LAUGHING GAS

Key mechanisms of airway relaxation in asthma revealed in new study

Novel role for nitric oxide in treatment of asthma and other obstructive airway diseases detailed by team at University Hospitals and Case Western Reserve University

Peer-Reviewed Publication

UNIVERSITY HOSPITALS CLEVELAND MEDICAL CENTER

CLEVELAND--Many therapeutics for asthma and other obstructive lung diseases target the β2-adrenergic receptor (β2AR), a G protein-coupled receptor (GPCR) that rapidly supports airway relaxation when stimulated. Yet, overuse of these agents is associated with adverse health outcomes, including death, which has limited their utility as frontline therapies.  

Now, a mouse model study published in today’s issue of Molecular Cell, from investigators at University Hospitals (UH) and Case Western Reserve University, identifies a novel strategy to isolate the beneficial effects of β2AR stimulation. This suggests a new therapeutic approach to airway diseases as well as numerous other conditions involving the aberrant function of GPCRs.

“Not only is the β2-adrenergic receptor the mainstay for keeping airways open, it's often studied as a prototype for how GPCRs work, which constitute the targets of 50% of all drugs,” explained Jonathan S. Stamler, MD, President, Harrington Discovery Institute at UH, Robert S. and Sylvia K. Reitman Family Foundation Distinguished Professor of Cardiovascular Innovation, and Professor of Medicine and Biochemistry at UH and Case Western Reserve School of Medicine.

“Our discovery highlights an obvious benefit to asthma and it's exemplary of what to expect in GPCR regulation. It opens the area for broad-based research in maximizing the therapeutic benefits of GPCRs.”

All GPCRs, including the β2AR, operate via a feedback loop in which the same molecules that the receptors help generate can circle back and turn the receptors “off” or inactivate them. In the new study, the research team reveal nitric oxide to be a key molecule in the β2AR feedback loop, showing that the production of nitric oxide after β2AR stimulation mediates airway relaxation, but overproduction of the molecule also inactivates β2AR, leading to bronchoconstriction.

“If you prevent that feedback, you’re left with a very powerful airway relaxant that before now had not been thought to be that important in airway relaxation,” said Dr. Stamler.

The study also demonstrates that mice harboring a specific mutation in the β2AR gene that prevents nitric oxide from binding to and inactivating the receptor are resistant to bronchoconstriction, inflammation, and asthma.

Other GPCR receptors shown in the study to be regulated by nitric oxide-based protein modification include the β1 adrenergic receptor and the angiotensin II receptor 1.

“Nitric oxide should be thought of as a key new player in how this class of receptors works,” Dr. Stamler added. “It’s responsible for both the beneficial effects of the receptors and for turning them off. And if you can understand how they're being turned off--how that nitric oxide is popping on to the receptor--and you can block that, you're going to be left with a new pathway for opening airways. The next step in our research will focus on leveraging this new pathway therapeutically.”

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Fonseca, F. V., Stamler, J.S., et al. S-nitrosylation is required for β2AR desensitization and experimental asthma. Molecular Cell (2022). DOI: 10.1016/j.molcel.2022.06.033.

About University Hospitals / Cleveland, Ohio
Founded in 1866, University Hospitals serves the needs of patients through an integrated network of more than 20 hospitals (including five joint ventures), more than 50 health centers and outpatient facilities, and over 200 physician offices in 16 counties throughout northern Ohio. The system’s flagship quaternary care, academic medical center, University Hospitals Cleveland Medical Center, is affiliated with Case Western Reserve University School of Medicine, Northeast Ohio Medical University, Oxford University and the Technion Israel Institute of Technology. The main campus also includes the UH Rainbow Babies & Children's Hospital, ranked among the top children’s hospitals in the nation; UH MacDonald Women's Hospital, Ohio's only hospital for women; and UH Seidman Cancer Center, part of the NCI-designated Case Comprehensive Cancer Center. UH is home to some of the most prestigious clinical and research programs in the nation, with more than 3,000 active clinical trials and research studies underway. UH Cleveland Medical Center is perennially among the highest performers in national ranking surveys, including “America’s Best Hospitals” from U.S. News & World Report. UH is also home to 19 Clinical Care Delivery and Research Institutes. UH is one of the largest employers in Northeast Ohio with more than 30,000 employees. Follow UH on LinkedIn, Facebook and Twitter. For more information, visit UHhospitals.org.

About Case Western Reserve University
Case Western Reserve University is one of the country's leading private research institutions. Located in Cleveland, we offer a unique combination of forward-thinking educational opportunities in an inspiring cultural setting. Our leading-edge faculty engage in teaching and research in a collaborative, hands-on environment. Our nationally recognized programs include arts and sciences, dental medicine, engineering, law, management, medicine, nursing and social work. About 5,800 undergraduate and 6,300 graduate students comprise our student body. Visit case.edu to see how Case Western Reserve thinks beyond the possible.

