Culture

Disadvantaged and marginalised people face worsening health inequalities as a result of the difficult choices made by NHS hospitals in response to the Covid-19 pandemic. Public health doctors, writing in the Journal of the Royal Society of Medicine, say that the restriction of non-urgent clinical services, such as gynaecology, sexual health and paediatrics, and the precipitous decline in emergency department attendances, will affect marginalised groups, disproportionately. Emergency departments, which in March 2020 saw a 44% decline in attendances, are often used for routine care by vulnerable people, such as homeless people and migrants, who can find it difficult to access general practice and other community services.

In their article, the authors explore the nature of health inequalities relating to the response to Covid-19 by hospital trusts and suggest approaches to reduce them. One concern highlighted is the suspension of carbon monoxide screening for pregnant women. Younger women, and those living in more deprived areas, are more likely to smoke during pregnancy. Lead author Sophie Coronini-Cronberg, consultant in public health at Chelsea and Westminster NHS Foundation Trust, said: "It remains vital that maternity services continue to ask women (and their partners) if they smoke or have recently quit, and continue to refer those who smoke for specialist cessation support." Official guidance advises postponing face-to-face smoking cessation clinics during the pandemic. Ms Coronini-Cronberg said: "We encourage providers to provide alternative remote services, to ensure these are equitable and to promote these tenaciously."

The authors also point to the problem of inaccurate baseline data for disease prevalence and progression which for many conditions can vary by ethnicity. Miss Coronini-Cronberg said: "It is imperative that we rigorously capture baseline data so that we understand the impact of key risk factors on disease prognosis, including Covid-19." The authors write that while ethnicity data are generally accurately captured for white British patients, for minority groups only 60-80% of hospital records capture ethnicity correctly. "We risk reaching incorrect conclusions based on flawed data", they say.

Other areas of concern highlighted by the authors include the inequalities faced by contracted workers who may provide critical hospital functions such as security, cleaning, portering and catering and who are more likely to be migrants.

The authors conclude: "The NHS has taken swift action to expand capacity and reorganise services to help ensure that health services can help with an influx of seriously ill Covid-19 patients. Difficult choices have been made, and some unintended consequences are inevitable. Policymakers, managers and clinicians should take pause during this phase to protect the most vulnerable groups in our society from negative unintended consequences and avoid worsening health inequalities."

ITHACA, N.Y. - A new Cornell University study on bees, plants and landscapes in upstate New York sheds light on how bee pathogens spread, offering possible clues for what farmers could do to improve bee health.

The study, "Landscape Simplification Shapes Pathogen Prevalence in Plant-Pollinator Networks," which used empirical data and mathematical modeling, reveals how surrounding landscapes might affect the ways that bees and flowers interact, and how interconnected networks of plants and pollinators influence disease spread in bees. The findings are important because bee diseases have contributed to pollinator declines worldwide.

"Our results are telling us that we need to think about [bee, flower, pathogen and landscape] interactions," said Laura Figueroa, the paper's lead author and a doctoral student in the lab of Scott McArt, assistant professor of entomology.

The study found that 65% of bee species and 75% of flower species carried pathogens, and that pathogens are transmitted between bees and flowers.

Figueroa and colleagues began with an empirical study of the bee species present on wildflower strips in upstate New York. In 2012, the researchers began planting uniform plots of wildflowers on 11 sites with varying amounts of surrounding farmland. In 2015, the team observed, tracked and recorded which bee species visited which flowers, ultimately describing the interaction patterns of 46 bee species and 13 plant species. They found that the common eastern bumblebee, as the dominant bee species in upstate New York, has a greater influence than other species on disease transmission dynamics.

The researchers also collected bees and flowers from each site and screened them for pathogens in the lab.

"In more simplified landscapes [with more farmland], the dominant species visited more plant species," Figueroa said.

This study found the bumblebees' increased diet breadth spread pathogens across many more flowers, she said, which in turn reduced each individual bee's exposure to new pathogens.

The researchers then entered the data from their empirical study into a mathematical model. They found that on a community level, accounting for all bee and flower species, the likelihood of a communitywide outbreak of disease decreased when the network of flowers and bees was highly interconnected, again, because pathogens were diluted across more flowers.

This is especially important when farmers plant wildflower strips to improve pollinator health.

While simple farm landscapes might lower disease spread on a communitywide level, each individual species behaves differently, depending on which flowers they visit, and which pathogens affect them. Future studies will parse out how individual species fare in simplified landscapes, which has important conservation implications.

"Potentially," Figueroa said, "we could develop mixtures of wildflower species that can not only maximize food for the pollinators, but can shape interactions in a way that reduce the likelihood of disease spread."

Scientists at the Stem Cell Research program at Boston Children's Hospital and Dana-Farber Cancer Institute/Harvard Medical School have devised a mouse model that lets researchers track every cell in the body, from the embryonic stage until adulthood. Using a "barcoding" technique and CRISPR gene editing technology, the model can identify different cell types as they emerge and what genes each is turning on. Described May 14 in the journal Cell, the system is the first of its kind and should yield a greater understanding of development, aging, and disease.

"The dream that many developmental biologists have had for decades is a way to reconstruct every single cell lineage, cell-by-cell, as an embryo develops, or as a tissue is built up," says Fernando Camargo, PhD, a senior investigator in the Stem Cell program and co-senior author on the paper with Sahand Hormoz, PhD, of Dana-Farber Cancer Institute/Harvard Medical School. "We could use this mouse model to follow its entire development."

Camargo, Hormoz, and co-first authors for their respective labs -- Sarah Bowling, PhD, and Duluxan Sritharan -- created the mouse model using a method they call CRISPR Array Repair Lineage tracing, or CARLIN. The model can reveal cell lineages -- the "family tree" in which parent cells create different types of daughter cells -- as well as what genes are turned on or off in every cell over time.

