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PHILADELPHIA -- Patients with COVID-19 who were admitted to an intensive care unit were 10 times more likely than other hospitalized COVID-19 patients to suffer cardiac arrest or heart rhythm disorders, according to a new study from researchers in the Perelman School of Medicine at the University of Pennsylvania.

Researchers say the results suggest that cardiac arrests and arrhythmias suffered by some patients with COVID-19 are likely triggered by a severe, systemic form of the disease and are and not the sole consequence of the viral infection. The findings--which differ significantly from early reports that showed a high incidence of arrhythmias among all COVID-19 patients--provide more clarity about the role of the novel coronavirus, SARS-COV-2, and the disease it causes, COVID-19, in the development of arrhythmias, including irregular heart rate (atrial fibrillation), slow heart rhythms (bradyarrhythmia) or rapid heart rate that stops by itself within 30 seconds (non-sustained ventricular tachycardia).

The study was published today in the Heart Rhythm Journal--the official journal of the Heart Rhythm Society.

"In order to best protect and treat patients who develop COVID-19, it's critical for us to improve our understanding of how the disease affects various organs and pathways within our body--including our heart rhythm abnormalities," said the study's senior and corresponding author Rajat Deo, MD, MTR, a cardiac electrophysiologist and an associate professor of Cardiovascular Medicine at Penn. "Our findings suggest that non-cardiac causes such as systemic infection, inflammation and illness are likely to contribute more to the occurrence of cardiac arrest and arrhythmias than damaged or infected heart cells due to the viral infection."

Recent studies from China have suggested that COVID-19 is associated with a high incidence of cardiac arrhythmias, particularly among critically ill patients--early reports showed 44 percent of patients admitted to the ICU suffered arrhythmias. Heart rhythm problems occur when electrical impulses that coordinate your heartbeats don't work properly, causing your heart to beat too fast, too slow, or irregularly. If left untreated, cardiac arrhythmias can lead to serious medical conditions, including stroke and cardiac arrest--the abrupt loss of heart function.

To evaluate the risk and incidence of cardiac arrest and arrhythmias among hospitalized patients with COVID-19, the Penn team evaluated 700 patients with COVID-19 who were admitted to the Hospital of the University of Pennsylvania between early March and mid-May. Researchers evaluated cardiac telemetry and clinical records for patient demographics and medical comorbidities--such as heart disease, diabetes and chronic kidney disease--and recorded patient vitals, test results and treatment.

The cohort of patients had a mean age of 50 years, with Black patients accounting for more than 70 percent of the population. Researchers identified a total of 53 arrhythmic events: nine patients who suffered cardiac arrest, 25 patients with atrial fibrillation who required treatment, nine patients with clinically significant bradyarrhythmias and 10 non-sustained ventricular tachycardia events. The team did not identify any cases of heart block, sustained ventricular tachycardia or ventricular fibrillation.

Of the 700 patients hospitalized, about 11 percent were admitted to the ICU. None of the other hospitalized patients suffered a cardiac arrest. After controlling for underlying demographic and clinical factors, researchers found cardiac arrest and arrhythmias were more likely to occur among patients in an ICU compared to the other hospitalized patients.

Researchers noted that the study has several limitations, including that the analysis was conducted from a single center serving a large urban population.

"More research is needed to assess whether the presence of cardiac arrhythmias have long-term health effects on patients who were hospitalized for COVID-19," Deo said. "In the meantime, it's important that we launch studies to evaluate the most effective and safest strategies for long-term anticoagulation and rhythm management in this population."

Last year, MIT engineers developed a double-sided adhesive that could quickly and firmly stick to wet surfaces such as biological tissues. They showed that the tape could be used to seal up rips and tears in lungs and intestines within seconds, or to affix implants and other medical devices to the surfaces of organs such as the heart.

Now they have further developed their adhesive so that it can be detached from the underlying tissue without causing any damage. By applying a liquid solution, the new version can be peeled away like a slippery gel in case it needs to be adjusted during surgery, for example, or removed once the tissue has healed.

"This is like a painless Band-Aid for internal organs," says Xuanhe Zhao, professor of mechanical engineering and of civil and environmental engineering at MIT. "You put the adhesive on, and if for any reason you want to take it off, you can do so on-demand, without pain."

The team's new design is detailed in a paper published in the Proceedings of the National Academy of Sciences. Zhao's co-authors are first authors Xiaoyu Chen and Hyunwoo Yuk along with Jingjing Wu at MIT, and Christoph Nabzdyk at Mayo Clinic Rochester.

Unbreakable bonds

In considering designs for their original adhesive, the researchers quickly realized that it is extremely difficult for tape to stick to wet surfaces, as the thin layer of water lubricates and prevents most adhesives from taking hold.

To get around a tissue's natural slipperiness, the team designed their original adhesive out of biocompatible polymers including polyacrylic acid, a highly absorbent material commonly used in diapers and pharmaceuticals, that soaks up water, then quickly forms weak hydrogen bonds with the tissue's surface. To reinforce these bonds, the researchers embedded the material with NHS esters, chemical groups that form stronger, longer-lasting bonds with proteins on a tissue's surface.

While these chemical bonds gave the tape its ultrastrong grip, they were also difficult to break, and the team found that detaching the tape from tissue was a messy, potentially harmful task.

"Removing the tape could potentially create more of an inflammatory response in tissue, and prolong healing," Yuk says. "It's a real practical problem."

Scotch tape for surgeons

To make the adhesive detachable, the team first tweaked the adhesive itself. To the original material, they added a new disulfide linker molecule, which can be placed between covalent bonds with a tissue's surface proteins. The team chose to synthesize this particular molecule because its bonds, while strong, can be easily severed if exposed to a particular reducing agent.

