Monday, April 27, 2020

U.S. states build stockpiles of malaria drug touted by Trump

by Brady McCombs and Lindsay Whitehurst

This Monday, April 6, 2020, file photo shows an arrangement of Hydroxychloroquine pills in Las Vegas. At least 13 states have obtained a total of more than 10 million doses of malaria drugs to treat COVID-19 patients despite warnings from doctors that more tests are needed before the medications that President Trump once fiercely promoted should be used to help people with the coronavirus. (AP Photo/John Locher,File)

State and local governments across the United States have obtained more than 30 million doses of a malaria drug touted by President Trump to treat patients with the new coronavirus, despite warnings from doctors that more research is needed.

At least 22 states and Washington, D.C. secured shipments of the drug, hydroxychloroquine, according to information compiled from state and federal officials by The Associated Press. Sixteen of those states were were won by Trump in 2016, although five of them including North Carolina and Louisiana are now led by Democratic governors.

Supporters say having a supply on hand makes sense in case the drug is shown to be effective against the pandemic that's devastated the global economy and killed nearly 200,000 people worldwide, and to ensure a steady supply for people who need it for other conditions like lupus.

But health experts worry that having the drug easily available at a time of heightened public fear could make it easier to misuse it. The U.S. Food and Drug Administration on Friday warned doctors against prescribing the drug, hydroxychloroquine, for treating the new coronavirus outside of hospitals or research settings, because of reports of serious side effects, including dangerous irregular heart rhythms, and death among patients.

It's the latest admonition against the drug that Trump mentioned 17 times in various public appearances, touting its potential despite his own health advisors telling him it is unproven.

This Monday, April 6, 2020 file photo shows an arrangement of hydroxychloroquine pills in Las Vegas.At least 13 states have obtained a total of more than 10 million doses of malaria drugs to treat COVID-19 patients despite warnings from doctors that more tests are needed before the medications that President Trump once fiercely promoted should be used to help people with the coronavirus. (AP Photo/John Locher,File)

Oklahoma spent $2 million to buy the drugs and Utah and Ohio have spent hundreds of thousands on purchases. The rest of the cities and states have received free shipments from drug companies or the U.S. government in the last month. Ohio also received a large donation from a local company.

Several states including New York, Connecticut, Oregon, Louisiana, North Carolina and Texas received donations of the medication from a private company based in New Jersey called Amneal Pharmaceutical. Florida was given 1 million doses from Israeli company Teva Pharmaceutical.

And the Federal Emergency Management Agency has sent 19 million doses of hydroxychloroquine to 14 cities including Washington, D.C., Philadelphia and Baltimore from the federal government's national stockpile, a source that also provided South Dakota and California with supplies. The U.S. government received a donation of 30 million doses from Swiss drugmaker Novartis on March 29 to build up the stockpile.

"If he (Trump) hadn't amplified the early and inappropriate enthusiasm for the drug, I doubt if the states would have even been aware of it," said Dr. Kenneth B. Klein, a consultant from outside of Seattle who has spent the last three decades working for drug companies to design and evaluate their clinical trials.

Klein said it's understandable that government and health officials looked into hydroxychloroquine—which is approved for treating malaria, rheumatoid arthritis and lupus—as a possible remedy during a frightening pandemic, but the time and energy has been misspent. The potential side effects are worrisome, especially because many coronavirus patients already have underlying health conditions, he said.

In this April 21, 2020 file photo Utah Gov. Gary Herbert speaks during a news conference in South Jordan, Utah. Herbert, a Republican, acknowledged that hydroxychloroquine for COVID-19, is "not without controversy," but said an $800,000 purchase from a local company whose CEO appeared alongside GOP lawmakers touting the drugs last month was part of the state's effort to make rational decisions based on "good science and good data." (AP Photo/Rick Bowmer,File)

"The states and the federal government are reacting in light of that fear but it's not a rational response," Klein said.

Doctors can already prescribe the malaria drug to patients with COVID-19, a practice known as off-label prescribing, and many do. Medical and pharmacy groups have warned against prescribing it for preventative purposes. The FDA has allowed it into the national stockpile, but only for narrowly defined purposes as studies continue.

