Culture

July 2, 2021 - For health care organizations looking to improve performance and patient experiences, implementing data-driven solutions can be effective when focusing on addressing health equity and reducing patient length of stay. These topics are explored in selected member-submitted abstracts from the 2020 Vizient® Connections Education Summit that appear in a special supplement to the July/August 2021 issue of the American Journal of Medical Quality, the official journal of the American College of Medical Quality (ACMQ).

Interventions for addressing health equity

To help health care organizations address health equity, Andrew S. Resnick, MD, MBA, Brigham and Women's Hospital, Karthik Sivashanker, MD, MPH, CPPS, Brigham and Women's Hospital, and Tam Duong, MS, Institute for Healthcare Improvement, developed an intervention framework that "provides a road map for organizations to advance equitable and safe care to all patients by using current patient safety reporting mechanisms to identify events pertaining to explicit, implicit, individual, group, and structural biases." The events identified are then analyzed to identify effective solutions and track their implementation. The authors tested the framework at Brigham and Women's Hospital and saw an "80-fold increase in actions taken from root cause analysis to addressing inequities." Learn more in the abstract "Equity Is a Patient Safety Emergency."

Using data to reduce length of stay

Over the last four years, the Vizient length of stay (LOS) index at Memorial Hermann Texas Medical Center has had a downward trend that plateaued in the past year. The stall in the LOS index has led to nursing units reaching capacity and to an increase in patient wait times for beds. To ensure that resources are allocated appropriately, Stephen W. Simington, MS, MPH, Memorial Hermann Texas Medical Center, and Bela Patel, MD, Memorial Hermann Texas Medical Center/UT Health, developed a statistical dashboard using the Vizient Clinical Data Base to help the health system "identify data-driven opportunities that focus on maximizing resources in the greatest areas of opportunity." The authors expect that the use of the tool and subsequent interventions will show a reduction in the LOS index over time. Learn more in the abstract "Four Clicks from Vizient Data to Actional Information."

GAINESVILLE, Fla. --- Archaeologists have unearthed a rare trove of more than 80 metal objects in Mississippi thought to be from Hernando de Soto's 16th-century expedition through the Southeast. Many of the objects were repurposed by the resident Chickasaws as household tools and ornaments, an unusual practice at a time when European goods in North America were few and often reserved for leaders.

The researchers believe Spaniards left the objects behind while fleeing a Chickasaw attack that followed frayed relations between the two groups in 1541. The victors took advantage of the windfall of spoils - axe heads, blades, nails and other items made of iron, lead and copper alloy - modifying many of them to suit local uses and tastes. Chickasaw craftspeople turned pieces of Spanish horseshoes into scrapers, barrel bands into cutting tools and bits of copper into jingling pendants.

The sheer abundance of objects from the site, an area of northeastern Mississippi known as Stark Farms, is one of the factors that makes the find unique, said Charles Cobb, the study's lead author and Florida Museum of Natural History Lockwood Chair in Historical Archaeology.

"Typically, we might find a handful of European objects in connection with a high-status person or some other special context," Cobb said. "But this must have been more of an open season - a pulse of goods that became widely available for a short period of time."

If the researchers' diagnosis is correct, Stark Farms is only the second place to yield convincing archaeological evidence of direct contact with de Soto's expedition, after the historic site of the Apalachee capital of Anhaica in present-day Tallahassee, Cobb said.

'Unconquered and unconquerable'

By the time de Soto arrived in Mississippi in 1540, the conquistador had trekked through the Southeast for more than a year with about 600 people, hundreds of horses and pigs and heavy equipment in tow. A shrewd man with a reputation for bloodshed, de Soto was previously a key figure in the Spanish destruction of the Inca Empire in South America and came to Florida with an eye to further increase his wealth. Finding little gold, he pressed deeper into the interior, alternately befriending and warring with the Native Americans he encountered.

The Spaniards began on a friendly, if aloof, footing with the Chickasaws, whose leader, known as Chikasha Minko, gave them a modest village in which to spend the winter. But tensions rose as the months dragged on: De Soto executed two Chickasaws and cut off the hands of another accused of stealing pigs. The Chickasaws, who farmed maize in the region's rich prairie soil, also must have grown tired of providing food and shelter for such a large encampment of uninvited guests, Cobb said.

With spring drawing near, de Soto demanded that Chikasha Minko provide him with hundreds of Chickasaws to carry the Spaniards' equipment to their next destination. According to Spanish accounts of the expedition, the conversation did not go well.

Shortly afterwards, the Chickasaws launched a surprise attack under the cover of night, torching the Spanish camp and killing at least a dozen men, as well as many horses and pigs. The retreating Spaniards set up another camp about a mile away, where they were assaulted a second time. Better prepared, they fought back, but soon picked up and headed north, having lost much of their livestock, clothing and goods.

Meanwhile, the Chickasaws collected from the battlefield dozens of prized metal objects, usually reserved by the Europeans for strategic trades or as gifts to smooth relationships with local leaders.

"It's kind of like inflation," Cobb said. "You don't want too much stuff to get out or that gift will be devalued. That's what makes this site unusual."

After the Chickasaws sent the Spanish packing, the region remained largely free of European presence for nearly 150 years.

