Study of 670,450 American Women Shows Almost Half of Them Are Receiving the Wrong UTI Treatment

Many American healthcare professionals are still prescribing incorrect antibiotics treatments for too long of a duration.

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Across the United States, in both rural and urban settings, most women with private health insurance are receiving inappropriate treatment for their urinary tract infections (UTIs), according to a new study. 

Of the 670,450 women included in this research, all of whom had been diagnosed with uncomplicated UTIs between the ages of 18 and 44, nearly half received the wrong antibiotics and over three quarters were prescribed the medicine for too long. (A UTI is declared ‘uncomplicated’ when the patient has no abnormality or disease that could predispose them to more frequent infections.)

The results are largely consistent from location to location, although patients in more rural settings were more likely to be prescribed antibiotics for longer. 

Over the course of the study, from 2011 to 2015, there was only a slight improvement in proper antibiotic prescriptions based on current clinical guidelines.

“Inappropriate antibiotic prescriptions for uncomplicated urinary tract infections are prevalent and come with serious patient- and society-level consequences,” says epidemiologist Anne Mobley Butler from the Washington University School of Medicine, St. Louis.

“Our study findings underscore the need for antimicrobial stewardship interventions to improve outpatient antibiotic prescribing, particularly in rural settings.” 

The research was funded in part by several pharmaceutical companies, including Sanofi Pasteur, Pfizer, and Merck. The results were peer-reviewed and fall largely in line with the findings of previous studies, which suggest up to 60 percent of antibiotics prescribed in intensive care units are “unnecessary, inappropriate, or suboptimal”.

Nor is this just a problem in the US. Around the world, UTIs are one of the most common infections leading to emergency room visits. In the United Kingdom, it’s the second most common reason for prescribing antibiotics. 

Not only does taking the wrong antibiotic have worse outcomes for the individual patient, longer prescriptions are not necessarily better and can cause bacteria to grow resistant, making recurrence more likely and future infections harder to treat. 

Today, it’s estimated one in three uncomplicated UTIs in women are resistant to the popular combined antibiotic drug Bactrim (sulfamethoxazole and trimethoprim), and one in five are resistant to five other common antibiotics. 

An estimate of the number of deaths related to antibiotic-resistant UTIs is hard to establish due to a lack of research and monitoring, but some studies suggest that in US hospitals alone it could be around 13,000 lives lost per year. And some people suffer recurrent, resistant infections for years on end with little to no relief.

In light of these emerging concerns, in 2010 the Infectious Diseases Society of America (IDSA) and the European Society for Microbiology and Infectious Diseases updated their clinical practice guidelines. Based on results from various studies, they now recommend several first-line antibiotic agents and durations to best treat UTIs while minimizing the risk of antibiotic resistance.

That advice, however, is clearly not getting through to physicians and healthcare professionals. Many are still prescribing non-recommended antibiotics for improper durations.

Figuring out where the most inappropriate prescriptions are happening could help us target areas where we need to improve adherence to antibiotic guidelines. In the US, rural areas experience numerous health disparities compared to more urban areas, and yet this is the first large-scale study to evaluate how that impacts UTI treatment.

The authors are not sure why longer antibiotic treatments for UTIs are especially prevalent in rural areas, but suggest it could have to do with access to care and physician awareness. In rural areas, women may be given longer prescriptions to avoid future travel if that treatment fails.

Studies also show late-career physicians are more prevalent in rural locations and are more likely to prescribe antibiotics for longer, possibly because they have not heard of updated guidelines. 

“Accumulating evidence suggests that patients have better outcomes when we change prescribing from broad-acting to narrow-spectrum antibiotics and from longer to shorter durations,” explains Butler.

“Promoting optimal antimicrobial use benefits the patient and society by preventing avoidable adverse events, microbiome disruption, and antibiotic-resistant infections.”

When up to 60 percent of women can suffer from a UTI at some point in their life, it’s clearly vital that guidelines for treatment are better enforced, especially as antibiotic resistance increases.

This particular study was only based on commercially insured individuals, which means those who are uninsured or who receive public insurance were not considered. Rural areas were also loosely defined, including small towns as well as ‘exurbs’ on the edges of urban areas, and men, who also suffer from UTIs (albeit at a lower rate), were not included. 

Future research should focus on filling these gaps, but in the meantime, the trend reinforces the idea that clinicians need to periodically review clinical practice guidelines, even for common conditions that they have been treating for years.

“In recent years, little effective progress has been achieved to reduce inappropriate antibiotic prescribing for uncomplicated UTI,” the new paper concludes

“Given the large quantity of inappropriate prescriptions annually in the United States, as well as the negative patient- and society-level consequences of unnecessary exposure to antibiotics, antimicrobial stewardship interventions are needed to improve outpatient UTI antibiotic prescribing, particularly in rural settings.”

The study was published in Infection Control & Hospital Epidemiology.

Giraffes That Are More Social Live Longer

This study on giraffes might might mean something for human populations too.

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A research team led by Monica Bond, research associate at the Department of Evolutionary Biology and Environmental Studies of the University of Zurich (UZH), studied giraffes in Tanzania for five years. The biologists examined the relative effects of sociability, the natural environment, and human factors on survival of the mega-herbivore. They have now shown that adult female giraffes living in larger groups have higher survival chances than more socially isolated individuals.

Gregariousness leads to better survival

Giraffe group formations are dynamic and change throughout the day, but adult females maintain many specific friendships over the long term. “Grouping with more females, called gregariousness, is correlated with better survival of female giraffes, even as group membership is frequently changing,” says Bond. “This aspect of giraffe sociability is even more important than attributes of their non-social environment such as vegetation and nearness to human settlements.”

The benefits of many friends

Aside from poaching, the main causes of adult female giraffe mortality are likely to be disease, stress or malnutrition, all of which are interconnected stressors. “Social relationships can improve foraging efficiency, and help manage intraspecific competition, predation, disease risk and psychosocial stress,” says UZH professor Barbara König, senior author of the study. Female giraffes may seek out and join together with an optimal number of other females in order to share and obtain information about the highest-quality food sources. Other benefits to living in larger groups might be lowering stress levels by reducing harassment from males, cooperating in caring for young, or simply experiencing physiological benefits by being around familiar females. The study also finds that females living closer to towns had lower survival rates, possibly due to poaching.

