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Differences in immunity and blood vessels likely protect children from severe COVID-19

Credit: Thiago Cerqueira Differences in the immune systems and better blood vessel health were among the factors protecting children from

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Differences in the immune systems and better blood vessel health were among the factors protecting children from severe COVID-19, according to a new review.

A huge body of global COVID-19 literature was reviewed by experts at the Murdoch Children’s Research Institute (MCRI), the University of Melbourne and the University of Fribourg and published in the Archives of Disease in Childhood to unravel the reasons for age-related differences in COVID-19 severity and symptoms.

MCRI and University of Melbourne Professor Nigel Curtis said that while a number of hypotheses provided potential explanations as to why adults were at higher risk and children protected from severe disease and death from COVID-19, most do not explain why COVID-19 severity rises steeply after the age of 60-70 years.

Professor Curtis said in stark contrast to other respiratory viruses, severe disease and death due to COVID-19 was relatively rare in children.

“Most children with COVID-19 have no or only mild symptoms, most commonly fever, cough, sore throat and changes in sense of smell or taste,” he said. “Even children with the usual risk factors for severe infections, such as immunosuppression, were not at high risk of severe COVID-19 disease.”

Professor Curtis said damage to the thin layer of endothelial cells lining various organs, especially the blood vessels, heart, and lymphatic vessels, increased with age and there was an association between conditions that affect these cells and severe COVID-19.

“We know pre-existing blood vessel damage plays an important role in COVID-19 severity and can lead to blood clots, causing strokes and heart attacks. COVID-19 can infect these endothelial cells and cause blood vessel inflammation,” he said.

“The endothelium in children has experienced far less damage compared with adults and their clotting system is also different, which makes children less prone to abnormal blood clotting.”

Professor Curtis said diseases associated with chronic inflammation that develop with advanced age including diabetes and obesity were also linked with severe COVID-19.

He said more recent immunisation with live vaccines, such as the MMR vaccine against measles, mumps, and rubella, that could boost the immune system might play a role in protecting children.

Dr Petra Zimmermann from the University of Fribourg said there were also other important differences in the immune system between children and adults.

“Children have a stronger innate immune response, which is the first-line defence against COVID-19,” she said.

“Another important factor is ‘trained immunity’ which primes innate immune cells after mild infections and vaccinations, leading to a type of ‘innate immune memory’.

“Children infected with COVID-19 often have co-infections with other viruses. Recurrent viral infections could lead to improved trained immunity, making kids more effective at clearing COVID-19.”

Dr Zimmermann said different levels of microbiota (bacteria and other germs) in the throat, noise, lung and stomach, also influenced susceptibility to COVID-19.

“The microbiota plays an important role in the regulation of immunity, inflammation and in the defence against illnesses,” she said. “Children are more likely to have viruses and bacteria, especially in the nose, where these bugs might limit the growth of COVID-19.”

Dr Zimmermann said the vitamin D level, with its anti-inflammatory properties, was also generally higher in children.

“The overlap between risk factors for severe COVID-19 and vitamin D deficiency, including obesity, chronic kidney disease and being of black or Asian origin, suggests that vitamin D supplementation may play a role in helping prevent or treat COVID-19,” she said.

“In many countries, vitamin D is routinely supplemented in infants younger than one year of age and in some countries even up to the age of three years.”

Professor Curtis said understanding the underlying age-related differences in the severity of COVID-19 would provide important insights and opportunities for prevention and treatment of SARS-CoV-2 infections.

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MCRI COVID-19 ongoing research project highlights:

  • BRACE trial testing the BCG vaccine to see if it trains the ‘innate’ immune system of frontline healthcare workers to reduce the severity of COVID-19. Australian recruitment has been completed, the team is now recruiting in the UK, Netherlands, Spain and Brazil.
  • COVID Immune study investigating COVID-19 effects on children’s immune systems. Studying whether some children are more vulnerable to COVID-19 due to differences in their immune system and how long immunity lasts.
  • Age-specific blood clotting study investigating the biological factors underlying viral interaction with the clotting system and the differences between adults and children. Study could help identify drug targets that alleviate the progression of disease in adults versus children.
  • Multiple studies looking at differences in children’s and their parents’ immune systems when a family member is infected with COVID-19. The underlying differences between children’s and adults’ immune responses to the virus are yet to be determined.

