Tag Archives: Heart

Microbiology

University of Louisville researchers receive $5.8 million to prevent immune system dysregulation

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Reviewed by Megan Craig, M.Sc.Jun 2 2023

Researchers at the University of Louisville have received $5.8 million in two grants from the National Institutes of Health to expand their work to better understand and prevent immune system dysregulation responsible for acute respiratory distress, the condition responsible for serious illness and death in some COVID-19 patients. A separate $306,000 NIH Small Business Innovation Research grant supports early testing of a compound developed at UofL as a potential treatment.

The three grants combined total $6.1 million.

During the pandemic, health care providers worked tirelessly to treat patients who became seriously ill with COVID-19. Some of those patients developed severe lung disease known as acute respiratory distress syndrome (ARDS) due to an excessive response of the immune system often called cytokine storm.

As they treated these critically ill patients, physicians and other providers at UofL Health shared their clinical insights and patient samples with researchers at UofL to discover the cause of the immune system overresponse.

At one time we had over 100 patients with COVID in the hospital. Once they were on a ventilator, mortality was about 50%. We were looking at this issue to see why some people would do well while some developed bad lung disease and did not do well or died.”

Jiapeng Huang, an anesthesiologist with UofL Health and professor and vice chair of the Department of Anesthesiology and Perioperative Medicine in the UofL School of Medicine

The UofL researchers, led by immunologist Jun Yan, discovered that a specific type of immune cells, low-density inflammatory neutrophils, became highly elevated in some COVID-19 patients whose condition became very severe. This elevation signaled a clinical crisis point and increased likelihood of death within a few days due to lung inflammation, blood clotting and stroke. Their findings were published in 2021 in JCI Insight.

With the new NIH funding, Yan is leading research to build on this discovery with deeper understanding of what causes a patient’s immune system to respond to an infection in this way and develop methods to predict, prevent or control the response.

“Through this fruitful collaboration, we now have acquired NIH funding for basic and translational studies and even progress toward commercialization of a potential therapy,” Yan said. “That’s why we do this research – eventually we want to benefit the patients.”

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Yan, chief of the UofL Division of Immunotherapy in the Department of Surgery, a professor of microbiology and immunology and a senior member of the Brown Cancer Center, will lead the new research, along with Huang and Silvia M. Uriarte, university scholar and professor in the Department of Oral Immunology and Infectious Diseases in the UofL School of Dentistry.

“COVID-19 continues to spotlight the impactful synergy between the clinical and research teams at the University of Louisville,” said Jason Smith, UofL Health chief medical officer. “Innovation is in the DNA of academic medicine. We collaborate to provide each patient the best options for prevention and treatment today, while developing the even better options for tomorrow.”

In addition to two research grants of $2.9 million each awarded directly to UofL, a $306,000 grant to a startup company will support early testing of a compound developed in the lab of UofL Professor of Medicine Kenneth McLeish that shows promise in preventing the dangerous cytokine storm while allowing the neutrophils to retain their ability to kill harmful bacteria and viruses. The compound, DGN-23, will be tested by UofL and Degranin Therapeutics, a startup operated by McLeish, Yan, Huang, Uriarte and Madhavi Rane, associate professor in the Department of Medicine.

“This is one more example of how UofL has led the charge in finding new and innovative ways to detect, contain and fight COVID-19 and other potential public health threats,” said Kevin Gardner, UofL’s executive vice president for research and innovation. “This team’s new research and technology could help keep people healthy and safe here and beyond.”

The knowledge gained through these studies may benefit not only COVID-19 patients, but those with other conditions in which immune dysregulation can occur, such as other types of viral and bacterial pneumonia and autoimmune diseases, and patients undergoing cancer immunotherapy and organ transplantation.

The grants

Grant 1 – $2.9 million, four-year grant to UofL. Investigators will study the new subset of neutrophils Yan identified to better understand how they contribute to acute respiratory distress and clotting. They also will determine whether a novel compound will prevent these complications. They will use lab techniques and studies with animal models that allow for manipulation of certain conditions that cannot be done in human subjects.

Grant 2 – $2.9 million, five-year grant to UofL. This work examines a more comprehensive landscape to characterize different subsets of neutrophils and measure their changes over the course of COVID-19 disease progression and how neutrophils contribute to immune dysfunction.

Grant 3 – $306,000, one-year grant to Degranin Therapeutics and UofL for early testing of DGN-23, a compound developed at UofL, to determine its effectiveness in preventing or reducing immune dysregulation.

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University of Louisville

Microbiology

New Study: Even Mild COVID-19 Can Have Long-Term Detrimental Effects on Heart Health

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A groundbreaking study conducted a comparison of arterial stiffness between participants before and after contracting COVID-19.

New research indicates that even mild instances of COVID-19 can lead to lasting harm to cardiovascular health.

The study is the first comparison of levels of arterial stiffness before and after a COVID-19 infection, a parameter closely tied to the aging process and performance of our arteries. The lingering effects of a COVID-19 infection, often referred to as long COVID, are connected with a heightened risk of cardiovascular disease, dementia, and in severe scenarios, death.

An international team of scientists was able to do this research using baseline measurements from a group of participants involved in a separate study that began pre-pandemic, also investigating arterial stiffness.

In those who had been diagnosed with mild COVID-19, artery and central cardiovascular function were affected by the disease two to three months after infection. Side effects include stiffer and more dysfunctional arteries that could lead to cardiovascular disease development.

The paper, published in the Journal of Clinical Medicine, revealed age and time from COVID infection are associated with increased aging of the arteries.

Co-author, Dr Maria Perissiou from the University of Portsmouth’s School of Sport, Health & Exercise Science, said: “We were surprised to observe such a decline in vascular health, which deteriorated even further with time since COVID-19 infection. Usually, you’d expect inflammation to decrease with time after infection, and for all the physiological functions to go back to normal or a healthy level.

“We can only speculate on what causes this phenomenon without further investigation, but emerging evidence suggests that it stems from COVID-19 triggering the auto-immune process that leads to vasculature deterioration.”

While COVID-19 has been associated with a type of acute heart failure and vascular dysfunction, the long-term consequences of the disease on vascular health still need to be explored.

The study was part of the University of Split’s NormPreven project funded by the Croatian Science Foundation, and the team formation was facilitated by EU COST VascAgeNet action.

Participants were monitored between October 2019 and April 2022 in the Laboratory for Vascular Aging at the University of Split School of Medicine.