Utah Gov. Gary Herbert, a Republican, acknowledged that the drug is "not without controversy," but said an $800,000 purchase from a local company was part of the state's effort to make rational decisions based on "good science and good data."

The Utah health department said earlier this week it planned to spend $8 million more to buy 200,000 additional treatments from the company, but said Thursday after media inquiries about the deal that those plans are on hold as the state researches FDA requirements for compounding and distribution of the drugs.

South Dakota, with a population of 885,000 people, received 1.2 million doses from the federal government and is using the drug for a trial as well as doctor-approved prescriptions for COVID-19 positive patients. South Dakota Gov. Kristi Noem, a Republican and Trump ally, said earlier this month she pushed the White House to provide enough hydroxychloroquine to give it to every hospitalized person, others who are vulnerable to the coronavirus and "front line" health care workers. As of Tuesday, 200 people in South Dakota were being treated with the drug, according to Sanford Health.

In this March 23, 2020 file photo Dr. Lee Norman, Kansas secretary of health and environment, answers questions about the coronavirus pandemic as Gov. Laura Kelly watches during a news conference in Topeka, Kan. Norman said of hydroxychloroquine that the state has no intention of buying the drug because there's not enough evidence it helps treat COVID-19. "It's just not been shown to be worthwhile," Norman said. "It hasn't been shown to be effective for COVID-19 patients in any disciplined professional study." (AP Photo/John Hanna,File)

Many states, however, have opted to steer clear over concerns about side effects and lingering questions about the effectiveness. At least one of those states is led by a Republican governor, Tennessee, where the state's Department of Health sent a letter warning against using the drug, or hoarding it.

"We were seeing a flood of inappropriate prescribing and hoarding, quite frankly," Health Commissioner Lisa Piercey told reporters.

Kansas health director Dr. Lee Norman said the state has no intention of buying the drug because there's not enough evidence it helps treat COVID-19.

Most states aren't paying for the drug, and it's not clear why Utah didn't get it from the federal reserve or a donation from a business like Amneal Pharmaceutical. News releases from state governments show the New Jersey-based company has sent millions of doses of the drug free of cost to states, including 2 million to New York and 1 million to Texas. A company spokesperson declined to provide a list of donations or answer other questions from The Associated Press

Pharmaceutical companies can often manufacture pills they already make fairly cheaply and the donations may have been done to earn good publicity while setting it up to make future sales if hydroxychloroquine ends up being a reliable treatment for the virus, Klein said.

In this April 22, 2020 file photo President Donald Trump watches as Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, speaks about the coronavirus in the James Brady Press Briefing Room of the White House in Washington. After weeks of near-daily plugs for the use of hydroxychloroquine to help treat COVID-19 patients, Trump and the White House abruptly stopped discussing the drug a week ago. His promotion of the drug, based on isolated reports and instinct, frequently put him at odds with medical professionals, including Fauci, the nation's top infectious disease expert, who said evidence for the efficacy of the drug for COVID-19 patients was "anecdotal." (AP Photo/Alex Brandon,File)
Controversy has swirled around the drug since Trump started promoting it from the podium in the White House briefing room on March 19.

He mentioned the drug in briefings through April 14, and the White House distributed press releases praising Trump's efforts to stockpile it for use in areas of the country hard-hit by the virus. But for the past week, as studies have shown mixed or even harmful results, Trump has gone silent on the drug.

Asked about it Thursday, Trump said he hadn't heard of the a study done at U.S. veterans hospitals with preliminary results that showed no benefit, and rejected the notion he had stopped promoting hydroxychloroquine as a cure.

"I haven't at all. I haven't at all," Trump said. "We'll see what happens."

Understanding changing guidance on mask use

by Johns Hopkins Universit y

In early April, the Centers for Disease Control and Prevention revised its guidance to recommend that in addition to social distancing measures, all Americans should wear masks when leaving the house for essential trips such as going to the grocery store or the pharmacy. Thursday, Brigham and Women's Hospital in Boston reported that new COVID-19 infections among hospital staff dropped by half after instituting a universal masking policy.

