Culture

DURHAM, N.C. - When patients complain of coughing, runny nose, sneezing and fever, doctors are often stumped because they have no fundamental tool to identify the source of the respiratory symptoms and guide appropriate treatments.

That tool might finally be on its way. In a study proving feasibility, researchers at Duke Health showed that their testing technology can accurately distinguish between a viral and a bacterial infection for respiratory illness - a critical difference that determines whether antibiotics are warranted. And, importantly, the test provided results in under an hour.

"This is exciting progress," said study lead Ephraim Tsalik, associate professor in the departments of Medicine and Molecular Genetics and Microbiology at Duke University School of Medicine.

"We've been working on this for over a decade," Tsalik said. "We knew in 2016 that our test worked in the research setting, but it's always been our goal to have a test that could produce results rapidly, while patients are at their doctor's office. It's important that the distinction can be made quickly to ensure that antibiotics are not inappropriately prescribed."

Tsalik and colleagues published results of their study in the journal Critical Care Medicine, which confirm the test's accuracy with results available in under an hour.

The researchers have developed a gene expression method that diverges from current diagnostic strategies, which focus on identifying specific pathogens. The current tests are time-consuming and can only identify a pathogen if it's specifically targeted by the test in the first place.

Host gene expression, however, looks for a distinct immune signal that is unique to the type of infection the body is fighting. The immune system activates one set of genes when fighting bacterial infections and a different set of genes in response to a viral infection. After the team discovered these gene expression signatures for bacterial and viral infection, they collaborated with BioFire Diagnostics, a company that specializes in molecular diagnostics, to develop this first-of-its kind test.

In a multisite study of more than 600 patients presenting to hospital emergency departments with respiratory infections, the tests identified bacterial infections with 80% accuracy and viral infections with nearly 87% accuracy. The current standard tests have about 69-percent accuracy. Tests provided results in less than an hour, and their accuracy was confirmed retrospectively using two different methods.

"Acute respiratory illness is the most common reason that people visit a health care provider when feeling sick," Tsalik said. "Patients with these symptoms are inappropriately treated with antibiotics far too often due to challenges in discriminating the cause of illness, fueling antibiotic resistance. Our study shows that a rapid test to distinguish between these two sources of illness is possible and could improve clinical care."

Tsalik said additional studies are underway to validate this approach in additional groups of patients. The researchers are also working to adapt the technology to produce more specific information, including whether the virus causing illness is influenza or SARS-CoV-2.

A new study published in Medical Care Research and Review found that the Affordable Care Act, which expanded Medicaid programs to cover people previously uninsured, provided a financial boost to hospitals.

The study conducted by faculty at the Colorado School of Public Health on the University of Colorado Anschutz Medical Campus is the first to investigate the effects of Medicaid expansion by comparing estimates using data from both the Internal Revenue Service (IRS) and the Centers for Medicare and Medicaid Services (CMS).

"The IRS and CMS data sources serve as primary resources for assessing the impact of Medicaid expansion on hospitals' financial status. The comparison of the two is timely and can inform the decisions of health practitioners, policymakers and regulators at a state and national level," said lead author Tatiane Santos, MPH, PhD, faculty at the Colorado School of Public Health and fellow at the Wharton School and Leonard Davis Institute of Health Economics at the University of Pennsylvania.

Santos adds, "This is especially relevant in the context of the recently passed American Rescue Plan Act of 2021, which provides additional incentives for the 12 states that have not yet expanded Medicaid."

The researchers examined the state-level impact of Medicaid expansion on hospital finances and based on the IRS data found that uncompensated care costs declined by 28 percent in states that expanded Medicaid relative to uncompensated care costs in 2013, the year before Medicaid expansion (9.3 percent of operating expenses in 2013). The findings based on the CMS data showed that there was a 32 percent decline in uncompensated care costs relative to costs in 2013 (5.0 percent of operating expenses in 2013).

These results are in line with previous studies that have reported that expansion has resulted in substantial reductions in hospitals' uncompensated care costs and increases in their Medicaid shortfalls (these shortfalls are the difference between Medicaid reimbursement and what it costs providers to care for patients).

Nationally, the estimated net effect of expansion reduced not-for-profit hospital costs by two percentage points based on IRS data and 0.83 percentage points based on CMS data. Across expansion states, the estimated net effects varied widely with approximately a 10-fold difference for hospitals based on IRS data and a two-fold difference based on CMS data.

Another key finding revealed that the increase in hospital's Medicaid shortfalls has been occurring more gradually, a result that may be partially attributable to a growing Medicaid population in expansion states.

The authors mention that while Medicaid expansion has clearly had an impact on hospitals' financial status, assessment of the actual magnitude of the effects is sensitive to the data sources used.

"Expansion effects have also varied by state, which may be an indicator of how states may potentially weather the COVID-19 pandemic financial shocks, including unemployment and increasing Medicaid enrollment. These are important findings for future consideration as Medicaid expansion continues to be a source of debate across the United States as a health policy initiative," added Santos.

The authors suggest that future studies should further explore the differences across IRS and CMS data. They suggest that as the pandemic unfolds Medicaid will be especially critical in serving the most vulnerable populations. States will need to make difficult financial decisions to protect their safety net hospitals and hospitals at highest risk of financial distress.

BOSTON - Researchers at Massachusetts General Hospital (MGH) have identified the protein "signature" of severe COVID-19, which they describe in a new study published in Cell Reports Medicine. "We were interested in asking whether we could identify mechanisms that might be contributing to death in COVID-19," says MGH infectious disease expert Marcia Goldberg, MD, who studies interactions between microbial pathogens and their hosts, and is senior author of the study. "In other words, why do some patients die from this disease, while others--who appear to be just as ill--survive?"

In March 2020, when the first patients with symptoms of COVID-19 began arriving at MGH's emergency department (ED), Goldberg was contacted by her colleague, Michael Filbin, MD, MS, an attending physician and director of Clinical Research at MGH's ED, and lead author of the study. Filbin and Goldberg had earlier begun collaborating with MGH immunologist Nir Hacohen, PhD, to develop methods for studying human immune responses to infections, which they had applied to the condition known as bacterial sepsis. The three agreed to tackle this new problem with the goal of understanding how the human immune system responds to SARS-CoV-2, the novel pathogen that causes COVID-19.

To undertake this study, the MGH team used proteomics, which is the analysis of the entire protein composition (or proteome) of a cell, tissue or organism. In this case, proteomic analysis was used to study blood specimens taken from patients arriving at the hospital's ED with respiratory symptoms consistent with COVID-19. Collecting these specimens required a large team of collaborators from many departments, which worked overtime for five weeks to amass blood samples from 306 patients who tested positive for COVID-19, as well as from 78 patients with similar symptoms who tested negative for the coronavirus. (For more on this extraordinary effort, click here.)

