Culture

The DNA-cutting proteins central to CRISPR-Cas9 and related gene-editing tools originally came from bacteria, but a newfound variety of Cas proteins apparently evolved in viruses that infect bacteria.

The new Cas proteins were found in the largest known bacteria-infecting viruses, called bacteriophages, and are the most compact working Cas variants yet discovered -- half the size of today's workhorse, Cas9.

Smaller and more compact Cas proteins are easier to ferry into cells to do genome editing, since they can be packed into small delivery vehicles, including one of the most popular: a deactivated virus called adeno-associated virus (AAV). Hypercompact Cas proteins also leave space inside AAV for additional cargo.

As one of the smallest Cas proteins known to date, the newly discovered CasΦ (Cas-phi) has advantages over current genome-editing tools when they must be delivered into cells to manipulate crop genes or cure human disease.

"Adenoviruses are the perfect Trojan horse for delivering gene editors: You can easily program the viruses to reach almost any part in the body," said Patrick Pausch, a postdoctoral fellow at the University of California, Berkeley, and in UC Berkeley's Innovative Genomics Institute (IGI), a joint UC Berkeley/UCSF research group devoted to discovering and studying novel tools for gene editing in agriculture and human diseases. "But you can only pack a really small Cas9 into such a virus to deliver it. If you would have other CRISPR-Cas systems that are really compact, compared to Cas9, that gives you enough space for additional elements: different proteins fused to the Cas protein, DNA repair templates or other factors that regulate the Cas protein and control the gene editing outcome."

Apparently these "megaphages" use the CasΦ protein -- the Greek letter Φ, or phi, is used as shorthand for bacteriophages -- to trick bacteria into fighting off rival viruses, instead of itself.

"The thing that actually made me interested in studying this protein specifically is that all the known CRISPR-Cas systems were originally discovered in bacteria and Archaea to fend off viruses, but this was the only time where a completely new type of CRISPR-Cas system was first found, and so far only found, in viral genomes," said Basem Al-Shayeb, a doctoral student in the IGI. "That made us think about what could be different about this protein, and with that came a lot of interesting properties that we then found in the lab."

Among these properties: CasΦ evolved to be streamlined, combining several functions in one protein, so that it can dispense with half the protein segments of Cas9. It is as selective in targeting specific regions of DNA as the original Cas9 enzyme from bacteria, and just as efficient, and it works in bacteria, animal and plants cells, making it a promising, broadly applicable gene editor.

"This study shows that this virus-encoded CRISPR-Cas protein is actually very good at what it does, but it is a lot smaller, about half the size of Cas9," said IGI executive director Jennifer Doudna, a UC Berkeley professor of molecular and cell biology and of chemistry and a Howard Hughes Medical Institute investigator. "That matters, because it might make it a lot easier to deliver it into cells than what we are finding with Cas9. When we think about how CRISPR will be applied in the future, that is really one of the most important bottlenecks to the field right now: delivery. We think this very tiny virus-encoded CRISPR-Cas system may be one way to break through that barrier."

Pausch and Al-Shayeb are first authors of a paper describing CasΦ that will appear this week in the journal Science.

Biggiephages carry their own Cas proteins

The CasΦ protein was first discovered last year by Al-Shayeb in the laboratory of Jill Banfield, a a UC Berkeley professor of earth and planetary science and environment science, policy and management. The megaphages containing CasΦ were part of a group they dubbed Biggiephage and were found in a variety of environments, from vernal pools and water-saturated forest floors to cow manure lagoons.

"We use metagenomic sequencing to discover the Bacteria, Archaea and viruses in many different environments and then explore their gene inventories to understand how the organisms function independently and in combination within their communities," Banfield said. "CRISPR-Cas systems on phage are a particularly interesting aspect of the interplay between viruses and their hosts."

While metagenomics allowed the researchers to isolate the gene coding for CasΦ, its sequence told them only that it was a Cas protein in the Type V family, though evolutionarily distant from other Type V Cas proteins, such as Cas12a, CasX (Cas12e) and Cas14. They had no idea whether it was functional as an immune system against foreign DNA. The current study showed that, similar to Cas9, CasΦ targets and cleaves foreign genomes in bacterial cells, as well as double-stranded DNA in human embryonic kidney cells and cells of the plant Arabidopsis thaliana. It also can target a broader range of DNA sequences than can Cas9.

The ability of CasΦ to cut double-stranded DNA is a big plus. All other compact Cas proteins preferentially cut single-stranded DNA. So, while they may fit neatly into compact delivery systems like AAV, they are much less useful when editing DNA, which is double-stranded, inside cells.

As was the case after Cas9's gene-editing prowess was first recognized in 2012, there is a lot of room for optimizing CasΦ for gene editing and discovering the best rules for designing guide RNAs to target specific genes, Pausch said.

Osaka, Japan — Phantom-limb pain is as mysterious as the name implies. The vast majority of amputees experience "phantom-limb" sensations that make them feel their missing limb is still part of their body. The cause is still unknown, and 50% to 80% of the cases, the sensations are painful. With no established treatments or medication, phantom-limb pain can have a large impact on the quality of life and recovery for amputees.

Although the cause is unknown, one theory is that it happens when areas of the brain that used to control the amputated limb remain strongly connected to the mental image of the limb. To weaken this connection, one idea is to train the brain regions that control the intact limb to also control the phantom limb. Takufumi Yanagisawa and his team at Osaka University hypothesized that the key to accomplishing this was to do it unconsciously.

"It is very difficult to intentionally activate the part of your brain that controls your right hand without actually thinking about moving that hand," explains Yanagisawa. "Instead, we designed a system in which the patients did not even know they were using those parts of their brains."

In order to train the brains of patients with phantom-hand pain, the group used a brain-computer-interface. First they recorded brain activity when patients opened and closed their intact hands and used the pattern of brain activity as a template. Then they continuously recorded brain activity related to the intact hands, but asked the patients to try to control a virtual hand with their phantom hand. For half the experiments, this training was real; the recorded brain activity was decoded based on the template and the image of the opening/closing virtual hand was adjusted accordingly. For the other half, the images of the virtual hand were randomly adjusted with no connection to brain activity. All patients thought they were actually controlling the virtual hand. Patients trained for about 30 min/day for 3 days, and after each session they rated the intensity of their phantom-limb pain.

The team found that pain was reduced by 30% even on the first day of training and the effect lasted up to five days after training was complete. Importantly, only patients who received real training reported less phantom pain. They also found that after training, the mental image of the phantom hand was weakened in the brain regions that once controlled the amputated hand.

"These findings are promising," says Yanagisawa, "especially given that alternatives like mirror training require a month of training to have the same effect. However, in order for this treatment to become truly practical, the cost must be reduced."

Water, so ordinary and so essential to life, acts in ways that are quite puzzling to scientists. For example, why is ice less dense than water, floating rather than sinking the way other liquids do when they freeze?