Single-cell tracking, live

Previously, scientists have only been able to trace small groups of cells in mice using dyes or fluorescent markers. Tags or barcodes have also been used, but previous approaches required prior knowledge of markers to isolate different cell types, or required time-consuming extraction and manipulation of cells, which could affect their properties. The advent of CRISPR has enabled researchers to barcode cells without perturbing the cells and to follow the lineage of thousands of cells simultaneously.

Using an inducible form of CRISPR, the researchers can create up to 44,000 different identifying barcodes at any time point in a mouse's lifespan. The scientists can then read out the barcodes using another technology called single cell RNA sequencing, enabling collection of information on thousands of genes that are turned on in each barcoded cell. This, in turn, provides information about the cells' identity and function.

As a test case, the researchers used the new system to reveal unknown aspects of blood development during embryonic development, and to observe the dynamics of blood replenishment after chemotherapy in adult mice.

But the researchers believe their system could also be used to understand the changes in cellular lineage trees during disease and aging. Additionally, the system could be used to record the response to environmental stimuli like pathogen exposure and nutrient intake.

"Being able to create single-cell lineage maps of mammalian tissues is unprecedented," says Camargo, who is also a member of the Harvard Stem Cell Institute. "Besides its many applications to studying developmental biology, our model will provide important insight on the cell types and hierarchies that are affected as organisms respond to injury and disease."

HOUSTON - (May 14, 2020) - A sandwich of molybdenum, sulfur and selenium turns out to be deliciously useful for detecting biomolecules.

Tests at Rice University's Brown School of Engineering of a two-dimensional Janus compound showed it could be an effective and universal platform for improving the detection of biomolecules via surface-enhanced Raman spectroscopy (SERS).

Using glucose to test the material proved its ability to boost its Raman enhancement factor by more than 100,000 times, which the researchers say is comparable to the highest-reported enhancement factor for 2D substrates.

SERS is an established technique that enables the detection and identification of small concentrations of molecules -- or even single molecules -- that get close to or adsorbed by metallic surfaces, including nanoparticles. It's often used to detect nanoscale proteins in bodily fluids, helping to detect diseases and determine treatments, and in environmental analysis.

But metallic SERS media often prompt side reactions that create background noise. Janus MoSSe synthesized at Rice is nonmetallic. "This work mainly addresses whether we can enhance the target molecules' signal strength," said materials scientist and principal investigator Jun Lou. "We wanted to know if we could make it stand out from the background noise."

The answer was clearly yes, as Lou and his team reported in Nanoscale.

MoSSe introduced by the Lou lab in 2017 was produced by chemical vapor deposition. Molybdenum sits in the middle with a layer of sulfur on one side and another of selenium on the other; hence the two-faced Janus characterization.

The different electronegativities of each layer make it a SERS superstar, said lead author and Rice alumnus Shuai Jia, a former graduate student in Lou's lab.

"The dipole created between the top sulfur and the bottom selenium lands out-of-plane, and this creates an electrical field a few nanometers beyond the MoSSe," Jia said. That field interacts with molecules that come close, enhancing their vibrational intensity enough to be detected.

The researchers noted tests with MoSSe also detected molecules of the neurotransmitter dopamine and that the substrate should be adaptable to sense other molecules.

Lou said there's room for improvement. "We're looking at hybrids of MoSSe with some metallic nanoparticles, and also trying to enhance the dipole strength," he said.

Below please find a summary and link(s) of new coronavirus-related content published today in Annals of Internal Medicine. The summary below is not intended to substitute for the full article as a source of information. A collection of coronavirus-related content is free to the public at http://go.annals.org/coronavirus.

1. Key Considerations for Effective Serious Illness Communication Over Video or Telephone During the COVID-19 Pandemic

In-person communication with patients hospitalized with COVID-19 and their families is often not possible. Researchers from University of California-San Francisco, and Geriatrics, Palliative, and Extended Care Service Line of the San Francisco Veterans Affairs Medical Center provide helpful guidance on how to have meaningful conversations about serious illness using telecommunication. Read the full text: https://www.acpjournals.org/doi/10.7326/M20-1982.

Media contacts: A PDF for this article is not yet available. Please click the link to read full text. The lead author, Ashwin Kotwal, MD, MS, can be reached at news@ucsf.edu.

2. Pulmonary arterial thrombosis in COVID-19 with fatal outcome

The clinicopathological basis for morbidity and mortality with SARS-CoV-2 infection is not well understood. Researchers from Hospital Graz II, Academic Teaching Hospital of the Medical University of Graz, Graz, Austria, and Institute of Pathology, School of Medicine, Johannes Kepler University, Linz, Austria, report the clinical and autopsy findings of patients who died of COVID-19. They report that COVID-19 predominantly involves the lungs, causing diffuse alveolar damage and leading to acute respiratory insufficiency. Death may be caused by the thrombosis observed in segmental and subsegmental pulmonary arterial vessels despite the use of prophylactic anticoagulation. Read the full text: https://www.acpjournals.org/doi/10.7326/M20-2566.

Media contacts: A PDF for this article is not yet available. Please click the link to read full text. The lead author, Sigurd F. Lax, MD, PhD, can be reached at sigurd.lax@jku.at.

In a small pool nestled between two waterfalls in Hidalgo, Mexico, lives a population of hybrid fish - the result of many generations of interbreeding between highland and sheepshead swordtails. The lab of Molly Schumer, assistant professor of biology at Stanford University, has been collecting these fish for years to study the evolution of hybrids.

"We're just realizing that hybridization affects species all across the tree of life, including our own species - many of us carry genes from Neanderthals and Denisovans," said Schumer, referring to two ancient human species that interbred with our ancestors. "Understanding hybridization and the negative and positive effects that can come from genes that have moved between species is important in understanding our own genomes and those of other species with which we interact."

In a new paper, published May 14 in Science, the researchers pinpoint two genes responsible for a melanoma that often develops near the tails of male highland-sheepshead hybrids. The finding marks only the second time that a hybrid dysfunction has been traced to specific genes in vertebrates. (The only other case where scientists have narrowed hybrid dysfunction in vertebrates down to the single-gene level is in a longstanding hybrid population of mice in Europe and their relatives.)

