People who have experienced a traumatic brain injury (TBI) are susceptible to many types of infections, especially in the lungs. Yet previous studies have shown that bladder infections in this population are not uncommon: 15% of adult brain injury patients experience a urinary tract infection (UTI) within a year, and UTIs are responsible for up to 20% of hospital readmissions that occur within a year after a TBI. In addition, UTIs are known to cause delirium-like symptoms in medically vulnerable people.

This new study, led by researchers at The Ohio State University and published recently in the Journal of Neurotrauma, is the first publication to examine neuroimmune and cognitive effects of a post-brain injury bladder infection in an animal model.

“This very common infection is happening in TBI survivors and probably those who don’t even report it and go to the hospital, and it’s associated with observed and perceived cognitive changes. We thought UTI could be something that’s having a much bigger impact on recovery after brain injury than we currently appreciate,” said senior author Olga Kokiko-Cochran, an investigator in the Chronic Brain Injury Program and the Institute of Brain, Behavior, and Immunology (IBBI) at Ohio State and associate professor of neuroscience in the College of Medicine.

“Let’s not overlook UTI,” she said. “Sometimes these common experiences that are overlooked are important, and I think we can’t presume that an infection of any sort is no big deal.”

Injuries in this work are moderate in severity and resemble the type of TBI that could result from a fall – the most common cause of traumatic brain injury.

The experiments involved four groups of female mice: those with a TBI (performed surgically under anesthesia) and “sham” mice, which had surgery but no brain injury. Three days later (again, under anesthesia), either uropathogenic E. coli bacteria, the main cause of UTIs, or a control treatment was injected into their urethras.

Results from behavioral tests six days after injury showed that the TBI impaired the animals’ spatial memory, and UTI following the injury “greatly exaggerated those cognitive impairments,” said first author Zachary Zimomra, a neuroscience research associate and manager of Kokiko-Cochran’s lab.

That UTI-induced cognitive impairment was associated with delayed increases of two inflammation-related proteins in two different cell types in several regions of the injured brains compared to controls. This finding suggested that brain immune cells were responding to not just the TBI, but to the bladder infection as well. And bladder immune cells changed after brain injury alone – an intriguing clue that could help explain why infections follow a TBI.

“Maybe there’s some susceptibility we don’t even appreciate,” Kokiko-Cochran said. “Because we do see, post-TBI, a higher immune cell presence in the bladder.”

The team looked further into changes in inflammatory protein signaling linked to the injury and infection, finding one cytokine, IL-6, elevated in the blood after TBI and then muted by the UTI – suggesting that clearance of the infection prompted anti-inflammatory activity.

Cellular changes seen in the bladder and brain also offer hints at the biology behind post-injury infection that researchers plan to investigate further. A better understanding of how the brain and bladder communicate – beyond their known neural connection related to urination – could lead to infection prevention strategies that improve long-term TBI outcomes, the researchers say.

“Clinically, there is something about UTI that causes a behavioral change in cognition that you don’t necessarily see from influenza or a cold or some other infection. It may be something with the bladder itself,” Zimomra said. “We want to learn what happens within the brain, but also how bladder change following TBI exaggerates or enhances these behavioral effects.”

UTIs affect 400 million people worldwide each year, and females are 30 times more likely than males to experience a bladder infection – which is why this initial study was done in female mice. But UTI after a brain injury is not restricted to females, meaning future research will include animals of both sexes, Kokiko-Cochran said.

“This has been an opportunity for our lab to contribute something new that has, we think, important translational relevance and could raise awareness and help us think about how this type of infection was layered on top of a brain injury,” she said. “There’s a lot more we can do to understand the brain-bladder connection.”

This work was supported by pilot funding from the Chronic Brain Injury Program and IBBI at Ohio State. Co-authors included Christina Lepak, Rebecca Boland, Morgan Taylor, Amber McCraw, Irene Crescenze and Dana McTigue of Ohio State, and Henry Schreiber of Washington University School of Medicine.

In current practice, patients answer a series of questionnaires – subjective self-reported data – that’s combined with objective lung function and exercise test results to help clinicians gauge patients’ mental outlook on living with a difficult illness. 

For the study, researchers added a visual element, providing patients a simple outline of the human lungs and asking them to color in the proportion of their own lungs that they perceived to be diseased. 

Statistical analysis showed that patients’ visual perceptions of illness were equally effective as standard questionnaires and test results in conveying the symptom-related quality of patients’ lives – and provided additional predictive value when combined with both verbal assessments and test results. 

“What has always been fascinating to me about working with medical patients is that the objective numbers absolutely do not tell the whole story,” said lead study author Charles Emery, professor emeritus of psychology at The Ohio State University. 

“The broad construct here is illness perception, which becomes especially important for people who have terminal illnesses or chronic illness. If you have less control over quantity of life because of the terminal nature of your illness, then quality of life becomes that much more important. And one important factor linked to quality of life is illness perceptions – essentially, the broad cognitive mental model of your illness,” he said. 

“Illness perception is an avenue through which patients can talk about how they view their illness and consider alternate perspectives that enhance quality of life, even in the face of a terminal illness.” 

The study is published in the May issue of the Journal of Cardiopulmonary Rehabilitation and Prevention. 

The 40 patients between ages 32 and 85 who participated in the study had been diagnosed with interstitial lung disease, which encompasses over 200 pulmonary diseases characterized by shortness of breath, low blood oxygen, chronic coughing, and varying degrees of inflammation and lung tissue stiffening. The average survival among patients with a new diagnosis ranges from about four to seven years. 

Emery witnessed the effect of lung disease on quality of life early in his faculty career when a physician colleague described two patients with the same pulmonary function very differently: “One was waltzing into the office seeming fine, and the other was dragging themselves in,” he recalled. 

“That is linked to quality of life, and it’s linked to perception,” said Emery, also professor emeritus of internal medicine in Ohio State’s College of Medicine. “Perception has so many consequences in terms of how you approach an illness and whether you see it as a problem to be solved that you take on as a challenge or you think, ‘life is out to get me, so why bother?’” 

While earlier studies of visualized illness perception have asked patients to draw free-form pictures of the affected part of their body, Emery and colleagues used a standardized image of the lung to allow them to quantify each patient’s perception of the lung disease. 

On average, participants perceived about a fifth of their overall lung volume to be affected by disease, with depictions of disease involvement ranging from zero to 73%. 

Questionnaires that these patients routinely answer assess symptoms, especially cough and shortness of breath; symptom impact on the ability to carry out daily activities; and perceptions of how long the illness will last and treatment effectiveness. They are combined with results of spirometric testing of pulmonary function and a six-minute walk test of exercise capacity. 

Statistical analysis and modeling of the data showed that lung function test results and self-reported illness perception – whether described verbally or visually – were equally predictive of illness-related quality of life.

“If you’re seeing a patient and want to assess this person’s quality of life, you can get an idea by looking at pulmonary function, but the data show you’re getting important additional information by asking them questions about illness perception,” Emery said. “Self-report is probably the most reliable way of understanding a patient’s quality of life because, ultimately, they’re the ones who are determining it.”

Emery noted that the questionnaires are reliable and effective, but that they may not capture the full picture from people who have limited language abilities or don’t want to tell anyone, even a doctor or family member, how they feel about being sick. 

Incorporating a visual measure of illness perception into medical exams could serve patients with a range of language limitations and help identify those who may benefit from psychological counseling, he said. 

He also said this technique could apply to a wide range of diseases that affect specific organs, and that using computer graphics and machine-learning for data analysis could speed up computation of a visual illness perception measure during exams. 

“One of our responsibilities in working with patients is to get as clear a read of that patient’s experience as we can,” Emery said. “And so you want a measure that you can give to a patient, and they can completely do it on their own, with no input from anyone else.” 

Co-authors of the study, all from Ohio State, included Ihsan Rodriguez, Nitin Bhatt, Vincent Esguerra and Alice Staaby.

Reporting today (April 29, 2026) in Nature, the researchers describe building upon a technique called prime editing by inserting DNA that attaches to the genome through a series of overlapping flaps. This method, which they call a prime assembly approach, avoids a bottleneck in the gene therapy field – a double-strand break to the donor DNA that can cause toxicity and kill cells.

“Using this method, we are doing genome assembly rather than making a small edit in a gene,” said Bin Liu, a co-lead author of the study and assistant professor of biological chemistry and pharmacology at The Ohio State University College of Medicine. “If we think of the genome as a book, we can remove one paragraph and replace it with a new one – or even rewrite a chapter.” 

This distinction is important: Because some diseases involve hundreds of mutations, pursuit of a gene therapy treatment would require hundreds of gene edits that would be subject to individual federal approval, Liu said. 

“The biggest impact of this technology is we can correct 1,000 heterogeneous mutations at once,” he said. 

In the study using mammalian cells, Liu and co-lead authors from the University of Massachusetts Chan Medical School show the technique can allow for efficient insertion of a DNA segment containing up to 11,000 base pairs – compared to a maximum of about 800 base pairs successfully inserted with other methods. 

“We tried to hit the upper limit of the technology to see how large we can go,” he said. “Using our method, we envision setting up a universal platform and incorporating a healthy copy of a gene directly into a patient, no matter what mutation they have.” 

Achieving the insertion of a large DNA segment involved a combination of techniques. 

Any healthy “donor” DNA used for this type of therapy can be manufactured in a lab. The researchers used a twin prime editing method to generate programmable flaps on the target DNA that introduces the DNA insertion to the genome. The flaps complement the ends of the donor DNA, avoiding a double-strand break. This insertion does induce a single-strand DNA break, which is considered less likely than a double-strand break to be toxic to a cell, Liu said. 

Assays evaluating and visualizing the efficiency of the insertion in mammalian cell cultures demonstrated the method’s promise, he said. 

The editing steps removed the need for reliance on a repair mechanism, called homology directed repair, that has been a key part of gene-editing techniques that involved cuts to DNA. By ruling out that repair step, which occurs in actively dividing cells, the prime assembly technique can incorporate both single- and double-stranded DNA donors and be used as therapy in non-dividing cells such as neurons and heart cells. 

“Previous applications that relied on homology-directed repair have worked well in cells, but in animal models, its efficiency is often very low,” Liu said. “That’s why our method provides a big advantage by harnessing prime editing.” 

The team calls the technology “prime assembly” in a nod to the common lab technique “Gibson assembly cloning,” which joins DNA in a test tube. 

There is more work to do, including determining the best delivery vehicle for the donor DNA segment and delivering editor – likely a lipid nanoparticle or adeno-associated virus. Additionally, testing the effectiveness of in vivo editing is planned in Liu’s lab and with collaborators in Ohio State’s Gene Therapy Institute, including ophthalmologist Tom Mendel. 

The work was co-led by Erik Sontheimer, professor, and Wen Xue, associate professor, in the RNA Therapeutics Institute at UMass Chan Medical School. Additional co-authors include Yanjun Zhang of Ohio State; Andrew Petti, Xuntao Zhou, Haoyang Cheng, Jenny Gao, Matthew Yee, Youwei Qiao, Lin Zhou and Scot Wolfe of UMass Chan Medical School; and Tingting Jiang of Icahn School of Medicine at Mount Sinai. 

This work was supported by the National Institutes of Health, the Leducq Foundation Translatlantic Network of Excellence Program and the Cystic Fibrosis Foundation.

Many of the academic experts who have advanced the science behind concussions in student-athletes – and, in collaboration with the Department of Defense, in soldiers as well – are now focused on addressing these head injuries in a population that’s similar, but different: first responders. 

The considerations are many, spanning from a first responder’s potential sports or military injuries in a previous life to the factors that signal when it’s safe to return to duty after a strike to the head. Getting a clinical diagnosis is key to putting an injured first responder on the proper trajectory of recovery – not just working safely, but also maintaining a satisfying quality of life, experts agree. 

Researchers will soon publish the first evidence-based guidelines for traumatic brain injury (TBI) recognition and management and return to duty in first responders – a group encompassing law enforcement officers, corrections personnel, firefighters and emergency medical technicians (EMTs). 

The authors will be the nearly 60 experts who convened at The Ohio State University in late March to pursue consensus on protocols surrounding six frameworks: workplace policies, injury prevention measures, challenges of recognizing injuries, diagnosis and treatment of the injury, mental health monitoring, and steps needed to get a concussed first responder back to work. 

“This is a critical step in improving the care and support for our first responders who risk so much for us every day,” said Jaclyn Caccese, associate professor in the School of Health and Rehabilitation Sciences (HRS) at The Ohio State University. 

Caccese co-hosted the 1st International Conference on TBI in First Responders with James Oñate, interim director of HRS, interim vice dean for health and rehabilitation sciences in the College of Medicine, and a professor in the HRS Division of Athletic Training. 

One universally accepted fact drove the work: Brain health in first responders is a matter of public safety – for the injured personnel, their colleagues, their families and the public they are sworn to protect. 

After working together for several months in six workgroups, the scholars, clinicians and first responders met March 26-27 to share what they’ve learned and vote on a series of recommended guidelines. The final recommendations and consensus statement will be published early next year in the Journal of Head Trauma Rehabilitation. 

While head injury data on first responders is minimal, a meta-analysis of studies to date suggests that about 60% of law enforcement and corrections officers have suffered at least one traumatic brain injury in their lifetime, and 17% have experienced a TBI on the job. Among firefighters, lifetime TBI prevalence ranges from 62% to 77%. There have been no studies of head injuries in EMTs. 

Though what has been learned by studying sports and military concussions has given these teams a head start, most workgroups indicated that the need for more research specific to the first responder workforce is apparent. 

“We’ve lumped first responders together. We’re going to stop doing that,” Oñate said. “This is the beginning, and we’re starting with many things we’ve advanced already. We’re not starting from scratch.” 

In a first-of-its-kind survey of Ohio law enforcement officers in 2024, Caccese, Oñate and colleagues reported that 74% of officers had a lifetime history of one or more head injuries, and 30% had a head injury that happened on the job. Further analysis showed post-traumatic stress disorder and depressive symptoms were higher in those who had experienced one or more head injuries.  

At the conference, each of the six workgroups brought forward four to five recommendations for a vote. Consensus was reached on all but two, though many will undergo refinements before publication. 

Overarching themes included standardizing methods of recognizing and treating TBIs and assessing return-to-duty readiness; ensuring no punitive actions are taken against an injured and recovering first responder; protecting the head as much as possible during training intended to expose new personnel to risks linked to blasts and being hit at work; and educating agencies, first responders, families and health care providers about TBI risks, prevalence and potential lasting effects when they’re not managed well. 

“Almost every workgroup talked about the importance of education,” Caccese said. 

The educational component is critical because this effort is still very new. Many agencies are unaware that an international effort is afoot to address TBI in first responders. In addition to publishing the conference outcomes in a scientific journal, the group plans to present at academic and first responder-specific conferences and approach publications targeted to first responder agencies. 

Conference attendees acknowledged TBI in this workforce is a delicate subject for so many reasons, not the least of which is the stigma linked to injuries that affect performance in a profession characterized by a mission-first mindset that leads to underreporting. First responders served on every workgroup alongside the academic researchers to help keep suggestions realistic for the workplace cultures and practices that are being asked to change. 

The conference featured a panel discussion with three law enforcement officers who had received a head injury on the job. They described symptoms including double vision, dizziness, chronic migraines, short-term memory loss, speech problems and temporary paralysis, as well as complications navigating recovery – with one eventually losing her job as a result of her occupational injury. 

Hearing from these officers “helps give us context about the stakes to come up with recommendations for first responders to return to full capacity,” said Nathan Edwards, a research scientist in Ohio State’s Human Performance Collaborative. 

Improving care for first responders isn’t stopping with the brain: Researchers are investigating musculoskeletal issues, physical performance and heart health in the first responder population as well, Oñate said. 

“It’s on us to get the level of evidence much higher,” he said. “It’s also on us to communicate with the first responder community to look at what impacts they’re looking for and what they need to have happen.” 

This work was supported by the Assistant Secretary of Defense for Health Affairs endorsed by the Department of Defense, through the Traumatic Brain Injury and Psychological Health Research Program. The conference was also supported by HRS and Ohio State’s Center for Brain Injury Recovery & Discovery.

A new study suggests another dietary pitfall could have a similar damaging effect in a similarly short amount of time in older adults: a lack of fiber. 

The study in rats also points to the amygdala – the small structure governing emotional memories, especially related to bad experiences – as a brain region that is particularly sensitive to a highly processed diet. Every type of refined diet fed to old animals was associated with cellular and behavioral signs of cognitive problems traced to this emotional memory center of the brain. 

“The amygdala is important for learning the association between something fearful and a bad outcome. And we found that all of the refined diets, whether they were high fat, high sugar, low fat, low sugar, it didn’t matter. They all impaired memory that’s governed by the amygdala,” said co-lead author Ruth Barrientos, an investigator in the Institute of Brain, Behavior and Immunology at The Ohio State University. 

“And when we looked to see the common thread among all of those diets, the one thing that became very obvious was that they all lack fiber.” 

Not learning the association between an action and its outcome, especially when it’s dangerous or risky, may increase the risk for physical or financial harm, said Barrientos, also an associate professor of psychiatry and behavioral health and neuroscience in Ohio State’s College of Medicine. 

“The amygdala plays a role in that kind of awareness and learning,” she said. “Its vulnerability to a refined diet is therefore concerning for older adults who are at greater risk of financial exploitation and scams.” 

The research was published recently in the journal Brain, Behavior, and Immunity. 

Barrientos has studied the effects of high-fat and highly processed diets on the aged brain for several years, seeing behavioral results and related indications of inflammation in both the amygdala and the hippocampus, which is important for spatial, autobiographical and episodic memory. 

In this work, she and colleagues focused on disentangling the diet contents to see whether fat or sugar, or something else, had the strongest link to cognitive impairment in rats.

Young and aged male rats were fed either normal chow or one of five experimental diets for three days: low fat, low sugar; low fat, high sugar; medium fat, low sugar; medium fat, high sugar; or high fat, low sugar. 

Behavioral tests showed that old animals that were fed all of the refined diets – no matter the level of fat or sugar – had impaired long-term emotional memory based in the amygdala compared to young rats on the same diets. In contrast, memory-related behavior traced to the hippocampus was negatively affected only by the high-fat, low-sugar diet. 

And then there was the no-fiber factor. All of the experimental diets lacked fiber, and examination of the rats’ guts and blood showed a significant reduction in a key molecule, called butyrate, that is produced in the gut and circulated in the blood when dietary fiber is broken down by gut microbes. 

Previous research by other labs has shown that butyrate has anti-inflammatory effects and can cross the blood-brain barrier, which may mean a deficiency in butyrate caused by a lack of dietary fiber could be linked to unregulated inflammation in the brain, Barrientos said. 

“What our study really brings to light is the complexity of diet and how it affects so many different things, even the brain,” said co-lead author Kedryn Baskin, assistant professor of physiology and cell biology at Ohio State. “There’s not a magic bullet, but in this case, low butyrate, as a result of a lack of fiber, is a culprit.” 

At the cellular level, the researchers found the most compelling evidence of refined diet-related damage in the mitochondria of microglia, cells that have multiple functions important to memory function. When exposed to experimental energy demands in cell cultures, mitochondria from young brains could adapt to the changes, but these power centers in aged brain cells were not able to rise to the challenge. 

“The mitochondria are still functioning, but they’re showing depressed respiration and are functioning at a much, much lower rate in the aged compared to the young,” Baskin said. 

Though the refined diets caused some weight gain, Barrientos said the findings put to rest the notion that obesity brought on by a highly processed diet is the primary driver of impaired cognition.  

“These effects on the brain after you eat something are pretty rapid,” she said. “You can experience this unhealthy cognitive dysfunction well before you reach obesity.” 

And while she and Baskin said the data imply increasing fiber in the diet could be beneficial to the brain, the team plans to study whether fiber or butyrate supplementation in animals could reverse the age-related cognitive problems that follow poor eating. 

This work was supported by the National Institute on Aging, the National Center for Advancing Translational Sciences, the Foods for Health Research Initiative at Ohio State, and the National Heart, Lung, and Blood Institute. 

Additional co-authors were Michael Butler, Jade Blackwell, Andrew Sanchez, Hannah Sanders, Dominic Kolonay, Jeferson Jantsch, Stephanie Muscat, Sabrina Mackey-Alfonso and Bryan Alvarez, all of Ohio State; and Maria Elisa Caetano-Silva, Akriti Shrestha, Casey Kin Yun Lim, Robert McCusker and Jacob Allen of the University of Illinois Urbana-Champaign.

Specifically, the research shows that fragmented sleep worsens symptoms that a traumatic brain injury (TBI) alone produces – and that mice without a head injury can make up for some REM sleep loss brought on by interruptions to sleep, but injured mice do not.

REM sleep has a major role in helping the brain consolidate and process new information and is associated with better concentration and mood regulation. Loss of REM sleep can lower brain and cellular function.

“I think sleep has gone underappreciated as a key determinant of traumatic brain injury outcomes for a long time,” said senior author Olga Kokiko-Cochran, an investigator in the Chronic Brain Injury Program and the Institute of Brain, Behavior, and Immunology (formerly the IBMR) at The Ohio State University and associate professor of neuroscience in the College of Medicine. 

“A brain injury doesn’t occur in isolation. We have to think about the recovery environment and acknowledge that there are effects of external stimuli,” she said. “We set up the paper to think about recovery in a hospital, rehabilitation or even a home setting where there are lots of things in the environment that might influence someone’s sleep – and oftentimes those may go unrecognized or unnoticed or even downplayed as to how important they could be in influencing recovery.”

The research was published recently in the journal Experimental Neurology.

Injuries in this work were moderate in severity and resembled the type of TBI that could result from a fall – the most common cause of traumatic brain injury.

The experiments involved four groups of mice: those with a TBI (performed surgically under anesthesia) exposed to either sleep fragmentation or no sleep disturbance, and “sham” mice, which had surgery but no brain injury, that got either normal or fragmented sleep.

Select mice from each group were implanted with telemetry sensors to detect brain (EEG) and muscle (EMG) activity, body temperature and cage activity for 30 days after the surgery or injury – the equivalent of several months in a human.

Sleep was interrupted in the sleep fragmentation groups by a bar that swept across the floor of the mouse cage every two minutes during the first four hours of the animals’ sleep phase – intended to mimic a period when sleep need is high, such as when a patient might have trouble falling asleep in a clinical setting.

Results showed that after about a week, mice with TBI were less active than uninjured mice, and their activity continued to decrease over weeks three and four. Sleep fragmentation alone also brought on fatigue – but interrupted sleep on top of the TBI significantly intensified the fatigue.

Analysis of data on the animals’ biological rhythms showed there was more to the story of TBI coupled with interrupted sleep: changes to their rest-activity patterns over time.

“Just looking at the activity alone you can’t differentiate that the fatigue is worse until you look at some more nuanced statistical tests,” said Christopher Cotter, co-first author of the paper and a student in Ohio State’s Neuroscience Graduate Program. “That’s really important when we think about clinical populations – they might get sleep recordings that suggest nothing is wrong. One of the points of this analysis was to show that there are a lot of biological things happening that you may not be able to see with sleep analysis alone.”

Sleep fragmentation affected both non-REM and REM sleep in all of the mice, which was not a surprise. The analysis of interrupted sleep on the REM phase focused on what recovery looked like in the mice after the fragmentation exposure stopped.

Findings show that mice with TBI and TBI with fragmented sleep displayed decreased REM sleep, while uninjured mice with sleep fragmentation made up for the sleep loss.

“So the sham mice are compensating for the loss, but all of the animals with TBI are not compensating for that loss and they continue not compensating for the loss over the four weeks. They just lose that REM sleep and they don’t get it back,” Cotter said. “We looked to see if they were sleeping more when they were not supposed to be, and the answer was no. So they just lost that sleep, and that was a really striking finding.”

The EEG provided data on electricity released by different structures of the brain that are associated with specific biological functions. Results showed that injured mice with interrupted sleep had deficits not seen in uninjured mice: These animals had an increased need for non-REM sleep but didn’t get more non-REM sleep, and their loss of REM sleep – especially in the acute recovery phase – could be linked to loss of cognitive function.

“Change in sleep quality really happens between one and 14 days, so that is a more vulnerable time for disruption after traumatic brain injury,” Cotter said. “There is this sensitized injury response period.”

Kokiko-Cochran said the collection of 30 days of continuous EEG and EMG data provided insights that will enhance future sleep-related TBI research in her lab.

“This model of brain injury and sleep fragmentation gives us an opportunity to study things like fatigue – something understudied in the space of traumatic brain injury that can be difficult to model,” she said. “It’s important because many survivors have an opportunity for extended lifespans. They’re surviving sometimes decades after their brain injury, but there are still persistent symptoms.

“We are trying to be conscious of the fact that people are having lots of other experiences that could influence their recovery.”

This work was supported by the National Institutes of Health.

Additional co-authors, all from Ohio State, included co-first author Zoe Tapp, Cindy Ren, Sam Houle, Jessica Mitsch, John Sheridan, Jonathan Godbout, Juan Peng and Ashley Ingiosi.

Following up on previous work showing a connection between negative changes to gut bacteria after a traumatic brain injury (TBI) and poor decision making, researchers at The Ohio State University are now exploring whether the gut problems may actually cause some long-term symptoms. 

They found that adding the prebiotic galacto-oligosaccharide (GOS) to rat diets before and after a TBI lowered their impulsivity in a decision-making gambling test in which they are rewarded with sweets. 

