Culture

Addressing the widespread concern over transparency and reproducibility in biomedical research, one of the largest institutions in German science has begun to provide a framework, interventions, and incentives for improving the quality and value of translational research. The program is described by its leader, Ulrich Dirnagl of Berlin Institute of Health (BIH), and colleagues in a new article publishing on February 11 in the open-access journal PLOS Biology.

Despite the progress of modern biomedical science and approval of new drugs, there is a wide and growing recognition that the practice of biomedical research has significant weaknesses that lead to exorbitant waste, failed "breakthrough" treatments, and inability to replicate "landmark" findings. To address these concerns, the Berlin Institute of Health founded the QUEST Center for Transforming Biomedical Research, which developed the quality improvement program. The QUEST Center is implementing the program in BIH's two member institutions, Charité- Universitätsmedizin Berlin and the Max Delbrück Center for Molecular Medicine.

The program offers training, tools, and incentives to researchers to improve the quality of research, based on the principles of trustworthiness, usefulness, and ethics. For instance, the Center offers courses in reducing bias in research design, provides a guide to publishing negative or inconclusive findings, and offers financial rewards for making data publicly available. Program evaluations are ongoing and will be published in the near future.

"Conceptually, we are conducting and evaluating a large-scale behavior change intervention," said Dirnagl. "While such changes at a single institution can have little effect by themselves, we hope this program can provide a model for widespread adoption by other research institutions globally."

Our microbiomes -- the complex communities of microbes that live in, on and around us -- are influenced by our diets, habits, environments and genes, and are known to change with age. In turn, the makeup of our microbiomes, particularly in the gut, is well-recognized for its influence on our health. For example, gut microbiome composition has been linked to inflammatory bowel disease, autoimmune disease, obesity, even neurological disorders, such as autism.

Given a microbiome sample (skin, mouth or fecal swab), researchers have demonstrated they can now use machine learning to predict a person's chronological age, with a varying degree of accuracy. Skin samples provided the most accurate prediction, estimating correctly to within approximately 3.8 years, compared to 4.5 years with an oral sample and 11.5 years with a fecal sample. The types of microbes living in the oral cavity or within the gut of young people (age 18 to 30 years old) tended to be more diverse and abundant than in comparative microbiomes of older adults (age 60 years and older).

The predictive tool, described in a paper published February 11, 2020 by mSystems, was developed as a collaboration between researchers at University of California San Diego and IBM.

"This new ability to correlate microbes with age will help us advance future studies of the roles microbes play in the aging process and age-related diseases, and allow us to better test potential therapeutic interventions that target microbiomes," said co-senior author Zhenjiang Zech Xu, PhD, who was at the time of the study a postdoctoral researcher in the UC San Diego School of Medicine lab of co-senior author Rob Knight, PhD, professor and director of the UC San Diego Center for Microbiome Innovation.

The team's ultimate goal is to create similar machine learning models to correlate microbiome and clinical conditions, such as inflammation in autoimmune conditions. This approach could someday form the basis for a noninvasive microbiome-based test that potentially helps clinicians better diagnose or assess a person's risk for a disease.

In a 2014 study, Washington University researchers compared "microbial age" -- age as predicted by the fecal microbiome -- and actual chronological age in the context of malnourished infants during the first months of life. The researchers noted that the difference between chronological and microbial age was associated with the degree of the children's developmental maturity. In the new study, UC San Diego researchers took this idea a step further to see if this association could apply to adults, and how well it generalized to other body sites.

According to Xu, one of the most important requirements for a good statistical model is a large sample size and a representative population. To do that, the researchers mined microbiome sequencing data available from the public databases of several citizen science projects, such as the American Gut Project, in which participants mail in fecal, saliva or skin swabs, receive their personalized microbiome readouts, and contribute their anonymized data to the scientific community.

The study relied on a total of 4,434 fecal samples from the US and China, 2,550 saliva samples from the US, Canada, UK and Tanzania, and 1,975 skin samples from the U.S. and U.K. The participants whose data were used in the study ranged in age from 18 to 90 years old, with body mass indices of 18.5 to 30, did not have inflammatory bowel disease or diabetes, and had not used antibiotics for at least one month prior to sampling. The study also excluded pregnant, hospitalized, disabled or critically ill individuals.

"This was the most comprehensive investigation of microbiome and age to date," said first author Shi Huang, PhD, a postdoctoral researcher in Knight's lab and the UC San Diego Center for Microbiome Innovation.

The team found gender-specific differences in gut microbiome results, but no difference between males and females when it came to oral and skin microbiome results. Despite the diversity of microbes living on different sites across the human body, it also made no difference whether the skin samples had been collected from foreheads or hands, meaning future skin microbiome studies can boost their statistical power by combining collection sites and genders.

One potential reason the microbes living on our skin change so consistently as we age, the researchers said, is due to the predictable changes in skin physiology that everyone experiences, such as decreased serum production and increased dryness.

"The accuracy of our results demonstrate the potential for applying machine learning and artificial intelligence techniques to better understand human microbiomes," said co-author Ho-Cheol Kim, PhD, program director of the Artificial Intelligence for Healthy Living Program, a collaboration between IBM Research and UC San Diego under the IBM AI Horizons Network. "Applying this technology to future microbiome studies could help unlock deeper insights into the correlation between how microbiomes influence our overall health and a wide range of diseases and disorders from neurological to cardiovascular and immune health."

According to co-author Yoshiki Vázquez-Baeza, PhD, associate director of bioinformatic integration at the UC San Diego Center for Microbiome Innovation, age prediction is a particularly attractive method for training predictive models because participants don't need to meet special criteria in order to become a sample donor, and assessing age typically does not require a visit to a hospital.

"Other studies that focus on one particular condition, such as inflammatory bowel disease, often struggle to get enough participants who meet the study criteria and who are willing to participate in order to be able to draw meaningful conclusions," Vázquez-Baeza said. "But here, the wide applicability of age-prediction allowed us to explore the limits of microbial modeling at an unprecedented scale."

"Learning how to create accurate and robust microbiome-based models will open the door to a number of biotechnological applications, and help us better understand the relationship of certain bacteria with outcomes of interest," Knight said.

