Culture

BLOOMINGTON, Ind. -- HBO's popular television series "Game of Thrones" returns in April, but millions of fans continue to illegally download the program, giving it the dubious distinction of being the most pirated program.

Many may wonder why the TV network hasn't taken a more aggressive approach to combating illegal streaming services and downloaders. Perhaps it is because the benefits to the company outweigh the consequences. Research analysis by faculty in Indiana University's Kelley School of Business and two other schools found that a moderate level of piracy can have a positive impact on the bottom line for both the manufacturer and the retailer -- and not at the expense of consumers.

"When information goods are sold to consumers via a retailer, in certain situations, a moderate level of piracy seems to have a surprisingly positive impact on the profits of the manufacturer and the retailer while, at the same time, enhancing consumer welfare," wrote Antino Kim, assistant professor of operations and decision technologies at Kelley, and his co-authors.

"Such a win-win-win situation is not only good for the supply chain but is also beneficial for the overall economy."

While not condoning piracy, Kim and his colleagues were surprised to find that it can actually reduce, or completely eliminate at times, the adverse effect of double marginalization, an economic concept where both manufacturers and retailers in the same supply chain add to the price of a product, passing these markups along to consumers.

The professors found that, because piracy can affect the pricing power of both the manufacturer and the retailer, it injects "shadow" competition into an otherwise monopolistic market.

"From the manufacturer's point of view, the retailer getting squeezed is a good thing," Kim said. "It can't mark up the product as before, and the issue of double marginalization diminishes. Vice versa, if the manufacturer gets squeezed, the retailer is better off.

"What we found is, by both of them being squeezed together -- both at the upstream and the downstream levels -- they are able to get closer to the optimal retail price that a single, vertically integrated entity would charge."

In the example of "Game of Thrones," HBO is the upstream "manufacturer" in the supply chain, and cable and satellite TV operators are the downstream "retailers."

Kim and his co-authors -- Atanu Lahiri, associate professor of information systems at the University of Texas-Dallas, and Debabrata Dey, professor of information systems at the University of Washington -- presented their findings in the article, "The 'Invisible Hand' of Piracy: An Economic Analysis of the Information-Goods Supply Chain," published in the latest issue of MIS Quarterly.

They suggest that businesses, government and consumers rethink the value of anti-piracy enforcement, which can be quite costly, and consider taking a moderate approach. Australia, for instance, due to prohibitive costs, scrapped its three-strikes scheme to track down illegal downloaders and send them warning notices. Though the Australian Parliament passed a new anti-piracy law last year, its effectiveness remains unclear until after it is reviewed in two years.

As with other studies, Kim and his colleagues found that when enforcement is low and piracy is rampant, both manufacturers and retailers suffer. But they caution against becoming overzealous in prosecuting illegal downloaders or in lobbying for more enforcement.

"Our results do not imply that the legal channel should, all of a sudden, start actively encouraging piracy," they said. "The implication is simply that, situated in a real-world context, our manufacturer and retailer should recognize that a certain level of piracy or its threat might actually be beneficial and should, therefore, exercise some moderation in their anti-piracy efforts.

"This could manifest itself in them tolerating piracy to a certain level, perhaps by turning a blind eye to it," they add. "Such a strategy would indeed be consistent with how others have described HBO's attitude toward piracy of its products."

Athens, Ga. - The result of football instant replay video reviews can alter a consumer's perception of a brand, according to a study conducted by researchers at the University of Georgia Grady College of Journalism and Mass Communication.

The upcoming Super Bowl, often referred to as the "Ad Bowl," provides a variety of advertising opportunities, including when officials pause game action to analyze an instant replay video.

A pair of Grady College researchers have linked the outcomes of those football replay reviews to consumers having a positive perception of a brand.

Jihoon "Jay" Kim, a doctoral student at Grady College, and Jooyoung Kim, an associate professor of advertising, investigated how the use of advertising in sporting events' replay review affected consumer feelings toward sponsored brands.

"I watched a tennis game one day and saw the replay system," Jay Kim said. "While the video was reviewed live, I saw a brand logo on the screen and thought it was interesting because two groups of fans were watching it; the result of the replay video would make one group happy and the other group unhappy."

To untap this psychological phenomenon, they researched the concept of "schadenfreude," a German word for the experience of joy when observing another's misfortune, or in this case, the joy fans have when a referee makes a call that helps their team and hurts the opponent.

"An advertisement used correctly can have a positive emotional transfer to a consumer," Jooyoung Kim said. "A traditional view is that attitudes toward advertising leads to attitudes toward the brand, which then drives consumer behavior."

Jay Kim and Jooyoung Kim developed an online experiment where nearly 400 students watched brand-sponsored instant replay videos in college football games. Participants were then asked a series of questions based on the result of the replay review.

The study measured responses in four game situations varied by the caliber of rivalry and level of suspense: rivalry games, non-rivalry games, suspenseful games and non-suspenseful games.

Results showed increased focus and attention from spectators during rivalry games and during suspenseful moments. Also, spectators felt a greater amount of positive emotion when a referee's decision through an instant replay video benefited their team late in a game with a close score compared to a less suspense-filled moment.

Jooyoung Kim said the results of this study could lead to a series of exciting advancements for advertisers of sporting events.

"Advertisers want to be present at the place where their audiences are happy rather than mad. They want to be associated with the positive memory," Jooyoung Kim said.

According to Jooyoung Kim, in the past it was not possible to understand an audience down to the individual level. Individual targeting is becoming possible because of the technological advances. Programming systems will be able to use algorithms to choose whether to show a certain brand logo to a specific fan watching the game. The typical broadcast delay of approximately seven seconds for live-streaming sporting events will enable marketers to tailor the brand logo to match the happy fan.

