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Inside Pediatrics, Neonatology

Debriefing after Resuscitation: A Quality Improvement Initiative

Resuscitation_WEB

In October 2018, the Children’s of Alabama Neonatal Intensive Care Unit embarked on a quality improvement project, Debriefing Following Resuscitation/Code Events in the NICU, to identify opportunities to improve the resuscitation process, including staff satisfaction. It is one of several quality initiatives led by the Children’s Hospitals Neonatal Consortium.

The Neonatal Intensive Care Unit (NICU) can be an intimidating and stressful place to work.  One of the most stressful events in the NICU is a neonatal code or resuscitation, which may require intubation, chest compressions and special medications, all delivered under the pressure of knowing that seconds count. This requires that the team of doctors, nurses, respiratory therapists, pharmacists and other practitioners work together like a well-oiled machine.

Resuscitation codes are, by definition, rare events, said Children’s of Alabama neonatologist Hannah Hightower, M.D. Weeks may go by without any and then they might have several in one month. But they are definitely disruptive and stressful.

In October 2018, the Children’s of Alabama NICU embarked on a quality improvement project, Debriefing Following Resuscitation/Code Events in the NICU, to identify opportunities to improve the resuscitation process, including staff satisfaction. It is one of several quality initiatives led by the Children’s Hospitals Neonatal Consortium (CHNC), a group of more than 30 children’s hospitals around the country dedicated to using performance improvement methods to improve the delivery and quality of care in Level IV NICUs, which care for high acuity and medically complicated neonates.

The premise is simple. As soon as possible after the code, everyone gathers for a few minutes to discuss what went well, any equipment or medication problems, communication quality, and, of course, highlighting what could go better next time. They also complete a short form documenting the discussion. In just three months, the team at Children’s exceeded its goal of holding post-resuscitation debriefings after 80 percent of codes.

Such approaches can lead to improved resuscitation quality and reduced mortality, research finds. [1]

“The goal is to help everyone involved in the process improve skills, cope with the stress, and ultimately and most importantly, improve the process and patient outcomes by identifying potential latent safety threats,” Hightower said. “We want everyone on the team to feel free to express any concerns as well as provide support. Even the caregivers need a chance to decompress.”  “Not only does it provide a venue for raising issues related to caring for the patient, she said, “but it also lets us show appreciation for the things that went well.”

“It wasn’t a surprise to hear that one of the biggest issues is communication in a stressful period,” Hightower said. “We can always improve communication, whether that means discussing who is leading the code or controlling the volume so everyone can hear and understand what’s going on.” Discussing communication issues shortly after the code is important, she said, “because it’s at the front of your mind. By doing this immediately, you remember things you may not later and can articulate issues that might not be apparent in a week or two.”

Since implementing the initiative, the team has begun a proposal to further improve communication by emphasizing who is leading the code. Future projects include providing each member a way to give real time feedback not just to the code event, but also to the quality and effectiveness of the debrief. “We want to quickly identify systemic matters that can be improved for the next event. This is to develop a culture of freely expressing ideas and working through issues together as a team,” Hightower said.

The team is still collecting data on the primary outcome of latent safety events, a key component of any quality improvement initiative. Secondary outcomes include quality of the debriefs and composition of the responding code team.

“I credit our success to our strong nursing leadership and the willingness of the staff to be actively involved in quality improvement and do the extra work required to accomplish that goal,” Hightower said. “They have to step away from the patient and cover for each other during the debrief and even though it may take just a few minutes, to ask a nurse to step away from the patient is a big task.”

Although the team is still collecting data on the impact on staff satisfaction, she said, “anecdotally we have heard from nurses and other staff who feel they had a chance to say what they needed during the code or might need in the future. That’s gotten positive feedback.”

“It’s important to highlight the goal of this project is improved patient care, patient outcomes and staff satisfaction,” Hightower said. It’s also important that Children’s of Alabama is a part of a national collaborative with other major children’s hospitals, she said, and has been one of the most successful programs in the CHNC in terms of demonstrated outcomes. Other performance improvement initiatives with the CHNC include improving pain management and reducing nephrotoxic injury.

