Culture

The longer your commute, the more you're exposed to a chemical flame retardant that is a known carcinogen and was phased out of furniture use because it required a Proposition 65 warning label in California.

That is the conclusion of a new UC Riverside study published this month in the journal Environment International.

While much research on automobile pollution focuses on external air pollutants entering vehicle interiors, this study shows that chemicals emanating from inside your car could also be cause for concern.

Though there are other Proposition 65-list chemicals that are typically used in the manufacture of automobiles, this flame retardant is a new addition to the list. Known as the Safe Drinking Water and Toxic Enforcement Act, Proposition 65 requires the state to maintain and update a list of chemicals known to cause cancer or reproductive harm.

Some scientists assumed that humans stopped being exposed to the chemical, called TDCIPP or chlorinated tris, after it was placed on California's Proposition 65 list in 2013. However, it is still widely used in automobile seat foam. The study shows that not only is your car a source of TDCIPP exposure, but that less than a week of commuting results in elevated exposure to it.

David Volz, associate professor of environmental toxicology at UCR, said the results were unexpected.

"I went into this rather skeptical because I didn't think we'd pick up a significant concentration in that short a time frame, let alone pick up an association with commute time," Volz said. "We did both, which was really surprising."

Over the past decade, Volz has studied how various chemicals affect the trajectory of early development. Using zebrafish and human cells as models, the Volz laboratory has been studying the toxicity of a newer class of flame retardants called organophosphate esters since 2011.

Little is known about the toxicity of these organophosphate esters -- TDCIPP is one of them -- but they've replaced older flame-retardant chemicals that lasted longer in the environment and took longer to metabolize.

Using zebrafish as a model, Volz found TDCIPP prevents an embryo from developing normally. Other studies have reported a strong association between TDCIPP and infertility among women undergoing fertility treatments.

Knowing its use is still widespread in cars, Volz wondered whether a person's exposure is elevated based on their commute. UC Riverside undergraduates made for excellent study subjects, as a majority of them have a daily commute.

The research team included collaborators at Duke University and was funded by the National Institutes of Health as well as the USDA National Institute of Food and Agriculture.

Participants included around 90 students, each of whom had commute times that varied from less than 15 minutes to more than two hours round trip. All of them were given silicone wristbands to wear continuously for five days.

The molecular structure of silicone makes it ideal for capturing airborne contaminants. Since TDCIPP isn't chemically bound to the foam, Aalekyha Reddam, a graduate student in the Volz laboratory, said it gets forced out over time and ends up in dust that gets inhaled.

Multiple organophosphate esters were tested, but TDCIPP was the only one that showed a strong positive association with commute time.

"Your exposure to TDCIPP is higher the longer you spend in your vehicle," Reddam said.

While Volz and his team did not collect urine samples to verify that the chemical migrated into the bodies of the participants, they believe that's what happened.

"We presume it did because of how difficult it is to avoid the ingestion and inhalation of dust," Volz said. Additionally, other studies have examined the accumulation of TDCIPP in urine, but not as a function of how long a person sits in a car.

Going forward, the research team would like to repeat the study with a larger group of people whose ages are more varied. They would also like to study ways to protect commuters from this and other toxic compounds.

Until more specific reduction methods can be identified, the team encourages frequently dusting the inside of vehicles, and following U.S. Environmental Protection Agency guidelines for reducing exposure to contaminants.

Until safer alternatives are identified, more research is needed to fully understand the effects of TDCIPP on commuters.

"If we picked up this relationship in five days, what does that mean for chronic, long-term exposure, for people who commute most weeks out of the year, year over year for decades?" Volz asked.

The areas of Indonesia where Dutch colonial rulers built a huge sugar-producing industry in the 1800s remain more economically productive today than other parts of the country, according to a study co-authored by an MIT economist.

The research, focused on the Indonesian island of Java, introduces new data into the study of the economic effects of colonialism. The finding shows that around villages where the Dutch built sugar-processing factories from the 1830 through the 1870s, there is today greater economic activity, more extensive manufacturing, and even more schools, along with higher local education levels.

"The places where the Dutch established [sugar factories] persisted as manufacturing centers," says Benjamin Olken, a professor of economics at MIT and co-author of a paper detailing the results, which appears in the January issue of the Review of Economic Studies.

The historical link between this "Dutch Cultivation System" and economic activity today has likely been transmitted "through a couple of forces," Olken suggests. One of them, he says, is the building of "complementary infrastructure" such as railroads and roads, which remain in place in contemporary Indonesia.

The other mechanism, Olken says, is that "industries grew up around the sugar [industry], and those industries persisted. And once you have this manufacturing environment, that can lead to other changes: More infrastructure and more schools have persisted in these areas as well."

To be sure, Olken says, the empirical conclusions of the study do not represent validation of Dutch colonial rule, which lasted from the early 1600s until 1949 and significantly restricted the rights and self-constructed political institutions of Indonesians. Dutch rule had long-lasting effects in many areas of civic life, and the Dutch Cultivation System used forced labor, for one thing.

"This paper is not trying to argue that the [Dutch] colonial enterprise was a net good for the people of the time," Olken emphasizes. "I want to be very clear on that. That's not what we're saying."

Instead, the study was designed to evaluate the empirical effects of the Dutch Cultivation System, and the outcome of the research was not necessarily what Olken would have anticipated.

"The results are striking," Olken says. "They just jump out at you."

The paper, "The Development Effects of the Extractive Colonial Economy: The Dutch Cultivation System in Java," is co-authored by Olken and Melissa Dell PhD '12, a professor of economics at Harvard University.

On the ground

Historically in Java, the biggest of Indonesia's many islands, the main crop had been rice. Starting in the 1830s, the Dutch instituted a sugar-growing system in some areas, building 94 sugar-processing factories, as well as roads and railroads to transport materials and products.

Generally the Dutch would export high-quality sugar from Indonesia while keeping lower-quality sugar in the country. Overall, the system became massive; at one point in the mid-19th century, sugar production in Java accounted for one-third of the Dutch government's revenues and 4 percent of Dutch GDP. By one estimate, a quarter of the population was involved in the industry.

In developing their research, Olken and Dell used 19th century data from government archives in the Netherlands, as well as modern data from Indonesia. The Dutch built the processing plants next to rivers in places with enough flat land to sustain extensive sugar crops; to conduct the study, the researchers looked at economic activity near sugar-processing factories and compared it with economic activity in similar areas that lacked factories.

