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Tag: National Institutes of Health (NIH)

  • High School Students Learn the Basics of Base Editing to Cure “GFP-itis”

    High School Students Learn the Basics of Base Editing to Cure “GFP-itis”

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    Newswise — Genome editing is used to modify the genes of living organisms to elicit certain traits, such as climate-resilient crops or treating human disease at the genetic level. It has become increasingly popular in agriculture, medicine and basic science research over the past decade, and will continue to be relevant and utilized well into the future. Given this prevalence, researchers at the University of California San Diego have started an outreach program that introduces genome-editing technologies to high school students.

    Assistant Professor of Chemistry and Biochemistry Alexis Komor, and Ph.D. candidates Mallory Evanoff and Carlos Vasquez, designed the Genome Editing Technologies Program as a way to educate students on base-editing technologies, expose them to scientists from diverse backgrounds and invite questions about college, professional development, and the everyday life of a graduate student or faculty member within academia. The program is detailed in April 20 issue of The CRISPR Journal.

    Base editors enable scientists to introduce point mutations at targeted sites in the genome of living cells with high efficiency and precision and, thus, have the therapeutic potential to treat thousands of human genetic disorders. Proof-of-concept studies have already demonstrated this technology’s potential in cell therapies and in treating progeria, sickle cell disease and liver diseases.

    “As we were testing out some of these tools, we asked ourselves, how do we make base editors accessible to high schoolers? How do we make this process really visible?” said Evanoff.

    Komor’s team generated a base-editing reporter system using E. coli bacteria. In this system, base-editing activity results in the expression of green fluorescent protein (GFP). The team installed a mutation in the bacterium’s GFP gene to remove its fluorescence. To emphasize the connection to genetic diseases, this phenotype is called “GFP-itis,” and students are tasked with “curing” the bacteria. Using base-editing technology, students correct the mutation back to wild-type, resulting in bacterial cells that fluoresce green.

    The program happens over three days, creating a more meaningful partnership with the school and building a better foundation of trust with the students. “We wanted the students to get to know us better and feel comfortable asking questions about a career in STEM,” said Komor. “A popular question is simply, ‘How do I get into undergraduate research?’ One of the students in the first school we visited, Sage Creek High School, is actually an undergraduate researcher in our lab now.”

    That student is Preety Iyer, a first-year human biology major, who recalled Komor’s visit to her high school as “an amazing opportunity to get hands-on experience with gene-editing technology. It seemed like an intangible concept to me when I was learning about it in my biology classes. Being walked through the entire process and being able to do it myself strengthened my understanding of DNA and gene editing.” 

    Iyer plans to become a doctor working with patients who have rare genetic disorders, and she’s excited to gain more valuable hands-on experience in Komor’s lab: “I’ve been able to use equipment and practice techniques, like flow cytometry and plasmid preparation, that other students don’t get to use until later in their academic careers.” 

    So far, the Genome Editing Technologies Program has visited three local high schools. The schools have had well-developed science classes and much of the equipment needed to run the experiment. The majority of students had also heard of or learned about genome engineering before. Now that Komor’s team has run the program a few times and solicited feedback from students, they hope to expand to schools without such robust science programming. 

    “My high school background in science wasn’t strong in large part because of the lack of mentorship,” said Vasquez. “It’s important to us to reach students who may not have even considered a career in STEM or medicine. To look in their eyes and instill confidence, to show we believe in them — having someone like that when I was in high school would have made a world of difference.”

    The make the experiment as accessible as possible, the team has simplified the base-editing experiment and provides all the necessary equipment. Accessibility also means making the program available to other institutions that may want to implement something similar. Interested scientists or instructors can order plasmid materials from AddGene, a worldwide nonprofit plasmid repository. These plasmids are the DNA needed to make the GFP-itis cells, as well the plasmids needed to as “cure” GFP-itis.

    The goal of the program is not only to make base editing accessible to high school students, but also to encourage critical thinking and reflect on base editing in social and cultural contexts. Komor’s team asked students to think about the difference between a disease and a trait and to consider the implications of germline genome editing, in which edits are inherited by all future descendants of the edited individual, regardless of whether those descendants consent to the procedure.

    “The ethical discussion is what hits a home run with the students,” said Vasquez. “They’ll be responsible for future gene-editing policies. It’s interesting to see them thinking about the ethical side of science.”

    “We’ve had some really good discussions about what is a disease and what is a trait,” stated Evanoff. “If we have the ability to make genetic-disease corrections, who will be able to afford those treatments? Where does the equitability lie in this technology? We don’t have the answers to that. I say to students, ‘That’s going to be your job to figure out!’”

    This research was supported by the National Science Foundation (MCB-2048207), the National Institute of General Medical Sciences (T32 GM007240-41), the National Institute of Health (T32 GM112584), the Howard Hughes Medical Institute (GT13672 and the Gilliam Fellowship Program) and the National Academies of Sciences, Engineering, and Medicine Ford Foundation Predoctoral Fellowship Program.

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    University of California San Diego

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  • Reviving exhausted T cells to tackle immunotherapy-resistant cancers

    Reviving exhausted T cells to tackle immunotherapy-resistant cancers

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    Newswise — LA JOLLA, CALIF. – May 03, 2023 – When the cells of our immune system are under constant stress due to cancer or other chronic diseases, the T cells of the immune system shut down in a process called T cell exhaustion. Without active T cells, which kill tumor cells, it’s impossible for our bodies to fight back against cancer. One of the biggest goals of immunotherapy is to reverse T cell exhaustion to boost the immune system’s ability to destroy cancerous cells.

    Researchers at Sanford Burnham Prebys studying melanoma have found a new way to make this happen. Their approach, described in Cell Reports, can reduce T cell exhaustion even in tumors that are resistant to clinically approved immunotherapies. It can also help T cells from becoming exhausted.

    “Slowing or reversing T cell exhaustion is a huge focus in cancer research, and many researchers are working on different ways to accomplish this,” says first author Jennifer Hope, Ph.D., who completed this research as a postdoctoral researcher at Sanford Burnham Prebys and is now an assistant professor at Drexel University. “This new approach could be a viable treatment on its own, but it also has tremendous potential to work synergistically with existing therapies.”

    Although there are established immunotherapies that target T cell exhaustion, the new approach is unique in that it targets several different aspects of the process at once. This means that it could help people overcome resistance to various anti-cancer immunotherapies that are currently available.

    “One of the foundational ideas of modern cancer treatment is not relying on a single therapy, since this can cause the cancer to become resistant to that treatment,” says senior author Linda Bradley, Ph.D., a professor in the Cancer Metabolism and Microenvironment Program at Sanford Burnham Prebys. “The more tools at our disposal to slow down or reverse T cell exhaustion in different ways, the better chance we have of improving precision medicine and helping more people with cancer benefit from immunotherapy.”

    Their approach hinges on a protein called PSGL-1, which is found in most blood cells. By studying mice with a genetic deficiency in PSGL-1, the researchers determined that this protein helps facilitate T cell exhaustion, a major roadblock to effective anti-cancer immunity.

    The researchers then used an antibody to block the activity of PGSL-1 in mice with immunotherapy-resistant melanoma. They found that targeting PSGL-1 slowed the process of T cell exhaustion and helped exhausted T cells switch back into functioning T cells. These two effects significantly reduced tumor growth in the mice.

    “One of the things that makes this approach unique compared to existing immunotherapies is that it directly alters the way T cells become exhausted and helps them regain their function,” says Hope. “I think this is going to be crucial in terms of its translational potential.”

    The researchers were also able to replicate this effect in mice with mesothelioma, suggesting that the approach could be applicable to a wide range of cancers. Although the treatment they used in this study is not yet suited for clinical use in humans, the overall approach of using antibodies or recombinant proteins for immunotherapy is well established. This means that translating these results for people with cancer may just be a matter of time and testing.

    “Once we’ve done all the necessary science, this could be really valuable, or even lifesaving, for a lot of people with cancers that are resistant to current treatments,” says Bradley. “We still have a long way to go, but I’m optimistic that we’re onto something game-changing here.”

    ###

    Additional authors on the study include Dennis C. Otero, Eun-Ah Bae, Christopher J. Stairiker, Ashley B. Palete, Hannah A. Faso, Michelle Lin, Monique L., Henriquez, Sreeja Roy, Xue Lei, Eric S. Wang, Savio Chow, Roberto Tinoco, Kevin Yip, Alexandre Rosa Campos, Jun Yin, Peter D. Adams and Linda M. Bradley, Sanford Burnham Prebys; Anjana Rao and Hyungseok Seo, La Jolla Institute for Immunology; and Gregory A. Daniels, Moores Cancer Center at UC San Diego Health.

    The study was supported by grants from the American Cancer Society (PF-20-113-01-LIB), the National Institutes of Health (T32 AI125209, R01 AI106895, R21 CA249353, R21 CA216678, R03 CA252144, R01 AI040127, R01 AI109842, P30 CA030199), the Melanoma Research Alliance (MRA 696326), the Department of Defense (W81XWH-20-1-0324), the American Association of Immunologists, the San Diego Cancer Centers Council (C3 2018), the Association of Immunologists Careers in Immunology Fellowship Program, and was supported in part by the following Sanford Burnham Prebys Core facilities: Flow Cytometry, Vivarium, Histology, Bioinformatics, Proteomics, and Cancer Metabolism.

    The study’s DOI is 10.1016/j.celrep.2023.112436

    About Sanford Burnham Prebys

    Sanford Burnham Prebys is an independent biomedical research institute dedicated to understanding human biology and disease and advancing scientific discoveries to profoundly impact human health. For more than 45 years, our research has produced breakthroughs in cancer, neuroscience, immunology and children’s diseases, and is anchored by our NCI-designated Cancer Center and advanced drug discovery capabilities. For more information, visit us at SBPdiscovery.org or on Facebook facebook.com/SBPdiscovery and on Twitter @SBPdiscovery.

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    Sanford Burnham Prebys

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  • Quantum-Enhanced Microscope Doubles Resolution

    Quantum-Enhanced Microscope Doubles Resolution

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    Newswise — Using a “spooky” phenomenon of quantum physics, Caltech researchers have discovered a way to double the resolution of light microscopes.

    In a paper appearing in the journal Nature Communications, a team led by Lihong Wang, Bren Professor of Medical Engineering and Electrical Engineering, shows the achievement of a leap forward in microscopy through what is known as quantum entanglement. Quantum entanglement is a phenomenon in which two particles are linked such that the state of one particle is tied to the state of the other particle regardless of whether the particles are anywhere near each other. Albert Einstein famously referred to quantum entanglement as “spooky action at a distance” because it could not be explained by his relativity theory.

    According to quantum theory, any type of particle can be entangled. In the case of Wang’s new microscopy technique, dubbed quantum microscopy by coincidence (QMC), the entangled particles are photons. Collectively, two entangled photons are known as a biphoton, and, importantly for Wang’s microscopy, they behave in some ways as a single particle that has double the momentum of a single photon.

