Culture

BOSTON -- For women hoping to achieve a pregnancy using freshly retrieved donor eggs, a new retrospective study led by researchers from Brigham and Women's Hospital may provide important insight. Brigham senior author Janis H. Fox, MD, had observed that when freshly retrieved donor eggs were used, pregnancy rates were higher for fresh compared to frozen embryo transfers. Fox and her colleagues were intrigued by this observation. The team set out to scientifically determine if this observation would be replicated in a larger sample of recipients. Leveraging national data from the Society for Assisted Reproductive Technology (SART), the Brigham researchers found that, in cycles using freshly retrieved donor eggs, fresh embryo transfers were indeed associated with significantly higher live birth rates compared to frozen embryo transfers. The team's findings are published in JAMA.

"In cycles using one's own eggs, recent randomized controlled trials comparing pregnancy rates between fresh and frozen embryo transfers have suggested that pregnancy rates are equivalent or possibly higher following frozen embryo transfers," said corresponding author Iris Insogna, MD, MBE, a fellow in Reproductive Endocrinology and Infertility at the Brigham. "Our study suggests the opposite in cycles using freshly retrieved donor eggs. In fresh donor egg recipients, pregnancy rates were actually higher following fresh embryo transfers compared to frozen embryo transfers."

The use of donor eggs has been steadily increasing in the United States since the first American child was born from egg donation in 1984. Since 2007, there has been a notable rise in the use of frozen rather than fresh embryo transfers in donor egg cycles. This is in part due to greater interest in preimplantation genetic testing to ensure the embryo has the correct number of chromosomes (a process that necessitates freezing the embryo while awaiting the results), and also because fresh donor embryo transfers present unique logistical challenges in that they require synchronizing the recipient's uterine lining with the egg donor's stimulation.

To determine whether fresh embryos derived from freshly retrieved donor eggs offered any benefit compared to frozen embryos, the Brigham team used data from SART, which collects cycle information from 370 in vitro fertilization clinics in the U.S., accounting for more than 95 percent of all assisted reproduction volume nationwide. The current study includes more than 33,000 recipients.

"The extensive data set that SART makes available for research and analysis is an incredibly valuable resource to answer questions such as ours," said Fox, an attending reproductive endocrinologist in the Brigham's Center for Infertility and Reproductive Surgery and an assistant professor at Harvard Medical School.

The team found that fresh embryos derived from fresh donor eggs were associated with significantly higher live birth and clinical pregnancy rates, while miscarriage rates were the same between both groups. For fresh embryos, the live birth rate was 56.6 percent compared to 44 percent for frozen embryos. Clinical pregnancy rates were 66.7 percent for fresh embryos compared to 54.2 percent for frozen. Interestingly, the Brigham team found that live birth rates remained higher following the transfer of fresh embryos, even when compared to the transfer of frozen embryos that had undergone preimplantation genetic testing and were known to contain the normal number of chromosomes.

The authors note this is a retrospective study so can only demonstrate associations between exposures and outcomes. Though the SART database is extensive, some information is missing, including age and demographic information of some anonymous donors included in the study.

While fresh embryos derived from fresh donor eggs conferred a statistically significant and clinically meaningful higher rate of live births compared to frozen embryos, the authors emphasize that live birth rates were high for both groups.

"The transfer of either fresh or frozen embryos derived from freshly retrieved donor eggs provides an excellent chance of achieving a pregnancy," said Insogna.

Fox adds, "For women contemplating achieving a pregnancy using freshly retrieved donor eggs, as well as for their physicians, we feel this study provides valuable guidance."

COLUMBUS, Ohio - An unfortunate truth about the use of mechanical ventilation to save the lives of patients in respiratory distress is that the pressure used to inflate the lungs is likely to cause further lung damage.

In a new study, scientists identified a molecule that is produced by immune cells during mechanical ventilation to try to decrease inflammation, but isn't able to completely prevent ventilator-induced injury to the lungs.

The team is working on exploiting that natural process in pursuit of a therapy that could lower the chances for lung damage in patients on ventilators. Delivering high levels of the helpful molecule with a nanoparticle was effective at fending off ventilator-related lung damage in mice on mechanical ventilation.

"Our data suggest that the lungs know they're not supposed to be overinflated in this way, and the immune system does its best to try to fix it, but unfortunately it's not enough," said Dr. Joshua A. Englert, assistant professor of pulmonary, critical care and sleep medicine at The Ohio State University Wexner Medical Center and co-lead author of the study. "How can we exploit this response and take what nature has done and augment that? That led to the therapeutic aims in this study."

The work builds upon findings from the lab of co-lead author Samir Ghadiali, professor and chair of biomedical engineering at Ohio State, who for years has studied how the physical force generated during mechanical ventilation activates inflammatory signaling and causes lung injury.

Efforts in other labs to engineer ventilation systems that could reduce harm to the lungs haven't panned out, Ghadiali said.

"We haven't found ways to ventilate patients in a clinical setting that completely eliminates the injurious mechanical forces," he said. "The alternative is to use a drug that reduces the injury and inflammation caused by mechanical stresses."

The research is published today (Jan. 12, 2021) in Nature Communications.