Most were young, less than 40 years old, and healthy. Only nine percent of the group had high blood pressure, and none had high cholesterol. Two were diabetic, and 78 percent did not smoke. The group was also almost an even split between males (56 percent) and females (44 percent).

Professor Ana Jeroncic from the University of Split, who led the study, said: “Given the number of people infected with COVID-19 worldwide, the fact that infection can have harmful effects on cardiovascular health in young people who had a mild form of the disease warrants close monitoring.

“The question remains as to whether this harmful effect is irreversible or permanent, and if not, for how long it lasts.”

Dr. Perissiou added: “This study, while small, does support the prediction amongst vascular physiologists that we’ll have an increase in cardiovascular disease in the future as a result of COVID-19 infections. But we have to consider what other variables would have contributed to this increase.”

The paper concludes the results have important implications for understanding the long-term cardiovascular consequences of COVID-19 infection and may guide prevention and management strategies for associated vascular disease.

However, it recommends further research is needed to strengthen our understanding of causes and contributing factors.

Reference: “Long-Term Adverse Effects of Mild COVID-19 Disease on Arterial Stiffness, and Systemic and Central Hemodynamics: A Pre-Post Study” by Mario Podrug, Pjero Koren, Edita Dražić Maras, Josip Podrug, Viktor Čulić, Maria Perissiou, Rosa Maria Bruno, Ivana Mudnić, Mladen Boban and Ana Jerončić, 8 March 2023, Journal of Clinical Medicine.
DOI: 10.3390/jcm12062123

University of Portsmouth

Microbiology

Breathing New Life: Oxygen Therapy Improves Heart Function in Long COVID Patients

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A small trial has found that hyperbaric oxygen therapy (HBOT) may help restore proper heart function in patients with post-COVID syndrome, with participants in the HBOT group experiencing a significant increase in global longitudinal strain (GLS), an indicator of heart function.

A small randomized trial in patients with post-COVID syndrome has found that hyperbaric oxygen therapy promotes the restoration of the heart’s ability to contract properly. The research is presented at EACVI 2023, a scientific congress of the European Society of Cardiology (ESC).[1]

“The study suggests that hyperbaric oxygen therapy can be beneficial in patients with long COVID,” said study author Professor Marina Leitman of the Sackler School of Medicine, Tel Aviv University and Shamir Medical Centre, Be’er Ya’akov, Israel. “We used a sensitive measure of cardiac function which is not routinely performed in all centers. More studies are needed to determine which patients will benefit the most, but it may be that all long COVID patients should have an assessment of global longitudinal strain and be offered hyperbaric oxygen therapy if heart function is reduced.”

Most COVID-19 sufferers fully recover, but after the initial illness approximately 10–20% of patients develop long COVID, also called post-COVID condition or syndrome.[2] Symptoms include shortness of breath, fatigue, cough, chest pain, rapid or irregular heartbeats, body aches, rashes, loss of taste or smell, nausea, vomiting, diarrhea, headache, dizziness, insomnia, brain fog, depression and anxiety. Patients with post-COVID syndrome may also develop cardiac dysfunction and are at increased risk of a range of cardiovascular disorders.[3]

This randomized controlled double-blind trial evaluated the effect of hyperbaric oxygen therapy (HBOT) on the cardiac function of long COVID patients. HBOT involves inhalation of 100% pure oxygen at high pressure to increase delivery to the body’s tissues, which is particularly beneficial for tissues that are starved of oxygen due to injury or inflammation. HBOT is an established treatment for non-healing wounds, decompression sickness in divers, carbon monoxide poisoning, radiation injury, and certain types of infections

The study enrolled 60 post-COVID syndrome patients with ongoing symptoms for at least three months after having mild to moderate symptomatic COVID-19 confirmed by a PCR test. Both hospitalized and non-hospitalized patients were included. Severe COVID cases were excluded. Patients were randomized to HBOT or a sham procedure in a 1:1 ratio. Each patient had five sessions per week over eight weeks, for a total of 40 sessions. The HBOT group received 100% oxygen through a mask at a pressure of 2 atmospheres for 90 minutes, with 5 minute air breaks every 20 minutes. The sham group breathed 21% oxygen by mask at 1 atmosphere for 90 minutes. All participants underwent echocardiography at baseline (before the first session) and 1 to 3 weeks after the last session.

Echocardiography was used to assess left ventricular global longitudinal strain (GLS), which is a measure of the heart’s ability to contract and relax lengthwise. It indicates how well the heart is functioning and can help detect early signs of heart disease. A healthy heart will have a GLS value of around -20% which means that the heart muscle is able to properly contract and relax in the longitudinal direction. Reduced GLS is an early marker that the heart is not able to contract and relax effectively.

At baseline, nearly half of study participants (29 out of 60; 48%) had reduced GLS. Of those, 13 (43%) and 16 (53%) were in the sham and HBOT groups, respectively. The average GLS at baseline across all participants was -17.8%. In the HBOT group, GLS significantly increased from -17.8% at baseline to -20.2% after the intervention (p=0.0001). In the sham group, GLS was -17.8% at baseline and -19.1% after the sessions, with no statistically significant difference between the two measurements.

Professor Leitman said: “It was notable that almost half of long COVID patients had impaired cardiac function at baseline according to GLS despite all participants having a normal ejection fraction, which is the standard method for measuring the heart’s ability to contract. This means that ejection fraction is not sensitive enough to identify long COVID patients with reduced heart function.”

She concluded: “The findings suggest that HBOT promotes recovery of cardiac function in patients with post-COVID syndrome. More research is needed to collect long-term results and determine the optimal number of sessions for maximum therapeutic effect.”

Meeting: EACVI 2023

Notes

European Society of Cardiology

Microbiology

Novel gene-editing strategy harnesses an unusual protective ability to eliminate HIV-1 infection

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Reviewed by Danielle Ellis, B.Sc.May 19 2023

Genetic alterations that give rise to a rare, fatal disorder known as MOGS-CDG paradoxically also protect cells against infection by viruses. Now, scientists at the Lewis Katz School of Medicine at Temple University have harnessed this unusual protective ability in a novel gene-editing strategy aimed at eliminating HIV-1 infection with no adverse effects on cell mortality.