"This research shows how Chickasaws adapted to invasion by alien intruders and secured their reputation as unconquered and unconquerable," said study co-author Brad Lieb, director of Chickasaw archaeology for the Chickasaw Nation's Heritage Preservation Division. "The findings are remarkable in their success in addressing a baseline event in Chickasaw cultural history - the first encounter with Hernando de Soto and the Spanish invaders."

History confirmed by metal detectors

When Cobb, Lieb and their colleagues first arrived at Stark Farms in 2015, they weren't just looking for traces of de Soto. The Chickasaw Nation, removed from its traditional homeland to Oklahoma by the U.S. Department of War in 1837, had commissioned the team to identify and preserve ancestral sites and provide Chickasaw university students the opportunity to reconnect with their heritage through an archaeology fieldwork program.

The team focused on studying the environmental factors in the movements of Native Americans across the landscape, where radiocarbon dates showed people had lived since the 14th or 15th century. Curious about early residents' potential interactions with outsiders, the researchers brought metal detectors, a speedy way of finding objects of European origin. The first day they deployed the detectors, the machines began pinging. Soon, the team was uncovering dozens of items, including a small cannon ball, a mouth harp and what could be a Spanish bridle bit, emblazoned with a golden cross.

"We couldn't believe it," Cobb said. "There was a lot of serendipity for sure."

The style and type of objects, as well as their location, aligned with Spanish accounts of the de Soto expedition and the 1541 battle at Chikasha, the main Chickasaw town. But the researchers found no evidence of a burned village or the remains of horses and pigs. Cobb said the site was likely a village near Chikasha, whose inhabitants visited the site of the conflict and brought items back to their households. They may also have acquired some of the objects during the previous winter through under-the-table trading with Spanish soldiers.

The Chickasaws generally relied on bone, cane or stone as raw materials for their cutting and scraping tools, making the haul of metal a particular boon. While some of the objects retain their original form, the Chickasaws painstakingly reworked others into more familiar shapes. They bent metal back and forth until it broke and ground down and smoothed edges, modifying tools to mimic the design of their traditional Chickasaw counterparts.

"One of the most stunning things we've found is an exact iron replica of a Native American stone celt, or axe head," Cobb said. "I've never seen anything like this in the Southeast before."

Among the more sobering finds were chain links, pulled apart with sharpened edges. "The Spanish brought reams of chain with them to shackle Native Americans as captives and porters," Cobb said. "This is evidence of some of the first examples of European enslavement of people in what is now the U.S."

The refashioned items from Stark Farms represent a stage of Native American experimentation and improvisation with foreign items that largely faded by the late 1700s and 1800s, as they folded European materials and technology more completely into their own.

"In the 1500s, a thimble might be turned into a bangle. By the late 1700s, a thimble is a thimble," Cobb said. "You tend to see a more regular adoption of goods over time."

Spanish survivors did their own repurposing

De Soto failed to establish any permanent settlements in the Southeast, joining a line of ill-fated expeditions that demonstrated the precariousness of Europeans' early attempts to dominate the region. He succumbed to a fever on the banks of the Mississippi River in 1542, and his remaining band of men made rafts and floated south to Mexico where they found passage back to Spain.

There, they undertook a repurposing effort of their own: Having failed to find fame and fortune in the Americas, they sold their stories, many of which became bestselling books, Cobb said.

"There was a thriving industry in explorer and survival tales, which is probably one of the reasons why some of these individuals provided their accounts. From that perspective, it was very modern."

The objects will be repatriated to the Chickasaw Nation for permanent curation and exhibits.

MANHATTAN, KANSAS -- A recent study by Kansas State University virologists demonstrates successful postinfection treatment for SARS-CoV-2, the virus that causes COVID-19.

College of Veterinary Medicine researchers Yunjeong Kim and Kyeong-Ok "KC" Chang published the study in the prestigious journal Proceedings of the National Academy of Sciences of the United States of America, or PNAS. They found that animal models infected with SARS-CoV-2 and treated with a deuterated protease inhibitor had significantly increased survival and decreased lung viral load.

The results suggest that postinfection treatment with inhibitors of proteases that are essential for viral replication may be an effective treatment against SARS-CoV-2. These protease inhibitors are a class of antiviral drugs that prevent viral replication by selectively binding to viral proteases and blocking the activation of proteins that are necessary for the production of infectious viral particles.

"We developed the protease inhibitor GC376 for treating a fatal coronavirus infection in cats, which is now under commercial development as an investigational new animal drug," said Kim, associate professor of diagnostic medicine and pathobiology. "After COVID-19 emerged, many research groups reported that this inhibitor is also effective against the coronavirus that causes COVID-19, and many are currently pursuing the development of protease inhibitors as a treatment."

Kim and Chang modified GC376 using a tool called deuteration to test its efficacy against SARS-CoV-2.

"Treating SARS-CoV-2-infected mice with deuterated GC376 significantly improved survival, viral replication in lungs and weight losses, which shows the efficacy of the antiviral compound," said Chang, professor of diagnostic medicine and pathobiology. "The results suggest deuterated GC376 has a potential for further development, and this deuteration method can be utilized to other antiviral compounds to generate potent inhibitors."

The virologists are continuing to develop improved inhibitors using various methods. Deuterated GC376 is currently being evaluated for further potential development.

It is the membrane of cancer cells that is at the focus of the new research now showing a completely new way in which cancer cells can repair the damage that can otherwise kill them.

