In one family, genetic lightning struck twice. Two sisters were diagnosed with mitochondrial trifunctional protein (MTP) deficiency. This is a rare condition that stops the body from converting fats to energy, which can lead to lactic acidosis, recurrent breakdown of muscle tissue and release into the bloodstream (rhabdomyolysis), enlarged heart (cardiomyopathy) and liver failure.
Mitochondria are the cell’s powerplants and inside them the MTP enzymatic complex catalyzes three steps in beta-oxidation of long-chain fatty acids. MTP deficiency is so rare that fewer than 100 cases have been reported in the literature says Hostensia Beng, M.D., who presented an MTP case study during the American Society of Nephrology’s Kidney Week.
The 7-month-old girl with known MTP deficiency arrived at Children’s National lethargic with poor appetite. Her laboratory results showed a low corrected serum calcium level, elevated CK level and protein in the urine (proteinuria) at a nephrotic range. The infant was treated for primary hypoparathyroidism and rhabdomyolysis.
Even though the rhabdomyolysis got better, the excess protein in the girl’s urine remained at worrisome levels. A renal biopsy showed minimal change disease and foot process fusion. And electron microscopy revealed shrunken, dense mitochondria in visceral epithelial cells and endothelium.
“We gave her tacrolimus, a calcineurin inhibitor that we are well familiar with because we use it after transplants to ensure patient’s bodies don’t reject the donated organ. By eight months after treatment, the girl’s urine protein-to-creatinine (uPCR) ratio was back to normal. At 35 months, that key uPCR measure rose again when tacrolimus was discontinued. When treatment began again, uPCR was restored to normal levels one month later,” Dr. Beng says.
The girl’s older sister also shares the heterozygous deletion in the HADHB gene, which provides instructions for making MTP. That missing section of the genetic how-to guide was predicted to cause truncation and loss of long-chain-3-hydroxyacl CoA dehydrogenase function leading to MTP deficiency.
The older sister was diagnosed with nephrotic syndrome and having scar tissue in the kidney’s filtering unit (focal segmental glomerulosclerosis) when she was 18 months old. By contrast, she developed renal failure and progressed to end stage renal disease at 20 months of age.
“Renal involvement has been reported in only one patient with MTP deficiency to date, the older sister of our patient,” Dr. Beng adds.
Podocytes are specialized cells in the kidneys that provide a barrier, preventing plasma proteins from leaking into the urine. Podocytes, however, need energy to function and are rich in mitochondria.
“The proteinuria in these two sisters may be related to their mitochondrial dysfunction. Calcineurin inhibitors like tacrolimus have been reported to reduce proteinuria by stabilizing the podocyte actin cytoskeleton. Tacrolimus was an effective treatment for our patient, who has maintained normal renal function, unlike her sister,” Dr. Beng says.
American Society of Nephrology’s Kidney Week presentation
- “Treatment of nephrotic-range proteinuria with tacrolimus in mitochondrial trifunctional protein deficiency
Hostensia Beng, M.D., lead author; Asha Moudgil, M.D., medical director, transplant, and co-author; Sun-Young Ahn, M.D., MS, medical director, nephrology inpatient services, and senior author, all of Children’s National Health System.
Children’s urologist Michael H. Hsieh, M.D., Ph.D., knew from age 10 that he would become a doctor. Proof is at his parents’ home. For an elementary school art project, students were instructed to fashion a coat of arms out of clay. In addition to panels for truth, justice and Taiwan, in the shield’s M.D. panel, a snake twists around a rod, like the staff for Asclepius, a Greek god associated with healing.
“I liked science. When I can use it to help patients, that is very rewarding,” says Dr. Hsieh, the first doctor in his family.
Tinker/tailor is shorthand for the mystery drama, “Tinker Tailor Solider Spy,” he explains, adding that the “tinker” part also refers “to the fact that I am always questioning things, and science is about experimentation, trying to seek answers to questions.”
While still in medical school during a rotation Dr. Hsieh saw a bladder operation on a young child and thought it was “amazing.” That experience in part inspired Dr. Hsieh to become a urologist and bladder scientist. His training in immunology and study of the bladder naturally led him to study urinary tract infections and parasitic worms that affect the urinary tract. In addition, thanks to R01 funding from the National Institutes of Health (NIH), Dr. Hsieh is co-principal investigator with Axel Krieger, University of Maryland, and Jin U. Kang, Johns Hopkins, on a project to develop imaging robots for supervised autonomous surgery on soft tissue.
The $1 million in NIH funding pushes the boundaries on amazing by using multi-spectral imaging technology and improved techniques to reduce surgical complications.
Anastomosis is a technique used by surgeons to join one thing to another, whether it’s a vascular surgeon suturing blood vessels, an orthopedic surgeon joining muscles or a urologist stitching healthy parts of the urinary tract back together. Complications can set in if their stitching is too tight, prompting scar tissue to form, or too loose, letting fluid seep out.
“The human eye can see a narrow spectrum of electromagnetic radiation. These multi-spectral imaging cameras would see across greater set of wavelengths,” he says.
The project has three aims: figuring out the best way to place sutures using multi-spectral imaging, accurately tracking soft tissue as they model suturing and comparing the handicraft of a robot against anastomosis hand-sewn by surgeons.