"In the 1850s, the Dutch spent four years on the ground collecting detailed information for the over 10,000 villages that contributed land and labor to the Cultivation System," Dell notes. The researchers digitized those records and, as she states, "painstakingly merged them" with economic and demograhic records from the same locations today

As the results show, places close to factories are 25-30 percentage points less agricultural in economic composition than those away from factories, and they have more manufacturing, by 6-7 percentage points. They also have 9 percent more employment in retail.

Areas within 1 kilometer of a sugar factory have a railroad density twice that of similar places 5 to 20 kilometers from factories; by 1980, they were also 45 percent more likely to have electricity and 4 percent more likely to have a high school. They also have local populations with a full year more of education, on average, than areas not situated near old sugar factories.

The study shows there is also about 10 to 15 percent more public-land use in villages that were part of the Dutch Cultivation System, a data point that holds steady in both 1980 and 2003.

"The key thing that underlies this paper, in multiple respects, is the linking of the historical data and the modern data," Olken says. The researchers also observed that the disparity between industrialized places and their more rural counterparts has not arisen since 1980, further suggesting how much Java's deep economic roots matter.

Net Effects?

The paper blends the expertise of Olken, who has spent years conducting antipoverty studies in Indonesia, and Dell, whose work at times examines the effects of political history on current-day economic outcomes.

"I had never really done a historical project before," Olken says. "But the opportunity to collaborate with Melissa on this was really exciting."

One of Dell's best-known papers, published in 2010 while she was still a PhD student at MIT, shows that in areas of Peru where colonial Spanish rulers instituted a system of forced mining labor from the 1500s to the 1800s, there are significant and negative economic effects that persist today.

However, somewhat to their surprise, the researchers did not observe similarly pronounced effects from the Dutch Cultivation System.

"One might have thought that could have had negative consequences on local social capital and local development in other respects," says Olken, adding that he "wasn't sure what to expect" before looking at the data.

"The differences between the long-run effects of forced labor in Peru and Java suggest that for understanding persistent impacts on economic activity, we need to know more than just whether there was forced labor in a location," Dell says. "We need to understand how the historical institutions influenced economic incentives and activities initially, and how these initial effects may or may not have persisted moving forward."

Olken adds that the study "can't measure every possible thing," and that "it's possible there are other effects we didn't see."

Moreover, Olken notes, the paper cannot determine the net effect of the Dutch Cultivation System on Indonesian economic growth. That is, in the absence of Dutch rule, Indonesia's economy would have certainly grown on it own -- but it is impossible to say whether it would have expanded at a rate faster, slower, or equivalent to the trajectory it had under the Dutch.

"We can't say what would have happened if the Dutch had never showed up in Indonesia," Olken says. "And of course the Dutch [colonizing] Indonesia had all kinds of effects well beyond the scope of this paper, many of them negative for the contemporaneous population."

At the heart of any electronic device is a cold, hard computer chip, covered in a miniature city of transistors and other semiconducting elements. Because computer chips are rigid, the electronic devices that they power, such as our smartphones, laptops, watches, and televisions, are similarly inflexible.

Now a process developed by MIT engineers may be the key to manufacturing flexible electronics with multiple functionalities in a cost-effective way.

The process is called "remote epitaxy" and involves growing thin films of semiconducting material on a large, thick wafer of the same material, which is covered in an intermediate layer of graphene. Once the researchers grow a semiconducting film, they can peel it away from the graphene-covered wafer and then reuse the wafer, which itself can be expensive depending on the type of material it's made from. In this way, the team can copy and peel away any number of thin, flexible semiconducting films, using the same underlying wafer.

In a paper published in the journal Nature, the researchers demonstrate that they can use remote epitaxy to produce freestanding films of any functional material. More importantly, they can stack films made from these different materials, to produce flexible, multifunctional electronic devices.

The researchers expect that the process could be used to produce stretchy electronic films for a wide variety of uses, including virtual reality-enabled contact lenses, solar-powered skins that mold to the contours of your car, electronic fabrics that respond to the weather, and other flexible electronics that seemed until now to be the stuff of Marvel movies.

"You can use this technique to mix and match any semiconducting material to have new device functionality, in one flexible chip," says Jeehwan Kim, an associate professor of mechanical engineering at MIT. "You can make electronics in any shape."

Kim's co-authors include Hyun S. Kum, Sungkyu Kim, Wei Kong, Kuan Qiao, Peng Chen, Jaewoo Shim, Sang-Hoon Bae, Chanyeol Choi, Luigi Ranno, Seungju Seo, Sangho Lee, Jackson Bauer, and Caroline Ross from MIT, along with collaborators from the Uniersity of Wisconsin at Madison, Cornell University, the University of Virginia, Penn State University, Sun Yat-Sen University, and the Korea Atomic Energy Research Institute.

Buying time

Kim and his colleagues reported their first results using remote epitaxy in 2017. Then, they were able to produce thin, flexible films of semiconducting material by first placing a layer of graphene on a thick, expensive wafer made from a combination of exotic metals. They flowed atoms of each metal over the graphene-covered wafer and found the atoms formed a film on top of the graphene, in the same crystal pattern as the underlying wafer. The graphene provided a nonstick surface from which the researchers could peel away the new film, leaving the graphene-covered wafer, which they could reuse.

In 2018, the team showed that they could use remote epitaxy to make semiconducting materials from metals in groups 3 and 5 of the periodic table, but not from group 4. The reason, they found, boiled down to polarity, or the respective charges between the atoms flowing over graphene and the atoms in the underlying wafer.

Since this realization, Kim and his colleagues have tried a number of increasingly exotic semiconducting combinations. As reported in this new paper, the team used remote epitaxy to make flexible semiconducting films from complex oxides -- chemical compounds made from oxygen and at least two other elements. Complex oxides are known to have a wide range of electrical and magnetic properties, and some combinations can generate a current when physically stretched or exposed to a magnetic field.

Kim says the ability to manufacture flexible films of complex oxides could open the door to new energy-havesting devices, such as sheets or coverings that stretch in response to vibrations and produce electricity as a result. Until now, complex oxide materials have only been manufactured on rigid, millimeter-thick wafers, with limited flexibility and therefore limited energy-generating potential.