In both normal cells and cancer cells, the cell membrane acts as the skin of the cells. And damage to the membrane can be life threatening. The interior of cells is fluid, and if a hole is made in the membrane, the cell simply floats out and dies - a bit like a hole in a water balloon.

Therefore, damage to the cell membrane must be repaired quickly, and now research from a team of Danish researchers shows that cancer cells use a technique called macropinocytosis. The technique, which is already a known tool for cells in other contexts, consists in the cancer cells pulling the intact cell membrane in over the damaged area and sealing the hole in a matter of minutes. Next, the damaged part of the cell membrane is separated into small spheres and transported to the cells' 'stomach' - the so-called lysosomes, where they are broken down.

In the laboratory, the researchers damaged the membrane of the cancer cells using a laser that shoots small holes in the membrane and triggers macropinocytosis. Here they can see that if the process is inhibited with substances blocking the formation of the small membrane spheres, the cancer cell can no longer repair the damage and dies.

- Our research provides very basic knowledge about how cancer cells survive. In our experiments, we have also shown that cancer cells die if the process is inhibited, and this points towards macropinocytosis as a target for future treatment. It is a long-term perspective, but it is interesting, says group leader Jesper Nylandsted from the Danish Cancer Society's Research Center and the University of Copenhagen, who has headed the new research and who for many years has investigated how cancer cells repair their membranes.

Possibility of recycling

One of the most dangerous properties of cancer is when the disease spreads in the body. If tumors occur in new parts of the body, the disease becomes more difficult to treat and typically requires more extensive forms of treatment. It is also when cancer cells spread through the body's tissues that they are particularly prone to damage to their membrane.

Researchers at the Danish Cancer Society have previously shown how cancer cells can use another technique to repair the membrane, namely by tying off the damaged part, rather like when a lizard throws its tail.

However, the experiments in the laboratory could indicate that especially the aggressive cancer cells use macropinocytosis. This may be due to the fact that the cancer cell has the opportunity to reuse the damaged membrane when it is degraded in the lysosomes. This type of recycling will be useful for cancer cells because they divide frequently, requiring large amounts of energy and material for the new cells.

And although the researchers have now published the new results, their work is not over. This is explained by another member of the research team, postdoc Stine Lauritzen Sønder:

- We continue to work and investigate how cancer cells protect their membranes. In connection with macropinocytosis in particular, it is also interesting to see what happens after the membrane is closed. We believe that the first patching is a bit rough and that a more thorough repair of the membrane is needed afterwards. It can be another weak point in the cancer cells, and is something we want to examine closer, she says.

(Boston)--Would you be more willing to get vaccinated against the COVID-19 virus if you could participate in a lottery for cash and prizes? The answer was surprisingly no, according to Boston University School of Medicine (BUSM) researchers who found that Ohio's "Vax-a-Million" lottery-based incentive system, intended to increase COVID-19 vaccination rates, was not associated with an increase in COVD-19 vaccinations.

Prior reports in the media had suggested that the Ohio lottery increased COVID-19 vaccinations, leading other states to use COVID-19 vaccine incentive lotteries in an attempt to increase slowing vaccination rates. "However, prior evaluations of the Ohio vaccine incentive lottery did not account for other changes in COVID-19 vaccination rates in the United States, such as those that may have been due to expansion of vaccination to ages 12-15," explained corresponding author Allan J. Walkey, MD, MSc, professor of medicine at BUSM.

Using data from the U.S. Centers of Disease Control to evaluate trends in vaccination rates among adults 18 and older, the researchers compared vaccination rates before and after the Ohio lottery versus other states in the U.S. that did not yet have vaccine incentive lottery programs. Vaccination rates in other states served as a "control" for vaccination trends measured in Ohio, allowing the researchers to account for factors besides the Ohio lottery (such expanding vaccine eligibility to adolescents) throughout the country.

"Our results suggest that state-based lotteries are of limited value in increasing vaccine uptake. Therefore, the resources devoted to vaccine lotteries may be more successfully invested in programs that target underlying reasons for vaccine hesitancy and low vaccine uptake," said Walkey, a physician at Boston Medical Center.

The researchers believe identifying interventions that can successfully increase COVID-19 vaccination rates is a critical public health issue necessary to curb the pandemic. "It is important to rigorously evaluate strategies designed to increase vaccine uptake, rapidly deploy successful strategies, and phase out those that do not work," Walkey said.

Although Walkey and his colleagues were sorry to see that state lottery incentives were not associated with an increase COVID-19 vaccinations, they hope their findings will lead to a shift in focus away from ineffective and expensive lotteries, and on to further study of other programs that may more successfully increase vaccine uptake.

Some three quarters of the biomass in hop plants used in beer-making ends up in landfills. But a group of Japanese researchers has developed a technique that 'upcycles' that waste hop into cellulose nanofibers (CNFs). A paper describing the technique was published in the journal ACS Agricultural Science & Technology on June 11.

In the past few years, craft beer-making has exploded in popularity around the world, including many beer styles that make use of many more and different types of hops than conventional commercial beers. A traditional preservative in beer, hops also add a rich bitterness and impart floral or citrus aromas and flavors. As a result, hop production hit a record high in 2019.

However, only the flower of the hop plant is used in beer making. The stems and leaves, which make up about 75 percent of the biomass produced in hop cultivation, are typically burned or tossed in a landfill after harvest. As some 75% of hop plants end up in landfills, the technique should reduce the beer industry's growing waste and land footprint while also cutting back on petroleum feedstocks.

