrodes are effective.

“The biggest benefit of the three-procedure method is we know where the wires need to be in the patient’s brain for the most effective treatment,” Dr. Sanger says. “By the time we get to the third surgery, we know exactly what’s going to happen. As an engineer, I’m a big believer in measuring twice and cutting once, and effectively, that’s what these three procedures allow us to do. Every child’s brain is different, so we have to learn about how each brain operates before we can perform a successful surgery.”

In addition to his revolutionary procedure for secondary dystonia, Dr. Sanger believes in the future of neuroscience at CHOC.

“At CHOC, our tagline for research is ‘Go beyond,’ and I’ve never seen that belief more exemplified than in the work I’ve seen at our Neuroscience Institute,” Dr. Sanger says. “We are not going to improve pediatric neurology care by doing what other hospitals do, but better. We are going to improve by doing something different, like we’ve done with DBS for secondary dystonia. It’s very exciting, and I believe we have the opportunity to make a huge difference.”

Our Care and Commitment to Children Has Been Recognized

CHOC Children’s Hospital was named one of the nation’s best children’s hospitals by U.S. News & World Report in its 2020-21 Best Children’s Hospitals rankings and ranked in the neurology/neurosurgery specialty.

USNWR Neurology and Neurosurgery award

Learn how CHOC’s neuroscience expertise, coordinated care, innovative programs and specialized treatments preserve childhood for children in Orange County, Calif., and beyond.

Rapid Whole Genome Sequencing continues to provide answers and hope for parents of critically ill children with rare diseases

If a Major League Baseball player were to step up to the plate 150 times and get a hit 76 times, his batting average would be an unthinkably torrid .507. 

When it comes to identifying genetic causes for some of the rarest and serious diseases in children, CHOC has put up numbers that even Mike Trout couldn’t dream of achieving. 

Since July 2017, CHOC has ordered the comprehensive and cutting-edge test of rapid whole genome sequencing (rWGS) on 150 patients, with 76 of them getting a precise diagnosis that, in many cases, has resulted in life-changing care. 

“We took what could have been a diagnostic odyssey for these patients and families and cut it down from weeks, months, and sometimes years to, in some cases, only three days,” says CHOC pediatric intensive care unit medical director Dr. Jason Knight, part of an informal leadership team that oversees treatment of critically ill kids with rare diseases in the NICUPICU and CVICU. Other ICU physician team leaders include Dr. Adam SchwarzDr. Juliette Hunt and Dr. John Cleary

CHOC’s rWGS research program was championed by the late Dr. Nick Anas, CHOC’s former pediatrician-in-chief who was director of pediatric intensive care and a beloved figure at the hospital. Dr. Anas, who started at CHOC in 1984, died on April 3, 2018. 

Dr. Anas’ vision for the rWGS research program continues to be realized with successful patient outcomes, from the 2019 diagnosis of an infant girl with the extremely rare cardiac condition Timothy Syndrome to, more recently, a baby boy – Oliver Marley – with a genetic disorder that has been detected in only 10 children worldwide. 

“The CHOC team believed in Oliver – they loved him and took care of him and saw worth in him,” says Caroline Marley of her son, who turns 10 months old this May and was cared for by CHOC clinical teams during two stays, once in the NICU and the second time in the PICU. 

“They told me, ‘We want you to take your baby home,’” Caroline says. 

Testing began in 2017 

Each of us has some 22,000 genes in our bodies that dictate things ranging from the color of our hair to whether we are tall or short. Genes also produce the proteins that run everything in our bodies. Although individually rare, there are more than 6,200 single-gene diseases. RWGS is the technology that, with just a teaspoon of our blood, allows us to look at all the genes in our cells.  

At CHOC, rWGS testing became prominent with the launch of Project Baby Bear in fall 2018. CHOC was among five hospitals to participate in that program, led by Rady Children’s Institute for Genomic Medicine (RCIGM) in San Diego. RCIGM has a lab that runs sequencing. 

“To have (the RCIGM) close by and to be a close partner with them has been great,” Dr. Knight says. “We are way ahead of many other pediatric hospitals in this area. It’s a great success story, and something I’m really glad to be a part of.” 

