Tag Archive for: Brown

Stroke alert teams beneficial to timely diagnosis of pediatric stroke patients

Key driver diagram

1 – Interdisciplinary stroke simulations were canceled due to short staffing and insufficient nursing support during COVID-19 pandemic.

Diagnosis times improved for pediatric arterial ischemic stroke (AIS) patients in the emergency department after the implementation of a quality improvement initiative. According to a new study, published in Pediatrics, the median door-to-imaging time for children with suspected AIS improved from 128 minutes to 68 minutes post-intervention.

What it means

Pediatric AIS is an important cause of morbidity and mortality that requires early recognition to benefit from hyperacute therapies. A quality improvement study at Children’s National Hospital aimed to improve timely diagnosis of AIS through an interdisciplinary stroke response protocol. The researchers implemented a quality improvement initiative from November 2019 to June 2023 in the emergency department that included interventions under two categories – workflow efficiency improvement and staff education. A total of 71 patients who met the criteria for the study were analyzed. Median door-to-imaging time for all patients improved from 128 minutes during the baseline period to 68 minutes.

The researchers note that establishing a well-functioning stroke response protocol is a critical step in detecting pediatric stroke in the community and expediting care for this vulnerable patient population.

“This study highlights the value of quality improvement methodologies in coordinating multiple hospital divisions for the greater goal of improving patient care,” says Theodore Trigylidas, MD, corresponding author and emergency medicine physician at Children’s National. “We hope it serves as a template for other healthcare organizations in developing their own pediatric stroke protocols.”

Code Stroke management algorithm

Code Stroke management algorithm. CT/CTA, computed tomography with or without angiography. MRI/MRA, magnetic resonance imaging with or without angiography.

The hold up in the field

The rarity of AIS in pediatric patients and stroke mimics, like hemiplegic migraine, may cause challenges for a timely diagnosis, and treatments for AIS – thrombolysis and thrombectomy – must be performed within specific time frames.

Moving the field forward

“By taking into consideration local staffing structures and institutional resource availability, the quality improvement approach described here can serve as a framework for how institutions might implement a pediatric acute stroke response protocol given their own unique systems of care and resource considerations,” says Dana Harrar, MD, PhD, study author and director, Pediatric Stroke Program at Children’s National.

The authors plan to expand this initiative to incorporate children at outside facilities with the goal of creating a stroke network with nearby hospitals.

Authors from Children’s National include: Theodore Trigylidas, MD, Nichole McCollum, MD, Kathleen Brown, MD, Paola Pergami, MD, Elizabeth Wells, MD, Jonathan Murnick, MD, PhD, Josh Heffren, PharmD, BCPPS and Deborah LaViolette, BSN, Dana Harrar, MD, PhD.

You can read the full study, Improving Timely Diagnosis of Arterial Ischemic Stroke at the Pediatric Emergency Department in Pediatrics.

The link between metabolic acidosis and cardiovascular disease in children with CKD

Denver Brown

Denver D. Brown, MD, nephrologist at Children’s National Hospital, presented at Kidney Week 2024 on the connection between metabolic acidosis and cardiovascular disease risk in children with chronic kidney disease (CKD).

Denver D. Brown, MD, nephrologist at Children’s National Hospital, presented at Kidney Week 2024 on the connection between metabolic acidosis and cardiovascular disease risk in children with chronic kidney disease (CKD). This research aimed to investigate whether untreated metabolic acidosis could potentially contribute to cardiovascular outcomes in children with CKD, a group at high risk for cardiovascular disease and death from cardiovascular complications. Dr. Brown explains her motivation, findings and future directions for this critical research.

Q: Why did you choose to research this topic?

A: My interest in this area stems from my research interest in pediatric CKD outcomes, with a specific focus on the consequences of metabolic acidosis as well as my larger passion which is to improve the quality and longevity of life for children with CKD. There are several adult focused studies investigating theorized links between untreated metabolic acidosis and poor outcomes such as CKD progression, worse bone health/growth and higher cardiovascular risk. However, in the pediatric CKD population, the consequences of chronic metabolic acidosis remain largely unexplored but is of importance since data shows that nearly one third of children with metabolic acidosis are not receiving treatment to correct their acidosis.

