Culture

Changes in a few small molecules involved in a cell's metabolism seem to indicate whether a restricted "life extension" diet will actually extend, shorten, or have no effect on lifespan, a study of fruit flies has found.

The findings suggest that analyzing the level of small molecules in cells, an approach called metabolomics, may help us understand how calorie-restricted diets affect aging, and how genes, environment, and other factors influence an individual's response to calorie restriction.

"If we can use the metabolome to understand variation in something as complex as lifespan extension, we should be able to use it to understand many other differences we see across populations," said Kelly Jin, a computational biologist in pathology at the University of Washington (UW) School of Medicine. She was lead author on the new study.

A cell's metabolism involves basic chemical reactions that occur for the cell to develop, survive, and proliferate. The small molecules that participate in, and are generated by, these reactions are called metabolites. Metabolites include such things as amino acids that are the building blocks for proteins, sugars and fats that are broken down to generate energy, and products of those reactions. Collectively these molecules make up the metabolome.

In the new study, the UW researchers worked with collaborators at the Buck Institute for Research on Aging and others to understand how calorie-restricted diets may prolong life in different strains of flies.

Such diets can extend lifespans, according to previous studies of different species, including yeast, worms, fruit flies, and mice. Although low-calorie diets have not been shown to lengthen humans' lives, they have been shown to cause weight loss and improve such disease-risk factors as high blood pressure and elevated blood sugar and cholesterol.

The effects of these diets, however, are not uniform. A strain of fruit flies with one particular genetic makeup, or genotype, might see an increased lifespan while a strain with another genotype might see no effect or even a decrease in lifespan.

Clearly genetic differences between the strains are playing a role, but discerning which genetic differences are important is difficult: A fruit fly has about 14,000 genes, many of which are likely to influence lifespan.

A cell's metabolome, on the other hand, distills variation in the complex upstream processes, such as gene expression, gene transcription and protein synthesis, said Daniel Promislow, the paper's senior author. He is a UW School of Medicine professor of pathology and a professor of biology in the UW College of Arts & Sciences.

The complex interplay of these factors and factors in the environment ends up being filtered down to a much smaller number of metabolites, which are simpler to measure and closer to the trait you're studying," Promislow said.

The UW researchers compared the levels of 105 metabolites in fruit flies from 178 strains, which had been fed a normal diet or a restricted diet. They analyzed whether there was a relationship between the flies' diets, their metabolite levels, and changes in their lifespans.

"Dietary restriction dramatically remodeled the metabolome in consistent ways across all 178 fruit fly genotypes," Jin said. These included levels of some key amino acids used in the synthesis of proteins as well as metabolites involved in the alpha-ketoglutarate/glutamine pathway, a process involved in energy generation, among other things.

Genetic analysis was able to identify only one gene clearly associated with the fruit flies' lifespan response to diet restriction. So the researchers used a novel statistical tool, called network analysis, to link the metabolites to changes in lifespan, and then looked for genes linked to those metabolites.

With this approach they identified several genes that appeared to play a role, including one variant of a gene called CCHa2-R that codes for a neuropeptide receptor found in the brain and the gut and which is involved in nutrient sensing and satiety response.

"Our findings show how studying an organism's metabolome not only can help reveal the genetic variation behind complex traits, but also help explain the mechanisms that underlie variation seen in these traits," said Jin.

The benefits of using inhalers and nebulisers containing steroids outweigh the risks despite warnings to the contrary during the COVID-19 pandemic, a study by University of Huddersfield researchers has found.

A warning issued by WHO in March advised that steroids used in inhalers and nebulisers could have a negative effect on a user's immunity system, leaving them more susceptible to COVID-19. The concern was that regular steroid use could leave users vulnerable to contracting the virus, or developing a more severe version than non-users.

WHO's cautionary note caused worry for people with asthma or chronic obstructive pulmonary disease (COPD), leaving them unsure about whether they could keep using inhalers and nebulisers or not. The British Thoracic Society had reported that demand for inhalers had jumped by 400%, leading to shortages in the UK, following WHO's announcement.

However, Dr Hamid Merchant and Dr Syed Shahzad Hasan from the University of Huddersfield commissioned research into the use of steroids and risk of infections, especially viral infections of the upper respiratory tract. That included previous outbreaks of SARS, as well as the COVID-19 pandemic.

"It confused a lot of people," says Dr Hasan. "After the WHO advice, people thought that continuous use of steroids would leave them at a greater risk of contracting the virus or developing more than a mild version of CoViD-19."

Inhaled corticosteroids (ICS) and oral corticosteroids (OCS) are prescribed to help asthma sufferers and those with COPD, with inhalers used to prevent attacks.

The study has been published in Respiratory Medicine, having assessed evidence and findings from a range of bodies including the British Thoracic Society and the National Institute for Health and Care Excellence (NICE). The other authors in the study included Toby Capstick (a consultant pharmacist on respiratory medicine at Leeds Teaching Hospitals NHS Trust), Syed Tabish Zaidi (Associate Professor in Pharmacy at the University of Leeds) and Chia Siang Kow (a clinical pharmacist from Malaysia).

"We found there is strong evidence that the benefits of continuing with steroids outweighs the risk," declares Dr Merchant.

"There is a risk that the immune system goes down, and there is a chance of acquiring infections but the benefits of continuing with steroids throughout were higher than the risks. We concluded by saying that the patients should continue their regular medicines including steroids."

HERSHEY, Pa. -- Women who deliver their first child by cesarean section (C-section) are less likely to conceive a second child than those who deliver vaginally, despite being just as likely to plan a subsequent pregnancy, according to Penn State College of Medicine researchers. The team followed more than 2,000 women for three years after they delivered their first child.

Kristen Kjerulff, professor of public health sciences, said that although previous studies showed that women who delivered by C-section were less likely to bear subsequent children, it was unclear to researchers whether this was due to maternal choice or a lower rate of conception.

The researchers followed women from before the birth of their first child and interviewed them every six months until three years after their first delivery. During each interview, they asked women to report how often they had unprotected intercourse in each of the previous six months.

