Publisher Health

As of April 2021, about 2.8 million people worldwide have died of COVID-19. Early in the pandemic, researchers developed accurate diagnostic tests and identified health conditions that correlated with worse outcomes. However, a clinical predictor of who faces the highest risk of being hospitalized, put on a ventilator or dying from the disease has remained largely out of reach.
This week in mSphere, an open-access journal of the American Society for Microbiology, researchers describe a two-step prognostic test that can help predict a patient’s response to infection with SARS-CoV-2. The test combines a disease risk factor score with a test for antibodies produced early in the infection. It could be administered at the time of diagnosis to help guide therapeutic choices before the most severe symptoms appear, the researchers said.
“You can predict with really high sensitivity that someone is going to have a severe case of COVID-19,” said Emily Sanders, a graduate student in the lab of chemical biologist Gregory Weiss, Ph.D, at the University of California, Irvine. Sanders led the study together with Sanjana Sen and Kristin Gabriel, also graduate students in Weiss’s lab.
Most diagnostic tests search for antibodies associated with interrupting the virus. Weiss said the group initially set out to develop their own diagnostic, following this same strategy, but quickly realized that plenty of competing tests would soon be available. Instead, they pivoted to focus on other, unstudied antibodies — ones that wouldn’t necessarily disrupt the virus or help the immune system fight the infection.
“Everyone else was looking for the good antibodies that neutralize the virus,” said Weiss, senior author on the study. “We weren’t seeing enough about antibodies that are unhelpful.”
“Being able to identify a ‘bad’ antibody response helps to fill in a research gap,” said Gabriel.
Previous studies have predicted that the SARS-CoV-2 particle has more than 55 epitopes, or sites on the virus where antibodies can attach. The best studied epitopes to date are those found on the S, or spike, protein, but the virus has three other structural proteins, each with epitopes worth investigating, said Sen. Using ELISAs, or enzyme-linked immunosorbent assays, the researchers compiled a list of antibodies that might correlate with worse prognosis and ultimately focused on one that attaches to epitope 9 on the N, or nucleocapsid, protein. The group also developed a tool that used data on factors including age, sex, and pre-existing health conditions to produce a disease risk factor score (DRFS).
They tested their tool on a group of 86 people who had tested positive for the coronavirus. Patients whose tests revealed the presence of epitope 9 antibodies were more likely to have prolonged illness and worse outcomes than people without the antibodies. Of the 23 people in the study who did have the antibodies associated with epitope 9, a high DRFS predicted disease severity with more than 92% sensitivity.
The test uses technology and tools readily available in testing labs, Weiss said. “Detecting antibodies is super easy to do,” he said, and an inexpensive prognostic test could inform treatment decisions early in the disease progression. The researchers found that the epitope-9 antibodies become detectable between 1 and 6 days after the onset of symptoms.
“We’ve all had friends and family impacted by this disease,” said Weiss, “and we wanted to do something that might be useful, that might help the physicians who are being overwhelmed.”
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Materials provided by American Society for Microbiology. Note: Content may be edited for style and length.

Tiny molecules called nanobodies, which can be designed to mimic antibody structures and functions, may be the key to blocking a tick-borne bacterial infection that remains out of reach of almost all antibiotics, new research suggests.
The infection is called human monocytic ehrlichiosis, and is one of the most prevalent and potentially life-threatening tick-borne diseases in the United States. The disease initially causes flu-like symptoms common to many illnesses, and in rare cases can be fatal if left untreated.
Most antibiotics can’t build up in high enough concentrations to kill the infection-causing bacteria, Ehrlichia chaffeensis, because the microbes live in and multiply inside human immune cells. Commonly known bacterial pathogens like Streptococcus and E. coli do their infectious damage outside of hosts’ cells.
Ohio State University researchers created nanobodies intended to target a protein that makes E. chaffeensis bacteria particularly infectious. A series of experiments in cell cultures and mice showed that one specific nanobody they created in the lab could inhibit infection by blocking three ways the protein enables the bacteria to hijack immune cells.
“If multiple mechanisms are blocked, that’s better than just stopping one function, and it gives us more confidence that these nanobodies will really work,” said study lead author Yasuko Rikihisa, professor of veterinary biosciences at Ohio State.
The study provided support for the feasibility of nanobody-based ehrlichiosis treatment, but much more research is needed before a treatment would be available for humans. There is a certain urgency to coming up with an alternative to the antibiotic doxycycline, the only treatment available. The broad-spectrum antibiotic is unsafe for pregnant women and children, and it can cause severe side effects.