Resuscitation_CHART

In just three months after embarking on its quality improvement project, the NICU team at Children’s of Alabama exceeded its goal of holding post-resuscitation debriefings after 80 percent of codes.


[1] Wolfe H, Zebuhr C, Topjian AA, et al. Interdisciplinary ICU Cardiac Arrest Debriefing Improves Survival Outcomes Crit Care Med. 2014 Jul; 42(7): 1688–1695.

 

Inside Pediatrics, Nephrology

Pediatric Extracorporeal Photopheresis Offers New Option for Transplant Patients at Children’s of Alabama

Photopheresis_WEB

Children’s of Alabama nurses Daryl Ingram and Suzanne Gurosky next to the hospital’s photopheresis machine. After months of planning and training, Children’s of Alabama’s first photopheresis treatment was successfully provided on April 12, 2017. Previously, Children’s of Alabama patients were being transported to and from the University of Alabama at Birmingham (UAB) for treatment.

Children’s of Alabama’s Acute Renal Therapy team is now able to offer extracorporeal photopheresis (ECP) for heart transplant patients experiencing chronic rejection and bone marrow transplant patients who develop graft-versus-host-disease (GVHD). It is the only program in the state to provide the service to pediatric patients.

The U.S. Food and Drug Administration first approved ECP in 1988 to treat patients with a certain form of cutaneous T-cell lymphoma. Since then, ECP has demonstrated efficacy in GVHD, solid organ transplant rejection and rheumatoid arthritis, among others.

During the three-hour procedure, the patient’s leukocytes are separated from the peripheral blood, combined with a photoreactive drug and then exposed to ultraviolet irradiation, resulting in massive apoptosis. The cells are then reinfused into the patient.

It’s not quite clear how the process works, although theories suggest that when antigen-presenting cells clear the apoptotic cells, they differentiate into a more tolerogenic phenotype, resulting in decreased stimulation or depletion of effector T cells. Another theory is that it results in greater production of anti-inflammatory cytokines (interleukin 10) and reduced production of pro-inflammatory cytokines (especially interleukin 12 and TNFα), or that it triggers the generation of several T-regulatory cells.[1]

“Basically”, said Sahar Fathallah-Shaykh, M.D., medical director the Pediatric Dialysis Unit at Children’s of Alabama, “the leukocytes are now less reactive to the foreign tissue, reducing organ rejection and GVHD. However, she said, while studies find good rates of success in reversing organ rejection and GVHD, it’s not a cure. “It is used in conjunction with other immunosuppressive medications when other things haven’t worked. We add this and hopefully it works.”

Previously, Children’s of Alabama patients had to be transported to and from the University of Alabama at Birmingham (UAB) for this treatment. “It wasn’t an ideal setup,” said David Askenazi, M.D., who directs the Pediatric and Infant Center for Acute Nephrology at Children’s of Alabama. “There were different medical record systems, which wasn’t optimal for timely patient care of pediatric patients in an adult hospital.” So when the cardiology and bone marrow transplant team needed to bring the therapy to Children’s, Askenazi and his team, which already had experience with extra-corporeal therapies, stepped forward to run it.

“Bringing the program to Children’s was challenging,” Fathallah-Shaykh said. “The medical staff and physicians required extensive training, particularly in using the single lumen port needed for vascular access, which is unique to this procedure. But it was worth it.”

“Even though we don’t have many patients who require ECP,” she said, “the message is that we’re here, we’re available and we can help improve the care of our patients in a pediatric-friendly environment with pediatric nursing care.”


[1] Klassen J. The role of photopheresis in the treatment of graft-versus-host disease. Curr Oncol. 2010 Apr; 17(2): 55–58.