Kjerulff and colleagues analyzed data from 2,021 women between the ages of 18 and 35 who provided data on unprotected intercourse and resulting conceptions for three years after their first birth. Nearly 600 of those women delivered their first child by C-section and those women were more likely to be older, overweight and obese, shorter, and more likely to have sought fertility advice, testing or treatment.

Approximately 69% of women who delivered by C-section conceived after unprotected intercourse compared to approximately 78% of women who delivered vaginally. Women who delivered by C-section also had a reduced likelihood of a live birth. The association remained after researchers accounted for maternal age, pre-pregnancy body mass index, time to conception of the first child, gestational weight gain, prior induced abortions, diabetes, hypertension, hospitalization during pregnancy and other factors.

Dr. Richard Legro, a coauthor of the manuscript published in JAMA Network Open and chair of the Department of Obstetrics and Gynecology at Penn State Health Milton S. Hershey Medical Center, says that controlling for intercourse was a key strength of the study and allowed the researchers to rule out trauma or lingering pain from C-section. Although the study didn't investigate the reasons for the decreased conception rate, he suspects there may be some physiological reasons.

"It's possible that pelvic or [fallopian] tubal scarring as a result of being exposed to open air and contaminants may affect subsequent attempts at getting pregnant," Legro said. "It is also possible that scar formation from the surgical wound in the uterus, though not in an area where pregnancies implant, may have lingering effects on the process of implantation."

Based on the findings from this study, Kjerulff and Legro recommend that women under 35 who fail to conceive after a year of unprotected intercourse following a C-section seek medical help. Legro noted the data from this study may be useful for physicians counseling women who elect to have C-sections.

"It's important that women who elect to have a C-section know that there is a chance they may have difficulty conceiving in the future," Legro said.

A person's sensitivity to external stimuli depends not only on the state of their nervous system, but also on their cardiac cycle. Usually we do not notice our heartbeat, paying attention to it only in unusual situations, such as in moments of excitement before a performance or while experiencing arrhythmia. The brain actively suppresses the perception of our heartbeat, but as a result, our perception of other sensory stimuli may also be affected. This conclusion was made in a paper by a team of scientists from the Max Planck Institute for Human Cognitive and Brain Sciences (Leipzig) with the participation of Vadim Nikulin, a leading researcher at the Institute of Cognitive Neurosciences at HSE University.

A cardiac cycle consists of two phases: systole and diastole. During systole, the heart muscles contract, and during diastole, they relax. It has been suggested earlier that a person is more susceptible to various stimuli during diastole and less sensitive during systole.

To find out what happens to the brain during different phases of the cardiac cycle, the scientists conducted an experiment by stimulating the fingers of 37 subjects with a barely perceptible electrical current. After each test, participants were asked if they felt any stimulation. At the same time, their brain and heart activity was monitored with EEG and ECG, respectively.

As expected, during systole, participants often did not notice the presence of stimuli. A decrease in sensitivity was accompanied by a change in brain activity. EEG recordings can show the P300 potential associated with the detection of the stimuli. During systole, this potential was less pronounced. Interestingly, the amplitude of the pre-stimulus heart-beat evoked potential correlated negatively with the detection and localization of somatosensory stimuli. Thus, the greater the potential caused by the heartbeat, the lower the potential of P300, and the more likely the subject would not sense the current.

Researchers believe that the brain predicts when the next contraction of the heart will occur, and suppresses the perception of stimuli more strongly in the systole phase, so that we are not distracted by our heart rhythm or confuse it with an external stimulus.

'These results are interesting since they show that our conscious perception of the external world can change within every heartbeat cycle, which is a rhythmic event that we mostly don't pay attention to,' says Esra Al, the lead author of the study. 'Therefore, these findings suggest that not only the brain but also the body plays an important role in shaping our consciousness.'

The results of the study may provide new insight into the understanding of neuronal processes associated with anxiety conditions. Such conditions are associated not only with a change in the heart rate, but also with a change in one's perception of their heartbeat.

Microbial cells are found in abundance in marine sediments beneath the ocean and make up a significant amount of the total microbial biomass on the planet. Microbes found deeper in the ocean, such as in hydrocarbon seeps, are usually believed to have slow population turnover rates and low amounts of available energy, where the further down a microbe is found, the less energy it has available.

A new study published out of a collaboration with the University of Delaware and ExxonMobil Research and Engineering shows that perhaps the microbial communities found deeper in the seafloor sediments in and around hydrocarbon seepage sites have more energy available and higher population turnover rates than previously thought.

Using sediment samples collected by ExxonMobil researchers, UD professor Jennifer Biddle and her lab group -- including Rui Zhao, a postdoctoral researcher who is the first author on the paper; Kristin Yoshimura, who received her doctorate from UD; and Glenn Christman, a bioinformatician -- worked on a study in collaboration with Zara Summers, an ExxonMobil microbiologist. The study, recently published in Scientific Reports, looks at how microbial dynamics are influenced by hydrocarbon seepage sites in the Gulf of Mexico.

Biddle and her lab members received the frozen sediments, collected during a research cruise, from ExxonMobil and then extracted the DNA and sequenced it at the Delaware Biotechnology Institute (DBI).

The samples Biddle's lab group studied were ones collected from deeper in hydrocarbon seeps that usually get ignored.

"Most people only look at the top couple of centimeters of sediment at a seep, but this was actually looking 10-15 centimeters down," said Biddle associate professor in the School of Marine Science and Policy in UD's College of Earth, Ocean and Environment. "We then compared seepage areas to non-seepage areas, and the environment looked really different."

Inside the seep, the microbes potentially lead a fast, less efficient life while outside the seep, the microbes lead a slower but more efficient life. This could be attributed to what energy sources are available to them in their environment.

"Understanding deep water seep microbial ecology is an important part of understanding hydrocarbon-centric communities," said Summers.

Biddle said that microbes are always limited by something in the environment, such as how right now during the quarantine, we are limited by the amount of available toilet paper. "Outside of the seep, microbes are likely limited by carbon, whereas inside the seep, microbes are limited by nitrogen," said Biddle.

While the microbes found inside the seep seem to be racing to make more nitrogen to keep up and grow with their fellow microbes, outside of the seep, the researchers found a balance of carbon and nitrogen, with nitrogen actually being used by the microbes as an energy source.