In 2016 and 2017, a surge of mumps cases at Boston-area universities prompted researchers to study mumps virus transmission using genomic data, in collaboration with the Massachusetts Department of Public Health and local university health services. As the outbreaks unfolded, the teams analyzed mumps virus genomes collected from patients, revealing new links between cases that first appeared unrelated and other details about how the disease was spreading that weren't apparent from the epidemiological investigation.

The teams shared their sequencing data and findings in real-time during the outbreaks, with both each other and the broader scientific community, and now report their conclusions in PLOS Biology.

Analyzing viral genomes from an outbreak can show how a virus is evolving and being transmitted -- data that can help public health officials slow and stop the spread of disease.

"High-resolution genomic data about a virus, gathered from patient samples, allows us to reconstruct parts of an outbreak that aren't evident at first," said co-senior author Pardis Sabeti, institute member at the Broad Institute, professor at Harvard University, and Howard Hughes Medical Institute investigator. "The better we understand transmission chains in situations like this, the better we can inform efforts to control outbreaks and devise strategies to predict and stop them in the future."

In Massachusetts, the typical rate of mumps is less than 10 cases per year -- but more than 250 cases were reported in 2016 and more than 170 in 2017, despite high rates of vaccination. Many of the cases were from 18 colleges and universities in the state, including Harvard University, University of Massachusetts Amherst, and Boston University (these three universities met certain criteria to ensure patient privacy protection in this study and agreed to be named in the paper). Other outbreaks flared elsewhere in Boston and across the country around the same time.

These patterns of cases raised questions about how much the virus was circulating in the Massachusetts and US populations. To learn more, the research teams paired traditional epidemiological data with analysis of mumps virus whole genome sequences from 201 infected individuals, focusing primarily on the Massachusetts university communities.

Mumps insight

The viral genomic data revealed details about the Boston-area outbreaks that could not be reconstructed by relying solely on more traditional approaches. For example, the researchers found a clear link between cases at Harvard and an outbreak in East Boston, which were classified as distinct outbreaks during the initial public health investigation.

Public health officials first thought the cases in these two communities were unrelated based on several pieces of evidence: epidemiological data, the different demographic makeup of the two populations (older adults with no obvious university connection versus mostly college-aged students), and a long gap between the apparent end of the outbreak at Harvard and the cases in the local community.

However, the genomic data indicated that the mumps viruses in the East Boston cases were genetically similar to those in the Harvard virus samples. This finding enabled the teams to identify contacts and transmission links between the university and the wider community.

"Even though the two outbreaks were occurring at different places and different times, we were able to show connections between these outbreaks that were operationally informative," explained senior co-author Bronwyn MacInnis, associate director of malaria and viral genomics in the Infectious Disease and Microbiome Program and co-lead of the Global Health Initiative at Broad. "The public health teams could determine that they were essentially dealing with one problem, not two."

Understanding such transmission routes can help guide the outbreak response -- for example, by determining whether efforts should be focused more on controlling transmission within a single community or between different ones.

"Whole-genome sequencing of patient samples helps us reconstruct the progression of an outbreak," said co-first author Shirlee Wohl, formerly a Harvard graduate student in the Sabeti lab and now a postdoctoral fellow at Johns Hopkins University. "Traditional outbreak surveillance efforts can help identify possible sources of infection, but whole-genome sequencing can confirm these links and even suggest new, unexplored connections."

The team emphasized that this study was made possible by the close partnerships it had with the Massachusetts Department of Health and the health services teams at several universities. "I am proud to be part of the Massachusetts higher education community," Sabeti added. "They worked together and demonstrated the necessity of transparency in outbreak response. This is not a story of mumps at these universities, but of outstanding mumps reporting."

Mutating mumps?

Another question of particular interest to the local teams was whether a new mutation in the mumps virus -- for example, one that allows it to evade the immune system in a vaccinated individual -- might have sparked the outbreak. Of the infected individuals, 65 percent had received the recommended two doses of the MMR vaccine. However, given the available data, the researchers found no evidence that genetic variants arising specifically during this outbreak contributed to the disease spread. This finding suggests that, in the Boston area, the virus wasn't evolving into one that could dodge vaccine-induced immunity.

In addition to the findings related to the Boston-area outbreaks, the study's broader geographic analysis suggested that the mumps virus has been circulating continuously at a low rate around the US, only rarely flaring up into notable outbreaks as in 2016 and 2017.

"This whole endeavor demonstrated the value of genetic data to the epidemiological health response, and of data-sharing among collaborating teams," Sabeti said. "One of our goals is to build this capacity in many areas around the world so that public health officials can rapidly mobilize and do this type of analysis whenever they need to."

Washington, DC - February 11, 2020 - Diets like the Keto, Paleo and Atkins focus on high-fat, high-protein meals that are often low in carbohydrates. This mix may appeal to Clostridioides difficile bacteria, too.

In a new study published this week in mSystems, an open-access journal of the American Society for Microbiology, researchers report that mice fed a high-protein, high-fat diet were more likely to acquire a deadly C. difficile infection than mice eating a standard diet. Their findings also suggest that a diet high in carbohydrates protects against infection.

Every year in the United States, hundreds of thousands of people are diagnosed with C. difficile infections and more than 10,000 die, according to the Centers for Disease Control and Prevention. Taking antibiotics increases a person's risk of infection.

The researchers behind the new work caution that their study was done on mice and additional research is needed to establish a connection between these diets and infections in people. At the same time, they argue, it's an avenue of research that's important to explore.

"We have to look at humans to see if it correlates," said chemist Ernesto Abel-Santos, Ph.D., at the University of Nevada, Las Vegas (UNLV). "We know that people have been following these different extreme diets and we really don't have a good handle on what these changes are doing to our systems."

"We know very well that diet affects the gut microbiome," added microbiologist Brian Hedlund, Ph.D., also at UNLV. Hedlund and Abel-Santos co-led the new study.

The group studied 4 groups of mice with 5 animals each. Each group received antibiotics and was fed a different diet: one was high-fat, high-protein; another was high-fat, low-protein; a third was high-carbohydrate; and the fourth was a standard laboratory diet for experimental mice.

