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The addition of the monoclonal antibody therapy Trastuzumab to radiotherapy did not reach the protocol objective of a 36% reduction in the ipsilateral breast tumor recurrence rate for women with HER2-positive ductal carcinoma in situ (DCIS) on the NRG Oncology clinical trial NSABP B-43. The trial did find a statistically non-significant, modest (19%) reduction in the rate of recurrence among women that received trastuzumab, but this difference was not statistically significant. These results were recently exhibited during an oral presentation at the virtual Annual Meeting of the American Society for Clinical Oncology.

The Phase III NRG-NSABP B-43 trial accrued 2014 women and randomly assigned trial participants in a 1:1 fashion to receive either whole-breast radiotherapy alone or radiotherapy with two doses of trastuzumab following lumpectomy. The goal of the trial was to determine if the addition of trastuzumab can assist in preventing recurrence of ipsilateral breast cancer, ipsilateral skin cancer, ipsilateral DCIS, or ipsilateral breast tumor recurrence in women with DCIS. This hypothesis was developed in response to data from previous preclinical studies that suggested that trastuzumab can boost the effectiveness of radiotherapy.

Of the 2014 patients that were accrued to the trial, 1998 patients (99.2%) had follow up information available at the median follow up time point of 79.2 months. 2001 women had radiotherapy information; 98.2% of patients completed radiotherapy treatment on the radiotherapy alone treatment arm (RT) and 98.1% completed radiotherapy on the radiotherapy plus trastuzumab arm (RT+T). In the RT+T group, 94.3% patients completed both doses of trastuzumab therapy, while 2.5% had only one dose of the therapy. Another 3.2% did not start trastuzumab.

The NRG-NSABP B-43 protocol required that 163 in-breast tumor recurrence (IBTR) events be confirmed or that all patients be on study for at least five years to trigger a definitive analysis. Since less than 163 IBTR events were confirmed, analysis was performed because all patients were on the trial for five years or longer.

At this preliminary analysis based on information through December 31, 2019, 114 IBTR events were confirmed with 63 being in the RT arm and 51 in the RT+T treatment arm. In those that had a recurrence, 38 were invasive including 18 in the RT arm and 20 in the RT+T treatment arm. The remaining 76 IBTR events were DCIS with 45 in the RT treatment arm and 31 in the RT+T treatment arm. Annual IBTR event rates were 0.99% per year in the RT group and 0.80% per year in the RT+T group. There were 48 deaths on the trial with 26 in the RT arm and 22 in the RT+T arm.

"This is the first prospective, randomized study of HER2-targeted treatment for HER2-positive DCIS. It provides important insight into the natural history and impact of HER2-targeted treatment on outcomes," stated Melody Cobleigh, MD, of Rush University Medical Center and the lead author of the NRG-NSABP B-43 abstract.

ATLANTA--Paid sick leave (PSL) mandates like those found in the federal government's Families First Coronavirus Response Act may be helping to slow the spread of COVID-19, according to a new study by health economists at Georgia State and Tulane universities.

Since 2007, several state and local governments have enacted laws requiring employers to provide their workers with paid sick leave. Michael Pesko, an associate professor in Georgia State's Andrew Young School of Policy Studies, and co-author Kevin Callison studied the effects of these staggered mandate adoptions using multiple government-collected survey data sources from 2005 to 2018.

The mandates were effective in increasing the number of workers holding Paid Sick Leave coverage, particularly those in low-wage industries who were unlikely to have previously received PSL benefits from their employers, they found. Women and racial/ethnic minorities benefitted disproportionately from the PSL mandates.

"These mandates reduced the number of people attending work while sick, which is similar to an earlier study showing influenza-like disease rates decreased after employees gained access to paid sick leave," said Pesko. "If paid sick leave helps stop people from attending work while sick and prevents the spread of disease as a result, this has important policy implications in today's fight to contain COVID-19."

Paid Sick Leave reduces the rate of those working while sick by 4.5 percentage points on average for workers in industries with historically low rates of PSL, such as the accommodation and food service industries. PSL mandates are particularly likely to increase work absences among women and households with children, where workers may be using their benefits to care for a sick child or other family obligations.

"What are the policy implications? The Families First Coronavirus Response Act, which went into effect April 1, is the first congressionally passed bill that provides Paid Sick Leave for employees in medium- and small-sized businesses with coronavirus issues," Pesko said. "We believe that the bill will reduce people attending work with COVID-19 because it pays for them to stay home and recover. This bill is, therefore, an important component in COVID-19 containment efforts."

MINNEAPOLIS, MN- May 29, 2020 - According to the National Autism Association, people with autism spectrum disorder (ASD) may experience sensory hypersensitivity. A University of Minnesota Medical School researcher recently published an article in Nature Communications that illustrates why that may be true by showing the differences in visual motion perception in ASD are accompanied by weaker neural suppression in the visual cortex of the brain.

