Brain

Whether they are synthetic materials such as PET and Teflon, medicines or flavourings, life without synthetically produced compounds is barely conceivable in our everyday lives today. The chemical industry depends on efficient, long-term methods of producing synthetically derived molecules. For this purpose, chemists often use catalysts, i.e. additives with which they can facilitate and control chemical reactions. But how are such reactions discovered and developed?

A high degree of knowledge and understanding are required - but, not infrequently, chance also plays a decisive role. A team of chemists at the University of Münster (Germany) have developed a strategy for generating such "random hits" in a systematic way, with the aim of discovering new, unexpected reactions. The study has been published in the Chem journal.

Background and method:

The process of systematically conducting a large number of experiments is called 'screening' and is established practice in particular in pharmaceutical research relating to active ingredients. The screening method developed in Münster for discovering reactions combines two steps which cover a variety of individual elements in a reaction and which, in combination, are designed to discover new, synthetically relevant reactions. In the first step, chemists examine whether a potential substrate actually interacts at all with the catalyst. For this purpose, in the case of photo-catalysts, the phenomenon of emission quenching is used. If a substrate reduces the emission of the catalyst, an interaction between catalyst and substrate is likely. By systematically screening a large number of randomly selected compounds, new molecules can be identified whose interaction with catalysts was previously unknown.

The interaction between substrate and catalyst does not by itself create a reaction, however. For this reason, the second stage of the screening process involves examining whether a reaction does actually take place when a reaction partner and the catalyst are present. This means that for the first time, as a result of combining two screening steps, both partners in a new reaction can be identified which react to form a new product. "This two-dimensional strategy enables us not only to find new catalyst-substrate interactions, but also to actually discover new reactions - including some we hadn't previously expected," explains Prof. Frank Glorius from the Institute of Organic Chemistry at Münster University.

Discovering unexpected reactivity

The study shows that the authors were able to discover and further develop three previously unknown reactions. One of these reactions is a so-called photochemical cycloaddition, in which simple, flat molecules - benzothiophenes - are transferred to complex three-dimensional structures. "As formulated on paper, I would not have considered this reaction to be possible," says Felix Strieth-Kalthoff, a PhD student and lead author of the study, "because, from an energetic point of view, the key step in this reaction shouldn't actually be possible."

To investigate this in more detail, the Münster chemists contacted Prof. Dirk Guldi at the University of Erlangen, who is considered to be the world's leading expert on investigations into photochemical processes. Working with colleagues from the Leibniz Institute of Surface Engineering in Leipzig, the team was able to throw light on the matter by carrying out measurements in the form of ultrafast spectroscopy. The chemists used ultrashort laser pulses in order to systematically observe and investigate the individual steps in the reaction. "We're now able to provide much better explanations for the underlying molecular processes in the triplet-triplet energy transfer - the key activation step," says Dirk Guldi. "This greater understanding will allow the development of new processes and catalysts," he adds.

This example shows that the results of such a screening approach not only deliver new reactions but can also, in addition, contribute to a deeper understanding of the subject. "We are convinced that this strategy can be used in other areas of catalysis - and beyond," says Frank Glorius.

Using, among other things, the latest computer technologies, the team of researchers is already working all out on the development of new screening methods for discovering and understanding new classes of reactions. There is one thing Frank Glorius is certain of: "I believe that the discovery of new types of reactions resulting from data-based strategies, such as these screening methods are, will make a decisive difference to the development of synthetic chemistry."

(Boston)--"Integrating the Educators," a pilot internship program at Boston University School of Medicine (BUSM), is successful in training biomedical science trainees (graduate students/PhD and postdocs) in the skills of being a medical educator.

In medical education, there is an ongoing push for greater integration of the basic and clinical sciences content. Current basic science PhD training programs rarely prepare trainees for this new educational environment. "Our program addressed this gap by providing participants with experiences to augment their scientific training," explained corresponding author Ann Zumwalt, PhD, associate professor of anatomy & neurobiology at BUSM and co-director of the program.

According to the authors, the novelty of the program is that it provides a combination of experiences. For example, the postdoctoral trainees (a biochemist and a cancer biologist) participated in a course on effective teaching with basic science educators, and also shadowed clinician educators to observe methods of clinical teaching. In addition to the benefits to the trainees, this initiative provided opportunities for clinicians to work together with basic scientists.

Data from this pilot program showed that trainees had increased knowledge about teaching despite differences in their previous teaching experience as well as modifications to their lesson plans demonstrating that they gained insights into how to teach basic science topics to a clinical audience.

The authors believe this internship is important in the context of career exploration because it provides the opportunity for PhD trainees to explore medical education as a potential career path. "There are many career opportunities for trainees in the biomedical sciences, but frequently trainees are not aware of all of their options besides the typical paths of either research in academia or working in industry. Our internship highlights other potential career options as well as provides skills to be successful as educators," said co-author Isabel Dominguez, PhD, assistant professor of medicine at BUSM and co-director of the program.

