Tag Archives: Pediatrics

Microbiology

COVID-19’s Ripple Effect: The Youth Suicide Surge

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A recent study found that suicide rates among US youth aged 5-24 years increased during the COVID-19 pandemic, particularly among males, preteens, young adults, and specific racial and ethnic groups. This highlights disparities that have likely been worsened by the pandemic and underscores the need for targeted suicide prevention efforts.

Suicide is a leading cause of death among young people in the United States. Rates of youth suicide deaths were rising before the coronavirus (COVID-19) pandemic began, so it is critical to understand how the pandemic impacted this public health crisis. In a new study supported by the National Institute of Mental Health, researchers examined national youth suicide trends and characteristics in the United States before and during the COVID-19 pandemic.

A research team led by Jeffrey Bridge, Ph.D., Donna Ruch, Ph.D., and Lisa Horowitz, Ph.D., MPH, analyzed national suicide data from the Centers for Disease Control and Prevention. The researchers first identified all U.S. youth aged 5 to 24 years with suicide listed as the cause of death over the first 10 months of the pandemic (March 1, 2020–December 31, 2020). They calculated the total and monthly suicide deaths overall and by sex, age, race and ethnicity, and suicide method. Then, they examined how many young people died by suicide during the first 10 months of the pandemic and compared it to an estimated number of suicide deaths during that same period had the pandemic not occurred (calculated using data from the previous 5 years).

The researchers identified 5,568 youth who died by suicide during the first 10 months of the pandemic, which was higher than the expected number of deaths had the pandemic not occurred. Higher than expected suicide rates were found a few months into the pandemic, starting in July 2020.

The increase in suicide deaths varied significantly by sex, age, race and ethnicity, and suicide method. During the pandemic, there were higher than expected suicide deaths among males, preteens aged 5–12 years, young adults aged 18–24 years, non-Hispanic American Indian or Alaskan Native youth, and non-Hispanic Black youth as compared to before the pandemic. Suicide deaths involving firearms were also higher than expected.

The significantly higher number of suicide deaths reported for certain racial and ethnic groups, specifically non-Hispanic American Indian or Alaskan Native and non-Hispanic Black youth, highlights ongoing disparities in rates of suicide that the pandemic may have exacerbated. The increase in suicide deaths among preteens also suggests that more attention may need to be paid to this age group, who tend to be understudied in suicide prevention research and have different developmental needs than older adolescents and young adults.

This research is only a first step in examining the pandemic’s impact on youth mental health and points to several areas for further investigation. First, it is possible that other events or factors unrelated to the pandemic that occurred during the study’s time frame contributed to the rise in youth suicide deaths but were unmeasured. Second, research is still needed to identify the underlying causes of the increase in youth suicide deaths, both overall and for specific groups. Third, the COVID-19 pandemic period analyzed in this study was limited to 10 months in 2020 and does not reflect longer-term trends in youth suicide that may have changed as the pandemic wore on. Last, suicide deaths for some groups may have been underreported due to inaccurate or misclassified data; ongoing monitoring of suicide rates will help clarify the suicide risk faced by young people in the United States.

This study shows that the pandemic impacted youth suicide rates, but the impact was not the same for everyone and varied based on sex, age, and race and ethnicity. As such, the authors suggest that it may be helpful to broadly implement suicide prevention efforts in settings that serve young people, while also tailoring those efforts to address the disparities faced by specific groups. Moreover, given the extended duration of the pandemic and its ongoing impact on young people in the United States, it will be important to monitor long-term trends in suicide rates associated with COVID-19 and identify factors driving the increased risk for suicide among some people.

For more on this study, see Youth Suicide Rates Surged During COVID-19 Pandemic.

Reference: “Youth Suicide During the First Year of the COVID-19 Pandemic” by Jeffrey A. Bridge, PhD; Donna A. Ruch, PhD; Arielle H. Sheftall, PhD; Hyeouk Chris Hahm, PhD, LCSW; Victoria M. O’Keefe, PhD; Cynthia A. Fontanella, PhD; Guy Brock, PhD; John V. Campo, MD and Lisa M. Horowitz, PhD, MPH, 15 February 2023, Pediatrics.
DOI: 10.1542/peds.2022-058375

National Institute of Mental Health

Microbiology

Mouse study offers clues to developing an effective vaccine for Klebsiella bacteria

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Reviewed by Danielle Ellis, B.Sc.May 18 2023

A mouse study at Washington University School of Medicine in St. Louis points to data that could be key to developing an effective vaccine for the bacterium Klebsiella pneumoniae. The bug is often resistant to antibiotics, making it difficult to treat in some.

In the U.S., the bacterium Klebsiella pneumoniae is a common cause of urinary tract infection, bloodstream infection and pneumonia. While infections with the bacterium can be easily treated in some, Klebsiella has a dangerous flip side: It also is frequently resistant to antibiotics, making it extraordinarily difficult to treat in others. About half of people infected with a hypervirulent, drug-resistant strain of the bacterium die.

