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  • Artificially intelligent software provides a detailed look at jets of plasma used to treat cancer

    Artificially intelligent software provides a detailed look at jets of plasma used to treat cancer

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    Artificially intelligent software has been developed to enhance medical treatments that use jets of electrified gas known as plasma. The computer code predicts the chemicals emitted by plasma devices, which can be used to treat cancer, promote healthy tissue growth and sterilize surfaces.

    The software learned to predict the cocktail of chemicals coming out of the jet based on data gathered during real-world experiments and using the laws of physics for guidance. This type of artificial intelligence (AI) is known as machine learning because the system learns based on the information provided. The researchers involved in the project published a paper about their code in the Journal of Physics D: Applied Physics.

    The plasma studied in the experiments is known as cold atmospheric plasma (CAP). When the CAP jet is turned on, numerous chemical species in the plasma take part in thousands of reactions. These chemicals modify the cells undergoing treatment in different ways, depending on the chemical composition of the jet. While scientists know that CAPs can be used to kill cancer cells, treat wounds and kill bacteria on food, it’s not fully understood why. 

    “This research is a step toward gaining a deeper understanding of how and why CAP jets work and could also one day be used to refine their use,” said Yevgeny Raitses, a managing principal research physicist at the U.S. Department of Energy’s Princeton Plasma Physics Laboratory (PPPL). 

    The project was completed by the Princeton Collaborative Low Temperature Plasma Research Facility (PCRF), a collaboration between researchers at PPPL and the George Washington University (GWU).

    PPPL has a growing body of work that combines its 70 years of pioneering plasma research with its expertise in AI to solve societal problems. The Lab’s mission extends beyond using plasma to generate fusion power to its use in fields such as medicine and manufacturing, among others. 

    The software uses an approach known as a physics-informed neural network (PINN). In a PINN, data is organized into parts called nodes and neurons. The flow of the data mimics the way information is processed in the human brain. Laws of physics are also added to the code.

    “Knowing what comes out of the jet is very important. Knowing what comes out accurately is very difficult,” said Sophia Gershman, a lead PPPL research engineer from the PCRF who worked on this collaborative project. The process would require several different devices to collect different kinds of information about the jet. “In practical studies, it is difficult to go and utilize all of the various technologically advanced diagnostics all at once for each device and for various types of surfaces that we treat,” Gershman explained.

    Calculating the chemical composition one nanosecond at a time

    Li Lin, a research scientist from GWU and the paper’s primary author, said it’s also difficult to calculate the chemicals in a CAP jet because the interactions need to be considered a nanosecond at a time. “When you consider that the device is in operation for several minutes, the number of calculations makes the problem more than simply computationally intensive. It’s practically impossible,” Lin said. “Machine learning allows you to bypass the complicated part.”

    The project began with a small set of real-world data that was gathered using a technique known as Fourier-transform infrared absorption spectroscopy. The researchers used that small dataset to create a broader set of data. That data was then used to train the neural network using an evolutionary algorithm, which is a type of computer code inspired by nature that searches for the best answers using a survival-of-the-fittest approach. Several successive batches of data are generated using slightly different approaches, and only the best datasets from each round are carried through to the next round of training until the desired results are achieved.

    Ultimately, the team was able to accurately calculate the chemical concentrations, gas temperature, electron temperature and electron concentration of the cold atmospheric plasma jet based on data gathered during real-world experiments. In a cold atmospheric plasma, the electrons — small, negatively charged particles — can be very hot, though the other particles are close to room temperature. The electrons can be at a low enough concentration that the plasma doesn’t feel hot or burn the skin while still being able to have a significant effect on the targeted cells. 

    On the path to personalized plasma treatment

    Michael Keidar, the A. James Clark Professor of Engineering at GWU and a frequent collaborator with PPPL who also worked on this project, said the long-term goal is to be able to perform these calculations fast enough that the software can automatically adjust the plasma during a procedure to optimize treatment. Keidar is currently working on a prototype of such a “plasma adaptive” device in his lab. “Ideally, it can be personalized. The way we envision it, you treat the patient, and the response of every patient will be different,” Keidar explained. “So, you can measure the response in real-time and then try to inform, using feedback and machine learning, the right settings in the plasma-producing device.” 

    More research needs to be done to perfect such a device. For example, this study looked at the CAP jet over time but at only one point in space. Further research would need to broaden the work so it considers multiple points along the jet’s output stream. The study also looked at the plasma plume in isolation. Future experiments would need to integrate the surfaces treated by the plasma to see how that impacts the chemical composition at the treatment site. 

    This research was funded by the U.S. Department of Energy, Grant DE-SC0022349 and by the Princeton Collaborative Research Facility, which is supported by the Department of Energy under Contract No. DE-AC02-09CH11466.

    PPPL is mastering the art of using plasma — the fourth state of matter — to solve some of the world’s toughest science and technology challenges. Nestled on Princeton University’s Forrestal Campus in Plainsboro, New Jersey, our research ignites innovation in a range of applications including fusion energy, nanoscale fabrication, quantum materials and devices, and sustainability science. The University manages the Laboratory for the U.S. Department of Energy’s Office of Science, which is the nation’s single largest supporter of basic research in the physical sciences. Feel the heat at https://energy.gov/science and http://www.pppl.gov.



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    Princeton Plasma Physics Laboratory

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  • Subcutaneous Nivolumab as Effective as IV for Renal Cell Carcinoma — With Much Faster Treatment Time

    Subcutaneous Nivolumab as Effective as IV for Renal Cell Carcinoma — With Much Faster Treatment Time

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    • Subcutaneous formula slashes treatment time to under 5 minutes
    • Broad impact seen for greater access to and experience with treatment
    • Study has implications for treatment of many cancer types

    Newswise — SAN FRANCISCO — Subcutaneous injection of the immunotherapy nivolumab (brand name Opdivo) is noninferior to intravenous delivery and dramatically reduces treatment time in patients with renal cell carcinoma, as seen in the results of a large phase 3 clinical trial reported today at the 2024 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium in San Francisco, California. Saby George, MD, FACP, Professor of Oncology and Medicine and Director of Network Clinical Trials at Roswell Park Comprehensive Cancer Center, will deliver an oral abstract summarizing the findings of “A Study of Subcutaneous Nivolumab Versus Intravenous Nivolumab in Participants with Previously Treated Clear Cell Renal Carcinoma That Is Advanced or Has Spread (CheckMate-67T)” (NCT04810078).

     “The burden of treatment felt by cancer patients is tremendous. If nivolumab can be given as a subcutaneous injection instead of an intravenous infusion, their treatment experience will be significantly improved,” says Dr. George, who is the presenting author, a member of the clinical trial steering committee and site principal investigator at Roswell Park. “Instead of one hour in an infusion chair, they will get the injection done in five minutes.”

    He points to the high demand for infusion chair appointments at most cancer centers, which can result in treatment delays of a week or more.

    “If nivolumab becomes available subcutaneously, we can administer it in the clinic instead of sending patients to infusion centers,” he says. That outcome could simultaneously speed treatment time for patients receiving nivolumab and shorten wait times for patients who still need to receive treatment in an infusion center.

    The availability of injectable nivolumab could also reduce health disparities. “One of the major problems is access to treatment,” says Dr. George, noting that some patients live a long distance from an infusion center and do not have a way to get there. “Patients who don’t live near an infusion center could get treatment closer to home, at a clinic, and that could improve access and help reduce disparities.”

    Sponsored by Bristol Myers Squibb, the drug’s manufacturer, the clinical trial began in May 2021, randomizing 495 patients at 73 centers in 17 countries. Roswell Park was one of only three participating sites in the U.S. and the only one in New York State.

    Patients in the study had advanced or metastatic renal cell carcinoma, had received no more than two prior treatments with systemic therapies and no prior immunotherapy. They were randomized 1:1 to receive nivolumab either subcutaneously or intravenously. Nivolumab is FDA-approved and the standard-of-care treatment for those patients.

    The study’s primary objective was to evaluate the pharmacokinetics of subcutaneous vs. intravenous delivery — how the body interacted with the nivolumab, including whether blood levels of the drug were comparable in the two groups over time. Those measures included the daily average concentration of the drug in the blood over 28 days (Cavgd28) and the concentration of the drug at the end of the dosing cycle (Cminss). Both measures were noninferior to intravenous nivolumab, as evidenced in pharmacokinetic measures and overall response rate.

    The objective response rate for the subcutaneous group — the percentage of patients who achieved a complete or partial response, measured by blinded independent central review — proved noninferior to the intravenous group, at 24.2% vs. 18.2%, respectively. Median progression-free survival stood at 7.23 months for the subcutaneous group vs. 5.65 months for the IV group. The safety profile was similar for both groups.

    More than 80,000 new cases of renal cell carcinoma are diagnosed in the U.S. each year.

    Because nivolumab is already FDA-approved for more than 20 indications across multiple malignancies, CheckMate-67T will likely serve as a gateway to additional studies evaluating the effectiveness of the subcutaneous formula in other patient populations.

    “This is a groundbreaking achievement for patients and physicians, and will definitely make treatment easier for patients,” says Dr. George.

    ASCO GU Presentation Details

    Abstract LBA360: “Subcutaneous nivolumab (NIVO SC) vs. intravenous nivolumab (NIVO IV) in patients with previously treated advanced or metastatic clear cell renal cell carcinoma (ccRCC): Pharmacokinetics (PK), efficacy, and safety results from CheckMate 67T.”

    Time/date: Saturday, Jan. 27, 2024, 8:47 a.m. PST, Moscone West, Level 3, Ballroom

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    From the world’s first chemotherapy research to the PSA prostate cancer biomarker, Roswell Park Comprehensive Cancer Center generates innovations that shape how cancer is detected, treated and prevented worldwide. Driven to eliminate cancer’s grip on humanity, the Roswell Park team of 4,000 makes compassionate, patient-centered cancer care and services accessible across New York State and beyond. Founded in 1898, Roswell Park was among the first three cancer centers nationwide to become a National Cancer Institute-designated comprehensive cancer center and is the only one to hold this designation in Upstate New York. To learn more about Roswell Park Comprehensive Cancer Center and the Roswell Park Care Network, visit www.roswellpark.org, call 1-800-ROSWELL (1-800-767-9355) or email [email protected].



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    Roswell Park Comprehensive Cancer Center

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  • Researchers aim to streamline brain surgery with a new soft robotic system

    Researchers aim to streamline brain surgery with a new soft robotic system

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    Newswise — Navigating the labyrinthine vasculature of the brain with standard surgical instruments can be incredibly challenging, even for the steadiest of hands. But with some robotic assistance, brain surgeons could potentially operate with far greater ease.

    Researchers at Johns Hopkins University and the University of Maryland have laid the groundwork for a soft robotic tool and control system that could grant surgeons an unprecedented degree of maneuverability within the brain. A recent study published in the International Journal of Computer Assisted Radiology and Surgery demonstrates that the new system is both intuitive and highly accurate. The early results suggest that, with further development, the robot could one day speed up and improve the efficacy of minimally invasive surgeries for life-threatening brain aneurysms and other serious conditions.

    One of the common approaches for treating a brain aneurysm — a weakened blood vessel that bulges and fills with blood — involves threading a plastic tube called a catheter through an artery, typically in the groin, with the goal of reaching and sealing off the aneurysm without causing any perforations along the way.