Analysis of data from a lightning mapper and a small, hand-held radiation detector has unexpectedly shed light on what a gamma-ray burst from lightning might look like — by observing neutrons generated from soil by very large cosmic-ray showers. The work took place at the High Altitude Water Cherenkov (HAWC) Cosmic Ray Observatory in Mexico.
“This was an accidental discovery,” said Greg Bowers, a scientist at Los Alamos National Laboratory and lead author of the study published in Geophysical Research Letters. “We set up this system to study terrestrial gamma-ray flashes — or gamma-ray bursts from lightning — that are typically so bright you can see them from space. The idea was that HAWC would be sensitive to the gamma-ray bursts, so we installed a lightning mapper to capture the anatomy of the lightning development and pinpoint the lightning processes producing them.”
The team, including Xuan-Min Shao and Brenda Dingus also from Los Alamos, used a small, handheld particle detector, expecting that a terrestrial gamma-ray flash would generate a clear gamma-ray signal in the small particle detector.
“Our system ran for almost two years, and we saw a lot of lightning,” said Bowers. But during those storms, they did not observe anything that looked like terrestrial gamma-ray flashes. “We did, however, see large count-rate bursts during clear, fair-weather days, which made us scratch our heads.”
HAWC data gathered during these times showed that, in every case, the large array that comprises HAWC had been overwhelmed by extremely large cosmic-ray showers — so large that the Los Alamos researchers couldn’t estimate their size.
UC Santa Cruz collaborator David Smith found that these fair-weather bursts had previously been observed by scientists in Russia, who called them “neutron bursts,” and determined that they were the result of neutron production in the soil around the impact point of cosmic ray shower cores.
Previous work that simulated these events had only considered hadrons — a type of subatomic particle — in the core of the showers. In addition to hadrons and other particles, cosmic-ray shower cores also contain a lot of gamma rays.
For this work, William Blaine, also of Los Alamos, simulated large cosmic ray-showers, and included both hadrons and gamma rays. “We were able to match our observations with the simulations,” said Bowers. “We found that the gamma rays produce the same type of neutron burst as the hadrons.”
This study suggests that any natural phenomena that produces a beam of gamma-rays pointed towards the ground (such as downward terrestrial gamma-ray flashes), could produce a similar “neutron burst” signature. This is significant for future terrestrial gamma-ray flash observation modeling efforts.
“It tell us that you can’t just model the gamma rays hitting your detector, you’ll also have to consider the neutron burst that’s happening nearby,” said Bowers.
The HAWC Observatory comprises an array of water-filled tanks high on the flanks of the Sierra Negra volcano in Puebla, Mexico, where the thin atmosphere offers better conditions for observing gamma rays. When gamma rays strike molecules in the atmosphere they produce showers of energetic particles. When some of those particles strike the water inside the HAWC detector tanks, they produce flashes of light called Cherenkov radiation. By studying these Cherenkov flashes, researchers reconstruct the sources of the showers to learn about the particles that caused them.
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Materials provided by DOE/Los Alamos National Laboratory. Note: Content may be edited for style and length.

College students across the country struggle with a vicious cycle: Test anxiety triggers poor sleep, which in turn reduces performance on the tests that caused the anxiety in the first place.
New research from the University of Kansas just published in the International Journal of Behavioral Medicine is shedding light on this biopsychosocial process that can lead to poor grades, withdrawal from classes and even students who drop out. Indeed, about 40% of freshman don’t return to their universities for a second year in the United States.
“We were interested in finding out what predicted students’ performance in statistics classes — stats classes are usually the most dreaded undergrad class,” said lead author Nancy Hamilton, professor of psychology at KU. “It can be a particular problem that can be a sticking point for a lot of students. I’m interested in sleep, and sleep and anxiety are related. So, we wanted to find out what the relationship was between sleep, anxiety and test performance to find the correlation and how it unfolds over time.”
Hamilton and graduate student co-authors Ronald Freche and Ian Carroll and undergraduates Yichi Zhang and Gabriella Zeller surveyed the sleep quality, anxiety levels and test scores for 167 students enrolled in a statistics class at KU. Participants completed an electronic battery of measures and filled out Sleep Mood Study Diaries during the mornings in the days before a statistics exam. Instructors confirmed exam scores. The study showed “sleep and anxiety feed one another” and can hurt academic performance predictably.
“We looked at test anxiety to determine whether that did predict who passed, and it was a predictor,” Hamilton said. “It was a predictor even after controlling for students’ past performance and increased the likelihood of students failing in class. When you look at students who are especially anxious, it was almost a five-point difference in their score over students who had average levels of anxiety. This is not small potatoes. It’s the difference between a C-minus abd a D. It’s the difference between a B-plus and an A-minus. It’s real.”
Beyond falling grades, a student’s overall health could suffer when test anxiety and poor sleep reinforce each other.

