Plasmin could be the link between COVID-19 comorbidities and serious illness

Sadis Matalon, Ph.D., of the University of Alabama at Birmingham and colleagues in Texas and San Francisco asked that question in a hypothesis paper published online in Physiological Reviews. This study was made available online in March 2020 ahead of final publication in issue on July 1, 2020. They reviewed, in detail, research literature for comorbidities like hypertension, diabetes, coronary heart disease, cerebrovascular illness, chronic obstructive pulmonary disease and kidney dysfunction, as well as many viral studies, studies of COVID-19 pathology and clinical presentation, and literature on the life-threatening acute respiratory distress syndrome.

Twelve days later, UAB Professor Emeritus Timothy Ness, M.D., Ph.D., posted plans on ClinicalTrials.gov for an exploratory COVID-19 outpatient study to test Matalon’s hypothesis and prevent worse clinical outcomes.

In the Physiological Reviews paper, the researchers noted that all those comorbidities feature elevated levels of the extracellular protease plasmin. Plasmin is able to nick proteins at amino acid sequences called furin sites. For many viruses, this nicking at furin sites increases their infectivity. Both SARS and MERS — the two virulent coronaviruses that are related to the COVID-19 virus — “have evolved an unusual two-step furin activation for fusion, suggestive of a role during the process of emergence into the human population,” the researchers wrote.

They noted that the COVID-19 virus, SARS-CoV-2, also has a furin site on its spike protein, the vital, viral protein for viral attachment to a lung cell. The researchers proposed that plasmin may cleave that furin site in the spike protein to increase its infectivity and virulence, and they hypothesized that, “the plasmin system may prove a promising therapeutic target for combating COVID-19.”

Ness already knew there is an inexpensive, commonly used drug — tranexamic acid, or TXA — that targets plasmin by inhibiting its conversion from the inactive precursor, plasminogen, to the active protease, plasmin.

TXA is approved by the U.S. Food and Drug Administration for treatment of heavy menstrual bleeding because having lower plasmin levels allows better clotting. TXA has a long track record of safety and is commonly given off-label. At UAB Hospital, TXA is used perioperatively as a standard-of-care for orthopedic and cardiac bypass surgeries; it is commonly used for hemorrhaging trauma patients and also has been used for spinal surgery, neurosurgery and corrective jaw surgeries. It is currently being studied for perioperative use in Cesarean section surgeries.

For the clinical trial, Ness and colleagues have started a double-blind study, giving either TXA or a placebo pill to COVID-19 outpatients who were recently diagnosed with COVID-19. Patients also receive an anticoagulant. The overall goal of the exploratory study is to assess both safety and efficacy of five days of TXA versus placebo in the COVID-19 population. Enrollment is ongoing.

Ness and colleagues hypothesize that the TXA treatment will reduce the infectivity and virulence of the virus, as measured by reduced need for hospitalization within a week if a patient’s condition deteriorates. Adults 19 years old and older are eligible, and all patients — whether in the control group or the TXA group — receive standard care as directed by their primary caretakers.

Other principal investigators for the trial are Sonya Heath, M.D., professor in the UAB Department of Medicine Division of Infectious Diseases; and Brant Wagener, M.D., Ph.D., associate professor, and Sadis Matalon, Ph.D., distinguished professor, both in the UAB Department of Anesthesiology and Perioperative Medicine. Ness is professor emeritus in that department.

Authors of the Physiological Reviews paper, “Elevated plasmin(ogen) as a common risk factor for COVID-19 susceptibility,” are Hong-Long Ji and Runzhen Zhao, University of Texas Health Science Centre at Tyler; Michael A. Matthay, University of California, San Francisco; and Matalon.

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An unprecedented discovery of cell fusion

Like humans, bacteria live together in communities, sometimes lending a hand — or in the case of bacteria, a metabolite or two — to help their neighbors thrive. Understanding how bacteria interact is critical to solving growing problems such as antibiotic resistance, in which infectious bacteria form defenses to thwart the medicines used to fight them.