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JOURNAL

Molecular Cell

DOI

10.1016/j.molcel.2022.06.033 

Looking inside a neutron star – new model will improve insights gleaned from gravitational waves

Peer-Reviewed Publication

UNIVERSITY OF BIRMINGHAM

The unique oscillations in binary neutron stars right before they merge could have big implications for the insights scientists can glean from gravitational wave detection.

Researchers at the University of Birmingham have demonstrated the way in which these vibrations, caused by the interactions between the two stars’ tidal fields as they get close together, affect gravitational-wave observations. The study is published in Physical Review Letters.

Taking these movements into account could make a huge difference to our understanding of the data taken by the Advanced LIGO and Virgo instruments, set up to detect gravitational waves – ripples in time and space – produced by the merging of black holes and neutron stars.

The researchers aim to have a new model ready for Advanced LIGO’s next observing run and even more advanced models for the next generation of Advanced LIGO instruments, called A+, which are due to begin their first observing run in 2025.

Since the first gravitational waves were detected by the LIGO Scientific Collaboration and Virgo Collaboration in 2016, scientists have been focused on advancing their understanding of the massive collisions that produce these signals, including the physics of a neutron star at supra nuclear densities.

Dr Geraint Pratten, of the Institute for Gravitational Wave Astronomy at University of Birmingham, is lead-author on the paper. He said: “Scientists are now able to get lots of crucial information about neutron stars from the latest gravitational wave detections. Details such as the relationship between the star’s mass and its radius, for example, provide crucial insight into fundamental physics behind neutron stars. If we neglect these additional effects, our understanding of the structure of the neutron star as a whole can become deeply biased.”

Dr Patricia Schmidt, co-author on the paper and Associate Professor at the Institute for Gravitational Wave Astronomy, added: “These refinements are really important. Within single neutron stars we can start to understand what’s happening deep inside the star’s core, where matter exists at temperatures and densities we cannot produce in ground-based experiments. At this point we might start to see atoms interacting with each other in ways we have not yet seen – potentially requiring new laws of physics.”

The refinements devised by the team represent the latest contribution from the University of Birmingham to the Advanced LIGO programme. Researchers in the University’s Institute for Gravitational Wave Astronomy have been deeply involved in design and development of the detectors since the programme’s earliest stages. Looking ahead, PhD student Natalie Williams is already progressing work on calculations to further refine and calibrate the new models.

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JOURNAL

Physical Review Letters

DOI

10.1103/PhysRevLett.129.081102. 

METHOD OF RESEARCH

Computational simulation/modeling

SUBJECT OF RESEARCH

Not applicable

ARTICLE TITLE

Impact of dynamical tides on the reconstruction of the neutron star equation of state

Dentists should give antibiotics to high-risk patients to help prevent life-threatening heart infection

Current NICE guidelines, advising against routine use of antibiotics before invasive dental procedures for those at high IE-risk, should be reconsidered

Peer-Reviewed Publication

UNIVERSITY OF SHEFFIELD

●      University of Sheffield study finds that antibiotics reduce the risk of a life-threatening heart infection following invasive dental treatment - for high-risk patients

●      Infective endocarditis (IE) is an infection of the heart valves, that causes heart failure, strokes and other serious disabilities that result in a 30 per cent, first year death rate

●      A causal link between dental treatment and IE has long been suspected with 30 to 40 per cent of cases being caused by bacteria from the mouth, however this link has been questioned due to a lack of robust research. Until now there has also never been a study to demonstrate that antibiotics are effective in reducing the risk of IE

●      Guideline committees around the world, except in the UK, recommend antibiotics are given to people at high-risk of IE before undergoing invasive dental treatment to reduce the risk of developing IE

●      University of Sheffield research is the biggest ever study to examine the link between IE and dental treatment and for the first time confirms that giving antibiotics to those at high IE-risk before invasive dental procedures, significantly reduces the risk of them developing IE

People who are at high risk of developing a life-threatening heart infection should be given antibiotics before undergoing invasive dental procedures, according to new research from the University of Sheffield.

These results suggest that current NICE guidelines, advising against routine use of antibiotics before invasive dental procedures for those at high IE-risk, should be reconsidered.

The study, led by Professor Martin Thornhill from the University’s School of Clinical Dentistry, suggests that current UK guidelines against the use of antibiotics, issued by the National Institute for Health and Care Excellence (NICE), could be putting high-risk patients at unnecessary extra risk when undergoing invasive dental procedures.

At the same time, the results validate guidance in the USA, Europe and elsewhere that recommend that those at high-risk are given antibiotics before invasive dental procedures.

Professor Martin Thornhill, Professor of Translational Research in Dentistry at the University of Sheffield and lead author of the study, said: “Infective endocarditis is a rare but devastating heart infection in which around 30 per cent of people die within the first year of developing it. We know that 30-45 per cent of IE cases are caused by bacteria that derive from the mouth, but what has been unclear and disputed until now is whether there is a strong link between invasive dental procedures, such as tooth extractions, and IE in patients who are at high risk of developing the infection.