“I like challenges, and I like new things. I am definitely not interested in doing permutations of other people’s work,” Dr. Hsieh explains. “I would much rather go on a path that hasn’t been tread. It is more difficult in some ways, but on a day-to-day basis, I know I am making a contribution.”
In another innovative research project, Dr. Hsieh leveraged a protein secreted by a parasitic worm, Schistosoma haematobium, that suppresses inflammation in hosts as a new therapeutic approach for chemotherapy-induced hemorrhagic cystitis, a form of inflammation of the bladder.
Watching his first surgery nearly 30 years ago, he had no idea robots might one day vie to take over some part of that complicated procedure, or that parasite proteins could be harnessed as drugs. However, he has a clear idea which innovations could be on the horizon for urology in the next three decades.
“My hope is 30 years from now, we will have a solid UTI vaccine and more non-antibiotic therapies. UTIs are the second-most common bacterial infection in childhood and, in severe cases, can contribute to kidney failure,” he says.
Globally, parasitic worms pose an ongoing challenge, affecting more than 1 billion worldwide – second only to malaria. People persistently infected by schistosome worms fail to reach their growth potential, struggle academically and lack sufficient energy for exercise or work.
“There is a feeling that the infection prevalence might be decreasing globally, but not as quickly as everyone hopes. In 30 years perhaps with more mass drug administration and additional drugs – including a vaccine – we’ll have it close to eliminated globally. It would become more like polio, casting a slim shadow with small pockets of infection here or there, rather than consigning millions to perpetual poverty.”
Emerging evidence suggests that the variety and volume of bacteria that reside in the bladder – the urinary microbiome – significantly impact whether people’s genitourinary systems remain healthy or become susceptible to disease.
Already, clinicians suspect that taking probiotics and making changes to diet may prevent urinary diseases that occur commonly among pediatric patients. A research team led by Children’s faculty is exploring whether changes in the built environment also affect the urinary microbiome.
Using experimental models, they looked at how stable the urinary microbiome was over time. Then, they measured the potential effect of changing the built environment on the urinary microbiome of preclinical models.
They did this by following six C57BL/6 experimental models for five months, starting from when they were nine weeks old. They collected urine specimens when the study began and repeated sample collections each month. The multidisciplinary team isolated microbial DNA from these specimens to determine the makeup of the bacterial community present in their urinary tracts.
All of the experimental models shared a single cage, drank the same water and ate the exact same chow. At four months, however, they moved the preclinical models to a different facility within the same county. Their chow and bedding remained unchanged, but the water source changed since they received tap water at both locations.
“There were no changes in the proportion of specific bacteria in the urinary microbiomes from month zero through month five, which means the urinary microbiomes of healthy experimental models remain stable over time,” says Michael Hsieh, M.D., Ph.D., a urologist at Children’s National Health System and senior author of the work presented during the Pediatric Urology Fall Conference. “However, the convergence of the Shannon Diversity Index, the clustering seen on Principal coordinate analyses and changes in functional analyses taken as a whole suggest that an overall shift of the urinary microbiome occurred due to a change in the physical environment.”
This work suggests that where patients live could influence which bacteria grow in the urinary tracts, including during urinary tract infections.
The Societies for Pediatric Urology’s Pediatric Urology Fall Conference
- “Effects of time and the built environment on the stability of the mouse urinary microbiome: implications for clinical utility.”
Catherine S. Forster, M.D., MS, pediatric hospitalist, Children’s National; James Cody, Ph.D., Biomedical Research Institute; Nirad Banskota, MS, Biomedical Research Institute; Crystal Stroud, MS, Children’s National; Ljubica Caldovic, Ph.D., principal investigator, Children’s National; and Michael Hsieh, M.D., Ph.D., urologist, Children’s National.
Pediatric anesthesiologist Julia C. Finkel, M.D., of Children’s National Health System, gazed into the eyes of a newborn patient determined to find a better way to measure the effectiveness of pain treatment on one so tiny and unable to verbalize. Then she realized the answer was staring back at her.
Armed with the knowledge that pain and analgesic drugs produce an involuntary response from the pupil, Dr. Finkel developed AlgometRx, a first-of-its-kind handheld device that measures a patient’s pupillary response and, using proprietary algorithms, provides a diagnostic measurement of pain intensity, pain type and, after treatment is administered, monitors efficacy. Her initial goal was to improve the care of premature infants. She now has a device that can be used with children of any age and adults.
“Pain is very complex and it is currently the only vital sign that is not objectively measured,” says Dr. Finkel, who has more than 25 years of experience as a pain specialist. “The systematic problem we are facing today is that healthcare providers prescribe pain medicine based on subjective self-reporting, which can often be inaccurate, rather than based on an objective measure of pain type and intensity.” To illustrate her point, Dr. Finkel continues, “A clinician would never prescribe blood pressure medicine without first taking a patient’s blood pressure.”
The current standard of care for measuring pain is the 0-to-10 pain scale, which is based on subjective, observational and self-reporting techniques. Patients indicate their level of pain, with zero being no pain and ten being highest or most severe pain. This subjective system increases the likelihood of inaccuracy, with the problem being most acute with pediatric and non-verbal patients. Moreover, Dr. Finkel points out that subjective pain scores cannot be standardized, heightening the potential for misdiagnosis, over-treatment or under-treatment.