“We found in this study that their impulse control has improved,” said senior author Cole Vonder Haar, assistant professor of neuroscience in the Ohio State College of Medicine. 

“In our task, we basically ask them to make a decision, but they have to wait for the cue light to come on. And that’s hard to do if you’re a hungry rat, right? So it sets up a measure of impulsivity, and that’s where we saw one of the most robust effects.” 

The poster was presented Nov. 17 at Neuroscience 2025, the annual meeting of the Society for Neuroscience. 

Almost 3 million TBI-related emergency department visits are reported in the United States each year, and over 11 million Americans over 40 who lost consciousness with a TBI are living with a disability, according to the Brain Injury Association of America. 

“There’s no FDA-approved treatment for TBI. People are stuck with their symptoms and do whatever they can to manage those symptoms, whether it’s rehabilitation or pharmacological help for specific symptoms like depression,” Vonder Haar said. 

His lab is studying several interventions to see if a gut-based treatment could provide some relief. “We’re trying to improve the quality of life for people who are suffering and struggling with brain injury-related problems,” he said. 

The work focuses on symptoms that follow a moderate TBI – an injury in rats (occurring under anesthesia) intended to mimic what might happen to a person in a car accident or a fall from a ladder. 

Within the past decade, researchers in the field have determined that gut dysbiosis – a negative change to the collection of bacteria in the digestive tract – occurs in patients after they suffer a moderate brain injury. 

“The core question we’re trying to understand now is whether this is a causal force,” Vonder Haar said. “We’ve previously published data showing that there’s a very strong predictive correlation: If you measure the gut microbiome acutely after the brain injury, it can predict very long-term deficits in decision making. So it seems something is going on, but this earlier work was all correlative.” 

In the new study, rats were fed a control diet or a diet supplemented with 2% GOS beginning six weeks before the injury and continuing for another 60 days after injury. The animals were then tested for anxiety-like and depressive-like behavior, learning and memory, and impulsivity and decision making. 

During the rodent gambling task, which assesses decision making and impulsivity, rats are offered four choices resulting in rewards of varying amounts of sugar pellets, and they learn over time what each option provides. 

“And one of the key things we see is that brain injuries really suppress the ability to do this well,” Vonder Haar said. “Our rat models really show this long-term chronic impairment, which patients also struggle with.” 

Rats on the GOS diet had better outcomes in impulsivity after TBI than injured rats that ate a non-supplemented diet. 

“It’s a modest effect. They’re still more impulsive than control animals without injury, but it’s reduced compared to their counterparts,” Vonder Haar said. “Most of the studies we’ve done to try to treat impulsivity haven’t worked out. This is one of the few times where it looks like a treatment has some beneficial effects.” 

Vonder Haar also chaired a Nov. 16 Neuroscience 2025 minisymposium on the gut microbiome in traumatic brain injury and is the lead author of a new Journal of Neuroscience article reviewing the evidence establishing the gut as a modulator of TBI and potential underlying mechanisms. 

“We know what the behavioral outcome from TBI looks like, but the mechanism, why and how this is happening, is the other big question,” he said. 

The prebiotic study was supported by the U.S. Department of Defense. 

Co-authors of the study include Alexandra Dorinsky, Katie Koontz, Berkin Bilgin, Lizza O’Connell, Jenna McCloskey, Michael Bailey and Kris Martens, all of Ohio State, and Miranda Hilt of Nationwide Children’s Hospital.

A team led by researchers at The Ohio State University compared the annual out-of-pocket and total costs of 33 neurologic medications either covered by insurance and sold by commercial pharmacies or bought online through the Mark Cuban Cost Plus Drug Company. Out-of-pocket costs include copay, coinsurance and deductible charges, and total costs reflect all consumer out-of-pocket and insurance premium payments as well as what insurers pay. 

Overall, direct-to-consumer out-of-pocket neurologic drug costs were 75% higher than for insured medicines at retail pharmacies, but the total annual costs of the drugs from Cuban’s online pharmacy were 431% lower than those sold by commercial pharmacies to insured patients. 

Because health plan out-of-pocket costs are in addition to insurance premiums paid by beneficiaries, the findings suggest the direct-to-consumer pharmacy may offer uninsured patients similar pricing for medications without having to pay the premium. 

The higher out-of-pocket costs at Cuban’s pharmacy reflected an average across the board, but many of the medications are inexpensive – so the higher price did not reflect a significant amount of money, said first author Amanda Gusovsky Chevalier, assistant professor in the Division of General Internal Medicine at Ohio State’s College of Medicine. 

For 76% of the online pharmacy drugs, the difference in out-of-pocket payments was less than $200 per year. 

“The difference was close to zero for a lot of these different medications,” Gusovsky Chevalier said. “The reason that’s notable is because this price that patients can get directly from a website is the same as the cost to patients who, on top of buying medications, are paying a premium for an insurance plan that’s probably coming out of their paycheck. 

“So the cost you’re paying that is subsidized by your insurance provider is the same as what you could pay at the Mark Cuban pharmacy. This could be a great option for uninsured patients who are paying completely out of pocket.” 

The study was published recently in JAMA Network Open. 

Gusovsky Chevalier and colleagues had previously published an analysis of neurologic drug costs from commercial pharmaceutical and Medicare supplemental insurance claims databases from 2012-2021, enabling the team to calculate 2024 estimates for out-of-pocket and total costs of the medications. For this new study, those estimates were compared to prices posted on the Cost Plus Drug Company website on Dec. 10, 2024. 

“I had heard about the Mark Cuban pharmacy through colleagues and thought it would be interesting to compare the costs because his pharmacy is very direct-to-consumer – they cut out the middleman and whatever is advertised on the website is what you’re paying for, and that’s your only cost,” she said. 

The analysis included drugs used to manage 11 neurologic conditions, among them Alzheimer’s disease, multiple sclerosis (MS), peripheral neuropathy and Parkinson’s disease. 

The highest-priced medications (annual costs) in the direct-to-consumer pharmacy – and therefore all paid out of pocket – were the MS drugs glatiramer acetate ($24,186) and fingolimod ($2,185), and cyclosporine ($2,185), a treatment for myasthenia gravis. All other medications examined in the study from the Mark Cuban pharmacy cost less than $635 per year. 

The medications with the highest 2024 insurance plan annual out-of-pocket and total costs, respectively, were teriflunomide for MS ($286 and $11,739), droxidopa for orthostatic hypotension ($238 and $11,618) and fingolimod ($240 and $8,394). 

Out-of-pocket costs for only two medications, teriflunomide and droxidopa, were lower (40% and 18%, respectively) in the direct-to-consumer pharmacy compared to commercial insurance plans. Eighteen of the 33 medications had lower total annual costs at Cuban’s pharmacy compared to private plans. 

Those two drugs and one other MS medication, dimethyl fumarate, stood out for their markedly reduced total costs: Results estimated aggregate annual savings of at least $11 million each by using the direct-to-consumer pharmacy instead of commercial insurance plans at a retail pharmacy. 

“Total costs represent system-level spending, and we look at them because we want to know how much money is moving around to be able to cover these medication costs,” Gusovsky Chevalier said.

The authors noted that there can be drawbacks to relying on a direct-to-consumer pharmacy – the Cost Plus online pharmacy listed only 33 of 79 commercially available neurologic medications at the time of the analysis. And patients who work both sides of the system to pay the lowest prices would risk having fragmented prescription records that could lead to unintended drug interactions.

Even so, the findings suggest direct-to-consumer online pharmacies may be an attractive alternative source of prescription medications, especially for patients who lack insurance coverage, the authors concluded. 

“Our research has shown that the costs of medications just continue to rise through insurance plans, and it’s really important to find ways for patients to access medicines,” Gusovsky Chevalier said. “I think this adds to a larger body of evidence showing that these direct-to-consumer pharmacies have the potential to disrupt the market in some significant way in the future. 

“It’s important for people to know that online pharmacies like this are available.” 

Co-authors of the study include Chun Chieh Lin, Kevin Kerber and senior author James Burke of Ohio State; Evan Reynolds of Michigan State University; and Brian Callaghan of the University of Michigan.

In a series of experiments, pregnant mice were exposed to a combination of two liquids used to create vaping’s throat hit and smoke plume. Compared to two other experimental conditions, the offspring of mothers exposed to a specific ratio of these compounds weighed less and were born with narrowed facial features and shortened skulls. 

The finding was surprising to researchers not only because no nicotine was present, but because the ratio of chemicals that produced the skull defect was designed by the e-cigarette industry to be a safer available option than the proportions in earlier products.

“This had no nicotine, and it’s still having effects on the development of the skull in our model, which was not anything we expected,” said lead study author James Cray, professor of anatomy in The Ohio State University College of Medicine. 

The research was published recently in the journal PLOS One.

Cray’s developmental biology lab has studied the effects of in utero exposure to nicotine on head and face development for years, reporting in 2020 that exposure to nicotine through breastmilk caused skull defects in mice. About 3% of babies are born annually with a birth defect, according to the Centers for Disease Control and Prevention, and alterations to the head and neck are among the most common – particularly cleft lip and/or cleft palate. 

In this study, the team was developing a model to serve as an experimental control for comparison to animals exposed in utero to nicotine through vaping.

Pregnant mice were exposed to either filtered free air or two humectants – hydrating substances that function as carriers of other e-cigarette contents – at differing concentrations: 50% each of propylene glycol and glycerol (also called vegetable glycerin), or 30% propylene glycol and 70% glycerol (30/70 PG/VG). 

Because propylene glycol in e-cigarettes has been linked to increasing uptake of nicotine, Cray said, “a lot of companies have moved toward getting away from a high percentage of propylene glycol toward more glycerol, trying to position this as a safer alternative.” 

Female mice were exposed to these three different conditions at a rate of one puff per minute, four hours per day on five days each week during the roughly 20-day pregnancy. 

The cranial width and height of mouse pup skulls were scanned two weeks after birth. The analysis showed statistically significant reduced measures in the offspring of pregnant mice exposed to the presumed safer 30/70 PG/VG mixture compared to mice exposed to free air and the 50/50 formula. 

“What we see is a consistent narrowing of all of the facial features, and the same thing as we move back into the cranium as well. So globally they’re narrower and a little bit shorter-headed, which does mimic some observable changes that we see in children,” Cray said. “We also saw a bit of a reduction in weight. These animals were within the normal range of an animal that age, but they still weighed less.” 

The findings were consistent across several litters of mice and in both biological sexes. 

“The 50/50 mixture had no dramatic statistical changes – and that’s where we were looking for the difference. We thought heavier propylene glycol should be causing more effects, and it was the exact opposite,” Cray said. 

The Food and Drug Administration began regulating electronic nicotine delivery systems in 2016, but has faced legal pushback from e-cigarette companies – which prevailed in a June 20 U.S. Supreme Court ruling that makes it easier to sue the FDA over efforts to block products from the market. In April, the court sided with the FDA’s crackdown on sweet-flavored products after a major increase in teen vaping. 

Though researchers continue to study the health effects of multiple ingredients detected in e-cigarettes, many unknowns remain as the products grow in popularity. 

“The majority of users are young adults and teenagers, so we are talking about people who are in peak reproductive years. And with development of the head happening very early in fetal development, people could be using these products and not even realize that they are pregnant, which is of great concern,” Cray said. 

“This is a small study that speaks to the possibility that nicotine-free vaping is not safe. And it’s a sign that we probably should study the nicotine-free products as much as we study the nicotine-laden products.” 

This work was funded by the Ohio State colleges of Medicine and Dentistry. 

Co-authors include Logan Shope, Ethan Leonard, Leslie Sewell, Tyler Maykovich, Roy Miller, Matthew Gorr and Loren Wold of Ohio State; Ethan Richlak of Nationwide Children’s Hospital and the University of Pittsburgh; and Amr Mohi of UT Health San Antonio.

Adriana Forero and Fernanda Novais will each receive a five-year, $505,000 award supporting their research projects while they’re still early-career scientists.

Eugene Oltz, chair of the Department of Microbial Infection and Immunity, said this ultracompetitive award recognizes Forero and Novais’ contributions to scientific discoveries that advance our understanding of the interaction between human biology and infectious agents.

“Their work advances our ability to improve human health,” Oltz said. “To our knowledge, they are the first from Ohio State to even make it to the interview stage, let alone receive not one, but two awards.”

In her lab, Forero investigates how genes linked to neurodevelopmental disorders shape immune defenses not in the brain, but in the lungs. She says the PATH funds for her study, titled “Resident nuclear factors drive heterogeneity in the antiviral response,” will allow her to examine how transcriptional regulators influence the way epithelial cells fight off viral infections.

“With the flexibility this award provides, I can combine cutting-edge genomic tools and virology techniques to uncover hidden connections between genetics and immune vulnerability,” Forero said. “It is a bold step into an underexplored intersection of fields, with real potential to uncover new genetic, epigenetic and transcriptional regulatory processes that coordinate the host response to viral infection.”

Forero’s work creates a deeper understanding of the link between genetic variants found in neurodevelopmental disorders and increased susceptibility to viral infections, such as influenza A. Through her work, she will contribute to the development of targeted interventions that enhance protection against infectious agents and mitigate adverse infection outcomes.

“In doing so, we also hope to reveal broader principles about immune defense that apply to other pathogens and at-risk populations,” Forero said.

Novais is an expert in immune responses to Leishmania parasites, which cause cutaneous leishmaniasis, a neglected tropical disease that affects millions worldwide. With more than 20 years of experience in the field, Novais has uncovered how the body’s own immune cells can contribute to skin damage during infection, and how this knowledge could guide the development of new therapies.

With support from the PATH award, Novais now aims to understand how Leishmania parasites manage to survive indefinitely in the human body, even after cutaneous ulcers have resolved, posing a risk for reactivation or the development of metastatic lesions. This is an enduring mystery.

“This award provides the freedom and flexibility to explore new scientific directions that would be difficult to pursue through traditional funding mechanisms,” Novais said. “We’re especially interested in how these parasites manipulate the host’s iron metabolism to evade immune detection and persist in tissues.”

Her project, titled “Immune evasion strategy of an intracellular parasite,” will investigate how Leishmania alters the biology of immune cells to create a hospitable environment for long-term survival. The findings could have broad implications – not only for leishmaniasis, but for understanding how other chronic infections operate and how we might intervene to restore health.

“This research will help us better understand the tug-of-war between host and pathogen,” Novais said. “By uncovering the strategies that allow microbes to hide from our immune system, we can begin to design smarter ways to prevent or treat infection.”

Scientists first reported in 2016 that specific gut microbes known as commensal bacteria, which cause no harm and often contribute to host health, set off production and release of a gut-originated T cell that drives up body-wide autoimmune disease in mice. Since then, the team has focused on explaining this unexpected twist in the typically harmonious relationship between these microbes and the body. 

The gut is where the action begins, but the overall outcome can be attributed to T cells’ “plasticity” – their flexibility to respond to a changing environment, such as in our body’s barrier, the gut. 

In this case, reprogrammed T helper cells adopt characteristics of a new T helper cell type while preserving some of their original traits, making them “super powerful and potent – and if you are dealing with autoimmune disease, that’s bad news,” said senior study author Hsin-Jung Joyce Wu, professor of internal medicine, division of rheumatology and immunology, at The Ohio State University College of Medicine.   

“This is really the first time it’s been shown that T cell plasticity, which typically occurs in the gut, can have this dramatic impact outside the gut with systemic impact on autoimmune disease.” 

The findings likely have relevance to human patients, Wu said: Many of the gene expressions detected in these abnormal cells in mice also exist in the same cells in people with rheumatoid arthritis. 

The research was published April 30 in Nature Immunology.

An estimated 18 million people worldwide are affected by rheumatoid arthritis (RA), a chronic autoimmune disease causing inflammation throughout the body and pain in the joints. Like other autoimmune diseases, RA is caused by the immune system attacking the body’s tissues and organs. Though the exact cause is unknown, genetics and environmental exposures – such as smoking and changes of gut commensal bacteria, or dysbiosis – are among the risk factors. 

The abnormal T cell in question is called a T follicular helper 17 (T_FH17) cell – meaning it functions as a T_FH cell but also displays T helper 17 (T_H17) cell signatures. Several previous studies have reported that the human equivalent of these types of cells are found in the blood of patients with autoimmune diseases, and are linked to more severe symptoms, but little has been known about the cells’ backstory. 

These cells have been a puzzle, Wu said, because the conventional T_FH cells are expected to be nonmobile, and just reside in B cell follicles to help B cells, another immune cell type critical for the development of RA. But unlike conventional T_FH cells, the T_FH17 cells also have the traveling capabilities of T helper 17 cells, which are known to migrate rapidly to infection sites where they produce a proinflammatory protein called IL-17.

Following their 2016 study, Wu’s lab has now discovered that the systemic T_FH cells traced back to Peyer’s patches, lymphoid tissue in the small intestine, and induced by typically harmless microbes called segmented filamentous bacteria, are enriched with T_FH17 cells. 

More specifically, fate-mapping mouse models showed that the hybrid cells derived from T helper 17 (T_H17) cells in the gut transformed into T follicular helper cells inside Peyer’s patches, and that the segmented filamentous bacteria enhanced the cell reprogramming process. 

“The key is T cell plasticity only happens in very few places, which is why it’s been overlooked – the dominant place to find them is in the gut barrier,” Wu said. “And that’s one of few places in the body where the environment can change from one second to the next, and therefore induction of T cell plasticity occurs to accommodate the ever-changing environmental challenge.” 

The team then used fluorescent tagging of cells in the arthritic mouse model to observe the cells’ movement from the gut to the rest of the body.

“That’s how we knew they were really traveling,” Wu said. Importantly, these cells also acquire a stronger capability to help B cells compared to conventional T_FH cells. 

“That’s what makes them ultra-pathogenic T_FH cells in RA, a systemic disease, because they are very mobile and can potently help B cells,” she said. 

To demonstrate the hazard associated with these abnormal T_H17-derived T_FH cells, researchers compared RA development in genetically susceptible mouse models injected with only conventional T_FH cells (as a control group) or conventional T_FH cells mixed in with around 20% of T_H17-derived T_FH cells. 

Substituting a small number of the conventional cells with these aberrant cells increased the arthritis-related ankle thickening in mice by 4.8-fold compared to control mice, a finding that took Wu and colleagues by surprise.

Researchers also sequenced the gene expression profiles of the aberrant T follicular helper cells isolated from the gut of RA mouse models and found that they shared several similarities with those of T_FH cells circulating in the blood of people with RA – including the gut signature, hinting that a similar mechanism is behind human disease as well.

“That, to me, was exciting, to find this cross-species signature, which suggests the translational potential of this research,” Wu said. “We are hoping to improve patients’ health and life. For the future, as T_FH17 cells can be found in other type of autoimmune patients, such as lupus patients, if we can determine that these abnormal T_FH cells are a potential target not just for RA, but across autoimmune diseases, that would be very useful.” 

This work was supported by the National Institute of Allergy and Infectious Diseases and the National Heart, Lung, and Blood Institute. 

Co-authors include Tingting Fan, Chi Tai, Madeline Cutcliffe, Haram Kim, Ye Liu, Jianying Li, Gang Xin, Mollyanna Grashel, Laurie Baert, Chinwe Ekeocha, Paige Vergenes, Judith Lin, Beatriz Hanaoka and Wael Jarjour of Ohio State; Kiah Sleiman and Trevor Tankersley of the University of Arizona; Svetlana Lima and Randy Longman of Weill Cornell Medicine; Wan-Lin Lo of the University of Utah; Min Wang and Xuan Zhang of the National Center of Gerontology in Beijing; and George Tsokos of Harvard Medical School.

General social support was also protective, but the association was less robust and lasting than a satisfying intimate partnership, which was characterized by fewer declines in both objective measures of cognitive setbacks and patient self-reports of subtle changes such as forgetting grocery list items and being unable to multitask. 

The findings suggest that couples therapy aimed at enhancing relationship quality could be a helpful option for partnered patients undergoing chemo, researchers said. 

The team also found that blood levels of the hormone oxytocin, an important player in social bonding, decreased significantly over the course of chemotherapy treatment, which may hint at a biological mechanism that could one day be targeted to reduce chemo’s side effects. 

“There are a lot of cancer treatments, but there are very few treatments for the behavioral side effects of cancer. So we need to understand how they’re happening in order to create useful interventions for the side effects,” said senior author Leah Pyter, director of the Institute for Behavioral Medicine Research at The Ohio State University and associate professor of psychiatry and behavioral health in the College of Medicine. 

“Before this study, we didn’t understand that bolstering the intimate partnership before the patient undergoes chemo might attenuate their cognitive side effects.” 

The research was published recently in the journal Psychoneuroendocrinology. 

The 48 participating women with breast cancer were part of a larger study examining links between chemo-induced disruption of the gut microbiome, inflammation and cognitive decline. 

Participants completed objective tests assessing verbal learning, word association, visual attention and short-term memory. Separately, they reported on changes to their concentration, memory, word retrieval and mental clarity and how any declines affected their quality of life. These measures were taken before, during and after chemo treatment. 

Decreases in mental fitness did not meet the clinical definition of cognitive impairment, but several changes were considered clinically meaningful. 

“It was nice to be able to test these patients before they had chemo and then again after, because people can be affected by chemo and still be within normal ranges – but for them, it’s not normal,” Pyter said. 

For this study, first author Melina Seng, then a master’s student and now a senior research technician in Pyter’s lab, followed up with the partnered patients to assess their intimate relationship satisfaction and how much social support from friends and family they received during chemo treatment. 

Statistical analysis revealed associations between changes in cognitive scores and social factors, finding that the more satisfied the patients were in their relationship, the more protected they were from cognitive changes over the course of chemotherapy. 

“There was less decline in cognitive function for those who had a good amount of social support, but there were more associations and more enduring associations between protected cognition and the highly satisfying relationship than just with general social support,” Pyter said. “We interpreted that as an indication that the most important social relationship is that intimate partnership. 

“There’s group therapy for chemo patients, which is social support, and this study would suggest that while that therapy might be beneficial, marital or partner therapy used in other medical contexts to improve the quality of the relationship might also be a good approach for patients receiving chemo.” 

While Seng hoped to find associations between oxytocin levels, cognitive function and social support, no clear connections could be detected. The results did show, however, that the hormone and its receptor were affected by chemo. 

In particular, the level of oxytocin circulating in the blood decreased significantly during chemo and returned to baseline levels after treatment, suggesting that chemotherapy could be affecting the hypothalamus region of the brain, where oxytocin is made. 

“Oxytocin is well-known to play roles in social interactions and has been called the ‘love’ hormone, but it does so many other things,” Seng said. “To our knowledge, no one has ever studied oxytocin and chemotherapy before, so the fact that we saw a very strong decrease in oxytocin from pre-chemotherapy to during chemotherapy is very interesting and is something that should be investigated further.” 

Both Pyter and Seng noted that with increased breast cancer survivorship comes an urgent need to address lingering side effects of treatment.

“Chemotherapy is one of the best treatments we have for cancer and for other diseases beyond cancer. It affects a lot of people and is very effective,” Pyter said. “We have more survivors, which is fantastic. Our research is focused on issues that are less well-studied, trying to make sure that survivors’ quality of life is as high as possible.”

This work was supported by the National Center for Advancing Translational Sciences and The Ohio State University Wexner Medical Center. 

Additional co-authors, all from Ohio State, were Seth Adarkwah Yiadom, Lauren Otto-Dobos, Sagar Sardesai, Nicole Williams, Margaret Gatti-Mays, Daniel Stover, Preeti Sudheendra, Erica Dawson, Robert Wesolowski, Baldwin Way, Erica Glasper and Rebecca Andridge. 

In mouse experiments, scientists introduced a specific type of recombinant protein to the site of a spinal cord injury where these cells, called pericytes, had flooded the lesion zone. Once exposed to this protein, results showed, pericytes change shape and inhibit the production of some molecules while secreting others, creating “cellular bridges” that support regeneration of axons – the long, slender extensions of nerve cell bodies that transmit messages. 

Researchers observed axon regrowth in injured mice that received a single treatment injection of the growth-factor protein, and the animals also regained movement in their hind limbs. An experiment involving human cells suggests the results are not restricted to mice. 

“There’s a lot more that can be learned and a lot that can be expanded, but the more we worked on this, the more stunned we really were by the potency of this single treatment and how effective it was,” said senior study author Andrea Tedeschi, associate professor of neuroscience in The Ohio State University College of Medicine. “This finding goes beyond spinal cord injury – it has implications in brain injury and stroke, and neurodegenerative diseases as well.” 

The work underscores how important blood vessel restoration is to recovery of neurological function after a spinal cord injury, researchers said. 

“Spinal cord injuries are severe not only because they prevent transmission of information across the site of the injury, but because all of the vasculature structure and function is also compromised,” said first study author Wenjing Sun, assistant professor of neuroscience at Ohio State. “Even if you are able to reestablish neuronal connectivity from one end to the other, the overall effect will still not be maximized unless you take care of everything else that falls apart.” 

The study was published April 18 in the journal Molecular Therapy. 

Previous research suggesting pericytes interfere with spinal cord injury recovery had led some scientists to recommend clearing them from the lesion site to aid repair. But cancer research has indicated pericytes’ properties change when they’re exposed to a protein called platelet-derived growth factor BB (PDGF-BB) – which is one way tumors generate their own blood supply. In cancer, the aim is to block PDGF-BB signaling. 

