The Consortium of Rural States (CORES) Research Collaborative, which includes UAMS, recently released its interinstitutional pilot award request for applications (RFA), with up to $25,000 available per award per participating institution.

All UAMS-affiliated faculty are invited to apply, including those based at Arkansas Children’s Research Institute and the Central Arkansas Veterans Healthcare System.

Letters of intent are due Jan. 19, 2024.

The interinstitutional pilot awards involve eight institutions with Clinical and Translational Science Awards (CTSA). In addition to UAMS, the collaborative includes Dartmouth College, Penn State University, the University of New Mexico Health Sciences Center, University of Kansas Medical Center, University of Kentucky, University of Iowa, and the University of Utah Health.

The RFA requires the participation of at least two of the CORES institutions on each pilot application.

Funding emphasis for this RFA will be given to proposals that address one of the following: Climate change and environmental health; health equity for underrepresented populations; rural health; and maternal health.

Read the Request for Applications.

Contact: Crystal Sparks, CSparks@uams.edu. 

The Translational Research Institute (TRI) is pleased to invite applications for its K12 (formerly KL2) Mentored Research Career Development Scholar Award Program.

K12 scholars receive two years of didactic and mentored research training, including 75% salary support (up to $100,000) and $25,000 each year for research related expenses such as supplies, travel, etc.

The overall goal of the program is to increase the number and quality of independently funded clinical and translational science investigators.

Letters of Intent are due Feb. 1, 2024.

Early-career researchers are encouraged to attend the K12 Program information session on Wednesday, Dec. 13, 2-3 p.m., via Zoom. 

During the session, K12 program leaders John Arthur, M.D., Ph.D., Elisabet Borsheim, Ph.D., and Mario Schootman, Ph.D., will provide an overview and answer questions about this prestigious translational research training program.

Register here for the information session.

Read the 2024 K12 RFA here.

Contact: Nik Berardi, NDBerardi@uams.edu

Alberto Ramirez, Ph.D., was excited to attend Research Expo 2023, with its 50 research services and resources on display.

“As an early-career researcher, the event proved to be remarkably valuable as it allowed me to gain insight into the numerous resources offered by UAMS, including TRI, Research & Innovation, and more, which have the potential to greatly support my nascent research journey,” said Ramirez, a postdoctoral fellow in the College of Medicine Department of Obstetrics and Gynecology.

Sponsored by the Translational Research Institute (TRI), the Oct. 11 event at the UAMS Jackson T. Stephens Spine & Neurosciences Institute building drew 114 attendees who got to visit with leaders of all the key research services at UAMS, Arkansas Children’s Research Institute (ACRI) and Central Arkansas Veterans Healthcare System (CAVHS).

“This expo is great for new faculty members like me who are conducting research,” said Lipika Sarangi, Ph.D., an assistant professor in the College of Health Professions Department of Audiology & Speech Pathology. “It’s wonderful to have an event where you can meet new people, build your network, and find exactly the information that might be useful for your research today or in the future.”

For example, she was able to learn how to access potential research volunteers in the ARresearch database established by TRI. The database includes more than 9,000 Arkansans who have agreed to be contacted for research studies.

“They told me the process, and I will definitely use ARresearch in the future,” she said. “The resources I have found here will be very helpful for participant recruitment, grant writing and manuscript writing. I am looking forward to using these resources for my independent and collaborative research.”

Emel Seker, M.S., an applications system analyst in the College of Medicine, said the expo provided a unique opportunity to discover cutting-edge resources and connect with individuals who share a passion for research.

“The expo was an invaluable experience for me, underscoring the significance of collaborative platforms in research,” Seker said. “I was particularly impressed by the number of representatives from various research services. Meeting like-minded professionals who are not only knowledgeable but also open to collaboration was a highlight. I believe these connections have the potential to lead to meaningful collaborations in the future.”

Ramirez said he was particularly interested in the opportunities available to assist with the grant-writing process and the potential benefits of the TRI Community Engagement Program. “I am definitely planning to establish connections with these resources.”

