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Study Identifies Cause for Mysterious Cases of Epilepsy in Children

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International collaboration uncovers mosaicism, a condition in which cells within the same person have a different genetic makeup, as a cause for pediatric seizures

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Credit: Pixabay
By studying resectioned brain tissue for mutations, researchers have identified genetic factors that may cause malformations of cortical development, a form of pediatric epilepsy.
« Study Identifies Cause for Mysterious Cases of Epilepsy in Children

Newswise — Epilepsy is present in 4% of the population, and is among the most common brain disorders in children. Modern medicine can prevent most seizure recurrences, but approximately 20% of patients do not respond to treatment.

In these cases, the reason may originate in patches of damaged or abnormal brain tissue known as “malformations of cortical development” (MCD), which results in a diverse group of neurodevelopment disorders. Surgical resection or removal of the patch can cure the seizures, and epilepsy surgery to improve neurological outcomes is now a key part of the modern medical armamentarium, but what causes the patches has largely remained a mystery.

Writing in the January 12, 2023 issue of Nature Genetics, researchers at University of California San Diego School of Medicine and Rady Children’s Institute for Genomic Medicine, collaborating with an international consortium of more than 20 children’s hospitals worldwide, report a significant breakthrough in understanding the genetic causes of MCD.

Members of the Focal Cortical Dysplasia Neurogenetics Consortium investigated 283 brain resections from children across a range of MCD types, with parental consent, looking for potential genetic causes. Because most brain tissue in these children is normal, the scientists focused on mutations present in a small subset of brain cells, a phenomenon termed genetic somatic mosaicism.

“This was a decade-long journey, bringing specialists together from around the world, to recruit patients for this study,” said senior study author Joseph Gleeson, MD, Rady Professor of Neuroscience at UC San Diego School of Medicine and director of neuroscience research at the Rady Children’s Institute for Genomic Medicine. “Until recently, most hospitals did not study resected brain tissue for genetic causes. The consortium organized a biobank to store tissue for high-throughput mosaicism analysis.”

Previous research by Gleeson and colleagues had shown that genetic somatic mosaicism in the mTOR signaling pathway was a contributing factor, said co-first author Changuk Chung, PhD, a postdoctoral fellow in the Gleeson lab.

“But most patients remain undiagnosed, which hinders treatment. We tested for hidden mutations, detectable only by greatly expanding the cohort size and improving methods so that the results could be meaningful. We collaborated to solve technical and logistical bottlenecks. The pieces fell into place, but it took 10 years.”

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The team conducted intensive genomic discovery using state-of-art somatic mosaic algorithms developed by the National Institutes of Health-sponsored Brain Somatic Mosaicism Network, of which UC San Diego is a member.

“We tried our best to detect mutations in as little as 1 percent of cells,” said co-first author Xiaoxu Yang, PhD, a postdoctoral scholar in Gleeson’s lab. “Initially we failed. To solve these problems, we needed to develop novel artificial intelligence methods to overcome barriers in sensitivity and specificity.”

The team ultimately identified 69 different genes carrying somatic brain mutations, the majority of which have never previously reported in MCD.

“We can draw parallels with the cancer field because these mutations disrupt cellular function and need to be resected,” said co-first author Chung. “However, unlike cancer cells, brain cells mostly do not divide so these cells misbehave by stimulating epileptic seizures. The question that arose was whether the newly found gene mutations were sufficient to cause MCD disease.”

Gleeson said the scientists found that the genes converged on calcium signaling, gene expression and synaptic functions, and noted that when the mutations were introduced into a mouse model, abnormalities similar to those seen in patients were observed. The study authors suggest the findings could be used to improve diagnosis and develop cures for MCD disease.

“The MCD genes in patient brains have demonstrated critical roles during cortical development,” said Gleeson. “These findings could lead to new molecular classifications for MCD, and ultimately to personalized therapies for epilepsy.”

For a complete list of co-authors, see full study.