The new approach, described online April 28 in the journal Molecular Therapy – Nucleic Acids, is based on a combination of two gene-editing constructs, one that targets HIV-1 DNA and one that targets a gene called MOGS – defects in which cause MOGS-CDG. In cells from persons infected with HIV-1, the Temple researchers show that disrupting the virus’s DNA while also deliberately altering MOGS blocks the production of infectious HIV-1 particles. The discovery opens up new avenues in the development of a cure for HIV/AIDS.

Proper MOGS function is essential for glycosylation, a process by which some cellular proteins synthesized in the body are modified to make them stable and functional. Glycosylation, however, is leveraged by certain kinds of infectious viruses. In particular, viruses like HIV, influenza, SARS-CoV-2, and hepatitis C, which are surrounded by a viral envelope, rely on glycosylated proteins to enter host cells.

In the new study, lead investigators Kamel Khalili, PhD, Laura H. Carnell Professor and Chair of the Department of Microbiology, Immunology, and Inflammation, Director of the Center for Neurovirology and Gene Editing, and Director of the Comprehensive NeuroAIDS Center at the Lewis Katz School of Medicine, and Rafal Kaminski, PhD, Assistant Professor at the Center for Neurovirology and Gene Editing at the Lewis Katz School of Medicine designed a genetic approach to exclusively turn on CRISPR to impede MOGS gene expression through DNA editing within immune cells that harbor replication competent, HIV-1. Their novel approach is expected to avoid any impact on the health of uninfected cells that retain normal MOGS gene function. Stimulation of the apparatus in HIV-1 infected cells disrupted the glycan structure of the HIV-1 envelope protein, culminating in the production of non-infectious virus particles.

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“This approach is conceptually very interesting,” said Dr. Khalili, who is also senior investigator on the new study. “By mitigating the ability of the virus to enter cells, which requires glycosylation, MOGS may offer another target, in addition to the integrated viral DNA for developing the next generation of CRISPR gene-editing technology for HIV elimination.”

Dr. Kaminski, Dr. Khalili, and Tricia H. Burdo, PhD, Professor and Vice Chair in the Department of Microbiology, Immunology, and Inflammation and the Center for Neurovirology and Gene Editing at Temple and an expert in the use of non-human primate models for HIV-1, have been working together to further assess the efficacy and safety of CRISPR-MOGS strategy in preclinical studies. In previous work, the team demonstrated that CRISPR-based technology can successfully remove viral DNA from the cells of infected non-human primates.

Other researchers who contributed to the study include Hong Liu, Chen Chen, Shuren Liao, and Shohreh Amini, Department of Microbiology, Immunology, and Inflammation, Center for Neurovirology and Gene Editing, Lewis Katz School of Medicine at Temple University; Danielle K. Sohaii, Conrad R.Y. Cruz, and Catherine M. Bollard, Center for Cancer and Immunology Research, Children’s National Health System, The George Washington University; Thomas J. Cradick and Jennifer Gordon, Excision Biotherapeutics, San Francisco, CA; Anand Mehta, Stephane Grauzam, and James Dressman, Department of Cell and Molecular Pharmacology, Medical University of South Carolina; and Carlos Barrero and Magda Florez, Department of Pharmaceutical Sciences, School of Pharmacy, Temple University.

The research was supported in part by grants from the National Institutes of Health and the W.W. Smith Charitable Trust.

Source:

Temple University Health System

Journal reference:

Liu, H., et al. (2023) Strategic Self-Limiting Production of Infectious HIV Particles by CRISPR in Permissive Cells. Molecular Therapy — Nucleic Acids. doi.org/10.1016/j.omtn.2023.04.027.

Microbiology

Scarring to the collagen framework causes dysfunction in Duchenne muscular dystrophy

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Reviewed by Emily Henderson, B.Sc.May 11 2023

Muscles that ache after a hard workout usually don’t hurt for long, thanks to stem cells that rush to the injured site along “collagen highways” within the muscle and repair the damaged tissue. But if the cells can’t reach their destination, the damaged tissue can’t regenerate. Over time, it breaks down completely and ceases to function.

In a study recently published in npj Regenerative Medicine, a group of researchers led by biochemists at UCLA show for the first time that scarring to the collagen framework that carries these healing cells causes muscles to gradually stop working in Duchenne muscular dystrophy. The discovery in mice illuminates one reason stem cell therapy has not been effective for the disorder: The cells simply can’t get where they’re needed most.

Duchenne muscular dystrophy is the most common -; and one of the most severe -; hereditary muscular dystrophies. The muscle-wasting disease, which usually affects boys, begins in childhood and inevitably ends in death as the muscles that power the heart, lungs and other vital organs fail. It is caused by a mutation in the gene for the dystrophin protein, which regulates the organization of muscle cells. In healthy people, dystrophin helps bundles of muscle cells called myofibers attach to the collagen framework -; the extracellular matrix that gives muscles their shape, holds them together and provides the “highway” for stem cells to repair and regenerate damaged tissue.

Rachelle Crosbie, a UCLA professor of integrative biology and physiology who is looking for ways to treat Duchenne muscular dystrophy, suspected that the dysfunction caused by this mutation led to scarring and stiffening of the extracellular matrix, a process known as fibrosis.

Crosbie and Kristen Stearns-Reider, a postdoctoral fellow in Crosbie’s laboratory, designed a unique experiment to find out. Using facilities at UCLA’s California NanoSystems Institute, they devised a process to “wash” all the cells off the collagen extracellular matrix in healthy mice and those with Duchenne muscular dystrophy.

Under a microscope, the two cell-free matrices, which Crosbie calls “myoscaffolds,” appeared very different: The healthy one looked like delicate lace, while the Duchenne one looked more like a dense sponge.

Next, the researchers seeded each myoscaffold with stem cells and watched as the cells tried to grow muscle tissue. Muscle stem cells grew on the myoscaffolds exactly as they would in healthy and diseased muscle: In the healthy, lacy myoscaffold, cells migrated along the smooth threads and deposited themselves in evenly spaced holes. However, the bumpy, thickened surfaces of the Duchenne myoscaffold made travel difficult and threw up roadblocks that caused the cells to pile up in clumps; the cells were stressed an unable to progress efficiently.

Like suburban commuters, resident stem cells live on outskirts of the muscle fiber and travel along the muscle fiber to damaged areas and regenerate muscle. The extracellular matrix is the highway they use. It’s like the difference between driving to work on a regular day versus the day a landslide fell on the freeway.”