Though a therapy for humans is years away, the progress comes at a time when more patients than ever before are requiring mechanical ventilation: Cases of acute respiratory distress syndrome (ARDS) have skyrocketed because of the ongoing COVID-19 pandemic. ARDS is one of the most frequent causes of respiratory failure that leads to putting patients on a ventilator.

"Before COVID, there were several hundred thousand cases of ARDS in the United States each year, most of which required mechanical ventilation. But in the past year there have been 21 million COVID-19 patients at risk," said Englert, a physician who treats ICU patients.

The immune response to ventilation and the inflammation that comes with it can add to fluid build-up and low oxygen levels in the lungs of patients already so sick that they require life support.

The molecule that lessens inflammation in response to mechanical ventilation is called microRNA-146a (miR-146a). MicroRNAs are small segments of RNA that inhibit genes' protein-building functions - in this case, turning off the production of proteins that promote inflammation.

The researchers found that immune cells in the lungs called alveolar macrophages - whose job is to protect the lungs from infection - activate miR-146a when they're exposed to pressure that mimics mechanical ventilation. This action makes miR-146a part of the innate, or immediate, immune response launched by the body to begin its fight against what it is perceiving as an infection - the mechanical ventilation.

"This means an innate regulator of the immune system is activated by mechanical stress. That makes me think it's there for a reason," Ghadiali said. That reason, he said, is to help calm the inflammatory nature of the very immune response that is producing the microRNA.

The research team confirmed the moderate increase of miR-146a levels in alveolar macrophages in a series of tests on cells from donor lungs that were exposed to mechanical pressure and in mice on miniature ventilators. The lungs of genetically modified mice that lacked the microRNA were more heavily damaged by ventilation than lungs in normal mice - pointing to miR-146a's protective role in lungs during mechanical breathing assistance. Finally, the researchers examined cells from lung fluid of ICU patients on ventilators and found miR-146a levels in their immune cells were increased as well.

The problem: The expression of miR-146a under normal circumstances isn't high enough to stop lung damage from prolonged ventilation.

The intended therapy would be introducing much higher levels of miR-146a directly to the lungs to ward off inflammation that can lead to injury. When overexpression of miR-146a was prompted in cells that were then exposed to mechanical stress, inflammation was reduced.

To test the treatment in mice on ventilators, the team delivered nanoparticles containing miR-146a directly to mouse lungs - which resulted in a 10,000-fold increase in the molecule that reduced inflammation and kept oxygen levels normal. In the lungs of ventilated mice that received "placebo" nanoparticles, the increase in miR-146a was modest and offered little protection.

From here, the team is testing the effects of manipulating miR-146a levels in other cell types - these functions can differ dramatically, depending on each cell type's job.

"In my mind, the next step is demonstrating how to use this technology as a precision tool to target the cells that need it the most," Ghadiali said.

Toronto (Jan. 12, 2021) - More than half the clinicians surveyed at the Peter Munk Cardiac Centre reported burnout and high levels of distress according to a series of studies published today in the Canadian Medical Association Journal Open (CMAJ-OPEN). In these studies carried out before the COVID-19 pandemic, 78% of nurses, 73% of allied health staff and 65% of physicians described experiencing burnout.

"In my 35 years as a physician I have never seen a more serious issue for clinicians than burnout," says lead author Dr. Barry Rubin, Chair and Medical Director, the Peter Munk Cardiac Centre, UHN.

Completed in 2019, the study used the Well-Being Index, a survey tool developed by the Mayo Clinic, a globally recognized academic medical centre. 414 physicians, nurses and allied health staff answered a series of questions about the level of stress they experienced in the previous month.

The index measured fatigue, depression, burnout, anxiety or stress, mental and physical quality of life, work-life integration, meaning in work and distress.

The study also evaluated the respondent's perception of the adequacy of staffing levels, and of fair treatment in the workplace. The results were then compared to outcomes for corresponding healthcare professionals at academic health science centres in the United States.

Main Findings and Impact:

78% of nurses, 73% of allied health staff and 65% of physicians described burnout in the month prior to when the survey was administered.

79% of nurses, 56% of allied health staff and 55% of physicians had high levels of distress.

Lower levels of distress among all clinicians were associated with a perception of fair treatment at work and a perception of adequate staffing levels.

The impact of burnout on clinicians can include extreme fatigue, professional dissatisfaction, job turnover, decreased quality of life, and thoughts of suicide.

"Burnout also has a negative impact on the care we provide," says Dr. Rubin. "It is associated with an increased incidence of medical errors, serious safety events, readmission to hospital, worse patient outcomes and in some situations even increased patient mortality. Clinician burnout is a public health crisis that we must address now."

The findings of these studies are the first step in acknowledging the existence, depth, and degree of distress and burnout among clinicians at the Peter Munk Cardiac Centre.

"Our next steps will be to meet with nurses, doctors and allied health staff, so that we can understand the key drivers of burnout in the PMCC and develop targeted intervention strategies," says Dr. Rubin. "It is critical we address these issues and work together to bring about much-needed change. Healthcare workers give their all to care for others, it is time they are cared for too."

Maunakea, Hawaii - The most distant quasar known has been discovered. The quasar, seen just 670 million years after the Big Bang, is 1000 times more luminous than the Milky Way, and is powered by the earliest known supermassive black hole, which weighs in at more than 1.6 billion times the mass of the Sun. Seen more than 13 billion years ago, this fully formed distant quasar is also the earliest yet discovered, providing astronomers with insight into the formation of massive galaxies in the early universe. The result was released today at the January 2021 meeting of the American Astronomical Society (AAS). 