    To address the twists and turns of the vasculature, physicians can bend the tips of the catheters in a desired direction before inserting them. Then using their hands, they rotate the catheter as needed while pushing it toward the aneurysm. But this approach comes with a significant drawback.

    “With normal catheters, you can’t bend the tip in a different direction on demand once it’s inserted which causes trouble if an aneurysm is hard to reach,” said study co-author Ryan Sochol, Ph.D., a professor of mechanical engineering at the University of Maryland. “This particular problem appears to be quite consistent among neurosurgeons and others that perform endovascular interventions.”

    After hearing from neurosurgeons and studying surgical procedures, the authors of the new study concluded that a steerable robotic tool could greatly improve the process.

    The researchers designed an air pressure operated — or pneumatic — catheter tip which they 3D printed using a soft and flexible resin. The design includes two hollow channels running in parallel along the length of the tip, which, if pressurized individually, causes the tip to deflect to either the left or the right.

    While the catheter tip itself was inspired by existing designs, the authors sought to address a need that those previous robotic systems had not yet tackled — a control system that would fit well into the current clinical workflow.

    To provide physicians with a similar but improved method, the team developed a hand dial that allows for precise adjustments of the tip’s position, providing more control than rotating a pre-bent tip. Additionally, the dial offers haptic feedback that indicates when the tip is bent. With this system, the researchers grant the ability to simultaneously move a catheter forward with one hand while adjusting the angle of the tip with the other.

    To assess the device’s performance, the authors had two users — a skilled neurosurgeon and another with no prior surgical training — adjust the robotic tip’s position to hit an array of five 2-millimeter-wide cylindrical targets spaced less than 2 millimeters apart.

    Through 80 trials each, the users drove the catheters toward the cylinders with one hand and operated the dial with their other, bending the tips even closer to each target.

    The authors tracked how far off the tips were from the targets and the time it took the users to accomplish the tasks. The surgeon was clearly faster and more accurate, however, after several trials, the novice began closing the gap, almost matching their counterpart’s accuracy.

    “Both users were able to use the robotic system for sub-millimeter precision control, which is smaller than the two-millimeter diameter of brain vessels and the openings of aneurysms in the brain,” said senior author Axel Kreiger, Ph.D., a professor of mechanical engineering at Johns Hopkins University. “Overall, it was really nice to see that the results support the feasibility of the system.”

    With the study putting more wind in their sails, the authors are eager to continue developing the robotic tool with plans to shrink it to a more clinically relevant size and test it against targets in more anatomically accurate environments, Krieger explained.

    In the future, the authors also intend to increase their design’s functionality by adding tips in series, which could allow the device to bend into more complicated shapes and navigate difficult vascular environments.

    “The soft microcatheter tip is highly innovative and could be key for widespread use of robotics in endovascular surgery,” said Moria Bittmann, Ph.D., director of the NIBIB Robotics Program.

    This research was funded by a grant from NIBIB (R01EB033354), the Maryland Robotics Center and the Center for Engineering Concepts Development at the University of Maryland.

    This Science Highlight describes a basic research finding. Basic research increases our understanding of human behavior and biology, which is foundational to advancing new and better ways to prevent, diagnose, and treat disease. Science is an unpredictable and incremental process — each research advance builds on past discoveries, often in unexpected ways. Most clinical advances would not be possible without the knowledge of fundamental basic research.

    Study reference: Noah Barnes et al. Toward a novel soft robotic system for minimally invasive interventions. International Journal of Computer Assisted Radiology and Surgery (2023). DOI: 10.1007/s11548-023-02997-w

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    National Institute of Biomedical Imaging and Bioengineering

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  • Commonly Used Herbicide is Harmful to Adolescent Brain Function

    Commonly Used Herbicide is Harmful to Adolescent Brain Function

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    Newswise — Herbicides are the most used class of pesticides worldwide, with uses in agriculture, homes and industry. Exposures to two of the most popular herbicides were associated with worse brain function among adolescents, according to a study led by researchers at the Herbert Wertheim School of Public Health and Human Longevity Science at University of California San Diego.

    In the Oct. 11, 2023 online issue of Environmental Health Perspectives, the researchers reported measuring metabolite concentrations of two commonly used herbicides — glyphosate and 2,4-dichlorophenoxyacetic acid (2,4-D) — and the insect repellent DEET in urine samples collected in 2016 from 519 adolescents, aged 11 to 17, living in the agricultural county of Pedro Moncayo, Ecuador. Researchers also assessed neurobehavioral performance in five areas: attention and inhibitory control, memory and learning, language, visuospatial processing, and social perception.

    “Many chronic diseases and mental health disorders in adolescents and young adults have increased over the last two decades worldwide, and exposure to neurotoxic contaminants in the environment could explain a part of this increase,” said senior author Jose Ricardo Suarez, M.D., Ph.D., M.P.H., associate professor in the Herbert Wertheim School of Public Health.

    Among the findings:

    • Glyphosate, a nonselective herbicide used in many crops, including corn and soy, and for vegetation control in residential settings, was detected in 98 percent of participants.
    • 2,4-D, a broadleaf herbicide used on lawns, aquatic sites, and agricultural crops, was detected in 66 percent of participants.
    • Higher amounts of 2,4-D in urine were associated with lower neurobehavioral performance in the domains of attention and inhibitory control, memory and learning, and language.
    • Glyphosate concentration in urine was associated with lower scores in social perception only, while DEET metabolites were not associated with neurobehavioral performance.

    Following the introduction of genetically modified, glyphosate-resistant “Roundup-ready” crops in 1996 and 2,4-D resistant crops in 2014, there have been substantial increases in glyphosate and 2,4-D use, making them the most widely used herbicides in the world, wrote the authors.

    “There is considerable use of herbicides and insecticides in agricultural industries in both developed and developing nations around the world, raising exposure potential for children and adults, especially if they live in agricultural areas, but we don’t know how it impacts each stage of life,” said first author Briana Chronister, doctoral candidate in the UC San Diego – San Diego State University Joint Doctoral Program in Public Health.

    Previous studies have linked exposure to some of the most used insecticides to altered neurocognitive performance while other insecticides may also affect mood and brain development. Today, 20 percent of adolescents and 26 percent of young adults have diagnosable mental health conditions such as anxiety, depression, impulsivity, aggression or learning disorders.

    The authors reported that 2,4-D was negatively associated with performance in all five neurobehavioral areas, but statistically significant associations were observed with attention and inhibitory control, memory and learning, and language. Glyphosate had a significant negative association only with social perception, a test that measures the ability to recognize emotions, while DEET metabolites were not associated with neurobehavioral alterations.

    “Hundreds of new chemicals are released into the market each year, and more than 80,000 chemicals are registered for use today,” said Suarez. “Sadly, very little is known about the safety and long-term effects on humans for most of these chemicals. Additional research is needed to truly understand the impact.”

    This research is a study within ESPINA: The Study of Secondary Exposures to Pesticides Among Children and Adolescents, a prospective cohort study funded by the National Institute of Environmental Health Sciences, part of the National Institutes of Health, the National Institute of Occupational Safety and Health, and other private funding sources. ESPINA aims to understand the effect of pesticide exposures on the development of humans from childhood thru adulthood.

    In 2022, Suarez and his team completed year 14 of follow-up of study participants with plans to evaluate whether the observed associations persist into early adulthood.

    Co-authors include: Kun Yang, Audrey R. Yang, Tuo Lin, Xin Tu, Harvey Checkoway, Jose Suarez-Torres, Sheila Gahagan, and Raeanne C. Moore, UC San Diego; Dolores Lopez-Paredes and Danilo Martinez, Fundación Cimas del Ecuador; and Dana Barr, Emory University.

    This research was funded, in part, by the National Institutes of Health (R01ES025792, R01ES030378, R21ES026084, U2CES026560, P30ES019776, 5T32MH122376).

    Disclosures: The authors do not have any conflicts of interest to report.

    DOI: 10.1289/EHP11383

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    University of California San Diego

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  • Largest-Ever Genetic Study of Suicide Finds New Risk Factors

    Largest-Ever Genetic Study of Suicide Finds New Risk Factors

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    BYLINE: Caroline Seydel

    Newswise — The reasons why people attempt suicide are complex and include external triggers like trauma and stress, as well as inherited genetic factors. A new study has identified 12 DNA variants, or variations in the human genetic code, that are associated with risk of attempting suicide. The research highlights strong genetic links between suicide attempt and factors that influence physical and behavioral health—including impulsivity, smoking, chronic pain, ADHD, pulmonary conditions, and heart disease. These findings suggest that some of the genetic underpinnings of suicide are shared with these conditions.

    One day, this information could lead to a better understanding of biological causes of suicide and improvements in prevention strategies. Eventually, such advances could help health care providers identify people who may need mental health support.

    “Many people who die from suicide have significant health conditions associated with that risk,” says Anna Docherty, Ph.D., the study’s corresponding author and associate professor of psychiatry at Huntsman Mental Health Institute at the University of Utah. “If we can use genetic information to characterize the health risks of those who attempt suicide, we can better identify those patients who need contact with the mental health care system.” The research published online on October 1 in the American Journal of Psychiatry.

    Scientists at HMHI, Icahn School of Medicine at Mount Sinai, Duke University School of Medicine, Durham Veterans Affairs Health Care System, and Vanderbilt University Medical Center led the collaboration with multiple institutions worldwide. They analyzed data from 22 different populations across the globe, including people of diverse ancestral and ethnic backgrounds.

    Understanding genetic risk of suicide

    No single gene causes suicide. Rather, the cumulative effect of many different genes influences a person’s risk. “In psychiatry, we have many tiny genetic effects, but when we account for all of them together, we start to see a real genetic risk signal,” Docherty explains.

    To tease out such a diffuse signal, researchers applied statistical methods to data collected from a large number of people and identified genetic variations that are more common among individuals who have attempted suicide. The new analysis combines data from the Million Veteran Program (MVP) and the International Suicide Genetics Consortium (ISGC). Together, these include 43,871 documented suicide attempts and 915,025 ancestry-matched controls, making this the largest genetic study of suicide to date.

    A meta-analysis of the studies identified new genetic variants that correlated with suicide attempt. The researchers then compared all variant signals with previously published genetic data on more than 1,000 other traits and disorders, including psychiatric conditions (e.g., ADHD), physical conditions (e.g., heart disease), and behaviors (e.g., smoking), and determined that genetic variants linked to suicide attempt are also linked to other health conditions.

    “That allowed us to look at how genetic risk for suicide overlaps with genetic risk for depression, heart disease, and many other risk factors,” Docherty says. “It showed significant overlap with mental health conditions, but also a lot of physical health conditions, particularly for smoking and lung-related illnesses. This is something we can’t necessarily see in medical records of people who die from suicide.”

    The results do not mean that people with any one of these health factors are at high risk for attempting suicide, notes Hillary Coon, Ph.D., study co-author and professor of psychiatry at HMHI. Rather, combining the genetic predisposition with other stressors—which could include other genetic risk factors, health conditions, life circumstances, or traumatic events—could increase that risk, she explains.

    Initial analyses support the idea that many of the DNA variants that the scientists identified are located in genes with known biological functions, bolstering the case that changes in these genes could affect a person’s physiology or behavior. Several of the genes control processes in cells such as managing cellular stress, repairing damaged DNA, and communicating with the immune system. Most are also highly expressed in the brain and are known targets of antipsychotic and antidepressant drugs.