"Usually, we don't think of nitrogen as being used for energy. It's used to make molecules, but something that was striking for me was thinking about nitrogen as a significant energy source," said Biddle.

This difference between the microbes found inside the seeps and those found outside the seeps could potentially mirror how microbes behave higher in the water column.

Previous research of water column microbes shows that there are different types of microbes: those that are less efficient and lead a more competition-based lifestyle where they don't use every single molecule as well as they could and those that are really streamlined, don't waste anything and are super-efficient.

"It makes me wonder if the microbes that are living at these seeps are potentially wasteful and they're fast growing but they're less efficient and the organisms outside of the seeps are a very different organism where they're way more efficient and way more streamlined," said Biddle, whose team has put in a proposal to go back out to sea to investigate further. "We want to look at these dynamics to determine if it still holds true that there is fast, less efficient life inside the seep and then slower, way more efficient life outside of the seep."

In addition, Biddle said this research showed that the deeper sediments in the seepages are most likely heavily impacted by the material coming up from the bottom, which means that the seep could be supporting a larger amount of biomass than previously thought.

"We often think about a seep supporting life like tube worms and the things that are at the expression of the sediment, but the fact that this could go for meters below them really changes the total biomass that the seep is supporting," said Biddle. "One of the big implications for the seepage sites with regards to the influence of these fluids coming up is that we don't know how deep it goes in terms of how much it changes the impact of subsurface life."

Summers added that these are interesting insights "when considering oil reservoir connectivity to, and influence on, hydrocarbon seeps."

Bats are often considered patient zero for many deadly viruses affecting humans, including Ebola, rabies, and, most recently, the SARS-CoV-2 strain of virus that causes coronavirus.

Although humans experience adverse symptoms when afflicted with these pathogens, bats are remarkably able to tolerate viruses, and, additionally, live much longer than similar-sized land mammals.

What are the secrets to their longevity and virus resistance?

According to researchers at the University of Rochester, bats' longevity and capacity to tolerate viruses may stem from their ability to control inflammation, which is a hallmark of disease and aging. In a review article published in the journal Cell Metabolism, the researchers--including Rochester biology professors Vera Gorbunova and Andrei Seluanov--outline the mechanisms underlying bats' unique abilities and how these mechanisms may hold clues to developing new treatments for diseases in humans.

WHY ARE BATS 'IMMUNE' TO VIRUSES?

The idea for the paper came about when Gorbunova and Seluanov, who are married, were in Singapore in March before COVID-19 travel bans began. When the virus started to spread and Singapore went into lockdown, they were quarantined at the home of their colleague Brian Kennedy, director of the Centre for Healthy Aging at the National University of Singapore and co-author of the paper.

The three scientists, all experts on longevity in mammals, got to talking about bats. SARS-CoV-2 is believed to have originated in bats before the virus was transmitted to humans. Although bats were carriers, they seemed to be unaffected by the virus. Another perplexing factor: generally, a species' lifespan correlates with its body mass; the smaller a species, the shorter its lifespan, and vice versa. Many bat species, however, have lifespans of 30 to 40 years, which is impressive for their size.

"We've been interested in longevity and disease resistance in bats for a while, but we didn't have the time to sit and think about it," says Gorbunova, the Doris Johns Cherry Professor of Biology at Rochester. "Being in quarantine gave us time to discuss this, and we realized there may be a very strong connection between bats' resistance to infectious diseases and their longevity. We also realized that bats can provide clues to human therapies used to fight diseases."

While there have been studies on the immune responses of bats and studies of bats' longevity, until their article, "no one has combined these two phenomena," Seluanov says.

Gorbunova and Seluanov have studied longevity and disease resistance in other exceptionally long-lived animals, including naked mole rats. One common theme in their research is that inflammation is a hallmark of the aging process and age-related diseases, including cancer, Alzheimer's, and cardiovascular disease. Viruses, including COVID-19, are one factor that can trigger inflammation.

"With COVID-19, the inflammation goes haywire, and it may be the inflammatory response that is killing the patient, more so than the virus itself," Gorbunova says. "The human immune system works like that: once we get infected, our body sounds an alarm and we develop a fever and inflammation. The goal is to kill the virus and fight infection, but it can also be a detrimental response as our bodies overreact to the threat."

Not so with bats. Unlike humans, bats have developed specific mechanisms that reduce viral replication and also dampen the immune response to a virus. The result is a beneficial balance: their immune systems control viruses but at the same time, do not mount a strong inflammatory response.

WHY DID BATS ACQUIRE A TOLERANCE FOR DISEASES?

According to the researchers, there are several factors that may contribute to bats having evolved to fight viruses and live long lives. One factor may be driven by flight. Bats are the only mammals with the ability to fly, which requires that they adapt to rapid increases in body temperature, sudden surges in metabolism, and molecular damage. These adaptations may also assist in disease resistance.

Another factor may be their environment. Many species of bats live in large, dense colonies, and hang close together on cave ceilings or in trees. Those conditions are ideal for transmitting viruses and other pathogens.

"Bats are constantly exposed to viruses," Seluanov says. "They are always flying out and bringing back something new to the cave or nest, and they transfer the virus because they live in such close proximity to each other."

Because bats are constantly exposed to viruses, their immune systems are in a perpetual arms race with pathogens: a pathogen will enter the organism, the immune system will evolve a mechanism to combat the pathogen, the pathogen will evolve again, and so on.

"Usually the strongest driver of new traits in evolution is an arms race with pathogens," Gorbunova says. "Dealing with all of these viruses may be shaping bats' immunity and longevity."

CAN HUMANS DEVELOP THE SAME DISEASE RESISTANCE AS BATS?

That's not an invitation for humans to toss their masks and crowd together in restaurants and movie theaters. Evolution takes place over thousands of years, rather than a few months. It has only been in recent history that a majority of the human population has begun living in close proximity in cities. Or that technology has enabled rapid mobility and travel across continents and around the globe. While humans may be developing social habits that parallel those of bats, we have not yet evolved bats' sophisticated mechanisms to combat viruses as they emerge and swiftly spread.