For more projects visit http://www.mcri.edu.au/covid-19/research

Publication: Petra Zimmermann and Nigel Curtis. ‘Why is COVID-19 less severe in children? A review of the proposed mechanisms underlying the age-related difference in severity of SARS-CoV-2 infections,’ Archives of Disease in Childhood. DOI: 10.1136/archdischild-2020-320338

Available for interview:

Professor Nigel Curtis, MCRI Group Leader Infectious Diseases

Dr Petra Zimmermann, University of Fribourg, Switzerland

Professor Curtis said in stark contrast to other respiratory viruses, severe disease and death due to COVID-19 was relatively rare in children.

Source: https://bioengineer.org/differences-in-immunity-and-blood-vessels-likely-protect-children-from-severe-covid-19/

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Reduced microbial stability linked to soil carbon loss in active layer under alpine permafrost degra

Credit: NIEER Chinese researchers have recently discovered links between reduction in microbial stability and soil carbon loss in the active

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Chinese researchers have recently discovered links between reduction in microbial stability and soil carbon loss in the active layer of degraded alpine permafrost on the Qinghai-Tibet Plateau (QTP).

The researchers, headed by Prof. CHEN Shengyun from the Northwest Institute of Eco-Environment and Resources (NIEER) of the Chinese Academy of Sciences (CAS), and XUE Kai from University of Chinese Academy of Sciences, conducted a combined in-depth analysis of soil microbial communities and their co-occurrence networks in the active permafrost layer along an extensive gradient of permafrost degradation.

The QTP encompasses the largest extent of high-altitude mountain permafrost in the world. This permafrost is different than high-latitude permafrost and stores massive soil carbon. An often ignored characteristic of permafrost is that the carbon pool in the active layer soil is more active and directly affected by climate change, compared to deeper layers.

Triggered by climate warming, permafrost degradation may decrease soil carbon stability and induce massive carbon loss, thus leading to positive carbon-climate feedback. However, microbial-mediated mechanisms for carbon loss from the active layer soil in degraded permafrost still remain unclear.

In this study, the researchers found that alpine permafrost degradation reduced the stability of active layer microbial communities as evidenced by increased sensitivity of microbial composition to environmental change, promoted destabilizing network properties and reduced resistance to node or edge attacking of the microbial network.

They discovered that soil organic carbon loss in severely degraded permafrost is associated with increased microbial dissimilarity, thereby potentially contributing to a positive carbon feedback in alpine permafrost on the QTP.

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The results were published in PNAS in an article entitled “Reduced microbial stability in the active layer is associated with carbon loss under alpine permafrost degradation”.

This research was financially supported by the National Natural Science Foundation of China, the Strategic Priority Research Program (A) of CAS and the Second Tibetan Plateau Scientific Expedition and Research Program.

Triggered by climate warming, permafrost degradation may decrease soil carbon stability and induce massive carbon loss, thus leading to positive carbon-climate feedback. However, microbial-mediated mechanisms for carbon loss from the active layer soil in degraded permafrost still remain unclear.

Source: https://bioengineer.org/reduced-microbial-stability-linked-to-soil-carbon-loss-in-active-layer-under-alpine-permafrost-degra/

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SNMMI Image of the Year: PET imaging measures cognitive impairment in COVID-19 patients

Credit: G Blazhenets et al., Department of Nuclear Medicine, Medical Center – University of Freiburg, Faculty of Medicine, University of

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Credit: G Blazhenets et al., Department of Nuclear Medicine, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg.

Reston, VA–The effects of COVID-19 on the brain can be accurately measured with positron emission tomography (PET), according to research presented at the Society of Nuclear Medicine and Molecular Imaging (SNMMI) 2021 Annual Meeting. In the study, newly diagnosed COVID-19 patients, who required inpatient treatment and underwent PET brain scans, were found to have deficits in neuronal function and accompanying cognitive impairment, and in some, this impairment continued six months after their diagnosis. The detailed depiction of areas of cognitive impairment, neurological symptoms and comparison of impairment over a six-month time frame has been selected as SNMMI’s 2021 Image of the Year.

Each year, SNMMI chooses an image that best exemplifies the most promising advances in the field of nuclear medicine and molecular imaging. The state-of-the-art technologies captured in these images demonstrate the capacity to improve patient care by detecting disease, aiding diagnosis, improving clinical confidence, and providing a means of selecting appropriate treatments. This year, the SNMMI Henry N. Wagner, Jr., Image of the Year was chosen from more than 1,280 abstracts submitted to the meeting and voted on by reviewers and the society leadership.