“Results from our study validate for the first time the guidance of the major guideline committees around the world, such as The American Heart Association and the European Society for Cardiology, which recommend that those at high IE risk should receive AP before undergoing invasive dental procedures. In contrast, our data suggests that current UK NICE guidance against the routine use of AP, could be putting high risk patients at unnecessary extra risk of developing IE, and should be reviewed in light of this new evidence.”

Published in the Journal of the American College of Cardiology, the research is the biggest ever study to examine the association between infective endocarditis (IE) - a life-threatening infection of the heart often caused by bacteria that derive from the mouth - and invasive dental procedures.

The study was performed in the USA where patients at high IE-risk (those with artificial or repaired heart valves, patients with certain congenital heart conditions or a previous history of IE) are recommended to receive antibiotics before invasive dental procedures - called antibiotic prophylaxis (AP) - to reduce their risk of developing IE.

The research is the first to demonstrate that AP reduces the risk of IE following invasive dental treatment for those at high-risk of developing the infection.

Since the 1950’s, guideline committees around the world have recommended that people at increased risk of IE should be given AP before undergoing invasive dental procedures. However, there has never been any robust research directly linking dental procedures with the development of IE or any study to demonstrate that AP is effective in reducing the risk of developing IE.

Due to this lack of evidence, concerns about the unnecessary use of antibiotics and the risk that AP could promote the development of antibiotic resistant bacteria, guideline committees have since reduced the number of people that AP is recommended for - recommending that only those at high risk for IE should receive AP before invasive dental procedures. In the UK, however, NICE went even further stating that “Antibiotic prophylaxis against infective endocarditis is not recommended routinely for people undergoing dental procedures.”

The study from Sheffield analysed the medical history of nearly eight million people in the USA over a 16 month period, including 36,773 individuals at high-risk of IE. The researchers looked at whether the patients had invasive dental treatment, if they then went on to develop IE within 30 days and whether they had been given AP before the procedure.

Researchers found that 3,774 of those studied developed IE within 30 days of dental treatment. They also found that the risk of developing IE was 160 times greater in those at high IE-risk than in the general low-risk population.

The association between invasive dental procedures an IE was particularly strong for dental extractions and oral surgical procedures. For patients at high IE-risk, the risk of developing IE was one in every 250 extractions and one in every 100 oral surgery procedures without AP cover. The risk in the general low risk population was extremely small.

The study found however, that only 32.6 per cent of high IE-risk patients received AP before invasive dental procedures. This allowed the researchers to study the effectiveness of AP. They found that the risk of developing IE was nearly 10 times greater when dental extractions were performed in high-risk patients without AP cover than when performed with AP cover. Similarly, the risk of IE was 12.5 times greater when oral surgery procedures were performed in high-risk patients without AP cover than when performed with AP cover.

For the USA, even though the study’s results validate The American Heart Association guidance, the research found that compliance with this advice was low –only 32.6 per cent of those at high risk of IE were given AP before undergoing invasive dental procedures.

Professor Thornhill added: “It is reassuring for patients, cardiologists and dentists that our data validates the American, European and other guidelines from around the world that recommend that patients at high risk for IE should receive AP before invasive dental procedures. It is concerning, however, that compliance with this guidance by dentists in the USA was so low. Clearly, more needs to be done to improve compliance with the American Heart Association guidelines.”

The study, Antibiotic Prophylaxis Against Infective Endocarditis Before Invasive Dental Procedures, is published in the Journal of the American College of Cardiology. It was performed in the United States using data from IBM Health and was funded by Delta Dental of Michigan and Renaissance Health Service Corporation in the US. To access the paper, visit: https://doi.org/10.1016/j.jacc.2022.06.030 

Ends

 Media contact: Amy Huxtable, Media and PR Officer at the University of Sheffield, 07568116781 or a.l.huxtable@sheffield.ac.uk

 Dentistry at the University of Sheffield

The University of Sheffield

With almost 29,000 of the brightest students from over 140 countries, learning alongside over 1,200 of the best academics from across the globe, the University of Sheffield is one of the world’s leading universities.

A member of the UK’s prestigious Russell Group of leading research-led institutions, Sheffield offers world-class teaching and research excellence across a wide range of disciplines.

Unified by the power of discovery and understanding, staff and students at the university are committed to finding new ways to transform the world we live in.

Sheffield has six Nobel Prize winners among former staff and students and its alumni go on to hold positions of great responsibility and influence all over the world, making significant contributions in their chosen fields.

Global research partners and clients include Boeing, Rolls-Royce, Unilever, AstraZeneca, GlaxoSmithKline, Siemens and Airbus, as well as many UK and overseas government agencies and charitable foundations.