"In an international competition such as FIFA World Cup or the Wimbledon Championships, sponsoring brands could use geographical information to decide whether their ads should be used with an IRV based on whether the outcome benefits a particular team or player. This would need a lot of coordination among the sponsors, media, and the sporting event hosts," Jay Kim added.

Future research will focus on schadenfreude's inverse concept, gluckschmerz, or feeling unhappy about the good fortune of others.

"Both concepts show how morally weak humans can be in social settings: we like when our opponent fails and don't like when the opponent succeeds. But that's the reality of being human, and the marketers can seize this untapped opportunity for their brands," Jooyoung Kim said.

A team of researchers have solved a 20-year riddle of how a crucial step in the biosynthesis of 'last-resort' antibiotics occurs.

In two recent papers published in prestigious journals, the researchers, led by Monash Biomedicine Discovery Institute's Associate Professor Max Cryle, have opened the way to potentially redesigning the antibiotics by altering the peptide assembly involved. This work is linked by a common enzymatic machinery that has great potential to produce highly complex bioactive molecules.

In a study published today in the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS), the team of Monash BDI researchers structurally characterised the peptide bond forming domain in the enzyme 'Ebony' for the first time. Ebony - which is related to the machineries that produce peptide antibiotics in bacteria - plays a central role in the regulation of the neurotransmitters dopamine and histamine in Drosophila. Deletion of Ebony affects external pigmentation but has also been found to alter important functions like vision and circadian regulation.

The study is expected to generate widespread interest in the scientific community from scientists studying protein structure and function, bioengineers and researchers interested in mechanisms of neurotransmitter regulation.

"Ebony is a rare example of a non-ribosomal peptide synthetase (NRPS) from a higher eukaryote," Associate Professor Cryle said, who is also a member of EMBL Australia and the ARC Centre of Excellence in Advanced Molecular Imaging.

"We showed it contains novel types of condensation domain for a NRPS and explained the structure, function and relationship of this enzyme for the first time," he said.

"Ebony helps to moderate the activity of potential neurotransmitters by inactivating them very quickly when required, and also is able to behave differently with different neurotransmitters in a tissue-dependant manner."

Although this domain appears confined to Drosophila, examples of enzymes related to Ebony have been identified in plants and vertebrates, he said.

"Beyond the interest for neural signalling, this system could be used as an interesting example of taking a eukaryotic enzyme and exploiting it in a bacterial system to make new bioactive compounds."

The rate at which this process works is about 60,000 times faster than that used in the bacteria in the complementary study on peptide-based condensation domains, where specificity is more important than speed.

The team published their findings on the glycopeptide antibiotic biosynthesis of vancomycin and teicoplanin-type antibiotics in the journal Chemical Science late last year.

It sought to reconcile two conflicting hypotheses on the process that had previously been generated based on different approaches - in vitro and in vivo.

"These peptide antibiotics are in clinical use so it's important to understand how they're made," Associate Professor Cryle said.

"This is a prerequisite for re-engineering the biosynthetic machinery to make new ones," he said.

Associate Professor Cryle's team collaborated with the German scientists who concentrated on in vivo approaches, and found that the different approaches used were looking at the biosynthetic machinery working at different rates, and hence affecting the outcomes of each experiment.

"These results show how critical the timing of peptide assembly is to the effective production of these antibiotics, and establishes guidelines for re-engineering efforts to produce new, effective antibiotics," he said.

"That's very important given the rise in antibiotic resistance, which is now recognised as a serious problem."

These two studies have improved our understanding of how the enzymatic machinery that produces many important bioactive peptides ensures the exquisite selectivity naturally found in such assembly lines.

More importantly, it shows ways in which such machineries can be effectively redesigned to produce new, more effective compounds. Many important clinical antibiotics are produced through these machineries. With the threat of antimicrobial resistance looming ever larger, there has never been a greater need to be able to alter these biosynthetic processes to generate new, highly active compounds to control infection. These two studies provide important steps along the road to this goal.

A Massachusetts General Hospital (MGH) research team has found that the overgrowth of connective called fibrosis may block the effectiveness of immunotherapies against metastatic breast cancer. Their report published in PNAS also finds that plerixafor, a drug approved to mobilize blood system stem cells in the treatment of lymphoma and multiple myeloma patients, can reduce fibrosis in both primary and metastatic breast tumors and improve response to immunotherapy in mouse models.

"Improving the survival of patients with metastatic breast cancer remains a significant challenge; and while immunotherapy, which harnesses the power of the immune system against cancer, has shown some promise, it remains less effective against metastatic breast cancer," says Ivy Chen, PhD, post-doctoral fellow in the Edwin L. Steele Laboratories for Tumor Biology in the MGH Department of Radiation Oncology and lead author of the PNAS report. "While fibrosis has been extensively studied in primary breast tumors, little is known about the level of fibrosis and its role in immunosuppression in metastatic lesions."

A key focus of research in the Steele Labs, directed by Rakesh Jain, PhD, senior author of the PNAS report, has been understanding how physical features of tumors can impede the effectiveness of cancer therapies. Many treatment-resistant tumors are what is called desmoplastic - characterized by an overgrowth of connective tissue, which can block or even repel cancer-killing T cells from entering tumors, as well as inhibiting the effectiveness of traditional anti-cancer therapies. Studies in other types of cancer have identified a role for the CXCL12/CXCR4 signaling pathway, known to regulate immune cells, in resistance to immunotherapies.

In their investigation of this potentially important signaling pathway in metastatic breast cancer, the MGH team found the following:

Analysis using The Cancer Genome Atlas database identified a role for CXCL12/CXCR4 signaling in the exclusion of cancer-fighting CD8 T cells from human breast cancers.

