Culture

Antibiotic resistance surveillance in the Philippines has moved into the genomic era, enabling better tracking of dangerous bacteria. Researchers at the Centre for Genomic Pathogen Surveillance (CGPS housed at the Wellcome Sanger Institute and The Big Data Institute (BDI), University of Oxford), and the Philippine Research Institute for Tropical Medicine (RITM), set up local DNA sequencing and analysis of drug resistant bacteria in the Philippines. This genomic capacity has enhanced ongoing national infection control including tracking the spread of resistance to last-line antibiotics and identifying drug resistant infections in a hospital baby unit, helping control the outbreak.

Reported in Nature Communications this week, this study shows the power of local genomic sequencing within national surveillance networks in low- and middle-income countries, and could be extended to other locations to tackle the global challenge of antimicrobial resistance.

Antimicrobial resistance (AMR) is a global health problem, with resistance to common antibiotics found in all regions of the world. This means it can be extremely difficult to treat some bacterial diseases such as MRSA, tuberculosis and gonorrhoea, and raises risks of any surgery.

Surveillance of AMR is critical to understand and try to halt its spread, and DNA sequencing can pinpoint resistance mechanisms and uncover transmission patterns. However, genomic surveillance is less common in low- and middle-income countries (LMICs), which are predicted to be the most affected by AMR.

The Philippines has a very well established Antimicrobial Resistance Surveillance Program within the Philippine Department of Health, which uses laboratory-based methods to track antimicrobial resistance. In 2018 the researchers helped set up a DNA sequencing facility within this to build local capacity for genomic surveillance in the Philippines*. This has included establishing local capacity in genomics and data interpretation through shared training.

Samples were sequenced from more than 20 sites across the Philippines, focusing on bacteria that are resistant to the last-line antibiotics, and listed by the World Health Organisation as top priority pathogens for the development of new antibiotics**. The teams collectively analysed the data, creating phylogenetic trees that showed how the bacterial strains are related to each other, and uncovered several high-risk clones.

Combining the genetic findings with epidemiological data allowed the researchers to pinpoint strains in particular locations. In one hospital they identified a cluster of the same strain of carbapenem-resistant Klebsiella pneumoniae in a neonatal intensive care unit, and revealed that this was being spread within the hospital. This evidence enabled the hospital to bolster their infection control team, to control potential future outbreaks.

Dr Celia Carlos, joint lead of the project from the Research Institute for Tropical Medicine, Philippines, said: "Here in the Philippines we have more than 30 years of experience developing laboratory methods to track AMR, with our Antimicrobial Resistance Surveillance Program. Now, working with our partners in the UK, we have established local capacity and expertise for whole genome sequencing in the Philippines, adding genomic surveillance to these other methods. This is helping us to identify emerging resistant strains much faster, so we can understand what is happening, prevent transmission of AMR and save lives."

Dr Silvia Argimón, first author on the paper from the Centre for Genomic Pathogen Surveillance said: "The programme not only helped set up the genomic infrastructure in the Philippines, but also enabled close collaboration between the teams in the UK and the Philippines. This included exchange visits between the researchers and training to transfer ownership of the sequencing, analysis and understanding to the team in the Philippines, and ensured that everyone understood the resourcefulness and challenges of the sentinel sites."

Genomic surveillance allows the team to describe drug-resistant bacteria in terms of their strains, which genes enable the resistance, and how those genes are transferred between bacteria. Through genomics the Philippines now have a greater lens on AMR at the local, the national and international scale, allowing data analysis at a previously difficult level. The data are shared with Philippine public health agencies and with the WHO to inform both local and global understanding of the spread of carbapenam resistance.

Professor David Aanensen, Director of the Centre for Genomic Pathogen Surveillance and joint lead on the project, said: "Understanding national dynamics in antimicrobial resistance is important in every country in the world to prevent spread globally, and new technology and tools that enhance this capacity are required. The work by the Philippines team to establish genomics within a national surveillance network is an exemplar for adoption that could be extended to tackle the global challenge of antimicrobial resistance or other infections. "

Spain is one of the European countries besides the UK and Italy that was particularly hard hit by the coronavirus pandemic in March. Early on, it was not possible to predict the extent of the outbreak. The first case in Spain was a German tourist who brought the virus to La Gomera in the Canary Islands at the end of January; a second case, this time a British tourist, was identified on Mallorca on February 10. Three days later, the first patient in Spain died of COVID-19 (however it was diagnosed later on postmortem)- followed by a rapidly rising death toll. By the end of March, there were more than 238,000 confirmed cases and 29,000 deaths in Spain, out of a total population of almost 47 million. The UK, with a total population of 66 million, had 38,000 deaths at that time, while Italy, with 60 million, had more than 33,000 deaths.

On March 31, 789 COVID-19 patients were receiving treatment at the Hospital Vall d'Hebron in Barcelona, 168 of them on the ICU. But what were the outcomes among end-stage renal disease/ESRD patients (dialysis patients and transplanted patients)? At what rate did they fall ill and what was their prognosis?

At the Opening Conference of the ERA-EDTA Congress, Dr. Maria Jose Soler Romeo presented data gathered at the Hospital Vall d'Hebron. Of 400 dialysis patients with the Vall d´Hebron as a reference hospital, 21 or a good 5% had COVID-19. In the whole of Spain, 238,000 out of 47 million people (about 0.5%) had contracted the disease at that time. The figures obtained from the Hospital Vall d'Hebron on the incidence of COVID-19 are not representative, of course, as it is only one center, but they do indicate a significantly higher rate of infection for dialysis patients. Of the 21 dialysis patients who contracted COVID-19, 15 were discharged, one was on the ICU at the time of the survey, and five had died. The mortality rate in this center was 24%. This high death rate among infected dialysis patients was also verified in an analysis of the Spanish COVID-19 Dialysis/Transplantation Registry, which included a total of 1572 ESRD patients, including 998 HD patients, 51 PD patients and 523 kidney transplant patients. The mortality rate among HD patients was more than 27% for the whole Spain, but was also more than 23% for kidney transplant patients. PD patients had a significantly lower mortality rate of 15%, but their number is so small in proportion that it is almost impossible to make statistically valid statements about this patient group.

