Culture

When we think of wrinkles, we usually envision the lines etched into our skin, for some an unwelcome reality and for others a proud sign of a life well-lived. In material science, wrinkles can also be either wanted or unwanted. But the physical factors that cause wrinkling to occur are not yet fully understood.

Now, in a paper recently published in Applied Physics Letters, researchers from the Mathematics, Mechanics, and Materials (MMM) Unit at the Okinawa Institute of Science and Technology Graduate University (OIST) have shown how wrinkles can be increased or reduced by altering the curvature at the edge of a material.

"Historically, scientists and engineers have focused on preventing wrinkling, which can adversely affect the performance of pressure sensors, aircraft panels, and lightweight spacecraft structures including deployable space booms and telescopes," said Professor Eliot Fried, who leads the MMM unit. "But recent research has also shown that wrinkling can give materials useful properties. For example, it can be used to make a material super hydrophobic or to make coatings that reflect light in unique ways."

Diamond windows of opportunity

The unit first encountered the phenomenon of wrinkling while working with ultra-thin nanocrystalline diamond films, grown on a sheet of glass.

"I was removing the layer of glass underneath small areas of the nanocrystalline diamond film to create diamond windows," said Dr. Stoffel Janssens, first author of the study and postdoctoral researcher in the MMM unit. "Diamond windows are extremely difficult to make but they have really exciting potential applications, including being used as a transparent structure upon which a cell culture can be grown and easily visualized."

The scientists found that wrinkling was an unavoidable part of fabricating diamond windows. The process of growing the nanocrystalline diamond film on top of the glass sheet involves heating and cooling the substrate, which causes the two layers to expand and contract by different amounts, generating stress in the layers, Dr. Janssens explained. Then, when a hole in the glass substrate is made by lasers and acids to form a diamond window, the residual stress causes the now suspended portion of nanocrystalline diamond film, which is no longer bonded to the sheet of glass, to deform and wrinkle around the edge.

"We realized that diamond windows provided a great opportunity to understand some of the physical factors that affect wrinkling," said Prof. Fried. "Using circular diamond windows, we experimentally demonstrated the effect of diameter and boundary curvature on wrinkling, and then we also developed a simple theoretical model to explain what we observed."

Bridging experiment and theory

In the study, the researchers created different sized diamond windows, and then measured the wavelength and number of wrinkles that formed in the suspended film around the curved edge of each diamond window.

They found that as the size of the diamond windows increased, reducing the curvature at the boundary between the bonded and suspended nanocrystalline diamond film, the density of wrinkles decreased, and the wavelength of each wrinkle was longer.

The researchers also measured the level of strain - the amount of deformation caused by the stress in the layers - across the diamond windows.

"Measuring strain across a 2D material in a conventional way is very complicated and expensive, but we were able to devise a technique where we instead determined the surface profile of the diamond window -- how high each point is -- and then developed algorithms to retrieve the strain values," said Dr. Janssens.

The team then used the experimental results to develop a theoretical model, which they believe could be used to design devices with functional wrinkles or reduced wrinkling.

The model also expanded on the experiments, suggesting that devices containing a negative curvature would see further reductions in wrinkling.

Going forward, the unit are interested in creating diamond windows in the shape of rings, rather than circles. While more challenging to fabricate, these structures have two boundaries between the suspended and attached portions of nanocrystalline diamond films - one with positive curvature and one with negative curvature - allowing the scientists to use experiments to further explore the validity of their model.

"Overall, this study integrates theory, computation, experimentation, and analysis," said Prof. Fried. "The interdisciplinary environment fostered at OIST made this work possible and has ultimately allowed all the researchers of our unit to collaborate and expand their expertise."

Researchers at Kumamoto University in Japan have discovered that uric acid, an antioxidant, protects against declining lung function from age or lung disease, especially in women. High uric acid levels can cause health problems such as gout and renal damage, but this study showed that it protects against lung function decline in females. The function of uric acid and other antioxidants in the lungs, as well as gender differences, will likely be considered for prospective management of lung diseases.

While uric acid can cause gout and kidney disease, it is also a known antioxidant--reducing tissue damaging oxidative stress--and is an essential factor for the living body. It can be found in lung tissue but, until now, its function in the lung was unknown. Because of this, and the fact that men and women differ in the degree of lung function decline that accompanies aging and disease, the researchers decided to analyze the role of uric acid in the lungs.

First, they created a murine lung disease model with high uric acid levels in the blood. Compared to humans, mouse uric acid levels are low so the researchers used gene disruption and inhibitor treatments to suppress uricase (UOX), a murine urate-metabolizing enzyme, to increase uric acid levels. They then created lung disease mouse model with emphysema or chronic obstructive pulmonary disease (COPD) with elevated uric acid blood levels. They found that uric acid levels were high in female mice that had UOX gene disruption or UOX inhibitor treatments, and that their respiratory functions had improved. On the other hand, when uric acid levels in male mice increased, symptoms of lung disease did not change or even worsened. This surprising finding suggests that uric acid protects the lungs of female mice.

Further experiments revealed that uric acid also suppresses oxidative stress in human lung epithelial cells. An analysis of female lung epithelial cells showed that the antioxidant effect of uric acid disappeared in the presence of female hormones. In other words, women with lower female hormone levels are more likely to benefit from the antioxidant effect of uric acid in lung tissue. This suggests that the protective effect of uric acid may be strongly exerted in elderly women who have decreased female hormone levels.