In addition, he said, “the event emphasized the importance of networking, facilitating connections among all the stakeholders involved in the research process, from the initial spark of an

idea in the researcher’s mind to the practical implementation of results, all aimed at making a positive impact on the community.”

TRI is supported by the National Center for Advancing Translational Sciences at the National Institutes of Health, Clinical and Translational Science Award number UL1 TR003107.

Before the terms “life-course” and “lifespan” research became more commonplace, Rosalind Wright, M.D., MPH, began studying how early-life experiences were contributing to the conditions she was seeing in her adult pulmonary patients.

Wright, a research leader at the Icahn School of Medicine at Mount Sinai, was a keynote speaker for the inaugural Advancing Arkansas Lifespan Research Conference in September, sponsored by TRI, Arkansas Children’s Research Institute (ACRI), and the Lifespan Cardiometabolic Health Creativity Hub in the College of Medicine.

To help make her case for lifespan research, she invoked the quote, “It’s easier to build strong children than to repair broken men.” 

“When I’m taking care of patients in their 40s, 50s and 60s and they’ve already got multiple comorbidities and their lungs are shot, there’s only so much I can do,” she told a diverse audience of UAMS-affiliated researchers at the Robinson Center in Little Rock. “But if we pursue this life-course perspective, we have a real opportunity to make a difference.”

Wright is dean for Translational Biomedical Sciences and holds the Horace W. Goldsmith Professorship in Children’s Health Research at Mount Sinai Kravis Children’s Hospital and principal investigator for the Institute for Clinical and Translational Sciences at the Icahn School of Medicine. She is a developmental epidemiologist with transdisciplinary training in environmental health and stress mechanisms.

Wright gave one of three keynote presentations during the Sept. 13, 14 conference.

Other keynote speakers were Fred Prior, Ph.D., distinguished professor and chair of the UAMS College of Medicine Department of Biomedical Informatics, and Amanda Dettmer, Ph.D., a research scientist at the Child Study Center, Yale School of Medicine.

Elisabet Borsheim, Ph.D., Laura James, M.D., and Peter Mourani, M.D., served as the event’s moderators. 

Borsheim, a professor in the College of Medicine departments of Pediatrics and Geriatrics, leads the Cardiometabolic Health Creativity Hub.

James is TRI director and UAMS associate vice chancellor for Clinical and Translational Research.

Mourani is president of ACRI and senior vice president and chief research officer for Arkansas Children’s.

Life-course research is a key part of ACRI’s strategic plan and it is advocated by the NIH and its National Center for Advancing Translational Sciences (NCATS) to strategically promote health and combat diseases as they progress across the lifespan.

ARLife

Prior’s presentation introduced an exciting new data integration system called ARLife that will be key to lifespan research for UAMS-affiliated researchers.

“ARLife is the first baby step toward building an informatics and data management resource that allows us to really do lifespan research effectively here in Arkansas, to be able to track all of our people across their lifespan,” he said.

It will be pilot tested as part of a new life-course research grant opportunity announced during the conference. The one-year $100,000 award is being offered by ACRI with funds from the Arkansas Biosciences Institute.  

Prior and his team have expertise in data integration having led development of similar tools and processes nationally and internationally.

“We’re using what we’ve learned to crosslink databases in a privacy-preserving way,” Prior said.

ARLife can link and harmonize electronic health records data from UAMS, Arkansas Children’s Hospital, and the UAMS Arkansas Center for Health Improvement, which maintains the Arkansas All-Payer Claims Database.

Dettmer said the CTSA-funded Yale Center for Clinical Investigation (YCCI) is working to harmonize datasets and find collaborating institutions as part of the effort.

“We’re really keen to foster collaborations with other CTSAs so that we can show NCATS that we’re collaborating across CTSAs to really leverage existing resources to spawn and launch lifespan research,” she said.

Primate Studies

The YCCI lifespan initiative emphasizes critical developmental periods and how early-life stress may impact typical biological development and lifelong health.