The researchers then looked through the literature to identify a suitable reducing agent that was both biocompatible and able to sever the necessary bonds within the adhesive. They found that glutathione, an antioxidant naturally found in most cells, was able to break long-lasting covalent bonds such as disulfide, while sodium bicarbonate, also known as baking soda, could deactivate the adhesive's shorter-lasting hydrogen bonds.

The team mixed concentrations of glutathione and sodium bicarbonate together in a saline solution, and sprayed the solution over samples of adhesive that they placed over various organ and tissue specimens, including pig heart, lung, and intestines. In all their tests, regardless of how long the adhesive had been applied to the tissue, the researchers found that, once they sprayed the triggering solution onto the tape, they were able to peel the tape away from the tissue within about five minutes, without causing tissue damage.

"That's about the time it takes for the solution to diffuse through the tape to the surface where the tape meets the tissue," Chen says. "At that point, the solution converts this extremely sticky adhesive to just a layer of slippery gel that you can easily peel off."

The researchers also fabricated a version of the adhesive that they etched with tiny channels the solution can also diffuse through. This design should be particularly useful if the tape were used to attach implants and other medical devices. In this case, spraying solution on the tape's surface would not be an option. Instead, a surgeon could apply the solution around the tape's edges, where it could diffuse through the adhesive's channels.

"Our hope is that some day, operating rooms can have dispensers of these adhesives, alongside bottles of triggering solution," Yuk says. "Surgeons can use this like Scotch tape, applying, detaching, and reapplying it on demand."

The team is working with Nabzdyk and other surgeons to see whether the new adhesive can help repair conditions such as hemorrhages and leaky intestines.

"Our goal is to use bioadhesive technologies to replace sutures, which is a thousands-of-years-old wound closure technology without too much innovation," Zhao says. "Now we think we have a way to make the next innovation for wound closure."

LA JOLLA, CA--Scientists at the La Jolla Institute for Immunology (LJI) have discovered a potential new way to better fight a range of infectious diseases, cancers and even autoimmune diseases.

The new study, published recently in Nature Immunology, shows how a protein works as a "master regulator" in the immune system. The research is an important step toward designing vaccines and therapies that can "switch on" the immune cells that help produce disease-fighting antibodies. Scientists may also be able to "switch off" these cells to counteract immune cells dysfunction in autoimmune diseases.

"This cell type (Tfh cells) sometimes does bad things in autoimmune diseases--particularly autoantibody diseases like lupus, rheumatoid arthritis and Sjogren's syndrome," says LJI investigator Shane Crotty, Ph.D., who led the new research. "So, hopefully, our fundamental knowledge about the circuitry of this cell can help us understand how to turn it off in autoimmune diseases."

Crotty's laboratory studies key immune system players, such as different kinds of helper T cells. In 2009, his laboratory published work showing that a protein called Bcl6 controls how helper T cells differentiate to do different jobs in the body. They found that Bcl6 prompts helper T cells to become T follicular helper (Tfh) cells, which work with B cells to produce powerful antibodies.

This was an important breakthrough, but Crotty's lab still wanted to know: What exactly was Bcl6 doing to Tfh cells? Answering this question could open the door to controlling immune
responses.

"There is great interest in the use of Tfh-cell-associated biology for enhancement of vaccines," says Crotty. "There is also great interest in targeting Tfh cell-associated biology for therapeutic interventions in human autoimmune diseases, allergies, atherosclerosis, organ transplants and cancer."

For the new study, Crotty led a complex effort to test competing theories for how Bcl6 controls Tfh. The researchers used mouse models and a range of genetic sequencing tools to determine that Tfh cells actually need Bcl6 to even exist.

Looking closer, the researchers found that Bcl6 acts mainly as a repressor in helper T cells, meaning that it blocks the expression of other proteins in these cells through a series of genetic switches, which they mapped.

These new maps show that Bcl6 controls a "double negative circuit." Crotty explains, "The protein Bcl6 switches this cell type on, but it is a protein that is only known to switch things off. So, we did a lot of experiments to figure out that it controls cells by a series of double negatives. It turns off genes that turn off other genes."

Bcl6 blocks the expression of two proteins that normally stop Tfh cell differentiation. When Bcl6 does its job, helper T cells are free to become Tfh cells when the body needs them.

The new research gives scientists a guide to how they could potentially switch Bcl6 on or off to control immune responses, says Crotty. "Increasing emphasis will surely now be placed on how to apply that knowledge to Tfh-related therapeutics," he adds.

The body also uses the kinds of genetic circuits controlled by Bcl6 to stay healthy and not produce antibodies that mistakenly attack the body's own cells. "The system needs to self-correct and stop the attack. If an immune response is needed to fight off a pathogen, the body needs to reset itself and return to a steady state," Crotty says. But deficiencies in this Bcl6-Tfh system can lead to autoimmunity or immunodeficiency. The new research suggests that tweaking immune responses through Bcl6 could also help control autoimmune diseases such as multiple sclerosis and type 1 diabetes.

Via Bcl6, Tfh can theoretically also be tuned down to treat allergies, rejection from transplanted organs, and to help prevent atherosclerosis. "Heart disease is now understood to have a large immunological component, as in too much inflammation," Crotty says. Better cancer treatments could also include tweaking Tfh to decrease unwanted immune responses to therapy, he adds.

Crotty adds that the way Bcl6 operates to control positive Tfh gene expression may represent a model by which to study other puzzling biological switches. "We had to do a lot of genetics to connect the dots, but this double negative circuit may actually be the way many immune system cells get controlled," he says.