Earlier neuroscience research also indicated that pericytes are highly “plastic,” meaning they are very responsive to changes in the microenvironment – including the presence of PDGF-BB. Tedeschi and colleagues saw potential to harness that cell-protein relationship to stabilize the vasculature surrounding a spinal cord injury. In the process, they found the newly sprouted blood vessels established a pathway for regenerated axons to follow. 

Starting with imaging studies, the team showed that when a spinal cord is severed, pericytes migrate into the injury site over time but don’t promote growth of functional blood vessels that are needed to support axon regeneration. 

In cell-culture experiments, the researchers established a “carpet” of pericytes, added PDGF-BB, and then placed a layer of adult mouse sensory neurons on top and evaluated how much axons grew in 24 hours. The treated axons grew nearly as much as healthy axons extend under normal conditions. 

PDGF-BB alone did not produce this result. Instead, experiments showed that pericytes combined with the growth factor rearranged fibronectin, a multifunctional adhesive glycoprotein that plays a critical role in tissue repair, cell attachment and motility. The cells themselves also change shape, becoming more elongated. 

“We know these cells are going to infiltrate and deposit at the lesion epicenter. These elongated fiber structures that they become are far more permissive in promoting axons to regenerate from one end to the other and bypass the injury,” Tedeschi said. 

“To extend the clinical relevance of our findings, we cultured mouse neurons on top of human pericytes that were exposed to PDGF-BB, and that was sufficient to trigger a growth-promoting effect, suggesting that this might really be a generalized phenomenon that is not restricted to mice.” 

Turning to experiments in animals with spinal cord injury, researchers waited for seven days after the injury – the equivalent of about nine months in a human adult – before injecting a single dose of PDGF-BB at the injury site. Analysis of tissue four weeks after the injury showed that the PDGF-BB injection produced robust axon regenerative growth compared to the axon response in injured control mice. 

“When we looked at formation of these pericyte structures that crossed the injury site, we saw the treatment promoted the growth of these bridges. And most if not all of these regenerating axons were able to escape the injury site by riding these cellular bridges that have formed in response to PDGF-BB administration,” Sun said. 

Electrophysiological and movement assessments of injured animals treated with PDGF-BB detected sensory activity beyond the lesion site and showed the mice regained better control of their hind limbs compared to control mice. The animals also were less sensitive to a non-painful stimulus, suggesting they did not experience the neuropathic pain that is often triggered by a spinal cord injury. 

Analysis of the presence of inflammatory proteins during the repair process suggested that PDGF-BB administration not only promotes axon regeneration, but also reduces inflammation. RNA sequencing showed that spinal cord injury led to decreased gene expression by pericytes, but that the cells retained their core properties and did not convert into a different kind of cell – for example, a cell type that could end up being destructive to the injury environment. 

“There was a decrease in some classical pericyte markers, but a gain of some additional function linked to the attempt to rebuild cellular bridges and functional vessels,” Sun said. “From the overall gene signature in our data, they’re still classified as a pericyte.” 

Because Tedeschi, Sun and colleagues have previously shown in mice that gabapentin promotes regeneration of neural circuits after spinal cord injury, there’s potential to consider a multipronged approach to therapy, Sun said. 

“We could combine both – modulating intrinsic properties of adult neurons with a drug, and what we are doing here, modulating the non-neuronal environment to produce cellular interactions that provide a more permissive substrate for the neuron to grow on,” she said. 

More work is planned to determine the precise timing for administration of PDGF-BB – with the presumption that pericytes take some time to migrate to the injury – as well as the ideal concentration of the treatment and a potential time-released delivery system. 

This research was supported by the National Institute of Neurological Disorders and Stroke and Ohio State’s Chronic Brain Injury Program. 

Additional co-authors were Elliot Dion, Fabio Laredo, Allyson Okonak, Jesse Sepeda, Esraa Haykal, Min Zhou, Heithem El-Hodiri, Andy Fischer, Juan Peng and Andrew Sas, all of Ohio State, and Jerry Silver of Case Western Reserve University.

A new study suggests that perceived stress and depression factor into the relationship between the two conditions – perhaps not a surprise. But because the relationship between insomnia and heavy drinking goes in both directions, the influence of stress or depression depends on which condition came first, the analysis found. 

“We were most interested in how insomnia leads to drinking, and we found that seems to occur primarily through stress. But when we switched pathways, it appeared that drinking primarily led to insomnia through depression,” said Jessica Weafer, senior author of the study and associate professor of psychiatry and behavioral health in The Ohio State University College of Medicine. 

“Identifying these types of mediating factors can have important treatment implications,” she said. “If people who have insomnia are experiencing a lot of stress, then if we can target the stress, that might reduce the likelihood that their insomnia would lead to heavy drinking. That’s the long-term ideal, or hope, that this work could have an impact on treatment.” 

The study was published recently in the journal Alcohol. 

Insomnia and hazardous drinking can cause upheaval in one’s life: Both are associated with missed work and lower productivity on the job. Chronic insomnia can increase the risk for cardiovascular disease, Alzheimer’s and other chronic illnesses. A defining characteristic of alcohol use disorder (AUD) is continuing to drink even when encountering interpersonal problems, getting sick or hurt, or driving while intoxicated. 

Weafer has expanded her research focus on risks for problem drinking to address the fact that poor sleep can lead to increased drinking and those with AUD commonly have difficulty with sleep. 

“The number of people with AUD who also have insomnia is very, very high. It’s striking, and important,” she said. 

Participants in this study were part of a larger project testing the effectiveness of a digital insomnia intervention for people with poor sleep who are heavy drinkers. A total of 405 volunteers completed questionnaires assessing insomnia severity, current and historic drinking behaviors, perceived stress and depression symptoms. 

Stress and depression often overlap, but are distinct – the stress scale measures the degree to which situations in life are perceived as stressful, and the depression scale measures behaviors and feelings related to hope, fear, happiness and loneliness. 

Previous research has suggested that stress or depression, or both, contribute to troubled sleep or heavy drinking, said first study author Justin Verlinden, a cognitive neuroscience PhD student at the University of Kentucky. 

“There are so many different pathways that could explain insomnia and alcohol use. We wanted to connect the dots and see if there’s anything there,” he said. 

Analyzing the data with a range of statistical models revealed the many ways stress and depression influence the relationship between insomnia and hazardous drinking. 

“If you look at stress and depression separately, we find there is an indirect relationship between insomnia and drinking as well as drinking and insomnia – meaning a good chunk of the relationship between insomnia and drinking can be explained through perceived stress or depression,” Verlinden said. 

“When you put both stress and depression in the same models, that’s where we get unique findings, even though there are a lot of shared characteristics between stress and depression.” 

A model of insomnia predicting heavy use of alcohol showed that the characteristics of stress – beyond any symptoms shared with depression – better described this relationship. In a model reversing the order, where drinking predicts the onset of insomnia, symptoms of depression that aren’t shared with stress better explain the link. 

“That finding was very surprising, but showed the benefit of looking at both stress and depression in the same model, to see how those pathways might differ depending on what the directionality is,” Weafer said. 

Both stress and depression are described as partial indirect paths – meaning there are any number of other factors that could help explain the connection between bad sleep and problem drinking, the researchers said. 

The findings represent a snapshot rather than explaining the progression of how insomnia and heavy drinking become linked over time, and where depression and stress fit into that evolving relationship, Weafer said. The team is collecting a final dataset that will enable the researchers to trace insomnia, stress and depression over the course of 12 months to get a better idea of the connected pathways. 

The researchers are also testing the effectiveness of a digital version of cognitive behavioral therapy for insomnia called SHUTi (Sleep Healthy Using the internet) in heavy drinkers. Their December 2023 pilot study showed that SHUTi was effective at reducing insomnia in heavy drinkers – even without an emphasis on curbing alcohol use. 

This research was supported by the National Institute on Alcohol Abuse and Alcoholism and the University of Kentucky. 

Additional co-authors include Mairead Moloney of the University of Miami and Olga Vsevolozhskaya and Lauren Whitehurst of the University of Kentucky.

The AAAS Fellowship, recognizing scientifically or socially distinguished efforts to advance science or its applications, is one of the most prestigious honors a U.S. scientist can receive. Fellows are elected by their academic peers.  

“Ohio State’s newly elected Fellows have devoted their professional lives to protecting health, investigating complex principles of physics, and analyzing social behavior and labor economics,” said Peter Mohler, executive vice president for research, innovation and knowledge. “The American Association for the Advancement of Science Fellowship is an important acknowledgment of the key role scientists play in solving critical problems and improving lives.”   

The 2024 class consists of 471 scientists, engineers and innovators spanning 24 scientific disciplines.   

Ohio State’s newest Fellows represent the colleges of Arts and Sciences; Food, Agricultural, and Environmental Sciences; Medicine; and Veterinary Medicine. This year’s class, joining over 540 Ohio State scholars who have been granted this lifetime recognition since 1874, are:   

John Beacom, professor of physics and astronomy. For distinguished contributions to the fields of nuclear and particle astrophysics, particularly regarding neutrinos. 

Pierluigi (Enrico) Bonello, professor of molecular and chemical ecology of trees in the Department of Plant Pathology. For distinguished contributions to the fields of forest pathology, chemical ecology, tree disease resistance and early detection of tree infections. 

Prosper Boyaka, professor and chair of veterinary biosciences. For distinguished contributions to the field of mucosal immunology, particularly in the field of vaccinology to develop alternative novel strategies to optimize protective immunity to pathogens at mucosal surfaces. 

David Robert Cole, professor of earth sciences and Ohio Research Scholar. For distinguished contributions to the field of subsurface mineralogy and geochemistry from the molecular to the geological formation scale. 

Ian Hamilton, professor of evolution, ecology and organismal biology and mathematics. For distinguished contributions to the fields of behavioral ecology and complexity science in both theory and empirical studies. 

Chun Ning Jeanie Lau, professor of physics. For distinguished experimental contributions to the field of 2D van der Waals materials, leading to new insights into the thermal, mechanical and electronic properties, and emergent phases in few-layer graphene. 

Roland Kenji Kawakami, professor of physics. For seminal contributions to spintronics and magnetism in two-dimensional materials, and for the investigation of epitaxial magnetic films and heterostructures using molecular beam epitaxy and surface-sensitive characterizations. 

Abhay Satoskar, professor of pathology and microbiology. For distinguished contributions to the field of parasitology, particularly mechanisms of immunity and immune evasion in leishmaniasis and development of novel therapies and vaccines for this disease. 

Bruce Weinberg, professor of economics. For distinguished contributions to the field of labor economics, particularly for a multidisciplinary approach to studying creativity and innovation, socioeconomic determinants of youth outcomes and technological impact on wage structure. 

Fellows are recognized for their achievements across disciplines, from research, teaching and technology to administration in academia, industry and government, to excellence in communicating and interpreting science to the public. 

The 2024 class of Fellows will be honored at a forum in Washington, D.C., in June.

Researchers fed separate groups of young and old rats the high-fat diet for three days or for three months to compare how quickly changes happen in the brain versus the rest of the body when eating an unhealthy diet. 

As expected based on previous diabetes and obesity research, eating fatty foods for three months led to metabolic problems, gut inflammation and dramatic shifts in gut bacteria in all rats compared to those that ate normal chow, while just three days of high fat caused no major metabolic or gut changes.

When it came to changes in the brain, however, researchers found that only older rats – whether they were on the high-fat diet for three months or only three days – performed poorly on memory tests and showed negative inflammatory changes in the brain. 

The results dispel the idea that diet-related inflammation in the aging brain is driven by obesity, said senior study author Ruth Barrientos, an investigator in the Institute for Behavioral Medicine Research at The Ohio State University. Most research on the effects of fatty and processed foods on the brain has focused on obesity, yet the impact of unhealthy eating, independent of obesity, remains largely unexplored. 

“Unhealthy diets and obesity are linked, but they are not inseparable. We’re really looking for the effects of the diet directly on the brain. And we showed that within three days, long before obesity sets in, tremendous neuroinflammatory shifts are occurring,” said Barrientos, also an associate professor of psychiatry and behavioral health and neuroscience in Ohio State’s College of Medicine.  

“Changes in the body in all animals are happening more slowly and aren’t actually necessary to cause the memory impairments and changes in the brain. We never would have known that brain inflammation is the primary cause of high-fat diet-induced memory impairments without comparing the two timelines.” 

The research was published recently in the journal Immunity & Ageing. 

Years of research in Barrientos’ lab has suggested that aging brings on long-term “priming” of the brain’s inflammatory profile coupled with a loss of brain-cell reserve to bounce back, and that an unhealthy diet can make matters worse for the brain in older adults. 

Fat constitutes 60% of calories in the high-fat diet used in the study, which could equate to a range of common fast-food options: For example, nutrition data shows that fat makes up about 60% of calories in a McDonald’s double smoky BLT quarter pounder with cheese or a Burger King double whopper with cheese. 

After the animals were on high-fat diets for three days or three months, researchers ran tests assessing two types of memory problems common in older people with dementia that are based in separate regions of the brain: contextual memory mediated by the hippocampus (the primary memory center of the brain), and cued-fear memory that originates in the amygdala (the fear and danger center of the brain). 

Compared to control animals eating chow and young rats on the high-fat diet, aged rats showed behaviors indicating both types of memory were impaired after only three days of fatty food – and the behaviors persisted as they continued on the high-fat diet for three months. 

Researchers also saw changes in levels of a range of proteins called cytokines in the brains of aged rats after three days of fatty food, which signaled a dysregulated inflammatory response. Three months after being on the high-fat diet, some of the cytokine levels had shifted but remained dysregulated, and the cognitive problems persisted in behavior tests. 

“A departure from baseline inflammatory markers is a negative response and has been shown to impair learning and memory functions,” Barrientos said. 

Compared to rats eating normal chow, young and old animals gained more weight and showed signs of metabolic dysfunction – poor insulin and blood sugar control, inflammatory proteins in fat (adipose) tissue, and gut microbiome alterations – after three months on the high-fat diet. Young rats’ memory and behavior and brain tissue remained unaffected by the fatty food. 

“These diets lead to obesity-related changes in both young and old animals, yet young animals appear more resilient to the high-fat diet’s effects on memory. We think it is likely due to their ability to activate compensatory anti-inflammatory responses, which the aged animals lack,” Barrientos said. 

“Also, with glucose, insulin and adipose inflammation all increased in both young and old animals, there’s no way to distinguish what is causing memory impairment in only old animals if you look only at what’s happening in the body. It’s what is happening in the brain that’s important for the memory response.” 

This work was supported by grants from the National Institute on Aging. 

Co-authors include Michael Butler, Stephanie Muscat, Brigitte González Olmo, Sabrina Mackey-Alfonso, Nashali Massa, Bryan Alvarez, Jade Blackwell, Menaz Bettes and James DeMarsh of Ohio State; and Maria Elisa Caetano-Silva, Akriti Shrestha, Robert McCusker and Jacob Allen of the University of Illinois at Urbana-Champaign.

The analysis of health insurance claims data from almost 3 million U.S. patients investigated prescribed stimulants’ impact on prescription opioid use over 10 years, looking for origins of the so-called “twin epidemic” of combining the two classes of drugs, which can increase the risk for overdose deaths. 

“Combining the two drugs is associated with an increase in overdose deaths. This is something we know. But we didn’t know whether stimulant use has a causal role in high use of opioids, so we conducted a big data analysis of how these two patterns interacted over a long period of time,” said senior study author Ping Zhang, associate professor of computer science and engineering and biomedical informatics at The Ohio State University.

“What we found is that if someone is taking a stimulant and an opioid at the same time, they’re generally taking a high dose of the opioid,” he said. “And if the patient in this study population takes the stimulant before beginning opioid use, they are more likely to have higher doses of subsequent opioids.” 

The study was published Feb. 17 in The Lancet Regional Health – Americas.     

The research team obtained data on 22 million patients with 96 million opioid prescriptions from MarketScan Commercial Claims and Encounters, a large U.S. health insurance database. Researchers established a cohort for this study of 2.9 million patients with an average age of 44 who had at least two independent opioid prescriptions between 2012 and 2021. 

Because these prescriptions included a range of oral formulas – codeine, hydrocodone, methadone, oxycodone, morphine and others – researchers standardized every prescription to morphine milligram equivalents (MME) and calculated each patient’s monthly intake of opioids. The MME computation from electronic health records was previously co-developed by co-senior author Wenyu Song, an instructor at Harvard Medical School. 

First author Seungyeon Lee, a PhD student in Zhang’s lab, used statistical modeling and classified patients into five baseline groups of opioid dosage trajectory over the 10-year study period: very low-dose, low-dose decreasing, low-dose increasing, moderate-dose increasing and high-dose sustained use. 

“Some patients had stable low-dose opioid use, while others had increasing or high dose patterns over time,” Lee said. 

Of the total cohort, 160,243 patients (5.5%) also were prescribed stimulants. The addition of a monthly calculated cumulative number of stimulant prescriptions to the model and statistical analysis showed a shift in the trajectory groups. Characteristics that could serve as risk factors for increasing opioid use also emerged in the data, Lee said. 

Moderate-dose increasing and high-dose groups had an overall higher average MME and a higher proportion of patients with diagnoses of depression, anxiety and attention-deficit/hyperactivity disorder compared to other groups. The low-dose increasing group also had a higher proportion of patients with ADHD compared to the low-dose decreasing group. 

The most common diagnoses linked to co-prescription of stimulants and opioids were depression and ADHD or ADHD and chronic pain. 

“This was an important finding, that many patients with ADHD and depression, also experiencing chronic pain, have an opioid prescription,” said Zhang, also a core faculty member in the Translational Data Analytics Institute at Ohio State. “This cohort represents a very realistic health care problem.” 

Even taking those factors into account, the model showed that stimulant use was key to driving up the odds that patients who took both stimulants and opioids would belong to a group of people who increased their doses of opioids. 

“Stimulant use before initiating opioids and stimulant co-prescription with opioids are both positively associated with escalating opioid doses compared to other factors,” Lee said. 

Analysis of geographic and gender data also offered some clues to opioid use patterns in the United States. Patients in the South and West regions had higher total opioid intakes over the 10-year study period compared to the Northeast and North Central regions, with the highest frequency of opioid prescriptions in the South and higher MMEs per prescription in the West. Males also had higher average daily opioid intakes than females. 

The results linking high opioid doses and stimulant use suggest stimulants may be a driving force behind the emergence of the twin epidemic and offer evidence that regulation of stimulant prescribing may be needed for patients already taking prescription opioids, the researchers said. In addition to the increased risk of overdose death, co-using prescription stimulants and opioids can increase the risk for cardiovascular events and mental health problems, previous research has shown. 

Zhang’s Artificial Intelligence in Medicine Lab focuses primarily on using AI to aid in clinician decision making, and these findings are part of a larger project aimed at development of safer personalized treatment recommendations for people who are prescribed both opioids and stimulants. 

“We want to reduce the risk of opioid- or stimulant-related adverse drug events in real-world practice,” Zhang said. 

This work was funded by the National Institute of General Medical Sciences, the National Institute on Drug Abuse and the National Science Foundation. 

Additional co-authors were David Bates of Harvard Medical School and Richard Urman, chair of anesthesiology in Ohio State’s College of Medicine.

These particles, called extracellular vesicles, are considered attractive vehicle models for new drug therapies. But until now, researchers haven’t had the complete picture of how they work. 

In a new study, a team led by medical researchers at The Ohio State University determined that these vesicles contain an ion channel – a protein that opens a corridor allowing electrical charges to pass through the protective outer membrane, a necessary step to keep contents and conditions stable inside. 

Animal experiments also showed the ion channel influences the cargo, meaning the protein is important not just to the structure of extracellular vesicles (EVs), but also their function. Researchers compared the effects of RNA molecules delivered by EVs with and without the membrane protein to mice with ailing hearts. Only molecules carried by EVs with ion channels were able to repair the heart damage. 

Harpreet Singh, professor of physiology and cell biology, and Mahmood Khan, professor of emergency medicine, both in Ohio State’s College of Medicine, co-led the study. 

“We have not only discovered ion channels in these vesicles. We have recorded functional ion channels for the first time ever,” Singh said. “From forming a simple fundamental hypothesis that these vesicles should have ion channels all the way to showing that these vesicles will contain different cargo that can either protect or harm your cells – in this case, the heart – we have told the whole story.” 

The paper was published Jan. 2 in Nature Communications. 

Extracellular vesicles carry proteins and other molecules from donor to recipient cells to alter physiological and biological responses. In addition to facilitating cellular communication and maintaining cellular balance, the particles have been linked to immune responses, viral infectiousness, and cardiovascular disease, cancer and neurological disorders. 

Based on his specialization in the study of ion channels, Singh predicted that EVs must have ion channels to safely transport molecules from cellular interiors to the extracellular environment and back into another type of cell. Otherwise, their membranes would be subject to bursting – caused by a rush of water triggered by osmotic stress or shock – as positive and negative electrical charges of ions in those varying environments ebb and flow. 

“We know from our experience and from all this great work done in the last hundred years that ion channels are really, really important to maintain any structure which has a membrane,” Singh said. 

Take the electrolyte potassium, for example. It is the most abundant positively charged ion inside cells, but its concentration is 30-fold lower in the extracellular environment. 

“Suddenly an extracellular vesicle is coming from a huge potassium concentration to a low potassium concentration. What is going to happen if you can’t maintain ionic balance? You are going to feel the osmotic shock,” he said. 

For this work, researchers isolated mouse EVs provided by Khan, also director of basic and translational research in the Department of Emergency Medicine, whose lab focuses on repairing damaged heart muscle with stem-cell therapy. 

Because these particles are extremely small, the scientists created a technique they called near-field electrophysiology to record currents in the EV membranes. The method established the presence of a calcium-activated large-conductance potassium channel (BKCa). 

They followed by isolating EVs from normal mice and knockout mice lacking the gene that encodes the BK potassium channel, and found the cargo in EVs from the knockout mice were very different in number and size – suggesting a functional role for the BKCa channel. 

Several small RNA segments that regulate gene activation that were found among the cargo in the normal mouse vesicles were known to help protect the heart against oxidative stress, Khan said. EVs from the mice lacking the BK channel gene contained a different set of these segments, called microRNAs. 

This finding led to the animal experiments in Khan’s lab, where EVs from normal mice and mice lacking the BK gene were injected into mice with diseased hearts. 

“EVs from the wild-type animals protected the heart,” Singh said. “EVs that came out of the knockout mice could not protect the heart properly and, in fact, made things worse. Bad microRNAs were enriched in the vesicles that don’t have the channel. 

“Is the cargo different because of different packaging, or is it because the vesicles without the channels are not surviving? That is an open question, and we are trying to address that.” 

Another chief open question is identifying proteins, called transporters, that enable vesicles to maintain ionic balance as they transition from the extracellular environment back into a cell with a high potassium concentration. 

Besides increasing fundamental knowledge about extracellular vesicles, Singh said, this work has potential to advance development of their use as therapeutics.   

“People talk about loading these vesicles with charged molecules – whether it’s a drug, RNA proteins, or something else. If you’re loading them with charged molecules and you’re not managing ion homeostasis, you will have some sort of consequences,” he said. “That’s our big point, that if you are bioengineering EVs, you have to have the right combination of ion channels and transporters.”

This work was supported by an Ohio State President’s Predoctoral Fellowship, the Department of Physiology and Cell Biology, and a Graduate School Alumni Grant; the American Heart Association; the National Heart, Lung, and Blood Institute; the National Institute of Arthritis and Musculoskeletal and Skin Diseases; and the National Center for Advancing Translational Sciences. 

Additional co-authors are Shridhar Sanghvi, Divya Sridharan, Parker Evans, Julie Dougherty, Kalina Szteyn, Denis Gabrilovich, Mayukha Dyta, Jessica Weist and Lianbo Yu of Ohio State; Sandrine Pierre of Marshall University; Shubha Gururaja Rao of Ohio Northern University; Dan Halm of Wright State University; and Tingting Chen, Panagiotis Athanasopoulos and Amalia Dolga of the University of Groningen.

In a new study involving interviews of people with long COVID, researchers from The Ohio State University describe how the prolonged illness has affected not only patients’ job status, but also their overall well-being. 

On top of symptoms including brain fog, fatigue, weakness and headaches, study participants reported lacking enough energy to do anything after work, loss of income and added insurance expenses when employment ended or changed, and emotional distress that comes with managing a misunderstood illness. 

“For many individuals we talked to, their lives have been completely changed because of this chronic condition. And that’s really changed how they see themselves, how they experience life, how they interact with their families, how they provide for their families,” said lead author Sarah MacEwan, assistant professor of general internal medicine in Ohio State’s College of Medicine. 

“In some cases, incredible financial instability has upended their lives. They’re facing extremely difficult choices and also trying to take care of themselves. It’s so important that we hear from them so we can improve the ways we can support them.” 

Awareness of these employment-related challenges may help clinicians provide more holistic care to people with long COVID, researchers say. Examples include connecting patients to financial assistance, referring them to mental health practitioners or expediting requests for workplace accommodations. 

The research was published recently in the Journal of General Internal Medicine. 

MacEwan and colleagues conducted one-on-one interviews in late summer 2022 with 21 adult patients receiving treatment in the post-COVID recovery clinic at Ohio State Wexner Medical Center. Participants reported they had been doing well in daily life before having COVID-19 and were struggling with the effects of lingering symptoms for three or more months after an acute infection. They ranged in age from 19 to 68, three-fourths were women, and most were first infected with the SARS-CoV-2 virus in 2020. 

