Culture

During the height of the pandemic, researchers at Children's National Hospital discovered that as many as one half of children diagnosed with multisystem inflammatory disease in children (MIS-C) at the hospital developed cardiac complications including coronary artery abnormalities, even when diagnosed and treated promptly.

The data was shared as part of a poster presentation at the American Heart Association Scientific Sessions in November 2020. Though analysis was limited to the data from one institution's confirmed MIS-C cases, the findings are significant enough to warrant further study.

Interestingly, the authors noted that the high rate of cardiac complications far exceeds the rate of similar issues in children with Kawasaki disease -- another pediatric inflammatory syndrome that shares many common symptoms with MIS-C. The two are so similar that immunomodulation therapies successfully deployed in children with MIS-C were based on those developed to treat Kawasaki disease.

Knowledge of common cardiac complications in Kawasaki disease also flagged the need for routine echocardiograms in patients with MIS-C, which helped identify the higher rates of cardiac complications seen in the MIS-C patient population.

"This finding, however, is another data point that shows how MIS-C and Kawasaki disease have some specific differences needing further study," says Ashraf Harahsheh, M.D., a pediatric cardiologist at Children's National Hospital who studies Kawasaki disease and the first author on the new study.

"Previous clinical advancements made in Kawasaki disease set the stage for our response to MIS-C early on," he said. "Now we also need to understand MIS-C as its own syndrome so we can better address what we are seeing in this patient population," he says.

While most of the cardiac findings resolved during follow up, long-term studies are needed to determine if the cardiac abnormalities are associated with major cardiac events later.

"This work will help inform the community of the importance of diagnosing children with MIS-C promptly and following clinical guidelines for necessary tests and treatments once MIS-C is diagnosed," Harahsheh concludes.

Next, the research team plans to take a deep dive into patient demographics as well as findings from clinical, laboratory and electrocardiogram data for children who developed cardiac complications with MIS-C. The goal will be to refine treatment algorithms and potentially identify a subgroup of patients who may require different or more intense therapy to prevent cardiac complications.

New research from the University of Southern California measured the use of Medicaid's annual wellness visits and the receipt of structured cognitive assessments among Medicaid beneficiaries.

Lead author Mireille Jacobson, an economist and associate professor at the USC Leonard Davis School of Gerontology, and colleagues surveyed a sample of adults with either Medicare Advantage (MA) or fee-for service Medicare. Among the findings, approximately one-half of beneficiaries reported having an annual wellness visit, but only about a quarter of total respondents reported receiving a structured cognitive assessment at an annual wellness visit, even though, under the Affordable Care Act (ACA), detection of cognitive impairment is a required component of the visit.

The study, Cognitive Assessment at Medicare's Annual Wellness Visit In Fee-For-Service And Medicare Advantage Plans appears in the November issue of the journal Health Affairs and provides new insights - the self-reports of survey respondents - into cognitive assessments at annual wellness visits, an area that has been somewhat hidden from view.

"Until now there has been little clarity on whether any assessments actually take place because providers bill for the visit not the services," said Jacobson, who is also co-director of the Aging and Cognition Program at the USC Leonard D. Schaeffer Center for Health Policy & Economics. "In addition, because Medicare offers limited policy guidance on how to perform an assessment, it has been unclear who, if anyone, receives a structured cognitive assessment versus direct observation, in which the clinician might be looking at them and talking to a caregiver or a spouse but not actually doing much formal testing."

The researchers say variations in wellness visits and cognitive assessments by Medicare coverage type are even less understood. According to the study, Medicare Advantage (MA) enrollees were nearly 20 percentage points more likely to report that they had an annual wellness visit and more than eight percentage points more likely than those in fee-for-service Medicare to report a structured cognitive assessment at an annual wellness visit, primarily because of their higher likelihood of receiving such a visit. MA beneficiaries were also more likely to have a cognitive screen at any health care visit. The team states that the differences suggest that the rate of structured cognitive assessment in fee-for-service Medicare might be increased if incentives for take-up were similar to those in Medicare Advantage, but they say more research is needed to validate these differences and understand what accounts for them.

The Medicare annual wellness visit and required cognitive screening are part of efforts to promote early detection of dementia and have been available since 2011. According to data from study co-author, Julie Zissimopoulos, co-director of the Aging and Cognition program at the USC Schaeffer Center, around one in 12 Americans age 65 and older is estimated to be living with dementia, with costs of medical and long term care approaching $3 trillion. Costs associated with Alzheimer's disease, the most common form of dementia, are expected to exceed $1.5 trillion by 2050.

"Increases in the number of people living with dementia and in the financial and nonfinancial costs of care are major policy concerns," said Zissimopoulos, who is also an associate professor at the USC Price School. "Early detection of cognitive impairment can have benefits that include the identification of treatment or improvement in quality of life."

The researchers note that the ACA does not specify that screenings for cognitive impairment need to be structured assessments - and that there has not yet been a direct analysis comparing the two methods. The Alzheimer's Association developed a toolkit that includes recommendations for when to administer structured tests, along with specific five-minute tests to choose from; these ask people to perform tasks like drawing a clock, identifying a picture or recalling words.

