Culture

Scientists have built a computer 'brain circuit', or artificial neural network, that mirrors human decision-making processes and sheds light on how circuits might be altered in psychiatric diseases, a new study published today in eLife reports.

The model identifies a potential mechanism for the impaired decision making that is commonly seen in schizophrenia, involving the reduced activity of molecules in the brain called NDMA receptors. These results provide new insight that may inform the development of future treatments for neuropsychiatric conditions.

"A major challenge in psychiatry is to relate changes that occur at nerve synapses in the brain to the cognitive processes that cause symptoms of disorders such as schizophrenia," explains lead author Dr. Sean Cavanagh, who is an MBPhD student at the UCL Queen Square Institute of Neurology, London, UK. "Computational modelling of brain circuits can fill in these gaps. By altering the circuit model at the synapse level, you can make predictions of nerve activity and behaviours, and then test these experimentally."

The team built a model that reproduces how the brain accumulates evidence and makes a decision. The types of decisions they were interested in were those that involve combining multiple pieces of information. For example, when deciding about where to go on holiday, we must combine information about many factors including the cost, weather and cultural experience. Initially, the team wanted to see whether their computer model showed the same decision-making bias that healthy humans show on these sorts of choices, called the 'pro-variance bias'. This describes how humans tend to choose options with more variable evidence. For example, when planning a holiday and facing two options, people generally tend to prefer a holiday which is very appealing in one attribute but less so in another (expensive price, but excellent weather), when compared with another holiday which is mediocre in all attributes (acceptable price and acceptable weather).

The researchers began by setting a decision-making task for two macaque monkeys and recording the pattern of their behaviours. The monkeys were presented with two series of eight bars, one on either side of a computer screen, and they had to decide which side had the taller average height. The monkeys made decisions based on nearly 30,000 sets of information, and the researchers studied the effect of timing and variability of the evidence on the monkeys' choices. They found that, as with humans, the monkeys generally preferred to choose options with greater variability across the evidence.

To explore the brain processes that underlie this preference, the team built a computer-based circuit model. This model includes two groups of excitatory nerve cells (neurons) assigned to either the right or left option, such that high activity in one group signals a decision towards that option. Both groups of neurons are also connected to inhibitory neurons, which counteract and balance the activity of the excitatory neurons. The circuit was then tested with the same decision tasks as the monkeys and was shown to be able to reproduce the same bias that the monkeys used (and which humans use) to make their decisions.

To understand how these decision processes may be impaired in neuropsychiatric diseases such as schizophrenia, the team reduced the activity of synaptic NMDA receptors that connect the neurons in each excitatory and inhibitory group. They found that the decision-making performance in the model was dependent on the balance between excitation and inhibition, which in turn was influenced by the relative changes to NDMA receptors on the two groups of neurons.

The drug ketamine is known to block NDMA receptors and is used as an experimental model of schizophrenia, as it temporarily reproduces many of the symptoms of schizophrenia in healthy humans. To test if the predictions from the model were consistent with behavioural changes, the team studied the effects of ketamine on the monkeys' decision making. Although the monkeys became less accurate in their decision making after ketamine, they retained the same pro-variance bias. In the computer model, this change in decision-making behaviour was consistent with lowered excitation/inhibition balance.

Taken together, this suggests that the changes in decision-making behaviour seen in schizophrenia and other disorders could arise from reduced activity at the NMDA receptors present on excitatory neurons. The team hopes this insight could pave the way for the development of new treatments.

"Decision-making biases can be features of normal behaviour or deficits underlying neuropsychiatric symptoms," concludes senior author Steve Kennerley, Professor of Cognitive Neuroscience at the UCL Queen Square Institute of Neurology. "Developing mechanistic accounts of neurological disease is very challenging, requiring well-designed experimental tasks, normal versus abnormal neurological groups, and computational modelling. This study was only possible with collaborations with Oxford University (Dr. Laurence Hunt) and Yale University (Dr. Norman Lam; Professor John Murray). Our results provide a circuit-level mechanism that bridges from the synaptic to behavioural level in neuropsychiatric disorders where decision-making biases are prominent."

HAMILTON, ON, Sept. 29, 2020 -- An international team led by current and former McMaster University researchers has developed an artificial lung to support pre-term and other newborn babies in respiratory distress.

The group has proven the concept using a live piglet, a major step along the route toward approval for use in humans, where the portable device could save many lives and prevent catastrophic damage by taking up some of the placenta's role in oxygenating the blood until babies are able to breathe independently.

"This technology, which is complicated to create but simple to use, is going to create a situation where more and more of these babies can be saved, and that is what is driving all of us to do this," says Ravi Selvaganapathy, a professor of Mechanical and Biomedical Engineering at McMaster who holds the Canada Research Chair in Biomicrofluidics.

The device, designed to be connected to a newborn's umbilical cord, uses the existing power of the heart to drive blood through channels of a fine membrane whose structure resembles the lining of the lungs, allowing the release of carbon dioxide and the uptake of oxygen while protecting the blood from outside infection.

The membrane is only 35 to 50 microns thick - about half the thickness of a human hair - permitting natural diffusion of carbon dioxide and oxygen. The baby's own heart beats at a rate to regulate the supply of oxygen.

Independent breathing is a particular obstacle to the survival of pre-term babies, since the lungs are not fully formed in many pre-term infants, placing them in respiratory distress from the moment they are born because they cannot take up enough oxygen on their own.