Quasars, which are powered by the feeding frenzies of colossal supermassive black holes, are the most energetic objects in the universe. They occur when gas in the superheated accretion disk around a supermassive black hole is inexorably drawn inwards, radiating light across the electromagnetic spectrum. The amount of energy emitted by quasars is enormous, with the most massive examples easily outshining entire galaxies. 

At an AAS press conference today, January 12, 2021, an international team of astronomers announced the discovery of J0313-1806, the most distant quasar known to date with a redshift of z = 7.64. 

The study, which includes data from several Maunakea Observatories in Hawaii - UKIRT, W. M. Keck Observatory, and the international Gemini Observatory, a Program of NSF's NOIRLab - as well as Pan-STARRS1, a survey telescope on Maui operated by the University of Hawaii Institute for Astronomy, has been accepted in The Astrophysical Journal Letters and is available in pre-print format on arXiv.org.

"The most distant quasars are crucial for understanding how the earliest black holes formed and for understanding cosmic reionization -- the last major phase transition of our universe," said Xiaohui Fan, study co-author and Regents Professor of Astronomy at the University of Arizona.

The presence of such a massive black hole so early in the universe's history challenges theories of black hole formation.

"Black holes created by the very first massive stars could not have grown this large in only a few hundred million years," says Feige Wang, NASA Hubble fellow at the University of Arizona and lead author of the research paper.

The observations that led to this discovery were made using a variety of observatories around the world, including several world-class telescopes in Hawaii.  

Data from Pan-STARRS1 and the UKIRT Hemisphere Survey helped to first identify J0313-1806. Once the team confirmed its identity as a quasar, they obtained high-quality spectra from Keck Observatory and Gemini North to measure the mass of the central supermassive black hole. 

"Measurement of spectral lines that originate from gas surrounding the quasar's accretion disk allows us to determine the black hole's mass and study how its rapid growth influences its environment. For such distant quasars, the most important spectral lines are redshifted to near-infrared wavelengths and Keck's NIRES spectrograph is an excellent instrument for these observations," said co-author Aaron Barth, a professor of Physics and Astronomy at the University of California, Irvine. 

"Observing infrared light requires low temperatures. The near-freezing climate prevailing at the sky-scraping summit of Maunakea (13,796 ft or 4205 m) make it one of the only sites on Earth with instruments sensitive enough to observe such red wavelengths," said Joe Hennawi, a professor at UC Santa Barbara who helped execute the observations with the Keck/NIRES spectrograph.

In addition to weighing the monster black hole, the Keck Observatory and Gemini North observations uncovered an extremely fast outflow emanating from the quasar in the form of a high-velocity wind traveling at 20% of the speed of light. 

"The energy released by such an extreme high-velocity outflow is large enough to impact the star formation in the entire quasar host galaxy," said co-author Jinyi Yang, Peter A. Strittmatter postdoctoral fellow of Steward Observatory at the University of Arizona. 

This is the earliest known example of a quasar sculpting the growth of its host galaxy, making J0313-1806 a promising target for future observations.

The galaxy hosting J0313-1806's is undergoing a spurt of star formation, producing new stars 200 times faster than the Milky Way. The combination of this intense star formation, the luminous quasar, and the high-velocity outflow make J0313-1806 and its host galaxy a promising natural laboratory for understanding the growth of supermassive black holes and their host galaxies in the early universe.

"This would be a great target to investigate the formation of the earliest supermassive black holes," concluded Wang. "We also hope to learn more about the effect of quasar outflows on their host galaxy -- as well as to learn how the most massive galaxies formed in the early universe."

A new structural arrangement of atoms shows promise for developing safer batteries made with solid materials. Scientists at Kyoto University's Institute for Integrated Cell-Material Sciences (iCeMS) designed a new type of 'antiperovskite' that could help efforts to replace the flammable organic electrolytes currently used in lithium ion batteries. Their findings were described in the journal Nature Communications.

Perovskite compounds are being tested and used in a wide range of technologies due to their excellent ability to conduct electricity, among other properties. They can be made from a large combination of atoms with the formula ABX3, where A and B are positively charged atoms and X is a negatively charged one.

Recently, scientists have been tinkering with compounds called antiperovskites. These flip the formula, combining two types of negatively charged 'anions' and one type of positively charged 'cation'. They also have numerous intriguing properties, including superconductivity and , in contrast to most materials, contraction upon heating.

Lithium- and sodium-rich antiperovskites, such as Li3OCl and Na3OCl, have been attracting much attention due to their high ionic conductivity and alkali metal concentration, making them promising candidates to replace liquid electrolytes used in lithium ion batteries. "But achieving a comparable lithium ion conductivity in solid materials has been challenging," explains iCeMS solid-state chemist Hiroshi Kageyama, who led the study.

Kageyama and his team synthesized a new family of lithium- and sodium-rich antiperovskites that begins to overcome this issue. Instead of 'hard' oxygen and halogen anions, their antiperovskites contain a hydrogen anion, called a hydride, and 'soft' chalcogen anions like sulphur.

