Culture

Fraud is going uninvestigated by police who are "hiding behind the veil" of the Action Fraud national crime reporting agency.

In his paper published this week in Policing, Professor Mark Button, director of the Centre for Counter Fraud Studies at the University of Portsmouth argues that, Action Fraud, which has been widely derided, has become a useful veil from which the police can hide their inadequate response.

Figures from Action Fraud, the arm of the police responsible for recording scams and fraud, show that between 2019 and 2020, over 800,000 people reported being a victim of fraud, with £2.3bn finding its way into criminal hands. However, Professor Button calculated just 0.6 per cent of police officers are dedicated to investigating fraud.

The research focused on reviews and investigations carried out over the past 20 years and found that these have consistently highlighted the low priority given to the investigation of financial crimes in England and Wales. In 2018 the House of Commons home affairs committee said that "the proportion of fraud cases being investigated is shockingly low".

Professor Button says: "Action Fraud is in reality a call centre provided by a private company under contract to the City of London Police.

"The staffs it employs are largely low-skilled and paid at around the minimum wage. It has no capacity to investigate. However, even in the area it does have responsibility for there is an evidence of areas in need of improvement."

"Considering fraud and computer misuse crime amounts to a third to half of all crime against individuals this is a huge mismatch".

Professor Button suggests radical change is required to address the investigative gap through either a move towards regional investigation of economic crime or a national solution, through a National Economic Crime Agency.

Economic crime is the most common type of crime and costs society billions of pounds. In the current policing structures economic crime will always be the 'Cinderella' crime falling behind other policing priorities and lacking the resources required for agencies to effectively tackle it. Much of economic crime requires specialist knowledge.

The paper aims to start a debate around the future structures of policing for economic crime centred around a national body or regional forces rather than the traditional local forces.

For two decades, the number of Americans who die each year from drug overdoses has steadily risen, from less than 20,000 in 1999 to more than 80,000 in 2020. By studying patterns of these drug-related fatalities, researchers at University of California San Diego School of Medicine, San Diego State University (SDSU), and international collaborators have designed and validated a prediction model to signal counties at risk of future overdose death outbreaks. The goal of the open-source tool is to predict and prevent deaths through early deployment of public health resources.

Findings were published June 9, 2021 by Lancet Public Health.

"A big challenge for public health experts is figuring out which parts of the country are at greatest risk of future overdose outbreaks. If we can predict where such outbreaks may happen, then we will be empowered to intervene and stop deaths from occurring," said senior author Annick Borquez, PhD, an epidemiologist and assistant professor in the Division of Infectious Disease and Global Public Health at UC San Diego School of Medicine.

The opioid epidemic has been described as an overlapping triple wave of fatal overdoses due to prescription opioids, heroin and highly potent synthetic opioids, including fentanyl. The investigators used this third wave to investigate whether a tool could be developed to predict and prevent deaths.

"This study provides a novel, rigorously validated tool to inform policy planning in the context of overdose epidemics driven by emerging drugs and sets a new standard for the development of a data-driven response to drug use epidemics," said first author Charlie Marks, MPH, graduate research assistant, SDSU-UC San Diego joint doctoral program in Interdisciplinary Research in Substance Abuse.

Using CDC data from 2013 (when the fentanyl epidemic began) up to 2018 (the most recent data available at the time), the research team designed and trained a retrospective statistical model to find patterns in the relationship between county characteristics and overdose deaths, then used the data to predict fatality rates in the next year. The predictions were then compared with actual overdose death rates in each county.

"We found that our approach brought substantial improvement to predicting counties with high fatal overdose rates compared to a simple benchmark that relied on past year rates alone. We also found that increased overdoses in a neighboring county are very predictive of future overdoses in a given county, indicating that the overdose epidemic spreads geographically," said Marks.

The team developed the OD Predict Explorer web tool, a publicly available interface where results of the time-limited model are presented and available for research purposes. Users can click on a map and compare what the model predicted from 2013 to 2018 versus what was observed and determine whether the tool actually identified the counties with the highest overdose across the country, including those experiencing new spikes.

"Many of the counties with the most deaths were concentrated in the Midwest and Northeast, where the fentanyl epidemic has hit hardest, but an increasing number of states in the West are affected as well. There's this idea that this epidemic has been focused in rural areas where the prescription opioid epidemic started, but the reality is overdose deaths have been increasing in cities too. For example, San Francisco and San Diego have seen steep increases in fentanyl overdose deaths in the past year," Borquez added.

Borquez and Marks note that that all predictive models are limited by the data sets used to inform them and said more timely and available information related to deaths, drug markets and seizures and prescription data at both county and state levels, is urgently needed.

"While our approach can be effective, it also requires that fatal overdose data from all the counties in the U.S. be accessible and available for the current year, which unfortunately is not yet standard practice," said Borquez. "Our model will only be useful in predicting and preventing deaths if there is no lag in getting data from local and national agencies."

"Further model refinement and securing access to restricted data through broad collaborations will be next steps to improve model performance. Imagine if we could develop predictive tools for substance use epidemics, similar to what was developed to predict COVID-19 infections and deaths."

Borquez predicted it would be one to two years before the tool is sufficiently refined to make real-time predictions at a national level based on available data, but that a promising avenue in the short term will involve applying it in states that share recent overdose death information.

"We urgently need methods to predict where these overdoses and other outbreaks may occur. Outbreaks such as hepatitis and HIV are also connected to drug use, and can be prevented too," said Borquez. "Investing in drug use surveillance and harm-reduction infrastructure doesn't solve one problem, it solves multiple problems at once."

Medulloblastoma is a rare but devastating childhood brain cancer. This cancer can spread through the spinal fluid and be deposited elsewhere in the brain or spine. Radiation therapy to the whole brain and spine followed by an extra radiation dose to the back of the brain prevents this spread and has been the standard of care. However, the radiation used to treat such tumors takes a toll on the brain, damaging cognitive function, especially in younger patients whose brains are just beginning to develop.

A national study led by Washington University School of Medicine in St. Louis and St. Jude Children's Research Hospital suggests that children with what is called "average risk medulloblastoma" can receive a radiation "boost" to a smaller volume of the brain at the end of a six-week course of radiation treatment and still maintain the same disease control as those receiving radiation to a larger area. But the researchers also found that the dose of the preventive radiation treatments given to the whole brain and spine over the six-week regimen cannot be reduced without reducing survival. Further, the researchers showed that patients' cancers responded differently to therapy depending on the biology of the tumors, setting the stage for future clinical trials of more targeted treatments.