Epidemiological analyses targeting people 50 years or older revealed that uric acid levels and FEV1/FVC ratios (an indicator of respiratory function) were high among females with the SLC2A9/GLUT9 T/T genotype--a genotype known to have protective lung function qualities. Structural equation modeling further showed that this genotype is involved in lung function maintenance via elevated uric acid levels. Previous studies reported that female hormone therapy for menopausal women has a positive effect on maintaining lung function. It is therefore suggested that the antioxidative effect of uric acid is particularly important for the protection of lung function in women whose hormones decrease with menopause.

This is the first study to show that uric acid protects women against the lung function decline that progresses with aging and lung disease.

"The results of this study strongly suggest that antioxidants such as uric acid are important for maintaining lung function in women with advanced age and advanced disease," said study leader Associate Professor Tsuyoshi Shuto. "We also previously reported that the antioxidant vitamin C and the antioxidant N-acetylcysteine slow the progression of lung disease. In the future, we expect that the functions of uric acid and other antioxidants in the lungs will be reexamined, taking gender differences into account, so that they may be applied to improve health and treat lung diseases."

The team then examined these liquid jets using soft X-rays at BESSY II and subsequently has been able to analyse this process in detail from the data they acquired combined with theoretical predictions. The work has been published in Science and appears even on the cover.

What distinguishes metals from other materials is generally well understood. In a metal, some of the atoms' outer electrons move through the crystalline lattice in what is called a conduction band. This is how metals conduct electric current. In contrast to metals, the ions in electrolytes are disordered and electrical conductivity even decreases with increasing ion concentration. So how does metallic behaviour arise from the many individual metal atoms dissolved in the electrolyte? At what concentration and exactly how does a conduction band form, and how do the electron orbitals behave during this process?

A large international collaboration has now developed a sophisticated experimental technique that makes it possible to observe these processes for the first time. 17 authors at renowned institutes in Kyoto, Los Angeles, Paris, Prague and Berlin have contributed their expertise.

One of the main authors is Dr. Bernd Winter from the Fritz-Haber-Institut Berlin, who set up the experiment at BESSY II together with Dr. Robert Seidel, head of the HZB Operando Interfacial Photochemistry Young Investigator Group and his team. As a first step, the physicists dissolved alkali metals such as lithium and sodium in ammonia, forming solutions. The metal atoms become positively charged ions and their outer electrons are drawn into the liquid ammonia solution. These solutions are slightly blue at low metal concentrations, but as the metal concentration is increased, the blue colour becomes more intense until it transitions to a golden hue. This surprising color change is related to the electron states in the dissolved metals, the scientists assumed.

Using the SOL³PES instrument at the BESSY II U49/2-PGM-1 beamline that Seidel supervises, the team was able to study different concentrations of the alkali-metal/ammonia solutions as extremely narrow liquid jets under ultra-high vacuum using photoelectron spectroscopy. The solutions had to be cooled to about -60 degrees Celsius. At this temperature, ammonia is a liquid and its evaporation is sufficiently low. This enabled them to actually measure the transition from electrolyte to metal precisely.

"We were able for the first time to capture the photoelectron signal of the excess electrons in liquid ammonia. We observed a narrow peak at about 2 electron volts (eV), which indicates the presence of dissolved electrons and dielectrons", says Winter. Seidel adds: "This also explains why the solution is initially blue at low and medium concentrations of metal ions: the solution absorbs light in the red region, which corresponds to the peak at 2 eV." As a result, the solution appears slightly blue as long as there are only individual dissolved electrons. This blue colour intensifies with the appearance of the first "electron pairs"- called dielectrons. The colour changes to golden as the alkali metal concentration increases. At the same time, this narrow absorption peak widens into a band with a sharp Fermi edge in the spectrum, as is characteristic of metals, accompanied as well by signals associated with collective excitations (plasmons) - characteristic of free metallic electrons.

"The groups headed by the theoreticians Pavel Jungwirth and Ondrej Marsalek in Prague had been able to model the electronic structure of solvated electrons in solution in advance", says Winter. "We found that the binding energies they calculated fit very well with our experimentally determined values. This gave us confidence in our interpretation of the X-ray data."

The work is being published in Science because it makes an important contribution to the fundamental understanding of the transition from a non-conducting to metallic character in electrolytes. Moreover, there are even practical applications of solvated electrons, i.e electrons in solution, in organic chemistry as reducing agents for aromatic systems, in battery eletrolytes, and electronic capacitors.

Tsukuba, Japan - The presence of dreaming during rapid-eye-movement (REM) sleep indicates that memory formation may occur during this sleep stage. But now, researchers from Japan have found that activity in a specific group of neurons is necessary for memory consolidation during REM sleep.

In a study published this month in Neuron, researchers from University of Tsukuba and the University of Tokyo have revealed that adult-born neurons (ABNs) in the hippocampus, which is a brain region associated with memory, are responsible for memory consolidation during REM sleep.

Neurogenesis, the process by which new neurons are formed, takes place in the hippocampus throughout the lifespan of animals, including humans. At present, little is known about the contribution of ABNs to memory formation during sleep, something the researchers at University of Tsukuba and the University of Tokyo aimed to address.

"Although ABNs in the dentate gyrus region of the hippocampus are rare and not frequently active, they show heightened plasticity, indicating their potential role in the formation of memories," says lead author of the study Associate Professor Masanori Sakaguchi. "We wanted to investigate how manipulating ABN activity would affect memory consolidation in freely behaving mice."