Cardiovascular disease is the number one cause of death in children with CKD. Even though overt cardiovascular disease often does not manifest until adulthood, we do see risk factors emerging during childhood such as high blood pressure and abnormal cholesterol levels. So, if metabolic acidosis contributes to cardiovascular disease risk, it’s crucial to identify and treat it — especially since metabolic acidosis is very treatable

This research was in collaboration with the Chronic Kidney Disease in Children (CKiD) study, which is the largest cohort study of pediatric CKD across North America. It provided robust data on laboratory values, blood pressure, cardiovascular measurements and echocardiograms which allowed me to look deeper into the potential cardiovascular implications of metabolic acidosis.

Q: Where do you see this research going?

A: My ultimate goal is to conduct clinical trials focused on the pediatric CKD population. Children are not well represented in CKD trials as pediatric CKD is relatively rare, making recruitment for studies challenging. However, we can’t keep applying adult data to children because the causes and manifestations of CKD in kids are different.

It is my hope that this research serves as evidence that can be used for a pediatric clinical trial that investigates the benefits of alkali therapy, the treatment for metabolic acidosis. I envision studying how alkali therapy impacts not only cardiovascular outcomes but also growth and other important health domains. The data gathered from my study could ultimately be used in a multi-site trial, aiming to test alkali therapy on a broader scale across various pediatric CKD centers.

Q: Is any work being done between nephrologists and cardiologists to address this issue?

A: This specific study was more exploratory. In adults, the data on the link between metabolic acidosis and cardiovascular disease is mixed. Some studies suggest a connection, while others find no such effect when treating metabolic acidosis. My current work is focused on gathering data to determine if there’s a potential link in the pediatric population and whether it should be examined further in a future trial.

I haven’t collaborated directly with cardiologists on this research. However, this could lead to collaboration with cardiologists down the line.

Q: How is Children’s National Hospital leading the way in this research?

A: Although my research data wasn’t exclusively from Children’s National, the hospital played a pivotal role in the CKiD study, both as an enrollment site and through the involvement of Marva Moxey-Mims, M.D., chief of Nephrology at Children’s National, who played a key role in the CKiD study design and initiation.

Children’s National actively participates in, and encourages, novel and innovative research studies. Being at an institution that prioritizes and contributes to research that advances the health of children has been instrumental in my research career.

Advancements in nephrology: Highlights from ASN 2024 Kidney Week

Kidney Week attendees from Children's National HospitalThousands of medical professionals and researchers from around the world gathered in San Diego this October for Kidney Week 2024. The American Society of Nephrology’s (ASN) annual meeting and scientific exposition featured advances in treatment, research and technology in the fight against kidney disease.

Doctors, fellows and faculty from Children’s National Hospital participated, presenting their latest research and clinical advancements in pediatric kidney disease.

Posters and topics from Children’s National included:

  • Jordy Salcedo-Giraldo, M.D., FAAP: Structured Application of Nephrogenetics in a Pediatric Kidney Clinic Is Clinically Impactful and Challenging
  • Jordy Salcedo-Giraldo, M.D., FAAP: Unmasking the Mimickers: HNF1B Variants in Pediatric Kidney Diseases
  • Sarah Rogal, M.D., Ph.D.: Rapidly Progressive Kidney Failure in a Patient with Longstanding Juvenile Dermatomyositis
  • Jennifer Nhan, M.D.: AKI in Patients with Multisystem Inflammatory Syndrome in Children
  • Krista Wink: The Inherited and Polycystic Kidney Disease Program
  • Kaushalendra Amatya, Ph.D.: Barriers to Communication with Transplant Providers Among Pediatric Kidney Transplant Patients and Their Caregivers

Additionally, there was a presentation from Denver Brown, M.D.: Low Serum Bicarbonate and Cardiovascular Disease Risk in Children with CKD.

Learn more about the IPKD program and the division of Nephrology at Children’s National.

Novel AI platform matches cardiologists in detecting rheumatic heart disease

Artificial intelligence (AI) has the potential to detect rheumatic heart disease (RHD) with the same accuracy as a cardiologist, according to new research demonstrating how sophisticated deep learning technology can be applied to this disease of inequity. The work could prevent hundreds of thousands of unnecessary deaths around the world annually.