"Despite unanswered questions about the benefits of screening for patients and caregivers and the accuracy of tools, our survey data indicate that structured cognitive assessment is valued by older people," said Zissimopoulos. "Combined with randomized controlled trial evidence that screening in the primary care setting does not increase depressive symptoms or anxiety, these data provide further evidence to support the use of structured cognitive assessments
at the annual wellness visit."

The US Preventive Services Task Force also refrains from recommending structured assessments, stating, "there is insufficient evidence to sasses the balance of benefits and harms of screening for cognitive impairment in older adults." However, Jacobson warns about the issue of leaving assessment to direct observation when findings from other settings suggest that our own observations are subject to overconfidence, confirmation, and other psychological biases.

"The current assessment requirements are quite vague, and I hope this study can prompt some discussion and new research around what the costs and benefits are in leaving this evaluation up to physician observation versus doing more structured assessments," she said.

Bottom Line: Deaths from cancer accounted for more than 4 million potential years of life lost in 2017. While the cancer types with the highest death rates per capita accounted for the greatest number of years lost, cancers that typically occur at younger ages bore a disproportionate share of the burden.

Journal in Which the Study was Published: Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research

Author: Minkyo Song, MD, PhD, a research fellow at the National Cancer institute, part of the National Institutes of Health.

Background: "Potential years of life lost (PYLL) is an estimate of the average years a person would have lived if he or she had not died prematurely. Given that cancer is the leading cause of death in those younger than 80 years old, it is important to study the effect of cancer death rates among younger people," Song explained.

In 2017, there were 599,099 cancer deaths in the United States, according to death certificate data from the National Center for Health Statistics.

How the Study was Conducted: Song and colleagues used national mortality data from the U.S. National Center for Health Statistics, coupled with a commonly used definition of PYLL as the number of years lost prior to age 75, to quantify how many years of life were prematurely lost.

Results: The researchers calculated that 4,280,128 years of life were prematurely lost due to cancer in 2017.

For the most part, PYLL mirrored overall U.S. cancer mortality trends. For example, lung cancer, the cancer type that causes the largest number of deaths, accounted for approximately 24.3 percent of U.S. cancer deaths and 20.8 percent of PYLL. Colon/rectum cancer accounted for 8.8 percent of deaths and 9.6 percent of PYLL. Pancreatic cancer accounted for 7.3 percent of deaths and 6.6 percent of PYLL, while breast cancer accounted for 7.1 percent of deaths and 9.4 percent of PYLL.

One exception to this pattern was prostate cancer, which causes about 5.1 percent of U.S. cancer deaths but only 2 percent of PYLL. "Many of the deaths caused by this cancer occurred at older ages, resulting in fewer PYLL," Song noted.

Another metric, PYLL per death, provided a useful tool to measure the burden from several rare cancers that typically affect younger people, Song said. For example, testicular cancer accounted for 0.1 percent of cancer deaths in 2017, and 0.3 percent of PYLL. Bone cancer accounted for 0.3 percent of deaths, but 0.7 percent of PYLL. Although these cancers did not contribute dramatically to overall cancer mortality, they caused the highest numbers of life years lost per death: Testicular cancer had the highest PYLL per death, with an average of 34 years lost, followed by bone cancer, with an average of 26.4 years lost, and endocrine cancers including thymus cancer, with an average of 25.2 years lost.

The total number of PYLL increased slightly from 1990, despite an overall decrease in cancer deaths. In 1990, there were 4,262,397 PYLL, compared with the 4,280,128 recorded in 2017. During this time, overall cancer mortality dropped from 214.9 per 100,000 in 1990 to 152.7 per 100,000 in 2017. The researchers found that the increase in PYLL was due to the growth of the U.S. population.

The study also showed that ethnic and racial minority groups account for a disproportionate share of the burden of premature cancer death. In 2017, 78 percent of all cancer deaths occurred in non-Hispanic whites, but only 70 percent of PYLL occurred in this group. By contrast, Hispanics accounted for 7 percent of cancer deaths and 10 percent of PYLL, while Blacks accounted for 12 percent of cancer deaths and 15 percent of PYLL.

Author's Comments: Overall, Song said, "PYLL is a useful 'complementary measure' to cancer mortality rates. Together, they provide a more detailed picture of the social and economic toll of cancer. PYLL can be used to estimate the impact of cancer death in younger populations. This metric highlights the enormous loss of life due to certain cancers that occur at younger ages, even if they occur infrequently."

Study Limitations: As a limitation, the researchers noted that the study relied on the cause of death reported on death certificates, which are subject to error. They also pointed out that other studies have used different definitions of PYLL, contributing to some differences across the body of research on this topic.

Funding & Disclosures: This study was funded by the Intramural Research Program at the National Cancer Institute. Song declares no conflicts of interest.

ARLINGTON HEIGHTS, Ill (November 13, 2020) - Throughout the course of the COVID-19 pandemic, those able to wear a face mask have been encouraged to do so to prevent transmission of the virus. For some people with skin allergies, wearing a mask can cause further problems. A medically challenging case presented at this year's virtual American College of Allergy, Asthma and Immunology (ACAAI) Annual Scientific Meeting revealed that for a man with several skin allergies, mask-wearing triggered his contact dermatitis.

