1. Researchers develop model to predict likelihood of testing positive for COVID-19, disease outcomes
Prediction model reveals new characteristics that may affect risk
Date:June 15, 2020
Source: Cleveland Clinic
Summary:A new risk prediction model for healthcare providers can forecast an individual patient's likelihood of testing positive for COVID-19 as well as their outcomes from the disease.Share:
FULL STORY Cleveland Clinic researchers have developed the world's first risk prediction model for healthcare providers to forecast an individual patient's likelihood of testing positive for COVID-19 as well as their outcomes from the disease.
According a new study published in CHEST, the risk prediction model (called a nomogram) shows the relevance of age, race, gender, socioeconomic status, vaccination history and current medications in COVID-19 risk. The risk calculator is a new tool for healthcare providers to aid them in predicting patient risk and tailoring decision-making about care. It provides a more scientific approach to testing which is important for the healthcare community which has faced increased demand for testing and limited resources.
"The ability to accurately predict whether or not a patient is likely to test positive for COVID-19, as well as potential outcomes including disease severity and hospitalization, will be paramount in effectively managing our resources and triaging care," said Lara Jehi, M.D., Cleveland Clinic's Chief Research Information Officer and corresponding author on the study. "As we continue to battle this pandemic and prepare for a potential second wave, understanding a person's risk is the first step in potential care and treatment planning." The nomogram, which has been deployed as a freely available online risk calculator at https://riskcalc.org/COVID19/, was developed using data from nearly 12,000 patients enrolled in Cleveland Clinic's COVID-19 Registry, which includes all individuals tested at Cleveland Clinic for the disease, not just those that test positive.
Data scientists, including co-author on the study Michael Kattan, Ph.D., Chair of Lerner Research Institute's Department of Quantitative Health Sciences, used statistical algorithms to transform data from registry patients' electronic medical records into the first-of-its-kind nomogram.
This study revealed several novel insights into disease risk, including:
Patients who have received the pneumococcal polysaccharide vaccine (PPSV23) and flu vaccine are less likely to test positive for COVID-19 than those who have not received the vaccinations.
Patients actively taking melatonin (over-the-counter sleep aid), carvedilol (high blood pressure and heart failure treatment) or paroxetine (anti-depressant) are less likely to test positive than patients not taking the drugs.
Patients of low socioeconomic status (as measured in this study by zip code) are more likely to test positive than patients of greater economic means.
Patients of Asian descent are less likely than Caucasian patients to test positive.
"Our findings corroborated several risk factors already reported in existing literature -- including that being male and of advancing age both increase the likelihood of testing positive for COVID-19 -- but we also put forth some new associations," said Dr. Jehi. "Further validation and research are needed into these initial insights but these correlations are extremely intriguing."
In a previous network medicine study led by Lerner Research Institute scientists, 16 drugs (including melatonin, carvedilol and paroxetine) and three drug combinations were identified as candidates for repurposing as potential COVID-19 treatments. While these findings suggest an association between taking these medications and reduced risk of testing positive for COVID-19, additional studies are needed to assess how these drugs may affect disease progression.
"The data suggest some interesting correlations but do not confer cause and effect," said Kattan. "For example, our data do not prove that melatonin reduces your risk of testing positive for COVID-19. There may be something else about patients who take melatonin that is indeed responsible for their apparent reduced risk, and we don't know what that is. Consumers should not change anything about their behavior based on our findings." The nomogram, developed using data from patients tested at Cleveland Clinic for COVID-19 before April 2, 2020, showed good performance and reliability when used in a different geographic region (Florida) and over time (patients tested after April 2, 2020). This suggests that the patterns and predictors identified in the model are consistent across regions and communities and can be potentially adopted for clinical practice in healthcare systems across the country.
"This nomogram will bring precision medicine to the COVID-19 pandemic, helping to enable researchers and physicians to predict an individual's risk of testing positive," said Kattan. "Additionally, while testing solutions continue to be needed, it is so important to make sure we are responsibly and optimally dispatching our resources ¬- including clinical personnel, personal protective equipment and hospital beds. Our risk prediction model stands to greatly assist hospital systems in this planning."