Babies born after being exposed to both opioids and benzodiazepines before birth are more likely to have severe drug withdrawal, requiring medications like morphine for treatment, compared to infants exposed to opioids alone, according to a Vanderbilt University Medical Center study published in Hospital Pediatrics.

Benzodiazepines are a class of psychoactive drugs, including Xanax and Ativan, commonly prescribed for anxiety and other conditions.

The new findings shed light on which factors complicate and intensify signs of neonatal abstinence syndrome (NAS), which can occur when babies are chronically exposed to opioids before birth. People with substance use disorders often report taking a combination of substances. For example, many people report use of opioids as well as alcohol, benzodiazepines, and other prescribed or non-prescribed substances.

The study shows concurrent benzodiazepine exposure impacts the severity of NAS more so than other legal or illicit substances, said Lauren Sanlorenzo, MD, MPH, assistant professor of Pediatrics, neonatologist at Monroe Carell Jr. Children's Hospital at Vanderbilt and first author of the study.

Infants with NAS and exposed to benzodiazepines were more than 50% likelier to require the use of medications to treat symptoms than infants not exposed.

"Our findings reflect the reality that many women who use opioids also use benzodiazepines, which now we know has real implications for the baby, who is more likely to have severe incidence of disease. If we focus just on opioids, we can overlook other medications that can be risky to both the mother and infant," said Sanlorenzo.

Researchers conducted a statewide analysis of medical records from 112,029 mother and baby pairs who were covered under Tennessee's Medicaid program, TennCare, from 2009 to 2011. There were 822 confirmed cases of NAS, of which 72.7% required pharmacological treatment.

The disease severity link to benzodiazepines is important for all providers who treat and care for women before and during pregnancy as well as those who deliver and treat babies. For pregnant women, taking a benzodiazepine like Xanax along with an opioid can increase risk of an overdose.

Researchers used a combination of data, filled prescriptions, medical history and toxicology testing to gather information about both legal and illegal substances used. While the researchers found that benzodiazepine use increased NAS severity, other substances, including marijuana, cocaine, methamphetamines, tobacco and antidepressants, did not increase the syndrome's severity.

Vanderbilt Center for Child Health Policy researchers have shown previously that one consequence of the nation's opioid crisis has been a sharp increase in the number of newborns who show signs of withdrawal from opioids. From 2000 to 2014, the rate of NAS rose from 1.2 cases per 1,000 hospital births to 8 cases per 1,000 births. In 2014, the average was one infant born every 15 minutes in the U.S. with NAS.

"Even though benzodiazepines are often left out of the conversation about substance use, the number of prescriptions written for benzodiazepines has tripled in the U.S. in recent years. Long-term use of benzodiazepines, which are designed for short-term treatment of anxiety, with an opioid in pregnancy can be risky for moms and babies. Reducing the use of this particular combination may be beneficial to mothers and may reduce risk of severe withdrawal in infants," said Stephen Patrick, MD, MPH, MS, director of the Vanderbilt Center for Child Health Policy and senior author of the paper.

More than 60 years ago, British physician Denis Parsons Burkitt and his associates achieved one of the signal successes in cancer medicine when they cured children in sub-Saharan Africa with a form of lymphoma by treating them with high doses of the chemotherapy drug cyclophosphamide. Now, Dana-Farber Cancer Institute researchers have shown that the traditional understanding of the drug's mode of action is incomplete.

In a paper in today's issue of the journal Cancer Discovery, the researchers demonstrate that large doses of cyclophosphamide not only kill cancer cells directly, as has been known, but also spur an immune system attack on the cells. The discovery resolves long-standing questions about how cyclophosphamide and other alkylating agents - among the oldest and most widely used types of chemotherapy - work, and suggests a novel way of sparking an immune system strike on certain cancers.

"Our results show that, at high doses, cyclophosphamide and other alkylating agents blur the line between chemotherapy and immunotherapy," said Dana-Farber's David Weinstock, MD, the senior author of the study. "These findings offer insights into how to switch on key immune system cells to augment existing therapies."

Cyclophosphamide was just the eighth anti-cancer drug to enter standard therapy when it was approved by the U.S. Food and Drug Administration in 1954. It became a mainstay of cancer treatment after Burkitt and others used high doses to cure children with what's now known as Burkitt lymphoma - which had a 100% mortality rate at the time - sometimes with only one dose. Cyclophosphamide and other alkylating agents are now used at lower doses to treat many types of cancer, including breast, ovarian, and pediatric cancers.

Alkylating agents work by attaching chemical components called alkyl groups to cancer cells' DNA, leading to breaks in the DNA molecule. The damage undermines the cells' ability to duplicate their DNA and, ultimately, to divide.

Over the years, clues emerged that there's more to the drugs' effectiveness than damaging DNA. Researchers discovered, for example, that while high doses are much more effective against certain cancers than low doses, they inflict about the same amount of DNA damage, suggesting that something else comes into play at high doses. Sporadic data pointed to the immune system.