"Typically, a newborn immediately takes over breathing, feeding, and other organ functions that have been provided in utero via the placenta," says Christoph Fusch, a McMaster faculty member in Pediatrics and Chief of Pediatrics at Nuremberg General Hospital in Germany, which is affiliated with Paracelsus Medical School.

"When this transition is disturbed due to disease or immaturity, our device will enable neonatal caregivers to mimic the intrauterine supply. It will improve survival, reduce brain damage and improve long-term health in pre-term and term newborns with life-threatening postnatal lung failure."

Though the design of the artificial lung is complex, the device itself operates without external power and is simple to deploy - compared to existing technology which is much riskier and far more expensive - making it a promising contender for use in developing countries, where the risk of death among pre-term babies is greatest.

"Our research takes Mother Nature as a blueprint," says Niels Rochow, a former fellow in Neonatology at McMaster and now a staff neonatologist working with Fusch at the Nuremberg General Hospital. "The artificial placenta will allow gentle and efficient care in newborn babies with life-threatening postnatal lung failure. Families will benefit having babies with better chances for a normal life."

The device would ideally be paired with still-developing technology to supply pre-term babies with nutrition, also through the umbilical cord, thereby replacing the major functions of the placenta long enough for vulnerable pre-term babies to finish developing safely outside the womb.

"Developing this device seemed like an impossible mission in so many ways," says Mohammadhossein Dabaghi, who earned his PhD in Biomedical Engineering at McMaster and is now a post-doctoral fellow in the university's Department of Medicine. "A pumpless device that is capable of gas exchange in ambient air is something that one would expect to be bulky, but we were able to keep it compact and by using microfabrication technologies we developed in our group."

The proof-of-concept research is published today in the journal Advanced Science. The nine-person research team showed that the device worked in a live newborn piglet, restoring its reduced blood-oxygen levels to normal. Piglets are close in weight to human babies and are very similar physiologically.

Subject to successful larger-scale animal trials and regulatory approvals, Selvaganapathy says the new device could become available for clinical use within the next six to eight years.

A team of researchers found out that children with autistic spectrum disorder (ASD) have increased levels of the amino acid hydroxyproline. According to the medics, this may be associated with joint hypermobility, a common symptom in ASD patients. This information can help improve anti-ASD therapy. The work was published in the Research in Autism Spectrum Disorders journal.

Amino acids are the building blocks of proteins, and proteins are what our muscles, internal organs, and also enzymes and hormones are made of. They control our daily functioning and secure healthy growth and development of our bodies. Both lack and excess of amino acids can cause health issues. One of the factors that can have a negative impact on the balance of amino acids is autistic spectrum disorder or ASD. It manifests itself in a patient's early childhood and remains with them for the rest of their life. It is still unknown how exactly ASD affects a patient's amino acid profile and what effects it has on their body. However, a team of researchers found out that children with ASD have increased levels of the amino acid hydroxyproline. This may be associated with joint hypermobility, a common symptom in ASD patients.

"The available data about the amino acid profile of ASD patients is quite contradictory which may be due to age and gender differences, specifics of clinical treatment, and other parameters. Information about the levels of several amino acids at a given time can help better understand the specifics of metabolism in ASD patients. That is why in our work we focused on studying the levels of amino acids in children's blood serum," said Alexey Tinkov, a Candidate of Medical Sciences, and a lecturer at the Department of Elementology at RUDN University and Yaroslavl State University.

The participants of the study were 97 boys from 3 to 14 years of age, of which 64 were diagnosed with ASD. The levels of amino acids in their blood serum were measured using high-efficiency liquid chromatography with UV detection. This method allowed the researchers to break the samples down to their components and measure their concentrations.

Four amino acids (leucine, serine, tyrosine, and hydroxyproline) turned out to be associated with ASD. Hydroxyproline is a component of collagen, the basis of all connective tissues: tendons, bones, and cartilages. Therefore, the team assumed that increased hydroxyproline levels might be the cause of joint hypermobility. By various estimates, this disorder is found in 15% to 50% of young ASD patients. The level of hydroxyproline in the blood of healthy children amounted to 0.87 mg per liter, while in ASD patients it reached 1.7 mg/l. The team also found out that the levels of arginine, glutamine, histidine, leucine, lysine, phenylalanine, serine, taurine, tryptophan, and threonine in the blood of children with ASD were 15% to 28% lower than in healthy ones. Among other things, these amino acids regulate the growth and reconstruction of body tissues. According to the researchers, their deficiency can negatively affect a child's psychomotor development.

"We assumed that increased hydroxyproline levels might be associated with joint hypermobility, and the deficiency of other amino acids might affect the neuronal dysfunction. Further studies may identify potential targets for proactive treatment. Theoretically, the normalization of amino acid balance can become an additional tool for ASD therapy," added Prof. Anatoly Skalny, MD, the head of the Department of Medical Elementology at RUDN University.

By examining preexisting research for other conditions, researchers at the University of Cincinnati have found a potential treatment that could be applied to COVID-19.

The findings, published in the Journal of Biological Chemistry, established that a lipid found in the human body could be used to prevent or treat infections with SARS-CoV-2, the virus that causes COVID-19. That lipid, called sphingosine, is a natural element taken from the body and is important in the lipid metabolism of all cells and the local immune defense in epithelial cells, a type of cell that lines the surfaces of the body including skin, blood vessels, urinary tract and organs. They serve as a barrier between the inside and outside of your body and protect it from viruses.