Participants reported the illness interfered with both their work responsibilities and efforts to maintain work-life balance. 

“Some quit their jobs because they just couldn’t handle working anymore. Some reduced their hours. And then some were involuntarily terminated from their jobs because of their symptoms,” said MacEwan, an investigator in Ohio State’s Center for the Advancement of Team Science, Analytics and Systems Thinking in Health Services and Implementation Science Research. 

There were both financial and emotional repercussions. Loss of income followed either being unable to work, changing to a job with lower pay or having to reduce work hours. Those whose insurance status changed often had to spend more on policies that provided less coverage – all in the context of needing more care because they were chronically ill. 

Participants also described feelings of loss of identity related to their professional and home lives and fear of judgment and stigma at work and among friends and family. In an earlier paper, the research team noted some patients faced skepticism in health care settings. 

“One thing we’ve uncovered through this work is people not being believed by their providers about their symptoms or being brushed off or pushed into other diagnoses that they feel don’t reflect their experience,” MacEwan said. “It’s a real question of whether they are getting what they need from the providers they’re able to reach where they are.” 

The current article focused in part on how patients made adjustments to get through the day – developing coping strategies they created or that were recommended by their care team, and accessing employer disability benefits and workplace accommodations. 

“Some came up with solutions on their own, but it was wonderful to hear that great suggestions also came from additional specialists or therapists that these individuals were seeing,” MacEwan said. 

Respondents reported taking frequent rest breaks, eliminating distractions, making lists, emailing themselves a daily report of completed projects, using visual prompts on whiteboards or talking themselves through tasks. Some patients were encouraged by health care providers to seek short- or long-term disability benefits or workplace accommodations such as remote work and flex time. Many participants said initial support from employers eventually waned. 

Long COVID is federally recognized as a potential disability, which provides some employment protection to patients. The study authors noted that clinicians recommending established interventions such as rest and pacing may need to anticipate how such treatment strategies affect employment, financial status and mental health – and be ready to connect patients with resources to address the strains linked to making complex life choices. 

“It’s important that we use lived experience to understand the needs of the population and not make assumptions. There are a lot of good ideas already out there, and people with other chronic conditions have solutions for some of these problems,” MacEwan said. “So maybe we don’t need to reinvent the wheel, but we certainly need to identify the needs and take steps to fill those gaps.” 

This work was supported by a grant from the National Cancer Institute. 

Co-authors, all from Ohio State, were Saurabh Rahurkar, Willi Tarver, Leanna Perez Eiterman, Halia Melnyk, Ramona Olvera, Jennifer Eramo, Lauren Teuschler, Alice Gaughan, Laura Rush, Stacy Stanwick, Susan Bowman Burpee, Erin McConnell, Andrew Schamess and Ann Scheck McAlearney.

The protein also helps prevent unfamiliar viruses from mutating after they infect a new host, the study found – meaning its absence during an immune response could enable an animal virus spilled over to people to adapt rapidly to human hosts. 

The combined findings by scientists at The Ohio State University add up to potential trouble for people deficient in the protein, called IFITM3 – especially if an avian or swine flu were to gain hold in humans and cause widespread disease. 

IFITM3 deficiency is not rare: About 20% of Chinese people and 4% of people of European ancestry have genetic mutations that disable the immune system’s production of the protein. 

“An IFITM3 deficiency makes it easier for a low dose of virus to be infectious,” said senior study author Jacob Yount, professor of microbial infection and immunity in Ohio State’s College of Medicine. 

Currently, the Centers for Disease Control and Prevention is tracking the H5N1 avian flu that is widespread in wild birds worldwide and causing outbreaks in poultry and U.S. dairy cows. To date, 45 human cases have been reported. 

“It’s these emergent viruses that we’ve never encountered before where IFITM3 is really the most important,” Yount said. “Our study supports the idea that not only would you get a more severe infection, but you’re more likely to get infected in the first place and more likely to help the virus adapt if you are IFITM3 deficient.” 

The research was published Oct. 30 in Nature Communications.

IFITM3 (pronounced I-fit-M-3, for interferon-induced transmembrane protein 3) is key to the innate immune system’s clearance of viruses. It is produced in large quantities after flu is present and lowers the severity of infection by sequestering the virus so that it can’t make copies of itself, or replicate. 

Yount has studied flu and this protein for years, and his lab developed a mouse model lacking the gene that codes for IFITM3 – making the animals highly susceptible to flu. 

In this new work, his team sought to extend what is known about IFITM3 to risks related to interspecies infection – specifically the spillover of avian or swine flu to humans, which caused the 1918 influenza pandemic and three others since. 

The researchers compared the infectiousness of two strains of avian flu, including H5N1, at different viral particle levels in mice lacking the IFITM3 gene and normal mice. At levels roughly equivalent to 10 and 50 particles, viral loads could be detected in all mice, but in the protein-deficient mice, the equivalent of a single viral particle was able to cause infection and inflammation – while normal mice could not be infected by the low dose. 

“IFITM3 has been known to prevent severity of infection, but we’re newly showing that it’s also controlling how much virus it takes initially to cause infection,” Yount said. “And I think that’s one of the most fundamental textbook-level findings ever to come out of my lab.” 

Additional experiments in cultures of human cells that line the lung and immune cells showed that cells in which the gene for IFITM3 was silenced were more susceptible to infection by 11 avian, three swine and two human influenza viruses. 

“Every single one of those viruses infected at a higher rate when IFITM3 was deficient. So this really seems to be a universal property where IFITM3 needs to be there to inhibit flu infections,” Yount said. 

The team then used lab techniques to mimic repeated transmission of a human-origin virus in mice, testing the protein’s role in the pace of mutations that lead to interspecies adaptation. Experiments showed that flu viruses were able to replicate more rapidly and induce higher levels of inflammation in mice deficient in IFITM3 compared to normal mice. 

“So a virus from a different species adapts faster when IFITM3 is not there. This was a proof of principle, because we’re testing it in a mouse,” Yount said. 

“Overall, our study is a demonstration that IFITM3 is broadly important for zoonotic virus defense against a whole range of different influenza viruses that could potentially infect humans. And our research suggests that people with hereditary deficiency in IFITM3 are a uniquely vulnerable population for new viruses from animals entering humans.” 

The research suggests that individuals with IFITM3 deficiency should be considered in pandemic prevention efforts, he said. 

This work was supported by grants from the National Institutes of Health. 

Co-authors are Parker Denz, Samuel Speaks, Adam Kenney, Adrian Eddy, Jonathan Papa, Jack Roettger, Sydney Scace, Emily Hemann, Adriana Forero and Andrew Bowman of Ohio State, and Adam Rubrum and Richard Webby of St. Jude Children’s Research Hospital.

They spend their time providing free physical therapy to the center’s patients, many of whom do not have insurance or struggle with another barrier to accessing care.

“The parameters for who we see at the clinic are intentionally loose,” said Marka Salsberry, associate professor of practice. “We say ‘a patient with a financial barrier.’ That could be someone without insurance. That could be someone with Medicare who can’t afford their 20% co-pay for physical therapy. It could be someone with 100% insurance coverage but they’ve exhausted all their allotted visits for the year and need more.”

The Ohio State University Student Physical Therapy Clinic is a nonprofit, student-run, full-service clinic. Patients see second-year doctoral students, who are guided on-site by third-year students as well as two licensed physical therapists. Between 70 and 75 students spend three hours, Mondays and Wednesdays, at the clinic each autumn and spring semester.

Many of the clinic’s patients struggle with injuries that are routine but that have plagued them for years, Salsberry said.

“A patient may come in with something presenting like frozen shoulder, which is tightening of the shoulder joint due to inflammation. It’s painful and limiting in terms of function, and all these patients continue to work,” she said. “It takes us four weeks and then they can use that arm again.”

A valuable skill that students learn, Salsberry said, is creating treatment programs that are actually usable for patients. Many physical therapy programs involve exercises at home, which may not be viable.

“These are individuals who work two or three jobs,” she said. “That’s often a 12-hour day or more. We need to give patients programs they can work into their days. We’ve try to give them something they can do if they’re working on an assembly line, like marches or squats. So, it’s a mind shift [for students]. The approach is different because of the needs of the population.”

Claire Black, a third-year doctoral student, found another consideration when working in the clinic: patients’ families.

After working with a patient who had experienced a stroke, Black was approached by the man’s daughter with complaints of back pain. Black realized that the cause of the young woman’s pain was lifting her father.

“How do we teach family members to help without hurting their own bodies?” she said. “Helping is a reality for so many of our patients and their families. We adapt things to make it feasible and safe for everyone. That’s so important.”

The clinic is run by a student board. Black is chair of the board this year. She said the experience has been valuable with graduation on the horizon.

“I serve in a manager role for the clinic,” she said. “I’m in charge of supervising the other board members and also things like making sure the clinic runs smoothly. It’s prepared me to handle things like scheduling challenges, providing exercise programs and making sure we’re teaching the second-year students.”  

Second-year students are paired with third-year mentors. This partnership helps both students. Second-years learn tips from their peers and third-years get experience as instructors.

More importantly, though, said Black, the students are providing care to people who do not have access to it.

“It continues to surprise me – the lack of access to care,” she said. “We are filling a gap.”

Community service is central to physical therapy, Salsberry said.

“I do feel that that is our responsibility, as a profession,” she said. “And I feel the university takes that responsibility seriously, too. … It’s heartbreaking when you see someone with an injury that can be easily fixed; just a couple of visits to a physical therapist would change their day-to-day life. It’s so rewarding when you can reach those people.”

“It’s important, not just as an Ohio State student, but as a person representing the profession of physical therapy [to give back to the community],” Black said. “It’s important that our care meets the needs of every single person, not just those with money, and not just those with high health care literacy. There is an access issue, and we are helping to close that gap.”

Patients can be seen at the clinic this year through Nov. 20. To schedule an appointment, call 614-859-1952.

The finding came from a planned study of secondary outcomes of the HEALing (Helping to End Addiction Long-Term) Communities Study (HCS), which tested an intervention encompassing data-driven adoption of evidence-based practices for reducing overdose deaths in Kentucky, Massachusetts, New York and Ohio. 

Death rates from specific combinations of opioids with stimulants other than cocaine, most commonly fentanyl mixed with methamphetamine, were 8.9 per 100,000 adults in intervention communities compared to 14.1 per 100,000 adults in comparison communities that did not receive the intervention – a statistically significant difference.

The findings were published today (Oct. 21, 2024) in JAMA Network Open. 

With the prescription medications that started the opioid crisis harder to obtain by the time the trial began, fentanyl was rapidly entering the illicit drug market in combination with methamphetamine, cocaine, counterfeit pills and other stimulants, said Bridget Freisthler, lead author of the new study and a professor at The Ohio State University. 

“Now we have a whole new group of people developing addiction to opioids,” said Freisthler, Ohio’s principal investigator for the HEALing Communities Study. “It was nice to see that we were able to achieve reductions in overdose deaths involving this combination of opioids, primarily fentanyl and psychostimulants, not including cocaine, because that’s the most recent wave in the epidemic that we’re seeing.” 

Analysis of other drug combinations showed that intervention communities had lower rates of overdose deaths from an opioid mixed with cocaine (6%) and an opioid mixed with benzodiazepine (1%), but that these differences did not reach statistical significance. 

The National Institutes of Health (NIH) launched the HEALing Communities Study in 2019. Participating community coalitions implemented 615 strategies to address opioid-related overdose deaths across health care, justice and behavioral health settings. Based on data indicating which interventions were best suited to areas they served, agencies selected from three “menus” of evidence-based practices focused on overdose education and naloxone distribution, increasing exposure to medication for opioid use disorder, and safer opioid prescribing.  

Researchers reported in June on the main outcome of HCS – that the intervention did not result in a statistically significant reduction in opioid overdose death rates during the evaluation period. In this study, the authors found that intervention communities had an 8% lower rate of all drug overdoses compared to control communities, which was estimated to represent 525 fewer drug overdose deaths. 

In the new paper, researchers reported that more than 40% of overdose deaths in the study involved the combination of at least one opioid and a stimulant. 

The evidence of higher prevalence of fentanyl in the illicit drug market led coalition agencies to adjust communication efforts accordingly, said Freisthler, also the Cooper-Herron Professor in Mental Health at the University of Tennessee, Knoxville. 

“We were already shifting to where psychostimulants had fentanyl in them and messages weren’t reaching the right folks because people who use psychostimulants think of themselves as using meth or cocaine, not opioids,” she said. “So we had to make it clear that fentanyl could be in every drug and that nobody was really immune from the possibility of an overdose. Communities emphasized that this is a multiple-drug issue, not just a fentanyl issue or an opioid issue. 

“In many ways, the fact we’re looking at this particular outcome is because communities were so invested in it and so concerned, and wanted it to be a focus of the study.” 

The potential for naloxone to prevent overdose deaths in people who use multiple drugs was also incorporated into communication campaigns implemented by all intervention communities, which may have helped prevent deaths, researchers said. 

Participating agencies were very good at advocating for themselves, Freisthler said, and the front-end work ideally will leave communities even better prepared to address overdoses going forward. 

“The HCS was beneficial to Brown County in numerous ways,” said Deanna Vietze, executive director of the Brown County Board of Mental Health and Addiction Services in southwest Ohio. “It affirmed the work already underway, allowed for expansion of best practices, helped engage new partners, strengthened existing partnerships, and allowed innovative purchases that forged outreach opportunities that will continue to positively impact Brown County citizens for years to come.” 

Ohio study leaders are intent on making sure lessons and success stories from the study are widely available through a website providing a range of materials, and are meeting with groups interested in implementing the evidence-based practices in their own communities. 

“The drug overdose crisis is pervasive in our communities, and we’ve got multigenerational and intergenerational trauma affecting families. That’s not going to change overnight,” Freisthler said. “That means we need to continue to improve understanding of this crisis, and reduce overdose deaths so we don’t have another generation experiencing the same sort of trauma.” 

The HEALing Communities Study was supported and carried out in partnership between the National Institute on Drug Abuse and the Substance Abuse and Mental Health Services Administration through the NIH HEAL Initiative.  

A $65.9 million NIH award funding Ohio State’s leadership of the Ohio portion of the study was housed in the university’s College of Medicine. Co-authors of the paper included study site principal investigators Sharon Walsh of the University of Kentucky, Nabila El-Bassel of Columbia University, T. John Winhusen of the University of Cincinnati, Jeffrey Samet of Boston Medical Center and Emmanuel Oga of RTI International.

In a new study, using a ventilator-on-a-chip model developed at The Ohio State University, researchers found that shear stress from the collapse and reopening of the air sacs is the most injurious type of damage.

This miniature “organ-on-a-chip” model simulates not only lung injury during mechanical ventilation, but also repair and recovery, in human-derived cells in real time, said co-lead author Samir Ghadiali, PhD, professor and chair of biomedical engineering at Ohio State.

“The initial damage is purely physical, but the processes after that are biological in nature – and what we’re doing with this device is coupling the two,” Ghadiali said.

The team hopes the device will also help in the hunt for therapies to address ventilator-induced lung injury.

“This is an important advance in the field that will hopefully allow for a better understanding of how lung injury develops in mechanically ventilated patients and identification of therapeutic targets so that we can give drugs to prevent that kind of injury or treat it when it happens,” said co-lead author Joshua Englert, MD, associate professor of pulmonary, critical care and sleep medicine at The Ohio State University Wexner Medical Center.

The research was published recently in the journal Lab on a Chip.

Ventilators save the lives of patients with severe respiratory problems related to disease or trauma, but it has been known for a long time that the mechanical forces exerted on the lungs also cause injury. The damage at the cellular level can make the barrier between tiny air sacs and capillaries carrying blood become leaky, leading to fluid buildup that interferes with oxygen getting to the lungs.

Of particular value is the ventilator-on-a chip’s measurement of real-time changes to cells that affect the integrity of that barrier, enabled by an innovative approach: growing human lung cells on a synthetic nanofiber membrane mimicking the complex lung matrix. It’s closer to the authentic ventilated lung microenvironment than any similar lung chip systems to date, the researchers say.

The device measures the effects of three types of mechanical stress on the integrity of the barrier: lung cell stretch from overinflation, increased pressure on lung cells, and cyclical collapse and reopening of air sacs.

Experiments showed that overinflation with a high volume of air and cyclic collapse and reopening of air sacs both led the barrier to become leaky, but the cells could recover more quickly from overinflation than from the repetitive opening and closing of air sacs.

Englert said the collapse and reopening may be more problematic because it makes fluid in the lungs move, exposing cells to high amounts of shear stress.

“There really hasn’t been a lot of data that could allow for the comparison of those two injurious forces in the same system,” he said. “But now for the first time, we can use the same device with the same cells and induce both types of injury and see what happens. Our data suggests neither one of them is good, they’re both injurious, but that the collapse and reopening seems to be more severe and makes recovery harder.”

This finding was a demonstration of the model’s sophistication, Ghadiali said.

“We knew for a long time that collapse and reopening is a pretty injurious force, but we never could measure it in real time,” he said. “Now that we know that collapse and reopening injury happens much quicker and takes a long time to recover, we plan to use the ventilator on a chip to figure out how to prevent this injury and/or enhance the repair.”

Next steps involve modeling diseases such as pneumonia and traumatic injuries experienced by ICU patients in combination with mechanical action.

“We’re in the early stages of developing some of those models, diving a little bit deeper into the complexity of lung injury in ICU patients,” Englert said. “This model is a platform we can build upon.”

Ghadiali and Englert, also investigators in Ohio State’s Davis Heart and Lung Research Institute, credited first author Basia Gabela-Zuniga, who recently received her PhD in biomedical engineering, with getting the project over the finish line, and acknowledged the contributions of College of Engineering co-authors Heather Powell and Natalia Higuita-Castro. Additional co-authors were Vasudha Shukla and Christopher Bobba of Ohio State.

This work was supported by the National Institutes of Health and the U.S. Department of Defense.

The system involves two proteins that team up to disable plasmids, small DNA molecules that exchange genetic information among different bacterial strains. While plasmids provide evolutionary benefits, they can also be seen by host bacteria as threats.

The research team determined that one protein uses a short piece of DNA – known as a DNA guide – to set off events that recruit another protein to chop up the plasmid.

Beyond revealing a secret to bacterial survival, the research has uncovered components that could be applied to gene editing: guide DNA, which is more stable and cheaper to synthesize than guide RNA, and a functional protein small enough to deliver into mammalian cells for DNA sensing and gene-editing purposes.

“This system has great potential to be developed into a genome-editing tool,” said Tianmin Fu, assistant professor of biological chemistry and pharmacology in The Ohio State University College of Medicine. “We’re now trying to test whether it can be reprogrammed into a useful technology.”

The paper was published on Aug. 21 in the journal Cell.

The presence of plasmids in bacteria is well-known – some bacteria secrete plasmids, and the molecules can also move from one cell to another to share genetic information.

“It’s why bacteria evolve so rapidly,” Fu said. “Sometimes, plasmids can integrate into genomic DNA, but this happens quite randomly. They might cause difficulty for individual bacterial survival, but plasmids benefit the community in the long run because genetic information allows bacteria to acquire new features.”

Still, bacteria tend to want to eliminate plasmids to prevent any random threatening actions they might take.

Fu and colleagues used Vibrio cholerae bacteria as a model for studying the plasmid defense system known as DdmDE, consisting of proteins called DdmD and DdmE, using cryo-electron microscopy to observe their functions.

The process begins with DdmE binding to a very short DNA fragment, known as guide DNA, which enables the protein to recognize a target plasmid and snag it by creating a bubble formation using one of the plasmid’s double strands. The bubble complex recruits the DdmD protein, which can bind only to the plasmid’s free remaining strand. Once bound, DdmD dissociates into two separate molecules that both function as clippers to cut the plasmid into pieces.

Preliminary data from the team’s experiments suggested that a plasmid fragment remaining after DdmD chops it up could function as a segment of guide DNA to which DdmE could bind to repeat the process.

“There appears to be a feedback loop,” Fu said. “Once you create plasmid fragments, then more DdmE can acquire the fragments as guides to target more plasmids in the cell.”

However, he added, “How the first guide was created in the cell is unclear to us at the moment. It’s a ‘chicken and egg’ situation.”

The finding was unexpected because DdmE has similar qualities to a superfamily of Argonaute proteins that trigger their host bacteria’s death to avoid plasmid invasion. Argonautes, however, are aided by guide RNA, not guide DNA – and the guide DNA is a major reason the DdmDE system is attractive as a platform for genome editing aimed at disease prevention.

“Because DdmE needs guide DNA, we can synthesize guide DNA to target a very specific area in a genome,” Fu said. “We are testing this now in mammalian cells to see whether it will work, and we do see some potential there.”

This research was supported by the National Institutes of Health.

Co-authors, all from Ohio State, include Xiao-Yuan Yang, Zhangfei Shen, Chen Wang and Kotaro Nakanishi.

The system, called SepsisLab, was developed based on feedback from doctors and nurses who treat patients in the emergency departments and ICUs where sepsis, the body’s overwhelming response to an infection, is most commonly seen. They reported dissatisfaction with an existing AI-assisted tool that generates a patient risk prediction score using only electronic health records, but no input data from clinicians. 

Scientists at The Ohio State University designed SepsisLab to be able to predict a patient’s sepsis risk within four hours – but while the clock ticks, the system identifies missing patient information, quantifies how essential it is, and gives a visual picture to clinicians of how specific information will affect the final risk prediction. Experiments using a combination of publicly available and proprietary patient data showed that adding 8% of the recommended data improved the system’s sepsis prediction accuracy by 11%.

“The existing model represents a more a traditional human-AI competition paradigm, generating numerous annoying false alarms in ICUs and emergency rooms without listening to clinicians,” said senior study author Ping Zhang, associate professor of computer science and engineering and biomedical informatics at Ohio State.  

“The idea is we need to involve AI in every intermediate step of decision-making by adopting the ‘AI-in-the-human-loop’ concept. We’re not just developing a tool – we also recruited physicians into the project. This is a real collaboration between computer scientists and clinicians to develop a human-centered system that puts the physician in the driver’s seat.” 

The research was published Aug. 24 in KDD ’24: Proceedings of the 30th ACM SIGKDD Conference on Knowledge Discovery and Data Mining and will be presented orally Wednesday (Aug. 28) at SIGKDD 2024 in Barcelona, Spain.

Sepsis is a life-threatening medical emergency – it can rapidly lead to organ failure – but it’s not easy to diagnose because its symptoms of fever, low blood pressure, increasing heart rate and breathing problems can look like a lot of other conditions. This work builds upon a previous machine learning model developed by Zhang and colleagues that estimated the optimal time to give antibiotics to patients with a suspected case of sepsis. 

SepsisLab is designed to come up with a risk prediction quickly, but produces a new prediction every hour after new patient data has been added to the system. 

“When a patient first comes in, there are many missing values, especially for lab tests,” said first author Changchang Yin, a computer science and engineering PhD student in Zhang’s Artificial Intelligence in Medicine lab. 

In most AI models, missing data points are accounted for with a single assigned value – a process called imputation – “but the imputation model could suffer from uncertainty that can be propagated to the downstream prediction model,” Yin said. 

“If the imputation model cannot accurately impute the missing value and it’s a very important value, the variable should be observed. Our active sensing algorithm aims to find such missing values and tell clinicians what additional variables they might need to observe – variables that can make the prediction model more accurate.” 

Equally important to removing uncertainty from the system over the passage of time is providing clinicians with actionable recommendations. These include lab tests rank-ordered based on their value to the diagnostic process and estimates of how a patient’s sepsis risk would change depending on specific clinical treatments. 

Experiments showed adding 8% of the new data from lab tests, vital signs and other high-value variables reduced the propagated uncertainty in the model by 70% – contributing to its 11% improvement in sepsis risk accuracy. 

“The algorithm can select the most important variables, and the physician’s action reduces the uncertainty,” said Zhang, also a core faculty member in Ohio State’s Translational Data Analytics Institute. “This fundamental mathematics work is the most important technical innovation – the backbone of the research.” 

Zhang sees human-centered AI as part of the future of medicine – but only if AI interacts with clinicians in a way that makes them trust the system. 

“This is not about building an AI system that can conquer the world,” he said. “The center of medicine is hypothesis testing and making decisions minute after minute that are not just ‘yes’ or ‘no.’ We envision a person at the center of the interaction using AI to help that human feel superhuman.”

This research was supported by the National Science Foundation, the National Institutes of Health and an Ohio State President’s Research Excellence Accelerator Grant. Zhang has received additional NIH funding to continue collaborating with clinicians on this work. 

Additional co-authors include Jeffrey Caterino of The Ohio State University Wexner Medical Center, Bingsheng Yao and Dakuo Wang of Northeastern University, and Pin-Yu Chen of IBM Research.

Beyond the biggest sources of each dietary category – cheese for saturated fat and soft drinks for added sugar – the study identifies a longer list of popular sources that helps explain why it’s so hard to limit fat and sugar to the recommended 10% of daily calories. With that overconsumption of unexpected sources like chicken and ketchup, for example, comes a risk for a variety of ailments, such as cardiovascular disease, diabetes and cancer. 

The analysis of data on over 35,000 U.S. adults is part of a project aimed at developing a research tool that can streamline assessment of these dietary downsides. But the work also may open consumers’ eyes to the unexpected sources of fat and sugar that add up over the course of a day – and perhaps convince shoppers to read labels to see where these hidden sources are, researchers say. 