A group of researchers have developed a technique that 'upcycles' these waste products by using hop stems as raw material to extract CNFs. Since the 2000s, there has been increasing interest in CNFs due to their outstanding properties, including low weight and high strength and stabilization. Thanks to those advantages, CNFs are expected to be used as excellent plant-derived materials for reducing the amount of petroleum based plastics in various industrial applications such as automotive and housing industries as well as food and cosmetic fields.

"This really would deserve a hearty 'cheers' if we managed to reduce dependence on petroleum while also radically reducing the agricultural waste from the beer industry," said Izuru Kawamura, associate professor in the Graduate School of Engineering Science at Yokohama National University and the lead researcher on the project.

CNFs had been extracted successfully from wood and from agro-industrial wastes such as pineapple leaves, banana stems, grapefruit peels, and even spent coffee grounds from cafes.

"But until now, no attempt had been made to isolate CNFs from hop stems," Kawamura added.

Plant cell walls are made of cellulose microfibrils, or very small and slender fibers, in a matrix composed of lignin and hemicellulose. The particular chemical compositions of cellulose, hemicellulose, and lignin vary widely depending on the source of the fibers.

Generally, CNFs are extracted from wood pulp via a series of purification steps followed by refinement via treatment with chemicals or enzymes. Previously, a technique involving application of 2,2,6,6-tetramethylpiperidine-1-oxyl radical (described more simply as 'TEMPO) to pretreated cellulose from wood followed by a gentle mechanical disintegration in water had obtained CNFs of 3-4 nanometers in width.

The researchers used the TEMPO technique, but also reduced the pretreatment processes for removing lignin and hemicellulose in hop stems which is considered as lignocellulose fibers prior to the TEMPO step. Even without the pretreatments, they could obtain CNFs with a median of about 2 nanometers. Using the chemical composition analysis, they were able to conclude that the hop stems contained a proportion of cellulose that is almost equal in proportion to that of wood.

This means that not only could this technique replace petroleum, but in a third environmental win, hop waste could also be used instead of wood as an alternative source for CNFs.

"You might even say 'three cheers' for CNFs from hops."

As a next step, the team wants to actually prepare some emulsions stabilized by hop stem-derived CNFs and demonstrate to industry their feasibility. If successful, they should lead to a significant reduction in the amount of conventional synthetic surfactants used.

Wander around a desert most anywhere in the world, and eventually you'll notice dark-stained rocks, especially where the sun shines most brightly and water trickles down or dew gathers. In some spots, if you're lucky, you might stumble upon ancient art - petroglyphs - carved into the stain. For years, however, researchers have understood more about the petroglyphs than the mysterious dark stain, called rock varnish, in which they were drawn.

In particular, science has yet to come to a conclusion about where rock varnish, which is unusually rich in manganese, comes from.

Now, scientists at the California Institute of Technology, the Department of Energy's SLAC National Accelerator Laboratory and elsewhere think they have an answer. According to a recent paper in Proceedings of the National Academy of Sciences, rock varnish is left behind by microbial communities that use manganese to defend against the punishing desert sun.

The mystery of rock varnish is old, said Usha Lingappa, a graduate student at Caltech and the study's lead author. "Charles Darwin wrote about it, Alexander von Humboldt wrote about it," she said, and there is a long-standing debate about whether it has a biological or inorganic origin.

But, Lingappa said, she and her colleagues didn't actually set out to understand where rock varnish comes from. Instead, they were interested in how microbial ecosystems in the desert interact with rock varnish. To do so, they deployed as many techniques as they could come up with: DNA sequencing, mineralogical analyses, electron microscopy, and - aided by Stanford Synchroton Radiation Lightsource (SSRL) scientist Samuel Webb - advanced X-ray spectroscopy methods that could map different kinds of manganese and other elements within samples of rock varnish.

"By combining these different perspectives, maybe we could draw a picture of this ecosystem and understand it in new ways," Lingappa said. "That's where we started, and then we just stumbled into this hypothesis" for rock varnish formation.

Among the team's key observations was that, while manganese in desert dust is usually in particle form, it was deposited in more continuous layers in varnish, a fact revealed by X-ray spectroscopy methods at SSRL that can tell not only what chemical compounds make up a sample but also how they are distributed, on a microscopic scale, throughout the sample.

That same analysis showed that the kinds of manganese compounds in varnish were the result of ongoing chemical cycles, rather than being left out in the sun for millennia. That information, combined with the prevalence of bacteria called Chroococcidiopsis that use manganese to combat the oxidative effects of the harsh desert sun, led Lingappa and her team to conclude that rock varnish was left behind by those bacteria.

For his part, Webb said that he always enjoys a manganese project - "I've been a mangaphile for a while now" - and that this project arrived at the perfect time, given advances in X-ray spectroscopy at SSRL. Improvements in X-ray beam size allowed the researchers to get a finer-grained picture of rock varnish, he said, and other improvements ensured that they could get a good look at their samples without the risk of damaging them. "We're always tinkering and fine-tuning things, and I think it was the right time for a project that maybe 5 or 10 years ago wouldn't really have been feasible."