Another clue came from pathology studies of Burkitt lymphoma tissue. "Burkitt lymphoma and other high-grade lymphomas with rearrangements in the MYC gene have a 'starry sky' appearance under the microscope, with large numbers of macrophages [a type of immune system cell] dispersed among the lymphoma cells," Weinstock remarked.

In the new study, investigators focused on the effect of high doses of cyclophosphamide on macrophages - cells that, under the right conditions, eat infected cells or cells in the process of dying. In mouse models implanted with human lymphoma tissue, the researchers showed that high doses of the drug, but not normal doses, damaged tumor cells in a way that severely stressed the lymphoma cells. The stressed cells responded by secreting cytokines, substances that summon macrophages to eat the tumor cells.

The researchers analyzed thousands of these macrophages to determine which genes were active, or expressed, in each of them. They found that one subset, which expresses the proteins CD36 and FcgRIV, has a particularly voracious appetite for stressed lymphoma cells. Dubbed "super-macrophages," they devour lymphoma cells, Weinstock said.

Although high doses of cyclophosphamide and other alkylating agents may be too toxic for patients with diseases other than Burkitt lymphoma, researchers are investigating agents that mimic their ability to stress cancer cells, but with milder side effects.

The findings may be especially relevant for the treatment of "double-hit" lymphomas, which are marked by their aggressiveness and for a rearrangement in the MYC gene, Weinstock observed. Targeted therapies are currently lacking for this disease, which accounts for six to 10% of diffuse large B cell lymphomas and generally has poor outcomes for patients.

(Oslo, Sunday, 30 June, 2019) Stress of surviving the Holocaust has shown a lifelong and lasting negative impact on survivors' brain structure, as well as potentially impacting their offspring and grandchildren, a new study shows.

The novel research, presented today at the 5th European Academy of Neurology Congress, found that surviving the Holocaust had a life-long psychological and biological effect with grey matter reduction affecting the parts of their brain responsible for stress response, memory, motivation, emotion, learning, and behaviour.

Utilising MRI scanning, the study looked at the brain function of 56 people with an average age of 79-80, comparing 28 Holocaust survivors with 28 controls who do not have a personal or family history of the Holocaust. Survivors showed a significantly decreased volume of grey matter in the brain compared with controls of a similar age who had not been directly exposed via personal or family history to the Holocaust.

The study differentiated between survivors above and below the age of 12 years in 1945 and found that the reduction in grey matter was significantly more expressed in younger survivors, which may be attributed to the higher vulnerability to a stressful environment of the developing brain in childhood. In line with previous research, the study found a reduction of grey matter in areas of the brain associated with post-traumatic stress disorder (PTSD) in combat veterans and those suffering early-life stress experience. However, the research also showed that reductions in grey matter in other areas of the brain went far beyond what had previously been found in those suffering PTSD; with survivors suffering a higher level of stress but also higher levels of post-traumatic growth. Despite having suffered extreme stress the survivors reported that they were satisfied with their personal and professional life after the war.

The researchers are now investigating the impact of the Holocaust on survivors' children and grandchildren, and early results in survivors' children show reduced connectivity between structures of the brain involved in the processing of emotion and memory. Further research is set to identify biomarkers of stress resilience and post-traumatic growth and to determine whether transmission to offspring is based on behavioural and psychological factors or on genetic factors.

Commenting on their research findings, Professor Ivan Rektor, a neurologist from Brno, Czech Republic, explained, "After more than 70 years the impact of surviving the Holocaust on brain function is significant. We revealed substantial differences in the brain structures involved in the processing of emotion, memory and social cognition, in higher level of stress but also of post-traumatic growth between Holocaust survivors and controls. Early results show this is also the case in children of survivors too."

"Our hope is that these findings and our ongoing research will allow us to understand more about the effect of these experiences in order to focus therapy to support survivors' and their descendants' resilience and growth. We may also reveal strategies that Holocaust survivors used to cope with trauma during their later lives and to pass on their experience to further generations", added Professor Rektor.

We've all done it, offered an excuse for our poor behaviour or rude reactions to others in the heat of the moment, after a long commute or a tough day with the kids. Excuses are commonplace, an attempt to explain and justify behaviours we aren't proud of, to escape the consequences of our acts and make our undesirable behaviour more socially acceptable.

The things we appeal to when making excuses are myriad: tiredness, stress, a looming work dead-line, a wailing infant, poverty, a migraine, ignorance. But what do these various excuses have in common that allows us to recognize them all as plausible? Do they differ from the excuses used in criminal law, like duress or coercion? And what does having an excuse get us - does it really exon-erate us?

A researcher from Cambridge University has suggested that the answers lie in what they all tell us about our underlying motivation. When excuses are permissible, it's because they show that while we acted wrongly, our underlying moral intentions were adequate.

Intentions are plans for action. To say that your intention was morally adequate is to say that your plan for action was morally sound. So when you make an excuse, you plead that your plan for ac-tion was morally fine - it's just that something went awry in putting it into practice. Perhaps you tripped, and that's why you spilled the shopping you were helping to carry. Or you were stressed or exhausted, which meant you couldn't execute your well-intentioned plan.