Rachelle Crosbie, UCLA professor of integrative biology and physiology

This is the first time scientists have imaged living cells in a fibrotic myoscaffold, revealing specifically how fibrosis disrupts cell behavior, Crosbie said.

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The thin, supple threads of the healthy scaffold also yielded slightly as stem cells attached to them, a deformation critical to the successful development of muscle tissue. The stem cells were unable to deform the thick, stiff fibers of the Duchenne scaffold. Tissue grown on the Duchenne scaffold showed large clumps of myofibers interspersed with even larger clumps of collagen instead of the evenly distributed myofibers seen in the healthy sample.

Protein sarcospan offers a potential way forward

The research team then tested cell behavior on a Duchenne myoscaffold that was created using a therapeutic protein called sarcospan, which is known to stabilize the extracellular matrix. Stem cell function improved once sarcospan had minimized the formation of fibrotic scars.

“The results made it really clear why stem cell therapies have proven challenging for Duchenne muscular dystrophy,” Crosbie said. “Finding ways to prevent or reduce scarring on the extracellular matrix could make them more effective.”

These myoscaffolds offer several broad possibilities for studying stem cell–extracellular matrix interactions, stem cell niche formation, the microenvironments that influence stem cell behavior, muscle maturation and disease modeling, said study co-authors Michael Hicks, a UCLA postdoctoral fellow, and April Pyle, a UCLA professor of microbiology, immunology, and molecular genetics.

Crosbie also noted that because the new method requires only very small samples, these studies could potentially be extended to include individual patients, using tissue from a muscle biopsy to study treatments before they are administered and identifying ones more likely to be effective.

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Source:

University of California – Los Angeles

Journal reference:

Stearns-Reider, K. M., et al. (2023). Myoscaffolds reveal laminin scarring is detrimental for stem cell function while sarcospan induces compensatory fibrosis. Npj Regenerative Medicine. doi.org/10.1038/s41536-023-00287-2.

Microbiology

Cardiologists Explain Risks of Myocarditis From COVID Vaccines vs Risks of Heart Damage From Infection

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What the research shows about risks of myocarditis from COVID vaccines versus risks of heart damage from COVID – two pediatric cardiologists explain how to parse the data.

Rare cases of myocarditis have been reported after COVID-19 vaccination, but the risk is higher after infection, and the prognosis is better following vaccine-related myocarditis. The decision to vaccinate should consider factors like patient age, health problems, and community COVID-19 rates.

Soon after the first COVID-19 vaccines appeared in 2021, reports of rare cases of heart inflammation, or myocarditis, began to surface.

In most instances, the myocarditis has been mild and responded well to treatment, though up to four potentially mRNA vaccine-related deaths from myocarditis in adults have been reported worldwide. No known verified deaths of children have been reported based on publicly available data. The exact number remains a topic of very heated debate because of variability in the reporting of possible myocarditis-related deaths.

Studies have largely confirmed that the overall myocarditis risk is significantly higher after an actual COVID-19 infection compared with vaccination, and that the prognosis following myocarditis due to the vaccine is better than from infection. The specific myocarditis risk varies by age and has been debated because of differing views among a small group of physicians related to risk tolerance and support for or against COVID-19 immunization for specific age groups.

As pediatric cardiologists, we specialize in heart issues relevant to kids of all ages. We believe it is important to weigh the risk of myocarditis caused by COVID-19 immunization against not only viral myocarditis from COVID-19, but also all the other complications that COVID-19 can lead to.

Comparing risks of myocarditis from severe disease versus COVID-19 vaccination or infection is difficult to do well, and debate continues over which of those outcomes poses a higher risk.

Myocarditis is any condition that causes heart inflammation. A closely related condition called pericarditis refers to inflammation of the outside lining of the heart. For the purpose of this article, we focus primarily on myocarditis, since it has the potential for being a more severe condition. Most cases of myocarditis are caused by infections, particularly viral ones.

Myocarditis can be confirmed by a combination of an electrocardiogram, an ultrasound heart picture called an echocardiogram, and some blood testing. When it is available, cardiac magnetic resonance imaging, or MRI, is the most accurate method to diagnose myocarditis that doesn’t involve an invasive procedure.

A mistaken assumption is that all myocarditis is severe, since it implies damage to the heart. However, mild cases in which there is very little swelling and only temporary damage to the heart are more common than severe cases that require a machine to support heart function.

Symptoms of myocarditis include chest pain and shortness of breath.

The challenge of parsing risks of myocarditis from viral infection compared with COVID-19 vaccination is due in part to the difficulty of establishing a diagnosis of myocarditis and its population rates accurately.

The United States Vaccine Adverse Event Reporting System, or VAERS – which is an initial reporting system for vaccine side effects – is by itself inadequate to determine the rate of any vaccine-associated side effect. This is because any side effect can be reported, and verification of a reported event only takes place afterward by the Centers for Disease Control and Prevention.

That vetted data is then reported in more robust databases like the Vaccine Safety Datalink. A very small number of the myocarditis events following COVID-19 vaccination have resulted in significant long-term consequences like heart rhythm troubles. However, such cases do not reflect the majority.

Thankfully, severe myocarditis after mRNA vaccination for COVID-19 is extremely rare. A 2021 study from Nordic scholars, which looked at comparative risks of myocarditis and heart arrhythmia in patients who experienced myocarditis after COVID-19 infection versus immunization found that the risks vary significantly by age group.

This has been touted as a reason not to vaccinate healthy young men against COVID-19. The follow-up study, however, found that the comparative risks of negative outcomes were worse from myocarditis from COVID-19 infection and other viral myocarditis than from vaccination in all patients older than 12 years of age.

And it’s worth noting that, as of mid-March 2023, the U.S. still leads the world in COVID-19 hospitalizations.

There have also been rare myocarditis cases reported with the newer non-mRNA Novovax vaccine, though we researchers do not yet know population-level rates.

A survey of all currently available research reveals that the risk of myocarditis after COVID-19 vaccination is highest in young men between the ages of 18 and 39 and older teen boys in the age range of 12 to 17, with the highest risk after the second dose of vaccine. The cause appears to be related to how the immune system processes the mRNA and sometimes generates an excessive immune response.

Myocarditis risk related to COVID-19 immunization is markedly lower in children younger than 12 years of age and much lower in adult males older than 50. The risk of severe disease from COVID-19, particularly in those older than 50 years, has been far higher throughout the pandemic than the risk of myocarditis from COVID-19 vaccination. The risk of vaccination myocarditis is uniformly lower in girls than in boys.