The highly infectious SARS-CoV-2 variant that recently emerged in South Africa, known as B.1.351, has scientists wondering how existing COVID-19 vaccines and therapies can be improved to ensure strong protection. Now, researchers reporting in ACS’ Journal of Medicinal Chemistry have used computer modeling to reveal that one of the three mutations that make variant B.1.351 different from the original SARS-CoV-2 reduces the virus’ binding to human cells — but potentially allows it to escape some antibodies.
Since the original SARS-CoV-2 was first detected in late 2019, several new variants have emerged, including ones from the U.K., South Africa and Brazil. Because the new variants appear to be more highly transmissible, and thus spread rapidly, many people are worried that they could undermine current vaccines, antibody therapies or natural immunity. Variant B.1.351 bears two mutations (N501Y and E484K) that can enhance binding between the receptor binding domain (RBD) of the coronavirus spike protein and the human ACE2 receptor. However, the third mutation (K417N; a lysine to asparagine mutation at position 417) is puzzling because it eradicates a favorable interaction between the RBD and ACE2. Therefore, Binquan Luan and Tien Huynh from IBM Research wanted to investigate potential benefits of the K417N mutation that could have caused the coronavirus to evolve along this path.
The researchers used molecular dynamics simulations to analyze the consequences of the K417N mutation in variant B.1.351. First, they modeled binding between the original SARS-CoV-2 RBD and ACE2, and between the RBD and CB6, which is a SARS-CoV-2-neutralizing antibody isolated from a recovered COVID-19 patient. They found that the original amino acid, a lysine, at position 417 in the RBD interacted more strongly with CB6 than with ACE2, consistent with the antibody’s therapeutic efficacy in animal models. Then, the team modeled binding with the K417N variant, which changes that lysine to an asparagine. Although this mutation reduced the strength of binding between the RBD and ACE2, it decreased the RBD’s binding to CB6 and several other human antibodies to a much greater extent. Thus, variant B.1.351 appears to have sacrificed tight binding to ACE2 at this site for the ability to evade the immune system. This information could prove useful to scientists as they work to enhance the protection of current vaccines and therapies, the researchers say.
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Materials provided by American Chemical Society. Note: Content may be edited for style and length.

Using naturalistic driving data and machine learning techniques, researchers at Columbia University Mailman School of Public Health and Columbia’s Fu Foundation School of Engineering and Applied Science have developed highly accurate algorithms for detecting mild cognitive impairment and dementia in older drivers. Naturalistic driving data refer to data captured through in-vehicle recording devices or other technologies in the real-world setting. These data could be processed to measure driving exposure, space and performance in great detail. The findings are published in the journal Geriatrics.
The researchers developed random forests models, a statistical technique widely used in AI for classifying disease status, that performed exceptionally well. “Based on variables derived from the naturalistic driving data and basic demographic characteristics, such as age, sex, race/ethnicity and education level, we could predict mild cognitive impairment and dementia with 88 percent accuracy, “said Sharon Di, associate professor of civil engineering and engineering mechanics at Columbia Engineering and the study’s lead author.
The investigators constructed 29 variables using the naturalistic driving data captured by in-vehicle recording devices from 2977 participants of the Longitudinal Research on Aging Drivers (LongROAD) project, a multisite cohort study sponsored by the AAA Foundation for Traffic Safety. At the time of enrollment, the participants were active drivers aged 65-79 years and had no significant cognitive impairment and degenerative medical conditions. Data used in this study spanned the time period from August 2015 through March 2019.
Among the 2977 participants whose cars were instrumented with the in-vehicle recording devices, 33 were newly diagnosed with mild cognitive impairment and 31 with dementia by April 2019. The researchers trained a series of machine learning models for detecting mild cognitive impairment/dementia and found that the model based on driving variables and demographic characteristics was 88 percent accurate, much better than models based on demographic characteristics only (29 percent) and driving variables only (66 percent). Further analysis revealed that age was most predictive of mild cognitive impairment and dementia, followed by the percentage of trips traveled within 15 miles of home, race/ethnicity, minutes per trip chain (i.e., length of trips starting and ending at home), minutes per trip, and number of hard braking events with deceleration rates ≥ 0.35 g.
“Driving is a complex task involving dynamic cognitive processes and requiring essential cognitive functions and perceptual motor skills. Our study indicates that naturalistic driving behaviors can be used as comprehensive and reliable markers for mild cognitive impairment and dementia,” said Guohua Li, MD, DrPH, professor of epidemiology and anesthesiology at Columbia Mailman School of Public Health and Vagelos College of Physicians and Surgeons, and senior author. “If validated, the algorithms developed in this study could provide a novel, unobtrusive screening tool for early detection and management of mild cognitive impairment and dementia in older drivers.”
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Materials provided by Columbia University’s Mailman School of Public Health. Note: Content may be edited for style and length.