"We investigated whether a specific lipid is able to interfere with the binding of SARS-CoV-2 to human epithelial cells," says corresponding author Erich Gulbins, MD, a visiting professor in UC's Department of Surgery. He is also chair of the Department of Molecular Biology at the University of Duisburg-Essen, Germany.

"Sphingosine has been shown in past studies to prevent and eliminate bacterial infections of the respiratory tract, but it is unknown if it can be used to prevent viral infections. The coronavirus needs to bind to specific molecules on the surface of human cells as a prerequisite to infect them," Gulbins says. "This is similar to the key and lock principle of a door: To open the door you must insert the key into the lock. We show that the lipid sphingosine binds into the cellular 'lock,' the receptor ACE2, for SARS-CoV-2 and thereby prevents binding of the virus to and infection of human cells."

Researchers in this study analyzed the use of this lipid in regulating infection in cultured human cells with SARS-CoV-2 particles added.

"We showed that sphingosine prevented cellular infection in these cultures, and pretreatment of cultured cells or freshly obtained human nasal epithelial cells with low concentrations of sphingosine prevented adhesion of and infection with the virus," says Gulbins.

"These findings indicate that sphingosine prevents at least some viral infection by interfering with the interaction of the virus with its receptor; it could be used as a nasal spray to prevent or treat infections with SARS-CoV-2," he adds. "The nasal spray must be developed, but sphingosine is a natural product. More research is needed to see if this could be a treatment for COVID-19."

Co-author Syed Ahmad, MD, co-director of the UC Cancer Center, professor and chief of the division of surgical oncology at UC and a UC Health surgeon, says this collaboration is particularly fascinating because it takes medical research from other areas of study and applies it to a timely public health issue.

"The ACE2 receptor has been studied and identified as a treatment target in pancreatic cancer," says Ahmad, the Hayden Family Endowed Chair for Cancer Research. "This is an example of taking existing research and applying it to COVID-19 science in order to make progress in the field. This is how translational science works."

ROCHESTER, Minn. -- Patients with large polycystic kidneys in need of a kidney transplant can have their diseased kidneys safely removed laparoscopically at the same time as their transplant surgery. That is the finding of a Mayo Clinic study recently published in the American Journal of Transplantation.

Mikel Prieto, M.D., a transplant surgeon and the study's senior author, began offering this dual laparoscopic procedure to polycystic kidney disease patients six years ago. The study results confirm that this all-in-one surgical approach is a safe and viable option for these patients.

"Some patients with polycystic kidney disease have two big problems. The first one is that their kidneys do not work and they need a kidney transplant. The other one is that they have very large kidneys that can cause pain and other problems," Dr. Prieto says. "If you fix one problem with the transplant, you still have the other problem to fix. It's very unsatisfying for patients who can be miserable with these kidneys to be told they will need to wait six months after the transplant to have them removed."

Polycystic kidney disease is an inherited disorder that causes clusters of cysts to develop primarily within the kidneys. As these fluid-filled cysts grow larger, they damage the kidneys, which can ultimately lead to kidney failure. These kidneys can sometimes reach a very large size significantly impairing a patient's quality of life. An estimated 600,000 people in the U.S. have polycystic kidney disease, according to the National Kidney Foundation.

The study compared the results of 51 transplant patients who had the dual surgery versus 97 patients who had only a living donor kidney transplant between January 2014 and October 2019. Researchers discovered that the kidney function for both groups of patients after undergoing surgery was the same. The risk of complications for both groups was also the same at 2%.

Patients who had the dual surgery needed to be hospitalized an average of four days post-surgery versus three days for those who had the kidney transplant alone. Researchers found that patients who had the dual surgery were more likely to need additional care immediately after the surgery. However, the long-term outcomes for both sets of patients were comparable.

"This study shows that the removal of both kidneys laparoscopically and a living donor transplant at the same time can be done successfully and safely without a significant effect on kidney function," Dr. Prieto says.

Using a zebrafish model, researchers from North Carolina State University have found that vitamin D deficiency during early development can disrupt the metabolic balance between growth and fat accumulation. The results suggest a linkage between vitamin D and metabolic homeostasis, or equilibrium.

The research team, led by Seth Kullman, professor of biological sciences at NC State, looked at groups of post-juvenile zebrafish on one of three diets: no vitamin D (or vitamin D null), vitamin D enriched and control. The zebrafish spent four months on their particular diet, then the researchers looked at their growth, bone density, triglyceride, lipid, cholesterol and vitamin D levels. They also examined key metabolic pathways associated with fat production, storage and mobilization and growth promotion.

The zebrafish in the vitamin D deficient group were, on average, 50% smaller than those in the other two groups, and they had significantly more fat reserves.

"The vitamin D deficient zebrafish exhibited both hypertrophy and hyperplasia - an increase in both the size and number of fat cells," Kullman says. "They also had higher triglycerides and cholesterol, which are hallmarks of metabolic imbalance that can lead to cardio-metabolic disease. This, combined with the stunted growth, indicates that vitamin D plays an important role in the ability to channel energy into growth versus into fat storage."