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Funding for this research came, in part, from the National Institutes of Health (grants NIMH U01MH108898 and R01MH124890, NIA R21AG070462, NINDS R01NS083823), the San Diego Supercomputer Center and UC San Diego Institute of Genomic Medicine.

Source: University of California San Diego

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What the ‘moral distress’ of doctors tells us about eroding trust in health care

The article discusses the ethical dilemmas faced by healthcare providers when families demand life-sustaining treatments for patients unlikely to benefit, highlighting moral distress and trust issues.

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moral distress

Daniel T. Kim, Albany Medical College

I sit on an ethics review committee at the Albany Med Health System in New York state, where doctors and nurses frequently bring us fraught questions.

Consider a typical case: A 6-month-old child has suffered a severe brain injury following cardiac arrest. A tracheostomy, ventilator and feeding tube are the only treatments keeping him alive. These intensive treatments might prolong the child’s life, but he is unlikely to survive. However, the mother – citing her faith in a miracle – wants to keep the child on life support. The clinical team is distressed – they feel they’re only prolonging the child’s dying process.

Often the question the medical team struggles with is this: Are we obligated to continue life-supporting treatments?

Bioethics, a modern academic field that helps resolve such fraught dilemmas, evolved in its early decades through debates over several landmark cases in the 1970s to the 1990s. The early cases helped establish the right of patients and their families to refuse treatments.

But some of the most ethically challenging cases, in both pediatric and adult medicine, now present the opposite dilemma: Doctors want to stop aggressive treatments, but families insist on continuing them. This situation can often lead to moral distress for doctors – especially at a time when trust in providers is falling.

Consequences of lack of trust

For the family, withdrawing or withholding life-sustaining treatments from a dying loved one, even if doctors advise that the treatment is unlikely to succeed or benefit the patient, can be overwhelming and painful. Studies show that their stress can be at the same level as people who have just survived house fires or similar catastrophes.

While making such high-stakes decisions, families need to be able to trust their doctor’s information; they need to be able to believe that their recommendations come from genuine empathy to serve only the patient’s interests. This is why prominent bioethicists have long emphasized trustworthiness as a central virtue of good clinicians.

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However, the public’s trust in medical leaders has been on a precipitous decline in recent decades. Historical polling data and surveys show that trust in physicians is lower in the U.S. than in most industrialized countries. A recent survey from Sanofi, a pharmaceutical company, found that mistrust of the medical system is even worse among low-income and minority Americans, who experience discrimination and persistent barriers to care. The COVID-19 pandemic further accelerated the public’s lack of trust.

In the clinic, mistrust can create an untenable situation. Families can feel isolated, lacking support or expertise they can trust. For clinicians, the situation can lead to burnout, affecting quality and access to care as well as health care costs. According to the National Academy of Medicine, “The opportunity to attend to and ease suffering is the reason why many clinicians enter the healing professions.” When doctors see their patients suffer for avoidable reasons, such as mistrust, they often suffer as well.

At a time of low trust, families can be especially reluctant to take advice to end aggressive treatment, which makes the situation worse for everyone.

Ethics of the dilemma

Physicians are not ethically obligated to provide treatments that are of no benefit to the patient, or may even be harmful, even if the family requests them. But it can often be very difficult to say definitively what treatments are beneficial or harmful, as each of those can be characterized differently based on the goals of treatment. In other words, many critical decisions depend on judgment calls.

Consider again the typical case of the 6-month-old child mentioned above who had suffered severe brain injury and was not expected to survive. The clinicians told the ethics review committee that even if the child were to miraculously survive, he would never be able to communicate or reach any “normal” milestones. The child’s mother, however, insisted on keeping him alive. So, the committee had to recommend continuing life support to respect the parent’s right to decide.