Developed at Children’s National Hospital and detailed in the latest edition of the Journal of the American Heart Association, the new AI system combines the power of novel ultrasound probes with portable electronic devices installed with algorithms capable of diagnosing RHD on echocardiogram. Distributing these devices could allow healthcare workers, without specialized medical degrees, to carry technology that could detect RHD in regions where it remains endemic.

RHD is caused by the body’s reaction to repeated Strep A bacterial infections and can cause permanent heart damage. If detected early, the condition is treatable with penicillin, a widely available antibiotic. In the United States and other high-income nations, RHD has been almost entirely eradicated. However, in low- and middle-income countries, it impacts the lives of 40 million people, causing nearly 400,000 deaths a year.

“This technology has the potential to extend the reach of a cardiologist to anywhere in the world,” said Kelsey Brown, M.D., a cardiology fellow at Children’s National and co-lead author on the manuscript with Staff Scientist Pooneh Roshanitabrizi, Ph.D. “In one minute, anyone trained to use our system can screen a child to find out if their heart is demonstrating signs of RHD. This will lead them to more specialized care and a simple antibiotic to prevent this degenerative disease from critically damaging their hearts.”

The big picture

AI system that can detect RHD

The new AI system combines the power of novel ultrasound probes with portable electronic devices installed with algorithms capable of diagnosing RHD on echocardiogram.

Millions of citizens in impoverished countries have limited access to specialized care. Yet the gold standard for diagnosing RHD requires a highly trained cardiologist to read an echocardiogram — a non-invasive and widely distributed ultrasound imaging technology. Without access to a cardiologist, the condition may remain undetected and lead to complications, including advanced cardiac disease and even death.

According to the new research, the AI algorithm developed at Children’s National identified mitral regurgitation in up to 90% of children with RHD. This tell-tale sign of the disease causes the mitral valve flaps to close improperly, leading to backward blood flow in the heart.

Beginning in March, Craig Sable, M.D., interim division chief of Cardiology, and his partners on the project will implement a pilot program in Uganda incorporating AI into the echo screening process of children being checked for RHD. The team believes that a handheld ultrasound probe, a tablet and a laptop — installed with the sophisticated, new algorithm — could make all the difference in diagnosing these children early enough to change outcomes.

“One of the most effective ways to prevent rheumatic heart disease is to find the patients that are affected in the very early stages, give them monthly penicillin for pennies a day and prevent them from becoming one of the 400,000 people a year who die from this disease,” Dr. Sable said. “Once this technology is built and distributed at a scale to address the need, we are optimistic that it holds great promise to bring highly accurate care to economically disadvantaged countries and help eradicate RHD around the world.”

Children’s National Hospital leads the way

To devise the best approach, two Children’s National experts in AI — Dr. Roshanitabrizi and Marius George Linguraru, D.Phil., M.A., M.Sc., the Connor Family Professor in Research and Innovation and principal investigator in the Sheikh Zayed Institute for Pediatric Surgical Innovation — tested a variety of modalities in machine learning, which mimics human intelligence, and deep learning, which goes beyond the human capacity to learn. They combined the power of both approaches to optimize the novel algorithm, which is trained to interpret ultrasound images of the heart to detect RHD.

Already, the AI algorithm has analyzed 39 features of hearts with RHD that cardiologists cannot detect or measure with the naked eye. For example, cardiologists know that the heart’s size matters when diagnosing RHD. Current guidelines lay out diagnostic criteria using two weight categories — above or below 66 pounds — as a surrogate measure for the heart’s size. Yet the size of a child’s heart can vary widely in those two groupings.

“Our algorithm can see and make adjustments for the heart’s size as a continuously fluid variable,” Dr. Roshanitabrizi said. “In the hands of healthcare workers, we expect the technology to amplify human capabilities to make calculations far more quickly and precisely than the human eye and brain, saving countless lives.”

Among other challenges, the team had to design new ways to teach the AI to handle the inherent clinical differences found in ultrasound images, along with the complexities of evaluating color Doppler echocardiograms, which historically have required specialized human skill to evaluate.

“There is a true art to interpreting this kind of information, but we now know how to teach a machine to learn faster and possibly better than the human eye and brain,” Dr. Linguraru said. “Although we have been using this diagnostic and treatment approach since World War II, we haven’t been able to share this competency globally with low- and middle-income countries, where there are far fewer cardiologists. With the power of AI, we expect that we can, which will improve equity in medicine around the world.”