    Since quantum mechanics says that all particles are also waves, and that the wavelength of a wave is inversely related to the momentum of the particle, particles with larger momenta have smaller wavelengths. So, because a biphoton has double the momentum of a photon, its wavelength is half that of the individual photons.

    This is key to how QMC works. A microscope can only image the features of an object whose minimum size is half the wavelength of light used by the microscope. Reducing the wavelength of that light means the microscope can see even smaller things, which results in increased resolution.

    Quantum entanglement is not the only way to reduce the wavelength of light being used in a microscope. Green light has a shorter wavelength than red light, for example, and purple light has a shorter wavelength than green light. But due to another quirk of quantum physics, light with shorter wavelengths carries more energy. So, once you get down to light with a wavelength small enough to image tiny things, the light carries so much energy that it will damage the items being imaged, especially living things such as cells. This is why ultraviolet (UV) light, which has a very short wavelength, gives you a sunburn.

    QMC gets around this limit by using biphotons that carry the lower energy of longer-wavelength photons while having the shorter wavelength of higher-energy photons.

    “Cells don’t like UV light,” Wang says. “But if we can use 400-nanometer light to image the cell and achieve the effect of 200-nm light, which is UV, the cells will be happy, and we’re getting the resolution of UV.”

    To achieve that, Wang’s team built an optical apparatus that shines laser light into a special kind of crystal that converts some of the photons passing through it into biphotons. Even using this special crystal, the conversion is very rare and occurs in about one in a million photons. Using a series of mirrors, lenses, and prisms, each biphoton—which actually consists of two discrete photons—is split up and shuttled along two paths, so that one of the paired photons passes through the object being imaged and the other does not. The photon passing through the object is called the signal photon, and the one that does not is called the idler photon. These photons then continue along through more optics until they reach a detector connected to a computer that builds an image of the cell based on the information carried by the signal photon. Amazingly, the paired photons remain entangled as a biphoton behaving at half the wavelength despite the presence of the object and their separate pathways.

    Wang’s lab was not the first to work on this kind of biphoton imaging, but it was the first to create a viable system using the concept. “We developed what we believe a rigorous theory as well as a faster and more accurate entanglement-measurement method.  We reached microscopic resolution and imaged cells.”

    While there is no theoretical limit to the number of photons that can be entangled with each other, each additional photon would further increase the momentum of the resulting multiphoton while further decreasing its wavelength.

    Wang says future research could enable entanglement of even more photons, although he notes that each extra photon further reduces the probability of a successful entanglement, which, as mentioned above, is already as low as a one-in-a-million chance.

    The paper describing the work, “Quantum Microscopy of Cells at the Heisenberg Limit,” appears in the April 28 issue of Nature Communications. Co-authors are Zhe He and Yide Zhang, both postdoctoral scholar research associates in medical engineering; medical engineering graduate student Xin Tong (MS ’21); and Lei Li (PhD ’19), formerly a medical engineering postdoctoral scholar and now an assistant professor of electrical and computer engineering at Rice University.

    Funding for the research was provided by the Chan Zuckerberg Initiative and the National Institutes of Health.

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    California Institute of Technology

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  • Improved Gene Editing Method Could Power the Next Generation of Cell and Gene Therapies

    Improved Gene Editing Method Could Power the Next Generation of Cell and Gene Therapies

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    Newswise — PHILADELPHIA— A new approach to the genetic engineering of cells promises significant improvements in speed, efficiency, and reduction in cellular toxicity compared to current methods. The approach could also power the development of advanced cell therapies for cancers and other diseases, according to a study from researchers in the Perelman School of Medicine at the University of Pennsylvania.

    In the study, which appeared this week in Nature Biotechnology, researchers found that protein fragments used by some viruses to help them get into cells could also be used to get CRISPR-Cas gene editing molecules into cells and their DNA-containing nuclei with extraordinarily high efficiency and low cellular toxicity.

    The scientists expect the new technique to be particularly useful for modifying T cells and other cells from a patient’s own body to make cell therapies. One such application could be CAR T (chimeric antigen receptor T cell) therapy, which uses specially modified immune cells from a patient to treat cancer. The T cells—a type of white blood cell—are removed from the patient and reprogrammed to find and attack cancer cells when reintroduced to the bloodstream.  

    The first FDA-approved CAR T therapy was developed at Penn Medicine, and received Food & Drug Administration approval in 2017. There are now six FDA-approved CAR T cell therapies in the United States. The therapies have revolutionized the treatment of certain B cell leukemias, lymphomas, and other blood cancers, putting many patients who otherwise had little hope into long-term remission.

    “This new approach—building on Penn Medicine’s history of cell and gene therapy innovation—has the potential to be a major enabling technology for engineered cellular therapies,” said co-senior author E. John Wherry, PhD, Richard and Barbara Schiffrin President’s Distinguished Professor and chair of Systems Pharmacology & Translational Therapeutics at Penn Medicine.

    CRISPR-Cas molecules are derived from ancient bacterial antiviral defenses, and are designed to precisely remove DNA at desired locations in a cell’s genome. Some CRISPR-Cas-based systems combine the deletion of old DNA with the insertion of new DNA for versatile genome editing. This approach can be used to replace faulty genes with corrected ones or delete or modify genes to enhance cellular function. Some systems can also add genes that confer new properties to CAR T cells such as the ability to recognize tumors or withstand the harsh tumor microenvironment that normally exhausts T cells.

    Although CRISPR-Cas systems are already widely used as standard laboratory tools for molecular biology, their use in modifying patients’ cells to make cell-based therapies has been limited—in part because CRISPR-Cas molecules can be hard to get into cells and then into cells’ DNA-containing nuclei.

    “Current methods of getting CRISPR-Cas systems into cells, which include the use of carrier viruses and electric pulses, are inefficient for cells taken directly from patients (called primary cells). These methods also typically kill many of the cells they are used on, and can even cause broad unwanted changes in gene activity,” said co-senior author Shelley L. Berger, PhD, the Daniel S. Och University Professor in Cell and Developmental Biology and Genetics and director of the Penn Epigenetics Institute.

    In the study, researchers explored the use of small, virus-derived protein fragments, called peptides, to pilot CRISPR-Cas molecules more efficiently through the outer membranes of primary human cells and into their nuclei. Notably, researchers found that a fused combination of two modified peptides—one found in HIV and one in influenza viruses—could be mixed with CRISPR-Cas molecules to get them into primary human or mouse cells and their nuclei with efficiencies of up to nearly 100 percent, depending on the cell type—with almost no toxicity or gene-expression changes.

    The team demonstrated the approach, which they call PAGE (peptide-assisted genome editing), for several types of envisioned cell therapy including CAR T cell therapies.

    In addition to its potential use in cell and gene therapies, the authors note the PAGE approach could see wide application in basic scientific research. The inefficiency of standard CRISPR-Cas cell penetration methods has meant that gene-editing to create mouse models of diseases typically requires a multi-step, time-consuming process of generating transgenic mice—to introduce the gene-editing machinery into their DNA. By contrast, PAGE with its high efficiency and low toxicity might enable rapid, efficient, and straightforward gene editing in ordinary lab mice.

    “The simplicity and power of the peptide-assist concept suggests that it could potentially be adapted in the future for the delivery into primary cells of other genome-editing proteins, or even protein-based drugs,” said co-senior author Junwei Shi, PhD, an assistant professor of Cancer Biology and member of the Penn Epigenetics Institute and Abramson Family Cancer Research Institute.

    The study was a collaboration that included the laboratories of Penn co-author Rahul Kohli, MD, PhD, an associate professor of Infectious Diseases and Biochemistry and Biophysics, and co-author Gerd Blobel, MD, PhD, the Frank E. Weise III Professor of Pediatrics and co-director of the Epigenetics institute.

    This study was supported by the National Institute of Health (R01-HL119479, R01-GM138908, AI105343, AI082630, AI108545, AI155577, AI149680, U19AI082630, R35-CA263922, R01-CA258904), the Parker Institute for Cancer Immunotherapy, and institutional funds from University of Pennsylvania.

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    Perelman School of Medicine at the University of Pennsylvania

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  • 240 Mammal Genomes Reveal Human Disease Risks

    240 Mammal Genomes Reveal Human Disease Risks

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    Newswise — Why is it that certain mammals have an exceptional sense of smell, some hibernate, and yet others, including humans, are predisposed to disease? A major international research project, jointly led by Uppsala University, Sweden and the Broad Institute, USA, has surveyed and analysed the genomes of 240 different mammals. The results, now published in 11 articles in the journal Science, show how the genomes of humans and other mammals have developed over the course of evolution. The research shows which regions have important functions in mammals, which genetic changes have led to specific characteristics in different species and which mutations can cause disease.

    “In combination, the 11 articles we are now publishing in Science provide an enormous amount of information about the function and development of mammalian genomes,” says Kerstin Lindblad-Toh, Professor of Comparative Genomics at Uppsala University and one of two leaders of the international consortium of researchers. “Moreover, we have produced data that can be used for studies of evolution and medical research for many years to come.”

    In a large international project jointly led by Uppsala University and the Broad Institute, more than 30 research teams have together surveyed and analysed the genomes of 240 mammal species. The results, now published in 11 articles in the journal Science, show how the genomes of humans and other mammals have developed in the course of evolution.

    The human genome contains approximately 20,000 genes that constitute the code for manufacturing all the proteins in the body. The genome also contains instructions that direct where, when and how much of the proteins are produced. These parts of the genome, which are called regulatory elements, are much more difficult to identify than the parts that give rise to proteins. However, studying a great many mammals’ genomes makes it possible to figure out which parts of the genome are functionally important.

    The hypothesis shared by the researchers behind the publications in Science has been that if a position in the genome has been preserved throughout 100 million years of evolution, it likely serves a function in all mammals. For the first time, they have been able to test this hypothesis on a large scale. By making a detailed survey and systematic comparison of the genomes of 240 mammals, the researchers have identified regions of the human genome with previously uncharacterised function. These regions are likely regulatory elements and are significant for the correct functioning of the genome. Mutations in these can play an important role in the origin of diseases or in the distinctive features of mammal species.

    The researchers identified more than three million important regulatory elements in the human genome, about half of which were previously unknown. They were also able to ascertain that at least 10 per cent of the genome is functional, ten times as much as the approximately one per cent that codes for proteins.

    The 240 different mammals in the study vary widely in their characteristics, such as the acuteness of their sense of smell or the size of their brain. The researchers were able to find regions in the genomes that lead to some species having a superior sense of smell or to certain species hibernating.

    “It’s exciting to now have a picture of which mutations have steered the development of specific traits in these widely divergent mammals,” says Matthew Christmas, researcher and co-first author of one of the articles focusing on the function of the genome and how it affects distinctive features in different species.

    One of the studies shows that mammals had begun to change and diverge ven before the Earth was hit by the asteroid that killed the dinosaurs, approximately 65 million years ago.

    “Our results can also provide important information about whether mammals are at risk of extinction, depending on how much variation they have in their genome. This is information that can lay the foundation for understanding how to manage a species to help it survive,” says Professor Lindblad-Toh.