A total of 45 CHOC patients got tested through Project Baby Bear, a $2-million state program for critically ill infants age 1 or younger who were enrolled in Medi-Cal. Of those 45 patients, 55.6 percent – 25 children – were able to have their rare diseases properly diagnosed, says Dr. Neda Zadeh, a CHOC medical geneticist who was involved with setting up CHOC’s rWGS program with Dr. Anas and who has seen most of the 150 kids tested thus far. 

CHOC actually began ordering rWGS testing on patients the year before in a partnership with RCIGM and Illumina, a leading developer and manufacturer of life science tools and integrated systems for large-scale analysis of genetic variation and function. In that 2017 program, 82 CHOC patients were tested with a 47.6 percent positive diagnosis rate, says Ofelia Vargas-Shiraishi, a senior clinical research coordinator in critical care/neonatology research at CHOC. 

CHOC has paid for an additional 23 children to undergo rWGS testing outside of the now-completed Ilumina and Project Baby Bear programs, and continues to have funding on a case-by-case basis, says Dr. Schwarz. 

“In the long run,” Dr. Schwarz says, “we’re saving money by avoiding expensive workups.” 

Adds Dr. Knight: “For a lot of these families, having an answer – even one they might not want to hear – is extremely important.” 

For parents like Caroline Marley, the results have been priceless. 

‘Wouldn’t place money on your son’ 

Oliver was born at 33 weeks after a complicated pregnancy for Caroline, who had a partial placental abruption when she was 14 weeks pregnant. Caroline and her husband, Ted, have another son, Charlie, 4, who is healthy. 

Oliver Marley with his older brother, 4-year-old Charlie

Born weighing 5 pounds and 4 ounces, Oliver had bruises over much of his body and had to be intubated a day after birth when he went into respiratory failure. Doctors detected a small brain bleed and noticed that, at 6 days old, both of his middle fingers were contracted. 

“I’ve never seen this before,” a neurologist at another hospital where Oliver was being treated told the Marleys. 

Oliver also had difficulty swallowing. He could move his arms and legs a bit, but he couldn’t open his eyes. 

Doctors suspected he might have muscular dystrophy. 

After other complications, doctors told the Marleys that Oliver’s outlook looked grim and that he may have to be sent to an acute-care facility. 

“We can’t help him,” one doctor told Caroline. “I don’t believe he will ever come home. If I were going to Vegas, I wouldn’t place money on your son.”  

It got to the point where the Marleys felt Oliver wasn’t getting the best care, so they decided to transfer him to CHOC. A nurse at another hospital whom the Marleys knew recommended CHOC.  

“We will absolutely take him,” a CHOC nurse told the Marleys. 

Oliver transferred to CHOC on Aug. 11, 2020. 

At 8 weeks old, Oliver underwent a tracheotomy and was attached to a ventilator. 

“He literally started thriving,” Caroline recalls. “He started growing because he was not working so hard to breathe. You could just see he was doing better.” 

Still without a diagnosis, Oliver went home on Oct. 19, 2020 with a tracheostomy tube and a ventilator.  

He returned to CHOC after he contracted a viral infection. 

Not convinced Oliver had muscular dystrophy, Dr. Schwarz suggested him as a candidate for rWGS.  

Three days later, in mid-November 2020, the Marleys received an answer: Oliver had two extremely rare genetic changes in his AHCY gene that potentially resulted in S-AdenosylHomocysteine Hydrolase (SAHH) deficiency.  

It is an extremely rare condition with less than 30 patients reported in the world and CHOC’s Dr. Richard Chang, a metabolic disorders specialist and  biochemical geneticist, was consulted to confirm the diagnosis. The disease, which affects brain, muscle and liver development, is associated with high blood levels of methionine and extremely high levels of toxic S-AdenosylHomocysteine (SAH) that interferes with vital cellular growth. 

Oliver was put on a delicate protein-restricted diet to limit the production of SAH without causing protein malnutrition, and his condition immediately improved. Other medications were added subsequently to provide nutrients that deficient due to the toxicity of SAH. He has a condition that is identical to a girl in Pennsylvania who was diagnosed at age 3 and later underwent a liver transplant. That girl is now 9. 