The researchers did have to tweak their process to make complex oxide films. They initially found that when they tried to make a complex oxide such as strontium titanate (a compound of strontium, titanium, and three oxygen atoms), the oxygen atoms that they flowed over the graphene tended to bind with the graphene's carbon atoms, etching away bits of graphene instead of following the underlying wafer's pattern and binding with strontium and titanium. As a surprisingly simple fix, the researchers added a second layer of graphene.

"We saw that by the time the first layer of graphene is etched off, oxide compounds have already formed, so elemental oxygen, once it forms these desired compounds, does not interact as heavily with graphene," Kim explains. "So two layers of graphene buys some time for this compound to form."

Peel and stack

The team used their newly tweaked process to make films from multiple complex oxide materials, peeling off each 100-nanometer-thin layer as it was made. They were also able to stack together layers of different complex oxide materials and effectively glue them together by heating them slightly, producing a flexible, multifunctional device.

"This is the first demonstration of stacking multiple nanometers-thin membranes like LEGO blocks, which has been impossible because all functional electronic materials exist in a thick wafer form," Kim says.

In one experiment, the team stacked together films of two different complex oxides: cobalt ferrite, known to expand in the presence of a magnetic field, and PMN-PT, a material that generates voltage when stretched. When the researchers exposed the multilayer film to a magnetic field, the two layers worked together to both expand and produce a small electric current.

The results demonstrate that remote epitaxy can be used to make flexible electronics from a combination of materials with different functionalities, which previously were difficult to combine into one device. In the case of cobalt ferrite and PMN-PT, each material has a different crystalline pattern. Kim says that traditional epitaxy techniques, which grow materials at high temperatures on one wafer, can only combine materials if their crystalline patterns match. He says that with remote epitaxy, researchers can make any number of different films, using different, reusable wafers, and then stack them together, regardless of their crystalline pattern.

"The big picture of this work is, you can combine totally different materials in one place together," Kim says. "Now you can imagine a thin, flexible device made from layers that include a sensor, computing system, a battery, a solar cell, so you could have a flexible, self-powering, internet-of-things stacked chip."

The team is exploring various combinations of semiconducting films and is working on developing prototype devices, such as something Kim is calling an "electronic tattoo" -- a flexible, transparent chip that can attach and conform to a person's body to sense and wirelessly relay vital signs such as temperature and pulse.

"We can now make thin, flexible, wearable electronics with the highest functionality," Kim says. "Just peel off and stack up."

The way research in bioprinting will be taken forward has been laid out in a roadmap for the field.
Published today in IOP Publishing's Biofabrication, leading researchers define the status, challenges and opportunities in the field, and forecast the required advances in science & technology to overcome the challenges to a range of bioprinting techniques and applications.

In the roadmap:

Professor Binil Starly charts the progress from cell expansion to 3D cell printing

Dr Andrew C. Daly, Professor Jürgen Groll, and Professor Jason A. Burdick examine the developments and challenges in the bioinks used for bioprinting

Gregor Skeldon and Professor Wenmiao Shu look at the bioprinting of stem cells

Dr Jinah Jang and Dr Dong-Woo Cho present a strategy for bioprinting of tissue vascular system and tissue assembly

Dr Minghao Nie and Professor Shoji Takeuchi examine the potential for using 3D-printed biohybrid tissues as in-vitro biological models for studying disease

Dr Serge Ostrovidov and Professor Ali Khademhosseini examine how 3D bioprinting can be used for the development of organs-on-a-chip

Professor Roger D. Kamm covers the biomanufacturing of multi-cellular engineered living systems

Dr Vladimir Mironov and Professor Lorenzo Moroni explore how researchers are pushing boundaries with bioprinting in space

Professor Ibrahim T. Ozbolat examines the developments of bioprinting technologies

Introducing the collection, guest editor Professor Wei Sun, from Drexel University, Philadelphia, USA and Tsinghua University, Beijing, China, said: "Cells are nature's building blocks. Bioprinting uses cells, proteins and biomaterials as building blocks to 3D printed biological models, biological systems and therapeutic products.

"It has rapidly evolved into printing biomaterials for tissue scaffolds and implants, printing cells or organoids for 3D biological models, and printing micro-organ-chips for micro-physiological platforms and engineered living systems, such as cellular machining and biorobots.

"There are a number of challenges to overcome, including: the need for a new generation of novel bioinks with multi-functional properties to better transport, protect and grow cells during and after printing; better printing processes and printers to deliver cells with high survivability and high precision; efficient and effective crosslinking techniques and crosslinkers to maintain the structure integrity and stability after printing; integration with micro-fluidic devices to provide a long term and a simulated physiological environment to culture printed models.

"Due to the rapid advancements in bioprinting techniques and their wide-ranging applications, the direction in which the field should advance is still evolving. The roadmap aims to address this unmet need by providing a comprehensive summary and recommendations, useful to experienced researchers and newcomers to the field alike."

Hospitals, doctors and Medicare Advantage insurance plans that care for some of the most vulnerable patients are not reimbursed fairly by Medicare, according to recent findings in JAMA.

It costs more to care for patients who are frail, have dementia, are depressed or are poor. However providers that treat them and health insurance plans that provide their coverage are not paid fairly to treat these health conditions because Medicare doesn't account for them in its existing risk payment system. That system rates patients based upon how sick they are, which determines Medicare reimbursements.

"While it's an unintended consequence of the current Medicare payment policy, those who are among the most vulnerable are less likely to get the care that they need," said Kenton Johnston, Ph.D., assistant professor of health management and policy at Saint Louis University College for Public Health and Social Justice, and lead author of the paper.

"This disparity has already created an incentive for providers and plans to avoid treating Medicare beneficiaries with those conditions."

Medicare compensates health insurance plans in Medicare Advantage and medical providers under value-based payment models based on how sick their patients are, which is measured by a risk score. Because patients who have higher risk scores cost more to treat than those with lower scores, Medicare pays insurance plans and providers more to treat them.

In this paper, Johnston highlighted a problem with Medicare payments. Medicare does not include frailty, dementia, depression or poverty in its risk scores even though patients with those conditions are sicker and costlier to treat.

Johnston and his co-authors Julie P. W. Bynum, M.D., professor of internal medicine at the University of Michigan Medical School in Ann Arbor, Michigan, and Karen E. Joynt Maddox, M.D., assistant professor of cardiology at Washington University School of Medicine in St. Louis, recommend an easy fix to correct the disparity.

Medicare should include patient frailty, dementia, depression and poverty in its risk scores - conditions for which there are standard diagnosis codes that clinicians can enter at the time they treat patients.