“Chicken breast is promoted as a lower saturated fat food, but it still has a little bit of saturated fat. But it is helpful to know how foods with smaller amounts also slowly add saturated fat in a stealthy way into the diet,” said first author Christopher Taylor, professor and director of medical dietetics in the School of Health and Rehabilitation Sciences at The Ohio State University. 

“Being able to meet less than 10% is to identify the big contributors, but also to be able to see where saturated fat and added sugar may still exist in other food choices. It doesn’t make them poor choices – it’s about being aware of how the morning latte may be contributing.” 

And then there’s the abundance of added sugar, which raises a public health policy concern, said lead author Susan Schembre, associate professor of oncology at Georgetown University’s Lombardi Comprehensive Cancer Center. 

“It’s everywhere. It’s in so many unexpected foods, and often in surprising amounts,” she said. 

The study was published recently in the journal Nutrients. 

Researchers analyzed data from 36,378 U.S. adults aged 19 and older who had participated from 2005 to 2018 in the National Health and Nutrition Examination Survey. The survey collects 24-hour dietary recalls from each participant – detailing not just what, but when, all food and drinks were consumed over the previous two days.  

Overall, the top sources of saturated fat were cheese, pizza, ice cream and eggs. Leading sources of added sugar were soft drinks, tea, fruit drinks, and cakes and pies. Based on the USDA “What We Eat in America” food list, other categories contributing to saturated fat intake include cold cuts, cream substitutes, fried potatoes and whole milk. Categories with added sugar include tomato-based condiments, cereal bars, energy drinks and yeast breads. 

The research team also examined differences in the top sources of saturated fat and added sugar in a range of race/ethnicity subpopulations and age groups, an important detail when assessing diets to develop more personalized health interventions, Schembre said. 

“Before you understand what you can intervene on, you have to know what people are consuming,” she said. 

The team is creating an app for targeted assessment of “nutrients of concern,” and demonstrated that this analytic method produced a representative list of foods behind most saturated fat and added sugar intake. NHANES data is key to understanding nutrition in the United States, but for disease interventions, getting at the problem food and drink sources of fat, added sugar and, still to come, sodium, is more efficient and effective. 

Unsurprisingly, the results of this analysis showed that overall, saturated fat constituted at least 12% of a day’s calories, and added sugar consumption ranged from 14% to 16% of calories. Generally, dietary recommendations focus on avoiding the major contributors, like pizza and ice cream – which is what makes this longer list valuable and, for some, eye-opening, Taylor said. 

“There are the foods that are higher in saturated fat and added sugar that are consumed frequently, and they get targeted, but there’s also that smaller cumulative effect of things that are generally perceived as healthy, but they’re all contributing just a little bit,” he said. “And then when you top it off with some of those higher sources, it ends up taking you over the threshold for that 10% of the day’s calories. 

“We’re trying to hit the sweet spot of capturing the big front-seat items, but also understanding those things that are stealthy contributors.” 

This research was supported by the National Cancer Institute.

Additional co-authors were Peter Madril of Ohio State; Cynthia Thompson, Kelli Richardson and Edward Bedrick of the University of Arizona; Genevieve Dunton of the University of Southern California; Michelle Jospe of Georgetown Lombardi Comprehensive Cancer Center; and Rick Weiss of Viocare Inc.

The survey of Ohio law enforcement officers found that 74% reported a lifetime history of one or more head injuries, and 30% had a head injury that happened on the job. Many more of these injuries went unreported than were treated by a health care professional. And further analysis showed post-traumatic stress disorder and depressive symptoms were higher in those who had experienced one or more head injuries. 

“This is an area where we have to improve awareness, just like we did in the sport concussion world,” said lead author Jaclyn Caccese, PhD, assistant professor in the School of Health and Rehabilitation Sciences at The Ohio State University Wexner Medical Center. 

“The goal is really to improve officer safety and health in the long term,” said Caccese, also an investigator in Ohio State’s Chronic Brain Injury Program. “And I think there’s a lot of potential there, especially when it comes to improving career longevity – that although treating these injuries is difficult in the moment, it leads to a longer career, better health outcomes and better quality of life, not only in their service, but also in retirement. I think with that awareness, they will be more likely to report injuries as they sustain them.” 

The study was published Aug. 5 in the Journal of Head Trauma Rehabilitation. 

The medical and law enforcement researchers who co-authored the study have published a separate paper advocating for implementation of a concussion return-to-duty protocol for law enforcement officers – similar to practices already in place in sports and the military. 

The researchers surveyed 381 law enforcement personnel in central Ohio about their lifetime head injury history, years of service in the military and civilian law enforcement, and rank and section assignment (such as patrol, corrections or administration). The participants also completed questionnaires assessing symptoms of PTSD and depression. 

Of those respondents, 282 reported one or more prior head injuries, mostly from sports, followed by such incidents as falling or being hit by something or someone, a car accident, or exposure to a blast. Over 50% of participants reported head injuries involving loss of consciousness or followed by feeling dazed or confused, or having a gap in memory – all signs of a probable traumatic brain injury (TBI). A concussion is considered a mild TBI. 

Nine percent of total respondents screened positive for PTSD symptoms and 36% reported mild or greater depressive symptoms. Participants with a prior head injury reported higher symptoms for both conditions. Researchers estimated that fewer than 1 in 4 head injuries was diagnosed or treated by a health care provider.

Caccese said researchers are still learning about the long-term effects of concussions, but current evidence suggests head injuries that go untreated may increase risk for depression, anxiety, PTSD and problems with cognitive function and memory. 

For law enforcement officers, concussions often occur in the heat of their job. The stress associated with the role and poor sleep from shift work are also common in this population. The circumstances can contribute to worse outcomes following a head injury. 

“Sometimes law enforcement officers need to complete the task they’ve set out to do, or it’s not a safe environment to just pull yourself off duty right away. And I think adrenaline sometimes masks concussion symptoms,” Caccese said. “In sports, we’ve been able to increase removal from play, and improve rehabilitation and return-to-play following injury. Hopefully that will improve long-term health outcomes in athletes. We’re trying to get that information translated to the occupational context.”

Study co-author Josh Walters, a deputy in the Franklin County, Ohio, Sheriff’s Office, leads his office’s peer support team of deputies certified to work with personnel experiencing a range of problems. Teaming up for the study of head injuries and their association with PTSD and depressive symptoms grew out of the peer group’s long-term partnership with Ohio State researchers and clinicians to enhance deputy health with physical therapy, sleep studies and concussion-related training. 

“Part of what we’re doing with Ohio State is looking at, how can we extend the health of the deputy?” Walters said. “Being physically fit is an important part of our job because not only do my colleagues depend on me, but the community depends on me. And if I can’t physically keep up, then it could be a life-or-death situation for somebody.” 

The next step is working to adopt the return-to-duty protocol proposed by the team – removal from duty, a gradual increase in activity, and screening by a medical provider before returning to full duty – and testing its effectiveness and adaptability to different organizations. 

“Now we have some data that we can present to administrations, to unions, to leadership that says, ‘Here’s the problem. This is how we can fix it. Let’s start working that process,’” Walters said. 

Additional co-authors are Carly Smith, Nathan Edwards, Angela Emerson, Enora Le Flao, Jeffrey Wing, Joshua Hagen and James Onate of Ohio State and Scott Paur of the Franklin County Sheriff’s Office. 

This work was supported by the Assistant Secretary of Defense for Health Affairs endorsed by the Department of Defense, through the Traumatic Brain Injury and Psychological Health Research Program under Award No. HT9425-23-1-0520 and HT9425-23-1-0521. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense.

Since that study’s publication, scientists at The Ohio State University have been exploring how the SARS-CoV-2 virus that causes COVID-19 prompts this human molecule’s destructive activity, and outlined the series of steps needed to fully describe what’s going on – as well as potential strategies to stop the damage. 

The grant from the National Institutes of Health (NIH) will fund their five-year pursuit of definitive answers and development of new ways to treat acute SARS-CoV-2 infections and, ideally, fend off long COVID. The award is the largest of its kind funding infectious diseases research at Ohio State. 

The 2022 published research showed in mice infected with SARS-CoV-2 that blocking this molecule, an enzyme called caspase 11, resulted in lower inflammation and tissue injury and fewer blood clots in the animals’ lungs. The researchers also found that the human version of the enzyme, called caspase 4, was highly expressed in COVID-19 patients hospitalized in the ICU – confirming the molecule’s link to severe disease. 

The new work funded by the NIH will extend the investigation beyond the lungs based on predictions that in response to the viral infection, caspase 11 has compounding effects in multiple cells: driving up inflammation in the body and brain, interfering with the immune response and leading to clots in small blood vessels. The team will also explore how SARS-CoV-2 infection shapes host and viral RNA modifications, which occur during gene activation and alter cell functions. 

Many of the affected cells being investigated are related to the immune response – both the innate response, the body’s first line of defense against any foreign invader, and the adaptive response, which is a later, specific response to a given pathogen. Researchers will also examine cells that line organ surfaces and blood vessel walls (epithelial and endothelial cells, respectively) as well as RNA modifications.   

“When you pull it all together, offering the scientific community a basic understanding of what happens to every cell and every organ during SARS-CoV-2 is an achievement in itself,” said Amal Amer, professor of microbial infection and immunity in Ohio State’s College of Medicine and the contact principal investigator on the grant. 

“Once you know the mechanism, then you can design what to target, where to target it and how to target it in order to reduce the damage being done,” Amer said. “And this is especially needed for long COVID – it may be in the brain, it may be in the muscles, it may be in anything and everything – and that’s an important aspect of the disease.” 

The federal award is a multi-principal investigator (PI) research program project grant composed of three scientific projects and four core activities (see descriptions below). Along with Amer, Estelle Cormet-Boyaka and Jianrong Li, both professors of veterinary biosciences at Ohio State, are MPIs on the initiative. The group also involves other experts from Ohio State, Nationwide Children’s Hospital and the University of Chicago. 

Amer is an expert in innate immunity who has been studying the class of molecules called inflammasomes for years. She will lead studies of the role of caspase 11, which is an inflammasome-related enzyme, in causing inflammation in the brain and lung that drives the damaging interplay between the innate immune response and blood clot formation. 

Cormet-Boyaka is an expert in lung biology, physiology and pathology, and will oversee studies of the multiple cell types whose functions are influenced, mostly negatively, by the presence of caspase 11 during SARS-CoV-2 infection. 

“In addition to studying mice, we’ll also be using human cell samples that enable us to dissect mechanisms at the cellular level,” she said. “Having access to human primary epithelial cells is a strength because those are the cells that the virus infects first.”

Li is a virologist who has been studying respiratory viruses for more than 25 years. He and colleagues will map SARS-CoV-2-induced RNA modifications in host cells and work on experimental inhibitors of molecules that trigger the RNA changes as a strategy to suppress the virus’s ability to make copies of itself in infected cells. The team will develop and test RNA modification and caspase 11 blockers to synergistically reduce SARS-CoV-2 replication, pathology and clotting, protect tissue and prevent the over-production of pro-inflammatory proteins called cytokines. 

“The two major causes of death from COVID are the cytokine storm and uncontrolled virus replication,” Li said. “If we inhibit only one of these, it’s not ideal. If we inhibit both, that can lead to a better therapeutic approach.” 

Based on data collected since the 2022 study, blocking caspase 11 remains a chief goal – but getting the right drug formulated to do it requires the information that will be uncovered by the combined projects. Though mice lacking the gene to make caspase 11 look and act normal, the research team wants to zero in on inhibitors that pose the lowest risk for side effects. 

“When you inhibit caspase 11, you get rid of many cytokines, which damage the lung tissue and the blood-brain barrier and brain tissue,” Amer said. “Combining that together with stopping viral replication is going to be very effective at reducing deaths and severe illness from SARS-CoV-2 infection, and reducing the post-infection symptoms experienced by people with long COVID.” 

Conducting simultaneous studies on different tracks will accelerate the pace of the research, said Prosper Boyaka, chair of veterinary biosciences at Ohio State and the leader of one of the three projects. An expert in the adaptive immunity that is a major player in anti-viral immunity, Boyaka will also provide a strategy to tackle immune cells called neutrophils to avoid exacerbated immune responses. 

“Long COVID is extremely complex. And the way we do science is to understand mechanisms – but because of our collective own expertise and the tools we have, we will approach one area or one question at a time,” he said. “Having a team like this one allows us to look at those interactions and processes at the same time by experts in different fields, which makes it more likely we will capture information that would be difficult to capture otherwise. That’s why I think the outcome is likely to be more beneficial than if each project were done individually or in isolation.” 

Xiaoli Zhang, an associate professor-clinical in the Department of Biomedical Informatics and Center for Biostatistics at Ohio State, is a team scientist in a broad range of biomedical research areas, mainly in cancer and microbial infection and immunity. With expertise ranging from experimental design to biostatistics and bioinformatics data analysis and modeling, she will oversee all bioinformatic and statistical analysis in the project grant.

Amer noted that program grants are very competitive, and successful applications are those that prove the PIs have a track record of working together on significant research – an indication that the team will work together efficiently for the duration of the grant.

“Being at Ohio State, we have people specializing in everything we needed for this grant, and we provided a huge list of publications going back 10 years showing we have continuously worked together and published together on cutting-edge science,” she said. “And the NIH was convinced that this group is the one that can do this.”

Grant title: “Role of the non-canonical inflammasome in SARS-CoV-2-mediated pathology and coagulopathy.”

• Project 1: Role of caspase 11 in SARS-CoV-2-induced lung pathologies and long-term immune protection (Project Leader: Prosper Boyaka; Co-Investigators: Estelle Cormet-Boyaka, Jacob Yount)
• Project 2: Caspase 11-dependent immunothrombosis and neuroinflammation during SARS-CoV-2 infection (Project Leader: Amal Amer; Co-Investigators: Stephanie Seveau, Andrea Tedeschi)
• Project 3: Caspase 11-dependent RNA modifications and their Role in Multi-Organ Pathologies (Project Leader: Jianrong Li; Co-Investigators: Mark Peeples, Chuan He)
• Administrative Core (Core Leader: Amal Amer; Co-Investigators: Estelle Cormet-Boyaka, Jianrong Li)
• Biostatistics and Bioinformatics Core (Core Leader: Xiaoli Zhang; Co-Investigators: Maciej Pietrzak, Amy Webb)
• Biological Reagents and Infection Core (Core Leader: Jianrong Li; Co-Investigator: Mark Peeples)
• Cell Derivation and Maintenance Core (Core Leader: Estelle Cormet-Boyaka; Co-Investigator: Santiago Partida-Sanchez)

Researchers determined in mice that an enzyme related to cell growth and division is a culprit in the blood vessel invasion in the back of the eye that causes blurred central vision in wet AMD. Targeting the enzyme, called telomerase, with an experimental drug suppressed abnormal vascular growth in the animals’ retina. 

The only current treatment for wet AMD is injection into the eye of a medication that blocks the activity of a growth factor protein, called VEGF, which is also known to prompt formation of abnormal blood vessel growth in this condition. 

“Anti-VEGF treatment has shortcomings – after two years, about half of people stop responding. And patients can develop scarring under the retina,” said senior study author Nagaraj Kerur, associate professor of ophthalmology and visual sciences in The Ohio State University College of Medicine. 

“There is a need for better understanding of the mechanisms behind this problem, which, to me, means newer targets need to be tested.” 

The study was published recently in the journal Biochimica et Biophysica Acta – Molecular Basis of Disease. 

Dry age-related macular degeneration constitutes about 80% of all AMD cases, and occurs when the macula, a part of the retina, gets thinner, leading to buildup of proteins and cell death, which blur a person’s central vision. 

Wet AMD, also known as neovascular AMD, is caused by the growth of new blood vessels that invade the retina, a space normally free of vascular activity. 

“You don’t want to have blood vessels there,” said Kerur, who also has a faculty appointment in microbial infection and immunity at Ohio State. “And the blood vessels that invade are often not healthy – they leak their contents and cause inflammation.” 

Previous cancer research has linked high activity of telomerase to rapid production and migration of cells lining blood vessels that enables tumor growth, and has also shown the enzyme can stimulate production of VEGF. Based on those findings, Kerur and colleagues sought in this study to see if telomerase could have a similar damaging effect in the eye. 

A series of experiments first confirmed telomerase has a role in abnormal blood vessel formation in a mouse model of wet AMD. Researchers found that, compared to control mice, expression and activity of one of two genes carrying instructions for making telomerase were higher in the eyes of mice in which rapid growth of new blood vessels was induced with a laser. 

In addition, the abnormal blood vessel response to laser injury was significantly lower in mice lacking both telomerase genes, “providing genetically clear evidence that telomerase plays a critical role in development of the disease,” Kerur said. 

The team then tested the effects of an experimental compound that inhibits telomerase activity. They confirmed that the drug lowered telomerase activity in healthy mice, and found that injecting it into the eyes of mice with symptoms mimicking wet AMD significantly reduced the abnormal blood vessel invasion. 

Telomerase’s job is to rebuild telomeres, which function as protective caps at the end of chromosomes. Telomeres are known to shorten in many types of cells as a consequence of aging, but Kerur said the study suggested localized blocking of telomerase in the eye had no bearing on the enzyme’s telomere-building function. 

The experimental treatment’s effectiveness at curbing abnormal blood vessel growth in mice was similar to the current anti-VEGF treatment, Kerur said. But the researchers made an intriguing finding when testing both drugs at lower doses: Individually, a lower dose did not have much of a therapeutic effect, but a combination of both drugs at lower doses gave the best results of all. 

“Possibly, one goal would be using a combination therapy rather than one alone,” Kerur said. “But telomerase inhibition by itself can also be pursued independently, and that is the plan.” 

This work was supported by National Institutes of Health grants, the Ohio Lions Eye Research Foundation and a Research to Prevent Blindness grant. 

Co-authors include Aman Kumar, Vinodhini Jayananthan, Asmaa Zidan, Tyler Heisler-Taylor and Shigeo Tamiya of Ohio State, and Yosuke Nagasaka and Jayakrishna Ambati of the University of Virginia.

Adam Berinsky, the Mitsui Professor of Political Science at MIT, opened the meeting Monday night with a lecture about misinformation – and ways to combat it. He has studied the problem in the context of politics, but the work is easily adapted to virology in an age of heightened anti-science sentiment and lack of trust in experts of all kinds. 

ASV President Anne Moscona, who selected the keynote speaker, urged audience members to consider working alongside Berinsky to address misinformation that casts doubt on scientific evidence, which she called “a problem so worrisome to our community.” 

Ohio State expertise 

Shan-Lu Liu, a virology professor at Ohio State and co-director of the Viruses and Emerging Pathogens Program of the Infectious Diseases Institute, chaired the meeting’s organizing committee. Liu, a longtime HIV researcher who more recently has led numerous studies of SARS-CoV-2 variants’ immune evasion, transmissibility and infectivity, has been named president-elect of ASV at this year’s meeting and will become president of the society in 2025. 

The conference blends symposium presentations by leaders in a range of virology disciplines with poster sessions and dozens of trainee workshops on science, career development and communication. 

Linda Saif, Distinguished University Professor in Ohio State’s Center for Food Animal Health with faculty appointments in animal sciences and veterinary preventive medicine, opened Wednesday morning’s symposium with detailed documentation of coronaviruses’ ability to spill over from animals to humans – which has been happening for centuries. An international expert on coronaviruses, Saif described the wily strains as diverse infectious agents that are skilled at accommodating change thanks their large RNA genome. 

Like the coronavirus that leapt from wild animals to cattle and from cattle to poultry that Saif’s lab was the first to document in 1995, the virus that causes COVID-19 is known to infect mink, hamsters, cats and white-tailed deer. She’s among a team of researchers who found that white-tailed deer were infected by humans with SARS-CoV-2 across Ohio and that the animals function as reservoirs promoting ongoing viral mutation. 

“If we end up with a wildlife reservoir, will it persist, adapt and mutate in wildlife with new variants going back to humans, livestock or other animals?” Saif said. “The concern is, will we end up with a scenario with SARS-CoV-2 where we have two-way transmission to wildlife species and back into humans?” 

The World Health Organization has predicted the next pandemic will be caused by what it calls “Disease X” – and some coronaviruses currently circulating in animals are potential candidates, she said. 

The studies detecting SARS-CoV-2 in Ohio deer were co-led by Andrew Bowman, professor of veterinary preventive medicine at Ohio State, who presented an update on that research program at the meeting. Bowman has also led influenza surveillance at the swine-human interface in commercial settings and agricultural fairs for years, and recently made news by finding H5N1 (bird flu) viral RNA in over a third of commercial milk products he and a graduate student bought in the Midwest based on a hunch that viruses detected in dairy cows were making their way to grocery stores. 

The annual conference presents “an important opportunity to educate the public about virology research,” said Liu, also associate director of the Center for Retrovirus Research and professor of veterinary biosciences. “And we expect that attendees will also benefit from Adam Berinsky’s insights about the general phenomenon of misinformation.” 

Fighting misinformation 

Misinformation that circulated during the COVID-19 pandemic lockdown – conspiracy theories that the illness’ severity was exaggerated or that the virus was deliberately released for sinister reasons – persists to this day. Berinsky, who has extensively studied Americans’ beliefs in false political rumors (such as claims Barack Obama wasn’t born in the United States), has found that rumors are “sticky” – countering them is not just about sharing the facts, but requires a messenger that people will be willing to trust. 

His research has found that about 70% of people will endorse at least one false rumor when given a list to choose from and only 30% of people reject them all, and that misinformation correction should focus primarily on reaching the undecideds – people who aren’t sure about what’s true. His work has also shown that correcting misinformation is not a “one-and-done” endeavor – it requires repeated messaging as well as a series of strategies targeting people who share fake information online. 

Working with Facebook and Google, Berinsky and colleagues advanced interventions encouraging people through “accuracy nudges” to think before they share information – advising users to evaluate information before sharing it and investigate its sources – or even asking them how important it is to them to share only accurate information. 

“Most people don’t want to share bad information,” he said. “We want to remind them of this.” 

They found in experiments that at the individual level, these nudges turned the knob toward more sharing of true information. Though the prompts won’t stop people who are posting lies maliciously, the added “friction” makes it a little more difficult for casual users to do an easy thing that has negative effects. 

A megastudy of nine interventions designed to reduce online sharing of misinformation revealed that all of them work – but each one’s effect is relatively small, on the order of 2 to 3 percentage points. Hence, the frame of mind in combating misinformation should not be a search for a single solution, but deployment of the best bundle of solutions depending on the context. 

“There’s been this long search for a magic bullet. It doesn’t exist,” Berinsky said. “But don’t give up on the enterprise.”

Launched in 2019, the HEALing (Helping to End Addiction Long-Term) Communities Study (HCS) is the largest addiction prevention and treatment implementation study ever conducted. Researchers from the four participating states report today (June 16, 2024) in the New England Journal of Medicine and at the College on Problems of Drug Dependence (CPDD) annual meeting that the intervention did not result in a statistically significant reduction in opioid-related overdose death rates during the evaluation period. 

The data-driven intervention deployed evidence-based practices in 67 communities across states hit hard by the opioid crisis: Kentucky, Massachusetts, New York and Ohio. Though the goal to significantly reduce opioid overdose deaths was not met, Ohio implemented 137 evidence-based practice strategies in nine counties in Ohio. These strategies, implemented in complicated settings – hospital emergency departments and jails, to name just two – was an accomplishment that will have enduring positive effects, researchers say. 

“Implementing all of those evidence-based practices is the success,” said Bridget Freisthler, professor of social work at The Ohio State University and Ohio’s principal investigator for the HEALing Communities Study. “The practices are really about changing clinical care. The fact that many of those services are in place and are still working gives us some confidence that, going forward, these communities are going to be better prepared to address overdoses and overdose deaths. And hopefully they’ll see reductions over time.” 

T. John Winhusen, the HCS co-principal investigator for Ohio and director of the University of Cincinnati Center for Addiction Research, led the national group of experts convened to develop the Opioid-Overdose Reduction Continuum of Care Approach (ORCCA), a compendium of evidence-based practice strategies that guided the selection of interventions to be implemented in HCS intervention communities. 

ORCCA includes three “menus” of evidence-based practices: one devoted to overdose education and naloxone distribution, one focused on increasing exposure to medication for opioid use disorder, and a third focused on safer opioid prescribing. 

“ORCCA was designed to be flexible enough to meet the needs of a given community while also ensuring that strategies known to reduce opioid-related overdose deaths would be selected for implementation,” said Winhusen, also the Donald C. Harrison Endowed Chair in Medicine and professor and vice chair for addiction sciences in the Department of Psychiatry and Behavioral Neurosciences at UC.   

The National Institutes of Health (NIH) launched the four-year, multisite HCS to test a set of interventions for reducing overdose deaths across health care, justice and behavioral health settings. Over 100,000 people die annually of a drug overdose – 75% of which involve an opioid, according to the Centers for Disease Control and Prevention. Numerous evidence-based practices have been proven to prevent or reverse opioid overdose, but are gravely underused due to numerous barriers, according to the National Institute on Drug Abuse (NIDA).  

Between January 2020 and June 2022, intervention communities successfully implemented 615 evidence-based practice strategies to address opioid-related overdose deaths – but only 235 were implemented before the study period comparing outcomes in intervention and control communities began. The authors of the NEJM article noted the COVID-19 pandemic, a short timeframe for implementing the interventions, and increased prevalence of fentanyl in the illicit drug market may have diminished the mortality impact of the intervention. 