"We treated a 60-year-old Black man with adult-onset eczema, contact dermatitis and chronic nasal allergies in our clinic after he presented three times to our hospital emergency room (ER) because of an uncomfortable face rash," says allergist Yashu Dhamija, MD, ACAAI member and lead author of the paper. "Up until April 2020, his skin conditions had been under control, but with mask-wearing, his symptoms began occurring in areas that providers were not yet accustomed to."

The ER doctors who first saw the patient prescribed prednisone for the rash. When his symptoms were not relieved, the patient underwent a follow up telehealth visit with the hospital's allergy clinic. Further investigation revealed his skin allergies had begun to flare in April 2020, coinciding with the pandemic and his mask-wearing.

"We realized that his rash appeared right where the elastic parts of a mask would rest," said allergist Kristin Schmidlin, MD, ACAAI member and co-author of the paper. "We tapered down the prednisone and advised him to use a topical steroid and a topical immunosuppressant until the rash resolved. We also told him to use cotton-based, dye-free masks without elastic. At a follow up telephone visit one week later, the patient said his rash continued to improve."

The authors note common allergens that can affect contact dermatitis are found in masks, elastic bands, and other components of face masks. People with existing skin allergies should work with their allergist. Your board-certified allergist can perform patch testing to help identify specific components in masks which may be triggering symptoms.

Religion hampered the diffusion of knowledge and economic development in France during the Second Industrial Revolution (1870-1914), according to research by Mara Squicciarini of Bocconi University recently published in the American Economic Review.

By opposing the introduction of technical education in primary schools, the Catholic Church in fact prevented the accumulation of human capital in the most religious areas of the country. Higher levels of religious education translated into significant lower industrial employment 10 to 15 years later, when schoolchildren entered the labor market.

"And these findings have important implications for economic development today," says Professor Squicciarini, "since many developing countries - where religion plays a primary role in the personal and public spheres - are experiencing large-scale technological progress, similar to that of Western Europe during the Second Industrial Revolution."

"The more sophisticated industrial machinery of the Second Industrial Revolution required a technically skilled workforce. Consequently, the French state took an active role in promoting a more technical curriculum to form a skilled labor force," Professor Squicciarini explains. But the Church was promoting a conservative, antiscientific program, hindering the introduction of the technical curriculum and pushing for religious education, while secular schools became increasingly modern and professional, the study shows.

The religious intensity of an area is associated with the diffusion of religious education and this, in turn, is associated with lower industrial development. The effect is sizeable: moving from the tenth to the ninetieth percentile of the share of Catholic schools distribution would decrease the share of industrial employment by 6.2 percentage points, relative to a mean of 28%.

The economic development of areas with a high or low religiosity did not start to diverge, though, until the Second Industrial Revolution, when the school curricula and the accumulation of human capital among the population began to count for industrial development. These results suggest that the relationship between religion and economic development is not inherently negative. Rather, it varies over time, and it becomes negative when religion hinders the adoption of economically useful knowledge.

WEST LAFAYETTE, Ind. - Pearls have long been favored as objects of beauty. Now, Purdue University innovators are using the gem to provide potential new opportunities for spectral information processing that can be applied to spectroscopy in biomedical and military applications.

The Purdue team demonstrated light transport-assisted information processing by creating a pearl spectrometer.

Spectrometers probe interactions of matter and light as a function of the electromagnetic spectrum and are commonly used in biomedical and military applications. For example, they have been used for diagnostics of various types of cancer and for military gas sensing.

"Unfortunately, widespread uses and practical adaptions of spectroscopy are often limited due to the need of conventional spectrometers," said Young Kim, an associate professor of biomedical engineering at Purdue. "The current spectrometers rely on complex device assembly, high-precision alignment and large physical size or dimension, all of which prevent rapid translation into practical applications."

The work, which was funded by the U.S. Air Force Research Laboratory, is published in Nano Letters.

"We discovered that pearls are an ideal natural object for Anderson localization of light, named after Nobel laureate Philip Anderson, whose concept has been extended to describe how light undergoes on and off resonances inside materials due to their strong scattering," Kim said.

Yunsang Kwak, a postdoctoral fellow in the lab at Purdue, said, "Anderson light localization offers high randomness that is extremely helpful for compressive sensing, in particular to conduct information processing with a thin and plat form factor, by simply attaching a pearl-like multispectral filter array on a conventional camera."

Kim said, "We do not think that the direct use of a pearl would be a good option for mass production of multispectral filter arrays. Instead, pearls teach us how to design disordered nanostructures of Anderson light localization to develop a new class of spectral information processing machine."

The Purdue researchers are looking to their new discovery to provide scientists with an idea of hybridizing material and digital properties, which could be useful for innovations in biomedical and defense applications.

Researchers from Nanjing University, Temple University, Fudan University, and Waseda University published a new paper in the Journal of Marketing that examines the double-edged effects of ECR ads on customer purchases.

The study, forthcoming in the the Journal of Marketing, is titled "The Double-Edged Effects of E-Commerce Cart Retargeting: Does Too Early Retargeting Backfire?" and is authored by Jing Li, Xueming Luo, Xianghua Lu, and Takeshi Moriguchi.

Because consumers often abandon e-commerce carts, companies are shifting their online advertising budgets to immediate e-commerce cart retargeting (ECR). They presume that early reminder ads, relative to late ones, generate more click-throughs and web revisits.