Examination of paired biopsies of primary and metastatic breast tumors from the same patients revealed that CXCR4 expression correlated with high levels of desmoplasia and expression of immunosuppressive proteins in all subtypes of breast cancer.

Experiments using mouse models of metastatic breast cancer showed that plerixafor - which inhibits CXCR4 - reduced desmoplasia and the expression of profibrotic and immunosuppressive genes.

Silencing the CXCR4 gene in a mouse model revealed that these immunosuppressive effects are dependent on CXCR4 signaling in fibroblasts, cells that produce fibrosis and promote immunosuppression.

CXCR4 inhibition improved the infiltration of T cells into breast cancer metastases and decreased the formation of spontaneous metastases in the lung, one of the most common sites for metastatic breast cancer.

CXCR4 blockade sensitized three mouse models to immune checkpoint blockers, a form of immunotherapy that has transformed the treatment of a number of malignancies but not breast cancer.

Overall this study was the first to show that primary and metastatic breast tumors are highly fibrotic, and identified a correlation between CXCR4 expression, fibrosis and immunosuppression in primary and metastatic breast cancer. Significantly, it showed that CXCR4 inhibition may enhance the effectiveness of immunotherapy for metastatic breast cancer.

"Our findings suggest that fibrosis-targeting drugs, such as plerixafor, may be able to benefit breast cancer patients with late-stage, metastatic disease." says Jain, the Cook Professor of Radiation Oncology at Harvard Medical School "Most importantly, because not all metastatic breast cancers respond to immunotherapy, CXCR4 inhibition may improve response to those treatments by reducing fibrosis and immunosuppression. Our findings provide the necessary data and rationale for clinical trials to test the efficacy of combining CXCR4 inhibition using plerixafor, an FDA-approved drug for other indications, with immune checkpoint blockade for metastatic breast cancer patients."

Co-author Robert Langer, ScD, Koch Institute Professor at Massachusetts Institute of Technology, adds, "With more than 40,000 women dying from breast cancer annually in the U.S. alone, this work provides a rapidly translatable strategy and potential hope for these patients."

Texas A&M University professor Dr. Jodie L. Lutkenhaus is one step closer to realizing her goal of creating a battery made entirely of polymers, which has the potential to charge and discharge much faster than traditional batteries. Lutkenhaus, an associate professor in the Artie McFerrin Department of Chemical Engineering, has detailed her most recent findings on these polymers in a paper in Nature Materials.

A major hurdle to creating a metal-free, 100-percent polymer battery is finding a polymer that is electrochemically active -- meaning it has to be able to store and exchange electrons. Lutkenhaus, along with a team of researchers including doctoral candidate Shaoyang Wang, think that the organic radical polymers will do the trick. Owing to their chemical structure, organic radical polymers are very stable and reactive. They have a single electron on the radical group, and this unpaired electron allows rapid charge transfer in these polymers during redox reactions.

According to Lutkenhaus, the main appeal of this class of polymer lies in the speed of the reaction. "These polymers are very promising for batteries because they can charge and discharge way faster than any common battery in a phone or similar device. This rapid charging could dramatically change the way electric vehicles are used today."

The redox-active properties of organic radical polymers have been known for some time. However, prior to this research the exact mechanism by which electrons and ions are transported through the polymer had not been described. In part, the scale and speed at which these reactions take place make it difficult to capture reliable data. However, Lutkenhaus and her team were able to capture incredibly detailed measurements using a specialized device, an electrochemical quartz crystal microbalance with dissipation monitoring (EQCM-D).

The use of an EQCM-D is actually quite simple, but it operates on tremendously small scales. Lutkenhaus explained the experimental setup: "As we charge and discharge the polymer we are actually weighing it, so we know exactly how much it weighs even down to nanogram accuracy. The device is so sensitive that we can measure ions going in and out of the organic radical polymer."

The results of the EQCM-D analysis led to somewhat unexpected results. Before this research the consensus was that only anions were transported in this process. However, the results show that lithium ions are transported as well. Further, the behavior and transport of the ions seems to be more dependent on the electrolyte than the polymer itself.

With this deeper understanding of the underlying processes, Lutkenhaus plans to take a closer look at the electrolyte polymer interactions.

Viruses plague bacteria just as viruses like influenza plague humans.

Some of the largest of these so-called bacteriophages have now been found in the human gut, where they periodically devastate bacteria just as seasonal outbreaks of flu lay humans low, according to a new study led by University of California, Berkeley, scientists.

These "megaphages" -- which have genomes about 10 times larger than the average phage and twice as big as any phage previously found in humans -- were found in the human intestinal tract, but only from humans who eat a non-Western, high-fiber, low-fat diet.

Tellingly, they were also found in the guts of baboons and a pig, demonstrating that phages -- which can carry genes that affect human health -- can move between humans and animals and perhaps carry disease.

"Phage are well-known to carry genes that cause disease and genes that code for antibiotic resistance," said Jill Banfield, who leads the Innovative Genomics Institute's microbiology initiative and is a UC Berkeley professor of earth and planetary science and of environmental science, policy and management. "The movement of megaphages along with the movement of their host bacteria raises the possibility that disease also can move between animals and humans, and that the capacity for this is much larger with megaphage."

And because megaphages, which most biologists do not consider to be "living," are bigger than lifeforms like bacteria, they blur the distinction between what is alive and what isn't.

"These huge entities fill the gap between what we think of as non-life and life, and in a sense, we have mostly missed them," Banfield said.

Banfield and her colleagues reported their findings online Jan. 28 in the journal Nature Microbiology.