The evidence-based practices compiled for the ORCCA covered a lot of ground and required a lot of coordination to launch. 

“Some of the strategies were major undertakings,” Winhusen said. “For example, working with a jail to start a buprenorphine treatment program is one strategy out of the 137 strategies implemented in Ohio. Another example was working with emergency departments to identify people with opioid use disorder, get them started on buprenorphine, and link them to ongoing buprenorphine treatment. 

“Due to both COVID-19 and time constraints, only 38% of the strategies were implemented before the start of the comparison period so you’re not going to see the full effects. It just wasn’t enough time.” 

Freisthler co-led the charge to engage community coalitions and help them consult data to select interventions best suited to the areas they served. The team also developed communications campaigns addressing a range of topics – the stigma linked to opioid misuse and to taking medications to combat opioid addiction, and the necessity of adopting evidence-based practices – that were among written materials that will help sustain Ohio’s participation in the initiative, all housed on an Ohio State HCS website. 

“Communities have been at the forefront of addressing opioid use and overdoses for years. A success of Ohio’s implementation is peer-to-peer learning and feedback about the evidence-based practice strategies. This effort moved the needle and what had been barriers to services in the past,” she said. “It takes a coordinated effort, and some might need help and expertise, but really, that piece showed that communities can be an agent of change in this process.” 

The Ohio consortium brought together experts from Ohio State, UC and four other universities – Case Western Reserve University, Ohio University, University of Toledo and Wright State University – as well as the community organizations and leaders from state agencies. 

Freisthler noted that ongoing engagement with the RecoveryOhio multi-agency initiative created by Gov. Mike DeWine was an enabling force behind many features of the HEALing Communities Study, including establishment of the State of Ohio Integrated Behavioral Health Dashboard of county statistics and trend data, as well as streamlined navigation of policy and communication challenges over the course of the study. 

Many U.S. states have access to national opioid settlement funds specifically designated to address the opioid epidemic. Winhusen said that several free products developed from the Opioid-Overdose Reduction Continuum of Care Approach, including a practice guide and a guide for policymakers, are “perfect for communities that are trying to decide how to wisely invest their opioid settlement dollars.” 

“Back in 2019, the four states convened top experts to discuss the scientific literature in order to develop this,” he said. “A great deal of time and effort went into reaching consensus on the strategies included in the ORCCA, and we would love to see communities use this resource to determine how best to invest their opioid settlement funds.” 

The HEALing Communities Study was supported and carried out in partnership between NIDA (see NIDA’s HCS press release on the NEJM article) and the Substance Abuse and Mental Health Services Administration through the NIH HEAL Initiative. 

A $65.9 million NIH award funding Ohio State’s leadership of the Ohio portion of the study was housed in the university’s College of Medicine. Additional sites funded to conduct implementation research within communities in their state were the University of Kentucky, Lexington; Boston Medical Center, Boston; and Columbia University, New York City. RTI International, based in North Carolina, received an award to serve as the study’s data coordinating center.

Scientists engineered nanocarriers using mouse connective-tissue cells called fibroblasts as a model of skin cells and loaded them with genetic material for a protein key to tissue development. The team injected a solution containing the carriers into damaged discs in mice at the same time the back injury occurred. 

Assessing outcomes over 12 weeks, researchers found through imaging, tissue analysis, and mechanical and behavioral tests that the gene therapy restored structural integrity and function to degenerated discs and reduced signs of back pain in the animals. 

“We have this unique strategy that’s able to both regenerate tissue and inhibit some symptoms of pain,” said co-senior author Devina Purmessur Walter, associate professor of biomedical engineering at The Ohio State University. 

Though there is more to learn, the findings suggest gene therapy could offer an effective and long-lasting alternative to opioids for the management of debilitating back pain. 

“This can be used at the same time as surgery to actually boost healing of the disc itself,” said co-senior author Natalia Higuita-Castro, associate professor of biomedical engineering and neurological surgery at Ohio State. “Your own cells are actually doing the work and going back to a healthy state.” 

The study was published online recently in the journal Biomaterials. 

An estimated 40% of low-back pain cases are attributed to degeneration of the cushiony intervertebral discs that absorb shocks and provide flexibility to the spine, previous research suggests. And while trimming away bulging tissue from a herniated disc during surgery typically reduces pain, it does not repair the disc itself – which continues to degenerate with the passage of time. 

“Once you take a piece away, the tissue decompresses like a flat tire,” Purmessur Walter said. “The disease process continues, and impacts the other discs on either side because you’re losing that pressure that is critical for spinal function. Clinicians don’t have a good way of addressing that.” 

This new study builds upon previous work in Higuita-Castro’s lab, which reported a year ago that nanocarriers called extracellular vesicles loaded with anti-inflammatory cargo curbed tissue injury in damaged mouse lungs. The engineered carriers are replicas of the natural extracellular vesicles that circulate in humans’ bloodstream and biological fluids, carrying messages between cells. 

To create the vesicles, scientists apply an electrical charge to a donor cell to transiently open holes in its membrane, and deliver externally obtained DNA inside that converts to a specific protein, as well as molecules that prompt the manufacture of even more of a functional protein. 

In this study, the cargo consisted of material to produce a “pioneer” transcription factor protein called FOXF1, which is important in the development and growth of tissues. 

“Our concept is recapitulating development: FOXF1 is expressed during development and in healthy tissue, but it decreases with age,” Purmessur Walter said. “We’re basically trying to trick the cells and give them a boost back to their developmental state when they’re growing and at their healthiest.” 

In experiments, mice with injured discs treated with FOXF1 nanocarriers were compared to injured mice given saline or mock nanocarriers and uninjured mice. 

Compared to controls, the discs in mice receiving gene therapy showed a host of improvements: The tissue plumped back up and became more stable through production of a protein that holds water and other matrix proteins, all helping promote range of motion, load bearing and flexibility in the spine. Behavioral tests showed the therapy decreased symptoms of pain in mice, though these responses differed by sex – males and females showed varying levels of susceptibility to pain based on the types of movement being assessed. 

The findings speak to the value of using universal adult donor cells to create these extracellular vesicle therapies, the researchers said, because they don’t carry the risk of generating an immune response. The gene therapy also, ideally, would function as a one-time treatment – a therapeutic gift that keeps on giving. 

“The idea of cell reprogramming is that you express this transcription factor and the cell is then going to convert to this healthier state and stays committed to that healthier phenotype – and that conversion is not normally transient,” Higuita-Castro said. “So in theory, you would not expect to have to re-dose significantly.” 

There are more experiments to come, testing the effects of other transcription factors that contribute to intervertebral disc development. And because this first study used young adult mice, the team also plans to test the therapy’s effects in older animals that model age-related degeneration and, eventually, in clinical trials for larger animals known to develop back problems. 

Higuita-Castro, director of advanced therapeutics and engineering in the College of Medicine Davis Heart and Lung Research Institute and a core faculty member of Ohio State’s Gene Therapy Institute, and Purmessur Walter, an investigator in Ohio State’s Spine Research Institute and director of the Spinal Therapeutics Laboratory in the College of Engineering, are co-principal investigators on National Institutes of Health grants funding this research. 

Additional co-authors include co-first authors Shirley Tang and Ana Salazar-Puerta, Mary Heimann, Kyle Kuchynsky, María Rincon-Benavides, Mia Kordowski, Gilian Gunsch, Lucy Bodine, Khady Diop, Connor Gantt, Safdar Khan, Anna Bratasz, Olga Kokiko-Cochran, Julie Fitzgerald and Benjamin Walter, all of Ohio State; Damien Laudier of Icahn School of Medicine at Mount Sinai; and Judith Hoyland of the University of Manchester. 

Ohio State has filed a patent application on nonviral gene therapy for minimally invasively treating painful musculoskeletal disorders.

The model was front-loaded with de-identified data on millions of patients gleaned from health care claims information submitted by employers, health plans and hospitals – a foundation model strategy similar to that of generative AI tools like ChatGPT. 

By pre-training the model on a huge cache of general data, researchers could then fine-tune the model with information concerning specific health conditions and treatments – in this case, focusing on stroke risk – to estimate the causal effect of each therapy and determine which therapy would work best based on individual patient characteristics. 

The team from The Ohio State University reported today (May 1, 2024) in the journal Patterns that their model outperformed seven existing models and came up with the same treatment recommendations as four randomized clinical trials. 

“No existing algorithm can do this work,” said senior author Ping Zhang, associate professor of computer science and engineering and biomedical informatics at Ohio State. “Quantitatively, our method increased performance by 7% to 8% over other methods. And the comparison showed other methods could infer similar results, but they can’t produce a result exactly like a randomized clinical trial. Our method can.”

Replacing gold standard clinical research is not the point – but researchers hope machine learning could help save time and money by putting clinical trials on a faster track and support the personalization of patient care. 

“Our model could be an acceleratory module that could help first identify a small group of candidate drugs that are effective to treat a disease, allowing clinicians to conduct randomized clinical trials on a limited scale with just a few drugs,” said first author Ruoqi Liu, a computer science and engineering PhD student in Zhang’s lab. 

The team dubbed the proposed framework CURE: CaUsal tReatment Effect estimation. 

The beauty of a treatment effect estimation model pre-trained with massive amounts of unlabeled real-world data is its applicability to a multitude of diseases and drugs, Liu said. 

“We can pre-train the model on large-scale datasets without limiting it to any treatments. Then we fine-tune the pre-trained model on task-specific small-scale datasets so that the model can adapt quickly to different downstream tasks,” she said. 

Unlabeled data used to pre-train the model came from MarketScan Commercial Claims and Encounters from 2012-2017, providing 3 million patient cases, 9,435 medical codes (including 282 diagnosis codes) and 9,153 medication codes. 

Two of Liu’s model-constructing techniques added to CURE’s power: filling in gaps in patient records by pairing patient information with biomedical knowledge graphs that represent biomedical concepts and relationships, and pre-training a deep synergized patient data-knowledge foundation model using medical claims and knowledge graphs at scale. 

“We also proposed KG-TREAT, a knowledge-enhanced foundation model, to synergize the patient data with the knowledge graphs to have the model better understand the patient data,” said Liu, who was the first author of a March Proceedings of the AAAI Conference on Artificial Intelligence paper describing the knowledge graph work. 

To come up with treatment effect estimates, the model considers pre-trained data overlapped with more specific information on medical conditions and therapies, and after further fine-tuning, predicts which patient outcomes would correspond to different treatments. 

As part of comparing the model to other machine learning tools and validating it against clinical trial results, the study showed that the broad pre-training is the backbone of CURE’s effectiveness – and incorporation of knowledge graphs improved its performance further. 

Zhang envisions a day – pending Food and Drug Administration approval of AI as a decision-support tool – when clinicians could use this type of algorithm, loaded with electronic health record data from tens of millions of people, to access an actual patient’s “digital twin” and let the model function as a treatment guide. 

“This model is better than a crystal ball: Based on big data and foundation model AI, we can have reasonable confidence to be able to say what treatment strategy is better,” said Zhang, who leads the Artificial Intelligence in Medicine Lab and is a core faculty member in the Translational Data Analytics Institute at Ohio State. “We want to put physicians in the driver’s seat to see whether this is something that can be helpful for them when they’re making critical decisions.” 

This research was funded by the National Institutes of Health. Pin-Yu Chen of IBM Research was a study co-author of CURE in Patterns. Lingfei Wu of Anytime AI was a study co-author of KG-TREAT in AAAI.

Technological advances have enabled recent identification of the proteins involved in these systems, but scientists are still digging deeper into what those proteins do. 

In a new study, a team from The Ohio State University has reported on the molecular assembly of one of the most common anti-phage systems – from the family of proteins called Gabija – that is estimated to be used by at least 8.5%, and up to 18%, of all bacteria species on Earth. 

Researchers found that one protein appears to have the power to fend off a phage, but when it binds to a partner protein, the resulting complex is highly adept at snipping the genome of an invading phage to render it unable to replicate. 

“We think the two proteins need to form the complex to play a role in phage prevention, but we also believe one protein alone does have some anti-phage function,” said Zhangfei Shen, co-lead author of the study and a postdoctoral scholar in biological chemistry and pharmacology at Ohio State’s College of Medicine. “The full role of the second protein needs to be further studied.” 

The findings add to scientific understanding of microorganisms’ evolutionary strategies and could one day be translated into biomedical applications, researchers say. 

Shen and co-lead author Xiaoyuan Yang, a PhD student, work in the lab of senior author Tianmin Fu, assistant professor of biological chemistry and pharmacology at Ohio State. 

The study was published April 16 in Nature Structural & Molecular Biology. 

The two proteins that make up this defense system are called Gabija A and Gabija B, or GajA and GajB for short. 

Researchers used cryo-electron microscopy to determine the biochemical structures of GajA and GajB individually and of what is called a supramolecular complex, GajAB, created when the two bind to form a cluster consisting of four molecules from each protein. 

In experiments using Bacillus cereus bacteria as a model, researchers observed the activity of the complex in the presence of phages to gain insight into how the defense system works. 

Though GajA alone showed signs of activity that could disable a phage’s DNA, the complex it formed with GajB was much more effective at ensuring phages would not be able take over the bacterial cell. 

“That’s the mysterious part,” Yang said. “GajA alone is sufficient to cleave the phage nucleus, but it also does form the complex with GajB when we incubate them together. Our hypothesis is that GajA recognizes the phage’s genomic sequence, but GajB enhances that recognition and helps to cut the phage DNA.” 

The large size and elongated configuration of the complex made it difficult to get the full picture of GajB’s functional contributions when bound to GajA, Shen said, leaving the team to make some assumptions about protein roles that have yet to be confirmed. 

“We only know GajB helps enhance GajA activity, but we don’t yet know how it works because we only see about 50% of it on the complex,” Shen said. 

One of their hypotheses is that GajB may influence the concentration level of an energy source, the nucleotide ATP (adenosine triphosphate), in the cellular environment – specifically, by driving ATP down upon detection of the phage’s presence. That would have the dual effect of expanding GajA’s phage DNA-disabling activity and stealing energy that a phage would need to start replicating, Yang said. 

There is more to learn about bacterial anti-phage defense systems, but this team has already shown that blocking virus replication isn’t the only weapon in the bacterial arsenal. In a previous study, Fu, Shen, Yang and colleagues described a different defense strategy: bacteria programming their own death rather than letting phages take over a community. 

This work was supported by the National Institute of General Medical Sciences. 

Additional co-authors are Jiale Xie, Jacelyn Greenwald, Ila Marathe, Qingpeng Lin and Vicki Wysocki of Ohio State, and Wenjun Xie of the University of Florida.

After discovering the connection between dysregulated neuron function and the breakdown of triglycerides in fat tissue in mice, researchers found that a short course of the drug gabapentin, commonly prescribed for nerve pain, prevented the damaging metabolic effects of the spinal cord injury. 

Gabapentin inhibits a neural protein that, after the nervous system is damaged, becomes overactive and causes communication problems – in this case, affecting sensory neurons and the abdominal fat tissue to which they’re sending signals. 

“We believe there is maladaptive reorganization of the sensory system that causes the fat to undergo changes, initiating a chain of reactions – triglycerides start breaking down into glycerol and free fatty acids that are released in circulation and taken up by the liver, the heart, the muscles, and accumulating, setting up conditions for insulin resistance,” said senior author Andrea Tedeschi, assistant professor of neuroscience in The Ohio State University College of Medicine. 

“Through administration of gabapentin, we were able to normalize metabolic function.” 

The study is published today (April 24, 2024) in Cell Reports Medicine. 

Previous research has found that cardiometabolic diseases are among the leading causes of death in people who have experienced a spinal cord injury. These often chronic disorders can be related to dysfunction in visceral white fat (or adipose tissue), which has a complex metabolic role of storing energy and releasing fatty acids as needed for fuel, but also helping keep blood sugar levels at an even keel.  

Earlier investigations of these diseases in people with neuronal damage have focused on adipose tissue function and the role of the sympathetic nervous system – nerve activity known for its “fight or flight” response, but also a regulator of adipose tissue that surrounds the abdominal organs. 

Instead, Debasish Roy – a postdoctoral researcher in the Tedeschi lab and first author on the paper – decided to focus on sensory neurons in this context. Tedeschi and colleagues have previously shown that a neuronal receptor protein called alpha2delta1 is overexpressed after spinal cord injury, and its increased activation interferes with post-injury function of axons, the long, slender extensions of nerve cell bodies that transmit messages. 

In this new work, researchers first observed how sensory neurons connect to adipose tissue under healthy conditions, and created a spinal cord injury mouse model that affected only those neurons – without interrupting the sympathetic nervous system. 

Experiments revealed a cascade of abnormal activity within seven days after the injury in neurons – though only in their communication function, not their regrowth or structure – and in visceral fat tissue. Expression of the alpha2delta1 receptor in sensory neurons increased as they over-secreted a neuropeptide called CGRP, all while communicating through synaptic transmission to the fat tissue – which, in a state of dysregulation, drove up levels of a receptor protein that engaged with the CGRP. 

“These are quite rapid changes. As soon as we disrupt sensory processing as a result of spinal cord injury, we see changes in the fat,” Tedeschi said. “A vicious cycle is established – it’s almost like you’re pressing the gas pedal so your car can run out of gas but someone else continues to refill the tank, so it never runs out.” 

The result is the spillover of free fatty acids and glycerol from fat tissue, a process called lipolysis, that has gone out of control. Results also showed an increase in blood flow in fat tissue and recruitment of immune cells to the environment. 

“The fat is responding to the presence of CGRP, and it’s activating lipolysis,” Tedeschi said. “CGRP is also a potent vasodilator, and we saw increased vascularization of the fat – new blood vessels forming as a result of the spinal cord injury. And the recruitment of monocytes can help set up a chronic pro-inflammatory state.” 

Silencing the genes that encode the alpha2delta1 receptor restored the fat tissue to normal function, indicating that gabapentin – which targets alpha2delta1 and its partner, alpha2delta2 – was a good treatment candidate. Tedeschi’s lab has previously shown in animal studies that gabapentin helped restore limb function after spinal cord injury and boosted functional recovery after stroke. 

But in these experiments, Roy discovered something tricky about gabapentin: The drug prevented changes in abdominal fat tissue and lowered CGRP in the blood – and in turn prevented spillover of fatty acids into the liver a month later, establishing normal metabolic conditions. But paradoxically, the mice developed insulin resistance – a known side effect of gabapentin. 

The team changed drug delivery tactics, starting with a high dose and tapering off – and stopping after four weeks. 

“This way, we were able to normalize metabolism to a condition much more similar to control mice,” Roy said. “This suggests that as we discontinue administration of the drug, we retain beneficial action and prevent spillover of lipids in the liver. That was really exciting.” 

Finally, researchers examined how genes known to regulate white fat tissue were affected by targeting alpha2delta1 genetically or with gabapentin, and found both of these interventions after spinal cord injury suppress genes responsible for disrupting metabolic functions. 

Tedeschi said the combined findings suggest starting gabapentin treatment early after a spinal cord injury may protect against detrimental conditions involving fat tissue that lead to cardiometabolic disease – and could enable discontinuing the drug while retaining its benefits and lowering the risk for side effects. 

This work was supported by grants from the National Institute of Neurological Disorders and Stroke and the National Institutes of Health, and by the Chronic Brain Injury program at Ohio State. 

Co-authors, all from Ohio State, were Elliot Dion, Jesse Sepeda, Juan Peng, Sai Rishik Lingam, Kristy Townsend, Andrew Sas and Wenjing Sun.

Researchers analyzed data from a 2021 clinical trial that found psilocybin (magic mushrooms) combined with psychotherapy in adults was effective at treating major depressive disorder. 

Data included depression outcomes and participant reports about their experiences with the drugs and their connection with therapists. Results showed that the stronger the relationship between a participant and clinician – called a therapeutic alliance – the lower the depression scores were one year later. 

“What persisted the most was the connection between the therapeutic alliance and long-term outcomes, which indicates the importance of a strong relationship,” said lead author Adam Levin, a psychiatry and behavioral health resident in The Ohio State University College of Medicine. 

Past research has consistently found that as mental health treatments changed, a trusting relationship between clients and clinicians has remained key to better outcomes, said senior author Alan Davis, associate professor and director of the Center for Psychedelic Drug Research and Education in The Ohio State University College of Social Work. 

“This concept is not novel. What is novel is that very few people have explored this concept as part of psychedelic-assisted therapy,” Davis said. “This data suggests that psychedelic-assisted therapy relies heavily on the therapeutic alliance, just like any other treatment.” 

The study was published recently in the journal PLOS ONE. 

Twenty-four adults who participated in the trial received two doses of psilocybin and 11 hours of psychotherapy. Participants completed the therapeutic alliance questionnaire, assessing the strength of the therapist-participant relationship, three times: after eight hours of preparation therapy and one week after each psilocybin treatment. 

Participants also completed questionnaires about any mystical and psychologically insightful experiences they had during the drug treatment sessions. Their depression symptoms were assessed one week, four weeks, and up to one year after the trial’s end. 

The analysis showed that the overall alliance score increased over time and revealed a correlation between a higher alliance score and more acute mystical and/or psychologically insightful experiences from the drug treatment. Acute effects were linked to lower depression at the four-week point after treatment, but were not associated with better depression outcomes a year after the trial. 

“The mystical experience, which is something that is most often reported as related to outcome, was not related to the depression scores at 12 months,” Davis said. “We’re not saying this means acute effects aren’t important – psychological insight was still predictive of improvement in the long term. But this does start to situate the importance and meaning of the therapeutic alliance alongside these more well-established effects that people talk about.” 

That said, the analysis showed that a stronger relationship during the final therapy preparation session predicted a more mystical and psychologically insightful experience – which in turn was linked to further strengthening the therapeutic alliance. 

“That’s why I think the relationship has been shown to be impactful in this analysis – because, really, the whole intervention is designed for us to establish the trust and rapport that’s needed for someone to go into an alternative consciousness safely,” Davis said. 

Considering that psychedelics carry a stigma as Schedule I drugs under the Controlled Substances Act, efforts to minimize negative experiences in future studies of their therapeutic potential should be paramount – and therapy is critical to creating a supportive environment for patients, the authors said. 

This study ideally will help clearly position psychedelics treatment as a psychotherapeutic intervention moving forward – rather than its primary purpose being administration of a drug, Levin said. 

“This isn’t a case where we should try to fit psychedelics into the existing psychiatric paradigm – I think the paradigm should expand to include what we’re learning from psychedelics,” Levin said. “Our concern is that any effort to minimize therapeutic support could lead to safety concerns or adverse events. And what we showed in this study is evidence for the importance of the alliance in not just preventing those types of events, but also in optimizing therapeutic outcomes.” 

This work was supported by the Center for Psychedelic and Consciousness Research, funded by the Steven & Alexandra Cohen Foundation, the RiverStyx Foundation and private donors. It was also supported by the Center for Psychedelic Drug Research and Education (CPDRE), funded by anonymous donors. 

Additional co-authors are Rafaelle Lancelotta, Nathan Sepeda and Theodore Wagener of Ohio State, and Natalie Gukasyan, Sandeep Nayak, Frederick Barrett and Roland Griffiths of the Center for Psychedelic and Consciousness Research at Johns Hopkins University, where Davis is an affiliate.

The study, building upon previous research from the same lab at The Ohio State University, also showed that taking a DHA omega-3 fatty acid supplement for a month before the unhealthy eating and surgical procedure prevented the effects on memory linked to both the high-fat diet and the surgery in aged and young adult rats. 

Three days on a high-fat diet alone was detrimental to a specific type of fear-related memory in aged rats for as long as two weeks later – the same type of impairment seen in younger rats that ate fatty food and had a surgical procedure. The team has traced the brain inflammation behind these effects to a protein that activates the immune response. 

“These data suggest that these multiple insults have a compounding effect,” said senior author Ruth Barrientos, an investigator in Ohio State’s Institute for Behavioral Medicine Research and associate professor of psychiatry and behavioral health and neuroscience in the College of Medicine. 

“We’ve shown that an unhealthy diet, even in the short term, especially when it’s consumed so close to a surgery, which in and of itself will cause an inflammatory response, can have damaging results,” Barrientos said. “The high-fat diet alone might increase inflammation in the brain just a little bit, but then you have surgery that does the same thing, and when put together in a short amount of time you get a synergistic response that can set things in motion toward a longer-term memory issue.” 

The study was published recently in the journal Brain, Behavior, and Immunity. 

Barrientos’ lab studies how everyday life events might trigger inflammation in the aging brain as the nervous system responds to signals from the immune system reacting to a threat. Decades of research has suggested that with aging comes long-term “priming” of the brain’s inflammatory profile and a loss of brain-cell reserve to bounce back. 

Researchers fed young adult and aged rats a diet high in saturated fat for three days before a procedure resembling exploratory abdominal surgery – an event already known to cause about a week of cognitive issues in an older brain. Control rats ate regular food and were anesthetized, but had no surgery. (Barrientos’ lab has determined anesthesia alone does not cause memory problems in rats.) 

In this study, as in previous research on aged rats treated with morphine after surgery, the team showed that an immune system receptor called TLR4 was the culprit behind the brain inflammation and related memory problems generated by both surgery and the high-fat diet, said first author Stephanie Muscat, assistant clinical professor of neuroscience at Ohio State. 