“As the SARS-CoV-2 pandemic proceeds, it has become increasingly clear that neurocognitive long-term consequences occur not only in severe COVID-19 cases, but in mild and moderate cases as well. Neurocognitive deficits like impaired memory, disturbed concentration and cognitive problems may persist well beyond the acute phase of the disease,” said Ganna Blazhenets, PhD, a post-doctoral researcher in Medical Imaging at the University Medical Center Freiburg, in Freiburg, Germany.

To study cognitive impairment associated with COVID-19, researchers carried out a prospective study on recently diagnosed COVID-19 patients who required inpatient treatment for non-neurological complaints. A cognitive assessment was performed, followed by imaging with 18F-FDG PET if at least two new neurological symptoms were present. By comparing COVID-19 patients to controls, the Freiburg group established a COVID-19-related covariance pattern of brain metabolism with most prominent decreases in cortical regions. Across patients, the expression of this pattern showed a very high correlation with the patients’ cognitive performance.

Follow-up PET imaging was performed six months after the initial COVID-19 diagnosis. Imaging results showed a significant improvement in the neurocognitive deficits in most patients, accompanied by an almost complete normalization of the brain metabolism.

“We can clearly state that a significant recovery of regional neuronal function and cognition occurs for most COVID-19 patients based on the results of this study. However, it is important to recognize the evidence of longer-lasting deficits in neuronal function and accompanying cognitive deficits is still measurable in some patients six months after manifestation of disease,” noted Blazhenets. “As a result, post-COVID-19 patients with persistent cognitive complaints should be presented to a neurologist and possibly allocated to cognitive rehabilitation programs.”

“18F-FDG PET is an established biomarker of neuronal function and neuronal injury,” stated SNMMI’s Scientific Program Committee chair, Umar Mahmood, MD, PhD. “As shown the Image of the Year, it can be applied to unravel neuronal correlates of the cognitive decline in patients after COVID-19. Since 18F-FDG PET is widely available, it may therefore aid in the diagnostic work-up and follow-up in patients with persistent cognitive impairment after COVID-19.”

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Abstract 41. “Altered regional cerebral function and its association with cognitive impairment in COVID 19: A prospective FDG PET study.” Ganna Blazhenets, Johannes Thurow, Lars Frings and Philipp Meyer, Department of Nuclear Medicine, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Nils Schroeter, Tobias Bormann, Cornelius Weiller, Andrea Dressing and Jonas Hosp; Department of Neurology and Clinical Neuroscience, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; and Dirk Wagner, Department of Internal Medicine, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

All 2021 SNMMI Annual Meeting abstracts can be found online at https://jnm.snmjournals.org/content/62/supplement_1.

About the Society of Nuclear Medicine and Molecular Imaging

The Society of Nuclear Medicine and Molecular Imaging (SNMMI) is an international scientific and medical organization dedicated to advancing nuclear medicine and molecular imaging, vital elements of precision medicine that allow diagnosis and treatment to be tailored to individual patients in order to achieve the best possible outcomes.

SNMMI’s members set the standard for molecular imaging and nuclear medicine practice by creating guidelines, sharing information through journals and meetings and leading advocacy on key issues that affect molecular imaging and therapy research and practice. For more information, visit http://www.snmmi.org.

“As the SARS-CoV-2 pandemic proceeds, it has become increasingly clear that neurocognitive long-term consequences occur not only in severe COVID-19 cases, but in mild and moderate cases as well. Neurocognitive deficits like impaired memory, disturbed concentration and cognitive problems may persist well beyond the acute phase of the disease,” said Ganna Blazhenets, PhD, a post-doctoral researcher in Medical Imaging at the University Medical Center Freiburg, in Freiburg, Germany.

Source: https://bioengineer.org/snmmi-image-of-the-year-pet-imaging-measures-cognitive-impairment-in-covid-19-patients/

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Scientists demonstrate promising new approach for treating cystic fibrosis

Scientists led by UNC School of Medicine researchers Silvia Kreda, Ph.D., and Rudolph Juliano, Ph.D., created an improved oligonucleotide therapy

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Scientists led by UNC School of Medicine researchers Silvia Kreda, Ph.D., and Rudolph Juliano, Ph.D., created an improved oligonucleotide therapy strategy with the potential for treating other pulmonary diseases, such as COPD and asthma

CHAPEL HILL, NC – UNC School of Medicine scientists led a collaboration of researchers to demonstrate a potentially powerful new strategy for treating cystic fibrosis (CF) and potentially a wide range of other diseases. It involves small, nucleic acid molecules called oligonucleotides that can correct some of the gene defects that underlie CF but are not addressed by existing modulator therapies. The researchers used a new delivery method that overcomes traditional obstacles of getting oligonucleotides into lung cells.