Oliver is scheduled to receive a liver transplant soon, Caroline says. 

Expanding access to rWGS testing 

A lawmaker in San Diego, in partnership with Rady Children’s Hospital and Health Center, is pushing for a new law that would expand access to rWGS testing by qualifying it as a Medi-Cal covered benefit for babies hospitalized in intensive care. 

Assembly Bill 114, The Rare Disease Sequencing for Critically Ill Infants Act, not only would expand availability of such testing to more families, but also would reduce state spending by eliminating many unneeded procedures, treatments and longer hospital stays, State Assemblyman Brian Maienschein wrote in a recent op-ed piece.  

“For critically ill infants hospitalized with unexplained rare diseases,” Maienschein wrote, “the opportunity to benefit from a medical miracle has arrived.” 

Caroline Marley sees that miracle daily with Oliver, who now is up to 20 pounds and moving around more. 

“We at CHOC are slowly building a case for early introduction of rWGS into the clinical management of these difficult cases in high-acuity settings to improve lifelong clinical outcomes and quality of life,” says Brent Dethlefs, executive director of the CHOC Research Institute. 

“There’s growing evidence that early introduction of this technology results in overall cost savings,” Brent adds. “It’s important to get more insurance carriers to cover the cost of this testing over time, which will make rapid whole genome sequencing more available to vulnerable and underserved populations. CHOC always has been an advocate for social justice in health care, which includes greater access to genomic testing.” 

Caroline Marley praises the entire collaborative team at CHOC and the entire CHOC Specialists Metabolic Disorders division, including Dr. Chang, who is in charge of maintaining Oliver’s health until transplant; Erum Naeem, clinical research coordinator, NICU; and Cathy Flores, clinical research nurse coordinator, critical care. 

“It was a team effort involving the critical care, neonatology, metabolic and genetics teams, just to name a few, and a very strong partnership with RCIGM,” says Ofelia Vargas-Shiraishi, a clinical research coordinator at CHOC. 

“We had everyone by our side every step of the way,” Caroline adds. “Child life was amazing, and so is the spiritual care team. If you’re willing to learn, they’re willing to teach you.” 

Dr. Zadeh says the success of CHOC’s rWGS program – with its whopping .507 batting average – is a result of “a very unique blend of the right people coming together at the right time and the right institution with the right set-up.” 

She adds, “I don’t think it would have worked necessarily at every hospital. I think CHOC is unique. We have the right group of kids we are testing. And we have the right group of specialists involved. 

“We love our families. We get to have really great relationships with them. This program just shows that CHOC is all about the whole care of the child and the family.” 

Landmark study of COVID-19 infection among K-12 students debunks early fears about transmission at schools

Debunking a fear that was widespread at the beginning of the COVID-19 pandemic, a novel CHOC- and UC Irvine-led study of SARS-CoV-2 infection rates among the K-12 population concludes that within-school transmission of the virus is limited.

The “Healthy School Restart Study,” one of the first to provide essential research on COVID-19 transmission in children and adolescents as schools started reopening last fall, also concludes that although the compliance rate to such mitigation guidelines as wearing face coverings and practicing social distancing at the four Orange County schools directly observed by investigators varied, it averaged about 90 percent.

The seminal research paper is under review and is expected to be published soon, says Dr. Dan Cooper, who treats kids with lung conditions at CHOC and who serves as director of UC Irvine’s Institute for Clinical & Translational Science. Dr. Cooper is a multiple principal investigator of the study along with Dr. Erlinda Ulloa, a CHOC infectious disease specialist and an assistant professor in the Department of Pediatrics at the UCI School of Medicine.

Dr. Dan Cooper, pediatric pulmonologist at CHOC

“The number one fear was that, just like influenza, children would be a reservoir for COVID-19 and would spread it to each other at schools and then spread it to adults,” Dr. Cooper says. “The data is showing us, fortunately, that that’s not the case. While such spread can occur, it is limited and when schools follow standard mitigation procedures, spread is minimal.”