Scientists are working on vaccines for Klebsiella, but the optimal vaccine design is still unknown. However, a new study in mice by scientists at Washington University School of Medicine in St. Louis and Omniose, a St. Louis startup company specializing in vaccine production, provides critical data that could be key to developing an effective vaccine for Klebsiella. The findings, published in PLoS Pathogens, are a step toward taming the superbug.

When you think about the bugs that can be resistant to almost all antibiotics — the scary superbugs in the news — a lot of them are strains of Klebsiella. For a long time, the bacterium wasn’t even a pressing issue. But now it is, due to an explosion in antibiotic-resistant Klebsiella. Our goal is to diminish Klebsiella’s superbug status by developing a vaccine before hypervirulent or resistant strains sicken and kill even more people.”

David A. Rosen, MD, PhD, study’s senior author, assistant professor of pediatrics and of molecular microbiology at Washington University

Hypervirulent Klebsiella strains have spread globally, often causing community-acquired infections.

In the U.S., Klebsiella infections primarily occur in health-care facilities where medically vulnerable patients are immunocompromised, require long courses of antibiotics to treat other conditions, have chronic diseases, or are elderly people or newborns. “But now we’re seeing the emergence of hypervirulent strains dangerous enough to cause serious disease or death among healthy people in the community,” Rosen said.

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Most concerning among scientists are the strains of Klebsiella impervious to carbapenems, a class of broad-spectrum antibiotics used to treat the most severe bacterial infections. For this reason, the World Health Organization and the U.S. Centers for Disease Control and Prevention have identified carbapenem-resistant Klebsiella as an urgent threat to public health.

The rod-shaped bacterium is immobile and, like chocolate-covered candies, encapsulated in sugar coatings. In the new study, researchers created two experimental vaccines based on two different sugars, or polysaccharides, on Klebsiella’s surface: the terminal sugars on lipopolysaccharide, called O-antigen, and a capsular polysaccharide, or K-antigen. Since sugars by themselves tend to produce weak immune responses, the researchers linked each of the sugars to a protein to boost the immune response, creating so-called conjugate vaccines. Sugar-protein conjugate vaccines have proven successful in combating several bacteria including Streptococcus pneumoniae, the most common cause of pneumonia. Historically, this connection between the sugar and protein carrier has been achieved using synthetic chemistry in a test tube; however, the vaccines created for this study are called bioconjugate vaccines, because the researchers connected the sugar to the protein all within an engineered bacteria system.

Once the vaccines were created, the researchers tested the experimental bioconjugate vaccines’ ability to protect mice from disease caused by Klebsiella.

“It turned out that the capsule vaccine was far superior to the O-antigen vaccine,” said the study’s first author, Paeton Wantuch, PhD, a postdoctoral associate in Rosen’s lab. “Mice that received the capsule vaccine were significantly more likely to survive Klebsiella infection in their lungs or their bloodstream than mice that received the O-antigen vaccine.”

Both vaccines elicited high levels of antibodies against their respective targets. But the antibodies against the O-antigen just weren’t as effective as the ones against the capsule. In some strains of Klebsiella, the O-antigen may be obscured by other sugars, so the antibodies that target the O-antigen cannot make contact with their target.

“Our findings suggest that we may also need to include the capsule-based antigens in vaccine formulations developed against Klebsiella,” Rosen said. “This is why it’s so important for us to continue studying antibody-antigen interactions in the different strains, with the goal of identifying the ideal vaccine composition for clinical trials soon. The need has never been more imperative, especially as Klebsiella’s drug-resistant, hypervirulent strains become stronger, bolder and more dangerous to human health.”

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Source:

Washington University School of Medicine

Journal reference:

Wantuch, P. L., et al. (2023) Area-deprivation, social care spending and the rates of children in care proceedings in local authorities in Engl Capsular polysaccharide inhibits vaccine-induced O-antigen antibody binding and function across both classical and hypervirulent K2:O1 strains of Klebsiella pneumoniae. PLOS Pathogens. doi.org/10.1371/journal.ppat.1011367.

Microbiology

Better Than Antibiotics – Stool Transplants Show Promising Results in Treating Life-Threatening Infections

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According to a recent Cochrane Review, stool transplantation has proven to be a more effective method of treating Clostridioides difficile infection as compared to standard antibiotic treatment. 

According to a recent Cochrane Review headed by a professor at Upstate Medical University, stool transplantation has been found to improve the rate of recovery from Clostridioides difficile (C. diff) infection, a serious condition that can cause life-threatening diarrhea, compared to standard antibiotic treatment. The review revealed that 77% of patients who underwent a stool transplant did not experience a reinfection within 8 weeks, whereas only 40% of those who received antibiotics alone achieved the same outcome.