This research presents for the first time a unified account of excuses - the Good Intention Account - that argues our everyday excuses work in much the same way as those offered in a courtroom. When lawyers appeal to duress or provocation in defense of their client, they are claiming that the client may have broken the law but had a morally adequate intention: she was just prevented from acting on it because fear or anger led her to lose self-control.

Until now little light has been shed on what unifies the diverse bunch of everyday reasons we of-fer when making excuses. Dr Paulina Sliwa's study from the Faculty of Philosophy, suggests a mor-ally adequate intention is the crucial ingredient.

Recent work in psychology suggests that intentions have a distinctive motivational profile, with philosophers and psychologists both arguing that they are key to understanding how we make choices. Dr Sliwa argues that intentions are the key to making sense of our everyday morality.

Dr Sliwa goes on to explain that appealing to excuses has its limits. "Successful excuses can mitigate our blame but they don't get us off the hook completely. Saying we were tired or stressed doesn't absolve us from moral responsibility completely, though they do change others' perceptions of what we owe to make up for it and how the offended party should feel about our wrongdoing."

This means that when we make excuses we are trying to haggle, to negotiate whether we deserve anger and resentment, or punishment and how much we need to apologise or compensate. This is why it can be so annoying if someone makes spurious excuses - and also probably why we contin-ue to make excuses in the first place.

Dr Sliwa said, "A successful excuse needs to make plausible that your intention really was morally adequate - but something beyond your control prevented you from translating it into action. That's why considerations like the following often work: I am sorry for forgetting the appointment - I had a terrible migraine / I haven't slept for the last three nights / I was preoccupied with worries about my mother's health; or I'm sorry I broke your vase - I stumbled over the rug. They all indi-cate an adequate underlying moral motivation that was thwarted by external circumstances.

"Things that will never work are appeals to weakness of will 'I just couldn't resist' or 'it was too tempting' don't work. Nor do appeals to things that are obviously immoral.

"The same is true of legal excuses: not every appeal to duress, coercion or provocation will be suc-cessful - it will depend on the details of the case.

"Philosophy can give us a better understanding of our mundane, everyday moral phenomena. There are a lot more puzzles to think about in relation with excuses: what's the difference be-tween explaining someone's bad behavior and excusing it?"

Boulder, Colo., USA: Shortly before the beginning of the 2017-2018 winter rainy season, one of the largest fires in California (USA) history (Thomas fire) substantially increased the susceptibility of steep slopes in Santa Barbara and Ventura Counties to debris flows. On 9 Jan. 2018, before the fire was fully contained, an intense burst of rain fell on the portion of the burn area above Montecito, California. The rainfall and associated runoff triggered a series of debris flows that mobilized ~680,000 cubic meters of sediment (including boulders larger than 6 m) at velocities up to 4 meters per second down urbanized alluvial fans. The resulting destruction included 23 fatalities, at least 167 injuries, and 408 damaged homes.

The tragic outcome in Montecito underscores the challenges of rapidly identifying post-fire hazards and risks. Given projected increases in wildfire size and severity, precipitation intensity, and development in the wildland-urban interface, the need to address those challenges is growing.

As part of an effort to improve methods for post-fire risk assessment, the U.S. Geological Survey (USGS) and the California Geological Survey (CGS) spent 12 days immediately following the Montecito debris flows collecting field data to characterize the inundation, flow dynamics, and damage along the five main runout paths. These data provide rare spatial and dynamic constraints for testing debris-flow runout models, which are needed for advancing post-fire debris-flow hazard assessments. They also used the observations of damage in Montecito to develop unique "fragility curves" for wood frame construction. These curves link the probability of damage to measures of debris-flow intensity.

The USGS-CGS team found that the patterns of debris-flow inundation differed substantially from the flow paths expected for ordinary water floods. They also found that road culverts and bridge underpasses, which became choked with debris, played a significant role in causing the widespread damage, because they redirected flow away from the main channels and into neighborhoods. The complexity of the flow paths on the developed fans makes the event a particularly challenging test case for runout models.

It is hoped that subsequent testing of runout models using this data set and combining model results with the fragility curves developed here will help communities better identify their risks following future fires.

Malaysia is facing many challenges caused by various parasitic pathogens. The lack of awareness among disadvantaged populations such as the Orang Asli community and the dependency on foreign workers has led to an influx of immigrants to Malaysia from countries endemic with various parasitic diseases. Amoebiasis is mainly encountered in poor rural areas in Malaysia, however it has the potential to re-emerge. Routine mass-drug administration on newly arriving foreign workers and health education programs are needed to prevent its re-emergence.

Researchers from MAHSA University in Malaysia have published a review on the epidemiology of various parasitic diseases in the country over the last 20 years. The report has been published in The Open Microbiology Journal. The report stresses that Malaysian authorities must implement strategies that provide better water treatment to avoid the emergence of blastocystis. Lymphatic filariasis has the potential to re-emerge due to its easy mode of transmission as well as the presence of a large number of immigrant workers in Malaysia from endemic countries. To prevent the emergence of giardiasis in Malaysia, a multidisciplinary approach is required to determine the level of water contamination with Giardia as well as Cryptosporidium. The epidemiology of malaria is becoming more complex in Malaysia. There is a shift towards infections among men and adults rather than women and children. Therefore, the ministry of health should raise public awareness and the use of point-of-care diagnostics.