A special population

People have long known that the offspring of two different species tend to have genetic flaws. For example, mules - which are donkeys-horse hybrids - are infertile. Ironically, in order to find the genes responsible for such dysfunctions, researchers need hybrids that are fit enough to breed for several generations after the initial hybridization. Otherwise, the pieces of their genomes that come from the parental species are so large that it is nearly impossible to trace the influence of any one gene.

This is what makes the highland-sheepshead hybrids an exceptional case study. They have been interbreeding for about 45 generations, resulting in genomes that contain smaller chunks of parental DNA, which are easier to inspect at a single-gene level.

"We've known about genetic incompatibility between the genes of two species since the 1940s. Despite that, we don't know many of the genes that cause these negative interactions," said Daniel Powell, a postdoctoral fellow in the Schumer lab and lead author of the paper. "Our lab has clearly defined natural hybrids and we've developed the genomic resources for both parental species. These fish represent a unique system for addressing this question."

In order to home in on the genes responsible for melanoma in hybrids, the researchers first turned their attention to the pure sheepshead swordtails and the genetic origin of a black spot some of these fish develop - which is non-cancerous but found in the same location as the hybrids' melanoma. Analyzing the genomes of nearly 400 individual fish, they linked the black spot with the presence of a gene called xmrk. Following that lead, the researchers concluded that xmrk was also more highly expressed in hybrids with melanoma compared to those without it - altogether, it could explain 75 percent of all variation in the spotting they studied in both the pure sheepshead and hybrid fishes.

The researchers also found that another gene called cd97 - which some hybrids inherit from their highland swordtail ancestors - was more highly expressed in the highland swordtails and in hybrids than in sheepshead swordtails. Further genetic evidence suggests that cd97 and xmrk interact in some way to produce melanoma in the hybrids.

Interestingly, even though neither gene is associated with melanoma in the parental swordtails species, they're both linked to cancer in other animals. In a distantly related swordtail hybrid, for example, xmrk interacts with another gene - not cd97 - to cause melanoma, and a gene related to cd97 has been associated with cancer in humans.

Taken together, these findings yield a puzzling picture. "We've ended up with competing but not mutually exclusive ideas about hybrid incompatibility and disease," said Powell. "We've lent credibility to the idea that some genes might be vulnerable to breaking down in different species - which is surprising, given the randomness of evolution. But we also have evidence for the idea that there is a diversity of genetic causes for similar dysfunctions."

The best kind of project

Schumer says she took a bit of a gamble when she focused her studies on hybridization, but her bet is paying off.

"When I started my PhD in 2011, it was really not accepted that hybridization was common in animals. The best-known examples were mules and fruit flies. It's been such a massive shift and a fun time to be working on this question," said Schumer, who is senior author of the paper and a member of Stanford Bio-X. "What we've arrived at now is the best kind of project in science: one that raises way more questions than answers and spins you off in a bunch of different directions."

Through future work, the researchers want to figure out why hybrid swordtails with melanoma are less likely to survive in the wild and in captivity. They are also curious to know why so many of these fish have the melanoma - it's possible that, when it comes to mate selection, females prefer males with the large black spots generated by melanoma. Already, they have lined up several ideas to further understand whether genes go wrong in a repeatable way in hybrids, or if what they've found in xmrk and cd97 is closer to coincidence.

In a recently published study, researchers from the University of Hawai'i at Mānoa School of Ocean and Earth Science and Technology revealed the largest and hottest shield volcano on Earth. A team of volcanologists and ocean explorers used several lines of evidence to determine Pūhāhonu, a volcano within the Papahānaumokuākea Marine National Monument now holds this distinction.

Geoscientists and the public have long thought Mauna Loa, a culturally-significant and active shield volcano on the Big Island of Hawai'i, was the largest volcano in the world. However, after surveying the ocean floor along the mostly submarine Hawaiian leeward volcano chain, chemically analyzing rocks in the UH Mānoa rock collection, and modeling the results of these studies, the research team came to a new conclusion. Pūhāhonu, meaning 'turtle rising for breath' in Hawaiian, is nearly twice as big as Mauna Loa.

"It has been proposed that hotspots that produce volcano chains like Hawai'i undergo progressive cooling over 1-2 million years and then die," said Michael Garcia, lead author of the study and retired professor of Earth Sciences at SOEST. "However, we have learned from this study that hotspots can undergo pulses of melt production. A small pulse created the Midway cluster of now extinct volcanoes and another, much bigger one created Pūhāhonu. This will rewrite the textbooks on how mantle plumes work."
 

In 1974, Pūhāhonu (then called Gardner Pinnacles) was suspected as the largest Hawaiian volcano based on very limited survey data. Subsequent studies of the Hawaiian Islands concluded that Mauna Loa was the largest volcano but they included the base of the volcano that is below sea level that was not considered in the 1974 study. The new comprehensive surveying and modeling, using methods similar to those used for Mauna Loa show that Pūhāhonu is the largest.

This study highlights Hawaiian volcanoes, not only now but for millions of years, have been erupting some of the hottest magma on Earth. This work also draws attention to an infrequently visited part of the state of Hawai'i that has ecological, historical and cultural importance.

"We are sharing with the science community and the public that we should be calling this volcano by the name the Hawaiians have given to it, rather than the western name for the two rocky small islands that are the only above sea level remnants of this once majestic volcano," said Garcia.

CAMBRIDGE, MA -- When MIT announced in March that most research labs on campus would need to ramp down to help prevent the spread of Covid-19, Canan Dagdeviren's lab was ready.

For the past two years, Dagdeviren and her lab manager, David Sadat, have run the Conformable Decoders Group using "lean lab" management principles, working closely with MIT's Environment, Health and Safety Office (EHS). Every item in their lab has an assigned function and location, and there are strict procedures in place describing how everything is to be used, put away, and replenished. As a result, it took the lab just 15 minutes to close down operations on March 13.