Children with average risk medulloblastoma have five-year survival rates of 75% to 90%. In contrast, children with what's called "high risk medulloblastoma" have five-year survival rates of 50% to 75%. Other factors -- such as a child's age and whether the tumor has spread -- help determine the risk category. For this study, the researchers focused on patients with average risk medulloblastoma.

The findings appears online June 10 in the Journal of Clinical Oncology.

"Medulloblastoma is a devastating disease," said first and corresponding author Jeff M. Michalski, MD, the Carlos A. Perez Distinguished Professor of Radiation Oncology at Washington University. "It is a malignant brain tumor that develops in the cerebellum, the back lower part of the brain that is important for coordinating movement, speech and balance. The radiation treatment for this tumor also can be challenging, especially in younger children whose brains are actively developing in these areas. There's a balance between effectively treating the tumor without damaging children's abilities to move, think and learn."

Children with average risk medulloblastoma typically undergo surgery to remove as much of the tumor as possible. They also receive chemotherapy and radiation therapy to prevent the spread of the tumor to other parts of the brain and spine through the cerebrospinal fluid.

"We wanted to investigate whether we could safely reduce the amount of radiation these patients receive -- sparing normal parts of the brain and lessening the side effects for children with this type of brain cancer -- while also maintaining effective treatment," said Michalski, also vice chair and director of clinical programs in the Department of Radiation Oncology. "We found that reducing the dose of radiation received over the six-week course of treatment had a negative impact on survival. But we also found that we could safely reduce the size of the volume of the brain that receives a radiation boost at the end of the treatment regimen. We hope such measures can help reduce the side effects of this treatment, especially in younger patients."

Collaborating with children's hospitals across the U.S. and internationally, the researchers evaluated 464 patients treated for average risk medulloblastoma that was diagnosed between ages 3 and 21. Younger patients, ages 3 to 7 -- a key time for brain development -- were randomly assigned to receive either standard dose (23.4 gray) or low dose (18 gray) radiation to the head and spine region in each of 30 treatments given over six weeks. Older patients all received the standard dose, since their brain development is less vulnerable to radiation. In addition, all patients were randomly assigned to receive two different sizes of a radiation "boost" at the end of the six weeks of therapy. For the boost, all patients received a cumulative radiation dose of 54 gray to either the entire region of the brain called the posterior fossa, which includes the cerebellum, or to a smaller region of the brain that includes the original outline of the tumor plus an additional margin of up to about two centimeters beyond the original tumor boundary.

"The patients who received the smaller boost did just as well as those who received the whole posterior fossa boost," said Michalski, who treats patients at Siteman Kids at Washington University School of Medicine and St. Louis Children's Hospital. "Many doctors have already adopted this smaller boost volume, but now we have high-quality evidence that this is indeed safe and effective."

For patients receiving the smaller boost volume, 82.5% survived five years with no worsening of the cancer. And for those receiving the larger boost volume to the entire posterior fossa, 80.5% survived five years with no worsening of the disease. These numbers were not statistically different. In a subset of tumors with mutations in a gene called SHH, patients actually showed improved survival with the smaller boost volume.

But for the younger children, the lower dose of radiation over six weeks did not result in similar survival numbers. Of those receiving the standard dose of craniospinal radiation, about 83% survived five years with no worsening of the cancer. Of those receiving the lower dose, about 71% survived five years with no worsening of the cancer. That difference in survival was statistically significant.

"We saw higher rates of recurrence and tumor spreading in the younger patients receiving the lower dose of craniospinal radiation," Michalski said. "In general, it's not safe to lower the dose of radiation in children with medulloblastoma even if we know the lower dose might spare their cognitive function. However, a specific subgroup of patients -- those with mutations in a gene called WNT -- did well on the lower dose, so we're now doing studies just with these specific patients to see if we can safely lower the radiation dose for them."

The tumors were categorized into four molecular subgroups based on their gene expression and predicted biology. The first group's tumors have mutations in WNT signaling pathways; the second have mutations in the SHH gene; and the third and fourth groups' tumors each have different and more complex patterns of gene mutations. The researchers found differences in tumors' responses to treatment based on tumor biology that can guide the design of future clinical trials.

"We've made great strides over the last 15 years in appreciating the molecular diversity of medulloblastoma," said senior author Paul Northcott, PhD, of St. Jude Children's Research Hospital. "We performed whole-exome sequencing and DNA methylation profiling to assign patients to molecular subgroups. This was a critical step in contextualizing this trial based on the latest biology and showed us some important differences in how children respond to therapy that would otherwise not have been clear. Results from this study will play a vital role in designing the next generation of clinical trials for children with medulloblastoma."

Increasing evidence shows that physical activity and exercise training may delay or prevent the onset of Alzheimer's disease (AD). In aging humans, aerobic exercise training increases gray and white matter volume, enhances blood flow, and improves memory function. The ability to measure the effects of exercise on systemic biomarkers associated with risk for AD and relating them to key metabolomic alterations may further prevention, monitoring, and treatment efforts. However, systemic biomarkers that can measure exercise effects on brain function and that link to relevant metabolic responses are lacking.

To address this issue, Henriette van Praag, Ph.D., from Florida Atlantic University's Schmidt College of Medicine and Brain Institute and Ozioma Okonkwo, Ph.D., Wisconsin Alzheimer's Disease Research Center and Department of Medicine at the University of Wisconsin-Madison and their collaborators, tested the hypotheses that three specific biomarkers, which are implicated in learning and memory, would increase in older adults following exercise training and correlate with cognition and metabolomics markers of brain health. They examined myokine Cathepsin B (CTSB), brain derived neurotrophic factor (BDNF), and klotho, as well as metabolomics, which have become increasingly utilized to understand biochemical pathways that may be affected by AD.

Researchers performed a metabolomics analysis in blood samples of 23 asymptomatic late middle-aged adults, with familial and genetic risk for AD (mean age 65 years old, 50 percent female) who participated in the "aeRobic Exercise And Cognitive Health (REACH) Pilot Study" (NCT02384993) at the University of Wisconsin. The participants were divided into two groups: usual physical activity (UPA) and enhanced physical activity (EPA). The EPA group underwent 26 weeks of supervised treadmill training. Blood samples for both groups were taken at baseline and after 26 weeks.