Phages and CRISPR

Banfield is a pioneer of metagenomic sequencing, that is, simultaneously sequencing all the genes from a soup of all the organisms in a community. She and her colleagues then reconstruct the genomes of each creature in the community, often turning up microbes never before seen. By exploring microbial communities in mine runoff, geysers, the human intestinal tract and deep underground, she has discovered so many new microbes through metagenomic sequencing that the tree of life has had to be redesigned to accommodate them all.

In the process, she has uncovered many genes of bacteriophage, as phage are formally known. In fact, the CRISPR cluster found in some bacteria is a reservoir of phage genome fragments that the bacteria keep to remind them of previous phage infections, allowing them to quickly fend off subsequent infections by the same phage. The Cas9 protein mobilized by these bacteria to target and cut up viral invaders was adapted by UC Berkeley and University of Vienna scientists as a powerful tool, CRISPR-Cas9, that has revolutionized biology and revitalized the field of gene therapy.

While sequencing gut bacteria from people in Bangladesh -- part of a study led by collaborator Joanne Santini of University College London to explore the effects of arsenic-tainted water on intestinal flora -- Banfield identified these megaphages. Once she had reassembled their entire genomes, she saw that all of them were 10 times bigger than the average phage encountered in other microbiomes. To accommodate these phages' bloated genomes, their packaging, called a capsid, is presumably larger than those of other known phages, possibly between 200 and 300 nanometers across.

She and her colleagues found a CRISPR segment in one type of bacteria, Prevotella, that contained snippets of megaphage DNA, suggesting that the megaphage prey on Prevotella primarily. Prevotella is not common in people eating a Westernized diet, with lots of meat, fat and sugar, and fewer gut microbiomes from those eating a non-Western, "hunter-gatherer" type of diet have been sequenced.

Prevotella is also associated with upper respiratory tract infections and is prevalent in periodontal disease, according to coauthor Joanne Santini. This means the new megaphage may open up the development of new phage-based treatments for infections caused by Prevotella.

Hunter-gatherer microbiomes

Banfield and her team named the group or clade of megaphages "Lak phage" after the area of Bangladesh where they found them, Laksam Upazila. Subsequently, first author Audra Devoto found Lak phages in the gut microbiomes of members of the hunter-gatherer Hadza tribe of Tanzania, in two separate social groups of baboons that had been studied in Kenya and in the gut microbiota of pigs from Danish farms.

"The Lak phages in the pig are more closely related to humans than baboons are, so it's quite probable that these phages are moving across animal cohorts," Banfield said. "We suspect that the Prevotella and the Lak phage were pretty recently acquired by the baboons, because the baboons have so little resistance to them and they are so widespread among them."

Phages are known to carry genes that exacerbate many human illnesses. They can carry genes that encode botulism, cholera and diphtheria toxins, for example, making symptoms much worse for those infected with the bacteria. One of Banfield's goals is to see how populations of phage and the bacteria they prey on in the gut change over time and with diet, and how that affects health.

In the four humans whose gut microbiomes were sampled, the team found changing levels of phage and Prevotella over time, indicating a constant cycle where rising populations of phage drive down bacterial populations, followed by a drop in phage that allows Prevotella to rebound.

Banfield speculates that megaphages have larger genomes in order to produce the proteins necessary to prevent the bacterial host from interfering with the phage's efforts to make more copies of itself, a process that takes longer because of the bigger genome.

Banfield and her lab in the Innovative Genomics Institute, a joint UC Berkeley/UCSF initiative to widely deploy CRISPR-Cas9, are searching through other metagenomic databases for megaphage, and hope to learn more about how they work and whether they harbor interesting and potentially useful proteins.

"These genomes are full of proteins of unknown function, probably pathways for processes not even imagined to date. There is a lot of new biology to be discovered in these new genomes," she said.

NBA players who excelled during the first part of their career were able to retain more of their skill as they aged. They also displayed a slower decline in performance after the peak of their career, according to a study published in the Springer journal Behaviour Research Methods.

Dr Nemanja Vaci and colleagues at the University of Oxford used data collected by the NBA to assess the interaction between aging and the development and deterioration of basketball skills in professional players. The authors analysed data from a total of 2,845 players over 50 years. This included player demographics and performance level variables, such as positions played in the game, minutes of game play, players' contribution to team wins and how efficient a player was. The authors found early career development to be an important factor in the rate of skill decline after a player's career peak.

Dr Nemanja Vaci, corresponding author of the study, said: "Interestingly, our results challenge a large body of evidence that demonstrates that age is not kinder to more able, active, or knowledgeable people. One explanation for these findings is that once the decline in physical performance begins, more knowledgeable or more able players may utilize knowledge (i.e. motoric and context specific information) from earlier in their career to help effectively preserve their performance while ageing."

Dr Vaci added: "However, it is probable that other factors, such as physical ability, personality, motivation, or even genetic makeup, which may enable certain players to acquire knowledge and skill more quickly, may also affect this correlation."

The researchers found that a player's position on the court did not affect their rate of skill decline. However, those who played more minutes per game had a greater increase in performance during the first part of their career and slower decline in performance with age.

Dr Vaci said: "Studying the changes that occur as people age is challenging for a number of reasons, including the immense time scale that needs to be captured. Fortunately, this study was able to use a dataset where players have taken part in an activity throughout their lives, and a vast amount of data has been systematically recorded. This allowed us to investigate age-related changes in greater detail. The flexibility and general nature of the model created in this study makes it a perfect candidate for use across other studies of changes throughout the lifespan."

CHICAGO - Headlines filled with frightening news of opioid abuse, overdoses and reports that 90 percent of addictions start in the teen years could make any parent worry. Yet parents remain conflicted about opioids: while more than half express concern their child may be at risk for opioid addiction, nearly two-thirds believe opioids are more effective at managing their child's pain after surgery or a broken bone than non-prescription medication or other alternatives, according to a nationwide survey commissioned by the American Society of Anesthesiologists (ASA).