Social habits similar to humans and primates

The team documented the social behaviors of the wild free-ranging giraffes using network analysis algorithms similar to those used by big-data social media platforms. According to the results, the giraffes are surprisingly similar in their social habits to humans and other primates, for whom greater social connectedness offers more opportunities. Chimpanzees and gorillas, for example, live in communities where ties between many individuals facilitate the flexibility of feeding strategies. “It seems to be beneficial for female giraffes to connect with a greater number of others and develop a sense of larger community, but without a strong sense of exclusive subgroup affiliation,” adds Monica Bond.

Study of a giraffe population in Tanzania

For the past decade the research team has been conducting the largest study to date of a giraffe population. The vast scale of their study area in the Tarangire region of Tanzania spans more than a thousand square kilometers and includes multiple social communities, each with about 60 to 90 adult female members. Thus, the study was able to disentangle individual from community-level influences on survival. The study is also unique in combining social network analysis and modeling of vital rates such as survival in a sample of hundreds of individuals.

Teaching Young Students Empathy Improves Their Creativity, University of Cambridge Finds

Having students become more skilled at looking at things from different perspectives may be what drove the increase in their creativity. The power of enhanced creativity can obviously be leveraged in many fields to boost levels of success.

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Teaching children in a way that encourages them to empathise with others measurably improves their creativity, and could potentially lead to several other beneficial learning outcomes, new research suggests.

The findings are from a year-long University of Cambridge study with Design and Technology (D&T) year 9 pupils (ages 13 to 14) at two inner London schools. Pupils at one school spent the year following curriculum-prescribed lessons, while the other group’s D&T lessons used a set of engineering design thinking tools which aim to foster students’ ability to think creatively and to engender empathy, while solving real-world problems.

Both sets of pupils were assessed for creativity at both the start and end of the school year using the Torrance Test of Creative Thinking: a well-established psychometric test.

The results showed a statistically significant increase in creativity among pupils at the intervention school, where the thinking tools were used. At the start of the year, the creativity scores of pupils in the control school, which followed the standard curriculum, were 11% higher than those at the intervention school. By the end, however, the situation had completely changed: creativity scores among the intervention group were 78% higher than the control group.

The researchers also examined specific categories within the Torrance Test that are indicative of emotional or cognitive empathy: such as ’emotional expressiveness’ and ‘open-mindedness’. Pupils from the intervention school again scored much higher in these categories, indicating that a marked improvement in empathy was driving the overall creativity scores.

The study’s authors suggest that encouraging empathy not only improves creativity, but can deepen pupils’ general engagement with learning. Notably, they found evidence that boys and girls in the intervention school responded to the D&T course in ways that defied traditional gender stereotypes. Boys showed a marked improvement in emotional expression, scoring 64% higher in that category at the end of the year than at the start, while girls improved more in terms of cognitive empathy, showing 62% more perspective-taking.

The research is part of a long-term collaboration between the Faculty of Education and the Department of Engineering at the University of Cambridge called ‘Designing Our Tomorrow’ (DOT), led by Bill Nicholl and Ian Hosking. It challenges pupils to solve real-world problems by thinking about the perspectives and feelings of others.

The particular challenge used in the study asked pupils at the intervention school to design an asthma-treatment ‘pack’ for children aged six and under. Pupils were given various creative and empathetic ‘tools’ in order to do so: for example, they were shown data about the number of childhood asthma fatalities in the UK, and a video which depicts a young child having an attack. They also explored the problem and tested their design ideas by role-playing various stakeholders, for example, patients, family-members, and medical staff.

Nicholl, Senior Lecturer in Design and Technology Education, who trains teachers studying on the University’s D&T PGCE course, said: “Teaching for empathy has been problematic despite being part of the D&T National Curriculum for over two decades. This evidence suggests that it is a missing link in the creative process, and vital if we want education to encourage the designers and engineers of tomorrow.”

Dr Helen Demetriou, an affiliated lecturer in psychology and education at the Faculty of Education with a particular interest in empathy, and the other researcher involved in the study, said: “We clearly awakened something in these pupils by encouraging them to think about the thoughts and feelings of others. The research shows not only that it is possible to teach empathy, but that by doing so we support the development of children’s creativity, and their wider learning.”

The gender differences charted in the study indicate that the intervention enabled students to overcome some of the barriers to learning that assumed gender roles often create. For example, boys often feel discouraged from expressing emotion at school, yet this was one of the main areas where they made significant creative gains according to the tests.

In addition to the Torrance Tests, the researchers conducted in-depth interviews with pupils at both the intervention school and a third (girls-only) school who also undertook the asthma challenge. This feedback again suggested that pupils had empathised deeply with the challenges faced by young asthma-sufferers, and that this had influenced their creative decisions in the classroom.

Many, for example, used phrases such as ‘stepping into their shoes’ or ‘seeing things from another point of view’ when discussing patients and their families. One boy told the researchers: “I think by the end of the project I could feel for the people with asthma… if I was a child taking inhalers, I would be scared too.”

Another responded: “Let’s say you had a sister or brother in that position. I would like to do something like this so we can help them.”

Overall, the authors suggest that these findings point to a need to nurture ’emotionally intelligent learners’ not only in D&T classes, but across subjects, particularly in the context of emerging, wider scientific evidence that our capacity for empathy declines as we get older.

“This is something that we must think about as curricula in general become increasingly exam-based,” Demetriou said. “Good grades matter, but for society to thrive, creative, communicative and empathic individuals matter too.”

Nicholl added: “When I taught Design and Technology, I didn’t see children as potential engineers who would one day contribute to the economy; they were people who needed to be ready to go into the world at 18. Teaching children to empathise is about building a society where we appreciate each other’s perspectives. Surely that is something we want education to do.”

The study is published in the journal, Improving Schools.

Teenagers With Better Childhoods Drink Less and Do Drugs Less

If we structured a system where there was less poverty and despair, more people would have better childhoods, and less people would end up with damaging drug addictions.

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Teenagers with happy childhood memories are likely to drink less, take fewer drugs and enjoy learning, according to research published in the peer-reviewed journal Addiction Research & Theory.

The findings, based on data from nearly 2,000 US high school students, show a link between how pupils feel about the past, present and future and their classroom behavior. This in turn influences their grades and risk of substance misuse, according to the study.

The authors say action is needed now because Covid-19 has left many teenagers struggling with online study, suffering mentally and turning to drink and drugs.