Malaysia harbors a large variety of ecological niches that favor the transmission of Toxoplasma spp. Which has led to an increase in the incidence of toxoplasmosis. Therefore, surveillance programs should be initiated to facilitate early diagnosis and treatment. The existence of human trypanosomiasis from neighboring Thailand and reporting cases in cattle from neighboring Indonesia, can all lead to its emergence in Malaysia. Parasitic infectious diseases will continue to appear in Malaysia leading to unpredictable outbreaks that challenge healthcare personnel and emphasize the urgent need for effective surveillance and control measures. Despite the challenges, Malaysia is strongly committed to curb the spread of these diseases.

Almost 300,000 people worldwide develop malignant melanoma each year. The disease is the most serious form of skin cancer and the number of cases reported annually is increasing, making skin cancer one of Sweden's most common forms of cancer. A research team at Lund University in Sweden has studied a protein that regulates a gene which is linked to metastasis of malignant melanoma.

Over the past ten years, new treatment alternatives that use different methods to strengthen the immune system or attack specific cancer cells have been developed for patients with metastatic skin cancer. The introduction of these treatments is due to an increased understanding of how melanoma develops. However, there is still a lack of knowledge about how the tumour cells spread to other parts of the body.

"We have discovered that a specific protein, called DDX3X, regulates the gene that is central to the development of the pigment cells in the skin. The gene is called MITF. Previously, other researchers have found that MITF is a melanoma-specific oncogene, i.e. a gene that can trigger the development of tumours. The general function of DDX3X was known, but the link to the MITF gene was not understood. We understand more about it now", say Cristian Bellodi, who led the study with Göran Jönsson.

The Lund researchers have now seen that the DDX3X protein does not affect whether or not you develop malignant melanoma, but that it plays a considerable role in the aggressiveness of the tumour. The patient's level of DDX3X can therefore serve as a biomarker for predicting how intractable the disease will be.

"The activity of the MITF gene determines the melanoma cells' specific characteristics, which are then linked to the disease prognosis. The lower the level of DDX3X protein the patient has in the tumour cell, the more aggressive the disease and the worse the prognosis will be", says Göran Jönsson, professor of Molecular Oncology at Lund University.

Both researchers consider that more knowledge is needed about how the MITF gene is regulated in order to understand the mechanisms behind how tumour cells move around in the body, with an aim for the future to prevent the spread of the cancer and improve treatment for melanoma patients.

Mild cognitive impairment is often precursor to Alzheimer's disease

The greater the deep sleep enhancement, the better the memory response

Improving deep sleep eventually could be a viable therapy in people with mild cognitive impairment

'This technology can be adapted for home use as a potential treatment'

Deep sleep is critical for memory consolidation

CHICAGO --- Gentle sound stimulation played during specific times during deep sleep enhanced deep or slow-wave sleep for people with mild cognitive impairment, who are at risk for Alzheimer's disease.

The individuals whose brains responded the most robustly to the sound stimulation showed an improved memory response the following day.

"Our findings suggest slow-wave or deep sleep is a viable and potentially important therapeutic target in people with mild cognitive impairment," said Dr. Roneil Malkani, assistant professor of neurology at Northwestern University Feinberg School of Medicine and a Northwestern Medicine sleep medicine physician. "The results deepen our understanding of the importance of sleep in memory, even when there is memory loss."

Deep sleep is critical for memory consolidation. Several sleep disturbances have been observed in people with mild cognitive impairment. The most pronounced changes include reduced amount of time spent in the deepest stage of sleep.

"There is a great need to identify new targets for treatment of mild cognitive impairment and Alzheimer's disease," Malkani added. Northwestern scientists had previously shown that sound stimulation improved memory in older adults in a 2017 study.

Because the new study was small -- nine participants -- and some individuals responded more robustly than others, the improvement in memory was not considered statistically significant. However, there was a significant relationship between the enhancement of deep sleep by sound and memory: the greater the deep sleep enhancement, the better the memory response. 

"These results suggest that improving sleep is a promising novel approach to stave off dementia," Malkani said.

The paper will be published June 28 in the Annals of Clinical and Translational Neurology.

For the study, Northwestern scientists conducted a trial of sound stimulation overnight in people with mild cognitive impairment. Participants spent one night in the sleep laboratory and another night there about one week later. Each participant received sounds on one of the nights and no sounds on the other. The order of which night had sounds or no sounds was randomly assigned.  Participants did memory testing the night before and again in the morning. Scientists then compared the difference in slow-wave sleep with sound stimulation and without sounds, and the change in memory across both nights for each participant.

The participants were tested on their recall of 44 word pairs. The individuals who had 20% or more increase in their slow wave activity after the sound stimulation recalled about two more words in the memory test the next morning. One person with a 40% increase in slow wave activity remembered nine more words.