Now a new study provides strong evidence for a controversial theory that at very cold temperatures water can exist in two distinct liquid forms, one being less dense and more structured than the other.

Researchers at Princeton University and Sapienza University of Rome conducted computer simulations of water molecules to discover the critical point at which one liquid phase transforms into the other. The study was published this week in the journal Science.

"The presence of the critical point provides a very simple explanation for water's oddities," said Princeton's Dean for Research Pablo Debenedetti, the Class of 1950 Professor in Engineering and Applied Science, and professor of chemical and biological engineering. "The finding of the critical point is equivalent to finding a good, simple explanation for the many things that make water odd, especially at low temperatures."

Water's oddities include that as water cools, it expands rather than contracting, which is why frozen water is less dense than liquid water. Water also becomes more squeezable -- or compressible -- at lower temperatures. There are also at least 17 ways in which its molecules can arrange when frozen.

A critical point is a unique value of temperature and pressure at which two phases of matter become indistinguishable, and it occurs just prior to matter transforming from one phase into the other.

Water's oddities are easily explained by the presence of a critical point, Debenedetti said. The presence of a critical point is felt on the properties of the substance quite far away from the critical point itself. At the critical point, the compressibility and other thermodynamic measures of how the molecules behave, such as the heat capacity, are infinite.

Using two different computational methods and two highly realistic computer models of water, the team identified the liquid-liquid critical point as lying in a range of about 190 to 170 degrees Kelvin (about -117 degrees to -153 degrees Fahrenheit) at about 2,000 times the atmospheric pressure at sea level.

The detection of the critical point is a satisfying step for researchers involved in the decades-old quest to determine the underlying physical explanation for water's unusual properties. Several decades ago, physicists theorized that cooling water to temperatures below its freezing point while maintaining it as a liquid -- a "supercooled" state that occurs in high-altitude clouds -- would expose water's two unique liquid forms at sufficiently high pressures.

To test the theory, researchers turned to computer simulations. Experiments with real-life water molecules have not so far provided unambiguous evidence of a critical point, in part due to the tendency for supercooled water to rapidly freeze into ice.

Francesco Sciortino, a professor of physics at the Sapienza University of Rome, conducted one of the first such modeling studies while a postdoctoral researcher in 1992. That study, published in the journal Nature, was the first to suggest the existence of a critical point between the two liquid forms.

The new finding is extremely satisfying for Sciortino, who is also a co-author of the new study in Science. The new study used today's much faster and more powerful research computers and newer and more accurate models of water. Even with today's powerful research computers, the simulations took roughly 1.5 years of computation time.

"You can imagine the joy when we started to see the critical fluctuations exactly behaving the way they were supposed to," Sciortino said. "Now I can sleep well, because after 25 years, my original idea has been confirmed."

In the case of the two liquid forms of water, the two phases coexist in uneasy equilibrium at temperatures below freezing and at sufficiently high pressures. As the temperature dips, the two liquid phases engage in a tug of war until one wins out and the entire liquid becomes low- density.

In the simulations performed by postdoctoral researcher Gül Zerze at Princeton and Sciortino in Rome, as they brought down the temperature well below freezing into the supercooled range, the density of water fluctuated wildly just as predicted.

Some of the odd behaviors of water are likely to be behind water's life-giving properties, Zerze said. "The fluid of life is water, but we still don't know exactly why water is not replaceable by another liquid. We think the reason has to do with the abnormal behavior of water. Other liquids don't show those behaviors, so this must be linked to water as the liquid of life."

The two phases of water occur because the water molecule's shape can lead to two ways of packing together. In the lower density liquid, four molecules cluster around a central fifth molecule in a geometric shape called a tetrahedron. In the higher density liquid, a sixth molecule squeezes in, which has the effect of increasing the local density.

The team detected the critical point in two different computer models of water. For each model, the researchers subjected the water molecules to two different computational approaches to looking for the critical point. Both approaches yielded the finding of a critical point.

Peter Poole, a professor of physics at St. Francis Xavier University in Canada, and a graduate student when he collaborated with Sciortino and coauthored the 1992 paper in Nature, said the result was satisfying. "It's very comforting to have this new result," he said. "It's been a long and sometimes lonely wait since 1992 to see another unambiguous case of a liquid-liquid phase transition in a realistic water model."

C. Austen Angell, Regents Professor at Arizona State University, is one of the pioneers of experiments in the 1970s on the nature of supercooled water. "No doubt that this is a heroic effort in the simulation of water physics with a very interesting, and welcome, conclusion," said Angell, who was not involved in the present study, in an email. "As an experimentalist with access to equilibrium (long-term) physical measurements on real water, I had always felt 'safe' from preemption by computer simulators. But the data presented in the new paper shows that this is no longer true."

* Even if all contacts are successfully traced, a delay of three days or more between symptom onset and testing will not reduce onward transmission of the virus sufficiently to control further spread, according to modelling study

* In the best-case scenario, with zero delays and at least 80% of contacts traced, the R number is reduced from 1.2 to around 0.8, and 80% of onward transmission per person diagnosed could be prevented

* For conventional contact tracing to work, test results need to be delivered within a day of an individual developing symptoms

* Mobile apps can speed up contact tracing and keep R below 1, even if only 20% of the population use them

Speed of contact tracing strategies is essential to slowing COVID-19 transmission, according to a mathematical modelling study in The Lancet Public Health journal which models the effectiveness of conventional and app-based strategies on community transmission of the virus.

If COVID-19 testing is delayed by three days or more after a person develops symptoms, even the most efficient contact tracing strategy cannot reduce onward transmission of the virus.

The researchers say improving access to COVID-19 testing, combined with digital that minimise tracing delays, will be key to the success of a contact tracing approach to reduce spread of the virus.

Professor Mirjam Kretzschmar, one of the lead authors of the study, from the University of Utrecht, the Netherlands, said: "This study reinforces findings from other modelling studies, showing that contact tracing can be an effective intervention to prevent spread of the SARS-CoV-2 virus, but only if the proportion of contacts traced is high and the process is fast. Our study builds on this to show, in detail, what role each step in the process plays in making this approach successful. This will help policy makers understand where best to prioritise resources to maximise the chances of success. For example, we found that mobile apps can speed up the process of tracking down people who are potentially infected, but if testing is delayed by three days or more even these technologies can't stop transmission of the virus." [1]

Contact tracing involves tracking down all of the people who have been in contact with an infected individual so they can be isolated to prevent further spread of the virus. This approach is an established public health measure recommended by the World Health Organisation as a potential exit strategy to enable the alleviation of COVID-19 lockdown measures.

Conventional contact tracing methods involve a public health professional contacting the infected person and asking them to recall everyone they have been in contact with over a defined period before the onset of symptoms. Several countries have introduced mobile apps to speed up this process, by automatically alerting people who have been in proximity to the infected person using data from their mobile device.