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JOURNAL

Journal of the American College of Cardiology

DOI

10.1016/j.jacc.2022.06.030 

METHOD OF RESEARCH

Observational study

SUBJECT OF RESEARCH

People

ARTICLE TITLE

Antibiotic Prophylaxis Against Infective Endocarditis Before Invasive Dental Procedures

COVID OUT clinical trial suggests metformin effective at reducing odds of serious outcomes for COVID-19 patients seeking early treatment

Trial compared effect of ivermectin, fluvoxamine, and metformin in randomized double-blinded placebo- controlled trial

Peer-Reviewed Publication

UNIVERSITY OF MINNESOTA MEDICAL SCHOOL

 

VIDEO: DR. CAROLYN BRAMANTE FROM THE UNIVERSITY OF MINNESOTA ANSWERS QUESTIONS ABOUT COVID OUT. view more 

CREDIT: UNIVERSITY OF MINNESOTA MEDICAL SCHOOL

Published in the New England Journal of Medicine, researchers — led by the University of Minnesota Medical School and School of Public Health — have found that metformin, a commonly prescribed diabetes medication, lowers the odds of emergency department visits, hospitalizations, or death due to COVID-19 by over 40 percent; and over 50 percent if prescribed early in onset of symptoms. The study also found no positive effect from treatment with either ivermectin or low-dose fluvoxamine.

“We are pleased to contribute to the body of knowledge around COVID-19 therapies in general, with treatments that are widely available,” said Carolyn Bramante, MD, principal investigator of the study and an assistant professor of internal medicine and pediatrics at the U of M Medical School. “Our trial suggests that metformin may reduce the likelihood of needing to go to the emergency room or be hospitalized for COVID-19.”

Bramante noted that this was a secondary outcome of the trial; the primary outcome included whether someone had low oxygen on a home oxygen monitor, and none of the medications in the trial prevented the primary outcome.

The COVID-OUT trial was the nation’s first to study whether metformin, a medication for type 2 diabetes; low-dose fluvoxamine, an antidepressant; and ivermectin, an antiparasitic, or their combinations could serve as possible treatments to prevent ER visits or hospitalization, as well as Long-COVID.

The study design was simple — patients were randomly assigned to receive one of the three drugs individually, placebo, or a combination of metformin and fluvoxamine or metformin and ivermectin. Although the study was placebo-controlled with exact-matching placebo pills, Dr. Bramante says 83% of volunteers received medications supported by existing data because of the six-arm design. Each participant received 2 types of pills to keep their treatment assignment masked, for 3 to 14 days of treatment. Each volunteer tracked their symptoms, and after 14 days, they completed a survey.

The 1323 participants in the trial were limited to adults with a body mass index greater than or equal to 25 kg/m2, which qualifies as overweight – for instance, someone who was at least five feet and six inches tall and weighed more than 155 pounds. To qualify for the study, volunteers enrolled within three days after receiving a positive COVID-19 test. It was among the first randomized clinical trials for COVID-19 to include pregnant women.

The study included those who were vaccinated and those who were not. This is the first published trial where the majority of participants were vaccinated. 

“Although we know COVID-19 vaccines are highly effective, we know that some new strains of the virus may evade immunity and vaccines may not be available worldwide. So we felt we should study safe, available and inexpensive outpatient treatment options as soon as possible,” said Bramante. “Understanding whether outpatient treatments could ensure more people survive the illness if they contract it and have fewer long-term symptoms is an important piece of the pandemic response.”

The clinical trial launched in January 2021 after U of M Medical School researchers identified, through computer modeling and observational studies, that outpatient metformin use appeared to decrease the likelihood of mortality from, or being hospitalized for COVID-19. Their research, in partnership with UnitedHealth Group, was published in the Journal of Medical Virology and in The Lancet Healthy Longevity. Test-tube studies also found that metformin inhibited the Covid-19 virus in lab settings. These findings, along with additional prospective studies supporting the use of higher-dose fluvoxamine and ivermectin, provided the evidence to include all three medications as well as combination arms.

“Observational studies and in vitro experiments cannot be conclusive but do contribute to bodies of evidence,” said Bramante, who is also an internist and pediatrician with M Health Fairview. “To complete this study, we enrolled volunteers nationwide through six institutions in the U.S., including in Minneapolis.”

Participating clinical trial sites included M Health Fairview and Hennepin Healthcare in Minneapolis, Northwestern University in Chicago, Olive View – UCLA Education & Research Institute in Los Angeles, Optum in Colorado and Indiana, and University of Colorado Denver. Co-investigators on the study include Jared Huling, PhD; Thomas Murray, PhD; Hrishikesh Belani, MD; Michelle Biros, MD; David Boulware, MD; David Leibovitz, MD; Jacinda Nicklas, MD; David Odde, PhD; Matt Pullen, MD; Mike Puskarich, MD; John Buse, MD, PhD; Jennifer Thompson, MD; and Christopher Tignanelli, MD.

The trial received monetary support from the Parsemus Foundation, Rainwater Charitable Foundation, Fast Grants, and UnitedHealth Group.