The scientists conducted a wide range of theoretical and experimental investigations on these antiperovskites, and found that the soft anion lattice provides an ideal conduction path for lithium and sodium ions, which can be further enhanced by chemical substitutions.

The advantages of this new family of antiperovskites appear to be due, in part, to the hydride's ability to change its size and expand its compositional space. This helps stabilize the compound's structure. Additionally, its anomalous vibrational mode assists ionic conductivity.

"There is still much room for improvement by further experimentation with chemical substitutions," says Kageyama. "This could eventually lead to solid-state electrolytes in all-solid-state metal-ion batteries for high performance electrical vehicles."

For other measures, however, the behaviour of the generations differs: "Of those under 40 years of age, 18 percent say they have food delivered more frequently", says BfR-President Professor Dr. Dr. Andreas Hensel. "In the age group 60 years and older, on the other hand, only seven percent make use of such offers."

https://www.bfr.bund.de/cm/349/210105-bfr-corona-monitor-en.pdf

In addition to more frequent ventilation, the respondents try to protect themselves from an infection mainly by wearing masks, keeping distance to other people and washing their hands more frequently. The mandatory use of masks was approved by 93 percent of the respondents, the distance regulation by 96 percent. With the end of the Christmas holidays, the closure of day-care centres and schools is still considered appropriate by 67 percent - this is four percentage points less than in the week before Christmas.

The population is still aware that proximity to others plays a central role in the transmission of the coronavirus. Around three quarters of the respondents still consider the probability of contracting the virus via this pathway to be high. In comparison: Door handles are seen by 47 percent as a likely route of infection. Only 13 percent consider transmission through food to be probable.

The BfR continually adapts its FAQs on the topic of coronavirus to the current state of science:

https://www.bfr.bund.de/en/can_the_new_type_of_coronavirus_be_transmitted_via_food_and_objects_-244090.html

In patients with anorexia, it could remain at the same level as before the start of the illness. The researchers led by Professor Martin Diers recommend a combination of cognitive behavioural therapy and the use of virtual reality to correct the distorted body schema. The study is published in the International Journal of Eating Disorders on 20 December 2020.

Understanding the unconscious

The distorted perception of one's own body is a characteristic symptom of anorexia nervosa. It has long been known that patients overestimate the dimensions of their body. "This discrepancy relates to the conscious part of body perception, body image," explains Martin Diers. Alongside this is the body schema, unconscious body awareness, which tells us, for instance, where we are in a room. It is usually flexible and adapts to current dimensions. This is why we do not normally bump into things when we are wearing a hat or a rucksack.

In order to find out about this unconscious aspect of body perception, the team from the University hospital developed an experiment involving 23 people with anorexia nervosa and 23 healthy volunteers. To not influence the results, a cover story was used to justify the research which had nothing to do with the real purpose of the study. The experiment consisted of asking the subjects to pass through door frames of different widths. "The opening was adapted to the shoulder width of the subjects and varied between 0.9 times and 1.45 times this width," says Diers. The researchers then observed from which door width the participants turned sideways before they passed the door.

It was shown that patients turn their shoulders to the side with much wider doors than healthy control subjects. "This shows us that they also unconsciously assess their proportions to be larger than they actually are," concludes lead author Nina Beckmann. The tendency to turn at wider door widths was also accompanied by a negative assessment of one's own body, which the researchers investigated in various questionnaires. In order to have a positive influence on the distorted unconscious body perception and adapt the person's possibly outdated body schema to suit their current physical proportions, the research team recommends using virtual reality alongside cognitive behavioural therapy. This makes it possible to virtually step into another person's body for a certain amount of time and influence the representation of the body.

In a major register-based study, scientists at University of Gothenburg, Sweden, have now demonstrated a connection between inferior physical fitness in young adults and elevated risk of the autoimmune disease psoriasis. For the male recruits to compulsory military training who were rated as the least fit, the risk of developing psoriasis later was 35 percent higher than for the fittest.

The study was based on data on more than 1.2 million men conscripted, aged 18, into the Swedish Armed Forces between the years 1968 and 2005. During the enrollment process, all these young men underwent the same fitness test on an exercise bicycle. The researchers divided the data, according to how fit the men were, into three levels (low, medium, and high fitness). They then merged the data with other registers, using Sweden's National Patient Register to obtain diagnostic codes for psoriasis and the joint disease psoriatic arthritis. The men who had already received one of these diagnoses before conscription were excluded from the study.

Later in life, between the ages of 37 and 51, just over 23,000 of the conscripts developed psoriasis or psoriatic arthritis. In the low-fitness group, 2.5 percent developed one or both of these diseases, while only 1.7 percent in the high-fitness group did so. In calculating this risk differential, the scientists adjusted for other risk factors, such as body mass index (BMI).

Association not causal

Thus, the less fit the men were when they were recruited, the higher the proportion of them who later fell ill with psoriasis or psoriatic arthritis. In the low-fitness group, the risk of developing psoriasis was 35 percent higher, and that of developing psoriatic arthritis 44 percent higher, than in the high-fitness group.

"We show that there's an association between lower fitness and raised risk of developing psoriasis and psoriatic arthritis, but we don't show a causal connection. So we can't say that these health conditions can be prevented by exercising," says the study's first author Marta Laskowski, a doctoral student in dermatology at the University of Gothenburg and resident physician (specialist trainee) at Sahlgrenska University Hospital.

