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Flu Vaccine Supply Gaps Can Intensify Flu Seasons, Make Pandemics Deadlier

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More than 50 million people died in the Spanish flu pandemic of 1918-19. Its 100th anniversary this flu season serves as a reminder to close flu vaccine supply gaps that may be costing hundred to thousands of lives now and could cost many more when the next “big one” strikes, researchers say.

U.S. flu vaccine distribution logistics could use an update, according to Pinar Keskinocak. The researcher at the Georgia Institute of Technology co-led a recent study that compared the current approach with a proposed allocation method calculated to save many more lives in a pandemic or similar influenza outbreak.

The study’s recommendations, which apply to resupplying vaccine stocks during a running outbreak, boil down to this: To put a bigger dent in the spread of flu, replenish vaccine stocks in regions where they are being used up and don’t replenish them in areas where vaccines are just sitting on shelves, because few people are getting flu shots there.

A simple tweak

The tweak in the supply chain could also save thousands of lives annually in regular flu seasons in the U.S., which can be plenty deadly. Reportedly, 80,000 people died in the 2017-18 flu season. For comparison’s sake, murder took about 19,300 lives in 2017 in the U.S.

“Even seasonal flu kills thousands to tens of thousands of people each year, so we would benefit immediately,” said Keskinocak, who is William W. George Chair and Professor in Georgia Tech’s H. Milton Stewart School of Industrial and Systems Engineering and Director for the Center of Health and Humanitarian Systems.

“In a pandemic, nearly no one would have natural immunity, so the death toll could be significantly high if we don’t improve vaccine coverage.”

In a pandemic, the flu virus represents a mutation that human immune systems may not have had a chance to build prior resistance to, thus the lack of natural immunity. When the next one strikes, in addition to the many lives saved, the researchers’ recommendations could massively prevent flu infections, secondary infections like bronchitis, hospitalizations, and unnecessarily high medical costs.

Keskinocak, co-principal investigator Julie Swann from North Carolina State University, and first author Zihao Li of Georgia Tech published their results in the journal Plos One in October 2018, around the start of the 2018-19 flu season. The research was supported by the Harold R. and Mary Anne Nash Junior Faculty Endowment Fund.

A logic breakdown

When a pandemic hits, vaccine supply may become limited but then catch up over time. When that happens, the vaccine distributors commonly take what’s called the population-based approach.

“Areas with larger populations get more vaccine, proportional to the population. It’s a straightforward approach that seems fair,” Swann said.

As more vaccine becomes available over time, restocking follows the same principle, and that is where distribution logic breaks down. In some regions, few people get vaccinated, but under population-based allocation, resupply stocks go there anyway and may go to waste. Meanwhile, restocking may fall short of demand elsewhere, where people are lining up for inoculations.

A mathematical fix

As a result, in a pandemic, people eager for a vaccination might not get one despite adequate vaccine production, and the resulting additional unvaccinated people are more likely to get the flu and also spread it to others. That intensifies the outbreak for the entire population.

The wasted vaccine stocks also drain medical finances.

“Production, storage, and delivery of vaccine are costly, and unused inventory can’t just be thrown away. It costs money to dispose of,” Keskinocak said.

Restocking doses where they are actually being used would benefit the entire population by boosting the total number of vaccinated individuals, who would then be less likely to get sick and to infect other people. That would tamp down the flu wave for everybody.

A data dearth

Leftover inventory could be slashed to about 20 percent of current levels, saving considerable costs, and the data about which areas were not resupplied could be used to identify areas where more people need encouragement to get vaccinated.

“The data would tell you where you need continued education about the importance of vaccination, and some of the money saved from unnecessary resupplying could be invested in public health campaigns,” said Swann, who collaborated with the Centers for Disease Control and Prevention during the 2009-10 H1N1 Swine flu pandemic.

But the needed data is missing at present in the U.S. vaccine distribution system.

“Surprisingly few states have systems in place that tell them how much vaccine has been administered where and how much is still left in inventory at provider locations,” Swann said.

The next “big one”

The next “big one” flu will sneak up on humanity someday.

Ultimately, the best way to cut its death toll by more than half and save possibly hundreds of thousands of lives will be for virtually everyone to get vaccinated against influenza annually. Currently, fewer than 50 percent of Americans do.