Next, Arnav Mehta, MD, PhD, a postdoctoral researcher at the Broad Institute of MIT and Harvard, was brought on board to oversee interpretation of the complex data produced by the proteomic analysis. Mehta also works in Hacohen's lab, and the two had long been interested in using proteomic analysis of blood as an alternative to biopsies (which are invasive and painful). "We have been asking, What can we learn about what's happening in the body just by looking at protein signatures in the blood?" says Mehta.

The study found that most patients with COVID-19 have a consistent protein signature, regardless of disease severity; as would be expected, their bodies mount an immune response by producing proteins that attack the virus. "But we also found a small subset of patients with the disease who did not demonstrate the pro-inflammatory response that is typical of other COVID-19 patients," says Filbin, yet these patients were just as likely as others to have severe disease. Filbin notes that patients in this subset tended to be older people with chronic diseases, who likely had weakened immune systems.

The next step was to compare the protein signatures of patients with severe disease (defined as those who required intubation or who died within 28 days of hospital admission) with patients with less-severe cases of COVID-19. The comparison allowed the researchers to identify more than 250 "severity associated" proteins. Importantly, notes Mehta, blood was drawn from patients three times (on enrollment, then three and seven days later). "That allowed us to look at the trajectory of the disease," says Mehta. Among other revelations, this showed that the most prevalent severity-associated protein, a pro-inflammatory protein called interleukin-6, or IL-6, rose steadily in patients who died, while it rose and then dropped in those with severe disease who survived. Early attempts by other groups to treat COVID-19 patients experiencing acute respiratory distress with drugs that block IL-6 were disappointing, though more recent studies show promise in combining these medications with the steroid dexamethasone.

However, Hacohen notes that many of the other severity-associated proteins the analysis identified are likely important for understanding why only a portion of COVID-19 develop severe cases. Learning how the disease affects the lungs, heart and other organs is essential, he says, and proteomic analysis of the blood is a relatively easy method for getting that information. "You can ask which of the many thousands of proteins that are circulating in your blood are associated with the actual outcome," says Hacohen, "and whether there is a set of proteins that tell us something."

Goldberg believes that the proteomic signatures identified in this study will do just that. "They are highly likely to be useful in figuring out some of the underlying mechanisms that lead to severe disease and death in COVID-19," says Goldberg, noting her gratitude to the patients involved in the study. Their samples are already being used to study other aspects of COVID-19, such as identifying the qualities of antibodies that patients form against the virus.

BOSTON - Researchers from Massachusetts General Hospital (MGH) appear to have solved the 120-year-old mystery surrounding the failing health of famed Antarctic explorer Sir Ernest Shackleton over the course of his daring expeditions to Antarctica in the early part of the twentieth century. In a paper published online in the Journal of Medical Biography, the team moved beyond past theories of congenital heart defect and scurvy advanced by physicians and historians to conclude that the British explorer suffered from beriberi, a serious and potentially life-threatening condition caused by a deficiency of the nutrient thiamine.

"Historians have traditionally looked at Shackleton's symptoms in isolation and speculated about their cause," says lead author Paul Gerard Firth, MD, head of the Division of Community and Global Health in the Department of Anesthesia, Critical Care and Pain Medicine at MGH. "We looked at other explorers on the expedition, as well as members of other early expeditions, and found that some had symptoms--such as breathlessness, neuropathy and effort intolerance--similar to Shackleton's that could be attributed to beriberi. With the benefit of what we now know about nutritional diseases, we believe that beriberi-induced cardiomyopathy--a disease of the heart muscle that makes it difficult for the heart to pump blood--is the correct diagnosis for Ernest Shackleton's deteriorating health."

The researchers learned that Edward Wilson, one of two physicians on Shackleton's first voyage to Antarctica beginning in 1901--when the explorer fell seriously ill and had to return home after voyaging closer to the South Pole than any previous human--may have suspected beriberi after consulting his medical textbooks, but didn't settle on that diagnosis at a time when so little was known about the condition. Instead, the prolonged bouts of extreme shortness of breath and physical weakness Shackleton experienced on the British "Discovery" expedition of 1901 to 1903 were ascribed by his contemporaries and subsequent historians to scurvy or underlying heart disease.

"While Wilson concluded that Shackleton's condition was the result of scurvy--a vitamin C deficiency--that appeared to us to be an incomplete explanation for his labored breathing," says Firth. "Shackleton, after all, had very slight symptoms of scurvy when his breathing difficulties began, and mild scurvy does not cause heart problems."

This careful parsing of the historical evidence led Firth and his colleagues to an alternative nutritional cause of Shackleton's health struggles. "Many of the signs and symptoms of beriberi seen in early explorers developed after three months of thiamine deficiency," explains co-author Lauren Fiechtner, MD, director of the Center for Pediatric Nutrition at MGH. "And that would be consistent with a thiamine-deficient diet they experienced during the grueling months of winter explorations. Fortunately, replacement of thiamine with vitamin B1 supplements can resolve the deficiency within days or hours, although that was not known at the time."

Even severe health challenges were not enough to prevent Shackleton from setting out on a third attempt to reach the South Pole in 1914, a fateful voyage since recounted in books and movies of how his ship Endurance became trapped in packed ice and broke apart, with all 28 crewmen reaching safety after two years and two heroic rescue efforts engineered by Shackleton. In late 1921, the intrepid explorer embarked on his fourth expedition, but suffered a heart attack on January 5, 1922, and died on his ship at age 47.

"The exact nature of Ernest Shackleton's faltering health has puzzled historians and the public for years," says Firth, "and almost 100 years after the start of his fourth and final expedition we're satisfied that we have finally uncovered a medically and scientifically valid explanation."

Researchers have found that people who live beyond 105 years tend to have a unique genetic background that makes their bodies more efficient at repairing DNA, according to a study published today in eLife.

This is the first time that people with 'extreme longevity' have had their genomes decoded in such detail, providing clues as to why they live so long and manage to avoid age-related diseases.

"Aging is a common risk factor for several chronic diseases and conditions," explains Paolo Garagnani, Associate Professor at the Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Italy, and a first author of the study. "We chose to study the genetics of a group of people who lived beyond 105 years old and compare them with a group of younger adults from the same area in Italy, as people in this younger age group tend to avoid many age-related diseases and therefore represent the best example of healthy aging."

Garagnani and colleagues, in collaboration with several research groups in Italy and a research team led by Patrick Descombes at Nestlé Research in Lausanne, Switzerland, recruited 81 semi-supercentenarians (those aged 105 years or older) and supercentenarians (those aged 110 years or older) from across the Italian peninsula. They compared these with 36 healthy people matched from the same region who were an average age of 68 years old.

They took blood samples from all the participants and conducted whole-genome sequencing to look for differences in the genes between the older and younger group. They then cross-checked their new results with genetic data from another previously published study which analysed 333 Italian people aged over 100 years old and 358 people aged around 60 years old.

They identified five common genetic changes that were more frequent in the 105+/110+ age groups, between two genes called COA1 and STK17A. When they cross-checked this against the published data, they found the same variants in the people aged over 100. Data acquired from computational analyses predicted that this genetic variability likely modulates the expression of three different genes.