The study, a joint effort of CHOC, UCI Health and the Orange County Health Care Agency, found that infection rates at schools reflected those of the community, and that neither remote learning nor highly mitigated onsite school attendance could eliminate SARS-CoV-2 infection.

“It would be disingenuous to say it’s 100-percent safe to return to schools – we’re still in a pandemic,” Dr. Cooper says. “It would be wrong to say there’s absolutely no risk in sending your child back to school, but it would also be wrong to say there’s no risk in not sending your child back to school.”

A total of320 students ages 7 to 17, as well as 99 school staff members, participated in the research project by agreeing to nasal swab and blood testing. Two of the schools in the study serve low-income Hispanic learners. One school serves a high proportion of kids with special needs, and the fourth school serves predominately white kids from upper- and middle-class families. The first three schools mainly provided remote instruction, while the fourth school predominantly provided onsite instruction.

“The four participating schools reflected the enormous diversity of income, community COVID-19 case rates, school type (private, charter, public), and learning status (remote vs. onsite) that face learners, school staff, and policy makers across the United States,” the paper states.

The study was done in two phases – in early fall, when there were lower levels of COVID-19 cases, and a second time during the late fall-winter surge, when there was a tenfold increase in COVID-19 cases. Trained observers studied kids four times a day – during classroom learning, at active recess, during PE, and during communal lunch.

During the first testing phase, no kids tested positive for COVID-19. During the second phase, 17 kids tested positive for the virus, along with six staff members.

School A, which primarily serves lower-income Hispanic students and had 97 percent of its students engaged in remote learning, had the highest infection rate, at 12.9 percent. School D, which serves upper- and middle-class students who primarily attended class in person, had the lowest infection rate, at 1.2 percent.

In the aggregate, there was no statistically significant difference in SARS-CoV-2 positive rates among remote or onsite learners, the study found.

In addition, the study found there was a significant relationship between SARS-CoV-2 positivity and presence of symptoms – data that supports the use of limited symptom screening as a mechanism to enhance healthy school reopening.

Investigators also tested for 21 other circulating respiratory pathogens and turned up no signs of the influenza virus – just the common-cold rhinovirus, which stays functional on surfaces such as desktops for much longer intervals than the coronavirus or influenza virus.

“The mitigation procedures and cleanliness procedures that had been put in place got rid of the flu,” Dr. Cooper notes.

He adds: “This study should make parents feel better and prompt them to ask the right questions to their school. Parents should ask, ‘What are your mitigation plans? How are you making sure people are paying attention to your plan? What happens to a child who reports symptoms during the day? Do you have a plan?’ That’s what I would want to know as a parent.”

Mitigation procedures should remain

With widespread implementation of pediatric COVID-19 vaccination still many months away, it’s likely that adherence to COVID-19 mitigation procedures, including physical distancing and face covering, will need to continue for the near future, the study concluded.

Dr. Cooper notes that some students, mostly from lower-income families, are going on a year without in-classroom learning – an unfortunate situation that comes with many disadvantages, such as more sedentary time at home on the computer and increased obesity and depression.

“We have to weigh the damage to kids of keeping schools closed,” he says. “Who is being impacted most? It’s the low-income kids.”

In addition to Dr. Cooper and Dr. Ulloa, other CHOC and UCI personnel who participated in the “Healthy School Restart Study” included Jessica Ardo, Kirsten Casper, Andria Meyer, and Diana Stephens, clinical research coordinators; Dr. Charles Golden, vice president and executive medical director of the CHOC Primary Care Network; and Dr. Michael Weiss, vice president of population health at CHOC.

The authors of the research paper also acknowledged the “outstanding management” of the complex study by Phuong Dao, director of research operations; Brent Dethlefs, executive director of research; and other staff members of the CHOC Research Institute.

In another research paper, published in late February 2021 in the journal Pediatric Research, Dr. Cooper and Dr. Ulloa addressed the biologic, ethical, research and implementation challenges of SARS-CoV-2 vaccine testing and trials in the pediatric population.