To be successful, contact tracing measures must keep the rate of transmission of the virus, known as the Reproduction or R number, below 1. This means that, on average, the number of individuals who will be infected by a single infected person must be less than one.

In the new study, the researchers used a mathematical model that reflects the various steps and delays in the contact tracing process. This enabled them to quantify how such delays affect the R number and the fraction of onward transmission cases that can be prevented for each diagnosed person.

The model assumes that around 40% of virus transmission occurs before a person develops symptoms. In the absence of any strategies to mitigate the spread of the virus, each infected person will transmit the virus to an average of 2.5 people. Introducing physical distancing alone, assuming that close contacts are reduced by 40% and casual contacts by 70%, will reduce the reproduction number to 1.2.

In the best case scenario, the model predicts that contact tracing could reduce the number of people a person with COVID-19 passes the virus on to from 1.2 to 0.8. For this to work, at least 80% of people who are eligible must be tested, there must be no delays in testing after the onset of symptoms and at least 80% of contacts must be identified on the same day as the test results are received.

If testing is delayed by two days, keeping the R number below 1 would require contacts to be traced within a day and at least 80% of contacts must be identified, the model predicts.

The model assumes that conventional contact tracing takes a minimum of three days and is less efficient at tracking down contacts than mobile app technologies, which are assumed to be instantaneous.

The findings predict that conventional contact tracing will only work to keep the R number below 1 if people with COVID-19 receive a positive test result on the same day they develop symptoms of the virus.

Contact tracing based on mobile app technology can accommodate a delay in testing of up to 2 days and keep the R number below 1, as long as at least 80% of contacts are tracked down. In this case, the number of people infected from those contacts would be reduced by half.

Once testing is delayed by three days or more, even a perfect system that [would] trace 100% of contacts with no delays cannot bring the R number below 1, according to the model.

Overall, the study found that reducing the time between a person developing symptoms and receiving a positive test result is the most important factor for improving contact tracing effectiveness.

Professor Marc Bonten, one of the lead authors of the study, from the University of Utrecht, the Netherlands, said: "In our model, minimising testing delays had the largest impact on reducing transmission of the virus and testing infrastructure is therefore the most critical factor for the success of a contact tracing system. This means that as many infectious people as possible need to be tested, and policymakers might consider lowering the eligibility threshold for access to testing. This will lead to a large proportion of negative test results, however, and future studies should focus on identifying the optimal balance between the proportion of negative tests and the effectiveness of contact tracing." [1]

The authors note that their model does not take into account the age structure of the population. This might influence the proportion of asymptomatic cases, as these are more common in younger people and children, and might also influence mobile app usage. The model also does not account for infections acquired in hospitals and other healthcare settings, such as care homes.

Writing in a linked Comment Article, Professor Louise Ivers and Daniel J. Weitzner, who were not involved in the study, highlight four crucial questions that remain to be investigated. Firstly, an assessment is needed of how well smartphones measure proximity. Secondly, better understanding of how mobile apps will integrate with overall contact tracing programmes needs to be investigated. The Comment authors also call for further research to understand what factors will encourage users to trust the privacy and security properties of mobile apps. Finally, they highlight the potential for conventional and digital contact tracing strategies to perpetuate health disparities, and further evaluation is needed to prevent this.

Professor Ivers, of Harvard Medical School, and Daniel J. Weitzner, from the Massachusetts Institute of Technology, USA, said: "As contact tracing remains a crucial component of the COVID-19 response, mobile apps offer promise, especially when considering the speed and scale required for tracing to be effective--as highlighted in Kretzschmar and colleagues' study.4 However, understanding the potential impact of apps as part of a comprehensive integrated approach requires more evaluation of their use in real life and multidisciplinary engagement of technologists, epidemiologists, public health experts, and the public."

WASHINGTON, July 16, 2020--Since 2011 the U.S. Department of Education has published two annual lists of higher education institutions with the highest percentage changes in tuition and fees and average net price. A study published today found that inclusion in either of these College Affordability and Transparency Center (CATC) lists does not affect institutional pricing policies or students' enrollment decisions. The findings appear in Educational Evaluation and Policy Analysis, a peer-reviewed journal of the American Educational Research Association.

VIDEO: Watch Author Dominique J. Baker discuss study findings and implications--https://youtu.be/OtSFYiZDNMw

"This attempt by the federal government to hold colleges and universities accountable by 'naming and shaming' them does not appear to be effective at changing institutional or student behavior," said study author Dominique J. Baker, an assistant professor at Southern Methodist University. "The Education Department is required by federal law to publish these lists, but there is little evidence they are having the intended effect."

"Many higher education observers have long questioned the value of these lists and expressed concerns about the ability of students and institutions to use the data," said Baker. "My findings are in line with these concerns."

Congress amended the Higher Education Act in 2008 to mandate that the Education Department publish annual lists of institutions that rank in the top five percent of their sector of U.S. colleges and universities in terms of absolute published tuition price or average net price, and percentage increase in published tuition and required fees or average net price (published tuition minus student aid). Sectors are identified by sorting institutions by control (public, private, and nonprofit) and level (four-year, two-year, less-than-two-year). Baker's study looked at just the percentage increase lists.

To analyze the effect of inclusion on these CATC lists on subsequent tuition and net price decisions and on student enrollment, Baker compared institutions that were within the top five percent cutoff to those that had just missed it, from 2014 to 2017. The Education Department dataset she used for her analysis is also used by the department to calculate its CATC lists. She found little evidence that institutions included on either list differed from those that were not included, in terms of student enrollment and institutional affordability in the subsequent two years.

"These policy efforts are built on the assumption that with the right information, potential students will be able to make better informed choices," Baker said. "However, the lists did not discourage students from attending institutions with larger increases in average net prices. And institutions did not modify their pricing."

Baker noted that her study is one of the few that has produced causal evidence regarding the effectiveness of low-stakes, non-punitive federal accountability policies focused on higher education.

The findings provide evidence that simply relying on students to seek out and review affordability information is unlikely to influence their behaviors, Baker noted. This may be due partially to confusion caused by the lists relying on percentage increases rather than absolute dollar amount increases. Some institutions with large dollar changes over time are not included on the lists because the changes are measured as a percentage of what was charged in the previous year.

"For example, in 2017, Carver Bible College was included in the change-in-tuition list while Loyola Chicago was not," Baker said. "As a result, one might expect that Carver Bible College would be significantly more expensive than Loyola. In actuality, the 2015-2016 tuition and fees for Carver were $9,860, while that same year the tuition and fees for Loyola were $40,426."

"Not only is it difficult to understand what these lists are actually telling students about institutions' affordability, but also, the fact that an institution is included on these lists does not mean it is automatically a good or bad place to pursue higher education," said Baker.