The high mortality rate among dialysis patients was also verified in a study that monitored the course of disease in 36 HD patients between March 12 and April 10 in Hospital Gregorio Marañón in Madrid. The death rate here was as high as 30.5%, but what is particularly interesting about this study is that it analyzed predictors of mortality. The conclusion was that, in addition to patient older age and pneumonia, there are three factors that significantly influence the mortality rate among coronavirus-positive dialysis patients: (1) the number of years on dialysis (dialysis vintage), (2) lymphopenia, which describes a low number of special white blood cells (lymphocytes) that protect the body from infections, and (3) elevated LDH levels, a surrogate for tissue damage.

"What we had to learn from nephrologists in Spain is that dialysis patients are more susceptible to the virus and that the risk of patients dying is very high at a rate of 1:4. These patients need special protection. Many studies have shown that even people without symptoms or with asymptomatic symptoms can carry and pass on the virus. In dialysis units, therefore, we cannot rely on always being able to detect infected patients and to isolate them in time. To protect our highly vulnerable patients, it is essential that all the patients and staff be tested on a regular basis in order to minimize the risk of infection in COVID-19 outbreaks. We must continually remind ourselves that, of four coronavirus-positive dialysis patients, one will not survive. Outbreaks in dialysis units must therefore be prevented at all costs", Dr. Soler concluded.

For more than 40 years, scientists and commercial companies have been recreating human skin in laboratories around the world. Yet all of these products lack important aspects of normal skin--hair, nerves, and fat.

In new research, cultured human skin cells embedded with fat and nerves and capable of growing hair are a reality. The achievement represents more than five years of study that started in the laboratory of Karl Koehler, PhD (then at Indiana University School of Medicine) and completed in Koehler's new laboratory at Boston Children's Hospital in the departments of otolaryngology and communication enhancement and plastic and oral surgery research. The technique appears in a paper published this week in Nature.

"In this latest work, we discovered a way to grow both layers of human skin together," says Koehler, referring to the top and bottom layers of human skin (the epidermis and dermis, respectively). "Those cells talk to each other in a skin organoid culture - or skin in a dish we created - and sprout hair follicles accompanied by fat cells and neurons."

Taking the discovery a step further, the team transplanted the human hairy skin into mice. The mice eventually sprouted human hair follicles at the site of transplantation. Potential applications include testing cosmetics, drugs, and burn treatments.

Skin in a dish includes mini organs

Skin in a dish models are not new. And like many, Koehler and his colleagues thought that the challenge of growing fully functional, hairy skin cells, had long been solved. Skin cells are some of the first cells to have been grown in cultures outside of the body and incubator.

But the skin that people make in a dish never has mini organs or appendages, like hair follicles or sweat glands, embedded in the skin. These mini organs are important for heat regulation, touch sensation, and appearance.

In 2018, the team published a paper showing they could generate hairy skin from mouse stem cells. To create human hairy skin cells, the team started with human induced pluripotent stem cells, which are human adult skin cells that are coaxed back to an embryonic form.

"So we applied a cocktail of growth factors and small molecules, kind of a cooking recipe for human pluripotent stem cells," says Koehler.

The team first noticed co-development of skin epidermis and the dermis. The interaction and signaling between the two tissue layers led to budding of hair follicles at 70 days, which lines up well with the timing of hair development in the human fetus.

In addition to growing hair, the organoids produce fat and muscle-like cells of the skin, as well as, nerves similar to those that mediate touch sensation. "The fat is an unsung hero of the skin and recent studies suggest it plays a critical role in wound healing," says Jiyoon Lee, PhD, first-author on the paper and research associate in the department of otolaryngology at Boston Children's Hospital.

The organoids also produce Merkel cells, specialized touch responsive cells of the skin that have also been implicated in diseases such as Merkel cell carcinoma. "The inclusion of these other cell types likely expands the potential uses of the skin organoid model to research on sensory disorders and cancer," she adds.

Mice grew pigmented human hairs

To see if the technique worked in a living animal, the team cultured the organoids for over four months and then implanted them on the back of mice specially developed not to reject the grafts. "We noticed that within a month, tiny brown hairs sprang up from the transplant site," explains Lee. "This showed us, amazingly, that pigment cells also developed in the organoids."

They compared the transplanted skin with adult human skin samples observing several unique features of human skin in the transplants. One includes 'rete ridges' or valleys in the wavy pattern of human epidermis that helps anchor it into skin membranes. And, the transplanted hair developed elaborate sebaceous glands that produced sebum, the natural oil that lubricates human skin.

An unexpected and fortuitous discovery

This new discovery is literally an outgrowth of work Koehler began at Indiana University when working on a system of recapitulating the inner ear. His goal at the time was to create cells that sense auditory stimuli - sound - to model hearing loss disorders and test gene therapies for hearing loss and balance disorders.

There, he manipulated human induced pluripotent stem cells with the same cocktail of chemicals and proteins used during normal embryonic development guiding them to become inner ear structures.

In the production of this technique, as the inner ear cells were budding during early development, the team found that skin tissue formed as a byproduct.

"This was surprising and we initially tried to get rid of the skin tissue, thinking it was a pesky off-target tissue, like a weed in a garden," recalls Koehler. "Once we saw the scientific value of growing hairy skin in dish, we switched tactics, trying to eliminate the inner ear organoids in favor of growing skin."