Physicians inform, recommend and engage in shared decision-making with families to help clarify their values and preferences. But if there’s mistrust, the process can quickly break down, resulting in misunderstandings and conflicts about the patient’s best interests and making a difficult situation more distressing. https://www.youtube.com/embed/MY4e4l-eAFk?wmode=transparent&start=0 Moral distress in health care.

Moral distress

When clinicians feel unable to provide what they believe to be the best care for patients, it can result in what bioethicists call “moral distress.” The term was coined in 1984 in nursing ethics to describe the experience of nurses who were forced to provide treatments that they felt were inappropriate. It is now widely invoked in health care.

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Numerous studies have shown that levels of moral distress among clinicians are high, with 58% of pediatric and neonatal intensive care clinicians in a study experiencing significant moral distress. While these studies have identified various sources of moral distress, having to provide aggressive life support despite feeling that it’s not in the patient’s interest is consistently among the most frequent and intense.

Watching a patient suffer feels like a dereliction of duty to many health care workers. But as long as they are appropriately respecting the patient’s right to decide – or a parent’s, in the case of a minor – they are not violating their professional duty, as my colleagues and I argued in a recent paper. Doctors sometimes express their distress as a feeling of guilt, of “having blood on their hands,” but, we argue, they are not guilty of any wrongdoing. In most cases, the distress shows that they’re not indifferent to what the decision may mean for the patient.

Clinicians, however, need more support. Persistent moral distresses that go unaddressed can lead to burnout, which may cause clinicians to leave their practice. In a large American Medical Association survey, 35.7% of physicians in 2022-23 expressed an intent to leave their practice within two years.

But with the right support, we also argued, feelings of moral distress can be an opportunity to reflect on what they can control in the circumstance. It can also be a time to find ways to improve the care doctors provide, including communication and building trust. Institutions can help by strengthening ethics consultation services and providing training and support for managing complex cases.

Difficult and distressing decisions, such as the case of the 6-month-old child, are ubiquitous in health care. Patients, their families and clinicians need to be able to trust each other to sustain high-quality care.

Daniel T. Kim, Assistant Professor of Bioethics, Albany Medical College

This article is republished from The Conversation under a Creative Commons license. Read the original article.

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Child Health

Prenatal supplements largely lack the recommended amount of omega-3 fatty acids to help prevent preterm birth − new research

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Few women of childbearing age consume adequate amounts of omega-3 fatty acids. Caroline Purser/The Image Bank via Getty Images

Mary J. Scourboutakos, Eastern Virginia Medical School

Most prenatal supplements lack the amount of omega-3 fatty acids that could help prevent preterm birth, meaning delivery before 37 weeks’ gestation. This is a key finding of a new study, published by my team, in the American Journal of Perinatology.

Omega-3 fatty acids are essential nutrients that are found largely in fatty fish. They help prevent inflammation and, by doing so, decrease the risk of preterm birth.

Our study, however, showed that roughly 1 in 6 prenatal supplements on the market in the U.S. that contain omega-3 fatty acids provide the amount that is needed by most pregnant women.

My colleagues and I used the U.S. Department of Agriculture’s Dietary Supplement Label Database to identify prenatal supplements that contained omega-3 fatty acids. We then compared the stated amount of omega-3s on the product labels with the recommended amounts in the new guidelines published in the American Journal of Obstetrics and Gynecology Maternal-Fetal Medicine by a team of experts representing international obstetric and child health organizations.

The guidelines recommend different doses of omega-3 fatty acids depending on whether a woman’s baseline intake prior to pregnancy was adequate or inadequate.

We found that 70% of the prenatal supplements that contained omega-3s provided the amount that is recommended for women with adequate intakes. However, previous research has shown that only 5% of pregnant women and women of childbearing age consume adequate amounts of omega-3 fatty acids. Thus, for women with insufficient intakes, a prenatal supplement with a higher amount of omega-3s would be helpful.