According to Baker, weak sanctions attached to being included on the CATC lists--at most being required to complete additional paperwork explaining the large change--did not create enough negative media attention or other disincentives for institutions to change their pricing decisions for future years, even when institutions had the autonomy to do so.

"With the United States now in a recession, it is likely that more students and their families will struggle with affording college in the fall," Baker said. "The federal government has to be concerned with finding ways to ensure that institutions remain or become more affordable. This study suggests that at least one of the key policies that is supposed to be holding institutions accountable does not appear to be effective."

"The next update of the Higher Education Act needs to either remove this policy or revise it," said Baker. "Until then, it is not clear why college administrators or Education Department staff are required to compile data and complete reports on this."

"As federal policy leaders engage in discussions about ensuring that higher education is affordable during the pandemic, it is important that they holistically assess current policies and their efficacy," Baker added.

About AERA

The American Educational Research Association (AERA) is the largest national interdisciplinary research association devoted to the scientific study of education and learning. Founded in 1916, AERA advances knowledge about education, encourages scholarly inquiry related to education, and promotes the use of research to improve education and serve the public good. Find AERA on Facebook, Twitter, and Instagram.

Journal

Educational Evaluation and Policy Analysis

DOI

10.3102/0162373720937672

Skoltech researchers and their industry colleagues have created a data-driven model that can forecast the production from an oil well stimulated by multistage fracturing technology. This model has high commercialization potential, and its use can boost oil production via optimized fracturing design. The research, supported by Gazprom Neft Science and Technology Center, was published in the Journal of Petroleum Science and Engineering.

Hydraulic fracturing, essentially pumping fluid at high pressures into the reservoir formation, which creates fractures and help bring hydrocarbons to the well and ultimately to the surface, is one of the most widely used techniques for stimulation of oil and gas production. Over the last decades, the technical complexity of HF has grown so much that it now requires extensive design and prior modeling with complex multi-module simulators.

"At the same time, bridging the predictions of these simulators with reality is still a major problem of calibrating, verifying and validating models on real data. Moreover, to close the loop between fracturing simulator and production data, one needs to couple fracturing design modeling with a reservoir simulator, which increases complexity and uncertainty even more. As an alternative, we decided to look right at the field data on frac design and production, which is the measure of success," explains Professor Andrei Osiptsov, Head of Multiphase Systems Lab at the Skoltech Center for Hydrocarbon Recovery and a coauthor of the study.

Researchers of the M-Phase Lab together with their colleagues at CDISE led by Professor Evgeny Burnaev, head of ADASE group, decided to see whether a data-driven approach to HF design based on machine learning can help address this challenge.

The key component of their project, which was initiated in 2018, is a digital database on fracturing jobs and oil production from some 6 thousand wells in around 20 oilfields in Western Siberia, Russia, within the perimeter of JSC Gazprom Neft. Each data point contains 92 variables on the reservoir, well and the fracturing design parameters as well as 16 oil production parameters.

"We managed to collect and clean up a very big database of completed works on hydraulic fracturing. By applying machine learning methods to this database, we can already predict hydraulic fracturing results with good accuracy, depending on the process parameters. We still have to solve the difficult task of building optimal recommendations for choosing the parameters of the hydraulic fracturing process based on this forecast," says Professor Burnaev, a coauthor of the study.

Albert Vainshtein, senior engineer and project manager at the M-Phase Lab and a coauthor of the study, notes that the project was "very challenging right from the start" due to ambiguity of real data, high uncertainty and heterogeneity.

"I think that the development of a digital database will allow us to test various hypotheses which, in turn, will clear up multiple hidden patterns of the fracturing processes. As an example, it is important to determine at which injected proppant tonnage our cumulative oil production stops increasing. Depending on the conditions, a common approach is to inject 60 tons per fracturing stage. Using the machine learning model and statistics, we can confirm or reject this hypothesis," says Anton Morozov, a Skoltech PhD student and research intern at the M-Phase Lab.

Scientists have already produced pilot well fracturing design recommendations based on their machine learning approaches, which have been delivered to the industry partner. They hope an upcoming field-testing campaign will show the potential of their technology for oil production. Still, Burnaev reiterates that there is "quite a large amount of uncertainty in the input data describing the design of a hydraulic fracturing system". In the next phase of the project, they aim to develop new methods for estimating this uncertainty.

"Working with real field data takes courage and care, as it is very sensitive and requires special handling procedures. It would have been impossible without unconditional support from our technology partner, Gazpromneft Science and Technology Center, and the largest production entity of the operator, Gazpromneft Khantos, which is our ultimate client on this project," Osiptsov says.

"Our data-driven approach opens an avenue towards a recommendation system which would advise DESC engineers on the optimum set of fracturing design parameters, or at least narrowing down the intervals, where this optimum design can be found," he concludes.

Grigory Paderin, who leads the Optimal Hydraulic Fracturing project at the Gazprom Neft Science and Technology Center, also noted that this project "is not just a unique scientific challenge aimed at optimizing hydraulic fracturing design, it is also very important for the digitization of processes at Gazprom Neft. It allows us to take a new look at the value of our data and to reconsider our attitudes towards collecting, storing and processing this data."

Have you thought about what you'd like your life to look like when you're 84?

When a leading health system leader put that question to Lewis A. Lipsitz, MD, Director, Hinda and Arthur Marcus Institute for Aging Research at Hebrew SeniorLife and Professor of Medicine at Harvard Medical School, Dr. Lipsitz published an essay in the Journal of the American Geriatrics Society that outlined his thoughts. What follows is a summary of his essay, titled "When I'm 84: What Should Life Look Like in Old Age."

Knowing that I am a geriatrician, an esteemed health system leader once asked me: "What would you like your life to look like in old age?" I immediately listed the top contributors to a healthy longevity: Regular exercise, a well-balanced diet, a sense of purpose, social and family connections, intellectual stimulation and preventive health care.

However, many of us have trouble meeting these goals for various reasons. While we all hope to live long, productive lives, the field of geriatrics is more focused on achieving a long "health span," in which we're free of disease and disability, cognitively intact, and socially engaged. Since social factors account for most poor health outcomes, we need to help older adults address healthy longevity in our environment, our homes, communities, and lifestyles.

Here's what I envision:

Housing

Like most people, I'd like to live in my own home until the day I die, but only if I can avoid social isolation and loneliness. Loneliness is a life-threatening condition, causing as much damage as smoking 15 cigarettes a day.

Living alone can be isolating and dangerous to our health as we age, especially as we face various diseases that limit mobility and the loss of partners, siblings, and friends. That's why I want to live in a multigenerational, multicultural community where I can interact with other people of all ages. I'd like to be within a safe five to 10-minute walk or wheelchair ride across smooth sidewalks and safe street crossings to the retail stores, banks, restaurants, places of worship, parks, and entertainment venues that help me remain physically, emotionally, intellectually, and spiritually engaged.