Dr. Finkel, who serves as director of Research and Development for Pain Medicine at the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National, says that a key step in addressing the opioid crisis is providing physicians with objective, real-time data on a patient’s pain level and type, to safely prescribe the right drug and dosage or an alternate treatment.,
She notes that opioids are prescribed for patients who report high pain scores and are sometimes prescribed in cases where they are not appropriate. Dr. Finkel points to the example of sciatica, a neuropathic pain sensation felt in the lower back, legs and buttocks. Sciatica pain is carried by touch fibers that do not have opioid receptors, which makes opioids an inappropriate choice for treating that type of pain.
A pain biomarker could rapidly advance both clinical practice and pain research, Dr. Finkel adds. For clinicians, the power to identify the type and magnitude of a patient’s nociception (detection of pain stimuli) would provide a much-needed scientific foundation for approaching pain treatment. Nociception could be monitored through the course of treatment so that dosing is targeted and personalized to ensure patients receive adequate pain relief while reducing side effects.
“A validated measure to show whether or not an opioid is indicated for a given patient could ease the health care system’s transition from overreliance on opioids to a more comprehensive and less harmful approach to pain management,” says Dr. Finkel.
She also notes that objective pain measurement can provide much needed help in validating complementary approaches to pain management, such as acupuncture, physical therapy, virtual reality and other non-pharmacological interventions.
Dr. Finkel’s technology, called AlgometRx, has been selected by the U.S. Food and Drug Administration (FDA) to participate in its “Innovation Challenge: Devices to Prevent and Treat Opioid Use Disorder.” She is also the recipient of Small Business Innovation Research (SBIR) grant from the National Institute on Drug Abuse.
Decades ago, researchers thought that the native bacteria scattered throughout the human body—such as in the gut, the oral cavity and the skin—served little useful purpose. This microbiota, whose numbers at least match those of the cells in the body they live on and in, were considered mostly harmless hitchhikers.
More recently, research has revealed that these natural flora play key roles in maintaining and promoting health. In addition, studies have shown that understanding what a “typical” microbiome looks like and how it might change over time can provide an early warning system for some health conditions, including cancer.
Now, a small, multi-institutional study conducted in experimental models suggests that as bladder cancer progresses, it appears to be associated with a unique bacterial fingerprint within the bladder—a place thought to be bacteria-free except in the case of infection until just a few years ago. The finding opens the possibility of a new way to spot the disease earlier.
Bladder cancer is the fourth-most common malignancy among U.S. men but, despite its prevalence, mortality rates have remained stubbornly high. Patients often are diagnosed late, after bladder cancer has advanced. And, it remains difficult to discern which patients with non-invasive bladder cancer will go on to develop muscle-invasive disease.
Already, researchers know that patients with grade 4 oral squamous cell carcinoma, women with increasingly severe grades of cervical cancer and patients with cirrhosis who develop liver cancer have altered oral, vaginal and gut microbiomes, respectively.
New technological advances have led to identification of a diverse community of bacteria within the bladder, the urinary microbiome. Leveraging these tools, a research team that includes Children’s National Health System investigators studied whether an experimental model’s urinary bacterial community changed as bladder cancer progressed, evolving from a microbiome into a urinary “oncobiome.”
To test the hypothesis, the research team led by Michael H. Hsieh, M.D., Ph.D., a Children’s urologist, exposed an experimental model of bladder cancer to a bladder-specific cancer-causing agent, n-butyl-n-(4-hydroxybutyl) nitrosamine (BBN). Bladder cancers induced by BBN closely resemble human cancers in tissue structure at the microscopic level and by gene expression analyses. Ten of the preclinical models received a .05 percent concentration of BBN in their drinking water over five months and were housed together. Ten other experimental models received regular tap water and shared a separate, adjacent cage.
Researchers collected urine samples ranging from 10 to 100 microliters at the beginning of the longitudinal study, one week after it began, then once monthly. They isolated microbial DNA from the urine and quantified it to determine how much DNA was microbial. All of the bladders from experimental models exposed to BBN and two bladders from the control group were analyzed by a pathologist trained in bladder biology.
According to the study published online July 5, 2018, by the biology preprint server Biorxiv, they found a range of pathologies:
- Five of the experimental models that received BBN did not develop cancer but had histology consistent with inflammation. Three had precancer on histology: urothelial dysplasia, hyperplasia or carcinoma in situ. Two developed cancer: invasive urothelial carcinomas, one of which had features of a squamous cell carcinoma.
- The experimental model that developed invasive carcinoma had markedly different urinary bacteria at baseline, with Rubellimicrobium, a gram negative organism found in soil that has not been associated with disease previously, Escherichia and Kaistobacter, also found in soil, as the most prominent bacteria. By contrast, in the other experimental models the most common urinary bacteria were Escherichia, Prevotella, Veillonella, Streptococcus, Staphyloccoccus and Neisseria.
- By month four, the majority of experimental models exposed to BBN had significantly higher proportion of Gardnerella and Bifidobacterium compared with their control group counterparts.