Medicare has resisted the change, Johnston said, arguing clinicians and facilities might over-code those conditions to increase their reimbursement.

"That can be addressed through existing fraud procedures that Medicare already has in place. A clinician who codes a patient for those conditions when the patient does not have the conditions is committing Medicare fraud and can be penalized," Johnston said.

"It is unfair to clinicians, facilities and plans that do treat patients with those conditions to not reimburse them fairly for their services."

The ability to forget our memories - for better or worse - is dependent on microglia and their inclination to weaken and eliminate the synapses connecting engram neurons, according to a new study in mice. The findings - which answer questions about whether microglia, known to be active in brain development, also affect forgetting later in life - present an important mechanism underlying memory erasure and may help aid our understanding of forgetting and amnesia. It's thought that our brains encode and store memories in engrams - neuronal ensembles stitched together by dynamic synaptic circuits. Reactivation of engrams by way of these synaptic connections allows us to recall specific memories; failure to reactivate an engram results in losing the related memory. Synaptic connections in the brain are highly dynamic. Rewiring of synaptic circuits could contribute to the loss of previously formed memories by weakening or severing the networks connecting engram cells. Microglia - the brain's resident macrophage cells - are responsible for trimming excessive synapses during brain development and in regulating the dynamics of synapses throughout life. However, it's unknown if microglial activity also regulates forgetting and memory erasure in the adult brain. Chao Wang and colleagues observed and manipulated microglia and engram cells in the healthy brains of memory-trained mice to reveal their role in regulating forgetting. Depleting microglia or inhibiting their activity prevented forgetting, the authors showed. Intact microglia mediate the dissociation of engram cells, leading to degradation and eventual erasure of the associated memories, the findings suggest. Inhibiting the activity of engram cells also facilitated the elimination of engram cell synapses by microglia, resulting in less active memories to be forgotten.

Clumps of proteins inside cells are a common thread in many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) or Lou Gehrig's disease. These clumps, or solid aggregates of proteins, appear to be the result of an abnormality in the process known as liquid-liquid phase separation (LLPS), in which individual proteins come together to form a liquid-like droplet.

To understand how the process goes awry, researchers need a better understanding of the mechanism that drives LLPS in the first place. What is it about any protein that would cause it to condense into a liquid?

Collaborative research between the Pappu Lab, led by Rohit Pappu in the McKelvey School of Engineering at Washington University in St. Louis, and the lab of Tanja Mittag at St. Jude Children's Research Hospital has uncovered the key to translating the patterns written into specific types of protein sequences that contribute to LLPS.

Importantly, they also have uncovered how specific arrangements of amino acids, which stray from the pattern, can negatively impact phase separation and give rise to the formation of solid aggregates instead of liquids.

Their research was published today in Science.

When certain cells are stressed, which happens regularly, cellular response proteins condense into membraneless organelles -- squishy, liquid-like droplets that have defined boundaries but no delimiting membranes.

The droplets form by LLPS, a phenomenon that is conceptually similar to the process by which oil and vinegar separate from one another, forming coexisting liquid droplets.

Although it is called phase separation, LLPS is really a process of coming together, or condensing. Loosely condensed proteins are in a liquid-type phase; the more tightly they are packed, the more solid they become.

Under some circumstances, often due to mutations, an errant process causes some of the material in these protein-rich droplets, also known as biomolecular condensates, to morph into more solid aggregates.

The condensation, in many cases, is driven by the intrinsically disordered regions (IDR) of the protein. These are stretches of the protein with no defined three-dimensional shape, and yet they feature prominently in key functional roles, especially in the brain.

Pappu, the Edwin H. Murty Professor of Engineering, and his coworkers had shown that certain parts of the IDRs were sticky -- they had a tendency to stick to each other on the same protein, or on those nearby. These "stickers," which are actually amino acids on the protein chain, and the material between them, called spacers, are the basis for the sticker-and-spacer model, a framework used to describe LLPS.

The collaboration, which involved Mittag's team at St. Jude team, was driven by experiments performed in the Mittag lab to try to identify the key stickers that are responsible for driving phase separation. To do this, they started by observing interactions essentially down at single amino acid resolution using nuclear magnetic resonance spectroscopy.

The results of their experiments uncovered which amino acids were sticky, but couldn't provide the kind of holistic picture needed to fully understand the relationship between stickers, spacers and LLPS.

That's where Pappu's team came in. Building on experimental data from Mittag's team, Pappu and his colleague Alex Holehouse (who until the end of 2019 was a postdoctoral fellow in the Pappu lab and is now an assistant professor of biochemistry and molecular biophysics in the School of Medicine) developed an open source computational approach known as PIMMS (Polymer Interactions in Multicomponent Mixtures) to arrive at a quantitative and predictive understanding of the interactions among stickers that drive phase separation.

Additional lab experiments at St. Jude were used to test and confirm their predictions.

Together, the models and experiments revealed new aspects of the relationship between these stickers and phase separation.

Although the model showed variations in the number and placement of stickers, "the patterning of the stickers along the chain was very well conserved," Pappu said. "When you see something that is very well conserved in evolution, you decide that it is evolutionarily important."

So, naturally, Holehouse, an assistant professor of biochemistry and molecular biophysics, and Pappu used PIMMS to see what would happen if the important pattern was changed.

The team asked, "What happens if we just bring all of these stickers and put them right next to one another?" The first key finding showed the interactions between the stickers became so strong that proteins began sticking to each other, piling up and growing, eventually growing dense enough to become more solid than liquid.

The second key finding was a better understanding of the importance of the regions between the stickers -- the spacers. Like noncoding or "junk" DNA, the spacers at first showed some interesting traits, but did not seem to have an integral role in protein's functioning.

It turns out, spacers are crucial to understanding LLPS. "The spacers dilute the interaction strength of the stickers, which allows for the formation of a liquid," Mittag said. "Without spacers, the stickers would be too close and proteins would always condense to solids.

Understanding the rules that drive LLPS gives researchers a new way to "read" proteins to determine whether they will condense into a liquid or into the more problematic solid form.

LLPS is relevant to more than neurodegenerative diseases. It also has the potential to transform our understanding of the underlying mechanisms of many biological processes. "This model is relevant to understanding cancers," Mittag said, because of its application to different types of proteins.

The potential held by further collaboration is powerful, Pappu noted.