    Scientists will need to carry out additional studies to determine whether the variants directly or indirectly impact suicide risk, and how. The research so far has shown an association and not cause and effect.

    Understanding how suicide is linked to other health conditions could open doors to new ways of assessing—and treating—suicide risk, Docherty adds. “We want to start to explore the biological underpinnings that are common across suicide and these health factors, because that will lead to the most convincing drug targets,” she says.

    # # #

    The research published as “Genome-wide association study meta-analysis of suicide attempt identifies twelve genome-wide significant loci and implicates genetic risks for specific health factors” with support from the National Institutes of Health, Huntsman Mental Health Institute, the American Foundation for Suicide Prevention, Janssen Research and Development, LLC, Clark Tanner Research Foundation, Clinical Science Research and Development Sevice of the Veterans Health Administraton Officde of Research and Development, and the Brain and Behavior Research Foundation.

    About Huntsman Mental Health Institute  

    Huntsman Mental Health Institute (HMHI) was established in 2021 following the Huntsman Foundation’s historic gift of $150 million to the University of Utah. HMHI is a university-wide Institute with a reputation throughout the Mountain West as a leader in advanced psychiatric treatment and care, serving a diverse population from young children to geriatric patients. Researchers at HMHI develop and apply the most advanced methods in genetics, imaging, epidemiology, and big data analysis. HMHI is also the regional training center for psychiatry and other mental health disciplines. HMHI’s main 170-bed full-service hospital is adjacent to the University of Utah campus, and HMHI’s 1,644 faculty, staff, and students provide clinical, research, and training programs in more than 20 locations across Utah and Idaho.   

    For more information, visit HMHI.utah.edu and join the conversation on TikTok, Instagram, Twitter, LinkedIn, YouTube, and Facebook. 

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    University of Utah Health

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  • Cleveland Clinic Researchers Develop New Model for Prioritizing Lung Transplant Candidates

    Cleveland Clinic Researchers Develop New Model for Prioritizing Lung Transplant Candidates

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    Newswise — CLEVELAND: A team from Cleveland Clinic has developed a new model for prioritizing patients waiting for a lung transplant, aimed at improving outcomes and reducing deaths among those in need of donor lungs. The new method offers an improved strategy for organ allocation by taking into account how the time a patient has spent on the waiting list could impact the severity of their disease and the urgency of their need for a transplant.

    The results of a study looking at this new method were published today in The American Journal of Respiratory and Critical Care Medicine.

    Currently, lung transplant candidates are ranked by a scoring equation called the Composite Allocation Score (CAS). Candidates are assigned a number based on factors including how stable they are while waiting, chances of survival after receiving a new organ, and how easily they can be matched for available organs. Those with the highest scores are given priority and offered donor lungs first. However, the scores are based on tests given twice a year at transplant centers. That means that unless a patient’s health suddenly and drastically changes, their score will remain the same for at least six months.

    “The problem with this method is that the scoring equations fail to consider how a patient’s health status changes as they spend more time on the list,” said Maryam Valapour, M.D., M.P.P., director of Lung Transplant Outcomes at Cleveland Clinic. “The longer a patient lives with a severe lung disease, the more their risk of developing severe complications increases. This is something clinicians observe every day – that our patients’ risk of developing complications changes over time. Therefore, some patients’ scores may not reflect how urgently they need a transplant.”

    To determine how the amount of time on the waitlist affects clinical outcomes, the team of researchers analyzed data from 12,000 American adults listed for lung transplant between 2015 to 2020. The study showed that for many patients, their risk of death prior to transplant increased as they spent longer times waiting for donor lungs.

    When the team looked at patients who died on the waiting list, they found that many had not been given enough priority in the CAS. To more accurately score the candidates, the team developed a more dynamic method called the multistate composite model that accounted for the type of lung disease and time on the waiting list. When they recalculated the original scores with their new equation, it consistently marked those patients as high priority. However, for patients who originally received low-priority scores and remained stable over time, using the new method did not change their scores. 

    “The approaches we present in our paper are capable of identifying whose trajectory is more stable on the waiting list versus those whose trajectory is worsening between six-month clinical updates. The estimates in our model more closely align with observed trends in individual U.S. lung transplant patients,” says Jarrod Dalton, Ph.D., director of Lerner Research Institute’s Center for Populations and Health Research, who is first author of the paper. “This approach may allow us to more accurately prioritize time-sensitive lung transplant candidates and decrease waitlist mortality for patients with end-stage lung disease.”

    This study was done with the support of the National Institutes of Health.

    “This research advances us towards development of a more comprehensive prediction model for risk of mortality among lung transplant candidates that could help guide decisions about patients who are in greater need for lung transplant and increase their odds for survival,” said James P. Kiley, Ph.D., director of the Division of Lung Diseases at the National Heart, Lung, and Blood Institute (NHLBI).

    In 2022, there were over 3,000 candidates added to the lung transplant waitlist with over 2,600 lung transplants performed, according to UNOS. While the numbers of donors and transplants are improving, there is still a shortage of available organs in the United States.

    Research reported in this publication was supported by the National Institutes of Health under Award Number R01HL153175. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Health.

     

    About Cleveland Clinic 

    Cleveland Clinic is a nonprofit multispecialty academic medical center that integrates clinical and hospital care with research and education. Located in Cleveland, Ohio, it was founded in 1921 by four renowned physicians with a vision of providing outstanding patient care based upon the principles of cooperation, compassion and innovation. Cleveland Clinic has pioneered many medical breakthroughs, including coronary artery bypass surgery and the first face transplant in the United States. Cleveland Clinic is consistently recognized in the U.S. and throughout the world for its expertise and care. Among Cleveland Clinic’s 77,000 employees worldwide are more than 5,658 salaried physicians and researchers, and 19,000 registered nurses and advanced practice providers, representing 140 medical specialties and subspecialties. Cleveland Clinic is a 6,699-bed health system that includes a 173-acre main campus near downtown Cleveland, 23 hospitals, more than 275 outpatient facilities, including locations in northeast Ohio; southeast Florida; Las Vegas, Nevada; Toronto, Canada; Abu Dhabi, UAE; and London, England. In 2022, there were 12.8 million outpatient encounters, 303,000 hospital admissions and observations, and 270,000 surgeries and procedures throughout Cleveland Clinic’s health system. Patients came for treatment from every state and 185 countries. Visit us at clevelandclinic.org. Follow us at twitter.com/ClevelandClinic. News and resources available at newsroom.clevelandclinic.org. 

     

    Editor’s Note: Cleveland Clinic News Service is available to provide broadcast-quality interviews and B-roll upon request.

     

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    Cleveland Clinic

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  • A Fourth of U.S. Health Visits Now Delivered by Non-Physicians

    A Fourth of U.S. Health Visits Now Delivered by Non-Physicians

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     At a glance

    • From 2013 to 2019 the share of U.S. health care visits delivered by non-physicians such as nurse practitioners or physician assistants increased from 14 to 26 percent.
    • This rapid shift requires caregivers, medical educators, and policymakers to understand and manage this growing segment of the health care workforce.

    Newswise — The proportion of health care visits delivered by nurse practitioners and physician assistants in the US is increasing rapidly and now accounts for a quarter of all healthcare visits, according to a study published Sept. 14 in the BMJ.

    The analysis, led by researchers from the Department of Health Care Policy in the Blavatnik Institute at Harvard Medical School, highlights the rising importance of this rapidly growing segment of the U.S. health care system.

    The research is the first nationally representative study of the share of health care delivered by nurse practitioners and physician assistants, collectively known as advanced practice providers. It is also the first study to look at care delivered across different clinical conditions. The researchers analyzed 276 million visits from a nationally representative sample of Medicare insured patients.

    Study co-authors Ateev Mehrotra, professor of health care policy at HMS, and Sadiq Patel, a former NIH postdoctoral fellow at HMS, spoke with HMNews about the increasingly important role these providers play in our health care system.

    Harvard Medicine News: How did we get to the point where a quarter of all medical visits are conducted by nurse practitioners and physician assistants, not by physicians?

    Mehrotra: The roles of nurse practitioners and physician assistants were created in the mid 1960s to address what were already identified at that time as physician shortages. We looked specifically at the years from 2013 to 2019, when the proportion of all traditional health care visits delivered by nurse practitioners and physician assistants increased from 14 to 25.6 percent. 

    That’s the average, but it varied across different conditions. Forty-seven percent of respiratory infection visits and 31 percent of visits for anxiety disorders were conducted by nurse practitioners and physician assistants, but it was only 13 percent for eye disorders and 20 percent for hypertension.

    HMNews: What’s driving this recent growth? 

    Mehrotra: The short answer is supply and demand. The U.S. has fewer physicians per capita than most of our peer nations. Who is going to provide that care? The number of nurse practitioners and physician assistants has grown more quickly than the number of physicians. And this trend will only continue as we move forward.  

    The U.S. Bureau of Labor Statistics estimates that between 2019 and 2031 the number of nurse practitioners in the U.S. will increase by 80 percent and the number of physician assistants by nearly 50 percent. In contrast, the growth rate for physicians over the next decade or so is estimated at less than 5 percent.

    HMNews: Are there some patients who are more likely to see nurse practitioners or physician assistants than others?

    Patel: Nurse practitioners and physician assistants are very widespread: Among all patients with at least one visit in 2019, 42 percent had one or more nurse practitioner or physician assistant visits. But there were some groups more likely to see nurse practitioners and physician assistants. The likelihood was greatest among patients who were lower income, rural residents, and people with disabilities.

    That’s another reason it’s so important to get this right. We’ve known that these groups often have greater difficulty accessing care, and nurse practitioners and physician assistants are critical to providing this access.

    HMNews: When people are sick, they usually think about “going to the doctor.” Is this change worrying? Is there a difference in quality or cost between the care delivered by nurses and physician assistants versus the care delivered by physicians?

    Mehrotra: First of all, it’s very important to emphasize that it’s not really a question of one or the other. Almost all these practitioners work in teams that include physicians, nurse practitioners, and physician assistants working together.

    Most of the research agrees that all three professions can do a good job delivering care in most settings, especially primary care. And it turns out that there is not a significant difference in spending. But there are clinical conditions that might be better suited to one profession or another.

    Patel: One of the things that we wanted to do with this study was to start looking at the specific types of care these allied professionals were most likely to deliver.

    HMNews: What did you learn?

    Patel: As Ateev mentioned, patients were less likely to see a nurse practitioner or a physician assistant for an eye disorder, and more likely to see them for a respiratory infection. That seems like a reasonable allocation of resources, given the relative complexity of the clinical conditions. 

    The high use of nurse practitioners and physician assistants for anxiety disorders is another interesting example. There simply aren’t enough psychiatrists to treat all the people who need care for mental health conditions. But the good news is that there are highly effective evidence-based treatments that can help a lot of people with depression and anxiety that do not require a physician to deliver.

    Mehrotra: Hopefully one benefit that will follow from this research is that we will be able to identify the services that allied health professionals can deliver and provide the training and support services they need to take care of their patients, like proactively planning for remote supervision in more complex psychiatric services or specialist consults by telemedicine.

    HMNews: Any predictions on how these changes will shape health care going forward?