“Closely analyzing the urinary bacterial community among experimental models exposed to BBN, we saw distinct differences in microbial profiles by month four that were not present in earlier months,” Dr. Hsieh says. “While Gardnerella is associated with the development of cancer, Bifidobacterium has been shown to exert antitumor immunity, and its increasing abundance points to the need for additional research to understand its precise role in oncogenesis.”
Dr. Hsieh adds that although the study is small, its findings are of significance to children who are prone to developing urinary tract infections (UTIs), including children with spina bifida, due to the association between UTIs and bladder cancer. “This work is important because it not only suggests that the urinary microbiome could be used to diagnose bladder cancer, but that it could also perhaps predict cancer outcomes. If the urinary microbiome contributes to bladder carcinogenesis, it may be possible to favorably change the microbiome through antibiotics and/or probiotics in order to treat bladder cancer.”
In addition to Dr. Hsieh, co-authors include Catherine S. Forster, M.D., M.S., and Crystal Stroud, of Children’s National; James J. Cody, Nirad Banskota, Yi-Ju Hsieh and Olivia Lamanna, of the Biomedical Research Institute; Dannah Farah and Ljubica Caldovic, of The George Washington University; and Olfat Hammam, of Theodor Bilharz Research Institute.
Research reported in this news release was supported by the National Institutes of Health under award number R01 DK113504 and the Margaret A. Stirewalt Endowment.
Children’s National rose in rankings to become the nation’s Top 5 children’s hospital according to the 2018-19 Best Children’s Hospitals Honor Roll released June 26, 2018, by U.S. News & World Report. Additionally, for the second straight year, Children’s Neonatology division led by Billie Lou Short, M.D., ranked No. 1 among 50 neonatal intensive care units ranked across the nation.
Children’s National also ranked in the Top 10 in six additional services:
- Neurology and Neurosurgery (No. 5), led by Roger Packer, M.D., and Robert Keating, M.D.
- Nephrology (No.6), led by Marva Moxey-Mims, M.D., FASN
- Cancer (No. 7), led by Jeffrey Dome, M.D., Ph.D.
- Orthopedics (No. 8), led by Matthew Oetgen, M.D.
- Pulmonary (No. 9), led by Anastassios Koumbourlis, M.D., M.P.H., and
- Diabetes and Endocrinology (a tie for No. 10), led by Fran Cogen, M.D., acting division co-chief
For the eighth year running, Children’s National ranked in all 10 specialty services, which underscores its unwavering commitment to excellence, continuous quality improvement and unmatched pediatric expertise throughout the organization.
“It’s a distinct honor for Children’s physicians, nurses and employees to be recognized as the nation’s Top 5 pediatric hospital. Children’s National provides the nation’s best care for kids and our dedicated physicians, neonatologists, surgeons, neuroscientists and other specialists, nurses and other clinical support teams are the reason why,” says Kurt Newman, M.D., Children’s President and CEO. “All of the Children’s staff is committed to ensuring that our kids and families enjoy the very best health outcomes today and for the rest of their lives.”
The excellence of Children’s care is made possible by our research insights and clinical innovations. In addition to being named to the U.S. News Honor Roll, a distinction awarded to just 10 children’s centers around the nation, Children’s National is a two-time Magnet® designated hospital for excellence in nursing and is a Leapfrog Group Top Hospital. Children’s ranks seventh among pediatric hospitals in funding from the National Institutes of Health, with a combined $40 million in direct and indirect funding, and transfers the latest research insights from the bench to patients’ bedsides.
“The 10 pediatric centers on this year’s Best Children’s Hospitals Honor Roll deliver exceptional care across a range of specialties and deserve to be highlighted,” says Ben Harder, chief of health analysis at U.S. News. “Day after day, these hospitals provide state-of-the-art medical expertise to children with complex conditions. Their U.S. News’ rankings reflect their commitment to providing high-quality care.”
The 12th annual rankings recognize the top 50 pediatric facilities across the U.S. in 10 pediatric specialties: cancer, cardiology and heart surgery, diabetes and endocrinology, gastroenterology and gastrointestinal surgery, neonatology, nephrology, neurology and neurosurgery, orthopedics, pulmonology and urology. Hospitals received points for being ranked in a specialty, and higher-ranking hospitals receive more points. The Best Children’s Hospitals Honor Roll recognizes the 10 hospitals that received the most points overall.
This year’s rankings will be published in the U.S. News & World Report’s “Best Hospitals 2019” guidebook, available for purchase in late September.
Every year, hundreds of thousands of U.S. patients – and even more throughout the world – are prescribed cyclophosphamide or ifosfamide. These two chemotherapy drugs can be life-saving for a wide range of pediatric cancers, including leukemias and cancers of the eyes and nerves. However, these therapies come with a serious side effect: Both cause hemorrhagic cystitis in up to 40 percent of patients. This debilitating condition is characterized by severe inflammation in the bladder that can cause tremendous pain, life-threatening bleeding, and frequent and urgent urination.
Infection with a parasitic worm called Schistosoma haematobium also causes hemorrhagic cystitis, but this organism has a fail-safe: To keep its host alive, the parasite secretes a protein that suppresses inflammation and the associated pain and bleeding.
In a new study, a Children’s-led research team harnessed this protein to serve as a new therapy for chemotherapy-induced hemorrhagic cystitis.