As the scientists reported in the journal Nucleic Acids Research, they demonstrated the striking effectiveness of their approach in cells derived from a CF patient and in mice.

“With our oligonucleotide delivery platform, we were able to restore the activity of the protein that does not work normally in CF, and we saw a prolonged effect with just one modest dose, so we’re really excited about the potential of this strategy,” said study senior author Silvia Kreda, PhD, an associate professor in the UNC Department of Medicine and the UNC Department Biochemistry & Biophysics, and a member of the Marsico Lung Institute at the UNC School of Medicine.

Kreda and her lab collaborated on the study with a team headed by Rudolph Juliano, PhD, Boshamer Distinguished Professor Emeritus in the UNC Department of Pharmacology, and co-founder and Chief Scientific Officer of the biotech startup Initos Pharmaceuticals.

About 30,000 people in the United States have CF, an inherited disorder in which gene mutations cause the functional absence of an important protein called CFTR. Absent CFTR, the mucus lining the lungs and upper airways becomes dehydrated and highly susceptible to bacterial infections, which occur frequently and lead to progressive lung damage.

Treatments for CF now include CFTR modulator drugs, which effectively restore partial CFTR function in many cases. However, CFTR modulators cannot help roughly ten percent of CF patients, often because the underlying gene defect is of the type known as a splicing defect.

CF and splicing defects

Splicing is a process that occurs when genes are copied out – or transcribed – into temporary strands of RNA. A complex of enzymes and other molecules then chops up the RNA strand and re-assembles them, typically after deleting certain unwanted segments. Splicing occurs for most human genes, and cells can re-assemble the RNA segments in different ways so different versions of a protein can be made from a single gene. However, defects in splicing can lead to many diseases – including CF when CFTR’s gene transcript is mis-spliced.

In principle, properly designed oligonucleotides can correct some kinds of splicing defects. In recent years the U.S. Food and Drug Administration has approved two “splice switching oligonucleotide” therapies for inherited muscular diseases.

In practice, though, getting oligonucleotides into cells, and to the locations within cells where they can correct RNA splicing defects, has been extremely challenging for some organs.

“It has been especially difficult to get significant concentrations of oligonucleotides into the lungs to target pulmonary diseases,” Kreda said.

Therapeutic oligonucleotides, when injected into the blood, have to run a long gauntlet of biological systems that are designed to keep the body safe from viruses and other unwanted molecules. Even when oligonucleotides get into cells, the most usually are trapped within vesicles called endosomes, and are sent back outside the cell or degraded by enzymes before they can ever do their work.

A new delivery strategy

The strategy developed by Kreda, Juliano, and their colleagues overcomes these obstacles by adding two new features to splice switching oligonucleotides: Firstly, the oligonucleotides are connected to short, protein-like molecules called peptides that are designed to help them to distribute in the body and get into cells. Secondly, there is a separate treatment with small molecules called OECs, developed by Juliano and Initos, which help the therapeutic oligonucleotides escape their entrapment within endosomes.

The researchers demonstrated this combined approach in cultured airway cells from a human CF patient with a common splicing-defect mutation.

“Adding it just once to these cells, at a relatively low concentration, essentially corrected CFTR to a normal level of functioning, with no evidence of toxicity to the cells,” Kreda said.

The results were much better with than without OECs, and improved with OEC dose.

There is no mouse model for splicing-defect CF, but the researchers successfully tested their general approach using a different oligonucleotide in a mouse model of a splicing defect affecting a reporter gene. In these experiments, the researchers observed that the correction of the splicing defect in the mouse lungs lasted for at least three weeks after a single treatment – hinting that patients taking such therapies might need only sporadic dosing.

The researchers now plan further preclinical studies of their potential CF treatment in preparation for possible clinical trials.

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Yan Dang, Catharina van Heusden, Veronica Nickerson, Felicity Chung, Yang Wang, Nancy Quinney, Martina Gentzsch, and Scott Randell were other contributors to this study from the Marsico Lung Institute; Ryszard Kole a co-author from the UNC Department of Pharmacology.

The Cystic Fibrosis Foundation and the National Institutes of Health supported this work.

Scientists Demonstrate Promising New Approach for Treating Cystic Fibrosis

Source: https://bioengineer.org/scientists-demonstrate-promising-new-approach-for-treating-cystic-fibrosis/

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