In their purification attempts, they discovered that the skin tissue contained both layers of skin, epidermis and dermis. In culture, the skin formed outgrowing hair follicles.

A proof of concept

Translating any mouse study into humans is a long road. "But we think we have developed a proof of concept showing that the cells integrate into skin and form outgrowing hair follicles," says Koehler.

The team hopes that in the long term, they can use the technology to seed wound beds with cultured skin to reconstruct skin, such as in the case of extensive burns or scars.

And while it might be tempting to think of the approach as a "cure" for baldness, Koehler cautions that many challenges lay ahead. "We now have a technique that could generate nearly unlimited hair follicles for transplantation" he says. "But immune rejection is a major hurdle and generating follicles tailored to an individual will be incredibly costly and take a year or more." To meet these challenges, the team is working on ways to accelerate development in a dish, engineer organoids to evade immune detection, or produce similar skin organoids from adult patient-derived cells.

To answer a question crucial to technologies such as energy conversion, a team of researchers at the University of Michigan, Purdue University and the University of Liverpool in the U.K. have figured out a way to measure how many "hot charge carriers"--for example, electrons with extra energy--are present in a metal nanostructure.

"For example, if you wanted to employ light to split water into hydrogen and oxygen, you can use hot charge carriers because electrons that are more energetic can more readily participate in the reaction and drive the reaction faster. That's one possible use for hot carriers in energy conversion or storage applications," said Edgar Meyhofer, a professor of mechanical engineering at U-M, who co-led the research.

Vladimir Shalaev, a professor of electrical and computer engineering, led the contribution from Purdue. The findings also confirm that thinner metals are more efficient at using light for generating hot charge carriers. Light can drive the motion of electrons on the surfaces of materials such as gold and silver, creating waves known as surface plasmons. These waves, in turn, can generate hot charge carriers.

The researchers compared the usual distribution of charge carrier energies to air at room temperature: The molecules in air do not all have the same energy--their average energy is reflected by the temperature. The energies of negatively-charged electrons and positively-charged holes ordinarily follow similar distributions within a material. But in materials that support surface plasmons, light can be used to give extra energy to some charge carriers as though the material were much hotter--more than 2,000 degrees Fahrenheit.

The team created the hot charge carriers by shining laser light onto a gold film just 13 nanometers thick, or hundred or so gold atoms thick, with tiny ridges spaced so that they would resonate with the laser light and generate the surface plasmon waves. Then they measured the energies of the charge carriers by drawing them through gatekeeper molecules into a gold electrode--the tip of a scanning tunneling microscope.

The key to the experiment is those gatekeeper molecules, which were synthesized by the Liverpool team as well as a private company. The molecules allow only charge carriers with certain energies to pass. By repeating the experiments with different molecules, the researchers figured out the energy distribution of the charge carriers.

"Electrons can be thought of as cars running at different speeds on a highway. The molecule acts like an operator--it only allows cars travelling at a certain speed to pass through," said Kun Wang, a postdoctoral fellow in Meyhofer's group.

The researchers also compare it to a prism that separates the spectrum of electron energies rather than the colors in light.

Wang spent more than 18 months working with Harsha Reddy, a Ph.D. student in electrical and computer engineering at Purdue, on how to make this idea work.

"This idea of molecular filters was something no one else in the field has realized in the past," said Reddy, who works in Shalaev's lab.

Once they had developed a successful method, Wang and Reddy repeated the experiments with a second gold structure, this one about 6 nanometers thick. This structure generated hot charge carriers more efficiently than the 13 nanometer version.

"This multidisciplinary basic research effort sheds light on a unique way to measure the energy of charge carriers. These results are expected to play a crucial role in developing future applications in energy conversion and photocatalysis and photodetectors, for instance, that are of great interest to the Department of Defense," said Chakrapani Varanasi, program manager of the team's Multidisciplinary University Research Initiative funded by the Army Research Office.

With the method now demonstrated, the team believes that others can use it to explore and optimize nanostructures. This is important in applications such as converting sunlight to chemical energy because the number of hot charge carriers affects how well a catalyst can direct light energy toward a chemical reaction.

A new study published in Economic Modelling by researchers at Ca' Foscari University and CMCC shows that owning and using an Air Conditioner greatly increases the electricity bills of households, with important implications for the energy poverty of the less well-off.

Previous studies, mainly focused on the US, estimated an increase of household spendings for electricity bills of about 11%. This new study, analysing the socio economic characteristics of households in eight other OECD countries (Australia, Canada, France, Japan, the Netherlands, Spain, Sweden, and Switzerland) and climate data coming from a NASA dataset, finds that on average, using an AC brings 42% more spending for electricity bills, with respect to the ones who do not have an AC unit in their home.

The actual increases will depend on the intensity of the change in climate households will have to face in the future. Those additional spendings are thus a new factor influencing the energy poverty of the poorest households, a situation arising when the families spend more than 5% of their annual income on electricity.

According to BPIE, in 2014 the population already affected by fuel poverty in Europe ranged from 10% to 15%, depending on the member state. This new study shows a more worrying situation.

"The concept of energy poverty is usually related to ensuring adequate heating during the coldest months - explains Enrica De Cian, professor of Environmental Economics at Ca' Foscari and leader of the Energya team which drafted the study. - Our data, however, indicate that we should widen the concept to include the increasing role of cooling during the summer months. Poorest households already spend a consistent share of their budget for basic goods such as food and electricity. The latest will have to increase to ensure adequate protection of our health especially among the most vulnerable members of households during heatwaves."

Owning an AC has already important implications for the energy expenditures of households, up to the scale of countries and beyond, with great variations across countries: it represents about 11% of the total final energy use in buildings in the US, while only 1.2% in Europe.