Infants younger than 6 months can get immunity only from their mother’s antibodies unless they are exposed to COVID-19 themselves, as vaccines for this age group are not available.

While the risks of myocarditis have been highest in teen boys and young men regardless of cause, the severity and outcome of myocarditis was much worse at the 90-day mark when it stemmed from COVID-19 infection or other viral diseases. This mirrors our team’s research on this same topic.

This discussion also doesn’t take into account the clot and heart attack risks from COVID-19 itself. Because COVID-19 damages blood vessels in all parts of the body, some organ damage such as kidney failure, blood clots, heart attacks and strokes can occur.

We recognize a need for more research into how people fare over the medium and long terms following a case of immunization-related myocarditis. This is why research is ongoing, and researchers like us are committed to following the data for years to come.

While there have been far fewer deaths from COVID-19 in children than adults, COVID-19 is still one of the leading causes of childhood death in the U.S., based on an early 2023 study. But COVID-19 deaths are not the only relevant measure of its effect in kids. COVID-19 has also killed more children in a shorter time period than several other vaccine-preventable diseases, such as hepatitis A and meningitis before the availability of their vaccines.

The argument that some have made that fewer children than adults die from COVID-19, or that it is often mild in children, has never been an acceptable justification to not do everything possible to protect children from it. For instance, doctors don’t stop treating pediatric cancer patients purely because there are fewer of them than adult cancer patients. And we don’t retire the measles vaccines only because most kids who get measles get only a mild case.

The primary risk that COVID-19 presents now to children is long COVID, followed by the risk of severe disease. The estimated percentage of children acquiring long COVID is still being debated, but the symptoms from long COVID can be extraordinarily debilitating. These include severe fatigue, brain fog, sleep disturbance, dizziness, nerve pain and more.

Many children with long COVID-19 report lingering fatigue and frequent headaches.

We believe that the decision of whether to vaccinate against COVID-19 should be based upon the patient’s age, other health problems, relative risk from vaccines, how much and what type of COVID-19 is in your community, and the patient’s and family’s preference.

Two ways that have been suggested by the CDC and the Public Health Agency of Canada to decrease the risk of COVID-19 vaccine myocarditis are to opt for Pfizer and to space your doses out by at least eight weeks. This is because Pfizer has slightly lower rates of myocarditis than Moderna.

Adults who are immunocompromised or have other medical problems known to worsen COVID-19 disease severity still carry the highest risk of severe disease. They should therefore follow the CDC COVID-19 vaccination schedule with additional boosters, if advised by their physician.

While COVID-19 immunizations are not as efficient at preventing viral transmission now as they were with the earliest variant, they remain highly effective at reducing severe illness and hospitalization, even in kids, and particularly in the high-risk state of pregnancy.

Thankfully kids have fared far better from COVID-19 infection than adults. The primary risks of severe COVID-19 for children are among babies and infants, as well as children with health problems that put them at high risk, children with the most significant types of congenital heart disease or those with other medically complex conditions. Children in those groups derive the most benefit from the primary COVID-19 vaccine series; therefore, the decision to vaccinate in their case should be easier.

Informed consent that comes with vaccination should involve discussion of infection risks. The risk of immunization will never be zero because of variability in immune system responses; therefore, making the decision should always involve considering the most-up-to date information available.

Written by:

This article was first published in The Conversation.The Conversation

Frank Han and Jennifer H. Huang

Microbiology

Bioengineered drug candidate can counter S. aureus infection in early tests

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Reviewed by Emily Henderson, B.Sc.Apr 24 2023

Researchers at NYU Grossman School of Medicine and Janssen Biotech, Inc. have shown in early tests that a bioengineered drug candidate can counter infection with Staphylococcus aureus – a bacterial species widely resistant to antibiotics and a major cause of death in hospitalized patients.

Experiments demonstrated that SM1B74, an antibacterial biologic agent, was superior to a standard antibiotic drug at treating mice infected with S. aureus, including its treatment-resistant form known as MRSA.

Published online April 24 in Cell Host & Microbe, the new paper describes the early testing of mAbtyrins, a combination molecule based on an engineered version of a human monoclonal antibody (mAb), a protein that clings to and marks S. aureus for uptake and destruction by immune cells. Attached to the mAb are centyrins, small proteins that prevent these bacteria from boring holes into the human immune cells in which they hide. As the invaders multiply, these cells die and burst, eliminating their threat to the bacteria.

Together, the experimental treatment targets ten disease-causing mechanisms employed by S. aureus, but without killing it, say the study authors. This approach promises to address antibiotic resistance, say the researchers, where antibiotics kill vulnerable strains first, only to make more space for others that happen to be less vulnerable until the drugs no longer work.

To our knowledge, this is the first report showing that mAbtyrins can drastically reduce the populations of this pathogen in cell studies, and in live mice infected with drug-resistant strains so common in hospitals. Our goal was to design a biologic that works against S. aureus inside and outside of cells, while also taking away the weapons it uses to evade the immune system.”

Victor Torres, PhD, Lead Study Author, the C.V. Starr Professor of Microbiology and director of the NYU Langone Health Antimicrobial-Resistant Pathogen Program

One-third of the human population are carriers of S. aureus without symptoms, but those with weakened immune systems may develop life-threatening lung, heart, bone, or bloodstream infections, especially among hospitalized patients.

Inside out

The new study is the culmination of a five-year research partnership between scientists at NYU Grossman School of Medicine and Janssen to address the unique nature of S. aureus.

The NYU Langone team together with Janssen researchers, published in 2019 a study that found that centyrins interfere with the action of potent toxins used by S. aureus to bore into immune cells. They used a molecular biology technique to make changes in a single parental centyrin, instantly creating a trillion slightly different versions of it via automation. Out of this “library,” careful screening revealed a small set of centyrins that cling more tightly to the toxins blocking their function.

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Building on this work, the team fused the centyrins to a mAb originally taken from a patient recovering from S. aureus infection. Already primed by its encounter with the bacteria, the mAb could label the bacterial cells such that they are pulled into bacteria-destroying pockets inside of roving immune cells called phagocytes. That is unless the same toxins that enable S. aureus to drill into immune cells from the outside let it drill out of the pockets to invade from the inside.