After the initial testing, the vitamin D deficient zebrafish were given a vitamin D enriched diet for an additional six months, to see if the results could be reversed. While the fish did continue to grow and begin to utilize fat reserves, they never caught up in size with the other cohorts and they retained residual fat deposits.

"This work shows that vitamin D deficiency can influence metabolic health by disrupting the normal balance between growth and fat accumulation," Kullman says. "Somehow the energy that should be going toward growth is getting shunted into creating fat and lipids, and this occurrence cannot be easily reversed. While we don't yet understand the mechanism, we are beginning to tease that out."

Future work will involve looking at the offspring of vitamin D deficient mothers, to determine whether this vitamin deficiency has epigenetic effects that can be passed down.

Jizhong Zhou, the Director of the Institute for Environmental Genomics, a George Lynn Cross Research Professor in the OU College of Arts and Sciences and the lead for the study, tackles a problem that has challenged scientists for more than a decade.

"Soil microbial respiration, which is the carbon dioxide flux from the soil to the atmosphere, is an important source of uncertainty in projecting future climate and carbon cycle feedbacks," said Zhou. "Our study illustrates that warming-induced respiratory adaptation is subject to the adaptive changes in microbial community functional structure, so that the positive feedback of soil microbial respiration in response to climate warming may be less than previously expected."

He adds that this study is also unique in its approach to integrate omics data, the term for the comprehensive approach for analysis of complete genetic profiles of organisms and communities, into ecosystem models for better predictions.

"Integrating microbial omics information to inform global climate change models is extremely challenging," Zhou said. "The findings from this study have important implications for understanding and predicting the ecological consequences of climate warming."

STONY BROOK, NY, September 29, 2020 - Diet remains an important part of disease prevention and management, and a new study suggests that consumption of fructose may worsen intestinal inflammation common to inflammatory bowel diseases (IBD). Led by David Montrose, PhD, of the Renaissance School of Medicine at Stony Brook University, the study is currently published early online in Cellular and Molecular Gastroenterology and Hepatology.

Rates of IBD have been increasing worldwide. According to the Centers for Disease Control and Prevention (CDC), approximately three million Americans are diagnosed with IBD each year, up one million from incidence in the late 1990s. Consumption of a western diet, including fructose, is associated with increasing rates of obesity and diabetes, and IBD may be an additional disease exacerbated by fructose intake.

“The increasing incidence of IBD parallels higher levels of fructose consumption in the United States and other countries,” says Montrose, an Assistant Professor in the Department of Pathology and faculty researcher in the Stony Brook University Cancer Center. "Our findings provide evidence of a direct link between dietary fructose and IBD and support the concept that high consumption of fructose could worsen disease in people with IBD. This is important because it has the potential to provide guidance on diet choices for IBD patients, something that is currently lacking."

Montrose, along with colleagues at Weill Cornell Medicine, tested three mouse models of IBD. They were fed high amounts of fructose, which worsened colonic inflammation along with notable effects in their gut bacteria including changes in their type, metabolism and localization within the colon. Complementary mechanistic work demonstrated that the microbiota is causally linked to the detrimental effects of the high fructose diet.

The paper concludes that the "excess dietary fructose consumption had a pro-colitic effect that can be explained by changes in the composition, distribution and metabolic function of resident enteric microbiota."

Montrose says several next steps are planned to expand upon these findings. These include the development of interventions to prevent the pro-inflammatory effects of dietary fructose as well as evaluating whether this diet increases colitis-associated tumorigenesis. This second point is particularly important because IBD patients are at increased risk of developing colon cancer due to a lifetime of chronic inflammation of the gut.

In 2016, the world's largest ever data leak dubbed "The Panama Papers" exposed a scandal, uncovering a vast global network of people--including celebrities and world leaders, who used offshore tax havens, anonymous transactions through intermediaries and shell corporations to hide their wealth, grow their fortunes and avoid taxes.

Researchers at USC Viterbi School of Engineering have now conducted a deep analysis of the entities and their interrelationships that were originally revealed in the 11.5 million files leaked to the International Consortium of Investigative Journalists. The academic researchers have made some discoveries about how this network and transactions operate, uncovering uniquely fragmented network behavior, vastly different from more traditional social or organizational networks, demonstrating why these systems of transactions and associations are so robust and difficult to infiltrate or take down. The work has been published in Applied Network Science.

Lead author Mayank Kejriwal is an assistant professor working in the Daniel J. Epstein Department of Industrial and Systems Engineering and USC's Information Sciences Institute who studies complex (typically, social) systems like online trafficking markets using computational methods and network science. He said the research team's aim was to study the Panama Papers network as a whole, in the same way you might study a social network like Facebook, to try to understand what the network behavior can tell us about how money can be moved.

"In general, in any social network like LinkedIn or Facebook, there is something called 'Small World Phenomenon', which means that you're only ever around six people away from anyone in the world," Kejriwal said.

"For instance, if you want get from yourself to Bill Gates, on average you would be around six connections away," he said.

However the team discovered that the Panama Papers network was about as far removed from this traditional social or organizational network behavior as it could possibly be. Instead of a network of highly integrated connections, the researchers discovered a series of secretive disconnected fragments, with entities, intermediaries and individuals involved in transactions and corporations exhibiting very few connections with other entities in the system.

"It was really unusual. The degree of fragmentation is something I have never seen before," said Kejriwal. "I'm not aware of any other network that has this kind of fragmentation."