Among others, the paper was co-authored by Dr. Coleen Cunningham, CHOC’s new senior vice president and pediatrician-in-chief, as well as chair of the UCI Department of Pediatrics, and Dr. Jasjit Singh, a CHOC infectious disease specialist.

Children under the age of 12, this paper notes, have yet to be enrolled in COVID-19 vaccine trials.

The paper states that enrolling children in medical research involves a balance between access to experimental but potentially life-saving therapeutics and protection from unsafe or ineffective therapeutics.

The paper notes that in the early stages of the pandemic, a national working group convened and published a commentary outlining the challenges ahead that would inevitably need to be addressed as schools reopened. That commentary, the paper says, included a message that resonates with the immediate challenge of pediatric SARS-CoV-2 vaccine testing and clinical trials:

“This could be accomplished by building public health-focused collaboratives capable of continuous learning and rapid cycles of implementation, as COVID-19 information evolves at breakneck speed. Otherwise, we risk further compounding the incalculable damage already incurred by COVID-19 among children across our country and the world.”

Read more about the Healthy School Restart Study.

CHOC partners buzzing about new virtual reality app that will teach parents about their child’s surgical devices

Two CHOC associates have spent the past year developing an app  to help parents caring at home for kids with medical devices such as gastric tubes, tracheostomy tubes, PICC lines, and central venous catheters.

The app, CareXR, will immerse parents in a virtual reality world created by pediatric gastroenterologist Dr. Ashish Chogle in partnership with veteran nurse Wanda Rodriguez, an instructor in the CHOC HELPs program.

Dr. Ashish Chogle, pediatric gastroenterologist at CHOC

The two gave a short demo on the new app during Pediatric Innovation Start-up Demo Day, an online forum hosted by The Innovation Lab in Newport Beach on May 20, and will present the app again at CHOC Innovation Day on June 25. 

Dr. Chogle designed the app in collaboration with Wanda, The Innovation Lab — which CHOC is affiliated with — and BioflightVR, a virtual reality app development company based in Santa Monica.

The CareXR platform will feature practice modules intended to provide parents and caregivers peace of mind when caring for kids at home. Forty-two percent of children are discharged from U.S. hospitals with some medical technology, the majority being G tubes and central lines.

CareXR is the first app developed by Dr. Chogle, whose philosophy includes pushing the envelope. His email signature reads, “No one made a difference by being like everyone else.” 

“That’s my life philosophy,” Dr. Chogle says. “I follow it. I’m a physician and I like taking care of my patients, but I always try to go beyond that. I’m always trying to do something extra for my patients.” 

Details about what the immersive world of the CareXR will look like, and what equipment parents will need to experience it, will be previewed at CHOC Innovation Day — “A Celebration of Innovation at CHOC” — on Friday, June 25, from 1-3 p.m. The online session, held in honor of the late Dr. Nick Anas for his contributions to innovation and medical intelligence, is open to all CHOC physicians and associates.

The virtual event will feature remarks by CHOC CEO Kim Cripe and Dr. Anthony Chang and also will showcase chief technology officer Adam Gold’s uTine autism app, groundbreaking artificial intelligence projects, innovation by nurses and much more.

“I’m very excited,” says Wanda, who will celebrate 43 years as a CHOC medical surgical nurse this July. “My biggest excitement is for the families. They’ll be able to see what they were taught here before their child was discharged and watch it as many times as they want, and wherever they want — on their smart phones or computer.”

Wanda conducts the virtual reality teaching sessions. The first module will detail PEG tube care (Percutaneous Endoscopic Gastrostomy tube). PEG tubes allow patients to receive nutrition through their stomachs.

A virtual reality module detailing tube care.

CHOC already sends parents home with reading materials followed by a one-hour, in-person class Wanda teaches to make them feel comfortable in caring for the device. The new app takes this instruction to an entire new level, says Wanda and Dr. Chogle, both of whom believe this is the first such app developed at any pediatric hospital.

“I feel like God gave me this project,” says Wanda, who became involved in it after hearing the concept that was pitched by Dr. Chogle at a pediatric “Hack-A-Thon” hosted by CHOC in February 2020. A hack-a-thon is a session where a group comes together to create software to accomplish a set goal.