To test this presumption, the researchers developed a conceptual framework of the double-edged effects of ECR ads and empirically support it with a multi-study multi-setting design. In Study 1, they find that customers who received an early ECR ad within 30 minutes to one hour are less likely to make a purchase compared to those who did not receive it. In other words, delivering ECR ads too early can engender worse purchase rates than without delivering them, thus wasting online advertising budgets. By contrast, a late ECR ad after one to three days has a positive incremental impact on customer purchases. Study 2 replicates this double-edged impact of ECR ads delivered by mobile SMS and explores cart characteristics. Both the negative impact of early ECR and positive impact of late ECR can be amplified when the products in the retargeted carts are larger in quantity and at higher average prices.

Li says that "Given the prevalence of retargeting ads in practice, our findings provide managers with specific guidance on implementing ECR ads to boost ROI on retargeting campaigns. First, companies should not heedlessly follow the recency bump and shift all their online ad budgets to immediate retargeting. Delivering ECR ads too early can engender worse purchase rates than without delivering them. That is, too-soon reminder ads may annoy consumers and backfire, thus not only squandering ad budgets, but also likely hurting customers' long-term satisfaction." Prudent marketers should resist the temptation of immediate retargeting even though advanced digital e-commerce technologies can deliver retargeting ads within minutes after consumers abandon carts online. However, early ECR with price discounts or scarcity framing may allow managers to engender more purchase responses. But price discounts are not a panacea: When repeatedly used, they may train strategic customers who purposefully cart products and then wait for price discounts before purchasing.

"It is pivotal to scientifically gauge the causal impact of ECR ads. Firms should not rely on the absolute purchases as a measure of success, but rather adopt the relative purchase" adds Luo. "Without comparing the retargeting with the control, managers may mistakenly conclude that the early ECR is most effective."

The study also finds that a late ECR ad can be effective and win back potential customers with an increase in ROI on advertising. Moriguchi points out that "Firms can better deploy ECR ad campaigns with a delay after consumers abandon carts to minimize negative ad annoyance as well as maximize the positive ad reminder effects on customer purchases. Retargeting carts in e-commerce has enormous business potential because more than 69% of consumers abandon carts online, which amounts to more than $4.6 trillion each year." The right timing of ECR does not incur additional financial costs in retargeting, but can significantly lift customer purchases.

Finally, managerial actions call for an appropriate match between the timing of ECR ads and retargeted products. It is necessary to use ECR to cater to different types of cart abandonment. Different cases include carts with a high quantity of products versus carts with only one item or carts with an expensive product versus a cheap one. Thus, the researchers reveal a tactic e-commerce retailers can use to more accurately retarget customers with different digital carts. "Firms can strategically decide the time to turn on ECR, depending on its suitability for different types of carts, to maximize conversions" says Lu. For example, managers can win back more customers by implementing late ECR ads for carts with a larger quantity of products abandoned.

Much like investors on the stock market, cell populations prepare for changes in the environment by spreading the risk. The tool box they use contains a repertoire of sensory receptors on the surface of individual cells. These receptors can be tweaked to make individual members of the population responsive to different environmental signals. It was thought that cells could only modify this diversity relatively slowly, by producing new receptor proteins or degrading them. Scientists at AMOLF (Amsterdam, the Netherlands) and Yale University (New Haven, CT) now report the discovery of a mechanism that enables cell populations to tune their diversity much faster, by a combination of physical and chemical interactions between existing proteins. The findings are published in the journal Science Advances on November 13th.

The new experimental findings reveal that populations of E. coli bacteria cells maintain a high diversity in their sensory portfolio when environmental signals are absent, but this diversity decreases drastically (by a factor of 10) when subjected to new environmental signals. "This makes a lot of sense," explains Tom Shimizu, a group leader at AMOLF and senior author of the study. "When environmental signals are scarce, uncertainty about the future is at a maximum, so the smart thing to do is to spread your bets broadly across many possible new signals. But the game changes once you sense a certain stimulus. Evidently, cell populations use that new information to 'focus' their attention to a particular signal, so that the whole population can respond together."

What was surprising, however, was how rapidly cells could switch to this new strategy. In biological cells, updates of the portfolio of sensory capabilities were until now assumed to require changes in gene expression, a time consuming process that involves the synthesis of new protein molecules or degradation of old ones. "However, these cell populations could adjust the way they spread their bets over different sensory modes within seconds," says Keita Kamino, lead author of the study who initiated the study at AMOLF and finished it at Yale. "This immediately ruled out the possibility that the cells were updating their bets by gene expression, which takes minutes to hours". To investigate the mechanism at work, the team then built a mathematical model of the observed diversity, based on known interactions between receptors and other molecules that process and relay signals across the cell. Although the model does not include a way for cells to change their gene expression, they found that it very accurately predicts the changes in the sensory diversity of cells observed in the earlier experiments. "Remarkably, diversity tuning emerges from the a combination of allosteric interactions and covalent modifications between protein molecules", says Thierry Emonet, Professor at Yale University and co-corresponding author of the study, referring to the physical influence of proteins in contact with one another to cause changes in their shape (known as "allosteric interactions"), and the addition and removal of chemical groups to those same receptors (known as "covalent modification"). "Although a model capturing these interactions had already been established by a large body of experimental work, the consequences of this allostery for diversity tuning had not been appreciated."