C. diff is a bacterium that can cause life-threatening diarrheal illness in individuals with an unhealthy mixture of gut bacteria, known as dysbiosis. The most common cause of dysbiosis is treatment with antibiotics, and while antibiotics can be very effective against bacterial infections, they can also harm the beneficial bacteria colonizing the gut, known as the intestinal microbiome. Usually, this ecosystem of “good” bacteria recovers quickly, but occasionally “bad” species like C. diff take over and cause serious diarrhea.

The standard treatment of C. diff infection includes antibiotics, which may further exacerbate dysbiosis. This can lead to a vicious cycle of brief treatment effect followed by a recurrent infection. This happens in nearly a third of infected individuals. According to the CDC, every year there are around a quarter of a million C. diff infections in the US alone, causing approximately 12,000 fatalities.

Transplanting healthy donor stool into a gut with dysbiosis is intended to balance the gut microbes and reestablish a healthy microbiome, thus significantly reducing the risk of C. diff recurring. Stool donation operates much the same way as blood donation. Donors are screened for diseases and infections before they can donate their stool. The stool can be transplanted via colonoscopy, nasogastric or nasoduodenal tube, enema or via a capsule. The US Food and Drug Administration has recently approved a stool transplant product for the prevention of the recurrence of C. diff that can be administered as an enema.

The new Cochrane Review, led by pediatric gastroenterologist Aamer Imdad MBBS, examined data from six clinical trials with a total of 320 adults that assessed the efficacy and safety of stool transplantation for the treatment of repeated C. diff infection. Two studies were conducted in Denmark, and one each in the Netherlands, Italy, Canada, and the United States. Most of the included studies compared stool transplantation with a standard antibiotic treatment using vancomycin, which is commonly used for this kind of infection.

The review found that stool transplantation leads to a larger increase in resolution of repeated infections of C. diff than other treatments studied, as well as a decrease in side effects when compared with standard treatment using antibiotics.

“After a person with a C. diff infection gets treated with antibiotics, there is about a 25 percent chance that they will have another episode of C. diff infection in the next 8 weeks”, Imdad said. “The risk of recurrence increases to about 40 percent with the second episode and to nearly 60 percent with the third episode. So, once you are in this cycle, it gets more and more difficult to break out of it. Stool transplants can reverse the dysbiosis and thus decrease the risk of recurrence of the disease.”

A second Cochrane Review, also led by Dr. Imdad, looks at the use of stool transplants for the treatment of inflammatory bowel disease (IBD), a term mainly used to describe two conditions: ulcerative colitis and Crohn’s disease. The review shows promising results for ulcerative colitis; however, the data is not conclusive yet. Results for Crohn’s disease are even less conclusive. More research will be required before stool transplants can be considered for the treatment of IBD.

References:

“Fecal microbiota transplantation for the treatment of recurrent Clostridioides difficile (Clostridium difficile)” by Nathan Zev Minkoff, Scheherzade Aslam, Melissa Medina, Emily E Tanner-Smith, Joseph P Zackular, Sari Acra, Maribeth R Nicholson and Aamer Imdad, 25 April 2023, Cochrane Database of Systematic Reviews.
DOI: 10.1002/14651858.CD013871.pub2

“Fecal transplantation for treatment of inflammatory bowel disease” by Aamer Imdad, Natasha G Pandit, Muizz Zaman, Nathan Zev Minkoff, Emily E Tanner-Smith, Oscar G Gomez-Duarte, Sari Acra and Maribeth R Nicholson, 25 April 2023, Cochrane Database of Systematic Reviews.
DOI: 10.1002/14651858.CD012774.pub3

Imdad collaborated with doctors around the country on both studies, including Nathan Zev Minkoff, a graduate from the Norton College of Medicine, Upstate students Natasha Pandit and Muiz Zaman, Class of 2023 in the Norton College of Medicine and Melissa Medina, Class of 2026 in the Department of Public Health and Preventative Medicine, on the C-diff study. The other collaborators included Dr. Maribeth Nicholson and Dr. Sari Acra from Vanderbilt University Medical Center, Dr. Scheherzade Asalam from University of Nebraska, Dr. Emily E Tanner Smith from University of Oregon, Dr. Oscar Gomez from University of Buffalo and Dr.  Joseph Zackular from University of Pennsylvania.

Cochrane

Microbiology

Avanced genome editing technology could be used as a one-time treatment for CD3 delta SCID

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Reviewed by Emily Henderson, B.Sc.Mar 21 2023

A new UCLA-led study suggests that advanced genome editing technology could be used as a one-time treatment for the rare and deadly genetic disease CD3 delta severe combined immunodeficiency.

The condition, also known as CD3 delta SCID, is caused by a mutation in the CD3D gene, which prevents the production of the CD3 delta protein that is needed for the normal development of T cells from blood stem cells.

Without T cells, babies born with CD3 delta SCID are unable to fight off infections and, if untreated, often die within the first two years of life. Currently, bone marrow transplant is the only available treatment, but the procedure carries significant risks.

In a study published in Cell, the researchers showed that a new genome editing technique called base editing can correct the mutation that causes CD3 delta SCID in blood stem cells and restore their ability to produce T cells.