The results were startling. In the high-protein, high-fat group, all the animals developed severe infections and died within 4 days. In the high-fat, low-protein group, only 2 animals died. In the high-carbohydrate group, 2 mice showed mild symptoms and recovered and in the standard diet group, all of the animals showed signs of infection but also recovered.

Recent studies suggest that because antibiotics kill bacteria species indiscriminately, the medications decimate populations of organisms that compete for amino acids, leaving C. difficile free to propagate. But Hedlund said the story is even more complex. "It's clear that it's not just a numbers game," he said. The new work suggests that diet may promote microbial groups that can be protective, even after antibiotics. For an infection to flourish, he said, "you might need this combination of wiping out C. difficile competitors with antibiotics and then a diet that promotes overgrowth and disease."

The new study raised questions that the researchers will pursue in future studies. For example: The high-carb diet, which seemed protective against C. difficile infection, gave rise to the least diverse community of microbes. "Lots of papers say that a lower microbial diversity is always a bad thing, but in this case, it had the best disease outcome," said Abel-Santos. However, he cautions that a high-carb diet could lead to animals becoming asymptomatic carriers that can disseminate the infection to susceptible subjects.

The group will also begin looking at ways to understand the connection between diet and C. difficile infection in people. "Whether this will translate to humans or not, I'm not totally sure," said Abel-Santos. "But the next time I take antibiotics, I'm not going to be eating a high-protein or Atkins diet."

Laws affecting the labeling, marketing and taxation of sugary soft drinks impact the behavior of both consumers and manufacturers, according to two studies published this week in PLOS Medicine.

In the first study, Camila Corvalán of the University of Chile and colleagues analyzed the impact of Chile's Law of Food Labeling and Advertising, implemented in 2016. The law mandates front-of-packaging warning labels, restricts child-directed marketing and bans sales in schools of all foods and beverages containing added sugars, sodium or saturated fats over threshold levels. The new study used national data on packaged beverage purchases from 2,383 urban households in Chile between 2015 and 2017. The researchers concluded that after the implementation of the new policies, the purchase of beverages high in sugar, sodium, saturated fat or calories decreased by 22.8 mL per capita per day (95% CI 22.7-22.9, p

"Future research will be needed to understand to what degree these changes are attributable to product reformulation and/or to changes in consumer behavior as well as the impact of these regulations on dietary intake and health-related outcomes," the researchers say.

In the second study, Peter Scarborough of University of Oxford, UK, and colleagues looked at the effect of the UK Soft Drinks Industry Levy (SDIL). This levy, announced in March 2016 and implemented in April 2018, charges manufacturers and importers a levy on soft drinks of 18p per litre for drinks with between 5 grams and 8 grams of sugar per 100mL, and 24p per litre for drinks with greater than 8 grams of sugar per 100mL. In the new study, researchers used a total of 209,637 observations of soft drinks available from UK supermarket websites at 85 time points between September 2015 and February 2019. Over that time period, the proportion of drinks with more than 5 grams of sugar per 100mL fell by 33.8% (95%CI 33.3-34.4, p

"The SDIL incentivized many manufacturers to reduce sugar in soft drinks. Some of the SDIL was passed onto consumers as higher prices, but not always on targeted drinks," the researchers say. The authors suggest the SDIL may have resulted in reformulation of sugar sweetened beverages and that these changes could reduce population exposure to liquid sugars and associated health risks.

The U.S. East and Gulf Coasts differ in how ocean and atmospheric circulation and sea level interact to produce storm surges, and both regions will experience greater storm surges as global warming progresses, according to new research from a University of Arizona-led team.

The research is the first to compare how different parts of the Atlantic Coast might fare during storms. The scientists examined the impacts of both tropical cyclones, including hurricanes, and extra-tropical cyclones, such as nor'easters.

The team did so by using a new global climate computer model that allowed them to combine information on weather, climate and sea level in a fully integrated way.

The scientists found that even in the absence of global warming, the Gulf Coast, and especially New Orleans, is particularly vulnerable to storm surge. As the climate warms, the Gulf Coast will be even more susceptible to extreme storm surges, said first author Jianjun Yin, an associate professor of geosciences.

More than 60 million people live in the Atlantic and Gulf of Mexico regions. Between 2000 and 2017, those regions were hit by 13 hurricanes that each caused more than $10 billion in damages.

For both regions, storm surge heights will increase in the future as warming progresses, Yin and his colleagues found. Stronger hurricanes will affect the Gulf Coast and increased sea level will affect the East Coast.

"For the Gulf of Mexico coast, the extreme sea level is highly sensitive to tropical cyclone characteristics like the storm winds. So if the hurricane becomes stronger, there's an elevated storm surge height because the region is highly sensitive to the storm's winds," Yin said.

"But for the East Coast of the U.S., especially the Northeast coast of the U.S., the story is different - the maximum storm surge is mainly influenced by the background sea level rise," Yin said.

The paper, "Response of Storm-related Extreme Sea Level along the US Atlantic Coast to Combined Weather and Climate Forcing," by Yin and his co-authors is published in the Journal of Climate. Yin's co-authors are listed at the bottom of this release. The National Oceanic and Atmospheric Administration and the National Science Foundation funded the research.

Yin had done previous research on sea level rise using computer climate models and wanted to investigate what scientists call "extreme sea level events" - big spikes in daily coastal sea level, generally caused by storms.

However, previous models could not handle the complex interactions between the ocean and the atmosphere Yin wanted to include, either because the models lacked an integrated approach or were too coarse.

New technology, in the form of a new global climate model developed by the NOAA Geophysical Fluid Dynamics Laboratory in Princeton, New Jersey, came to the rescue.

By using the new model, GFDL CM4, Yin and his colleagues could incorporate information about tropical and extra-tropical cyclones, atmospheric and oceanic circulation, weather and sea level rise. Having such rich information in the model allowed the team to more accurately predict how the seas along the eastern seaboard of the U.S. would respond to storms.

The team studied the coastline from Halifax, Nova Scotia, to Houston, Texas.

The researchers analyzed several simulations using the model. The control used pre-industrial conditions similar to those in the 1800s. Another simulation added more and more CO2 into the model's atmosphere at a rate of increase similar to that observed since the mid-20th century.

The pre-industrial control simulation revealed the underlying differences driving storm surge in the two regions - wind strength along the Gulf Coast and sea level along the East Coast.