"So (without any documentation or leak), if you wanted to find the chain between one organization and another organization, you would not be able to find it, because the chances are that that there is no chain - it's completely disconnected," Kejriwal said.

Most social, friendship or organizational networks contain a series of triangular structures in a system known as the 'friend of a friend phenomenon."

"The simple notion is that a friend of a friend is also a friend," Kejriwal said. "And we can measure that by counting the number of triangles in the network."

However, the team discovered that this triangular structure was not a feature of the Panama Papers network.

"It turns out that not only is it not prevalent, but it's far less than prevalent than even for a random network," Kejriwal said. "If you literally randomly connect things, in a haphazard fashion and then you count the triangles in that network, this network is even sparser than that." He added, "Compared to a random network, in this type of network, links between financial entities are scrambled until they are essentially meaningless (so that anyone can be transacting with anyone else)."

It is precisely this disconnectedness that makes the system of secret global financial dealings so robust. Because there was no way to trace relationships between entities, the network could not be easily compromised.

"So what this suggests is that secrecy is built into the system and you cannot penetrate it," Kejriwal said.

"In an interconnected world, we don't expect anyone to be impenetrable. Everyone has a weak link," Kejriwal said. "But not in this network. The fact it is so fragmented actually protects them."

Kejriwal said the network behavior demonstrates that those involved in the Panama Papers network of offshore entities and transactions were very sophisticated, knowing exactly how to move money around in a way that it becomes untraceable and they are not vulnerable through their connections to others in the system. Because it is a global network, there are few options for national or international bodies to intervene in order to recoup taxes and investigate corruption and money laundering.

"I don't know how anyone would try to bring this down, and I'm not sure that they would be able to. The system seems unattackable," Kejriwal said.

PHILADELPHIA (September 29, 2020) - Serious traumatic injuries are a health event that can begin a trajectory toward chronic health and social challenges. Research on patient outcomes following traumatic injuries establishes the pervasive nature of injuries' long-term consequences in physical, psychological, social and economic well-being, which may persist months and even years after an injury hospitalization. In light of this research, emerging interventions have targeted enhanced and coordinated healthcare services to support recovery and address patients' long-term rehabilitative needs.

Across a numerous of other health conditions, mobile technology-based prevention and treatment interventions have been used successfully to monitor and transform health outcomes. But until now, their potential for addressing inter-related physical, psychological, and social challenges in long-term injury recovery has not been unexplored.

A new study - recently published in mHealth - from the University of Pennsylvania School of Nursing (Penn Nursing) is the first of its kind to examine how mobile health applications and text-based elicitation of patient-reported outcomes can be used better understand persistent challenges to recovery after a serious injury and hospitalization. This study showed that mobile health monitoring was feasible and acceptable including for select biometric indicators of physical activity and sleep, in a sample of Black men recovering from serious trauma in Philadelphia, PA who described past and current barriers to their access to health and social care resources.

"This study adds evidence to support efforts to more systematically and comprehensively conceptualize the aftermath of physical trauma as an often long-term and chronic health condition," writes the article's lead-author Sara F. Jacoby, MPH, MSN, PhD, Assistant Professor in the Department of Family and Community Health. "This pilot research is a first step in identifying the utility and implementation specifications of real-time monitoring for long-term physical, psychological, and social outcomes in trauma patients using mobile technology."

A new treatment for breast cancer patients with hormone receptor (HR+) early stage disease who are at a high risk of recurrence has been shown to reduce the risk by 25%, according to a study led by The Royal Marsden NHS Foundation Trust.

The results of the monarchE study presented at the European Society for Medical Oncology Virtual Congress (ESMO) and published simultaneously in the Journal of Clinical Oncology (JCO) on Sunday 20 September 2020, have been described as one of the most promising breakthroughs for patients with this type of breast cancer in the last 20 years.

The global randomised Phase III study with 5,637 patients in 38 countries tested if patients taking the CDK 4/6 inhibitor abemaciclib along with hormone therapy following standard of care treatments (chemotherapy, surgery and/or radiotherapy) would reduce the risk of recurrence compared with the standard hormone treatment alone.

Approximately 70% of breast cancer patients have hormone receptor positive tumours, and of those a proportion of patients will have a higher risk of relapsing in the first two of years. Patients with disease that has spread to lymph nodes, a large tumour size at the time of diagnosis, or an increased cellular proliferation (determined by high grade of the tumour, or number of dividing cells) were considered to be at "high risk" of recurrence and recruited to the study.

The study found a 25% reduction in recurrence of cancer when abemaciclib was added to the standard hormone therapy compared to the hormone therapy alone for two years. During this time 11.3% of patients in the control group had a relapse of their cancer compared with 7.8% of those in the abemaciclib group.

Professor Stephen Johnston, Consultant Medical Oncologist at The Royal Marsden and Professor of Breast Cancer Medicine at The Institute of Cancer Research, said: "The monarchE research has given us a confidence that we will soon be to offer our high risk HR+ patients a greater chance of keeping them cancer free . While there have been many advances in other early breast cancer subtypes such as HER2 positive disease, there has been no significant advancements for the large group of patients who have hormone receptor positive breast cancer since the late 1990s when aromatase inhibitors were introduced. This research could potentially save many lives in the future."