The potential therapy is the result of a collaboration between the laboratories of Dr. Donald Kohn and Dr. Gay Crooks, both members of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA and senior authors of the study.

Kohn’s lab has previously developed successful gene therapies for several immune system deficiencies, including other forms of SCID. He and his colleagues turned their attention to CD3 delta SCID at the request of Dr. Nicola Wright, a pediatric hematologist and immunologist at the Alberta Children’s Hospital Research Institute in Canada, who reached out in search of a better treatment option for her patients.

CD3 delta SCID is prevalent in the Mennonite community that migrates between Canada and Mexico.

Because newborns are not screened for SCID in Mexico, I often see babies who have been diagnosed late and are returning to Canada quite sick.”

Dr. Nicola Wright, pediatric hematologist and immunologist at the Alberta Children’s Hospital Research Institute

When Kohn presented Wright’s request to his lab, Grace McAuley, then a research associate who joined the lab at the end of her senior year at UCLA, stepped up with a daring idea.

“Grace proposed we try base editing, a very new technology my lab had never attempted before,” said Kohn, a distinguished professor of microbiology, immunology and molecular genetics, and of pediatrics.

Base editing is an ultraprecise form of genome editing that enables scientists to correct single-letter mutations in DNA. DNA is made up of four chemical bases that are referred to as A, T, C and G; those bases pair together to form the “rungs” in DNA’s double-helix ladder structure.

While other gene editing platforms, like CRISPR-Cas9, cut both strands of the chromosome to make changes to DNA, base editing chemically changes one DNA base letter into another -; an A to a G, for example -; leaving the chromosome intact.

“I had a very steep learning curve in the beginning, when base editing just wasn’t working,” said McAuley, who is now pursuing an M.D.-Ph.D. at UC San Diego and is the study’s co-first author. “But I kept pushing forward. My goal was help get this therapy to the clinic as fast as was safely possible.”

McAuley reached out to the Broad Institute’s David Liu, the inventor of base editing, for advice on how to evaluate the technique’s safety for this particular use. Eventually, McAuley identified a base editor that was highly efficient at correcting the disease-causing genetic mutation.

Because the disease is extremely rare, obtaining patient stem cells for the UCLA study was a significant challenge. The project got a boost when Wright provided the researchers with blood stem cells donated by a CD3 delta SCID patient who was undergoing a bone marrow transplant.

The base editor corrected an average of almost 71% of the patient’s stem cells across three laboratory experiments.

Next, McAuley worked with Dr. Gloria Yiu, a UCLA clinical instructor in rheumatology, to test whether the corrected cells could give rise to T cells. Yiu used artificial thymic organoids, which are stem cell-derived tissue models developed by Crooks’ lab that mimic the environment of the human thymus -; the organ where blood stem cells become T cells.

When the corrected blood stem cells were introduced into the artificial thymic organoids, they produced fully functional and mature T cells.

“Because the artificial thymic organoid supports the development of mature T cells so efficiently, it was the ideal system to show that base editing of patients’ stem cells could fix the defect seen in this disease,” said Yiu, who is also a co-first author of the study.

As a final step, McAuley studied the longevity of the corrected stem cells by transplanting them into a mouse. The corrected cells remained four months after transplant, indicating that base editing had corrected the mutation in true, self-renewing blood stem cells. The findings suggest that corrected blood stem cells could persist long-term and produce the T cells patients would need to live healthy lives.

“This project was a beautiful picture of team science, with clinical need and scientific expertise aligned,” said Crooks, a professor of pathology and laboratory medicine. “Every team member played a vital role in making this work successful.”

The research team is now working with Wright on how to bring the new approach to a clinical trial for infants with CD3 delta SCID from Canada, Mexico and the U.S.

This research was funded by the Jeffrey Modell Foundation, the National Institutes of Health, the Bill and Melinda Gates Foundation, the Howard Hughes Medical Institute, the V Foundation and the A.P. Giannini Foundation.

The therapeutic approach described in this article has been used in preclinical tests only and has not been tested in humans or approved by the Food and Drug Administration as safe and effective for use in humans. The technique is covered by a patent application filed by the UCLA Technology Development Group on behalf of the Regents of the University of California, with Kohn and McAuley listed as co-inventors.

Source:

University of California – Los Angeles Health Sciences

Journal reference:

McAuley, G.E., et al. (2023) Human T cell generation is restored in CD3δ severe combined immunodeficiency through adenine base editing. Cell. doi.org/10.1016/j.cell.2023.02.027.

Microbiology

Decreased viral infection severity in females may be due to extra copy of X chromosome-linked gene

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Reviewed by Emily Henderson, B.Sc.Mar 17 2023

It has long been known that viral infections can be more severe in males than females, but the question as to why has remained a mystery – until possibly now. The key may lie in an epigenetic regulator that boosts the activity of specialized anti-viral immune cells known as natural killer (NK) cells.