New grant to conduct single center pilot trial of alkali therapy in children with CKD

Denver Brown

Denver D. Brown, M.D., recipient of the Child Health Research Career Development Award.

Linear growth (i.e., height) impairment is commonly observed in children with chronic kidney disease (CKD). Several studies have suggested metabolic acidosis, a frequent consequence of mild to moderate CKD in children, as a contributing factor to linear growth failure in these patients. Grant awardee Denver D. Brown, M.D., aims to conduct a pilot trial in children with mild metabolic acidosis and CKD, comparing differences in linear growth between an observation period versus a period of supplementation with alkali therapy (i.e., treatment for metabolic acidosis).

“This grant is so important because there has never been a clinical trial of alkali therapy in children with CKD despite its frequent use in this population” says Dr. Brown. “This research has the potential to better inform treatment practices with the aim of improving the care of our young, vulnerable patients.”

The Child Health Research Career Development Award (CHRCDA) of $125,000 will support Dr. Brown in her efforts to carry out this pilot trial.

“Funding for this pilot study could lay the groundwork for a large, randomized controlled clinical trial, which would help fill a major gap in knowledge as to the precise benefits of alkali therapy, especially regarding growth in children with impaired kidney function.”

Children’s National expands its nationally ranked nephrology division

Children’s National Hospital has added five physicians to its nationally ranked Nephrology Division. Denver Brown, M.D., Celina Brunson, M.D., Ashima Gulati, M.D., Melissa Meyers, M.D., Catherine Park, M.D., all have joined the department over a span of the past two years.

“These physicians are incredible additions to our nephrology division,” said Marva Moxey-Mims, M.D., chief of the Division of Nephrology at Children’s National. “We are excited about the expertise these young physicians already contribute to our division and can’t wait to share more as we continue to expand our efforts as one of the top nephrology programs in the country. We are elated to have them on our team.”

Each of the new faculty members has specific areas of clinical and research interests. Dr. Brown’s focus is chronic kidney disease (CKD) and the impact of acidosis on growth and disease progression. Dr. Brunson’s interest is dialysis, health disparities and social determinants of health for children with CKD. She is a JELF Advocacy scholar through the American Society of Nephrology. Dr. Gulati is an expert in inherited kidney diseases with a particular focus on polycystic kidney disease for which she has external grant support. Dr. Meyers’ interest is kidney transplantation and Dr. Park, our newest addition, is interested in systemic inflammatory diseases, especially lupus nephritis.

The nephrology team will continue to provide comprehensive inpatient and outpatient care to children throughout the full spectrum of kidney diseases.

Denver Brown, M.D., Celina Brunson, M.D., Ashima Gulati, M.D., Melissa Meyers, M.D., Catherine Park, M.D.

Denver Brown, M.D., Celina Brunson, M.D., Ashima Gulati, M.D., Melissa Meyers, M.D. and Catherine Park, M.D., recently joined the nephrology division.

New study examines treatment for diabetic ketoacidosis

IV Bag

Brain injuries that happen during episodes of diabetic ketoacidosis (DKA) – where the body converts fat instead of sugar into energy, and where the pancreas is unable to process insulin, such as in type 1 diabetes – are rare, and happen in less than 1 percent of DKA episodes, but these injuries can carry lasting consequences – including mild to severe neurological damage.

A new 13-center, randomized, controlled trial published on June 13, 2018, in the New England Journal of Medicine finds two variables – the speed of rehydration fluids administered to patients and the sodium concentrations in these intravenous fluids – don’t impact neurological function or brain damage.

“One medical center would never be able to study this independently because of the relatively small volume of children with DKA that present to any one site,” says Kathleen Brown, M.D., a study author, the medical director of the emergency medicine and trauma center at Children’s National Health System and a professor of pediatrics and emergency medicine at George Washington University School of Medicine. “The strength of this research lies in our ability to work with 13 medical centers to study almost 1,400 episodes of children with DKA over five years to see if these variables make a difference. The study design showcases the efficiency of the Pediatric Emergency Center Applied Research Network, or PECARN, a federally-funded initiative that powers collaboration and innovation.”