BOSTON - A novel liquid biopsy method can detect kidney cancers with high accuracy, including small, localized tumors which are often curable but for which no early detection method exists, say scientists from Dana-Farber Cancer Institute.

The report in Nature Medicine suggests that if validated in larger trials and applied widely, the non-invasive test could find more early kidney cancers when they haven't spread, thus reducing the mortality of the disease. "Hopefully we can scale this to a much larger level and detect cancer earlier so we can act earlier," said Toni Choueiri, MD, a co-senior author of the study. He is the director of the Lank Center for Genitourinary Oncology at Dana-Farber.

It's estimated that 73,750 new kidney cancer cases will be diagnosed in 2020, and about 14,830 will die of the disease. About 35 percent of cancers are diagnosed only after they have spread beyond the kidney and are more difficult to treat. Small, early kidney tumors usually cause no symptoms, and increasingly are found incidentally in scans of the abdomen performed for another purpose. However, there is no imaging or other screening test recommended for the general population to look for early kidney cancers. Initially, a test based on the method described in the new report might be used to screen people with a family history of kidney cancer, or who had a previous kidney cancer, said Choueiri. "We need to be specific first, before making it totally mainstream," he said.

Non-invasive liquid biopsies, which search for cancer-related DNA shed by tumors into blood or other body fluids, are moving rapidly toward clinical use as a means of early detection for some kinds of tumors. However, "kidney cancer is one of the hardest tumors to detect, because it doesn't shed as much DNA as other tumors," said Matthew Freedman, MD, a medical oncologist at Dana-Farber and co-senior author of the report. "That's where this test performs really well" because it can identify abnormal patterns in small amounts of tumor-shed DNA. "And it's a proof of principle that early stage disease is detectable."

The test was nearly 100 percent accurate when used with blood samples to distinguish patients with kidney cancer from those known to be free of kidney cancer. The method achieves less accuracy in testing urine samples, but the researchers believe that performance can be improved. If the test is validated in larger trials and becomes widely applicable clinically, a urine sample would be even less-invasive than a blood draw.

The technical name for the testing method is cfMeDIP-seq, which stands for cell-free methylated DNA immunoprecipitation and high-throughput sequencing. Where other liquid biopsy methods search for mutations in tumor-shed DNA that reveal the type and location of cancer, cfMeDIP-seq detects abnormal methylation - the addition of chemical tags to DNA, which doesn't alter their genetic code but can affect their function.

The method was tested on samples from 99 patients with early and advanced kidney cancer, 15 patients with stage IV urothelial bladder cancer, and 28 healthy, cancer-free control subjects. In analyzing blood serum with the test, the study reported "near-perfect" classification of patients across all stages of kidney cancer. While urine-based classification was not as accurate, "we believe that performance can ben improved through technical and computational optimization," the authors wrote.

DUARTE, Calif. -- Scientists at City of Hope, working in collaboration with researchers at Translational Genomics Research Institute (TGen) and other colleagues across the country, have found that the actions of circulating immune cells -- namely how they differentiate and signal -- at the start of immunotherapy treatment for cancer can inform how a patient will respond to the therapy. The team's findings will publish this week in the Proceedings of the National Academy of Sciences of the United States of America.

"We used an ecological population model to understand the interactions between circulating white blood cell abundance and tumor response to immunotherapy," explained Andrea Bild, M.D., professor in the Division of Molecular Pharmacology within the Department of Medical Oncology & Therapeutics Research at City of Hope and a senior author on the study.

Immunotherapy has the potential to treat a wide range of cancers, but response varies greatly, with approximately 40% of patients receiving no benefit from the therapies. In an effort to find ways of identifying who is more likely to respond to immunotherapy at the start of treatment, or possibly even before it starts, researchers used a mathematical model developed by Bild and colleagues.

The team used the model to analyze data from the results of patients with advanced colorectal or other gastrointestinal cancers who were enrolled in a clinical trial led by Sunil Sharma, M.D., deputy director of Clinical Services at TGen, an affiliate of City of Hope. The trial involved a chemotherapy regimen followed by a combination of chemotherapy and immunotherapy. It measured the strength of patients' tumor-immune cell interactions, which was then related to different immune cells categorized by their behavior.

The findings highlight, for the first time, an important predator-prey relationship between circulating immune cell dynamics and a tumor's response to immunotherapy. In particular, "predator" T cells showed increased differentiation and activity of interferon, a protein that exerts anti-tumor effects, during immunotherapy treatment in patients that respond to treatment, said Bild. This relationship was not found in patients during chemotherapy, nor was it seen in those who were nonresponsive to immunotherapy.

"The study shows that subsets of immune cells in the blood indicate how each cancer patient responded to this combination of chemotherapy and immunotherapy," said Sharma, who also is director of TGen's Applied Cancer Research and Drug Discovery Division and one of the study's senior authors.

The ability to identify such potential biomarkers, or molecules that can be measured to show how well the body is responding to treatment, would enable clinicians to offer more precise treatment plans to patients. City of Hope, with the help of TGen, is working to offer precision medicine to all patients.

"We found, using this combination drug approach, that the body's own immune response and its activation correlated with a higher response to the therapy among cancer patients," said Sharma.

According to Bild, next steps include further testing the ability of circulating immune cells to reflect tumor response to therapy in a clinical trial at City of Hope in collaboration with TGen, including Sharma and others.

"We believe there is potential to measure a tumor's response to specific drugs using circulating immune cell dynamics, which are accessible and collected from a blood draw," says Bild. A noninvasive test to measure immune-tumor interaction strength would lead to better personalized medicine for cancer patients, with the potential to improve overall outcomes.