One of the challenges studying humans, Dettmer said, is that much of the work necessarily relies on retrospective accounts, and if the studies are prospective it takes decades to get age-related health outcomes.

Long-term research at Yale with rhesus monkeys, which have about a 30-year lifespan, can be an important complement to human lifespan studies, she said.

“Rhesus monkeys are an extremely valuable comparative and causal model for lifespan health,” she said.

Conference attendee and poster presenter Andrew Brown, Ph.D., was excited to see UAMS and ACRI-based researchers come together with wide-ranging expertise for conducting lifespan research.

“The conference was an inspiring collaboration between ACRI and TRI that really walked the talk of needing to work across disciplinary silos if we want to improve the lives of Arkansans,” said Brown, associate professor in the Department of Biostatistics and a biostatistics core director for the Center for Childhood Obesity Prevention at ACRI.

He said the announcement of the $100,000 grant demonstrates the commitment to lifespan research.

The conference also included a poster session as well as oral presentations from Keshari Thakali, Ph.D., Steven Barger, Ph.D., Jamie I. Baum, Ph.D., Ashley Acheson, Ph.D., Tatiana Wolfe, Ph.D., and Craig Porter, Ph.D.

In this issue of The TRIbune, we feature a research project co-led by one of our KL2 scholar graduates, Taren Swindle, Ph.D., that is utilizing the resources of the UAMS Rural Research Network. Swindle and Lorraine McKelvey, Ph.D., are using the network to study an expansion of their innovative nutrition education program, Together, We Inspire Smart Eating (WISE).

This issue also includes our Study of the Month, featuring a multi-site stroke study led at UAMS by Sanjeeva Onteddu, M.D., with research services provided by TRI.  

We also highlight the results of our Summer Writing Challenge 2023, which concluded with an ice cream celebration and award ceremony.

Read The TRIbune. 

The UAMS Translational Research Institute (TRI) and UAMS Division of Diversity, Equity, and Inclusion (DDEI) recently named five scholars for the 2023 Strategies for Training and Advancing underrepresented Researchers (STARs) Program.

The scholars and their project titles are:

The STARs program enables eligible faculty to build on their research skills and grantsmanship. Program participants receive $10,000 in Equity, Diversity, and Grantsmanship Expertise (EDGE) funding for a research project upon completion of the STARs didactics.

Shuk Mei-Ho, Ph.D., vice chancellor for UAMS Research and Innovation, provided funding to support a fifth STARs scholar this year.

The program is available to faculty who meet the NIH definition of underrepresented individuals in the scientific workforce. This includes faculty from racial and ethnic groups, individuals with disabilities, and those from disadvantaged backgrounds. All UAMS-affiliated researchers are eligible to apply.

The three-month program is led by faculty with extensive grant-writing and mentorship experience:

Antiño R. Allen, Ph.D., professor, UAMS College of Pharmacy, associate director of Diversity Initiatives at TRI, leads the STARs program didactics. He is also associate dean of Pipeline and Career Development at the Graduate School

Mario Schootman, Ph.D., professor, Department of Medicine, UAMS College of Medicine; co-director, TRI Workforce Development, serves as a STARs program reviewer and mentor.

Jessica Snowden, M.D., M.S., professor and chief, Division of Pediatric Infectious Diseases; vice dean for Research, UAMS College of Medicine; co-director, TRI Workforce Development, serves as a STARs program reviewer and mentor.

To learn more about the STARs program, its eligibility criteria, and the benefits it offers, please visit the program’s webpage https://tri.uams.edu/funding-opportunities/stars-program.

At the COVID-19 pandemic’s start, there were no proven, effective medications to treat the disease. In the search for therapies, repurposing existing drugs offered a faster route to answers than developing drugs from scratch. Scientists scoured drug compound catalogs for contenders that worked in ways that might show promise against COVID-19.

Metformin was just such a contender.