The simulation that added CO2 into the atmosphere year after year projected that as warming progresses, there will be fewer - but stronger - tropical cyclones.

"For the CO2 experiment, we found that the elevated storm surge is influenced by different factors on the East Coast than the Gulf Coast," Yin said.

In addition, as CO2 in the atmosphere increases, the model reveals that the Atlantic Ocean's Atlantic Meridional Overturning Circulation will slow down, exacerbating sea level rise and storm surge on the East Coast.

"AMOC transports a lot of heat northward. It's mainly responsible for the mild climate over Europe," Yin said. "If AMOC slows down, it can influence the weather and climate over Europe and North America and cause regional sea level rise."

In an article published in the journal PLOS ONE, a group of researchers supported by FAPESP has updated the description of the Ghost knifefish Tembeassu marauna, a Neotropical electric fish species found only once in the wild.

The study, conducted in Brazil, was based on an analysis of external anatomy and, above all, on internal details that could be seen thanks to an advanced, high-resolution computed tomography (CT) technique that revealed characteristics of the fish's bones without requiring dissection.

"The only three known specimens of T. marauna are preserved in the University of São Paulo's Zoology Museum [MZ-USP], and because they're the only ones, they can't be dissected or bathed in iodine to make their internal organs and other soft tissues visible in a CT scan. These problems hinder studies of this species," Luiz Antonio Wanderley Peixoto, first author of the article, told.

The study was conducted during Peixoto's postdoctoral fellowship with a scholarship from São Paulo Research Foundation - FAPESP at MZ-USP, supervised by Professor Aléssio Datovo da Silva, a coauthor of the article.

The scientists studied the osteology (bone structure) of the 17 cm specimens by X-ray microcomputed tomography (microCT scanning), comparing their internal details with those of similar fish to establish a better classification of the species. The previous classification was based only on observation of its external anatomy and conventional X-rays.

They conducted the research in collaboration with colleagues at the Federal University of Rio de Janeiro State (UNIRIO) in Brazil and the National Museum of Natural History (NMNH), administered by the Smithsonian Institution in the United States, as part of the Thematic Project "Diversity and evolution of Gymnotiformes (Teleostei, Ostariophysi)", for which Naércio Aquino Menezes, a professor at MZ-USP, is principal investigator.

The group's objective is to advance knowledge of electric fish. There are currently more than 250 known species of fish that can emit and detect low-voltage electric discharges to guide navigation, find mates or stun prey. The same research group recently described two new species of electric eel, the only electric fish capable of producing a powerful enough shock to capture their prey. One of these new species can produce the highest voltage of any known living being (read more at: agencia.fapesp.br/31386).

Single occurrence

The three known specimens of T. marauna were collected from the Paraná River in Brazil in 1965 during construction of the Ilha Solteira dam and hydroelectric power plant on the border between the states of São Paulo and Mato Grosso do Sul. They appeared to inhabit the main channel, the deepest part of the river, and were caught only because they were in a cofferdam area that had been drained to enable construction work below the waterline.

The specimens were deposited in the MZ-USP's collection, but the species was not formally described until 1998. The description was based on external anatomy and carried out by Mauro Triques, who earned a PhD at MZ-USP with a scholarship from FAPESP. Triques is now a professor at the Federal University of Minas Gerais (UFMG).

At the time, Triques noted the existence of "an enlarged, fleshy, lateral lobe on the chin," concluding that it was a distinctive feature that was absent or less developed in related species. He considered this trait sufficient to differentiate T. marauna from other species in the same order.

In 2005, Ricardo Campos-da-Paz, currently a professor and researcher at UNIRIO, described a set of some 15 extra teeth on the upper lip of all three specimens with no connection to the premaxillary bones, as occurs in other species.

"The presence of these teeth may have something to do with a specific diet, possibly a type of prey only the species in question is able to capture. We have no way of knowing because we have no information on the stomach content of these specimens," Peixoto said. "Another hypothesis is that the teeth reflect some specific behavior, such as competing for resources with adversaries. The function of the hypertrophied lobe on the chin or lower lip could be to receive electric signals and communicate with potential mates. We can't be certain without an analysis of the inside of these structures."

Expeditions to the dam and environs have been conducted over the years to try to collect more specimens and answer these and other questions, but without success. Because of the single occurrence in the Paraná River and the lack of new specimens, the species is considered "critically endangered" by the Brazilian authorities and classed as "possibly extinct" in the Fish & Aquatic Invertebrates section of the Official National List of Endangered Species, where its common name is "ituí-maraúna", which is not found in any scientific record.

Genetic tests are also a problem because the specimens were originally preserved in formalin, which destroys DNA and prevents its extraction using the currently available techniques. However, researchers are attempting to use antiquated DNA extraction techniques, which are expensive and do not always work but, in some cases, may recover part of the genetic code.

MicroCT scanning proved the most appropriate technique to study the specimens in light of these difficulties. Analysis of the ultra-high-resolution images of the skeletons produced by the microCT scan enabled the researchers to class T. marauna more precisely in the family Apteronotidae (Ghost knifefish), which, in turn, is part of the electric fish order Gymnotiformes.

Phylogenetic analysis confirmed that this species is the only one in the genus Tembeassu. It also showed that this animal may be closest in evolutionary terms to the genera Megadontognathus and Apteronotus. Species in the latter genus, such as A. albifrons and A. jurubidae, are popular knifefish among home aquarium lovers.

"This study exemplifies how cutting-edge technology can help analyze biological material deposited in zoological collections. The microCT technique enables researchers to perform noninvasive examination of rare specimens whose internal anatomy couldn't otherwise be studied in detail. In addition, the high-resolution images and 3D videos it produces can serve as classroom material and can be used for scientific dissemination," said co-author Carlos David de Santana, a research associate at NMNH.

Kidney transplantation is the gold standard treatment for end-stage kidney disease and is associated with an advantage over dialysis in both survival and quality of life.

Researchers at the University of Cincinnati are among the first to adopt genotyping that helps identify and predict the risk accompanying individuals wishing to donate a kidney. Those who are high-risk of developing disease can be removed from the pool of potential donors which will reduce their chances of developing kidney disease.