Thus, the team identified a simple explanation for the fast changes in risk spreading achieved by the cell population. Instead of building and breaking down protein molecules, the mechanism works through chemical modifications of existing proteins and their effects on the physical cross-talk between those proteins, thus allowing a much faster shift. Such protein modifications are used widely to process and relay signals inside individual cells, but it was not previously known that they could also play a role in the diversification of entire cell populations. Because such modifications are so prevalent throughout cells of all organisms, the authors believe this basic mechanism for fast changes in cellular diversity could be at work in many cell types across biology.

Researchers from the Hubrecht Institute and Utrecht University developed an advanced technique that makes it possible to monitor a virus infection live. The researchers from the groups of Marvin Tanenbaum and Frank van Kuppeveld expect that the technique can be used to study a wide variety of viruses, including SARS-CoV-2 - the virus responsible for the current pandemic. The technique named VIRIM ('virus infection real-time imaging') is therefore very valuable for gaining insights in virus infection in the human body. Eventually, this can lead to more targeted treatments for viral infection. The results were published in the leading scientific journal Cell on the 13th of November.

Viruses have a large negative impact on society. This is demonstrated once again by the enormous consequences of the current global outbreak of SARS-CoV-2 for our physical- and mental health and for the economy.

Intruder

RNA-viruses represent a large group of viruses, which carry their genetic information in the form of RNA: a molecule that is similar to DNA, the genetic material of humans. After infection of a host cell, an RNA-virus hijacks many of the host cell's functions and turns it into a virus-producing factory. This way, the intruder can quickly replicate inside cells in the body. The new virus particles are subsequently released through the respiratory tract and can infect other people. Examples of RNA-viruses include coronaviruses, the hepatitis C virus, the zika virus, and enteroviruses - a group of viruses that includes rhinoviruses, causing the common cold, coxsackieviruses, that are an important cause of viral meningitis and encephalitis, and the poliovirus, that causes paralytic poliomyelitis.

Live stream

Until now, available techniques could only provide a snapshot of virus-infected cells. In other words, researchers could see the infected cells at a certain point in time, but it was not possible to monitor the process of virus infection from beginning to end. The newly developed microscope technology VIRIM ('virus infection real-time imaging') changes that: researchers from the groups of Marvin Tanenbaum (Hubrecht) and Frank van Kuppeveld (Utrecht University) developed this advanced method with which the entire course of a virus infection can be visualized in the lab with great precision. "This new method enables us to address many important questions about viruses", says Sanne Boersma, first author of the study.

Fluorescent virus

The method uses SunTag - a technology previously developed by Tanenbaum - in an enterovirus, a group of viruses in which Van Kuppeveld has extensive expertise. The SunTag is introduced into the RNA of the virus and labels viral proteins with a very bright fluorescent tag. Using this fluorescent tag, viral proteins can be seen using a microscope, allowing researchers to see when, where and how quickly a virus produces it proteins and replicates in its host cell. VIRIM is much more sensitive than other methods: protein production from a single viral RNA can be detected. This allows researchers to track the course of the infection from the very beginning.

Competition

The building blocks of our bodies -cells -have their own defense system to detect and eliminate a virus upon infection. Once a virus enters a cell, a competition arises between the virus and the host cell: the virus aims to hijack the cell to replicate itself, while the host tries very hard to prevent this. Using VIRIM, researchers were able to see the outcome of this competition. They found that in a subset of cells, the host cell won the competition. Boersma: "These host cells were infected by a virus, but the virus failed to replicate." This triggered the curiosity of Boersma and her colleagues and led to a new experiment.

Achilles' heel of the virus

The researchers helped host cells by boosting their defense system. As it turned out, the very first viral replication often failed in the cells that had received the boost, which prevented the virus from taking over the host. "The first step in the replication process is the Achilles' heel of this virus: this moment determines whether the virus can spread further", Boersma explains. "If the host cell does not manage to eliminate the virus at the very beginning of an infection, the virus will replicate and win the competition." Boersma and her colleagues used a picorna virus for the development of VIRIM. Members of this virus family can cause diseases ranging from the common cold to severe diseases such as Polio.

Wide variety of viruses

VIRIM enables the identification of the vulnerable phases of a wide variety of viruses. The researchers expect the technique to be valuable for research into many life-threatening viruses, including SARS-CoV-2. Boersma explains: "Understanding viral replication and -spreading can help us determine the Achilles' heel of a virus. This knowledge can contribute to the development of treatments, for example a treatment that intervenes during a vulnerable moment in the virus' life. That allows us to create more efficient therapies and hopefully mitigate the impact of viruses on society."