The COVID-19 research registry, which now has data from more than 23,000 patients, is being used to inform a variety of studies. Researchers from across the Cleveland Clinic enterprise are using the dynamic registry data in more than 140 COVID-19-related research projects in areas such as cancer, pediatrics and intensive care. Story Source: Materials provided by Cleveland Clinic. Note: Content may be edited for style and length. Journal Reference:
Lara Jehi, Xinge Ji, Alex Milinovich, Serpil Erzurum, Brian Rubin, Steve Gordon, James Young, Michael W. Kattan. Individualizing risk prediction for positive COVID-19 testing: results from 11,672 patients.. Chest, 2020; DOI: 10.1016/j.chest.2020.05.580
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Cleveland Clinic. "Researchers develop model to predict likelihood of testing positive for COVID-19, disease outcomes: Prediction model reveals new characteristics that may affect risk." ScienceDaily. ScienceDaily, 15 June 2020. <www.sciencedaily.com/releases/2020/06/200615140852.htm>.
2. Molecules that reduce 'bad' gut bacteria reverse narrowing of arteries in animal study
Promoting a healthy gut microbiome may be a powerful strategy for lowering cholesterol and other heart attack risk factors
Date:June 15, 2020
Source: Scripps Research Institute
Summary: Scientists have developed molecules that can remodel the bacterial population of intestines to a healthier state. They also have shown -- through experiments in mice -- that this approach reduces cholesterol levels and strongly inhibits the thickened-artery condition known as atherosclerosis.Share:
FULL STORY Scientists at Scripps Research have developed molecules that can remodel the bacterial population of intestines to a healthier state and they have shown -- through experiments in mice -- that this reduces cholesterol levels and strongly inhibits the thickened-artery condition known as atherosclerosis.
The scientists, who report their findings in Nature Biotechnology, created a set of molecules called peptides that can slow the growth of less-desirable species of gut bacteria. In mice that develop high cholesterol and atherosclerosis from a high-fat diet, the peptides beneficially shifted the balance of species in the gut microbiome, which refers to the trillions of bacteria that live inside the digestive system. This shift reduced cholesterol levels and dramatically slowed the buildup of fatty deposits in arteries -- symptoms that are the hallmarks of atherosclerosis.
Atherosclerosis is the condition that leads to heart attacks and strokes, the two leading causes of death among humans. "It was surprising to us that simply remodeling the gut microbiome can have such an extensive effect," says study co-senior author Reza Ghadiri, PhD, professor in the Department of Chemistry at Scripps Research.
Gut microbes shape our health The gut microbiome, which includes hundreds of bacterial species, evolved long ago as part of a fundamental symbiosis: The bacteria get a place to live and plenty to eat, and in return they assist their animal hosts, largely by helping them digest food.
In the past two decades, these symbiotic bacteria have become a focus of intense study around the world, as scientists have discovered that the microbes -- in part by their production of molecules called metabolites -- not only help digest food, but play a role in metabolism, immunity and other important functions.
Scientists also have learned that this symbiosis can have a downside for the bacteria's human hosts. When people overuse antibiotics or consume "Western" diets rich in carbs, fats and sugar, the gut microbiome can be altered in ways that promote disease. Indeed, it now appears that the increased risks of obesity, diabetes, hypertension and atherosclerosis that are conferred by the Western diet are due in part to adverse changes in the microbiome.
That recognition has led researchers to look for ways to remodel the microbiome, with the goal of rolling back those adverse changes to restore good health. Ghadiri and his team have been working on a method that involves delivering small molecules to kill or slow the growth of bad gut bacteria without affecting good gut bacteria.
"Our approach, using small molecules called cyclic peptides, is inspired by nature," says co-senior author Luke Leman, PhD, an assistant professor in the Department of Chemistry at Scripps Research. "Our cells naturally use a diverse collection of molecules including antimicrobial peptides to regulate our gut microbe populations."
A screening system to identify microbiome remodelers Prior to the experiments, the team already had a small collection of cyclic peptides that had been made using chemistry techniques. For the study, they set up a screening system to determine if any of those peptides could beneficially remodel the mammalian gut microbiome by suppressing undesirable gut bacterial species.
Using mice that are genetically susceptible to high cholesterol, they fed the animals a Western-type diet that swiftly and reliably produces high blood cholesterol and atherosclerosis, as well as adverse shifts in the gut microbiome. The researchers then sampled the animals' gut contents and applied a different cyclic peptide to each sample. A day later, they sequenced the bacterial DNA in the samples to determine which peptides had shifted the gut bacteriome in the desired direction.