Individual behaviour has a significant effect on preventing a large second wave of COVID-19 infections. In fact, maintaining social distancing and other interventions such as the use of face masks and hand hygiene could remove the need for future lockdowns, according to a modelling study performed by the Barcelona Institute for Global Health (ISGlobal), an institution supported by the "la Caixa" Foundation. The findings, published in Nature Human Behaviour, also show that, in countries that have not yet reached the peak of active cases, lockdowns must remain in place for at least 60 days and deconfinement must be gradual in order to decrease the risk of second waves.

Several countries that initially imposed strict lockdown measures to limit the spread of SARS-CoV-2 are in the process of lifting them. However, how and when to ease the restrictions is a difficult decision - a delicate balance between the need to reactivate the economy and the risk of a second wave of infections that could overwhelm healthcare systems. "The problem is that assessing this risk is difficult, given the lack of reliable information on the actual number of people infected or the extent of immunity developed among the population", explains Xavier Rodó, head of ISGlobal's Climate and Health programme. In this study, Rodó's team present projections based on a model that divides the population into seven groups: susceptible, quarantined, exposed, infectious not detected, reported infectious and confined, recovered and death. It also allows to simulate both the degree of population confinement and the different post-confinement strategies.

"Our model is different because it considers the return of confined people to the susceptible population to estimate the effect of deconfinement, and it includes people's behaviours and risk perception as modulating factors", explains Xavier Rodó. "This model can be particularly useful for countries where the peak of cases has not yet been reached, such as those in the Southern hemisphere. It would allow to evaluate control policies and minimise the number of cases and fatalities caused by the virus" explains co-author and ISGlobal researcher Leonardo López.

The use of face masks, hand hygiene and 'shelter in place' mandates have already demonstrated benefits. The aim of this study was to quantitatively evaluate their relevance as containment strategies. The results clearly show that the length of the first confinement will affect the timing and magnitude of subsequent waves, and that gradual deconfinement strategies always result in a lower number of infections and deaths, when compared to a very fast deconfinement process.

In Spain, where the deconfinement was fast for half of the population and gradual for the rest, individual behaviour will be key for reducing or avoiding a second wave. "If we manage to reduce transmission rate by 30% through the use of face masks, hand hygiene and social distancing, we can considerably reduce the magnitude of the next wave. Reducing transmission rate by 50% could avoid it completely", says Rodó.

The results show that, even in countries that do not have the resources to test and trace all cases and contacts, social empowerment through the use of masks, hand hygiene and social distancing, is key to stopping viral transmission.

Simulations also show that loss of immunity to the virus will have significant effects on the spacing between epidemic waves - if immunity has a long duration (one year instead of a few months), then the time between the epidemic waves will double.

The model considered total lockdowns and used data available until May 25, but did not take into account a possible effect of temperatures on viral transmission.

Whilst most organisms try to stop their DNA from mutating, scientists from the UK and China have discovered that a common fungus found on bread actively mutates its own DNA as a way of fighting virus-like infections.

All organisms mutate all of the time. You were born with between ten and a hundred new mutations, for example. Many do little harm but, if they hit one of your genes, mutations are much more likely to be harmful than beneficial. If harmful enough they contribute to genetic diseases.

Whilst mutations can enable species to adapt, most mutations are harmful, and so evolutionary biologists have postulated that natural selection will always act to reduce the mutation rate.

While prior data has supported this view, recent work by Professor Laurence Hurst of the Milner Centre for Evolution at the University of Bath (UK) and Sihai Yang, Long Wang and colleagues at Nanjing University (China) have found that Neurospora crassa, a type of bread mould, is a remarkable exception to the rule.

Professor Hurst, Director of the Milner Centre for Evolution at the University of Bath, said: "Many organisms have a problem with transposable elements, otherwise called jumping genes.

"These are virus-like bits of DNA that insert themselves into their host's DNA, copy themselves and keep on inserting - hence the name jumping genes.

"Organisms have found different ways of combatting this nuisance, many of which try to prevent the transposable elements from expressing their own genes. Neurospora has evolved a different solution: it hits them exceptionally hard with mutations to rapidly degrade them."

The study, published in Genome Biology, found that Neurospora distinguishes jumping genes from its own DNA by detecting two or more copies of the same bit of DNA. The fungus then attacks the jumping genes by mutating them in a process called Repeat-Induced Point mutation (RIP).

To understand how RIP affects the fungus's own DNA, the team sequenced the whole genome from both parents and offspring for many strains of Neurospora to see how many mutations could be found and where they were in the DNA.

Overall, they found that each base pair in the Neurospora genome has about a one in a million chance of mutating every generation; over a hundred times higher than any non-viral life on the planet.

Professor Hurst said: "This was a real surprise to us - any organism that hits its own genes with that many mutations is likely one that will not persist for very long. It would be like opening up the back of a watch, stabbing at all the cog wheels that look a bit similar and expecting the watch to still function!

"Our findings show that Neurospora has not only a high mutation rate but is also a massive outlier. It appears to use RIP to destroy transposable elements but at a cost, with considerable collateral damage.

"This organism thus goes against the standard theory for mutation rate evolution which proposes that selection should always act to reduce the mutational burden.

"It is the exception that proves the rule."

The first nationwide analysis of drinking water quality in United States correctional facilities found average arsenic concentrations in drinking water in Southwestern United States correctional facilities were twice as high as average arsenic concentrations in other Southwest community drinking water systems. More than a quarter of correctional facilities in the Southwest reported average arsenic levels exceeding the U.S. Environmental Protection Agency 10 μg/L maximum contaminant level.