The 1918-19 outbreak, which may have consisted of multiple concurrent influenzas, killed 678,000 people in the U.S. Other “big ones:” The 1957 “Asian flu” killed 116,000 in the U.S.; the 1968 “Hong Kong flu” killed 100,000. The 2009 bird flu pandemic, which was a less contagious virus, killed 12,500 people in the U.S. and hospitalized some 275,000.

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When Activated, ‘Social’ Brain Circuits Inhibit Feeding Behavior In Mice

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Researchers at Stanford demonstrated that direct stimulation of fewer than two dozen neurons linked to social interaction was enough to suppress a mouse’s drive to feed itself.

Feeding behavior and social stimulation activate intermingled but distinct brain circuits, and activating one circuit can inhibit the other, according to a new study by researchers at Stanford University.

The researchers demonstrated in mice that direct stimulation of fewer than two dozen nerve cells, or neurons, linked to social interaction was enough to suppress the animals’ drive to feed themselves — a finding with potential clinical significance for understanding and treating eating disorders such as anorexia.

The researchers made these findings by developing a technique for teasing apart separate but closely intertwined sets of neurons in the brain.

A paper detailing the findings and the method used to obtain them was published online Jan. 16 in Nature. The senior author is Karl Deisseroth, MD, PhD, the D.H. Chen Professor and professor of bioengineering and of psychiatry and behavioral sciences and a Howard Hughes Medical Institute investigator. Lead authorship is shared by postdoctoral scholars Joshua Jennings, PhD, and Christina Kim, PhD, along with staff scientist James Marshel, PhD.

Social curbs on eating behavior

“We know social situations can inhibit the urge to eat,” Deisseroth said.

“One example is the behavior of people at different levels of dominance in a social hierarchy. You’re not going to dive into that plate of ribs when you’re dining in the presence of royalty.”

Anorexia is another example.

“People with anorexia report that a powerful driver, at the disorder’s onset, was feedback from others indicating they’d be rewarded for restricting their food intake,” said Deisseroth.

Virtually nothing is known about the neural underpinnings of this inhibition, he said.

“We sought to understand, at the level of individual neurons, how these potentially competing drives may negotiate with each other, and how the brain circuits associated with feeding versus social behavior may interact.”

Deisseroth’s group focused on a part of the brain called the orbitofrontal cortex, a sheet of cells that, in both mice and humans, lies on the brain’s outer surface toward the front of the organ. This brain region, which is similar in the two species, has been shown in human imaging studies to be active when subjects are wishing for, seeking, obtaining and consuming food, or when they’re socially engaged.

Exploring the interactions of feeding and social drives was guaranteed to be tricky.

“It’s not as if there is a cluster of ‘feeding’ neurons’ and another cluster of ‘social’ neurons sitting in two neatly labeled clumps in the orbitofrontal cortex, so you can just position an electrode in one or the other cluster and find out all you need to know,” Deisseroth said.

The neurons driving and responding to these different activities are interspersed, scarce and scattered throughout the orbitofrontal cortex like sprinkles on a cupcake. Plus, they all look pretty much the same.

So the researchers designed a sophisticated system for simultaneously stimulating and monitoring activity in multiple designated neurons. This let them determine which orbitofrontal-cortex neurons were active during feeding-associated or social activities, or both, or neither. The technology also allowed them to stimulate on the order of 20 neurons identified as dedicated to one or the other activity and watch what behavior resulted.

Over the past decade and a half, Deisseroth has pioneered the development of an experimental approach called optogenetics, in which a gene for a light-sensitive protein called an opsin is inserted into neurons so they can be activated by pulses of laser light reaching them via an implanted optical fiber. Recent advances in his lab have optimized one such opsin to the point where his team can stimulate numerous selected, behaviorally categorized neurons at a time in a mammal.

“This study builds on our initial demonstration in mammals of single cell control with optogenetics in 2012, but now marks the first demonstration of control of mammalian behavior by the manipulation of multiple, individually specified neurons,” he said.

The scientists inserted the gene for this improved opsin into the orbitofrontal cortex of mice, along with another gene that causes neurons to fluoresce in proportion to their activity. A tiny lens at the tip of the optical fiber guided light across numerous targeted neurons with near simultaneity, causing as many as two dozen designated neurons to fire together.