NCATS’ role in finding and testing metformin as a treatment for COVID-19 has spanned the entire drug development process — from early observational studies all the way to large-scale clinical trials. Now, the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) partnership’s ACTIV-6 clinical trial, overseen by NCATS, is testing metformin as an outpatient treatment for people with mild-to-moderate COVID-19. Metformin’s addition to the nationwide ACTIV-6 testing lineup could bring clarity to the drug’s value in treating COVID-19 and potentially preventing long COVID.

“By leveraging our networks and data-driven tools, we are speeding the delivery of important answers on metformin’s ability to help people manage acute and long COVID symptoms,” said NCATS Director Joni L. Rutter, Ph.D. “These innovative approaches to study existing therapies could provide a foundation for integrating clinical trial and real-world data to get definitive answers from future clinical studies faster.”

The Case for Metformin in COVID-19

Metformin is a mainstay in type 2 diabetes treatment. Effective, safe and affordable, metformin does more than just moderate blood sugar levels. Metformin also suppresses key molecules that promote inflammation and blood clots. Those pro-inflammatory molecules contribute to type 2 diabetes and obesity — conditions that are primary risk factors for more severe COVID-19. Metformin may also have relevant antiviral activity. Research has shown that metformin blocks SARS-CoV-2 from replicating itself.

These properties spawned a hypothesis. If metformin reduces the inflammatory molecules that drive COVID-19 and the conditions known to increase COVID-19 risk, and if it also has antiviral activity, the diabetes drug might be repurposed as an effective COVID-19 treatment.

Observational Glimmers of Promise

Observational studies early in the COVID-19 pandemic pointed to just such potential.

In a 2020 review, NCATS Clinical and Translational Science Awards (CTSA) Program-supported researcher Carolyn Bramante, M.D., assistant professor of medicine at the University of Minnesota, and her colleagues examined electronic health records (EHRs) from adults with type 2 diabetes or obesity. They found that women taking metformin before they developed COVID-19 were significantly less likely to die after being hospitalized — although men didn’t see the same protective effect. Another 2021 observational study of EHRs found that people with diabetes who were on metformin when they developed COVID-19 were significantly less likely to die from COVID-19.

The NCATS National COVID Cohort Collaborative (N3C) enclave of EHR-derived data powered two large studies that reinforced a potential link between metformin and less-severe COVID-19 outcomes. One study of EHRs from more than 6,600 adults found that those with type 2 diabetes who were taking metformin before developing COVID-19 were less likely to be hospitalized, need mechanical ventilation or die. A second study of people with either prediabetes or polycystic ovary syndrome (a condition commonly treated with metformin) showed that metformin use was linked to less severe COVID-19.

Observational studies usually aren’t enough to change medical practice, however. Metformin would have to deliver results in large randomized, placebo-controlled trials specifically designed to answer the question of whether metformin is helpful for treating COVID-19.

Two such trials, TOGETHER and COVID-OUT, would give metformin the chance to prove itself as an effective COVID-19 treatment.

TOGETHER Trial: The First Clinical Test

Metformin’s first large randomized, placebo-controlled clinical trial was the TOGETHER trial —and it didn’t deliver clear evidence of effectiveness against COVID-19.

TOGETHER put a handful of repurposed drugs to the test as COVID-19 treatments in high-risk people in low- and middle-income countries. In TOGETHER’s metformin arm, researchers randomized high-risk adults in Brazil with COVID-19 to outpatient care with either metformin or placebo. Those on metformin took a 750-mg dose twice a day — 1,500 mg daily — for 10 days.

In their published results, the TOGETHER trial researchers found no benefit to back metformin as an outpatient treatment for early-stage COVID-19. Among the 418 people in the trial’s metformin arm, metformin didn’t significantly top placebo at reducing hospitalization or delivering better clinical improvement after 28 days.

Among those who stuck with the TOGETHER trial’s 1,500-mg dosing treatment regimen, data in the study’s appendix did show metformin presented an advantage over placebo.

COVID-OUT: Metformin Shows Promise

The 2022 COVID-OUT trial put metformin to a second test. Bramante and her fellow researchers conducted the trial at six sites in the United States. The COVID-OUT research team relied in part on grants from NCATS, as well as regulatory and logistical support from the University of Minnesota’s Clinical and Translational Science Institute, a CTSA Program-funded institution.