My housing needs to be affordable, easy to maintain, safe, and accessible to nutritional services, housekeeping, maintenance, and transportation. Hopefully, it includes technology that automatically adjusts to my needs and allows me to get around and enjoy independence, despite any disabilities I may develop.

Engagement

I hope to remain engaged in meaningful, productive work. This could be part- or full-time, paid or unpaid, as long as it provides a sense of purpose, intellectual stimulation, and social interaction. There is a large, untapped workforce of retirees who have the knowledge, skill, experience, and stamina to make meaningful contributions to society. Areas where such a workforce is greatly needed include the care of children and older adults; environmental protection through recycling, shared transportation, and organic farming; food preparation and delivery; education; organizational leadership; and philanthropy.

Security

Older adults fear many kinds of insecurity, including insecurity that is related to our finances (inadequate pensions or savings), health care (poor affordability, access, or quality of health care), physical (assault or theft), transportation (inadequate, inaccessible, or unsafe public transportation), food (inability to cook, access, or afford), and housing (loss of property value or increases in rent).

I would like to see the availability of government- and community-sponsored safety nets such as entitlement programs, shared ride services, communal dining areas or home-delivered meals, subsidized apartments, security alarms and guards, and trusted advisors. In a perfect world, you could access these services in community hubs, through an internet connection or telephone contact, supported in part by a senior workforce and funded through government and commercial partnerships.

Health Care

As people grow older and develop age-related diseases, two of the most common, feared, costly, yet least understood impairments are the loss of mobility and cognition (the abilit to think and make decisions). These often mark the onset of frailty and decline. People with these conditions may turn to healthcare professionals in medical practices, emergency departments, or hospitals for help. However, the most effective interventions, including age-friendly home renovations and exercise, can take place in your home or community.

Currently in the United States, the hospital is the center of the healthcare universe. Medical practices are owned by or affiliated with hospital-based medical centers and networks. While many community-based health-promotion services exist, they are often disconnected from mainstream medical facilities, and most physicians are unaware of them.

I would like to see health care centered in the home and community with healthcare providers in each apartment complex or neighborhood. Home visits would be routine and technology would enable healthcare to be delivered safely and effectively at home. Practices would be equipped to provide a "hospital at home" when necessary. You could access services for vaccinations and treatment for chronic diseases in neighborhood settings. I also can see the day when using wearable and/or at-home monitors could signal healthcare professionals of your personal risks so that they could step in to prevent problems.

Progress

Several aspects of my hopes for healthy aging are influenced by programs that already exist, especially for traditionally underserved populations. For example, many cities are building more affordable and subsidized senior housing facilities, although they often lack architectural and environmental standards or supportive services that can promote the health of their residents.

- The "Community Aging in Place--Advancing Better Living for Elders" (CAPABLE) program developed at the Johns Hopkins School of Nursing provides home-based nursing, occupational therapy, and repair services for low-income older adults to increase mobility, functionality, and capacity to age in place.

- Vermont's "Support and Services at Home" (SASH) deploys a wellness nurse and care coordinator who engage social-service agencies, community health providers, and nonprofit housing organizations to enable Vermonters to live independently at home.

- The Massachusetts Health Policy Commission is supporting Hebrew SeniorLife's "Right Care, Right Place, Right Time" (R3) project in low income senior housing to test the effect of supportive services on health care utilization.

These worthwhile initiatives are unfortunately limited to select populations. We need ways to fund programs like these across the country.

By combining the resources of government agencies, states, cities, private insurers, developers, and others, we could build model communities and test their impact on public health. I hope that by thinking about what we would like our later years to look like, future leaders can be more deliberate in creating living environments that promote a long and productive health span.

This summary is from "When I'm 84: What Should Life Look Like in Old Age?"(https://onlinelibrary.wiley.com/doi/full/10.1111/jgs.16408) It appears in the Journal of the American Geriatrics Society. The author is Lewis A. Lipsitz, MD, Hebrew SeniorLife, Beth Israel Deaconess Medical Center, Harvard Medical School.

A vaccine additive known as an adjuvant can enhance responses to a vaccine containing the exotic avian flu virus H5N1, so that both rookie and veteran elements of the immune response are strengthened, according to results from an Emory Vaccine Center study.

The findings have implications for the effort to develop vaccines against multiple strains of flu, as well as the current push for vaccines against SARS-CoV-2. The Emory study was a test of what happens when the body sees something new - in contrast to seasonal flu vaccination, which often re-activates the same memory B cells the immune system relied upon in past years.

The study provides guidance on how adjuvants might become part of a proposed "universal" flu vaccine, aimed at protecting people against a wider variety of influenza strains. In addition, vaccine designers are considering how to optimize immune responses against SARS-Cov-2, which few had encountered before 2020.

The results were published online July 13 by Proceedings of the National Academy of Sciences.

"We saw that an adjuvant makes it possible to efficiently engage both memory and naive B cells, expanding the repertoire of the antibody immune response to influenza," says first author Ali Ellebedy, PhD, who did the study while he was a postdoctoral fellow in Rafi Ahmed's lab at Emory Vaccine Center.

"For a new pathogen like SARS-CoV-2, nobody has immunity," Ahmed says. "So the important thing is to have the vaccine bring out good responses from naïve B cells, whose frequency is low."

"For universal flu, the situation is more complicated. You want to bring out both the cross-reactive memory cells and the naïve strain-specific cells," adds Ahmed, whose lab is part of a NIH-funded consortium developing flu vaccine candidates. "Looking ahead, adjuvants are going to be an important element of universal flu vaccine research."

The particular adjuvant studied in the paper is called AS03, whose manufacturer GlaxoSmithKline is making it available for COVID-19 vaccine trials. The AS03 adjuvant could be relevant for extending the efficacy of limited doses of protein or viral subunit-based vaccines, but less so for newer mRNA-based vaccines, Ahmed says.

The Hope Clinic study recruited 50 healthy young adults, who were (most likely) exposed to other flu viruses and vaccines earlier in their lives. The H5N1 vaccine, with AS03, was approved by the FDA in 2013 and is part of the national stockpile in case of pandemic flu. More information about the AS03-adjuvanted flu vaccine is available from the FDA.

Emory researchers had previously observed that when the immune system encounters an unfamiliar flu virus, which occurred for many during the 2009 H1N1 pandemic, the antibodies produced are able to neutralize a broader range of viruses. This came from the skew of the antibodies toward the "stem" (or stalk) region of the viral hemagglutinin protein, versus the "head." The stem region doesn't mutate and change as much as the head from year to year.

A similar phenomenon occurred in the H5N1 study, because the head region of the virus was unfamiliar, but the stem region was not. Without an adjuvant, the immune response to a low dose of the H5N1 flu vaccine was poor, the researchers found.