BOSTON -- Gaurav Gaiha, MD, DPhil, a member of the Ragon Institute of MGH, MIT and Harvard, studies HIV, one of the fastest-mutating viruses known to humankind. But HIV's ability to mutate isn't unique among RNA viruses -- most viruses develop mutations, or changes in their genetic code, over time. If a virus is disease-causing, the right mutation can allow the virus to escape the immune response by changing the viral pieces the immune system uses to recognize the virus as a threat, pieces scientists call epitopes.

To combat HIV's high rate of mutation, Gaiha and Elizabeth Rossin, MD, PhD, a Retina Fellow at Massachusetts Eye and Ear, a member of Mass General Brigham, developed an approach known as structure-based network analysis. With this, they can identify viral pieces that are constrained, or restricted, from mutation. Changes in mutationally constrained epitopes are rare, as they can cause the virus to lose its ability to infect and replicate, essentially rendering it unable to propagate itself.

When the pandemic began, Gaiha immediately recognized an opportunity to apply the principles of HIV structure-based network analysis to SARS-CoV-2, the virus that causes COVID-19. He and his team reasoned that the virus would likely mutate, potentially in ways that would allow it to escape both natural and vaccine-induced immunity. Using this approach, the team identified mutationally constrained SARS-CoV-2 epitopes that can be recognized by immune cells known as T cells. These epitopes could then be used in a vaccine to train T cells, providing protective immunity. Recently published in Cell, this work highlights the possibility of a T cell vaccine which could offer broad protection against new and emerging variants of SARS-CoV-2 and other SARS-like coronaviruses.

From the earliest stages of the COVID-19 pandemic, the team knew it was imperative to prepare against potential future mutations. Other labs already had published the protein structures (blueprints) of roughly 40% of the SARS-CoV-2 virus, and studies indicated that patients with a robust T cell response, specifically a CD8+ T cell response, were more likely to survive COVID-19 infection.

Gaiha's team knew these insights could be combined with their unique approach: the network analysis platform to identify mutationally constrained epitopes and an assay they had just developed, a report on which is currently in press at Cell Reports, to identify epitopes that were successfully targeted by CD8+ T cells in HIV-infected individuals. Applying these advances to the SARS-CoV-2 virus, they identified 311 highly networked epitopes in SARS-CoV-2 likely to be both mutationally constrained and recognized by CD8+ T cells.

"These highly networked viral epitopes are connected to many other viral parts, which likely provides a form of stability to the virus," says Anusha Nathan, a medical student in the Harvard-MIT Health Sciences and Technology program and co-first author of the study. "Therefore, the virus is unlikely to tolerate any structural changes in these highly networked areas, making them resistant to mutations."

You can think of a virus's structure like the design of a house, explains Nathan. The stability of a house depends on a few vital elements, like support beams and a foundation, which connect to and support the rest of the house's structure. It is therefore possible to change the shape or size of features like doors and windows without endangering the house itself. Changes to structural elements, like support beams, however, are far riskier. In biological terms, these support beams would be mutationally constrained -- any significant changes to size or shape would risk the structural integrity of the house and could easily lead to its collapse.

Highly networked epitopes in a virus function as support beams, connecting to many other parts of the virus. Mutations in such epitopes can risk the virus's ability to infect, replicate, and ultimately survive. These highly networked epitopes, therefore, are often identical, or nearly identical, across different viral variants and even across closely related viruses in the same family, making them an ideal vaccine target.

The team studied the identified 311 epitopes to find which were both present in large amounts and likely to be recognized by the vast majority of human immune systems. They ended up with 53 epitopes, each of which represents a potential target for a broadly protective T cell vaccine. Since patients who have recovered from COVID-19 infection have a T cell response, the team was able to verify their work by seeing if their epitopes were the same as ones that had provoked a T cell response in patients who had recovered from COVID-19. Half of the recovered COVID-19 patients studied had T cell responses to highly networked epitopes identified by the research team. This confirmed that the epitopes identified were capable of inducing an immune reaction, making them promising candidates for use in vaccines.

"A T cell vaccine that effectively targets these highly networked epitopes," says Rossin, who is also a co-first author of the study, "would potentially be able to provide long-lasting protection against multiple variants of SARS-CoV-2, including future variants."

By this time, it was February 2021, more than a year into the pandemic, and new variants of concern were showing up across the globe. If the team's predictions about SARS-CoV-2 were correct, these variants of concerns should have had little to no mutations in the highly networked epitopes they had identified.

The team obtained sequences from the newly circulating B.1.1.7 Alpha, B.1.351 Beta, P1 Gamma, and B.1.617.2 Delta SARS-CoV-2 variants of concern. They compared these sequences with the original SARS-CoV-2 genome, cross-checking the genetic changes against their highly networked epitopes. Remarkably, of all the mutations they identified, only three mutations were found to affect highly networked epitopes sequences, and none of the changes affected the ability of these epitopes to interact with the immune system.

"Initially, it was all prediction," says Gaiha, an investigator in the MGH Division of Gastroenterology and senior author of the study. "But when we compared our network scores with sequences from the variants of concern and the composite of circulating variants, it was like nature was confirming our predictions."

In the same time period, mRNA vaccines were being deployed and immune responses to those vaccines were being studied. While the vaccines induce a strong and effective antibody response, Gaiha's group determined they had a much smaller T cell response against highly networked epitopes compared to patients who had recovered from COVID-19 infections.