Researchers have speculated about the techniques of administering intravenous fluids, specifically speed and sodium concentrations, to patients experiencing a DKA episode, with many assuming a faster administration rate of fluids would produce brain swelling. Others argued, from previous data, that these variables may not matter – especially since higher levels of brain damage were noted among children with higher rates of dehydration before they were treated. Some thought DKA created a state of inflammation in the brain, which caused the damage, and that speed and sodium concentration wouldn’t reverse this initial event. The researchers set out to determine the answers to these questions.

The PECARN research team put the data to the test: They created a 2-by-2 factorial design to test the impact of providing 1,255 pediatric patients, ages zero to 18, with higher (.9 percent) and lower (.45 percent) concentrations of sodium chloride at rapid and slow-rate administration speeds during a DKA episode. They administered tests during the first DKA episode and again during a recurrent episode. After analyzing 1,389 episodes, they found that the four different combinations did not have a statistically significant impact on the rate of cognitive decline during the DKA episode or during the 2-month and 6-month recovery periods.

“One of the most important lessons from this study is that diabetic ketoacidosis should be avoided because it can cause harm,” says Dr. Brown. “But the best way to treat diabetic ketoacidosis is to prevent it. Parents can monitor this by checking blood sugar for insulin control and taking their children for treatment as soon as they show signs or symptoms that are concerning.”

According to the National Institute of Diabetes and Kidney Disease, symptoms of diabetic ketoacidosis include nausea and vomiting, stomach pain, fruity breath odor and rapid breathing. Untreated DKA can lead to coma and death.

An accompanying video and editorial are available online in the New England Journal of Medicine.

The study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the Health Resources and Services Administration. The PECARN DKA FLUID ClinicalTrials.gov number is NCT00629707.

Children’s National Health System’s Division of Pediatric Emergency Medicine has been a lead site for the PECARN network since its inception in 2001.

Improving asthma care at community emergency departments

Through partnerships with community health care facilities, children suffering from severe asthma attacks can receive the type of state-of-the-art care championed by Children’s National.

Asthma is an exceedingly common pediatric disease, affecting nearly 7 million children in the United States, particularly in urban areas. Asthma is responsible for more than 775,000 Emergency Department (EDs) visits each year. However, the vast majority of these visits are to community EDs closest to patients’ homes, rather than to medical centers that specialize in pediatric care.

This fact could potentially lead to big problems for small patients, says Theresa A. Walls, M.D., M.P.H., Director of Emergency Department Outreach at Children’s National Health System. Nearly 70 percent of EDs in the United States treat fewer than 14 children a day, leaving many without the requisite experience or resources critical to effectively treat pediatric patients. Research shows that children seen for asthma in general community EDs are less likely to receive corticosteroid medications systemically — an essential first-line therapy during an asthma attack per National Institutes of Health guidelines — compared with children seen at pediatric EDs. Additionally in these general EDs, children are also more likely to receive unnecessary testing and treatment.

“In our experience, the emergency care of children with asthma in our area mirrors what has been found in national studies: Children are not treated as aggressively in community EDs. If we partner with them and get them to treat asthma as aggressively as we do, it would be a great thing for pediatric patients.”

That’s why when a nurse educator from a local community hospital’s ED contacted them to try to improve pediatric asthma care, Dr. Walls and Children’s colleagues jumped at the opportunity. “They were motivated participants,” she says. “It was a great way to start a partnership.”

The team worked with the community hospital’s ED to implement a pediatric asthma care plan known as a “pathway,” similar to the one currently in place at Children’s National, to ensure that children in the throes of an asthma attack receive evidence-based care that significantly decreases their chances of hospital admission or transfer to a specialty center.

The treatment pathway includes elements such as assigning each patient an asthma score — a number ranging from 1 to 10 that characterizes the severity of the patient’s asthma attack. The treatment plan also includes providing corticosteroids as quickly as possible to more eligible patients.

Effectively implementing this plan requires the efforts of a multidisciplinary team of providers and experts. Beyond the physicians, nurses and respiratory therapists who care for patients directly, this includes pharmacists to ensure proper doses of medications are available in child-friendly liquid forms and information technology specialists to revamp the hospital’s electronic charting system, automatically requesting an asthma score or recommending appropriate medication orders.