"Given that everyone in our lab is very well-trained with these checklists, everyone took care of their own experiments and the tools that they use. I was then able to spend the rest of the time before the campus shutdown communicating with my students, motivating them and preparing them mentally for this upcoming period of time," says Dagdeviren, an assistant professor in MIT's Media Lab.

The lean lab approach has had other benefits as well, including cost savings, increased productivity, and a strong safety record, says Dagdeviren, who reported these effects in a paper appearing today in the journal Advanced Intelligent Systems. The paper also offers guidance on how other labs might implement this approach.

Sadat and Tolga Durak, the managing director of MIT EHS, are also authors of the paper.

Maximizing resources

Dagdeviren joined MIT's Media Lab as an assistant professor in 2017. As a junior faculty member, she had limited funding and space, so she wanted to maximize her use of the resources that she had. Her lab, the Conformable Decoders Group, develops novel materials and devices that can interact with the environment and with living organisms to detect phenomena such as heartbeats, neural activity, and temperature, among many others.

She spent nine months designing and building her 1,000-square-foot cleanroom -- a type of workspace whose environmental conditions are rigorously controlled to avoid contamination of experiments. She hired Sadat as a senior lab manager, and he suggested implementing an organizational strategy known as 5S. Sadat and Dagdeviren subsequently partnered with EHS on the lean lab project.

This method, which originated in Japan, is used in industries such as auto manufacturing but has not been widely applied in academic settings. The system consists of five guiding principles to organize a workspace for efficiency and effectiveness: sort, set in order, shine, standardize, and sustain.

Working closely with Durak, Dagdeviren and Sadat set out to implement this organization approach in their lab, which they call the YellowBox. One major element of the system is the visual organization of everything in the lab, which includes making sure every item has an assigned location. Each item is color-coded according to its function -- raw materials, instruments, hazardous chemicals, etc. -- and its location is outlined in colored tape so it can be easily spotted and later returned to the right spot.

"The idea behind it is to reduce the amount of mental calculation that a researcher would have to do when they walk in the lab," Sadat says. "Instead of seeing a cluttered lab and taking time, energy, and brain focus to look for a specific tool, they can walk into the lab and see color-coded and highlighted structures and do what they need to do without thinking much about it."

Dagdeviren's lab also developed standard operating procedures: step-by-step instructions to help researchers carry out complex experiments, to help ensure consistency in their research. This overall system not only improves workflow in the lab, it also has financial benefits. Between 2018 and 2019, the lab reduced its spending on chemicals by 41 percent and its spending on materials by 52 percent. The lab uses a "just-in-time" ordering system that works because their setup makes it easy to see when supplies are getting low, so they don't have to store a lot of extra material, or risk having supplies expire before they are used.

These efforts have also translated to a boost in productivity. Between 2018 and 2019, the lab increased the number of fabricated devices it produced by 119 percent.

"This is not a practice lab where nothing is happening. This is a lab where novel research is taking place every day," Durak says. "However, this is also a lean laboratory that is efficient, data-driven, productive, and safe."

Any potentially hazardous item or chemical is marked in yellow and black, and areas for storing those materials are similarly marked. Because each item in the lab, down to the stools, has an assigned location, it's easier to keep exit pathways clear. Since implementing the 5S system, the lab has had no accidents, injuries, or near misses.

Dagdeviren's lab is also the first research group at the Media Lab to receive MIT's Green Lab certification, which recognizes labs that use environmentally sustainable practices to reduce resource consumption, waste, and carbon emissions.

A model for others

When Dagdeviren's lab first started up, members spent more than an hour a day on management and cleaning of the lab, but as everyone got used to the routine and the setup, that dropped to about 10 or 15 minutes a day.

"Initially it was a little bit hard for people to understand and apply, but over time they got enough experience to be used to it," Dagdeviren says. "Now my lab manager can focus on the most important things rather than cleaning the clutter."

Dagdeviren's students are now continuing their research at home, running computer simulations of experiments in preparation for resuming their experimental work in the lab. When research operations are able to start up again, she expects that the lab will be able to open up nearly as quickly as it was shut down.

"This lean lab project has really positioned Canan's lab so that when it is time, this lab is going to be able to start operating very rapidly, function very effectively in a socially distanced world, and employ fiscal frugality, right off the bat," Durak says.

He says that EHS hopes to be able to pilot the lean lab approach with other types of labs, such as biology or chemistry labs, or maker spaces.

"The lean lab project is an exciting project and a true collaboration between the academy and administration with implications that span above and beyond MIT's campus. This project could also serve as a model for labs at other universities, especially those with limited research space," he says.

Archaeological sites on the far southern shores of South Africa hold the world's richest records for the behavioral and cultural origins of our species. At this location, scientists have discovered the earliest evidence for symbolic behavior, complex pyrotechnology, projectile weapons and the first use of foods from the sea.

The Arizona State University Institute of Human Origins (IHO) field study site of Pinnacle Point sits at the center of this record, both geographically and scientifically, having contributed much of the evidence for these milestones on the evolutionary road to being a modern human.

The scientists working on these sites, led by IHO Associate Director Curtis Marean, have always faced a dilemma in understanding the context of these evolutionary milestones -- much of the landscape used by these ancient people is now submerged undersea and thus poorly known to us. Marean is a Foundation Professor with the ASU School of Human Evolution and Social Change and Honorary Professor with Nelson Mandela University in South Africa.

The archaeological records come from caves and rockshelters that now look out on to the sea, and in fact, walking to many of the sites today involves dodging high tides and waves. However, through most of the last 200,000 years, lowered sea levels during glacial phases, when the ice sucks up the water, exposed a vast plain. The coast was sometimes as much as 90 km distant! Our archaeological data shows that this was the prime foraging habitat for these early modern humans, and until recently, we knew nothing about.

That has now changed with the publication of 22 articles in a special issue of Quaternary Science Reviews titled "The Palaeo-Agulhas Plain: A lost world and extinct ecosystem." About ten years ago, Marean began building a transdisciplinary international team to tackle the problem of building an ecology of this ancient landscape. ASU, Nelson Mandela University, the University of Cape Town, and the University of California, Riverside anchored the research team. Funded primarily by a $1 million National Science Foundation grant to Marean, with significant funding and resources from the Hyde Family Foundations, the John Templeton Foundation, ASU, IHO, and XSEDE, they developed an entirely new way to reconstruct "paleoecologies" or ancient ecosystems.