To do this, the researchers exposed mice to a context-specific fear memory task. Then, they recorded activity in specific ABNs across the learning, consolidation, and retrieval stages of memory.

"We found that young ABNs that were most active during REM sleep after the memory task were most likely to have been active during learning," explains Professor Masashi Yanagisawa, the other senior author of the study. "Further, when we then examined the effects of optogenetic silencing on young ABN activity during sleep, we found that the consolidation of contextual fear memories was impaired."

Their data represent causal evidence that activity in young ABNs during REM sleep is necessary for memory consolidation. This is an important development as the activity and role of ABNs in memory consolidation during sleep was previously unknown, as was the type of hippocampal neuron responsible for memory consolidation during sleep.

"During learning, specific ABNs may undergo synaptic changes that enable memory consolidation. Further, these synaptic changes may depend on synchronization between specific ABNs and brain oscillations that take place during REM sleep," says Professor Sakaguchi.

Clarification of these possibilities may lead to a deeper understanding of how memories are formed, retrieved, and consolidated, and could facilitate the development of new treatments for memory disorders.

The increase in antibiotic resistance and the lack of new antibiotics is currently a major global health problem. Reducing the use of antibiotics appears to be one of the only solutions to preserve their effectiveness and limit the emergence of resistance. Relatively long courses of treatment remain standard, however, although they seem to be based on medical tradition rather than on sound scientific evidence. For example, in the case of bacteraemia, a common but potentially dangerous bloodstream infection, it is common practice to automatically prescribe a 14-day course of antibacterial treatment. Physicians from the University of Geneva (UNIGE), the University Hospitals of Geneva (HUG), the University of Lausanne (UNIL), the Centre Hospitalier Universitaire Vaudois (CHUV) and the Cantonal Hospital St. Gallen, in Switzerland, wanted to test, in a multicentre study including more than 500 patients, whether a shorter treatment, which therefore would be less likely to select for resistance, was possible. Their results, published in the journal JAMA, show that a treatment duration reduced by half is equally effective. In addition, the scientists demonstrate that tailoring the antibiotic regimen to each patient's individual characteristics and disease patterns would allow the drug dose to be reduced even further without loss of therapeutic benefit. This work leads to new recommendations aimed at promoting the rational use of antibiotics, which remain our best weapons against bacteria responsible for many diseases.

Bacteraemia is a blood infection that usually originates from urinary or pulmonary infections that can be caused by several types of bacteria. Although very common in the elderly, it is still severe and must be treated effectively by antibiotics. Most physicians routinely prescribe an antibiotic for 14 days, even if the patient's condition improves rapidly. "We only have a limited catalogue of antibiotics, the effectiveness of which is constantly decreasing", explains Angela Huttner, a researcher in the Departments of Pathology and Immunology and of Medicine at UNIGE Faculty of Medicine and a physician at HUG Division of Infectious Diseases, who led this work. "We must therefore absolutely preserve our resources, and this means using them sparingly. Nevertheless, we had to demonstrate that a shorter treatment did not preclude the recovery of patients." Indeed, since the 1990s, the development of new antibiotics has nearly come to a halt due to the pharmaceutical industry's lack of interest in these unprofitable drugs, and the paucity of new therapeutic targets.

Fourteen days, seven days or less?

The research team set up a large-scale randomized study involving 504 patients recruited in three Swiss hospitals between April 2017 and May 2019. "We randomly divided our sample into three groups", says Werner Albrich, an infectious diseases physician at St. Gallen Hospital. "The first group, the control group, received the usual 14-day course of antibiotics. The second group received the same antibiotic, but only for seven days. The third group had their antibiotic duration determined individually, depending on each patient's level of inflammation."

Towards personalised treatment

"In addition, our work also shows that it is possible to customize treatment for each patient", adds Pierre-Yves Bochud, a professor at CHUV/UNIL Division of Infectious Diseases. "This requires daily measurement of CRP - a protein present in the blood that marks inflammation - a routine test that is carried out anyway in the case of bacteraemia." In this study, the scientists stopped the treatment course in the patients assigned to the third group as soon as their individual CRP level had dropped from its peak by 75%, though ensuring a minimum of five days of antibiotics, with the same success as the other two groups.

In addition, they identified certain risk factors: older age, in particular, as well as the pathogen involved. Escherichia coli is indeed more easily eliminated than other bacteria, regardless of the duration of treatment. "The principle of 'one size fits all' is less and less true in medicine, and the characterization of biomarkers of inflammation could lead to truly personalized treatments, while limiting the risk of resistance. As a first step, we can already recommend reducing the treatment of bacterial bloodstream infections to seven days", the authors conclude.

WESTMINSTER, Colorado - June 05, 2020 - Greenskeepers and landscape managers consider annual bluegrass to be a significant pest. It has an unsightly appearance, competes with desirable grasses, and produces an uneven surface that affects golf and other sports. In addition, the weed has now developed resistance to multiple herbicides.

In an study featured in the journal Weed Science, researchers in Australia examined 31 populations of annual bluegrass suspected to be herbicide resistant. All 31 were found to be resistant to multiple turf herbicides. Three populations had evolved resistance to herbicides with five different mechanisms of action.