"We're talking about something that's written into a molecule giving you something that's manifest almost at the cellular scale," Pappu said. "Now you can play engineer and design things. You can think about neurodegenerative disorders and make sense of what might be going wrong.

"The funding provided by St. Jude has been key to catalyzing the collaboration that continues between the Mittag lab and my lab," Pappu said. "The collaboration also benefits from contributions of the Holehouse and Soranno labs in the School of Medicine -- labs that also are an integral part of the Center for Science and Engineering of Living Systems."

WASHINGTON, DC and SAN DIEGO, CA - Feb. 6, 2020 - Empowering Medicare to directly negotiate drug prices, accelerating the adoption of value-based care, using philanthropy as a catalyst for reform and expanding senior-specific models of care are among recommendations for reducing healthcare costs published in a new special report and supplement to the Winter 2019-20 edition of Generations, the journal of the American Society of Aging (ASA).

The report, "Older Adults and America's Healthcare Cost Crisis," sponsored by West Health, a family of nonprofit and nonpartisan organizations committed to lowering healthcare costs to enable seniors to successfully age in place, includes a dozen articles by experts and leaders from healthcare, business, academia and philanthropy.

The authors examine the major drivers of the high cost of healthcare and its impact on patients and then offer solutions that can reduce costs and improve the quality of care for older adults and society at large. Topics include the employer's role in reining in healthcare prices, the high cost of prescription drugs, investing in the social determinants of health, the value of home-based acute care, the need for oral health programs for older adults, value-based payment reform and the geriatric emergency care movement.

"Skyrocketing healthcare costs represent a significant and growing public health crisis that requires more action and less debate," said Shelley Lyford, president and CEO, West Health, one of the authors. "We can all agree Americans are hurting, in some cases dying or going bankrupt, because of a broken system that costs too much and delivers too little. We can no longer delay or defer common sense reforms and better and more cost-effective models of care when the health and financial security of millions hang in the balance."

In the report's lead article, Lyford and Timothy Lash, chief strategy officer of West Health and president of the West Health Policy Center, call for allowing Medicare to directly negotiate drug prices with manufacturers, which is currently prohibited by law. They write it "would be a game-changing lever that could force prescription drug manufacturers to bring down prices and lower costs for older Americans." They also state it's essential to quickly move from unfettered fee-for-service to value-based payment models and that more transparency on price and quality is needed so consumers and other purchasers can make more informed decisions about care.

Other articles offer recommendations including:

Employers demanding greater price accountability from hospitals and health plans and taking the lead in adopting value-based payment models

Value-based payment reform for serious illness

Establishing senior-specific models of care including geriatric emergency departments, which may improve health outcomes and reduce hospital admissions, and senior dental centers, which can address a silent epidemic of oral health problems among older adults

Supporting widespread use of home-based acute care, which increases the value of healthcare and better allows older adults to age in place

In an introduction to the special report, guest editor Robert Blancato, M.P.A., Immediate Past Board Chair of the ASA and a member of the National Board of AARP writes, "As the U.S. population ages, it is increasingly vital to support common sense steps that can reverse the trend of runaway healthcare costs. Unless we advocates take bold actions now to lower healthcare costs, our nation's older adults cannot hope to successfully age in place in the communities they cherish."

As spiraling U.S. healthcare costs dominate policy agendas at the state and federal level, older adults--the largest consumers of healthcare services--have a particularly high stake in solving the crisis. According to a 2019 West Health-Gallup poll, seniors withdrew an estimated $22 billion from long-term savings in the past year to pay for healthcare and an estimated 7.5 million were unable to pay for a prescribed medicine.

Engineers with the University of Cincinnati have created a tiny portable lab that plugs into your phone, connecting it automatically to a doctor's office through a custom app UC developed.

The lab the size of a credit card can diagnose infectious diseases such as coronavirus, malaria, HIV or Lyme disease or countless other health conditions like depression and anxiety.

The patient simply puts a single-use plastic lab chip into his or her mouth then plugs that into a slot in the box to test the saliva.

The device automatically transmits results to the patient's doctor through a custom app UC created for nearly instant results.

UC professor Chong Ahn and his research team used the smartphone device to test for malaria. But the device could be used for smart point of care testing for countless chronic or infectious diseases or to measure hormones related to stress.

"Right now it takes several hours or even days to diagnose in a lab, even when people are showing symptoms. The disease can spread," Ahn said.

The study was published in the Nature journal Microsystems & Nanoengineering.

His research team created a novel lab chip that uses natural capillary action, the tendency for a liquid to adhere to a surface, to draw a sample down two channels called a "microchannel capillary flow assay." One channel mixes the sample with freeze-dried detection antibodies. The other contains a freeze-dried luminescent material to read the results when the split samples combine again on three sensors.

Ahn said the device is accurate, simple to use and inexpensive.

"The performance is comparable to laboratory tests. The cost is cheaper. And it's user-friendly," Ahn said. "We wanted to make it simple so anyone could use it without training or support."

UC doctoral student Sthitodhi Ghosh, the study's lead author, said the biggest advancement in the device is in the novel design of its tiny channels that naturally draw the sample through the sensor arrays using capillary flow. Ahn is Ghosh's Ph.D. advisor.

"The entire test takes place on the chip automatically. You don't have to do anything. This is the future of personal healthcare," Ghosh said.

While the device has applications for diagnosing or monitoring viruses or other diseases, Ahn said he sees potential in the field of mental health, where doctors already utilize smartphones to help track the wellness of patients.

Tinder's meteoric rise in popularity has cemented its position as the go-to dating app for millions of young and not-so-young users. Although it is widely known as a platform to facilitate hookups and casual dating, some of the app's estimated 50 million+ worldwide users are employing it for something altogether different.

From multilevel marketing to political and health campaigning to promoting local gigs, Tinder users are appropriating the platform for their own purposes. And these can often have little to do with sex or dating. This so-called "off-label use" -- a term borrowed from pharmacology describing when people use a product for something other than what the package says -- is explored in a new paper published in the journal The Information Society.

"When people encounter a new technology, whether it's a hammer or a computer, they use it in ways that fit their needs and lifestyle," says author Stefanie Duguay, assistant professor of communication studies in Concordia's Faculty of Arts and Science.

"This is commonly referred to as user appropriation in science and technology studies. However, once you buy a hammer, it doesn't undergo regular updates or develop new features -- apps do. They come with their own marketing, vision for use and sets of features, which they regularly update and often change in response to user activity."