Torso of a pregnant woman holding a glass of water in one hand and vitamins in the other.
Most prenatal vitamins on the market in the U.S. do not contain sufficient levels of omega-3 fatty acids. Andersen Ross Photography Inc./DigitalVision via Getty Images

Why it matters

Preterm birth is the leading cause of infant mortality worldwide. It is also the leading cause of infant illnesses that lead to costly stays in neonatal intensive care units. And then there is the heavy emotional toll that it has on parents and families.

Preterm birth also significantly increases a child’s risk for long-term health consequences such as intellectual disability, chronic diseases such as hypertension and diabetes and psychiatric illness in adulthood.

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Yet there are few treatment options for preterm birth.

This is where omega-3 fatty acids come in. They lower risk of preterm birth by decreasing production of the signaling molecules that kick-start labor.

A Cochrane review of 26 randomized controlled trials demonstrated that 1,000 milligrams of supplemental omega-3 fatty acids per day can decrease risk of preterm birth by 11%, and risk of early preterm birth – delivery before 34 weeks’ gestation – by 42%.

Considering that prenatal supplements often don’t contain the required amount of omega-3s, one option is to simply take an additional omega-3 supplement alongside a prenatal vitamin to supply the difference and obtain the benefit.

Nevertheless, omega-3 supplements are not always necessary. The new guidelines recommend that all women of childbearing age should consume 250 milligrams of omega-3s per day. This amount can be obtained from roughly two 3-ounce servings per week of fatty fish such as salmon, mackerel, herring, sardines and anchovies.

When women increase their intake of omega-3 fatty acids prior to pregnancy, the recommended intake levels during pregnancy are lower. This is a way to eliminate the need for supplements in the first place.

However, women of childbearing age must also consider levels of mercury in fish because of its adverse effects on fetal neurodevelopment. While most species of salmon are low in mercury, certain fish that are rich in omega-3s can be moderately high in mercury. It’s important to consult local public health guidelines on mercury levels in fish to ensure safe consumption levels.

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What still isn’t known

Omega-3 fatty acids are chemically unstable molecules that are inherently fragile, and thus prone to oxidation, a process whereby oxygen degrades the molecule, rendering it ineffective. Studies have shown wide variation in the oxidation levels in commercial omega-3 supplements. Worse yet, there are few predictors of omega-3 supplement quality.

Nevertheless, despite their high risk for oxidation, commercially available omega-3 supplements have exhibited demonstrable benefits in clinical trials.

What’s next

Taking into consideration the inconsistent levels of omega-3 fatty acids in prenatal supplements, their instability and the potential for dietary sources prior to pregnancy offsetting the need for supplements, more research is needed to understand how to motivate increased omega-3 intakes in women of childbearing age.

Recognizing that many women will still require omega-3s from supplemental sources, longitudinal studies tracking omega-3 levels in prenatal supplements will be crucial.

In addition, ongoing efforts are needed to foster the translation of this information into clinical settings to ensure that pregnant women, and the health care professionals who care for them, are able to make use of the great potential for omega-3 fatty acids in the prevention of preterm birth.

The Research Brief is a short take on interesting academic work.

Mary J. Scourboutakos, Family Medicine Resident and Nutrition Expert, Eastern Virginia Medical School

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This article is republished from The Conversation under a Creative Commons license. Read the original article.


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Child Health

Sesame Workshop and NewYork-Presbyterian Join Forces to Champion Children’s Health

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The two organizations will partner to foster healthy habits in young children and their families by offering free resources and videos and “Sesamatized” spaces

Sesame Workshop,

NEW YORK /PRNewswire/ — Today, Sesame Workshop, the global impact nonprofit behind Sesame Street, and NewYork-Presbyterian announced a partnership to improve health outcomes for young children by supporting their physical and emotional well-being through joyful learning moments engaging parents, caregivers, and community providers. Sesame Workshop is collaborating with NewYork-Presbyterian’s physicians and community partners on a social impact and mass media campaign featuring videos, educational materials, and “Sesamatized” physical spaces, to promote children’s health.