The most frequently seen genetic changes were linked to increased activity of the STK17A gene in some tissues. This gene is involved in three areas important to the health of cells: coordinating the cell's response to DNA damage, encouraging damaged cells to undergo programmed cell death and managing the amount of dangerous reactive oxygen species within a cell. These are important processes involved in the initiation and growth of many diseases such as cancer.

The most frequent genetic changes are also linked to reduced activity of the COA1 gene in some tissues. This gene is known to be important for the proper crosstalk between the cell nucleus and mitochondria - the energy-production factories in our cells whose dysfunction is a key factor in aging.

Additionally, the same region of the genome is linked to an increased expression of BLVRA in some tissues - a gene that is important to the health of cells due to its role in eliminating dangerous reactive oxygen species.

"Previous studies showed that DNA repair is one of the mechanisms allowing an extended lifespan across species," says Cristina Giuliani, Senior Assistant Professor at the Laboratory of Molecular Anthropology, Department of Biological, Geological and Environmental Sciences, University of Bologna, and a senior author of the study. "We showed that this is true also within humans, and data suggest that the natural diversity in people reaching the last decades of life are, in part, linked to genetic variability that gives semi-supercentenarians the peculiar capability of efficiently managing cellular damage during their life course."

The team also measured the number of naturally occurring mutations that people in each age group had accumulated throughout their life. They found that people aged 105+ or 110+ had a much lower burden of mutations in six out of seven genes tested. These individuals appeared to avoid the age-related increase in disruptive mutations, and this may have contributed in protecting them against diseases such as heart disease.

"This study constitutes the first whole-genome sequencing of extreme longevity at high coverage that allowed us to look at both inherited and naturally occurring genetic changes in older people," says Massimo Delledonne, Full Professor at the University of Verona and a first author of the study.

"Our results suggest that DNA repair mechanisms and a low burden of mutations in specific genes are two central mechanisms that have protected people who have reached extreme longevity from age-related diseases," concludes senior author Claudio Franceschi, Professor Emeritus of Immunology at the University of Bologna.

TAMPA, Fla. (May 4, 2021) -- Repetitive transcranial magnetic stimulation, or rTMS, was FDA approved in 2008 as a safe and effective noninvasive treatment for severe depression resistant to antidepressant medications. A small coil positioned near the scalp generates repetitive, pulsed magnetic waves that pass through the skull and stimulate brain cells to relieve symptoms of depression. The procedure has few side effects and is typically prescribed as an alternative or supplemental therapy when multiple antidepressant medications and/or psychotherapy do not work.

Despite increased use of rTMS in psychiatry, the rates at which patients respond to therapy and experience remission of often-disabling symptoms have been modest at best.

Now, for the first time, a team of University of South Florida psychiatrists and biomedical engineers applied an emerging functional neuroimaging technology, known as diffuse optical tomography (DOT), to better understand how rTMS works so they can begin to improve the technique's effectiveness in treating depression. DOT uses near-infrared light waves and sophisticated algorithms (computer instructions) to produce three-dimensional images of soft tissue, including brain tissue.

Comparing depressed and healthy individuals, the USF researchers demonstrated that this newer optical imaging technique can safely and reliably measure changes in brain activity induced during rTMS in a targeted region of the brain implicated in mood regulation. Their findings were published April 1 in the Nature journal Scientific Reports.

"This study is a good example of how collaboration between disciplines can advance our overall understanding of how a treatment like TMS works," said study lead author Shixie Jiang, MD, a third-year psychiatry resident at the USF Health Morsani College of Medicine. "We want to use what we learned from the application of the diffuse optical tomography device to optimize TMS, so that the treatments become more personalized and lead to more remission of depression."

DOT has been used clinically for imaging epilepsy, breast cancer, and osteoarthritis and to visualize activation of cortical brain regions, but the USF team is the first to introduce the technology to psychiatry to study brain stimulation with TMS.

"Diffuse optical tomography is really the only modality that can image brain function at the same time that TMS is administered," said study principal investigator Huabei Jiang, PhD, a professor in the Department of Medical Engineering and father of Shixie Jiang. The DOT imaging system used for USF's collaborative study was custom built in his laboratory at the USF College of Engineering.

The researchers point to three main reasons why TMS likely has not lived up to its full potential in treating major depression: nonoptimized brain stimulation targeting; unclear treatment parameters (i.e., rTMS dose, magnetic pulse patterns and frequencies, rest periods between stimulation intervals), and incomplete knowledge of how nerve cells in the brain respond physiologically to the procedure.

Portable, less expensive, and less confining than some other neuroimaging equipment like MRIs, DOT still renders relatively high-resolution, localized 3D images. More importantly, Dr. Huabei Jiang said, DOT can be used during TMS without interfering with treatment's magnetic pulses and without compromising the images and other data generated.

DOT relies on the fact that higher levels of oxygenated blood correlate with more brain activity and increased cerebral blood flow, and lower levels indicate less activity and blood flow. Certain neuroimaging studies have also revealed that depressed people display abnormally low brain activity in the prefrontal cortex, a brain region associated with emotional responses and mood regulation.

By measuring changes in near-infrared light, DOT detects changes in brain activity and, secondarily, changes in blood volume (flow) that might be triggering activation in the prefrontal cortex. In particular, the device can monitor altered levels of oxygenated, deoxygenated, and total hemoglobin, a protein in red blood cells carrying oxygen to tissues.

The USF study analyzed data collected from 13 adults (7 depressed and 6 healthy controls) who underwent DOT imaging simultaneously with rTMS at the USF Health outpatient psychiatry clinic. Applying the standard rTMS protocol, the treatment was aimed at the brain's left dorsolateral prefrontal cortex - the region most targeted for depression.

The researchers found that the depressed patients had significantly less brain activation in response to rTMS than the healthy study participants. Furthermore, peak brain activation took longer to reach in the depressed group, compared to the healthy control group.

This delayed, less robust activation suggests that rTMS as currently administered under FDA guidelines may not be adequate for some patients with severe depression, Dr. Shixie Jiang said. The dose and timing of treatment may need to be adjusted for patients who exhibit weakened responses to brain stimulation at baseline (initial treatment), he added.

Larger clinical trials are needed to validate the USF preliminary study results, as well as to develop ideal treatment parameters and identify other dysfunctional regions in the depression-affected brain that may benefit from targeted stimulation.

"More work is needed," Dr. Shixie Jiang said, "but advances in neuroimaging with new approaches like diffuse optical tomography hold great promise for helping us improve rTMS and depression outcomes."

Relatives of the giant crocodile might have been kings of the waterways during the Cretaceous period, eating anything--including dinosaurs--that got a little too close to the water's edge, but the largest of these apex predators still started off small. Figuring out how these little crocs grew up in a world surrounded by giants is no small task. Now crocs fossils from Texas are shedding light on how these animals changed their diets as they grew, helping them find a place of their own in environments alongside their bigger, badder relatives.