In addition, this research was supported by the National Institutes of Health’s National Center for Advancing Translational Sciences, grants UL1TR002494 and KL2TR002492, and the National Institute of Digestive, Diabetes, and Kidney diseases K23 DK124654. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health’s National Center for Advancing Translational Sciences.

 

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JOURNAL

New England Journal of Medicine

DOI

10.1056/NEJMoa2201662 

METHOD OF RESEARCH

Randomized controlled/clinical trial

SUBJECT OF RESEARCH

People

ARTICLE TITLE

Randomized trial of metformin, ivermectin, and fluvoxamine for Covid-19

Metformin drastically reduces COVID hospitalization, study shows

Widely available drug reduced emergency room visits, hospitalization, and death by COVID-19 by more than half if started within 4 days of symptoms

Peer-Reviewed Publication

PARSEMUS FOUNDATION

The widely available diabetes drug metformin reduced serious outcomes by more than half if started within 4 days of COVID symptoms in a large, randomized, double blind controlled trial, the University of Minnesota announced today. The results were published Aug. 18 in the New England Journal of Medicine.

The study was primarily funded by three philanthropic foundations: Parsemus Foundation, Rainwater Charitable Foundation, and Fast Grants.

“This was really intriguing to us early on when we learned that people who take metformin were catching COVID less and being hospitalized less,” said Elaine Lissner, founder and trustee of small California nonprofit Parsemus Foundation, which works on low-cost solutions neglected by the pharmaceutical industry. “But you don’t know whether it’s just coincidence until you start at the beginning, with a rigorous randomized trial.”

“When we learned that researchers at the University of Minnesota were already trying to raise funds to test it, we jumped at the opportunity.”

A little-known past

Metformin, also known as Glucophage, has an added benefit: a little-known past in the 1950s as an anti-viral called “Fluamine.” In more recent research, it also seems to affect mTOR inflammation pathways. Since COVID involves viral inflammation, lead researcher Dr. Carolyn Bramante and team thought the combination of anti-inflammatory plus antiviral action was intriguing enough to put to the test.

The study almost didn’t happen, though. At the time, most government and pharmaceutical funds were going to vaccine research, or the search for profitable new drugs.

“We took a chance and gave what we could, enough to get the first few study sites started and generate preliminary data to strengthen the case for other funders,” said Linda Brent, executive director of the Parsemus Foundation. “But the study never would have made it if it weren’t for the dedicated larger funders who believed in it right away and came on board with critical support.”

Three medications studied

For added rigor, the large University of Minnesota study compared three medications that were considered promising at the time—fluvoxamine, an antidepressant that had shown strong results in previous studies; ivermectin, the object of much interest and passion; and metformin — and provided valuable answers, even about the drugs that were not the clear winner.

“You can argue about details, but in the end, this was kind of ‘three strikes and you’re out’ for ivermectin,” said Lissner. “But ivermectin deserved this kind of careful study, head-to-head with other medications, to finally get solid answers. You have to give everything a fair test.”

“And I think a lot of us were pretty disappointed that the fluvoxamine results were not conclusive. We did learn that the dose the study used, which was a third to half as much as used in previous studies in an attempt to avoid side effects, was not enough to make a significant difference. I don’t think the door is closed on fluvoxamine at higher doses, though.”

“But in the end,” added Lissner, “you have to accept what the science tells you, no matter which you were rooting for. And it’s probably better this way. Metformin is an incredibly common drug, taken by millions of people all over the world. There’s no stigma like with an antidepressant, and it’s a lot easier to take than the other two.”

In 2019, metformin was the fourth-most commonly prescribed medication in the United States, with more than 85 million prescriptions written for over 17 million patients. FDA guidelines indicate that it should not be taken by people with advanced kidney disease, and should be taken with food, or in extended-release formulation, to avoid stomach upset. Side effects are minor and include loose stools. Metformin is also considered safe for use in pregnant women.

The study included 1323 participants most at risk of serious outcomes—adults over 30 and with BMI over 25 kg/m2—to get lifesaving results more quickly. Future studies could include lower-risk participants. However, studies of metformin for other indications, such as the national TAME trial by the American Federation for Aging Research, remain unfunded.

“I think there are lessons for all of us in making sure our global clinical trial systems are more robust and ready to jump in on globally critical studies like this in the future,” emphasized Lissner. “It shouldn’t be little foundations like us funding studies of global importance. In the meantime, I hope all the hard work and late nights pay off, and clinicians around the world take notice: metformin, an exceedingly inexpensive drug they prescribe every day, if given to high-risk people with COVID right away, can reduce serious outcomes by more than half.”

Details about the study results were published online August 18 in the New England Journal of Medicine and can be found in the University of Minnesota’s COVID-OUT study press release.