Results of the study, published in the journal Frontiers in Endocrinology, showed that plasma CTSB levels were increased following this 26-week structured aerobic exercise training in older adults at risk for AD. Verbal learning and memory correlated positively with change in CTSB but was not related to BDNF or klotho. The present correlation between CTSB and verbal learning and memory suggests that CTSB may be useful as a marker for cognitive changes relevant to hippocampal function after exercise in a population at risk for dementia.

Plasma BDNF levels decreased in conjunction with metabolomic changes, including reductions in ceramides, sphingo- and phospholipids, as well as changes in gut microbiome metabolites and redox homeostasis. Indeed, multiple lipid metabolites relevant to AD were modified by exercise in a manner that may be neuroprotective. Serum klotho was unchanged but was associated with cardiorespiratory fitness.

"Our findings position CTSB, BDNF, and klotho as exercise biomarkers for evaluating the effect of lifestyle interventions on brain function," said van Praag, corresponding author, an associate professor of biomedical science, FAU's Schmidt College of Medicine, and a member of the FAU Brain Institute and the FAU Institute for Human Health & Disease Intervention (I-HEALTH). "Human studies often utilize expensive and low throughput brain imaging analyses that are not practical for large population-wide studies. Systemic biomarkers that can measure the effect of exercise interventions on Alzheimer's-related outcomes quickly and at low-cost could be used to inform disease progression and to develop novel therapeutic targets."

CTSB, a lysosomal enzyme, is secreted from muscle into circulation after exercise and is associated with memory function and adult hippocampal neurogenesis. Older adults with cognitive impairment have lower serum and brain CTSB levels. BDNF is a protein that is upregulated in the rodent hippocampus and cortex by running and is important for adult neurogenesis, synaptic plasticity, and memory function. Klotho is a circulating protein that can enhance cognition and synaptic function and is associated with resilience to neurodegenerative disease, possibly by supporting brain structures responsible for memory and learning.

"The positive association between CTSB and cognition, and the substantial modulation of lipid metabolites implicated in dementia, support the beneficial effects of exercise training on brain function and brain health in asymptomatic individuals at risk for Alzheimer's disease," said van Praag.

Scientists say naked mole rats - a rodent native to West Africa - may hold the key to new treatments for degenerative diseases such as cancer and dementia.

The reclusive animals have a lifespan far in excess of other rodents - for example, mice and rats live about two years, whereas naked mole rats can live for 40 or 50 years.

Researchers at the University of Bradford say the animals have a unique DNA repair mechanism that enables them to prevent cancers and other degenerative conditions, including dementia.

Cancer resistant

Professor Sherif El-Khamisy, Director of the Institute of Cancer Therapeutics at the University, said: "Naked mole rats are fascinating creatures, not least because they are so long lived compared to other rodents of the same size. They also do not suffer from - what we call in humans - age associated disorders, such as cancer, dementia and neurological decline.

"What we're trying to do is to understand what makes them so resistant and then to try to harness that knowledge to come up with new treatments for cancer and conditions like dementia in people.

"This is not about extending life but extending the quality of life."

DNA mutations

Prof El-Khamisy, from the University's Faculty of Life Sciences, is the lead author of a paper, DNA Homeostasis and Senescence: Lessons from the Naked Mole Rat, recently published in the International Journal of Molecular Sciences.

It states: "As we age, our bodies accrue damage in the form of DNA mutations. These mutations lead to the generation of sub-optimal proteins, resulting in inadequate cellular homeostasis and senescence*. The build-up of senescent cells negatively affects the local cellular micro-environment and drives ageing associated disease, including neurodegeneration.

"Which processes show an increased burden as naked mole rats age may identify novel biological targets to mitigate our own degeneration."

Prof El-Khamisy added: "This is a new area of research, so there are still lots of things we don't know. For example, Alzheimer's and dementia are caused by protein aggregations in the brain and this has been a puzzle to scientists for many years. There are questions around how those proteins form and also how the body deals with them. Clearly, naked mole rats are much better than us at dealing with them.

"If we can work out how they do this, we could look to adopt similar systems in humans or to use these markers as a predictive tool to be able to say 'this person is more likely to develop dementia or cancer as they age', and then take appropriate steps."

Naked mole rats fact file

Naked mole rats are mostly hairless, wrinkly rodents that grow to between three and 13 inches.

They live for 40 or 50 years and are immune to cancer and some types of pain, such as that from biting insects and spicy plants.

In the wild, they live in hierarchical colonies (with a queen, soldiers and workers) sometimes numbering up to 300, creating a warren of underground tunnels and rooms the size of several football pitches.

They live most of their lives in caves or underground, yet despite their lack of exposure to the sun, they have a strong circadian rhythm.

A pup naked mole rat weighs less than a penny.

* In biology, homeostasis is the state of steady internal, physical, and chemical conditions maintained by living systems; whereas senescence is the condition or process of deterioration with age.

People often think about human behavior in terms of what is happening in the present--reading a newspaper, driving a car, or catching a football. But other dimensions of behavior extend over weeks, months, and years.

Examples include a child learning how to read; an athlete recovering from a concussion; or a person turning 50 and wondering where all the time has gone. These are not changes that people perceive on a day-to-day basis. They just suddenly realize they're older, healed, or have a new development skill.

"The field of neuroscience looks at the brain in multiple ways," says Franco Pestilli, a neuroscientist at The University of Texas at Austin (UT Austin). "For example, we're interested in how neurons compute and allow us to quickly react--it's a fast response requiring visual attention and motor control. Understanding the brain needs big data to capture all dimensions of human behavior."

As an expert in vision science, neuroinformatics, brain imaging, computational neuroscience, and data science, Pestilli's research has advanced the understanding of human cognition and brain networks over the last 15 years.

Pestilli likes to compare the brain to the Internet, a powerful set of computers connected by cables simultaneously keeping many windows open and programs running. If the computer is healthy but the cables are not, long range communication between computers in different parts of the brain begins to fail. This in turn creates problems for our long-term behavior.

Pestilli and team are also interested in how biological computations change over longer time periods--such as how does our brain change as we lose our vision?

"We've shown that if you change the input into the eye, it can change the brain's white matter, which is equivalent to the brain's cabling system--just like computers are connected with cables, our brain has millions of cables connecting millions of tiny computers called neurons."