"The consequences may be that our bodies experience more inflammation," Gorbunova says.

The researchers also recognize that aging seems to play an adverse role in humans' reactions to COVID-19.

"COVID-19 has such a different pathogenesis in older people," Gorbunova says. "Age is one of the most critical factors between living and dying. We have to treat aging as a whole process instead of just treating individual symptoms."

The researchers anticipate that studying bats' immune systems will provide new targets for human therapies to fight diseases and aging. For example, bats have mutated or completely eliminated several genes involved in inflammation; scientists can develop drugs to inhibit these genes in humans. Gorbunova and Seluanov hope to start a new research program at Rochester to work toward that goal.

"Humans have two possible strategies if we want to prevent inflammation, live longer, and avoid the deadly effects of diseases like COVID-19," Gorbunova says. "One would be to not be exposed to any viruses, but that's not practical. The second would be to regulate our immune system more like a bat."

Aquaculture, the relatively young but fast-growing industry of farming of fish and other marine life, now produces around half of all seafood consumed by humans. A new paper from American University published today examines the economics of an aquaculture industry of the future that is simultaneously environmentally sustainable and nutritious for the nearly 1 billion people worldwide who depend on it for health and livelihoods.

Of the scenarios the paper discusses, included are two approaches that illustrate what aquaculture might look like if nations refocus inward for food and nutrition security in the COVID-19 era.

"Seafood is essential to meeting global food and nutrition security goals," said Jessica Gephart, the paper's primary author and an assistant professor of environmental science at American University. "Under what circumstances, and with what policies, can we maximize aquaculture for its nutrition benefits and sustainability for all who rely on seafood?"

This is a challenging question to answer, especially in the COVID-19 era. As the pandemic is still unfolding, the full scope of long-term damage to food systems is unknown, the paper notes. Yet, the aquaculture industry is suffering major setbacks, as some exports are being halted, workers are being laid off, demand has dramatically decreased, production units are incurring large losses and some countries are reconsidering their reliance on foreign seafood. The authors note that such setbacks "can be particularly long-lasting for a budding sector, with many young farms that potentially lack the capital to weather the storm and the political clout to secure sufficient recovery aid."

The demand for seafood is expected to increase significantly by 2050, the paper notes, if historical trends in income and population growth, urbanization, and diets are maintained. This has prompted researchers to contemplate the future role of aquaculture in meeting demand and supporting nutrition needs. "Nutrition sensitivity" refers to the multiple benefits derived from diverse foods, including improving nutrition, valuing the social significance of food, and supporting livelihoods.

For aquaculture, this means a food system that supports public health through production of diverse seafood, provides multiple, rich sources of essential nutrients, and supports equitable access to nutritious, safe, and culturally acceptable diets that meet food preferences for all populations, without compromising ecosystem functions, other food systems, and livelihoods.

The paper describes and discusses four possible scenarios for the future of the growth of aquaculture, with the first two outlining what an inward approach might look like. Elements of each of these scenarios exist in current production systems from around the world:

Growth-first, nationalistic approach. In this scenario, countries throughout the world turn inward for economic growth and focus on supporting national industries to meet seafood demand. Overall, diversity of seafood available in each country generally declines. Countries with mature aquaculture sectors that already supply a diversity of production technologies, species and product types will continue to meet some nutritional needs, but for a narrower range of consumers and at increased cost, and to a more limited extent.

Sustainable growth, localized approach. In this approach, countries throughout the world adopt sustainable local food production approaches focused on small-holder production. While some traditional production systems are highly productive, in general, global aquaculture production grows at a relatively slow rate - if at all - and total production is relatively low. Countries that have retained a cultural history of developing small-scale aquaculture will see an increase in these production systems, supported by government-backed schemes and extension services. When production is at the household scale, women are more likely to play a key role, increasing the likelihood that nutritional benefits flow directly to the most vulnerable.

Sustainable growth, globalized world. The world fully embraces the application of sustainable development principles, taking advantage of the benefits of globalized food systems while strengthening environmental governance. Global competition and high levels of technology transfer lead to relatively high global inland and marine seafood production. Favoring production of seafood in line with local environmental contexts, this world leads to moderate global species diversity. High global seafood production and low trade barriers enable low seafood prices, improving seafood access in urban areas and areas with transportation infrastructure connections and access to electricity for refrigeration.

Growth first, globalized world. In this scenario, the world moves toward further economic globalization and encourages boundless economic growth. Through genetic selection and modification, as well as technological innovations, the aquaculture industry develops intensive production systems with limited environmental regulation. Production systems rely on globalized supply chains, sourcing feed ingredients internationally, and taking advantage of low labor costs for processing. Through competition, massive production of only a few species results, which are highly traded and spread rapidly (akin to the dominance of four species in the meat market, led by chicken). Targeted policy interventions would be necessary to help nutritionally vulnerable populations.

AMSTERDAM, NETHERLANDS - Teva Pharmaceutical Europe B.V. has presented results from a pooled analysis of three randomized, double-blind, placebo-controlled Phase 3 studies assessing AJOVY® ▼ (fremanezumab), indicated for the preventative treatment of migraine in adults, which demonstrate clinically significant reductions in headache and migraine-related disability in the majority of patients studied.

The findings, presented at the 14th European Headache Federation (EHF) Congress, show that by comparison to placebo, individuals receiving fremanezumab treatment experienced a downward shift in disability severity, as defined by the validated HIT-6 and MIDAS assessment tools. At baseline, 87-89 per cent of patients had severe impact on HIT-6 and 74-75 per cent of patients had severe disability on MIDAS. In this analysis, the proportion of patients experiencing a downward shift of between 1 and 3 categories in severity of headache impact on HIT-6 was significantly greater than placebo with both doses of fremanezumab (47 to 50 per cent) versus placebo (33 per cent). Similarly, the number of patients experiencing a downward shift of 1, 2 or 3 grades in disability severity according to MIDAS scores was significantly greater with fremanezumab (55 to 58 per cent) versus placebo (40 per cent).