About the Parsemus Foundation (San Francisco): The Parsemus Foundation works to create meaningful improvements in human and animal health and welfare by advancing innovative and neglected medical research. The foundation’s focus is on supporting proof-of-concept studies and then pursuing press coverage of the results, so that the advances change treatment practice rather than disappearing into the scientific literature. As a small, agile nonprofit organization, the Parsemus Foundation was able to pivot from its regularly funded programs to a new focus on COVID-19 treatment during the pandemic. More information on the Parsemus Foundation and the work presented here can be found at: https://www.parsemus.org/humanhealth/covid-19/

 

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JOURNAL

New England Journal of Medicine

METHOD OF RESEARCH

Randomized controlled/clinical trial

SUBJECT OF RESEARCH

People

ARTICLE TITLE

Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19

Durable coating kills COVID virus, other germs in minutes

Polyurethane locks in the antimicrobial power of tea tree and cinnamon oils. The new technology could start making public spaces safer within a year

Peer-Reviewed Publication

UNIVERSITY OF MICHIGAN

Images

There may soon be a new weapon in our centuries-old battle against germs: the first durable coating that can quickly kill bacteria and viruses and keep on killing them for months at a time. 

Developed by a team of University of Michigan engineers and immunologists, it proved deadly to SARS-CoV-2 (the virus that causes COVID-19), E. coli, MRSA and a variety of other pathogens. It killed 99.9% of microbes even after months of repeated cleaning, abrasion and other punishment on real-world surfaces like keyboards, cell phone screens and chicken-slathered cutting boards.

The coating could be a game changer in traditionally germ-laden public spaces like airports and hospitals, according to Anish Tuteja, a professor of material science and engineering at U-M and co-corresponding author of the paper published in Matter.

"We’ve never had a good way to keep constantly-touched surfaces like airport touch screens clean," he said. "Disinfectant cleaners can kill germs in only a minute or two but they dissipate quickly and leave surfaces vulnerable to reinfection. We do have long-lasting antibacterial surfaces based on metals like copper and zinc, but they take hours to kill bacteria. This coating offers the best of both worlds."

The coating, which is clear and can be brushed or sprayed on, gets its durability and germ-killing power by combining tried-and-true ingredients in a new way. It uses antimicrobial molecules derived from tea tree oil and cinnamon oil, both used for centuries as safe and effective germ killers that work in under two minutes. The coating’s durability comes from polyurethane, a tough, varnish-like sealer that’s commonly used on surfaces like floors and furniture.

"The antimicrobials we tested are classified as 'generally regarded as safe' by the FDA, and some have even been approved as food additives," Tuteja said. "Polyurethane is a safe and very commonly used coating. But we did do toxicity testing just to be sure, and we found that our particular combination of ingredients is even safer than many of today’s antimicrobials."

The results of the study’s durability tests suggest that the coating could keep killing germs for six months or longer before its oil begins to evaporate and reduce its disinfectant power. But even then, Tuteja says it can be recharged by wiping it with fresh oil; the new oil is reabsorbed by the surface, starting the cycle again.

Tuteja estimates that the technology could be commercially available within a year; it has been licensed to Hygratek, a spinoff company that Tuteja founded with assistance from U-M Innovation Partnerships.

The key challenge was to combine the oil and polyurethane in a way that let the oil molecules do their germ-killing work while preventing them from evaporating quickly.
The research team—including associate professor of materials science and engineering and biomedical engineering Geeta Mehta, a co-corresponding author; and materials science and engineering PhD students Abhishek Dhyani and Taylor Repetto, co-first authors—found a possible solution in cross-linking, a well-known process that uses heating to link materials together at the molecular level. The smaller oil molecules readily combined with the cross-linking polymer molecules, forming a stable matrix.

But to kill germs, the oil molecules need to penetrate their cell walls, which they can’t do if they’re tightly tethered into the matrix. Eventually, they found a middle ground by partially cross-linking the materials—enough to keep some of the oil molecules free to do their work, but keeping others bound tightly to the polyurethane.

"There was some trial and error, but we eventually found that cross-linking only some of the oil did what we needed," Tuteja said. "The free oil tends to stay with the oil that’s cross-linked into the matrix, helping the coating last longer."

Once the basic recipe was set, the researchers set about finding a combination of active ingredients that would kill a wide variety of the germs that trouble humans most. To identify a representative sample of microbes, they worked with co-corresponding authors Christiane E. Wobus, an associate professor of microbiology and immunology, and J. Scott VanEpps, an associate professor of emergency medicine, both at the U-M Medical School. Ultimately, they found a precise balance of antimicrobial molecules that were effective, safe and inexpensive.

Tuteja emphasizes that they’re not locked into one specific formula; the team’s understanding of individual ingredients’ properties enables them to tweak the formula for specific applications or rebalance the antimicrobial agents to kill specific germs.

"It’s never our goal just to develop a one-off coating, but instead to develop a library of underlying material properties to draw from," Tuteja said. "If we can understand those properties, then we can develop coatings to meet the needs of specific applications."