"The survey results shed light on the country's conflicted relationship with and understanding of opioids. While most parents said they were concerned about side effects and risks such as addiction, improper or recreational use and overdose, they still thought opioids work best to manage pain," said ASA President Linda J. Mason, M.D., FASA. "Opioids may not always be the best option. It really depends on the type of surgery and how long they are required. It is, however, important for parents to know that there are many alternatives available that are as - or more - safe and effective for pain management. But only about a third of parents whose children were prescribed opioids even asked their doctor about pain management alternatives."

Although short-term use of opioids can be effective when managed safely and the risks minimized, more than 2 million Americans abuse them and more than 90 people die of an opioid overdose every day. Opioid-related deaths among children and adolescents nearly tripled between 1999 and 2016, driven mostly by prescription opioids.* During Physician Anesthesiologists Week (Jan. 27 - Feb. 2), ASA wants parents to know that a physician anesthesiologist or other pain management specialist can create an individualized plan to best address patients' pain based on the condition or type of surgery and decrease the risk of opioid misuse and addiction.

The new survey of more than 1,000 parents of children aged 13-24, one-third of whom had been prescribed opioids, revealed that while 83 percent of parents believe they are prepared to safely manage their child's opioid use if prescribed, the facts don't quite bear out. The results suggest there is a need for improved awareness on: opioid alternatives; safe storage and proper disposal; talking to children about risks; and the benefits of naloxone, an emergency medication that reverses the effects of an opioid overdose.

Parents aren't asking about effective alternatives

While opioids can help with pain management for a few days after surgery or injury, there are effective alternatives that do not have the side effects and risks of opioids, including non-opioid medications and non-drug therapies. But the survey results suggest parents often don't ask about alternatives, or aren't aware of the range of options.

59 percent said they would talk to their physician about pain management options, but only 37 percent of those whose children were prescribed opioids actually did.

88 percent recognized non-opioid, over-the-counter medications, such as acetaminophen (Tylenol), ibuprofen (Advil or Motrin) and aspirin, are used to effectively help treat pain. However, few were aware the same applies to other non-opioid options, including steroids (23 percent), antidepressants (9 percent), and anti-seizure medications (7 percent).

15 percent incorrectly said antibiotics are an effective pain reliever.

Beyond medications, a number of non-drug therapies can help with ongoing pain, including nerve blocks, physical therapy, biofeedback, meditation, virtual reality, massage and acupuncture.

Parents are unaware that safe storage and proper disposal are key

More than half of people who misuse prescribed opioids get them from a friend or relative. That's why safe storage and proper disposal of the drugs are important to help curb the epidemic. But the survey results suggest parents don't fully understand the benefits and appropriate methods of safe storage and disposal.

Only 50 percent said they stored or would store opioids in a safe and secure place (not the medicine cabinet, where they can be accessed by others).

60 percent of those whose children took opioids said they needed fewer than were prescribed and, consequently, had leftover medication. But only 39 percent of all parents disposed or would dispose of leftover opioids as recommended, including taking them to a local pharmacy or health clinic, flushing them down the toilet or mixing them with dirt, kitty litter or coffee grounds before throwing them away.

Yet, 61 percent correctly identified the ideal method of disposing leftover opioids, which involves taking them to a collection center at a local police station or drug disposal program at a pharmacy or health clinic.

Parents understand importance of communication

When a child is prescribed opioids, parents need to have an open and honest discussion about the potential side effects and risks - not only with the child taking the medication, but other family members as well. Surveyed parents generally understood that.

74 percent said they have talked to their child about the dangers of abusing prescription and over-the-counter medications and 20 percent said they intend to have the conversation.

89 percent of those whose children have been prescribed opioids said they've had those discussions.

91 percent said they are confident their children know that prescribed and over-the-counter medications can be just as dangerous as illegal drugs.

Parents recognize naloxone saves lives

Naloxone (Narcan®) is a lifesaving medication administered via nasal spray or injection that rapidly reverses the effects of an overdose. It's important to know about naloxone because anyone who uses opioids - even if they've been prescribed by a doctor - may be at risk for an overdose.

The availability of naloxone varies by state. In most states it is available by prescription and some pharmacies sell it over the counter. Most parents recognize naloxone's value.

71 percent agreed that having naloxone on hand is the same as having other life-saving medication available for people who suffer from conditions such as allergies, asthma or diabetes.

29 percent were concerned that having it on hand encourages risky opioid use.

80 percent said they would be more comfortable having it at home if their child or another family member was taking opioids.

92 percent thought all first responders should carry it.

"It's critical that we recognize the gaps in opioid knowledge and work to correct them, ensuring everyone understands how to use them safely and minimize their risks. A physician anesthesiologist or other pain management specialist can help parents address their child's pain and decrease the risk of opioid misuse and addiction," said Dr. Mason. "We also need to reassure parents that naloxone saves lives and needs to be widely available."

The 17-question Engine CARAVAN® Omnibus Survey was conducted online November 25-December 2, 2018 among 1,007 parents of children ages 13-24. If their children were ever prescribed opioids, parents were asked to think of their child with the most recent prescription when answering the questions. If their children were never prescribed opioids, parents were asked to answer for their oldest child between the ages of 13 and 24.

EVANSTON, Ill. --- More than 40 billion capillaries -- tiny, hair-like blood vessels -- are tasked with carrying oxygen and nutrients to the far reaches of the human body. But despite their sheer number and monumental importance to basic functions and metabolism, not much is known about their inner workings.

Now a Northwestern University team has developed a new tool that images blood flow through these tiny vessels, giving insight into this central portion of the human circulatory system. Called spectral contrast optical coherence tomography angiography (SC-OCTA), the 3D-imaging technique can detect subtle changes in capillary organization for early diagnosis of disease.