    The new knowledge also helps researchers understand how diseases arise, by linking the positions in the genome conserved by evolution to known conditions. This can be done for all species and will also be usable with reference to human diseases.

    “Our analyses of 240 mammals give us a better insight into the regulatory signals in the genome. We calibrated our results on positions that are known to contribute to disease, and then could use these to suggest additional positions which could be prioritised for neurological traits, such as schizophrenia or immune conditions including asthma or eczema,” says Jennifer Meadows, researcher and co-first author of the second article, which focuses on how the project’s data can contribute to knowledge about diseases.

    The genome of healthy and sick people is compared to understand which mutations lead to disease. This produces a picture of the region in the genome that may be important, but does not yield an exact knowledge of which mutation causes the disease.

    “A large proportion of the mutations that lead to common diseases, like diabetes or obsessive-compulsive disorder, lie outside the genes and have to do with gene regulation. Our studies make it easier to identify the mutations that lead to disease and to understand what goes wrong,” says Lindblad-Toh.

    The researchers also studied the cancer medulloblastoma, which is the most common type of malignant brain tumour in children. Although modern treatments have improved the prognosis, not all children can be cured. Moreover, those that survive often experience lifelong side-effects from the aggressive treatment.

    “In patients with medulloblastoma, we found many new mutations in evolutionarily conserved positions. We hope that analysis of these mutations will lay the ground for new diagnostics and therapies,” says Karin Forsberg-Nilsson, Professor of Stem Cell Research at Uppsala University, who led the cancer part of the study.

    This work was supported in part by the National Institutes of Health (US), the Swedish Research Council (SWE), the Knut and Alice Wallenberg Foundation (SWE), and the National Science Foundation (US).

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    Uppsala University

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  • Achieving Prevention and Health, Rather Than More Healthcare

    Achieving Prevention and Health, Rather Than More Healthcare

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    Newswise — If more people have access to health insurance, we have to be sure the death rates of those with certain chronic conditions are decreasing.

    This is one of the statements Gregory Peck, an acute care surgeon and associate professor at Rutgers Robert Wood Johnson Medical School, will be researching on behalf of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at the National Institutes of Health.

    Funded by NIH grants totaling more than $1 million through a recent two-year award from the New Jersey Alliance for Clinical and Translational Science (NJ ACTS), a Rutgers hub of the National Center for Advancing Translation Science, and now a four-year award from the NIDDK, Peck is on average one of just two critical care surgeons funded nationally annually creating new models of health for NIH consideration.

    Peck recently published two studies investigating death rates for gallstone disease, a disease of the abdomen that causes right-sided belly pain after eating, which share risk factors with other deadly diseases. His study, published in Gastro Hep Advances, found that between 2009 and 2018 the number of deaths of people in New Jersey with diagnosed gallstone disease (1,580) remained steady and did not improve, and that deaths in Latinos ages 65 and older potentially increased.

    His study in the Journal of Surgical Research found that after Medicaid expansion in 2014 as compared to before, the amount of emergency surgery to remove the gallbladders for gallstone disease decreased in the state overall, but increased in people with Medicaid. While fatality from gallbladder removal surgery decreased for those 65 or older, there was increased death from surgery in the younger population and a trend of more death in the population with Medicaid. Further, the relatively decreased amount of gallbladder removal surgery occurring in ambulatory outpatient care centers did not necessarily help this.

    Peck discusses the implications of the findings on a new shift in healthcare to prevention model.

    Why did you focus on gallstone disease?

    As a metabolic disease, gallstone disease is also linked to heart disease, cancer, diabetes, obesity and a sedentary lifestyle. In fact, heart disease, which is the No. 1 killer in America, and gallstone disease, which is the No. 1 digestive disease requiring surgery in America, share the risk factors of high levels of bad cholesterol type and obesity.

    How do these studies inform public policy?

    The amount of people dying with gallstone disease – most of whom require surgery – over the past decade has not gotten better. That’s 160 people a year who still are dying from a preventable death such as gallstone disease. Making progress is what this type of epidemiologic study focuses on, and concerningly, we might not have made good progress.

    If Medicaid expansion didn’t positively affect the death rate of people with gallstone disease and we see it increase specifically in older Latino populations, we need to be asking if we are helping people of color and those who live in communities with lower socioeconomic status improve health or treating them sooner to prevent emergency surgery and especially decreasing death from emergency surgery. Insurance expansion is certainly needed, but we have to ensure the action specific pieces of policy impact the population requiring surgery in a patient-centered way.

    The real goal is preventing the disease from even occurring. When we pass public health policy, we need to advocate for preventive care that reaches people through their community. Right now, the findings show that we might just be providing people with insurance cards who find themselves still needing to use the emergency department. Instead, that insurance should help them visit their primary care doctor, who can help them make changes like decreasing their bad cholesterol levels, which contribute to gallstone disease, and help them access care in ambulatory surgery centers sooner.

    We need to cultivate preventive healthcare rather than ballooning the investment in emergency healthcare, which does not solve current inequities.

    What other steps to improve access to care should be taken?

    We propose a novel population health approach that shifts from the reactive treatments of emergency disease to proactive prevention. One place to start is increasing access to appropriate outpatient elective healthcare for underrepresented groups with barriers to preventive care, such as by increasing health insurance that incentivizes the behaviors toward improved health. A first step for my research group is to focus on diseases that currently require as much emergency as elective care, such as gallstone disease, and understand this by understanding who presents to the hospital, as to dial this back into the community level, to decrease hospital care.

    In addition, in primary care, laboratory, radiology or ambulatory care settings we need to improve communication with people with low English proficiency – especially how well prevention is explained in a patient’s primary language. Language barriers might also prevent them from understanding the importance of cholesterol or blood pressure control over the one, two and three decades of life, or how they find access to diagnostic tests or treatment needed earlier.

    How is Rutgers working to increase primary care knowledge in underserved communities?

    Shawna Hudson, the co-director of community engagement for NJ ACTS, and my research mentor, is researching how representatives rooted in the community can help healthcare providers and researchers better understand how we can use community engagement to involve people in a communities’ preventive care as to decrease risk factors for chronic disease before they need hospital-based care and, more importantly, emergency surgery.

    One initiative is the Community Engagement Virtual Salons, which help researchers and health care providers at NJ ACTS engage with patients and community members about how biomedical and clinical research leads to action through understanding disease and then enacting policy. In these sessions, the public serves as experts to provide feedback from a community perspective. This allows the medical profession to build relationships with community partners and increase the culturally sensitive participation of hard-to-reach populations.

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    Rutgers University-New Brunswick

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  • Too Much Insulin Can Be as Dangerous as Too Little

    Too Much Insulin Can Be as Dangerous as Too Little

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    Newswise — Just over a century has passed since the discovery of insulin, a time period during which the therapeutic powers of the hormone have broadened and refined. Insulin is an essential treatment for type 1 diabetes and often for type 2 diabetes, as well. Roughly 8.4 million Americans use insulin, according to the American Diabetes Association.

    One hundred years of research have greatly advanced medical and biochemical understanding of how insulin works and what happens when it is lacking, but the reverse, how potentially fatal insulin hyper-responsiveness is prevented, has remained a persistent mystery.

    In a new study, published in the April 20, 2023 online edition of Cell Metabolism, a team of scientists at the University of California San Diego School of Medicine, with colleagues elsewhere, describe a key player in the defense mechanism that safeguards us against excessive insulin in the body.

    “Although insulin is one of the most essential hormones, whose insufficiency can result in death, too much insulin can also be deadly,” said senior study author Michael Karin, PhD, Distinguished Professor of Pharmacology and Pathology at UC San Diego School of Medicine.

    “While our body finely tunes insulin production, patients who are treated with insulin or drugs that stimulate insulin secretion often experience hypoglycemia, a condition that if gone unrecognized and untreated can result in seizures, coma and even death, which collectively define a condition called insulin shock.”

    Hypoglycemia (low blood sugar) is a significant cause of death among persons with diabetes.

    In the new study, Karin, first author Li Gu, PhD, a postdoctoral scholar in Karin’s lab, and colleagues describe “the body’s natural defense or safety valve” that reduces the risk of insulin shock.

    That valve is a metabolic enzyme called fructose-1,6-bisphosphate phosphatase or FBP1, which acts to control gluconeogenesis, a process in which the liver synthesizes glucose (the primary source of energy used by cells and tissues) during sleep and secretes it to maintain steady supply of glucose in the bloodstream.

    Some antidiabetic drugs, such as metformin, inhibit gluconeogenesis but without apparent ill effect. Children born with a rare, genetic disorder in which they do not produce sufficient FBP1 can also remain healthy and live long lives.

    But in other cases, when the body is starved for glucose or carbohydrates, an FBP1 deficiency can result in severe hypoglycemia. Without a glucose infusion, convulsions, coma and possibly death can ensue.

    Compounding and confounding the problem, FPB1 deficiency combined with glucose starvation produces adverse effects unrelated to gluconeogenesis, such as an enlarged, fatty liver, mild liver damage and elevated blood lipids or fats.

    To better understand the roles of FBP1, researchers created a mouse model with liver specific FBP1 deficiency, accurately mimicking the human condition. Like FBP1-deficient children, the mice appeared normal and healthy until fasted, which quickly resulted in the severe hypoglycemia and the liver abnormalities and hyperlipidemia described above.

    Gu and her colleagues discovered that FBP1 had multiple roles. Beyond playing a part in the conversion of fructose to glucose, FBP1 had a second non-enzymatic but critical function: It inhibited the protein kinase AKT, which is the primary conduit of insulin activity.

    “Basically, FBP1 keeps AKT in check and guards against insulin hyper-responsiveness, hypoglycemic shock and acute fatty liver disease,” said first author Gu.

    Working with Yahui Zhu, a vising scientist from Chongqing University in China and second author of the study, Gu developed a peptide (a string of amino acids) derived from FBP1 that disrupted the association of FBP1 with AKT and another protein that inactivates AKT.

    “This peptide works like an insulin mimetic, activating AKT,” said Karin. “When injected into mice that have been rendered insulin resistant, a highly common pre-diabetic condition, due to prolonged consumption of high-fat diet, the peptide (nicknamed E7) can reverse insulin resistance and restore normal glycemic control.”

    Karin said the researchers would like to further develop E7 as a clinically useful alternative to insulin “because we have every reason to believe that it is unlikely to cause insulin shock.”

    Co-authors include: Kosuke Watari, Maiya Lee, Junlai Liu, Sofia Perez, Melinda Thai, Joshua E. Mayfield, Bichen Zhang, Karina Cunha e Rocha, Alexander C. Jones, Igor H. Wierzbicki, Xiao Liu, Alexandra C. Newton, Tatiana Kisseleva, Wei Ying, David J. Gonzalez and Alan R. Saltiel, all at UC San Diego; Fuming Li, University of Pennsylvania and Fudan University, China; Laura C. Kim and M. Celeste Simon, University of Pennsylvania; Jun Hee Lee, University of Michigan.