“Blocking the TLR4 signaling pathway prior to the diet and surgery completely prevented that neuroimmune response and memory impairments, which confirmed this specific mechanism,” Muscat said. “And as we had found before in another model of an unhealthy diet, we showed that DHA supplementation did mitigate those inflammatory effects and prevent memory deficits after surgery.” 

There were some surprising memory findings in the new work. Different behavioral tasks are used to test two types of memory: contextual memory based in the hippocampus and cued-fear memory based in the amygdala. In contextual memory tests, rats with normal memory freeze when they re-enter a room in which they had an unpleasant experience. Cued-fear memory is evident when rats freeze in a new environment when they hear a sound connected to that previous bad experience. 

For aged rats in this study, as expected, the combination of a high-fat diet and surgery led to problems with both contextual and cued-fear memory that persisted for at least two weeks – a longer-lasting effect than the researchers had seen before. 

The high-fat diet alone also impaired the aging rats’ cued-fear memory. And in young adult rats, the combination of the high-fat diet and surgery led to only cued-fear memory deficits, but no problems with memory governed by the hippocampus. 

“What this is telling us in aged animals, along with the fact we’re seeing this same impairment in young animals after the high-fat diet and surgery, is that cued-fear memory is uniquely vulnerable to the effects of diet. And we don’t know why,” Barrientos said. “One of the things we’re hoping to understand in the future is the vulnerability of the amygdala to these unhealthy diet challenges.” 

With increasing evidence suggesting that fatty and highly processed foods can trigger inflammation-related memory problems in brains of all ages, the consistent findings that DHA – one of two omega-3 fatty acids in fish and other seafood and available in supplement form – has a protective effect are compelling, Barrientos said. 

“DHA was really effective at preventing these changes,” she said. “And that’s amazing – it really suggests that this could be a potential pretreatment, especially if people know they’re going to have surgery and their diet is unhealthy.” 

This work was supported by grants from the National Institute on Aging and the National Institute of Neurological Disorders and Stroke.

Co-authors included Michael Butler, Menaz Bettes, James DeMarsh, Emmanuel Scaria and Nicholas Deems, all of Ohio State.

In recognition, the inpatient tower will have two named spaces: the John F. Wolfe Lobby and the Wolfe Foundation Crossroads, pending approval by the university’s board of trustees at its February meeting.

John F. Wolfe was well known as the publisher of The Columbus Dispatch and served as chair and CEO of The Dispatch Printing Company. Beyond his professional contributions, Wolfe had a deep spirit of altruism that came from the generations before him and continues in his family today. As a civic leader, he made an impact on projects across the city to help Columbus realize its potential.

Ohio Gov. Mike DeWine had many opportunities to work with John F. Wolfe over about 30 years of their careers. He reflected on the understated way the Wolfe family has influenced progress in the community.

“Few people know, or will ever know, even half of the good works John F. Wolfe and Ann Wolfe put their shoulders behind to benefit Columbus and central Ohio. They preferred to be a quiet force for good with lasting impact,” DeWine said. “I think John F. Wolfe would be delighted about his family’s continued efforts to improve the quality of life in central Ohio, and health care is vital to quality of life.”

John F. Wolfe spent much of his time and resources stewarding the vision and growth of The Ohio State University and its health care system through 20-plus years of service on various boards. His widow, Ann Wolfe, has a long tradition of championing health care institutions, including serving as a member of the University Hospitals Board and as the longtime chair of the Nationwide Children’s Hospital Foundation Board.

The Wolfe family’s legacy of service and generosity can be found across many Columbus institutions, including COSI, the Franklin Park Conservatory, the Scioto Mile and the Columbus Zoo and Aquarium. At Ohio State, the Wolfe family has supported many initiatives including cancer research, veterinary medicine, athletic facilities, scholarships and eight endowed chairs and professorships.

“This is a special day for our university, our region and our state,” said Ohio State President Walter “Ted” Carter Jr. “John F. Wolfe’s family and the Wolfe Foundation are building on his lifelong commitment to creating a bright future for the Columbus community. We are grateful for their remarkable investment in the inpatient tower and our medical center. It will enable us to continue serving Ohioans and providing expert care to patients and families that is at the forefront of medicine.”

At 1.9 million square feet and 24 floors, the inpatient tower is 75% complete. It is the single largest facilities project undertaken at Ohio State. The hospital is designed for flexible and team-based care that centers around the patient and their family. Its interdisciplinary focus will allow for collaborative teaching, research and clinical trials throughout the building. With up to 820 private rooms and 51 neonatal intensive care beds, it will add much-needed capacity to care for the growing community. According to the Mid-Ohio Regional Planning Commission, central Ohio is expected to add nearly 1 million people in the next 20-25 years.

“Patients and families are at the center of everything we do at the Ohio State Wexner Medical Center, and our new inpatient tower will further ensure that we are able to provide the very best care for everyone, every time,” said John J. Warner, CEO of the Wexner Medical Center and executive vice president at Ohio State. “Through this transformational gift honoring John F. Wolfe, the Wolfe family and the Wolfe Foundation remain steadfast in their commitment to improving people’s lives within our community. John F. Wolfe’s legacy as a community leader and philanthropist is still helping to shape the skyline of Columbus, and we are honored that our vision for the future of the Wexner Medical Center aligns with what he and others envisioned for the future of central Ohio and the entire state.”

John F. Wolfe also supported Ohio State’s goal to create a nationally renowned academic medical center. He was instrumental in the construction of the original James Cancer Hospital and Solove Research Institute, which opened in 1990 and has steadily grown ever since. When the inpatient tower opens, The James will gain 148 beds and become the second-largest cancer hospital in the country.

Philanthropic commitments such as this gift from the Wolfe Foundation play a critical role in speeding progress toward new treatments and teaching opportunities for the generations to come.

“John F. and the Wolfe family have been the catalyst for many of Ohio State’s accomplishments over the course of multiple decades,” said Andrew Thomas, who was honored as the inaugural Wolfe Foundation Chief Clinical Officer in 2021. “It is inspiring to see how Ann, her family and the Wolfe Foundation have continued to carry on John F.’s legacy, with this leadership commitment to the inpatient tower.”

The home environment can pose challenges for both the patient and those providing care – confusion and functional problems linked to dementia and a lack of caregiver support for friends and family members thrust into the role, to name a few. 

A new study led by researchers at The Ohio State University has laid the groundwork for a future intervention designed to help caregivers establish a safe and workable mealtime routine for people with dementia living at home. 

In addition to explaining the various barriers to patients’ mealtime participation, interviews with a range of health professionals for the study identified strategies to make eating go more smoothly. Among them: reducing distractions and clearing away clutter, using written cues, and leveraging assistance that can come from a community-based nutrition program like Meals-on-Wheels. 

“It comes down to keeping things simple. How do we keep that environment as simple as possible so people’s eyes and ears aren’t distracted and taking their attention away from their food?” said lead author Lisa Juckett, assistant professor of occupational therapy in The Ohio State University School of Health and Rehabilitation Sciences. 

“For people with dementia, it’s not just ‘I forget to eat and therefore that’s why I’m at risk of malnutrition,’ which some people might think. It’s the combination of all these other factors that really come into play, which is why eating is complex – it’s much more than bringing a fork to your mouth.” 

The study was published recently in the journal The Gerontologist. 

Over 80% of people with dementia in the United States live at home, according to the Centers for Disease Control and Prevention. An estimated 60% of home-based patients aren’t able to routinely eat or prepare food on their own. 

“We know that the older adult population is growing and older adults are living longer, but that doesn’t mean they’re living lives that are healthier and disease-free,” Juckett said. “Alzheimer’s and related dementias are expected to be on the rise over the next several decades, and it’s estimated that the health care system won’t be able to keep up with addressing the needs of people with dementia. That places more burden on caregivers who are not paid to do this but want their loved ones to stay at home, because that’s where the majority of people want to age – at homes and in communities of their choosing.” 

While organizations hold training sessions or support groups and offer educational resources about looking after dementia patients at home, a stressed and overwhelmed caregiver may not be able or want to take that route, Juckett said. 

“We wanted to give caregivers actionable steps and strategies that they can try out with loved ones at home because they already have a lot going on,” she said. 

Juckett interviewed 20 professionals whose work involved providing community-based care to people with dementia, including registered nurses, speech-language pathologists, social workers, occupational therapists, counselors and registered dietitians, as well as staff of the largest Meals-on-Wheels provider in Ohio, LifeCare Alliance. 

The sessions identified the main challenges to mealtime participation at home. For people with dementia, cognitive impairment may mean they forget to eat, don’t recognize unsafe food, and are distracted during preparation and eating. Some also lack the functional ability to open packages and operate a microwave. A cluttered home environment poses a fall risk, radio and TV sounds can be distracting, and even a patterned tablecloth can cause visual confusion. On top of these factors, caregiver training doesn’t typically cover these complexities surrounding mealtime in the home.

Strategies recommended in the study take these barriers into account. Professionals recommended:

• Lowering auditory and visual distractions.
• Eliminating household clutter, clearing pathways and improving lighting.
• Providing written instructions to guide patients’ mealtime activities. 

Establishing an association between a table and eating can improve the routine, but for people with dementia who prefer to eat on the couch, ensuring they’re sitting upright can help keep them safe when they swallow. 

Caregivers are also advised to sign up for a clinical assessment of the home environment to receive individualized guidance. If that’s not possible, Juckett said, this is where a Meals-on-Wheels program can help – staff and volunteers who have eyes on meal recipients on a daily or weekly basis can watch for behavioral or household hints that a referral or coordination of services is in order. 

“Meals-on-Wheels could be powerful for addressing the needs of people living with dementia, of course, but also at providing some relief and reduced burden for the caregiver as well,” Juckett said. 

Juckett has begun interviews with caregivers and the people with dementia in their care for insights into how their experiences line up against what the health professionals had to say. From there, the work will move into developing core components of an intervention focused on mealtime in the home and testing its effectiveness. 

“We don’t want to make recommendations that add to the caregivers’ burden,” she said. “It often goes unrecognized how much work goes into caregiving.” 

This work was supported by the National Institute on Aging’s IMbedded Pragmatic Alzheimer’s disease and Related Dementias Clinical Trials (IMPACT) Collaboratory.

Co-authors included Mequeil Howard, Shannon Jarrott and Lorraine Mion of Ohio State, Beth Fields of the University of Wisconsin-Madison and Kali Thomas of Brown University.

Women and men’s recovery patterns were similar on tests of cognitive function, symptoms and mental health, and in balance and reaction time. Though women as a group entered the return-to-play protocol later than men, there was no significant difference in the time it took for men and women to return to unrestricted participation in their respective sports. 

The findings are based on an analysis of medical data from 906 student-athletes competing in sports at National Collegiate Athletic Association (NCAA) institutions. 

“I think a lot of people will be surprised in such a large sample that women and men recover along the same trajectory,” said senior study author Jaclyn Caccese, assistant professor in The Ohio State University School of Health and Rehabilitation Sciences. “For many years we’ve thought women took longer to recover, but evidence suggests that if women get the same access to care, they do recover similarly.” 

The research was published recently in the journal Sports Medicine. 

Data came from the Concussion Assessment, Research and Education (CARE) Consortium, an initiative established by the NCAA and U.S. Department of Defense to fill gaps in knowledge about concussion effects and recovery among student-athletes at colleges, universities and military service academies. 

The study sample was 61% female and included student-athletes in 15 sex-comparable sports ranging from basketball and diving to ice hockey, soccer and volleyball. Members of all-male football and wrestling teams and all-female field hockey squads were excluded.

“Much of the concussion research came out of football, a predominantly male sport. This study is important because it’s the largest study of concussion recovery in women to date,” said Caccese, citing a 2022 review showing that 40% of 171 studies on which athlete concussion recovery consensus papers were based had no female participants and relied on samples that were overall 80% male.

“We’ve been making clinical decisions based on studies that included only a very small percentage of females,” she said. “But if student-athletes’ cognitive function, symptoms and mental health are recovering along the same trajectories, we probably don’t need to hold women back longer.” 

Participants in the CARE initiative completed pre-season baseline assessments that enabled, for this study, comparisons to their health status after a sport-related concussion. Post-concussion evaluations were taken within six hours of the injury, 24-48 hours later, the day they entered return-to-play protocol, the day they were cleared for unrestricted play and six months post-injury. 

The tests over that time period included assessments of cognition and memory, balance, reaction time, and overall symptoms and how distressing they were, as well as surveys on health, anxiety and depression, and satisfaction with life. 

Statistical analysis showed that recovery trajectories did not differ by sex, with the exception of women reporting more problems with eye and inner ear function than men within 48 hours of injury. As a group, women waited a day longer than men to start return-to-play workouts, but there was no statistical difference in student-athletes’ return to unrestricted competition – on average, about two weeks post-concussion. 

Women did report higher symptoms than men at baseline (headache, pressure in the head, fatigue, for example) and during recovery, though the study cannot explain why. The researchers posed the question in their paper: Could it be biological differences affecting symptom experience, or sociocultural differences in reporting behavior? 

Caccese said this finding suggests that individual baseline data or established data on sex-specific norms is needed to properly evaluate athletes’ overall condition after a sport-related head injury. 

“Otherwise, clinical providers might think women are not recovered who actually are,” she said. 

She also noted that high schools have tended to focus athletic trainer resources over past years on sports with the highest injury risk – namely, football – meaning there’s a good chance female athletes at the high school level haven’t received the same level of medical attention. 

“Student-athletes at the institutions in this study receive immediate access to the best sports medicine evaluation and treatment. I think that could be one of the driving factors in why we didn’t see much of a sex difference,” Caccese said. “Historically, some women’s sports didn’t have the same on-site access to health care, and what that does is result in delayed evaluation, delayed initiation of treatment and prolonged recovery. I think having someone on the field watching and taking care of athletes and knowing them and knowing how to provide concussion management is key.”

Co-authors of the study were investigators from multiple CARE Consortium member institutions, including its principal investigators.

Researchers analyzing data from surveys of over 20,000 people found that Americans averaged about 400 to 500 calories in snacks a day – often more than what they consumed at breakfast – that offered little nutritional value. 

Though dietitians are very aware of Americans’ propensity to snack, “the magnitude of the impact isn’t realized until you actually look at it,” said senior study author Christopher Taylor, professor of medical dietetics in the School of Health and Rehabilitation Sciences at The Ohio State University. 

“Snacks are contributing a meal’s worth of intake to what we eat without it actually being a meal,” Taylor said. “You know what dinner is going to be: a protein, a side dish or two. But if you eat a meal of what you eat for snacks, it becomes a completely different scenario of, generally, carbohydrates, sugars, not much protein, not much fruit, not a vegetable. So it’s not a fully well-rounded meal.” 

Survey participants who were controlling their type 2 diabetes ate fewer sugary foods and snacked less overall than participants without diabetes and those whose blood sugar levels indicated they were prediabetic. 

“Diabetes education looks like it’s working, but we might need to bump education back to people who are at risk for diabetes and even to people with normal blood glucose levels to start improving dietary behaviors before people develop chronic disease,” Taylor said. 

The study was published recently in PLOS Global Public Health. 

Researchers analyzed data from 23,708 U.S. adults over 30 years of age who had participated from 2005 to 2016 in the National Health and Nutrition Examination Survey. The survey collects 24-hour dietary recalls from each participant – detailing not just what, but when, all food was consumed. 

Respondents were categorized according to their HbA1c level, a measure of glucose control, into four groups: nondiabetes, prediabetes, controlled diabetes and poorly controlled diabetes. 

Among the whole survey sample, snacks accounted for between 19.5% and 22.4% of total energy intake – while contributing very little nutritional quality. 

In descending order of proportion, snacks consisted of convenience foods high in carbohydrates and fats, sweets, alcoholic beverages, non-alcoholic drinks that include sugar-sweetened beverages, protein, milk and dairy, fruits, grains and, lagging far behind, vegetables. 

Noting that capturing 24 hours of food consumption doesn’t necessary reflect how people usually eat, “it gives us a really good snapshot of a large number of people,” Taylor said. “And that can help us understand what’s going on, where nutritional gaps might be and the education we can provide.” 

Finding that people with diabetes had healthier snacking habits was an indicator that dietary education is beneficial to people with the disease. But it’s information that just about everyone can use, Taylor said – and it’s about more than just cutting back on sugar and carbs. 

“We need to go from just less added sugar to healthier snacking patterns,” he said. “We’ve gotten to a point of demonizing individual foods, but we have to look at the total picture. Removing added sugars won’t automatically make the vitamin C, vitamin D, phosphorus and iron better. And if we take out refined grains, we lose nutrients that come with fortification. 

“When you take something out, you have to put something back in, and the substitution becomes just as important as the removal.” 

And so, rather than offering tips on what foods to snack on, Taylor emphasizes looking at a day’s total dietary picture and seeing whether snacks will fulfill our nutritional needs. 

“Especially during the holidays, it’s all about the environment and what you have available, and planning accordingly. And it’s about shopping behavior: What do we have in the home?” he said.

“We think about what we’re going to pack for lunch and cook for dinner. But we don’t plan that way for our snacks. So then you’re at the mercy of what’s available in your environment.” 

This work was supported by Abbott and Ohio State. Co-authors included Kristen Heitman, Owen Kelly, Stephanie Fanelli and Jessica Krok-Schoen of Ohio State and Sara Thomas and Menghua Luo of Abbott.

The finding came about as the researchers focused on detailing how this defense mechanism works in bacteria that are infected by phages, viruses that invade and make copies of themselves inside bacterial cells. In addition to detailing the proteins’ structures and binding sites, the experiments unearthed this unprecedented switch in enzymatic functions.

“This was a big discovery,” said senior study author Tianmin Fu, assistant professor of biological chemistry and pharmacology in The Ohio State University College of Medicine. “When proteins form a complex, that usually increases or decreases an enzyme’s activity – but we’ve never seen a complete switch in function. That’s entirely new to the enzymology field.”

In the bigger picture, he said, a better understanding of how bacteria use defense systems to die versus staying infected by phages could be translated into therapies that convince cancer cells to program their own death as well.

“If we could introduce this type of system into a cancer cell, that could lead to development of a new strategy for cancer treatment,” said Fu, also an investigator in the Ohio State University Comprehensive Cancer Center.

The research is published today (Dec. 13, 2023) in Molecular Cell.

When infected by phages, bacteria opt for death to prevent phages from taking over a bacterial community. The complex examined in this study, the combination of proteins called SIR2 and HerA, was identified along with hundreds of other bacterial defense systems in previous research that focused on genomic analyses.

In an E. coli model, Fu and colleagues used cryo-electron microscopy to determine the biochemical structures of the proteins alone and during and after their assembly as a supramolecular complex.

“This system has been identified in many different bacteria, and though we studied it in E. coli, we think it would function very similarly in other bacteria,” Fu said.

The analysis suggested that SIR2 and HerA have an affinity for each other, showing that SIR2’s wheel-like structure functions as an organizer of HerA molecular clusters before the two settle into a complex consisting of six identical molecular subunits. However, exactly what triggers their connection is still a mystery.

Results showed that once assembled, the complex could exist in bacteria without incident, suggesting bacteria somehow inhibit the system’s defense activity unless a phage enters the scene. When phages were introduced, the bacteria quickly died – by their own design, because the defense system had been activated to deplete a small molecule called NAD+ that bacteria require to survive. That activation mechanism remains unknown, for now, as well.

Experiments confirmed SIR2 was responsible for discarding the NAD+, which was a surprise. SIR2’s first job as a nuclease is digesting nucleic acids to maintain proper cell functions. But when bound to HerA and activated as part of the defense system, its enzymatic function switched – SIR2 became an entirely different type of enzyme called an NADase, which generates a water-based reaction to dissipate NAD+.

“We now want to address this huge, fundamental biological question – how does complex assembly switch SIR2’s activity from a nuclease to an NADase?” Fu said. “Figuring out this mechanism would be big for the field, and this system is extremely interesting because it has so many different enzymatic activities in one preassembled complex.”

Fu also envisions a synthetic biology toolbox of the future in which bacterial tricks are adapted into cancer cell-killing strategies. “We’re starting to learn from bacteria, and hopefully we can reprogram them into powerful tools for cancer diagnosis and treatment,” he said.

This work was supported by the National Institutes of Health.

Co-authors include Zhangfei Shen, Qingpeng Lin, Xiao-Yuan Yang and Elizabeth Fosuah, all of Ohio State.

Krystof Bankiewicz, MD, PhD, professor in the Department of Neurological Surgery, and Michael Tweedle, PhD, professor emeritus in the Department of Radiology, are among the 162 academic inventors named NAI Fellows this year. They are the 17th and 18th Ohio State inventors selected for this prestigious honor over the years. Election as an Academy Fellow is the highest professional distinction awarded solely to inventors. 

The 2023 class of Fellows represents 35 U.S. states and 10 countries. 

“Members of this year’s class of NAI Fellows are making significant contributions to both science and society through their work,” said Paul R. Sanberg, president of the NAI. “This new class, in conjunction with our existing Fellows, are creating innovations that drive crucial advancements across a variety of disciplines and stimulate the global and national economy in immeasurable ways as they move these technologies from lab to marketplace.” 

Krystof Bankiewicz

Bankiewicz joined The Ohio State University Wexner Medical Center in 2019 as a professor in the Department of Neurological Surgery and holds the Gilbert and Kathryn Mitchell Endowed Chair.

He became the chief scientific officer of Ohio State’s Gene Therapy Institute when it launched in 2022. His research focuses on developing translational approaches to drug, gene and cell replacement therapies.

“I’m proud of the advances we’ve made to treat Parkinson’s disease and a rare genetic disorder called AADC deficiency, which causes severe physical and developmental disabilities in children, but more work still needs to be done. We want to cure every child in the world with this disease,” Bankiewicz said. 

In addition to his work at Ohio State, Bankiewicz is the co-founder of MedGenesis Therapeutix Inc., Voyager Therapeutics and Brain Neurotherapy Bio, Inc. 

He is a professor emeritus at the University of California, San Francisco, and he served as the former chief of molecular therapeutics at the National Institutes of Health. Additionally, he is the director of the Interventional Neuro Centers at Brodno Hospital in Warsaw, Poland.

Throughout his career, Bankiewicz has authored more than 230 peer-reviewed articles appearing in prestigious journals such as PNAS, Science, Nature, Nature Medicine and Nature Communications. He has developed several gene therapy-related patents, surgical devices and more. Bankiewicz is leading two ongoing gene therapy clinical trials in Parkinson’s disease, multiple system atrophy and pediatric neurotransmitter deficiency. 

He’s a member of several editorial boards and scientific organizations. 

“I am so honored to join the National Academy of Inventors as a Fellow and look forward to inventing new and improved gene therapies for a wide variety of brain disorders including Huntington’s, Alzheimer’s disease and alcohol use disorders” Bankiewicz said. 

Michael Tweedle

Tweedle joined Ohio State’s medical faculty in 2009 as a professor of radiology and director of the Imaging Agents Laboratory in the Wright Center for Innovation and Biomedical Imaging, and is one of the world’s most prominent and innovative researchers in diagnostic imaging and contrast media.

He held the Stefanie Spielman Chair in Cancer Imaging (2009-2023) and is a member of the Translational Therapeutics Program at Ohio State’s Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute (OSUCCC – James), where his research focuses on creating molecularly targeted therapies visualized in vivo (in the body) through diagnostic imaging technologies like positron emission tomography (PET) and magnetic resonance imaging (MRI). 

"I have always believed that if cancer can be imaged early enough, it can be cured,” Tweedle said. “That premise has underpinned all of my work to create new imaging agents."

Tweedle holds or co-holds 39 U.S. patents. He developed ProHance, a type of MRI agent that has been used in more than 20 million patients. In addition, he invented the first catalysts for producing technetium (a chemical element) radiopharmaceutical kits for the heart, and he created some of the earliest targeted molecular-imaging agents from monoclonal antibodies.

More recently, he was the co-inventor of first-in-class targeted imaging/therapeutic peptides for prostate, breast, and head and neck cancers, and a first-in-class angiogenesis (blood vessel formation) receptor-targeted agent. Most of his projects seek targeted imaging agents that are biochemically associated with treatment, so that patients’ therapy can be personalized to their biologically unique cancer.

Tweedle has co-authored more than 100 articles appearing in well-respected publications, including Journal of Nuclear Medicine, Molecular Imaging and Biology and The Journal of Clinical Endocrinology & Metabolism. He has also shared his research in hundreds of presentations at international events.

"I love research, but inventing, creating and driving new ideas to real-world practice is my passion,” Tweedle said. “So I am deeply moved by the election to Fellow in the NAI."  

“Currently, delivering the baby is the only treatment for these conditions, which often means babies are born too early and have increased risks for complications such as bleeding in the brain and infections,” said study principal investigator Maged Costantine, division director of maternal fetal medicine at Ohio State Wexner Medical Center and professor of obstetrics and gynecology. “Given the high frequency, related complications and inequities, it is important to improve treatment methods.”

Many professional societies, such as the Society for Maternal-Fetal Medicine, say that pregnant people at higher risk of these hypertensive disorders should take low-dose aspirin every day to prevent these blood pressure complications.

“While 81 mg is most often used, a higher dose may work better for patients, although that possibility has not been evaluated adequately,” said co-principal investigator Kara Rood, maternal fetal medicine physician and associate professor at Ohio State. “It is also important to identify whether aspirin works equally well for everyone – for example, those with diabetes versus those with chronic hypertension – and to understand any barriers to adhering to recommended low-dose aspirin therapy.”