In a study published March 16 in the peer-reviewed journal Nature Immunology, a collaborative team of UCLA researchers have found that female mouse and human NK cells have an extra copy of an X chromosome-linked gene called UTX. UTX acts as an epigenetic regulator to boost NK cell anti-viral function, while repressing NK cell numbers.

While it is well-known that males have more NK cells compared to females, we did not understand why the increased number of NK cells was not more protective during viral infections. It turns out that females have more UTX in their NK cells than do males, which allows them to fight viral infections more efficiently.”

Dr. Maureen Su, co-senior author, professor of microbiology immunology and molecular genetics, and of pediatrics, at the David Geffen School of Medicine at UCLA

The researchers noted that this held true whether or not the mice had gonads (ovaries in females; testes in males), indicating that the observed trait was not linked to hormones. Furthermore, female mice with lower UTX expression had more NK cells which were not as capable of controlling viral infection.

“This implicates UTX as a critical molecular determinant of sex differences in NK cells,” said the study’s lead author Mandy Cheng, graduate student in molecular biology at UCLA.

The findings suggest that therapies involving immune responses need to move beyond a “one-size-fits-all” approach and toward a precision medicine model, also known as personalized medicine, that tailors treatments that take into account people’s individual differences, such as genetics, environment and other factors that influence health and disease risk, the researchers write.

“Given the recent excitement with using NK cells in the clinic, we will need to incorporate sex as a biological factor in treatment decisions and immunotherapy design,” said co-senior author Tim O’Sullivan, assistant professor of microbiology, immunology and molecular genetics at the Geffen School.

Source:

University of California – Los Angeles Health Sciences

Journal reference:

Cheng, M.I., et al. (2023) The X-linked epigenetic regulator UTX controls NK cell-intrinsic sex differences. Nature Immunology. doi.org/10.1038/s41590-023-01463-8.

Microbiology

Healthy gut bacteria can travel to other parts of the body and boost antitumor immunity

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Reviewed by Emily Henderson, B.Sc.Mar 9 2023

Researchers at UT Southwestern Medical Center have discovered how healthy bacteria can escape the intestine, travel to lymph nodes and cancerous tumors elsewhere in the body, and boost the effectiveness of certain immunotherapy drugs. The findings, published in Science Immunology, shed light on why antibiotics can weaken the effect of immunotherapies and could lead to new cancer treatments.

Scientists have been stumped as to how bacteria inside your gut can have an impact on a cancer in your lungs, breasts, or skin. Now we understand that mechanism much better and, in the future, hope to use this knowledge to better fight cancer.”

Andrew Y. Koh, M.D., Associate Professor of Pediatrics, Microbiology, and in the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern

Previous studies, including one led by Dr. Koh at UT Southwestern, have shown an association between the composition of gut microbiomes – the microorganisms found inside the digestive tract – and the effectiveness of cancer treatments that target the immune system, including pembrolizumab (Keytruda) and ipilimumab (Yervoy). However, researchers have reached conflicting conclusions about the ideal balance of microorganisms to optimize therapy, with studies pointing to different beneficial bacteria.

Dr. Koh and colleagues used mice with melanoma tumors to probe how the drugs, called immune checkpoint inhibitors, affected the movement of gut microbes through the body. They found that immune checkpoint inhibitors, which boost the activity of the immune system against tumors, also cause inflammation in the digestive system that leads to remodeling of lymph nodes in the gut.

Due to these changes, bacteria can leave the intestines and travel to lymph nodes near the tumor and the tumor itself, the researchers found. Here, the microbes activate a set of immune cells that act to kill tumor cells.

“Immune checkpoint inhibitors work by releasing the brakes on the immune system to target cancer,” said Dr. Koh, who is also Director of the Cellular and ImmunoTherapeutics Program at UTSW and Children’s Health. “What we think is that these microorganisms and the immune cells they’re activating are essentially pressing on the accelerator of the immune system at the same time.”

The findings suggest that a course of antibiotics, which can eliminate most gut microbes, is detrimental to immune checkpoint inhibitors because the bacteria can no longer play this role of immune accelerant. It also helps explain why researchers have found many types of bacteria in patient microbiomes that seem to be beneficial for treatment.

“As long as a subset of beneficial bacteria can translocate from the gut to the lymph node or tumor, it may not matter exactly which bacteria it is,” said Dr. Koh.

Dr. Koh’s team is now working toward the development of bacterial-based treatments to boost the efficacy of immune checkpoint inhibitors.

Other UTSW researchers who contributed to the study include first author and UTSW graduate student Yongbin Choi, Lora Hooper, Jake Lichterman, Laura Coughlin, Nicole Poulides, Wenling Li, Priscilla Del Valle, Suzette Palmer, Shuheng Gan, Jiwoong Kim, Xiaowei Zhan, Yajing Gao, and Bret Evers.