Patient Sarah Ryder, 57, said: "When I was referred to The Royal Marsden last year and Professor Johnston told me about the monarchE trial I was so pleased to be part of something that could potentially save my life. By that stage my cancer had spread to 23 lymph nodes and I honestly did not feel much hope.

"The trial has helped me believe in a future again. I can see my daughter grow up, go off to university next year and maybe have a family of her own one day."

In the United States, the average American sleeps less than the minimum seven hours of sleep per night recommended by the Center for Disease Control, and nearly half of Americans report negative consequences from insufficient sleep. This problem appears to be especially prevalent in men, who report getting significantly less sleep, on average, than women.

A cultural complication is the notion that getting less than the recommended amount of sleep signals something positive about an individual. For example, US President Donald Trump has boasted about getting less than four hours of sleep per night and regularly derogates his political opponent Joe Biden as "Sleepy Joe."

"The Sleep-Deprived Masculinity Stereotype," a new paper in the Journal of the Association for Consumer Research, examines a possible stereotype connecting sleep and masculinity along with its underlying mechanisms and its social implications.

Authors Nathan B. Warren and Troy H. Campbell conducted 12 experiments involving 2,564 American participants to demonstrate that a sleep-deprived masculinity stereotype exists. In one experiment, participants were asked to imagine seeing a man shopping for a bed. Then, a salesperson asked the man, "How much do you normally sleep?" The results found that the mean masculinity rating for participants in the lots of sleep condition was significantly lower than the mean masculinity rating for participants in the little sleep condition.

In another experiment, participants were asked to ascribe different attributes to a male character, assigned to either a "very masculine and manly" man or a "not very masculine and not very manly" man. Participants in the masculine condition described their character sleeping 33 minutes less sleep per night than the characters described in the not masculine condition. A final experiment showed that participants who imagined stating they sleep more than average felt significantly less masculine than participants who imagined stating they sleep less than average.

Collectively, the experiments found that men who sleep less are seen as more masculine and more positively judged by society. The same patterns were not consistently observed for perceptions of women.

"The social nature of the sleep-deprived masculinity stereotype positively reinforces males who sleep less, even though sleeping less contributes to significant mental and physical health problems," the authors write. This may be particularly detrimental because men frequently have significantly more negative attitudes towards seeking psychological help. "Unfortunately, the problems created by the sleep-deprived masculinity stereotype may reach beyond individuals and into society, as men who sleep less are found to be more aggressive and violent." This is an example of the restrictive and toxic characteristics of masculinity, "which can be harmful to men's health and society at large."

The bright side of this research, the authors say, is that "as society continues to challenge traditional definitions of masculinity, attitudes toward sleep may become more positive, and all people might enjoy more nights full of healthy sleep."

LONDON, ONTARIO - A new study from Lawson Health Research Institute and Western University illustrates how the gut microbiome interacts with an oral medication in prostate cancer patients, suggesting bacteria in the gut play a role in treatment outcomes. The findings, published in Nature Communications, highlight how the drug abiraterone acetate is metabolized by bacteria in the gut to reduce harmful organisms while promoting those that fight cancer. The team suspects this is one of many examples of how the microbiome influences our response to medications.

"Research is beginning to uncover the ways in which the human microbiome influences cancer development, progression and treatment," explains Brendan Daisley, a PhD candidate at Western's Schulich School of Medicine & Dentistry who is conducting research at Lawson. "Our study highlights a key interaction between a cancer drug and the gut microbiome that results in beneficial organisms with anti-cancer properties."

Traditional prostate cancer therapies are designed to deprive the body of hormones called androgens, which are responsible for prostate cancer growth.

"Unfortunately, traditional androgen deprivation therapies are not always effective," explains Dr. Joseph Chin, Lawson Associate Scientist, Professor at Schulich Medicine & Dentistry and Urologist at London Health Sciences Centre (LHSC). "In those cases, alternative therapies are explored."

Abiraterone acetate is a highly effective therapy used in the treatment of prostate cancer that has been resistant to other treatments. While abiraterone acetate also works to reduce androgens in the body, it does so through a different mechanism and, unlike traditional therapies, it is taken orally.

"When drugs are taken orally, they make their way through the intestinal tract where they come into contact with billions of microorganisms," says Dr. Jeremy Burton, Lawson Scientist, Associate Professor at Schulich Medicine & Dentistry and lead researcher on the study. "While it's long been a mystery why abiraterone acetate is so effective, our team wondered if the gut microbiome plays a role."

The team's study included 68 prostate cancer patients from LHSC, including those being treated with abiraterone acetate and those being treated with traditional androgen deprivation therapies. The research team collected and analyzed patient stool samples, and conducted further experiments in their laboratory at St. Joseph's Health Care London.

They discovered that patients' gut microbiomes changed drastically after taking abiraterone acetate. Bacteria in the gut metabolized the drug leading to a significant increase in a bacterium called Akkermansia muciniphila. Referred to as a 'next-generation probiotic,' this bacterium's relevance has recently been explored in several large cancer studies. It's been shown to facilitate a better response to cancer immunotherapy drugs and it can elicit a wide range of other positive health benefits as well. The increase in Akkermansia muciniphila also led to an increased production of vitamin K2 which is known for anti-cancer properties that can inhibit tumour growth.