The team confirmed instances of resistance to propyzamide, simazine, rimsulfuron, foramsulfuron, endothall and pinoxaden. Levels of resistance ranged from two-fold for propyzamide and simazine to 56-fold for rimsulfuron.

It is clear the options for effective control of annual bluegrass are narrowing. "The extensive amount of herbicide resistance and the limited nonchemical methods available will make it challenging to manage multiple resistant annual bluegrass in turf," says Rajesh Barua of the University of Adelaide.

To learn more, read the article "Incidence of multiple herbicide resistance in annual bluegrass (Poa annua) across southeastern Australia," available online, free for a month.

What does it mean to be a metal and how is a metal formed? These seem like textbook questions with a simple answer: Metal is characterized by free electrons which give rise to its high electric conductivity. But how exactly is a metallic conduction band formed from originally localized electrons and what is the corresponding microscopic picture for the material involved?

In collaboration involving scientists from the Czech Republic, USA, and Germany, the research team of Pavel Jungwirth from the Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences (IOCB Prague) has succeeded in mapping at the molecular level the electrolyte-to-metal transition in alkali metal - liquid ammonia solutions using a combination of photoelectron spectroscopy (PES) and electronic structure calculations. The results of their research were recently published as a Research Article in Science, one of the most prestigious scientific journals in the world, which also selected the study for cover image.

Alkali metals dissolved in liquid ammonia represent archetypal systems to explore the transition from blue electrolytes at low concentrations to bronze or gold colored metallic solutions (with conductivity comparable to a copper wire) with higher concentrations of excess electrons. At the same time, PES represents an ideal tool for establishing the electronic structure pertinent to this transition. As an ultra-high vacuum technique, PES was long thought to be incompatible with volatile liquids until the technique of liquid microjets was developed for water and aqueous solutions. However, it was only in 2019 that the group of Pavel Jungwirth in collaboration with colleagues at the University of Southern California and at the BESSY II synchrotron in Berlin performed first successful PES measurements on a refrigerated polar liquid - pure liquid ammonia.

"This is what happens when you give a theory group a bit of lab space to play," says Pavel Jungwirth of the decision of the Institute's director to grant him a small laboratory.

This achievement opened the door to PES studies of alkali metal - liquid ammonia systems (as reported in the present paper in Science), which map the electrolyte-to-metal transition for lithium, sodium, and potassium dissolved in liquid ammonia by means of PES using soft X-ray synchrotron radiation. In this way, researchers captured for the first time the photoelectron signal of excess electrons in liquid ammonia as a peak at around 2 eV binding energy. This peak then broadens asymmetrically toward higher binding energies upon increasing the alkali metal concentration, gradually forming a conduction band with a sharp Fermi edge accompanied by plasmon peaks, both of which being fingerprints of the nascent metallic behavior.

Together with state-of-the-art electronic structure calculations, these measurements provide a detailed molecular picture of the transition from a non-metal to a metal, allowing us to better understand the onset of metallic behavior characterized by properties such as the very large electric conductivity.

"Hopefully the present work on metallic ammonia will open the path to realizing our most 'explosive' idea: The preparation of metallic water by very carefully mixing it with alkali metals," concludes Pavel Jungwirth.

Silicon is the main material in electronic engineering. All information and computing technologies that play a key role in modern civilization are based on silicon: computers, communications, astronautics, biomedicine, robotics and much more.

According to Alexey Mikhaylov, Head of the laboratory at the Lobachevsky University's Research Institute for Physics and Technology, the main stumbling block on the way to increasing the speed of integrated circuits is the limited speed of electrical signal propagation in metal interconnection wiring. "This requires the replacement of metal interconnections with optical waveguides and, thus, the transition from traditional electronics to optoelectronics, where the active elements are light emitters and receivers rather than transistors", says Alexey Mikhaylov.

Silicon shows satisfactory performance as light receiver, but, unlike A3B5 semiconductors, is a poor light emitter because of an indirect bandgap of this semiconductor. This feature of its electronic structure, according to the laws of quantum mechanics, strictly speaking, prohibits the emission of light (luminescence) under external excitation.

"It would be very undesirable to refuse from silicon at a new stage, as we would have to abandon the perfectly developed technology for mass production of integrated circuits. This would involve huge material costs, not to mention the environmental problems that arise when working with A3B5 materials," states Professor David Tetelbaum, Leading Researcher at Lobachevsky University.

Scientists are trying to find a way out of this situation by either using nanocrystalline silicon, or by coating silicon with films of other light-emitting materials. However, the emissivity (luminescence efficiency) of silicon nanocrystals is still insufficient for practical applications.

Besides, silicon nanocrystals emit in the area at the "red" edge of visible radiation, while many technical applications, in particular in fiber optics communication technology, require longer wavelengths (about 1.5 μm). The use of "foreign" material layers on silicon substrates, however, is poorly compatible with the traditional silicon technology.

An effective way to solve this problem is to introduce in silicon a special type of linear defects known as dislocations. Researchers have come to the conclusion that a high concentration of dislocations can be achieved in the silicon surface layer by irradiating it with silicon ions with the energy of the order of a hundred keV and then annealing it at high temperatures. In this case, silicon emits light at exactly the right wavelength - close to 1.5 μm.

"The luminescence intensity appears to depend on the implantation and annealing conditions. However, the main problem with dislocation-related luminescence is that it is most pronounced at low temperatures (below ~25 K) and decays quickly as the temperature rises. Therefore, it is very important to find ways to increase the thermal stability of dislocation-related luminescence", continues Alexey Mikhaylov.