The sound stimulation consisted of short pulses of pink noise, similar to white noise but deeper, during the slow waves. The system monitored the participant's brain activity. When the person was asleep and slow brain waves were seen, the system delivered the sounds. If the patient woke up, the sounds stopped playing.

"As a potential treatment, this would be something people could do every night," Malkani said.

The next step, when funding is available, is to evaluate pink noise stimulation in a larger sample of people with mild cognitive impairment over multiple nights to confirm memory enhancement and see how long the effect lasts, Malkani said.
 

ANN ARBOR--Many patients, especially those who are anesthetized or emotionally challenged, cannot communicate precisely about their pain.

For this reason, University of Michigan researchers have developed a technology to help clinicians "see" and map patient pain in real-time, through special augmented reality glasses. Their small feasibility study appears in the Journal of Medical Internet Research.

The technology was tested on 21 volunteer dental patients, and researchers hope to one day include other types of pain and conditions. It's years away from widespread use in a clinical setting, but the feasibility study is a good first step for dental patients, said Alex DaSilva, associate professor at the U-M School of Dentistry and director of the Headache and Orofacial Pain Effort Lab.

The portable CLARAi (clinical augmented reality and artificial intelligence) platform combines visualization with brain data using neuroimaging to navigate through a patient's brain while they're in the chair.

"It's very hard for us to measure and express our pain, including its expectation and associated anxiety," DaSilva said. "Right now, we have a one to 10 rating system, but that's far from a reliable and objective pain measurement."

In the study, researchers triggered pain by administering cold to the teeth. Researchers used brain pain data to develop algorithms that, when coupled with new software and neuroimaging hardware, predicted pain or the absence of it about 70% of the time.

Participants wore a sensor-outfitted cap that detected changes to blood flow and oxygenation, thus measuring brain activity and responses to pain. That information was transmitted to a computer and interpreted.

Wearing special augmented reality glasses (in this case, the Microsoft HoloLens), researchers viewed the subject's brain activity in real time on a reconstructed brain template, while the subjects sat in the clinical chair. The red and blue dots on the image denote location and level of brain activity, and this "pain signature" was mirror-displayed on the augmented reality screen. The more pain signatures the algorithm learns to read, the more accurate the pain assessment.

CAMBRIDGE, MA -- In the Iron Man movies, Tony Stark uses a holographic computer to project 3-D data into thin air, manipulate them with his hands, and find fixes to his superhero troubles. In the same vein, researchers from MIT and Brown University have now developed a system for interactive data analytics that runs on touchscreens and lets everyone -- not just billionaire tech geniuses --?tackle real-world issues.

For years, the researchers have been developing an interactive data-science system called Northstar, which runs in the cloud but has an interface that supports any touchscreen device, including smartphones and large interactive whiteboards. Users feed the system datasets, and manipulate, combine, and extract features on a user-friendly interface, using their fingers or a digital pen, to uncover trends and patterns.

In a paper being presented at the ACM SIGMOD conference, the researchers detail a new component of Northstar, called VDS for "virtual data scientist," that instantly generates machine-learning models to run prediction tasks on their datasets. Doctors, for instance, can use the system to help predict which patients are more likely to have certain diseases, while business owners might want to forecast sales. If using an interactive whiteboard, everyone can also collaborate in real-time.

The aim is to democratize data science by making it easy to do complex analytics, quickly and accurately.

"Even a coffee shop owner who doesn't know data science should be able to predict their sales over the next few weeks to figure out how much coffee to buy," says co-author and long-time Northstar project lead Tim Kraska, an associate professor of electrical engineering and computer science in at MIT's Computer Science and Artificial Intelligence Laboratory (CSAIL) and founding co-director of the new Data System and AI Lab (DSAIL). "In companies that have data scientists, there's a lot of back and forth between data scientists and nonexperts, so we can also bring them into one room to do analytics together."

VDS is based on an increasingly popular technique in artificial intelligence called automated machine-learning (AutoML), which lets people with limited data-science know-how train AI models to make predictions based on their datasets. Currently, the tool leads the DARPA D3M Automatic Machine Learning competition, which every six months decides on the best-performing AutoML tool.

Joining Kraska on the paper are: first author Zeyuan Shang, a graduate student, and Emanuel Zgraggen, a postdoc and main contributor of Northstar, both of EECS, CSAIL, and DSAIL; Benedetto Buratti, Yeounoh Chung, Philipp Eichmann, and Eli Upfal, all of Brown; and Carsten Binnig who recently moved from Brown to the Technical University of Darmstadt in Germany.

An "unbounded canvas" for analytics

The new work builds on years of collaboration on Northstar between researchers at MIT and Brown. Over four years, the researchers have published numerous papers detailing components of Northstar, including the interactive interface, operations on multiple platforms, accelerating results, and studies on user behavior.

Northstar starts as a blank, white interface. Users upload datasets into the system, which appear in a "datasets" box on the left. Any data labels will automatically populate a separate "attributes" box below. There's also an "operators" box that contains various algorithms, as well as the new AutoML tool. All data are stored and analyzed in the cloud.