They are calling on teachers — and parents — to help students develop more positive mindsets and become motivated to learn so they are less likely to binge drink or use marijuana.

“School often seems a source of stress and anxiety to students,” says John Mark Froiland from Purdue University in Indiana, US.

“This puts them at greater risk of not participating in lessons, getting lower grades and of substance misuse.

“Many teenagers also aren’t engaging with online learning during Covid or have lower engagement levels.

“But they’re more likely to be enthusiastic learners and not use drink and drugs if teachers take time to build more positive relationships with them. They can help students see that everything they’re learning is truly valuable. Parents have a role to play too.”

Teenagers with a balanced attitude towards their childhoods and other time periods have already been shown by studies to be more likely to abstain from drink and drugs and achieve academically. This is compared to those with a pessimistic outlook.

The aim of this study was to establish how substance misuse and behaviors towards learning are affected by students’ feelings about the past, present and future.

The data was based on assessments and questionnaires completed by 1,961 students at a high school in the San Francisco Bay Area. More than half (53%) of the pupils included in the study were female.

The study authors looked at responses from pupils where they rated how nostalgic they were towards their childhood, current happiness levels in life and how much they look forward to future happiness.

They also analysed marijuana and alcohol habits over the past 30 days including binge drinking, and average academic grades. They analysed motivation levels, and behavior in lessons such as how much teenagers paid attention and listened.

Statistical techniques were used by the researchers to assess the associations between all these different factors and establish the key predictors for alcohol and marijuana misuse.

In general, the study found that positive attitudes towards the past, present and future put adolescents at lower risk for alcohol use, binge drinking, and marijuana.

The opposite was true for those displaying pessimistic or negative ways of thinking or feeling about their life in the past, now or ahead of them.

The reason for this was that a content and optimistic outlook increased the likelihood they would be motivated and behave in a focused way on the chance to learn.

Other findings include girls having stronger levels of behavioral engagement than boys, and students who drank being most likely to use cannabis.

Experimental Drug Quickly Reduces Age-Related Mental Decline

The compound, known as ISRIB, holds potential for reversing numerous cognitive problems in humans. Mice are used in scientific studies due to having genes that are approximately 85 percent similar to the genes of humans.

Just a few doses of an experimental drug can reverse age-related declines in memory and mental flexibility in mice, according to a new study by UC San Francisco scientists. The drug, called ISRIB, has already been shown in laboratory studies to restore memory function months after traumatic brain injury (TBI), reverse cognitive impairments in Down Syndrome, prevent noise-related hearing loss, fight certain types of prostate cancer, and even enhance cognition in healthy animals.

In the new study, published December 1, 2020 in the open-access journal eLife, researchers showed rapid restoration of youthful cognitive abilities in aged mice, accompanied by a rejuvenation of brain and immune cells that could help explain improvements in brain function.

“ISRIB’s extremely rapid effects show for the first time that a significant component of age-related cognitive losses may be caused by a kind of reversible physiological ‘blockage’ rather than more permanent degradation,” said Susanna Rosi, PhD, Lewis and Ruth Cozen Chair II and professor in the departments of Neurological Surgery and of Physical Therapy and Rehabilitation Science.

“The data suggest that the aged brain has not permanently lost essential cognitive capacities, as was commonly assumed, but rather that these cognitive resources are still there but have been somehow blocked, trapped by a vicious cycle of cellular stress,” added Peter Walter, PhD, a professor in the UCSF Department of Biochemistry and Biophysics and a Howard Hughes Medical Institute investigator. “Our work with ISRIB demonstrates a way to break that cycle and restore cognitive abilities that had become walled off over time.”

Could Rebooting Cellular Protein Production Hold the Key to Aging and Other Diseases?

Walter has won numerous scientific awards, including the Breakthrough, Lasker and Shaw prizes, for his decades-long studies of cellular stress responses. ISRIB, discovered in 2013 in Walter’s lab, works by rebooting cells’ protein production machinery after it gets throttled by one of these stress responses — a cellular quality control mechanism called the integrated stress response (ISR; ISRIB stands for ISR InhiBitor).

The ISR normally detects problems with protein production in a cell — a potential sign of viral infection or cancer-promoting gene mutations — and responds by putting the brakes on cell’s protein-synthesis machinery. This safety mechanism is critical for weeding out misbehaving cells, but if stuck in the on position in a tissue like the brain, it can lead to serious problems, as cells lose the ability to perform their normal activities, Walter and colleagues have found.

In particular, recent animal studies by Walter and Rosi, made possible by early philanthropic support from The Rogers Family Foundation, have implicated chronic ISR activation in the persistent cognitive and behavioral deficits seen in patients after TBI, by showing that, in mice, brief ISRIB treatment can reboot the ISR and restore normal brain function almost overnight.

The cognitive deficits in TBI patients are often likened to premature aging, which led Rosi and Walter to wonder if the ISR could also underlie purely age-related cognitive decline. Aging is well known to compromise cellular protein production across the body, as life’s many insults pile up and stressors like chronic inflammation wear away at cells, potentially leading to widespread activation of the ISR.

“We’ve seen how ISRIB restores cognition in animals with traumatic brain injury, which in many ways is like a sped-up version of age-related cognitive decline,” said Rosi, who is director of neurocognitive research in the UCSF Brain and Spinal Injury Center and a member of the UCSF Weill Institute for Neurosciences. “It may seem like a crazy idea, but asking whether the drug could reverse symptoms of aging itself was just a logical next step.”

ISRIB Improves Cognition, Boosts Neuron and Immune Cell Function

In the new study, researchers led by Rosi lab postdoc Karen Krukowski, PhD, trained aged animals to escape from a watery maze by finding a hidden platform, a task that is typically hard for older animals to learn. But animals who received small daily doses of ISRIB during the three-day training process were able to accomplish the task as well as youthful mice, much better than animals of the same age who didn’t receive the drug.

The researchers then tested how long this cognitive rejuvenation lasted and whether it could generalize to other cognitive skills. Several weeks after the initial ISRIB treatment, they trained the same mice to find their way out of a maze whose exit changed daily — a test of mental flexibility for aged mice who, like humans, tend to get increasingly stuck in their ways. The mice who had received brief ISRIB treatment three weeks before still performed at youthful levels, while untreated mice continued to struggle.