The study also will be led by co-principal investigator Denise Scholtens, professor and division chief of biostatistics in preventive medicine at Northwestern University Feinberg School of Medicine and director of Northwestern’s Data Analysis and Coordinating Center.

Other key study investigators at Ohio State include William Grobman, maternal fetal medicine physician and professor of obstetrics and gynecology; Ann Scheck McAlearney, professor of family medicine, associate dean for health sciences research and director of CATALYST; Anne Trinh, director of programs and strategic initiatives at the Center for HOPES; and Melanie Paglione, the consortium’s lead research nurse coordinator. At Northwestern, Kiarri Kerhaw, associate professor and social epidemiologist, will assist in approach and data interpretation as well.

The research team aims to enroll more than 10,000 pregnant people at higher risk for hypertensive disorders in pregnancy at 11 clinical centers across the U.S. Participants will be randomized to two groups; one will take 81 mg aspirin daily and the other will take 162 mg daily. They will be followed until six weeks after delivery. Researchers will compare the two groups according to the frequency of developing hypertensive disorders, their overall health and birth experience, and whether they have a baby who is born too small or too early, receives special care after delivery, has issues with bonding or does not survive.

“This study will help answer an important question that will improve the health of all pregnant people and their babies and may also reduce health disparities,” said Costantine. “When completed, this will be the largest and most up-to-date study focused on the ideal dose of aspirin to prevent blood pressure problems in pregnancy.”

“This project was selected for PCORI funding not only for its scientific merit and commitment to engaging patients and other health care stakeholders, but also for its conduct in real-world settings,” said Nakela L. Cook, PCORI executive director. “It has the potential to answer an important question about prevention of hypertensive disorders of pregnancy and fill a crucial evidence gap. We look forward to following the study’s progress and working with The Ohio State University to share its results.”

Many clinical studies test whether an approach to care works under carefully controlled conditions in specialized research centers, but health care is rarely delivered in such optimized settings. Pragmatic clinical studies test a treatment’s effectiveness in “real-world” practice situations, such as typical hospitals and outpatient clinics, and also can include a wider range of study participants, making their findings more generally applicable.

Ohio State’s funding award has been approved pending completion of a business and programmatic review by PCORI staff and issuance of a formal award contract.

PCORI is an independent, nonprofit organization authorized by Congress in 2010. Its mission is to fund research that will provide patients, their caregivers and clinicians with the evidence-based information needed to make better informed health care decisions.

Researchers analyzed leishmaniasis lesions on mouse skin to detect metabolic signaling pathways that differed from uninfected mice. Results suggested the parasites that cause the disease change pain perception – presumably as a way to delay treatment and promote their own survival. 

“No one knows why these lesions are painless – but it has been thought that the parasite somehow manipulates the host physiological system,” said Abhay Satoskar, senior author of the study and professor of pathology in The Ohio State University College of Medicine. 

“Based on our data, something the parasites do triggers pathways that suppress pain. How they do that, we’re still investigating.” 

Beyond increasing understanding of this parasitic disease afflicting 1 million new patients each year, the research could lead to development of new non-narcotic pain medications. 

“We hypothesize that any molecules the parasite’s presence is producing could be potential painkillers for other health problems,” Satoskar said. 

The study was published recently in the journal iScience. 

The lack of pain in leishmaniasis lesions has puzzled scientists for years, especially when similar blisters caused by conditions like chicken pox, staphylococcus infections or the herpes virus are itchy, oozy and sore. 

After giving mice chronic infections with Leishmania mexicana, the species that causes cutaneous leishmaniasis in South, Central and North America, researchers used an unbiased mass spectrometry analysis of the lesions to identify molecules known to be associated with pain suppression. 

They found numerous metabolites – products of bio-chemical reactions that break down food to produce energy and perform other essential functions – that have been linked in previous research to blockage of pain perception. They also found pathways with pain-relief properties tied to the brain’s endocannabinoid system, which is involved in a host of physiological processes, including the pain response. 

Cell-culture experiments in infected macrophages, the immune cells in which Leishmania parasites live, showed an increase in most, but not all, of the same changes as in the lesions. 

The parasites use these metabolites as nutrition to help them replicate. But finding that certain pain-suppression pathways aren’t increased in infected macrophages leaves some questions unanswered, said Satoskar, also a professor of microbiology at Ohio State.  

“The infection does something in the cell that could be a direct or indirect effect – we don’t know. But the environment that the infection creates leads to production of these metabolites,” he said. “The exciting thing is that this is the first time we’ve begun to understand the cellular basis of why there is no pain in these lesions. 

“The next key question is, if we know these pathways are responsible, then how are they triggered? By the parasite, or something the parasite is doing to the host cell, or a combination of both? There could be a lot of things happening.” 

Skin test for immunity to Leishmania­-caused diseases 

Satoskar has also co-led an initiative to develop a standardized skin test to check for immunity to Leishmania donovani, the parasite that causes visceral leishmaniasis – a potentially lethal form of the disease that affects the organs and is fatal if untreated.

He and colleagues recently reported in Nature Communications on this work, which is critical for disease surveillance in the most affected regions of the world and will be needed for phase 3 clinical trials of leishmaniasis vaccines the team has developed. 

The test, using an antigen called leishmanin, is similar to a skin test for tuberculosis – a positive response means a person has been exposed to the parasite and has cellular immunity that prevents further clinical symptoms. 

No tests or reagents are available to detect sporadic cases of leishmaniasis reported in the southern United States, so the skin test being developed will facilitate surveillance studies to assess exposure throughout the endemic regions for leishmaniasis – which include the U.S. 

“This is a very important test in the field to understand who is exposed to this disease or not,” Satoskar said. “For many stakeholders going into a community to conduct surveillance, knowing who is immune and who is not immune is essential so they can deploy their limited resources appropriately for disease control.” 

Leishmanin skin tests have existed and been in use in past years but are no longer available. This research team developed the antigen following Good Laboratory Practice guidelines and tested it in hamsters, a model for human visceral leishmaniasis, to ensure the skin test triggers the expected immune response to both infection and vaccination. 

“This kind of data can be used for fast-track approval for Leishmania vaccines which are under development. We anticipate fulfilling the need of the entire global community,” Satoskar said. 

Co-lead authors of the Nature Communications paper were Sanjay Singh of Gennova Biopharmaceuticals, Shinjiro Hamano of Nagasaki University, Sreenivas Gannavaram and Hira Nakhasi of the Food and Drug Administration, Greg Matlashewski of McGill University, and Shaden Kamhawi and Jesus Valenzuela of the National Institute of Allergy and Infectious Diseases (NIAID).

The Nature Communications work was supported by the Global Health Innovative Technology Fund, the Canadian Institutes of Health Research, the FDA, the National Institutes of Health, NAIAD and the Fonds de recherche du Quebec-Sante. 

Nakhasi, Gannavaram and Nazli Azodi of the FDA also co-authored the iScience paper along with co-authors Greta Volpedo, Blake Cox, Yulian Mercado, Candice Askwith, and Matthew Bernier of Ohio State and Timur Oljuskin of the U.S. Department of Agriculture. 

The iScience study was supported by the Metabolomics Workbench/National Metabolomics Data Repository, Common Fund Data Ecosystem and Metabolomics Consortium Coordinating Center.

The research group is the first to determine that the two proteins, both among the dozens of proteins related to risk for the development of schizophrenia, bind to each other under normal conditions in multiple regions of the brain, and that their connection was found in mice to be key to maintaining normal movement, memory function and anxiety regulation.

When that connection doesn’t happen as it should, they found, behavior can be negatively affected – in mice, disruption to the proteins’ ability to interact increased hyperactivity, reduced risk avoidance and impaired memory. Though delusions and hallucinations are hallmark symptoms of schizophrenia, the condition also encompasses additional symptoms, including movement and memory problems. 

“These two proteins are seemingly unrelated, and our study has provided a link between them that wasn’t recognized before,” said lead author Chen Gu, associate professor of biological chemistry and pharmacology in The Ohio State University College of Medicine.  

“There are more than 100 genes that have been identified as risk genes for schizophrenia, but we still don’t know the real mechanisms behind those risks,” Gu said. “We’re hopeful that getting a better understanding of this mechanism could help in the long run to find a new treatment that could benefit patients with schizophrenia.” 

The study was published recently in the journal Molecular Psychiatry. 

Previous post-mortem studies have identified risk genes for schizophrenia based on signs of protein dysfunction detected in brain tissue. Among them are the proteins in this study: MAP6, which has a role in supporting a neuron’s cytoskeleton or, more specifically, microtubules, and Kv3.1, which helps control the maximal frequency of electrical signaling by neurons. 

Gu’s lab has studied Kv3.1 for many years, often working with genetically altered mice lacking its gene. As the team began exploring a connection between Kv3.1 and MAP6, first study author Di Ma, a graduate student in the lab, found that mice lacking the genes for both proteins experienced similar behavior changes. 

“That’s how we started looking at their relationship in more detail,” Gu said. 

In this study, Ma and her lab mates took a more nuanced look at how the proteins’ connection relates to behavior by disrupting their ability to bind to each other in specific brain regions in mice: the hippocampus, which governs learning and memory, and the nearby amygdala, where emotions are processed. 

The researchers found that disruption to the proteins’ connection in the amygdala led to a reduction in risk avoidance – shown in mice as a lack of fear of height. Blocking the proteins’ attachment in the hippocampus resulted in hyperactivity and lower recognition of a familiar object. Though some behavior changes in these experiments differed from the longer list of changes seen in mice completely lacking one or both genes, the finding provided important insights about where the proteins’ interactions, or lack thereof, have the strongest effect on behavior. 

“Different physiological functions we are engaged in daily are governed by different brain regions,” Gu said. “That’s an advance provided by our study – because previously we only knew global knockout mice had these behavioral alterations, we didn’t really know what brain region was responsible for them.” 

The next step in Gu’s lab will be exploring any links between social behavior in mice and these proteins’ functions in the prefrontal cortex, a brain region important to decision making and planning. 

In a series of biochemistry and cell biology experiments, the researchers also determined how the proteins bind and how that connection affects their positioning inside neurons. Results showed MAP6 stabilizes the Kv3.1 channel in a specific type of interneurons, where it helps these cells keep brain signals at an even keel. A drop in the expression of MAP6, on the other hand, dramatically decreased the level of Kv3.1 in those interneurons. 

The combined findings suggest that when the proteins don’t bind properly, there isn’t enough Kv3.1 available to maintain interneurons’ signal-control function, leading to an imbalance of neural inhibition and excitation in affected brain regions – and related negative behavioral symptoms. This type of interneurons, capable of generating nerve impulses in high frequencies, represent a key therapeutic target for schizophrenia. 

“Our study further provides a link between the MAP6 dysfunction and the interneuron signal dysfunction, and we now know that there are two proteins that interact and that one could alter the other,” Gu said. “That opens up potential new directions for treatment strategies.” 

This work was supported by grants from the National Institutes of Health.

Additional co-authors include Chao Sun, Rahul Manne, Tianqi Guo, Joshua Barry, Thomas Magliery and Houzhi Li of Ohio State and Christophe Bosc and Annie Andrieux of the Grenoble Institut Neurosciences in France.

Researchers found the Leishmania donovani parasites in blood-related stem cells in the bone marrow of chronically infected mice – precursor cells that can regenerate all types of cells in the blood-forming system. The finding may help explain why some people who develop visceral leishmaniasis, which is fatal if left untreated, often also have blood disorders such as anemia. 

Identifying these cells and other unexpected locations in which these parasites live improves scientists’ understanding of the disease and may lead to new treatment options, said senior study author Abhay Satoskar, professor of pathology in The Ohio State University College of Medicine. 

“Treating a patient with leishmania drugs never eliminates every parasite from the body – they persist for the rest of a patient’s life,” Satoskar said. “Perhaps these uncommon cells are the cells responsible for harboring these parasites in low numbers. Some drugs may not reach these cells properly or may not be effective with those parasites, and maybe the parasites in these kinds of cells are different compared to parasites in immune cells because they can adapt. It would be important to eliminate these hidden parasites if we want to stop the transmission of the disease. 

“It changes the way we think about this parasite: If uncommon cells are infected, what is the cells’ role? What are the parasites doing there? How did they evade the drug treatment? Are they different from parasites in other cells, or the same? There are lots of questions.” 

The research was published recently in the journal Cell Reports. 

Cutaneous leishmaniasis is a disfiguring skin disease caused by Leishmania major parasites that affects up to 1.2 million people annually in the tropics, while L. donovani parasites cause the less common visceral leishmaniasis that attacks internal organs, affecting an estimated 100,000 people per year. Scientists have suspected L. donovani may stray beyond their immune cell hosts because they linger in the body, but those suspicions have been difficult to confirm with most conventional technologies because the number of infected cells is low. 

Satoskar and colleagues used single-cell RNA sequencing in their search for parasites in spleen and bone marrow cells of chronically infected mice. The technique allowed the team to identify individual cell types based on the thousands of genes expressed by cells that function as a signature of each cell type. Simultaneously, the researchers identified which types of cells were – and were not – infected by L. donovani parasites based on the presence or lack of genes known to be expressed by these organisms. 

In the spleen, most of the infected cells detected were frontline immune cells – macrophages and monocytes – known as phagocytes whose job is to swallow up invading organisms. 

“Textbooks say Leishmania are parasites of immune cells, mainly phagocytes, that hijack those cells and live there. That is what we’ve learned for many years,” said Satoksar, also a professor of microbiology at Ohio State. “Though that was the dogma, it appears during chronic infection that they’re also infecting other cell types.” 

The study showed that these infectious organisms weren’t restricted to only phagocytic cells in either organ – in bone marrow, the blood-related (hematopoietic) stem cells were the main parasitized cells, a surprising finding that was verified through a separate single-cell analysis. The fact their outer surfaces feature some of the same receptors as typical immune cell targets hints at why and how they harbor the parasites, Satoskar said. 

Other types of cells in both organs whose gene expression signature suggested they contained L. donovani parasites included white blood cells that assist the immune system – but don’t engulf infectious organisms – and cells responsible for the production of platelets. 

“Finding Leishmania genes linked to other cell signatures gives us clues of which cells to look for next in follow-up protocols,” Satoskar said. 

This work has potential for rapid translation to human tissue testing in some tropical regions, where taking needle aspiration spleen and bone marrow samples is a routine procedure for people at risk for leishmaniasis. Such samples could be used to help determine if non-immune cells are occupied by parasites in humans as well. 

“These are organs where these parasites persist for many, many years after an infection has cleared and a person who becomes immune suppressed can develop disease again,” Satoskar said. “With our animal data and what we find in human samples, we hope to understand the pathways that are assisting parasites to survive and use that knowledge to develop new therapies targeting those pathways.” 

This work was funded by the Global Health Innovative Technology Fund and the National Institute of Allergy and Infectious Diseases. 

Co-authors include Konstantinos Karagiannis, Sreenivas Gannavaram, Thalia Pacheco-Fernandez, Parna Bhattacharya and Hira Nakhasi of the Food and Drug Administration and Chaitenya Verma of Ohio State.

The Ohio State University study in cell cultures found the omega-3 fatty acid DHA may help protect the brain from an unhealthy diet’s effects by curbing fat-induced inflammation at the cellular source. 

Separate experiments using brain tissue from aging mice showed a high-fat diet may lead specific brain cells to overdo cell-signaling management in a way that interferes with the creation of new memories. 

The same lab found in an earlier study in aging rats that a diet of highly processed ingredients led to a strong inflammatory response in the brain that was accompanied by behavioral signs of memory loss – and that DHA supplementation prevented those problems. 

“The cool thing about this paper is that for the first time, we’re really starting to tease these things apart by cell type,” said senior author Ruth Barrientos, an investigator in Ohio State’s Institute for Behavioral Medicine Research and associate professor of psychiatry and behavioral health and neuroscience in the College of Medicine. 

“Our lab and others have often looked at the whole tissue of the hippocampus to observe the brain’s memory-related response to a high-fat diet. But we’ve been curious about which cell types are more or less affected by these saturated fatty acids, and this is our first foray into determining that.”

The study was published recently in the journal Frontiers in Cellular Neuroscience. 

For this work, the researchers focused on microglia, cells in the brain that promote inflammation, and hippocampal neurons, which are important for learning and memory. They used immortalized cells – copies of cells taken from animal tissue that are modified to continuously divide and respond only to lab-based stimulation, meaning their behavior may not precisely match that of primary cells of the same type. 

Researchers exposed these model microglia and neurons to palmitic acid, the most abundant saturated fatty acid in high-fat foods like lard, shortening, meat and dairy products, to observe how it affected gene activation in the cells as well as functioning of mitochondria, structures inside cells that have a primary metabolic role of generating energy. 

Results showed the palmitic acid prompted gene expression changes linked to an increase in inflammation in both microglia and neurons, though microglia had a wider range of affected inflammatory genes. Pre-treatment of these cells with a dose of DHA, one of two omega-3 fatty acids in fish and other seafood and available in supplement form, had a strong protective effect against the increased inflammation in both cell types. 

“Previous work has shown that DHA is protective in the brain and that palmitic acid has been detrimental to brain cells, but this is the first time we’ve looked at how DHA can directly protect against the effects of palmitic acid in those microglia, and we see that there is a strong protective effect,” said Michael Butler, first author of the study and a research scientist in Barrientos’ lab. 

When it came to the mitochondria, however, DHA did not prevent the loss of function that followed exposure to palmitic acid. 

“The protective effects of DHA might, in this context, be restricted to effects on gene expression related to the pro-inflammatory response as opposed to the metabolic deficits that the saturated fat also induced,” Butler said. 

In another set of experiments, the researchers looked at how a diet high in saturated fat influenced signaling in the brains of aged mice by observing another microglial function called synaptic pruning. Microglia monitor signal transmission among neurons and nibble away excess synaptic spines, the connection sites between axons and dendrites, to keep communication at an ideal level. 

Microglia were exposed to mouse brain tissue containing both pre- and post-synaptic material from animals that had been fed either a high-fat diet or regular chow for three days. 

The microglia ate the synapses from aged mice fed a high-fat diet at a faster rate than they ate synapses from mice fed a regular diet – suggesting the high-fat diet is doing something to those synapses that gives the microglia a reason to eat them at a higher rate, Butler said. 

“When we talk about the pruning, or refinement, that needs to occur, it’s like Goldilocks: It needs to be optimal – not too much and not too little,” Barrientos said. “With these microglia eating away too much too soon, it outpaces the ability for these spines to regrow and create new connections, so memories don’t solidify or become stable.” 

From here, the researchers plan to expand on findings related to synaptic pruning and mitochondria function, and to see how palmitic acid and DHA effects play out in primary brain cells from young versus aged animals. 

This work was supported by grants from the National Institute on Aging and the National Institute of Dental and Craniofacial Research. Additional co-authors, all from Ohio State, were Sabrina Mackey-Alfonso, Nashali Massa and Kedryn Baskin.

The study, published in the journal PLOS Pathogens, found net viral loads among all community members declined after university vaccine requirements went into effect. Masking, isolation and antibodies from getting sick weren’t enough to decrease infection rates.  

“Before the vaccine was required, the virus was becoming more concentrated in saliva and easier to spread to vulnerable populations like young children and older adults,” said Richard Robinson, principal investigator and associate professor in the Department of Microbial Infection and Immunity. “Once the requirements were in place, we saw on average a 100% decrease in virus in saliva and up to 12,000% increase in antibody levels to block its spread.” 

Researchers looked at data generated as part of The Ohio State University’s COVID monitoring program, which occurred from August 2020 to June 2022. As part of this program, saliva specimens were collected on a weekly basis from asymptomatic students, staff and faculty. More than 850,000 diagnostic COVID tests were performed. 

“The COVID monitoring program focused on asymptomatic adults for several reasons,” Robinson said. “Asymptomatic infections are more common in young adults, asymptomatic individuals would still spread the virus and the isolation of symptomatic individuals alone wasn’t enough to flatten the curve of COVID infections.”  

Six Ohio State campuses in Columbus, Newark, Mansfield, Lima, Marion and Wooster participated in the monitoring program. The data found COVID positivity in asymptomatic adults occurred in waves which mirrored the infection rates in the regions surrounding the university campuses and were driven by newly emerging variants such as delta and omicron. 

“At the time, there was growing concern that college students were creating new waves and peaks in infection when they would return to communities after distance learning and breaks in their education, but that wasn’t the case,” Robinson said. “The rates of infection were already increasing when classes resumed, even in rural areas.” 

Additionally, researchers explored the causes of breakthrough infections in vaccinated people. They compared the antibody responses of uninfected vaccinated people with those of infected vaccinated people. The study found breakthrough infections in vaccinated people were not due to an absence of antibodies but depend on antibody levels at the time of exposure, the neutralizing ability of the antibodies and the amount of virus to which the person is exposed. 

Future research will focus on the conditions that make people more resistant to COVID infection. 

Other researchers involved in this study were Marlena R. Merling, Amanda Williams, Najmus S. Mahfooz, Marisa Ruane-Foster, Jacob Smith, Jeff Jahnes, Leona W. Ayers, Jose A. Bazan, Alison Norris, Abigail Norris Turner, Michael Oglesbee, Seth A. Faith and Mikkel B. Quam. 

But in new work, the research team has determined how these vaccine candidates, created using mutated disease-causing parasites, prompt molecular-level changes in host cells that have specific roles in helping generate the immune response. 

Despite using the same CRISPR gene-editing technique to make the vaccines, the two species of Leishmania parasites on which the vaccines are based produced very different effects in the immunized host: One enables the immune response to unfold by inhibiting a host metabolite that suppresses immune activity, and the other drives up activation of a chemical pathway in a way that primes immune cells to fight pathogens. 

“I think it’s an important finding in the sense that we show that in the big picture, yes, these vaccines are protective, but at the molecular level the mechanisms can be totally distinct,” said Abhay Satoskar, professor of pathology in The Ohio State University College of Medicine and co-leader of the research team.

“This is not only conceptually important, but if you can find how these things are modulating the immune response in the right direction, and identify the pathways, then perhaps those pathways could be used for developing new interventions,” said Satoskar, a senior author of two new papers describing the findings. 

The primary vaccine was made by editing the genome of Leishmania major, which causes cutaneous leishmaniasis in tropical and subtropical regions of the Eastern Hemisphere, and a backup vaccine was made using Leishmania mexicana, a more virulent species found in South, Central and North America. 

The study findings on the metabolic effects of the L. major and L. mexicana vaccines were published Aug. 29, 2023, in the journal iScience. 

Leishmaniasis is prevalent in 90 countries affecting about 12 million people globally at any given time, but no licensed human vaccine yet exists and the only drug treatment for the skin lesions requires weeks of daily injections with unpleasant side effects. The more lethal visceral leishmaniasis affects organs and is fatal if left untreated. 

In developing these live attenuated vaccines, Satoskar and colleagues applied new technology to the century-old Middle Eastern practice of leishmanization – introducing the live parasite to the skin to create a small infection that, once healed, leads to life-long immunity against further disease. 

The researchers previously reported using CRISPR to delete centrin, the gene for a protein that supports the parasite’s physical structure, from the genomes of both L. major and L. mexicana. Experiments showed vaccinated mice remained clear of skin lesions and the number of parasites at the infection site were held at bay. 

Digging deeper into the vaccines’ effects in these new studies, researchers inoculated mouse ears with a normal parasite, a mutated parasite vaccine or a placebo, mimicking the bite of a sand fly – in humans and animals, leishmania is transmitted through the bite of infected sand flies. 

The team used mass spectrometry at the inoculation site to identify the most prominent metabolites – the amino acids, vitamins and other small molecules produced as a result of metabolism, the many chemical reactions that keep the body functioning. 

Results showed the L. major vaccine promoted a pro-inflammatory metabolic response in mice by using the amino acid tryptophan to block signals from a molecule that helps suppress immunity. The L. mexicana vaccine, on the other hand, enriched a series of metabolic reactions that activated the necessary pro-inflammatory work of front-line immune cells.   

“We took an unbiased approach to analyze the metabolites detectable at the inoculation site. There is growing interest in understanding the role immune cell metabolism plays in modulating immune function,” said Satoskar, also a professor of microbiology at Ohio State. “We also learned that by removing the centrin gene, we got rid of the parasites’ ability to manipulate metabolic pathways in a way that would impair development of protective immunity and, in fact, promoted vaccine-induced immunity. That’s important to know for a live attenuated vaccine – there is a unique case for each parasite species.”

Though this information is not required for regulatory approval of these vaccines, the data could prove useful to supplementing vaccination. 

“There are only four existing drugs for leishmaniasis,” Satoskar said. “We need to know the mechanism of vaccines so the knowledge can be used to develop newer vaccines or newer drugs that target these pathways. What you learn from immunomodulation can be used for developing other therapeutic agents.” 

This research was funded by the Global Health Innovative Technology Fund and the Center for Biologics Evaluation and Research within the Food and Drug Administration (FDA). The FDA is a co-owner of two U.S. patents associated with the mutated Leishmania species. 

Co-authors of both papers include Sreenivas Gannavaram and Hira Nakhasi, who co-led the L. major study, and Nazli Azodi and Hannah Markle, all of the FDA; Greta Volpedo of Ohio State; Timur Oljuskin of the USDA Animal Parasitic Diseases Laboratory; Shinjiro Hamano of Nagasaki University; and Greg Matlashewski of McGill University. Thalia Pacheco-Fernandez of Ohio State co-authored the L. mexicana paper and Parna Bhattacharya of FDA co-authored the L. major paper.