“When I found out about the concept, I was just totally thrilled,” Wanda says. “And what BioflightVR and The Innovation Lab have come up with is amazing.”

The first module in the app is expected to be completed this June, Dr. Chogle says.

The “XR” in the app’s name stands for extended reality. 

“My concept is we’re extending the care for patients in terms of quality as well as location – we’re extending the care into their home,” Dr. Chogle says. “We’re going to keep adding modules so parents can pick and choose depending on what condition and device their child has.” 

Dr. Chogle, whose favorite TV show is, not surprisingly, “Shark Tank,” where inventors pitch projects to potential investors, plans to research the efficacy of the app at CHOC and other partner sites.

“I love the concept of coming up with new ideas to change the status quo,” explains Dr. Chogle, who has been at CHOC for six years. 

Wanda says the virtual reality program will be light years beyond the typically dry medical device videos now available. The immersive experience of the first module of CareXR will cover such topics such as site care, feeding, and more.

“I think CHOC is the first hospital out of the gate on this,” she says. “And everyone will be able to see it after May 20.”

Dr. Chogle says he became interested in the use of virtual reality in healthcare after seeing a presentation by another gastroenterologist, Dr. Brennan Spiegel at Cedars-Sinai. Dr. Spiegel uses virtual reality for pain management in adults.

“I started following Dr. Spiegel’s work,” Dr. Chogle says. His first foray into the virtual reality universe involved using biofeedback applications to treat patients with IBS (irritable bowel syndrome).

Dr. Chogle recalls a CHOC patient’s family distress at having to care for their child with a G-tube.

He recalls the flustered father telling him at a follow-up visit to his clinic: “I wish we were back in the ICU so the nurses could take care of our child. There’s this foreign thing sticking out of my kid’s belly and I’m afraid to touch it.” 

Recalls Dr. Chogle: “That’s when it struck me: Is there any way, I thought, to teach these parents in a better way where they can focus on what is being taught, then repeat if needed what is being taught, and they practice the tasks which they were taught without having to actually handle the tube on their child? I thought, ‘What if I use virtual reality technology to better educate these parents and let them practice in a virtual world so they become comfortable with it?’ Also, there’s always the question of when we discharge a patient. Sometimes the parents push back, saying, ‘Oh, no, we’re not comfortable leaving yet.’ What if we are able to determine the readiness of the parents to be discharged?”

There are four parts to the teaching app. The first is an animated video of exactly what is going to happen during the surgical procedure to implant the device. The module then teaches parents about the different parts of the device, how to hook it up, how to take care of it, and how to identify complications to seek help. The third section is interactive where parents can practice the task in virtual reality. The fourth section tests the parents on their newly acquired skills and lets the bedside team determine if the parents are ready to go home with the device.

“Basically,” says Dr. Chogle, “this is about optimal teaching, reinforcing that teaching, and building the confidence of parents and caretakers.” 

Register here for CHOC Innovation Day.

CHOC awarded $2.3-million grant to study how toxic stress and unpredictability in the early environment affects neurodevelopment

The state of California has awarded CHOC, in partnership with UC Irvine and Chapman University, a $2.3-million grant to screen patients for adverse childhood experiences (ACEs) and childhood unpredictability to assess how such high-stress events affect the brain and put kids at increased risk of later developing physical and mental illnesses.

In a novel aspect of the study, researchers also will determine if there are epigenetic markers on the DNA that predict whether any given child will be more adversely affected than another.

The team is among four awardees statewide that have been given a total of $9 million to assess which children are most vulnerable to the effects of ACEs and unpredictability in the home environment, and to design medical care to improve the outcomes for this particular group of patients – a model known as “precision medicine,” which eschews a one-therapy-fits-all approach to healthcare.

“The whole concept here is that kids who grow up in environments with frequent exposures to toxic levels of stress can have all kinds of internal things happen in their bodies related to prolonged or extensive stress hormone response – their brains can develop differently, and when they become adults, research has shown that they have a higher risk of developing medical conditions such as heart disease, asthma and cancer,  among other physical diseases, as well as mental disorders,” says Dr. Charles Golden, a co-investigator on the study and executive medical director of the CHOC Primary Care Network (PCN).