While experts in neuroscience and psychiatry recognize that differences in sensory functioning are common among people with ASD, it is not currently understood what is happening differently in the brain on a neural level to cause the variations in sensory perception.

Using functional MRI and visual tasks, lead author Michael-Paul Schallmo, PhD, assistant professor in the Department of Psychiatry at the U of M Medical School, and a team of researchers at the University of Washington found:

People with ASD show enhanced perception of large moving stimuli compared to neuro-typical individuals;

Brain responses to these visual stimuli are different among young adults with ASD compared to neuro-typical individuals. In particular, brain responses in visual cortex show less neural suppression in ASD;

A computational model can describe the difference in brain responses.

"Our work suggests that there may be differences in how people with ASD focus their attention on objects in the visual world that could explain the difference in neural responses we are seeing and may be linked to symptoms like sensory hypersensitivity," Schallmo said.

Schallmo is currently working with collaborators at the U of M on a follow-up study of visual and cognitive functioning in youth with ASD, Tourette syndrome, attention deficit hyperactivity disorder and obsessive-compulsive disorder. Having a better understanding of how these different disorders affect brain function could lead to new screenings to better identify kids who are at risk for ASD and related conditions. It may also help scientists to find new targets for studies seeking to improve treatments for sensory symptoms in these disorders.

BUFFALO, N.Y. -- Harm reduction strategies have proven effective for use of opioids, alcohol, and tobacco products. University at Buffalo and University of Michigan researchers say harm reduction techniques also have potential for cannabis users - but first, public health practitioners and organizations need to do a better job of making cannabis users aware of those strategies.

Researchers assessed harm reduction awareness by surveying nearly 500 participants at the 2019 Hash Bash, a popular marijuana advocacy event on the campus of the University of Michigan.

The research team has published a series of papers in recent years based on data collected by surveying Hash Bash attendees. Their latest study, published in Health Promotion Practice, shows that frequent cannabis users aren't as knowledgeable as they should be about harm reduction strategies, such as not driving within six hours of using cannabis. And that, the researchers argue, falls more squarely on public health's failure to properly provide that knowledge.

"Our findings should serve as a wake-up call to public health professionals to integrate harm reduction strategies into practice," said Jessica Kruger, PhD, the study's lead author and a clinical assistant professor of community health and health behavior in UB's School of Public Health and Health Professions.

"As more states legalize medicinal and recreational use of cannabis, it's important that public health equip people with proper knowledge about using cannabis. We know that abstinence just isn't realistic or desirable for some users. We can minimize the costs and risks of cannabis use by creating awareness around harm reduction strategies," Kruger added.

Fewer than half of the study participants believed that any of the listed strategies reduced the harm of using cannabis. Only 42% identified avoiding use when pregnant as an effective harm reduction strategy. Even less, 36%, identified avoiding driving within six hours of using cannabis as an effective strategy.

"This is really remarkable, given that both of these are common warnings for a variety of psychoactive and pharmaceutical substances," said co-author Daniel Kruger, PhD, a research associate professor of community health and health behavior in UB's School of Public Health and Health Professions. He is also a research investigator with the Population Studies Center at the University of Michigan.

About one-quarter of participants believed that using strains with high cannabidiol (CBD) CBD to tetrahydrocannabinol (THC) ratios, using a concentrate or dab without plant material, and putting ice in a bong to reduce cannabis potency were effective harm reduction techniques. Only using strains with a high CBD to THC ratio has been empirically supported, the researchers note.

Less than half of participants reported using any harm reduction strategy, and 39% reported using no effective strategy.

Although knowledge doesn't guarantee behavior or behavior change, the researchers note that providing cannabis users with accurate information on the risks and benefits of the drug will at least help users make informed decisions.

They point to two public health campaigns in Colorado, a state where cannabis is legal for adult use. That state's "Good to Know" campaign educated Colorado residents on new cannabis laws. The state's "Responsibility Grows Here" campaign shares information about the potential risks for teens and pregnant and breastfeeding women, and calls on users to consume cannabis responsibly.

"As more and more people have legal access to medical and recreational cannabis, the importance of effective cannabis-specific health education increases," said study co-author R. Lorraine Collins, PhD, associate dean for research in UB's School of Public Health and Health Professions and a professor of community health and health behavior.

Farmers in Bangladesh achieved significantly higher yields and revenues by growing insect-resistant, genetically engineered eggplant, a new Cornell study has found.

The four genetically engineered (Bt) varieties yielded, on average, 19.6% more eggplant - known as brinjal in Bangladesh - than non-Bt varieties and earned growers 21.7% higher revenue, according to the study, published May 25 in Frontiers in Bioengineering and Biotechnology.

The additional revenue per hectare (1 hectare is approximately 2 ½ acres) is the equivalent of around $664, a substantial sum for resource-poor farmers in Bangladesh.