    Funding for this research came, in part, from the National Institutes of Health (grants R01DK120714, R01CA234128, R01DK133448, P01CA104838, R35CA197602, R01DK117551, R01DK125820, R01DK76906, P30DK063491, R21HD107516, R00DK115998, R01DK125560 AND R35GM122523), the UC San Diego Graduate Training Program in Cellular and Molecular Pharmacology (GM007752) and the National Science Foundation Graduate Research Fellowship (#DGE-1650112).

    # # #

    Disclosure: Michael Karin and Alan Saltiel are founders and stockholders in Elgia Pharmaceuticals. Karin has received research support from Merck and Janssen Pharmaceuticals.

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    University of California San Diego

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  • Is the Language You Speak Tied to Outcome After Stroke?

    Is the Language You Speak Tied to Outcome After Stroke?

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    EMBARGOED FOR RELEASE UNTIL 4 P.M. ET, WEDNESDAY, APRIL 12, 2023

    Newswise — MINNEAPOLIS – Studies have shown that Mexican Americans have worse outcomes after a stroke than non-Hispanic white Americans. A new study looks at whether the language Mexican American people speak is linked to how well they recover after a stroke. The study is published in the April 12, 2023, online issue of Neurology®, the medical journal of the American Academy of Neurology.

    “Our study found that Mexican American people who spoke only Spanish had worse neurologic outcomes three months after having a stroke than Mexican American people who spoke only English or were bilingual,” said study author Lewis B. Morgenstern, MD, of the University of Michigan in Ann Arbor and a Fellow of the American Academy of Neurology. “More research is needed into what factors and barriers may influence these worse outcomes.”

    The study involved 1,096 Mexican American people in Corpus Christi, Texas, who had a stroke over a 10-year period. Researchers looked at results three months after the stroke in three areas: neurologic, functional and thinking and memory skills. Neurologic results cover areas such as muscle strength and coordination and problems with speech or vision. Functional results look at how well people can complete their daily activities such as showering and preparing meals.

    The 170 people who spoke Spanish only were compared to the 926 people who spoke English only or were bilingual. Those who spoke Spanish only were older, had received less education and had worse neurologic scores at the time of the stroke than those in the other group.

    Three months after the stroke, the Spanish-only speakers had average neurologic scores of seven, where scores of five to 14 indicate moderate effects from a stroke. The English-only and bilingual speakers had average scores of four, where scores of one to four indicate mild effects. The results remained after researchers adjusted for the differences between the two groups and other factors that could affect stroke risk, such as high blood pressure and diabetes.

    The study found no difference between the two groups in how well they recovered their ability to complete their daily activities or in their thinking and memory skills.

    “We conducted an earlier study in this same community finding that the language people spoke was not associated with any delay in their getting to the hospital or using emergency medical services after an ischemic stroke, so we definitely need more information to determine what is driving the differences in outcomes between these two groups,” Morgenstern said.

    A limitation of the study was that there was a low number of Spanish-only speakers. Also, the majority of Mexican Americans in Corpus Christi are born in the United States, so these results may not be applicable to areas with a larger population of people born outside the United States.

    The study was supported by the National Institutes of Health and the TRANSCENDS (Training in Research for Academic Neurologists to Sustain Careers and Enhance the Numbers of Diverse Scholars) program funded by the National Institutes of Health.  

    Learn more about stroke at BrainandLife.org, home of the American Academy of Neurology’s free patient and caregiver magazine focused on the intersection of neurologic disease and brain health. Follow Brain & Life® on Facebook, Twitter and Instagram.

    When posting to social media channels about this research, we encourage you to use the hashtags #Neurology and #AANscience.

    The American Academy of Neurology is the world’s largest association of neurologists and neuroscience professionals, with over 40,000 members. The AAN is dedicated to promoting the highest quality patient-centered neurologic care. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as Alzheimer’s disease, stroke, migraine, multiple sclerosis, concussion, Parkinson’s disease and epilepsy.

    For more information about the American Academy of Neurology, visit AAN.com or find us on Facebook, Twitter, Instagram, LinkedIn and YouTube.

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  • Small proteins in heart play big role

    Small proteins in heart play big role

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    BYLINE: Beth Miller

    Newswise — A heartbeat is a carefully coordinated series of electrical signals led by sodium ion channels, which tell the heart when to contract and to relax. Any disruption to these signals may lead to cardiac diseases such as an irregular heartbeat, or arrhythmia. Two researchers at Washington University in St. Louis have taken a closer look at this process at the molecular level and have found what may provide new insights into different heart conditions and how to develop better therapies.

    Jonathan Silva, the Dennis & Barbara Kessler Career Development Associate Professor at the McKelvey School of Engineering, and Jeanne Nerbonne, Alumni Endowed Professor of Molecular Biology & Pharmacology in Medicine and Developmental Biology at the School of Medicine, and their labs found distinct effects of novel proteins, known as intracellular fibroblast growth factors (iFGF), on the regulation of the kinetics of cardiac sodium channel gating. Their results were published in the Journal of General Physiology March 21.

    Intracellular fibroblast growth factors are small proteins that are known to bind to sodium channels and to influence how these channels open and close, or “gate.” The gating properties of cardiac sodium channels affect how the electromechanical propagate through the heart. In addition, drugs interact differently with the sodium channels in different gating (i.e., open and closed) states, Silva said.

    The team sought to determine how one intracellular fibroblast growth factor, iFGF12, works in a healthy human heart by observing how the iFGFs change the sodium channel at the molecular level. Nerbonne’s lab generated a mouse model with iFGF12 to observe how it modulates the sodium channel in myocytes. Using electrophysiology methods, they found that it modulated the channel differently than the comparable iFGF in the mouse heart and changed the properties of the sodium current.

    “One of the reasons we want to define how the iFGFs and other sodium channel accessory proteins affect channel properties at the molecular level is that we know from previous work that the protein components of functional channels influence the pharmacology of these channels,” said Nerbonne, who also is the director of the Center for Cardiovascular Research. “These channels are potential therapeutic targets for people with arrhythmias.”

    Silva’s lab looked at how the iFGF affects channel function through methods they have developed to watch the voltage sensing domains.

    “We looked at how these subunits affect native cell electrophysiology, and that’s an exciting part of our collaboration with the Nerbonne lab,” Silva said. “We were able to determine how these subunits change the channel at the molecular level to cause those cell-level effects.”

    Going forward, the team plans to take a closer look at how different drugs interact with sodium channels that have different iFGF compositions.

    ***

    Originally published by the McKelvey School of Engineering.

    Angsutararux P, Dutta AK, Marras M, Abella C, Mellor RL, Shi J, Nerbonne JM, Silva JR. Differential regulation of cardiac sodium channels by intracellular fibroblast growth factors. Journal of General Physiology, March 21, 2023. https://doi.org/10.1085/jgp.202213300

    This research was supported by the National Institutes of Health’s National Heart, Lung, and Blood Institute (R01 142520 and R01 HL150637); the NIH National Center for Research Resources (UL1 RR024992) and the Children’s Discovery Institute Pediatric Disease Mouse Models Core at Washington University.

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    Washington University in St. Louis

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  • Lab-made antibodies offer potential cure for yellow fever

    Lab-made antibodies offer potential cure for yellow fever

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    Newswise — PORTLAND, Oregon — New research from Oregon Health & Science University and collaborators indicates lab-made antibodies may be able to cure people infected with yellow fever, a virus for which there is no treatment.

    The natural immune response to invading pathogens normally involves making protective proteins called antibodies. A study published today in Science Translational Medicine suggests that a single monoclonal antibody infusion can strengthen the body’s fight against yellow fever.

    In the study, the yellow fever virus was undetectable in all animals that received monoclonal antibody infusions after being exposed to the virus.

    “Two monoclonal antibodies that we evaluated completely removed all signs of infection from research animals,” said the study’s corresponding author, Ben Burwitz, Ph.D., associate professor at OHSU’s Vaccine and Gene Therapy Institute and affiliate associate professor at OHSU’s Oregon National Primate Research Center.

    The collaborative research is a joint effort between scientists from OHSU, George Washington University, the biotechnology company Mabloc, LLC, and other organizations. Mabloc plans to use these findings to inform a future clinical trial in humans, in addition to their product development efforts.

    “Neglected tropical diseases like yellow fever, dengue and Zika are often overlooked by traditional pharmaceutical development, but we hope monoclonal antibody technology will change that,” said David Watkins, Ph.D., co-senior author on the study, professor of pathology at George Washington University and Mabloc’s chief executive officer. 

    “By showing such efficacy in a primate model that mimics severe human disease, we hope to advance this to clinical trials and be ready to deploy treatments for the next outbreak of yellow fever,” said the study’s first author, Michael Ricciardi, Ph.D., associate director of translational research at George Washington University and Mabloc’s director of product development.  

    Increasingly common yellow fever 

    As many as half of people who get severe yellow fever die from the virus, which causes flu-like symptoms and can lead to jaundice and organ failure in more serious cases. Every year, the virus infects about 200,000 people — killing about 30,000 worldwide. 

    Currently, most cases occur in tropical and sub-tropical areas of Africa and South America, but global climate change is expected to increase the range of the mosquitoes that spread the virus. Deaths in Africa alone are predicted to increase by 25% by the year 2050. 

    The disease is preventable with a highly effective vaccine, which has been available since the 1930s. Although the vaccine is safe for the vast majority of people, vaccine hesitancy leaves some vulnerable to infection. It is a live vaccine that uses a weakened form of the virus, which causes a very small percentage of recipients to experience an adverse reaction that has been fatal in rare cases. A treatment could benefit both unvaccinated individuals who get sick and the very few people who experience a vaccine-related reaction.

    When they began considering potential yellow fever treatments, the research team initially considered 37 antibodies cloned from people who had been vaccinated against yellow fever. The team then narrowed its focus to two monoclonal antibodies capable of controlling variants of the virus that were involved in recent yellow fever outbreaks. 

    The team manufactured these two monoclonal antibodies in the lab and studied how protective they could be against the yellow fever virus in two animal species: rhesus macaque monkeys and hamsters. After animals were exposed to the virus, each species was divided into three groups: one group that received the first antibody, another that received the second antibody, and a third that didn’t receive either antibody. 

    The virus couldn’t be detected in blood samples of any of the animals – eight rhesus macaques and 20 hamsters – that received either monoclonal antibody. All those in the control group developed severe disease. While one treated hamster died of an unknown cause, it neither showed signs of a yellow fever infection nor did it have signs of an adverse reaction to the monoclonal antibody.

    Both monoclonal antibody candidates also appeared to be safe. None of the animals that received either experimental treatment displayed liver dysfunction, a tell-tale sign of severe yellow fever infection and yellow fever vaccine-associated disease.

     

    This research was supported by the National Institutes of Health (grants R42 AI155275 and P51 OD01092) and by Mabloc, LLC.