To understand how ISRIB might be improving brain function, the researchers studied the activity and anatomy of cells in the hippocampus, a brain region with a key role in learning and memory, just one day after giving animals a single dose of ISRIB. They found that common signatures of neuronal aging disappeared literally overnight: neurons’ electrical activity became more sprightly and responsive to stimulation, and cells showed more robust connectivity with cells around them while also showing an ability to form stable connections with one another usually only seen in younger mice.

The researchers are continuing to study exactly how the ISR disrupts cognition in aging and other conditions and to understand how long ISRIB’s cognitive benefits may last. Among other puzzles raised by the new findings is the discovery that ISRIB also alters the function of the immune system’s T cells, which also are prone to age-related dysfunction. The findings suggest another path by which the drug could be improving cognition in aged animals, and could have implications for diseases from Alzheimer’s to diabetes that have been linked to heightened inflammation caused by an aging immune system.

“This was very exciting to me because we know that aging has a profound and persistent effect on T cells and that these changes can affect brain function in the hippocampus,” said Rosi. “At the moment, this is just an interesting observation, but it gives us a very exciting set of biological puzzles to solve.

ISRIB May Have Wide-Ranging Implications for Neurological Disease

It turns out that chronic ISR activation and resulting blockage of cellular protein production may play a role in a surprisingly wide array of neurological conditions. Below is a partial list of these conditions, based on a recent review by Walter and colleague Mauro Costa-Mattioli of Baylor College of Medicine, which could potentially be treated with an ISR-resetting agent like ISRIB:

  • Frontotemporal Dementia
  • Alzheimer’s Disease
  • Amyotrophic Lateral Sclerosis (ALS)
  • Age-related Cognitive Decline
  • Multiple Sclerosis
  • Traumatic Brain Injury
  • Parkinson’s Disease
  • Down Syndrome
  • Vanishing White Matter Disorder
  • Prion Disease

ISRIB has been licensed by Calico, a South San Francisco, Calif. company exploring the biology of aging, and the idea of targeting the ISR to treat disease has been picked up by other pharmaceutical companies, Walter says.

One might think that interfering with the ISR, a critical cellular safety mechanism, would be sure to have serious side effects, but so far in all their studies, the researchers have observed none. This is likely due to two factors, Walter says. First, it takes just a few doses of ISRIB to reset unhealthy, chronic ISR activation back to a healthier state, after which it can still respond normally to problems in individual cells. Second, ISRIB has virtually no effect when applied to cells actively employing the ISR in its most powerful form — against an aggressive viral infection, for example.

Naturally, both of these factors make the molecule much less likely to have negative side effects — and more attractive as a potential therapeutic. According to Walter: “It almost seems too good to be true, but with ISRIB we seem to have hit a sweet spot for manipulating the ISR with an ideal therapeutic window.

Researchers Claim Oral Drug Blocks COVID-19 Transmission Within 24 Hours

This drug (MK-4482) is notable because it has the distinction of “MK,” as in, it was developed in part by the Merck pharmaceutical company. I’m one to often disparage the pharmaceutical companies but Merck has done notable things in its past drug research. The Merck development of MK-677 — an experimental growth hormone secretagogue that has been shown to increase hunger, increase bone density in the frail, and improve healing in humans — has shown significant potential in medicine. A former Head of the US Biomedical Advanced Research and Development Authority has said that drugs similar to MK-4482 cause birth defects, but the study authors claim that toxicity studies on MK-4482 have already been done, with the results already approved by regulators as a sign to continue with research into the drug in people.


Treatment of SARS-CoV-2 infection with a new antiviral drug, MK-4482/EIDD-2801 or Molnupiravir, completely suppresses virus transmission within 24 hours, researchers in the Institute for Biomedical Sciences at Georgia State University have discovered.

The group led by Dr. Richard Plemper, Distinguished University Professor at Georgia State, originally discovered that the drug is potent against influenza viruses.

“This is the first demonstration of an orally available drug to rapidly block SARS-CoV-2 transmission,” said Plemper. “MK-4482/EIDD-2801 could be game-changing.”

Interrupting widespread community transmission of SARS-CoV-2 until mass vaccination is available is paramount to managing COVID-19 and mitigating the catastrophic consequences of the pandemic.

Because the drug can be taken by mouth, treatment can be started early for a potentially three-fold benefit: inhibit patients’ progress to severe disease, shorten the infectious phase to ease the emotional and socioeconomic toll of prolonged patient isolation and rapidly silence local outbreaks.

“We noted early on that MK-4482/EIDD-2801 has broad-spectrum activity against respiratory RNA viruses and that treating infected animals by mouth with the drug lowers the amount of shed viral particles by several orders of magnitude, dramatically reducing transmission,” said Plemper. “These properties made MK-4482/EIDD/2801 a powerful candidate for pharmacologic control of COVID-19.”

In the study published in Nature Microbiology, Plemper’s team repurposed MK-4482/EIDD-2801 against SARS-CoV-2 and used a ferret model to test the effect of the drug on halting virus spread.

“We believe ferrets are a relevant transmission model because they readily spread SARS-CoV-2, but mostly do not develop severe disease, which closely resembles SARS-CoV-2 spread in young adults,” said Dr. Robert Cox, a postdoctoral fellow in the Plemper group and a co-lead author of the study.

The researchers infected ferrets with SARS-CoV-2 and initiated treatment with MK-4482/EIDD-2801 when the animals started to shed virus from the nose.

“When we co-housed those infected and then treated source animals with untreated contact ferrets in the same cage, none of the contacts became infected,” said Josef Wolf, a doctoral student in the Plemper lab and co-lead author of the study. By comparison, all contacts of source ferrets that had received placebo became infected.

If these ferret-based data translate to humans, COVID-19 patients treated with the drug could become non-infectious within 24 hours after the beginning of treatment.

MK-4482/EIDD-2801 is in advanced phase II/III clinical trials against SARS-CoV-2 infection.

Flavanols Found in Cocoa, Fruits and Vegetables Shown to Boost Cognition and Brain Oxygenation

This study shows the benefits of good nutrition.

The brains of healthy adults recovered faster from a mild vascular challenge and performed better on complex tests if the participants consumed cocoa flavanols beforehand, researchers report in the journal Scientific Reports. In the study, 14 of 18 participants saw these improvements after ingesting the flavanols.

Previous studies have shown that eating foods rich in flavanols can benefit vascular function, but this is the first to find a positive effect on brain vascular function and cognitive performance in young healthy adults, said Catarina Rendeiro, a researcher and lecturer in nutritional sciences at the University of Birmingham who led the research with University of Illinois at Urbana-Champaign psychology professors Monica Fabiani and Gabriele Gratton.