The paper is the first to document the economic benefits of the four existing Bt brinjal varieties though the Bangladeshi market chain and their acceptability to farmers and consumers, said lead author Tony Shelton, professor of entomology and former director for the Feed the Future South Asia Eggplant Improvement Partnership based in Cornell's Department of Global Development. The study was based on a 2019 survey of Bt and non-Bt brinjal farmers.

Bt brinjal was developed by the Bangladesh Agricultural Research Institute (BARI) in conjunction with Mahyco (an India-based agricultural company), Cornell and the U.S. Agency for International Development, in an effort to stop the losses caused by eggplant fruit and shoot borer (EFSB) larvae caterpillars, and reduce pesticide use.

"The EFSB causes between 30% and 60% yield loss, even when insecticides are frequently sprayed," Shelton said. "Farmers typically apply insecticides more than 80 times during the four- to five-month brinjal growing season, a process that is both expensive and harmful to farmers, who spray without protective equipment."

Of Bt brinjal growers, 83% were satisfied with the yields obtained and 80% were satisfied with the quality of the plant; 59% of non-Bt brinjal growers were pleased with their yields. Some 28% of the non-Bt farmers also indicated that a large portion of their fruit was infested with EFSB larvae. This was not a concern for Bt brinjal, because it provides genetically inherent resistance.

"Bt brinjal varieties provide farmers a more sustainable crop that protects food security and the environment," said Maricelis Acevedo, director of the project since March 2020. "This study provides more evidence that Bt brinjal is being accepted in the market, but more work is needed to develop new varieties better adapted to local conditions and market preferences."

Because of the higher yields, increased revenue and fruit quality, about three-quarters of Bt brinjal farmers said they planned to grow the crop again next season. Brinjal is the second-most important vegetable grown in Bangladesh, cultivated by about 150,000 resource-poor farmers on 50,955 hectares, and consumed by the public on a daily basis.

The survey was conducted in the five most important brinjal producing districts in Bangladesh - Rangpur, Bogra, Rajshahi, Jessore and Tangail - through face-to-face interviews with 195 Bt farmers and 196 non-Bt farmers. Farmers made their own choices about which crop to grow.

A team of researchers led by Swansea University have developed new technology to monitor cholesterol in brain tissue which could uncover its relation to neurodegenerative disease and pave the way for the development of new treatments.

The research, published in the Proceedings of the National Academy of Sciences of the USA, shows the major locations of cholesterol in the brain and what molecules it can be converted to.

The brain is a remarkably complex organ, with cholesterol and its metabolites underpinning the brain's function. Dysregulated cholesterol metabolism is linked to a number of neurodegenerative disorders including Alzheimer's, Parkinson's, Huntington's disease, multiple sclerosis and motor neurone disease.

It is known that cholesterol is not evenly distributed across different brain regions; however, up until now there has been no technology available to map cholesterol metabolism in defined locations of the brain at microscopic levels, and to visualise how it changes in pathological niches in the brain.

Here, researchers describe an advanced mass spectrometry imaging platform to reveal spatial cholesterol metabolism in mouse brain at micrometre resolution from tissue slices. The researchers mapped not only cholesterol, but also biologically active metabolites arising from cholesterol turnover. For example, they found that 24S-hydroxycholesterol, the major cholesterol metabolite in the brain, is about ten times more abundant in striatum than in the cerebellum, two regions involved in different ways in voluntary movement and cognition.

The new technology comes from a decade of research at Swansea University where the team have worked out methods to reveal the different metabolites of cholesterol in very small quantities of the brain, as small as the tip of a ballpoint pen.

Professor William Griffiths, who co-led the study from Swansea University added: "Although our work was with a mouse, the technology can similarly be used in humans in a research lab or a clinical setting, and could have revolutionary value when linked to neurosurgery.

"Tissue excised during surgery could rapidly be profiled by our method in-clinic and used to distinguish healthy from diseased tissue, informing the surgeon on the next step of the operation."

Professor Yuqin Wang added: "This technology which precisely locates molecules in the brain will further our understanding of the complexity of brain function and how it changes in neurodegenerative disorders.

"Our results show that cholesterol turnover is particularly high in striatum, the area most affected in Huntington's disease. We will apply this method to find out how cholesterol metabolism is associated with this disease. This may lead to the development of new therapies to a disease which currently has no cure."

Plants produce the hormone jasmonic acid as a defence response when challenged. This is how they ensure that their predators no longer like the taste of their leaves. Biologists want to find out whether biological precursors and other variants of jasmonic acid lead to similar or different effects. But such derivatives of the hormone have so far been too expensive for experiments and difficult to come by. Researchers from the Faculties of Chemistry and Biology at Bielefeld University have now found a method that might make the production of a biologically significant precursor of jasmonic acid more efficient and cheaper. Their innovation: they imitate how plants produce the hormone. The result is 12-OPDA, a central precursor of jasmonic acid. In the long term, it could also be a potential precursor for high-quality perfume. The researchers present their method today (29.05.2020) in the research journal Advanced Science.