"Our analysis reveals that in Spain 18.5% of households already spend more than 5% of their annual budget in electricity - confirms the Venitian professor. Those percentages are generally higher in coldest countries, reaching for instance 24.2% in Sweden. In France and Switzerland, we find lower numbers, respectively 8% and 5%.

Who uses ACs and why

"The innovative element of this work - adds Teresa Randazzo, first author of the study - is that we take into account drivers of AC adoption and use in households that are difficult to observe and measure, such as the personal perception of thermal comfort, the risk aversion, or the environmental awareness."

The study disentangles the various characteristics of individuals and households to point out to the ones leading - or not - to a wider AC adoption. For instance, a larger share of younger members brings a wider adoption of AC, while more educated individuals tend to use those appliances less, suggesting they are more aware of the impact of energy on the environment.

Similarly, households that are more accustomed to adopting energy-saving behaviors are less likely to adopt AC. On the opposite, those with a high number of appliances tend to have a higher propensity for AC - which may be an indication that those used to higher standards of comfort are also more inclined to adopt AC.

"Living in an urban area increases the probability of having AC by 9 percentage points, a sizable effect compared to the role of income and climate, probably due to the heat island effect in cities" adds Malcolm Mistry, responsible for the climate data analyses for the Energya project and co-author of this study.

Data analysis of households and climate

To understand the dynamics of AC adoption in industrialized countries and its impact on the budget of households in the light of climate change, the Energya team examined eight OECD countries spanning across mid-latitudes: Australia, Canada, France, Japan, the Netherlands, Spain, Sweden, and Switzerland.

To do so, the researchers combined the information of 3,615 geocoded households from a dataset released by the OECD with a historical climate dataset based on NASA-GLDAS data. "Our elaboration of this climate dataset includes Cooling Degree-Days (CDDs) for the last 49 years, an indicator commonly used in the literature to capture the typical intensity and duration of warm days, and the corresponding cooling requirements" explains Malcolm Mistry.

AC global trends

From 1990 to 2016 global annual sales of air conditioners more than tripled to reach 135 million units worldwide, with figures from the residential sector alone underscoring the trend. China leads, with 41 million residential units registered, followed by 16 million in the US, and roughly 9 million in both Japan and Europe. Penetration of air conditioning in households is expected to continue to increase sharply, because of climate change and thanks to increasing standards of living, reaching 21% in Spain and 35% in France in 20 years from now" concludes prof. De Cian.

Germany was not hit as hard by the SARS-CoV-2 pandemic as many other European countries. The reason for this is that the wave of infection reached Germany later, that the authorities were warned by the situation in Italy and Spain and at an early stage ordered a lockdown and conducted extensive testing. Up to June 2, 2020, there were 182,028 cases of COVID-19 and 8,522 deaths. As in other countries, dialysis patients were at high risk, due to the fact that they often are of older age, have more comorbidities and, of course, suffer from an impaired immune system. A practical problem which adds to the risk is that they cannot stop their treatment and they have to go to a dialysis unit 3 times a week, this means: strict home isolation is not possible for these patients at risk.

A registry has been created in Germany to investigate the prevalence and outcome of SARS-CoV-2 infected dialysis patients. By the end of May, about 2% of the registered dialysis patients (about 300 people out of 14,000) had been tested positive for SARS-CoV-2, and, as it turned out, these patients had a poor prognosis: The mortality rate was around 20%. Phase 2 of the Registry will also include patients with acute kidney injury and chronic kidney disease, and will investigate outcomes and prognostic factors.

However, not only are patients with kidney disease at a higher risk of becoming infected with the coronavirus and have a more severe course of COVID-19 - data also suggest, that the kidneys might be a target organ of this viral disease.

Early data from China on COVID-19 included some startling revelations: Kidney involvement seems to be frequent in people who have been tested positive and have developed symptoms. A consecutive cohort study [1] of COVID-19 patients admitted in a tertiary teaching hospital with 3 branches following a major outbreak in Wuhan in 2020 analysed hematuria, proteinuria, serum creatinine concentration and other clinical parameters as well as the incidence rate for acute kidney injury (AKI). On admission, 44% of the patients had proteinuria and 26.7% had hematuria. AKI occurred in 5.1% patients. After adjustment for confounders, all kidney impairment indicators were associated with higher risk of in-hospital death. The authors recommended already in February that clinicians should increase their awareness of kidney impairment in hospitalized COVID-19 patients.

Indeed, one other study [2] showed that the incidence of AKI is significantly increased among hospitalized patients: Of 4259 patients not requiring mechanical ventilation, 925 had AKI (any stage) and nine needed kidney replacement therapy. The rate was significantly higher among ventilated patients - of 1190 patients, 276 (23.2%) needed dialysis treatment. The main conclusion drawn by the authors is that "AKI occurs frequently among patients with COVID-19. It occurs early and in temporal association with respiratory failure and is associated with a poor prognosis."

It is obvious that the COVID-19 causes kidney injury. In an autopsy study conducted in Hamburg [3], samples from different organ tissues of 27 autopsied COVID-19 patients were analyzed for viral load. It was found that, although the lungs are worst affected by the novel virus, other organs and especially the kidneys are also affected. The samples from seven patients were also used to investigate which renal compartments are particularly affected, and it was shown that the renal tubules and especially the glomerular cells had a high viral load. "These findings are consistent with clinical observations. The glomeruli perform the filtration function of the kidneys and the tubules are responsible for reabsorption. It has been found that, early in the course of Covid-19, many patients had abnormalities in their urine, in particular proteinuria", explained Dr. Hoxha at the press conference to launch the ERA EDTA Congress. "The question is how these findings can be used."