The study was funded by the Office of Naval Research, with additional support from the University of Michigan, Marie Skłodowska-Curie Actions, the National Institutes of Health and the Department of Defense, with raw materials provided by Covestro.

The University of Michigan has applied for a patent based on this technology. Tuteja and the University of Michigan have a financial interest in Hygratek.

Study: Surfaces with instant and persistent antimicrobial efficacy against bacteria
and SARS-CoV-2 (DOI: 10.1016/j.matt.2022.08.018)

JOURNAL

Matter

DOI

10.1016/j.matt.2022.08.018 

Hospital superbugs use thin stretchy fibers to attach to surfaces and cause infections

Peer-Reviewed Publication

UNIVERSITY OF TURKU

The antibiotic-resistant Acinetobacter baumannii bacterium is one of the most globally harmful bacteria that causes hospital-acquired infections. Researchers at the University of Turku have discovered that the bacterium spreads by attaching to surfaces using ultrathin stretchy fibers. The researchers also revealed how these fibers are formed on the bacterial surface and suggested new approaches to prevent bacterial infections. The new findings have been published in Nature, one of the leading scientific journals in the World.

Infections related to hospitals and medical devices form major healthcare problems worldwide. These infections are associated with the ability of pathogens to colonize both biotic and abiotic surfaces.

“The pan-antibiotic resistant Acinetobacter baumannii is one of the most troublesome pathogens for healthcare institutions globally and currently tops the World Health Organization’s priority pathogens list for the development of new antibiotics,” says the Head of the Joint Biotechnology Laboratory Anton Zavialov from the MediCity Research Center at the Faculty of Medicine, University of Turku, Finland.

Zavialov’s research group, consisting of the Doctoral Researcher Henri Malmi and Senior Researchers Natalia Pakharukova, Minna Tuittila, and Sari Paavilainen discovered unique surface structures that enables Acinetobacter baumannii and related pathogenic bacteria to colonize medical devices and infect patients.

“This discovery may help fighting many bacterial infections, because the same surface attachment mechanism is used by many important bacterial pathogens, including Pseudomonas aeruginosa, the second top priority pathogen on the WHO list,” says Zavialov.

Bacterium attaches to surfaces using ultrathin stretchy fibers

Acinetobacter baumannii is capable of colonizing medical devices by means of archaic chaperone-usher (ACU) pili. ACU pili are hair-like protein fibers found on the surface of many pathogenic bacteria.

Using cryo-electron microscopy, the researchers found that the pili have a unique ultrathin zigzag architecture. The fibers firmly attach the bacterium to various biotic and abiotic surfaces with tiny sticky finger-like structures at their ends. Once the sticky fingers grip the surface, the fiber is difficult to detach because it can stretch by changing its conformation from the zigzag to linear shape.

“This phenomenon is well known to sailors. It is now common to use stretchable elements in mooring lines to dock boats safely in relatively rough water. If you imagine a bacterium the same size as a human, then the attachment fibers of this giant bacterium will still be 100 times thinner than human hands. The ability to stretch is critical for such thin fibers to withstand high shear forces which bacteria experience in their environment,” Zavialov explains.

“Our results suggest that the unique zigzag structure of the fibers also plays an important role in their secretion to the bacterial surface. Fibers are secreted from the inside of the bacterium through its outer membrane in the extended linear conformation. On the surface, they change their conformation to the zigzag shape, which prevents them from slipping back into the bacterium. Theoretically, we can develop drugs preventing this conformational change. Such drugs would block fiber biogenesis, abolishing bacterial attachment,” Henri Malmi concludes.

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JOURNAL

Nature

DOI

10.1038/s41586-022-05095-0 

ARTICLE TITLE

Archaic chaperone-usher pili self-secrete into superelastic zigzag springs

THE GREAT BICYCLE RACE

La Vuelta air not always healthy

Utrecht researchers map air quality of all stages of La Vuelta

Reports and Proceedings

UTRECHT UNIVERSITY

 

IMAGE: MAP DEPICTING THE AIR QUALITY OF THE VUELTA STAGE IN UTRECHT. CREDIT: UTRECHT UNIVERSITY view more 

CREDIT: UTRECHT UNIVERSITY

The Netherlands is preparing for La Vuelta Holanda which starts on Friday 19 August. How clean is the air in the places that the peloton is visiting? Researchers from Utrecht University have mapped the annual average air quality of each stage of La Vuelta and demonstrate that the air is most polluted at the start (Utrecht) and finish (Madrid). They also conclude that for many stretches the air quality does not meet World Health Organization (WHO) guidelines. Nevertheless, the health benefits of cycling generally outweigh the risks.

It’s often said that "cycling is healthy" when we set off in all kinds of weather. But how clean is the air you breathe if you cycle the same route as the La Vuelta peloton on a normal day? This was the question researchers Roel Vermeulen and Jules Kerckhoffs asked themselves. Using satellite images, traffic information and air quality data about nitrogen dioxide, particulate matter and ozone, they made a stage map booklet [insert link] showing the air quality for each stage of La Vuelta.