This research was published in Nature Scientific Reports in March 2021.

Brainlife.io--The Platform Scientists Need to Do the Science They Want

New cloud technologies are becoming necessary to help researchers collaborate, process, visualize, and manage large amounts of data at unprecedented scales.

A key aspect of Pestilli's work started in 2017 when he received a grant from the BRAIN Initiative through the National Science Foundation (NSF) to launch Brainlife.io. At that time, he was an associate professor in Psychological and Brain Sciences with Indiana University.

The Brainlife.io computing platform provides a full suite of web services to support reproducible research on the cloud. More than 1,600 scientists from around the world have accessed the platform thus far. BrainLife.io allows them to upload, manage, track, analyze, share, and visualize the results of their data.

Currently, the platform serves different communities of scientists from psychology to medical science to neuroscience, and includes more than 600 data processing tools. Brainlife.io integrates different expertise and development mechanisms for making code and publishing it on the cloud--while tracking every detail that happens to the data.

"We've processed more than 300,000 datasets thus far--and we're serving many new users as the number of scientists accessing our platform has exploded during the pandemic," Pestilli said. "A lot of new people came to Brainlife.io because they lost access to their physical facilities."

The platform relies on supercomputing infrastructure to run simulations on high performance computing (HPC) hardware. "National systems like Jetstream (Indiana University/TACC), Stampede2 (TACC), and Bridges-2 (Pittsburgh Supercomputing Center) are fundamental to what we do. We've received a lot of support the Extreme Science and Engineering Discovery Environment (XSEDE) funded by NSF."

BrainLife.io is also funded via collaborative awards from the National Institutes of Health (NIH) and the Department of Defense.

Aina Puce is a professor in Psychological and Brain Science at Indiana University. She is a self-proclaimed neophyte with regard to Brainlife.io, yet she is a world expert in neuroimaging, and the principal investigator of an NIH grant that supports the development of neurophysiological data management and analyses on the platform.

"I jumped in at the deep end to help Franco and his team expand the functionality of the platform to neurophysiological data," Puce said.

"Brainlife.io is allowing us to start to perform cutting-edge analyses, integrating neurophysiological data and MRI-based data. Studies include research explicitly linking brain structure to brain function, such as how information gets transported from region to region, and how blood flow and brain electrical activity change when performing particular tasks."

Soon, a suite of new tools will be available on Brainlife.io for users to integrate EEG (electroencephalography), MEG (magnetoencephalography), and MRI (magnetic resonance imaging) data, which is "unique and will be tremendously helpful for both science and society," she said.

Puce and team are currently exploring brain activity by recording electrical output, both non-invasively from the scalp and invasively from the inside of the head. They are also detecting magnetic fields produced while a person is at rest and while they are performing tasks such as reading social messages from others.

"This is what we are bringing to Brainlife.io for the first time," Puce said.

Data Drives Discovery

The field of neuroscience is moving from small data sets to large data sets. Larger data sets mean that scientists can extract more statistically powerful insights from the information they collect.

From 1,000 subjects to 10,000 subjects to 500,000 subjects -- the data sets keep growing.

For example, the Adolescent Brain Cognitive Development Study is one of the largest, long-term studies of brain development and child health in the United States. The study is collecting data from over 10,000 adolescent brains to understand biological and behavioral development from adolescence into young adulthood. In another part of the world, the UK Biobank contains in-depth health information from more than 500,000 participants who donated their genetic and clinical data for the good of science; 100,000 of these participants donated brain scans.

"As each new project scales up," Pestilli said, "the size of the data set also scales up, and as a result, the needs for storage and computing change. We're building datasets of a size and impact that only supercomputers can effectively cope. With the recent advent of machine-learning and artificial intelligent methods, and their potential to help humans understand the brain, we need to change our paradigm for data management, analysis, and storage."

Pestilli says that neuroscience research can't survive unless a cohesive ecosystem is built that will integrate the needs of the scientists with hardware and software needs given the tremendous amount of data and the next-generation questions to be explored.

He says that many of the tools developed so far are not easily integrated into a typical work flow or ready to use.

"To make an impact in neuroscience and connect the discipline to the most cutting-edge technologies such as machine learning and artificial intelligence, the community needs a cohesive infrastructure for cloud computing and data science to bring all these tremendous tools, libraries, data archives, and standards closer to the researchers who are working for the good of society," he said.

Fortunately, Pestilli found a like-minded collaborator who shares this vision in Dan Stanzione, the executive director of the Texas Advanced Computing Center (TACC) and a nationally recognized leader in HPC.

Together, they plan to create a national infrastructure that provides a registry for permanent data and analyses records. Researchers will be able to find data and more transparently see the root of how the analysis was conducted. The infrastructure will facilitate what the NSF) requires in data proposals, and what researchers want, which is scientific impact and reproducibility.

In addition, this means that access to data, analysis methods, and computational resources will move toward a more equitable model, providing opportunities for many more students, educators, and researchers than ever before.

"This prospect made me very excited about joining The University of Texas at Austin," Pestilli said. He re-located to Austin in August 2020, right in middle of the COVID-19 pandemic. Being at UT Austin means collaborating with TACC--a key reason why he accepted a professorship in the Department of Psychology.

"I'm confident that we can get it done--this vision is a crucial part of my efforts here."

Researchers at Michigan Medicine found a subset of middle-aged men with cerebral palsy are up to 5.6 times more likely to suffer fractures than men without the disorder.

"We are not really sure why this happens," said Edward A. Hurvitz, M.D., professor and chair of the Michigan Medicine Department of Physical Therapy and Rehabilitation. "It may be related to structural differences that occur during adolescent growth, or to greater bone mineral loss at earlier age for people with cerebral palsy compared to peers."

For a study published in BONE, the team examined the timing and site of bone fractures for around 10 million people with and without cerebral palsy using public and private insurance claims from 2016. They found people with the disability have fragile bones that present high fracture risk, but at different times across the lifespan compared to the general population.

"Knowing that critical periods of bone health are different for people with cerebral palsy is vital for clinicians so they aren't missing windows to augment bone strength," said Daniel Whitney, Ph.D., the study lead and assistant professor of physical medicine and rehabilitation at Michigan Medicine.