The study by Columbia University Mailman School of Public Health researchers Anne Nigra, PhD, and Ana Navas-Acien, MD, PhD, professor of environmental health sciences, is published in the journal Environmental Research.

Disparities and injustices in water quality may contribute to the excess burden of disease experienced by incarcerated and formerly incarcerated people. Approximately 2.2 million people, disproportionately Black and low-income men, are incarcerated in the U.S. Incarcerated populations are at elevated risk for several chronic diseases that are associated with chronic low-to moderate-arsenic exposure, including hypertension and diabetes.

More than 90,000 people rely on drinking water from community water systems (CWSs, public water systems that serve the same population year-round) that exclusively serve correctional facilities located in the Southwestern U.S., a part of the country where there are high concentrations of naturally occurring inorganic arsenic in domestic wells and in public water systems.

The researchers analyzed 230,158 arsenic monitoring records from 37,086 community water systems from the EPA's Third Six Year Review of Contaminant Occurrence dataset covering 2006-2011. Average six-year water arsenic concentrations in Southwestern correctional facility CWSs were more than twice that of other Southwestern CWSs and nearly five times the level of other CWSs across the rest of the U.S. (6.41 μg/L vs. 3.11 μg/L vs. 1.39 μg/L). Although the EPA goal maximum contaminant level (MCL) for arsenic is 0 μg/L, EPA set the current arsenic MCL at 10 μg/L given feasibility and treatment costs.

Tap water is likely the sole water source available to incarcerated populations, who lack access to alternative drinking water (e.g. bottled water, domestic wells) or point-of-use treatment devices in the event of compromised drinking water quality. Incarcerated individuals may also be unaware of the arsenic levels in their drinking water despite EPA rules that mandate CWSs make yearly reports available to customers. "Mass incarceration is a public health crisis. People who are incarcerated have a right to safe drinking water. Correctional facilities with their own water systems need to reduce water arsenic concentrations as much as possible, even below current regulatory standards," says Anne Nigra.

The authors conclude: "Immediate, aggressive enforcement of water standards for water systems exclusively serving correctional facilities is critical to protect the health and human rights of all incarcerated persons, including adolescents, pregnant women, and the young children of incarcerated women."

The work developed in collaboration with researchers from France, Germany and South Korea was recently published in the scientific journal PNAS - Proceedings of the National Academy of Sciences USA.

Sepsis is a potentially fatal illness, that derives from a deregulated response of the organism to an infection, leading to organ malfunction. A study recently published in the scientific journal The Lancet, estimated that in 2017 sepsis affected 49 million people and 11 million people worldwide have died. With the aim of expanding knowledge about this disease, Luis Moita's team at IGC investigated whether the hormone known as GDF15 (growth and differentiation factor 15) could play a role in sepsis. This hormone has the specificity of being widely studied by several laboratories and pharmaceuticals as a treatment for obesity.

"We've discovered a critical effect of GDF15 on infection, which is relevant because this hormone increases in many common diseases, like obesity, pulmonary and cardiovascular diseases", explains Luís Moita.

IGC researchers measured GDF15 levels in blood samples from patients with sepsis, under treatment in intensive care units, and compared these levels with the ones of healthy individuals and of patients diagnosed with appendicitis. Results have shown that sepsis patients had increased levels of GDF15 when compared with the other groups, and that the high levels of the hormone were correlated with mortality.

The research proceeded with the study in mice that didn't had the GDF15 gene. The results obtained revealed that mice survived better to a bacterial abdominal infection that resembles sepsis in human patients, suggesting that the hormone plays a role in sepsis. Subsequently researchers studied what was causing the increased survival rate in mice that didn't had GDF15. They noted that these mice were able to substantially recruit more white blood cells for the abdomen, specially neutrophils, better controlling locally the infection and preventing it from spreading rapidly to the rest of body.

"At a time when many pharmaceutical companies and groups are considering using GDF15 as a complementary therapy for obesity, it's important to have in mind that this therapeutic strategy could increase the risk of severe infection, including sepsis", Luís Moita warns.

Regarding the results of this research work, IGC researcher says that "they raise the possibility that the inhibition of GDF15's action, perhaps using a blocking monoclonal antibody, could work as a new complementary therapy for sepsis, helping to control severe local infections and preventing it to become systemic and life-threatening".

Finding new therapeutic strategies to fight sepsis is essential for saving lives.

One goal of science is to find physical descriptions of nature by studying how basic system components interact with one another. For complex many-body systems, effective theories are frequently used to this end. They allow describing the interactions without having to observe a system on the smallest of scales. Physicists at Heidelberg University have now developed a new method that makes it possible to identify such theories experimentally with the aid of so-called quantum simulators. The results of the research effort, led by Prof. Dr Markus Oberthaler (experimental physics) and Prof. Dr Jürgen Berges (theoretical physics), were published in the journal "Nature Physics".

Deriving predictions about physical phenomena at the level of individual particles from a microscopic description is practically impossible for large systems. This applies not only to quantum mechanical many-body systems, but also to classical physics, such as when heated water in a cooking pot needs to be described at the level of the individual water molecules. But if a system is observed on large scales, like water waves in a pot, new properties can become relevant under certain preconditions. To describe such physics efficiently, effective theories are used. "Our research aimed to identify these theories in experiments with the help of quantum simulators," explains Torsten Zache, the primary author of the theoretical portion of the study. Quantum simulators are used to modify many-body systems more simply and to calculate their properties.