Dr. Hooper, a Howard Hughes Medical Institute Investigator, holds the Jonathan W. Uhr, M.D. Distinguished Chair in Immunology and is a Nancy Cain and Jeffrey A. Marcus Scholar in Medical Research, in honor of Dr. Bill S. Vowell.

The research was supported by funding from the National Institutes of Health (R01 CA231303, K24 AI123163, R01 DK070855), the Crow Family Fund, the UT Southwestern Medical Center and Children’s Health Cellular and ImmunoTherapeutics Program, National Research Service Award-Integrative Immunology Training Grant (5T32AI005284-43), The Welch Foundation (I-1874), and the Howard Hughes Medical Institute.

Source:

UT Southwestern Medical Center

Journal reference:

Choi, Y., et al. (2023) Immune checkpoint blockade induces gut microbiota translocation that augments extraintestinal antitumor immunity. Science Immunology. doi.org/10.1126/sciimmunol.abo2003.

Microbiology

Necrotizing Enterocolitis – The Horrifying Intestinal Disease Too Many Babies Are Still Dying From

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New research has found that in the US between 1999 and 2020, Black infants disproportionately died from necrotizing enterocolitis compared to White infants, despite overall improvements in the rates of death from the disease. This is according to a study published today (March 3, 2023) in JAMA Network Open 

Necrotizing enterocolitis (NEC) is one of the most common causes of death in preterm infants. Medically-fragile term infants, such as neonates born with a congenital heart defect, are also at an elevated risk of NEC. Two prior studies reported conflicting trends in NEC rates. One study from 2000-2011 showed increasing rates of death from the condition over time. Another study reported declining rates of NEC from 2006-2017.

Researchers in the current study wanted to determine the trends in NEC-related deaths in the US spanning both of these periods. They also examined racial disparities and geographic differences.

The study used data on US infant deaths from 1999 through 2020 from the Centers for Disease Control and Prevention and the National Center for Health Statistics. The researchers analyzed all infant deaths up to 1 year of age, with the underlying cause being NEC.

Of 88,125,233 live births, 8,951 infants died of NEC. Rates of NEC-related deaths per 100,000 live births were higher among Black infants (16.1) compared to White infants (6.4). The study found that in 2007, there was an inflection with a change in US trends in NEC-related deaths; NEC-related deaths decreased by 7.7% per year from 2007 through 2012. However, there were no additional declines after 2012. Racial differences in NEC-related deaths decreased over time, although in 2020, Black infants were still 2.5 times more likely to die from NEC than White infants.

Dr. Mattie Wolf, first-author of this study and a post-doctoral fellow at Emory University and Children’s Healthcare of Atlanta, notes, “These data clearly show improvements in NEC-related death in the US, although we do not know exactly what factors are driving these improvements.”

“Our results show we have made progress in reducing deaths related to NEC, but given the lack of improvements since 2012, we still have continued work to do to reduce the burden of this disease,” says Ravi Patel, MD, MSc, Associate Professor of Pediatrics at Emory University School of Medicine and Children’s Healthcare of Atlanta and senior author of this article.

Jennifer Canvasser, MSW, Founder and Executive Director of the NEC Society and co-author of the study, shares, “These data reveal that someone’s child died from NEC each day, on average, over this period. My son Micah is one of the 8,951 babies. Clinicians, scientists, and patient-families intimately understand the devastation of NEC. Together, with policy-makers and stakeholders who care, we are working tirelessly to improve outcomes and provide equitable care so that all babies can thrive and avoid the devastation of this disease.”

Reference: “Trends and Racial and Geographic Differences in Infant Mortality in the United States Due to Necrotizing Enterocolitis, 1999 to 2020” 3 March 2023, JAMA Network Open.
DOI: 10.1001/jamanetworkopen.2023.1511

Additional authors of this study include Allison Rose, MD, Ruchika Goel, MD, MPH, and Barbara J. Stoll, MD. The study was supported by the National Institutes of Health.

The NEC Society is a 501(c)(3) nonprofit organization dedicated to building a world without necrotizing enterocolitis (NEC) through research, advocacy, and education. The NEC Society is a patient-led organization that collaborates with expert clinicians and researchers to better understand, prevent, and treat this devastating neonatal intestinal disease.

Necrotizing Enterocolitis (NEC) Society

Microbiology

First clinical trial of GABA/GAD focused exclusively on children with recent onset Type 1 diabetes

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Reviewed by Emily Henderson, B.Sc.Feb 22 2023

For the first time, humans with newly diagnosed Type 1 diabetes, or T1D, have received two treatments called GABA and GAD that have shown promise in animal studies and in isolated human pancreas islets. This investigator-initiated clinical trial, published in Nature Communications, focused exclusively on children with recent onset T1D.

Diabetes is a disease affecting two pancreatic hormones -; insulin and glucagon. In healthy people, insulin helps cells take up glucose from the blood when glucose levels are high. In contrast, glucagon helps the liver release glucose into the bloodstream when glucose levels are low. Thus, levels of blood glucose remain steady.