"There has been a progressive push to image smaller and smaller blood vessels and provide more comprehensive, functional information," said Vadim Backman, who led the study. "Now we can see even the smallest capillaries and measure blood flow, oxygenation and metabolic rate."

The paper was published last week in the journal Light: Science and Applications. Backman is the Walter Dill Scott Professor of Biomedical Engineering in Northwestern's McCormick School of Engineering.

Researchers and physicians have long been able to see inside major veins and arteries with Doppler ultrasound, which uses high-frequency sound waves to measure blood flow. But this insight does not give a full picture of the circulatory system. Unlike veins and arteries, capillaries are responsible for oxygen exchange, or delivering oxygen to organs and tissues throughout the body while shuttling carbon dioxide away. Low blood oxygen can cause mild problems such as headaches to severe issues such as heart failure.

"You can have great blood flow through arteries and still have absolutely no blood sending oxygen to tissues if you don't have the right microvasculature," Backman said. "Oxygen exchange is important to everything the body does. But many questions about what happens in microvasculature have gone unanswered because there was no tool to study them. Now we can tackle that."

"SC-OCTA is a valuable diagnostic tool," added James Winkelmann, a graduate student in Backman's laboratory and the study's first author. "We can now detect alterations to capillary organization, which is evident in a variety of conditions ranging from cancer to cardiovascular disease. Detecting these diseases earlier has the potential to save lives."

Researchers have had difficulties peering inside capillaries because of the vessels' microscopic size. A single capillary is a mere 5-10 microns in diameter -- so small that red blood cells must flow through in single file.

SC-OCTA works by combining spectroscopy, which looks at the various visible light wavelengths, or color spectra, with conventional optical coherence tomography (OCT), which is similar to ultrasound except uses light waves instead of sound waves. Like a radar, OCT pinpoints the tissue of interest, and then spectroscopy characterizes it.

SC-OCTA has many advantages over traditional imaging: it does not rely on injected dyes for contrast or harmful radiation. Many types of imaging also only work if the area of interest is moving (for example, ultrasound can only image blood when it is flowing) or completely still. SC-OCTA can take a clear picture of both. This enables it to image stagnant blood or moving organs, such as a beating heart.

"It can measure blood flowing regardless of how fast it goes, so motion is not a problem," Backman said.

"SC-OCTA's unique ability to image non-flowing blood could also become a valuable tool for the booming field of organoids, which studies how organs develop and respond to disease," Winkelmann said. "I am excited to start exploring all the applications."

The new technology's only limitation is that it cannot image deeper than 1 millimeter. This might seem shallow compared to ultrasound, which can see several centimeters below the surface. Backman said this can be remedied by putting the tool on the end of an endoscopic probe. By inserting it into the body, the tool can image organs up-close. That is something that his laboratory is working on now.

Researchers at VTT Technical Research Centre of Finland have developed a new and more accurate method for estimating the probability of extreme events, such as storms, floods and earthquakes. The new method will be used in updating building codes and land-use regulations, and is applicable also in developing artificial intelligence, as well as in economics and medical data analysis.

Extreme events, such as storms, floods and earthquakes have always been disastrous to civilizations. Communities prepare for them by rigid constructions, flood banks, drainage channels and avoiding building at hazardous locations. For all such preparations, being able to estimate the probability of hazardous extremes is crucial. The estimation is based on the statistics of previously observed extremes, studied by so-called extreme value analysis. Many extreme value analysis methods exist and it has not been clear which of them should be preferred.

Researchers at VTT, Lasse Makkonen and Maria Tikanmäki, developed a new more accurate extreme value analysis method. The problem of how to appropriately evaluate the goodness of such methods was also solved in this connection.

Makkonen and Tikanmäki showed, by numerical Monte-Carlo simulations, that their new extreme value analysis method is much more accurate than the methods that are currently widely used. The difference is significant particularly when the number of available previously observed extremes is small. Typically, the current methods underestimate the probability of the most hazardous extreme events.

The new method, developed at VTT, will improve the estimation of the probability of extreme events and will thus contribute to preparation for natural hazards in an economically optimal but safe manner. This will happen via updating building codes and land-use planning regulations. The new method will have wide applications, because extreme value analysis is also in use e.g. in the development of artificial intelligence, in economics and in the analysis of medical data.

"Extreme value analysis of natural phenomena aims at appropriate preparation against hazardous extreme events. Therefore, it forms the foundation of all regulations that aim at securing the safety of buildings and infrastructure. Stronger constructions and protection arrangements increase costs, so that economic optimation is another issue here. Good estimation of the probability of extreme events is particularly important for those constructions for which indirect damage caused by a rare extreme event is exceptionally heavy, such as in the case of nuclear power plants and large dams", says Lasse Makkonen.

The study by Makkonen and Tikanmäki was published in the Journal of Hydrology and can be read at https://www.sciencedirect.com/science/article/pii/S2589915518300129.

Much like our fight-or-flight response, our cells also have a stress autopilot mode. An oxygen dropoff, overheating, or an invading toxin can trigger the cellular stress response - a cascade of molecular changes that are the cell's last-ditch effort to survive.

Among these survival strategies is the formation of "stress granules" - proteins and RNA molecules huddle together into membrane-less blobs when the cell is threatened. RNA is the essential biological molecule that translates genetic information from DNA to make proteins. During cellular stress, most RNA molecules stop their normal business of translation and cluster inside stress granules, as if running to hide.