Now, researchers at the University of Delaware have discovered that bacteria do more than just work together. Bacterial cells from different species can combine into unique hybrid cells by fusing their cell walls and membranes and sharing cellular contents, including proteins and ribonucleic acid (RNA), the molecules which regulate gene expression and control cell metabolism. In other words, the organisms exchange material and lose part of their own identity in the process.

This unprecedented observation, which was reported on Tuesday, Sept. 1 in mBio, a journal of the American Society for Microbiology, has the potential to shed light on unexplained phenomena affecting human health, energy research, biotechnology and more.

The research team, led by Eleftherios (Terry) Papoutsakis, Unidel Eugene Du Pont Chair of Chemical and Biomolecular Engineering, studied interactions between Clostridium ljungdahlii and C. acetobutylicum. These species of bacteria work together in a syntrophic system, producing metabolites that are mutually beneficial to each other’s survival.

The team found that C. ljungdahlii invades C. acetobutylicum. The two organisms combine cell walls and membranes and exchange proteins and RNA to form hybrid cells, some of which continue to divide and in fact differentiate into the characteristic sporulation program.

“They mix their machinery to survive or do metabolism, and that’s kind of extraordinary, because we always assumed that each and every organism has its own independent identity and machinery,” said Papoutsakis.

Previously, researchers have observed that bacteria could exchange some material through nanotubes. The combination into hybrid cells was unexpected.

“This is the first time we’ve shown this in this bacteria, and it’s also a new mechanism of how material is exchanged,” said Kamil Charubin, a doctoral student in chemical and biomolecular Engineering and first author of the paper.

Although this phenomenon of interspecies microbial fusion is now being reported for the first time, it is likely ubiquitous in nature among many bacterial pairs.

So why do bacteria bother to fuse together? The simple answer is likely because this process allows the microbes to share machinery that will increase their odds of survival.

For example, some pathogenic bacteria — those that can cause disease — may borrow proteins from other antibiotic-resistant bacteria in order to shore up their own resistance. Some bacteria might borrow machinery from others in order to evade detection by the immune system. This could also help to explain why some bacteria are difficult to culture, or grow for study or medical diagnostic purposes. These difficult-to-culture bacteria might combine with or work with and depend on other microorganisms for their existence instead of growing and multiplying on their own.

The team’s findings may influence understanding of the evolution of biology because once bacterial species share machinery, they can evolve together instead of only evolving on their own, said Papoutsakis.

“These findings will guide new thinking in not just the field of microbial evolution, but also toward biotechnological solutions that can benefit the soldier,” said Dr. Robert Kokoska, program manager, Army Research Office (ARO), an element of the U.S. Army Combat Capabilities Development Command’s Army Research Laboratory. “These include studies of how the human microbiome shapes soldier human health and cognition and how microbial communities can be better designed for a broad range of advances including strategies for reliable in-field biological sensing, waste remediation and novel means of biosynthesis.”

This work was supported by the Army Research Office (award no. W911NF-17-1-0343, and W911NF-19-1-0274) and the U.S. Department of Energy (DE-SC0019155).

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Materials provided by University of Delaware. Original written by Julie Stewart. Note: Content may be edited for style and length.

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Study examines the benefits of virtual stroke rehabilitation programs

While virtual medical and rehabilitation appointments seemed novel when COVID-19 first appeared, they now seem to be part of the new norm and might be paving the way to the future.

A recent review paper, co-authored by Brodie Sakakibara with the Centre for Chronic Disease Prevention and Management (CCDPM) has determined that virtual appointments, in the form of telerehabilitation, also work for people recovering from a stroke.

After a stroke, a client is provided with a therapy program to help re-gain loss of skills or motion — this can range from speech and memory, strength, balance and endurance. While not initially introduced for disease outbreaks, Sakakibara a UBCO assistant professor says research shows remote therapy can be effective during stroke recovery.