In T1D, autoantibodies destroy the pancreatic beta cells, insulin release is diminished, and glucagon release is excessive relative to the insulin deficiency. This can cause a vicious cycle of escalating blood glucose levels. Strategies to ameliorate or cure T1D, therefore, target the preservation of insulin-secreting beta cells and/or attenuation of the relative excess of alpha cell glucagon. Most importantly, concerning the inhibition of alpha cell glucagon in this trial by GABA/GAD, recent studies in animals made diabetic have shown that inhibition of glucagon leads to expansion of insulin-secreting beta cells and improvements in hyperglycemia.

Researchers in the study, led by University of Alabama at Birmingham physicians, were able to enroll children within the first five weeks of diagnosis, before the near total eradication of beta cells. Forty percent of the study participants were younger than 10 years old. The study -; which was constrained to lower-dose GABA therapy by the United States Food and Drug Administration because it was the first human trial with GABA -; did not achieve its primary outcome, the preservation of insulin production by beta cells. However, it did meet the clinically relevant secondary outcome of reduced serum glucagon. Significantly, the trial confirmed the safety and tolerability of oral GABA. Additionally, in collaboration with the immunology team of Hubert Tse, Ph.D., at the UAB Comprehensive Diabetes Center, a separate manuscript under review will describe a salutary effect of GABA alone and in combination with GAD on cytokine responses in peripheral blood mononuclear cells from trial participants.

GABA is gamma aminobutyric acid, a major inhibitory neurotransmitter. In the endocrine pancreas, GABA participates in paracrine regulation -; meaning a hormone that acts on nearby cells -; on the beta cells that produce insulin and the alpha cells that produce glucagon. In various mouse model studies, GABA was able to delay diabetes onset, and restore normal blood glucose levels after diabetes had already commenced. GABA treatment also led to significant decreases in the inflammatory cytokine expression that participates in the pathogenesis of T1D.

GAD is glutamic acid decarboxylase, the enzyme that acts on glutamate to form GABA. Animal and pancreatic islet cell studies show that immunization with GAD alone may help preserve beta cells. Both GABA and GAD are highly concentrated in the pancreatic islet, which is the autoimmune target of T1D.

The study, which was conducted between March 2015 and June 2019, screened 350 patients and enrolled 97, whose ages averaged 11 years. Forty-one took oral GABA twice a day; 25 took the oral GABA in combination with two injections of GAD, one at the baseline visit and one at the one-month visit. The remaining 31 children received a placebo treatment. Analysis after one year of treatment included 39 in the GABA group, 22 in the GABA/GAD group and 30 in the placebo group.

Given that GABA reduces immune inflammation at higher doses in several diabetic rodent models, it is plausible that increased GABA doses, or longer-acting preparations, could offer sufficiently prolonged, above-threshold GABA concentrations to preserve islet cells, particularly during stage 1 diabetes.”

Gail Mick, M.D., UAB Professor in the Department of Pediatrics’ Division of Pediatric Endocrinology and Diabetes

Mick and Kenneth McCormick, M.D., who recently retired from UAB Pediatrics, co-led the trial.

Alexandra Martin and Mick, UAB Department of Pediatrics, are co-first authors of the study, “A randomized trial of oral gamma aminobutyric acid (GABA) or the combination of GABA with glutamic acid decarboxylase (GAD) on pancreatic islet endocrine function in children with newly diagnosed type 1 diabetes.”

Other authors are Heather M. Choat, Alison A. Lunsford and Kenneth L. McCormick, UAB Department of Pediatrics; Hubert M. Tse, UAB Department of Microbiology; and Gerald G. McGwin Jr., Department of Epidemiology, UAB School of Public Health.

Source:

University of Alabama at Birmingham

Journal reference:

Martin, A., et al. (2022) A randomized trial of oral gamma aminobutyric acid (GABA) or the combination of GABA with glutamic acid decarboxylase (GAD) on pancreatic islet endocrine function in children with newly diagnosed type 1 diabetes. Nature Communications. doi.org/10.1038/s41467-022-35544-3.

Microbiology

How do parents decide if they should vaccinate their kids against SARS-CoV-2?

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For parents, the decision to vaccinate their kids against SARS-CoV-2 is complex, influenced by scientific evidence, political and social pressures, and views about individual versus collective benefits of vaccination, according to a new study published in CMAJ (Canadian Medical Association Journal).

Researchers conducted a qualitative study with in-depth interviews of 20 parents to understand their views about SARS-CoV-2 vaccination, with a goal to support future vaccination initiatives.

“Given the observed discrepancy between parental intention and decision to vaccinate their children against SARS-CoV-2, it is important to understand how and why parents make their decisions,” said Dr. Jonathon Maguire, a pediatrician at St. Michael’s Hospital, a site of Unity Health Toronto, and the University of Toronto. “Understanding the factors that influence parents’ decisions about SARS-CoV-2 vaccination for their children would help improve and interventions as well as inform about parents’ perspectives and concerns.”