“Flavanols are small molecules found in many fruits and vegetables, and cocoa, too,” Rendeiro said. “They give fruits and vegetables their bright colors, and they are known to benefit vascular function. We wanted to know whether flavanols also benefit the brain vasculature, and whether that could have a positive impact on cognitive function.”

The team recruited adult nonsmokers with no known brain, heart, vascular or respiratory disease, reasoning that any effects seen in this population would provide robust evidence that dietary flavanols can improve brain function in healthy people.

The team tested the 18 participants before their intake of cocoa flavanols and in two separate trials, one in which the subjects received flavanol-rich cocoa and another during which they consumed processed cocoa with very low levels of flavanols. Neither the participants nor researchers knew which type of cocoa was consumed in each of the trials. This double-blind study design prevents researchers’ or participants’ expectations from affecting the results.

About two hours after consuming the cocoa, participants breathed air with 5% carbon dioxide — about 100 times the normal concentration in air. This is a standard method for challenging brain vasculature to determine how well it responds, Gratton said.

The body typically reacts by increasing blood flow to the brain, he said.

“This brings in more oxygen and also allows the brain to eliminate more carbon dioxide,” he said.

With functional near-infrared spectroscopy, a technique that uses light to capture changes in blood flow to the brain, the team measured oxygenation in the frontal cortex, a brain region that plays a key role in planning, regulating behavior and decision-making.

“This allows you to measure how well the brain defends itself from the excess carbon dioxide,” Fabiani said.

Researchers also challenged participants with complex tasks that required them to manage sometimes contradictory or competing demands.

Most of the participants had a stronger and faster brain oxygenation response after exposure to cocoa flavanols than they did at baseline or after consuming cocoa lacking flavanols, the researchers found.

“The levels of maximal oxygenation were more than three times higher in the high-flavanol cocoa versus the low-flavanol cocoa, and the oxygenation response was about one minute faster,” Rendeiro said.

After ingesting the cocoa flavanols, participants also performed better on the most challenging cognitive tests, correctly solving problems 11% faster than they did at baseline or when they consumed cocoa with reduced flavanols. There was no measurable difference in performance on the easier tasks, however.

“This suggests that flavanols might only be beneficial during cognitive tasks that are more challenging,” Rendeiro said.

Participants varied in their responses to cocoa flavanols, the researchers found.

“Although most people benefited from flavanol intake, there was a small group that did not,” Rendeiro said. Four of the 18 study subjects had no meaningful differences in brain oxygenation response after consuming flavanols, nor did their performance on the tests improve.

“Because these four participants already had the highest oxygenation responses at baseline, this may indicate that those who are already quite fit have little room for improvement,” Rendeiro said. “Overall, the findings suggest that the improvements in vascular activity after exposure to flavanols are connected to the improvement in cognitive function.”

App That Listens to Coughing Developed to Tell if People Have COVID-19

If this app works effectively, it will be very important in allowing people to group up more freely again.

As millions of people worldwide battle the symptoms of COVID-19, a group of “silent patients” may not even know they’re sick and spreading the virus. Asymptomatic people, by definition, have no physical symptoms of the illnesses they carry.

Researchers at the Massachusetts Institute of Technology (MIT) however, say they may be showing symptoms after all — in the sound of their cough. Their study has created an artificial intelligence program that can identify if someone has coronavirus by the way their coughing sounds. Researchers programmed their AI model with thousands of different recorded coughs from both healthy and sick volunteers. When they fed in recordings of new patients, the system accurately detected 98.5 percent of coughs coming from people with a confirmed case of COVID-19. AI also successfully picked out 100 percent of asymptomatic cases from volunteers who reported not having any symptoms but tested positive for the virus.

The team is now working on turning their model into a user-friendly app. If approved by the Food and Drug Administration, the app would give people a non-invasive and quick way to screen themselves during the pandemic daily.

“The effective implementation of this group diagnostic tool could diminish the spread of the pandemic if everyone uses it before going to a classroom, a factory, or a restaurant,” says co-author Brian Subirana in a university release.

The MIT team notes researchers have been working on audio-based medical screenings since before the coronavirus emergency began. Their group in particular originally created this AI model to screen for Alzheimer’s disease.

Although the degenerative neurological condition is mostly associated with memory loss, it also affects the muscles and vocal cords. With this knowledge, researchers trained a general machine-learning algorithm called ResNet50 to detect changes in vocal cord strength. Subirana taught the neural network using an audiobook collection with over 1,000 hours of speech files. The AI model could eventually tell the difference between similar worlds like “them” and “the” or “then.”

The system can also read the emotions of the speaker based on the tone of their voice. The team says this is a key in Alzheimer’s detection because patients tend to display more frustration when they try to get words out. The program learned to assess these moods and put them into categories including neutral, calm, happy, and sad.

Finally, the team turned to coughing. Using recordings of patients coughing, the AI model could analyze the lung and respiratory performance of the cougher. An algorithm to detect muscular degradation was also added to help AI distinguish strong coughs from weaker ones.

With all of this data, study authors discovered that the technology could effectively screen for Alzheimer’s based on a patient’s vocal cord strength, sentiment, lung performance, and muscular degradation.

Once the pandemic began, the team at MIT changed gears and started looking at their model to see if it could detect COVID. Researchers say there is growing evidence coronavirus patients also suffer from neurological symptoms and temporary muscular impairment.

“The sounds of talking and coughing are both influenced by the vocal cords and surrounding organs. This means that when you talk, part of your talking is like coughing, and vice versa. It also means that things we easily derive from fluent speech, AI can pick up simply from coughs, including things like the person’s gender, mother tongue, or even emotional state. There’s in fact sentiment embedded in how you cough,” Subirana explains. “So we thought, why don’t we try these Alzheimer’s biomarkers [to see if they’re relevant] for COVID.”

The team created a website to collect audio samples from volunteers, including many with coronavirus. From nearly 200,000 forced-cough audio samples, the group was able to find 2,500 recordings that came from confirmed COVID-19 patients. Many of these patients were also asymptomatic. After adding more random samples to act as a control, the team chose 4,000 coughing samples to train their AI model to screen for the virus.