    Some of the researchers involved in this study — including Jonah Sacha, Ph.D., of OHSU; and Michael Ricciardi, Ph.D., and David Watkins, Ph.D., of George Washington University — have a significant financial interest in Mabloc, LLC, a company that may have a financial interest in the results of this research and technology. This potential individual and institutional conflict of interest has been reviewed and managed by OHSU.

    All research involving animal subjects at OHSU must be reviewed and approved by the university’s Institutional Animal Care and Use Committee (IACUC). The IACUC’s priority is to ensure the health and safety of animal research subjects. The IACUC also reviews procedures to ensure the health and safety of the people who work with the animals. The IACUC conducts a rigorous review of all animal research proposals to ensure they demonstrate scientific value and justify the use of live animals. 

     

    REFERENCE: Michael J. Ricciardi, Lauren N. Rust, Nuria Pedreno-Llpez, Sofiya Yusova, Sreya Biswas, Gabriela M. Webb, Lucas Gonzalez-Nieto, Thomas B. Voigt, Johan J. Louw, Fernanda D. Laurino, John R. DiBello, Hans-Peter Raue, Aaron M. Barber-Axthelm, Kimberly Chun, Samantha Uttke, Lidiane M.S. Raphael, Aaron Yrizarry-Medina, Brandon C. Rosen, Rebeca Agnor, Lina Gao, Caralyn Labriola, Michael Axthelm, Jeremy Smedley, Justin G. Julander, Myrna C. Bonaldo, Laura M. Walker, Ilhem Messaoudi, Mark K. Slikfa, Dennis R. Burton, Esper G. Kallas, Jonah B. Sacha, David I. Watkins,  Benjamin J. Burwitz, Therapeutic neutralizing monoclonal antibody administration protects against lethal yellow virus infection, Science Translational Medicine, March 29, 2023, https://doi.org/10.1126/scitranslmed.ade5795

     

    Links:

    Related OHSU News stories:

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  • Imaging brain connections can predict improvements in obsessive-compulsive disorder patients after deep brain stimulation

    Imaging brain connections can predict improvements in obsessive-compulsive disorder patients after deep brain stimulation

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    Newswise — Deep brain stimulation (DBS) is a promising therapy for treatment-resistant obsessive-compulsive disorder (OCD). A first-of-its-kind collaborative study led by researchers at Texas Children’s Hospital, Baylor College of Medicine, and Brigham & Women’s Hospital has found that mapping neural connections in the brains of OCD patients offers key insights that explain the observed improvements in their clinical outcomes after DBS. The study was published in Biological Psychiatry.

    Neuropsychiatric disorders such as obsessive-compulsive disorder are a result of dysfunction across broad neural networks and typically involve brain domains responsible for cognitive and higher-order decision-making such as the prefrontal cortex.

    “The goal of neuromodulatory therapies like DBS is to restore the functional balance within these networks. Since the extent of functional dysfunction in these networks varies between individuals, it is important to customize DBS surgery for each patient. To do that reliably, we first need to precisely map the neural connections involved in the specific condition and then understand how these connections are affected by DBS,” said co-corresponding author Dr. Sameer Sheth, professor in the department of neurosurgery at Baylor College of Medicine, director of the Cain Foundation Labs, and principal investigator at the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital.

    In 2020, a seminal study by Dr. Andreas Horn and his team at Brigham & Women’s Hospital identified an ‘OCD response tract’ – a white matter circuit that precisely mapped the specific fiber bundles and brain regions whose modulation by DBS could improve clinical outcomes in OCD patients. The present study is the first one to conduct blind testing of the OCD response tract model with the goal of developing a predictive ‘connectomic’ model.

    Connectomic imaging strategies such as white matter tractography – a three-dimensional magnetic resonance imaging (MRI) technique that maps the location and direction of white matter bundles and their constituent fibers within the brain – are becoming increasingly reliable methods to identify these networks that inform surgeons where to implant DBS electrodes in the brain of the patient during surgery. Here, Sheth and colleagues used this approach to rank and conduct ‘blind’ comparison of clinical outcomes in ten OCD patients who had undergone a specific DBS procedure six months prior to the study.

    DBS programming was performed by Dr. Wayne Goodman, Chair of the department of psychiatry at Baylor College, and patient outcomes were periodically assessed by Dr. Eric Storch, Vice Chair of psychology, for changes in the severity of their OCD and mood symptoms.

    Then the Brigham & Women’s Hospital (BWH) team led by Dr. Andreas Horn analyzed the imaging data and provided rank predictions based solely on the neuroimaging data and stimulation parameters. This team was not involved in DBS planning or programming and did not have prior knowledge of clinical outcomes. The outcomes predicted by the BWH team closely matched the actual clinical outcomes that the Baylor team observed in these patients.

    “To our knowledge, this is the first example of such a collaborative ‘blinded’ team effort by two research centers to validate DBS therapy for a brain tract proposed on the basis of retrospective data,” co-corresponding author, Dr. Horn added. “This is also a big step in the continued optimization and improving the efficacy of DBS procedures that target this brain tract to treat OCD, even as efforts are underway to make this therapy more widely available to patients. Finally, this two-center ‘blinded’ approach could serve as a model for validating and optimizing DBS therapies for other neurological conditions in the future.”

    Others involved in the study were Ron Gadot, Ningfei Li, Ben Shofty, Michelle Avendano-Ortega, Sarah McKay, Kelly Bijanki, Megan Robinson, Garrett Banks, and Nicole Provenza. They are affiliated with one or more of the following institutions: Baylor College of Medicine, Charité – Universitätsmedizin Berlin, Germany; University of Utah, and Brigham and Women’s Hospital. This research was funded by the National Institutes for Health and the McNair Foundation.

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  • ‘Smart’ bandages monitor wounds and provide targeted treatment

    ‘Smart’ bandages monitor wounds and provide targeted treatment

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    Newswise — Most of the time, when someone gets a cut, scrape, burn, or other wound, the body takes care of itself and heals on its own. But this is not always the case. Diabetes can interfere with the healing process and create wounds that will not go away and that could become infected and fester.

    These kinds of chronic wounds are not just debilitating for the people suffering from them. They are also a drain on healthcare systems, representing a $25 billion financial burden in the United States alone each year.

    A new kind of smart bandage developed at Caltech may make treatment of these wounds easier, more effective, and less expensive. These smart bandages were developed in the lab of Wei Gao, assistant professor of medical engineering, Heritage Medical Research Institute Investigator, and Ronald and JoAnne Willens Scholar.

    “There are many different types of chronic wounds, especially in diabetic ulcers and burns that last a long time and cause huge issues for the patient,” Gao says. “There is a demand for technology that can facilitate recovery.”

    Unlike a typical bandage, which might only consist of layers of absorbent material, the smart bandages are made from a flexible and stretchy polymer containing embedded electronics and medication. The electronics allow the sensor to monitor for molecules like uric acid or lactate and conditions like pH level or temperature in the wound that may be indicative of inflammation or bacterial infection.

    The bandage can respond in one of three ways: First, it can transmit the gathered data from the wound wirelessly to a nearby computer, tablet, or smartphone for review by the patient or a medical professional. Second, it can deliver an antibiotic or other medication stored within the bandage directly to the wound site to treat the inflammation and infection. Third, it can apply a low-level electrical field to the wound to stimulate tissue growth resulting in faster healing.

    In animal models under laboratory conditions, the smart bandages showed the ability to provide real-time updates about wound conditions and the animals’ metabolic states to researchers, as well as offer speed healing of chronic infected wounds similar to those found in humans.

    Gao says the results are promising and adds that future research in collaboration with the Keck School of Medicine of USC will focus on improving the bandage technology and testing it on human patients, whose therapeutic needs may be different than those of lab animals.

    “We have showed this proof of concept in small animal models, but down the road, we would like to increase the stability of the device but also to test it on larger chronic wounds because the wound parameters and microenvironment may vary from site to site,” he says.

    The paper describing the research, “A stretchable wireless wearable bioelectronic system for multiplexed monitoring and combination treatment of infected chronic wounds,” appears in the March 24 issue of the journal Science Advances. Co-authors are postdoctoral scholar research associates in medical engineering Ehsan Shirzaei Sani and Yu Song; medical engineering graduate students Changhao Xu (MS ’20), Canran Wang, Jihong Min (MS ’19), Jiaobing Tu (MS ’20), Samuel A. Solomon, and Jiahong Li; and Jaminelli L. Banks and David G. Armstrong of the Keck School of Medicine of USC.

    Funding for the research was provided by the National Institutes of Health, the National Science Foundation, the Office of Naval Research, the Heritage Medical Research Institute, the Donna and Benjamin M. Rosen Bioengineering Center at Caltech, the Rothenberg Innovation Initiative at Caltech, and a Sloan Research Fellowship.

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    California Institute of Technology

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  • Genes that form specific bones in the womb heal them later in life

    Genes that form specific bones in the womb heal them later in life

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    Newswise — Genes long known to control the formation of bones before birth also control bone healing later in life, a new study found.  

    Led by researchers at NYU Langone Health, a new study pinpointed key Hox genes, specific to each location in the body, as the controllers of stem cells involved in both forming and repairing bone. HOX proteins act like the body’s “zip code,” specifying the position of limbs in the fetus by encoding instructions for transcription factors, which attach to DNA and influence the action of genes.

    Such adjustments guide immature stem cells as they multiply and mature in the womb, say the study authors, to become heart muscle, nerves, bones, etc., and in the right places. Bone is among the tissues that keep pools of stem cells on hand into adulthood, ready to mature into needed replacement cells that maintain healthy tissue and heal broken bones.

    Published online recently in the journal Development, the new work found that Hox genetic programs in adulthood control a bone stem cell type called periosteal stem and progenitors cells or PSCPs. These cells play a central role in healing bones according to the womb-determined positions in which they first formed. Already known to encode the spatial code that sets the body’s formation plan, HOX genes were shown in the study to give adult stem cells from different locations the properties needed to regenerate the particular bone in which they reside.

    During aging, such stem cells become depleted, the researchers say, resulting in weaker bones that are more likely to fracture and slower to heal. In an effort to counter this loss in healing, the research team demonstrated that increasing the activity of the gene that directs the building of the Hoxa10 transcription factor in the tibia, the larger of the two “shin bones,” in aging mice caused a 32.5% restoration of fracture repair capacity.

    “Our data revealed a previously unknown function for Homeobox or Hox genes as essential location-specific regulators of stem cell maturity in adulthood, with short-term local increases in their expression able to drive healing,” said corresponding study author Philipp Leucht, MD, PhD, the Raj-Sobti-Menon Associate Professor in the Department of Orthopedic Surgery at NYU Langone Health. “The therapeutic promise of adult stem cells as a source of bone-making cells in healing-compromised people is massive.”

    Bone Requires Attention

    A fundamental question in the field has been whether bone healing is driven more by stem cells in the marrow in a bone’s center, or by those known to pool in the nearby periosteum, the outer bone layer made of up tough connective tissue and cell-filled areas. Both stem cell types have the capacity to mature into osteoblasts, the cells that lay down new bone in response to a fracture, but the current study argues that stem cells in the periosteum, the PSPCs, are the important contributors to bone repair.