In a new experiment published in Nature Cell Biology, biological imaging experts led by Tim Stasevich, assistant professor in the Department of Biochemistry and Molecular Biology at Colorado State University, have used a custom fluorescence microscope and a novel antibody tagging tool to watch living cells undergoing stress. With single-molecule precision, the researchers have captured individual RNA molecules interacting with stress granules, revealing how, when and where the RNAs move around - a process never before witnessed from start to finish. They have shown definitively, among other things, that RNA translation is completely silenced before the RNAs enter the stress granules.

The results sprung from a partnership with the lab of Roy Parker, professor in the Department of Biochemistry at University of Colorado Boulder. The two labs' combined expertise has illuminated unprecedented details of the cellular stress response, paving the way for future studies into the full dynamics of translational shutdown, and its relationship to many diseases.

"I think seeing is believing, and that's our contribution here," said Stasevich, a Boettcher Investigator whose lab previously published the biochemical tagging and imaging technique in the journal Science. "We are using live cells as test tubes to study dynamic processes that have never been seen before. The ability to image these processes at the single-molecule level in living cells will be a powerful tool to better understand the cellular stress response in normal and diseased cells."

Parker's lab at CU Boulder had long been interested in RNA interactions associated with cellular stress. "We saw Tim's Science paper on nascent chain tracking, and thought this would be the perfect technique to answer questions our lab had been trying to figure out for a while," explained CU postdoctoral researcher Stephanie Moon, co-first author on the Nature Cell Biology paper and a former CSU graduate student.

The dynamics of stress granule formation had only been inferred in previous research, Parker said. "But if cells don't make them, they die. So they must be important."

Previously, the only way scientists like Parker and Moon could "see" RNAs during cellular stress was through fixed cell imaging - the equivalent of taking a snapshot. "We knew the RNAs were in the stress granules, and we knew which RNAs were in there. We knew they could be affected by mutations that can cause disease. All that knowledge was based on static images," Parker said.

According to earlier research by Parker, several mutations can cause such RNA-protein assemblies to form incorrectly, and these aberrations are linked to neurodegenerative diseases like Amyotrophic Lateral Sclerosis.

By going to the movies with Stasevich's team, the cellular stress response has come alive in colorful detail, shedding light on previously hidden details. Among the paper's major findings is that while some RNAs come and go at the surfaces of the granules, some are peculiarly stuck, as if tethered in molasses, the researchers said.

"By showing that RNAs go to a granule, are translationally repressed, and they stay there, it suggests that the stress granules may have a role in keeping those RNAs out of gene expression," Moon said.

Tatsuya Morisaki, co-first author and a senior researcher in Stasevich's lab, led the imaging experiments with Moon and developed the translation tracking technique. Morisaki used a cell line developed by Parker's lab that contains a green fluorescent marker for stress granules. The Stasevich la's fluorescent labeling technology altered the cell line with markers that fluoresce far-red for RNA, and red for translation, allowing all three colors to be seen at once.

Stasevich called the collaboration a beautiful combination of two labs, moving toward a common goal. "I think we can really work together to answer some questions that have never been answered before," Stasevich said.

Parker agreed.

"Tim's lab is terrific at single-molecule imaging, including translation and RNA localization, while my group is interested in trying to understand these RNA-protein granules and how they form," he added. "This is how science should work."

Gender stereotypes can hurt children -- quite literally. When asked to assess how much pain a child is experiencing based on the observation of identical reactions to a finger-stick, American adults believe boys to be in more pain than girls, according to a new Yale study in the Journal of Pediatric Psychology. The researchers attribute this downgrading of the pain of girls and/or upgrading of the pain of boys to culturally ingrained, and scientifically unproven, myths like "boys are more stoic" or "girls are more emotive."

A diverse sample of American adults watched the same video of a 5-year-old receiving a finger-stick at a pre-Kindergarten doctor's visit, and afterwards were asked to rate how much pain they thought the child was actually experiencing. While all participants watched an identical video of an identical child exhibiting identical pain-display behaviors, the group who knew the child as "Samuel" said he was in more pain than the group who knew her as "Samantha." This new research backs up studies done on gender stereotyping and biased clinical assessment of pain in adult patient populations but is only the second of its kind to take these questions to the pediatric level.

"We really hope that these findings will lead to further investigation into the potential role of biases in pain assessment and health care more generally," said Joshua Monrad '20, second author on the study. "If the phenomena that we observed in our studies generalize to other contexts, it would have important implications for diagnosis and treatment. Any biases in judgments about pain would be hugely important because they can exacerbate inequitable health care provision."

Using a familiar tool in a way it was never intended to be used opens up a whole new method to explore materials, report UConn researchers in Proceedings of the National Academies of Science. Their specific findings could someday create much more energy-efficient computer chips, but the new technique itself could open up new discoveries in a broad range of stuffs.

Atomic force microscopes (AFM) drag an ultra sharp tip across materials, ever so close but never touching the surface. The tip can feel where the surface is, detecting electric and magnetic forces produced by the material. By methodically passing it back and forth, a researcher can map out the surface properties of a material in the same way a surveyor methodically paces across a piece of land to map the territory. AFMs can give a map of a material's holes, protrusions, and properties at a scale thousands of times smaller than a grain of salt.

AFMs are designed to investigate surfaces. Most of the time, the user tries very hard not to actually bump the material with the tip, as that could damage the surface of the material. But sometimes it happens. A few years ago, graduate student Yasemin Kutes and Justin Luria, a postdoc, studying solar cells in materials science and engineering professor Brian Huey's lab, accidentally dug into their sample. At first thinking it was an irritating mistake, they did notice that the properties of the material looked different when Kutes stuck the tip of the AFM deep into the ditch she'd accidentally dug.