Along with amazing accuracy in detecting coronavirus patients, researchers say the tests reveal “a striking similarity between Alzheimer’s and COVID discrimination.” They add that the same four biomarkers for detecting Alzheimer’s effectively screen out the virus as well.

“We think this shows that the way you produce sound, changes when you have Covid, even if you’re asymptomatic,” the research scientist in MIT’s Auto-ID Laboratory adds.

Subirana and his team stress that their AI system is not meant to diagnose what illness you may have; whether it be the flu, asthma, or COVID-19. The tool, instead, works by screening out who is healthy from who is asymptomatic but carrying an illness.

The MIT team is now partnering with several hospitals to collect more coughing samples to refine the system’s accuracy. Their hope is to introduce a free pre-screening app to the public which can cut down on clinical testing delays.

“Pandemics could be a thing of the past if pre-screening tools are always on in the background and constantly improved,” the study authors contend.

The study appears in the IEEE Journal of Engineering in Medicine and Biology.

Hangover Cure Found by Finland Researchers

This seems to be the most legitimate research done on a compound (amino acid L-cysteine) that will remove symptoms of an alcohol-induced hangover. The consumption of alcohol weakens the immune system and therefore might be something people might not want to have during a global pandemic, but if people do choose to consume alcohol, L-cysteine is relatively cheap to buy and (unlike many other remedies) has clinical data to support its efficacy.

Hangover Cure Successfully Tested on Drunk Subjects in Finland

A dose of 1,200 milligrams of amino acid L-cysteine was found to reduce alcohol-related nausea and headache, while a dose of 600 milligrams helped alleviate stress and anxiety, according to a study published in the journal Alcohol and Alcoholism by researchers at the University of Helsinki and the University of Eastern Finland.

The randomized, double-blind study had 19 healthy male volunteers consuming alcohol doses of 1.5 grams per kilogram over three hours in a controlled setting. The subjects were then asked to swallow placebo or L-cysteine tablets containing vitamin supplements.

Researchers say that as well as reducing or even eliminating hangovers entirely, L-cysteine also helps “reduce the need of drinking the next day,” thereby cutting the risk of alcohol addiction.

Binge drinking is common in Finland, with more than half a million Finns considered at risk from excessive drinking.

The researchers received funding from Catapult Cat Oy, which sells the L-cysteine supplements.

The study ran into certain difficulties. Some participants weren’t able to consume all the alcohol required and had to be excluded, some had such high tolerance levels that they experienced no hangover symptoms; and some were sidelined because they insisted on topping up the dose by heading for the bar, researcher Markus Metsala told local media.

Study: Honeybee Venom Contains a Chemical (Melittin) That Kills Breast Cancer Cells

A very real study out of Australia’s Harry Perkins Institute of Medical Research once again confirms that there are ways animal venom is applicable for medicine. This finding about honeybee venom is obviously significant since breast cancer is the most common cancer among women.

A groundbreaking discovery in Australia is giving new meaning to the term natural remedy. Using hundreds of honeybees, a new study reveals the venom in these insects’ stingers quickly kills breast cancer cells.

Dr. Ciara Duffy says honeybee venom destroys multiple types of breast cancer, even the hard to treat triple-negative variety. Her study in the journal npj Precision Oncology finds the venom not only eradicates these cancers, it also breaks up a cancerous cell’s ability to reproduce. It also contains a compound called melittin which researchers say helps this natural remedy stop the disease with remarkable speed.

“The venom was extremely potent,” the researcher from the Harry Perkins Institute of Medical Research says in a media release. “We found that melittin can completely destroy cancer cell membranes within 60 minutes.”

In just 20 minutes, melittin breaks down the chemical messages breast cancer cells transmits to trigger both cell growth and cell division. The compound suppresses the receptors that commonly overexpress themselves in triple-negative breast cancer and HER2-enriched breast cancer.

Venom was also tested against hormone receptor positive breast cancer cells and normal breast cells. With a specifically concentrated dose of the venom, researchers are able to kill 100 percent of cancer cells. At the same time, the study finds bee venom does little harm to normal cells.

“This study demonstrates how melittin interferes with signaling pathways within breast cancer cells to reduce cell replication. It provides another wonderful example of where compounds in nature can be used to treat human diseases,” Professor Peter Klinkenhe from the University of Western Australia says.

Do all bees carry this special venom?

Although there are around 20,000 different species of bees, the study finds not every insect can fight cancer. Dr. Duffy’s tests on 312 honeybees and bumblebees from Perth, Western Australia reveal bumblebee venom does not induce cancer cell death. Honeybees from other regions however, share this special ability to rapidly stop the disease.

“I found that the European honeybee in Australia, Ireland and England produced almost identical effects in breast cancer compared to normal cells,” Duffy reports.

Researchers add Perth bees are some of the healthiest members of their species. While the study dissects live bee stingers to extract melittin, it finds this compound can be successfully reproduced in labs.

“The synthetic product mirrored the majority of the anti-cancer effects of honeybee venom,” the Australian scientist adds.

Adding honeybee venom to chemotherapy treatments

Study authors say melittin can also help current cancer treatments like chemotherapy. The report discovers melittin also forms numerous pores (tiny holes) in the breast cancer cell membrane. Duffy suspects other cancer drugs may be able to use these openings to penetrate the cells and kill the disease.

“We found that melittin can be used with small molecules or chemotherapies, such as docetaxel, to treat highly-aggressive types of breast cancer. The combination of melittin and docetaxel was extremely efficient in reducing tumor growth in mice.”

Using bee venom as a medical remedy has been studied since the 1950’s, but Duffy’s team says it’s only been considered as treatment for cancer during the last two decades. More research needs to be done to find out what kind of a dose human patients will require.

Scientist’s Plasma Shot That Could Prevent COVID-19 Isn’t Being Considered by The Government

That the use of plasma (shown effective in many other cases) isn’t being considered is another inefficiency by the (U.S. at least) governmental response to the coronavirus pandemic.

It might be the next best thing to a coronavirus vaccine.

Scientists have devised a way to use the antibody-rich blood plasma of COVID-19 survivors for an upper-arm injection that they say could inoculate people against the virus for months.

Using technology that’s been proven effective in preventing other diseases such as hepatitis A, the injections would be administered to high-risk healthcare workers, nursing home patients, or even at public drive-through sites — potentially protecting millions of lives, the doctors and other experts say.