A parallel analysis assessed clinically meaningful improvements in HIT-6 and MIDAS scores in line with a recent American Headache Society (AHS) consensus statement. According to AHS, a ? 5 point reduction on HIT-6 is clinically meaningful, and this was achieved by 53-55 per cent of fremanezumab-treated patients versus 39 per cent of placebo patients. For MIDAS, AHS considers a ? 5 point reduction for patients with a baseline score of 11-20 or a ? 30% reduction for those with a baseline score > 20 to be clinically meaningful. The former was achieved by 70-71 per cent of fremanezumab treated patients versus 49 per cent of placebo patients, while the latter was achieved by 69-79 per cent of fremanezumab treated patients versus 58 per cent of placebo patients.

Collectively, the pooled analyses indicate that fremanezumab therapy in both quarterly and monthly regimens may result in clinically meaningful improvements particularly for patients with difficult-to-treat migraine, which can be debilitating and severely impact the quality of life for individuals.

"The personal impact of both episodic and chronic migraine cannot be underestimated," said Joshua M. Cohen, MD, MPH, FAHS, Sr. Director, Therapeutic Area Lead Migraine & Headache, Global Medical Affairs, Teva Pharmaceutical Europe B.V. "A continual need exists for new therapies which can help and support those affected and help individuals maintain a normal life where ability to work, be productive and look after families are not heavily compromised. These new analyses add to the positive data on fremanezumab and suggest it plays an important role in limiting and mitigating disability at several levels of severity, particularly for individuals who are finding their migraine difficult to treat and manage."

An additional study assessing long-term efficacy of fremanezumab in episodic and chronic migraine, also presented at the Congress, showed that over six to 15 months of long-term treatment, patients with difficult-to-treat migraine experienced progressive improvements in migraine days, with increasing numbers of patients achieving clinically meaningful response rates.

Migraine is a debilitating neurological disease that causes recurrent episodes of pain lasting 4-72 hours, often accompanied by nausea, vomiting, photophobia, phonophobia and a variety of other debilitating symptoms.

The pooled analyses follow primary results from the Phase FOCUS study in which fremanezumab was shown to significantly reduce the number of migraine and headache days of at least moderate severity as early as the first week of treatment in adult patients who had responded inadequately to two or more classes of migraine preventive therapy when compared to placebo. The proportion of patients experiencing a 50 percent or higher reduction of migraine days was also significantly greater than placebo. The incidence of adverse events (AEs) including AEs leading to treatment discontinuation and serious AEs was shown to be low and consistent with placebo.

The data presentations at EHF 2020 follow findings from the Teva-sponsored research project Beyond Migraine: The Real You survey of over 7,500 people living with the disease in Europe. The survey conducted across 10 European countries found that people living with migraine were struggling in how to better support themselves or advocate for improved disease management. The broader survey results went on to explore the often-devastating impact of migraine on all aspects of a patient's life, ranging from their relationships, work life, social life and education.

60% of people living with migraine indicated that migraine has negatively impacted their social life, their studies, work and career

40% of young people living with migraine indicate an impact on their education

Only 1 out of 8 were member of a patient support group

Of those patients who were receiving treatment from their HCP, almost 8 in 10 (77%) said that their treating doctor took their disease very seriously, but 30% felt their doctor was not sufficiently informed on the latest migraine treatments.2 One in 4 people said they would like to be more involved in decisions about their treatment.2

"While I have seen significant improvements in migraine management over recent decades, the survey data highlights the need for more work to be done to raise awareness, increase knowledge and continue to integrate a faster migraine diagnosis process" said Elena Ruiz de la Torre, Executive Director, European Migraine and Headache Alliance (EMHA).

Information for Europe about AJOVY® ▼ (fremanezumab) can be found here.

Adverse events should be reported.

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse events. Reporting forms and information can be found at https://www.hpra.ie. Adverse events should also be reported to Teva - please refer to local numbers.

AJOVY is available as a 225 mg/1.5 mL single dose injection in a prefilled syringe with two dosing options - 225 mg monthly administered as one subcutaneous injection, or 675 mg every three months (quarterly), which is administered as three subcutaneous injections. AJOVY can be administered in office by a healthcare professional or at home by a patient or caregiver. No starting dose is required to begin treatment. The AJOVY autoinjector has been approved by the FDA and is available in the U.S. In addition to the U.S., the AJOVY autoinjector has been approved by the EMA and is currently available in Germany and should soon be available in other select European markets.

CAMBRIDGE, MA -- Researchers at MIT and Brigham and Women's Hospital have designed a new face mask that they believe could stop viral particles as effectively as N95 masks. Unlike N95 masks, the new masks were designed to be easily sterilized and used many times.

As the number of new Covid-19 cases in the United States continues to rise, there is still an urgent need for N95 masks for health care workers and others. The new mask is made of durable silicone rubber and can be manufactured using injection molding, which is widely used in factories around the world. The mask also includes an N95 filter, but it requires much less N95 material than a traditional N95 mask.

"One of the key things we recognized early on was that in order to help meet the demand, we needed to really restrict ourselves to methods that could scale," says Giovanni Traverso, an MIT assistant professor of mechanical engineering and a gastroenterologist at Brigham and Women's Hospital. "We also wanted to maximize the reusability of the system, and we wanted systems that could be sterilized in many different ways."

The team is now working on a second version of the mask, based on feedback from health care workers, and is working to establish a company to support scaled-up production and seek approval from the FDA and the National Institute for Occupational Safety and Health (NIOSH).

Traverso is the senior author of a paper describing the new masks, which appears today in the British Medical Journal Open. The lead authors of the study are James Byrne, a radiation oncologist at Brigham and Women's Hospital and research affiliate at MIT's Koch Institute for Integrative Cancer Research; Adam Wentworth, a research engineer at Brigham and Women's Hospital and a research affiliate at the Koch Institute; Peter Chai, an emergency medicine physician at Brigham and Women's Hospital; and Hen-Wei Huang, a research fellow at Brigham and Women's Hospital and a postdoc at the Koch Institute.

Easy sterilization

The N95 masks that health care workers wear to protect against exposure to SARS-CoV-2 and other viruses are made from polypropylene fibers that are specially designed to filter out tiny viral particles. Ideally, a health care worker would switch to a new mask each time they see a different patient, but shortages of these masks have forced doctors and nurses to wear them for longer than they are meant to be worn.