“Urogenital Schistosoma infestation, which is caused by S. haematobium, also causes hemorrhagic cystitis, likely by triggering inflammation when the parasite’s eggs are deposited in the bladder wall or as eggs pass from the bladder into the urinary stream. S. haematobium eggs secrete proteins, including IPSE, that ensure human hosts are not so sickened that they succumb to hemorrhagic cystitis,” says Michael H. Hsieh, M.D., Ph.D., senior author of the study published April 3, 2018, by The FASEB Journal. “This work in an experimental model is the first published report of exploiting an uropathogen-derived host modulatory molecule in a clinically relevant model of bladder disease, and it points to the potential utility of this as an alternate treatment approach.”
S. mansoni IPSE binds to Immunoglobulin E (IgE), an antibody produced by the immune system that is expressed on the surface of basophils, a type of immune cell; and mast cells, another immune cell that mediates inflammation; and sequesters chemokines, signaling proteins that alert white cells to infection sites. The team produced an ortholog of the uropathogen-derived protein. A single IV dose proved superior to multiple doses of 2-Mercaptoethane sulfonate sodium (MESNA), the current standard of care, in suppressing chemotherapy-induced bladder hemorrhaging in an experimental model. It was equally potent as MESNA in dampening chemotherapy-induced pain, the research team finds.
“The current array of medicines we use to treat hemorrhagic cystitis all have shortcomings, so there is a definite need for novel therapeutic options,” says Dr. Hsieh, a Children’s National Health System urologist. “And other ongoing research projects have the potential to further expand patients’ treatment options by leveraging other urogenital parasite-derived, immune-modulating molecules to treat inflammatory bowel diseases and autoimmune disorders.”
Future research will aim to describe the precise molecular mechanisms of action, as well as to generate other orthologs that boost efficacy while reducing side effects.
In addition to Dr. Hsieh, Children’s study co-authors include Lead Author, Evaristus C. Mbanefo; Loc Le and Luke F. Pennington; Justin I. Odegaard and Theodore S. Jardetzky, Stanford University; Abdulaziz Alouffi, King Abdulaziz City for Science and Technology; and Franco H. Falcone, University of Nottingham.
Financial support for this research was provided by National Institutes of Health under award number RO1-DK113504.
Eric Vilain, M.D., Ph.D., is well versed in the “world of uncertainty” that surrounds differences of sex development. Since joining Children’s National as the director of the Center for Genetic Medicine Research in 2017, he’s shared with our research and clinical faculty and staff his expertise about the ways that genetic analysis might help address some of the complex social, cultural and medical implications of these differences.
Over the summer, he gave a keynote address entitled “Disorders/Differences of Sex Development: A World of Uncertainty” during Children’s National’s Research and Education Week, an annual celebration of research, education, innovation and scholarship at Children’s National and around the world. In January 2018, he shared a more clinically oriented version of the talk at a special Children’s National Grand Rounds session.
The educational objective of these talks is to inform researchers and providers about the mechanisms of differences of sex development (DSD), which are defined as congenital conditions in which the development of chromosomal, gonadal or anatomical sex is atypical.
The primary goal, though, is to really shine light on the complexity of this hot topic, and share how powerful genetic tools can be used to provide vital, concrete information for care providers, patients and families to assist with difficult treatment (and non-treatment) decisions.
“A minority of DSD cases are able to receive a genetic diagnosis today,” he points out. “But geneticists know how important it is to come to a diagnosis and so we seek to increase the number of patients who receive a concrete genetic diagnosis. It impacts genetic counseling and reproductive options, and provides a better ability to predict long term outcomes.”
“These differences impact physiology and medicine. We want to better understand the biology of reproduction, with an emphasis on finding ways to preserve fertility at all costs, and how these variations may lead to additional complications, including cancer risk.”
At conception, he explains, both XX and XY embryos have bipotential gonads capable of differentiating into a testis or an ovary, though embryos are virtually indistinguishable from a gender perspective up until six weeks in utero.
Whether or not a bipotential gonad forms is largely left up to the genetic makeup of the individual. For example, a gene in the Y chromosome (SRY) triggers a cascade of genes that lead to testis development. If there is no Y chromosome, it triggers a series of pro-female genes that lead to ovarian development.
Dr. Vilain notes that a variation of enzymes or transcription factors can occur at any single step of sex development and alter all the subsequent steps. Depending on the genotype, an individual may experience normal gonadal development, but abnormal development of the genitalia, for example.
He also noted that these genes are critical to determining the differences between men and women in non-gonadal tissues, including differences in gene expression within the brain. One study in the lab of investigator Matt Bramble, Ph.D., investigates if gonadal hormones impact sex differences in the brain by modifying the genome.
This work is a prime example of research informing the care provided to patients and families. Dr. Vilain is also a member of the multidisciplinary clinical team of the PROUD Clinic at Children’s National, a program completely devoted to caring for patients with a wide array of genetic and endocrine issues, including urogenital disorders and variations of sex development.
“Love is in the air, the sea, the earth and all over and inside our bodies,” the PBS Valentine’s Day-themed video begins. As the public television station notes, what humans consider romance can look vastly different for creatures big and small, including serenading mice, spiders who wrap their gifts in silk and necking giraffes.