Difficult-to-treat, chronic wounds in preclinical models healed with normal scar-free skin after treatment with an acellular product discovered at Mayo Clinic. Derived from platelets, the purified exosomal product, known as PEP, was used to deliver healing messages into cells of preclinical animal models of ischemic wounds. The Mayo Clinic research team documented restoration of skin integrity, hair follicles, sweat glands, skin oils and normal hydration.
Ischemic wounds occur when arteries are clogged or blocked, preventing important nutrients and oxygen from reaching the skin to drive repair. This groundbreaking study titled, “TGF-β Donor Exosome Accelerates Ischemic Wound Healing,” is published in Theranostics.
“This paper documents that PEP, an off-the-shelf, room-temperature-stable exosome, is capable of healing wounds that are depleted of adequate blood supply. Wounds healed with only a single application of exosome,” says Steven Moran, M.D., a Mayo Clinic plastic surgeon and senior co-author on the study. “I was surprised that this product regenerated healthy skin with normal biomechanical properties — not scar tissue. As this technology is now scaled and biomanufactured for clinical applications, it creates the potential for huge advancement in medical science and the field of plastic surgery.”
This study has laid the foundation for Food and Drug Administration approval to begin a first-in-class clinical trial to test safety of using the purified exosomal product for wound healing in patients. This research is supported by Mayo Clinic’s Center for Regenerative Medicine, which is a leader in advancing new, validated regenerative procedures from research into practice.
Chronic ischemic wounds are common in people with conditions such as diabetes, pressure ulcers, hardening of arteries, traumatic injury or side effects of radiation therapy. Standard treatments for these wounds include wound dressing, topical gels and surgery. Although these measures offer some relief, they often cannot fully close the wound. As a result, approximately 7 million people in the U.S. have wounds that don’t close properly, and efforts to find solutions have grown to a multibillion dollar industry, according to National Institutes of Health-sponsored research. When the condition progresses, nonhealing wounds lead to limb amputation.
The purified exosomal product is an extracellular vesicle that delivers cargo from one cell to another, targeting exact tissues in need of repair. This technology is manufactured under strict quality control measures and formulated as a dry powder to enable long-term storage at room temperature. In the operating room or at the bedside, the powder is mixed with a hydrogel solution on-site and can be applied directly to the wound. Unlike cellular products, it does not have to be sent to an outside laboratory to be cultured and scaled.
“What we see with this technology is not just that the wound is closed, but also that the blood supply to the tissue is restored. Our effort culminating in the development of this exosomal technology was to create a therapy that can be offered to all patients in need through elimination of logistical limitations often seen with more traditional regenerative therapy,” says Atta Behfar, M.D., Ph.D., deputy director of Translation, Mayo Clinic’s Center for Regenerative Medicine and senior author. “Our research hopes to answer whether this can be a new healing solution for patients suffering with nonhealing chronic wounds.” Dr. Behfar is director of the Mayo Clinic Van Cleve Cardiac Regenerative Medicine Program where the purified exosomal product was discovered.
The research
The research team replicated wounds with low blood supply in large animal models. They treated some of the wounds with the purified exosomal product and compared them to wounds that were treated with the hydrogel alone. They found wounds treated with the purified exosomal product were able to heal with skin restored to its normal architecture.
“We found that this exosome therapy has the ability to enhance regeneration of blood vessels in damaged tissues. Without treatment, chronic ischemic wounds grow larger and more problematic,” says Ao Shi, Ph.D., a student in the Regenerative Sciences Training Program in Mayo Clinic Graduate School of Biomedical Sciences and first author.
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Materials provided by Mayo Clinic. Note: Content may be edited for style and length.