 

 

Hematology and Oncology, Inside Pediatrics

Children’s of Alabama Ramps Up Pediatric Oncology Research Program

HemOncFaculty_WEB

The faculty of the Pediatric Hematology, Oncology, and Blood and Marrow Transplantation program at Children’s of Alabama and the University of Alabama at Birmingham (UAB). The program is currently working to offer more potentially life-saving clinical trials to patients.

It’s only been a year since Girish Dhall, M.D., moved from Los Angeles, where he was an associate professor of pediatrics and director of the Neuro-Oncology Program at Children’s Hospital Los Angeles, to Birmingham to become division director for the Pediatric Hematology, Oncology, and Blood and Marrow Transplantation program at Children’s of Alabama and the University of Alabama at Birmingham (UAB). Yet he’s already made significant progress on one of his key goals: offering more potentially life-saving clinical trials to patients.

“We’re trying to increase our research portfolio through multiple mechanisms,” he said. Children’s already belongs to the largest pediatric cancer research organization in the world, the Children’s Oncology Group (COG), an international consortium of more than 200 children’s hospitals, universities, and cancer centers. Children’s of Alabama and UAB participate in the COG Phase I Consortium, the Neurofibromatosis Consortium and the Next Consortium, all of which conduct cutting-edge clinical trials for pediatric patients with nervous system tumors.

While COG is a major force in pediatric oncology, the number of trials it offers is limited. With about 150 new cancer patients a year seen at Children’s of Alabama, Dhall said, more opportunities are needed. “Even though we’ve come from a survival rate of zero 50 or 60 years ago to nearly 70 percent, 30 percent of patients still relapse,” he said.

Thus, Children’s of Alabama and UAB joined the Sunshine Project, which is a part of the National Pediatric Cancer Foundation. It emphasizes basic and translational research in the areas of bone and soft tissue sarcoma and brain tumor immunology, Dhall said. In addition, Children’s of Alabama and UAB are joining the ReMission Alliance Against Brain Tumors (RAABT), a University of Florida-led network of neuro-oncology, tumor immunology and genetics experts from top peer institutions as well as a community of vested collaborators and influencers affected by brain cancer.

To manage the expected growth in clinical trials, Dhall is also reorganizing the department’s clinical trial infrastructure to improve efficiency and recruiting additional staff to prepare for the anticipated increase. He also wants to add other scientists who can build on the department’s portfolio not just in brain tumors, but also in sickle cell disease and leukemia. “That’s my hope for the next year,” he said.

He predicts that the number of clinical trials, today at about 10, will double within the next two years.

“Patients who relapse after front-line therapy have a very poor prognosis with poor survival,” Dhall said. “So, for us to be able to offer treatment options here means they don’t have to travel to other sites like Atlanta or Memphis, which is a huge disruption for patients at the end of life.”

“As a physician,” he said, “this gives me hope and it keeps me going.”

 

Inside Pediatrics, Pulmonology

Using Pharmacogenetics to Help Identify Patients with Cystic Fibrosis Most Likely to Respond to Targeted Therapies

Pharmacogenetics_WEB

Children’s of Alabama and the University of Alabama at Birmingham (UAB) are on a mission to determine how patients use Cystic Fibrosis Transmembrane Conductance Regulator modulators at the cellular level.

The discovery of the genetic mutation responsible for cystic fibrosis (CF) and the subsequent development of drugs that target this mutation, called Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators, together with improved supportive treatments, has revolutionized the management of the disease. Today, the median life expectancy of someone with CF has increased from age 10 in 1962 to 47, with many patients living into their 50s or 60s. With the newer drugs, many expect those with CF will be able to live a normal lifespan.

However, studies of the four currently available CFTR modulator therapies, three of which are combination drugs, find that between 20 and 25 percent of patients who should respond based on their disease’s genetic fingerprint don’t.1,2 Given that the drugs can cost up to $300,000 a year, it is important to find biomarkers to identify which drug will be most effective for which patient.3 Currently, the only option is a rectal biopsy followed by complicated testing or nasal brushing, neither of which are approved by the U.S. Food and Drug Administration, accepted by insurance or widely used.