    Mehrotra: The increase in care delivery by nurse practitioners and physician assistants represents a massive change. We need more research on how to best structure teams of clinicians — nurse practitioners, physician assistants, and physicians — so that they can work together to provide the most effective care possible. If we are thoughtful about how we move forward as those changes continue to happen, that’s millions of opportunities to do it better. I hope we take advantage of that opportunity.

    This interview was edited for length and clarity.

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    Harvard Medical School

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  • Machine learning tool simplifies one of the most widely used reactions in the pharmaceutical industry

    Machine learning tool simplifies one of the most widely used reactions in the pharmaceutical industry

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    BYLINE: Tracy Crane, Department of Chemistry

    Newswise — In the past two decades, the carbon-nitrogen bond forming reaction, known as the Buchwald-Hartwig reaction, has become one of the most widely used tools in organic synthesis, particularly in the pharmaceutical industry given the prevalence of nitrogen in natural products and pharmaceuticals. This powerful reaction has revolutionized the way nitrogen-containing compounds are made in academic and industrial laboratories, but it requires lengthy, time-consuming experimentation to determine the best conditions for a highly effective reaction.

    Now, Illinois researchers in collaboration with chemists at Hoffman La-Roche, a pharmaceutical company in Switzerland, have developed a machine learning tool that predicts in a matter of minutes the best conditions for a high-yielding reaction with no lengthy experimentation.

    In a recently published article in Science (DOI: 10.1126/science.adg2114), Illinois chemistry professor Scott Denmark and Ian Rinehart, a recent PhD graduate in the Denmark lab, describe how they developed, trained, and tested their machine learning model to drastically accelerate the identification of substrate-adaptive conditions for this palladium–catalyzed carbon-nitrogen bond forming reaction.

    Denmark said this reaction is a very general transformation so there is much structural diversity among reactant pairings and a lot of “levers to pull” to make it work.

    “And that’s what we have figured out,” Denmark said.

    User guides and cheat sheets have evolved in the nearly 30 years since this reaction was discovered, and they can provide some direction, Rinehart explained, but experimentation is often necessary. Basically, a trial-and-error process in a lab.

    “It’s a problem that everyone in the pharmaceutical industry recognized was ripe for intervention by informatics methods,” Denmark said. “Lots of people have tried to use the US Patent and Trademark Office or Chemical Abstracts™ or other huge databases to try to model to make predictive tools for this one very important reaction. But they haven’t been able to do very well because the information in the literature is just not very reliable.”

    The design and construction of their machine learning tool required the generation of an experimental dataset that explores a diverse network of reactant pairings across a set of reaction conditions. A large scope of C–N couplings was actively learned by neural network models by using a systematic process to design experiments.

    The challenge for a project like this, Denmark said, was the amount of potential data to collect and the thousands and thousands of experiments required to build a database of information for modeling.

    “One of Ian’s biggest contributions was figuring out the workflow to decide what experiments to do to get a valid predictive model with about 3,500 experiments and still be able to make predictions without an enormous database,” Denmark said.

    They also experimentally validated the predictions from the machine learning tool.

    “We tested them and found with pretty good statistics that the conditions were producing compounds when we expected,” Denmark said.

    The researchers report that their models showed good performance in experimental validation: Ten products were isolated in more than 85 percent yield from a range of couplings with out-of-sample reactants designed to challenge the models.

    Rinehart said they taught machine learning models to have a kind of chemical intuition like what an expert has.

    “So, we have now run or talked about so many of these couplings that we have a good intuition about what’s going to happen, but someone who hadn’t run hundreds or thousands of these might not have a good first guess. We have taught a model at a much more granular level [than user guides] to have an intuition. It’s not perfect. But that’s kind of the point. It doesn’t have to be. It just has to get you to the answer faster,” Rinehart said.

    And the coolest part, Rinehart explained, is that intuition gets honed over time as more people use the machine learning tool. The developed workflow continually improves the prediction capability of the tool as the corpus of data grows.

    “It’s an exciting time as data science merges with chemistry,” Denmark said. “And this is the perfect marriage. A lot of people recognized this, but no one has done it, at least not in a meaningful way that is experimentally validated.”

    The Denmark group is creating a cloud-based version of the workflow to enable scientists around the world to use this tool which will continuously add data to improve the model as more structurally diverse substrates are tested and different catalysts and conditions are added to the database.

    Rinehart said the code is public and on an open-source license, so anyone can download and use it. Also, he is currently working on a more user-friendly interface that will allow someone to draw the two molecules they want to react, copy and paste them into the program, and get predictions in minutes instead of hours, depending on the complexity of the molecules.

    “I think it’s really exciting to do something like that,” Rinehart said. “We don’t often publish a paper and put out a tool in the public domain that people can use in the field. People in academic labs like ours could use this tool and get an answer faster in their own research.”

     

    Funding for this project was provided through the National Science Foundation (NSF) (grant no. CHE 1900617) and the Molecule Maker Lab Institute, an AI Research Institutes program on the University of Illinois Urbana-Champaign campus that is supported by the NSF under grant no. CHE 2019897.

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    College of Liberal Arts and Sciences, University of Illinois Urbana-Champaign

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  • LJI scientists harness ‘helper’ T cells to treat tumors

    LJI scientists harness ‘helper’ T cells to treat tumors

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    Newswise — LA JOLLA, CA—Scientists are on the hunt for a unique set of mutations, called “neoantigens,” that let the immune system distinguish tumor cells from normal cells. Their goal is to help the immune system react to neoantigens and target tumor cells for destruction.

    This area of research has led to life-saving antibody therapeutics, such as immune checkpoint inhibitors, which rely on antibodies to help immune cells kill tumors. Unfortunately, antibody-based cancer immunotherapies don’t work for all patients.

    At La Jolla Institute for Immunology (LJI), Professor Stephen Schoenberger, Ph.D., and his colleagues are looking beyond antibodies. Schoenberger’s lab leads pioneering research into how the immune system’s CD4+ “helper” T cells detect neoantigens.

    Now Schoenberger and his colleagues have published a pair of studies that show how we might harness CD4+ T cells while boosting the cancer-fighting power of CD8+ “killer” T cells. In fact, the researchers demonstrate a new kind of vaccine design that recruits both types of T cells to destroy large tumors.

    “Therapeutic cancer vaccines can work,” says Schoenberger, who serves as a member of the LJI Center for Cancer Immunotherapy. “But they should leverage the natural synergy of CD4+ and CD8+ T cells.”

    Researchers help CD4+ T cells detect tumors

    As Schoenberger points out, CD4+ and CD8+ T cells already work together when fighting viruses and bacteria. “Why not learn from the immune system’s natural way of keeping us protected and turn that against cancer?” he says.

    In a paper published recently in Nature Immunology, Schoenberger worked closely with LJI Professor Bjoern Peters, Ph.D,. to demonstrate the essential role of CD4+ T cells in recognizing tumor cells. Their strategy depends on an innovative way to predict which tumor neoantigens will spark a strong CD4+ T cell response. 

    As Schoenberger explains, tumor cells arise from normal cells in the body. This means the body has a harder time recognizing tumor cells as dangerous. Other threats, such as viruses, tend to carry around very un-human looking peptide sequences. “With prompting from CD4+ T cells, immune cells called dendritic cells can capture these peptide sequences and show them to CD8+ T cells—sending the immune system into red alert. “CD8+ T cells execute the tumor,” says Schoenberger, “but they require the cooperation of CD4+ T cells to do so efficiently.”

    But tumor cells share most of their peptide sequences with normal cells, and are therefore harder for the immune system to “see.” To get around this problem, Schoenberger and Peters have devised computational tools to identify the genetic mutations and specific peptides that serve as neoantigens to distinguish tumor cells from their neighbors.

    The Nature Immunology study shows that CD4+ T cells that recognize a single target mutation can  drive a diverse CD8+ T cell response that eradicates large established tumors . The researchers tested T cells recognizing this target mutation for “avidity,” which is how strongly their antigen receptors bind to the neoantigen. Their surprising results showed that neoantigen-specific CD4+ T cells can mediate their effect across a range of affinities.

    “This is brand new because no one has ever studied the neoantigen-specific CD4+ repertoire at the level of T cell receptors,” says Schoenberger.

    The researchers also found that the most effective responses happened when the transferred CD4+ T cells were induced to develop into stem cell memory-like CD4+ T cells. This type of T cell are endowed with special properties of longevity and the ability to generate powerful effector cells. As Schoenberger’s research spans the lab to the clinic, these findings will be translated to clinical trials in the near future.

    New vaccine brings T cells together

    In a second study, published recently in the Journal of Clinical Investigation, Schoenberger and his colleagues showed how a new vaccine strategy can induce CD4+ T cells and CD8+ T cells to work together to destroy large, aggressive tumors in a mouse model.

    For the study, Schoenberger collaborated with Joseph Dolina, Ph.D., a senior scientist at Pfizer Inc., and former member of the Schoenberger Lab (Pfizer has no financial disclosures to this specific study).

    The team began with an aggressive squamous cell tumor that contained a low number of mutations, as many human cancers do. The researchers identified 270 mutations that make this tumor stand out from normal cells, and they performed in-depth studies on 39 of these mutations. They narrowed that group down to five mutations that were recognized by the natural anti-tumor T cell response—with some mutations targeted by CD4+ T cells and others by CD8+ T cells. Remarkably, only mutations targeted by both CD4+ and CD8+ T cells were capable of triggering protective or therapeutic responses against the tumor.

    “These neoantigens had to be physically linked to mediate therapy,” says Schoenberger. “We could make large tumors go away so long as the vaccine activated both CD4+ and CD8+ T cells via the same antigen-presenting cell.”

    Going forward, Schoenberger plans to work with his clinical colleagues at the UC San Diego Moores Cancer Center to study whether this type of linked vaccine is effective in human patients. He hopes a future clinical trial can give hope to patients with especially aggressive tumors.

    “The other message here is that we think we can greatly increase the number of patients who could benefit from checkpoint blockade immunotherapy if we combine it with a personalized cancer vaccine,” says Schoenberger.

    Additional authors of the Nature Immunology study, “Neoantigen-specific stem cell memory-like CD4+ T cells mediate CD8+ T cell-dependent immunotherapy of MHC class II-negative solid tumors,” include Spencer E. Brightman (first author), Angelica Becker, Rukman R. Thota, Martin S. Naradikian, Leila Chihab, Karla Soria Zavala, Ryan Q. Griswold, Joseph S. Dolina, Ezra E. W. Cohen and Aaron M. Miller.

    This study was supported by the National Institutes of Health (grant UO1 DE028227), the San Diego Center for Precision Immunotherapy, and the Sandor and Rebecca Shapery Family.

    Nature Immunology DOI: https://doi.org/10.1038/s41590-023-01543-9

    Additional authors of the Journal of Clinical Investigation study, “Linked CD4+/CD8+ T cell neoantigen vaccination overcomes immune checkpoint blockade resistance and enables tumor regression,” include Joey Lee, Spencer E. Brightman, Sara McArdle, Samantha M. Hall, Rukman R. Thota, Karla S. Zavala, Manasa Lanka, Ashmitaa Logandha Ramamoorthy Premlal, Jason A. Greenbaum, Ezra E.W. Cohen and Bjoern Peters.

    This study was supported by the National Institutes of Health (grants U01 DE028227, P30CA23100, S10 RR027366 and S10 OD016262), the San Diego Center for Precision Immunotherapy, and the Sandor and Rebecca Shapery Family.