Lobachevsky University scientists together with their colleagues from the RAS Institute of Solid State Physics (Chernogolovka) and the Alekseev State Technical University (Nizhny Novgorod) have made significant headway in solving this problem with the support of the Russian Foundation for Basic Research (grant No.17-02-01070).

Previously, it was found that one way to achieve dislocation-related photoluminescence in silicon samples is to implant silicon ions into silicon (self-implantation) with subsequent annealing. This proved to be not the only benefit of the implantation technology, when the team of Lobachevsky University discovered that additional boron ion doping can enhance the luminescence. However, the phenomenon of enhanced luminescence properties alone does not solve the main problem. Moreover, it remained unclear how boron ion doping affects the luminescence thermal stability, which is a key parameter, and under what conditions (if any) such effect will be most pronounced.

In this study, scientists have confirmed experimentally the increase in thermal stability of silicon doped with boron ions. Moreover, the effect is nonmonotonically dependent on the boron dose, and in a certain range of doses, a pronounced second maximum in the region of 90 to 100 K appears on the intensity versus temperature curve, along with the usual low-temperature maximum in the region of 20 K.

"It is important to note that the "beneficial" effect of boron is unique in the sense that the replacement of boron ions by another acceptor impurity does not lead to the effect described above. After refining the modes of boron ion doping and heat treatment of silicon samples where centers of dislocation-related luminescence were formed by irradiation with silicon ions, we have found that with the highest previously used dose of boron ions and an additional heat treatment at 830° C, it is possible to achieve a measurable level of luminescence at room temperature," concludes Professor Tetelbaum.

The results obtained during further optimization of the implantation and heat treatment conditions brighten up the prospects for silicon application in optoelectronics.

A study about grazing exclusion using fences on the Tibetan Plateau(TP) by a team of researchers from China (Dr. Jian Sun's research team at Institute of Geographic Sciences and Natural Resources Research, Chinese Academy of Sciences), Australia and Japan recently published in Science Bulletin, and commented in the Editors' choice column of Science.

Grazing exclusion using fences is a big issue across TP. Given the complexity of the effects of fencing on ecosystem processes, livestock carrying capacity, wildlife habitat, and herders' livelihoods and culture, authors do not consider the existing studies on the topic to be conclusive and suggest that further studies, especially long-term field research, are urgently needed. Nevertheless, according to results, they propose the following methods for improving current grassland management policies on the TP: (1) traditional free grazing is encouraged to maintain or resume the traditional grazing practices and culture if the grasslands have not been degraded; (2) in case fencing is necessary, such as in a severely overgrazed area, short-term fencing of four-eight years is preferable, with removable fences that can be reused elsewhere afterwards; (3) high fence density and connectivity should be avoided, and the existing long-term fences should be removed for the benefits of wildlife; and (4) regular and comprehensive assessments are needed to ensure the policy is being effectively managed to deliver benefits in a timely fashion.

COVID-19 restrictions in France should be lifted with caution because of the high risk of a second wave of infection, reports a new study, published in Frontiers in Medicine, which confirms the lockdown restrictions were successful in reducing the spread of this virus.

"The lockdown was effective at reducing the transmission rate of COVID-19 but the potential for a second wave of infections is extremely high," reports Dr Lionel Roques, first author of this research, based at the National Research Institute for Agriculture, Food and Environment (INRAE) in France.

He cautions, "Herd immunity is far from reached and many infectious cases still exist. It is therefore essential to follow restrictions to maintain an effective transmission rate value, or R-number, that remains below 1."

The R-value is an important way of measuring the transmission of diseases. When it falls below 1, each infected person will infect less than one other person, meaning the number of new infections will fall over time.

"COVID-19 was spreading rapidly in France when the World Health Organization assigned the virus pandemic status in early March 2020," explains Roques. "It arrived in small numbers in December 2019 and remained largely undetected, so the first battle, that of any early intervention to stop the spread of the disease, was already lost as the R value exceeded 1."

The actual number of infected cases was difficult to calculate. There were too many unreported cases and variations in testing strategies meant that scientists did not know who and how many had been infected.

"We thought that methods developed for our previous work may be able to help. By using mathematical equations that account for unreported cases and linking these to other equations that calculate the most probable number of infected cases, we could work out the R-number to understand the transmission rate of COVID-19," says Roques.

Widely used by ecologists, this mathematical approach has rarely been used to assess the spread of disease in humans. By using this method, Roques calculated an R-value of 3.2 at the start of the lockdown in France and an infection fatality rate of 0.8%.

"The virus was spreading so fast that the second battle, that of the containment of the epidemic, was lost and so lockdown was initiated. Our calculations suggest the restrictions were very efficient at slowing the transmission of COVID-19, with a 7-fold reduction in the R-number to 0.47," he explains.

Roques continues, "Though this third battle was won, our study suggests the potential for a second wave is extremely high. At the end of the restrictions in May, we calculate that 4% of the French population will have been infected by COVID-19 and this is far too low to reach herd immunity. The threshold for this is 69%."

The researchers also estimate that many infectious cases remain, so a second wave could be initiated with more infected cases than the first wave.

Roques highlights that further research is needed, "Crucially, we need to look at how the R-number and number of infected cases differ across the country. For example, in urban vs. rural communities. Having this information will help us to understand how other factors, which can vary within a country, such as the climate, population density and age of patient will affect the spread of this disease."