Children’s of Alabama pulmonologist Jennifer S. Guimbellot, M.D., Ph.D., together with Steven M. Rowe M.D., who directs the Gregory Fleming James Cystic Fibrosis Research Center at the University of Alabama at Birmingham (UAB), and  Edward P. Acosta, Pharm.D.,  who directs UAB’s Division of Clinical Pharmacology, are on a mission to change that.  Their research focuses on how patients use CFTR modulators at the cellular level.

Until fairly recently, Guimbellot said,We didn’t have the tools to measure levels in the tissue.” Now they can use a simple, minimally invasive test Guimbellot helped develop. The assay measures concentrations of CFTR modulators in plasma and nasal epithelial cells, which, like epithelial cells in the lungs, are the drug’s site of action. Obtaining the cells is simple and inexpensive, requiring only a nasal brush, and can be done repeatedly to monitor drug levels.

After obtaining cells from patients, Guimbellot said, her team found that while plasma concentrations seem to correlate with the drug response, concentrations in tissue differ from those in plasma.

The question is why.

The answer may be related to pharmacogenomics, or the genetic variation in the way individuals metabolize drugs. Thanks to the epithelial tissue assays, she said, “our lab found that there may be substantial differences in the levels of modulators and also of metabolism proteins in people with CF.” Thus, once the drug is delivered to the cell, the effect may differ between patients. For instance, one person may be a fast metabolizer and clear the drug quickly; while the other may be a slow metabolizer and the drug accumulates in the tissue.

The protein known to metabolize CFTR modulators, CYP3A4, is primarily active in the liver. But in about 20 percent of people, it may also be produced in other tissues. While Guimbellot’s team has not found CYP3A4 in the epithelial cells from CF patients they’ve examined, they have found substantial levels of mRNA from the almost identical CYP3A7 protein and its cousin, CYP3A5. “So we hypothesize the CFTR modulator drugs are substantially metabolized by those proteins since it’s so similar to CYP3A4, and that this could affect how well patients respond to the drug.” They also found wide variation in the expression levels of both, which could contribute to the amount of available modulator at the target site.

“By understanding how genetic variation may influence the expression of these proteins and how that might affect the amount of drug available to do its job in the target tissue we can then relate the findings back to whether or not a patient can be expected to respond well to it or not,” she said.

Which is the next step in their research.

The team’s work is currently funded by the Cystic Fibrosis Foundation.


[1] National Institutes of Health. Cystic Fibrosis. 2019; https://report.nih.gov/nihfactsheets/ViewFactSheet.aspx?csid=36&key=C.

[2] Cystic Fibrosis News Today. Cystic Fibrosis Statistics. 2019; https://cysticfibrosisnewstoday.com/cystic-fibrosis-statistics/. Accessed June 19, 2019.

[3] Starner CI. How much is too much? Prime Therapeutics. May 31, 2019. Available at: https://www.primetherapeutics.com/en/news/prime-insights/2019-insights/Story_Cystic_Fibrosis_Treatments.html.

 

 

Cardiology, Inside Pediatrics

Discharged with an iPad: Children’s of Alabama Uses Telehealth to Monitor Complex Heart Patients at Home

Telehealth_WEB

Children’s of Alabama has partnered with Locus Health to provide a special iPad app that connects parents with nurse practitioners who treat infants who have undergone complex surgery.

Babies born with a single ventricle must undergo three major open-heart surgeries by the time they are toddlers. The first and most complex surgery occurs at 1 to 2 weeks; the second between 4 and 12 months. The months spent at home between the two can be overwhelming for parents.

Now families served at Children’s of Alabama have a new tool to help them cope – an iPad containing a special app from Locus Health, a Charlottesville, Virginia-based company that develops software to ease the discharge process and transition from hospital to home. The app forms the core of a remote monitoring system that connects parents with the nurse practitioners at Children’s of Alabama who care for their infants.

“These parents have been through a tremendous amount of stress,” said Katelyn Staley, discharge coordinator for Cardiovascular Services at Children’s of Alabama. “Not only do they have a newborn, but the baby requires major open-heart surgery in that first week or two of life. Then they are discharged home; it’s an overwhelming process,” she said.