While the current vaccines provide strong protection against COVID-19, Gaiha explains, it's unclear if they will continue to provide equally strong protection as more and more variants of concern begin to circulate. This study, however, shows that it may be possible to develop a broadly protective T cell vaccine that can protect against the variants of concern, such as the Delta variant, and potentially even extend protection to future SARS-CoV-2 variants and similar coronaviruses that may emerge.

What The Study Did: Researchers estimated the frequency and magnitude of surprise bills for deliveries and newborn hospitalizations, which are the leading reasons for hospitalization in the United States, to illustrate the  potential benefits of federal legislation that will protect families from most surprise bills. Potential surprise bills were defined as claims from out-of-network clinicians and ancillary service providers, such as an ambulance.

Authors: Kao-Ping Chua, M.D., Ph.D., of the University of Michigan Medical School in Ann Arbor, is the corresponding author.

 To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamahealthforum.2021.1460)

Editor's Note: The article includes conflict of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

PHILADELPHIA-- While more women are entering the field of academic medicine than ever before, they are less likely to be recognized as experts and leaders; they are less likely to receive prestigious awards, be promoted to full professorships, hold leadership roles, or author original research or commentaries in major journals. What's more, articles published by women in high-impact medical journals also have fewer citations than those written by men, especially when women are primary and senior authors, according to new research from the Perelman School of Medicine and the Leonard Davis Institute of Health Economics at the University of Pennsylvania, published today in JAMA Open Network.

Researchers found that of the 5,554 articles published in 5 leading academic medical journals between 2015 and 2018, 35.6 percent had a female primary author, and 25.8 percent had a female senior author. During this period, the articles with women as primary author were referenced in other academic articles a median of 36 times, compared 54 citations of articles with male primary authors. The trend extended to articles with female senior authors, which were cited a median of 37 times, while articles by male counterparts received a median of 51 citations. Original articles with women as both primary and senior authors were cited the fewest times, with a median of 33 citations, whereas articles authored by men as both primary and senior author were cited the most, a median of 59 times.

"The number of times a peer-reviewed articles cited by other researchers is commonly used as a metric for academic recognition, influence, as well as in professional evaluations and promotions," says lead author Paula Chatterjee, MD, MPH, an assistant professor of General Internal Medicine at Penn Medicine. "Female academics already face a number of barriers to career advancement, and the disparity in citations only broadens the gap between them and their male peers."

Authors also note that some of the journals included in the study focus on the field of internal medicine, which typically has a higher proportion of women represented than other clinical specialties. As a result, the findings may actually underestimate differences in scholarly article citations between male and female authors.

"Gender disparities in citations are just one way in which inequities in academic medicine should be examined. Our findings highlight that disparities stem in part from inequities in recognition and amplification of research. This imbalance will not be solved through hiring and mentoring more women alone," said senior author, Rachel Werner, MD, PhD, Executive Director of the Leonard Davis Institute for Health Economics. "We must also work to ensure that women already in academic medicine are equally valued and promoted for their contributions and their successes. From the journals publishing this work, to academic institutions promoting articles once published, everyone should be invested in bridging this gender divide."

The human brain is a wonderfully enigmatic organ, helping to juggle multiple tasks efficiently to help us get through a long day! This feature, called executive function, seats primates like us at the pinnacle of evolution. The prospect of losing the spectacular flow of neural information in our brains because of an accident or disease is, thus, unnerving. In the event of such an unfortunate occurrence, to restore the brain to its previous working condition with full functionality--to reboot it, so to speak--would need a better understanding of the specific neural pathways involved in our daily activities that rely on working memory and decision-making--two important executive functions.

To achieve this objective, a group of researchers from National Institutes for Quantum and Radiological Science and Technology (QST), Japan, were hard at work at devising a technique they call "imaging-guided chemogenetic synaptic silencing" to decipher the specific neural pathways involved in high-order executive functions. In a pioneering study published in Science Advances, the researchers now report successfully delineating specific neural pathways involved in working memory and decision-making using this technique.

The group, led by eminent researcher Dr. Takafumi Minamimoto from the Department of Functional Brain Imaging, QST, focused on studying the dorsolateral part of the prefrontal cortex (dlPFC) in the monkey brain, to apply their novel technique, and further identify the neural pathways of interest. It is interesting to note this choice, not only because it is the brain region partially responsible for controlling executive functions, but also since this specialized region is only present in primates.

Importantly, the role of dlPFC is supported by brain regions like the dorsal caudate (dCD) and lateral mediodorsal thalamus (MDl) too. This intricate association is further explained by Dr. Kei Oyama, who is the first author of the study, as follows, "The primate prefrontal cortex (PFC), especially its dorsolateral part (dlPFC), is well known to serve as the center of higher-order executive functions; it is uniquely developed in primates and underlies their distinctive cognitive abilities. These functions, however, do not solely rely on dlPFC neurons but also on their cooperative interactions with subcortical structures, including the dorsal caudate (dCD) nucleus and lateral mediodorsal thalamus (MDl)."

Next, the researchers wanted to understand the who-does-what for working memory and decision-making. Given that the dlPFC, MDI, and dCD neurons are connected, they selectively silenced specific neuronal synapses to disrupt the flow of information, and achieve just dlPFC-dCD and dlPFC-MDl projections, either unilaterally (involving just one side of the brain), or bilaterally (involving both sides). To achieve this, they made the dlPFC neurons express designer receptors exclusively activated by designer drugs (DREADDs). Further, the monkeys involved in the study were analyzed for behavioral changes, to understand the effect of chemogenetic silencing.