Group in need of monitoring

The group of men who were least fit was also the smallest: just under 48,000 or 3.9 percent of all the conscripts in the study. This is a group that healthcare services should try to monitor regularly.

"Low fitness was already known to boost the risk of incurring cardiovascular disease, and psoriasis as such is linked to raised cardiovascular disease risk, too. The results from our study confirm the reasons for assessing people's fitness early in life, to identify individuals at a higher risk for adverse health outcomes later in life," Laskowski says.

Previous research has indicated that, in general, people with psoriasis are less fit than those without it who engage in an equal amount of physical activity. However, the reasons for this difference have not been fully clarified.

"One weakness of our study is that we weren't been able to monitor the trends of the men's fitness during the intervening years, between their conscription and the disease onset. We're also lacking data on smoking, which is a known risk factor for psoriasis," Laskowski explains.

Scaly skin patches

Some 300,000 Swedes have psoriasis in a mild, moderate, or severe form. It is a chronic, systemic inflammatory disease that affects women as often as men. What triggers its onset is not entirely clear, but heredity is known to play a large part in combination with external factors. The most common type, plaque psoriasis, causes reddened, flaking, and itchy skin lesions ("plaques").

Psoriasis sufferers also often have other diseases. Some 30 percent get the inflammatory joint condition known as psoriatic arthritis. Examples of other known comorbidities are obesity, cardiovascular disease, diabetes, and depression.

In recent years, treatment options have substantially improved. Today, besides ointments with local effects, there are drugs that have systemic effects. Recent years have also seen the emergence of efficacious biological agents that modulate the signaling cascade in the inflammatory process that drives psoriasis.

UK government plans to widen the roll out of the Innova lateral flow test without supporting evidence risks serious harm, warn experts in The BMJ today.

More than £1 billion have been spent on purchasing lateral flow tests, but Professor Jon Deeks and colleagues argue that the public is being misled about their accuracy, as well as the risks and implications of false negative results, and they call on the government urgently to change course.

Mass testing may be helpful and necessary in certain circumstances if delivered to high quality, they explain, but the Innova lateral flow test is not fit for this purpose.

For example, in the Liverpool pilot study, 60% of infected symptomless people went undetected, including 33% of those with high viral loads who are at highest risk of infecting others. And among students in Birmingham, only 3% of those who would have tested positive on the "gold standard" PCR test were detected.

Yet the government continues to claim that the Innova test detects 77%, they write, and has championed the use of negative tests to enable visiting relatives in care homes, returning to work or staying in school, despite known exposure to an infectious case.

The government is also relying on mathematical models rather than real world evaluations of testing. They argue that the models used rely on flawed assumptions about test performance and how results will affect human behaviour. "Together they tend to overestimate potential benefits and underestimate potential harms."

No one questions the need for evidence based approaches to covid 19 treatments and vaccines. Why then, in the face of so little evidence of benefit, and so much evidence of poor test performance, is the government pushing the rollout, they ask?

It seems at least plausible that this is because hundreds of millions of Innova testing kits were purchased before it was known how they would perform in people without symptoms and when administered by less than expert hands, they suggest. These tests are now sitting in warehouses around the country.

Given all of the above, they call on the government at least to pause the rollout of rapid asymptomatic testing using the Innova test, including its use in care homes, schools, communities and self-testing by untrained people at home, until clearer messaging on the risks of negative results can be developed.

They also ask for full documentation relating to Innova's approval, and for publication of full reports for all studies and models of the Innova test.

What's more, information materials should be revised to make explicit the extremely poor sensitivity of the Innova test for community and self-use among those without symptoms; and the aims, outcomes and full costings of mass testing of keyworkers, schoolchildren, university students, and care home visitors should be reviewed, they add.

"Finally, since testing makes no difference unless followed by appropriate action, the UK needs a national scheme to enable self-isolation of cases and contacts through support, including financial and accommodation for those in need," they conclude.

Remarkably well-preserved fossils are helping scientists unravel a mystery about the origins of early animals that puzzled Charles Darwin.

Analysis of the 547 million-year-old remains has enabled researchers to trace the ancestry of some of the world's earliest animals further back than ever before.

Their study has uncovered the first known link between animals that evolved during the so-called Cambrian Explosion some 540 million-years-ago and one of their early ancestors.

Until recently, little was known about the origins of animals that evolved during the Cambrian event because of a lack of well-preserved fossil evidence.

The mysterious origins of animals that evolved at this time - when the diversity of life on Earth increased rapidly, giving rise to almost all modern-day animal groups - baffled 19th century naturalist Charles Darwin. It is often referred to as Darwin's dilemma.

Prior to the new study, it had proven difficult to trace links with earlier animals because their soft tissues - which provide vital clues about the animals' ancestry - almost always break down over time.

During fieldwork in Namibia, scientists from the University of Edinburgh unearthed the fossil remains of tiny animals - known as Namacalathus - that resemble a pin cushion attached to a short stalk.

Using an x-ray imaging technique, the team found some of the animals' soft tissues immaculately preserved inside the fossils by a metallic mineral called pyrite. Until now, scientists had only ever identified skeletal remains of Namacalathus.