According to the study, published by Cambridge University Press, the crocodiless in question are members of the Deltasuchus motherali and lived along the coastline of Texas 96 million years ago. Previously known from a single adult skull, this 20-foot-long crocodile left behind bite marks on turtles and, yes, dinosaurs. The new discoveries include at least 14 more members of Deltasuchus, ranging from sizes as large as the original specimen down to a paltry (if still snappy) four feet in length.

Having so many crocs from the same fossil population is not common, and the smaller, more delicate bones of juveniles often did not survive the fossilization process.

"So many fossil groups are only known from one or a handful of specimens," said paleontologist Stephanie Drumheller, lead author of the study and a lecturer of earth and planetary sciences at the University of Tennessee, Knoxville. "It can be easy to fall into the trap of only thinking about the adults." The researchers ran into challenges piecing together this ancient ecosystem, however. Deltasuchus wasn't alone in its coastal swamps.

Living alongside Deltasuchus were other large crocs, like Terminonaris and Woodbinesuchus.

"These two large croc species were comparable in size to an adult Deltasuchus, but because they had long, narrow snouts with slender interlocking teeth, they were targeting smaller prey in the environment," said Thomas Adams, co-author of the new study and curator of paleontology and geology at the Witte Museum in San Antonio.

A smaller crocodile, Scolomastax, lived in the area as well, but its unusual jaw and chunky dentition hint that it preferred hard food and maybe even plants.

"These results confirm previous work that shows fossil crocs were much more diverse and creative when it came to coexisting in the same environments," said Chris Noto, co-author and associate professor at the University of Wisconsin-Parkside. "The very warm conditions of the Cretaceous supported a greater number of reptiles and allowed them to explore new niches not possible in the present day."

When these crocodiles died, their skeletons fell apart as they fossilized, getting jumbled together and complicating efforts to tell which bones went with which animal. To help solve this puzzle, the team turned to 3D scanning technology to help reconstruct the skulls. UT undergraduate student Hannah Maddox meticulously scanned each piece and stitched them together into 3D models of complete skulls.

"It was like solving a great puzzle," said Maddox. "Every piece brought you closer to seeing a toothy grin that hadn't been seen in millions of years."

As the models came together, a more complete picture of how Deltasuchus lived started to take shape.

The juveniles had lighter, skinnier snouts and teeth than their older relatives--faces better suited to snap up quicker, softer prey than the heavier, powerful jaws of their parents. This might have helped make sure that little Deltasuchus were not in direct competition with the similarly sized hard-prey specialists in their environments, but as they grew they had other neighbors to consider. The large-bodied, slender-snouted role was already filled by other species. So Deltasuchus shifted in another direction as it grew, bulking up and taking on the heavy jaws and sturdy teeth of an ambush predator.

"This is an amazing fossil discovery where we not only have a population of a single species, but in an ecosystem that has multiple predators coexisting by filling separate niches," said Adams.

Similar results were found in recent analyses of young tyrannosaurs, which spent their teenaged years outcompeting other medium-sized predators in their ecosystems.

Scientists have shed light on why some people who have a stroke do not also have abnormal heart rhythms, even though their hearts contain similar scar tissue.

Their results, published today in eLife, could help identify the best treatments for people who might be at risk of recurrent stroke, new heart disorders, or both.

Strokes are often caused by abnormal blood flow resulting from rapid, irregular beating in the upper chamber of the heart. This is also called atrial fibrillation (AFib). But some people have strokes that appear to have been caused by the heart, yet there is no evidence of AFib. In fact, around 25% of strokes fall into this group - called embolic strokes of undetermined source (ESUS).

"The absence of rhythm disorders in these people is confusing because we know that both atrial fibrillation and ESUS are associated with the build-up of a similar level of scar tissue in the heart," explains first author Savannah Bifulco, a graduate student at the Department of Bioengineering, University of Washington, Seattle, US. "We wanted to test whether there is some fundamental difference in the scar tissue between these two groups of patients that might explain why AFib patients suffer from rhythm disorders but ESUS patients do not."

The team developed 90 computer-based models using magnetic resonance imaging (MRI) scans from patients: 45 models were derived from patients who had a stroke of undetermined source and 45 from those who had AFib and had not yet received treatment. They compared the amount and location of the scar tissue in the upper-left heart chamber across all samples and then used simulations to test whether it was still possible to trigger an abnormal heart rhythm.

"Using real patient MRIs, we created computerised models of the hearts of patients who have had a stroke, but do not have AFib. We then ran those models through a battery of virtual stress tests we originally designed to help understand the effects of disease-related atrial changes in patients who did have AFib," explains co-senior author Patrick Boyle, Assistant Professor of Bioengineering, who leads the Cardiac Systems Simulation Lab at the University of Washington. "Interestingly, we found that models from ESUS and AFib patients were equally likely to be affected by this arrhythmia initiation protocol. This is surprising, because it suggests ESUS and AFib patients have the same proverbial tinderbox of fibrotic remodelling. We believe the implication is that these stroke patients are only missing the trigger to start the fibrillation process - the spark to light the fire."

Undetectable AFib is thought to be a potential cause of ESUS, and all people who have had a stroke of undetermined source are usually monitored for AFib and started on aspirin to prevent another stroke. If AFib is detected, stronger anti-clotting drugs would be recommended. As with all treatments, these drugs come with side effects and risks of their own, and it is important to know who really needs them. Yet only 30% of ESUS patients ever show evidence of AFib, making it impossible for clinicians to know which patients should be treated as high-risk for AFib and which ones are better with monitoring alone. Now, the team is moving towards using this modelling approach for stroke and arrhythmia risk stratification in potentially vulnerable groups.

"By using these tools of advanced imaging, computational power and outcomes data to create robust and validated computational models of arrhythmia, we're paving the way towards a better understanding and gaining valuable insights into the nature of each individual's disease course," says co-senior author Nazem Akoum, Director, Atrial Fibrillation Program, Division of Cardiology, University of Washington School of Medicine. "Our goal is to make computational modelling more integrated into how clinical decisions are made, placing what we see in simulations alongside many other factors like medical co-morbidites, diagnostic tests and family history. We want to help clinicians wring every last drop of information and insight from these images to help them paint the most complete picture possible for their patients."

The human immune system doesn't just protect our health, it reflects it. Each encounter with a potential disease-causing agent causes the body to produce specific immune agents -- proteins known as antibodies and T-cell receptors -- tailor-made to recognize and destroy the invader. Tasked with preventing re-infection, antibodies and T-cell receptors (TCR) from your previous encounters circulate throughout the body indefinitely, like a record of your personal medical history that you carry inside of you.