The two scientists who spearheaded the proposal — an 83-year-old shingles researcher and his counterpart, an HIV gene therapy expert — have garnered widespread support from leading blood and immunology specialists, including those at the center of the nation’s COVID-19 plasma research.

But the idea exists only on paper. Federal officials have twice rejected requests to discuss the proposal, and pharmaceutical companies — even acknowledging the likely efficacy of the plan — have declined to design or manufacture the shots, according to a Times investigation. The lack of interest in launching development of immunity shots comes amid heightened scrutiny of the federal government’s sluggish pandemic response.

There is little disagreement that the idea holds promise; the dispute is over the timing. Federal health officials and industry groups say the development of plasma-based therapies should focus on treating people who are already sick, not on preventing infections in those who are still healthy.

Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health, said an upper-arm injection that would function like a vaccine “is a very attractive concept.”

However, he said, scientists should first demonstrate that the coronavirus antibodies that are currently delivered to patients intravenously in hospital wards across the country actually work. “Once you show the efficacy, then the obvious next step is to convert it into an intramuscular” shot.

But scientists who question the delay argue that the immunity shots are easy to scale up and should enter clinical trials immediately. They say that until there’s a vaccine, the shots offer the only plausible method for preventing potentially millions of infections at a critical moment in the pandemic.

“Beyond being a lost opportunity, this is a real head-scratcher,” said Dr. Michael Joyner, a Mayo Clinic researcher who leads a program sponsored by the Food and Drug Administration to capitalize on coronavirus antibodies from COVID-19 survivors. “It seems obvious.”

The use of so-called convalescent plasma has already become widespread. More than 28,000 patients have already received the IV treatment, and preliminary data suggest that the method is safe. Researchers are also looking at whether the IV drip products would prevent new infections from taking root.

The antibodies in plasma can be concentrated and delivered to patients through a type of drug called immune globulin, or IG, which can be given through either an IV drip or a shot. IG shots have for decades been used to prevent an array of diseases; the IG shot that prevents hepatitis A was first licensed in 1944. They are available to treat patients who have recently been exposed to hepatitis B, tetanus, varicella and rabies.

[…]

The proposal for an injection approach to coronavirus prevention came from an immunization researcher who drew his inspiration from history.

Dr. Michael Oxman knew that, even during the 1918 flu pandemic, the blood of recovered patients appeared to help treat others. Since then, convalescent plasma has been used to fight measles and severe acute respiratory syndrome, or SARS, among other diseases.

Like other doctors, Oxman surmised that, for a limited time, the blood coursing through the veins of coronavirus survivors probably contains immune-rich antibodies that could prevent — or help treat — an infection.

[…]

Throughout May, researchers and doctors at Yale, Harvard, Johns Hopkins, Duke and four University of California schools sent a barrage of letters to dozens of lawmakers. They held virtual meetings with health policy directors on Capitol Hill, but say they have heard no follow-up to date.

Dr. Arturo Casadevall, the chair of the National COVID-19 Convalescent Plasma Project, said he spoke to FDA officials who told him they do not instruct companies on what to produce. Casadevall told The Times that the leaders of the national project were “very supportive of the need to develop” an IG shot rapidly and that he believed it would be “very helpful in stemming the epidemic.”

Joyner, of the Mayo Clinic, said there are probably 10 million to 20 million people in the U.S. carrying coronavirus antibodies — and the number keeps climbing. If just 2% of them were to donate a standard 800 milliliters of plasma on three separate occasions, their plasma alone could generate millions of IG shots for high-risk Americans.

“At a hot-spot meatpacking plant, or at a mobile unit in the parking lot outside a mall — trust me, you can get the plasma,” Joyner said. “This is not a biological problem nor a technology problem. It’s a back-of-the-envelope intelligence problem.”

The antibody injections, for now, do not appear to be a high priority for the government or the industry.

Grifols, on April 28 — the same day that the U.S. topped 1 million confirmed coronavirus cases — made a major product announcement that would “expand its leadership in disease treatment with immunoglobulins.”

The product was a new vial for IG shots — to treat rabies.

How Air Pollution Can Harm Brain Health

It has long been rather stunning to me how careless many people are about air pollution. One of the most important things that people shouldn’t do is drive with their windows down in areas with significant traffic (and thus significant amounts of air pollution from vehicles). The motive for caring is rather simple — air pollution’s negative impact on brain health means possibly reduced performance on a variety of tasks, and that can negatively correlate with achieving life goals, which in turn is detrimental to human happiness and satisfaction.

Long thought to primarily harm the lungs and cardiovascular system, air pollution is now catching the attention of neuroscientists and toxicologists.

The buzz of a leaf blower and its gaseous fumes fill the air outside a lab facility at the University of Washington in Seattle. Inside the building, neurotoxicologist Lucio Costa is investigating how polluted air—such as garden tool exhaust—could be bad for the brain.

Next to the building sits a 5,500-watt diesel generator, enclosed in a metal box. Pipes carry the diesel exhaust—the same stuff emitted by diesel engines in vehicles and heavy equipment—into the facility, across an exposed ceiling and into a room where plastic cages of mice are stacked high against the wall. Tubes filter the diesel exhaust through the cages, Costa explains, in an effort to mimic the contaminated air you might breathe while sitting in traffic or living near a busy road.

After spending most of his career studying mercury, pesticides, and flame retardants, Costa knows well that many toxins in the environment can hurt the brain. But only in the last several years has the possibility of air pollution as a culprit crossed his mind. A growing body of literature on the topic inspired him to begin research in this diesel lab. “For a long time, I thought that air pollution was affecting mostly the lungs and the cardiovascular system and not the brain,” says Costa. “So I stayed away from any issue related to air pollution.”

Now, mounting evidence seems to link a variety of neurological problems to dirty air. Troubling recent findings include hallmarks of Alzheimer’s disease found in the brains of children living in Mexico City (1) and a nearly doubled risk of dementias for older women in highly polluted parts of the United States (2). Costa’s own research has identified autism-like social and behavioral issues in mice exposed to diesel exhaust (3). Today, Costa is among a growing cadre of biologists, toxicologists, and doctors raising the alarm over this pervasive yet overlooked menace to our memory, attention, and behavior.