One of the key methods for improving the rate of kidney transplantation is improving the viability of organ donation. While encouraging the expansion of living kidney transplant programs, it is important that health care providers follow procedures that mitigate the negative health consequences for the donors themselves.

The focus of UC's research is a gene called apolipoprotein L1 (APOL1), which has been recently implicated in the development of kidney disease in African Americans. Thirteen percent of African Americans carry the high-risk APOL1 genotype and, as a result, are more predisposed to kidney failure.

"Discovering this gene allows us to determine whether individuals who step forward to donate are at risk for having kidney disease," says Bassam Abu Jawdeh, associate professor of clinical medicine in the Division of Nephrology, Kidney C.A.R.E. Program, and senior author of the study that examined the role of APOL1 in living kidney donation. "We can factor in this information when making our decision as to whether we're going to accept them as living donors or not."

This research is emblematic of the urban impact agenda highlighted in UC's Next Lives Here strategic direction.

In their paper, published in the American Journal of Nephrology, Abu Jawdeh and his colleagues report their experience applying APOL1 genotyping and using it to identify high-risk donor candidates, therefore bypassing them for donation. As a result of their research, they propose a protocol for systematic APOL1 genotyping in all potential African American donors.

According to Abu Jawdeh, donating a kidney puts the donor at an extremely small yet relatively increased risk of kidney disease.

"In the overall population of healthy individuals, the risk of having advanced kidney disease over the years is somewhere in the range of 3 to 5 in 10,000," says Abu Jawdeh. "For those who donate kidneys, their absolute risk -- although still very, very small -- will increase."

He says the reason for this small increase in kidney disease incidence is a combination of genetic and environmental factors. Abu Jawdeh also emphasizes that organ donors are volunteering precious organs so steps need to be taken to ensure their generous act doesn't negatively impact their own lives.

"As transplant specialists, it is our responsibility to find ways to optimize the health of donors, which includes protecting them from occurrence of kidney disease. By identifying high-risk genotype carriers, we are able to better counsel those who wish to donate," says Abu Jawdeh, who is also a UC Health physician. "We have even shown that universal APOL1 genotyping is likely cost-effective, however future larger studies are warranted to ascertain the favorable cost-benefit ratio of this approach."

The study also included contributions from Manish Anand, assistant professor, and Prakash Gudsoorkar, nephrology fellow, both in the Division of Nephrology, Kidney C.A.R.E. program in the UC College of Medicine. Abu Jawdeh is the principal investigator for the APOL1 Long-term Kidney Transplantation Outcomes Network for all three Cincinnati transplant programs (UC, Cincinnati Children's and Christ Hospitals). For that, he receives federal funding from the National Institute of Diabetes and Digestive and Kidney Diseases (U01).

The fossilized tail of a young dinosaur that lived on a prairie in southern Alberta, Canada, is home to the remains of a 60-million-year-old tumor.

Researchers at Tel Aviv University, led by Dr. Hila May of the Department of Anatomy and Anthropology at TAU's Sackler Faculty of Medicine and Dan David Center for Human Evolution and Biohistory Research, have identified this benign tumor as part of the pathology of LCH (Langerhans cell histiocytosis), a rare and sometimes painful disease that still afflicts humans, particularly children under the age of 10.

A study on the TAU discovery was published on February 10 in Scientific Reports. Prof. Bruce Rothschild of Indiana University, Prof. Frank Rühli of the University of Zurich and Mr. Darren Tanke of the Royal Museum of Paleontology also contributed to the research.

"Prof. Rothschild and Tanke spotted an unusual finding in the vertebrae of a tail of a young dinosaur of the grass-eating herbivore species, common in the world 66-80 million years ago," Dr. May explains. "There were large cavities in two of the vertebrae segments, which were unearthed at the Dinosaur Provincial Park in southern Alberta, Canada."

It was the specific shape of the cavities that attracted the attention of researchers.

"They were extremely similar to the cavities produced by tumors associated with the rare disease LCH that still exists today in humans," adds Dr. May. "Most of the LCH-related tumors, which can be very painful, suddenly appear in the bones of children aged 2-10 years. Thankfully, these tumors disappear without intervention in many cases."

The dinosaur tail vertebrae were sent for on-site advanced micro-CT scanning to the Shmunis Family Anthropology Institute at TAU's Dan David Center for Human Evolution and Biohistory Research, Sackler Faculty of Medicine, which is located at the Steinhardt Museum of Natural History.

"The micro-CT produces very high-resolution imaging, up to a few microns," Dr. May says. "We scanned the dinosaur vertebrae and created a computerized 3D reconstruction of the tumor and the blood vessels that fed it. The micro and macro analyses confirmed that it was, in fact, LCH. This is the first time this disease has been identified in a dinosaur."

According to Dr. May, the surprising findings indicate that the disease is not unique to humans, and that it has survived for more than 60 million years.

"These kinds of studies, which are now possible thanks to innovative technology, make an important and interesting contribution to evolutionary medicine, a relatively new field of research that investigates the development and behavior of diseases over time," notes Prof. Israel Hershkovitz of TAU's Department of Anatomy and Anthropology and Dan David Center for Human Evolution and Biohistory Research. "We are trying to understand why certain diseases survive evolution with an eye to deciphering what causes them in order to develop new and effective ways of treating them."

Today (Feb. 11) is the fifth annual International Day of Women and Girls in Science, a commemoration to emphasize that females should have full, equal access to the
sciences and encouragement to participate in them. Although this effort may someday
lead to a bright future of gender equality in academia, the road to get there is long.

One Texas Tech University researcher is now part of a nationwide collaboration hoping
to shorten the journey by providing a roadmap.

Emily Dhurandhar, an assistant professor in the Department of Kinesiology & Sport Management, is one of the authors of "Turning chutes into ladders for women faculty: A review and roadmap for equity in
academia," published today in the Journal of Women's Health.

Statistics show that women are underrepresented in the highest levels of academia,
particularly in science, technology, engineering, mathematics and medicine; they are
less likely than men to achieve tenure; and they constitute less than one-third of
full professors. Black and Hispanic women face even greater disparity. Such factors
contribute to women leaving academia at a disproportionately higher rate than men.