This began with using the high-resolution South African regional climate model -- running on U.S. and South African supercomputers -- to simulate glacial climate conditions. The researchers used this climate output to drive a new vegetation model developed by project scientists to recreate the vegetation on this paleoscape. They then used a wide variety of studies such as marine geophysics, deep-water diving for sample collection, isotopic studies of stalagmites and many other transdisciplinary avenues of research to validate and adjust this model output. They also created a human "agent-based model" through modern studies of human foraging of plants, animals, and seafoods, simulating how ancient people lived on this now extinct paleoscape.

"Pulling the threads of all this research into one special issue illustrates all of this science," said Curtis Marean. "It represents a unique example of a truly transdisciplinary paleoscience effort, and a new model for going forward with our search to recreate the nature of past ecosystems. Importantly, our results help us understand why the archaeological records from these South African sites consistently reveal early and complex levels of human behavior and culture. The Palaeo-Agulhas Plain, when exposed, was a 'Serengeti of the South"' positioned next to some of the richest coastlines in the world. This unique confluence of food from the land and sea cultivated the complex cultures revealed by the archaeology and provided safe harbor for humans during the glacial cycles that revealed that plain and made much of the rest of the world unwelcoming to human life."

BIRMINGHAM, Ala. - Is personalized medicine cost-effective? University of Alabama at Birmingham researcher Nita Limdi, Pharm.D., Ph.D., and colleagues across the United States have answered that question for one medical treatment.

Patients experiencing a heart attack -- known as a myocardial infarction or an acute coronary syndrome -- have sharply diminished blood flow in coronary arteries, with a high risk of heart failure or death. Coronary angioplasty, a procedure to open narrowed or blocked arteries in the heart, and percutaneous coronary intervention, known as PCI or stenting, can restore blood flow to minimize damage to the heart. These procedures reduce the risk of subsequent major adverse cardiovascular events, or MACE, which include heart attacks, strokes or death.

But then, a treatment decision has to be made.

After stenting, all patients are treated with two antiplatelet agents for up to one year. Which combination of antiplatelets is best? The answer comes through pharmacogenomics, says Limdi, a professor in the UAB Department of Neurology and associate director of UAB's Hugh Kaul Precision Medicine Institute.

Pharmacogenomics combines pharmacology, the study of drug action, with genetics, the study of gene function, to choose the best medication according to each patient's personal genetic makeup. This is also called precision medicine -- tailored medical treatment for each individual patient.

The most commonly used antiplatelet combination after PCI is aspirin and clopidogrel, which is trademarked as Plavix. Clopidogrel is converted to its active form by an enzyme called CYP2C19. However, patients respond to clopidogrel differently based on their genetic makeup.

More than 30 percent of people have loss-of-function variants in the CYP2C19 gene that decrease the effectiveness of clopidogrel. The FDA warns that these patients may not get the full benefit of clopidogrel, which would increase the risk of MACE. So the FDA advises doctors to consider a different treatment such as prasugrel or ticagrelor, trademarked as Effient and Brillinta, to replace clopidogrel.

While most patients undergoing PCI receive clopidogrel without receiving any CYP2C19 loss-of-function testing, academic institutions like UAB that offer precision medicine use pharmacogenomics to guide the selection of medication dosing.

In 2018, Limdi and other investigators across nine United States universities -- all members of the Implementing Genomics in Practice consortium, or IGNITE -- showed that patients with loss-of-function variants who were treated with clopidogrel had elevated risks. There was a twofold increase in MACE risk for PCI patients, and a threefold increase in MACE risk among patients with acute coronary syndrome who received PCI, as compared to patients prescribed with prasugrel or ticagrelor instead of clopidogrel. Prasugrel and ticagrelor are not influenced by the loss-of-function variant and can substitute for clopidogrel, but they are much more costly and bring a higher risk of bleeding.

The IGNITE group then leveraged this real-world data to conduct an economic analysis to determine the best drug treatment for these heart disease patients.

A study led by Limdi and colleagues, published in the Pharmacogenomics Journal, examines the cost-effectiveness of genotype-guided antiplatelet therapy for acute coronary syndrome patients with PCI. This cost-effectiveness study is the first to use real-world clinical data; many cost-effectiveness studies use clinical trial data, which tends to exclude the sicker patients normally seen in clinical practice.

The study compared three main strategies: 1) treating all patients with clopidogrel, 2) treating all patients with ticagrelor, or 3) genotyping all patients and using ticagrelor in those with loss-of-function variants.

"We showed that tailoring antiplatelet selection based on genotype is a cost-effective strategy," Limdi said. "Support is now growing to change the clinical guidelines, which currently do not recommend genotyping in all cases. Evidence like this is needed to advance the field of precision medicine."

Costs, QALYs and ICERs

In the analysis, Limdi and colleagues considered differences in event rates for heart attacks and stent thrombosis in patients receiving clopidogrel versus ticagrelor versus genotype-guided therapy, during the one-year period following stenting. They also included medical costs from those events that are borne by the payer, such as admissions, procedures, medications, clinical visits and genetic testing. The analysis considered variations in event rates and medication costs over time to ensure that the results held under different scenarios.

The study uses an economic measure -- the QALY, which stands for the quality-adjusted life year.

"First, we looked at which strategy provided the highest QALY," Limdi said. "The QALY is the gold standard for measuring benefit of an intervention -- in our case, genotype-guided treatment compared to treatment without genotyping. Universal ticagrelor and genotype-guided antiplatelet therapy had higher QALYs than universal clopidogrel -- so those are the best for the patient."

But health care resources are not infinite. So, Limdi and colleagues then evaluated whether those interventions that have higher QALYs were also reasonable from a cost perspective. This analysis considered the willingness to pay. What would a payor or a patient pay for the highest QALY?