The “spooning” parasites segment of the video is where viewers see research conducted by Michael H. Hsieh, M.D., Ph.D., director of the Clinic for Adolescent and Adult PedIatric OnseT UroLogy at Children’s National Health System, and video filmed in his lab.
Schistosomiasis, a chronic infection with schistosome worms, is a distinctly one-sided love affair. As shown in Dr. Hsieh’s video clips, the male worm is shorter and fatter and equipped with a groove, a love canal where the longer, thinner female lodges, enabling the pair to mate for decades. This lifelong bond and the thousands of eggs it produces daily can only occur when the worms are inside the human host, Dr. Hsieh says.
While the video stresses Valentine’s Day romance, there are few rosy outcomes for humans who are the subject of the schistosome worms’ attention.
“Heavily and chronically infected individuals can have lots of problems,” Dr. Hsieh says. “This is a stunting and wasting health condition that prevents people from reaching their growth potential, impairs their academic performance and leaves them sapped of the energy needed to exercise or work. It truly perpetuates a cycle of poverty, particularly for affected children.”
Even the potential bright spot in this sobering story, the ability of the body’s immune system to fend off the parasitic worms, is only partly good news.
Schistosome worms have co-evolved with their human hosts, learning to take advantage of human vulnerabilities. Take the immune system. If it kicks too far into overdrive in trying to wall off the eggs from the rest of the body, it can interfere with organ function and trigger liver failure, kidney failure and early onset of bladder cancer, he says.
However, Dr. Hsieh and other schistosomiasis researchers are working on ways to positively harness the human immune response to schistosome worms, including developing diagnostics, drugs and vaccines. He says he and his colleagues would “love” to eliminate schistosomiasis as a global scourge.
Journal club is a rite of passage for nearly everyone who works in an academic laboratory. What might sound like an exclusive group of readers and authors united by a secret handshake is actually a regular meeting of scientists – faculty members and young trainees alike – who gather to discuss a highlighted paper in their field of expertise.
Some of these gatherings might involve a handful of people from the same lab; others might include a larger group from the same institutional department or division. Typically, one person presents a paper, sharing all the relevant details about a study’s methodology and conclusions. Afterward, everyone has the chance to pose questions, make comments and thoroughly discuss conclusions.
“It’s an excellent academic opportunity in terms of teaching and training of early career scientists and clinicians, and it remains useful no matter what stage you are in your career,” says Michael Hsieh, M.D., Ph.D., a urologist who directs the Clinic for Adolescent and Adult PedIatric OnseT UroLogy (CAPITUL) at Children’s National Health System who has participated in a heavy share of journal club meetings over the years.
But, what if journal club didn’t have to adhere to this traditional format? What if this academic discussion could move to a venue more fitting for the 21st century, more inclusive of scientists in different geographic locations, with varying viewpoints and expertise?
That’s what Dr. Hsieh and others are trying to accomplish with a new pediatric urology-focused journal club on Twitter. When Christopher Bayne, a second-year fellow training in pediatric urology at Children’s National under Dr. Hsieh’s mentorship, approached him with the idea, Dr. Hsieh said that he jumped at the chance.
Traditional journal clubs, the two explain, can be hindered by several factors. One is a tendency toward “group think,” Dr. Hsieh says – members of the same lab, or even the same institution, tend to have the same training and practices, so they’re less likely to feel comfortable introducing new ideas about these areas into the discussion. Journal club discussions also are limited by uncertainties about what a study author might have had in mind with their methodology and conclusions. Study authors are rarely included in the discussion, Dr. Hsieh adds.
Twitter, Bayne says, offers an easy way around these barriers. Rather than including just members of the same lab, their Pediatric Urology Journal Club (PUJC) can accommodate any registered Twitter user in their discussions. That means that any interested person around the world – researchers, clinician-scientists, other health care providers, as well as patients and their families, for example – can participate in the monthly discussions.
Participation also isn’t dictated by geography. During recent PUJC meetings, individuals joined the thread from Brazil, Ireland and Turkey. The meetings, sponsored by the Journal of Pediatric Urology, take place in the first days to weeks after the selected paper has been available under “open access,” giving anyone a chance to read it – even if they lack a journal subscription. This format enables all participants to join threads, erasing the restrictions of geography or busy clinical and research schedules.
Thus far, the meetings have included papers on:
- A comparison of the cost and complications of performing a surgery either robotically or through an open procedure to fix the tubes that connect the kidneys to the bladder in patients with a condition known as vesicouretal reflux, in which urine flows in the wrong direction.
- The pros and cons of treating varicoceles, enlarged veins inside the scrotum that potentially cause fertility problems. The condition is asymptomatic in adolescents.
- The importance of the diameter of the ureter, the part of the tube closest to the outside of the body that carries urine to be expelled, for resolving vesicouretal reflux, an abnormal flow of urine.
This new platform has attracted a core group of relatively young and young-at-heart devotees, Bayne says. He and other organizers have included study authors in every meeting thus far, often guiding older and Twitter-naive scientists through the process of creating an account.
And the typical 140-character limit Twitter imposes on comments known as tweets? “It might be counterintuitive,” Bayne says, “but I see the character limit as one of this journal club’s biggest strengths.” This cutoff encourages discussion members to distill their thoughts, often including two or three distinct points, into concise and deeply meaningful statements. “Participants have really latched on to the efficiency of this approach to learning about a topic and having a lively discussion.”