For this reason, Duguay says, the paper engages with Tinder as a way to think through what appropriation looks like in this back-and-forth relationship between users and apps.

What's in a label?

Duguay began her study with a thorough investigation of the Tinder app's design, looking at the mechanics its developers created in order to guide users for its intended purpose. She next looked at dozens of media articles about people using it for purposes other than social, romantic or sexual encounters. Finally, she conducted in-depth interviews with four "off-label" users.

One user's profile was being used to conduct an anti-smoking campaign. Another, an anti-sex trafficking campaign. A third was using the app to market her health products and the last was supporting US Senator Bernie Sanders's Democratic Party presidential nomination run in 2016. She then compared and contrasted these different approaches to off-label use.

"I found that a lot of the time, Tinder's expected use -- dating and hooking up -- informed or complemented their campaigns," she says. "There would be an element of flirtatiousness or they would draw on users' perception of Tinder as a digital context for intimate exchanges."

She adds that many Tinder users who were on the app for its expected uses became upset when they discovered these profiles' actual aims. "That shows that off-label use can be somewhat disruptive on the platform," she says. "Though this depends on how narrowly people see that app's purpose."

A changing ecosystem

Duguay was also curious to gauge Tinder's own reaction to these kinds of user appropriation. Over the course of her research, she got the sense that this activity was only concerning to the company in high volumes.

Spam bots, for instance, became a serious problem soon after the app's launch. Duguay notes that Tinder responded quickly to this wave of off-label use, which often involved bots phishing for credit card numbers, by adding daily swipe limits and block-and-report buttons.

"But those measures also made it difficult to sell products or campaign for something," she says. "They may be very useful in getting rid of massive amounts of spam, but in other ways, this reasserting of on-label use can shut down innovation and creativity."

While profit-making multilevel marketers may be able to overcome swipe limits by affording premium accounts, she writes, non-profit campaigners find these obstacles can ultimately silence them.

Tinder also adopted some of the uses popping up on their platform, wading into the political arena with their "Swipe the Vote" feature, for instance. Non-official campaigns now need Tinder's specific authorization to promote their cause or product.

Not looking down on hooking up

Duguay says conversations involving Tinder tend to not to be taken very seriously because of the app's association with hookup culture. This dismissiveness obscures a larger point, she feels.

"I think sex and dating are very meaningful activities in our society," she says. "But I was also seeing this range of activity on Tinder. Platforms like this are more like an ecosystem, and when users adopt different purposes than the ones they are designed for, the platforms can change their guidelines or features in ways that greatly affect their users."

Giving people the ability to engage in off-label use means that apps like Tinder can feature not only in meaningful social and sexual encounters but also in individuals' political or financial participation and broader endeavours for social good.

New Orleans, LA - Pooja Mehta, M.D., clinical assistant professor of obstetrics & gynecology at LSU Health New Orleans School of Medicine, was a member of a research team that found 13% of deaths occurring during or up to one year after pregnancy among Louisiana women in 2016-17 were homicides. Results are published online in JAMA Pediatrics, available here.

The team conducted a retrospective analysis of vital records data provided by the Louisiana Department of Health of all cases of maternal death that year. Of the 119 maternal deaths, homicide accounted for more deaths than any other single cause. Mortality from homicide was 12.9 per 100,000 compared to mortality from hypertensive disorders at 3.2 or obstetric embolism at 4.8 per 100,000.

"This is distinct from findings that focus on 'pregnancy-related' death - a different definition of 'maternal mortality,' which are deaths confirmed on case review to be directly linked to or worsened by pregnancy," notes Dr. Mehta, who was the Medical Director for the Louisiana Pregnancy-Associated Mortality Review at the time of the study. "The key finding from this study is that pregnant and postpartum women in Louisiana are more likely than others of the same age to experience a homicide."

The authors write that their estimated rate is among the highest reported across a growing number of jurisdictions, possibly due in part to improved case ascertainment through the use of linked and verified data and/or reflecting a truly higher incidence within Louisiana, given the state's consistently high incidence of homicide among women and girls.

"This points to the fact that pregnant people are in fact more vulnerable to violence--those who interact with pregnant and postpartum individuals inside and outside of the health system need to work together to better support these individuals," adds Mehta. "We have to see each death as something that is worth preventing, and within our power to prevent."

Most cells in the tissues of most organisms proliferate through somatic cell division (mitosis). This is a continuous cycle where a single cell doubles its genetic information (chromosomes) and divides equally to create two copies of the original cell. In contrast, germ (egg and sperm) cells are produced through a special type of cell division called meiosis, which takes place in the gonads. This process begins like normal mitosis but switches after some time to create four genetically dissimilar germ cells that have half the original cell's genetic material. The mechanism that causes this switch has been a longstanding research problem and controlling it is an important, yet challenging, global issue in reproductive medicine.

Recently, a group of researchers from Kumamoto University in Japan set out to assess the proteins involved in meiosis to clarify its development. Using mass spectrometry, the group was able to identify a gene that acts as a meiosis on-switch, labeling it "Meiosin" (for meiosis initiator). The Meiosin gene has the extremely rare property of becoming activated only at a specific time--just before the beginning of meiosis in the gonads. In animal experiments, the researchers found that both male and female mice became infertile if the Meiosin gene was artificially inhibited. Further analysis of the mouse male and female gonads clarified that the gene plays an essential role in meiosis activation. The Meiosin gene acts as a control tower that simultaneously switches on hundreds of genes for germ cell formation, and appears to be involved with infertility. The group expects that the discovery will be a big step forward for reproductive medicine.

There are many cases of human infertility where the cause is unknown; this finding potentially reveals a new pathology. Even though these experiments were performed on animal models, the Meiosin gene is present in humans. Abnormal meiosis in the eggs of older women can cause chromosomal abnormalities resulting in miscarriage or Down syndrome. And in societies with increased age of pregnancy, therapies developed from this research could ensure meiosis quality and decrease the instances of these complications.

"Our work shows that the Meiosin gene is the switch that turns on meiosis, the special type of cell division that creates eggs and sperm, and this includes the turning-on of hundreds of other genes in the process. However, the functions of those genes have not yet been fully elucidated," said Associate Professor Kei-Ichiro Ishiguro of the Institute of Molecular Embryology and Genetics at Kumamoto University. "We were quite surprised to find so many genes with undefined functions lying dormant in this study. We have high expectations that the processes involved in germ cell formation will be greatly clarified as the role each of these genes plays is discovered. If it eventually becomes possible to control meiosis, the benefits would be far-reaching for reproductive medicine, agricultural production, and even assisting rare species reproduction."