Studying the soft tissues - and comparing them with those in animals that evolved later - revealed that Namacalathus was an early ancestor of species that appeared during the Cambrian Explosion. Among them are types of prehistoric worms and molluscs.

The study, published in the journal Science Advances, was funded by the Natural Environment Research Council. The work also involved a researcher from Lomonosov Moscow State University, Russia.

Professor Rachel Wood, of the University of Edinburgh's School of GeoSciences, said: "These are exceptional fossils, which give us a glimpse into the biological affinity of some of the oldest animals.

"They help us trace the roots of the Cambrian Explosion and the origin of modern animal groups. Such preservation opens up many new avenues of research into the history of life which was previously not possible."

Core technology includes promising bivalent single-domain antibodies simultaneously targeting two surface structures of the viral spike protein.

Lead candidates DIOS-202 and DIOS-203 are engineered for high potency and their potential to avoid the emergence of escape mutants.

DIOS-202 and DIOS-203 entered into accelerated development to initiate clinical studies later this year.

BONN, Germany, January 12, 2021 - DiosCURE SE announced a publication in Science describing its core technology of multivalent single-chain antibodies with a unique molecular mode-of-action to inactivate SARS-CoV-2 virions. An international team led by scientists at the University of Bonn developed and characterized the lead candidates, which are exclusively licensed by DiosCURE.

"This global pandemic requires an arsenal of therapeutic and preventative tools and our lead candidates will allow us to contribute to what will be an ongoing battle," stated Klaus Wilgenbus, Chief Executive Officer at DiosCURE. "DiosCURE was established with the goal of developing novel, best-in-class immunotherapies to protect a significant population which will remain at risk, including exposed healthcare workers, immunocompromised patients, non-responders to vaccines and patients experiencing post-acute COVID-19 syndrome. The data now published provides a solid foundation to continue our development efforts with the goal of entering the clinic later this year."

The company's lead candidates, DIOS-202 and DIOS-203, are synergistic combinations of single-domain antibodies derived from camelid heavy chain-only antibodies. These next-generation immunotherapies against SARS-CoV-2 were designed based on detailed structural information of the antibodies' interaction with its viral target protein and result from functional and evolutionary experiments. The discovery and promising early preclinical data were published in an article in Science entitled "Structure-guided multivalent nanobodies block SARS-CoV-2 infection and suppress mutational escape" on January 12, 2021. The study details the identification of DiosCURE's lead candidates out of millions of potential structures, as well as the rational design of multivalent constructs, which increased neutralizing activity more than 100-fold. Preclinical studies demonstrated that DIOS-202 and DIOS-203 selectively target two distinct epitopes of the SARS-CoV-2 spike protein at once, which largely prevents the emergence of escape mutants. The dual targeting induces the premature activation of the fusion machinery, rendering the virions non-infectious. These discoveries were accomplished through a collaborative effort of research groups at the University Hospital of the University of Bonn (led by the Institute of Innate Immunity and the Core Facility Nanobodies), The Scripps Research Institute and the Karolinska Institutet.

The lead candidates are expected to be highly efficacious, well-tolerated, cost-efficient in production and are amenable to a wide range of clinical applications. As immunotherapies, DIOS-202 and DIOS-203 are suitable as prophylactic and to treat infected patients to avoid severe COVID-19 disease.

"The structure-based multivalent single-chain antibodies we discovered have strong potential for clinical applications. This is owed to their highly potent neutralizing activity and in-built protection from the rapid emergence of escape mutants. The emergence of SARS-CoV-2 escape mutants will remain an ongoing challenge in this pandemic, and novel therapies are urgently needed to address this problem," stated Eicke Latz, Director of the Institute of Innate Immunity at the University of Bonn, co-founder and Board member of DiosCURE. "Our understanding of the short- and long-term consequences of SARS-CoV-2 is rapidly evolving, and rational therapeutics targeting the virus are needed to curb the potentially devastating consequences of COVID-19."

While most people are able to eat a normal diet, many of those managing distinct nutritional requirements related to a disease or health condition rely on medical foods. Medical foods help patients meet their nutritional needs, often improving nutritional and health outcomes and quality of life. A recent publication in Current Developments in Nutrition, titled "Medical Foods: Science, Regulation, and Practical Aspects. Summary of a Workshop," shares the historical and regulatory context of medical foods and perspectives on their role in the future.

Medical foods help patients manage their nutritional needs, yet it can be very difficult for patients to have access to them. In August 2019, the Healthcare Nutrition Council (HNC), in partnership with the American Society for Nutrition (ASN), held the Medical Foods Workshop: Science, Regulation, and Practical Aspects. The workshop discussions focused on:

Patient and healthcare professional considerations for and benefits from medical foods.

Opportunities for product innovation and future research. Real-world examples were discussed for enteral tube feeding, surgery and trauma, intractable epilepsy, diabetes, renal disease, and inflammatory bowel disease.

The role of clinical guidelines for developing and use of medical foods.

The use of medical foods in clinical practice under medical supervision.

The statutory term distinctive nutritional requirements.

The regulatory term modification of the diet alone.

Differentiation of medical foods from foods for special dietary use.