“Telerehabilitation has been promoted as a more efficient means of delivering rehabilitation services to stroke patients while also providing care options to those unable to attend conventional therapy,” says paper co-author Sakakibara. “These services can be provided to remote locations through information and communication technologies and can be accessed by patients in their homes.”

To learn how effective telerehabilitation can be, six different clinical trials — examining stroke telerehabilitation programs — were launched across Canada as part of a Heart and Stroke Foundation initiative. People recovering from a stroke were provided with interventions ranging from lifestyle coaching to memory, speech skills and physical-exercise training.

“Researchers from each of the six trials came together to write a review paper describing their experiences conducting a telerehabilitation study, and to report on the facilitators and barriers to the implementation of telerehab services within a research context,” says Sakakibara.

Going forward with telerehabilitation as a new reality, Sakakibara says the study authors determined there are important lessons learned from each of the six trials. Most notably, the efficacy and cost of telerehabilitation is similar to that of traditional face-to-face management. He also notes patients mostly reported satisfaction with the telerehabilitation when therapists were trained appropriately, and when there was some social interaction. Overall, clinicians prefer face-to-face interactions but will use telerehabilitation when face-to-face is not feasible.

And finally, since seniors are a key target group for stroke rehabilitation — as stroke is associated with aging — the technology needs to be easy to use and suit the needs of the end users.

“The older adult of today, in terms of technology comfort and use, is different than the older adult of tomorrow,” he says. “While there might be some hesitation of current older adults using technology to receive health and rehab services, the older adult of tomorrow likely is very comfortable using technology. This represents a large opportunity to develop and establish the telehealth/rehabilitation model of care.”

Sakakibara notes COVID-19 has amplified the necessity for telehealth and telerehabilitation for many Canadians — especially those in remote areas or for the estimated 70 per cent of stroke victims who are no longer able to drive.

“Prior to the outbreak, telehealth/rehabilitation was highly recommended in Canadian stroke professional guidelines, but was underused,” he says. “Now in response to COVID-19, the use of telerehabilitation has been accelerated to the forefront. Once these programs are implemented in practice, it’ll be part of the norm, even when the outbreak is over. It is important that we develop and study telerehabilitation programs to ensure the programs are effective and benefit the patients.”

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Greater Manchester lockdown easing U-turn after cases rise

Plans to ease restrictions in Bolton and Trafford are scrapped following a spike in Covid-19 cases.

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Coronavirus: Cheap steroids save lives from severe Covid

Eight lives would be saved for every 100 critically ill patients given steroids.

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Deaths at home higher than normal – ONS figures

People may be being discharged from hospital earlier or are choosing to die at home.

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Health24.com | ‘Aerosol boxes’ meant to protect Covid health teams might harm them

  • Aerosol containment methods may not be protecting health workers against SARS-CoV-2 as touted
  • The effectiveness of such devices was never properly tested
  • It was found that the aerosol box actually increases exposure to virus particles – by up to five times 

Aerosol boxes meant to protect health care workers when they intubate Covid-19 patients may actually increase their exposure to airborne virus particles, an Australian study warns.

Intubation is done when patients are placed on a ventilator.

Aerosol boxes have been touted as a quick, simple way to protect workers, but their effectiveness and safety were never clinically tested. No international guideline on personal protective equipment has endorsed their use.

Even though experts have raised concern that the devices may put health care workers at risk, they are in use worldwide.

Increased exposure to virus particles

In this study, researchers tested the effectiveness of five aerosol containment methods (aerosol box; sealed box with and without suction; vertical drape; and horizontal drape) compared with no intervention.

Volunteers held a bottle of harmless fluid just under their mouth, and coughed every 30 seconds. Detection devices were used to count different-sized airborne particles and assess particle spread for five minutes.

Compared with using no containment device, exposure to airborne particles of all sizes was higher when an aerosol box was used, the study found.

If Covid-19 particles act the same way as the fluid used in this simulation, the results suggest the aerosol box increases exposure to virus particles – in some cases by a factor of five times or more, according to findings published on in July in the journal Anaesthesia.