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  • New Grant to Optimize Gut Microbes, Boost Health Benefits of Broccoli

    New Grant to Optimize Gut Microbes, Boost Health Benefits of Broccoli

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    BYLINE: Lauren Quinn

    Newswise — URBANA, Ill. — Love it or hate it, broccoli is chock-full of health-promoting chemicals linked to heart health, cancer prevention, immune function, weight management, and more. However,  some people are less efficient than others at unlocking those chemical benefits. A research team at the University of Illinois Urbana-Champaign suggests gut microbe communities may be responsible for the variation. With a new grant from the USDA’s National Institute of Food and Agriculture, the team plans to identify which microbes maximize the benefits of broccoli and other brassica vegetables. 

    Gut microbes only factor in when we eat cooked broccoli. When eating the vegetable raw, healthy compounds — and a bitter taste — are unleashed with every gnash of our teeth, the result of a chemical reaction activated by physical damage. Eliminating the bitterness is easy; we just have to cook it. But cooking inactivates the enzyme involved in the reaction, myrosinase. Thankfully, some microbes manufacture their own version of myrosinase, making it possible for them to complete the reaction in the gut with varying levels of efficiency. 

    “Gut bacteria can metabolize glucosinolates in broccoli to isothiocyanates (ITCs), the bioactive compounds with known health benefits, but they can also break glucosinolates into other inactive materials that do nothing for us. We’re focusing on the flux between these metabolic outcomes and how we can potentially steer that flux towards ITCs and away from the non-bioactive products,” said Michael Miller, principal investigator of the grant and professor in the Department of Food Science and Human Nutrition, part of the College of Agricultural, Consumer and Environmental Sciences (ACES) at U. of I.

    The first step is identifying which bacteria are involved and how efficiently they produce ITCs versus non-beneficial compounds. Miller’s team has a study underway in mice, a model system that can provide clues for future human studies. He is feeding the mice broccoli and kale, both cooked and uncooked, to understand the chemical and microbial dynamics of the system. 

    Once ITCs are unlocked — whether in the mouth or the gut — they trigger bitter-taste receptors in cell membranes, starting a series of reactions that produce hormones affecting glucose homeostasis and the perception of fullness.

    “We actually have bitter taste receptors all the way down, not just in our mouths, but in our colon and small intestine, too,” Miller said. “The goal of our work is to show that the bitter compounds (ITCs) made by gut bacteria from metabolizing broccoli trigger bitter taste receptors in the gut and impact satiety, causing mice to eat less.”

    Once he identifies bacterial superstars that maximize ITC production for anti-cancer and weight management benefits, Miller says custom probiotics could be developed to help level the playing field for people with lower-efficiency microbial communities. He also predicts his research will inform recommendations about whether raw or cooked broccoli (or kale) might be more useful for weight loss.

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    College of Agricultural, Consumer and Environmental Sciences, University of Illinois Urbana-Champaign

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  • AI can predict certain forms of esophageal and stomach cancer

    AI can predict certain forms of esophageal and stomach cancer

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    BYLINE: Jina Sawani, Michigan Medicine

    Newswise — In the United States and other western countries, a form of esophageal and stomach cancer has risen dramatically over the last five decades. Rates of esophageal adenocarcinoma, or EAC, and gastric cardia adenocarcinoma, or GCA, are both highly fatal.

    However, Joel Rubenstein, M.D., M.S., a research scientist at the Lieutenant Colonel Charles S. Kettles Veterans Affairs Center for Clinical Management Research and professor of internal medicine at Michigan Medicine, says that preventative measures can be a saving grace.

    “Screening can identify pre-cancerous changes in patients, Barrett’s esophagus, which is sometimes diagnosed in individuals who have long-term gastroesophageal reflux disease, or GERD,” he said.

    “When early detection occurs, patients can take additional steps to help prevent cancer.”

    While current guidelines already consider screening in high-risk patients, Rubenstein notes that many providers are still unfamiliar with this recommendation.

    “Many individuals who develop these types of cancer never had screening to begin with,” he said.

    “But a new automated tool embedded in the electronic health record holds the potential to bridge the gap between provider awareness and patients who are at an increased risk of developing esophageal adenocarcinoma and gastric cardia adenocarcinoma.”

    Rubenstein and a team of researchers used a type of artificial intelligence to examine data regarding EAC and GCA rates in over 10 million U.S. veterans.

    Their findings were published in Gastroenterology. 

    Rubenstein and his team developed and tested the Kettles Esophageal and Cardia Adenocarcinoma predictioN tool, called K-ECAN for short.

    “K-ECAN uses basic information already readily available in the EHR, like patient demographics, weight, previous diagnoses and routine laboratory results, to determine an individual’s risk of developing esophageal adenocarcinoma and gastric cardia adenocarcinoma,” said Rubenstein.

    “We developed a prior tool, M-BERET, over a decade ago for identifying patients with Barrett’s esophagus. However, that tool requires measuring patients’ hip and waist circumferences, which is not something that routinely occurs. In addition, providers must remember to use the corresponding website to calculate their patient’s risk when using this tool.”

    To alleviate this burden, Rubenstein said that they “envisioned harnessing the large amount of data already present in the EHR, as well as presenting their patients’ risk to their providers at opportune times,” such as when an individual is due for a colorectal screening or refilling an acid reducing prescription medication.

    According to Rubenstein, K-ECAN is more accurate than published guidelines or previously validated prediction tools and can “accurately predict cancer at least three years prior to a diagnosis.”

    “Symptoms of GERD, like heartburn, are an important risk factor for esophageal adenocarcinoma,” he said.

    “But most people with GERD symptoms will never develop esophageal adenocarcinoma and gastric cardia adenocarcinoma. In addition, roughly half of the patients with this form of cancer never experienced prior GERD symptoms at all. This makes K-ECAN particularly useful because it can identify people who are at elevated risk, regardless of whether they have GERD symptoms or not.”

    Akbar Waljee, M.D., M.Sc., professor in the Departments of Learning Health Sciences and Internal Medicine and senior author on the study, adds that this research wouldn’t be possible without a collaborative effort.

    “This publication, which leveraged invaluable data from millions of U.S. veterans, was made possible through the dedicated efforts of numerous staff members at our VA Health Services Research & Development Center of Innovation, as well as through collaborative partnerships between the VA Center for Clinical Management Research, Michigan Medicine, the University of Michigan Department of Statistics, and members of U-M’s Institute for Healthcare Policy & Innovation and E-Health & Artificial Intelligence, or e-HAIL. This exemplifies the power of team science, data and machine learning to improve cancer prevention.”

    Incorporating this artificial intelligence tool into the EHR could alert providers with an automated notification regarding which patients are at an increased risk of developing esophageal adenocarcinoma and gastric cardia adenocarcinoma.

    And Rubenstein says that this can significantly decrease the burden of these cancers

    “Our devoted team was able to use sophisticated machine learning tools to develop this unique tool, and we are very excited that this could potentially lead to increased screening and a decrease in preventable deaths. We look forward to conducting additional work validating K-ECAN for use outside of the VA.”

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    Michigan Medicine – University of Michigan

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  • Short-Term Use of Immunosuppressants Not Linked to Cancer Risk

    Short-Term Use of Immunosuppressants Not Linked to Cancer Risk

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    Newswise — Relatively short-term use of immunosuppressant medications to control an inflammatory disease was not associated with an increased risk of later developing cancer, according to new research led by scientists at the University of Pittsburgh and Mass Eye and Ear, a member of the Mass General Brigham health care system, and published today in the journal BMJ Oncology.

    The findings should provide reassurance to patients and clinicians who may hesitate to prescribe the medications because they are known to increase the risk of cancer in people who take them over many years or a lifetime to prevent dire consequences, such as organ rejection in transplant recipients.

    “When we got these results, I was reassured, and I hope patients will be, too,” said lead author Jeanine Buchanich, Ph.D., associate dean for research and associate professor of biostatistics at Pitt’s School of Public Health. “Immunosuppressants are widely used and transformative for care of patients with inflammatory diseases, but the potential concern that they carry a cancer risk has forced people to make difficult decisions without enough information. Alleviating that concern with use for inflammatory diseases will help people make the treatment decision that’s right for them.”

    The  new findings were from the Systemic Immunosuppressive Therapy for Eye Diseases (SITE) Cohort, which began two decades ago when principal investigator John Kempen, M.D., Ph.D., senior scientist and director of epidemiology for ophthalmology at Mass Eye and Ear and professor of ophthalmology at Harvard Medical School, approached Buchanich, who directs Pitt Public Health’s Center for Occupational Biostatistics and Epidemiology, to partner in evaluating cancer risk for people with non-infectious ocular inflammatory diseases taking immunosuppressants. These eye diseases are caused by immune dysfunction and do not themselves cause cancer but can be very serious, with blindness as a possible outcome.

    The diseases are commonly treated with immunosuppressive medications, which patients generally take for several months to several years.

    This new research adds evidence to the limited cancer risk associated with immunosuppressant treatments uncovered by the SITE study consortium. In a study published last month in Ophthalmology, the researchers found no increased risk in cancer-related and overall mortality in individuals taking commonly used immunosuppressants. The study included 15,938 SITE participants who were tracked for an average of 10 years.

    The BMJ Oncology study included 10,872 participants, ultimately encompassing 84% of the enrolled SITE participants who lived in one of the 12 states from which the research team obtained data linking participants to each state’s cancer registries. Though most states track cancer incidence, there is no centralized federal cancer registry, and different states require different permissions and use different interfaces to share data. For this reason, it is difficult to do large-scale epidemiological cancer studies in the U.S., making this study incorporating years of data from multiple states a rarity.

    The research team tracked each participant for an average of 10 years after they took immunosuppressant medications, or for a similar amount of time for those not taking immunosuppression, to see if they ever developed cancer. Four different categories of immunosuppressants – TNF-inhibitors, antimetabolites, alkylating agents and calcineurin inhibitors – were covered by the study, with some patients taking more than one type. Patients were on the medications for a median of one year.

    Across all four classes of immunosuppressant medications the scientists found no evidence of excess risk of cancer in patients who took them on a short-term basis, regardless of medication dose.

    While the study only looked at people with noninfectious eye diseases and the researchers caution that the results aren’t generalizable to everyone taking immunosuppressants, the results probably are generalizable to patients with inflammatory diseases, Kempen said.

    “The patients in our study actually tended to have a lower incidence of cancer than non-immunosuppressed patients, suggesting that an increased risk of overall cancer from commonly used immunosuppressants given for the short- to medium-term is very unlikely,” said Kempen. “This result is foundational for a large number of patients with inflammatory eye conditions and a broad range of patients with other inflammatory diseases.”