Kutes and Luria didn't pursue it. But another graduate student, James Steffes, was inspired to look more closely at the idea. What would happen if you intentionally used the tip of an AFM like a chisel, and dug into a material, he wondered? Would it be able to map out the electrical and magnetic properties layer by layer, building up a 3D picture of the material's properties the same way it mapped the surface in 2D? And would the properties look any different deep inside a material?

The answers, Steffes, Huey, and their colleagues report in PNAS, are yes and yes. They dug into a sample of bismuth ferrite (BiFeO3), which is a room temperature multiferroic. Multiferroics are materials that can have multiple electric or magnetic properties at the same time. For example, bismuth ferrite is both antiferromagnetic - it responds to magnetic fields, but overall doesn't exhibit a North or South magnetic pole - and ferroelectric, meaning it has switchable electric polarization. Such ferroelectric materials are usually composed of tiny sections, called domains. Each domain is like a cluster of batteries that all have their positive terminals aligned in the same direction. The clusters on either side of that domain will be pointed in another direction. They are very valuable for computer memory, because the computer can flip the domains, 'writing' on the material, using magnetic or electric fields.

When a materials scientist reads or writes information on a piece of bismuth ferrite, they can normally only see what happens on the surface. But they would love to know what happens below the surface -- if that was understood, it might be possible to engineer the material into more efficient computer chips that run faster and use less energy than the ones available today. That could make a big difference in society's overall energy consumption - already, 5 percent of all electricity consumed in the US goes to running computers.

To find out, Steffes, Huey, and the rest of the team used an AFM tip to meticulously dig through a film of bismuth ferrite and map out the interior, piece by piece. They found they could map the individual domains all the way down, exposing patterns and properties that weren't always apparent at the surface. Sometimes a domain narrowed until it vanished or split into a y-shape, or merged with another domain. No one had ever been able to see inside the material in this way before. It was revelatory, like looking at a 3D CT scan of a bone when you'd only been able to read 2D X-rays before.

"Worldwide, there are something like 30,000 AFMs already installed. A big fraction of those are going to try [3D mapping with] AFM in 2019, as our community realizes they have just been scratching the surface this whole time," Huey predicts. He also thinks more labs will buy AFMs now if 3D mapping is demonstrated to work for their materials, and some microscope manufacturers will start designing AFMs specifically for 3D scanning.

Steffes has subsequently graduated from UConn with his Ph.D. and now works at GlobalFoundries, a computer chip maker. Researchers at Intel, muRata, and elsewhere are also intrigued with what the group found out about bismuth ferrite, as they seek new materials to make the next generation of computer chips. Huey's team, meanwhile, is now using AFMs to dig into all kinds of materials, from concrete to bone to a host of computer components.

"Working with academic and corporate partners, we can use our new insight to understand how to better engineer these materials to use less energy, optimize their performance, and improve their reliability and lifetime - those are examples of what materials scientists strive to do every day," Huey says.

Researchers at UT have discovered the largest individual of any cave salamander in North America, a 9.3-inch specimen of Berry Cave salamander. The finding was published in Subterranean Biology.

"The record represents the largest individual within the genus Gyrinophilus, the largest body size of any cave-obligate salamander and the largest salamander within the Plethodontidae family in the United States," said Nicholas Gladstone, a graduate student in UT's Department of Earth and Planetary Sciences, who made the discovery.

The find is making scientists reexamine growth limits of these animals in harsh environments and how hospitable underground environments really are.

Salamanders can be found in a variety of habitats across Tennessee. Some species have adapted to live in cave environments, which are thought of as extreme and inhospitable ecosystems due to the absence of light and limited resources.

Salamanders are one of only two vertebrate animal groups to have successfully colonized caves. The other is fish, said Gladstone.

The record-breaking specimen had some damage to the tail, leading researchers to believe that it was once nearly 10 inches long.

The Berry Cave Salamander can be found in only 10 sites in eastern Tennessee, and in 2003 it was placed on the US Fish and Wildlife Service's Candidate Species List for federal protection.

"This research will hopefully motivate additional conservation efforts for this rare and vulnerable species," said Gladstone.

An open label Phase 3 study conducted at Ann & Robert H. Lurie Children's Hospital of Chicago and other centers established that a combination of cystic fibrosis drugs lumacaftor and ivacaftor is safe and effective in children aged 2-5 years, whose disease is caused by two copies of F508del-CFTR gene mutation - the most common and severe form of cystic fibrosis. These data, published in Lancet Respiratory Medicine, were the basis for the Food and Drug Administration's extended approval for this treatment to include children 2 years and older. Previously, the drug combination was approved for patients 6 years and older.

"With earlier treatment that targets the genetic cause of cystic fibrosis we hope to arrest disease progression and substantially improve long-term outcomes," says study author Susanna A. McColley, MD, from Stanley Manne Children's Research Institute at Lurie Children's and Professor of Pediatrics at Northwestern University Feinberg School of Medicine. "In this study, we also saw evidence of improved pancreatic function, which suggests that we might be able to reverse damage to the pancreas from cystic fibrosis."

Cystic fibrosis is a progressive genetic disease that damages multiple organs, including the lungs and pancreas, with average predicted survival of 47 years. It is caused by mutations in the CFTR gene that lead to insufficient flow of salt and water in and out of cells. In the lungs, this creates buildup of thick, sticky mucus that can result in chronic lung infections and severe lung disease. Damage to the pancreas occurs even before birth, which interferes with nutrition absorption and growth.

"Our study also showed that treatment with lumacaftor/ivacaftor can improve growth for children with cystic fibrosis," says Dr. McColley. "We saw significant increases in weight, height and body mass index over six months of treatment."

In addition to efficacy, the study also confirmed that lumacaftor/ivacaftor is well tolerated in the younger population. No new safety concerns were identified.

Dr. McColley is now leading an open label Phase 3 trial of this drug combination for children 1-2 years of age.