This research was posted online in Developmental Cell on 6 February 2020.

NEW YORK -- The protein tau has long been implicated in Alzheimer's and a host of other debilitating brain diseases. But scientists have struggled to understand exactly how tau converts from its normal, functional form into a misfolded, harmful one. Now, researchers at Columbia University's Zuckerman Institute and Mayo Clinic in Florida have used cutting-edge technologies to see tau in unprecedented detail. By analyzing brain tissue from patients, this research team has revealed that modifications to the tau protein may influence the different ways it can misfold in a person's brain cells. These differences are closely linked to the type of neurodegenerative disease that will develop -- and how quickly that disease will spread throughout the brain.

The study, published today in Cell, employed two complementary techniques to map the structure of tau and decipher the effects of additional molecules, called post-translational modifications (PTMs), on its surface. These new structural insights could accelerate the fight against neurodegenerative diseases, by helping researchers identify new biomarkers that detect these disorders before symptoms arise and design new drugs that target specific PTMs, preventing the onset of disease before it wreaks havoc on the brain.

"Tau has long been a protein of significant interest due to its prevalence in disease," said Anthony Fitzpatrick, PhD, a Principal Investigator at Columbia's Mortimer B. Zuckerman Mind Brain Behavior Institute who led the study. "In today's publication, we lay out compelling evidence that PTMs play an important structural role in tauopathies, the collection of neurodegenerative diseases characterized by toxic buildup of misfolded tau."

No two tauopathies are exactly alike. Each affects different parts of the brain -- even different cell types -- which can lead to different symptoms. Alzheimer's, for example, arises in the hippocampus, and so affects memory. Chronic traumatic encephalopathy, a disorder most often seen in survivors of traumatic brain injury, can lead to problems with movement, memory or emotion, depending on which areas of the brain are affected.

Scientists have used traditional imaging techniques to find clues to how tangles of tau, comprised of individual fibers, or filaments, are implicated in these diseases. But painting a complete picture has proven difficult.

"The brains of patients with neurodegenerative diseases are easy to identify: entire sections have been eaten away, replaced by large clumps and tangles of misfolded proteins like tau," said Tamta Arakhamia, an undergraduate at Columbia's School of General Studies, a research assistant in the Fitzpatrick lab and the paper's co-first author. "However, tau filaments are 10,000 times thinner than the width of a human hair, making them extraordinarily difficult to study in detail."

To address this challenge, Dr. Fitzpatrick recently pioneered the use of cryo-electron microscopy, or cryo-EM, to visualize individual tau filaments from diseased human brain tissue. Cryo-EM is a Nobel Prize-winning technology developed, in part, by researchers at Columbia University. Cryo-EM images samples using a beam of electrons and has proven indispensable for investigations into extremely small biological structures. Using cryo-EM, Dr. Fitzpatrick's team has reconstructed the structures of tau filaments, providing new insights into how they form, grow, and spread throughout the brain.

For all its ability to provide highly detailed snapshots of proteins, cryo-EM has limits. To overcome these limits, Dr. Fitzpatrick and his team to paired it with a second technology: mass spectrometry.

"Cryo-EM does not provide a complete picture because it cannot fully recognize the microscopic PTMs on tau's surface," said Christina Lee, an undergraduate student at Columbia College, a research assistant in the Fitzpatrick lab and the paper's co-first author. "But mass spectrometry can pinpoint the chemical composition of PTMs on the surface of tau."

Working with co-corresponding author Leonard Petrucelli, PhD, Ralph B. and Ruth K. Abrams Professor of Neuroscience at Mayo Clinic in Florida, and Nicholas Seyfried, PhD, professor of biochemistry at Emory University School of Medicine, the researchers used cryo-EM and mass spectrometry to analyze the brain tissue from patients diagnosed with two tauopathies: Alzheimer's disease and corticobasal degeneration, or CBD. CBD is a rare but extremely aggressive tauopathy, affecting only one in every 10,000 people. Unlike Alzheimer's, which is thought to arise due to a number of factors including tau, CBD is primarily associated with misbehaving tau proteins.

"Studying a primary tauopathy like CBD helps us to figure out how tau becomes toxic to brain cells," said Dr. Petrucelli. "We hope to extrapolate that knowledge to secondary tauopathies, such as Alzheimer's disease."

The scientists' analysis of brain tissue samples revealed several key insights. Most notably, the researchers found that cross-talk between PTMs on the surface of tau influences the structure of the tau filaments, contributing to differences in tau filaments observed across the various tauopathies -- and even variations from patient to patient.

"Collectively, these results suggest that PTMs may not only be serving as markers on the proteins' surface, but are actually influencing the behavior of tau," said Dr. Fitzpatrick, who is also an assistant professor of biochemistry and molecular biophysics at Columbia's Vagelos College of Physicians and Surgeons.

Moving forward, Dr. Fitzpatrick and his team plan to expand this work to other tauopathies. Today's findings on Alzheimer's and CBD hold immense promise for the field, particularly in the development of new disease models -- such as lab-grown organoids, or mini-brains -- that may serve to accurately recapitulate what is actually happening in the brains of patients.

"Our findings will inspire new approaches for developing diagnostic tools and designing drugs, such as targeting PTM vulnerabilities to slow disease progression," said Dr. Fitzpatrick, who is also a member of Columbia's Taub Institute for Research on Alzheimer's Disease and the Aging Brain. "Neurodegenerative diseases are among the most complex and distressing class of illnesses, but through our work and that of our colleagues and collaborators, we are building a roadmap toward successful diagnostics and therapeutics."

DURHAM, N.C. -- Biomedical engineers at Duke University have developed the most advanced disease model for blood vessels to date and used it to discover a unique role of the endothelium in Hutchinson-Gilford Progeria Syndrome. Called progeria for short, the devastating and extremely rare genetic disease causes symptoms resembling accelerated aging in children.

The model is the first to grow both the smooth muscle and inner lining, or endothelium, layers of blood vessels from stem cells derived from the patients' own skin. Combined with an advanced experimental setup that pushes culture media that models blood through the engineered blood vessels, the model reveals that the endothelium responds differently to flow and shear stress with progeria than it does when healthy.