Participants were age 30–85 years, overweight or obese, and had a new COVID-19 diagnosis. COVID-OUT’s primary goal was to see how many people went on to develop severe disease after 14 days of outpatient treatment. Four factors defined “severe” COVID-19: low blood oxygen levels, tested by people at home; an emergency department visit; hospitalization; or death.

Like TOGETHER, COVID-OUT tested multiple repurposed drugs. Three groups of people were randomized to receive metformin in combination with fluvoxamine, ivermectin or placebo. A fourth group received placebo. Two more groups received either ivermectin or fluvoxamine with placebo.

Rather than starting at the TOGETHER Trial’s 1,500-mg daily metformin dose, COVID-OUT began lower and raised metformin doses over 6 days to reach the 1,500-mg level, where it remained through 14 days. The COVID-OUT trial also used immediate-release metformin, which has a higher systemic peak than the extended-release formulation used in the TOGETHER trial.

The COVID-OUT researchers analyzed data from 1,323 people who enrolled in the trial between December 2020 and January 2022. None of the three drugs — including metformin — significantly reduced people’s risk of severe COVID-19, compared with placebo.

Metformin’s outlook changed, however, when the researchers removed potentially problematic patient-measured oxygen levels from their definition of severe COVID-19. After the trial’s start, the U.S. Food and Drug Administration issued a safety communication on pulse oximeters’ accuracy.

When the researchers excluded low blood oxygen levels, people with COVID-19 who took metformin were 42% less likely to end up in the emergency department, hospitalized or dead. The effect was even greater when the researchers focused on the numbers for hospitalization or death — a 53% reduction with metformin.

COVID-OUT Zooms in on Long COVID

COVID-OUT’s results pointed to more than therapeutic potential in the early stages of COVID-19. In a separate research question, the investigators assessed the development of long COVID — the signs, symptoms, and conditions that linger or start after COVID-19 infection. Metformin use also showed links to lower rates of long COVID.

The COVID-OUT researchers followed study participants months after treatment. Among the 1,126 people followed long-term, 8.3% developed long COVID by 10 months. But those who took metformin for early-stage COVID-19 were 41% less likely to later develop long COVID (6.3% of people) than the people who received placebo (10.4% of people).

Metformin’s effect on reducing the risk of long COVID held regardless of people’s sex, body mass index, whether a person had been vaccinated, or the dominant SARS-CoV-2 variant during treatment. People who started metformin within three days of the start of COVID-19 symptoms were less likely to develop long COVID than those who started four or more days after their symptoms began.

ACTIV-6 Could Bring Greater Clarity

In the wake of TOGETHER and COVID-OUT, the ACTIV-6 trial could bring greater clinical-trial clarity on metformin.

ACTIV-6 is a large, randomized, placebo-controlled phase 3 clinical trial testing medications to treat mild-to-moderate COVID-19 in an outpatient setting. The trial is a public-private partnership that has already tested fluticasone, two dosages of fluvoxamine, and two dosages of ivermectin. None of those drugs delivered therapeutic benefit, compared with placebo, in ACTIV-6. A trial arm testing montelukast recently completed enrollment.

The trial’s new metformin arm(link is external) opened for enrollment Sept. 5, 2023. NCATS oversees ACTIV-6, and key players in the trial’s operations include CTSA Program-funded institutions. The Duke Clinical Research Institute is the ACTIV-6 clinical coordinating center, and the Vanderbilt Institute for Clinical and Translational Research is the trial’s data coordinating center. Other CTSA Program institutions are part of the trial’s enrollment treatment network, as is the Patient-Centered Outcomes Research Institute-funded National Patient-Centered Clinical Research Network (PCORnet)(link is external).