The investigation was conducted by a team at Intensive Care and Anaesthesia Specialists at Eastern Health in Melbourne. Peter Chan and Joanna Simpson, who led the effort, said the research team was surprised by the findings.

Minimal to no benefit

“Spikes of airborne particles were clearly seen, coinciding with patient coughing. We believe that these represent particles escaping from the arm access holes in the aerosol box,” the researchers reported.

The race to provide protective equipment has resulted in a variety of devices, but evidence of their safety and effectiveness has been lacking, the study authors said.

“This study demonstrates that devices such as the aerosol box we tested – which is typical of designs used worldwide – confer minimal to no benefit in containing aerosols during an aerosol-generating procedure and may increase rather than decrease airborne particle exposure,” the authors concluded.

In a journal news release, Chan said if the aerosol box were sold as a product and regulated, it would probably need to be recalled immediately due to the potential infection risk for healthcare workers.

“Unfortunately, because these devices have been donated and are not regulated in any way, healthcare workers might be continuing to increase their exposure to Covid-19 while thinking they are protecting themselves,” he added.

Image credit: Getty Images

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Health24.com | Gynaecological cancers not a risk for severe Covid-19

  • Women with gynaecological cancer may fear that they are more susceptible to Covid-19
  • A new study, however, revealed that these women were not more affected than those who only had Covid-19
  • The study could change the theory that cancer patients face worse odds when infected with Covid-19

Despite rampant fears that cancer patients are at higher risk of having severe cases of Covid-19, a new study suggests gynaecologic cancers do not boost the chances of hospitalisation or death.

“Our study should be reassuring for women with gynaecologic cancers who are worried that having cancer increases their risk of becoming seriously ill if they go to the hospital because of Covid-19,” said lead investigator Olivia Lara, an oncology fellow at NYU Langone’s Perlmutter Cancer Center.

For the study, Lara’s team reviewed the medical records of 121 women, aged 51 to 63, being treated simultaneously for gynaecologic cancers and Covid-19 in New York City between March and April.

The results, published online in July in the journal Cancer, revealed that these women had similar hospitalisation rates and death as those who only had Covid-19.

Only a mild form of the disease

More than half of the study patients required hospitalisation, and among those hospitalised one-quarter died, amounting to a 14% death rate.

The death rate among this sample is comparable to the 21% death rate identified in another study, which included 5 700 hospitalised Covid-19 patients in the city, the study authors noted.

The study could potentially alter the theory that cancer patients face worse odds when infected with Covid-19.

A full 75% of the women with gynaecological cancer experienced only a mild form of the disease, according to the report.

The women’s risk of dying from Covid-19 did not increase even if they had late-stage cancer, cancer surgery or high-dose chemotherapy, the study authors said in a New York University news release.

Sample size too small

Still, one risk factor related to cancer treatment seemed to increase the odds of death.

Women receiving immunotherapy – treatment that uses a person’s own immune system to fight cancer – were three times more likely to die than women who received standard cancer treatments such as radiation, surgery or chemotherapy.

But only eight out of the 121 participants included in the study were treated with immunotherapy, prompting the study authors to stress that the sample was too small to make any conclusions based on this finding.

The results do underscore the importance of receiving cancer screenings and treatments, despite Covid-19 fears.

“The basic rules of cancer care have not changed during the pandemic,” study senior investigator Dr Bhavana Pothuri said in the news release. “Early detection, screening and care lead to more people surviving what remains a leading cause of death among American women.”

Image credit: Getty Images

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Differing diets of bonobo groups may offer insights into how culture is created

Human societies developed food preferences based on a blend of what was available and what the group decided it liked most. Those predilections were then passed along as part of the set of socially learned behaviors, values, knowledge, and customs that make up culture. Besides humans, many other social animals are believed to exhibit forms of culture in various ways, too.

In fact, according to a new study led by Harvard primatologists Liran Samuni and Martin Surbeck, bonobos, one of our closest living relatives, could be the latest addition to the list.