'Jasmonic acid can, for example, trigger the release of toxic substances such as nicotine in the leaves, which harms predators,' explains biologist Professor Dr Karl-Josef Dietz. 'Tobacco plants emit a modified form of jasmonic acid which induces neighbouring plants to prepare for attacks,' says Dietz. 'Jasmonic acid also supports healing and can stimulate damaged plants to regenerate.'

Dietz heads the Plant Biochemistry and Physiology Working Group at Bielefeld University. He is researching how plants react to stress and is working on changing and optimising their response. 'This will enable us to prepare plants for the new environmental conditions resulting from climate change, for instance.' If the warmer climate leads to an increase in beetle populations, plants could be equipped with the ability to harm these attackers with bitter substances. 'We are interested in the effect of preforms of jasmonic acid, such as 12-OPDA, which is only available in the milligram range and then costs several hundred euros,' says Dietz.

'The high price is due to the labour-intensive production process, as the production of 12-OPDA is extremely complex and involves numerous reaction steps in the classical chemical process,' says chemist Professor Dr Harald Gröger. He heads the Industrial Organic Chemistry and Biotechnology Working Group at Bielefeld University. Together with Dietz, he developed the idea of producing 12-OPDA (12-oxophytodienoic acid) as a precursor of jasmonic acid by means of an efficient and innovative synthetic method. Both scientists conduct research at the Center for Biotechnology (CeBiTec) at Bielefeld University.

The new method adopts the principle from plant cells: it uses enzymes as plant catalysts in a form optimised for synthetic purposes. 'It is important that these enzymes are used in the right ratio,' says Jana Löwe. She is the lead author of the new study and a researcher in Gröger's working group. The best part of the new method is that if all the initial conditions are correct, it subsequently runs on its own.

'Like plants, we use easily accessible linolenic acid in combination with only three enzyme reactions,' explains Löwe. Linolenic acid can be extracted from rapeseed oil, for example. The first enzyme incorporates oxygen from the air into the linolenic acid. The second enzyme subsequently produces a highly unstable intermediate, which is then converted into 12-OPDA by the third enzyme.

'It sounds simple,' says Gröger. 'The difficulty so far, however, has been the sensitive, short-lived intermediate stage created by the second enzyme. If the third enzyme is not added immediately, the resulting products are unusable.'

Löwe solves the problem by using bacteria as producers of the enzymes for the second and final stage of the reaction--in combination with a commercial enzyme derived from soybeans for the first reaction stage. The bacteria (Escherichia coli) have been genetically modified to provide the two enzymes in the required quantities. 'As soon as the unstable intermediate is formed, the required enzyme is immediately available and ensures the production of 12-OPDA,' says Löwe.

The 12-OPDA can then be used directly in biological studies or converted into other substances needed for Dietz's experiments, for example. Löwe has also developed a method for this. 'This provides us with a library of descendants of 12-OPDA for plant physiological investigations,' says Dietz. 'With further reactions, the 12-OPDA could even be used to produce methyl dihydrojasmonate efficiently in the future,' says Gröger. 'This is a substance required as an ingredient in many well-known perfumes.'

A combination of genetic shuffling and evolutionary selection of near-identical genetic sequences among specific bat and pangolin coronaviruses may have led to the evolution of SARS-CoV-2 and its introduction into humans, a new study suggests. The results also showed that the virus' entire receptor binding motif (RBM), a component that plays a key role in viral entry into host cells, was introduced through recombination with pangolin coronaviruses. The study joins ongoing efforts to identify the source of the virus that causes COVID-19, which is critical for informing efforts to establish proper animal models, discover new drugs and vaccines, and ultimately prevent the rise of future zoonotic diseases. While the precise origin of SARS-CoV-2 remains a mystery, this study makes clear "that reducing or eliminating direct human contact with wild animals is critical to preventing new coronavirus zoonoses in the future," the authors say. Proximity of different species in a wet market setting, for example, may increase the potential for cross-species spillover infections, by enabling recombination between more distant coronaviruses and the emergence of mutations, the authors say. By analyzing 43 complete genome sequences from three strains of SARS-CoV-2-like coronaviruses from bats and pangolins, Xiaojun Li and colleagues delineated which strains were most and least similar to the novel coronavirus, with a special focus on genes related to the virus' spike protein complex, a critical component that facilitates viral entry into host cells. They found evidence of strong evolutionary selection around the RBM - part of the spike's amino acid sequence that directly contacts host cell receptors - among the bat, pangolin, and human coronaviruses they studied. Amino acid sequences from these viruses and SARS-CoV-2 were identical or nearly identical in the regions adjacent to the RBM, suggesting that common evolutionary mechanisms shaped these distinct viral strains. The scientists also demonstrated that SARS-CoV-2's entire RBM was introduced through recombination with coronaviruses from pangolins. Together, evolutionary selection and frequent recombination among coronaviruses from bats, pangolins, and humans may have allowed the closely related viruses to readily jump between species, the authors postulate, leading to the introduction of SARS-CoV-2 in humans.