Food vs. friends

During the experiments that followed, the mice were constrained by an apparatus that kept their heads comfortably fixed in place. In one set of experiments, mice were exposed to a spout that occasionally issued a drop of a high-calorie solution, which could be readily licked up. For each mouse, Deisseroth’s colleagues recorded which orbitofrontal-cortex neurons among the several hundred in their field of view lit up during this activity.

Optogenetically stimulating just 20 feeding-responsive neurons enhanced the mice’s licking activity in the presence of the high-calorie solution, tying those neurons causally to feeding behavior.

To identify social-responsive neurons in the mice’s orbitofrontal cortex, the scientists introduced juvenile mice — which older mice perceive as nonthreatening potential buddies and set about sniffing — and tracked activity levels in the neurons in the field of view. They were able to identify specific neurons responsive to the exploratory social interaction.

Optogenetically stimulating social-responsive orbitofrontal neurons in the presence of a caloric reward reduced the amount of time the mice spent licking the solution. So did the natural-stimulation equivalent: exposure to juvenile mice. The more the social interaction, the less the interest in calories.

While the mice in this study weren’t a disease model, Deisseroth noted the findings’ potential clinical significance.

“We’ve been able to pinpoint otherwise indistinguishable orbitofrontal-cortex neurons involved in feeding and social drive states,” he said.

“A key goal was to know which neurons actually matter for behavior. Now that we do, we can examine them more closely to look for, say, surface-protein markers or wiring differences that distinguish them from one another. If there are any distinctions like that, it will deepen our understanding of how competing drives are negotiated among neuronal cell types in the cerebral cortex — and could even lead to pharmaceutical interventions that reduce social inhibition of food consumption among people with anorexia.”

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Drexel and Arizona State Researchers Look at Risk of Infection From Water in the Air at Home

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Water spray from showers, faucets and toilets can carry Legionella bacteria. New research from Drexel and Arizona State is helping us to better understand our risk of infection if we inhale aerosols in the spray generated by these indoor water fixtures.

“Don’t drink the water” might be good enough advice to keep you from getting sick in some places, but according to researchers from Arizona State and Drexel University, the admonition should probably be expanded to “…try not to breathe the water either.”

In research recently published in the journal Environmental Science & Technology, the group takes a closer look at how the spray from showers, sinks and toilets can expose us to the bacteria responsible for the most waterborne disease outbreaks in the country.

“Most people in the United States think we have a handle on our water quality problems and drinking water isn’t something we need to worry about anymore. If anything, the recent water crisis in Flint, Michigan, and frequent Legionnaires’ disease outbreaks across the nation have demonstrated that’s not the case,” said Kerry Hamilton, PhD, an assistant professor in the Ira A. Fulton Schools of Engineering at Arizona State University and former doctoral researcher at Drexel, who led the investigation into how the Legionella pneumophila bacteria can grow and spread in indoor water supplies.

Legionella, the bacteria that causes pneumonia-like Legionnaire’s disease, has been responsible for a  number of recent outbreaks and can be fatal in 10-25 percent of infections, according to the Centers for Disease Control and Prevention. While it is considered one of the deadliest waterborne diseases in the United States, it is actually contracted via inhalation or aspiration. This means to accurately understand environments that could increase one’s risk of exposure, researchers need to examine places where people are exposed to water in the air.

“To protect people from infections, we first need to understand the risks,” Hamilton said.

“If we can better model and predict how water quality degrades under different circumstances, we can more efficiently target resources and prevent disease outbreaks.”

The research considered a variety of factors to assess risk of exposure — from any combination of showering, using a sink or flushing a toilet — using water with a range of bacterial concentrations. It also took into consideration that older people or people who already have a health condition are at greater risk of becoming ill from Legionellaexposure. And it is one of the first studies to closely examine how water-efficient fixtures, in a green building for example, can affect risks.

“We found that shower risks were highest, likely due to the amount of time a person would be exposed to the water spray. Risk of exposure from water efficient fixtures tended to be slightly less if concentrations are comparable to those at conventional water fixtures, because they produce fewer inhalable aerosol particles due to a less powerful or more distributed spray,” said Charles Haas, PhD, LD Betz Professor of Environmental Engineering in Drexel’s College of Engineering, who was a co-author of the paper and has been an advocate for the study of exposure risk from breathing water spray.

“However, modeling differences in Legionella concentrations in conventional and water efficient buildings remains a research gap our related work aims to address.”