* LDL Cholesterol Lowering Drugs Benefit Older and Younger Patients Equally: Older individuals face an increased incidence of cardiovascular events compared to younger individuals. Paradoxically, however, proven lipid-lowering therapies remain underused in older patients because these individuals have typically comprised small subsets of clinical trials and thus there has been a less persuasive evidence base. A new systematic review and meta-analysis of 29 trials which included 244,090 patients including 21,492 patients aged 75 years or older found that lipid-lowering therapies reduced the risk of major cardiovascular events in older patients just as much as they did in younger patients, with a 26 percent reduction in major cardiovascular events per 1 mmol/L reduction of LDL cholesterol (LDL-C). The benefit of LDL-C lowering in the elderly was consistent for cardiovascular death, myocardial infarction, stroke, and coronary revascularization and consistent, per 1 mmol/L reduction in LDL-C, for statin and non-statin lipid-lowering therapies (ezetimibe and the PCSK9 inhibitors, evolocumab and alirocumab).

"Our analysis indicates that these therapies, which are affordable drugs that have reduced risk of heart disease for millions of people worldwide, are as effective in reducing cardiovascular events and deaths in older people as they are in younger people," said corresponding author Marc Sabatine, MD, MPH, of the Division of Cardiovascular Medicine at the Brigham. "We found no offsetting safety concerns and, together, these results should strengthen guideline recommendations for the use of cholesterol-lowering medications, including statin and non-statin therapy, in elderly people."

The study will be presented Nov. 13 at 10 a.m. EST and published simultaneously in The Lancet.

* Over 80 Percent of Heart Failure Patients Eligible for Treatment with Recently FDA-Approved Therapy: In May 2020, the U.S. Food and Drug Administration (FDA) approved dapagliflozin, a blood sugar-lowering drug, as a therapy for patients with heart failure with reduced ejection fraction (HFrEF). While the drug, a type of SGLT2 inhibitor, was originally developed to treat type 2 diabetes, there is increasing evidence that SGLT2 inhibitors reduce risks of cardiovascular events in patients with and without diabetes. To determine what proportion of HFrEF patients might be candidates for dapagliflozin treatment according to the new FDA labeling, Brigham researchers and collaborators analyzed data from 154,714 patients hospitalized with HFrEF at over 400 hospital centers across the U.S. participating in the American Heart Association's Get With The Guidelines-Heart Failure registry. They found that 81.1 percent of participants would be eligible for dapagliflozin, with the most common explanation for non-candidacy being advanced kidney disease. HFrEF patients with type 2 diabetes had a lower proportion of eligibility (75.6 percent) compared to those without type 2 diabetes, of whom 85.5 percent were eligible.

"Despite accelerating scientific discoveries, few patients with heart failure are being treated with the best available treatment options in 2020," said lead author Muthiah Vaduganathan, MD, MPH, of the Division of Cardiovascular Medicine at the Brigham. "While SGLT2 inhibitors were first developed for treatment of diabetes, these therapies have now been recognized to reduce mortality, prevent worsening heart failure events, and improve health-related quality of life in patients with HFrEF, including those without diabetes. Our data suggest that effective implementation of SGLT2 inhibitors is poised to impact a large at-risk population across a broad range of US health systems."

The study will be presented Nov. 13 at 10 a.m. EST and published simultaneously in JAMA Cardiology. This work is the first of a series of studies under a new collaboration called TRANSLATE-HF led by Vaduganathan and investigators at 10 different institutions nationwide that is being launched by the American Heart Association and AstraZeneca to better understand how new therapies for heart failure can best be implemented in clinical practice to improve patient outcomes.

* Cardiothoracic Organ Transplantations Increase Among Non-U.S. Citizens, With No Evidence of Worse Outcomes: In the past decade, cardiothoracic organ transplants have increased in the United States for both citizens and non-citizens, with non-U.S. citizens now representing between 3 and 4 percent of heart- and lung-transplant recipients. However, federal funding for transplant and post-transplant care for non-US citizens is restricted and varies by residency status. While citizenship-based disparities in liver and kidney transplant outcomes were not identified in recent studies, similar investigations into cardiothoracic transplant outcomes have not been pursued. Brigham researchers and collaborators studied 31,033 transplant recipients from 2013-2018 from the United Network for Organ Sharing and found that non-U.S. citizens who received heart and lung transplants experienced similar rates of risk-adjusted graft failure and mortality compared to U.S. citizens.

"Our study shows that non-U.S. citizens and U.S. citizens have similar outcomes at one year after heart or lung transplant," said co-first author Lauren Sinnenberg, MD, of the Division of Cardiovascular Medicine at the Brigham. "It remains unknown whether there exist disparities in access to transplantation for non-U.S. citizens. This will be an important focus of future work."

According to the study, more non-U.S. citizens are now receiving cardiothoracic transplants than ever before. The absolute proportion of transplantations is growing steadily by 0.3 percent annually according to the researchers' data. Non-U.S. citizens in the study were more likely to be Hispanic (comprising 40 percent of recipients, versus 8 percent of U.S. recipients) and more likely to be supported by Medicaid (22 percent vs. 13 percent). U.S. citizens receiving transplants were more likely to be white (70 percent vs. 37 percent) and more likely to be supported by private insurance (46 percent vs. 35 percent).

The study will be presented Nov. 13 at 10 a.m. EST and paper will be published simultaneously in Circulation: Heart Failure.