The study shows that a diseased endothelium alone is enough to produce symptoms of progeria, and also demonstrates a new way of studying blood vessels in dynamic 3D models to better understand and test treatments for serious diseases.

The results appear online on February 6 in the journal Stem Cell Reports.

"The endothelium expresses the toxic protein that causes the symptoms of progeria, but it does so at much lower levels than the outer layer of blood vessels made of smooth muscle," said Nadia Abutaleb, a biomedical engineering PhD student at Duke and co-first author of the paper. "Because of this, the entire field has been focused on smooth muscle, and the few that have looked at the endothelium have mostly looked at it in a static 2D culture. But we've discovered that it's necessary to work dynamically in three dimensions to see the full effects of the disease."

Progeria is a non-hereditary genetic disease caused by a random single-point mutation in the genome. It is so rare and so deadly that there are only about 250 people known to be currently living with the disease worldwide.

Progeria is triggered by a defect in a protein called progerin that leads it to accumulate outside of a cell's nucleus rather than becoming part of the nuclear structural support system. This causes the nucleus to take on an abnormal shape and inhibits its ability to divide. The resulting symptoms look much like accelerated aging, and affected patients usually die of heart disease brought on by weakened blood vessels before the age of 15.

"Progeria isn't considered hereditary, because nobody lives long enough to pass it on," said George Truskey, the R. Eugene and Susie E. Goodson Professor of Biomedical Engineering at Duke. "Because the disease is so rare, it's difficult to get enough patients for clinical trials. We're hoping our platform will provide an alternative way to test the numerous compounds under consideration."

Blood vessels are difficult to simulate because their walls have multiple layers of cells, including the endothelium and the media. The endothelium is the innermost lining of all blood vessels that interacts with circulating blood. The media is made mostly of smooth muscle cells that help control the flow and pressure of the blood.

In 2017, the Truskey laboratory engineered the first 3D platform for testing blood vessels grown from skin cells taken from progeria patients. The blood vessels exhibited many of the symptoms seen in people with the disease and responded similarly to pharmaceuticals.

"While the smooth muscle cells in our previous study were created using cells from progeria patients, the endothelial cells were not," said Abutaleb. "We suspected that the endothelial cells might be responsible for some of the lingering symptoms in the original study, so we began working to grow blood vessels with both smooth muscle and endothelial cells derived from the same patient."

By successfully growing endothelial cells derived from progeria patients, the researchers were able to create a more complete model of the disease. They also tested the endothelium's unique contribution to the disease's symptoms by mixing impaired endothelium with healthy smooth muscle.

They found that a diseased endothelium alone was enough to produce many of the symptoms of progeria, but that these results only appeared when the cells were tested under dynamic conditions.

"One of the major findings is that the progeria endothelium responds to flow and shear stresses differently than healthy endothelium," said Abutaleb.

The new model's healthy blood vessels responded to pharmaceuticals more strongly than in past papers, and the diseased blood vessels showed a greater drop in functionality. With this advanced model in hand, the team is now beginning to investigate how new and current drugs for progeria affect a patient's blood vessels.

ANN ARBOR, Michigan -- Women with early stage breast cancer who test positive for an inherited genetic variant are not always receiving cancer treatment that follows current guidelines, a new study finds.

An inherited gene can increase risk of developing a second breast cancer, so strategies such as removing a woman's breasts or ovaries are intended to prevent a future cancer. But women who have already been diagnosed with breast cancer must also consider how best to treat the existing tumor.

"Cancer treatment options are increasingly more complex for patients. Patients must consider a myriad of treatment options for the cancer they have and the implications of genetic test results on cancer prevention strategies for themselves and their family members," says Steven J. Katz, M.D., MPH, senior author of a study led by the University of Michigan Rogel Cancer Center and Stanford University School of Medicine.

More women are receiving genetic testing when they're diagnosed with early stage breast cancer, with increasingly more sophisticated tests that include a panel of at least 30 different genes, each carrying different risks for future cancers.

"We found that breast cancer treatment among women who test positive for an inherited genetic mutation is less in line with practice guidelines, in particular for radiation therapy and chemotherapy," says lead study author Allison W. Kurian, M.D., M.Sc., associate professor of medicine and of health research and policy at Stanford.

"It's challenging to integrate genetic testing into breast cancer care," says Kurian. The significance of the results and future impact on the patient's risk vary widely while meanwhile we must focus on eliminating the cancer the patient faces today."

Researchers collected information from the Georgia and California Cancer Registries from 20,568 women diagnosed with early stage breast cancer and matched it to genetic testing results. All data was linked through an objective third party and deidentified for researchers to analyze. Results are published in JAMA Oncology.

Researchers looked at the characteristics of patients' tumors to assess what the recommended treatment options would be based on standard guidelines. Then they compared actual treatments for women who tested positive for BRCA1 or BRCA2 mutations, which carry the highest risk for additional cancers, those who tested positive for other genes associated with breast cancer, and those whose tests were negative or identified a variant not known to increase breast cancer risk.

They found distinct differences in surgery, radiation and chemotherapy treatments among women who were positive for an inherited genetic mutation.

Surgery: 66% of BRCA-positive patients underwent double mastectomy, compared to 24% of patients with a negative genetic test

Radiation: 51% of BRCA-positive patients who were candidates for radiation received it, compared to 82% of patients with a negative genetic test

Chemotherapy: 38% of BRCA-positive patients who were candidates to forgo chemotherapy got it, compared to 30% of patients with a negative genetic test

The observed relationship of surgical treatment to genetic test results are in line with guidelines supporting double mastectomy as an effective strategy to prevent future cancer risk. But guidelines do not recommend using genetic testing results to determine whether radiation or chemotherapy are needed to treat the diagnosed cancer.

The gaps in radiation were particularly striking as radiation after lumpectomy is considered key to achieving the best outcome with breast conservation. The researchers propose that some patients may have skipped radiation because they intend to have a mastectomy in the future. Another explanation could be concern about whether radiation would increase cancer risk for these patients.

"We need to understand this gap better, because it could have potential implications on patients' outcomes," says Katz, professor of general medicine and of health management and policy at the University of Michigan.

"Our findings should reinforce that physicians who treat cancer need to be increasingly attentive to the clinical implications of genetic testing after diagnosis. Test results must be optimally integrated into the patient's treatment to manage her cancer today and her risk in the future," Kurian says.