But with the adjuvant, immune responses changed markedly between the first and second dose. A week after the first adjuvanted vaccine dose, broadly cross-reactive antibodies produced by the immune system were mostly directed against the stem. This first wave came mostly from pre-existing memory B cells. After the second dose, the antibodies were more directed against the head, coming from strain-specific naïve B cells.

The researchers also offered an explanation for the shift in the antibody response after the second dose: essentially, the immune system is getting in its own way. After the second vaccination, the antibodies against the stem region are still in the body and they appear to be covering up those parts of the viral hemagglutinin protein, a phenomenon called "epitope blocking."

"This is something that many flu vaccine studies have observed, but now we have a possible mechanistic explanation and good evidence for it," Ahmed says.

An international team of researchers led by Baylor College of Medicine and Houston Methodist has discovered a strategy that can potentially address a major challenge to the current treatment for choroidal neovascularization (CNV), an aggressive form of age-related macular degeneration, the leading cause of irreversible blindness in the elderly.

Anti-vascular endothelial growth factor (anti-VEGF) has revolutionized the treatment for CNV; however, up to one-fourth of all treated patients are unresponsive to this treatment and about one-third of the responders become resistant to it after repeated administration over time.

Working with a mouse model they developed, the researchers found that combining apolipoprotein A-I binding protein (AIBP) with anti-VEGF overcomes anti-VEGF resistance and effectively suppresses CNV. The findings open the possibility of reducing anti-VEGF resistance in patients in the future. The study appears in the journal Communications Biology.

Addressing resistance to anti-VEGF treatment has been challenging. For instance, developing strategies to overcome the resistance has been limited by a poor understanding of its mechanism and the absence of suitable animal models.

"Various combination therapies have been explored in clinical trials. For example, targeting PDGF (Fovista) or the angiopoietin pathway. However, no major breakthrough has been reported. In fact, a phase III trial combining anti-VEGF and PDGF failed to demonstrate improved efficacy," said co-corresponding author Dr. Yingbin Fu, associate professor and Sarah Campbell Blaffer Endowed Chair of Ophthalmology at Baylor.

A new approach to combat anti-VEGF resistance

Fu joined forces with Dr. Longhou Fang, associate professor of cardiovascular sciences at Houston Methodist DeBakey Heart and Vascular Center and co-corresponding author of this work.

The inspiration for their study came from previous work suggesting that macrophages may play a role in anti-VEGF resistance and that increased cholesterol accumulation in macrophages may promote CNV. Such cholesterol accumulation also has been associated with the formation of abnormal new blood vessels invading the retina. These vessels leak, which promotes inflammation and rapid photoreceptor (light-detecting cells) damage.

In addition, Fu, Fang and their colleagues, as well as other researchers, had reported that AIBP promotes the removal of cholesterol from endothelial cells and macrophages, two cell types that are involved in the development of CNV.

"Together, these observations suggested the possibility that AIBP might help overcome anti-VEGF resistance and effectively suppress CNV," Fu said.

Developing an animal model to assess new approach to overcome anti-VEGF resistance

To test their hypothesis, the researchers developed a model of anti-VEGF resistance by combining advanced age with laser delivery in mice. As they became older, the mice showed increased resistance to anti-VEGF treatment that correlated with increased intracellular cholesterol accumulation in macrophages.

The researchers tested the effect of AIBP and anti-VEGF in disease progression in this mouse model.

In young mice that were about eight weeks old, both AIBP and anti-VEGF were equally effective in controlling disease progression. In intermediate age mice, which were about eight months old or the equivalent of middle-aged people, macrophages showed increased cholesterol accumulation. In this group, anti-VEGF treatment was less effective when compared with younger mice, but the AIBP treatment was as affective controlling the disease.

The oldest group of mice, which was about 18 months old or the equivalent of senior people, showed highest cholesterol accumulation inside macrophages and were resistant to anti-VEGF treatment. Interestingly, AIBP alone also did not inhibit CNV, but the combination of AIBP with anti-VEGF overcame the anti-VEGF resistance and robustly suppressed laser-induced CNV by 47 percent.

This study also has increased our understanding of the mechanism underlying anti-VEG resistance. The researchers provide strong evidence that the accumulation of cholesterol in old macrophages plays a central role in anti-VEGF resistance because the old mice became responsive to anti-VEGF treatment when macrophages were chemically depleted. Fu, Fang and colleagues propose that the beneficial effect of AIBP is likely due to both its ability to enhance cholesterol removal from macrophages and its anti-inflammatory function.

Clinical implications

"Our findings encourage us to test the combination therapy of AIBP and anti-VEGF in clinical trials to determine whether it can help patients with the condition," Fu said. "The projected number of people with age-related macular degeneration is 196 million in 2020 and 288 million in 2040. There is great interest in novel therapies for this devastating condition."

Co-author Dr. James Handa, Chief of the Retina Division at the Wilmer Eye Institute, Johns Hopkins School of Medicine said, "Age-related macular degeneration has multiple factors that contribute to its development; therefore, future treatments that target multiple pathways, such as what we describe here, may lead to more effective outcomes."

"As a cardiovascular scientist, my research is centered on cholesterol metabolism and angiogenesis, the formation of new blood vessels. My team has been collaborating with Dr. Fu for several years in developing AIBP as a potential treatment for age-related macular degeneration," Fang said. "Our studies show that AIBP can be a promising therapy for the treatment of CNV. Compared to the standard anti-VEGF therapy, AIBP targets multiple causes of age-related macular degeneration by correcting the adverse profiles associated with aging. The discovery that the combination therapy can overcome anti-VEGF resistance shows the power of multidisciplinary research."

OAK BROOK, Ill. (July 16, 2020) - Racial/ethnic minority patients admitted to the hospital with COVID-19 infection are more likely to have more severe disease on chest X-rays than white/non-Hispanic patients, increasing the likelihood of adverse outcomes, such as intubation or death, according to a study published in the journal Radiology.

Emerging data show that racial/ethnic minorities have been disproportionately affected by COVID-19. Socioeconomic factors and pre-existing medical conditions like hypertension are likely contributing factors to this disparity. Furthermore, limited English proficiency may introduce additional linguistic and health literacy barriers to care, potentially resulting in delays seeking medical attention and greater severity of disease at the time of admission to the hospital with COVID-19 infection.

Radiologists from Massachusetts General Hospital (MGH) saw these disparities firsthand in April among patients admitted to the hospital with confirmed COVID-19 infection, and at one of the hospital's respiratory infection clinics in Chelsea, a city just north of Boston that is home to a predominantly Spanish-speaking Hispanic community. A significant proportion of the patients who visited the Chelsea clinic had COVID-19, and the level of disease the radiologists observed on chest imaging was markedly more severe than that seen at other respiratory infection clinics in Boston. These disparities were more evident among patients admitted to the hospital with confirmed COVID-19 infection.

"It got to the point where half of our patient population admitted with COVID-19 were underrepresented minorities," said study coauthor Efren J. Flores, M.D., a radiologist at MGH.