"In our case, the payor would recognize that ticagrelor is more expensive than clopidogrel -- $360 per month vs. $10 per month -- and there is a $100 cost for each genetic test," Limdi said. "So, from the payor perspective, the more effective strategy (one with a higher QALY) -- if more expensive (higher cost) -- would have to lower the risks of bad outcomes like heart attacks and strokes for the gains in QALY that are at, or below, the willingness-to-pay threshold."

A calculation called incremental cost-effectiveness ratios, or ICERs, assesses the incremental cost of the benefit (improvement in QALY). In the United States, a treatment is considered cost-effective if its associated ICER is at or below the willingness-to-pay threshold of $100,000 per QALY.

"In our assessment, the two strategies with the highest QALY had very different ICERs," Limdi said. "The genotype-guided strategy was cost-effective at $42,365 per QALY. Universal ticagrelor was not; it had an ICER of $227,044 per QALY."

The researchers also looked at some secondary strategies for a real-world reason. A number of clinicians now prescribe ticagrelor or prasugrel for the first 30 days after PCI, which is considered a period of greater risk, and then switch their patients to the less expensive drug clopidogrel.

The secondary analysis allowed Limdi and colleagues to explore the cost-effectiveness of giving all patients ticagrelor for 30 days, and then switching them to clopidogrel, without genetic testing, versus switching the patients based on genotype. Both strategies were better -- in terms of QALYs -- than a universal switch to clopidogrel at 30 days. However, neither of the two appeared to be cost-effective. Because these secondary strategies used estimated parameters, "the findings should only be considered as hypothesis-generating," Limdi said.

LA JOLLA, CA--Scientists around the world are racing to develop a vaccine to protect against COVID-19 infection, and epidemiologists are trying to predict how the coronavirus pandemic will unfold until such a vaccine is available. Yet, both efforts are surrounded by unresolved uncertainty whether the immune system can mount a substantial and lasting response to SARS-CoV-2 and whether exposure to circulating common cold coronaviruses provides any kind of protective immunity.

A collaboration between the labs of Alessandro Sette, Dr. Biol. Sci. and Shane Crotty, Ph.D., at La Jolla Institute for Immunology is starting to fill in the massive knowledge gap with good news for vaccine developers and is providing the first cellular immunology data to help guide social distancing recommendations.

Published in today's online edition of Cell, the study documents a robust antiviral immune response to SARS-CoV-2 in a group of 20 adults who had recovered from COVID-19. The findings show that the body's immune system is able to recognize SARS-CoV-2 in many ways, dispelling fears that the virus may elude ongoing efforts to create an effective vaccine.

"If we had seen only marginal immune responses, we would have been concerned," says Sette, a professor in the Center for Infectious Disease and Vaccine Research, and adds, "but what we see is a very robust T cell response against the spike protein, which is the target of most ongoing COVID-19 efforts, as well as other viral proteins. These findings are really good news for vaccine development."

"All efforts to predict the best vaccine candidates and fine-tune pandemic control measures hinge on understanding the immune response to the virus," says Crotty, also a professor in the Center for Infectious Disease and Vaccine Research. "People were really worried that COVID-19 doesn't induce immunity, and reports about people getting re-infected reinforced these concerns, but knowing now that the average person makes a solid immune response should largely put those concerns to rest."

In an earlier study, Sette and his team had used bioinformatics tools to predict which fragments of SARS-CoV-2 are capable of activating human T cells. The scientists then, in this newest research, tested whether T cells isolated from adults who had recovered from COVID-19 without major problems, recognized the predicted protein fragments, or so-called peptides, from the virus itself. The scientists pooled the peptides into two big groups: The first so-called mega-pool included peptides covering all proteins in the viral genome apart from SARS-CoV-2's "spike" protein. The second mega-pool specifically focused on the spike protein that dots the surface of the virus, since almost all of the vaccines under development right now target this coronavirus spike protein.

"We specifically chose to study people who had a normal disease course and didn't require hospitalization to provide a solid benchmark for what a normal immune response looks like, since the virus can do some very unusual things in some people," says Sette.

The researchers found that all COVID-19 patients had a solid CD4, or "helper", T cell response, which helps antibody production. Almost all patients had produced virus-specific CD8, or "killer", T cells, which eliminate virus-infected cells. "Our data show that the virus induces what you would expect from a typical, successful antiviral response," says Crotty.

And, although these results don't preclude that the immune response to SARS-CoV-2 may be detrimental, they provide an important baseline against which individuals' immune responses can be compared; or, as Sette likes to put it, "if you can get a picture of something, you can discuss whether you like it or not but if there's no picture there's nothing to discuss."

"We have a solid starting foundation to now ask whether there's a difference in the type of immune response in people who have severe outcomes and require hospitalization versus people who can recover at home or are even asymptomatic," adds Sette. "But not only that, we now have an important tool to determine whether the immune response in people who have received an experimental vaccine resembles what you would expect to see in a protective immune response to COVID-19, as opposed to an insufficient or detrimental response."

The teams also looked at the T cell response in blood samples that had been collected between 2015 and 2018, before SARS-CoV-2 started circulating. Many of these individuals had significant T cell reactivity against SARS-CoV-2, although they had never been exposed to SARS-CoV-2. But everybody has almost certainly seen at least three of the four common cold coronaviruses, which could explain the observed crossreactivity.

It is still unclear, though, whether the observed crossreactivity provides at least some level of preexisting immunity to SARS-CoV-2 and therefore could explain why some people or geographical locations are hit harder by COVID-19.

¬¬"Given the severity of the ongoing COVID-19 pandemic, any degree of cross-reactive coronavirus immunity could have a very substantial impact on the overall course of the pandemic and is a key detail to consider for epidemiologists as they try to scope out how severely COVID-19 will affect communities in the coming months," says Crotty.

As unemployment rates skyrocket around the world in response to the COVID-19 pandemic, a world-first study has found social venture start-ups not only alleviate social problems but also are much more important for job creation than previously thought.