“The Locus platform was designed specifically for the pediatric patient population with congenital heart disease,” said Sarah Blair, RN, MSN, CRNP, of Children’s of Alabama’s Hearts at Home Program. More than a dozen of the country’s leading children’s hospitals now use the system, which studies find can reduce post-discharge emergency room visits as much as 40 percent and the total hospital days by up to two weeks.

Children’s of Alabama had been using another electronic program, but it was cumbersome, not user-friendly and difficult to extract data from. Before that, all data was collected the old-fashioned way – with paper and pencil.

With the Locus app, parents enter their child’s daily weight, oxygen saturation, heart rate, number of diapers, Synagis dosing and nutritional intake, noting if there is any vomiting or diarrhea. They can also upload photos and videos.

Timely information is critical. For instance, weight gain is vitally important because if the baby stops gaining or loses weight the team needs to intervene quickly before complications occur. In addition, values can be individualized for each infant depending on their medical status. “If a parent enters an out-of-range value it creates a red flag and prompts the caregiver to call the hospital immediately,” Staley said.

The data automatically populates the congenital heart clinical dashboard, which nurse practitioners and clinical nutritionists monitor. Parents can also see current and past data and even track trends across time, Blair said. Data can also be downloaded into a PDF and emailed to physicians.

The remote monitoring is also beneficial since many patients live hours from the hospital and may be followed by a local cardiologist. “Now we can share the information with the cardiologist where they live,” she said.

“It definitely keeps us in constant communication with the families,” Blair said. “We still call and talk to them, but it relieves some of that pressure.”

“Sending families home with the reassurance that nurse practitioners are logging into the system on a daily basis and that they have 24/7 access to a provider is very reassuring,” Staley said.

Nephrology

Cutting Out Sugar Intake, One Kid at a Time

The average American consumes almost 152 pounds of sugar a year, about three pounds a week or 42.5 teaspoons a day — more than triple the recommended amount.[1] While sugar consumption isn’t the only cause of the country’s obesity epidemic, it is definitely a major contributing factor — particularly in children. And the problem is not only obesity, says pediatric nephrologist Daniel I. Feig, M.D., Ph.D., who directs the University of Alabama at Birmingham (UAB) Division of Pediatric Nephrology at Children’s of Alabama, but all the downstream health effects of being overweight, including cardiovascular disease, hypertension, liver disease, kidney disease and type 2 diabetes.

One reason for the high sugar intake is economic. Over the past 35 years, the price of fruits and vegetables has tripled, he said, while the price of sugar-sweetened foods such as beverages fell 75%. “The availability of calories and nourishment in a low-sugar fashion is much more expensive than it was a few decades ago,” he said. “We can talk until we’re blue in the face in low-income, urban clinics about eating fruits and veggies, but that isn’t the only barrier to kids not eating them; their families can’t afford it.

Then there’s the issue of high-fructose corn syrup (HFCS), used as a sweetener and preservative in many foods. Research from Feig and others has found that HFCS is not simply sugar in another form but has a high relative fraction of fructose compared to glucose, which alters cellular carbohydrate metabolism. This results in a greater rise in triglycerides and uric acid than with sugar from sugar cane or sugar beets.

Researchers have also demonstrated that high levels of uric acid stiffen and thicken blood vessel walls, resulting in hypertension, as well as activating the renin-angiotensin system system, causing immediate vasoconstriction.

Clinical trials find that lowering uric acid levels in hypertensive adolescents, but not adults, improves blood pressure. “So we have a window of opportunity in children to reduce their long-term cardiovascular and renal risk factors by controlling sugar intake,” Feig said.

That’s why clinicians and nutritionists at the hypertension clinic at Children’s counsel patients and their families about the effects of sugar as well as where the sugar is found (i.e., the sweet tea that is ubiquitous throughout the South). “Adolescents get about 48% of their sugar from sugar-sweetened beverages,” Feig said, “so it isn’t a function of just telling them not to eat candy.”