June 5, 2020-- A new paper published online in the Annals of the American Thoracic Society examines ventilation and medication strategies that can help avoid psychological trauma for severe COVID-19 survivors treated for acute respiratory distress syndrome (ARDS) with mechanical ventilation.

In "Air Hunger and Psychological Trauma in Ventilated COVID-19 Patients: An Urgent Problem," Richard Schwartzstein, MD, and co-authors examine the medical literature and compare evidence-based practices with outdated or misguided practices that are still in use. These outdated practices may lead to psychological trauma for patients who suffer from "air hunger" - a feeling of severe breathlessness - due to ventilation strategies that protect the lungs but may cause other problems.

"Numerous studies have demonstrated that lungs injured by infection leading to ARDS and respiratory failure can be further injured if the size of the breath provided by the ventilator is too large or the pressure used to inflate the lung is too great," said Dr. Schwartzstein, chief, pulmonary, critical care and sleep medicine, Beth Israel Deaconess Medical Center and professor of medicine, Harvard Medical School. "So, we manage these patients with low breath sizes to try to protect their lungs from additional damage. This makes the sensation of air hunger much worse, however."

When the drive to breathe is very high, as it might be with exercise or an infection, a person often develops a sensation of air hunger, or a strong urge to breathe as well as an increase in the number of breaths a minute and the size of the breath; under these conditions, restricting the breath size can make the sensation of breathing discomfort worse.

In looking at recent reports of patients with severe COVID-19 infections admitted to ICUs in Seattle, as well the authors' own ICUs at Massachusetts General Hospital and Beth Israel Deaconess Medical Center, 88-91 percent of patients had shortness of breath prior to intubation and mechanical ventilation.

The authors stated, "With the likelihood that hundreds of thousands of short-of-breath patients around the world during this pandemic will require low tidal volume mechanical ventilation, we are concerned about the potential for mass psychological trauma among the survivors, induced by untreated air hunger." Research has shown that among ICU survivors, the experience of air hunger is often associated with post-traumatic stress disorder (PTSD).

Dr. Schwartzstein and colleagues believe that the problem is solvable, however. "Physicians who are treating ARDS due to COVID-19, some of whom may not be accustomed to treating patients with respiratory failure, must first be aware of the problem and then consider means by which air hunger can be ameliorated."

Dr. Schwartzstein points to a mistaken belief that paralysis reduces breathlessness. As a result, patients are often treated with neuromuscular blocking drugs, which serve as muscle relaxants, to minimize lung injury. "This does not diminish air hunger," he said. Paralysis may make the situation worse and prevents the patient from communicating or demonstrating their discomfort. While patients are often sedated as well, most sedatives that have been studied do not relieve shortness of breath.

The researchers refer to studies of the use of opiates for these patients: "Opiates are the most reliable agent for symptomatic relief of air hunger - they seem to act both through depression of ventilatory drive and ascending perceptual pathways, as they do with pain."

"There has been a tendency to equate 'sedation' with an 'anti-dyspnea' effect and the push has been to use sedation primarily because patients are often anxious and agitated when being treated with mechanical ventilation," said Dr. Schwartzstein. "We now know that many sedatives do not relieve dyspnea and we urge doctors to use opiates for dyspnea and sedatives, when needed, for anxiety and agitation."

Scientists from the University of Nottingham have developed a new way to control harmful fungi, without the need to use chemical bioactives like fungicides or antifungals.

Fungi cause diverse, serious societal and economic problems in the UK and globally. As well as causing fatal diseases in humans, fungi devastate food crops and spoil valuable products and materials. This has led to an antifungals/fungicide industry worth around $30bn globally.

There are tight regulations around the use of fungicides and antifungals and there is also growing resistance of fungi to these agents.

In a paper published today in Science Advances, experts from the University's Schools of Life Sciences, Pharmacy, and Engineering, show how they have developed an innovative solution to tackle fungi, by passively blocking fungal attachment to surfaces using a coating of (meth)acrylate polymers, and so negating the need to use potentially harmful anti-fungals or other bioactive chemicals.

Through previous work, the team found different combinations of fungicides which worked against fungi and also produced new understanding of preservative action against spoilage fungi.

Although these advances meant less use of certain fungicides and chemicals, frequent tightening of regulations around usage are restricting the take up of technologies that still rely on bioactive agents, while spread of resistance worsens the problem. Consequently, potential bioactive-free technologies for combatting fungi are highly attractive to the industry.

In this latest study, scientists show an alternative fungal control strategy, which doesn't have the 'killing affect' of fungicides.

The team identified polymers that resist the attachment of different kinds of fungi, including pathogens. They screened hundreds of (meth)acrylate polymers in high throughput, identifying several that reduce attachment of the human pathogen Candida albicans, the crop pathogen Botrytis cinerea, and other fungi.

Specific chemical features of the polymers were associated with weak fungal attachment. The materials were not toxic, supporting their passive utility. The team developed a formulation with the materials for inkjet-based 3D printing. Printed voice-prosthesis components showed up to 100% reduction in C. albicans biofilm versus commercial materials. Furthermore, spray-coated leaf surfaces resisted fungal infection, with no plant toxicity.

A similar approach against bacterial pathogens is also now being developed for a catheter coating to prevent infections in patients.

Professor Simon Avery, from the School of Life Sciences at the University is a lead investigator on the paper, he said: "This is the first high-throughput study of polymer chemistries resisting fungal attachment.