The team also observed the impact of androgen depletion on the microbiome. Both abiraterone acetate and traditional androgen deprivation therapies led to a decrease in organisms that utilize androgen.

"These findings clearly demonstrate that the gut microbiome is playing a role in treatment response," notes Dr. Burton.

The team hopes to further explore drug-microbiome interactions with a goal of harnessing the microbiome to improve treatment outcomes for a variety of diseases. In another study, they are exploring whether fecal microbiota transplants from a healthy donor can change the microbiome of melanoma patients to increase organisms like Akkermansia muciniphila and improve response to immunotherapy. They also plan to study whether analysis of a patient's microbiome can be used to predict their response to specific therapies.

"While more research is needed, we may one day be able to analyze a patient's microbiome to determine the best course of treatment or even influence the microbiome to improve outcomes," says Dr. Burton. "This could lead to a new frontier in personalized medicine."

Scientists at Boston University's National Emerging Infectious Diseases Laboratories (NEIDL) and the Center for Regenerative Medicine (CReM) joined forces to develop the most relevant research model possible for understanding how the coronavirus virus impacts the lungs, by engineering living, "breathing" human lung cells from stem cells for the task.

Their efforts have borne a leap forward in our understanding of how COVID-19 infections trigger deadly levels of lung inflammation. Their discovery of a pathway that sets the lungs ablaze with inflammation has launched a search for new therapeutics that could block this process before it can take off and turn fatal.

According to their new findings, published in Cell Stem Cell, the trouble starts soon after the air sacs in the lungs are infected with SARS-CoV-2, when the virus activates one of the body's biological pathways known as NFkB (the k is pronounced "kappa"). As that's happening, the virus also suppresses the lungs' ability to call in the help of the immune system to fight off the viral invaders.

When the signal for help finally goes out--several days after infection has taken hold--an army of immune cells swarms into lung tissue heavily laden with infected, dead, and dying cells and with unchecked levels of inflammation triggered by the early activation of NFkB. The incoming immune cells, by attempting to destroy every infected cell in their path, add more fuel to the fire. Every infected cell killed by the virus or by immune cells trying to thwart viral spread tips the scales of inflammation closer to sending the lungs and other organs into total failure.

The discovery of NFkB's role in this deadly cascade makes it a promising target for new therapeutics that could tamp down its activity early on after infection with the novel coronavirus. A new drug could help reduce inflammation before it gets out of control, and give the body critical time to recruit help from immune cells before conditions have deteriorated too far."We've learned [NFkB] is the primary pathway that drives inflammation [in COVID-19 patients]," says one of the study's corresponding authors, Darrell Kotton, who is a director of the CReM and a pulmonologist at BU's teaching hospital, Boston Medical Center (BMC). "Now the challenge is to find effective therapeutics that work in patients who are developing acute respiratory distress syndrome [ARDS]."Kotton says the revelation about NFkB's role in severe coronavirus infections is important because the data was gathered directly from observing human lung cells infected with live SARS-CoV-2 virus. That's different from the vast majority of coronavirus research written about to date, which has been based on infecting much more commonly available types of cells for research: kidney cells derived from African green monkeys. Those kidney cells are easily grown and maintained in culture dishes, but don't accurately represent human lung cells.

"You learn a lot more about how human beings respond to the virus and how drugs might work in them when you infect human lung cells, not kidney cells from monkeys," Kotton says.

For study co-corresponding author Elke Mühlberger, a virologist at the NEIDL who typically works with some of the world's most lethal viruses, like Ebola and Marburg, it was remarkable to witness the effect SARS-CoV-2 virus has on human lung cells.

"It was scary to see how much damage the virus does to these cells," Mühlberger says. "It disrupts the [membrane surrounding the cell nucleus], and causes significant changes to the cell's organelles," which are the internal parts of a cell that carry out essential functions. "The cells really suffer," she says, and not even Ebola or Marburg viruses have as much impact on the cell's internal organelles as the novel coronavirus does, she adds.

"I don't think the senior members of our research team and I have ever experienced anything like this in our careers," Kotton says. He and co-corresponding author Andrew Wilson, also a CReM scientist and a pulmonologist at BMC, have avoided stepping foot in their own labs in the CReM in order to protect their colleagues from the coronavirus exposure risks they endure inside BMC's intensive care unit.

At BMC, Kotton and Wilson frequently saw patients infected with the coronavirus who, despite having mild cold-like symptoms and feeling pretty healthy for a week or so, would suddenly crash, needing to be intubated and ventilated. "We saw this process taking place right in front of our eyes. It was so evident to us that we were trying to keep patients alive after the damage to their lungs had already happened," Kotton says.

That fueled their interest in looking at what's happening inside the lungs' air sac cells at the onset of coronavirus infection.

"We had to get a glance at what the cells are doing when the disease first takes off, because after that, it's probably too late to stop the process except to help keep patients alive with a ventilator," Kotton says. "The first day a lung cell gets infected, what is the cell telling us? We hypothesized that time frame might be a much more effective window to intervene." Peering into that window, they identified NFkB as the primary culprit.

To make that discovery, Adam Hume, a co-lead author of the study and a senior research scientist in Mühlberger's lab, performed the SARS-CoV-2 infections on sophisticated lung models created by stem cell researchers in Kotton and Wilson's CReM labs--Jessie Huang, Rhiannon Werder, and Kristy Abo, also co-lead study authors. Their models of human lung tissue--three-dimensional structures of lung cells, called "lung organoids"--are grown from human stem cells. The CReM's organoids have been used by researchers at BU and with collaborators elsewhere to study a range of chronic and acute lung diseases.