The scientists soon identified two peptides that had significantly slowed the growth of undesirable gut bacteria, shifting the species balance closer to what is seen in mice that are fed a healthier diet. Using these peptides to treat atherosclerosis-prone mice that were eating a high-fat Western diet, they found striking reductions in the animals' blood levels of cholesterol compared to untreated mice -- about 36 percent after two weeks of treatment. They also found that after 10 weeks, the atherosclerotic plaques in the arteries of the treated mice were about 40 percent reduced in area, compared to those in untreated mice.
"These were really remarkable effects," Ghadiri says. The cyclic peptides used in the study apparently interact with the outer membranes of certain bacterial cells in ways that slow or stop the cells' growth. Ghadiri and his team have been researching these peptides for years and have put together a set of dozens that show no toxicity to the cells of mammals. The molecules also transit through the gut without entering the bloodstream. In the study, the peptides were delivered to the mice in drinking water and were not associated with any adverse side effects. Cheered by the proof-of-principle demonstration, the researchers are now testing their peptides in mice that model diabetes, another common condition that has been linked to an unhealthy microbiome. Story Source: Materials provided by Scripps Research Institute. Note: Content may be edited for style and length. Journal Reference:
Poshen B. Chen, Audrey S. Black, Adam L. Sobel, Yannan Zhao, Purba Mukherjee, Bhuvan Molparia, Nina E. Moore, German R. Aleman Muench, Jiejun Wu, Weixuan Chen, Antonio F. M. Pinto, Bruce E. Maryanoff, Alan Saghatelian, Pejman Soroosh, Ali Torkamani, Luke J. Leman, M. Reza Ghadiri. Directed remodeling of the mouse gut microbiome inhibits the development of atherosclerosis. Nature Biotechnology, 2020; DOI: 10.1038/s41587-020-0549-5
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Scripps Research Institute. "Molecules that reduce 'bad' gut bacteria reverse narrowing of arteries in animal study: Promoting a healthy gut microbiome may be a powerful strategy for lowering cholesterol and other heart attack risk factors." ScienceDaily. ScienceDaily, 15 June 2020. <www.sciencedaily.com/releases/2020/06/200615140921.htm>.
3. Super-potent human antibodies protect against COVID-19 in animal tests
Scientists isolate powerful coronavirus-neutralizing antibodies from COVID-19 patients and successfully test in animals
Date:June 15, 2020
Source: Scripps Research Institute
Summary: Researchers have discovered antibodies in the blood of recovered COVID-19 patients that provide powerful protection against SARS-CoV-2, the coronavirus that causes the disease, when tested in animals and human cell cultures.Share:
FULL STORY Coronavirus illustration (stock image). Credit: © Mauro Rodrigues / stock.adobe.com A team led by Scripps Research has discovered antibodies in the blood of recovered COVID-19 patients that provide powerful protection against SARS-CoV-2, the coronavirus that causes the disease, when tested in animals and human cell cultures.
The research, published today in Science, offers a paradigm of swift reaction to an emergent and deadly viral pandemic, and sets the stage for clinical trials and additional tests of the antibodies, which are now being produced as potential treatments and preventives for COVID-19.
"The discovery of these very potent antibodies represents an extremely rapid response to a totally new pathogen," says study co-senior author Dennis Burton, PhD, the James and Jessie Minor Chair in Immunology in the Department of Immunology & Microbiology at Scripps Research.
In principle, injections of such antibodies could be given to patients in the early stage of COVID-19 to reduce the level of virus and protect against severe disease. The antibodies also may be used to provide temporary, vaccine-like protection against SARS-CoV-2 infection for healthcare workers, elderly people and others who respond poorly to traditional vaccines or are suspected of a recent exposure to the coronavirus. The project was led by groups at Scripps Research; IAVI, a nonprofit scientific research organization dedicated to addressing urgent, unmet global health challenges; and University of California San Diego School of Medicine.
"It has been a tremendous collaborative effort, and we're now focused on making large quantities of these promising antibodies for clinical trials," says co-lead author Thomas Rogers, MD, PhD, an adjunct assistant professor in the Department of Immunology & Microbiology at Scripps Research, and assistant professor of Medicine at UC San Diego.