DURHAM, N.C. -- A team of scientists studying the origin of SARS-CoV-2, the virus that has caused the COVID-19 pandemic, found that it was especially well-suited to jump from animals to humans by shapeshifting as it gained the ability to infect human cells.

Conducting a genetic analysis, researchers from Duke University, Los Alamos National Laboratory, the University of Texas at El Paso and New York University confirmed that the closest relative of the virus was a coronavirus that infects bats. But that virus's ability to infect humans was gained through exchanging a critical gene fragment from a coronavirus that infects a scaly mammal called a pangolin, which made it possible for the virus to infect humans.

The researchers report that this jump from species-to-species was the result of the virus's ability to bind to host cells through alterations in its genetic material. By analogy, it is as if the virus retooled the key that enables it to unlock a host cell's door -- in this case a human cell. In the case of SARS-CoV-2, the "key" is a spike protein found on the surface of the virus. Coronaviruses use this protein to attach to cells and infect them.

"Very much like the original SARS that jumped from bats to civets, or MERS that went from bats to dromedary camels, and then to humans, the progenitor of this pandemic coronavirus underwent evolutionary changes in its genetic material that enabled it to eventually infect humans," said Feng Gao, M.D., professor of medicine in the Division of Infectious Diseases at Duke University School of Medicine and corresponding author of the study publishing online May 29 in the journal Science Advances.

Gao and colleagues said tracing the virus's evolutionary pathway will help deter future pandemics arising from the virus and possibly guide vaccine research.

The researchers found that typical pangolin coronaviruses are too different from SARS-CoV-2 for them to have directly caused the human pandemic.

However, they do contain a receptor-binding site -- a part of the spike protein necessary to bind to the cell membrane -- that is important for human infection. This binding site makes it possible to affix to a cell surface protein that is abundant on human respiratory and intestinal epithelial cells, endothelial cell and kidney cells, among others.

While the viral ancestor in the bat is the most closely related coronavirus to SARS-CoV-2, its binding site is very different, and on its own cannot efficiently infect human cells.

SARS-CoV-2 appears to be a hybrid between bat and pangolin viruses to obtain the "key" necessary receptor-binding site for human infection.

"There are regions of the virus with a very high degree of similarity of amino acid sequences among divergent coronaviruses that infect humans, bats and pangolins, suggesting that these viruses are under similar host selection and may have made the ancestor of SARS-CoV-2 able to readily jump from these animals to humans," said lead co-author Xiaojun Li from Duke.

"People had already looked at the coronavirus sequences sampled from pangolins that we discuss in our paper, however, the scientific community was still divided on whether they played a role in the evolution of SARS-CoV-2," said study co-lead author Elena Giorgi, staff scientist at Los Alamos National Laboratory.

"In our study, we demonstrated that indeed SARS-CoV-2 has a rich evolutionary history that included a reshuffling of genetic material between bat and pangolin coronavirus before it acquired its ability to jump to humans," Giorgi said.

RIVERSIDE, Calif. -- How might the novel coronavirus be prevented from entering a host cell in an effort to thwart infection? A team of biomedical scientists has made a discovery that points to a solution.

The scientists, led by Maurizio Pellecchia in the School of Medicine at the University of California, Riverside, report in the journal Molecules that two proteases -- enzymes that break down proteins -- located on the surface of host cells and responsible for processing viral entry could be inhibited. Such protease inhibition would prevent SARS-CoV2, the coronavirus responsible for COVID-19, from invading the host cell.

The research is featured as the cover story of the journal (Volume 25, Issue 10).

Spike glycoprotein

The outer surface of coronaviruses contains a critical protein called spike glycoprotein, or S-glycoprotein. Responsible for giving the coronavirus its typical crown shape, the S-glycoprotein is essential for the entry of viral particles into host cells. Host cell proteases, however, must first process or cut this viral surface protein to allow the virus to enter the cells.

Pellecchia's lab and others have recognized that in addition to a previously identified protease called TMPRSS2, the new SARS-CoV2 coronavirus could also be processed by an additional human protease, called furin, for viral entry.

"The use of the host protease furin for processing is a common mechanism of cell entry by both viral fusion proteins and certain bacterial toxins," said Pellecchia, a professor of biomedical sciences, who led the research team. "SARS-CoV2 uses this mechanism also. The nature of the 'proteolytic cleavage' in its S-glycoprotein can determine whether this virus can be transmitted across species, for example from bats or camels to humans."

A fusion protein combines the attributes of more than one protein. Proteolytic cleavage refers to the process of breaking the peptide bonds between amino acids in a protein, which results in cutting the protein.

The coronavirus S-glycoprotein contains three cleavage sites that human host proteases process. The exact nature and sequence of these cleavage sites, and their respective processing proteases, can determine the level of pathogenicity and whether the virus can cross species.