For coronavirus research, CReM scientists leveraged their organoid expertise to grow lung air sac cells, the type of cell that lines the inside of lungs. Air sac cells are usually difficult to grow and maintain in traditional culture and difficult to extract directly from patients for research purposes. That's why many labs rely on the use of more readily available cell types, like kidney cells from monkeys.

"Our organoids, developed by our CReM faculty, are engineered from stem cells--they're not identical to the living, breathing cells inside our bodies, but they are the closest thing to it," Kotton says.

The CReM team then placed the human air sac cells into an experimental model they had previously developed to study the effects of smoking cigarettes. The cells are plated on a mesh membrane; on one side they are exposed to air, just like air sac cells experience in the lungs when we breathe. On the other side of the membrane, the cells are fed by a liquid concoction that mimics the nutrients and growth factors supplied by lungs' blood vessel network.

From there, the NEIDL team stepped in to infect the lung model. Hume added droplets of live coronavirus on top of the lung cells, infecting them from the air side of the membrane, similar to the way the virus infects cells lining the inside of the lungs when air containing the virus is breathed into the body. He and Mühlberger have run these experiments inside one of the NEIDL's Biosafety Level 4 (BSL-4) laboratories, the highest possible level of biosafety containment used for infectious agents that pose especially high risk to humans.

Based on the experiments implicating NKfB's role in severe coronavirus cases, the CReM and NEIDL researchers are now collaborating with researchers at BU and beyond who have libraries of drugs and novel chemical compounds. Together, the collaborators plan to screen for potential therapeutics that could block the train of inflammation from leaving the station.

Using the CReM lung model at the NEIDL, the researchers have confirmed that existing drugs remdesivir and camostat are effective in combating the virus, though neither is a perfect fix for controlling the inflammation unleashed by NFkB.

Remdesivir, a broad-use antiviral, has already been used clinically in coronavirus patients. Camostat, an antiviral and cancer drug sometimes used to treat pancreatitis, has previously been tested in a type of cell found higher up in the lungs, in the airway, and found to be effective. With the BU team's experiments confirming it also works to treat coronavirus infection in the lungs' air sac cells, Kotton says camostat is a good candidate for clinical trials.

"It's been wonderful to finally be on the offense, rather than on the defense, like we were early on in April and May," Wilson says. At BMC, he recalls during the springtime surge of coronavirus cases, "There was a period of time where overhead announcements, calling code teams to assist with a patient doing poorly, would go off at least once an hour. It was really, really intense."

As patients struggled to survive, Wilson says he and other clinicians felt like there was relatively little they could offer in terms of specific therapies for the coronavirus. "That was so hard--you so badly want to do something to help someone get better," he says.

Now, untangling the workings of the virus through research, he feels there has been an important change of mindset.

"How can we attack this virus? The cells we're using in these experiments are the cell type most prominently affected in sick patients, the patients we're caring for who have developed ARDS," Wilson says. "It's really important to do research on the right type of cell. It tells us how the virus is working and also what parts of the body's normal immune mechanisms aren't working like they're supposed to."

New research from the University of Georgia supports growing evidence for airborne transmission of COVID-19 in enclosed spaces.

Researchers were able to link a community outbreak of COVID-19 in China to a source patient who likely spread the virus to fellow bus riders through the bus's air conditioning system.

"The possibility of airborne transmission has long been suspected, but with limited empirical evidence. Our study provided epidemiologic evidence of transmission over long distances, which was likely airborne," said Ye Shen, an associate professor of epidemiology and biostatistics at UGA's College of Public Health and lead author on the study.

The study, which was published recently in JAMA Internal Medicine, calls into question the prevailing thought on how COVID-19 can spread.

"It was largely believed that close contact through droplets is a major route of transmission for COVID-19. However, the widely adopted social distancing and hand washing did not effectively prevent the transmission globally. Instead, the number of new COVID-19 cases increased steadily," said Shen.

Shen and his co-authors worked with epidemiologists from two regional Centers for Disease Control and Prevention in China to trace infections following a large outdoor worship event in Zhejiang province. Some of the attendees, it turns out, took two buses to the event creating a unique natural experiment for the researchers.

Both buses had closed windows and had air conditioning running, said Changwei Li, an associate professor of epidemiology at Tulane University and study co-author - but one bus carried a patient infected with the virus, and the other did not.

Of the passengers who later got sick, the majority of them rode on the same bus as the source patient. Even though the two groups later mixed in with the larger crowd at the worship event, the number of new cases attributed to the event were much lower, suggesting that the bus was the major point of transmission.

Further, some of the bus passengers who later showed symptoms of COVID-19, the authors found, were not sitting close to the infected passenger.

These findings highlight scenarios where COVID-19 could be spread through fine aerosol particles being circulated in an enclosed space, and as the weather turns colder, Shen and Li hope this work will persuade more people to wear face masks in public areas, particularly in indoor spaces.

"Understanding the transmission routes of COVID-19 is critical to contain the pandemic, so that effective prevention strategies can be developed targeting all potential transmission routes," said Shen. "Our findings provide solid support for wearing face covering in enclosed environments with poor ventilation."