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Disclosing Too Much Info Can Harm a Company’s Competitive Edge, Study Says

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Traders work on the floor of the New York Stock Exchange in the New York financial district on Wall Street. (Jeff Hutchens/Edit by Getty Images)
Traders work on the floor of the New York Stock Exchange in the New York financial district on Wall Street. (Jeff Hutchens/Edit by Getty Images)

Strict accounting laws, designed to help shareholders gain better insight into corporations, may ultimately harm a firm’s competitive position by forcing disclosure of proprietary information, according to Ying Zhou of the University of Connecticut, who has spent years analyzing the consequences of such mandates.

Zhou, assistant professor of accounting in the School of Business, presented her findings in January at the 2018 Financial Accounting and Reporting Section Meeting in Austin, Texas.

Ying Zhou
Ying Zhou, assistant professor of accounting

The focus of her research circles around a new requirement, widely implemented in 1998, that required companies to expand their segment disclosure. Previously, enterprises grouped products and services by industry lines. The loose definition of “industry” permitted flexibility and allowed managers of some diversified firms to report all operations in a single, broadly defined segment.

Under the original requirements, some large companies combined information about their myriad businesses in one report, failing to distinguish different factions of the business. They often cited proprietary information as the reason.

To study the impact of the new requirements, Zhou collected written evidence from companies that lobbied against the changes citing a competitive disadvantage. She tracked and studied 138 of those firms, examining their performance both two years prior to the initial proposal and two years after the accounting change was implemented.

“The results lend support to corporate concerns about competitive harm caused by extensive disclosure,’’ Zhou said. “Some of this information can truly be proprietary.”

With the new requirements, called SFAS-131, regulators had sought more expansive disclosure citing the interest of informing and protecting investors. The information revealed was not previously available through other channels. The Financial Accounting Standards Board adopted SFAS-131, noting that financial preparers could provide the additional information promptly and inexpensively.

An overwhelming majority of lobbying firms opposed the proposal and argued for a competitive-harm exemption, saying the reporting plan could compromise firms’ strategic and competitive interests.

In her study, Zhou found that among those companies that objected to the new accounting requirements, operating performance declined for firms that changed their segment reporting, but not for those that continued to report the same segments. She tested her results by comparing a separate control group.

Further analysis revealed that although there was little change in sales growth but a significant increase in selling, general, and administrative expenses per dollar of sales, suggesting an unusual sales effort to maintain market share in an intensified competitive environment. Segment profitability analysis showed that the decline in performance is attributable to the new segments disclosed under the new rule.

“In accounting literature, the existence of propriety costs has been used extensively as the rational explanation for non-disclosure in many settings,’’ she said. “However there is little evidence that mandatory disclose of propriety information really results in competitive harm—until now.’’

New Study Identifies Effective Treatments for Persistent Asthma

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Asthma inhaler and a pressurised gas cannister refill. (Getty Image)
Asthma inhaler and a pressurised gas cannister refill. (Getty Image)

When it comes to treating teens and adults with persistent asthma, using a single corticosteroid and long-acting bronchodilator treatment for both daily asthma control and for rescue relief during sudden asthma attacks is more effective than taking separate medications for daily control and rescue, according to an analysis led by University of Connecticut researchers.

The findings appear today in the Journal of the American Medical Association.

Diana Sobieraj, left, assistant professor of pharmacy practice, and William Baker '02 (Phr) '04 Pharm.D., associate professor of pharmacy practice at the Pharmacy/Biology Building on Feb. 28, 2018. (Peter Morenus/UConn Photo)
Diana Sobieraj, left, assistant professor of pharmacy practice, and William Baker ’02 (Phr) ’04 Pharm.D., associate professor of pharmacy practice at the Pharmacy/Biology Building. (Peter Morenus/UConn Photo)

Standard treatment guidelines for persistent asthma in the United States currently suggest using different medications for daily control and rescue relief. Patients use an inhaled corticosteroid, with or without a long-acting bronchodilator known as a long-acting beta-agonist or LABA, for daily asthma control. Patients usually carry a second inhaler containing a short-acting beta-agonist (albuterol) for rescue relief when they have symptoms of wheezing, coughing, or a full-blown asthma attack.

For patients 12 and older with persistent asthma, the researchers found that Single treatment for Maintenance and Reliever Therapy, also known as SMART, resulted in significantly fewer asthma attacks, hospitalizations, and emergency room visits, compared to patients following the current standard of separate medications for control and rescue.