A study group from Göttingen [4], which cooperates closely with groups in Hamburg, Cologne and Aachen, is currently investigating whether early signs of kidney involvement, such as proteinuria, hypoproteinemia and antithrombin III deficiency allow early risk assessment and stratification of patients. Such patients would be at higher risk for developing complications such as lung oedema and thrombembolisms, such as the dreaded pulmonary embolisms. Both could then be treated prophylactically in patients at risk. A recently launched study [5] is now being conducted to investigate the prognostic significance of kidney parameters.

Cystic fibrosis is the most frequent severe inherited disorder worldwide. Every year, hundreds of families are confronted with this diagnosis - and to date, there is no cure for this disease that mainly affects the respiratory system. Besides supportive treatments, a lung transplant is often the only option to save a patient's live. Researchers of the Universities of Münster and Regensburg have now discovered a novel disease that might lead to a better understanding of cystic fibrosis and new treatment options in the future. The results have been published in the scientific journal Journal of Medical Genetics.

The cause of cystic fibrosis are mutations in the cystic fibrosis transmembrane conductor regulator gene (CFTR). This gene contains the blueprint for a chloride channel on the surface of cells in the body. Normally, this channel mediates the accumulation of salt and fluids on the surface of the airways thereby leading to a continuous cleaning of the airways. Defects in the CFTR channel prevent the transport of chloride ions and thus the humidification of the respiratory tract. As a result, the airways of affected individuals literally get plugged by a thickened, viscous mucus that leads to airway obstruction - patients are at the risk of suffocating.

At the University of Münster, the lab of Prof. Thorsten Marquardt has now discovered a new disease that is caused by defects in another chloride channel, TMEM16A. This channel is also present on the surface of airway cells. In cooperation with the lab of Prof. Karl Kunzelmann of the University of Regensburg, the researchers evaluated the cellular effects of the disorder that is caused by a total loss of TMEM16A function. Surprisingly, they discovered that not only TMEM16A but also CFTR is not functional in these patients. Excitingly, this has the potential to improve the treatment of patients suffering from cystic fibrosis.

"We were astonished that children with TMEM16A deficiency don't have any respiratory symptoms at all. A loss of CFTR function due to lack of TMEM16A does not lead to clinincal symptoms of cystic fibrosis in these kids", states Dr. Julien Park, first author and researcher at the Marquardt lab at the Department of General Pediatrics at the University Hospital Münster. Similarly, the group of Prof. Karl Kunzelmann found in a mouse model that a double knock out of CFTR and TMEM16A does not develop lung disease.

Taken together, these results raise an intriguing question: Could the pharmacological inhibition of TMEM16A improve the respiratory symptoms of patients with cystic fibrosis? A significant reduction of mucus production and secretion as a consequence of TMEM16A inhibition has previously been shown under laboratory conditions. The researchers want to study this approach further in the future: "As a next step, we are planning clinical trials to evaluate a treatment of cystic fibrosis with TMEM16A inhibitors", states Karl Kunzelmann.

Early data from a clinical study suggest that blocking the Bruton tyrosine kinase (BTK) protein provided clinical benefit to a small group of patients with severe COVID-19. Researchers observed that the off-label use of the cancer drug acalabrutinib, a BTK inhibitor that is approved to treat several blood cancers, was associated with reduced respiratory distress and a reduction in the overactive immune response in most of the treated patients.

The findings were published June 5, 2020, in Science Immunology. The study was led by researchers in the Center for Cancer Research at the National Cancer Institute (NCI), in collaboration with researchers from the National Institute of Allergy and Infectious Diseases (NIAID), both part of the National Institutes of Health (NIH), as well as the U.S. Department of Defense's Walter Reed National Military Medical Center, and four other hospitals nationally.

These findings should not be considered clinical advice but are being shared to assist the public health response to COVID-19. While BTK inhibitors are approved to treat certain cancers, they are not approved as a treatment for COVID-19. This strategy must be tested in a randomized, controlled clinical trial in order to understand the best and safest treatment options for patients with severe COVID-19.

The BTK protein plays an important role in the normal immune system, including in macrophages, a type of innate immune cell that can cause inflammation by producing proteins known as cytokines. Cytokines act as chemical messengers that help to stimulate and direct the immune response. In some patients with severe COVID-19, a large amount of cytokines are released in the body all at once, causing the immune system to damage the function of organs such as the lungs, in addition to attacking the infection. This dangerous hyperinflammatory state is known as a "cytokine storm." At present, there are no proven treatment strategies for this phase of the illness. The study was developed to test whether blocking the BTK protein with acalabrutinib would reduce inflammation and improve the clinical outcome for hospitalized patients with severe COVID-19.

This prospective off-label clinical study included 19 patients with a confirmed COVID-19 diagnosis that required hospitalization, as well as with low blood-oxygen levels and evidence of inflammation. Of these patients, 11 had been receiving supplemental oxygen for a median of two days, and eight others had been on ventilators for a median of 1.5 (range 1-22) days.

Within one to three days after they began receiving acalabrutinib, the majority of patients in the supplemental oxygen group experienced a substantial drop in inflammation, and their breathing improved. Eight of these 11 patients were able to come off supplemental oxygen and were discharged from the hospital. Although the benefit of acalabrutinib was less dramatic in patients on ventilators, four of the eight patients were able to come off the ventilator, two of whom were eventually discharged. The authors note that the ventilator patient group was extremely clinically diverse and included patients who had been on a ventilator for prolonged periods of time and had major organ dysfunction. Two of the patients in this group died.