Clinical pathologist Ramy Arnaout, MD, DPhil, Associate Director of the Clinical Microbiology Laboratories at Beth Israel Deaconess Medical Center, wants to mine those personal medical records for information. In a recent perspective published in Frontiers in Immunology, Arnaout and colleagues in the Adaptive Immune Receptor Repertoire Community (AIRR-C) outline how the immunome -- all of the genes collectively expressed by an individual's immune cells -- holds the potential to provide researchers and physicians with unprecedented insight into an individual's health. Collecting that information from large numbers of patients could one day facilitate diagnostics via a near-universal blood test and pave the way to targeted therapies for a wide variety of conditions.

We asked Dr. Arnaout to tell us more about this new frontier of personalized medicine.

What exactly is the immunome and what can researchers and physicians learn from it?

The immunome is the complete set of immune cells -- antibodies and T cell receptors (TCR) -- that every person makes in response to infections, vaccinations, transplants and transfusions, autoimmune diseases, aging and cancers.

Right now, you have in your body something like a hundred billion to a trillion T and B cells, minding their own business, circulating through your blood, leaving to check out what's going on in all your organs, and then completing the loop and coming back around.

A number of us in the field have been thinking for some time that if we could just figure out which antibodies and T-cell receptors match to which disease or condition, then we would have a universal diagnostic. That is, we would be able to look at a person's antibodies and T-cell receptors, and just by seeing what's there, we'd be able to say, "Oh, these antibodies are against melanoma, that means you probably had it, but your immune system took care of it," or, "You probably had the flu."

One blood test, one jab -- everything else is computer science on the other end. But first we need to crack that code.

What could researchers and physicians do with this information?

If I looked at your immunome and your friend's immunome, you might assume that you'd have nothing in common. But, despite the underlying differences among us all, the antibodies and TCR we produce are similar enough even if they are not identical that scientists can look at them bioinformatically and recognize patterns.

We know now from data that despite extraordinary, unfathomable potential of diversity -- there are more different possible sequences than stars in the observable universe, certainly more than grams of mass in the sun -- you and I are not genetically that different. We live in the same world, we're sneezed on by the same people on the subway -- it is incredible that our actual diversity genetically is so unbelievably constrained that we have been able to and regularly do find patterns that we might have thought couldn't exist ten years ago.

So, by getting samples from people who have known conditions -- such as COVID-19, dengue, ebola and other infectious diseases -- and comparing them to control samples, scientists can computationally pull out patterns.

But the missing ingredient here is you. In this paper my colleagues and I just published in Frontiers in Immunology, we're trying to announce to the scientific community and beyond that we can find these patterns and put them to good use. But we need clinicians to be aware of this and connect with us.

For example, say an endocrinologist has a patient with a benign thyroid growth. In principle, we could take a sample of that patient's blood, find a sequence, and then use that sequence as an early diagnostic tool for future patients.

What technology is required to decode the immunome?

Step one was sequencing. Sequencing was the technology that made this kind of thinking possible. We now have the ability to sequence these antibody and TCR genes so that we can actually see what's in there.

Now that sequencing is more of a commodity, the frontier has moved to 'how can we find the patterns?' That's the mathematical and computational side of things, processing the sequencing data with artificial intelligence or machine learning algorithms.

But I don't want to overlook this third plank, even though it's not as splashy as sequencing and artificial intelligence: As I said before, the missing ingredient is you. We are past due for a nationwide, learning healthcare system.

Can we make sure that if a patient comes into a hospital in Massachusetts or Maine or Missouri, we can eventually get access to that blood sample that's about to be thrown out long after the patient has gone home, and sequence the millions of antibody and TCR genes it contains? And in addition to access to these discarded specimens across medical systems, we need them correlated to the information in electronic health records (EHR).

With the immunome, we have the chance again to use sequencing to learn about an individual's health, add that information to a database, correlate it to that person's health record, times millions of individuals -- we can untangle this code in relatively short order.

What is the good faith critique of this line of thought?

There is a point of view that if you want to diagnose an infection, for example, why look for the response? Just look for the infectious agent itself, right? Or if you want to see how person responds to cancer treatment, why look at the adaptive response of the immune as an indicator -- why not test cancer cells against drug? These are reasonable questions.

The answer is, the body takes a lot of these insults very seriously. Even if you have a rip-roaring, potentially life-threatening infection, the number of viable bacteria per milliliter of blood is vanishingly small -- around one viable bacterium per 5-10 milliliters of blood. Maybe there's a lot of bacteria somewhere in your body. But more typically, your body just takes infection with bacteria very seriously, so just a few bacteria are enough to set off a cascade of events that can kill you. Finding the actual bacteria, and distinguishing it from random bacterial DNA flotsam in the blood, is harder than it is to look at a person and say, "this person's white blood cell count is through the roof."

In other words, the immune response is not a proportional response, it's often a massively disproportionately response in many cases. It acts as a signal amplifier from a diagnostic perspective, and that's an advantage. If we can get enough samples to recognize a pattern, and if we can get enough samples, the track-record so far suggests we can determine what that signal is.

Why did you and your colleagues publish this Frontiers in Immunology paper now?

The Adaptive Immune Receptor Repertoire Community (AIRR-C) is a dedicated community that we wrote this paper with and on behalf of. We have the knowledge and expertise to lay the groundwork for the diagnostic potential of the immunome, but we can go so much faster with the help of others. That's why we are putting out a call to clinicians, researchers and others to join efforts with AIRR-C.

My hope is the next generation of doctors in medical school, when they hear about this they think, "I want to work on that."

This is the future of blood testing. It's a tremendously exciting time.

PHILADELPHIA - Lung cancer is the third most common cancer in the U.S. and the leading cause of cancer death, with about 80% of the total 154,000 deaths recorded each year caused by cigarette smoking. Black men are more likely to develop and die from lung cancer than persons of any other racial or ethnic group, pointing to severe racial disparities. For example, research has shown that Black patients are less likely to receive early diagnosis and life-saving treatments like surgery. Now researchers at Jefferson have found that a commonly used risk prediction model does not accurately identify high-risk Black patients who could gain life-saving benefit from early screening, and paves the way for improving screenings and guidelines. The research was published in JAMA Network Open on April 6.

"Black individuals develop lung cancer at younger ages and with less intense smoking histories compared to white individuals," explains Julia Barta, MD, Assistant Professor of Medicine in the Division of Pulmonary and Critical Care Medicine at Thomas Jefferson University, and researcher at the Jane and Leonard Korman Respiratory Institute. "Updated guidelines now recommend screening eligible patients beginning at age 50, but could still potentially exclude higher-risk Black patients. We are interested in finding methods that could help identify at-risk patients who are under-screened."

Screening for lung cancer is an annual CT scan to detect the presence of lung cancer in otherwise healthy people with a high risk of lung cancer. Current guidelines do not require a risk score for screening eligibility, but some researchers think that risk models could improve care. Risk prediction models are mathematical equations that take into account risk factors like smoking history and age to produce a risk score, which indicates the risk for developing lung cancer. Existing risk prediction models are derived from screening data that only include 5% or fewer African American individuals.