Asthma is a chronic lung disease that inflames and narrows the airways. About 25 million people in the U.S. have asthma; 7 million of them are children. While some individuals may only experience asthma when they exercise or in certain weather conditions, those with persistent asthma struggle to control their symptoms every day.

The UConn findings are part of a larger comprehensive review of asthma-related medical practices conducted for the federal Agency for Healthcare Research and Quality (AHRQ) at the request of the National Institutes of Health, National Heart, Lung, Blood Institute.  The complete AHRQ report is available online today.

The UConn-led review encompassed 16 randomized controlled trials involving more than 22,700 patients to evaluate the effectiveness of SMART. The formulation used for the SMART approach was almost exclusively a single inhaler with a dry powder formulation of budesonide (a corticosteroid) and formoterol (a long-acting beta-agonist).

“The use of the corticosteroid-bronchodilator treatment for daily control is well established. The whole concept behind SMART is to use the same treatment for quick relief when it is necessary, eliminating the need to carry another different medication,” said UConn Assistant Professor of Pharmacy Practice Diana Sobieraj, the study’s principal investigator. “These studies found that the corticosteroid-formoterol mix is effective not only when used for daily control, but also for quick relief.  However, we did not review the evidence about side effects related to this practice.”

New long-acting bronchodilators known as LAMAs found to be effective when added to inhaled corticosteroids for uncontrolled asthma

In a separate review also appearing today in JAMA, a UConn-led analysis found that a new class of long- acting bronchodilators – known as long-acting muscarinic antagonists or LAMAs – significantly reduced the risk of exacerbations in people over 12 years with uncontrolled asthma when added to an inhaled corticosteroid, compared to a placebo.

However, LAMAs were not associated with a significant reduction in asthma exacerbations when compared to the use of long-acting beta-agonists or LABAs, when used along with an inhaled corticosteroid, the researchers said.

“The available evidence does not suggest that there is a significant difference in the way the newer type of long-acting bronchodilators (LAMAs) impact asthma exacerbations, asthma symptoms, or lung function compared to the long-acting bronchodilators (LABAs) that have been used for years” Sobieraj said. “But the studies we reviewed are not robust enough to determine whether one of these two classes of long-acting bronchodilators may be better than the other.”

Commonly used to treat patients with chronic obstructive pulmonary disease or COPD, LAMAs are not currently incorporated into national treatment guidelines for asthma. The LAMA studies reviewed in the current meta-analysis focused almost exclusively on the long-acting muscarinic antagonist tiotropium.

The comprehensive scientific reviews reported in the two studies were led by a multidisciplinary team from the UConn School of Pharmacy’s Evidence-based Practice Center. The center is one of 13 nationally supported by the Agency for Healthcare Research and Quality, which is part of the U.S. Department of Health and Human Services. The centers review scientific evidence surrounding common medical conditions and new medical technologies to improve the quality and safety of national health care.

The AHRQ conducted its review of asthma treatments and protocols at the request of the National Heart Lung and Blood Institute (NHLBI). The Institute sponsors national asthma treatment guidelines. The Guidelines for the Diagnosis and Management of Asthma (Expert Panel Report-3) was published in 2007.

Evidence-based practice centers at Johns Hopkins University, the Mayo Clinic, and the ECRI Institute also contributed to the AHRQ review, providing scientific analysis on three other asthma-related topics.

UConn co-investigators on the systematic reviews were William Baker, Erin Weed, Elaine Nguyen, Craig Coleman, and C. Michael White. Also serving as co-investigators were Dr. Stephen Lazarus of the University of California, San Francisco; Dr. Jason Lang of Duke University; and Kathryn Blake of Nemours Children’s Specialty Care.

The research reviews were sponsored by the National Heart Lung and Blood Institute. They were awarded by the Agency for Healthcare Research and Quality through Contract No. 290-2015-00012-1.

The Most Complicated Object in the Universe

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Cover image for UConn Health Journal, The Brain Issue. (Getty Images)
UConn Health Journal: UConn Health pioneers explore new frontiers to better understand one of humankind’s perpetual mysteries. (Getty Images)

Part of a series of posts for Brain Awareness Week, March 12-16.

Theoretical physicist Michio Kaku said, “The human brain has 100 billion neurons, each neuron connected to 10,000 other neurons. Sitting on your shoulders is the most complicated object in the known universe.” As long as humans have existed, people have sought to comprehend the brain. Although scholars have tried to decipher its codes for centuries, we’ve only scratched the surface.