Blood samples from patients in the study showed that levels of interleukin-6 (IL-6), a major cytokine associated with hyperinflammation in severe COVID-19, decreased after treatment with acalabrutinib. Counts of lymphocytes, a type of white blood cell, also rapidly improved in most patients. A low lymphocyte count has been associated with worse outcome for patients with severe COVID-19. The researchers also tested blood cells from patients with severe COVID-19 who were not in the study. In comparison with samples from healthy volunteers, they found that these patients with severe COVID-19 had higher activity of the BTK protein and greater production of IL-6. These findings suggest that acalabrutinib may have been effective because its target, BTK, is hyperactive in severe COVID-19 immune cells.

Editorial: COVID-19 Pandemic Likely to Result in Lasting Changes to Medical School Curricula

Following disruptions to medical education that the COVID-19 pandemic brought to the United States this spring, "a return to a typical pre-COVID-19 teaching platform is unlikely," say Diane Wayne and colleagues in this Editorial. They suggest that "many creative changes are here to stay," including large-scale adoption of online education, noting that even faculty members who were previously resistant to remote learning now have evidence of technology's ability to meet the needs of pre-clinical students. Wayne and colleagues also note that adaptations made in recent months to ensure more focus on topics such as telemedicine, pandemic modeling, health equity, and population and public health could persist in medical school curricula going forward, helping to better prepare students for future pandemics and other unexpected medical scenarios. The knowledge that medical education may never be the same again will mean accrediting agencies will have to join in the adaptation effort, they write. "We now have an opportunity to create a better medical school experience with improved flexibility and outcomes that still ensures competence from this increasingly complex effort."

The drug acalabrutinib, FDA-approved for the treatment of several types of B cell cancers, improved the oxygenation levels and decreased molecular markers of inflammation in a majority of 19 patients hospitalized for the treatment of severe COVID-19, according to a new study by Mark Roschewski and colleagues. The drug was administered to 11 patients on supplemental oxygen and 8 patients on mechanical ventilation over a 10-to-14-day course of treatment. At the end of treatment, 8 of 11 patients on supplemental oxygen were breathing room air, and 4 of 8 patients on ventilation were extubated, with 2 of the 8 breathing room air. Measurements of two proteins related to inflammation decreased in the majority of patients, with no signs of toxicity from the drug. The study is not a clinical trial, but rather an off-label observational study to see if acalabrutinib could help dampen the massive immune response - sometimes called a "cytokine storm" - that is associated with the most severe cases of COVID-19. Acalabrutinib inhibits the Bruton tyrosine kinase (BTK) protein, which aids immune cells called macrophages in activating a variety of other proteins in the body's innate immune response. Patients with severe COVID-19 have a hyperinflammatory immune response that appears to be driven by macrophage activation, leading to acute respiratory distress syndrome (ARDS) and often death. Roschewski et al. also studied BTK activation and immune markers in whole blood from 4 COVID-19 patients and 5 healthy individuals. BTK activation levels and the presence of the inflammatory protein IL-6 were higher in the COVID-19 patients, further suggesting that BTK may play a critical role in the disease's progression. An international prospective randomized controlled clinical trial is now underway to confirm the safety and efficacy of this BTK inhibitor as a therapeutic strategy against COVID-19, the authors note.

Researchers at the University of Hawai?i Institute for Astronomy (IfA) have been hard at work studying the solar corona, the outermost atmosphere of the sun that expands into interplanetary space. The properties of the solar corona are a consequence of the Sun's complex magnetic field, which is produced in the solar interior and extends outward into space.

IfA graduate student Benjamin Boe conducted a new study that used total solar eclipse observations to measure the shape of the coronal magnetic field with higher spatial resolution and over a larger area than ever before. The results were published in the Astrophysical Journal on June 3.

The corona is most easily seen during a total solar eclipse -- when the moon is directly between the Earth and Sun, blocking sunlight. Significant technological advances in recent decades have shifted a majority of analysis to space-based observations at wavelengths of light not accessible from the ground, or to large ground-based telescopes such as the Daniel K. Inouye Solar Telescope on Maui. Despite these advances, some aspects of the corona can only be studied during total solar eclipses.

Boe was advised by UH Mānoa Astronomy Professor Shadia Habbal, a coronal research expert. Habbal has led a group of eclipse chasers, the Solar Wind Sherpas making scientific observations during solar eclipses for more than 20 years. These observations have led to breakthroughs in unveiling some of the secrets of the physical processes defining the corona.

"The corona has been observed with total solar eclipses for well over a century, but never before had eclipse images been used to quantify its magnetic field structure," explained Boe. "I knew it would be possible to extract a lot more information by applying modern image processing techniques to solar eclipse data."

Boe traced the pattern of the distribution of magnetic field lines in the corona, using an automatic tracing method applied to images of the corona taken during 14 eclipses the past two decades. This data provided the chance to study changes in the corona over two 11-year magnetic cycles of the Sun.

Boe found that there were very fine-scale structures throughout the corona. Higher resolution images showed smaller-scale structures, implying that the corona is even more structured than what was previously reported. To quantify these changes, Boe measured the magnetic field angle relative to the Sun's surface.

During periods of minimum solar activity, the corona's field emanated almost straight out of the Sun near the equator and poles, while it came out at a variety of angles at mid-latitudes. During periods of maximum, the coronal magnetic field was far less organized and more radial.

"We knew there would be changes over the solar cycle but we never expected how extended and structured the coronal field would be," Boe explained. "Future models will have to explain these features in order to fully understand the coronal magnetic field."

These results challenge the current assumptions used in coronal modeling, which often assume that the coronal magnetic field is radial beyond 2.5 solar radii. Instead, this work found that the coronal field was often non-radial to at least 4 solar radii.

This work has further implications in other areas of solar research--including the formation of the solar wind, which impacts the Earth's magnetic field and can have effects on the ground, such as power outages.