Spotlight on inhibitors

Pellecchia explained that the anthrax toxin, similar to SARS-CoV2, requires processing by human furin to infect macrophages, a type of white blood cell. Using anthrax toxin as model system, his team found an inhibitor of both TMPRSS2 and furin in cellular and animal models can efficiently suppress cell entry by the toxin.

A clinical trial with COVID-19 patients recently began using the TMPRSS2 inhibitor camostat.

"We found, however, that camostat is a poor furin inhibitor," Pellecchia said. "Our current study, therefore, calls for the development of additional protease inhibitors or inhibitor-cocktails that can simultaneously target both TMPRSS2 and furin and suppress SARS-CoV2 from entering the host cell."

Pellecchia added that until now the presence of a furin cleavage site in SARS-CoV2 had been linked to increased pathogenicity. But genetic elimination of furin in cellular laboratory studies failed to stop viral entry, suggesting TMPRSS2 remains the most relevant protease.

Using peptide sequences from SARS-CoV2 S-glycoprotein, however, his team has now demonstrated the new mutations in this coronavirus strain resulted in efficient and increased processing of viral entry by furin and TMPRSS2.

"In other words, SARS-CoV2, unlike other less pathogenic strains, can more efficiently use both proteases, TMPRSS2 and furin, to start the invasion of host cells," Pellecchia said. "While TMPRSS2 is more abundant in the lungs, furin is expressed in other organs, perhaps explaining why SARS-CoV2 is capable of invading and damaging multiple organs."

Pellecchia's lab has already identified potent and effective preclinical inhibitors of furin and demonstrated these inhibitors could be developed as potential COVID-19 therapeutics, perhaps in combination with drugs such as camostat, the TMPRSS2 inhibitor.

Funding sought

"We are seeking additional funding to pursue the design and development of dual inhibitors that can simultaneously target both TMPRSS2 and furin," Pellecchia said. "The funding would allow us to explore new possible effective therapeutics against COVID-19 and support studies that could have far reaching applications to ward off possible future pandemics resulting from similar activating mutations in other viral strains."

Pellecchia, who holds the Daniel Hays Chair in Cancer Research at the UCR School of Medicine, was joined in the research by Elisa Barile, Carlo Baggio, and Luca Gambini of UCR; and Sergey A. Shiryaev and Alex Y. Strongin of the Sanford Burnham Prebys Medical Discovery Institute in La Jolla.

In complex surgery, is there a correlation between the volume of services provided per hospital and the quality of treatment results? This is the question addressed in eight commissions on minimum volumes that the Federal Joint Committee (G-BA) awarded to the Institute for Quality and Efficiency in Health Care (IQWiG). The IQWiG report is now available for the sixth intervention to be tested, complex oesophageal surgery. According to the findings, there is a positive correlation between the volume of services and the quality of treatment results in complex oesophageal surgery: In hospitals with larger case volumes, the survival probabilities for patients who underwent surgery are higher overall. In addition, complications occur less frequently there.

High-risk procedures performed as elective surgery

Oesophageal operations, such as the complete or partial removal of the oesophagus or the reconstruction of the oesophageal passage that is then necessary, are considered high-risk procedures that are usually performed as elective surgery. In most cases (2015: 83%), malignant neoplasms are the reason for the procedure. In 2018, the German Federal Statistical Office registered about 4700 of these complex oesophageal operations. About 9.5% of the patients who underwent surgery between 2010 and 2015 died in hospital in connection with the procedure.

At present, a minimum of ten procedures per hospital location and year applies in Germany for complex oesophageal surgery.

Positive correlation between volume of services and survival probabilities

The IQWiG project team identified 37 studies investigating the correlation between the volume of services and the quality of treatment results in complex oesophageal surgery - 30 of these studies contain usable data.

The analysis of the data showed that the survival probabilities for patients who underwent oesophageal surgery are higher overall in hospitals with larger case volumes. This can be inferred from the studies for the outcome "all-cause mortality" as well as for the outcomes "surgery-related mortality" and "in-hospital mortality". Furthermore, in hospitals with larger case volumes, treatment-related complications such as tearing or leakage of the reconstructed tissue (anastomosis insufficiency) occur less frequently.

In relation to the volume of services per surgeon, the available data show that with increasing routine for oesophageal surgery, fewer patients die in hospital and treatment-related complications occur less frequently.

There are no meaningful studies examining the effects of specific minimum case volumes introduced into the health care system for complex oesophageal surgery on the quality of treatment results.

Due to the devastating worldwide impact of COVID-19, the illness caused by the SARS-CoV-2 virus, there has been unprecedented efforts by clinicians and researchers from around the world to quickly develop safe and effective treatments and vaccines. Given that COVID-19 is a complex new disease with no existing vaccine or specific treatment, much effort is being made to investigate the repurposing of approved and available drugs, as well as those under development.

In Frontiers in Immunology, a team of researchers from the U.S. Food and Drug Administration review all of the COVID-19 clinical and research findings to date. They provide a breakdown of key immunological factors underlying the clinical stages of COVID-19 illness that could potentially be targeted by existing therapeutic drugs.