"Some close female friends and colleagues from my postdoctoral fellowship and I started
our faculty positions and had children around the same time," Dhurandhar said. "We
were all running into so many issues when striving for tenure that we started a chat
group to brainstorm and exchange ideas. The issues we were troubleshooting seemed
to be universal to all women faculty striving to get tenure and succeed in academia,
so we decided to write this manuscript."

The article presents what its authors term "chutes" and "ladders" – respectively,
the things that prevent women from rising within academia or drive them out altogether,
and the policies and strategies institutions can adopt to help women stay and advance.

Chutes include biases against marriage or having children; shortages of working-mother
role models and female mentors in general; student evaluations, which consistently
rate men higher than women; and grant-funding disparities. Culturally, women are more
likely to be the caregivers of children and/or parents, leading to a more difficult
work/life balance.

"Sometimes the hours of academia being outside a typical 9-5 workday makes for challenging
childcare situations – for example, dinners with visiting speakers or faculty candidates
or early-morning or weekend data collection in the clinic with study participants,"
Dhurandhar said. "There also is an expectation to travel to conferences to present
research and connect with collaborators, which comes with the hidden cost of either
additional childcare to help my husband when he is home alone with the kids, or travel
for the kids to join me and childcare at the conference site itself, or the cost of
travel for my mother-in-law to come with me so she can watch the kids.

"It is frustrating that the infrastructure of academia, like many industries, was
built with the expectation that faculty will be living in a single-income family structure,
where one spouse is always available for household duties, and this has yet to change."

The ladders Dhurandhar and her coauthors suggest include mentoring programs, particularly
with senior women faculty members; equitable pay; using rubrics and peers or third
parties for standardized evaluations; and family-friendly policies such as paid family
leave, access to childcare, reimbursement for work-related childcare expenses and
scheduling networking events during the workday.

"To show a real commitment to gender equality, supportive policies at all institutions
should provide the infrastructure needed for dual-earning households to succeed without
overburdening themselves, or without one spouse having to sacrifice their success,"
Dhurandhar said. "Women need to be educated and empowered to understand their worth
when they have a career. Their role at home can, and should, change if they are expected
to contribute equally, if not more, to the financial stability of the family. But
ultimately, the demand to change the status quo in the household has to come from
women, and women first have to believe the burden of household and childcare duties
should no longer be on their shoulders alone."

Other researchers in the collaboration represent the University of Florida, the University
of Alabama-Birmingham, Drexel University, the University of Connecticut and Penn State
University.

DOI

10.1089/jwh.2019.8027

New research has shed fresh light on how the build-up of two proteins in the brain might affect the activity of genes involved in Alzheimer's disease.

Researchers at the University of Exeter worked in collaboration with Eli Lilly and Company to examine the brains of mice carrying mutations in the genes for the proteins amyloid and tau. The build-up of both proteins in specific regions of the brain is known to play a role in Alzheimer's disease.

In a paper published today in Cell Reports, the researchers found evidence that the levels of gene activity changed dramatically as tau and amyloid accumulated in the brain. The team, funded by Alzheimer's Research UK and Alzheimer's Society, observed significant changes in the levels of genes involved in inflammation in the immune system, which became more active as tau levels increased. The research also highlights new pathways potentially involved in the progression of Alzheimer's disease, and adds weight to theories that brain inflammation is a key component in the build-up of tau.

First author Dr Isabel Castanho, of the University of Exeter, said: "Our results suggest that the genes which are disrupted through the build-up of tau and amyloid in the entorhinal cortex region of the brain influence the function of the immune response in the brain, which is known to be a key component of Alzheimer's disease."

The team analysed the build-up of each protein in the brain and the expression of genes associated with them as the mutant mice got older. They observed a build-up of both tau and amyloid, with these changes associated with widespread changes in gene expression - particularly in the case of tau. This is interesting because it suggests that the accumulation of tau might have more dramatic effects on gene regulation in the brain than amyloid. Furthermore, a number of the identified genes are known risk factors for Alzheimer's disease, and overall the changes observed in mice mirror those seen in human Alzheimer's disease brains.

Professor Jonathan Mill, of the University of Exeter Medical School, who led the project said: "Currently, no treatments are available that can change the course of Alzheimer's disease. Understanding the interaction between genes and progression of the disease will help us identify new targets for treatment, which we hope will one day lead to drugs that can effectively treat this terrible disease."

Dr Sara Imarisio, Head of Research at Alzheimer's Research UK said: "Genetics plays an important role in the development diseases like Alzheimer's and teasing apart the processes contributing to disease is crucial in the hunt for new breakthroughs, which will change lives. Future research capitalising on genetic findings like this is a top priority for dementia researchers around the world. It's only thanks to the generosity of our supporters that Alzheimer's Research UK is able to fund vital dementia research like this."

Dr James Pickett, Head of Research at Alzheimer's Society, said: "We're proud to be funding research like this which plugs gaps in our knowledge about Alzheimer's disease, and lays strong foundations for the development of new lifesaving treatments. Through research we will beat dementia. We owe it to the 850,000 people in the UK currently living with dementia to understand the condition better and find a cure."

Not everyone who catches Ebola dies of the hemorrhagic virus infection. Some people mount a robust immune defense and recover fully. Yet risk factors for susceptibility to infection and disease severity remain poorly understood.

A team at the Center for Infection and Immunity (CII) at Columbia University Mailman School of Public Health has used a specially bred population of laboratory mice that mimics human patterns of tolerance and susceptibility to the Ebola virus to identify human immune factors that predict outcomes among people infected with the disease.

In a new paper published by Cell Reports, the team describes how they identified differences in immune response among mice who recovered from Ebola and those who perished. Further analysis revealed differences in gene expression between the two groups that account for disparities in immune response. Using machine learning, the team created a model that accurately predicts human disease outcomes based on expression of a small subset of genes.

The researchers tested their model using a data set collected from Ebola patients in western Africa; the data set contains details on the presence of types of RNA associated with immune function in people's blood, as well as whether they lived or died after infection. The model predicted the patients' outcomes with 75 percent accuracy, confirming the factors identified as valid in the mouse model were also associated with outcomes among humans infected with Ebola.