Written by Professor Martin Obschonka, Director of QUT's Australian Centre for Entrepreneurship Research, and its founding director, Professor Per Davidsson, along with collaborators from Sweden, the paper - The regional employment effects of new social firm entry - has just been published on Springer Open Access.

They contend the impact of social venture start-ups on regional job creation has been largely overlooked. They also argue the first-of-its-kind investigation could provide important input to employment policy, especially as global governments scramble to prop up ailing economies.

"It has long been acknowledged that the entry and growth of new firms contribute a large share of job creation in most countries. Social venture start-ups, however, are mostly celebrated for their worth in helping the disadvantaged or solving social concerns - their role in job creation has not really been considered," said Professor Obschonka.

"Yet using an established method for tracking direct and indirect job creation effects across 67 regions in Sweden over an eight-year period from start-up entry into the marketplace, our findings show the average job creation effect per firm was larger for social start-ups than for their commercial counterparts.

"Job creation is often a major focus of the social mission of these start-ups, especially for marginalised groups including people with disabilities and long-term unemployed individuals."

Professor Davidsson said the findings were contrary to the reliance on volunteers by many social endeavours.

"There appear to be a number of reasons social ventures create more jobs. First up, most 'commercial' start-ups represent individuals choosing self-employment which can mean they have no burning desire to grow and take on employees," Professor Davidsson said.

"Commercial start-ups also often operate in crowded markets with little room for growth. So even the high growth firms among the commercial category do not raise the average to high levels; partly because they outcompete or acquire some of their peers.

"By contrast, social ventures address underserved 'markets' of social problems, such as homelessness, substance abuse, domestic violence, refugees, environmental concerns, animal shelters, foodbanks, crisis centres, youth unemployment and so on.

"This creates room for growth without pushing out other social ventures. And being passionate about solving as much of 'their' social issue as they possibly can, social entrepreneurs are motivated to grow.

"They can also benefit from lower costs due to tax breaks and partial reliance on volunteers to have a growth advantage over commercial firms offering competing products or services."

The authors of the study acknowledge that as the commercial firm sector is much larger than the social sector, total job creation is greater overall.

The study compared regions in Sweden in terms of their social and commercial start-ups between 1990 to 2014 and their net job creation effects in each up to eight years after they entered the market.

"Similar comparisons for Australia or other countries do not yet exist," said Professor Obschonka.

"However, total employment in the social sector has grown recently in other countries, so our findings would most likely be valid in Australia and elsewhere along with Sweden."

Researchers from Tokyo Medical and Dental University (TMDU) identify a novel phosphorylation site of the protein Ulk1 to be an essential regulating factor for alternative autophagy, but not canonical autophagy.

Tokyo, Japan - Autophagy is a housekeeping process through which cells remove dysfunctional contents to balance energy sources during times of stress. Now, researchers from Tokyo Medical and Dental University (TMDU) identified a novel molecular mechanism by which a type of autophagy, called alternative autophagy, is activated. In a new study published in Nature Communications, they showed how a specific phosphorylation site of the protein Unc51-like kinase 1 (Ulk1) is essential for the cell to go down the alternative autophagy path.

As living structures, cells ensure homeostasis by carrying out specific processes by which they build and degrade their contents. Particularly at times of stress, for example during exposure to toxins, autophagy helps to ensure an orderly turnover process by which cells can recycle their contents to survive. Interestingly, the process of autophagy can take place by several distinct molecular mechanisms, two of which are canonical and alternative autophagy. While the protein Ulk1 is known to initiate both types of autophagy, the mechanism by which Ulk1 differentially regulates them has remained unclear.

"Autophagy is a very elaborate process by which cells recycle their contents," says the corresponding author of the study Shigeomi Shimizu. "The goal of our study was to understand how Ulk1 that has control over two types of autophagy, differentially regulates them."

To achieve their goal, the researchers used mouse embryonic fibroblasts (MEFs) deficient in the protein Atg5 to turn off canonical autophagy. By exposing them to etoposide, a DNA-damaging reagent, they then induced alternative autophagy. Using mass spectrometry, the researchers found that Ulk1 carried an additional phosphoryl group at its amino acid serine in position 746 (Ser746; p-Ulk1746), also called phosphorylation, when exposed to etoposide but not when left untreated. By developing a new antibody against p-Ulk1746, the researchers then showed that the protein localized to the Golgi complex within the cells. The Golgi complex is an organelle participating in many cellular processes, including alternative autophagy.

"While these were already exciting findings, our goal was to understand whether the specific phosphorylation of Ulk1 at the serine 746 site is required for alternative autophagy and which kinase is responsible for this phosphorylation step," says lead and the corresponding author of the study Satoru Torii.

To analyze the causal relationship between Ulk1 Ser746 phosphorylation and alternative autophagy, the researchers used a fluorescent tandem protein consisting of red fluorescent protein (RFP) and green fluorescent protein (GFP). Because GFP does not fluoresce within acidic environments, the tandem protein made autolysosomes, cellular compartments that are created during autophagy, become red. While the red fluorescence appeared after etoposide treatment, it was not generated in cells producing Ulk1 nonphosphorylated mutant, indicating that p-Ulk1746 is required for alternative autophagy. Next, the researchers demonstrated that receptor-interacting protein kinase 3 (RIPK3), a protein that phosphorylates other proteins involved in necroptosis, is responsible for the generation of p-Ulk1746 by showing that p-Ulk1746 and alternative autophagy occurred in normal cells but not in cells deficient in RIPK3. Intriguingly in MEFs that expressed Atg5, canonical autophagy was not affected by RIPK3-deficiency, indicating that p-Ulk1746 is not involved in canonical autophagy.

"These are striking results that shed new light on how cells regulate the complex process of autophagy," says Shimizu. "We hope that our findings will be helpful in understanding the role of alternative autophagy in normal biology and disease."

A pair of gigantic gamma-ray bubbles centered on the core of the Milky Way galaxy were discovered by the Fermi Gamma-ray Space Telescope 10 years ago. But how these so-called "Fermi bubbles" arose was a mystery.