At UConn, work with the brain spans disciplines, from psychology to linguistics to neuroscience and everything in between. In this special section, learn what UConn Health experts in neurology, physiology, gerontology, and even radiology are doing right now to further our knowledge of the brain and harness the latest discoveries and technology to improve patient care. More in the UConn Health Journal.

Dr. Alessi and the Concussion (R)evolution

3-D Printed Model Allows Brain Surgeons to Rehearse

New Epilepsy Monitoring Technology Tailors Patient Care

Pinpointing Risk Factors to Prevent Postoperative Delirium

Blood Vessels in Your Brain Don’t All Act the Same


Scientists Discover Evidence of Early Human Innovation, Pushing Back Evolutionary Timeline

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In this Olorgesailie Basin excavation site, red ocher pigments were found with Middle Stone Age artifacts. The light brown and gray layers provide evidence of ancient soils and of landscapes affected by earthquakes and other seismic activity, factors that rapidly altered the environment and resources on which human ancestors depended for survival. (Human Origins Program, Smithsonian)
In this Olorgesailie Basin excavation site, red ocher pigments were found with Middle Stone Age artifacts. The light brown and gray layers provide evidence of ancient soils and of landscapes affected by earthquakes and other seismic activity, factors that rapidly altered the environment and resources on which human ancestors depended for survival. (Human Origins Program, Smithsonian)

An international team of anthropologists, including UConn researcher David Leslie, have discovered that early humans in East Africa had – by about 320,000 years ago, much earlier than previously thought – begun trading with distant groups, using color pigments, and manufacturing more sophisticated tools than those of the Early Stone Age.

Handaxes from the Olorgesailie Basin, Kenya. (Human Origins Program, Smithsonian)
Handaxes from the Olorgesailie Basin, Kenya. (Human Origins Program, Smithsonian)

These newly discovered activities, reported March 15 in the journal Science, occur tens of thousands of years earlier – verified using radiometric dating – than previous evidence has shown in eastern Africa, and approximately date to the oldest known fossil record of Homo sapiens.

These behaviors, which are characteristic of humans who lived during the Middle Stone Age, replaced technologies and ways of life that had been in place for hundreds of thousands of years.

Evidence for these milestones in humans’ evolutionary past comes from the Olorgesailie Basin in southern Kenya, which holds an archeological record of early human life spanning more than a million years. The new discoveries indicate that these behaviors emerged during a period of tremendous environmental variability in the region. As earthquakes remodeled the landscape and climate fluctuated between wet and dry conditions, technological innovation, social exchange networks, and early symbolic communication would have helped early humans survive and obtain the resources they needed despite unpredictable conditions, the scientists say.

“The innovation to create these new tools and adapt these new suites of behaviors is likely driven by the changes in the environment these people were adapting to,” says Leslie, a research scientist in the Department of Anthropology at UConn, whose expertise in stone tools helped with the research. “Developing new tools to extract more resources from the environment is a particularly human characteristic.”

An animation showing the small stone-point obsidian tool sliding off the larger, unshaped piece of volcanic stone. (Human Origins Program, Smithsonian)
An animation showing a small stone-point obsidian tool sliding off a larger, unshaped piece of volcanic stone. The obsidian was not sourced locally, suggesting that exchange networks were in place to move quantities of the stone across the ancient landscape. (Human Origins Program, Smithsonian)

The first evidence of human life in the Olorgesailie Basin comes from about 1.2 million years ago. For hundreds of the thousands of years, people living there made and used large stone-cutting tools called handaxes. Beginning in 2002, the team discovered a variety of smaller, more carefully shaped tools in the Olorgesailie Basin. Isotopic dating by collaborators revealed that the tools were surprisingly old – made between 320,000 and 305,000 years ago. These tools were carefully crafted and more specialized than the large, all-purpose handaxes. Many were points designed to be attached to a shaft and potentially used as projectile weapons, while others were shaped as scrapers or awls.

While the handaxes of the earlier era were manufactured using local stones, the researchers found small stone points made of non-local obsidian at their Middle Stone Age sites. The team also found larger, unshaped pieces of the sharp-edged volcanic stone at Olorgesailie, which has no obsidian source of its own. The diverse chemical composition of the artifacts matches that of a wide range of obsidian sources in multiple directions 15 to 55 miles away, suggesting exchange networks were in place to move the valuable stone across the ancient landscape.