A Global Threat

Although the coronavirus disease 2019 (COVID-19) pandemic and associated “shelter in place” policies have reduced fossil fuel use to offer a temporary respite from extreme pollution in some places, most countries face an ongoing epidemic of dirty air as a result of growing urban congestion and an uptick in climate-driven wildfires, among other factors. Indoor air pollution further plagues many of the world’s poorest communities. Around 3 billion people cook indoors over open fires or stoves fueled by wood, biomass, kerosene, or coal. In 2018, the World Health Organization (WHO) identified air pollution as the second-largest risk factor for noncommunicable disease worldwide. And the WHO’s stats don’t include the full range of neurological effects now being discovered, notes neurotoxicologist Deborah Cory-Slechta at the University of Rochester in New York.

Globally, more than 90 percent of people breathe air that fails to meet WHO standards. That includes an estimated four in 10 people in the United States, although efforts such as the US Clean Air Act and its amendments of 1990 have helped. Between 2000 and 2016, the average concentration of particulate matter (PM) with a diameter of less than 2.5 micrometers (PM2.5), tiny particles produced by combustion, fell by around 40 percent in the United States. But the country’s overall air quality has worsened since 2016. Partly to blame is a rise in wildfire smoke, which is now responsible for an estimated 40 percent of particulate matter pollution.

Yet cleaner, healthier air remains achievable, notes Dean Schraufnagel, a pulmonologist at the University of Illinois at Chicago. “There are no death certificates that say air pollution exposure,” he says. “But we know that air pollution affects every organ in the body. If we stop the air pollution at its source, we can get strikingly important health benefits.”

Schraufnagel, also the director of the Forum of International Respiratory Societies, points to one easy target: idling diesel-powered school buses. A 2019 study out of Georgia in the United States found that districts that retrofitted school buses to reduce diesel emissions reported significant increases in students’ English test scores as well as smaller improvements in math (4).

The havoc air pollution can wreak on the brain is also a new area of interest for Schraufnagel, whose research and clinical practice has long focused on lung disease. Today, he is working with international organizations to get air pollution on the minds of not just pulmonologists but also neurologists and other medical experts. “This should be a call to action,” adds Schraufnagel.

Air pollution is a cocktail of suspended gases, solids, and liquid particles. While this mix contains numerous hazardous ingredients, such as ozone, sulfur dioxide, and carbon monoxide, the component that appears most concerning for the brain is PM.

The US Environmental Protection Agency (EPA) regulates PM10 and PM2.5, defined as particles less than 10 and 2.5 micrometers in diameter, respectively. PM2.5, also known as fine particulate matter, generally comes from smoke, dust, and vehicle exhaust. Because PM2.5 is so tiny—30 times smaller than the width of the average human hair—it can remain airborne for long periods of time, infiltrate buildings, and penetrate the body. Ultrafine particles, which measure less than 0.1 micrometer across, may be even worse offenders. Yet the miniscule mass of these particles makes them difficult to monitor. They remain unregulated by the EPA.

Fine and ultrafine particulate matter tends to circumvent the mechanisms that the human body has evolved to deflect, detain, and destroy unwelcome visitors. “The health effects of air pollution are all about particle size,” says Cory-Slechta. Studies suggest that these tiny particles can even go up the nose and be carried straight to the brain via the olfactory nerve (5)—hence bypassing the blood–brain barrier. And they don’t travel alone. On their surfaces these particles carry contaminants, from dioxins and other chemical compounds to metals such as iron and lead. “PM is simply acting as a vector,” says Masashi Kitazawa, a molecular neuropathologist at the University of California, Irvine. “It might be a number of chemicals that get into the brain and act in different ways to cause damage.”

Because of their large surface area relative to their volume, the smallest particles are the biggest offenders. Cory-Slechta’s research has largely focused on lead and mercury, neurotoxic metals that are abundant in air pollution. “Ultrafine particles are like little Trojan horses,” she says. “Pretty much every metal known to humans is on these.”

Metal-toting particles that reach the brain can directly damage neurons. Both the particles themselves and their toxic hitchhikers can also cause widespread harm by dysregulating the activation of microglia, the immune cells in the brain. Microglia may mistake the intruders for pathogens, releasing chemicals to try to kill them. Those chemicals can accumulate and trigger inflammation. And chronic inflammation in the brain has been implicated in neurodegeneration (6).

Particles may also afflict the brain via the bloodstream. Research shows that small particles can slip through the plasma membrane of alveoli—the tiny air sacs in the lungs—and get picked up by capillaries. The particles are then distributed around the body in the blood. Although some of these particles may eventually breach the blood–brain barrier, a pollutant need not enter the brain to cause trouble there. The immune system can react to particles in the lung or bloodstream, too, triggering widespread inflammation that affects the brain.

Even an ingested particle could have indirect neurological effects, via the gut. Researchers now recognize strong connections between the gut microbiome and the brain (7), and studies show that delivering fine particles to the gut can cause systemic inflammation (8).

In January 2010, Cory-Slechta received a surprising request from some University of Rochester environmental medicine colleagues. Typically, the group researched the effects of air pollution on the lungs and hearts of adult animals. But they had just exposed a group of newborn mice and asked Cory-Slechta’s team to look at the brains.

At first she didn’t think much of the request. Cory-Slechta was much more concerned about deadly lead exposure in children, her research focus at the time. “I didn’t think of air pollution as a big problem for the brain,” she says. Then she examined the animals’ tissue. “It was eye-opening. I couldn’t find a brain region that didn’t have some kind of inflammation.”

Her team followed up with their own studies. In addition to inflammation, they saw classic behavioral and biochemical features of autism, attention-deficit disorder, and schizophrenia in mice exposed to pollutants during the first days after birth. The mouse brains had noticeably less white matter, particularly in the corpus callosum connecting the right and left cerebral hemispheres. In work published last November, Cory-Slechta’s group further linked short-term exposures to air pollution with impaired learning and memory in aged mice, based on measures of spontaneous movement, navigation of a maze, short-term object recognition, and the ability to discriminate odors (9). The concentrations of particulate matter used, she notes, “easily include sitting in traffic in major cities.”

[…]

Research in Ontario, Canada, found that living farther away from a major road lowered the risk of developing dementia (13). A study of nearly 3,000 Barcelona schoolchildren found that those attending schools with more traffic pollution had slower cognitive development (14). And in the United States, a study found that living in locations where ambient particulate matter exceeded EPA recommendations nearly doubled women’s risk of developing dementia. When those researchers looked specifically at older women with two copies of the APOE4 gene variant, a strong genetic factor for Alzheimer’s disease, the dementia risk associated with living in those locations jumped almost threefold (2).