Recently, however, researchers at the Shanghai Astronomical Observatory (SHAO) of the Chinese Academy of Sciences have presented a new model that for the first time simultaneously explains the origins of both the Fermi bubbles and the Galactic center biconical X-ray structure, which was discovered in 2003.

According to this model, the two structures are essentially the same phenomenon and was caused by the forward shock driven by a pair of jets emanating from Sagittarius A* (Sgr A*) - the supermassive black hole lurking at the Galactic center - about five million years ago. The study was published in The Astrophysical Journal.

Fermi bubbles are two colossal blobs filled with very hot gas, cosmic rays and magnetic fields. Although they cannot be seen with the naked eye, they are very bright in diffuse gamma-ray emissions. In gamma rays, the Fermi bubbles have very sharp edges and the edges coincide well with an X-ray structure called the Galactic center biconical X-ray structure.

Seeing the very similar edges of Fermi bubbles and the Galactic center biconical X-ray structure, the SHAO researchers realized these structures might share the same origin. Furthermore, the biconical X-ray structure could be naturally explained by the shock-compressed thin shell of hot thermal gas driven by a past energy outburst from the Galactic center.

In previous theoretical models and computer simulations of the Fermi bubbles, two major competing energy sources were proposed, i.e., star formation at the Galactic center and Sgr A*. However, in both models, the Fermi bubbles are explained as ejecta bubbles, while the forward shock is always located much further away from the edge of the Fermi bubbles. In other words, these models could not explain the Fermi bubbles and the Galactic center biconical X-ray structure simultaneously.

In contrast, the theoretical model in this study, proposed by GUO Fulai and his graduate student ZHANG Ruiyu from SHAO, used computer simulations to demonstrate for the first time that the Fermi bubbles and the Galactic center biconical X-ray structure are the same phenomenon.

In this model, the edge of the Fermi bubbles is the forward shock driven by a pair of jets emanating from Sgr A* about five million years ago. "One good thing about this model is that the energy and age of the Fermi bubbles can be constrained by the X-ray observations quite well," said corresponding author GUO Fulai. The age of the bubbles inferred in this study is also consistent with that derived from recent ultraviolet observations of some high velocity clouds along many sightlines towards the bubble region.

The new model indicates that the total energy injected during the Fermi bubble event by the supermassive black hole is close to that released by about 20,000 supernovae. The total matter consumed by Sgr A* during this event is about 100 solar masses.

"Another very interesting thing that we found in our study is that if the bubbles and the biconical X-ray structure share the same origin, they are very unlikely to be produced by star formation or black hole winds," said GUO. Near the Galactic center, the biconical X-ray structure has a very narrow base, while the forward shock produced by star formation or black hole winds can easily propagate to large distances, leading to a base much wider than observed.

In contrast, collimated jets deposit most of the energy quickly to large distances along the jet direction, naturally leading to a narrow base for the shock front near the Galactic plane. The supermassive black hole in our own Galaxy has been very quiescent in recent years without any evidence of current jet activities, but "our study strongly suggests that a pair of powerful jets emanated from it about five million years ago, lasted for about one million years, and produced the gigantic Fermi bubbles still seen today," added GUO.

New research conducted at CRIOBE and ENTROPIE research units, with the collaboration of the Swire institute of Marine Science of The University of Hong Kong, The Cawthron Institute and James Cook University, highlights the impacts of benthic species assemblages on the giant clams Tridacna maxima. The findings were recently published in the journal Microbiome.

The researchers explored for the first time the influence of benthic species-assemblages on giant clams health, with or without increasing temperature. To do so, they created artificial benthic assemblages using two coral species (Pocillopora damicornis and Acropora cytherea) and one giant clam species (Tridacna maxima). The results showed that the health status of giant clams depended on the neighbouring species. Moreover, using cutting-edge DNA multiplexing-metabarcoding technology adapted by Dr. Xavier Pochon, the team studied the microbial community of the giant clams. The researchers newly discovered distinct microbiotypes (group of specific bacteria) in the studied T. maxima population, one of which was linked to clam mortality.

Giant clams are less studied by scientists, yet they are important members of coral reefs and play numerous ecological roles. They are the largest living bivalves and serve as food for fish and human. Like coral, they contribute to primary production through photosynthesis by hosting unicellular algae. They also host a large community of bacteria as well as animals such as shrimps or crabs. However, all of the 12 currently recognised species are under threat and more than 50% of the wild population are either locally extinct or severely depleted.

"For decades we have been focusing on the effect of climate change on single species but this doesn't reflect what could happen within coral reef as a whole. This is why we decided to explore the effect of neighbouring species on the giant clam. We were extremely surprised to discover that the presence of some corals, particularly Acropora cytherea, led to an acute sensitivity of giant clams to increasing temperature which therefore exhibited a high death rate." explains Dr. Isis Guibert.

Microbiomes are an integral part of multicellular organisms, contributing to their health and physiological performance. The scientists noted that despite a surge of interest in this research focus, very few invertebrate microbiomes have been studied. The microbiome of giant clams is particularly interesting because clams are exposed to an extreme abundance and diversity of microbes through filter feeding. The discovery of specific microbiome structure, detectable from the genus level, is the first description of microbiotypes in invertebrates. "The results of our study suggest that, similarly to humans, genetic factors might drive the microbiotype of a giant clam." said Dr. Isis Guibert.

Interestingly, the clams with compromised health were characterised by a prominence of vibrio and therefore a distinct microbiome. "The relative proportion of Vibrionaceae could be used as an early indicator of clam health in natural populations." explains Dr.Véronique Berteaux-Lecellier, who supervised the study, "We hypothesise that A. cytherea could secrete metabolites that might have weakened the clams' defenses against Vibrio infection; future research should explore this possibility." The findings of this study suggest that the composition of the coral reef benthos, together with increasing water temperatures, could negatively impact the health of giant clams and potentially other reef organisms. Therefore, the findings support the idea that, like terrestrial conservation and restoration, taking account of the entire benthic assemblages should be the goal of marine conservation strategies.