While the work has not yet been translated into a clinically approved test for use among human patients, the findings could guide the development of new tools to triage patients in resource-poor countries, support immune function among those at higher risk of death, and boost vaccine response among those at greatest risk. "Since the current Ebola therapeutics being tested in the DRC [Democratic Republic of Congo] are most effective when given as early as possible in infection our model could be used to develop tests with a huge impact on clinical care and patient outcomes," says senior author Angela Rasmussen, PhD, an associate research scientist with the Center for Infection and Immunity.

Studies of Ebola infection and response among humans have historically been limited by the difficulty of obtaining samples during an outbreak, says co-first author Adam Price, PhD, an analyst at Columbia Mailman's Center for Infection and Immunity. "The human data set we used to test our machine learning model is one of the only ones in existence that contains the information we needed on gene transcription among people infected with Ebola," Price explains.

"Human data collected during an outbreak rarely contains the combined breadth and specificity of information scientists need to perform detailed analyses of immune function," says co-first author Atsushi Okumura, PhD, DVM, an associate research scientist at CII. "Mouse models can help fill in the information gaps."

Rasmussen points out that by contrast to relying on patient data, the right mouse model can allow for comparatively expedited, low-cost studies to guide the study of human disease and the design of effective medications. "A common criticism of mouse models of Ebola is that they don't faithfully recapitulate human infection, and thus can't be used to develop diagnostic or prognostic tools," says Rasmussen. "Here we show that data generated in our mouse model can be applied to patient data to correctly predict outcomes."

Due to its size and low cost, the new mouse model removes research hurdles by making it easier for scientists to perform pre-clinical studies in maximum biocontainment, and with more robust statistical power than can be achieved with larger animal models. Using AI-driven approaches like machine learning to apply this to patients also overcomes the challenge of obtaining human samples.

The fidelity of the team's mouse model in replicating human responses to Ebola may prove helpful in understanding other viruses, such as the coronavirus outbreak that began in Wuhan, China. While much is still unknown about the new coronavirus, Rasmussen explains that the mouse model may be a useful model in guiding further understanding of the disease.

As if recovering from surgery wasn't hard enough, a new study shows that one in five operations could result in an unwelcome surprise: a bill for hundreds or thousands of dollars that the patient didn't know they might owe.

On average, that potential surprise bill added up to $2,011, a team from the University of Michigan reports in the new issue of JAMA. That’s on top of the nearly $1,800 the average privately insured patient would already owe after their insurance company paid for most of the costs of their operation.

All the patients in the study chose a surgeon who accepts their insurance, and had one of seven common, non-emergency operations at an in-network hospital or at an outpatient surgery center.

But they still ended up potentially owing large sums to pay other people involved in their operation or their follow-up care. The average potential surprise bill ranged from $86 for medical imaging specialists involved in a hysterectomy, to more than $8,000 for surgical assistants involved in a breast lumpectomy. These out-of-network bills were significantly more common for patients who had complications after surgery.

If the patient had an outpatient procedure with an in-network surgeon, but it took place at an ambulatory surgery center that was out-of-network, the potential surprise bill could add up to more than $19,000.

"These are eye-popping numbers, which most clinicians are likely unaware of, and which patients can't prepare for," says Karan Chhabra, M.D., M.Sc., the study's first author and a National Clinician Scholar at the U-M Institute for Healthcare Policy and Innovation, which funded the study.

The study looked at the claims that a large insurance company received from in-network and out-of-network medical providers for more than 347,000 patients under age 65 who had one of the seven operations between 2012 and 2017. Even though all the lead surgeons and the surgery locations were in-network, 20.5% of the operations led to an out-of-network bill.

The researchers couldn't see the actual "balance bills" that patients were told they must pay, which may vary depending on the insurance plan's provisions. Some insurers may pay part of the bill for out-of-network providers, while others charge patients for the entire added cost.

For the study, the researchers tallied all out-of-network charges billed to the insurer for the care episode related to each operation, and deducted the insurer's typical payment for that care.

State and federal implications

The findings shine a light on the need for federal-level measures to address surprise billing, says Chhabra, a research fellow in the Department of Surgery at Michigan Medicine, U-M's academic medical center, and a house officer at Brigham and Women's Hospital in Boston.

That's because state-level policies can't regulate what are called self-insured health insurance plans - the kind of plan that covers most people who get insurance through their jobs or the job of a family member.

Congressional committees have worked on legislation to address surprise billing but have still not agreed on a final legislative fix, though several states have passed provisions that provide some protection.

Depending on what state the patient lives in, the risk of getting a surprise bill differed from the average. In some states, less than 10% of the operations covered by the insurer led to a surprise bill, while in others more than a third did. Southern states had the highest proportion of surprise bills.

The team matters, not just the lead surgeon

"Even if a patient takes care to choose an in-network surgeon, and an in-network hospital or surgery center, they have little to no control over the rest of the team involved in their care, and whether they take part in their insurance plan," says U-M surgery chair Justin Dimick, M.D., M.P.H., senior author of the new paper. "This study reveals the extent and size of the bills that these other providers can incur if they're not in-network."

Chhabra notes that he and his colleagues were especially surprised that 37% of surprise bills sought payment for "surgical assistants." This is a catch-all term for other people with hands-on involvement in the operation or in post-operative care. They include additional surgeons, nurse practitioners or physician assistants with surgical training, or mid-level providers called certified surgical assistants or sometimes surgical first assistants.

When such a person was involved and wasn't part of the insurance network, the average bill for their services was $3,633.

Surgical assistants or their employer can bill the insurance company separately for their services, and seek payment above and beyond the rate that the insurer might have agreed on with the hospital.

Other types of physicians also submitted out-of-network bills as part of the care time. For instance, 37% of operations involved an out-of-network anesthesiologist, but the potential average surprise bill from them was lower than for surgical assistants, at around $1,200.

"Even if patients do their homework before they have elective surgery, this study shows they can be at risk of receiving large bills they never expected, from providers they never met or even knew about," says Chhabra.

The researchers also did a separate analysis of 83,000 operations performed at ambulatory surgery centers, for patients who had in-network surgeons. In this group, 17% of patients might have received a surprise bill for an out-of-network provider on their surgical team - but 6.7% might have received a bill from the surgery center itself because it was out-of-network.