The metformin trial arm will have two primary outcomes. The first will be the time to sustained recovery from COVID-19 symptoms, assessed for up to 28 days after the start of treatment. The second will be hospitalization or death among study participants, also measured for up to 28 days. In addition, ACTIV-6 researchers will assess whether metformin prevents urgent care and emergency department visits, as well as any effects on quality-of-life measures. Those quality-of-life assessments will extend to six months after treatment begins. Researchers will use the trial’s extended follow-up to explore potential links between metformin treatment and symptoms suggestive of long COVID.

“Confronted by a global public health catastrophe, NCATS and the CTSA Program institutions have used a flexible, holistic approach to accelerate the search for effective COVID-19 treatments,” said Michael G. Kurilla, M.D., Ph.D., director of NCATS’ Division of Clinical Innovation. “By innovating in real time, we are working to deliver evidence-based COVID-19 therapies that demonstrably help people.”

Our latest TRIbune newsletter features a UAMS academic-community partnership recently funded by the Patient-Centered Outcomes Research Institute (PCORI) that was informed and inspired by TRI’s Community-Based Participatory Research Scholars Program. 

The team led by Melissa Zielinski, Ph.D., is using a $250,000 PCORI award to address health disparities among women involved in the justice system. 

Our TRI Study of the Month features Laura Hays, Ph.D., and her UAMS Rural Research Network-supported study in collaboration with the UAMS North Central Family Medical Center in Batesville. 

We also highlight our two new Health Sciences Innovation and Entrepreneurship (HSIE) trainees, postdoctoral fellows who will receive two years of support as they learn how to commercialize their ideas. 

Read The TRIbune.

Akilah Jefferson, M.D., M.Sc., a TRI KL2 Mentored Research Career Development Award scholar, has been published in the journal Pediatrics, with an article titled, “Asthma Quality Measurement and Adverse Outcomes in Medicaid-Enrolled Children.”

Jefferson and her coauthors found that a key tool used to evaluate pediatric risk of asthma-related adverse events may be a poor method for guiding pediatric population health management programs across diverse settings. The findings related to the tool, called the asthma medication ratio (AMR), were based on analyses using the Arkansas All-Payer Claims Database to identify Medicaid-enrolled children.

“AMR performed poorly in identifying risk of adverse outcomes among Medicaid-enrolled children with asthma,” the article concluded. “New population health frameworks incorporating broader considerations that accurately identify at-risk children are needed to improve equity in asthma management and outcomes.”

Jefferson is an assistant professor in the College of Medicine Department of Pediatrics, Division of Allergy and Immunology.

The TRI KL2 Scholars Program provides promising young clinical and translational investigators the training, mentoring, and protected time to develop an independent research program. Learn more about the program here.

Congratulations to Dr. Akilah Jefferson, one of our early-career KL2 Scholars, who was recently published in the prestigious journal Pediatrics. Her research found that a key tool used to evaluate pediatric risk of asthma-related adverse events may be a poor method for guiding asthma care in diverse populations of children.

The UAMS Translational Research Institute Health Sciences Innovation and Entrepreneurship (HSIE) Postdoctoral Training Program has named two postdoctoral scholars for its class of 2023. The scholars, selected in a competitive application process, will receive two years of mentored entrepreneurship training.

The HSIE postdoctoral trainees, their research goals and mentors are:

Henry A. Palfrey, Ph.D., is a postdoctoral fellow in the College of Pharmacy Department of Pharmaceutical Sciences. His research goal is to conduct studies to screen a library of compounds and determine the ability of novel epoxylipid drugs to provide protection against radiation-induced kidney and cardiovascular injury

Mentor: John D. Imig, Ph.D., professor and chair, Department of Pharmaceutical Sciences; and vice president for therapeutics at BioVentures LLC. 

Ashley Pike, Ph.D., a postdoctoral fellow in the Brain Imaging Research Center of the Psychiatric Research Institute (PRI). Her primary research goal is to implement advanced neuroimaging techniques for clinical problem solving in multiple sclerosis (MS). Mentor: Tatiana Wolfe, Ph.D., assistant professor, medical imaging physicist, PRI, College of Medicine Department of Psychiatry