    The study result builds on the understanding that, to keep stem cells pools on hand, they must get signals to continually divide and multiply without maturing, maintaining their “stemness” until needed. The body regulates bone repair by controlling the degree to which stem cells stay immature, with the most primitive cells playing the largest role in healing due to their flexibility and ability to quickly multiply.

    In the current study, the researchers found that Hox deficiency leads to an increase in the stem cells’ propensity to differentiate into mature bone cell types. Conversely, when the team increased Hoxa10 expression in tibia stem and progenitor cells, it reprogrammed them into a more stem-cell-like state, a needed step if they are to become new bone-making cells as part of healing.

    Specifically, say the authors, PSPCs exist as a mixed stem cell population that includes those with the most stemness, naïve periosteal stem cells (PSCs), alongside more mature periosteal progenitor 1 (PP1s) and periosteal progenitor 2 (PP2s) cells. The current study authors found that Hoxa10 expression was most abundant in PSCs and was significantly reduced as cells progressed along the lineage hierarchy to PP1 and PP2. Experiments that increased the activity of the Hox genes in these more mature progenitors brought about a 3-fold increase of PSCs as cells were reprogrammed into a more primitive stem cell identity.  

    “PSPCs have distinguishing characteristics that form the basis for future cell-based therapies, including their greater tendency to naturally regenerate bone than many related stem cell groups,” said co-corresponding lead author Kevin Leclerc, a post-doctoral scholar in Leucht’s lab. “By modifying Hox activity in these cells, we can help them regenerate bone more effectively in individuals with deficient bone-healing capacity.”     

    Along with Leucht and Leclerc, study authors from the Department of Orthopedic Surgery are Lindsey Remark, Malissa Ramsukh, Anne Marie Josephson, Laura Palma, Paulo EL Parente, Margaux Sambon, Sooyeon Lee, Emma Muiños Lopez, and co-senior author Sophie Morgani. The study was funded by National Institutes of Health grants R01AG056169, K08AR069099, S10OD010751, 5P30CA016087 642, and P41 EB017183, as well as by Perlmutter Cancer Center support grant P30CA016087, the Patricia and Frank Zarb Family, and the CTSI TL1 post-doctoral scholarship of the New York Stem Cell Foundation.

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    NYU Langone Health

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  • Can ChatGPT be Counted On?

    Can ChatGPT be Counted On?

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    Newswise — A study in the Journal of The National Cancer Institute Cancer Spectrum looked at chatbots and artificial intelligence (AI), as they become popular resources for cancer information. They found these resources give accurate information when asked about common cancer myths and misconceptions. In the first study of its kind, Skyler Johnson, MD, physician-scientist at Huntsman Cancer Institute and assistant professor in the department of radiation oncology at the University of Utah (the U), evaluated the reliability and accuracy of ChatGPT’s cancer information.

    Using the National Cancer Institute’s (NCI) common myths and misconceptions about cancer, Johnson and his team found that 97% of the answers were correct. However, this finding comes with some important caveats, including a concern amongst the team that some of the ChatGPT answers could be interpreted incorrectly. “This could lead to some bad decisions by cancer patients. The team suggested caution when advising patients about whether they should use chatbots for information about cancer,” says Johnson.

    The study found reviewers were blinded, meaning they didn’t know whether the answers came from the chatbot or the NCI. Though the answers were accurate, reviewers found ChatGPT’s language was indirect, vague, and in some cases, unclear.

    “I recognize and understand how difficult it can feel for cancer patients and caregivers to access accurate information,” says Johnson. “These sources need to be studied so that we can help cancer patients navigate the murky waters that exist in the online information environment as they try to seek answers about their diagnoses.”

    Incorrect information can harm cancer patients. In a previous study by Johnson and his team published in the Journal of the National Cancer Institute, they found that misinformation was common on social media and had the potential to harm cancer patients.

    The next steps are to evaluate how often patients are using chatbots to seek out information about cancer, what questions they are asking, and whether AI chatbots provide accurate answers to  uncommon or unusual questions about cancer.

    The study was supported by the National Institutes of Health/National Cancer Institute including P30 CA042014 and Huntsman Cancer Foundation.

    About Huntsman Cancer Institute at the University of Utah

    Huntsman Cancer Institute at the U is the official cancer center of Utah and the only National Cancer Institute-designated Comprehensive Cancer Center in the Mountain West. The campus includes a state-of-the-art cancer specialty hospital and two buildings dedicated to cancer research. Huntsman Cancer Institute provides patient care, cancer screening, and education at community clinics and affiliate hospitals throughout the Mountain West. It is consistently recognized among the best cancer hospitals in the country by U.S. News and World Report. The region’s first proton therapy center opened in 2021 and a major hospital expansion is underway. Huntsman Cancer Institute is committed to creating a diverse and inclusive environment for staff, students, patients, and communities. Advancing cancer research discoveries and treatments to meet the needs of patients who live far away from a major medical center is a unique focus. More genes for inherited cancers have been discovered at Huntsman Cancer Institute than at any other cancer center, including genes responsible for breast, ovarian, colon, head and neck cancers, and melanoma. Huntsman Cancer Institute was founded by Jon M. and Karen Huntsman.

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    University of Utah Health

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  • Step Forward in Gene Therapy to Treat Cause of Sudden Cardiac Arrest in Athletes

    Step Forward in Gene Therapy to Treat Cause of Sudden Cardiac Arrest in Athletes

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    BYLINE: Jennifer Michalowski

    Newswise — University of Utah Health scientists have corrected abnormal heart rhythms in mice by restoring healthy levels of a protein that heart cells need to establish connections with one another. That protein, GJA1-20k, is underproduced in people with a genetic condition called arrhythmogenic cardiomyopathy, one of the leading causes of sudden cardiac arrest in athletes under the age of 35.

    The finding, reported in the journal Circulation Research, suggests a new strategy for treating the abnormal heart rhythms caused by arrhythmogenic cardiomyopathy.

    The results may also have implications for treating dangerous arrhythmias associated with more common conditions, such as those that can develop soon after a heart attack.

    “This is really a new paradigm for the treatment of heart rhythm disorders,” says Joseph Palatinus, M.D., Ph.D., an investigator at the Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI) and critical care cardiologist at Intermountain Healthcare. Palatinus is the first author of the study, which was led by U of U Health colleague Robin Shaw, M.D., Ph.D., director of the CVRTI.

    An unusual pattern in patients

    People with arrhythmogenic cardiomyopathy are born with normal hearts but begin to develop an irregular heartbeat in their 20s or 30s. These arrhythmias can raise the heart rate to dangerous levels and explain why some individuals with the condition experience sudden cardiac arrest during exercise.

    Patients diagnosed with arrhythmogenic cardiomyopathy are advised to restrict exercise. They may also benefit from an implantable defibrillator to control their heartbeat. As the disease progresses, the heart muscle becomes fatty and fibrotic. This prevents the heart from pumping blood efficiently, and eventually patients need a heart transplant.

    Palatinus, Shaw, and their colleagues studied heart tissue from patients with arrhythmogenic cardiomyopathy who underwent transplant and discovered a problem with a protein called Connexin 43. In healthy hearts, Connexin 43 forms channels between adjacent cells, facilitating communication. The diseased hearts made normal amounts of Connexin 43, but it wasn’t at the edges of cells where it belonged.

    This, the team determined, was likely because there wasn’t enough of a trafficking protein, called GJA1-20ka. The researchers knew from previous experiments that without it, the heart’s cells wouldn’t be able to get Connexin 43 to the right place.

    Fixing an abnormal heartbeat at the source

    To determine if they could restore the heart’s normal rhythm, the scientists turned to mice that have similarities to people with arrhythmogenic cardiomyopathy. They both have low levels of GJA1-20k and develop arrhythmias. Palatinus and colleagues used low doses of gene therapy to bring the trafficking protein GJA1-20k back to normal levels. This, they confirmed, enabled heart muscle cells to transport Connexin 43 to its proper locations.

    Most importantly, it gave the animals a more normal heartbeat. “The ease and low dose needed to fix the arrhythmias of even an inherited heart disease suggests that we have identified a critical pathway to stabilize cardiac electrical activity,” said Shaw.

    Although arrhythmia improved, the animals still had heart scarring, a symptom from a different underlying condition. Palatinus noted that was actually an encouraging result. It suggests arrhythmia and heart scarring can occur independently and that it could be possible to treat abnormal heart rhythms even when the heart is severely scarred. “This is a new paradigm,” he says.

    The treatment success in mice suggests that raising levels of GJA1-20k might restore normal heart rhythms in patients with arrhythmogenic cardiomyopathy, too. For patients, Palatinus says, it might be possible to deliver the therapeutic protein directly to the heart. Further research will be needed to develop the treatment for clinical use.

    Disruptions in protein trafficking are thought to contribute to arrhythmias beyond those caused by arrhythmogenic cardiomyopathy, and Palatinus is optimistic that a similar treatment strategy might be useful for those conditions, too. If so, that could one day give patients and their doctors an alternative to the ion channel-blocking drugs currently used to treat many arrhythmias, which can slow the heart and even lead to new rhythm problems for some patients.

    # # #

    The research was supported by the National Institutes of Health, The Harold Geneen Charitable Trust, and the Nora Eccles Treadwell Foundation and published as “GJA1-20k Rescues Cx43 Localization and Arrhythmias in Arrhythmogenic Cardiomyopathy.”

    About University of Utah Health

    University of Utah Health  provides leading-edge and compassionate care for a referral area that encompasses Idaho, Wyoming, Montana, and much of Nevada. A hub for health sciences research and education in the region, U of U Health has a $458 million research enterprise and trains scientists and the majority of Utah’s physicians and health care providers at its Colleges of Health, Nursing, and Pharmacy and Schools of Dentistry and Medicine. With more than 20,000 employees, the system includes 12 community clinics and five hospitals. U of U Health is recognized nationally as a transformative health care system and provider of world-class care.

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  • Family’s participation key to advancing diabetes research

    Family’s participation key to advancing diabetes research

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    Newswise — Individuals with Type 1 diabetes have a smaller pancreas than people without diabetes. This is surprising because insulin-producing beta cells account for just a small fraction of the pancreas, so the loss of beta cells in Type 1 diabetes would not be expected to reduce pancreas size.

    Now, a study of one family from Alabama has led Vanderbilt University Medical Center researchers to discover that insulin deficiency, independent of the autoimmunity associated with Type 1 diabetes, is the principal factor leading to a markedly smaller pancreas.

    Four members of this family of eight have monogenic diabetes from a rare mutation in the insulin gene, leading to insulin deficiency without autoimmunity. Magnetic resonance imaging (MRI) of the pancreas showed a reduced size and altered shape in the individuals with diabetes. This was similar to what had previously been observed in individuals with Type 1 diabetes. These new findings are published in Diabetes Care, a journal of the American Diabetes Association.