Implications for surgeons

He notes that when all providers are in-network, such as at a large health system with employed physicians, the patient doesn't necessarily need to know or choose which pathologist looks at the tissue removed from them, which radiologist looks at the medical images made of them, or which specialist has the lead in the intensive care unit where they recover.

But when some of those providers are out-of-network, it can make a major difference in their ultimate costs.

It's possible that in many of the cases in the study, the lead surgeon had no idea that some of the people involved in the operation or post-op care were outside the patient's insurance network.

This may be especially true for patients who have narrow-network coverage that they bought on a federal or state marketplace. In the study, more than a quarter of operations paid for by Marketplace plans involved a surprise bill.

"We as surgeons need to make sure we are doing right by our patients," Chhabra says. "This disproportionately affects vulnerable populations, such as those who have weaker insurance coverage, and those with more health issues. For them, a surprise bill is adding insult to injury."

He also notes that provider groups may use out-of-network bills as a bargaining chip to try to get higher reimbursement from insurers if and when they become part of their network. Even if they never send the bill for the balance to the patient, the increased cost to the insurer could mean higher costs for everyone covered by that company.

What patients can do

In light of their findings, the authors advise patients to take care to check their insurance network, and ask about billing practices, when scheduling an operation.

If they receive a surprise bill, they should not shy away from asking the insurance company to pay the requested charge, asking for discounts or write-offs of their share of the bill, or filing complaints with state insurance regulators.

LA JOLLA, CALIF. - Feb. 11, 2020 - Scientists at Sanford Burnham Prebys Medical Discovery Institute have shown that two prebiotics, mucin and inulin, slowed the growth of melanoma in mice by boosting the immune system's ability to fight cancer. In contrast to probiotics, which are live bacterial strains, prebiotics are "food" for bacteria and stimulate the growth of diverse beneficial populations. The study, published today in Cell Reports, provides further evidence that gut microbes have a role in shaping the immune response to cancer, and supports efforts to target the gut microbiome to enhance the efficacy of cancer therapy.

The research specifically opens new avenues to address important unmet clinical needs in melanoma, as it highlights the possible impact of prebiotics on tumor growth control and therapy resistance.

"Earlier studies have demonstrated that prebiotics limit tumor growth, but until now the mechanism by which they do so has been unclear," says Ze'ev Ronai, Ph.D., professor in Sanford Burnham Prebys' Tumor Initiation and Maintenance Program and senior author of the study. "Our study shows for the first time that prebiotics limit cancer growth by enhancing anti-tumor immunity. The study supports further exploration of the potential benefits of prebiotics in treating cancer or augmenting current therapies."

Ronai cautions that these findings require much more study before considering any evaluation in people with cancer.

"Prebiotics represent a powerful tool to restructure gut microbiomes and identify bacteria that contribute to anti-cancer immunity," says Scott Peterson, Ph.D., professor in Sanford Burnham Prebys' Tumor Microenvironment and Cancer Immunology Program and co-corresponding author of the study. "The scientific advances we are making here are getting us closer to the idea of implementing prebiotics in cutting-edge cancer treatments."

Adds Jennifer Wargo, M.D., associate professor of Surgical Oncology and Genomic Medicine at the University of Texas MD Anderson Cancer Center, “Immunotherapies and targeted treatments such as MEK inhibitors are helping people with melanoma, but not everyone. While some patients respond to therapy, others do not. In addition, many patients develop resistance to treatment which requires alternate medicine combinations. Manipulating the microbiome with prebiotics might be a helpful addition to current treatment regimens, and today’s finding should be further tested in independent models and systems.”

In the study, the scientists set out to identify specific prebiotics that promote the growth of good bacteria and activate anti-tumor immunity. Based on previous studies conducted in a lab dish, they homed in on mucin, a protein that is part of the mucus found in our intestine and other tissues; and inulin, a fiber found in plants such as asparagus and onions.

The researchers then embarked on a series of studies that involved feeding healthy mice either mucin or inulin in their water and food, respectively, and then transplanting melanoma or colon cancer cells to determine the effect of the prebiotics. Their experiments showed that:

Growth of melanoma was slowed in the mice that received either mucin or inulin, while growth of a colon cancer cell line was slowed only in mice that received inulin.

Mice with melanoma that received either prebiotic showed an increase in the proportion of immune system cells that had infiltrated the tumor--indicating that the prebiotics enhanced the immune system's ability to attack the cancer.

The microbiota communities of the mice that received the prebiotics were altered. Importantly, mucin and inulin created different, distinct bacterial populations, although in both cases they were able to induce anti-tumor immunity--indicating that the distinct mode of action by these prebiotics is beneficial for stimulating anti-tumor immunity.

NRAS-mutant melanoma is treated with an MEK inhibitor drug, which often results in tumors that develop resistance to this drug. Mice carrying NRAS-mutant melanoma that received inulin were able to delay the development of resistance to treatment with an MEK inhibitor.

Mice with a "cold" BRAF-mutant melanoma tumor, meaning it partially responds to immune checkpoint therapy, were as responsive to the prebiotics as immune checkpoint therapy.

"Our findings are a step forward in our understanding of how certain prebiotics affect tumor growth, but we are far from applying these to humans," says Ronai. "Future studies need to be conducted in more complex animal models of different genetic backgrounds and ages to address the complex nature of human tumors before we may consider evaluating these prebiotics in people."

Bottom Line: Claims data from a large health insurer were used to examine how often patients unexpectedly receive out-of-network bills after having in-network elective surgery. These "surprise bills" typically occur when a patient receives care from a clinician, such as an anesthesiologist or surgical assistant, who doesn't participate in that patient's insurance network. This analysis included nearly 350,000 commercially insured patients who underwent elective surgery at in-network facilities with in-network primary surgeons between 2012 and 2017. The authors report that approximately 1 in 5 of these procedures resulted in an out-of-network bill, with an average potential balance of $2,011. Out-of-network bills were associated with anesthesiologists and surgical assistants in 37% of these surgeries. A limitation of the study is that claims data came from only one insurer.

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

Authors: Karan R. Chhabra, M.D., M.Sc., University of Michigan, Ann Arbor, and coauthors.

(doi:10.1001/jama.2019.21463)

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, financial disclosures, funding and support, etc.