"These results are of particular interest for solar wind formation. It indicates that the leading ideas for how to model the formation of the solar wind are not complete, and so our ability to predict and defend against space weather can be improved," Boe said.

Boe is already planning to be part of his team's next eclipse expeditions. The next one is slated for South America in December 2020.

June 4, 2020 - Incorporating cover crops with tillage reportedly results in increased cover crop decomposition rates and increased mineralization of nutrients from cover crop biomass. Multiple studies have reported mixed results for corn-soybean grain yields when planted after cover crops.

In an article recently published in Agronomy Journal, researchers reported results of a four-year study on corn-soybean rotation. Treatments were completed under either conventional tillage or no-tillage, and with and without cover crop. Researchers included three rotations: cereal rye-soybean-hairy vetch-corn, cereal rye-soybean-oat+radish-corn, and no cover crop-soybean-no cover crop-corn.

The team found that rotation with hairy vetch as a preceding cover crop increased corn grain yield by 14.09 and 12.35% compared to rotations having no cover crop and oat+radish as preceding cover crops, respectively. Cereal rye cover crop biomass had 16-20 kg ha-1 greater N uptake compared to winter annual weeds in rotation without cover crops. Researchers reported that cereal rye preceding soybean reduced soybean yield by 0.3 to 0.6 Mg ha-1 compared to soybean following no cover crop.

Cover crops are touted for their soil and water quality related benefits. However, their adoption and success will depend on the selection of cover crop species available that do not reduce grain yields in following crops.

Computer scientists have developed a way to measure staff comfort and concentration in flexible working spaces using artificial intelligence.

While hot desking and activity-based working allow cost savings and greater flexibility - and are said to increase staff collaboration and satisfaction - studies also show the noise and lack of privacy can be distracting.

With coronavirus restrictions beginning to ease in some parts of the world and employers planning the return to office-based work, a new sensor-based system developed by RMIT and Arup can offer insights on how to get the best out of these flexible working spaces.

The RMIT team behind the study are experts in using AI to uncover patterns in human behaviour.

For this project they worked with psychologists to identify several key variables for concentration and comfort levels in work environments, then set about measuring these with sensors.

They worked with global design and engineering firm Arup to develop and test their new AI-driven system on 31 staff in two of the company's activity-based working offices over four weeks.
Study lead author and Research Fellow in RMIT University's School of Science, Dr Mohammad Saiedur Rahaman, said data was collected on noise levels, indoor temperature and air quality, humidity, air pressure, and even electromagnetic fields.
"We used that information along with survey data to train machine learning algorithms that could identify patterns in perceived concentration and activity, and then provided solutions for making these spaces work best for people," Rahaman said.

What they found

Staff were generally supportive of their activity-based working setup.

However, data showed different people concentrated better in different zones, as well as other important insights for managing staff in the space.

For example, many people had a favourite spot - such as near the window, kitchen or their manager - and found concentrating more difficult if they weren't able to sit there. They were also more sensitive to the office temperature not being exactly right if they missed out on their favourite seat.

Regardless of where they sat, office temperature was a major factor in how comfortable and focused people were.

Most found temperatures below 22.5C too cold to fully concentrate and, as the day progressed, it was observed that people became increasingly sensitive to this.

A major influence on perceived concentration in the mornings, unsurprisingly, was sleep quality the night before.

The number of formal and informal meetings was also shown to have a large impact on perceived concentration, with those who had five formal meetings in a day reporting lower concentration levels compared with those who had fewer.

'Informal meetings' - run-ins encouraged by activity based working - were also measured. While they were preferred by some workers and could be used to reduce the number of formal meetings, they were seen as another source of distraction for others.

Rahaman said high CO2 levels, due to high occupant densities, were also a barrier in people's ability to concentrate.

"The results for CO2 and thermal comfort underline just how important a high-quality heating, cooling and ventilation system is in office design, as well as indoor plants to reduce CO2," Rahaman said.

Making work spaces work better

"We see this type of system having the potential to eventually be used to enable informed decision-making regarding workplace design and layout, or even to suggest to people when to take breaks, what zone might suit them best and so on," Rahaman said.

Arup engineer and project partner, Shaw Kudo, said beyond the useful insights on their own office, they also saw it as an opportunity to help the wider property industry.

"Modern offices, new and existing, are likely to undergo change and potentially redesign workplaces post COVID-19," he said.

"The valuable findings from this work can feed into future designs and allow Arup to better service our clients as they plan their future workplace - whether this is a new-build, or a return to the office after COVID-19.'

Fellow Arup engineer Tim Rawling said they were also looking to adapting the work to assess the impact of working from home on people's work experience given variability in spaces.

"Given the changing landscape of work environments, we’re excited by the opportunity to explore application of this research to new working environments and flexible working arrangements,” he said.

Study leader from RMIT's School of Science, Associate Professor Flora Salim, said recent technological developments and the proliferation of pervasive technologies had opened up many opportunities to collect data from various sensors and smart devices.

"Despite the myriad applications harnessing this data for smart decision-making systems, this is the first research we're aware of that has used pervasive sensing passively to measure workers perceived concentration levels while they are at work," Salim said.

"We hope it can make a real contribution to work practices that reflect what people need to perform their best."

AUSTIN, Texas -- When the novel coronavirus began spreading during the early months of 2020, it put kinks in multinational production chains -- first in China and then around the globe. But it didn't have to happen that way, according to Francisco Polidoro, associate management professor at the McCombs School of Business at The University of Texas at Austin.

In a forthcoming paper published online in advance by the Academy of Management Review, he suggests companies use redundancy as a way to fortify their operations against unforeseeable events such as pandemics.

It's a matter of preparing for the unexpected.