    Additional researchers on this study are Craig Newcomb, M.S., Nirali Bhatt, M.D., Tonetta Fitzgerald, Ebenezer Daniel, Ph.D., and Naira Khachatryan, M.D., Dr.P.H., all of the University of Pennsylvania (Penn); Terri Washington, of Pitt; C. Stephen Foster, M.D., of the Massachusetts Eye Research and Surgery Institution (MERSI) and Harvard Medical School; Lucia Sobrin, M.D., of Mass Eye and Ear and Harvard Medical School; Jennifer Thorne, M.D., Ph.D., Douglas Jabs, M.D., M.B.A., Kurt Dreger, Hosne Begum and Kathy Helzlsouer, M.D., all of Johns Hopkins University; Eric Suhler, M.D., M.P.H., James Rosenbaum, M.D., and Teresa Liesegang, all of the Oregon Health & Science University; H. Nida Sen, M.D., of George Washington University; Grace Levy-Clarke, M.D., of West Virginia University; the late Robert Nussenblatt, M.D., of the National Eye Institute; Careen Lowder, M.D., Ph.D., of the Cleveland Clinic; Debra Goldstein, M.D., of Northwestern University; Yannek Leiderman, M.D., Ph.D., of the University of Illinois, Chicago; Nisha Acharya, M.D., of the University of California San Francisco; Gary Holland, M.D., of the University of California Los Angeles; Russel Read, M.D., Ph.D., of the University of Alabama at Birmingham; James Dunn, M.D., of the Wills Eye Hospital; Pichaporn Artornsombudh, M.D., of Somdech Phra Pinkloa Hospital, Thailand; Srishti Kothari, of Penn and MERSI; Abhishek Payal, M.D., of Mahatme EyeBank Eye Hospital, India; Sapna Gangaputra, M.D., of Vanderbilt University Medical Center; R. Oktay Kacmaz, M.D., of Santen Pharmaceutical Co Ltd; Siddharth Pujari, M.D., of Siddharth Netralaya Superspecialty Eye Hospital, India; Armin Maghsoudlou, M.D., of Northwell Health; Hilkiah Suga, M.D., Myungsung Christian Medical Center (MCM), Ethiopia; and Clara Pak, of MCM and University of Rochester.

    This research was supported by National Institutes of Health (NIH) grants R01 EY14943 and R21 EY02617, NIH University of Pennsylvania Core Grant for Vision Research 2P30EYEY001583, the Massachusetts Eye and Ear Global Surgery Program, Sight for Souls and Research to Prevent Blindness.

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    About the University of Pittsburgh School of Public Health

    Founded in 1948, the University of Pittsburgh School of Public Health is a top-ranked institution of seven academic departments partnering with stakeholders locally and globally to create, implement and disseminate innovative public health research and practice. With hands-on and high-tech instruction, Pitt Public Health trains a diverse community of students to become public health leaders who counter persistent population health problems and inequities. 

    About Mass Eye and Ear

    Massachusetts Eye and Ear, founded in 1824, is an international center for treatment and research and a teaching hospital of Harvard Medical School. A member of Mass General Brigham, Mass Eye and Ear specializes in ophthalmology (eye care) and otolaryngology–head and neck surgery (ear, nose and throat care). Mass Eye and Ear clinicians provide care ranging from the routine to the very complex. Also home to the world’s largest community of hearing and vision researchers, Mass Eye and Ear scientists are driven by a mission to discover the basic biology underlying conditions affecting the eyes, ears, nose, throat, head and neck and to develop new treatments and cures. In the 2022–2023 “Best Hospitals Survey,” U.S. News & World Report ranked Mass Eye and Ear #4 in the nation for eye care and #4 for ear, nose and throat care. For more information about life-changing care and research at Mass Eye and Ear, visit our blog, Focus, and follow us on Instagram, Twitter and Facebook.

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    University of Pittsburgh

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  • Research aims to uncover genetic and environmental risk factors of nonalcoholic fatty liver disease

    Research aims to uncover genetic and environmental risk factors of nonalcoholic fatty liver disease

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    Newswise — DETROIT – Wanqing Liu, Ph.D., professor of pharmaceutical sciences in the Wayne State University Eugene Applebaum College of Pharmacy and Health Sciences and of pharmacology in Wayne State’s School of Medicine, received a $3 million, five-year award from the National Institute of Environmental Health Sciences of the National Institutes of Health. The study, “Interaction between Genome and Heavy Metals in Nonalcoholic Fatty Liver Disease,” aims to discover and validate the gene Х heavy metal (GXM) interactions in human livers and to understand their role in nonalcoholic fatty liver disease (NAFLD).

    Andrea Cassidy-Bushrow, Ph.D., senior scientist and epidemiologist in the Department of Public Health Sciences at Henry Ford Health, is the co-principal investigator on the study.  

    NAFLD is the most common chronic liver disease, affecting more than 30% of the U.S. population. NAFLD is characterized by a spectrum of histological changes with multiple cells involved. There are no approved drug treatments available currently for the disease.

    “There is an urgent need to identify both the genetic and environmental risk factors of NAFLD to aid in developing diagnostic, prevention and therapeutic strategies,” said Liu. “Over the past decade, a number of genetic risk alleles have been identified, but a growing body of research demonstrates that exposure to heavy metals increases NAFLD risk. However, more research is needed to assess the correlation between various naturally occurring accumulated metals in human livers and the NAFLD histology.”

    Liu and Cassidy-Bushrow said that critical knowledge about how naturally and chronically accumulated metals interact with the liver genome and together to confer risks for NAFLD is lacking. Their preliminary studies in human liver tissues have successfully demonstrated that multiple metals are indeed correlated with NAFLD.

    “By leveraging our previously collected data, we have begun to identify numerous metal-response genes, expression quantitative traits loci and allele-specific expression loci, which are further enriched to NAFLD and its related pathways,” said Cassidy-Bushrow. “We aim to expand our study to a large-scale, highly detailed and integrated analysis to thoroughly understand the role of GXM interactions in NAFLD in humans.”

    The project also involves Hongmin Ni, M.D., associate professor of pharmacology, toxicology and therapeutics at the University of Kansas Medical Center, as a co-investigator. Ni will supply human liver tissue and isolated liver cells for a cell-specific, in vitro analysis of genome-metal interactions.

    The collaborative study will generate important data that has the potential to identify high-risk metals and their essential response genes, ultimately promoting the development of new strategies for NAFLD diagnosis, prevention and treatment, as well as advance research for other related diseases.

    The project number for this National Institute of Environmental Health Sciences of the National Institutes of Health grant is ES034410.

     

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    About Wayne State University

    Wayne State University is one of the nation’s pre-eminent public research universities in an urban setting. Through its multidisciplinary approach to research and education, and its ongoing collaboration with government, industry and other institutions, the university seeks to enhance economic growth and improve the quality of life in the city of Detroit, state of Michigan and throughout the world. For more information about research at Wayne State University, visit research.wayne.edu.

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  • UTEP to Boost Training of Next-Gen Engineers with $5.3M Grant

    UTEP to Boost Training of Next-Gen Engineers with $5.3M Grant

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    Newswise — EL PASO, Texas (Aug. 21, 2023) – The University of Texas at El Paso is scaling up its role in preparing the next generation of engineers for U.S. aerospace and defense manufacturing sectors. The effort is supported by a new $5,300,000 grant from the Air Force Research Laboratory (AFRL).

    The funds will enhance a variety of training programs offered by the UTEP Aerospace Center’s Digital Engineering Aerospace and Defense Systems Design Centers (DEDCs) in El Paso; Youngstown, Ohio; and Huntsville, Alabama. The new funds are a follow-up investment to a fiscal year 2021 grant from the AFRL that supported the creation of the DEDCs. 

    “UTEP stands among the top 5% of research universities in the United States,” said Ahmad Itani, Ph.D., UTEP vice president for research. “That fact, along with the growing stature of our engineering expertise and instructional capabilities, make our University uniquely well-suited for the critical task of preparing the workforce that will ensure our country remains competitive in a world where design and engineering processes of systems of all kinds evolve at an unprecedented rate.”

    Digital engineering entails the use of computing and software instruments to expedite and enhance various phases of engineering, including system design, production, testing, evaluation, adaptation and upkeep. This method holds the potential to accelerate design, reduce expenditures and facilitate collaboration. It can also substantially decrease the costs associated with long-term system maintenance. 

    “Digital engineering will allow America to keep and increase its technological advantage,” said Ahsan Choudhuri, Ph.D., UTEP associate vice president for the Aerospace Center and the grant’s principal investigator. “That is why innovation in digital engineering and talent development with advanced digital skills are crucial. This grant represents a substantial vote of confidence from AFRL in our ability to carry out this important task.” 

    The project will leverage the expertise of the UTEP Aerospace Center’s DEDCs. Using an immersive learning approach, it will provide pre-professional experiences to 200 engineering and technology students. Undergraduate and graduate students from various universities, as well as students from two-year colleges and Career and Technical Education (CTE) programs in grades 9 through 12, will be recruited for the program.

    Many of these students will have the opportunity to work as interns and undergraduate and graduate research assistants at the DEDCs for a 12-month program.

    In addition to student development, the DEDCs will offer a course in the principles of digital engineering. Approximately 100 participants from federal agencies, aerospace and defense contractors and small and medium manufacturers will have the opportunity to enhance their knowledge in this field. 

    To learn more about the UTEP Aerospace Center and the Digital Engineering Aerospace and Defense Systems Design Centers, visit www.utep.edu/aerospace/Design%20Centers/index.html.

    About The University of Texas at El Paso

    The University of Texas at El Paso is America’s leading Hispanic-serving University. Located at the westernmost tip of Texas, where three states and two countries converge along the Rio Grande, 84% of our 24,000 students are Hispanic, and half are the first in their families to go to college. UTEP offers 169 bachelor’s, master’s, and doctoral degree programs at the only open-access, top-tier research university in America.

     

     

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  • Remote learning during pandemic aids medical students with disabilities

    Remote learning during pandemic aids medical students with disabilities

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    BYLINE: Patricia DeLacey

    Newswise — Medical students who reported a disability to their school increased by more than 25% during the COVID-19 pandemic, a study shows.

    The proportion of students reporting attention deficit hyperactivity disorder or chronic health and/or psychological disabilities has increased between 2015 and 2021.

    Despite the increase in medical students reporting these conditions, the requests for more inclusive preclinical testing accommodations, like extra time for test completion or a less distracting environment, decreased during the pandemic between 2019 and 2021.

    According to authors of the new research letter in JAMA Network Open, the remote curriculum delivery during the pandemic may have allowed students to create an optimal learning and testing environment, decreasing the need for accommodation.

    “Medical education was at its most flexible during COVID,” said Lisa Meeks, Ph.D., clinical associate professor of learning health sciences and family medicine at the University of Michigan Medical School.

    She adds that this could have reduced the need for testing accommodations, but it is unclear whether the need for accommodations will rise again after the recent return to in-person lectures and testing.

    Documenting the rise

    The study results are part of a long-term research project led by Meeks that follows the prevalence of medical students in the United States who disclose disabilities to their respective schools.

    This study on disability disclosure in medicine was the first large scale study of its kind, encompassing all types of disability, including psychological, learning, sensory, physical and chronic health conditions.

    Since 2015, researchers have seen an increase of medical students reporting a disability to their institution from 2.8% in 2015 to 4.7% in 2019, and to 5.9% in 2021.

    When asked to describe why we see such large increases in the population of medical students with disabilities, Meeks posited that “growth in this population could mean that we are reducing bias and stigma, and therefore people who were already in medicine are more willing to disclose.”

    “It could also mean that our research sparked a conversation to change policies, which then led to individuals with disabilities who didn’t think they could make it in medical school choosing to apply to these schools.”

    Doctors with disabilities improve patient care

    According to Meeks, there is still significant work to be done to increase the representation of doctors with disabilities in medicine.

    Only 5.9% of medical school students report a disability, but 27% of adults in the U.S. currently live with some type of disability.

    As the population ages, this number is expected to increase.