Interestingly, the researchers observed that silencing the bilateral dlPFC-MDl projections in the monkeys, but not their dlPFC-dCD projections, caused problems in the working memory related to their surroundings. On the contrary, silencing their unilateral dlPFC-dCD projections, but not their unilateral dlPFC-MDl projections, altered their preference in decision-making. These results reveal that the two higher-brain functions, working memory and decision-making, which are essential for our daily lives, are controlled by different neural pathways linking specific brain areas.

Overall, this study lays the foundation for further explorations of the intricacies of the complex primate brain. In this regard, Dr. Oyama explains the potential clinical and research applications of these findings, "Many psychiatric disorders, including depression, are thought to be associated with disturbances in the transmission of neural information through neural circuits between specific brain regions. Our findings are expected to deepen our understanding of mental disorders and lead to the discovery of treatments and remedies. The successful development of a novel technique in our study will serve as a key technology for the next-generation of researchers to investigate primate brain functions, which will contribute to broad areas in life by dramatically deepening our understanding of the mechanism of higher-brain functions."

The world will indeed wait with bated breath for future mysteries to unravel as explorations take researchers deeper into the labyrinthine maze that is the mind.

Guadalupe fur seals (Arctocephalus townsendi) have established a large resting colony in the Gulf of California--bringing the total number of sites where this endangered species now occurs to just four. This new haul-out was discovered on El Farallón de San Ignacio Island, along the mainland coast of Mexico, according to researchers from Mexico and the University of British Columbia.

Guadalupe fur seals were hunted for their furs and declared extinct in the late 1800's. However, 14 individuals were discovered on Guadalupe Island in 1950--and the population has grown since then. While still designated as vulnerable to extinction, according to IUCN, the population is believed to total 41,000 individuals and is growing at an annual rate of 10-11 per cent per year.

While the only breeding site for this species continues to be on Guadalupe Island, a large resting colony or 'haul-out' was established in the late 1990s on the nearby San Benito Islands in the Pacific Ocean, off the coast of Baja California.

Now, a second, well-populated haul-out colony has also begun forming, this time off the Mexican coast in the Gulf of California.

"We observed a single adult male Guadalupe fur seal ashore at El Farallón de San Ignacio Island in 2008, and later spotted several juvenile fur seals in 2014 and 2016. This led us to increase our observation efforts in 2019, with wonderful results," said Claudia Hernández-Camacho, corresponding author, and professor in the Centro Interdisciplinario de Ciencias Marinas, Instituto Politécnico Nacional. "During our visits to El Farallón in 2020, we counted 492 individuals in January, and 771 in November. Most of the animals we have seen have been juveniles, and all have appeared to be in good body condition."

"We at first thought that the animal sighted in 2008 was an anomaly," said Andrew Trites, professor in the Marine Mammal Research Unit, based in UBC's Institute for the Oceans and Fisheries, and co-author of the research findings. "El Farallón is a small, hot and arid island, and not a place where anyone would have expected to find fur seals. However, the past six years of observation have shown that the young Guadalupe fur seals clearly like it. The question is why?"

Trites and Hernández-Camacho suspect this new haul-out is centered in a new seasonal feeding area used by young Guadalupe fur seals. Guadalupe fur seals are known to feed mainly on opalescent squid, Humboldt squid and purpleback squid.

In addition to the new colony discovered at El Farallón de San Ignacio Island, a smaller haul-out also in the southern Gulf of California has also been growing since 2019 on nearby Las Animas Islet.

Both of these haul-outs in the Gulf of California are in protected areas, known as Áreas de Protección de Flora y Fauna Islas del Golfo de California. However the needs of Guadalupe fur seals are not addressed by those protected areas because the seals were previously considered only as occasional visitors.

With the confirmed establishment of the El Farallón colony, it is important that Mexico develop a conservation policy that addresses the importance of the southern Gulf of California as a feeding ground for vulnerable Guadalupe fur seals.

Overall, Guadalupe fur seals are slowly increasing in the southern Gulf of California--and are known to range as far as the coastlines of Washington and British Columbia. However, they only occur in just four places in Mexico.

"Guadalupe fur seals have only one breeding colony, so the new haul-outs in the southern Gulf of California provide some good news. However, the new sites will need regular monitoring to document their growth and possible changes in body conditions, age and sex-composition, and breeding potential", said Trites.

"This species escaped extinction once and remains vulnerable."

Fukuoka, Japan--Medical researchers led by Kyushu University have revealed a possible underlying genetic pathway behind the neurological dysfunction of Rett syndrome. The team found that deficiencies in key genes involved in the pathology triggers neural stem cells to generate less neurons by producing more astrocytes--the brain's maintenance cells.

The researchers hope that the molecular pathology they identified, as reported in the journal Cell Reports, can lead to potential therapeutic targets for Rett syndrome in the future.

Rett syndrome is a progressive neurodevelopmental disorder characterized by impairments in cognition and coordination--with varying severity--and occurs in roughly one in every 10,000 to 15,000 female births. However, it is difficult to initially identify because children appear to develop normally in the first 6-18 months.