Processed diets, which are low in fiber, may initially reduce the incidence of foodborne infectious diseases such as E. coli infections, but might also increase the incidence of diseases characterized by low-grade chronic infection and inflammation such as diabetes, according to researchers in the Institute for Biomedical Sciences at Georgia State University.
This study used mice to investigate how changing from a grain-based diet to a highly processed, high-fat Western style diet impacts infection with the pathogen Citrobacter rodentium, which resembles Escherichia coli (E. coli) infections in humans. The findings are published in the journal PLOS Pathogens.
Gut microbiota, the microorganisms living in the intestine, provide a number of benefits, such as protecting a host from infection by bacterial pathogens. These microorganisms are influenced by a variety of environmental factors, especially diet, and rely heavily on complex carbohydrates such as fiber.
The Western-style diet, which contains high amounts of processed foods, red meat, high-fat dairy products, high-sugar foods and pre-packaged foods, lacks fiber, which is needed to support gut microbiota. Changes in dietary habits, especially a lack of fiber, are believed to have contributed to increased prevalence of chronic inflammatory diseases such as inflammatory bowel disease, metabolic syndrome and cancer.
In this study, the researchers found switching mice from a standard grain-based rodent chow to a high-fat, low-fiber Western-style diet resulted in a rapid reduction in the number of gut bacteria. Mice fed the Western-style diet were frequently unable to clear the pathogen Citrobacter rodentium from the colon. They were also prone to developing chronic infection when re-challenged by this pathogen.
The researchers conclude the Western-style diet reduces the numbers of gut bacteria and promotes encroachment of microbiota into the intestine, potentially influencing immune system readiness and the body’s defense against pathogenic bacteria.
“We observed that feeding mice a Western-style diet, rather than standard rodent grain-based chow, altered the dynamics of Citrobacter infection, reducing initial colonization and inflammation, which was surprising. However, mice consuming the Western-style diet frequently developed persistent infection that was associated with low-grade inflammation and insulin resistance,” said Dr. Andrew Gewirtz, senior co-author of the study and professor in the Institute for Biomedical Sciences. “These studies demonstrate potential of altering microbiota and their metabolites by diet to impact the course and consequence of infection following exposure to a gut pathogen.”
“We speculate that reshaping gut microbiota by nutrients that promote beneficial bacteria that out-compete pathogens may be a means of broadly promoting health,” said Dr. Jun Zou, senior co-author of the study and assistant professor in the Institute for Biomedical Sciences at Georgia State.
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Materials provided by Georgia State University. Note: Content may be edited for style and length.

Researchers at the University of Bath investigating how virtual reality (VR) can help improve balance believe this technology could be a valuable tool in the prevention of falls.
As people grow older, losing balance and falling becomes more common, which increases the risk of injury and affects the person’s independence.
Falls are the leading cause of non-fatal injuries in over 65-yearolds and account for over 4 million bed days per year in England alone, at an estimated cost of £2 billion.
Humans use three ways of keeping their balance: vision, proprioceptive (physical feedback from muscles and joints) and vestibular system (feedback from semi-circular canals in the ear). Of these, vision is the most important.
Traditional ways of assessing balance include patient surveys and physical tests such as using a treadmill or testing agility when performing specific movements or exercises.
However, the accuracy of these tests can be affected by age, sex and motivation, and the movements measured aren’t necessarily reflective of real-life scenarios.

It’s well established that infectious disease is the greatest threat to the endangered chimpanzees made famous by the field studies of Jane Goodall at Gombe National Park in Tanzania. Now, new research led by scientists at Emory University shows that nearly half of the fecal samples from wild chimpanzees contain bacteria that is resistant to a major class of antibiotics commonly used by people in the vicinity of the park.
The journal Pathogens published the findings.
“Our results suggest that antibiotic-resistant bacteria is actually spreading from people to non-human primates by making its way into the local watershed,” says Thomas Gillespie, senior author of the study and associate professor in Emory’s Department of Environmental Sciences and Rollins School of Public Health. “People are bathing and washing in the streams, contaminating the water with drug-resistant bacteria where wild chimpanzees and baboons drink.”
The researchers tested for genes conferring resistance to sulfonamides — drugs often used by people in the region to treat diarrheal diseases — in fecal samples from humans, domestic animals, chimpanzees and baboons in and around Gombe National Park. They also tested stream water used by these groups.
Sulfonamide resistance appeared in 74 percent of the human samples overall, 48 percent of chimpanzee samples, 34 percent of baboon samples, and 17 percent of the domestic animal samples. Sulfonamide also showed up in 19 percent of the samples taken from streams shared by people, domestic animals and wildlife.
The researchers also tested all the groups in the study for genes conferring resistance to tetracycline — another class of antibiotics that is used much less frequently by people in the vicinity, likely due to its greater expense and the fact that it is less available in the area. As expected, very few of the fecal samples from any of the groups, and none of the water samples from the streams, showed evidence of tetracycline resistance.