Thus far, their approach has been increasing in popularity. Their very first PUJC meeting in February 2017 attracted a modest number of just 24 active participants who sent 310 tweets, but generated nearly 136,000 impressions, or views.
The researchers plan to continue the monthly PUJC meetings through the Twitter handle @pedurojc. You can follow updates from Dr. Hsieh on his handle: @perforin and updates from Bayne’s on his: @chrbayne.
The clock starts ticking for a child with testicular torsion as soon as the pain starts. To increase the likelihood of successfully salvaging the twisted testicle and spermatic cord, surgical intervention – which involves restoring blood flow to the testis – should ideally occur within six hours from the onset of pain.
That’s six hours for a parent to identify that there is a problem, bring a child to the emergency department (ED) and go through all the steps required to get the child to the operating room. This process starts with an emergency physician, who probably doesn’t see many cases of this relatively rare condition, being able to identify the potential issue and contact the pediatric urologist on call. Next, diagnostic imaging orders need to be placed and actual imaging needs to occur for the diagnosis to be made. Finally, the patient needs to be moved to the pre-operative area, assessed by the anesthesia team and then taken to surgery.
In April 2016, the Division of Urology at Children’s National launched a new, accelerated care pathway for testicular torsion assessment and treatment that was developed collaboratively with the Emergency Department, Diagnostic Imaging and Radiology, the Department of Anesthesiology, and the peri-operative and operating room team.
“What stood out to us when we looked at the total time from identifying the problem to getting to surgery, was the length of time from when the diagnosis was made in the emergency department to the operating room,” says Tanya Davis, M.D., a pediatric urologist who led this new initiative along with Harry Rushton, Jr., M.D., chief of the Division of Urology. “It was an area where we could easily identify and streamline the process to accelerate the time for a patient to get from arrival in the ED to the surgical suite.”
Now, when a patient presents in the emergency department with the symptoms of testicular torsion, there is a straightforward path mapped out for the physician. “Who you need to talk to, how to reach them, relevant phone numbers, details on when to communicate to the attending physician, the ideal order of activities, the ability for residents to quickly transport the patient rather than waiting for hospital transport to surgery, and, most important, making it clear to everyone involved that this condition is a true emergency when every second matters,” Dr. Davis adds.
Since the initiative’s launch, 21 cases, from referrals and direct diagnosis, have come into the ED. The new protocol is working efficiently, reducing the mean time from the ED to the OR by more than an hour, now averaging below the team’s target goal of less than 2.5 hours from ED arrival to the OR.
Though salvage rates have not improved yet, the team will continue to collect data and monitor the impact of the accelerated pathway. Additionally, Dr. Davis says that a significant need remains for referring emergency and primary care physicians, as well as parents, to understand the condition and its need for urgent treatment. Children’s National urologists are developing handouts for both physicians and families to help raise awareness.
The hope is that more general knowledge of testicular torsion will allow parents, primary care doctors and emergency department staff to expedite diagnosis when a child complains of scrotal pain or has visible discoloration, further reducing the time from onset of pain to successful intervention. With such a short window of time for treatment, the accelerated care pathway is showing promising results.
Daniel Casella, M.D,, wants to design a bracelet that uses ultrasound waves to stimulate the posterior tibial nerve in pediatric patients with overactive and underactive bladders. “Realistically and optimistically, we might be five years away from that,” says Dr. Casella, a pediatric urologist at Children’s National Health System who has been studying the ability of ultrasound mediated neuromodulation of the posterior tibial nerve to affect bladder function. For this work, he was named a research finalist at the Pediatric Urology Fall Congress in September.
Up to 40 percent of patients seen in a pediatric urology clinic have an element of voiding dysfunction. The majority of these patients can be managed with behavior modification and conservative measures; however there is a subset of these patients who will require more aggressive therapy. With the possibilities that this research holds, he suggests ultrasound mediated tibial nerve stimulation as potentially an ideal outpatient treatment of overactive bladder and dysfunctional elimination.
What we know
The S3 sacral nerve root contains neurons that play an important role in regulating bladder function. Stimulation of the S3 nerve root with a surgically placed neurostimulator is an effective treatment for overactive or underactive bladders in adults and more recently pediatric patients. The problem: Placement of the S3 nerve stimulator is an invasive surgical procedure that requires revision or additional procedures in up to 50 percent of pediatric patients.
Another treatment: Stimulation of the posterior tibial nerve (a peripheral extension of the S3 nerve root), with an electrical current is also an effective treatment of both overactive and underactive bladders. The problem: For a durable response, the posterior tibial nerve must be stimulated with an electrical current that produces a moderate level of discomfort for 30 minutes. These treatment sessions must then be repeated weekly for approximately 12 weeks, making it very difficult to offer this therapy to pediatric patients.
New hope for patients with bladder dysfunction
Using targeted ultrasound to stimulate nerves is an area of active research within the radiology and neuroscience community. To date, studies in humans are limited, however there have been promising results when transcranial ultrasound was used to stimulate the deep brain motor centers, potentially offering a novel treatment for movement disorders such as Parkinson’s.
Dr. Casella started this research during his pediatric fellowship at Vanderbilt with the support of a $25,000 grant from the Society of Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction.