The Heidelberg physicists recently demonstrated their newly developed method in an experiment on ultracold rubidium atoms, which are captured in an optical trap and brought out of equilibrium. "In the scenario we prepared, the atoms behave like tiny magnets whose orientation we are able to precisely read out using new processes," according to Maximilian Prüfer, the primary author on the experimental side of the study. To determine the effective interactions of these "magnets", the experiment has to be repeated several thousand times, which requires extreme stability.

"The underlying theoretical concepts allow us to interpret the experimental results in a completely new way and thereby gain insights through experiments into areas that have thus far been inaccessible through theory," points out Prof. Oberthaler. "In turn, this can tell us about new types of theoretical approaches to successfully describe the relevant physical laws in complex many-body systems," states Prof. Berges. The approach used by the Heidelberg physicists is transferrable to a number of other systems, thus opening groundbreaking territory for quantum simulations. Jürgen Berges and Markus Oberthaler are confident that this new way of identifying effective theories will make it possible to answer fundamental questions in physics.

Philadelphia, June 22, 2020 - A team of researchers from Children's Hospital of Philadelphia (CHOP) has demonstrated how to easily and effectively monitor for seizures in newborn infants, catching more instances than typical methods and improving the quality of care for infants in hospitals that lack the on-site resources to detect these seizures. The findings were published today in the Journal of Clinical Neurophysiology.

"This study allowed us to test a framework for expanding remote continuous monitoring of at-risk neonates, beginning at two regional affiliate hospital NICUs within our network," said Mark P. Fitzgerald, MD, PhD, a pediatric neurologist in the Division of Neurology at CHOP and lead author of the study. "Not only did we show that such monitoring was technically feasible and effective, allowing neonates to receive care locally, but we also demonstrated that the approach positively impacted clinical care."

A variety of underlying conditions, including an acquired structural injury to the brain, ischemic stroke, and intracranial hemorrhage, are responsible for neonatal seizures, which occur in as many as 4 of every 1,000 live births. Continuous electroencephalogram (CEEG) monitoring is important for identifying seizures, since more than 80% of these seizures do not have any identifiable symptoms. Even skilled clinicians must rely on this technology to identify these seizures when they occur, and an accurate diagnosis is critical in making sure that these newborns receive the appropriate amount of anti-seizure medication.

Although the American Clinical Neurophysiology Society and World Health Organization have recommended CEEG as the gold standard for seizure identification, there are barriers to implementing its use in neonatal intensive care units, including lack of equipment and experienced personnel. Many centers have used amplitude-integrated EEG (aEEG) monitoring instead, but its sensitivity for seizure detection is lower than CEEG.

In order to overcome some of the barriers preventing widespread adoption of CEEG, the researchers developed a framework to use the technology remotely to monitor for seizures. Under this framework, a network hospital identifies a newborn who should undergo CEEG based on clinical concerns, such as therapeutic hypothermia or unexplained encephalopathy, or concern for seizures that may not otherwise be detected. Once these newborns have been identified, an EEG technologist at the network hospital places the EEG leads and gathers a set of standardized clinical data, notifying an EEG technologist at the main hospital (in this instance, CHOP).

The study team reviewed the EEG results and clinical care notes of the newborns monitored during the first 27 months of the pilot program. Between June 2017 and September 2019, 76 newborns underwent CEEG between the two network hospital NICUs. Seizures occurred in about one-quarter of the records. According to the care notes, CEEG impacted clinical care in three-quarters of the cases, decisions to treat with anti-seizure medications in approximately half of the patients, and discussions about the future course of care in approximately two-thirds of patients.

"In the first two years of this pilot program, we demonstrated that neonatal seizures are common in at-risk neonates and that CEEG often impacted outcomes," Fitzgerald said. "By providing remote CEEG to network hospitals, we allow these neonates to remain in centers that could meet their overall medical needs and alleviate the safety risks associated with transferring critically ill newborns between hospitals."

UNIVERSITY PARK, Pa. - Many epidemiologists believe that the initial COVID-19 infection rate was undercounted due to testing issues, asymptomatic and alternatively symptomatic individuals, and a failure to identify early cases.

Now, a new study from Penn State estimates that the number of early COVID-19 cases in the U.S. may have been more than 80 times greater and doubled nearly twice as fast as originally believed.

In a paper published today (June 22) in the journal Science Translational Medicine, researchers estimated the detection rate of symptomatic COVID-19 cases using the Centers for Disease Control and Prevention's influenza-like illnesses (ILI) surveillance data over a three week period in March 2020.

"We analyzed each state's ILI cases to estimate the number that could not be attributed to influenza and were in excess of seasonal baseline levels," said Justin Silverman, assistant professor in Penn State's College of Information Sciences and Technology and Department of Medicine. "When you subtract these out, you're left with what we're calling excess ILI - cases that can't be explained by either influenza or the typical seasonal variation of respiratory pathogens."

The researchers found that the excess ILI showed a nearly perfect correlation with the spread of COVID-19 around the country.

Said Silverman, "This suggests that ILI data is capturing COVID cases, and there appears to be a much greater undiagnosed population than originally thought."

Remarkably, the size of the observed surge of excess ILI corresponds to more than 8.7 million new cases during the last three weeks of March, compared to the roughly 100,000 cases that were officially reported during the same time period.

"At first I couldn't believe our estimates were correct," said Silverman. "But we realized that deaths across the U.S. had been doubling every three days and that our estimate of the infection rate was consistent with three-day doubling since the first observed case was reported in Washington state on January 15."

The researchers also used this process to estimate infection rates for each state, noting that states showing higher per capita rates of infection also had higher per capita rates of a surge in excess ILI. Their estimates showed rates much higher than initially reported but closer to those found once states began completing antibody testing.