The conclusion is clear: the most polluted stages are those in the Netherlands and the Spanish stage from La Rozas to Madrid. Particularly in the urban areas, the air quality does not meet WHO guidelines. On top of that, there are a few places where the European limit value is exceeded. It is generally accepted that places with poor air quality can cause adverse health effects. In the Netherlands, researchers estimate that approximately five thousand people die prematurely each year due to poor air quality. Worldwide, that is estimated to be around 7 million.

Alternative stage map book
The stage maps created by Utrecht University researchers as part of the Expanse project, illustrate average air pollution over the course of a year. Vermeulen and Kerckhoffs focus on the value recommended by the WHO for nitrogen dioxide in a year: ten micrograms per cubic meter. If you were to cycle the route to work or study every day, this is a critical value. If you cycle the route occasionally the 24-hour guideline of 25 micrograms per cubic meter is more relevant. According to the WHO, exceeding these guidelines results in damage to health. However, the EU limit value that is used in the Netherlands is a lot higher: 40 micrograms per cubic meter. This value is also reflected in the graphs accompanying the maps.

“Much has been done in recent years to improve air quality, but we see that there are still many places where the air is not healthy," said Vermeulen, who studies how environmental factors affect our health. "So improving air quality still requires attention." Vermeulen therefore calls on municipalities to look beyond the EU standard to which they must adhere, and to improve air quality according to WHO guidelines. For example, municipalities could encourage residents to travel by bike instead of by car for short distances and indirectly stimulate this behaviour when designing cities. "The so-called 15-minute cities, where facilities can be reached on foot or by bike within fifteen minutes, are a good example of this."

For the cyclists of the Vuelta, their trip will not directly result in damage to their health; after all, they ride each stage once only and not every day. Furthermore, there is no regular traffic on the road on the day of La Vuelta. This means that the air quality during the stage will be better, as was also previously demonstrated during the Grand Depart of the Tour de France.

CAPTION

Map depicting the air quality of the Vuelta stage in Vitoria. Credit: Utrecht University

CREDIT

Utrecht University

The most polluted routes of La Vuelta
The research shows that the air quality of the first three stages in the Netherlands and of the final stage in and near Madrid, does not come close to the WHO advisory value for nitrogen dioxide (10 micrograms per cubic meter).

During a part of the third stage (Breda - Breda), the concentration of nitrogen dioxide is higher than the 24-hour WHO guidelines for nitrogen dioxide, and a small part is even higher than the EU limit (about 40 kilometers). The average pollution of the total ride is 21 micrograms per cubic meter. The other stages in the Netherlands are also on average substantially more polluted than those in Spain, both for nitrogen dioxide and particulate matter. The prologue in Utrecht even has an average concentration of 32 micrograms per cubic meter. Because this stage is only 23.3 kilometers long, stages two (Den Bosch - Utrecht) and three (Breda - Breda) are worse for health. This is because you inhale more polluted air and therefore have a higher average over a 24 hours period.

If we look at the average concentration of nitrogen dioxide of the last stage (Las Rozas - Madrid), we see that it is even higher than the stages in the Netherlands. 35 kilometers of this stage exceed the EU limit of 40 micrograms of nitrogen dioxide per cubic meter. As in Utrecht, this is because a large part of the stage is cycled in the inner city of Madrid.

Vitoria-Gasteiz - Laguardia: the cleanest stage
By comparing previous stages with that of Vitoria-Gasteiz to Laguardia in Spain, we can see how great the differences are. During stage four the concentration of nitrogen dioxide was below the WHO advisory value for almost the entire stage (142.5 km). The average of this route is 6.5 micrograms per cubic meter. Interestingly the stage is not the cleanest for ozone. Ozone is formed from reactions of nitrogen oxides and volatile organic compounds in warm and sunny weather. Because the temperature is higher in Spain, ozone concentrations are typically higher than those in the Netherlands.

Ban the bicycle?
This research shows that nitrogen dioxide concentrations above 25 micrograms per cubic meter (the daily limit according to the WHO) in urban areas are often unavoidable for cyclists. Does this mean you should have to take the bus to work from now on? "No," say Kerckhoffs and Vermeulen. "Even if you compare polluted air and other risks such as accidents to the health benefits of cycling, the risks are smaller than the benefits. Our evaluation is therefore not intended to discourage cycling. What we do want is to raise awareness about air quality in the Netherlands, and show that from a health perspective, there is still work to be done. Part of the solution can be found in the stimulation of active transport (cycling, walking) especially for short distances. We can stimulate this for example, by improving cycling infrastructure and by designing our urban living environment in such a way that all basic daily needs can be found within a 15-minute walk or bike ride from your home (the 15-minute city).

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METHOD OF RESEARCH

Experimental study