Dr. Casella says: “Using an established model of bladder overactivity in rats, we demonstrated that 2-3 minutes of ultrasound stimulation of the posterior tibial nerve can suppress bladder contractions for an average of 10 minutes.”
Dr. Casella plans to refine his techniques in animal models and work toward designing an ultrasound probe that can be used in humans. He is hopeful that his protocol will be ready for application in a clinical trial in the next one to two years. “Ultimately our goal is to design something that can be used at home,” Dr. Casella says. Ultrasound devices can be more compact if imaging isn’t the primary use. Ideally we would like to have the ultrasound transducer in the form of an ankle bracelet attached to a generator similar in size to a smartphone.
One of the most common causes of premature death is cancer. But today, survival rates for many childhood cancers have surpassed 90 percent and the emphasis of care has shifted from survival to quality of life after survival. That’s according to Michael Hsieh, M.D., Ph.D., who is leading the program at Children’s National Health System and getting much support from oncology and neonatology.
“One of the important aspects of quality of life is fertility,” Dr. Hsieh says. “For those adult survivors of childhood cancer who want to have children, I think it’s imperative that we do whatever we can to help them.”
The program at Children’s National, part of a multi-institutional consortium based at the University of Pittsburgh, had one of the highest recruitment of all the satellite sites for this study, which offers cryopreservation of boys’ testicular tissue. From Dr. Hsieh’s program, tissue from 11 patients has been harvested in a year and a half.
Radiation and chemotherapy are toxic to the gonads, which have testicular and ovarian function. “The idea is that if we can freeze the testicular tissue until the technology catches up in such that we can restore fertility down the road, that’s a wonderful thing. Most of these children are in grade school and not interested in having children until at least 15-20 years.”
Getting the tissue samples
For the first time, parents of young cancer patients are having this discussion, and Hsieh says they are extremely appreciative, even if they decline to participate in the study.
Young men can provide a sperm sample, which can easily be frozen. For boys who haven’t gone through puberty or boys who are not able to give a sample because they are too sick or unwilling to do so, a biopsy can collect a tissue sample, which can then be frozen.
Storing samples at a cost
Hsieh says his work also is focused on improving funding for storage of tissues. The out-of-pocket costs to store samples are several hundred dollars a year, and it can be cost-prohibitive for some patients and families.
Hsieh has applied for financial assistance from Children’s National internal funding opportunities for the program to help even the playing field.
“I don’t think it’s fair that a child who is born into a poor family is unable to participate in fertility preservation whereas a child who happens to be born more affluent is able to,” Hsieh says.
A hot topic at national urology meetings is how to transition patients with pediatric-onset urologic conditions as they grow into adults. Michael Hsieh, MD, PhD, is leading the way in the U.S. by serving as a bridge for patients at the first dedicated transitional urology program in the mid-Atlantic region. The Clinic for Adolescent and Adult PedIatric OnseT UroLogy (CAPITUL) is a joint venture between Children’s National and George Washington University Hospital that started two years ago.
What’s most unique about the clinic is that Dr. Hsieh has a foot in both the pediatric world of urology and one in the adult world, with clinical privileges at both institutions. He sees the full span of pediatric urology patients, including expectant moms with fetuses that have suspected urologic anomalies to adults who may have congenital conditions that require follow-up. However, he sees more teenagers and young adults than his urology colleagues both at hospitals.
The clinic’s patients have included a 19-year-old man with multiple urethrocutaneous fistulas after failed hypospadias repairs, a 25-year-old woman with cloacal exstrophy and continent urinary diversion with a urinary tract infection and stones, and a 25-year-old man with spina bifida with incontinence urethral erosion from an indwelling catheter.
A number of significant urological conditions until recently led to premature death because of medical complications, Dr. Hsieh says. Today, 90 percent of spina bifida patients live past the age of 30. “There’s a synchronized wave of patients who are all now young adults with spina bifida, and they are facing issues of reproduction and sexuality,” Dr. Hsieh says. “These are issues that pediatric urologists generally speaking are not comfortable in managing. It makes sense: It’s been many, many years since they did that type of urology.”
The program is specifically following this transitional group on conditions that are long term and that may affect fertility, such as cancer and varicoceles.
One in five teenage boys have varicoceles, or varicose veins on the scrotum. “The relationship between having varicocele as a teenager and infertility as an adult is not clear, so we felt it important to include this diagnosis in the transitional program so we can follow these patients long term and monitor their testicular growth,” Dr. Hsieh says.
Proof that the program’s working
Dr. Hsieh tracks the messages from colleagues referring patients from one institution to the other. “Unfortunately, some patients and families—for a range of issues—fall through the cracks, so it is really important to have that direct link. If we didn’t have the program set up as it is, there would be fewer successful transitions between institutions,” he says.
Another way Dr. Hsieh knows the program is working is because of the uptick in adolescent and young adult patients in his practices at Children’s and at GW.
Dr. Hsieh says the optimal time to begin transition is at age 12, when the team makes the patient and family aware of the transition policy. From ages 14-16, it’s time to initiate the health care transition plan and begin discussing the adult model of care. By age 18, Dr. Hsieh recommends the transition to adult care, and by ages 23-26, patients are integrated into adult care.