In New York, for example, the researchers' model suggested that at least 9% of the state's entire population was infected by the end of March. After the state conducted antibody testing on 3,000 residents, they found a 13.9% infection rate, or 2.7 million New Yorkers.

Excess ILI appears to have peaked in mid-March as, the researchers suggest, fewer patients with mild symptoms sought care and states implemented interventions which led to lower transmission rates. Nearly half of U.S. states were under stay-at-home orders by March 28.

The findings suggest an alternative way of thinking about the COVID-19 pandemic.

"Our results suggest that the overwhelming effects of COVID-19 may have less to do with the virus' lethality and more to do with how quickly it was able to spread through communities initially," Silverman explained. "A lower fatality rate coupled with a higher prevalence of disease and rapid growth of regional epidemics provides an alternative explanation of the large number of deaths and overcrowding of hospitals we have seen in certain areas of the world."

A surge in flu-like infections in the U.S. in March of 2020 suggests that the likely number of COVID-19 cases was far larger than official estimates, according to a new study of existing surveillance networks for influenza-like infections (ILIs). The findings support a scenario where more than 8.7 million new SARS-CoV-2 infections appeared in the U.S. during March, and estimate that more than 80% of these cases remained unidentified as the outbreak rapidly spread. Furthermore, the results suggest that surveillance networks for influenza-like disease offer an important tool to estimate the prevalence of COVID-19, which has been hard to pin down. Many scientists suspect that the true rate of SARS-CoV-2 infections is higher than the number of confirmed cases due to the low availability of testing and because some infected individuals show no symptoms or only mild flu-like symptoms. Using an outpatient surveillance system for diseases with symptoms that resemble influenza, Justin Silverman and colleagues determined the prevalence of non-influenza ILIs in the U.S. annually using surveillance data starting from 2010. In March of 2020, they observed a huge spike in ILIs exceeding normal seasonal numbers in various states - New York, for example, showed twice its previous record for ILIs in the fourth week of March. The authors also saw that the dynamics of non-influenza ILIs closely matched patterns of confirmed COVID-19 cases. After calculating that approximately 32% of people infected with SARS-CoV-2 sought medical care, Silverman et al. found that at least 8.7 million SARS-CoV-2 infections occurred between March 8 and March 28 in the U.S., with new deaths doubling approximately every 3 days. The team concludes that the initial spread of COVID-19 therefore included a large undiagnosed outpatient population who potentially showed milder symptoms compared with those who were hospitalized.

Researchers at São Paulo State University (UNESP) in Araçatuba, Brazil, have developed a computational tool that acts like a "COVID-19 accelerometer," plotting in real time the rate at which growth is accelerating or decelerating in more than 200 countries and territories.

Available free of charge online, the application automatically loads the most recent notified case numbers from the European Center for Disease Prevention and Control (ECDC), updated daily, and applies mathematical modeling techniques to diagnose the current stage of the pandemic in each country.

"The application democratizes access to information. Everyone can understand exactly what's happening in their city, state or country. It also helps public administrators and policymakers evaluate whether measures taken to mitigate transmission of the novel coronavirus are having the desired effect," Yuri Tani Utsunomiya told. Utsunomiya is a professor at UNESP's Araçatuba School of Veterinary Medicine (FMVA) and first author of an article published in Frontiers in Medicine showing how the mathematical modeling framework can be used to assess the effects of public health measures.

To explain how an epidemic progresses, Utsunomiya offered an analogy to a fast car. Initially, the disease spreads slowly, and daily cases grow slowly, just as a car takes some time to pick up speed. The rate of growth is called the 'incidence' and is measured by the number of new cases per day. Prevalence is the total number of cases since counting began and can be compared to the distance traveled by this imaginary car.

"Stepping on the throttle makes the number of cases rise rapidly, like a car accelerating and picking up speed. Exponential growth in the number of cases occurs in this second stage of the epidemic. What every country wants is to stop this acceleration and begin to slow transmission. These are two distinct operations," Utsunomiya explained. "The first consists of taking one's foot off the throttle so that the acceleration falls to zero. Incidence peaks as a result. The second operation entails exerting negative acceleration on the disease [stepping on the brake] so that the rate of growth falls to zero. Without velocity, the car stops. This is what we all want. We want COVID-19 to stop spreading."

The COVID-19 accelerometer shows almost in real time whether a country is accelerating or braking, with a degree of imprecision in countries with undernotification of cases.

However, Utsunomiya stressed that the four stages of growth in the epidemic - flow (green), exponential (pink), deceleration (yellow) and stationary (blue) - may not unfold in that order. Even after a period of deceleration or stationary growth, the disease could again start spreading exponentially if control measures are abandoned. Hence, tools that help continuously monitor transmission are important.

"Our analysis of more than 200 countries and territories showed that effective control measures quickly affect the acceleration curve, well before the number of daily cases starts to fall. This behavior of the curve is highly relevant to any assessment of public policy to control the disease," Utsunomiya said.

Sinuous curves

Using official notification data, the application plots incidence - the growth curve everyone wants to flatten so that hospitals are not overwhelmed - and acceleration in real time, and detects transitions between the four stages. This is made possible by two mathematical techniques: moving regression and a hidden Markov model.

"We developed a simple but highly robust method that takes data available from national and international databases to produce precise information on the progress and movement of the pandemic. Of course, the calculations are based on data that essentially depend on diagnosis [testing]," noted José Fernando Garcia, a professor at UNESP Jaboticabal and a coauthor of the article.