An international study led by scientists at the University of Sussex has provided strong evidence for an effective new target for breast cancer treatment. The five-year study, called "The structure-function relationship of oncogenic LMTK3" to be published in Science Advances, involved researchers from seven institutions across three countries including the UK's Diamond Light Source. It suggests that LMTK3 inhibitors could be effectively used for the treatment of breast cancer, and potentially other types of cancer. The structure of oncogenic LMTK3 (Lemur Tyrosine Kinase 3 ) determines its role and functions allowing drug inhibition as a new therapeutic strategy

It is hoped the research will allow the further development and optimisation of LMTK3 inhibitors as a new type of orally-administered anticancer drug for patients and have potential value not only for breast cancer patients but also for lung, stomach, thyroid and bladder cancer patients.

LMTK3 is a protein implicated in the development and progression of different malignancies and other diseases (eg. central nervous system related), which is not typically included in commercial kinase screening assays. The research successfully demonstrates that LMTK3 is an active kinase and reports a compound which binds to, and effectively inhibits, this protein resulting in anticancer effects in cells and in breast cancer models in mice.

Georgios Giamas, Professor of Cancer Cell Signalling at the University of Sussex, who led the research, says: "By solving the crystal structure of LMTK3, we have demonstrated that it possesses all of the hallmarks of an active protein kinase. LMTK3 plays a pivotal role in controlling cellular processes, and we have previously shown that active LMTK3 makes some cancer treatments (eg. chemotherapy and endocrine therapies) less effective."

"We are now in the process of taking this research to the next stage by developing LMTK3 specific drugs. We hope that in the next five years we will be undertaking clinical trials, which is incredibly quick for this type of process."

It is expected that the development of oral LMTK3 inhibitors may have the potential for broad clinical utility, either as a monotherapy, or as a combinational therapy, for example combined with chemotherapy, immunotherapy or endocrine treatments. Consequently, an LMTK3 inhibitor could be used alongside complementary therapies to increase the therapeutic efficacy and help overcome mechanisms of resistance to existing cancer therapies.

The researchers say that the work is a great example of international science collaboration with several groups coming together to help with a challenging project. In particular the OPPF (Oxford Protein Production Facility) and the UK's synchrotron, Diamond Light Source worked with the groups to produce their protein of interest (LMTK3) and to help solve its crystal structure. "It is often difficult to obtain large well diffracting crystals and LMTK3 was no exception. Through close collaboration between the OPPF and I24 and exploiting the microfocused X-ray beam at I24 to collect wedges of data from multiple crystals we were able to obtain diffraction data key to the study," commented Robin Owen, Principal Beamline Scientist of MX beamline I24 at Diamond. This research project is also a great demonstration of the powerful synergy between Diamond and its neighbouring research institutes like the Research Complex at Harwell which housed sample preparation.

What The Study Did: This Viewpoint discusses the need for new and better testing for COVID-19 to help prevent community transmission, and it explains the limitations of such testing, including performance in the asymptomatic phase and access in resource-limited communities.

Authors: Yukari C. Manabe, M.D., of Johns Hopkins University in Baltimore, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jama.21694)

Editor's Note: The article includes conflict of interest disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

What The Study Did: The rare incidence of nosocomial SARS-CoV-2 infection is reviewed in this Viewpoint, which also discusses ways it can be minimized, including use of surgical masks, proper ventilation, physical distancing, eye protection, regular testing and the availability of sick leave for health care workers.

Authors: Aaron Richterman, M.D., of the Hospital of the University of Pennsylvania in Philadelphia, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jama.2020.21399)

Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

SINGAPORE, 3 Nov 2020 - Long RNA molecules carrying DNA codes that don't get translated into proteins have long been a mystery of the human genome. Now, scientists at Duke-NUS Medical School have found a way to systematically investigate their functions and discovered some could play a role in pancreatic cancer. Their findings, published in the journal Genome Medicine, highlight the importance of investigating long non-coding RNAs (lncRNAs) in living organisms.

RNA had long been considered an intermediary molecule; DNA codes for RNA, which, in turn, codes for protein. More recently, scientists found that of the three billion bases in the human genome, only two per cent encode proteins. Much of the remaining 98 per cent of the genome are non-coding, and once thought to be the 'dark matter' of the human genome, with no known functions. Some lncRNAs, a major component of this genomic dark matter, have been shown to play key roles in diverse biological processes, ranging from development to diseases.

"By combining several advanced tools, we were able to investigate the role and function of 'the dark matter that matters' in pancreatic cancer," said the study's lead author, Mr Shiyang Liu, who is an MD/PhD student at Duke-NUS.

Specifically, the research team wanted to identify lncRNAs that were regulated by a well-known pathway called Wnt signalling. This pathway regulates many genes that code for proteins, but its influence on lncRNAs has been unclear.

Wnt signalling is known to fuel the growth of some pancreatic cancers. Turning off this pathway could not only help treat pancreatic cancer but also help researchers identify the parts of the genome that are regulated by it.

To do this, the research team turned to a ETC-159, a made-in-Singapore Wnt-suppressing drug jointly developed by Duke-NUS and the Agency for Science, Technology and Research (A*STAR), which is currently progressing through clinical trials as a treatment for a range of cancers, including pancreatic.

The scientists compared what happened to lncRNAs when ETC-159 turned off Wnt signalling in preclinical model of pancreatic cancer and in pancreatic cancer cells cultured in the laboratory. They found it changed the expression of 1,503 lncRNAs in the former but only changed the expression of half that number in the latter. This highlights the importance of studying lncRNAs within the context of a more natural environment, the researchers say.