The team also discovered black and red rocks – manganese and ocher – at the sites, along with evidence that the rocks had been processed for use as coloring material.

“The pigments are really interesting and important in that they show early signs of symbolic representation,” Leslie says. “They were maybe painting their bodies, perhaps their clothing, or using them for rock art. What is striking about the use of the pigment is that it shows people were thinking 320,000 years ago in very similar ways to how we think about the world too.”

Hoping to understand what might have driven such fundamental changes in human behavior, the research team integrated data from a variety of sources to assess and reconstruct the ancient environment in which the users of these artifacts lived. Their findings suggest that the period when these behaviors emerged was one of changing landscapes and climate, in which the availability of resources would have been unreliable.

Developing new tools to extract more resources from the environment is a particularly human characteristic.— David Leslie

Geological, geochemical, paleobotanical, and faunal evidence indicates that an extended period of climate instability affected the region beginning around 360,000 years ago, at the same time earthquakes were continually altering the landscape. Although some researchers have proposed that early humans evolved gradually in response to an arid environment, Potts says his team’s findings support an alternative idea. Environmental fluctuations would have presented significant challenges to inhabitants of the Olorgesailie Basin, prompting changes in technology and social structures that improved the likelihood of securing resources during times of scarcity.

The paper also highlights the published contributions of the Kapthurin Formation project, also in Kenya, led by UConn anthropology professor Sally McBrearty.

The research teams for this study published in Science include collaborators from the following institutions: the Smithsonian Institution, the National Museums of Kenya, George Washington University, the Berkeley Geochronology Center, the National Science Foundation, the University of Illinois at Urbana-Champaign, the University of Missouri, the University of Bordeaux (Centre National de la Recherche Scientifique), the University of Connecticut, Emory University, and the University of Bergen.

Funding for this research was provided by the Smithsonian, the National Science Foundation (grant numbers EAR-1322017, BCS-0218511 (RP) 2011116368 (AMZ), BCS-1240694 (ASB and AMZ), DGE-0801634, EAR-1322017, BCS-0802757, BCS-0814304), and George Washington University.

Brain Awareness: Toward Growing an Artificial Mind

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A brain-shaped printed circuit board. (Alfred Pasieka,/Science Photo Library via Getty Images)
UConn Health/JAX researcher Min Tang-Schomer is experimenting with nerve cells and electrical signals in a dish to recreate the way neurons ‘talk’ to each other in the brain. She hopes that eventually insights from her work could be used to help and heal people who don’t have the normal connections between neurons that a healthy brain takes for granted. (Alfred Pasieka,/Science Photo Library via Getty Images)

Part of a series of posts for Brain Awareness Week, March 12-16.

The structure of the brain is beautiful, an enormous web of interwoven neurons that constantly fire thoughts back and forth in crackles of bioelectrical impulses. But although we can map the physical structure, no one has been able to observe a living, thinking brain building itself. So we don’t know how neurons self-organize to create their web – or why they sometimes fail to, as in certain kinds of mental illness and intellectual deficits.

Instead of grappling with the brain’s complexity, UConn Health assistant professor of pediatrics and biomedical engineer Min Tang-Schomer wondered if she could create a simple, single brain circuit from scratch. Tang-Schomer, who also has a joint appointment as research scientist at the Jackson Laboratory for Genomic Medicine, began growing neurons in a dish. Even just a few neurons in a dish are beautiful.

“They look like the cosmos,” she says. And when she attached a few electrodes to the cells and began to send them electrical signals, the cells responded. With a couple of electrodes and some experimenting, she was able to make the neurons pulse in synchrony. It’s a sign they’re wired together in a functional way.

Min-Tang Schomer hopes insights from her neurons in a dish could ultimately be used to help and heal people who don’t have the normal connections between neurons that a healthy brain takes for granted.

The electrodes might seem artificial, but the electrical signal, after being converted to a chemical signal, is the natural way our neurons talk to each other. When a photon hits a receptor in your eye, the receptor flashes a pulse of electrical signal through your optical nerve that tells your brain ‘purple’. When you brush your hand along a stove, the nerves send an electrical impulse to your brain that screams ‘hot!’ That’s how a baby’s brain learns to organize itself. The sight of a flame quickly gets linked to the feeling of pain the first time a toddler reaches for a lit candle. Over time, the functional associations of different parts of the brain get reinforced into stronger and thicker nerve connections. Connections less frequently used might disappear.