A period of critical bone health is when a person's bones are rapidly changing. In developmental years, they grow larger and stronger. They lose bone mineral density over time and may become weaker - for women, that can happen during menopause. Physicians often use these critical periods as reference points for fracture prevention efforts and post-fracture health care management.

The team examined fracture risk across the lifespan to see if the critical periods of bone health from the general population align with the timing of fracture vulnerability for people with cerebral palsy.

The result? Well, it's complicated.

In addition to the revelation about the surprisingly elevated fracture risk in middle aged-men, researchers found that adolescence and young adult years are a particularly vulnerable time for fractures for people with cerebral palsy, but in different ways for females and males.

Finding that both age and sex influence fracture risk at different times across the lifespan, the team developed new sex-specific critical periods of bone health for this population.

While this study positions clinical care to better align with the timing of the skeletal needs for people with cerebral palsy, it also raises a number of questions, Whitney said.

"Why do middle-aged men with cerebral palsy exhibit such a drastic increase in fracture risk?" he said. "Do women with cerebral palsy experience a similar timing or effect by the menopause transition on bone health? What is going on with the bone biology and structure early in life that sets the stage for their premature and profound bone fragility?"

It is well known that people with cerebral palsy have a higher risk of fractures, but this new study will change the way we think about fracture prevention, especially for adults, Hurvitz said.

"When we consider the high risk of chronic disease and early mortality associated with fractures that we have discovered in our previous work, fracture prevention for this population is a critical aspect of their care," he said.

The claims data used for the study doesn't reveal the severity of cerebral palsy patient's condition, which, researchers noted, would have added to their understanding of bone fragility.

This study will allow physicians to be more proactive with fracture prevention, and the next step is understanding exactly why bone health presents differently with these patients compared to the general population, Whitney said.

"When we only have a screwdriver, every problem will look like a screw," he said. "This study provides novel insight into the magnitude and unique timing of bone fragility across the lifespan for individuals with cerebral palsy, and it expands our toolkit to identify new ways to address a long-standing problem."

JUNE 10, 2021, NEW YORK - A Ludwig Cancer Research study adds to growing evidence that immune cells known as macrophages inhabiting the body cavities that house our vital organs can aid tumor growth by distracting the immune system's cancer-killing CD8+ T cells.

Reported in the current issue of Cancer Cell and led by Ludwig investigators Taha Merghoub and Jedd Wolchok at Memorial Sloan Kettering (MSK) and Charles Rudin of MSK, the study shows that cavity-resident macrophages express high levels of Tim-4, a receptor for phosphatidylserine (PS), a molecule that they surprisingly found on the surface of highly activated, cytotoxic and proliferative CD8+ T-cells.

"We believe T-cells that infiltrate the peritoneal cavity can be distracted by the interaction with Tim-4-expressing macrophages," explained study first author Andrew Chow, an assistant attending physician at the Ludwig Collaborative Laboratory at MSK.

The researchers also show that blocking Tim-4 in mouse models of cancer can prevent this distractive interaction and enhance the effectiveness of immunotherapies.

"I think in patients who have these serous cavity macrophages expressing high levels of Tim-4, blocking Tim-4 will make immune based therapies more effective," Merghoub, co-director of the Ludwig Collaborative Laboratory at MSK, said.

Just as people living in different cities might have distinct customs or accents, the macrophages in our bodies can adopt specialized functions and respond to disease differently depending on which tissue they inhabit. Scientists are increasingly interested in such localized responses because macrophage activities can influence recovery from illness or injury and responses to therapy.

Merghoub, Wolchok, Rudin, Chow and colleagues began exploring the role of macrophages in tumor immunosuppression after noticing that cancer patients with lesions in their pleural and peritoneal cavities--which house the lungs and organs of the gastrointestinal tract, respectively--were substantially less responsive to immune checkpoint blockade therapy, which stimulates a CD8+ T cell attack on tumors.

"That told us there was something immunosuppressive in these cavities, so we went hunting for what that could be," Chow said.

Previous studies have shown that other immunosuppressed sites in the body, such as the liver and bone, harbor macrophages expressing high levels of Tim-4. Others have shown that macrophages living in the pleural and peritoneal cavities of mice also exhibit a strong Tim-4 signal.

The researchers therefore suspected that cavity-resident macrophages might impair the anti-tumor activity of CD8+ T cells through the actions of Tim-4.

These suspicions were partly vindicated when the researchers analyzed the cavity macrophages of human lung cancer patients and found that while Tim-4 levels varied between individuals, those with higher levels of the receptor tended to have a reduced presence of CD8+ T cells that had features of responding to the tumor.

Based on these observations, the researchers explored whether blocking Tim-4 would enhance the efficacy of PD-1 blockade therapies in a pre-clinical mouse model of colon and lung cancer in the peritoneal cavity.

"We showed that you get the best tumor protection when you block both molecules," Chow said.

While blocking Tim-4 alone didn't reduce the number of tumors or improve survival in the mice, it did enhance the tumor protection afforded by PD-1 blockade and boost the numbers of CD8+ T cells in the peritoneal cavity. The researchers also showed that Tim-4 blockade reduces immunosuppression in adoptive T-cell therapy, in which tumor-targeting T-cells are isolated and selectively grown in a lab before they're reinfused into the patient.

"Together, these results suggest that Tim-4 blockade is a strategy to improve immunotherapy, regardless of whether you're trying to boost your immune response through immune checkpoint blockade therapy or via adoptive T-cell therapy," said Chow.

For Merghoub, the new findings demonstrate the need to better understand the diversity of immune landscapes in and around tumors. "In the same way we profile tumor genomes to guide the use of small molecule inhibitors for targeted therapies, we need to profile the immune landscapes of tumors and personalize immune-based therapies on the basis of such studies," he said.

ROCKVILLE, Md. - June 10, 2021 - The Association for Molecular Pathology (AMP), the premier global, molecular diagnostic professional society, today published consensus recommendations to aid in the design and validation of clinical CYP2D6 assays, promote standardization of testing across different laboratories and improve patient care. The manuscript, "Recommendations for Clinical CYP2D6 Genotyping Allele Selection: A Joint Consensus Recommendation of the Association for Molecular Pathology, College of American Pathologists, Dutch Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association, and European Society for Pharmacogenomics and Personalized Therapy," was released online ahead of publication in The Journal of Molecular Diagnostics.