"What makes our study unique is that our screening cohort included more than 40% Black individuals," says senior author Dr. Barta, a member of Sidney Kimmel Cancer Center - Jefferson Health. "To our knowledge, our study is the first to examine lung cancer risk in a diverse screening program and aims to strengthen the argument for more inclusive guidelines for screening eligibility."

The most well-validated model used in screening research is the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial modified logistic regression model (PLCOm2012). "It uses 10-12 risk factors that include age, race, smoking history, as well as some socioeconomic factors like education to calculate a risk score," says Christine Shusted, MPH, first author of the study and research data analyst for Jefferson's Lung Cancer Screening Program through the Korman Respiratory Institute at Thomas Jefferson University. "The higher the score, the higher the risk of developing lung cancer. We wanted to see how well this model identifies patients with the highest risk of lung cancer in this diverse patient population."

The researchers conducted a cross-sectional, retrospective study in 1,276 Black and white patients (mean age, 64.25 years; 42.7% Black; 59.3% women) who enrolled in the Jefferson Lung Cancer Screening Program between January 2018 and September 2020. From this screening cohort, lung cancer was detected in 32 patients, 44% of whom were Black - these patients formed the cancer cohort. The researchers then calculated risk scores using the PLCOm2012 model. In the screening cohort, more Black patients than white patients were in high-risk groups, indicating that Black patients in this cohort had a higher risk of developing lung cancer.

As anticipated, white patients with screen-detected lung cancer generally had high lung cancer risk scores. "Among Black patients, we would have expected to see a similar trend," explains Dr. Barta. "However, we saw that despite having a lung cancer diagnosis through screening, Black patients were actually defined as lower risk. This indicates that the model is not accurately predicting risk of lung cancer in Black patients."

"These findings allowed us to identify weaknesses in this model for risk calculation for lung cancer," explains Shusted. "It indicates that we need to not only expand criteria for lung cancer screening so that more diverse populations are included, but that these prediction models need to include factors, like environmental contributors, access to health care, and other social determinants of health."

The researchers hope to continue building on these findings, with the ultimate goal of defining comprehensive risk factors and improving lung cancer screening uptake and adherence especially among vulnerable populations.

"This work is an important step to reducing disparities in the screening and early detection of lung cancer, and making sure we can trust our models to predict those individuals at the highest risk," says Dr. Barta.

Researchers at AMBER, the SFI Centre for Advanced Materials and BioEngineering Research, and from Trinity's School of Physics, have developed next-generation, graphene-based sensing technology using their innovative G-Putty material.

The team's printed sensors are 50 times more sensitive than the industry standard and outperform other comparable nano-enabled sensors in an important metric seen as a game-changer in the industry: flexibility.

Maximising sensitivity and flexibility without reducing performance makes the teams' technology an ideal candidate for the emerging areas of wearable electronics and medical diagnostic devices.

The team - led by Professor Jonathan Coleman from Trinity's School of Physics, one of the world's leading nanoscientists - demonstrated that they can produce a low-cost, printed, graphene nanocomposite strain sensor.

They developed a method to formulate G?putty?based inks that can be printed as a thin-film onto elastic substrates, including band-aids, and attached easily to the skin.

The team developed a method to formulate G?putty?based inks that can be printed as a thin-film onto elastic substrates, including band-aids, and attached easily to the skin.

Creating and testing inks of different viscosities (runniness) the team found that they could tailor G-Putty inks according to printing technology and application.

They published their results in the journal Small.

In medical settings, strain sensors are a highly valuable diagnostic tool used to measure changes in mechanical strain such as pulse rate, or the changes in a stroke victim's ability to swallow. A strain sensor works by detecting this mechanical change and converting it into a proportional electrical signal, thereby acting as mechanical-electrical converter.

While strain sensors are currently available on the market they are mostly made from metal foil that poses limitations in terms wearability, versatility, and sensitivity.

Professor Coleman said:

"My team and I have previously created nanocomposites of graphene with polymers like those found in rubberbands and silly putty. We have now turned G-putty, our highly malleable graphene blended silly putty, into an ink blend that has excellent mechanical and electrical properties. Our inks have the advantage that they can be turned into a working device using industrial printing methods, from screen printing, to aerosol and mechanical deposition.

"An additional benefit of our very low cost system is that we can control a variety of different parameters during the manufacturing process, which gives us the ability to tune the sensitivity of our material for specific applications calling for detection of really minute strains."

Current market trends in the global medical device market indicate that this research is well placed within the move to personalised, tuneable, wearable sensors that can easily be incorporated into clothing or worn on skin.

In 2020 the wearable medical device market was valued at USD $16 billion with expectations for significant growth particularly in remote patient monitoring devices and an increasing focus on fitness and lifestyle monitoring.

The team is ambitious in translating the scientific work into product. Dr Daniel O'Driscoll, Trinity's School of Physics, added:

"The development of these sensors represents a considerable step forward for the area of wearable diagnostic devices - devices which can be printed in custom patterns and comfortably mounted to a patient's skin to monitor a range of different biological processes.

"We're currently exploring applications to monitor real-time breathing and pulse, joint motion and gait, and early labour in pregnancy. Because our sensors combine high sensitivity, stability and a large sensing range with the ability to print bespoke patterns onto flexible, wearable substrates, we can tailor the sensor to the application. The methods used to produce these devices are low cost and easily scalable - essential criteria for producing a diagnostic device for wide scale use."

Professor Coleman was recently awarded a European Research Council Proof of Concept grant to build on these results to begin to develop a prototype for a commercial product. The ultimate aim of the group is identify potential investors and industry partners, and form a spin-out around the technology focusing on both recreational and medical applications.

A state of the art plenary session during the Pediatric Academic Societies (PAS) 2021 Virtual Meeting will bring together national experts on child poverty, racism and racial inequities, immigrant health, Native American culture, and environmental threats to discuss the intersectionality of child poverty.

Poor children do not just suffer from double jeopardy, but frequently multiple jeopardy from many overlapping threats to their health and development. The COVID-19 pandemic has further unearthed and intensified these threats to children including loss of financial resources, loss of nutritional supports, loss of family members, and loss of educational opportunity.

"Children are the poorest age group in our society," said Benard P. Dreyer, MD, FAAP. "On the hopeful side, we seem to be finally recognizing that the nation needs to address this issue, and with the passage of the reformed Child Tax Credit in March, there is hope that the level of poverty for children will be reduced by 40% this year. We have invited a powerhouse group of researchers and advocates to discuss the issue of child poverty and its intersection with racism, the issues of Native American children and families, as well as experts on environmental justice and primary care designed to address the needs of poor children."

Speakers will elucidate and contextualize the living Venn diagram of these intersections for children and families. They will also address the specific impact of the COVID-19 pandemic on these families who are vulnerable because of being under-resourced and often marginalized, and will leave the attendees with what is a call for action to all of us.