While the undernotification of cases is a limitation and may create scale distortions, the epidemiological curves produced by the model are sufficiently accurate, according to the researchers.

An analysis of the curves for Brazil at this time shows that no state has thus far succeeded in leaving behind the exponential growth stage, despite quarantine measures and lockdowns. China reached the stationary stage after only six weeks of well-organized social isolation. Australia, New Zealand, Austria and South Korea have now reached the stationary stage. Italy, Spain and Germany are in the deceleration stage, in which the number of new cases falls daily, thanks to the confinement measures taken.

Utsunomiya divides the measures designed to contain the spread of COVID-19 into two categories: suppression, meaning more intense and severe measures aimed at rapidly reversing the growth curve, e.g., lockdown, and mitigation measures aimed at lowering the growth rate, e.g., requiring face masks and discouraging crowds.

"Our study clearly points to the effectiveness of suppression in combating COVID-19," he said. "However, suppressive measures have been criticized for creating social problems and having a profoundly negative effect on the economy. Mitigation has less severe social and economic impacts, but it's also less efficient. There really isn't a silver bullet."

São Paulo Research Foundation - FAPESP awarded Utsunomiya scholarships in the past to support his PhD research and master's research.

According to Utsunomiya, Japan is one of the only countries that managed to decelerate the growth of new cases with mitigation measures alone. "Comparing strategies across countries requires caution," he said. "The effectiveness of mitigation depends on factors like healthcare infrastructure, the amount and frequency of testing, population density, and the extent to which people in general comply with the recommendations of the health authorities."

TAMPA, Fla (June 22, 2020) -- A receptor that plays an essential role in safely clearing chronic unresolved cardiac inflammation may offer new targets for treating an increasing type of heart failure associated with age-related obesity, suggests a preclinical study led by researchers at the University of South Florida Health (USF Health) Heart Institute, Morsani College of Medicine.

Heart failure with preserved ejection fraction, or HFpEF, is one of two types of heart failure - both characterized by shortness of breath, exercise intolerance, fatigue and fluid retention. Unlike the second type of heart failure, known as heart failure with reduced ejection fraction, HFpEF currently has no FDA-approved drugs to improve the weakened heart's pumping function.

More than half of all patients with clinical heart failure have HFpEF, a growing public health problem because of the aging population and growing incidence of obesity. In HFpEF, the heart contracts normally and seems to pump out a normal proportion of blood; however, the heart muscle can thicken and weaken causing the ventricle to withhold an abnormally small volume of blood. So, while the heart's output as measured by ejection fraction may appear within the normal range, it is insufficient to meet the body's demands.

In a study published June 16 in The FASEB Journal, the USF Health-led team identified a mouse model that thoroughly mimics HFpEF syndrome in humans. These obesity-prone mice lack the inflammation clearing (resolution) receptor, ALX/FPR2 or ALX for short -- a deficiency previously shown to drive cardiac and kidney inflammation in aging mice.

Using this unique model, the researchers defined how the ALX resolution receptor promotes the activity of specialized proresolving mediators (SPMs), fatty-acid derived signaling molecules. These SPM molecules support the body's innate immune response to help clear out chronic inflammation and advance cardiac repair following an acute heart attack. Conversely, the researchers noted that sustained, unresolved inflammation after heart attack can aggravate abnormalities in endothelial cells lining the heart and kidneys. These abnormalities prompt endothelial dysfunction that changes blood vessel integrity -- a primary sign of both age-related obesity and HFpEF.

"Remarkably, the deficiency of a single receptor triggers obesity in mice at an early age and this, in turn, gives rise to many molecular and cellular processes ultimately leading to heart failure with preserved ejection fraction," said senior author Ganesh Halade, PhD, associate professor of cardiovascular sciences at the USF Health Heart Institute.

The FASEB study's three key findings were:

The obesity-prone ALX-deficient mice had increased food intake and impaired energy metabolism compared to normal mice (with a working ALX receptor) of the same ages. The obesity-driven metabolic dysfunction led to heart structural remodeling, defective cardiac electrical activity and weakened heart muscle.

Deletion of the ALX receptor increased ion channel gene expression and disrupted multiple ion channels, which supported electrocardiogram evidence of heart rhythm disturbances in the mice.

Obesity-prone, ALX-deficient mice develop heart muscle damage characteristic of HFpEF with steady inflammation in the heart and kidneys. This suboptimal inflammation is directed remotely by immune cells (leukocytes) in the spleen and advanced by dysfunctional (leaky) cardio-renal endothelial tissue in older ALX-deficient obese mice.

Overall, the research describes the importance of the resolution receptor essential for SPM action, particularly resolvins that suppress the inflammatory response to acute injury without compromising a healthy immune response. In fact, a specific resolvin (D1) is a key that unlocks the ALX resolution receptor to enable pharmacological action and, eventually, safe clearance of inflammation, Dr. Halade said.

The study offers insight into potential targeted treatments for HFpEF that would harness the benefits of naturally-produced SPMs. Omega 3-rich diets and/or SPM supplements to preserve the receptor's normal function may help prevent this type of heart failure, Dr. Halade said, while SPMs or other molecules specifically designed to reactivate a dysfunctional receptor might help treat existing HFpEF.

This latest research builds upon previous work by Dr. Halade's laboratory - all focused on discovering the best ways to prevent, delay or treat the unresolved inflammation influencing heart failure. The team's goal is to contribute to individualized therapies that may account for possible sex, racial/ethnic or age-related physiological differences.

Approximately, 6.5 million Americans have heart failure, which contributes to one in every eight deaths, according the Centers for Disease Control and Prevention.