In a dish, Tang-Schomer’s lab wants to re-create the process with neurons, electrodes, and some experimenting. Previously she has fabricated an artificial circuit with paved “highways” for the nerve bundles, called axons. Now she plans to connect this circuit to the synchronization program she just found, and explore how the neurons adapt. She has also tried different pulsing programs to direct the growth of nerve connections in three dimensions, work she recently published in Brain Research. Combining all these technologies, Tang-Schomer hopes that one day, we can not only observe how the brain grows in a dish, but also play with an artificial mind.

No one knows what Tang-Schomer’s neurons in a dish are thinking about, if you can even call the pulsing of a single circuit of neurons in a dish a ‘thought’. But she hopes that these simple circuits will lead to more complex circuits, and a better understanding of how neurons organize into brains. Eventually she hopes insights from her neurons in a dish could be used to help and heal people who don’t have the normal connections between neurons that a healthy brain takes for granted.

Read more about UConn research on the brain in the series Brainstorm

Brain Awareness: Can Caffeine Save the Tiniest Babies’ Brains?

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Tiffany Johnson of Bloomfield holds her son, Quincey, who was born at 25 weeks, weighing one pound 14 ounces. (Peter Morenus/UConn File Photo)
A mother holds her son, who was born at 25 weeks. Two UConn researchers are exploring ways to mitigate the effects of extended development outside the mother’s womb on the brains of pre-term babies. (Peter Morenus/UConn File Photo)

Part of a series of posts for Brain Awareness Week, March 12-16.

Babies born too early have to do much of their developing outside of their mother’s womb, and the stress of that can be hard on their brains. Bleeding or lack of oxygen often injure preemie brains like strokes injure an adult. This can lead to lifelong disabilities, and right now doctors have no way to help them.

“Spending the last 10 weeks of the pregnancy in the NICU, instead of in utero, has enormous effects on brain development,” says Ted Rosenkrantz, professor of pediatrics at UConn Health and neonatologist in the Connecticut Children’s Medical Center NICU at UConn Health.

Spending the last 10 weeks of the pregnancy in the NICU, instead of in utero, has enormous effects on brain development.— Ted Rosenkrantz

Rosenkrantz teamed up with UConn developmental neuroscientist Holly Fitch, professor of psychological sciences, to see if they could find potential treatments for preemies.

In the February 21 issue of the International Journal of Developmental Neuroscience, they assess two of them. The first, hypothermia, lowers the baby’s body temperature to about 33.5 degrees Celsius (92 degrees Fahrenheit) for three days. This slows down the metabolism of brain cells, giving them time to recover from the lack of oxygen. Cooling is already used to treat full-term babies who have suffered from oxygen deprivation during birth, and it helps reduce future intellectual disabilities by about 25 percent.

But pre-term babies’ brains are different from those of full-term babies. A baby born at 30 weeks gestation – 10 weeks early – has an area in the brain called the germinal matrix. It has a good blood supply and is full of young cells destined to populate other parts of the brain. But the tissue supporting the blood vessels in the germinal matrix is fragile, and if the baby gets stressed and has a big dip or rise in blood pressure, those vessels can burst and bleed into the rest of the brain. Brain cells in this area are also very vulnerable to lack of blood flow and oxygen. The bleeding can kill these young brain cells, which then never make it to the brain regions they were destined for. Depending on the age of the baby, this can cause cerebral palsy, or learning, memory, or other intellectual deficits.

Because preemies’ brains are different than full-terms’, they might respond differently to hypothermia. One small study had suggested that it might actually hurt them. So Rosenkrantz and Fitch also wanted to test caffeine. Other researchers had noticed that pre-term babies given caffeine to help them breathe – a standard treatment for babies who have been on ventilators – seemed to have lower incidence of cerebral palsy and learning deficits later in life, but no one had tested this directly.

To see whether either of these treatments might work, the researchers tested these therapies in a study using rats. Rats are born less developed than humans; the brain of a six-day old rat is approximately like that of a baby born two months early, at 32 weeks gestation.

The rats tested confirmed the researchers’ suspicions about hypothermia. It wasn’t helpful to the rats with oxygen deprivation to the brain, and even seemed to harm the healthy rats. All the rats treated with hypothermia had learning and memory disabilities.

Caffeine, on the other hand, seemed to help both with motor learning and with listening skills that in humans are used for understanding speech.

Now the researchers plan to do a much larger study, testing different dosages of caffeine and tracking whether male and female rats respond differently.