The AMP Pharmacogenetics (PGx) Working Group is developing a series of guidelines designed to help standardize clinical testing for frequently used genotyping assays. The latest CYP2D6 report builds on the earlier recommendations for clinical genotyping of CYP2C19, CYP2C9, and genes important for warfarin testing. The recommendations should be implemented together with other relevant clinical guidelines such as those issued by the Clinical Pharmacogenetics Implementation Consortium (CPIC), Dutch Pharmacogenetics Working Group (DPWG), Canadian Pharmacogenomics Network for Drug Safety (CPNDS), and the American College of Medical Genetics and Genomics (ACMG), which mostly focus on the interpretation of PGx test results and therapeutic recommendations for specific drug-gene pairs.

"CYP2D6 is known to be responsible for the metabolism of many commonly prescribed medications including some antidepressants, atypical and typical antipsychotics, beta-blockers, opioids, antiemetics, and atomoxetine," said Victoria M. Pratt, PhD, Professor and Director of Pharmacogenetics and Molecular Genetics Laboratories, Indiana University School of Medicine, and AMP PGx Working Group Chair. "The ultimate goal of the AMP PGx Working Group is to promote standardization of PGx gene/allele testing across clinical laboratories. While the CYP2D6 gene is especially complex, with this latest report, we have been able to define a minimum set of variants that should be included in all future clinical CYP2D6 PGx genotyping assays."

Similar to the previous reports in the series, the CYP2D6 genotyping guideline offers a two-tier categorization of alleles that are recommended for inclusion in clinical PGx genotyping assays. Using criteria such as allele frequencies in different populations and ethnicities, the availability of reference materials, and other technical considerations, the AMP PGx Working Group recommended a minimum set of alleles and their defining variants that should be included in all clinical CYP2D6 genotyping tests (Tier 1). The team also defined a Tier 2 list of optional alleles that do not currently meet one or more of the criteria for inclusion in Tier 1. These recommendations are meant to be a reference guide and not to be interpreted as a restrictive list. AMP intends to update these recommendations as new data and/or reference materials become available.

"AMP is committed to collaborating with the broader laboratory community to continuously improve professional PGx practices amidst a rapidly evolving molecular diagnostic landscape," said Antonia R. Sepulveda, MD, PhD, AMP President and Professor and Chair of the George Washington School of Medicine Department of Pathology. "Standardizing clinical testing for frequently used PGx genotyping assays will improve concordance across laboratories and enable healthcare professionals to provide high-quality patient care."

(Boston)--Medical education aspires to mitigate bias in future professionals by providing a robust curriculum that includes perspectives and practices for caring for sexual and gender minority (SGM) populations, including lesbian, gay, bisexual, transgender and intersex (LGBTQI) persons. To provide medical schools with a more systematic, uniform approach to teaching these topics in their curriculum, the Association of American Medical Colleges (AAMC) in 2014 published 30 SGM competencies and topics that curricula should address. However, implementation of these ideals remains challenging.

Building off the AAMC's comprehensive resource guide, medical education leaders at Boston University School of Medicine (BUSM) have developed a curriculum assessment tool to efficiently assess whether a medical school adequately incorporates recommended SGM core competencies.

"Medical schools vary in how they cover SGM topics and to what extent graduating students feel prepared to meet the needs of these populations. Medical school leaders motivated to improve curricula on caring for SGM populations must survey their school's current curricula to identify their school's strengths and opportunities for improvement," said corresponding author Ann Zumwalt, PhD, associate professor of anatomy and neurobiology at BUSM and chair of the Gender and Sexual Diversity Vertical Integration Group (GSD VIG).

In 2018, the school convened the GSD VIG, comprising a group of BUSM faculty and students with experience and expertise regarding SGM health, to examine the state of BUSM's curriculum on SGM health. The group distilled the 30 AAMC competencies into 12 SGM topic areas that should be addressed in any medical school curriculum. They then developed the SGM Curriculum Assessment Tool (SGM-CAT), which employs targeted curriculum assessment questions to assess whether these topic areas are addressed within the curriculum--and, if they are, how and where.

This tool was distributed to all course and clerkship directors responsible for the required curriculum at BUSM to investigate where these core topics are addressed. The curriculum assessment tool identified several strengths in the pre-clerkship and clerkship curricula, including faculty willingness and enthusiasm to include SGM topics, but also revealed that some SGM topics are underrepresented in the BUSM curriculum.

"What is exciting about our tool is that we used our proficiency to distill the 30 AAMC competencies into 12 easily understandable topics that should be taught in any curriculum. We then surveyed all course and clerkship directors on whether they teach any of those 12 topics. The process/tool we developed is a straightforward way to get a snapshot of what is being taught where across the entire curriculum," added Zumwalt.

"As it is still not a requirement of medical training, identifying where SGM content even exists in medical schools is extremely difficult. This tool aims to easily and quickly reveal where SGM content is addressed in undergraduate medical education, thereby allowing for more rapid and comprehensive interventions to improve training," explained co-author Carl Streed, Jr., MD, MPH, FACP, assistant professor of medicine at BUSM and a primary care physician and research lead in the Center for Transgender Medicine & Surgery at Boston Medical Center (BMC).

According to the researchers, many faculty may miss opportunities to teach about SGM health because they do not recognize how the material fits with their topic. "The tool was designed to be used by individuals who are less familiar with SGM health and makes curricular change easier by helping users understand how SGM health is incorporated into existing curricula," added Jenny Siegel, MD, assistant professor of medicine at BUSM and medical director, Center for Transgender Medicine & Surgery at BMC.

Breakthrough in metamaterials: for the first time in the world, researchers at Tel Aviv University developed an innovative nanotechnology that transforms a transparent calcite nanoparticle into a sparkling gold-like particle. In other words, they turned the transparent particle into a particle that is visible despite its very small dimensions. According to the researchers the new material can serve as a platform for innovative cancer treatments.

In a new paper published in Advanced Materials, an international team of scientists, coordinated by Dr. Roman Noskov and Dr. Pavel Ginzburg from the Iby and Aladar Fleischman Faculty of Engineering at Tel Aviv University, Prof. Dmitry Gorin from the Center for Photonics and Quantum Materials at the Skolkovo Institute of Science and Technology (Skoltech) and Dr. Evgeny Shirshin from M.V. Lomonosov Moscow State University, has introduced the concept of biofriendly delivery of optical resonances via a mesoscopic metamaterial, a material with properties that are not found in nature. This approach opens promising prospects for multifunctionality in biomedical systems, allowing the use of a single designer-made nanoparticle for sensing, photothermal therapy, photoacoustic tomography, bioimaging, and targeted drug delivery.