“When I see a child in our hypertension clinic with obesity-related hypertension, about a third of the time very high sugar and caloric intake in their beverages, up to 2,000 calories a day, is a major contributing factor,” he said. “Simply eliminating those liquids could make a huge difference in their health.”

He cites a recent study that polled new parents about the sugar content of various foods. More than 80% of parents underestimated the sugar content of foods with a “health halo,” like fruit juice and yogurt. “We have an educational deficit in terms of dietary literacy,” he said.

“So a big push in our clinic is helping families learn more about the nutritional content of food.”

Blood Pressure Control

Learn more about the hypertension clinic at Children’s of Alabama.


[1] Department of Health and Human Services. How Much Sugar Do You Eat? You May Be Surprised! https://www.dhhs.nh.gov/dphs/nhp/documents/sugar.pdf.

Cardiology, Uncategorized

Understanding Xenotransplantation’s Potential to Save Babies

The issue is simple: there are simply not enough hearts for all the children who need them. So 17% of all children who need a heart transplant die while waiting; this translates to 20% to 25% of infants.[1]

The University of Alabama at Birmingham (UAB) and Children’s of Alabama aim to change those dismal statistics with one of the most revolutionary approaches since the first heart was transplanted from one human to another in 1967 – xenotransplantation.  

Thanks to a $19.5 million grant from biotechnology magnate United Therapeutics Corporation, UAB and Children’s have launched one of the top programs in the world dedicated to developing genetically modified solid organs from pig models for transplantation.

The idea isn’t new. Pig tissue has been used to replace heart valves for years, said cardiothoracic surgeon David Cleveland, M.D., MBA, who leads the program at Children’s. The greatest challenge with solid organs, he said, is overcoming immunological and physiological barriers.

If they can do that, “We believe that there’s huge potential to improve the lives of children,” he said.  

Supporting Evidence

Earlier this year, Cleveland presented preliminary results from a study showing little reactivity in an infant’s blood to cells from a triple-knockout (TKO) pig. The pig had been genetically modified to delete the three major antigens that react with natural human anti-pig antibodies. Even those human cells that did react demonstrated a very mild reaction.

“We found that very promising,” Cleveland said.

Another area of interest is producing immune tolerance by transplanting porcine thymus tissue to “re-educate” the immune system to accept the pig heart, said cardiac intensivist Leslie Rhodes, M.D. The idea comes from the fact that children can develop an immune system via a human thymus transplant. “We wonder if we could we train their immune system to be tolerant to the pig thymus transplant,” she said.

Infants are the ideal starting place, Cleveland said, not only because they have the highest wait list mortality of any other demographic waiting for a solid organ transplant, but because their immune systems are still naïve. Indeed, they do not develop antibodies to pig glycans during at least the first three months of life, Cleveland and his team wrote in a recent journal article, providing a “window of opportunity” for the transplant.[2]

The next step is a transplant in a non-human primate. “The FDA won’t even consider it until we can prove consistent survival in a non-human primate,” Rhodes said. They hope to perform their first transplant later this year.

Societal Concerns Addressed

The team is also aware of the societal issues around xenotransplantation. To address that, they surveyed the families of patients on the transplant list and the nurses and physicians who will care for these children.

”I was surprised by how positive they were,” Cleveland said. “I thought there would be more pushback than there was.” Still, he said, “I think there has to be major education,” once xenotransplantation becomes a reality. “The idea of replacing a heart with a pig heart will take some people a little time to get over.”

He’s confident it will happen, though. “UAB is going to be one of the centers in the world with the potential to make this happen,” he said. “We have children living in our ICU because there’s not enough cardiac function; they are having their birthdays here. It totally changes entire families to have a child in the hospital forever. There has to be another way.“


[1] Dipchand AI. Current state of pediatric cardiac transplantation. Ann Cardiothorac Surg. 2018;7(1):31–55. doi:10.21037/acs.2018.01.07

[2] Cleveland D, Adam Banks C, Hara H, Carlo WF, Mauchley DC, Cooper DKC. The Case for Cardiac Xenotransplantation in Neonates: Is Now the Time to Reconsider Xenotransplantation for Hypoplastic Left Heart Syndrome? Pediatr Cardiol. 2019;40(2):437-444.