In recent months, many hospitals have begun sterilizing N95 masks with hydrogen peroxide vapor, which can be used up to 20 times on a single mask. However, this process requires specialized equipment that is not available everywhere, and even with this process, one mask can be worn for only a single day.

The MIT/BWH team set out to design a mask that could be safely sterilized and reused many times. They decide on silicone rubber -- the material that goes into silicone baking sheets, among other products -- because it is so durable. Liquid silicone rubber can be easily molded into any shape using injection molding, a highly automated process that generates products rapidly.

The masks are based on the shape of the 3M 1860 style of N95 masks, the type normally used at Brigham and Women's Hospital. Most of the mask is made of silicone rubber, and there is also space for one or two N95 filters. Those filters are designed to be replaced after every use, while the rest of the mask can be sterilized and reused.

"With this design, the filters can be popped in and then thrown away after use, and you're throwing away a lot less material than an N95 mask," Wentworth says.

The researchers tested several different sterilization methods on the silicone masks, including running them through an autoclave (steam sterilizer), putting them in an oven, and soaking them in bleach and in isopropyl alcohol. They found that after sterilization, the silicone material was undamaged.

Fit test

To test the comfort and fit of the masks, the researchers recruited about 20 health care workers from the emergency department and an oncology clinic at Brigham and Women's Hospital. They had each of the subjects perform the standard fit test that is required by the Occupational Safety and Health Administration (OSHA) for N95 masks. During this test, the subject puts the mask on and then performs a series of movements to see if the mask stays in place. A nebulized sugar solution is sprayed in the room, and if the subject can taste or smell it, it means the mask is not properly fitted.

All 20 subjects passed the fit test, and they reported that they were able to successfully insert and remove the N95 filter. When asked their preference between the new mask, a typical N95 mask, and a standard surgical mask, most either said they had no preference or preferred the new silicone mask, Byrne says. They also gave the new mask high ratings for fit and breathability.

The researchers are now working on a second version of the mask, which they hope to make more comfortable and durable. They also plan to do additional lab tests measuring the masks' ability to filter viral particles.

As many regions of the United States have seen a surge in Covid-19 cases over the past month, hospitals in those areas face the possibility of mask shortages. There is also a need for more masks in parts of the world that don't have the equipment needed for hydrogen peroxide sterilization.

"We know that Covid is really not going away until a vaccine is prevalent," Byrne says. "I think there's always going to be a need for masks, whether it be in the health care setting or in the general public."

One could say that mitochondria, the energy-producing organelles inside every human cell, dance to their own beat. After all, they have their own genome ­­- a set of DNA-containing chromosomes - completely separate from the genome of the cell's nucleus.

Mitochondria are essential to life because they power the cell's biochemical reactions, but they make a lot of missteps - that is, their genomes do. Human mitochondrial genomes are notoriously prone to mutation, which is why so many genetic disorders - from diabetes mellitus to mitochondrial myopathy - are linked to malfunctioning genes in this organelle.

Seeking to understand why human mitochondrial genomes mess up so much, Colorado State University biologist Dan Sloan thinks we have a lot to learn from our very distant evolutionary cousins - plants. Like us, plants maintain a separate mitochondrial genome, but unlike us, plant mitochondrial genomes have some of the slowest known mutation rates of any living thing - about one mutation at each DNA position in a billion years. Just how they keep their genetic sequences on lockdown, while we don't, has long been a mystery for many biologists.

Sloan is funded by a grant from the National Institutes of Health to investigate why plants have such stable mitochondrial genomes, and his lab has recently come across a tantalizing lead. They have traced this stability to a particular gene - MSH1 - that plants have but animals (including us) don't. Their experiments, described in Proceedings of the National Academy of Sciences, could lend insight into why animal mitochondrial genomes tend to mutate, possibly leading to breakthrough therapies to prevent such mutations.

"Understanding how some systems have been able to maintain these really accurate, low mutation rates, sets up the opportunity for understanding the flip side of the coin - how it is that humans suffer such high mitochondrial mutation rates," said Sloan, associate professor in the Department of Biology. "It's not as simple as just the nasty chemistry going on inside these mitochondrial compartments, as some have thought. It probably comes down to more differences between organisms' error correction machinery. That's one of the punchlines that comes out of this research."

The researchers tested several plant genes they thought might be responsible for mitochondrial genomic stability. They found that disrupting the MSH1 gene in a common plant, Arabidopsis thaliana, led to massive increases in frequency of point mutations and changes to the mitochondrial DNA. MSH1, it turns out, contains molecular features that may make it able to recognize mismatches of nucleotide base pairings during the process of DNA copying. They researchers plan to follow up on this hypothesis in later studies.

The MSH1 gene exists in plants, but not animals, which offers a good explanation for why human mitochondrial genomes mutate so often. The researchers then asked, where did this gene come from?

To find an answer, undergraduate researcher and paper co-author Connor King set out to explore the distribution of the gene across the tree of life. He computationally mined nucleotide and protein sequence repositories to find what species have the gene. He found evidence of the gene not only in plants but also in many lineages of complex organisms, including single-celled eukaryotic organisms, as well as some prokaryotic and viral species.

King's analysis raises the possibility that the gene came from so-called giant viruses that have genomes almost the size of bacteria, and are much more complex than typical viruses. They may have been shared with other organisms via an ancient horizontal gene transfer, in which one species transfers DNA into another.

"Connor's results pretty clearly tell us that this gene has been transferred around different parts of the tree of life," Sloan said. This insight would be consistent with the idea that some organisms manage to borrow machinery from viruses and replace it with their own.

The study was made possible by advanced DNA sequencing, in which huge amounts of DNA can be mined to find very rare mutations. A key enabling innovation was led by graduate student and co-author Gus Waneka, who customized a technique called duplex sequencing to increase its accuracy within the margin of error the team needed to draw their conclusions.

Researchers from Bentley University, in partnership with Pine Street Inn, New England's largest homeless shelter, have been exploring the ideas of process modeling to better understand and improve triage practices at homeless shelters. Conventional wisdom places the sequencing of standard tasks at the center of process models. In contrast, work in homeless shelters requires customizing work processes in response to individual guests.