"This concept is the result of cross-disciplinary thinking at the interface between the physics of metamaterials and bioorganic chemistry, aiming to meet the needs of nanomedicine. We were able to create a mesoscopic submicron metamaterial from biocompatible components that demonstrates strong Mie resonances covering the near-infrared spectral window in which biological tissues are transparent," says Dr. Roman Noskov.

The nanostructures capable of nanoscale light localization as well as performing several functions are highly desirable in a plethora of biomedical applications. However, biocompatibility is typically a problem, as engineering of optical properties often calls for using toxic compounds and chemicals. The researchers have resolved this issue by employing gold nanoseeds and porous vaterite (calcium carbonate) spherulites, currently considered promising drug-delivery vehicles. This approach involves controllable infusion of gold nanoseeds into a vaterite scaffold resulting in a mesoscopic metamaterial - golden vaterite - whose resonance properties can be widely tuned by changing the quantity of gold inside the vaterite. Additionally, high payload capacity of vaterite spherulites allows simultaneous loading of both drugs and fluorescent tags. To exemplify the performance of their system, the researchers demonstrated efficient laser heating of golden vaterite at red and near?infrared wavelengths, highly desirable in photothermal therapy, and photoacoustic tomography.

Prof. Pavel Ginzburg summarizes: "This novel platform enables the accommodation of multiple functionalities - as simple add-ons that can be introduced almost on demand. Alongside optical imaging and thermotherapy, MRI visibility, functional biomedical materials and many other modalities can be introduced within a miniature nano-scale particle. I believe that our collaborative efforts will lead to in-vivo demonstrations, which will pave the way for a new biomedical technology."

Through the biological fixation of the element nitrogen by the enzyme nitrogenase, organisms gain access to molecular nitrogen (N2) in the Earth's atmosphere, which is essential for building cellular structures. In addition, a vanadium-dependent variant of nitrogenase can reduce the toxic gas carbon monoxide (CO) to hydrocarbons. These reductions of N2 and CO are among the most important processes in industrial chemistry, as they are used to produce both fertilizers and synthetic fuels. However, researchers have not yet been able to decipher the different pathways of the two reactions. Dr. Michael Rohde from Prof. Dr. Oliver Einsle's team at the Institute of Biochemistry at the University of Freiburg, in collaboration with two research groups at Freie Universität Berlin, has now been able to show how the active site of the vanadium-dependent nitrogenase is able to bind two CO molecules simultaneously, thereby creating the basis for combining the spatially adjacent carbon atoms of both molecules in a reductive process. The researchers recently presented their results in the journal Science Advances.

The industrial reductions of N2 and CO - known as the Haber-Bosch and Fischer-Tropsch processes, respectively - require high temperatures and pressure. While N2 reduction leads to the bioavailable product ammonium (NH4+), at least two carbon atoms combine during the conversion of CO. The predominant reaction product is ethylene (ethene, C2H4), a colorless gas that plays an important role not only in fuels but also in the production of plastics. Although the cleavage of an N-N bond in nitrogen fixation is chemically quite fundamentally different from the formation of a C-C bond in CO reduction, scientists previously suspected that nitrogenase uses the same basic mechanistic principles for both reactions.

In a previous work, the team led by Rohde and Einsle used nitrogenase to react with CO gas, resulting in the specific binding of a single molecule. In their current study, which builds on this work, the researchers show that they gassed crystals of this first state with CO under pressure and then subjected them to X-ray crystallographic analysis. This allowed them to directly observe how a second CO molecule binds. "The form of nitrogenase obtained in this way, with two CO molecules at the active site, probably represents a blocked state," Rohde explains, "but it provides direct clues to the mechanism of the enzyme." As a result, Einsle's team can now outline a detailed mechanism of CO reduction through nitrogenase.

MINNEAPOLIS/ST.PAUL (06/10/2021) -- New findings from the University of Minnesota Medical School are helping uncover why some people are more likely to be overweight and develop Type 2 diabetes -- and it starts in the womb.

Previous association studies have shown that low birthweight among infants is a strong determinant for eventual obesity and Type 2 diabetes. The placenta of infants with a low birthweight have reduced levels of mTOR (mechanistic target of rapamycin), and the placenta of bigger infants have increased levels of mTOR. Building off of that research, a U of M Medical School study, published in JCI Insight, is the first to directly implicate mTOR, a nutrient-sensor protein in the placenta, as a possible regulator of an infant's birthweight.

"It is clear from human and preclinical studies that Type 2 diabetes has fetal origins, but we do not yet know the mechanisms of how this programming of metabolic dysfunction or Type 2 diabetes occurs," said senior author, Emilyn Alejandro, PhD, an associate professor in the Department of Integrative Biology and Physiology. "Our study is the first to show a direct role of a placental protein, like mTOR."

They found that in preclinical studies:

- After eliminating mTOR in the placenta, female offspring had lower birthweights and had an increased risk for obesity and insulin resistance in adulthood.

- In contrast, after increasing mTOR signaling in the placenta, female adult offspring were protected from high-fat diet induced obesity.

"A causal relationship between placental mTOR and the metabolic health of the offspring has not been tested before, and our study suggests that manipulating mTOR in the placenta is sufficient to cause permanent and lasting impact on the health trajectory of the offspring" said Brian Akhaphong, first author and a post-baccalaureate trainee in the Alejandro Lab. "Our hope is that we can identify proteins that we may target therapeutically through maternal health to reduce the prevalence of Type 2 diabetes."

The research team will continue their study, probing which metabolic tissues in the offspring are permanently impacted by placental mTOR signaling. Megan Beetch, PhD, a postdoctoral fellow, will look at the epigenetics, or heritable changes in gene expression, that do not involve changes to the underlying DNA sequence.

Genova (Italy) 10 June, 2021 - The U-Vip (Unit for Visually Impaired People) research team led by Monica Gori at the IIT- Istituto Italiano di Tecnologia (Italian Institute of Technology) has recently published a study which shows for the first time how children aged from 3 to 5 years old have problems in recognising the emotions of people wearing surgical masks. This collateral effect of the preventive measures linked to the Covid-19 health emergency could influence the correct development of children's capabilities of social interaction. The research paper has been published in Frontiers in Psychology.