Cutting-Edge Research

Learn more about various research areas at the University of Alabama at Birmingham.

Pulmonology

Using Antisense Oligonucleotides to Improve CFTR Function in Cystic Fibrosis

oligotherapeutics research

Therapeutic development in cystic fibrosis (CF), a fatal pediatric lung disease affecting 1 in 3500 newborns annually, is rapidly advancing. “Although exciting progress has been made,” said Children’s of Alabama pediatric pulmonologist William T. Harris, M.D., an associate scientist at the Gregory Fleming James CF Research Center at the University of Alabama at Birmingham (UAB) who treats patients at Children’s of Alabama, “we are just midstream.” 

Where previous advances focused on the downstream consequences of disease, such as malnutrition, chronic infection and mucopurulent secretion, recent drug developments target genetic mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein itself. Dr. Harris’ research focuses on improving the efficacy of these agents, called CFTR modulators.

One key therapeutic clue is to identify why certain children with exactly the same CFTR genotype have widely different disease trajectories. Dr. Harris has studied the mechanisms behind this disease disparity and has discovered the mechanism through which transforming growth factor beta (TGF-β), a leading gene modifier of CF lung disease severity, inhibits CFTR functional expression. Dr. Harris now targets this mediator of disease progression as a therapeutic opportunity to optimize CFTR modulator response.

His research discovered that small, non-coding nucleotide sequences called microRNA (miRNA) regulate CFTR function. miRNA diminish gene expression by degrading the gene transcript or inhibiting protein translation. In CF, TGF-β stimulates miR-145 expression, which binds to and degrades the CFTR gene transcript. This prevents protein expression and diminishes channel function. Both TGF-β and miR-145 are markedly increased in CF lungs and airway epithelia, posing a significant barrier to effective intervention. 

Introducing miR-145 antagonists to airway epithelia reverses TGF-β suppression of CFTR and potentiates CFTR modulator response. However, TGF-β signaling and miR-145 activity are involved in multiple functions throughout the body, raising concern for off-target consequences. “As CF outcomes improve, the tolerance for side effects becomes very low,” he said. “Thus, the therapeutic intervention must be highly specific with a clearly defined target that only blocks the effects on CFTR.”

Antisense oligonucleotides (ASOs) offer that option. These short nucleic acid sequences bind to specific molecules of RNA, regulating expression of the gene. The FDA has already approved a handful of ASOs to treat congenital pediatric diseases such as Duchenne muscular dystrophy and spinal muscular atrophy.

 “ASOs are appealing in CF because they can be delivered directly to the lungs (via inhalation) to bypass systemic side effects,” Dr. Harris said. He is partnering with Ionis Pharmaceuticals, a leader in the development of ASOs, to test an ASO that prevents miR-145 binding to the CFTR transcript. This approach is called target site blockade (TSB).

“TSB offers a nuanced strategy to address the problem of CFTR inhibition without interrupting TGF-β/miR-145 availability for other regulatory processes,” he explained.  “I expect oligotherapeutics to benefit CF patients across genotype and improve next-generation therapeutics whether that be small molecule correctors or evolving gene editing strategies.”

Get More Information
Learn more about the Cystic Fibrosis Center’s resources for physicians.

Hematology and Oncology

Cancer Predisposition Clinic Aims to Change the Trajectory of Genetically Based Cancer

Li-Fraumeni syndrome. Von Hippel-Lindau. Rhabdoid tumor predisposition syndrome. Beckwith-Wiedemann syndrome. Retinoblastoma.