To gauge whether mimicking Children’s asthma pathway made a significant difference at the community ED, Dr. Walls and colleagues launched a study that was published online December 8, 2016, in Pediatrics. Comparing data collected for 19 months after the new guidelines were put into place with data from 12 months prior, the researchers made some promising initial findings. Following the pathway implementation, 64 percent of children ages 2 to 17 who arrived at the community ED with asthma symptoms received an asthma score. About 76 percent of these patients with asthma received corticosteroids after the pathway was in place, compared with 60 percent of comparable patients prior to the switchover. The mean time to corticosteroid administration dropped by nearly half, falling from 196 to 105 minutes. Additionally, Dr. Walls says, 10 percent of patients required transfer to another hospital after pathway implementation, compared with 14 percent before — another significant drop.

Dr. Walls notes that there is significant room for improving these metrics and overall asthma care at community EDs. The research team hopes to continue working with the first community hospital and expand their partnership to form a network of other local hospitals. By working together in a large collaboration, she says, hospitals can share resources and knowledge while learning from each other’s successes and mistakes.

“The more we can deliver this state-of-the-art care to the community,” she says, “the better, because that’s where most kids go.”

Biomarkers sensitive to daily corticosteroid use

Using a mass spectrometer, Yetrib Hathout, Ph.D., is able to quantify 3,000 to 4,000 proteins from a tissue sample to identify proteins associated with cancer.

Using a Somascan proteomics assay – which simultaneously analyzes 1,129 proteins in a small volume of serum – a team led by Children’s National Health System researchers identified 21 biomarkers that respond to corticosteroids taken daily by children with Duchenne muscular dystrophy (DMD) and inflammatory bowel disease.

Corticosteroids are commonly prescribed to treat inflammatory conditions. High daily doses of corticosteroids are considered the standard of care for DMD, a type of muscular dystrophy characterized by worsening muscle weakness that affects 1 in 3,600 male infants. However, depending on the age of the child and drug dosage, chronic use is associated with such side effects as changes in bone remodeling that can lead to stunted growth, weight gain, facial puffiness caused by fat buildup, mood changes, sleep disturbances, and immune suppression. The research team sought to identify blood biomarkers that could be leveraged to create a fast, reliable way to gauge the safety and efficacy of corticosteroid use by children. The biomarkers also could guide development of a replacement therapy with fewer side effects.

“Ten pro-inflammatory proteins were elevated in untreated patients and suppressed by corticosteroids (MMP12, IL22RA2, CCL22, IGFBP2, FCER2, LY9, ITGa1/b1, LTa1/b2, ANGPT2 and FGG),” Yetrib Hathout, Ph.D., Proteomic Core Director at Children’s National, and colleagues write in the journal Scientific Reports. “These are candidate biomarkers for anti-inflammatory efficacy of corticosteroids.”

The blood biomarkers sensitive to corticosteroids fit into three broad groups, according to the authors. The children taking corticosteroids were matched with children of the same age who had never taken the medicine. Five biomarkers significantly increased in this corticosteroid-naïve group and decreased in kids prescribed corticosteroids. The biomarkers generally were inflammatory proteins and included chemokine, insulin-like growth factor binding protein 2, and integrin alpha-I/beta-1 complex.

The second group of biomarkers included nine proteins associated with macrophage and T-lymphocytes that were significantly reduced in concentration in kids taking corticosteroids. According to the study, this finding hints at corticosteroids blunting the ability of the immune system’s most able fighters to respond to infection.

In the third group were five proteins that were significantly increased by corticosteroid treatment in DMD and included matrix metalloproteinase 3, carnosine dipeptidase 1, angiotensinogen, growth hormone binding protein, insulin, and leptin, a hormone linked to appetite.

What researchers learned with this study will help them more accurately design the next phase of the work, Hathout says.

“We are the first team to report a number of novel discoveries, including that growth hormone binding protein (GHBP) levels increase with corticosteroid use. This represents a candidate biomarker for stunted growth. In order to use that new information effectively in drug development, the next studies must corroborate the role of serum GHBP levels as predictors of diminished stature,” he adds. “The study finding that four adrenal steroid hormones are depressed in kids taking corticosteroids raises additional questions about the broader impact of adrenal insufficiency, including its role in the delay of the onset of puberty.”

This work was supported by National Institutes of Health grants (R01AR062380, R01AR061875, P50AR060836, U54HD071601, K99HL130035, and R44NS095423) and Department of Defense CDMRP program grant W81XWH-15-1-0265. Additional support was provided by AFM-Telethon (18259) and the Muscular Dystrophy Association USA (MDA353094).