The team then used the gene editing tool CRISPR to study what happened when the 1,503 Wnt-regulated lncRNAs were turned off in the preclinical model and in pancreatic cell cultures. Twenty-one lncRNAs were found to be able to modify pancreatic cancer cell growth in the living model, whereas only half that number were identified in the cancer cell culture tests.

"Our study provides a unique window in the largely unknown role of the dark matter of the genome that plays a functional role in pancreatic cancer, and will be a valuable resource for the scientific community studying Wnt-regulated lncRNAs in cancer," said Professor David Virshup, director of Duke-NUS' Cancer and Stem Cell Biology Programme, a senior co-author of the study. Prof Virshup's seminal research on Wnts led to the development of ETC-159. "Understanding that a subset of Wnt-regulated lncRNAs can act as mediators of the oncogenic function of Wnt signalling in cancers provides potential new targets for precision cancer therapies."

Associate Professor Enrico Petretto, from Duke-NUS' Cardiovascular and Metabolic Disorders Programme, also a senior co-author of the study, said, "Compared with previous studies we identified twice as many lncRNAs in vivo than what you might detect in vitro, and many of these are important for cancer cell growth only in vivo, providing important clues for the development of more effective cancer treatments."

How hot is the Universe today? How hot was it before? A new study by an international team of researchers, including members of the Kavli Institute for the Physics and Mathematics of the Universe (Kavli IPMU), suggests that the mean temperature of gas in large structures of the Universe has increased about 3 times in the last 8 billion years, to reach about two million Kelvin today.

The large-scale structure of the Universe refers to the global pattern of how galaxies and galaxy clusters are distributed in space. This cosmic net formed from tiny irregularities in the matter distribution in the early Universe, which were amplified through gravitational attraction. "As the Universe evolves, gravity pulls dark matter and gas in space together into galaxies and clusters of galaxies," said Yi-Kuan Chiang, the lead author of the study, and a research fellow at the Ohio State University Center for Cosmology and AstroParticle Physics. "The drag is violent--so violent that more and more gas is shocked and heated up."

This heated gas can then be used to measure the mean temperature of the Universe over cosmic time. In particular, the researchers used the so-called "Sunyaev-Zeldovich" effect, named after Rashid Sunyaev, director emeritus at the Max Planck Institute for Astrophysics, and Soviet-era physicist Yakov Zeldovich, who first predicted this phenomenon theoretically. This effect arises when low-energy photons of the cosmic microwave background radiation are scattered by hot electrons in the large-scale structure of the Universe. The scattering transfers energy from electrons to photons, making the hot electron gas visible. The intensity of the Sunyaev-Zeldovich effect is proportional to the thermal pressure of the gas, which, in turn, is proportional to the temperature of electrons.

While this measurement is straightforward in principle, collecting the necessary data was a major undertaking. The study, which has been published in the Astrophysical Journal, was done in a collaboration of researchers at the Kavli IPMU, the Ohio State University, the Johns Hopkins University, and the Max Planck Institute for Astrophysics.

The researchers used data collected by two observatories, the Planck satellite and the Sloan Digital Sky Survey (SDSS). Planck is the European Space Agency mission which measured the cosmic microwave background radiation. SDSS collected detailed images and light spectra of galaxies. Combining the two data sets, the scientists were able to measure the amount of thermal pressure around the locations of galaxies and clusters of galaxies.

"It took astronomers more than 15 years to collect the necessary data using a telescope on the ground and one in space," said Brice Ménard who led the analysis with Chiang. Ménard, who has been a visiting scientist at the Kavli IPMU since 2011, added: "On the analysis side, our team spent four years developing the algorithms necessary to extract the signal from these data."

What's more, interpretation of the data required a physical model, which was provided by Ryu Makiya, a research fellow at the Kavli IPMU. "Combining the latest data with a state-of-the-art theoretical model, we were able to reveal how the temperature of the Universe evolved, and how it was linked to formation of the large-scale structure of the Universe," Makiya said. "The next goal is to understand details of the physics of thermal and non-thermal phenomena."

Chiang, from the Ohio Stated University, added: "Our new measurement provides a direct confirmation of the seminal work by Jim Peebles--the 2019 Nobel Laureate in Physics--who laid out the theory of the emergence of large-scale structure of the Universe."

The study determined that about eight billion years ago (at a redshift z=1), the mean electron temperature was some 700,000 Kelvin, rising to about two million Kelvin today. Furthermore, the scientists determined that its evolution is almost entirely driven by the growth of structures, as gas is shock heated in collapsing large-scale structures.

Back in 2000, Eiichiro Komatsu, a Principal Investigator at the Kavli IPMU and Director at the Department of Physical Cosmology at the Max Planck Institute for Astrophysics, was also involved in a previous effort to calculate how the temperature of the Universe evolved. "For 20 years, we have been studying how to measure this using the Sunyaev-Zeldovich effect," he remembered. "We now have finally measured the temperature of the Universe, not only thanks to the remarkable progress in observational data, but also due to the dedicated efforts of brilliant young scientists such as Yi-Kuan Chiang and Ryu Makiya. This is very satisfying," Komatsu added.