The research, published today in eLife, is the result of a five-year examination of the hunting and feeding habits of two neighboring groups of bonobos at the Kokolopori Bonobo Reserve in the Democratic Republic of Congo. They looked at whether ecological and social factors influence those habits. Four of those years were spent tracking the neighboring groups of great apes using GPS and some old-fashioned leg work to record each time they hunted.

Analyzing the data, the scientists saw many similarities in the lives of the two bonobo groups, given the names the Ekalakala and the Kokoalongo. Both roam the same territory, roughly 22 square miles of forest. Both wake up and fall asleep in the bird-like nests they build after traveling all day. And, most importantly, both have the access and opportunity to hunt the same kind of prey. This, however, is precisely where researchers noticed a striking difference.

The groups consistently preferred to hunt and feast on two different types of prey. The Ekalakala group almost always went after a type of squirrel-like rodent called an anomalure that is capable of gliding through the air from tree to tree. The Kokoalongo group, on the other hand, favored a small to medium-sized antelope called a duiker that lives on the forest floor.

“The idea is that if our closest living relatives, chimpanzees and bonobos, both have some cultural traits, then [it’s likely] our ancestors already had some capacity for culture.” — Liran Samuni

Out of 59 hunts between August 2016 and January 2020, the Ekalakala captured and ate 31 anomalure, going after duikers only once. Kokoalongo ate 11 duikers in that time and only three gliding rodents.

“It’s basically like two cultures exploiting a common resource in different ways,” said Samuni, a postdoctoral fellow in Harvard’s Pan Lab and the paper’s lead author. “Think about two human cultures living very close to each other but having different preferences: one preferring chicken more while the other culture is more of a beef-eating culture. … That’s kind of what we see.”

Using statistical modeling, the scientists found this behavior happens independent of factors like the location of the hunts, their timing, or the season. They also found the preference wasn’t influenced by hunting party size or group cohesion. In fact, the researchers’ model found that the only variable that could reliably predict prey preference was whether the hunters were team Ekalakala or team Kokoalongo.

The researchers make clear in the paper that they didn’t investigate how the bonobo groups learned this hunting preference, but through their analysis they were able to rule out ecological factors or genetic differences between the two groups. Basically, it means all evidence points toward this being a learned social behavior.

“It’s the same population, and it’s neighboring communities,” said Surbeck, an assistant professor in the Department of Human Evolutionary Biology and the paper’s senior author. He founded and directs the Kokolopori Bonobo Research Project. “These two communities basically live in the same exact forest. They use the exact same places, but, nevertheless, they show these differences.”

The paper amounts to what’s believed to be the strongest evidence of cultural behavior in this primate species.

The researchers believe this paper is only the tip of the iceberg and are already planning the next part of the work: looking at how the bonobo groups learned these behaviors.

One of the main goals driving this work is helping characterize the cultural capabilities of the last common ancestor between humans and our two closely related great ape cousins.

“The idea is that if our closest living relatives, chimpanzees and bonobos, both have some cultural traits, then [it’s likely] our ancestors already had some capacity for culture,” Samuni said.

Bonobos can play a special role in this mystery. Like chimpanzees, which they are often mistaken for, bonobos share 99 percent of their DNA with humans. Bonobos are often seen as less aggressive and territorial, however, favoring sex in various partner combinations over fighting. Chimp groups, on the other hand, sometimes battle when they meet in the wild, occasionally to the death.

Different Bonobo population groups are known to interact and even share meals, which along with their socio-sexual behavior has earn them the moniker “hippie apes.” It’s those free love and peace traits that make them prime for this type of study since scientists can observe two neighboring bonobo groups to distinguish whether a behavior that differs between two groups that interact regularly comes about because of some sort of a learning mechanism (or social preference) or because the environment dictates it, the researchers said.

The authors of the paper were not much surprised by their findings.

They had noticed this hunting preference anecdotally, and it’s already believed that bonobos have subtle cultural traits. After all, a number of social animals display cultural behavior, especially when it comes to feeding habits. Chimps teach their young to use sticks to fish for termites. Dolphin mothers teach offspring to fit marine sponges to their noses to protect them as they forage on the seafloor.