As one might expect, risk is greater when exposure from multiple sources is considered or when it is adjusted for populations that are less able to fight off infection.

The researchers created their assessment using available data on aerosol particle volume, size and spray for a variety of showers, faucets, and toilets.

While the study focuses specifically on Legionella pneumophila bacteria, it sets a framework for assessing the risk of being exposed to any bacteria lurking in indoor water sources. Thus, it could be used more broadly to guide prescriptions for “acceptable levels” of bacteria in building water systems.

This is an understudied area of water quality, according to Hamilton, because the Environmental Protection Agency’s regulatory responsibility ends at the property line. So most existing indoor water quality guidelines are not based on risk assessment research.

But that doesn’t mean Legionella can’t make its way into household water supplies. In homes with particularly elaborate systems or where water can rest or stagnate for long periods of time, such as seasonal homes or new homes designed for water efficiency, Legionella colonies can form.

“There are many guidelines in the literature about how to create a ‘cutoff’ value, but none are based on technical reasoning,” Hamilton said.

“Most of the guidelines are based on what people are doing in practice. Our research simulates an appropriate concentration limit based on a risk level that is consistent with other water quality policies in order to give better guidance for monitoring water quality in buildings.”

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Nudging Does Not Necessarily Improve Decisions

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Nudging is a well-known and popular concept in behavioral economics. It refers to non-coercive interventions that influence the choices people make by changing the way a situation is presented. A well-known example of this is placing the salad bar near the cafeteria entrance to promote a healthy diet. It has been shown that simple change has an effect on the food people choose to eat for lunch. However, is a light salad really the best option from the employee’s perspective, or is it their employer who will benefit from staff who perform better in the afternoon? And, is improving the decisions we make really that simple?

Measuring the quality of a decision

Whether a nudge ultimately results in a person making decisions that are better suited to their needs is an important factor in assessing the effectiveness of nudges. This is the starting point of the research work of Nick Netzer and Jean-Michel Benkert from the Department of Economics at the University of Zurich. How do you measure whether a nudge improves a decision in the eyes of the person being nudged? “We can’t determine whether a nudge improves the choices  a person makes until we understand how they reach their decisions,” says Nick Netzer, putting the hype surrounding nudging into perspective.

“Depending on which behavioral model we take as a starting point, it is possible to measure the effectiveness of nudges – or not.”

Traditional economics assumes that a person’s preferences can be inferred from their decisions and behavior. According to the rational behavior model, a person’s decision to have a salad or a steak for lunch is based on which meal meets their needs. When it comes to assessing nudges, however, this model is problematic, since nudging manipulates precisely the behavior that is supposed to shed light on a person’s preferences. The researchers therefore looked to alternative behavioral models to determine the assumptions under which a nudge can be assessed in a meaningful way.

First-best choice

According to the “satisficing” model, a person will consider their alternatives subsequently and choose the first one that meets their needs in a satisfactory way. The person will order the salad because it is the first option that adequately fulfills their requirements. Although they might have enjoyed the steak more, they will not consider that option,  since they have already made up their mind. In this model, hardly any conclusions can be drawn about the true preferences of a person, and their decisions cannot be improved through nudging either.

Limited attention

If we assume decisions are made according to the limited attention model, however, the situation changes: This model is based on the idea that a person will only ever consider a certain number of possibilities – for example, only the first three meals on a menu that features five options. The person will then ponder these options and choose the best meal out of this selection. Unlike with the satisficing model, conclusions can be drawn about a person’s preferences, as the UZH researchers have now shown. Decisions that are based on such a decision-making process can be improved by nudging. Therefore, if you know that a salad is indeed an ideal meal, then placing it among the first three items on the menu will ensure that a person will at least consider this meal and maybe also choose it.

Success of nudges depends on decision-making process

It is therefore necessary to know what a person’s true needs and preferences are in order to assess the success of nudges when it comes to improving decisions. If we do not have this information, any nudging that takes place is done without knowing what is in a person’s best interests.

“Our findings show that the success of nudging greatly depends on how we view the human decision-making process,” says Nick Netzer.

“We can’t conclusively determine whether nudging makes sense as long as current scientific knowledge in economics, psychology and neuroscience doesn’t allow nudging to be assessed in a consistent manner.”

 

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