Dr. Montserrat Puig of the U.S. Food and Drug Administration, senior author of the review, stated that "there are multiple factors involved in determining if the patient's immune response will be insufficient or successful in combating the infection. Our review is an overview of these factors and how they can be considered to define the context in which medications currently used for other diseases, or development of novel agents, can be utilized to prevent, ameliorate or cure COVID-19."

We know that during the early stage of COVID-19 people can show no symptoms or mild symptoms, and for many the disease resolves.

For others it can be catastrophic. The illness can progress to a severe stage with manifestations including Acute Respiratory Distress Syndrome, accompanied by severe lung inflammation and damage. Patients with severe COVID-19 are often admitted to intensive care units and require life support with medical ventilation.

This review compiles and summarizes published up-to-date studies unraveling the factors leading to the cytokine storm and its consequences observed in COVID-19, including the immunological events underlying the severe manifestation of the disease.

The analysis is further supplemented with knowledge previously acquired from other coronaviruses including SARS-CoV and MERS-CoV.

The authors underscore key immunological events that might tip the balance from a protective to a hyperinflammatory response leading to life-threatening conditions. They outline a promising list of currently available drugs that are either under study or under consideration for use in COVID-19 based on their potential to influence these key immunological events.

These drugs include those that could inhibit SARS-CoV-2 entry into host cells, antivirals with the potential to block SARS-CoV-2 replication or factors that could boost the antiviral response, monoclonal antibodies targeting pro-inflammatory cytokines that drive the hyperinflammatory response and therapeutics that could improve the function of the lungs.

Puig states that "approaches to therapy in the early stage of the disease will differ from those in its severe late stage." Adding that "as the results of clinical trials become available, it may become increasingly clear that there is likely no single magic bullet to resolve the disease but a combination of several interventions that target different key factors of COVID-19 may well be required."

Puig cautions that "the research and data obtained from COVID-19 studies are rapidly evolving and continuously updated. Thus, as clearly stated in our review, the information provided is a 'lessons learned' to date and describes the knowledge available at the time of the publication of the review."

The description of the immunological profile of the clinical stages of COVID-19 provided in this review will enable more informed decisions about the type and timing of treatments to be evaluated in clinical trials.

Puig explains that "our hope is that the information contained in our review will help professionals in COVID-19 research develop new tools and agents to better treat those at high risk of severe COVID-19."

EL PASO, Texas - Active coping, denial, emotional support, humor and religion are among the coping strategies that help people with chronic conditions and disabilities deal with stress caused by the COVID-19 pandemic, according to a recently published study written by researchers at The University of Texas at El Paso.

Emre Umucu, Ph.D., assistant professor of rehabilitation counseling, and Beatrice Lee, an incoming rehabilitation counseling faculty member, examined the perceived stress levels and coping mechanisms related to COVID-19, and how coping affects well-being in people with self-reported chronic conditions and disabilities.

Umucu said their exploratory work has provided some preliminary information on how these individuals perceive COVID-19 and how the coping strategies they are using are related to their well-being.

Their findings were recently published in the Rehabilitation Psychology.

"Given that COVID-19 is a new and highly evolving stressor for everyone, especially for people with chronic conditions and disabilities, it is important to understand how individuals cope with it," said Umucu, director of UTEP's Veteran VVell-Being Lab (V3). "Measuring and quantifying COVID-19-related stress and coping strategies in individuals with chronic conditions and disabilities can help clinicians and researchers understand the potential negative effects of COVID-19 among people with chronic conditions and disabilities."

A new UC San Francisco study has pinpointed a specific pattern of brain waves that underlies the ability to let go of old, irrelevant learned associations to make way for new updates. The research is the first to directly show that a particular behavior can be dependent on the precise synchronization of high-frequency brain waves in different parts of the brain, and might open a path for developing interventions for certain psychiatric disorders, including schizophrenia.

Swapping old rules for new ones is something we do constantly. It happens when you get a new phone, switch cars or update the software on your laptop -- the first few times you try to turn on the headlights in a rental car, you might fire up the windshield wipers instead. But eventually, you get it.

Making such adjustments is critical for adapting as the world changes around us. But struggling to let go of old rules doesn't just sometimes make it difficult to complete day-to-day tasks. It might also contribute to certain forms of psychosis, like schizophrenia, by disrupting people's ability to reappraise and update distorted beliefs and delusions despite contradicting evidence and logic.

"Perseveration is a term we use to describe individuals sticking to something that's no longer appropriate," said Vikaas Sohal, MD, PhD, an associate professor of psychiatry and member of the UCSF Weill Institute for Neurosciences. "It's a problem in a lot of different neuropsychiatric conditions."