Presentations include:

The intersection of race and poverty: addressing health care inequities in children; presenter: Tumaini R. Coker, MD, MBA - University of Washington/Seattle Children's

Structural racism in medicine, poverty, and child population health; presenter: Nia J. Heard-Garris, MD, MSc - Ann & Robert H. Lurie Children's Hospital of Chicago/Northwestern University Feinberg College of Medicine

Native American communities, poverty, and child health; presenter: Shaquita Bell, MD - University of Washington School of Medicine, Department of Pediatrics

Environmental threats to poor children and the triple threat of environmental toxins, poverty, and racism; presenter: Mona Hanna-Attisha, MD, MPH - Michigan State University

Dr. Dreyer and Adam Schickedanz, MD, PhD, will chair the plenary, "The Intersection of Child Poverty With Race, Immigrant Status, and Environmental Threats in the Age of COVID-19," on Tuesday, May 4 at 5:30 p.m. EDT. Reporters interested in an interview with the presenters should contact PAS2021@piercom.com.

The PAS Meeting connects thousands of pediatricians and other health care providers worldwide. For more information about the PAS Meeting, please visit http://www.pas-meeting.org.

Next-generation gene sequencing (NGS) technologies --in which millions of DNA molecules are simultaneously but individually analyzed-- theoretically provides researchers and clinicians the ability to noninvasively identify mutations in the blood stream. Identifying such mutations enables earlier diagnosis of cancer and can inform treatment decisions. Johns Hopkins Kimmel Cancer Center researchers developed a new technology to overcome the inefficiencies and high error rates common among next-generation sequencing techniques that have previously limited their clinical application.

To correct for these sequencing errors, the research team from the Ludwig Center and Lustgarten Laboratory at the Johns Hopkins Kimmel Cancer Center developed SaferSeqS (Safer Sequencing System), a major improvement to widely used technologies based on a previous technology called SafeSeqS (Safe Sequencing System) that Hopkins investigators invented a decade ago. The new SaferSeqS technology detects rare mutations in blood in a highly efficient manner and reduces the error rate of commonly used technologies for evaluating mutations in the blood more than 100-fold.

Their findings were reported May 3 in Nature Biotechnology.

The presence of a mutation in a clinical sample could be an early indicator that a person has developed cancer, says study lead author and M.D./Ph.D. candidate Joshua Cohen. Cancer is a genetic disease, driven by oncogenes and tumor suppressor genes. A small portion of cancer cells shed their DNA into the bloodstream, allowing their mutations to be detected via blood sample. Detecting such mutations in blood rather through surgical biopsy of a cancerous tissue is called "a liquid biopsy." Such blood-based tests have the potential to detect cancer at an earlier stage, when it can be put into remission by surgery and/or chemotherapy. The challenge, Cohen explains, is that the vast majority of DNA present in the blood sample is shed by noncancer cells, and only a tiny fraction of the DNA is derived from the tumor. In patients with relatively early-stage cancers, a 10 mL blood sample will only contain a handful of molecules with a mutation.

"To detect cancers when they have the best chance of being cured requires a detection method that will pick up cancer signals that are present at extremely low frequencies," says Cohen. "The technical challenge in detecting these mutations is akin to finding a needle in a haystack."

The researchers addressed this challenge, with SaferSeqS, by efficiently tagging both strands of each original molecule present in an individual's blood with a unique barcode. It required new biochemical approaches to do this in an efficient manner with the small number of degraded DNA molecules that are usually present in blood. The investigators use the structural redundancy of the double-stranded DNA molecule to distinguish real mutations from errors, an approach called duplex sequencing. If both strands of a DNA molecule contain the identical mutation, it is far more likely that it is a real mutation and not an error.

"What makes SaferSeqS unique is the efficient tagging of both strands of the majority of DNA molecules circulating in the blood, the low error rate achieved through analysis of both strands of these DNA molecules, and the manner in which the molecules of interest are enriched prior to sequencing. Altogether, these advancements underlie the power of the new technology," says Cohen.

"Every molecule is sacred because it has the potential to be the one with the mutation we're looking for," says Cohen. "Because the absolute number of molecules is low, the technology has to be highly efficient at capturing each molecule to sensitively identify mutations."

To test the specificity and sensitivity of SaferSeqS in a clinically relevant setting, the researchers compared the samples to previous results from the CancerSEEK test, a single blood test that screens for eight common cancer types, developed and reported by the same research team (Science, 2018).

The researchers revisited 74 blood samples from patients with cancer that had false negative results -- undetectable mutations -- in the 2018 CancerSEEK study using SafeSeqS. In their newest study describing SaferSeqS, the researchers reassessed these blood samples. Using SaferSeqS, they observed a marked improvement in sensitivity, finding previously undetectable mutations in 68% of the samples tested.

"The SaferSeqS strategy affords highly reliable technical specificity, which translates to a better way to provide clinically meaningful results for patients with relatively early-stage and small tumors," says Cohen.

Taking these results together, the researchers conclude that SaferSeqS is highly sensitive and specific for detecting extremely rare cancer-related mutations, is potentially efficient and cost effective for clinical use, and reduces the error rate of existing mutation-detection approaches more than 100-fold.

The next step, they say, is to validate the results and demonstrate the clinical usefulness of the technology in prospective clinical trials.

The researchers say SaferSeqS will be the underlying platform for future CancerSEEK studies.

The most complete picture yet is coming into focus of how antibodies produced in people who effectively fight off SARS-CoV-2 work to neutralize the part of the virus responsible for causing infection. In the journal Science, researchers at The University of Texas at Austin describe the finding, which represents good news for designing the next generation of vaccines to protect against variants of the virus or future emerging coronaviruses.

Previous research focused on one group of antibodies that target the most obvious part of the coronavirus's spike protein, called the receptor-binding domain (RBD). Because the RBD is the part of the spike that attaches directly to human cells and enables the virus to infect them, it was rightly assumed to be a primary target of the immune system. But, testing blood plasma samples from four people who recovered from SARS-CoV-2 infections, the researchers found that most of the antibodies circulating in the blood -- on average, about 84% -- target areas of the viral spike protein outside the RBD -- and, apparently, for good reason.

"We found these antibodies are painting the entire spike, both the arc and the stalk of the spike protein, which looks a bit like an umbrella," said co-corresponding author Greg Ippolito, who is a research associate professor in UT Austin's Department of Molecular Biosciences and an assistant professor of oncology at the university's Dell Medical School. "The immune system sees the entire spike and tries to neutralize it."

Many of these non-RBD-directed antibodies the team identified act as a potent weapon against the virus by targeting a region in a part of the spike protein located in what would be the umbrella's canopy called the N-terminal domain (NTD). These antibodies neutralize the virus in cell cultures and were shown to prevent a lethal mouse-adapted version of the virus from infecting mice.

The NTD is also a part of the viral spike protein that mutates frequently, especially in several variants of concern. This suggests that one reason these variants are so effective at evading our immune systems is that they can mutate around one of the most common and potent types of antibody in our arsenals.