“Parents are so concerned about their baby just surviving that they’re not focused on problems that may not come out until years later. But for those parenting a child with learning disabilities, the impact is huge,” says Fitch. “I’d really like to see this research translate into something that will help babies, and potentially reduce the number of school-age children with learning disabilities.”

Read more about UConn research on the brain in the series Brainstorm

Brain Awareness: Brainstorming Better Seizure Treatments

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UConn researchers are studying the complex science of seizures, with the ultimate goal of developing new, more targeted, anti-seizure treatments. (Video by UConn)

Part of a series of posts for Brain Awareness Week, March 12-16.

UConn researchers are studying the complex science of seizures. This research will play an important role in the development of new, more targeted, anti-seizure treatments.

Read more about UConn research on the brain in the series Brainstorm. 

Brain Awareness: Soccer Players May Offer Clues to Collective Movement

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As part of an investigation into why humans move as they do in crowds, UConn researchers compare the flocking behavior of soccer players with that of inanimate particles. (MLADEN ANTONOV/AFP/Getty Images)
As part of an investigation into why humans move as they do in crowds, UConn researchers compare the flocking behavior of soccer players with that of inanimate particles. (MLADEN ANTONOV/AFP/Getty Images)

Part of a series of posts for Brain Awareness Week, March 12-16.

Playing a team sport like soccer requires balance, coordination, judgement of depth, and speed. You might think we can do all these things thanks to our brains. But it turns out that to move in a coordinated group, you don’t need a brain. In fact, sometimes things that aren’t even alive can do it.

UConn psychologist and director of the Center for the Ecological Study of Perception and Action James Dixon and Maurici López-Felip, a graduate student in his lab who formerly played on the Catalan National Team, are researching why humans move as they do in crowds, on the street, and especially on the soccer field. To do this, they’ve teamed up with UConn chemist Jim Rusling and Dilip Kondepudi, a physicist at Wake Forest University, as well as soccer gurus from FC Barcelona. The first behavior they’re looking at is flocking.

Birds flock. Little kids chasing a soccer ball flock, too. Inanimate objects can also flock. For example, little bits of benzoquinone floating on the surface of a pool of water tend to flock, even when they start out randomly strewn across the surface. See video. The bits gradually dissolve in the water, and it’s this dissolving action that makes them move around. Inevitably, they end up flocking together. Dixon and the other researchers have shown that when the dissolving particles flock, they dissipate energy more efficiently. Since natural systems tend to move toward lower-energy states – think of rocks rolling downhill – if flocking helps particles spend energy faster, it’s the natural thing to do.

What does this have to do with brains? Humans and other living beings are essentially energy dissipation systems that sustain themselves through generations. If flocking is a natural behavior, something that dissipative systems just do, maybe it’s something our brain doesn’t have to think about. There’s probably other behaviors that come equally naturally to us, cued either by the environment or other people. Dixon and López-Felipe are currently analyzing data from FC Barcelona’s soccer players to develop a model of collective movement that includes flocking and potentially other behaviors. The team is interested in learning how they could potentially help their players move better and faster – you might even say instinctually – and win more. 

“Brains are a good thing, we like having them,” Dixon says. “But it seems like a good idea to put as little burden on our computational systems as possible.” Evolution doesn’t want us to strain our brain. And neither do soccer coaches. 

Dixon’s research is supported by grants from the Connecticut Institute for the Brain and Cognitive Sciences, as well as the National Science Foundation’s INSPIRE program (#1344275).

Read more about UConn research on the brain in the series Brainstorm

Major Cardiovascular Study of Gout Patients Has Unexpected Finding

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Illustration of the internal anatomy of a foot, showing a tophus (swelling) due to gout. The large toe is commonly affected. (John Bavosi/Science Photo Library via Getty Images)
The internal anatomy of a foot, showing a tophus (swelling) due to gout. Newly released findings show that the drug febuxostat – used to treat gout – increased the risk of death for those with heart disease, compared with the alternate drug allopurinol. (John Bavosi/Science Photo Library via Getty Images)

A large study of cardiovascular events in gout patients taking one of two medications to prevent excess build-up of uric acid has found that one of the drugs, febuxostat, increased the risk of death for those with heart disease, compared to study participants taking allopurinol.

Yet the two drugs were comparable with respect to a combination of non-fatal heart attack, non-fatal stroke, urgent surgery to treat angina, and death due to cardiovascular causes.