"The objectives of our workshop were to advance the dialogue on the scientific and regulatory status of medical foods in the U.S., drive consensus on terms and definitions for medical foods, and ultimately help improve patient access to these important products," said Robert Rankin, Executive Director of HNC. "It was extremely important that the workshop included a variety of stakeholders, encompassing patients, clinicians, government officials, and the medical food industry. We have more work ahead to improve the landscape for medical foods, assuring that the regulatory framework fosters research, innovation, and development for these important products as well as assuring patients have access to products which improve their clinical care."

What is the endgame for SARS-CoV-2, the virus that is causing worldwide devastation? If it becomes endemic -- circulating in the general population -- and most people are exposed in childhood, SARS-CoV-2 may join the ranks of mild cold-causing coronaviruses that currently circulate in humans, according to a model developed by Emory and Penn State scientists.

The model, published January 12 in Science, draws upon studies of the four common cold coronaviruses and SARS-CoV-1. For those viruses, the term "herd immunity" is incomplete and possibly misleading, says postdoctoral fellow Jennie Lavine, PhD, first author of the Science paper.

The four common cold-causing coronaviruses have been circulating in humans for a long time and almost everyone is infected at a young age - younger than measles before a vaccine was available. Natural infection in childhood provides immunity that protects people later in life against severe disease, but it doesn't prevent periodic reinfection, says Lavine.

"Reinfection is possible within one year, but even if it occurs, symptoms are mild and the virus is cleared from the body more quickly," she says. "It highlights the need to tease apart the components of immunity to SARS-CoV-2. How long does immunity that prevents pathology last, and how long does immunity that prevents transmission last? Those durations may be very different."

Studies are now emerging that provide concrete data on how long antibodies and immune cells against SARS-CoV-2 last after infection, Lavine says. However, researchers are still figuring out how those components translate to protection against disease or transmission.

"Overall, we're asking: how does SARS-CoV-2 compare to other viruses such as seasonal influenza or respiratory syncytial virus," she says. "This model assumes immunity to SARS-CoV-2 works similar to other human coronaviruses. We don't really know what it would be like if someone got one of the other coronaviruses for the first time as an adult, rather than as a child."

The model predicts that the infection fatality ratio for SARS-CoV-2 may fall below that of seasonal influenza (0.1 percent), once an endemic steady-state is reached.

"We are in uncharted territory, but a key take-home message from the study is that immunological indicators suggest that fatality rates and the critical need for broad-scale vaccination may wane in the near term, so maximum effort should be on weathering this virgin pandemic enroute to endemicity," said Ottar Bjornstad, Distinguished Professor of Entomology and Biology and J. Lloyd & Dorothy Foehr Huck Chair of Epidemiology, Penn State.

Lavine developed the model, together with Bjornstad and Rustom Antia, PhD, Samuel C. Dobbs professor of biology at Emory University and Emory Vaccine Center.

A safe and effective vaccine against COVID-19 could save hundreds of thousands of lives in the first year or two of vaccine roll-out, but continued mass vaccination may be less critical once SARS-CoV-2 becomes endemic, the authors say. Targeted vaccination in vulnerable subpopulations may still save lives, they say.

Another implication is: during the transition to endemicity, that using symptoms only as a surveillance tool to look for infections and curb the virus' spread will become more difficult. Thus, widely available testing may become particularly important during vaccine roll-out to protect vulnerable populations, the authors point out.

So far, the available data on SARS-CoV-2 infection in infants and young children suggest that severity is generally mild and mortality is low. There are exceptions on the individual level, with some experiencing rare complications such as MIS-C (multisystem inflammatory syndrome in children). In contrast, if SARS-CoV-2 infection in childhood were to become more severe - like MERS-CoV (Middle East respiratory syndrome-related coronavirus) - routine vaccination programs will be still necessary, the authors say.

Antibodies are an important weapon in the immune system's defense against infections. They bind to the surface structures of bacteria or viruses and prevent their replication. One strategy in the fight against disease is therefore to produce effective antibodies in large quantities and inject them into the patients. The outgoing US President Donald Trump probably owes his rapid recovery to this method. However, the antibodies used to treat him have a complex structure, do not penetrate very deeply into the tissue and may cause unwanted complications. Moreover, producing antibodies is difficult and time-consuming. They are therefore probably not suitable for widespread use.

Mass production in yeast or bacteria

"We focus on another group of molecules, the nanobodies," explains Dr. Florian Schmidt, who heads an Emmy Noether group on this promising new field of research at the University of Bonn's Institute of Innate Immunity. "Nanobodies are antibody fragments that are so simple that they can be produced by bacteria or yeast, which is less expensive."

However, the immune system produces an almost infinite number of different antibodies, and they all recognize different target structures. Only very few of them are for example capable of defeating the SARS coronavirus-2. Finding these antibodies is like searching for a single grain of sand on Germany's Baltic coast. "We first injected a surface protein of the coronavirus into an alpaca and a llama," Schmidt explains. "Their immune system then produces mainly antibodies directed against this virus. In addition to complex normal antibodies, llamas and alpacas also produce a simpler antibody variant that can serve as the basis for nanobodies."

A few weeks later, the researchers took a blood sample from the animals, from which they extracted the genetic information of produced antibodies. This "library" still contained millions of different construction plans. In a complex process, they extracted those that recognize an important structure on the surface of the coronavirus, the spike protein. "Altogether we obtained dozens of nanobodies, which we then analyzed further," explains Dr. Paul-Albert König, head of the Core Facility Nanobodies at the Medical Faculty of the University of Bonn and lead author of the study.