"There's an evolutionary arms race going on between the virus and our immune systems," said Jason Lavinder, research associate in the McKetta Department of Chemical Engineering and co-corresponding author of the new study. "We're all developing a standard immune response to this virus that includes targeting this one spot and that's exerting selective pressure on the virus. But then the virus is also exerting its evolutionary strength by trying to change around our selective immune pressures."

Despite these maneuvers by SARS-CoV-2, the researchers said about 40% of the circulating antibodies target the stalk of the spike protein, called the S2 subunit, which is also a part that the virus does not seem able to change easily.

"That's reassuring," Ippolito said. "That's an advantage our immune system has. It also means our current vaccines are eliciting antibodies targeting that S2 subunit, which are likely providing another layer of protection against the virus."

That's also good news for designing vaccine boosters or next-generation vaccines against variants of concern, and even for developing a vaccine that can protect against future pandemics from other strains of the coronavirus.

"It means we have a strong rationale for developing next-generation SARS-CoV-2 vaccines or even a pan-coronavirus vaccine that targets every strain," Ippolito said.

UT Austin researchers are among several in the world now aiming to develop a single coronavirus vaccine to fight infection from all coronaviruses, not just SARS-CoV-2.

BAR HARBOR, MAINE — Our kidneys are charged with the extraordinary task of filtering about 53 gallons of fluid a day, a process that depends on podocytes, tiny, highly specialized cells in the cluster of blood vessels in the kidney where waste is filtered that are highly vulnerable to damage.

In research at the MDI Biological Laboratory in Bar Harbor, Maine, a team led by Iain Drummond, Ph.D., director of the Kathryn W. Davis Center for Regenerative Biology and Aging, has identified the signaling mechanisms underlying podocyte formation, or morphogenesis. The discovery opens the door to the development of therapies to stimulate the regeneration of these cells, which are vital to ridding the body of toxins.

“Podocytes play a very important role in kidney function,” said Hermann Haller, M.D., president of the MDI Biological Laboratory and a nephrologist who leads the department of nephrology and hypertension at Hannover Medical School in Hanover, Germany. “The discovery of the signaling underlying podocyte morphogenesis by a team led by Iain Drummond is a major stride forward in the treatment of kidney disease.”

The study, entitled “Autonomous Calcium Signaling in Human and Zebrafish Podocytes Controls Kidney Filtration Barrier Morphogenesis,” was recently published in the Journal of the American Society of Nephrology.

In addition to Drummond, authors include Melissa Little, Ph.D., Aude Dorison, Ph.D., Irene Ghobrial and Alejandro Hidalgo-Gonzalez, Ph.D., all of The Royal Children’s Hospital, Murdoch Children’s Research Institute in Melbourne, Australia; Heiko Schenk, M.D., and Jan Hegermann of Hannover Medical School, Hanover, Germany; and Lynne Staggs of Hannover Medical School and the MDI Biological Laboratory.

The discovery of the signaling mechanism underlying podocyte formation is relevant to the treatment of a range of kidney conditions that can damage the glomerular filtration barrier, including acute kidney injury, developmental defects, premature birth defects, kidney cancer, polycystic kidney disease and chronic kidney disease (CDK) caused by diabetes or hypertension.

A major public health threat

In recent years, CDK has emerged as a major public health threat, especially among those age 60 and over, due to diabetes, hypertension and cardiovascular disease, all of which can contribute to kidney damage and all of which are increasing due to the aging of the world’s population. Approximately 38 million Americans, or 15 percent of the adult population, is estimated to have kidney disease.

When kidneys fail, the usual treatment is dialysis, an expensive, time-consuming procedure in which the blood is cleansed by an external filtering device. Though transplantation is another option, only a fraction of the tens of thousands of end-stage renal disease patients waiting for a kidney transplant receive one because the number of organ donors is insufficient to meet demand.

As a result of the limited options, kidney research at the MDI Biological Laboratory has focused on the regeneration of kidney tissue, and especially of nephrons, the functional units of the kidney, which include the glomerulus, in which the work of filtering the blood takes place. The approximately 1 million glomeruli in the body filter excess fluid and waste products from the blood, preventing the build-up of toxic waste.

The membrane of the glomerulus is lined with podocytes, whose interdigitated, foot-like projections (podo is Latin for “having a foot”) extend into the glomerular space. The podocytes are connected by a thin, mesh-like web called a “slit diaphragm” that functions as the final filtration barrier before fluid enters the glomerular space, from which it passes into collecting tubules and is ultimately excreted as urine.

“Podocytes are complex, which increases their vulnerability to injury,” Drummond explained. “There are many moving parts that have to come together just right in order to create the filtration barrier, and defects in any one of these can lead to disease. The more we know about how the individual parts and processes work together, the more targets we have for potential therapeutic interventions.”

In in vivo studies in zebrafish embryos and in vitro studies in maturing human kidney organoids, which are stem cell-derived “organs in a dish,” Drummond and his colleagues have discovered that calcium signaling is required for the formation of the podocyte foot process and slit diaphragm. The discovery supports the critical role of calcium signaling in the formation of the filtration barrier.

The discovery was enabled by a genetically encoded, green fluorescent calcium biosensor, GCaMP, that can be targeted to specific cell types. Because it lights up when calcium signaling is active, the biosensor allows scientists to image calcium signaling in the podocytes of transparent zebrafish embryos in real time under a fluorescence microscope to determine how they are made and what goes wrong during disease.

The zebrafish as a model for human disease

An important outcome of Drummond’s research is the establishment of the zebrafish as a model for human glomerular development and disease. The functional equivalency of podocytes in zebrafish and in human organoids suggests that their role has been conserved through evolution, thus validating the relevance of the zebrafish as a vertebrate model and as a screening platform for new therapies.

The research also identifies new routes for promoting kidney regeneration in humans. Unlike humans, zebrafish regenerate glomeruli throughout their adult lives. Though it is unknown if the signaling mechanisms employed during development are recapitulated during regeneration, Drummond thinks this is likely, in which case a deeper understanding could lead to therapies to trigger regeneration in humans.

“We wanted to go beyond looking at the shape and size and movement of cells during the process of forming the filter to the signals they are passing to generate this complex filter architecture,” Drummond said. “Once we understand these signals, we can accelerate tissue formation by promoting productive regenerative communication though our own messages in the form of signaling molecules.”

In recent years, the MDI Biological Laboratory has become a hub for kidney regeneration research due to its participation in a National Institutes of Health (NIH)-funded consortium, (Re)Building a Kidney (RBK), the aim of which is to develop a biological artificial kidney. The discovery of the signaling mechanism underlying podocyte formation will play a critical role in generating replacement kidney tissue.

In making his discovery, Drummond is building on the MDI Biological Laboratory’s distinguished historical reputation in kidney physiology. Much of what is known today about human kidney function was discovered at the MDI Biological Laboratory in the 20th century through comparative biological studies.