What excites the researchers about this discovery, however, is that it shows the value of studying this often-overlooked endangered species and diving into its culture.

“They’re like the missing puzzle piece,” Surbeck said.

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Study tracks human milk nutrients in infant microbiome

A new study in mice helps explain why gut microbiomes of breastfed infants can differ greatly from those of formula-fed infants.

The study, “Dietary Sphinganine Is Selectively Assimilated by Members of the Mammalian Gut Microbiome,” was published in July in the Journal of Lipid Research.

Sphinganine from milk Johnson Lab/Provided A new technique allows researchers to track specific nutrients as they are taken up by gut microbes in a mouse’s digestive tract. The image shows certain microbes (red) taking in a nutrient common in human milk called sphinganine; blue microbes have not taken it in.

The paper describes an innovative technique developed at Cornell to track the fate of metabolites — nutrients formed in or necessary for metabolism — through a mouse’s digestive tract and identify how they interact with specific gut microbes.

“We think the methods are expandable to many different microbiome systems,” said senior author Elizabeth Johnson, assistant professor of nutritional sciences in the College of Agriculture and Life Sciences. She noted that researchers investigating effects of a high-fat vs. low-fat diet, or a keto diet, might use the technique to track metabolites.

The methodology could reveal how specific metabolites promote specific bacteria. This could allow nutritionists to prescribe that patients eat foods containing specific metabolites to intentionally change the composition of their microbiomes, Johnson said.

Human milk and many other foods contain a class of lipid metabolites called sphingolipids. Previous research suggested that these metabolites help shape an infant’s microbiome, but it was not known if they actually interact with the microbiome.

The study identified two types of gut microbes, Bacteroides and Bifidobacterium, that use sphingolipids for their own metabolism.

While very little is known about the specific roles of gut microbes in human health, Bacteroides have been implicated in both beneficial and not-so-beneficial effects, depending on context. They are generally associated with microbiomes of healthy breastfed infants. Bifidobacterium, shown for the first time in this study to process dietary sphingolipids, are considered the quintessential beneficial bacteria, comprising up to 95% of breastfed infants microbiome.

They’re also a highly popular over-the-counter probiotic.

“Our lab is very interested in how the diet interacts with the microbiome in order to really understand how you can best modulate it to have positive effects on health,” Johnson said. “In this study, we were able to see that yes, these dietary lipids that are a big part of [breastfed] infants diets, are interacting quite robustly with the gut microbiome.”

Sphingolipids originate from three main sources: diet; bacteria that can produce them; and most host tissues.

Johnson, along with first author Min-Ting Lee, a doctoral student, and Henry Le, a postdoctoral researcher, both in Johnson’s lab, created a technique to specifically track dietary sphingolipids as they passed through the mouse gut.

“We custom synthesized the sphingolipid we added to the diet,” Johnson said. “It is almost identical to ones derived from breast milk but with a small chemical tag so we could trace the location of the sphingolipid once it was ingested by the mice.”

Lee then used a fluorescent label that attached to cells or microbes that absorbed the tagged lipid, such that any bacteria that had taken up sphingolipids lit up red. Microbes from the mice’s microbiomes were then isolated and analyzed. Populations with red microbes were separated from the others, and these were then genetically sequenced to identify the species of bacteria.

With further investigation, Le was able to identify the metabolites that Bacteroides and Bifidobacterium produce when exposed to dietary sphingolipids. Further investigations are underway to determine whether these microbially-produced metabolites are beneficial for infant health.

Johnson recently received a five-year, $1.9 million Maximizing Investigators’ Research Award from the National Institutes of Health (NIH) to expand on this work, to better understand how lipid-dependent host-microbe interactions affect human health..

The study was supported by seed funds from the Genomics Facility of the Biotechnology Resource Center at Cornell’s Institute of Biotechnology.

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Materials provided by Cornell University. Original written by Krishna Ramanujan. Note: Content may be edited for style and length.

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