Dr. Flores and colleagues set out to study these observed disparities in greater detail with an eye toward developing a better understanding of some of the factors involved. They hope to use this information to guide risk mitigation strategies and improve outcomes among racial/ethnic minority groups. They looked at data from 326 patients hospitalized with confirmed COVID-19 infection between March 27 and April 10, 2020. Analysis of chest X-ray results revealed that non-white patients had significantly more severe lung disease on admission than white/non-Hispanic patients. Increased disease severity on chest X-rays increased the likelihood of adverse clinical outcomes, including admission to the intensive care unit, intubation and death.

As expected, the increased severity of lung disease on chest X-rays among non-white patients correlated with a combination of factors, including delay in seeking care at the hospital, higher prevalence of pre-existing comorbidities and limited English proficiency.

"Limited English proficiency is an additional socioeconomic factor that really influences many aspects of access to care," Dr. Flores said. "When we were first learning how the disease spreads, there was all this rapidly evolving information coming out that was not available in languages other than English, and that lag in availability of actionable health information for non-English speaking individuals was really critical for many patients trying to navigate a complex medical system with a disease from a virus that is so aggressive."

The connection between limited English proficiency and disease severity underscores the importance of having multilingual, culturally tailored health information available, Dr. Flores said, especially as the number of infections climbs in different parts of the country.

Disparities in access to care and disease severity are not limited to linguistic barriers. Racial/ethnic non-white communities disproportionately experience lower socioeconomic status, adding another layer of complexity when accessing care. Living and working arrangements also likely played a role in the severity of COVID-19 among these patients, the study authors said. Racial and ethnic minority populations tend to live in multigenerational households and communities of higher population density, making social distancing difficult. In addition, they are more often employed in jobs not conducive to remote work with limited paid time off, thus increasing their exposure to COVID-19.

"Many of these patients delay their care because they're considered essential workers and they don't have a lot of sick leave, but also it's difficult for them to leave because they are living on a weekly paycheck and have other dependents," Dr. Flores said. "It wasn't uncommon for us to go into the medical record when we were interpreting their exams and see that many of them worked at grocery stores or warehouses."

The study findings highlight the important role radiologists play in providing earlier identification of higher-risk patients and developing multidisciplinary collaborations to help address these disparities, according to Dr. Flores.

"Health equity is every medical specialty's responsibility, but I believe radiology is uniquely positioned to take a bigger role not only in population health but in public health efforts," he said. "Our ability to provide care in different settings is what allowed us to make the clinical observation that patients coming to this one particular clinic and those being admitted to the hospital were presenting with a higher rate of positive findings that were also more severe. That really offered a window into the disparities that were translating into greater disease severity and worse outcomes."

Moving forward, the findings of this study could assist radiologists in the development of algorithms to identify vulnerable and at-risk populations. This could spur collaborations with other medical specialties, community stakeholders, and public health initiatives to enhance the effectiveness of public health interventions that increase access to care.

"We did this study not only to gain a better understanding of these emerging disparities, but also to discover how we can use this information to craft a better path towards equity together," Dr. Flores said.

OAK BROOK, Ill. (July 16, 2020) - COVID-19 is associated with life-threatening blood clots in the arteries of the legs, according to a study published in Radiology. Researchers said COVID-19 patients with symptoms of inadequate blood supply to the lower extremities tend to have larger clots and a significantly higher rate of amputation and death than uninfected people with the same condition.

COVID-19's association with blood clots in the pulmonary arteries is well-established. Less is known about the virus' connection to lower extremity arterial thrombosis, a condition characterized by blood clots in the arteries that impede the flow of oxygenated blood to the lower extremities.

During the peak of the COVID-19 pandemic in New York City, radiologists at the city's Montefiore Medical Center observed an increase in patients testing positive for lower extremity arterial thrombosis on CT angiography exams. The patients had arrived at hospitals with coldness, pain or discoloration of their legs. Frequently these symptoms of leg ischemia, a condition in which blood flow to the lower extremities is restricted, were accompanied by respiratory distress, cough, fever and altered mental status.

The alarming trend prompted the researchers to look more closely at a possible connection between COVID-19 and lower extremity arterial thrombosis and whether people with the virus had a worse prognosis.

In March and April 2020, they identified 16 COVID-19-positive patients, average age 70, who underwent CT angiography of the lower extremities for symptoms of leg ischemia. These patients were compared with 32 COVID-19-negative patients, average age 71, who underwent CT angiography with similar symptoms in previous years and who were well matched with COVID-19 cohort for demographic and clinical characteristics.

All patients with COVID-19 infection undergoing lower extremity CT angiography had at least one clot in the leg, compared with only 69% of controls. The clots in the COVID-19 patients were significantly larger and affected arteries higher up in the leg with greater frequency than those in controls. Death or limb amputation was more common in the COVID-19 patients.

"We found that arterial thrombosis associated with COVID-19 infection was characterized by dire outcomes, namely strikingly increased rates of amputation and death, which in our series were 25% and 38%, respectively," said study lead author Inessa A. Goldman, M.D., a radiologist at Montefiore and assistant professor at Albert Einstein College of Medicine in New York City. "For comparison, the rate of both amputation and death was only 3% among controls. It is unclear whether the patients' concurrent COVID-19-related pneumonia, the virulence of the COVID-19-related clotting disorder or delayed initial arrival to the hospital contributed to these outcomes."

COVID-19 patients presenting with symptoms of leg ischemia only were more likely to avoid amputation or death than patients who had symptoms of ischemia and systemic symptoms including cough, respiratory distress or failure, hypoxia, fever, or altered mental status.

"In our cohort none of the five patients presenting with complaints pertaining to leg symptoms only, such as pain or discoloration, without systemic symptoms sustained amputation or died," Dr. Goldman said.

Dr. Goldman noted that with infection rates rising in many parts of the country, it is important that physicians be mindful of the connection between COVID-19 and lower extremity arterial thrombosis.

"Awareness of lower extremity arterial thrombosis as a possible complication of COVID-19 infection is important for all providers who take care of these patients, because early diagnosis is usually crucial for limb preservation in lower extremity ischemia," she said.

COVID-19's association with lower extremity arterial thrombosis is likely related to a combination of factors, Dr. Goldman said, including an increased tendency of the blood to clot, damage to the lining of the arteries, and immune reactions tied to the SARS-CoV-2 virus and COVID-19 infection.

"This continues to be an area of intense study around the world," she said.