    “Physicians in the U.S. and many other countries report that they do not feel confident in their ability to provide equal quality of care to patients with disabilities as they provide to patients without disabilities,” said Karina Pereira-Lima, Ph.D., a research fellow in the Michigan Medicine neurology department.

    “The inclusion of professionals with disabilities in medicine can greatly improve the care for patients with disabilities and the health of the population overall.”

    Retaining medical trainees with disabilities

    Increasing the number of physicians with disabilities requires both the recruitment and retention of medical trainees.

    “Anonymous research with medical trainees with disability shows that about one in every five medical students and more than half of resident physicians do not request accommodations when they need them,” said Pereira-Lima.

    The two main reasons for not requesting needed accommodation were fear of stigma or bias and lack of a clear institutional process.

    “Program access, or simply having the ability to access accommodations should they need them, improves medical trainees with disabilities performance in relation to testing and patient care. It also reduces the likelihood of reporting depressive symptoms or burnout,” added Pereira-Lima.

    Meeks advocated for “standardization in support for students with disabilities in medical education.”

    “Medical education strives for parity and continuity between medical schools, but when it comes to disability services and reasonable accommodations, there’s no standardization whatsoever,” said Meeks.

    “One school could have an incredible specialized disability support services with a qualified disability resource professional running the office, while another school does not have a specialized disability support service at all.”

    ‘A wave of change’

    The team notes that addressing the second common barrier to attaining needed disability accommodations and fear of stigma or bias requires a continued culture shift in medicine.

    “Disability is still incredibly stigmatized, and ableism is rampant in medicine and medical education. At the same time, I think the work from our lab, the Association of American Medical Colleges, the Accreditation Council for Graduate Medical Education and others in medicine started a wave of change that is extraordinarily strong,” said Meeks.

    This work is bolstered by the matriculation of individuals that Meeks calls the post Americans with Disabilities Act generation into medical school.

    “This generation has a lot of disability pride. They’ve had accommodations their entire lives, they know the law, they know their rights and they’re not ashamed of being disabled,” said Meeks.

    Next steps

    As this long term study continues, the research team plans to assess how other identities interact with the disability identity.

    “People with disabilities have different racial and ethnic backgrounds, sexual orientations and socio-economic statuses. We want to learn more about how the interaction between these different identities impacts the performance and mental health of medical students with disabilities,” said Pereira-Lima. 

    Meeks adds that thanks to new funding from the Robert Wood Johnson Foundation the DocsWithDisabilities team is doing just that.

    “We’re also developing methods to measure the efficacy of accommodations. We need to do more research on the quality of received accommodations and how easy the process was for them to receive the accommodations they needed” added Pereira-Lima.

    “Investing in a culture that acknowledges disability as a valuable form of diversity will improve patient care.”

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    Michigan Medicine – University of Michigan

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  • Department of Energy grant supports inclusive high energy physics research

    Department of Energy grant supports inclusive high energy physics research

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    Newswise — The new project creates opportunities for researchers from historically underrepresented groups to develop technology that will help us understand the forces behind an expanding universe.

    The U.S. Department of Energy’s (DOE) Argonne National Laboratory and the Missouri University of Science and Technology (Missouri S&T) have been awarded funding for a program that aims to generate insights about the universe while expanding diversity in the high energy physics field.

    Through the $589,000, three-year grant from DOE’s Funding for Accelerated, Inclusive Research (FAIR) initiative, the research team will create a computer modeling framework to map a set of distant galaxies known as emission line galaxies. The grant also supports the participation of students from historically underrepresented groups.

    Shun Saito, assistant professor of physics at Missouri S&T, is leading the research project with Andrew Hearin, an Argonne physicist, as the DOE national laboratory partner. The goal is to unravel some of the mystery surrounding dark energy, the force thought to drive the universe’s accelerated expansion.

    “You really need supercomputing resources to be able to make predictions for galaxies in the large volumes we are simulating. Our modeling approach has been designed from the ground up to do exactly that.” — Andrew Hearin, Argonne physicist

    The project relates to the DOE-funded Dark Energy Spectroscopic Instrument (DESI), which is measuring the trajectory of this expansion by mapping emission line galaxies. Emission lines are light signals emanating from galaxies across billions of years. These lines can be used in mapping the galaxies and determining their histories. Saito and team will build a simulation-based framework to predict a clustering pattern of faraway emission line galaxies that can then be used to understand the nature of dark energy.

    “In the last decade, we have seen a lot of progress in measuring the nearby universe,” Saito said. ​“Now we want to locate more distant galaxies to fully map out the evolution of cosmological expansion.”

    The research will take advantage of high performance computing at Argonne’s Laboratory Computing Resource Center.

    “You really need supercomputing resources to be able to make predictions for galaxies in the large volumes we are simulating,” Hearin said. ​“Our modeling approach has been designed from the ground up to do exactly that.”

    The project continues efforts by Saito and Hearin, who are longtime collaborators, to create a more inclusive community of high energy physics researchers. In 2019, they founded the Midwest Cosmology Network to provide a collaborative forum for researchers who belong to relatively small, isolated cosmology groups at colleges and universities.

    In addition to research positions for one undergraduate, doctorate and postdoctorate student each, the program will also enable the collaborative work at Argonne.

    The resulting framework and data will be available to other researchers who seek to analyze data from DESI and similar surveys. ​“People working on understanding galaxies can use the catalogs generated by this project,” Saito said.

    In total, the DOE Office of Science awarded $37 million in funding to 52 projects representing 44 institutions. Hearin’s and Saito’s project is one of 10 projects affiliated with Argonne to receive this funding. The FAIR initiative aims to build research capacity, infrastructure and expertise at institutions historically underrepresented in the Office of Science portfolio, including minority serving institutions and emerging research institutions.

    Argonne National Laboratory seeks solutions to pressing national problems in science and technology. The nation’s first national laboratory, Argonne conducts leading-edge basic and applied scientific research in virtually every scientific discipline. Argonne researchers work closely with researchers from hundreds of companies, universities, and federal, state and municipal agencies to help them solve their specific problems, advance America’s scientific leadership and prepare the nation for a better future. With employees from more than 60 nations, Argonne is managed by UChicago Argonne, LLC for the U.S. Department of Energy’s Office of Science.

    The U.S. Department of Energy’s Office of Science is the single largest supporter of basic research in the physical sciences in the United States and is working to address some of the most pressing challenges of our time. For more information, visit https://​ener​gy​.gov/​s​c​ience.

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  • Nematodes joy ride across electric voltages

    Nematodes joy ride across electric voltages

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    Newswise — Hokkaido University researchers found that tiny nematode worm larvae surf electric fields to hitch rides on passing insects.

    Many living organisms are known to make use of electric fields. Some fish species use them to detect predators or prey, and insects such as bees use them to attract pollen while foraging. Now, a research group including scientists from Hokkaido University has discovered that juvenile nematode worms can surf electric fields to leap through the air and hitch a ride on passing insects. Their findings have been published in the journal Current Biology.

    Nematodes are one of many species that rely on larger animals to help them travel and disperse, an interaction called phoresy. They have been observed lifting themselves up on the tips of their tails (nictation), thus reducing their surface connection, to make it easier to attach themselves to a passing organism.

    To explore how they achieve this, the research team bred the nematode worm Caenorhabditis elegans on dog food in a petri dish. They noticed that the larvae of the nematode, called dauer larvae, consistently moved to the lid of the dish. Some of the larvae reached the lid by crawling up the side of the dish, and others appeared on the lid in a fraction of a second.

    “To more directly confirm the leap of C. elegans dauer larvae and to see how the worms leap in the dish and the characteristics of the leaping action, we observed a worm leaping in the Petri dish with a high-speed camera,” says Associate Professor Katsuhiko Sato at the Research Institute for Electronic Science, Hokkaido University, corresponding author of the study.

    This showed that the larvae kept its body quite straight before the leap, and a single dauer larvae engaged in this behavior could also carry several other larvae with it in a leap.

    The research team speculated that the nematode larvae might be using electrostatic forces to travel across the millimeters-wide gap between the substrate and the lid of the petri dish. They set up an experiment using a petri dish filled with agar and studded with tiny glass electrodes, with a separate glass electrode set up parallel to it. The larvae were placed on the agar, and the researchers applied different voltages to the two sets of electrodes to see how the larvae would behave.

    When no electric charge was applied, the larvae did not leap. But when an electric field above a certain voltage was applied, the nematodes leapt from one electrode to another at an average speed just under one meter per second.

    They then performed a second experiment using the bumblebee Bombus terrestris, which is known to use electrostatic charge to help it collect pollen, and saw the same leaping behavior when the bumblebee came with one to two millimeters of the nematode larvae.

    “Although C. elegans has not been reported to attach to bees, it is known to attach to flying insects such as moths and flies in the wild,” Sato notes. “We assume that C. elegans uses electric interactions to attach to insects, including bumblebees, in the wild.”

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    Hokkaido University

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  • A new look inside Ebola’s “viral factories”

    A new look inside Ebola’s “viral factories”

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    Newswise — LA JOLLA, CA—New research in the journal Nature Communications gives scientists an important window into how Ebola virus replicates inside host cells. The study, led by scientists at La Jolla Institute for Immunology (LJI), reveals the inner workings of “viral factories,” clusters of viral proteins and genomes that form in host cells.

    The research team, which included experts from Scripps Research and UC San Diego School of Medicine, found that Ebola virus’s replication machinery forms fascinating microscopic structures that become viral factories. By understanding the architecture and function of these microscopic manufacturing hubs, researchers may be closer to developing new therapies that interrupt the Ebola virus life cycle and prevent severe disease.

    “We are imaging these fluid and dynamic assembly centers for the first time. Understanding how they work and what they require gives us the information needed to defeat them,” says LJI President and CEO Erica Ollmann Saphire, Ph.D., senior author of the new study.

    What is a viral factory?

    Scientists first spotted what would turn out to be “virus factories” in virus-infected animal cells back in the 1960s, but they didn’t know what they were seeing. Within a sea of normal cellular proteins, these areas looked like fuzzy splotches.

    “People had already seen that Ebola-infected cells had these ‘inclusions,’” says LJI Postdoctoral Researcher Jingru Fang, Ph.D., first author of the new study. For a long time, scientists thought of these “inclusions” as helpful visual indicators of infection, without understanding their true purpose. “But in fact, these ‘inclusion bodies’ actively gather an enormous quantity of viral proteins and viral RNAs.”

    Many viral pathogens, including rabies virus and RSV (respiratory syncytial virus) form inclusions in host cells, Fang explains. “Recent studies suggest that these cellular inclusions are the site where viruses make their RNA genomes. They are ‘viral factories’ with actual functional purpose: to offer a secured space for viral RNA synthesis,” says Fang. “The process of viral RNA synthesis involves flux of viral building blocks. This means molecules gathered inside viral factories should be able to move freely rather than being static.”

    For the new study, Saphire, Fang and their colleagues wondered: Can we observe the movement of viral building blocks directly in living cells?

    Fang began by tagging a viral protein called VP35 with a fluorescent marker that makes the protein glow in the dark. VP35 is a critical component of the viral factory and is important for viral RNA synthesis (and the making of new copies of Ebola virus). Working with imaging experts in the LJI Microscopy and Histology Core, Fang followed the glowing proteins in live cells, which express a simplified and non-infectious version of Ebola viral factories.