"Our engagement to date with industry has highlighted a clear need for a new approach to control fungi and the major socioeconomic problems that they cause, as the value of existing strategies using bioactives (antifungals, fungicides) is eroded by growing resistance and regulations.

"This passive, anti-attachment technology that we have been developing addresses this need. We have been able to show that different polymers are effective in resisting diverse fungi that have broad socio-economic impacts."

The clinical presentation of Covid-19 varies from patient to patient and understanding individual genetic susceptibility to the disease is therefore vital to prognosis, prevention, and the development of new treatments. For the first time, Italian scientists have been able to identify the genetic and molecular basis of this susceptibility to infection as well as to the possibility of contracting a more severe form of the disease. The research will be presented to the 53rd annual conference of the European Society of Human Genetics, being held entirely on-line due to the Covid-19 pandemic, today [Saturday].

Professor Alessandra Renieri, Director of the Medical Genetics Unit at the University Hospital of Siena, Italy, will describe her team's GEN-COVID project to collect genomic samples from Covid patients across the whole of Italy in order to try to identify the genetic bases of the high level of clinical variability they showed. Using whole exome sequencing (WES)1 to study the first data from 130 Covid patients from Siena and other Tuscan institutions, they were able to uncover a number of common susceptibility genes that were linked to a favourable or unfavourable outcome of infection. "We believe that variations in these genes may determine disease progression," says Prof Renieri. "To our knowledge, this is the first report on the results of WES in Covid-19."

Searching for common genes in affected patients against a control group did not give statistically significant results with the exception of a few genes. So the researchers decided to treat each patient as an independent case, following the example of autism spectrum disorder. "In this way we were able to identify for each patient an average of three pathogenic (disease-causing) mutations involved in susceptibility to Covid infection," says Prof Renieri. "This result was not unexpected, since we already knew from studies of twins that Covid-19 has a strong genetic basis."

Although presentation of Covid is different in each individual, this does not rule out the possibility of the same treatment being effective in many cases. "The model we are proposing includes common genes and our results point to some of them. For example, ACE2 remains one of the major targets. All our Covid patients have an intact ACE2 protein, and the biological pathway involving this gene remains a major focus for drug development," says Prof Renieri. ACE2 is an enzyme attached to the outer surface of several organs, including the lungs, that lowers blood pressure. It serves as an entry point for some coronaviruses, including Covid-19.

These results will have significant implications for health and healthcare policy. Understanding the genetic profile of patients may allow the repurposing of existing medicines for specific therapeutic approaches against Covid-19 as well as speeding the development of new antiviral drugs. Being able to identify patients susceptible to severe pneumonia and their responsiveness to specific drugs will allow rapid public health treatment interventions. And future research will be aided, too, by the development of a Covid Biobank accessible to academic and industry partners.

The researchers will now analyze a further 2000 samples from other Italian regions, specifically from 35 Italian Hospitals belonging to the GEN-COVID project.2

"Our data, although preliminary, are promising, and now we plan to validate them in a wider population," says Prof Renieri. "Going beyond our specific results, the outcome of our study underlines the need for a new method to fully assess the basis of one of the more complex genetic traits, with an environmental causation (the virus), but a high rate of heritability. We need to develop new mathematical models using artificial intelligence in order to be able to understand the complexity of this trait, which is derived from a combination of common and rare genetic factors.

"We have developed this approach in collaboration with the Siena Artificial Intelligence Lab, and now intend to compare it with classical genome-wide association studies3 in the context of the Covid-19 Host Genetics Initiative, which brings together the human genetics community to generate, share, and analyse data to learn the genetic determinants of COVID-19 susceptibility, severity, and outcomes. As a research community, we need to do everything we can to help public health interventions move forward at this time."

Chair of the ESHG conference, Professor Joris Veltman, Dean of the Biosciences Institute at Newcastle University, Newcastle upon Tyne, UK, said: "We are very excited to have this work on the genetics of COVID19 susceptibility presented as one of our late-breaking abstract talks at the ESHG. Our Italian colleagues present the first insight into the role of genetic susceptibility influencing the severity of the response to a COVID19 infection. It needs to be expanded to encompass much larger populations, but it is impressive to see the speed at which research on this virus has proceeded in just a few months' time."

A research team from Genethon, in collaboration with teams from CNRS/Inserm and from the biotechnology company Spark Therapeutics, announced today in Nature Medicine that it has succeeded in inhibiting the immune response induced by AAV antibodies present as a result of natural immunity or following gene therapy, thanks to the IdeS enzyme. This result opens up new therapeutic prospects and the possibility of treating more patients.

Gene therapy consists of injecting a therapeutic gene into an organism using a vector, a "means of transport" able to cross all biological barriers through the cell and into the nucleus. The most commonly used vectors are derived from viruses, such as AAVs (adeno-associated viruses), used particularly in gene therapy targeting the muscles, liver, eyes, etc. In many cases, once it comes into contact with this virus, the body develops immunoglobulins (IgG) known to be neutralising, i.e. specific antibodies that inhibit AAVs. It is considered that between 30% and 50% of humans are naturally immunized against most AAVs used for therapeutic purposes. As a result, a large number of patients cannot currently benefit from AAV gene therapy. Moreover, a first injection of an AAV leads to an immune response against the vector, precluding any subsequent AAV gene therapy.