Unlike risk, which covers events that have happened before and could strike again, uncertain events lack any data points to inform decisions. Uncertainty refers to what you do not even know that you don't know.

Polidoro, with co-authors Curba Lampert of Florida International University in Miami and Minyoung Kim of the University of Kansas, introduces a strategy called branching. A company, say the researchers, can build multiple branches into its value chain, the string of steps that lead from research and development through manufacturing and sales. When a crisis strikes one branch, the overall chain can keep running.

"With branching, the idea is to have a kind of redundancy by design. It makes you more resilient. If you wait until your value chain is disrupted, it may be too late," Polidoro said. "You invest in flexibility before you need it."

Apple Inc., for example, which assembles iPhones in China, struggled with both manufacturing and distribution when the pandemic shuttered its factories. The pandemic created ripple effects that negatively affected the design of new products, as communication between design and manufacturing teams was also disrupted.

Other companies are suffering similar versions of Apple's woes. Many pharmaceutical companies rely on China as the sole source of key ingredients for their drugs. Also, more than 60 medical manufactuers have facilities in China dedicated to essential medical devices. In fact, at least 200 of the Fortune Global 500 had a presence in Wuhan, China.

What appears to be sound strategy can risk a total collapse when uncertain events disrupt locations that companies heavily rely on to obtain efficiency gains. The current concerns with drug shortage risks due to the pandemic remind us that when uncertain events break down global supply chains, the entire economy can suffer.

The researchers said if branching had been put into practice, these companies would have facilities in other countries, thereby preventing financial losses. The researchers also said branching may reduce the value that companies get now, but it may sustain their value for a longer time. There's a trade-off between efficiency and flexibility. It's the difference between a somewhat higher cost for making a phone versus being able to make it at all.

"When you design your operations to optimize economies of scale, you've accounted for standard issues that could go wrong," Polidoro said. "Then a nonstandard event occurs that you have not accounted for, like a pandemic, a trade war or closing national borders. All of a sudden, the decisions that optimized your operations may lead to unprecedented disruptions."

The international First-line Radiosurgery for Small-Cell Lung Cancer (FIRE-SCLC) analysis led by University of Colorado Cancer Center researchers and published today in JAMA Oncology details clinical outcomes for 710 patients with brain metastases from small cell lung cancer treated with first-line stereotactic radiosurgery (SRS), without prior treatment with whole-brain radiation (WBRT) or prophylactic cranial irradiation (PCI).

The study represented a substantial research effort including international collaborators from 28 individual centers and one prospective clinical trial from Asia, North America, and Europe. Following first-line SRS, the outcomes were encouraging overall with a median time to brain progression of 8.1 months and a median overall survival of 8.5 months.

The investigators also compared these SRS results with a control group of 219 patients treated with first-line WBRT for brain metastases, which is the current standard of care for small cell lung cancer. Importantly, no overall survival benefit was observed with WBRT compared to SRS. In fact, the survival outcomes were slightly better with SRS even after matching for baseline characteristics. The authors were careful to note, however, that the observed differences in survival in favor of SRS could be related to uncontrolled treatment selection factors in the setting of a retrospective analysis.

"As expected, whole brain radiation was superior to focused treatment with radiosurgery in lengthening the time to disease progression in the brain. However, the improvement in brain control with whole brain radiation did not appear to translate into an improvement in overall survival," says Chad Rusthoven, MD, assistant professor in Radiation Oncology at the University of Colorado Cancer Center, the paper's lead author.

The study, with senior author Tyler Robin, MD, is the largest analysis of outcomes with first-line SRS for brain metastases from small cell lung cancer, offering important descriptive and comparative data on this potential treatment paradigm.

"Although SRS has become the preferred treatment strategy for limited numbers of brain metastases arising from many cancer types due to improved quality of life and cognitive preservation compared to WBRT, small cell lung cancer remains an important exception where WBRT has remained the standard of care for limited and even solitary brain metastases. The primary reason for this is that small cell lung cancer patients where excluded from the randomized trials that established SRS," Robin says.

Because small cell lung cancer patients were excluded from the landmark prospective trials evaluating SRS, understanding of SRS for small cell lung cancer has lagged behind other cancers, including non-small cell lung cancer.

"Small cell lung cancer is known to have an increased propensity for spread to the brain compared to many other cancers. Historical caution regarding first-line SRS for small cell lung cancer has generally been related to concerns that omission of WBRT could result in rapid disease progression and decreased survival times. Thus, it is an important observation that, in this large international study, the omission of WBRT in favor of first-line SRS did not result in diminished overall survival," Rusthoven says.

This analysis, which may represent the strongest data reported thus far in support of first-line SRS for small cell lung cancer, comes at a dynamic time in the evolution of small cell lung cancer management.

"Paradigms for the treatment of small cell lung cancer are evolving. In recent years, we have seen the integration of immunotherapy into small cell lung cancer management, a decrease in the administration of WBRT, and national guideline updates recommending routine brain MRI surveillance for all patients. These changes may be expected to increase the identification of small cell lung cancer patients with limited brain metastases who may be candidates for first-line SRS," Robin says.

The study also provided detailed analyses of outcomes with SRS by the number of brain lesions treated. Patients treated with SRS for a single brain metastasis experienced the best brain control and overall survival outcomes. After that, the clinical outcomes for patients with 2-4 vs 5-10 brain metastases where very similar, whereas patients with 11 or more metastases were seen to have the shortest time to brain progression and overall survival.

The authors note that prospective trials evaluating the role of first line SRS for small cell lung cancer patients are needed to confirm the encouraging results observed in this retrospective study. In the meantime, this large international analysis provides important descriptive and comparative data on first-line SRS as a potential emerging treatment option for brain metastases in carefully selected small cell lung cancer patients.