The partnership is launching with a six-part video series titled “Ask a Doctor,” featuring Sesame Street Muppets and NewYork-Presbyterian physicians. The videos are designed to educate and empower parents and caregivers on how to help young children stay healthy. They will cover topics including how to develop healthy sleep habits, deal with food allergies, and prepare for wellness visits. The series can be found on Sesame Workshop’s YouTube channel and will be available on NewYork-Presbyterian’s internal patient entertainment system.

“We are delighted to partner with NewYork-Presbyterian in our shared commitment to equity and health justice,” said Jeanette Betancourt, Ed.D., Senior Vice President of U.S. Social Impact at Sesame Workshop. “Our collaboration allows us to combine our expertise in healthcare, child development, and family and community engagement to make an impactful difference in the lives of those who need it most. In fostering healthy practices, especially in the early years, in ways that incorporate the perspectives and needs of parents and caregivers along with their community support networks, we are all working together to pave the way for a healthier, more equitable future.”

“We are thrilled to work with Sesame Workshop to empower parents and caregivers with important health information and meet families where they are,” said Dr. Deepa Kumaraiah, Senior Vice President and Chief Medical Officer of NewYork-Presbyterian. “Through fun learning moments that support the health and well-being of young people in our communities, we can help reduce health disparities and work toward health justice.”

A key focus of the partnership is a collaboration between Sesame Workshop and NewYork-Presbyterian’s neighboring community partners. Sesame Workshop will create educational materials with input from the children and caregivers in the communities NewYork-Presbyterian serves. Among the resources that will be available are bilingual Muppet videos, storybooks, parent guides, and activity books. “Sesamatized” physical spaces including décor featuring Sesame Street Muppets will open in the second half of 2025. The materials will be available where children and their families are, including community centers and NewYork-Presbyterian’s hospitals and clinics.

Additionally, two videos, featuring Elmo, Gabrielle, and other Sesame Street friends, that celebrate everyone of all hair and fur types complement NewYork-Presbyterian’s Dalio Center for Health Justice’s Crown Hair Care program, an initiative to provide inclusive hair care kits for pediatric and obstetric patients with curly, coiled, or tightly textured hair. These are also featured on NewYork-Presbyterian’s patient entertainment system.

About Sesame Workshop 
Sesame Workshop is the global impact nonprofit behind Sesame Street and so much more. For over 50 years, we have worked at the intersection of education, media, and research, creating joyful experiences that enrich minds and expand hearts, all in service of empowering each generation to build a better world. Our beloved characters, iconic shows, outreach in communities, and more bring playful early learning to families in more than 150 countries and advance our mission to help children everywhere grow smarter, stronger, and kinder. Learn more at www.sesame.org and follow Sesame Workshop on InstagramTikTokFacebook, and X

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About NewYork-Presbyterian
NewYork-Presbyterian is one of the nation’s most comprehensive, integrated academic healthcare systems, encompassing 10 hospitals across the Greater New York area, nearly 200 primary and specialty care clinics and medical groups, and an array of telemedicine services.

A leader in medical education, NewYork-Presbyterian Hospital is affiliated with two renowned medical schools, Weill Cornell Medicine and Columbia University Vagelos College of Physicians and Surgeons. This collaboration means patients have access to the country’s leading physicians, the full range of medical specialties, latest innovations in care, and research that is developing cures and saving lives.

Founded 250 years ago, NewYork-Presbyterian Hospital has a long legacy of medical breakthroughs and innovation, from the invention of the Pap test to pioneering the groundbreaking heart valve replacement procedure called TAVR.

NewYork-Presbyterian’s 50,000 employees and affiliated physicians are dedicated to providing the highest quality, most compassionate care to New Yorkers and patients from across the country and around the world.

For more information, visit www.nyp.org and find us on Facebook, Instagram, YouTube, LinkedIn, and Pinterest.

SOURCE NewYork-Presbyterian

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