    “This is a wonderful story about the power of a single family to inform us about the process of a disease that affects millions of people,” said Daniel Moore, MD, PhD, associate professor of Pediatrics in the Ian Burr Division of Pediatric Endocrinology and Diabetes. “There are not many families, especially not large families, who are known to have exactly this form of diabetes, who could come forward to help us answer this question. But they responded to the call, and they’ve provided a really clear answer to a fundamental biologic question.”

    About two decades ago, David Pursell and his wife, Ellen, agreed that he and three of their six children who were diagnosed with diabetes would participate in research with the hope more could be learned about the disease. It was as simple as giving a little blood.

    They were surprised years later when a researcher from the University of Chicago’s Kovler Diabetes Center called to tell them that advances in science had revealed that the four actually had monogenic diabetes due to a mutation in the insulin gene instead of Type 1 diabetes.

    Last year, the Pursells were contacted by VUMC researchers who were collaborating with Siri Greeley, MD, PhD, and colleagues at the Kovler Diabetes Center’s Monogenic Diabetes Registry. The Vanderbilt research team asked if the family could travel to Nashville to have precise measurements of their pancreas taken at the Medical Center.

    The VUMC research team, which includes Moore, Jordan Wright, MD, PhD, Jon Williams, PhD, Melissa Hilmes, MD, and Alvin C. Powers, MD, along with colleague Jack Virostko, PhD, at The University of Texas at Austin, had previously found the reduction in pancreas size was present at the time of Type 1 diabetes diagnosis. The Vanderbilt investigators had also organized an international team, the Multicenter Assessment of the Pancreas in Type 1 Diabetes (MAP-T1D), to develop a standardized MRI imaging protocol to assess pancreas volume and microarchitecture.

    “We know the pancreas is much smaller in individuals with Type 1 diabetes, but there haven’t been good models to understand exactly what’s going on,” said Wright, an instructor in the Division of Diabetes, Endocrinology and Metabolism and first author on the manuscript. “This is the first time we can actually demonstrate in humans that insulin is a major factor in determining pancreas size and the loss of it leads to a much smaller pancreas.”

    David and Ellen and their now adult children, Peggy Rice, Vaughan Spanjer, Chrissy Adolf, Ramsey Nuss, and twin sons Parker and Martin Pursell, each had their pancreas size measured using the standardized Vanderbilt MRI protocol. David, Chrissy, Parker and Martin have monogenic diabetes.

    “When we talked to the doctors at Kovler, they asked if we’d be interested in participating in some trials or research and we said, ‘Of course, anything we can do,’” said David Pursell. “When we learned our diabetes was not caused by an immune response due to our islet cells being attacked by antibodies, then we thought maybe we’ve got the chance of getting an islet cell transplant.

    “But also, we’re obviously all in this together. If, by virtue of our family volunteering for this research we can help anyone else, we felt like it would be worth it.”

    This research was performed with assistance from the Vanderbilt University Institute of Imaging Sciences (National Institutes of Health [NIH] project 1S10OD021771-01), the Vanderbilt Institute for Clinical and Translational Research (UL1-TR000445) and the Institute for Translational Medicine (UL1-TR000430) and with the support of the Leona M. and Harry B. Helmsley Charitable Trust, the Juvenile Diabetes Research Foundation, the Doris Duke Charitable Foundation, the NIH (DK104942, DK129979) and the Vanderbilt and Chicago Diabetes Research and Training Centers (DK20593, DK20595).

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  • New Class of Drugs May Prevent Infection by Wide Range of COVID-19 Variants

    New Class of Drugs May Prevent Infection by Wide Range of COVID-19 Variants

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    RESEARCH SUMMARY

    Publication: Nature Genetics https://www.nature.com/articles/s41588-023-01307-z

    Dana-Farber Cancer Institute author: Cigall Kadoch, PhD,

     

    Summary:

    A new class of oral drugs can inhibit a wide range of SARS-CoV-2 variants, researchers report, potentially identifying new antiviral agents providing broad activity against the constantly emerging new strains of the COVID-19 virus. The researchers discovered that the mammalian SWI/SNF (also called BAF) chromatin remodeling complex, a regulator of gene expression –controls the expression of the ACE2, the cellular receptor or “entry point” used by COVID-19 viruses.  When mSWI/SNF complexes were disrupted, the cell could no longer make ACE-2 receptor protein and became resistant to infection by any virus that uses that receptor. Kadoch’s work on mSWI/SNF complexes over the years has led to experimental drugs currently in phase 1 trials as anti-cancer agents. These oral drugs now are looking promising for use in COVID-19, since they can inhibit ACE2 activity and nearly completely block viral infection in multiple cell lines and human lung organoids.

    Impact:

    The formerly potent array of monoclonal antibody treatments for COVID-19 continue to lose their activity as new less-sensitve variants of the virus appear: indeed, one by one, they have gone off the market. The need for more broadly acting agents against new and drug-resistant viruses is great. With the identification of this new target – a druggable chromatin regulatory complex – inhibition of which prevents infection of host cells, Kadoch and co-author Craig Wilen, MD, PhD, of the Yale Cancer Center have found a promising novel approach to combating the constantly-changing SARS virus.

    Funding:

    This work was supported by NIH grants K08AI128043, Burroughs Wellcome Fund, Smith Family Foundation, Ludwig Family Foundation, Huffington Foundation, Mathers Foundation, Emergent Ventures Fast Grant, and NIH Director’s New Innovator Award 1DP2CA195762-01.

     

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  • Hospitals Face Challenges When Implementing Enhanced Recovery Programs for Surgery

    Hospitals Face Challenges When Implementing Enhanced Recovery Programs for Surgery

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    Key takeaways

    • Striving to improve patient care: Enhanced recovery programs (ERPs) provide hospitals with patient-centered protocols and standards to improve the safety and quality of care for patients undergoing surgery.
    • Understanding barriers to compliance: Although previous studies have shown substantial improvements when hospitals implement ERPs, some hospitals have reported difficulties successfully implementing these programs.
    • ERPs are not always easily implemented: This study found that out of 151 hospitals that implemented an ERP for colorectal surgery, most of them (85%) had difficulty improving compliance with a national protocol.

    Newswise — CHICAGO: Enhanced recovery programs (ERPs) provide hospitals with the highest-quality resources to improve patient care for surgery, but many hospitals still struggle to successfully implement these programs and may need more structured resources to boost compliance rates, according to findings published in the Journal of the American College of Surgeons (JACS). 

    “Enhanced recovery programs have been instrumental in promoting evidence-based, standardized perioperative care that focuses on engaging patients from the moment it’s decided they will have surgery, all the way to their transition back into the community,” said Elizabeth Wick, MD, FACS, a professor of surgery at the University of California, San Francisco (UCSF) and a study co-author. “While some previous studies have reported substantial improvements when hospitals implement these programs, the goal of this study was to take a deep dive into process compliance and understand how successful these hospitals were at implementing enhanced recovery programs.”

    The research stems from the Improving Surgical Care and Recovery Collaborative (ISCR), a partnership between the American College of Surgeons (ACS), the Agency for Healthcare Research and Quality, and the Johns Hopkins Medicine Armstrong Institute for Patient Safety and Quality. That collaboration began in 2016 with the goal of helping hospitals implement ERPs, also known as enhanced recovery after surgery, around the country by providing them with centralized support and tools for standardizing patient care — from guidelines on infection control to optimal nutrition. The program ran until 2022 and assisted about 300 hospitals in initiating and spreading ERPs across multiple surgical specialties, according to Dr. Wick.

    “Another principle we try to emphasize through the program is the importance of multidisciplinary or collaborative surgical care with surgeons, anesthesiologists, hospitals, and nurses,” Dr. Wick explained. “All members of the team need to come together to provide the best surgical care for patients and their families.”

    For this study, researchers analyzed data from 151 hospitals enrolled in an ISCR protocol for colorectal surgery to determine if they got better or worse at complying with ERP process measures — and by how much — over an 18-month period. Participating hospitals, which were located throughout the country but were mostly teaching hospitals in urban areas, entered data on process measure compliance and 30-day patient outcomes into a customized registry through the ACS National Surgical Quality Improvement Program® (ACS NSQIP®).

    The researchers looked at six common components of an ERP protocol for colorectal surgery:

    • Oral antibiotics: Did the patient receive oral antibiotics within 24 hours of the operation?
    • Mechanical bowel preparation: Did the patient complete a mechanical bowel preparation (oral medication used to cleanse the large bowel of fecal matter) before the operation?
    • Multimodal pain control: Did the patient use scheduled, nonopioid pain medication in addition to, or in place of, opioid pain medication within 24 hours of the operation?
    • Early mobilization: Was the patient mobile (able to walk and stand) within 24 hours of the operation?
    • Early liquid intake: Did the patient receive liquid within 24 hours of the operation?
    • Early solid intake: Did the patient receive solid food within 48 hours of the operation?

    Looking at changes in process measure compliance from the start of the program to the end, the team divided compliance rate changes into three categories: worsening (<0%), minimal improvement (0-20% change in compliance), and substantial improvement (greater than 20% change in compliance).

    Researchers looked at each of the six process measures separately as an individual opportunity for improvement and looked at a composite measure of all six process measures by the hospital.

    Key findings

    • Out of 151 hospitals studied, only 15% of the hospitals achieved substantial improvements in compliance across the entire protocol.
    • The researchers identified 663 individual opportunities available for improvement; of these opportunities, substantial improvement in compliance only occurred 20% of the time.
    • Process measures that involved simple interventions, such as pain control or oral antibiotics, improved the most by 23% and 16%, respectively. In contrast, early mobilization improved the least, by 2%.
    • On average, the individual components of the ERP were implemented for patients less than 70% of the time across all the hospitals.

    The research focused on a national ERP for colorectal surgery, but the authors note that the results may be generalizable across many surgical specialties.

    “I think these findings suggest that there’s a significant opportunity available to improve compliance with enhanced recovery programs, and in turn, improve patient outcomes, because prior studies have shown that high compliance leads to better outcomes,” said Tejen Shah, MD, a general surgery resident at Ohio State University Wexner Medical Center and lead author of the study.

    Addressing barriers

    Though the study only included data from hospitals that participated in the ISCR collaborative, which could cause selection bias, the trends reflected in the study paint a larger picture of barriers to implementing ERPs, the researchers said. When implementing ERPs, inadequate resources or limited leadership support may hinder progress, for example, or there may be ineffective collaboration and communication among team members.

    In their journal article, the researchers identified the ACS Quality Verification Program™ (ACS QVP) as one program that may offer hospitals a more structured approach to achieving quality improvement measures. The ACS QVP provides hospitals with customized, actionable recommendations on improving surgical quality, such as leadership and safety culture, based on the framework of 12 evidence-based standards vetted by the ACS. The program may help hospitals and providers break down each component of the ERP into manageable items, the researchers noted.

    “The overall structure of the ACS QVP may also be advantageous to hospitals. It really helps surgeons engage with hospital leadership at a very high level,” Dr. Wick said.