In a new approach to conservation genetics, researchers used a high-quality genome of the coral Acropora millepora, along with environmental data, to study this coral's variable responses to climate change, a trait of key conservation importance. Their results, which suggest a unique genetic signature in corals likely to bleach, could be used to forecast potential bleaching events before they occur and to identify the coral populations most vulnerable or tolerant to future climate warming. When sea temperatures get too hot, corals will expel the vital photosynthetic algae that live within their tissues, causing the coral to turn white, or "bleach," and ultimately to die. However, the thermal limits of corals and their responses to bleaching events vary within species. While it's thought that these tolerances are partly heritable, due to the lack of high-quality genomic resources for coral species, the genes responsible remain elusive. To identify any potential genetic variants associated with bleaching, Zachary Fuller and colleagues first produced a chromosome-level genome assembly of A. millepora - a shallow-water coral susceptible to bleaching - and compared it to genome-wide association (GWAS) data generated for 213 other A. millepora coral colonies collected during a bleaching event in the Great Barrier Reef. While Fuller et al. found no specific genetic variants directly associated with bleaching, they were able to show that a polygenic risk score comprising signals throughout the coral genome could be used to predict bleaching potential in the wild. The analysis also revealed a considerable amount of genetic diversity in the gene sacsin, which is involved in heat stress response. The diversity suggests local environmental adaptation. "The genome Fuller et al. created using long-read technology to cope with repetitive regions will be an enormous resource for future studies of coral ecology, evolution, cell biology and development, facilitating preciously untenable investigations in this ecologically important system," write Rachael Bar and Leslie Guerrero in a related Perspective.

In order to survive within the remote and harsh anatomical microenvironments of the central nervous system, the disseminated cancer cells that cause rare yet deadly leptomeningeal metastases (LM) hijack crucial iron micronutrients from native macrophages, researchers report. The work highlights the remarkable plasticity of tumor cells and reveals potential new avenues for treating these particularly intractable advanced cancer complications. On rare occasions, cancer cells infiltrate the relatively isolated spaces of the central nervous system filled with cerebrospinal fluid (CSF) and metastasize to the leptomeningeal membranes that line the brain and spinal cord. Nutrient-and oxygen-deprived, and loaded with patrolling immune cells, the CSF presents a hostile environment to outsiders - yet somehow, cancer cells survive and thrive in this challenging environment. To investigate how cancer cells overcome these constraints, Yudan Chi and colleagues used single-cell RNA sequencing to study CSF samples from five patients with LM. The authors found that these cells utilize a high-affinity iron collection system. In CSF, iron is a limited but highly sought resource crucial to cell metabolism and DNA synthesis. Cancer cells that express an iron-capturing gene collect iron more efficiently, outcompeting healthy CSF macrophages for the crucial resource. Thus, the mechanism allows LM cells to survive in nutrient-deprived environments while potentially escaping immune attack by limiting the supply of vital iron to macrophages. "Few studies have focused on the biochemical composition of the CSF in the setting of leptomeningeal metastasis, and the study of Chi et al. contributes to bridging this knowledge gap," writes Livia Garzia and Michael Taylor in a related Perspective.

A recently discovered hypercompact CRISPR enzyme found only in huge bacteriophages, and known as CRISPR-CasΦ, is functional, a new study by Patrick Pausch, Jennifer Doudna and colleagues reports, and it provides a powerful new tool in the CRISPR genome editing toolbox, including because it can target a wider range of genetic sequences compared to Cas9 and Cas12. The authors tested its target-expanding capabilities in human and plant cells. Given its small size, they also suggest CasΦ could offer novel advantages for cellular delivery relative to other CRISPR-Cas proteins. While commonly known as a tool for genetic engineering, in nature, CRISPR-Cas systems provide many single-celled organisms with an adaptive immunity against viruses and plasmids. CRISPR RNAs (crRNA) in the host recognize DNA in previously encountered viruses and direct CRISPR-associated or Cas enzymes to destroy the viruses. While CRISPR-Cas systems almost exclusively exist and operate in the genomes of bacteria and archaea, they've also recently been discovered in huge bacteriophages - the viruses of bacteria. However, these systems are different. They notably lack the Cas proteins commonly found in other CRISPR-Cas systems, yet exclusively harbor the genetically unique and unusually tiny CasΦ enzyme. Here, Pausch, Doudna and colleagues describe the functionality of the phage-derived CRISPR-CasΦ system and demonstrate its potential for expanding the CRISPR genome editing toolbox. Despite being nearly half the size of Cas9 and Cas12 systems commonly used for genome editing, Pausch et al. show that the biochemically unique CasΦ is fully functional and capable of both producing mature crRNA and cleaving the foreign DNA using only a single active site, making it the most compact CRISPR-Cas system yet identified. What's more, the authors demonstrate CasΦ's ability to be used successfully in both human and plant genome editing.

Leesburg, VA, July 16, 2020--An Online First Accepted Manuscript published in ARRS' American Journal of Roentgenology (AJR) finds that focusing on lung cancer screening (LCS) subjects less likely to remain in the program--those with negative low-dose CT (LDCT) exams and those who still smoke--can improve that program's cost-effectiveness and maximize its societal benefits.

For people with a long history of smoking, LDCT LCS has been shown to decrease mortality; however, adherence to an LCS program remains significantly lower than in randomized controlled trials.

To assess real-world LDCT LCS performance and factors predictive of adherence to recommendations, three radiologists from the University of Pennsylvania's Perelman School of Medicine retrospectively recorded patient demographics, smoking history and behavior changes, Lung-RADS category, PPV and NPV, and adherence to screening recommendations for 260 subjects returning for follow-up LDCT from 2014 to 2019.

Forty-three subjects (16.5%) had positive scans, of which 28/260 (10.8%) were Lung-RADS category 3, 8/260 (3.1%) were 4A, 6/260 (2.3%) were 4B, and 2/260 (0.8%) were 4X.

Four subjects were diagnosed with cancer: 3 lung, 1 metastatic melanoma.

Meanwhile, 143/260 (55%) subjects were current smokers at baseline, and 121/260 (46.5%) were current smokers during the last round of LCS.

Both LCS sensitivity and NPV were 100%, while specificity was 84.8% and PPV was 9.3%.

Overall adherence was 43%, though it increased progressively the higher the Lung-RADS category. Additionally, adherence was higher in former vs. current smokers (50% vs. 36.2%; p = 0.002). Ultimately, there were only two significant independent predictors of adherence: having smoked previously and a positive (? 3) Lung-RADS category.

"Our study demonstrates that a real-world LCS can perform similar to randomized controlled trials in regard to important performance metrics," concluded first author Eduardo J. Mortani Barbosa, Jr.

Acknowledging that an economic incentive, such as an insurance premium reduction, could improve LCS adherence, Barbosa, Jr. et al. added that multimodal communication (i.e., face-to-face discussions with radiologists, letters from referring providers, reminders via electronic health records) should be investigated and incentivized.

"Such communications should emphasize that a negative LCS exam does not confer immunity to future lung cancer development," the authors of this AJR article noted, "and that continued participation in LCS, combined with smoking cessation, is essential to accrue the maximum benefits of mortality reduction amongst persons with substantial smoking history."