In the new study, published in Nature Neuroscience on May 25, 2020, Sohal and colleagues provide a glimpse of what might be happening in the brain when a breakdown in rule-shifting leads to perseveration. They found that the precise coordination of a specific kind of brain waves, called gamma waves, was key to learning to let go of an old rule and, instead, pay attention to cues that were previously irrelevant.

The work helps to clarify a long-standing debate about the significance of brain waves. For decades, scientists have been able to measure these coordinated, rhythmic neural activity patterns, which can take varying forms. For just as long, the significance of brain waves has been hotly contested. Some researchers have argued that brain waves have important functions, and that some cognitive disorders might be linked to certain brain waves going awry. Gamma waves, for example, which arise from neural activity with a regular rhythm between 30 and 120 cycles per second, have been hypothesized to be involved in attention and conscious thought. But other scientists disagree, claiming that brain waves are an irrelevant byproduct of neural activity.

Trying to figure this question out has been something like what an alien might experience if they just landed outside a football stadium, said Sohal. "Imagine you're outside the stadium trying to figure out what's going on just by the sound," he said. "Mostly, you're just hearing random noise. But every once in a while, you hear that noise synchronize in a cheer or some chants, and you wonder, 'Hey -- does that mean something?'"

Instead of the noise of sports fans pouring out of a stadium, Sohal's team recorded the activity of neurons in different parts of the brain. Many past brain wave studies have relied on the faint electrical signals detectable in electroencephalogram (EEG) recordings made from the surface of the skull, but in the new study, the researchers put probes inside the brain to get a more precise look at the function of these oscillations. The researchers also used genetic engineering to pin a fluorescent activity indicator to neurons of a type that are ideal for capturing the fast-paced activity of gamma waves in areas of the brain important for cognition. Light flashes from these fluorescent tags indicated when the voltage of these neurons changed, allowing the team to visually track communication between the cells.

To see if gamma waves were linked to perseverative behaviors, the researchers designed a "mouse version" of the Wisconsin Card Sorting Task, a standard assessment tool that measures how human participants learn new rules on the fly, which tends to be challenging for people with schizophrenia. In the mouse task, researchers hid a reward under fine sand or coarse cat litter in one of two bowls, and gave each a distinctive smell, and left mice to figure out which odor marked the prize. Once the mice learned the task, researchers switched the rule on them by making the odor cue irrelevant, now cuing the reward only by whether the mice had to dig through sand or cat litter to reach it.

As mice learned to make the switch, the team observed an increase in gamma waves that were synchronized across both sides of the brain. When researchers knocked those waves out of sync by using light stimulation in mice with neurons genetically engineered to respond to it, the mice suddenly became very bad at this kind of learning. Perseverative errors shot up and the mice needed as many as twice the attempts to figure out the new cue for the reward.

"It seems like gamma synchrony is important for overcoming rule perseveration," said Sohal. "It fits with an emerging view that maybe communication between brain regions is impaired in schizophrenia and related disorders, which might give rise to certain symptoms."

Curiously, disrupting gamma synchrony did not throw off the mice's ability to learn new associations or flip a rule they had previously learned. When the scent of garlic stopped signaling a reward, for example, they were still able to reverse course and learn that the odor of coriander -- which previously marked a cold trail -- now coded for buried treasure. It was only when they had to switch from one kind of sensory cue to another (e.g., from scent to touch cues) that gamma synchrony really came into play, possibly because learning to drop that kind of perseveration may actually be much harder.

"It tells us there's something special about the type of learning that requires you to pay attention to something you were ignoring before," Sohal said.

Previous research, including in Sohal's lab, has suggested that deficits in gamma synchrony and the neurons that give rise to it might contribute to cognitive issues at the core of schizophrenia and Alzheimer's disease. A deeper understanding of normal gamma wave patterns and what happens when they are disrupted could eventually lead to help for patients who need it, said Kathleen Cho, PhD, a postdoctoral researcher in the Sohal lab and lead author on the paper.

"Treatments for these kinds of cognitive problems are underdeveloped, in large part because the relevant mechanisms are unclear," she added. "This study moves us towards a deeper understanding of how we might begin to treat this kind of neurological disruption."

Bee populations are experiencing a global decline as a result of climate change, parasites and pathogens, and pesticide exposure, as well as a lack of foraging resources due to human land use. The good news is that gardens and parks can be valuable sites for providing foraging resources to these urban pollinator communities because of their low pesticide use, complex landscapes, and protected environments.

Many home gardeners and landscapers are seeking ways to make their own green spaces more friendly to pollinators. Despite the public demand for information on how to create pollinator landscapes, little research has been conducted on which plants are best for pollinators, and the information that does exist is not usually regionally specific and may be inconsistent. More recently, researchers have begun investigating the potential of human-managed green spaces to support pollinator populations.

In "More Than Meets the Eye? The Role of Annual Ornamental Plants in Supporting Pollinators," Emily Erickson presents the findings of a 2-year field study and describes pollinator visitation to a variety of popular annual ornamental plants. She also provides basic recommendations for creating a backyard pollinator garden.