These are just a few of more than a dozen rare genetic conditions that predispose a child to cancer. Overall, at least 10% of children with cancer harbor a disease-associated pathogenic variant in a known cancer predisposition gene. While few can be prevented, regular surveillance can, at the very least, find malignancies early when treatment is most effective.

That’s the idea behind Children’s of Alabama’s Cancer Predisposition Clinic, now in its third year.

“We  provide comprehensive care and screening for these patients with the goal of detecting cancers at an early stage in order to provide the best care and outcomes for the patients,” said Elizabeth Alva, M.D., assistant professor in the University of Alabama at Birmingham (UAB) Division of Pediatric Hematology and Oncology. “It used to be there was nothing we could do about this terrible diagnosis,” she said. “Now we know there are definitely ways to look for cancers early and help patients.”

In addition, the clinic provides psychological support for families and determines if the genetic condition affects other family members, she said.

Typically, primary care physicians follow children with cancer predispositions. But those doctors may not be aware of or able to provide the level of evidence-based surveillance that Alva offers.

That’s why these clinics are a growing area in the pediatric hematology/oncology world, particularly at the larger children’s hospitals. “We felt that we definitely needed to provide that same level of care here in Alabama,” Alva said.

Alva and neuropsychologist Avi Madan-Swain, Ph.D., are currently following about 25 patients. Patients come to them through the pediatric cancer genetics clinic, where families are tested and counseled. Alva provides the screening, which ranges from regular ultrasounds to CT scans and MRI, while Madan-Swain addresses the family’s psychological needs.

One benefit to the clinic is that if there is a cancer diagnosis, the child and family are already comfortable with the hospital and the clinical team.

Alva is building a database of patients to gain a better understanding of disease development and progression, while Madan-Swain plans research around the psychological impact on families that have a child with a predisposition syndrome.

Understanding Genes
Learn more about the UAB Department of Genetics.

Neonatology

Initiative Targets Pain Management in NICU Babies

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Adults and children can tell you when they’re in pain. Infants can’t. Which is why Children’s of Alabama is participating in a national quality improvement initiative called Erase Post-Op Pain designed to reduce pain after invasive procedures. The initiative is part of the Children’s Hospital Neonatal Consortium (CHNC), an international group of children’s hospitals dedicated to improving care in the neonatal intensive care unit (NICU).

“There is really no ‘gold standard’ for pain assessment in preverbal children,” said NICU Associate Medical Director Allison Black, M.D. “Nor is there much data on the best way to treat pain in neonates.” However, there is data showing that preterm  babies who experience repeated pain can develop physiologic instability, altered brain development and abnormal stress response systems that persists into childhood. “The immature brain can potentially have a more diffuse and exaggerated response to pain,” she said.

The Erase initiative is designed to apply a multidisciplinary approach, including physicians, bedside nurses, pharmacologists, and even parents, to implement a standardized method to assess, document and manage postoperative pain.

The first action the team took was to adopt a single objective pain assessment tool, the N-PASS score, which measures sedation and pain based on vital signs such as heart rate and breathing, as well as behavior such as agitation, crying, facial expressions and neurologic resting tone. “These are things parents can help us assess as well,” Black said. Parents will also complete a survey after each procedure about how well they thought their baby’s pain was assessed and controlled.

The NICU pharmacist worked closely with other team members to develop different guidelines and different algorithms of what medications to use for each specific patient. Each guideline is unique, and the algorithm used depends upon the invasiveness of the procedure, whether the patient has had similar drugs in the past and if they are breathing spontaneously or with the help of assisted ventilation.

“By considering the history of the patient, the type of procedure performed. and looking closely at each drug’s  time to onset and duration of action, the treatment should be more effective,” Black said.

The initiative dovetails nicely with another CHNC performance improvement project, the STEPP-IN initiative. STEPP-IN works to reduce perioperative stress and instability  in NICU patients through improved handoffs and communication. “I think the projects will compliment each another and help improve our overall care of these small infants during the high-risk perioperative period,” Black said.

Babies in Need

Learn more about the Neonatal Intensive Care Unit at Children’s of Alabama.