The use of facemasks for children within the context of the COVID-19 pandemic was a focus of a document compiled by the World Health Organisation (WHO) and UNICEF to provide guidance for decision-makers and authorities in public and professional fields, discouraging exposure to the use of facemasks when dealing with children aged up to five years old. In addition, even for older children, WHO recommends giving careful consideration to the benefits of wearing facemasks in comparison with the potential damage that could include social and psychological problems, and difficulties in communication and learning.

The study by the IIT research team led by Monica Gori regards this context, and, for the first time it focuses on pre-school age group and it helps define the measures that can be taken to reduce the impact of the use of surgical masks amongst children. In fact, even though from 3 to 5 years of age, wearing facemasks is not mandatory, children are in any case exposed to the use of such preventive measures in various everyday social and educational contexts.

The IIT researchers prepared a quiz containing images of people with and without facemasks, and displayed them by computer, tablet or smartphone to 119 individuals comprising 31 children aged between 3 and 5 years old, 49 children between 6 and 8 years old, and 39 adults between 18 and 30 years old. The subjects, independently or with parental assistance in the case of the youngest participants, were asked to try to recognise the faces' expressions, with and without facemask, conveying different emotions such as happiness, sadness, fear and anger.

The results showed that children aged between 3 and 5 years old are capable of recognising facial expressions conveying happiness and sadness on only 40% of occasions when the faces are covered by a facemask. The percentages were higher for other age groups: children aged from 6 to 8 years old (55-65%) and adults (70-80%) but in general, all age groups showed a degree of difficulty in interpreting these emotions expressed while the face was partially covered by a facemask. As regards the other emotions, there were better results, but we can say that the age group that finds it hardest to recognise emotions expressed from behind a facemask is that of children in pre-school age.

"The experiment was performed in the earliest phases of the 2020 pandemic, and at that time facemasks were still a new experience for everyone.", comments Monica Gori, "Children's brains are highly flexible, and at the moment we are performing tests to ascertain whether children's understanding of emotions has increased or not", concludes Gori.

"In the study, we worked with children and adults with no forms of disability", explains Maria Bianca Amadeo, IIT researcher and co-author of the research study, "of course, these observations are even more important when considering children affected by disabilities". "Indeed", explains Lucia Schiatti, IIT researcher and co-author of the study "for example visual impairment implies difficulties in social interaction. For such individuals in particular, it will be even more necessary to concentrate on possible preventive measures or specific rehabilitation activities".

Over the next few years, it will be essential to perform work designed to explore the actual impact of this preventive health measure on children's ability to interact, both those affected by disabilities and those without disabilities.
In the meantime, the IIT study suggests considering the use of transparent facemasks for all operators in contact with children in the 3-5 year-old age group, or the formulation of specific training activities designed to teach children how to recognise emotions purely through observation of the eyes.

Because of a phenomenon called gravitational locking, the Moon always faces the Earth from the same side. This proved useful in the early lunar landing missions in the 20th century, as there was always a direct line of sight for uninterrupted radiocommunications between Earth ground stations and equipment on the Moon. However, gravitational locking makes exploring the hidden face of the moon--the far side--much more challenging, because signals cannot be sent directly across the Moon towards Earth.

Still, in January 2019, China's lunar probe Chang'e-4 marked the first time a spacecraft landed on the far side of the Moon. Both the lander and the lunar rover it carried have been gathering and sending back images and data from previously unexplored areas. But how does Chang'e-4 probe communicate with the Earth? The answer is Queqiao, a relay communications satellite, explains Dr. Lihua Zhang from DFH Satellite Co., Ltd., China.

As explained by Dr. Zhang in a review paper recently published in Space: Science & Technology, Queqiao is an unprecedented satellite designed specifically for one purpose: to act as a bridge between Chang'e-4 probe and the Earth. Queqiao was launched in 2018 and put into orbit around a point 'behind' the Moon. This point is known as the Earth-Moon Libration point 2, where a special case of gravitational balance allows Queqiao to maintain an orbit such that it has almost constant direct line of sight with both the far side of the Moon and the Earth. Getting the satellite into this peculiar orbit required careful planning and maintenance management, and the success of this operation set a precedent for future attempts at putting satellites in orbit around other Earth-Moon libration points.

From its stable place in space, Queqiao helped guide the soft-landing and surface operations of Chang'e-4 probe and has been our intermediary with it ever since. The satellite is equipped with two different kinds of antennas: a parabolic antenna and several spiral antennas. The former, which has a large diameter of 4.2 m, was designed to send and receive signals on the X band (7-8GHz) to and from the rover and lander on the surface of the Moon. Its large size is related the expected noise levels and the low intensity of the transmissions that are sent by surface equipment.

On the other hand, the spiral antennas operate on the S band (2-4 GHz) and communicate with Earth ground stations, forwarding commands to the lunar surface equipment and exchanging telemetry and tracking data. Most notably, all these different links can transmit and receive simultaneously, making Queqiao highly versatile. The review paper addresses other important design considerations for Queqiao and future relay satellites, such as the use of regenerative forwarding, the various link data rates involved, and data storage systems for when no Earth ground station is accessible.

Over two years of exploration, a great amount of data has been received from the rover and lander through Queqiao. "Scientists in both China and other countries have conducted analysis and research based on the retrieved data, and they have produced valuable scientific results. The longer the operational life of Queqiao, the more scientific outcomes will be achieved," remarks Dr. Zhang. Based on current predictions, Queqiao should be operable on mission orbit for at least five years.

Dr. Zhang also addressed the prospects for future lunar missions and how relay communication systems should evolve to support them. Many unexplored areas on the Moon, such as the largest crater at the South Pole, call for multiple relay satellites to maintain constant communication links, which poses an expensive and time-consuming challenge. But what if relay satellites were suitable for more than a single mission? "A sustainable communication and navigation infrastructure should be established to benefit all lunar missions rather than dealing with each mission independently," comments Dr. Zhang, "This infrastructure should adopt an open and extensible architecture and provide flexible, interoperable, cross-supportable, and compatible communications services, which are critical to the success of future lunar explorations." It's likely that future endeavors on the far side of the Moon will be a test on how well we can cooperate to unveil the secrets of our natural satellite.