Overcoming this impediment is an essential factor in treating the maximum number of patients. Therefore, the teams lead by Giuseppe Ronzitti, a Genethon researcher, Sébastien Lacroix-Desmazes, a CNRS-Inserm researcher, and Federico Mingozzi from the biotechnology company Spark Therapeutics, have used animal models to test the efficacy of the IdeS enzyme, an endopeptidase that naturally reduces the action of antibodies, in order to neutralise the immune response due to IgG immunoglobulins.

The study was carried out in two steps:
Researchers injected the IdeS enzyme into subjects with neutralizing anti-AAV IgG before injecting the gene therapy vector of the same serotype and then observed that the IdeS treatment neutralized the action of the antibodies. This first step provided proof of the efficacy of this approach for subjects with natural immunity.

Then, the teams tested this approach with a view to the possible reinjection of gene therapy drugs. So, they administered a first dose of AAV vector, then a second dose after injection of IdeS. They observed that IdeS, by reducing the level of circulating antibodies, allowed the re-administration of the vector.

These two studies demonstrate that treatment with IdeS allows repeated administration of AAV gene therapy. This is a significant and promising step forward in the treatment of rare genetic diseases because, if the efficacy of this technique is confirmed in humans, it will make it possible to treat patients at the first signs of the disease and to re-inject a gene therapy product if necessary.

"These studies should enable us to test this innovative approach in humans and thus, in the long term, to give AAV-positive patients the possibility of benefiting from gene therapy, despite the presence of antibodies. This could also make it possible to treat patients as soon as the first symptoms of the disease appear (affecting the liver, for example) and, if necessary, to re-administer the gene therapy treatment in an effective manner," stresses Christian Leborgne, research engineer at Genethon.

"This study represents an important step towards solving a complex and fundamental problem, namely the repeated administration of gene therapy treatments to patients who may need them, and also the treatment of patients who today are not eligible for gene therapy due to the existence of neutralizing antibodies in their systems. This study highlights, once again, the expertise of our researchers, who are imagining and developing new approaches to make gene therapy even more effective and to increase the number of patients able to access it," says Frédéric Revah, Chief Executive Officer of Genethon.

n 2017 and 2019, the German Institute for Quality and Efficiency in Health Care (IQWiG) had already examined the advantages and disadvantages of ribociclib in combination with an aromatase inhibitor or fulvestrant in comparison with the appropriate comparator therapy in patients after menopause, with hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer. Since the assessments were based on ongoing studies, the Federal Joint Committee (G-BA) had limited its corresponding decisions.

After expiry of the decisions, IQWiG now reassessed the combinations on the basis of further data from the same studies. According to the findings, an added benefit is not proven for initial endocrine therapy with ribociclib in combination with the aromatase inhibitor letrozole and for subsequent endocrine therapy with ribociclib plus fulvestrant. For initial endocrine therapy with ribociclib plus fulvestrant, in contrast, there is now an indication of a minor added benefit.

Newer data confirm survival advantages, but also severe side effects

In the first assessment conducted in 2017, on the basis of the data from the ongoing MONALEESA-2 study available at that time, the Institute found the drug in combination with an aromatase inhibitor to have lesser benefit than the comparator therapy due to partly very severe side effects. In 2019, the survival advantage for the combination with fulvestrant shown in the also still ongoing MONALEESA-3 was outweighed by the severe side effects; the resulting conclusion was therefore: An added benefit is not proven.

The new data cut-offs from both studies now confirmed the survival advantages for the combination with fulvestrant, and for the first time showed survival advantages for the combination with an aromatase inhibitor, but also confirmed the major disadvantages: Women treated with ribociclib developed severe side effects much more frequently than study participants in the comparator arms of the studies, particularly severe neutropenia. This means that the number of neutrophil granulocytes - immune cells which are essential for fighting infection - in their blood was too low.

In initial endocrine therapy for the advanced stage, these negative effects did not completely call into question the survival advantage of ribociclib plus fulvestrant versus placebo plus fulvestrant, but they resulted in a downgrading of the extent of the added benefit. An indication of a minor added benefit remained.

An added benefit is not proven for two of three research questions

In women who have already received endocrine therapy for the advanced stage, there was no statistically significant advantage in overall survival under ribociclib plus fulvestrant; this was only shown if results of the total study - including patients without pretreatment - were additionally taken into account. This and the major positive effect for emotional functioning in the outcome category "health-related quality of life" (but only for patients aged 65 years and older) did not have greater weight in the assessment than the mostly severe side effects of considerable or major extent, so that an added benefit is not proven for these patients.

Both positive and negative effects were also shown for the combination of ribociclib and the aromatase inhibitor letrozole in comparison with placebo and letrozole. The advantages in overall survival and future perspective (another aspect of the outcome category "health-related quality of life") and the disadvantages in severe side effects (besides the already mentioned neutropenia, also gastrointestinal disorders, infections and infestations) balanced each other out; an added benefit is not proven also in this case.

G-BA decides on the extent of added benefit

The dossier assessments are part of the early benefit assessment according to the Act on the Reform of the Market for Medicinal Products (AMNOG) supervised by the G-BA. After publication of the dossier assessments, the G-BA conducts commenting procedures and makes decisions on the extent of the added benefit.

More English-language information will be available soon (extracts of the dossier assessments as well as easily understandable information on informedhealth.org). If you would like to be informed when these documents are available, please send an e-mail to info@iqwig.de.