The findings of the CARES trial were first released at the American College of Cardiology’s 67th Annual Scientific Session on March 12, and published in the New England Journal of Medicine by UConn School of Medicine’s Dr. William B. White, principal investigator of the trial and the study’s lead author.

The mortality findings with regard to febuxostat were “entirely unexpected,” says White, professor of medicine at the Calhoun Cardiology Center of UConn School of Medicine, who in addition to helping with the design of the trial has served as chair of the cardiovascular events committee for the past seven years. “The results were consistent across many subgroups; there was no evidence of a relationship with age, gender, race or ethnicity, history of cardiovascular disease, or duration or severity of the gout.”

Previously, no cardiovascular clinical trial has ever demonstrated an increased risk of cardiovascular death without also showing a heightened risk of other cardiovascular outcomes such as non-fatal heart attack and stroke.

“A very extensive pre-clinical evaluation of febuxostat showed no explanation for the excess in sudden cardiac deaths,” he says, adding that there was no difference between patients taking either febuxostat or allopurinol with regard to any of the non-fatal events, including hospitalizations for heart failure, arrhythmias, pulmonary embolism, myocardial infarction, or stroke.

More than 8 million Americans suffer from gout, a complex form of arthritis that occurs when uric acid crystals form and cause intense joint pain in the big toe or other joints. Elevated uric acid levels have been associated with cardiovascular problems, including high blood pressure, angina, and heart attack.

The key to preventing gout attacks is a healthy diet and lifestyle modifications, but many patients with gout also need a type of medication known as xanthine oxidase inhibitors to prevent the excess build-up of uric acid in the body that leads to gout. The two medications approved for the treatment of elevated uric acid levels in patients with gout are allopurinol, approved in 1966, and febuxostat, approved in 2009.

Febuxostat was developed in an effort to offer a safer alternative to the mainstay therapy of allopurinol, which can cause kidney problems and is associated with rare but severe allergic reactions in some – particularly African-American – gout patients.

While febuxostat was in development, however, it showed a modest increase in non-fatal cardiovascular events compared to allopurinol, leading the FDA to require a major long-term cardiovascular event study to be conducted as a condition of approving the drug.

The seven-year CARES trial, which began in 2010, enrolled more than 6,000 gout patients at 320 centers in North America. All study participants had gout as well as established cardiovascular disease, such as a previous heart attack, stroke, hospitalization for chest pain (unstable angina), peripheral arterial disease, or both diabetes and small vessel disease. Half of the patients were randomly assigned to receive febuxostat and half received allopurinol; neither the patients nor their doctors knew which drug they had received.

Participants continued taking their assigned medication as researchers tracked their health outcomes for more than 2.5 years on average, and as long as 6.5 years in some patients.

A high proportion of patients (45 percent) stopped participating in the trial. In those who stopped taking febuxostat, the elevated risk of death decreased. However, little else is known about these patients, including whether they resumed taking allopurinol or febuxostat by prescription.

The research team will continue to explore the clinical trial’s database for insights on the optimal treatment for gout, especially for those who have both cardiovascular disease and chronic kidney disease. In the approximately 50 percent of study patients with a history of chronic kidney disease, mortality was not significantly different among those taking febuxostat and those taking allopurinol.

The trial was funded by Takeda Pharmaceuticals U.S.A. Inc., the maker of febuxostat.

Engineered Cartilage Template to Heal Broken Bones

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Syam Nukavarapu and Hyun Kim examine a specimen of the hybrid hydrogel in the laboratory at UConn Health. (Tina Encarnacion/UConn Health Photo)
Helping injured bones regenerate is no easy task, especially when it comes to the longer bones in our bodies. UConn Health researchers, including Professor Syam Nukavarapu, standing, and graduate student Hyun S. Kim, have developed a novel method to encourage long bones to regenerate, using a hybrid hydrogel system. (Tina Encarnacion/UConn Health Photo)

A team of UConn Health researchers has designed a novel, hybrid hydrogel system to help address some of the challenges in repairing bone in the event of injury. The UConn Health team, led by associate professor of orthopedic surgery Syam Nukavarapu, described their findings in a recent issue of Journal of Biomedical Materials Research-Part B, where the work is featured on the journal cover.

There are over 200 bones in an adult human skeleton, ranging in size from a couple of millimeters in length to well over a foot. How these bones form and how they are repaired if injured varies, and has posed a challenge for many researchers in the field of regenerative medicine.