The researchers like to demonstrate the system on a public dataset that contains information on intensive care unit patients. Consider medical researchers who want to examine co-occurrences of certain diseases in certain age groups. They drag and drop into the middle of the interface a pattern-checking algorithm, which at first appears as a blank box. As input, they move into the box disease features labeled, say, "blood," "infectious," and "metabolic." Percentages of those diseases in the dataset appear in the box. Then, they drag the "age" feature into the interface, which displays a bar chart of the patient's age distribution. Drawing a line between the two boxes links them together. By circling age ranges, the algorithm immediately computes the co-occurrence of the three diseases among the age range.

"It's like a big, unbounded canvas where you can lay out how you want everything," says Zgraggen, who is the key inventor of Northstar's interactive interface. "Then, you can link things together to create more complex questions about your data."

Approximating AutoML

With VDS, users can now also run predictive analytics on that data by getting models custom-fit to their tasks, such as data prediction, image classification, or analyzing complex graph structures.

Using the above example, say the medical researchers want to predict which patients may have blood disease based on all features in the dataset. They drag and drop "AutoML" from the list of algorithms. It'll first produce a blank box, but with a "target" tab, under which they'd drop the "blood" feature. The system will automatically find best-performing machine-learning pipelines, presented as tabs with constantly updated accuracy percentages. Users can stop the process at any time, refine the search, and examine each model's errors rates, structure, computations, and other things.

According to the researchers, VDS is the fastest interactive AutoML tool to date, thanks, in part, to their custom "estimation engine." The engine sits between the interface and the cloud storage. The engine leverages automatically creates several representative samples of a dataset that can be progressively processed to produce high-quality results in seconds.

"Together with my co-authors I spent two years designing VDS to mimic how a data scientist thinks," Shang says, meaning it instantly identifies which models and preprocessing steps it should or shouldn't run on certain tasks, based on various encoded rules. It first chooses from a large list of those possible machine-learning pipelines and runs simulations on the sample set. In doing so, it remembers results and refines its selection. After delivering fast approximated results, the system refines the results in the back end. But the final numbers are usually very close to the first approximation.

"For using a predictor, you don't want to wait four hours to get your first results back. You want to already see what's going on and, if you detect a mistake, you can immediately correct it. That's normally not possible in any other system," Kraska says. The researchers' previous user study, in fact, "show that the moment you delay giving users results, they start to lose engagement with the system."

The researchers evaluated the tool on 300 real-world datasets. Compared to other state-of-the-art AutoML systems, VDS' approximations were as accurate, but were generated within seconds, which is much faster than other tools, which operate in minutes to hours.

Next, the researchers are looking to add a feature that alerts users to potential data bias or errors. For instance, to protect patient privacy, sometimes researchers will label medical datasets with patients aged 0 (if they do not know the age) and 200 (if a patient is over 95 years old). But novices may not recognize such errors, which could completely throw off their analytics.

"If you're a new user, you may get results and think they're great," Kraska says. "But we can warn people that there, in fact, may be some outliers in the dataset that may indicate a problem."

Pathogenic fungal spores capitalize on host immune cells to escape the lung and gain access to the brain to cause fatal disease in mice, according to a study published June 27 in the open-access journal PLOS Pathogens by Christina Hull of the University of Wisconsin-Madison, and colleagues. These insights into the interactions between pathogenic fungal spores and lung immune cells provide new opportunities for understanding spore-mediated fungal diseases.

Little is known about how inhaled spores from human fungal pathogens cause infections and spread to other parts of the body. The most frequent cause of inhaled fatal fungal disease is Cryptococcus, which causes meningitis. To understand how Cryptococcus causes disease, Hull and her colleagues evaluated two types of cells (spores and yeast) in a mouse model of infection. They compared yeast strains that cannot cause disease to the spore offspring they produced during sexual reproduction.

They discovered that parental yeast that are not virulent produced spores that were fully virulent and caused fatal meningitis in 100% of the mice. This difference was associated with movement of spores to the lymph system; mice infected with spores had Cryptococcus in their lung-draining lymph nodes, but mice infected with yeast did not. Furthermore, when they infected mice that lacked immune cells in their lungs, no spores were found in their lymph nodes. This indicates that instead of protecting mice from the spore infection, the immune cells moved spores out of the lung to the lymph system where spores could then spread to the brain. According to the authors, the findings could open new avenues for the development of novel therapeutics that could be effective in the prevention of fatal cryptococcosis and other diseases caused by the spores of invasive human fungal pathogens.

"Inhaling fungal spores causes serious, and even fatal, infections more often than most people realize," adds Hull. "By understanding how spores move from the lungs to other tissues, we can develop new strategies for preventing spore-mediated fungal diseases and learn how to treat patients more effectively."

LEXINGTON, Ky. (June 28, 2019) - In a new study published in JAMA Network Open, University of Kentucky researchers, in collaboration with researchers from Ferris State University, examined whether legal mandates on naloxone coprescription in certain states increased naloxone dispensing.