In a “marvel of bioengineering,” part of the team’s mAbtyrin serves as the passport recognized by immune cells, which then engulf the entire, attached mAbtyrin, along with its centyrins, and fold it into the pockets along with bacteria. Once inside, the centyrins block the bacterial toxins there. This, say the authors, sets their effort apart from antibody combinations that target the toxins only outside of cells.

The team made several additional changes to their mAbtyrin that defeat S. aureus by, for instance, activating chain reactions that amplify the immune response, as well by preventing certain bacterial enzymes from cutting up antibodies and others from gumming up their action.

In terms of experiments, the researchers tracked the growth of S. aureus strains commonly occurring in US communities in the presence of primary human immune cells (phagocytes). Bacterial populations grew almost normally in the presence of the parental antibody, slightly less well in the presence of the team’s engineered mAb, and half as fast when the mAbtyrin was used.

In another test, 98% of mice treated with a control mAb (no centyrins) developed bacteria-filled sores on their kidneys when infected with a deadly strain of S. aureus, while only 38% of mice did so when treated with the mAbtyrin. Further, when these tissues were removed and colonies of bacteria in them counted, the mice treated with the mAbtyrin had one hundred times (two logs) fewer bacterial cells than those treated with a control mAb.

Finally, the combination of small doses of the antibiotic vancomycin with the mAbtyrin in mice significantly improved the efficacy of the mAbtyrin, resulting in maximum reduction of bacterial loads in the kidneys and greater than 70% protection from kidney lesions.

“It is incredibly important,” said Torres, “that we find new ways to boost the action of vancomycin, a last line of defense against MRSA.”

Along with Torres, authors from the Department of Microbiology at NYU Langone were Rita Chan, Ashley DuMont, Keenan Lacey, Aidan O’Malley, and Anna O’keeffe. The study authors included 13 scientists from Janssen Research & Development (for details see the study manuscript).

This work was supported by Janssen Biotech, Inc., one of the Janssen Pharmaceutical Companies of Johnson & Johnson, under the auspices of an exclusive license and research collaboration agreement with NYU. Torres has recently received royalties and consulting compensation from Janssen and related entities. These interests are being managed in accordance with NYU Langone policies and procedures.

Source:

NYU Langone Health / NYU Grossman School of Medicine

Journal reference:

Buckley, P. T., et al. (2023). Multivalent human antibody-centyrin fusion protein to prevent and treat Staphylococcus aureus infections. Cell Host & Microbe. doi.org/10.1016/j.chom.2023.04.004.

Microbiology

Study reveals alarming global burden of antimicrobial resistance in bacterial infections

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Neha MathurBy Neha MathurApr 23 2023Reviewed by Danielle Ellis, B.Sc.

In a recent article published in the Lancet journal, researchers quantified the global bacterial antimicrobial resistance (AMR) burden to present deaths and disability-adjusted life-years (DALYs) attributable to and associated with 23 pathogens, 12 major infectious syndromes, 18 drug categories, and 88 pathogen–drug combinations.

They considered two counterfactual scenarios and used consistent methods to arrive at the study estimates as they had no clue of the extent to which susceptible or no infection would replace drug-resistant infections in a scenario when there was no drug resistance.

Study: Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Image Credit: Tatiana Shepeleva / ShutterstockStudy: Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Image Credit: Tatiana Shepeleva / Shutterstock

Background

Bacterial AMR, an emerging public health threat, is making antibiotic use futile or less effective against many common bacterial diseases affecting animals and humans. A United Kingdom (UK) government-commissioned review of AMR stated that it could claim 10 million lives annually by 2050.

The World Health Organization (WHO) and numerous other researchers have also raised that AMR spread is a pressing issue that needs immediate attention; if left unaddressed, rising AMR will make several bacterial pathogens highly fatal in the near future. The challenge is to gather current data on pathogen–drug combinations contributing to actual bacterial AMR burden for all world regions, even those with minimal surveillance.

According to the authors, studies have only reported AMR-related data for specific regions and a limited number of pathogens and pathogen–drug combinations. For instance, the United States Centers for Disease Control and Prevention (US-CDC) published a report in 2019 on AMR-related deaths for 18 AMR-related threats using surveillance data.

Similarly, Cassini et al. estimated the burden of eight and 16 pathogens and pathogen–drug combinations, respectively, for the European region between 2007 and 2015. Despite the significant contributions made by these studies to the field of AMR, there is a lack of comprehensive global estimates covering all locations, all pathogens, and all pathogen–drug combinations contributing to the rising burden of bacterial AMR.

Key Takeaways

  • First comprehensive assessment of the global burden of antimicrobial resistance (AMR) for bacterial infections.
  • Estimated 4.95 million deaths associated with bacterial AMR in 2019, including 1.27 million deaths attributable to bacterial AMR.
  • Lower respiratory infections accounted for the most deaths associated with resistance in 2019.
  • Six leading pathogens for deaths associated with resistance.
  • One pathogen-drug combination, meticillin-resistant S aureus, caused more than 100,000 deaths attributable to AMR in 2019.
  • Burden of AMR is highest in low-resource settings, particularly in western sub-Saharan Africa.
  • Serious data gaps in many low-income settings

About the study

In the present study, researchers used predictive statistical modeling to generate global estimates of bacterial AMR burden for all world locations, covering 204 countries for which they used all available data from the Global Burden of Diseases (GBD), Injuries, and Risk Factors study. The GBD study collated age- and gender-specific estimates for 369 injuries and illnesses in 204 nations and territories between 1990 and 2019.

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They retrieved data from published scientific literature, multisite research collaborations, clinical trials, research institutes based in low-income and middle-income countries (LMICs), public and private hospital records, diagnostic testing data, surveillance systems of pharmaceutical companies, global, national, and enhanced surveillance systems, and other relevant sources, encompassing 471 million (MN) patient records or isolates and 7,585 study-location years, which they gathered using varied strategies and used for study estimations.

The researchers modeled deaths and DALYs for 204 countries and territories to present cumulative estimates of AMR burden globally and for 21 GBD regions, including seven GBD super-regions.

For the first counterfactual scenario, where susceptible infections substituted all drug-resistant infections, they estimated only deaths and DALYs directly due to AMR. For the second counterfactual scenario, where no infection substituted all drug-resistant infections, they estimated all deaths and DALYs related to resistant infections. Both estimates had different utilities; however, both could inform the development of intermediation strategies to regulate AMR spread.