    Under the microscope, Fang and colleagues could indeed see and even measure how molecules move inside the viral factories formed in host cells. This finding added evidence that viral proteins are clumping together like droplets so they can churn out the proteins needed to help the virus replicate. Those mysterious inclusions really are viral factories. The researcher dubbed these “droplet-like” viral factories.

    Then the scientists saw something odd. Some of the glowing proteins didn’t gather into clumps. Instead, they joined up with a smattering of other viral proteins, creating a fluorescent swirl that evoked van Gogh’s “Starry Night.” These trails of viral proteins still had the right ingredients to replicate Ebola virus, so the scientists dubbed them “network-like” viral factories.

    “These are two different flavors of the viral factory,” says Fang. “People have mostly focused on the droplet-like form, which is the majority, and not paid too much attention to this other form.”

    Besides their shapes, there was a key difference between the two factories. It appeared the network-like factories had the right ingredients for the incoming Ebola virus to express its genes, but they didn’t actually produce virus progenies.

    A multi-tasking machine

    Next, the researchers looked at a key player in infection: a protein called virus polymerase. Polymerase is a multifunctional nanomachine that comes with the virus. This machine not only copies the Ebola virus genomic material, it also transcribes the viral genome into messenger RNAs, which instruct infected cells to produce loads of viral proteins. The researchers wanted to understand how this viral machine functions inside viral factories.

    Ebola virus polymerase is already known as a hard-working protein—all Ebola viral proteins have to be. Ebola virus is a highly efficient pathogen because it gets by with just seven genes (humans have more than 20,000 genes). Saphire has led research showing that Ebola virus survives by making proteins that can transform and take on different jobs during the course of infection.

    Just last year, Saphire, Fang, and collaborators published a related discovery that viral polymerase actually harnesses a druggable human protein to help the virus replicate its genome. The team reported that while polymerase is essential for viral replication, the polymerase doesn’t actually jump into action until infection is well underway.

    This work was important for understanding how polymerase stepped into action, but scientists also needed to know where polymerase was active. Fang knew it would be important to look at what polymerase might be up to in viral factories.

    The researchers discovered that polymerase actually builds its own special structures inside viral factories. Many copies of polymerase gather in small bundles, called foci. The researchers found that these bundles spread out when a droplet-like viral factory starts replicating viral material.

    Scientists aren’t sure exactly why polymerase needs to form bundles before it can do its job, but the spatial arrangement of the bundles must be important. As Fang points out, the idea of many small components coming together to build a structure isn’t a new concept in nature. “You can use a beehive or coral reef as the analogy to help understand why a specific spatial arrangement is important for a biological system to function,” she says.

    With this finding, scientists now know how to find different kinds of viral factories and how polymerase organizes itself down on the factory floor.

    Fighting back

    More than 30 human pathogens are known to assemble viral factories inside host cells, including respiratory syncytial virus (RSV) and even rabies virus. With this new view of Ebola’s viral factories, the scientists are curious whether other viruses construct similar forms of viral factories—and whether other viruses use their own versions of polymerase in the same way.

    “If that’s true, maybe we can target the feature of viral factory formation that has been shared by multiple different viruses,” says Fang.

    Going forward, Fang would also like to study how Ebola virus forms viral factories in different kinds of host cells. Do these viral factories look different in cells from animals (such as the virus’s natural hosts, the fruit bats) that can carry the virus around without getting sick? “Can we find some explanation for host-specific viral pathogenesis?” she asks.

    The new study also demonstrates the importance of collaboration across San Diego’s Torrey Pines Mesa. The LJI team worked closely with Scripps Research Professor Ashok Deniz, Ph.D., and UC San Diego Professor Mark H. Ellisman, Ph.D., Director of the National Center for Microscopy and Imaging Research.

    “The combination of state-of-the-art tools available on the Torrey Pines Mesa allowed us to combine the biophysical characterization with the human health insight,” says Saphire

    Additional authors of the study, “Spatial and functional arrangement of Ebola virus polymerase inside phase-separated viral factories,” include Guillaume Castillon, Sebastien Phan, Sara McArdle, Chitra Hariharan, and Aiyana Adams.

    This study was supported by the National Institute of Health (grants NIH S10OD021831, R24GM137200, and S10OD021784), an Imaging Scientist grant (2019‐198153) from the Chan Zuckerberg Initiative, LJI institutional funds, and the Donald E. and Delia B. Baxter Foundation Fellowship.

    DOI: 10.1038/s41467-023-39821-7

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    About La Jolla Institute

    The La Jolla Institute for Immunology is dedicated to understanding the intricacies and power of the immune system so that we may apply that knowledge to promote human health and prevent a wide range of diseases. Since its founding in 1988 as an independent, nonprofit research organization, the Institute has made numerous advances leading toward its goal: life without disease. Visit lji.org for more information.

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  • Prestigious NSF Grants Awarded to UTEP Early-Career Faculty

    Prestigious NSF Grants Awarded to UTEP Early-Career Faculty

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    Newswise — EL PASO, Texas (Aug. 8, 2023) – Two University of Texas at El Paso researchers have earned one of the nation’s highest awards for early-career faculty in 2023.

    Laura Alvarez, Ph.D., an assistant professor in the Department of Earth, Environmental and Resource Sciences, received a $550,000 grant from the National Science Foundation’s (NSF) Faculty Early Career Development (CAREER) Program. The funds will support her research in understanding how river landscapes and their ecological and economic values such as hydroelectric power generation, water storage and recreational resources respond to severe droughts, floods, climate change and human interventions.

    Deepak K. Tosh, Ph.D., assistant professor in the Department of Computer Science, received a grant of $492,000 from the same program. The award will support his work toward enhancing the cyber resiliency of operational technology around critical national infrastructure such as powerplants, refineries and manufacturing facilities. The research also aims to provide a means to achieve global resiliency by sharing information among physically separated entities.

    “CAREER awards are very prestigious,” said Ahmad Itani, Ph.D., UTEP vice president for research. “Earning one is a remarkable achievement for any research institution, and it serves as further evidence of the superb quality of the research and instruction UTEP faculty offer.”

    The NSF CAREER Program recognizes junior faculty who have the potential to serve as role models in research and education. For her part, Alvarez will work with students to develop and implement models that allow the quantification and forecasting of the flow and sediment dynamics in field-scale rivers. The expected societal outcomes of the education component are focused on increasing the representation of women in Earth science and creating new literacy in gender equity.

    “With the support of this grant, my research and educational pursuits find validation, further affirming my dedication as a teacher-scholar. I am excited to embark on this journey, using it as a catalyst to synergize research and education to drive positive transformation within UTEP’s mission,” said Alvarez. “I am profoundly humbled and grateful for being a recipient of the National Science Foundation CAREER award.”

    The education plan in Tosh’s project aims to bolster critical infrastructure security skills among the next generation of engineers via the development of hands-on training modules for undergraduate and graduate students from various disciplines, cyber research immersion programs for community college students and summer training sessions for middle and high school teachers.

    “Developing cyber secure operational technology for critical infrastructure has been the core pillar of my research agenda,” said Tosh. “Therefore, this award is an important personal milestone of which I am absolutely proud. I’d like to thank NSF and my colleagues for all their support.”

    Alvarez’s and Tosh’s awards follow the NSF CAREER grant awarded in May to Alexander Friedman, Ph.D., assistant professor in the Department of Biological Sciences, in support of his work on the neural mechanisms of decision-making.

    About The University of Texas at El Paso

    The University of Texas at El Paso is America’s leading Hispanic-serving University. Located at the westernmost tip of Texas, where three states and two countries converge along the Rio Grande, 84% of our 24,000 students are Hispanic, and half are the first in their families to go to college. UTEP offers 169 bachelor’s, master’s, and doctoral degree programs at the only open-access, top-tier research university in America.

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  • Rocky Mountain Center for Occupational and Environmental Health Earns $8.6 Million Grant to Protect Workers

    Rocky Mountain Center for Occupational and Environmental Health Earns $8.6 Million Grant to Protect Workers

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    BYLINE: Bubba Brown

    Newswise — The Rocky Mountain Center for Occupational and Environmental Health (RMCOEH), a partnership between the University of Utah and Weber State University and one of the nation’s leading centers focused on the health and safety of workers and their environment, was recently awarded an $8.6 million grant that will allow it to further a mission that touches tens of thousands of people each year in Utah and across the West.  

    The purpose of the funding, from the National Institute for Occupational Safety and Health, is to provide students with graduate-level training in occupational and environmental health and safety, offer continuing education to professionals and businesses, and perform research that moves the needle on topics related to worker health and safety. RMCOEH is one of 18 NIOSH-sponsored Education and Research Centers in the U.S. RMCOEH has received funding from NIOSH since the center’s founding in 1977 and must reapply for the grant through a competing renewal process every five years. 

    “We are grateful for our partnership with NIOSH and pleased that we continue to demonstrate our ability to turn grant money into real-world impacts that improve lives of workers and aid businesses,” said Kurt Hegmann, M.D., who has directed RMCOEH since 2003. “We’re here to make sure as many workers as possible return to their families, healthy and whole, at the end of the day. That’s a responsibility that we, as well as the folks at NIOSH, take seriously.” 

    RMCOEH uses the NIOSH funding to support its academic programs in Occupational Medicine, Ergonomics and Safety, Industrial Hygiene, Occupational Injury Prevention, and Targeted Research Training, all housed at the University of Utah, as well as its Continuing Education program at Weber State. The grant also funds Outreach and Pilot Project Research Training initiatives.

    Since its inception, RMCOEH has produced 781 graduates from its degree programs. The vast majority of the center’s trainees assume professional positions in which they typically work to improve the health and safety of thousands of workers. The center’s Continuing Education and Outreach efforts, meanwhile, have touched an annual average of 93,000 people and 8,200 businesses over the last five years.

    RMCOEH’s research impacts are just as vast. Faculty and trainees publish approximately 80 peer-reviewed papers a year, producing groundbreaking work on topics ranging from musculoskeletal disorders among workers to wearable robotics that may enable people with debilitating conditions to return to work. During the pandemic, the center helped lead research on COVID-19 that resulted in two peer-reviewed articles in The New England Journal of Medicine, the world’s most prestigious medical journal, as well as several other papers. 

    “We’re immensely proud of what we have accomplished,” said RMCOEH Deputy Director Matthew Hughes, M.D. “It takes contributions from everyone involved with the center at both universities. It’s exciting to think about where we will be a few years from now when we are applying for this grant again.”

    This NIOSH award marks the first time RMCOEH has earned the funding as a multi-university partnership. After the center operated solely at the University of Utah for most of its existence, the Utah Legislature in 2021 passed a law bringing Weber State into its operating structure. Buoyed by the partnership, the first of its kind in Utah, RMCOEH has entered an era of growth that is unique in its history.

    The center is currently launching an Occupational Health Nursing graduate certificate program at Weber State alongside a bachelor’s degree in occupational safety and health. It will add graduate degree programs in Mining Safety and Occupational Health Psychology at the University of Utah next year. RMCOEH intends to apply for supplemental NIOSH support for the three new graduate-level offerings this fall.

    “Put simply, RMCOEH would not exist without the support NIOSH has given us over the last 40-plus years, and would certainly not have established such a remarkable legacy,” Hegmann said. “We are gratified that NIOSH continues to entrust us to carry out our mission, and we will do all we can to ensure that workers and employers would agree that it is money well spent.”

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    University of Utah Health

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