Recently, a Federal Drug Administration panel and the U.S. Department of Health & Human Services recommended prescribing the opioid reversal drug naloxone along with an opioid prescription (known as "coprescription"). In 2017, Virginia and Vermont mandated the coprescription of naloxone for potentially at-risk patients; several additional states followed suit in 2018.

Ultimately, the study found that naloxone dispensing increased following the implementation of legal mandates for naloxone coprescription. Nearly 88 naloxone prescriptions per 100,000 patients were dispensed in Virginia and 111 prescriptions per 100,000 were dispensed in Vermont during the first full month the legal requirement was effective. To contrast, a rate of just 16 naloxone prescriptions per 100,000 was dispensed in the 10 states (including Washington, D.C.) with the highest opioid overdose death rates; just six prescriptions per 100,000 were dispensed in the remaining 39 states. Population level modeling indicated that naloxone coprescription mandates were associated with a 7.75-fold increase in the rate of naloxone dispensing compared to states without mandates.

In 2017, 47,600 people died from opioid-involved overdose, representing almost 70 percent of all drug overdose deaths in the U.S.

"Increasing access to naloxone to those with elevated risk for opioid overdose is an important public health initiative," said Patricia Freeman, director of UK's Center for the Advancement of Pharmacy Practice and corresponding author of the study. "Our study findings demonstrate that naloxone coprescription laws dramatically increase access to naloxone in those states that adopt the policy. As states continue to search for ways to lower opioid-related overdose deaths, enacting similar laws or regulations has the potential to save lives."

According to Freeman, in addition to the recent coprescription mandates, states have taken a variety of other legal approaches to support naloxone access. This includes allowing prescription of naloxone to friends and family members of those at risk (known as third-party prescribing) and allowing pharmacists to dispense naloxone under a standing order or protocol.

"With the passage of Senate Bill 192 in 2015, Kentucky pharmacists have authority to initiate the dispensing of naloxone under a physician-approved protocol," Freeman said. "Since that time, naloxone dispensing in Kentucky has increased significantly."

Simply introducing a default physician order -- a "nudge" -- into electronic health records (EHRs) cut the use of unnecessary daily imaging in half during palliative radiation therapy sessions for patients with advanced cancer, according to a Penn Medicine study published today in JAMA Oncology. While daily imaging is typically used in curative cancer treatment, national guidelines recommend providers transition to weekly imaging for palliative radiotherapy sessions. Daily imaging unnecessarily extends the duration of each radiation therapy session for palliative care patients who are often in pain or discomfort from the progression of cancer.

"We recognized that patients were undergoing unnecessary scans due to the standard care habits, and we understood that this frequent imaging was causing more discomfort than benefit," said the study's lead author Sonam Sharma, MD, an assistant professor of Radiation Oncology at the Icahn School of Medicine at Mount Sinai, who conducted this research while in the Perelman School of Medicine at the University of Pennsylvania. "This shows that a minor adjustment can have a dramatic effect on medical practice."

The study took place across five Penn Medicine radiation oncology practices in New Jersey and Pennsylvania between 2016 and 2018, and included more than 1,000 patients undergoing palliative radiotherapy for cancers that had spread to other organs, including bone, soft tissue, and the brain.

The researchers applied insights from behavioral economics to design a default imaging order within the EHR that specified no daily imaging during palliative radiotherapy. Default options are a type of "nudge" that present an automatic choice unless a person actively opts to make a different one. For the study, radiation oncology practices were randomly assigned to take up the nudge over time, which allowed the researchers to parse out whether changes they were seeing could be tied to the nudge or potentially the result of any other unrelated happenings within the clinic, such as changes in practice trends or educational programs. It's also important to note that the study did not preclude doctors from choosing to order daily imaging if they felt it was the best option.

The researchers found that the introduction of the new default order led to a drop in daily imaging from 68 percent of treatment courses to 32 percent. Additionally, without unnecessary daily imaging, the radiotherapy session time -- which is often 10 to 15 minutes -- was cut by an average of two minutes per session.

"Cutting down on lower value health care is a hard nut to crack. Successfully doing so through the electronic health record in a scalable way opens a whole new set of tools we can bring to bear on the problem," said the study's co-senior author Justin E. Bekelman, MD, director of the Penn Center for Cancer Care Innovation at the Abramson Cancer Center and associate professor of Radiation Oncology and Medical Ethics & Health Policy. "By eliminating friction involved with ordering guideline-based cancer care, we showed that clinicians quickly adopt it."

The study's other co-senior author, Mitesh Patel, MD, MBA, director of the Penn Medicine Nudge Unit and assistant professor of Medicine and Health Care Management, pointed out that this study's application of the technique is unique.

"Nudges can be very powerful. Most previous interventions have been focused on increasing high-value care, such as boosting flu vaccination rates," Patel said. "This is one of the first cases where we applied a nudge to decrease a lower value, unnecessary behavior. It not only worked, but its effect has been sustained and implemented throughout our entire health system."