As best practices for limiting the spread of the coronavirus continue to evolve, the Hub spoke with Johns Hopkins Associate Professor Kirsten Koehler and Assistant Professor Ana Rule, both of the Department of Environmental Health and Engineering at the Bloomberg School of Public Health. They helped clarify how the "hierarchy of controls"—a prioritized method of controlling workplace hazards through actions such as social distancing and masks—can limit spread of the coronavirus. They also discussed the CDC's recent guidance and other questions related to mask use. This conversation has been edited for length and clarity.

Why did the CDC change its guidance to recommend that everyone wear a mask or face covering when leaving home?

Koehler: The CDC is concerned, in part, that there's a reasonably large portion of the population that are asymptomatic carriers of COVID-19 and are propagating the virus. For the general public, compliance will likely mean relying on a homemade mask, but it's important to do so with the mindset that we're wearing these masks to protect others, not necessarily to protect ourselves. The best self-protection is still the same: to stay home.

Rule: The CDC made the decision to encourage everyone to wear non-medical-grade masks, and we know that part of the rationale for that guidance was because of a concern that, without these guidelines, there could be hoarding of precious resources. In the past couple of weeks, we've seen how the stockpiles of essential medical personal protective equipment like N95 and surgical masks have dwindled greatly. The people who need these most are certainly the point of contact providers—those in hospitals and working with patients who are generating the aerosols that potentially contain the coronavirus. For those providers, PPE is their main protection.

Do homemade masks still offer adequate protection? What should people know about how best to approach the use of protective masks?

Koehler: To be clear, staying at home is the best option to protect yourself and others. If you can't do that, making a homemade mask is better than nothing. More broadly, my concern is that the general public has no training or guidance in the safe and proper way to use a homemade mask. If you use PPE as part of your job, you receive training about putting on and taking off this equipment. This training includes precautions like hand-washing whenever you put on or take off the mask. You should wash hands whenever you touch the mask and be careful about what you do whenever you take off the mask when you get home. A mask that you wear outside could potentially be covered in virus, and it's essential that when you take it off, you put it somewhere safe and out of the way, like where you keep laundry, and put on a different, clean mask whenever you have to go outside next.

Rule: In terms of the science, the bigger particles, which are the ones most likely to be filtered by a homemade mask, are going to fall quickly to the ground, anyway. The smaller particles will pass right through the mask. So, the mask will stop those larger particles from depositing on surfaces and potentially being picked up by the next person that touches that surface, for example at the supermarket. There's not a lot of science out there yet about tests to determine how a homemade mask protects the environment and people around you if you are contagious and shedding viruses. This is important, especially with so many asymptomatic people having this particular virus.

There are many different types of masks available, from the medical-grade N95 to surgical procedure masks to homemade masks and scarves. What is most preferable for non-medical workers? What types of materials from home might make for an effective mask?

Rule: There are a couple of papers that have actually tested different materials for filtration efficiencies against the most concerning and smallest particles, which are the ones that are the hardest to filter out. A couple of studies have shown that the materials that filter these particles the best are materials that are also the hardest to breathe through—thicker fabrics like hand towels or vacuum cleaner filters—but since it's really hard to breathe through them, they don't make for viable mask materials. Plus, none of them can provide a seal around the face. The smaller particles then go right around the filter. So there's no real protection from inhaling particles that might have virus. But any material will stop the bigger particles that could create contact points for the virus (such as on a hand railing or a table).

Koehler: For the small particles, I think there isn't a lot of difference in the various materials. Almost all of them remove less than 10% of really small particles.

Rule: But, and this is really important, even if you can get an N95 or surgical mask, please leave those for people who need to interact with patients. People who are actually caring for patients need to have those the most—we see people outside with these masks on and it's a problem since there's such a critical shortage for medical providers.

For those who decide to wear a mask, how can they do so effectively?

Koehler: Some people don't necessarily have a choice anymore—some states and cities have implemented mask requirements when in public. I do think that if people are going outside, whether required to or wearing a mask by choice, they should have the mindset that, "I'm wearing this to protect someone else, not to protect myself." Essentially, assuming that you are the contagious one, even if you feel perfectly healthy. If you think this way, it can lead to safer choices—for example, you might choose to limit your exposure by going to fewer stores and going outside less and maintaining social distancing standards of at least six feet of distance as much as possible, even if you are wearing a homemade mask.