By constructing a model of the triage work at the homeless shelters, the researchers demonstrate the need for this approach. The study illustrated challenges such as discretionary tasks and varying knowledge intensity, and explored an emerging technique that corresponds to the reality of triage work in the homeless shelters.

"A modeling approach that focused on the individual guests, providing options and tools to the employees and volunteers at the homeless shelter shows clear promise," says Dr. Sandeep Purao, a professor of information and process management and one of the lead researchers. A technique called CMMN (case management and modeling notation) has emerged over the last few years with industry backing and tool support that has the potential to support such work. "There are many approaches and tools that are developed in the for-profit domain that can be useful in humanitarian settings," says Dr. Monica Garfield, a computer information systems professor who also participated in the study.

The results of this work were published at the European Conference on Information Systems in June 2020. The team will continue the work by combining on-the-ground studies of work practices at homeless shelters and developing additional models and tools to support this work.

The work is important because homelessness continues to be a significant concern in the US. The 2019 Annual Homeless Assessment Report (AHAR) to Congress shows that 567,715 people - about 17 of every 10,000 - were experiencing homelessness across the United States. The homeless shelters represent the first line of defense for preventing homelessness. Understanding, improving and supporting work practices at the shelters can, therefore, have a direct impact on the problem.

BIRMINGHAM, Ala. - University of Alabama at Birmingham researchers have added fresh evidence that early exposure to vaccine-, bacterial- or microbiota-derived antigens has a dramatic effect on the diversity of antibodies an adult mammal will have to fight future infections by pathogens. This antibody diversity is called the clonal repertoire -- basically different single cells with distinct antibody potential that can multiply into a large clone of cells, all producing that distinct antibody.

In a mouse study published in the journal Immunity, they looked at a group of immune cells called B-1 B cells. Although all B cells have the ability to develop into antibody-secreting cells to control pathogens, innate-like B-1 B cells originate from a developmental program that is distinct from conventional B cells.

The UAB researchers, led by first author J. Stewart New, Ph.D., and co-senior authors John Kearney, Ph.D., and R. Glenn King, Ph.D., UAB Department of Microbiology, looked at a subset of B-1 B cells that react to N-acetyl-D-glucosamine-containing Lancefield Group A carbohydrate, or GAC, a cell wall polysaccharide of the bacterial pathogen Streptococcus pyogenes.

They asked the question, how much will clonal diversity differ in mice grown under sterile germ-free conditions, versus mice with a normal gut microbiota from birth, or mice with a normal microbiota that are also vaccinated as neonates with GAC-bearing S. pyogenes. To answer, they sequenced the immunoglobulin heavy chain variable region, or IGHV region, for single B cells labeled with GAC. Single-cell sequencing has exploded in the past decade as a powerful research tool that takes biology to a new depth of understanding.

New, Kearney, King and colleagues found that environmental antigen-dependent selection events play a significant role to shape the GAC-reactive B-1 B cell clonal repertoire. New is a postdoctoral fellow, Kearney is a professor, and King is assistant professor of microbiology in the UAB School of Medicine.

In general, germ-free mice had a low IGHV clonal diversity, while both conventional mice and neonatal-vaccination mice had high clonal diversities. However, the conventional and neonatal-vaccination mice differed. Both showed that the establishment of IGHV region 6-3 GAC-reactive B cell clonal dominance was microbiota-dependent; but in addition, the neonatal immunization with S. pyogenes expanded the typically minor IGHV region 7-3 GAC-reactive clonotypes, compared to those clonotypes in the conventional mice.

The researchers found that colonization of adult germ-free mice promoted N-acetyl-D-glucosamine-reactive B-1 B cell development and led to clonally related immunoglobulin A-positive plasma cells in the small intestine. Plasma cells differentiate from B cells, and they are the ones that produce antibody. Immunoglobulin A secretion in the gut is beneficial because it helps constrain the composition and inflammatory activity of the normal microbiota in the small intestine.

Kearney says that understanding how exposure to microbial antigens in early life determines the clonality and ensuing antibody responses of the B-1 B cell repertoire has implications for vaccination approaches and schedules.

B-1 B cells also are known to produce natural immunoglobulin M. Deficiencies of immunoglobulin M have been associated with increased rates of autoimmunity and allergic diseases. The dramatic effect of early exposure to vaccine or bacteria for clonal diversity seen in the current research, Kearney said, "may provide an alternative mechanistic explanation for the influence of environmental antigens on the allergic and autoimmune disease susceptibility, which is often discussed in context of the hygiene hypothesis."

The hygiene hypothesis suggests that a reduction in infections in Western countries -- due to better hygiene -- has led to an increase in autoimmune and allergic diseases.

A study from Ann & Robert H. Lurie Children's Hospital of Chicago found that children with a MED-EL Synchrony cochlear implant device can undergo MRI safely, with no discomfort and reduced need for sedation or anesthesia. Findings were published in the peer-reviewed journal Laryngoscope.

Cochlear implants allow people who are deaf to hear, and they contain a small magnet that is used to attach an external sound processor behind the ear. In most implant designs, the magnet had to be surgically removed before an MRI could be performed, and surgically replaced after the scan, because an MRI scanner also contains a powerful magnet. A later strategy to avoid magnet removal used a special head wrap to counteract the force on the cochlear implant magnet from the MRI. However, patients would still report feeling uncomfortable pressure or pain during the MRI, which often produced anxiety. The latest cochlear implant from MED-EL incorporates a revolutionary design change that allows the special internal magnet to rotate with the magnetic force from the MRI, making surgical removal of the magnet or a head wrap unnecessary. The greater safety and comfort level increases MRI access for children with MED-EL Synchrony cochlear implant devices.

"MRI is an increasingly important diagnostic tool, and access to MRI evaluation without pain and other complications is critical for children with cochlear implants," says lead author Nancy Young, MD, Medical Director of Audiology & Cochlear Implant Programs at Lurie Children's and Professor of Pediatric Otolaryngology at Northwestern University Feinberg School of Medicine. "Few children in our study required sedation or anesthesia during MRI, and none because they had an implant. In the past, all of our patients with cochlear implants required sedation during scanning, to avoid additional surgery to remove the magnet. This is a huge improvement, especially for children with conditions requiring repeated imaging."