Dr. Charles Golden, executive medical director of the CHOC Primary Care Network (PCN)

The California Governor’s Office of Planning & Research, in partnership with the Office of the California Surgeon General, awarded the three-year research project as part of the California Initiative to Advance Precision Medicine (CIAPM). The other three recipients were Children’s Hospital Los Angeles, University of California, San Francisco, and Loma Linda University.

The CHOC-UCI-Chapman research project begins in July 2021, with screening expected to start in CHOC PCN clinics by November 2021. Lead principal investigator on the project is Dr. Tallie Baram, Bren Distinguished Professor and director of the Conte Center at UCI. The National Institute of Mental Health-funded Conte Center also addresses how early-life experiences influence the brain and contribute to mental illnesses.

Results of the study are expected by the end of 2024, says Laura Glynn, PhD, a Professor of Psychology and Associate Dean for Research at Chapman University and one of the principal investigators on the study.

CHOC’s PCN has been screening its Medi-Cal patient population for ACEs since February 2020, and expanded such screening – using a tool called PEARLS, for Pediatric ACEs and Related Life Events Screener – to all patients in November 2020, Dr. Golden says.

The 17-question PEARLS tool screens for such experiences as a parent being jailed, the prevalence of alcohol or drug abuse in the household, and whether the child has been a victim of violence in his or her neighborhood, in the community at large, or at school.

“This existing infrastructure at CHOC was a very important part of the application for this grant,” Glynn says.

The CHOC-UCI-Chapman study, “Using Precision Medicine to Tackle Impacts of Adverse and Unpredictable Experiences on Children’s Neurodevelopment,” will dig deeper than standard PEARLS screening.

The children will be asked an additional five questions to assess exposure to unpredictability in the social, emotional, and physical domains. Such questions are an attempt by researchers to develop an instrument that will predict this population of kids’ resilience to, or risk of developing, physical or mental illnesses. Children from low socioeconomic and racial/ethnic minority communities are at greater risk of exposure to ACEs.

“This study will involve looking at whether routine, or lack of routine, in a child’s life contribute as an ACE,” Dr. Golden explains. “In other words, do they eat dinner every night at 6 p.m., do they have a routine bedtime, do they have a stable household versus a family with no routine or little structure.”

Such factors of unpredictability potentially are amenable to intervention, Glynn notes.

Emerging evidence from experiments with rodents show that fragmented or unpredictable maternal signals influence the maturation of systems governing emotional and cognitive function in the developing brain. In preclinical work led by Dr. Baram, the group has shown that rats exhibited diminished memory function when exposed to unpredictable maternal signals early in life, as well as anhedonia (reduced ability to experience pleasure) beginning in adolescence.

Also, as part of the study, DNA swabs will be performed on a cohort of 120 children who experience high levels of ACEs to determine if genetic expression patterns indicate a vulnerability to chaos and unpredictability in their lives. The team also will be examining whether epigenetics – the process of how genes may be altered based on environmental events – may play a role in the development of ACE-related medical conditions.

“We think potentially we can look at these epigenetic profiles to predict neurodevelopmental outcomes,” Glynn says.

Dr. Michael Weiss, vice president of population health at CHOC and a primary investigator on the study, says such information may make it easier for doctors to identify a child who has a genetic predisposition to experiencing a bad outcome from being exposed to ACEs – thus leading to targeted interventions to kids who need them the most.

“This project is a great demonstration of a collaboration between CHOC and UCI and Chapman University involving primary care research,” Dr. Weiss says.

Other CHOC researchers who will participate in the research project are Dr. Dan Cooper, who treats kids with lung conditions at CHOC and who serves as director of UC Irvine’s Institute for Clinical & Translational Science; Dr. Candice Taylor Lucas, co-director of LEAD-ABC (Leadership Education to Advance Diversity–African, Black and Caribbean) at UCI/CHOC; Louis Ehwerhemuepa, PhD, a senior data scientist; and Dr. Mary Zupanc, co-medical director of the Neuroscience Institute.