Few previous studies have explored how parents make decisions to vaccinate, or not vaccinate, their children once eligible for vaccination.

The decision was challenging for most parents in the study. Parents’ considerations related to the following:

These findings have implications for communicating information on SARS-CoV-2 vaccination.

“Future guidance should highlight both individual and collective benefits of SARS-CoV-2 vaccination for children; however, health care providers should prioritize individualized discussions with parents to help interpret evidence, consider their understanding of risks and benefits, and provide tailored recommendations,” said Dr. Janet Parsons, a research scientist at St. Michael’s Hospital, a site of Unity Health Toronto, and an associate professor at the University of Toronto.

Health care providers have a key role to play in supporting parents in decision making.

“It is important for health care providers to understand that parents who seem hesitant to vaccinate their children may have a variety of reasons for feeling this way and may be reticent to ask questions to for fear of stigma,” said Dr. Parsons. The authors recommend that these conversations be approached with empathy and openness.

More information:
Parents’ perspectives on SARS-CoV-2 vaccinations for children: a qualitative analysis, Canadian Medical Association Journal (2023). DOI: 10.1503/cmaj.221401

Journal information:
Canadian Medical Association Journal

Canadian Medical Association Journal

Science X Network

Microbiology

Youth Suicide Rates Surged During COVID-19 Pandemic – Especially Among Certain Subgroups

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Suicide is a significant public health concern. In fact, it is the second leading cause of death for individuals aged 5-24 years in the United States. Data suggest depression, anxiety, and social isolation increased during the COVID-19 pandemic, which may have contributed to suicide risk in youth. 

In a study published on February 15 in the journal Pediatrics, researchers in the Center for Suicide Prevention and Research at Nationwide Children’s Hospital found that in the United States, youth suicides increased during COVID-19, with significantly more suicides than expected among males, non-Hispanic American Indian/Alaskan Native youth, and non-Hispanic Black youth.  

“To our knowledge, no national study examined changes in youth suicide rates that occurred during the COVID-19 pandemic,” said Jeffrey A Bridge, PhD, lead author of the study and director of the Center for Suicide Prevention and Research at Nationwide Children’s Hospital. “We wanted to see if there were any changes in the youth suicide rate that occurred and whether these changes happened with the onset of the pandemic.” 

National trends in suicides were sourced from the Web-based Wide-Ranging Online Data for Epidemiologic Research (WONDER) database from the Centers for Disease Control and Prevention (CDC). Individuals aged 5-24 years between 2015 and 2020 with suicide listed as the cause of death were included in this analysis. The start of the COVID-19 period was defined as March 2020. 

A total of 5,568 youth living in the United States died by suicide during the COVID-19 pandemic in 2020. The majority of youth decedents were male (79.2%), non-Hispanic White (59.6%), and died by firearm (51.1%). 

Compared with pre-pandemic suicide deaths, more suicides during the COVID-19 pandemic occurred among males, preteens aged 5-12 years, young adults aged 18-24 years, non-Hispanic American Indian/Alaskan Native youth, and non-Hispanic Black youth. Suicides by firearm were higher than expected during the pandemic, whereas suicide deaths by hanging or suffocation and poisoning were lower than expected. 

Suicide rates during the pandemic were also higher than expected among non-Hispanic Asian/Pacific Islander females, non-Hispanic White males aged 5-12 years, non-Hispanic American Indian/Alaskan Native males, and non-Hispanic Black males aged 18-24 years.  

Most notably, no subgroup had significantly fewer suicides than expected. 

“We found an overall increase in the suicide rate, but that wasn’t distributed equally across all subgroups. A couple of findings really stand out, such as the higher-than-expected suicide rate among non-Hispanic Asian or Pacific Islander females, for example. This is a group of young people that typically have a very low rate of suicide relative to other young people, and to see an increase in their rate associated with the COVID-19 pandemic was a cause for concern,” said Donna Ruch, PhD, co-author of the study and principal investigator in the Center for Suicide Prevention Research at Nationwide Children’s Hospital. 

The findings of this study highlight the importance of suicide preventive interventions tailored to better address racial and ethnic disparities in youth at highest risk for suicide. An increase in suicide by firearms also draws attention to the continuing need to promote safe gun storage practices. Additionally, preteen rates of suicide are increasing, warranting further research and clinical attention for this understudied subpopulation at risk. 

Reference: “Youth Suicide During the First Year of the COVID-19 Pandemic” by Jeffrey A. Bridge, PhD; Donna A. Ruch, PhD; Arielle H. Sheftall, PhD; Hyeouk Chris Hahm, PhD, LCSW; Victoria M. O’Keefe, PhD; Cynthia A. Fontanella, PhD; Guy Brock, PhD; John V. Campo, MD and Lisa M. Horowitz, PhD, MPH, 15 February 2023, Pediatrics.
DOI: 10.1542/peds.2022-058375

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