The study included seven patients (ages 1.3 to 19 years) with MED-EL Synchrony cochlear implant devices, who underwent 17 episodes of 1.5 or 3.0 Tesla MRI. Seventy-six percent of MRI sessions were completed in awake patients. No patients had device-related discomfort and no magnet related complications occurred. Ninety-three percent of brain studies (13 of 14) and all body studies provided clinically useful diagnostic imaging.

To date, Lurie Children's has implanted 208 children with the MED-EL Synchrony cochlear device since it became available in 2015. More than 2000 cochlear implant surgeries have been done at Lurie Children's since the program began in 1991.

Scientists from the Vaccine and Infectious Disease Organization-International Vaccine Centre (VIDO-InterVac) at the University of Saskatchewan (USask) and Temple University (Philadelphia, U.S.) have demonstrated that a Salmonella biofilm protein can cause autoimmune responses and arthritis in animals.

Salmonella was previously thought to only form biofilms in the environment, such as on food processing surfaces. Biofilms are dense collections of bacteria that stick together on surfaces to protect the bacteria from harsh conditions, including antibiotics and disinfectants. Detecting biofilms in an animal during an infection was a surprise.

In research published today in PLOS Pathogens, a VIDO-InterVac team led by Aaron White discovered that Salmonella biofilms were formed in the intestines of infected mice. For the study, the team used a mouse model to replicate human food-borne illness and showed that a biofilm protein called "curli" that grows on the surface of bacteria was connected to negative health outcomes.

Curli are a special type of protein called amyloids. Similar human proteins have been associated with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease). Scientists don't know how these diseases start, but have speculated that something must "trigger" the accumulation of amyloids.

"We are the first to show that a food-borne pathogen can make these types of proteins in the gut," said White, a leading expert on Salmonella biofilms and curli amyloids.

"There has been speculation that bacteria can stimulate amyloid plaque formation in Alzheimer's, Parkinson's and ALS and contribute to disease progression. The discovery of curli in the gut could represent an important link, pointing to a potentially infectious cause for these diseases."

Collaborator Çagla Tükel and her team from Temple University determined that the presence of curli led to autoimmunity and arthritis--two conditions that are known complications of Salmonella infections in humans.

"In mice, these reactions were triggered within six weeks of infection, demonstrating that curli can be a major driver of autoimmune responses," said Tükel.

The next step in the research is to confirm that this also occurs in humans, and test if other food-borne pathogens related to Salmonella can cause similar autoimmune reactions.

"This important discovery suggests that food-borne pathogens could initiate or worsen autoimmunity and have the potential to contribute to amyloid disorders such as Alzheimer's and Parkinson's disease," said VIDO-InterVac Director Dr. Volker Gerdts.

The news about remdesivir, the investigational anti-viral drug that has shown early promise in the fight against COVID-19, keeps getting better.

This week researchers at Vanderbilt University Medical Center (VUMC), the University of North Carolina at Chapel Hill and Gilead Sciences reported that remdesivir potently inhibited SARS-CoV-2, the virus which causes COVID-19, in human lung cell cultures and that it improved lung function in mice infected with the virus.

These preclinical findings help explain the clinical effect the drug has had in treating COVID-19 patients. Remdesivir has been given to patients hospitalized with COVID-19 on a compassionate use basis since late January and through clinical trials since February.

In April, a preliminary report from the multicenter Adaptive COVID-19 Treatment Trial (which included VUMC) suggested that patients who received the drug recovered more quickly.

"All of the results with remdesivir have been very encouraging, even more so than we would have hoped, but it is still investigational, so it was important to directly demonstrate its activity against SARS-CoV-2 in the lab and in an animal model of disease," said VUMC's Andrea Pruijssers, PhD.

Pruijssers, research assistant professor of Pediatrics at VUMC and lead antiviral scientist in the laboratory of Mark Denison, MD, is the paper's co-corresponding author with Timothy Sheahan, PhD, assistant professor of Epidemiology at UNC-Chapel Hill.

Denison, the E.C. Stahlman Professor of Pediatrics at VUMC, directs the Division of Pediatric Infectious Diseases. He and Ralph Baric, PhD, the William R. Kenan, Jr. Distinguished Professor of Epidemiology at UNC-Chapel Hill, and colleagues have been studying remdesivir since 2014.

They were the first to perform detailed studies to demonstrate that the drug, which was developed by Gilead Sciences to combat hepatitis C and respiratory syncytial virus, and later the Ebola virus, also showed broad and highly potent activity against coronaviruses in laboratory tests.

The current findings, reported this week in the journal Cell Reports, provide "the first rigorous demonstration of potent inhibition of SARS-CoV-2 in continuous and primary human lung cultures." The study is also the first to suggest that remdesivir can block the virus in a mouse model.

Ongoing clinical trials will determine precisely how much it benefits patients in different stages of COVID-19 disease.

Meanwhile in the laboratory, Pruijssers said, "We also are focusing on how to use remdesivir and other drugs in combinations to increase their effectiveness during COVID-19 and to be able to treat at different times of infection."

COVID-19, which to date has infected more then 12 million people and killed nearly 600,000 worldwide, is at least the third instance since 2003 in which a coronavirus originally transmitted from bats has caused serious illness in humans.

Thus there is an urgent need to identify and evaluate broadly efficacious and robust therapies that can limit and prevent coronavirus infections. "Broad-spectrum antiviral drugs, antibodies, and vaccines are needed to combat the current pandemic and those that will emerge in the future," the researchers said.

In addition to SARS-CoV-2, studies in the Denison and Baric labs have shown that remdesivir is effective against a vast array of coronaviruses, including other bat viruses that could emerge in the future in humans.

"We hope that will never happen, but just as we were working to characterize remdesivir over the past six years to be ready for a virus like SARS-CoV-2, we are working and investing now to prepare for any future coronavirus," Denison said. "We want remdesivir and other drugs to be useful both now and in the future."