Two processes involved with human skeletal development help all the bones in our body form and grow. These processes are called intramembranous and endochondral ossification, IO and EO respectively. While they are both critical, IO is the process responsible for the formation of flat bones, and EO is the process that forms long bones like femurs and humeri.

Cartilage template formation via engineered extracellular matrix. (Syam Nukavarapu/UConn Photo)
Cartilage template formation via engineered extracellular matrix. (Syam Nukavarapu/UConn Photo)

For both processes, generic mesenchymal stem cells (MSCs) are needed to trigger the growth of new bone. Despite this similarity, IO is significantly easier to recreate in the lab since MSCs can directly differentiate, or become specialized, into bone-forming cells without taking any additional steps.

However, this relative simplicity comes with limitations. To circumvent the issues associated with IO, the UConn Health team set out to develop an engineered extracellular matrix that uses hydrogels to guide and support the formation of bone through EO.

“Thus far, very few studies have been focused on matrix designs for endochondral ossification to regenerate and repair long bone,” says Nukavarapu, who holds joint appointments in the departments of biomedical engineering and materials science and engineering. “By developing a hybrid hydrogel combination, we were able to form an engineered extracellular matrix that could support cartilage-template formation.”

Nukavarapu notes that vascularization is the key in segmental bone defect repair and regeneration. The main problem with IO-formed bone is caused by a lack of blood vessels, also called vascularization. This means that IO isn’t capable of regenerating enough bone tissue to be applied to large bone defects that result from trauma or degenerative diseases like osteoporosis. Although many researchers have tried various strategies, successfully vascularizing bone regenerated with IO remains a significant challenge.

On the other hand, vascularization is a natural outcome of EO due to the development of a cartilage template, chondrocyte hypertrophy, and eventual bone tissue formation.

While IO’s simplicity caused limitations, EO’s benefits result in an intricate balancing act. EO requires precise spatial and temporal coordination of different elements, like cells, growth factors, and an extracellular matrix, or scaffold, onto which the MSCs attach, proliferate, and differentiate.

Syam Nukavarapu examines a specimen of the hybrid hydrogel in the laboratory at UConn Health. (Tina Encarnacion/UConn Health Photo)
Syam Nukavarapu, associate professor of orthopedic surgery, examines a specimen of the hybrid hydrogel in the laboratory at UConn Health. (Tina Encarnacion/UConn Health Photo)

To achieve this delicate balance in the lab, Nukavarapu and his colleagues combined two materials known to encourage tissue regeneration – fibrin and hyaluronan – to create an effective extracellular matrix for long bone formation. Fibrin gel mimics human bone mesenchymal stem cells and facilitates their condensation, which is required for MSC differentiation into chondrogenic cells. Hyaluronan, a naturally occurring biopolymer, mimics the later stages of the process by which differentiated chondrogenic cells grow and proliferate, also known as hypertrophic-chondrogenic differentiation.

The researchers anticipate that cartilage templates with hypertrophic chondrocytes will release bone and vessel forming factors and will also initiate vascularized bone formation. Nukavarapu says that the “use of cartilage-template matrices would lead to the development of novel bone repair strategies that do not involve harmful growth factors.”

While still in the early research phase, these developments hold promise for future innovations.

“Dr. Nukavarapu’s work speaks not only to the preeminence of UConn’s faculty, but also to the potential real-world applications of their research,” says Radenka Maric, vice president for research at UConn and UConn Health. “UConn labs are buzzing with these types of innovations that contribute to scientific breakthroughs in healthcare, engineering, materials science, and many other fields.”

The researchers next plan to integrate the hybrid extracellular matrix with a load-bearing scaffold to develop cartilage templates suitable for long-bone defect repair. According to Nukavarapu, the UConn research team is hopeful that this is the first step towards forming a hypertrophic cartilage template with all the right ingredients to initiate bone tissue formation, vascularization, remodeling, and ultimately the establishment of functional bone marrow to repair long bone defects through EO.

The work was supported by grants from the AO Foundation (S-13-122N), NSF Emerging Frontiers in Research and Innovation (EFRI) (1332329), and NSF Emerging Frontiers and Multidisciplinary Activities (EFMA) (1640008).

Research in Syam Nukavarapu’s lab focuses on biomaterials and tissue engineering, with emphasis on bone, cartilage, and bone-cartilage interface tissue engineering. Other UConn authors include graduate students Paiyz E. Mikael and Hyun S. Kim.