The study approach comprised ten estimation steps within five all-encompassing modeling components, each with varied data requirements; consequently, input data for each modeling component also varied.

Study findings

Substituting drug-resistant infections by no infections (first counterfactual scenario) and susceptible infections (second counterfactual scenario) would have saved 4.95MN and 1.27MN deaths, respectively, in 2019, implying that in 2019, the global AMR burden related to drug-resistant infections for 88 pathogen–drug combinations was ~4.95MN deaths (95% UI), of which drug resistance alone caused 1.27MN deaths. Moreover, after ischaemic heart disease and stroke, AMR accounted for most deaths in 2019.

Additionally, the study analysis revealed that AMR-related all-age death rates were highest in some LMICs, as opposed to the common notion that the burden of bacterial AMR would be higher in high-resource settings with higher antibiotic consumption. Indeed, AMR is emerging as a more serious problem for some of the world’s poorest countries. The authors noted the highest AMR-related death rates in sub-Saharan Africa and South Asia as a function of the prevalence of resistance and critical lower respiratory, bloodstream, and intra-abdominal infections, in these regions.

The study also highlighted that in LMICs, there are other drivers of the higher AMR burden, like a scarcity of laboratory infrastructure for microbiological testing needed to narrow antibiotic use or make it more targeted. Among other factors, counterfeit antibiotics, poor sanitation and hygiene, poor regulations on antibiotics use, etc., also drive resistance.

Further, the researchers identified six pathogens, E. coli, K. pneumoniae, S. pneumoniae, A. baumannii, S. aureus, and P. aeruginosa, who contributed most to the burden of AMR in 2019; they accounted for 73.4% (95% uncertainty interval) of deaths attributable to bacterial AMR. WHO has recognized all six as priority pathogens; however, except S. pneumoniae, targeted primarily through pneumococcal vaccination, none is the focus of global health intervention programs.

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Seven pathogen–drug combinations caused more than 50000 deaths, highlighting the need for expanding infection prevention and control (IPC) policies targeting the deadliest combinations, bolstering vaccine and antibiotic development, and improving access to essential second-line antibiotics where needed. Furthermore, resistance to β-lactam antibiotics, e.g., penicillins and cephalosporins, and fluoroquinolones accounted for >70% of deaths attributable to AMR across pathogens. These antibiotics are the first line of empirical treatment for severe infections.

In 2017, the WHO published a priority list to inform research priorities related to new antibiotics for pathogens with multidrug resistance that caused deadly infections. However, this list covered only five of the seven pathogen–drug combinations estimated to have caused the most deaths in 2019; for instance, this list did not feature fluoroquinolone-resistant E. coli and meticillin-resistant S. aureus only as a “high” but not a “critical” priority.

Per study estimates, the magnitude of bacterial AMR as a global public health issue is as much as human immunodeficiency virus (HIV) and malaria, perhaps, much higher. Additionally, the AMR pattern varied with geographical location, pathogens, and pathogen–drug combinations. Thus, the regional estimates made in this study could help tailor local responses as the ‘One Size Fits All’ approach might not be appropriate.

Despite concerted data collection efforts, high-quality data on AMR was sparsely available for many LMICs. Nevertheless, an improved scientific understanding of this rapidly emerging health threat should be the highest priority for global health policymakers.

Conclusions

The present study used major methodological innovations, two varying AMR counterfactual scenarios, and comprehensive data to fetch novel insights into the global AMR burden. Most importantly, it incorporated models tested and iterated over years during GBD study analysis. So, when used collectively, these models provided a complete estimate of AMR burden with robust geographical coverage.

Further, the researchers compared findings with other causes of death, offering much-needed context on the scale of the burden of this rapidly growing public health problem. The study analysis confirmed that bacterial AMR posed the biggest threat to human health in sub-Saharan Africa and South Asia, involved a diverse set of pathogens, and is exceptionally high for multiple essential antibiotic classes, including β-lactams and fluoroquinolones.

Furthermore, efforts to build and enhance laboratory infrastructure and bolster national & global AMR plans of action are essential to addressing the universal AMR burden. Future studies should also evaluate the indirect effects of AMR, such as its effect on the prophylaxis of infections in organ transplant recipients.

In the future, the study estimates could inform treatment guidelines against many predominant bacterial pathogens for a given infectious syndrome, which, along with estimates of pathogen–drug burden, could inform their treatment guidelines customized for a specific location.

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Journal reference:
Microbiology

Most kids recover from Lyme disease within six months of completing antibiotic treatment

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Reviewed by Emily Henderson, B.Sc.Apr 21 2023

A majority of parents of children diagnosed with Lyme disease reported that their kids recovered within six months of completing antibiotic treatment, according to a new joint study from Children’s National Research Institute and the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, published in Pediatric Research. The findings, based on Lyme disease treatment outcome data from 102 children in the United States, also revealed that a notably small percentage of children took longer than six months to recover and experienced a significant impact on their daily functioning.

Lyme disease is the most common vector-borne disease in the United States, with most cases caused by the bacterium Borrelia burgdorferi transmitted through the bites of infected blacklegged or deer ticks. Children between the ages 5 and 9 years account for a large proportion of the approximately 476,000 Lyme disease cases diagnosed and treated annually in the United States. Common symptoms of Lyme disease include: fever; headache; fatigue; and a distinct skin rash called erythema migrans. Without treatment, the infection can spread to joints, the heart and the nervous system. Antibiotic treatment resulting in full recovery is successful in most Lyme cases. For some, however, symptoms of pain, fatigue, or difficulty thinking persist or return after antibiotic treatment. Symptoms that substantially reduce levels of activity and impact quality of life for more than six months after treatment are classified as post-treatment Lyme disease (PTLD) syndrome.

This research studied the long-term outcomes of children with Lyme disease through a cross-sectional evaluation using validated surveys. The study collected survey responses from the parents of 102 children ages 5 to 18 years who had been diagnosed with Lyme disease between six months and 10 years before enrollment. Adolescents ages 10 to 18 years old were also invited to complete adolescent-specific questionnaires. According to these parent survey responses, 75% of children fully recovered within six months of completing treatment: 31% of all children recovered within one month; 30% recovered in one-to-three months; and 14% recovered in four-to-six months. Approximately 22% of children in the study experienced at least one symptom that persisted six or more months after completing treatment; of those, 9% had symptoms classified as PTLD syndrome. Six percent of the children were not fully recovered at the time of the survey, with 1% experiencing symptoms significant enough to impair daily functioning, the authors noted.