Four out of several million

Four molecules actually proved to be effective against the pathogen in cell cultures. "Using X-ray structures and electron microscopy analyses, we were furthermore able to show how they interact with the spike protein of the virus," explains König. This work was done in the research groups around Martin Hällberg (Karolinska Institutet, Sweden) and Nicholas Wu as well as Ian Wilson (Scripps Research Institute, USA). The spike protein is crucial for the infection: It acts like a velcro fastener with which the pathogen attaches to the attacked cell. Next, the velcro changes its structure: It discards the component that is important for attachment and mediates fusion of the virus envelope with the cell. "Nanobodies also appear to trigger this structural change before the virus encounters its target cell - an unexpected and novel mode of action," says König. "The change is likely to be irreversible; the virus is therefore no longer able to bind to host cells and infect them."

The researchers also exploit another major advantage of nanobodies over antibodies: Their simple structure allows straight forward combinations to form molecules that can be several hundred times more effective. "We have fused two nanobodies that target different parts of the spike protein," explains König. "This variant was highly effective in cell culture. Furthermore, we were able to show that this drastically reduces the probability of the virus to become resistant to the active agent through escape mutations." The researchers are convinced that the molecules may be developed into a novel and promising therapeutic option.

Dioscure Therapeutics, a spin-off of the University of Bonn, will test the nanobodies in clinical studies. The success of the project is mainly based on the excellent cooperation of the participating research groups at the University with national and international cooperation partners, emphasizes Florian Schmidt, who is also a member of the Immunosensation2 Cluster of Excellence at the University of Bonn.

Researchers at Karolinska Institutet in Sweden have developed, in collaboration with researchers in Germany and the U.S., new small antibodies, also known as nanobodies, which prevent the SARS-CoV-2 coronavirus from entering human cells. The research study, published in Science, shows that a combined nanobody had a particularly good effect - even if the virus mutated. According to the researchers, the nanobodies have the potential to be developed into a treatment for COVID-19.

Specific proteins, spike proteins, on the surface of the SARS-CoV-2 coronavirus help the virus infect host cells. Therefore, antibodies that block the spike proteins and prevent them from binding to the cell can be a way to stop infection.

From the perspective of potential therapeutic interventions, small fragments of antibodies, referred to as single-domain antibodies (sdAb) or nanobodies, may be a better alternative than regular antibodies. That is because nanobodies are significantly smaller. They are therefore able to bind to the virus in more places than regular antibodies. Nanobodies also have greater stability and are easier to produce cost-effectively on a large scale.

Researchers at Karolinska Institutet are now publishing, in collaboration with researchers at the University of Bonn in Germany and the Scripps Research Institute in California, a study describing new nanobodies against SARS-CoV-2 infection.

"What is uniquely special here is that we have stitched together nanobodies that bind to two different places on the spike protein of the virus," explains Martin Hällberg, researcher at the Department of Cell and Molecular Biology at Karolinska Institutet, and one of the research study's corresponding authors.

"This combination variant binds better than individual nanobodies and is exceptionally effective in blocking the virus' ability to spread between human cells in cell culture."

Additionally, the combined nano-antibodies worked even when tested on a virus variant that mutates extremely quickly.

"This means that the risk is very small that the virus would become resistant to these combined nanobodies," notes Martin Hällberg.

To generate the nanobodies, alpacas and llamas - animals whose immune systems naturally produce both antibodies and nanobodies - were vaccinated with the spike protein of the coronavirus. Among the nanobodies generated by the animals, the researchers selected the best binders. Among these, four were identified as showing an exceptional ability to block the virus' ability to spread among human cultured cells.

The research group at Karolinska Institutet then used electron cryomicroscopy (cryo-EM) to study in detail how the various nanobodies bind to the virus' spike protein. Thanks to their structural knowledge, they were able to propose suitable protein links to bind different nanobodies together into combinations relevant for research, as well as provide a possible explanation for the mechanism of how the antibodies neutralise the virus.

"My 'favourite' is the nanobody from the llama," Martin Hällberg says. "It binds directly over the surface where the virus binds the host cell receptor ACE2, and the nanobody also shares a large majority of the amino acids critical for binding with ACE2. What this means is that the virus will have an extremely difficult time mutating extensively on that surface and at the same time being able to bind ACE2. A variant where this llama antibody is linked to one of the antibodies from alpaca was a fox trap that the virus never managed to get out of in our experiments."

The researchers now hope that their nanobodies will be able to be developed into a drug treatment as a complement to a vaccination against COVID-19.

"It possibly could be used clinically for those already ill, or for prevention for individuals who for one reason or another cannot be vaccinated, or who have a weakened immune system, and therefore may not form a sufficiently strong immune response after a vaccination," explains Martin Hällberg.

Dioscure Therapeutics, a spin-off company from the University of Bonn, will be conducting further testing of the nanobodies in clinical trials. The researchers at Karolinska Institutet will make attempts to improve the binding further by changing individual building blocks in the nanobodies.

The research was funded by the Swedish Research Council and the Knut and Alice Wallenberg Foundation, as well as by research funders in Germany and the U.S.