    “Lower compliance rates didn’t occur because of a lack of effort. People were passionate about trying to implement the enhanced recovery program. But it was challenging,” she added. “I think this study highlights the fact that we need to collectively figure out how to address those barriers and make this work easier. We have the opportunity to improve prioritization and access to resources, whether it’s project management or expertise in data skills, and then ultimately hold people accountable for doing the work.”

    “This research confirms what we as surgeons know — the work of improvement is challenging. It takes tremendous focus and determination,” Dr. Wick said. “The good news is that the ACS has exceptional expertise in how to improve surgical quality. With more than 17 surgical quality programs, the ACS is a valuable resource for every hospital’s quality journey.”

    Study coauthors are Leandra Knapp, MS; Mark E. Cohen, PhD; Stacy A. Brethauer, MD, MBA, FACS; and Clifford Y. Ko MD, MS, MSHS, FACS. All authors are affiliated with the Division of Research and Optimal Patient Care, the American College of Surgeons, Ohio State University Wexner Medical Center, the University of California, San Francisco (UCSF), or the University of California, Los Angeles (UCLA).

    The study authors have no relevant disclosures to report. This research was supported by funding from the Agency for Healthcare Research and Quality (AHRQ). Ms. Knapp is supported by funding from the U.S. Department of Health and Human Services and is employed by the American College of Surgeons, subcontracted under Johns Hopkins Medicine Armstrong Institute for Patient Safety and Quality for Improving Surgical Care and Recovery contract with the AHRQ. Dr. Wick is supported by funding from the National Institutes of Health.

    This research was also presented at the Southern Surgical Association 134th Annual Meeting in Palm Beach, Florida, December 2022. This study is published as an article in press on the JACS website.

    Citation: Shah T, Knapp L, Cohen M, et al. Truth of Colorectal Enhanced Recovery Programs: Process Measure Compliance in 151 Hospitals. Journal of American College of Surgeons. DOI: 10.1097/XCS.0000000000000562.

    # # #

    About the American College of Surgeons 

    The American College of Surgeons is a scientific and educational organization of surgeons that was founded in 1913 to raise the standards of surgical practice and improve the quality of care for all surgical patients. The College is dedicated to the ethical and competent practice of surgery. Its achievements have significantly influenced the course of scientific surgery in America and have established it as an important advocate for all surgical patients. The College has more than 84,000 members and is the largest organization of surgeons in the world. “FACS” designates a surgeon is a Fellow of the American College of Surgeons.  

    The Journal of the American College of Surgeons (JACS) is the official scientific journal of ACS. Each month, JACS publishes peer-reviewed original contributions on all aspects of surgery, with the goal of providing its readership the highest quality rapid retrieval of information relevant to surgeons.

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  • AI used to predict future flares of ulcerative colitis activity

    AI used to predict future flares of ulcerative colitis activity

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    Newswise — Ulcerative colitis assessment could be improved after new research shows that an artificial intelligence model could predict flare-ups and complications after reading biopsies.

    In a new paper published in Gastroenterology today (Friday 3 March), researchers supported by the National Institute for Health and Care Research Birmingham Biomedical Research Centre have trialled an AI diagnostic tool that can read digitised biopsies taken during colonoscopy.

    The Computer-Aided Diagnostic model was able to predict the risk of flare-ups for ulcerative colitis, which is a relapsing-remitting condition and makes the prognosis for the disease uncertain. In the trial, the model was able to predict patients at risk of a flare in the disease as well as humans.

    The system was trained on existing digitised biopsies and was able to detect activity related to ulcerative colitis with 89% accuracy for positive results. It was also able to identify markers of inflammation activity and healing in the same area as biopsies were taken with 80% accuracy, similar to human pathologists.

    Professor Marietta Iacucci from the Institute of Immunology and Immunotherapy at the University of Birmingham and University College Cork in Ireland, and co-lead author of the paper said:

    “The power of AI in healthcare is evident in trials like these, where a model can be used to standardize in real-time histological assessment of Ulcerative Colitis disease activity. But most importantly it provides analytical support and enables clinicians to support those at the greatest risk of relapsing symptoms and disease course.

    “Ulcerative Colitis is a complex condition to predict, and developing machine learning-derived systems to make this diagnostic job quicker and more accurate could be a game changer. As models like this further develop, the predictive quality is likely to improve even more, and our paper demonstrates how beneficial such technology could be for clinicians and, crucially patients.”

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  • Adding antipsychotic med to antidepressant may help older adults with treatment-resistant depression

    Adding antipsychotic med to antidepressant may help older adults with treatment-resistant depression

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    BYLINE: Jim Dryden

    Newswise — For older adults with clinical depression that has not responded to standard treatments, adding the drug aripiprazole (brand name Abilify) to an antidepressant they’re already taking is more effective than switching from one antidepressant to another, according to a new multicenter study led by Washington University School of Medicine in St. Louis.

    Aripiprazole originally was approved by the FDA in 2002 as a treatment for schizophrenia but also has been used in lower doses as an add-on treatment for clinical depression in younger patients who do not respond to antidepressants alone.

    The new findings are published March 3 in The New England Journal of Medicine and are to be presented that same day by Eric J. Lenze, MD — principal investigator and head of the Department of Psychiatry at Washington University — and colleagues at the annual meeting of the American Association for Geriatric Psychiatry in New Orleans.

    Many people with clinical depression don’t respond to medications used to treat the condition. Consequently, some doctors switch such patients to different antidepressants in the pursuit of finding one that works, while other physicians may prescribe another class of drugs to see if a combination of medications helps.

    Both strategies have been recommended by experts as options for older adults with treatment-resistant depression. However, the new study was designed to help determine which strategy is most effective. Augmenting an antidepressant with aripiprazole helped 30% of patients with treatment-resistant depression, compared to only 20% who were switched to another solo antidepressant, results of the study show.

    “Often, unless a patient responds to the first treatment prescribed for depression, physicians follow a pattern in which they try one treatment after another until they land on an effective medication,” said Lenze, the Wallace and Lucille Renard Professor and the study’s corresponding author. “It would be beneficial to have an evidence-based strategy we can rely on to help patients feel better as quickly as possible. We found that adding aripiprazole led to higher rates of depression remission and greater improvements in psychological well-being — which means how positive and satisfied patients felt — and this is good news. However, even that approach helped only about 30% of people in the study with treatment-resistant depression, underscoring the need to find and develop more effective treatments that can help more people.”

    Treatment-resistant depression is no more or less common in older people than younger people, but because it seems to accelerate cognitive decline, identifying more effective ways to treat it is very important.

    Lenze, along with colleagues at Columbia University, UCLA, the University of Pittsburgh and the University of Toronto, studied 742 people, ages 60 and older, with treatment-resistant depression, meaning their depression had not responded to at least two different antidepressant medications.

    The researchers evaluated strategies commonly used in clinical practice to help alleviate treatment-resistant depression in older patients and designed the study to have two distinct phases. In the first phase, 619 patients, each of whom was taking an antidepressant such as Prozac, Lexapro or Zoloft, were randomly divided into three groups. In the first group, patients remained on whatever antidepressant drug each already was taking but also received the drug aripiprazole (Abilify). A second group also continued taking antidepressants but added bupropion (brand names Wellbutrin or Zyban), and a third group tapered off of the antidepressant each had been taking and switched to bupropion entirely.

    Over the course of 10 weeks, the participants received biweekly phone calls or in-person visits with study clinicians. At these visits, the medications were adjusted according to the individual patient’s response and side effects. The researchers found that the group that experienced the best overall outcomes was the one in which patients continued with their original antidepressants but added aripiprazole.

    The researchers also anticipated that some people in the study wouldn’t respond to the various treatments, so they added a second phase that included 248 participants. In this phase, patients taking antidepressants such as Prozac, Lexapro and Zoloft were treated with lithium or nortriptyline — medications that were widely used before those other, newer antidepressants were approved more than two decades ago. Rates of alleviating depression in the study’s second phase were low, about 15%. And there was no clear winner when augmentation with lithium was compared with switching to nortriptyline.

    “Those older drugs also are a bit more complicated to use than newer treatments,” Lenze explained. “Lithium, for example, requires blood testing to ensure its safety, and it’s recommended that patients taking nortriptyline receive electrocardiograms periodically to monitor the heart’s electrical activity. Since neither lithium nor nortriptyline were promising against treatment-resistant depression in older adults, those medications are unlikely to be helpful in most cases.”

    But even the best treatment strategy — adding aripiprazole to an antidepressant — was not markedly successful for many older patients with treatment-resistant depression.

    “This really highlights a continuing problem in our field,” said senior author Jordan F. Karp, MD, professor and chair of the Department of Psychiatry at the University of Arizona College of Medicine – Tuscon. “Any given treatment is likely to help only a subset of people, and ideally, we would like to know, in advance, who is most likely to be helped, but we still don’t know how to determine that.”

    Lenze emphasized that overall, antidepressants are highly helpful for the majority of people suffering from clinical depression. At least half of all people with depression feel much better after they begin taking the first medication they try. And almost half of the remainder not helped by a first drug improve when switched to a second drug, But that leaves a sizeable group with clinical depression that does not respond to two treatments.

    The problem is particularly difficult in older adults, many of whom already are taking several medications for other conditions such as high blood pressure, cardiac issues or diabetes,” Lenze said. “So switching to new antidepressants every few weeks or adding other psychiatric drugs can be complicated. In addition, because depression and anxiety in older adults may accelerate cognitive decline, there’s an urgency to find more effective treatment strategies.

    “There definitely is something that makes depression harder to treat in this population, a population that’s only going to keep getting larger as our society gets older,” he added.

    Lenze EJ, et al. Trial of antidepressant augmentation vs. switching in treatment-resistant geriatric depression. The New England Journal of Medicine, March 3, 2023.

    The study was funded by a grant from the Patient-Centered Outcomes Research Institute (PCORI), grant TRD-1511-33321. No in-kind support was received from pharmaceutical companies. Other funding was provided by the Taylor Family Institute for Innovative Psychiatric Research at Washington University School of Medicine. Other support came from the National Center for Advancing Translational Sciences and the National Institute of Mental Health of the National Institutes of Health (NIH). Grant numbers: 5RO1 MH114980, K24 AT009198, R01 MH114981. Additional funding provided by the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto.

    About Washington University School of Medicine

    WashU Medicine is a global leader in academic medicine, including biomedical research, patient care and educational programs with 2,800 faculty. Its National Institutes of Health (NIH) research funding portfolio is the third largest among U.S. medical schools, has grown 52% in the last six years, and, together with institutional investment, WashU Medicine commits well over $1 billion annually to basic and clinical research innovation and training. Its faculty practice is consistently within the top five in the country, with more than 1,800 faculty physicians practicing at 65 locations and who are also the medical staffs of Barnes-Jewish and St. Louis Children’s hospitals of BJC HealthCare. WashU Medicine has a storied history in MD/PhD training, recently dedicated $100 million to scholarships and curriculum renewal for its medical students, and is home to top-notch training programs in every medical subspecialty as well as physical therapy, occupational therapy, and audiology and communications sciences.

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