"Rett syndrome is caused by mutations in a single gene called methyl-CpG binding protein 2, or MeCP2. The gene was identified over two decades ago and much has been uncovered since, but exactly how the mutations cause the pathology remains elusive," explains first author Hideyuki Nakashima of Kyushu University's Faculty of Medical Sciences

In their past research, the team had identified that MeCP2 acts as a regulator for the processing of specific microRNAs to control the functions of neurons. So, they went back to investigate if that pathway was also involved in the differentiation of neural stem cells.

Compared to messenger RNA, the final template transcribed from DNA that is used by a cell to synthesize proteins, microRNAs--or miRNAs--are much smaller and act to regulate messenger RNA to make sure the cell is making the correct amount of the desired protein.

"Through our investigation, we found several microRNAs associated with MeCP2, but only one affected the differentiation of neural stem cells: a microRNA called miR-199a," says Nakashima. "In fact, when either MeCP2 or miR-199a are disrupted, we found that it increased the production of cells called astrocytes."

Astrocytes are like the support cells of your brain. While neurons fire off the electrical signals, astrocytes are there to help maintain everything else. During development, astrocytes and neurons are generated from the same type of stem cells, known as neural stem cells, where their production is carefully controlled. However, dysfunction in MeCP2 or miR-199a causes these stem cells to produce more astrocytes than neurons.

"Further analysis showed that miR-199a targets the protein Smad1, a transcription factor critical for proper cellular development. Smad1 functions downstream of a pathway called BMP signaling, which is known to inhibit the production of neurons and facilitate the generation of astrocytes," states Nakashima.

To investigate the process further, the team established a brain organoid culture--a 3D culture of neural stem cells that can mimic aspects of brain development--from iPS cells derived from patients with Rett syndrome. When they inhibited BMP, short for bone morphogenetic protein, the team was able to reduce abnormal neural stem cell differentiation.

"Our findings have given us valuable insight into the role of MeCP2, miR-199a, and BMP signaling in the pathology of Rett syndrome," concludes Kinichi Nakashima, who headed the team. "Further investigation is needed, but we hope this can lead to clinical treatments for Rett syndrome symptoms."

Japanese astronomers have developed a new artificial intelligence (AI) technique to remove noise in astronomical data due to random variations in galaxy shapes. After extensive training and testing on large mock data created by supercomputer simulations, they then applied this new tool to actual data from Japan's Subaru Telescope and found that the mass distribution derived from using this method is consistent with the currently accepted models of the Universe. This is a powerful new tool for analyzing big data from current and planned astronomy surveys.

Wide area survey data can be used to study the large-scale structure of the Universe through measurements of gravitational lensing patterns. In gravitational lensing, the gravity of a foreground object, like a cluster of galaxies, can distort the image of a background object, such as a more distant galaxy. Some examples of gravitational lensing are obvious, such as the "Eye of Horus". The large-scale structure, consisting mostly of mysterious "dark" matter, can distort the shapes of distant galaxies as well, but the expected lensing effect is subtle. Averaging over many galaxies in an area is required to create a map of foreground dark matter distributions.

But this technique of looking at many galaxy images runs into a problem; some galaxies are just innately a little funny looking. It is difficult to distinguish between a galaxy image distorted by gravitational lensing and a galaxy that is actually distorted. This is referred to as shape noise and is one of the limiting factors in research studying the large-scale structure of the Universe.

To compensate for shape noise, a team of Japanese astronomers first used ATERUI II, the world's most powerful supercomputer dedicated to astronomy, to generate 25,000 mock galaxy catalogs based on real data from the Subaru Telescope. They then added realist noise to these perfectly known artificial data sets, and trained an AI to statistically recover the lensing dark matter from the mock data.

After training, the AI was able to recover previously unobservable fine details, helping to improve our understanding of the cosmic dark matter. Then using this AI on real data covering 21 square degrees of the sky, the team found a distribution of foreground mass consistent with the standard cosmological model.

"This research shows the benefits of combining different types of research: observations, simulations, and AI data analysis." comments Masato Shirasaki, the leader of the team, "In this era of big data, we need to step across traditional boundaries between specialties and use all available tools to understand the data. If we can do this, it will open new fields in astronomy and other sciences."

Microorganisms produce natural products, for example, as disease-causing virulence factors or as defense substances against predators and competitors. A team led by Dr. Robin Teufel and first author Ying Duan from the Institute of Biology II at the Faculty of Biology of the University of Freiburg, together with researchers from the University of Bonn, have now discovered a novel enzyme that is crucial for the production of so-called bacterial tropone natural products. The researchers presented their results in the current issue of the Journal of the American Chemical Society.

Previously unknown enzyme type

Bacteria found in terrestrial and marine environments produce tropone natural products, among other things, when they interact symbiotically with plants, algae or lower animals, for example as presumed protective substances against microbial pathogens in corals and sponges. The Freiburg researchers now investigated how the symbiotic bacteria produce these bioactive agents. Teufel and his team discovered a completely new type of enzyme that is essential for the production of these bacterial tropones.

Key intermediate in tropone biosynthesis

The scientists found that this enzyme activates oxygen in a previously unknown way and incorporates it into a chemical precursor compound. In the process, the basic structure of the tropone is generated. Using chemical and biochemical methods, the researchers were able to investigate the functions of this enzyme in more detail and thereby elucidate novel intermediates in tropone biosynthesis. "We succeeded in taking a crucial step toward better understanding the biological production of these significant compounds," Teufel explains. "These findings can serve as a basis for better combating certain pathogens in the future or for obtaining novel tropone compounds using biotechnological methods."