An approach that's worked for other deadly viruses Developing a treatment or vaccine for severe COVID-19 is currently the world's top public health priority. Globally, almost 8 million people have tested positive for SARS-CoV-2 infection, and more than 400,000 have died of severe COVID-19. The daily toll of new infections is still rising.
One approach to new viral threats is to identify, in the blood of recovering patients, antibodies that neutralize the virus's ability to infect cells.
These antibodies can then be mass-produced, using biotech methods, as a treatment that blocks severe disease and as a vaccine-like preventive that circulates in the blood for several weeks to protect against infection. This approach already has been demonstrated successfully against Ebola virus and the pneumonia-causing respiratory syncytial virus, commonly known as RSV.
Potent patient antibodies block the virus For the new project, Rogers and his UC San Diego colleagues took blood samples from patients who had recovered from mild-to-severe COVID-19. In parallel, scientists at Scripps Research and IAVI developed test cells that express ACE2, the receptor that SARS-CoV-2 uses to get into human cells. In a set of initial experiments, the team tested whether antibody-containing blood from the patients could bind to the virus and strongly block it from infecting the test cells.
The scientists were able to isolate more than 1,000 distinct antibody-producing immune cells, called B cells, each of which produced a distinct anti-SARS-CoV-2 antibody. The team obtained the antibody gene sequences from these B cells so that they could produce the antibodies in the laboratory. By screening these antibodies individually, the team identified several that, even in tiny quantities, could block the virus in test cells, and one that could also protect hamsters against heavy viral exposure.
All of this work -- including the development of the cell and animal infection models, and studies to discover where the antibodies of interest bind the virus -- was completed in less than seven weeks.
"We leveraged our institution's decades of expertise in antibody isolation and quickly pivoted our focus to SARS-CoV-2 to identify these highly potent antibodies," says study co-author Elise Landais, PhD, an IAVI principal scientist.
If further safety tests in animals and clinical trials in people go well, then conceivably the antibodies could be used in clinical settings as early as next January, the researchers say. "We intend to make them available to those who need them most, including people in low- and middle-income countries," Landais says.
In the course of their attempts to isolate anti-SARS-CoV-2 antibodies from the COVID-19 patients, the researchers found one that can also neutralize SARS-CoV, the related coronavirus that caused the 2002-2004 outbreak of severe acute respiratory syndrome (SARS) in Asia.
"That discovery gives us hope that we will eventually find broadly neutralizing antibodies that provide at least partial protection against all or most SARS coronaviruses, which should be useful if another one jumps to humans," Burton says.
"Rapid isolation of potent SARS-CoV-2 neutralizing antibodies and protection in a small animal model" was co-authored by 30 scientists including lead authors Thomas Rogers, Fangzhu Zhao, Deli Huang, and Nathan Beutler, all of Scripps Research. The corresponding authors were Devin Sok and Joseph Jardine of IAVI, and Dennis Burton of Scripps Research.
Funding was provided by the National Institutes of Health (UM1 AI44462), the IAVI Neutralizing Antibody Center, the Bill and Melinda Gates Foundation (OPP 1170236, OPP 1206647, OPP1196345/ INV-008813), the John and Mary Tu Foundation, and the Pendleton Foundation. Story Source: Materials provided by Scripps Research Institute. Note: Content may be edited for style and length. Journal Reference:
Thomas F. Rogers, Fangzhu Zhao, Deli Huang, Nathan Beutler, Alison Burns, Wan-Ting He, Oliver Limbo, Chloe Smith, Ge Song, Jordan Woehl, Linlin Yang, Robert K. Abbott, Sean Callaghan, Elijah Garcia, Jonathan Hurtado, Mara Parren, Linghang Peng, Sydney Ramirez, James Ricketts, Michael J. Ricciardi, Stephen A. Rawlings, Nicholas C. Wu, Meng Yuan, Davey M. Smith, David Nemazee, John R. Teijaro, James E. Voss, Ian A. Wilson, Raiees Andrabi, Bryan Briney, Elise Landais, Devin Sok, Joseph G. Jardine, Dennis R. Burton. Isolation of potent SARS-CoV-2 neutralizing antibodies and protection from disease in a small animal model. Science, June 15, 2020; DOI: 10.1126/science.abc7520