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According to the authors, this study supports previous data showing an excellent overall prognosis for children with Lyme disease, which should help alleviate understandable parental stress associated with lingering non-specific symptoms among infected children. They note that the findings of this study can help clinicians manage families’ expectations about the varying post-treatment recovery times of pediatric Lyme disease patients. The researchers suggest this new data could help reduce the potential for families seeking dangerous alternative therapies for children who experience prolonged recovery times. PTLD syndrome remains poorly understood in children and adults, and more research is needed to better understand these prolonged symptoms and identify treatment targets, according to the authors.

This study was supported through a partnership between NIAID and the Children’s National Research Institute (CNRI). Researchers at the Center for Translational Research at CNRI and the NIAID Laboratory of Clinical Immunology and Microbiology conducted the study.

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Source:

NIH/National Institute of Allergy and Infectious Diseases

Journal reference:

Monaghan, M., et al. (2023). Pediatric Lyme disease: systematic assessment of post-treatment symptoms and quality of life. Pediatric Research. doi.org/10.1038/s41390-023-02577-3.

Microbiology

Genomic study reveals Babesia duncani’s pathogenicity and virulence

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Reviewed by Emily Henderson, B.Sc.Apr 13 2023

‘Tis the season for hiking now that spring has arrived and temperatures are on the upswing. But with hikes come insect bites and on the increase in North America is babesiosis, a malaria-like disease spread especially between May and October by a tick.

Indeed, recent research suggests an increase in the incidence of diseases transmitted by ticks around the world, not just the United States and Canada, due likely to climate change and other environmental factors. Among the tick-borne pathogens, Babesia parasites, which infect and destroy red blood cells, are considered a serious threat to humans and animals. All cases of human babesiosis reported in the United States have been linked to either Babesia microti, B. duncani, or a B. divergens-like species.

Now a research team led by scientists at the University of California, Riverside, and Yale University reports the first high-quality nuclear genome sequence and assembly of the pathogen B. duncani. The team also determined the 3D genome structure of this pathogen that resembles Plasmodium falciparum, the malaria-causing parasite.

“Our data analysis revealed that the parasite has evolved new classes of multigene families, allowing the parasite to avoid the host immune response,” said Karine Le Roch, a professor of molecular, cell and systems biology at UC Riverside, who co-led the study with Choukri Ben Mamoun, a professor of medicine at Yale University.

According to Le Roch, who directs the UCR Center for Infectious Disease Vector Research, the study, published today in Nature Microbiology, not only identifies the molecular mechanism most likely leading to the parasite’s pathogenicity and virulence, but also provides leads for the development of more effective therapies.

By mining the genome and developing in vitro drug efficacy studies, we identified excellent inhibitors of the development of this parasite -; a pipeline of small molecules, such as pyrimethamine, that could be developed as effective therapies for treating and better managing human babesiosis. Far more scientific and medical attention has been paid to B. microti. The genome structure of B. duncani, a neglected species until now, will provide scientists with important insights into the biology, evolution, and drug susceptibility of the pathogen.”

Karine Le Roch, professor of molecular, cell and systems biology at UC Riverside

Human babesiosis caused by Babesia duncani is an emerging infectious disease in the U.S. and is often undetected because healthy individuals do not usually show symptoms. It has, however, been associated with high parasite burden, severe pathology, and death in multiple cases. Despite the highly virulent properties of B. duncani, little was known about its biology, evolution, and mechanism of virulence, and recommended treatments for human babesiosis against B. duncani are largely ineffective.

A strong immune system is required to fight the pathogen. A compromised immune system could lead to flu-like illness. The tick that spreads babesiosis is mostly found in wooded or grassy areas and is the same tick that transmits bacteria responsible for Lyme disease. As a result, around 20% of patients with babesiosis are co-infected with Lyme disease.

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B. duncani mostly infects deer, which serve as the reservoir host during the pathogen’s asexual development. The parasite’s sexual cycle occurs in the tick after the tick bites the infected deer. When this tick bites humans, infection begins. The full life cycle of Babesia parasites has not yet been determined. The tick that spreads babesiosis, called Dermacentor albipictus, lives longer than mosquitoes and could facilitate a long life cycle for B. duncani.

Even though scientists are discovering more Babesia species, diagnostics are mostly developed for B. microti. Le Roch is already working with Stefano Lonardi, a professor of computer science and engineering at UCR and co-first author of the study, on new Babesia strains that have evolved.

“The Babesia genomes are not very long,” said Lonardi, who assembled the B. duncani strain. “But they are challenging to assemble due to their highly repetitive content and can require years of research. Once the genome is assembled and annotated, it can provide valuable information, such as how the genes are organized, which genes are transcribed during infection, and how the pathogen avoids the host’s immune system.”

In older and immunocompromised people, if B. duncani is left unattended, babesiosis could worsen and lead to death. Once the pathogen enters the body and red blood cells start to get destroyed, fever, headache, and nausea can follow. People who get bitten by the ticks often don’t feel the bite, which complicates diagnosis. Skin manifestations of babesiosis are rare, Lonardi said, and difficult to separate from Lyme disease.

Le Roch and Lonardi urge people to be mindful of ticks when they go hiking.

“Check yourself for tick bites,” Le Roch said. “When you see your physician don’t forget to let them know you go hiking. Most physicians are aware of Lyme disease but not of babesiosis.”

Next the team plans to study how B. duncani survives in the tick and find novel vector control strategies to kill the parasite in the tick.

Le Roch, Mamoun, and Lonardi were joined in the study by colleagues at UCR, Yale School of Medicine, Université de Montpellier (France), Instituto de Salud Carlos III (Spain), Universidad Nacional Autónoma de México, and University of Pennsylvania. Pallavi Singh at Yale and Lonardi contributed equally to the study. The B. duncani genome, epigenome, and transcriptome were sequenced at UCR and Yale.

The study was supported by grants from the National Institutes of Health, Steven and Alexandra Cohen Foundation, Global Lyme Alliance, National Science Foundation, UCR, and Health Institute Carlos III.

Source:

University of California – Riverside

Journal reference:

Singh, P., et al. (2023). Babesia duncani multi-omics identifies virulence factors and drug targets. Nature Microbiology. doi.org/10.1038/s41564-023-01360-8.