Is it OK to reuse a mask, whether homemade or otherwise, and if so, how can one ensure that the mask is clean and safe to use again?

Koehler: To clean a homemade mask, throwing it in the washer and dryer is really fine. Make at least a couple of masks so that you can wash them between uses and, hopefully, since people should not be going out that much anyway, only having several masks should be enough.

Rule: I saw a video yesterday of someone making a mask made out of a sock—if it's that simple, really, you can have five or so around, and put them in the laundry after every use.

Koehler: I've seen bandanas folded up many times and held together with hair ties and looped over the ears—you could have several of those and keep putting them in the wash. You don't need to be a master seamstress to do this effectively. N95 and surgical masks should not be washed. To reuse these kinds of masks, it is best to place them in a paper bag in a warm place for at least 7 days before reusing them. This will give enough time for the virus to no longer be infectious.

For those without easy access to laundry facilities, storing homemade masks in paper bags is also an option. Recent data suggests the virus will lose infectivity after about 2 days from cloth masks.

When going to the pharmacy or grocery store for essentials, what can people do to minimize the risk of transmission? Should they wear other forms of PPE, like gloves?

Koehler: I don't recommend the use of gloves—if you're not a medical provider, they aren't helpful and, like with masks, people are likely using them incorrectly. If you were going to wear gloves, to do so effectively would mean never using your phone, wallet, or purse because as soon as you touch any of those high-touch surfaces then the gloves aren't effective anymore. They're also a huge environmental waste and it's not worth the effort and pollution and wastefulness to wear them.

Rule: Not only that, gloves can likely give you a false sense of security because someone might think they are protected when they're really just as susceptible and distracted from other important prevention steps—like washing your hands. Plus, if you don't dispose of gloves properly they could be another source of contamination in the environment. Really, we need to remember that, in the hierarchy of controls, PPE is the last resort—it's been shown for many years that wearing things like masks and gloves is the least effective factor at controlling exposure. That's why social distancing, cleaning, and washing hands are the best ways to protect yourself from the virus.

Study challenges reports of low fatality rate for COVID-19

by Robert Sanders, University of California - Berkeley

A comparison of daily deaths in Italy since January 2020 with those over the previous five years there indicates that the fatality rate in that country for those infected with the new coronavirus is at least 0.8%, far higher than that of the seasonal flu and higher than some recent estimates.

Extrapolating from the Italian data, University of California, Berkeley, and Lawrence Berkeley National Laboratory data scientists estimate that the fatality rate in New York City and Santa Clara County in California can be no less than 0.5%, or one of every 200 people infected.

These conclusions contrast with those of a study posted online last week by Stanford University epidemiologists, who pegged the fatality rate at between 0.1% and 0.2%. An affiliated team from the University of Southern California (USC) this week reported a similar fatality rate in Los Angeles.

"Their final number is much lower than our estimate," said senior author Uros Seljak, a UC Berkeley professor of physics, faculty scientist at Berkeley Lab and member of the Berkeley Institute for Data Science. He also is co-director of the Berkeley Center for Cosmological Physics (BCCP).

Seljak says that getting COVID-19 doubles your chance of dying this year.

"If you want to know what are the chances of dying from COVID-19 if you get infected, we observed that a very simple answer seems to fit a lot of data: It is the same as the chance of you dying over the next 12 months from normal causes," said Seljak.

Current uncertainties can push this number down to 10 months or up to 20 months, he added. His team discovered that this simple relation holds not only for the overall fatality rate, but also for the age stratified fatality rate, and it agrees with the data both in Italy and in the U.S.

"Our observation suggests COVID-19 kills the weakest segments of the population," Seljak said.

The paper was posted online Monday on MedRxiv in advance of peer review and submission to a journal.

Italy's deaths twice the official count

The study by Seljak and his colleagues predicts that the true number of deaths in Italy from COVID-19 is more than twice the official figure: around 50,000 people, as of April 18. The country's official statistics listed more than 150,000 confirmed cases, as of that date, and more than 20,000 attributed deaths.

The difference, the researchers say, is likely due to many deaths among older people that have not been counted in the official Italian statistics. The team found a much higher fatality rate for those over 70 years of age: In Lombardy, a region hit hard by the pandemic, those between 70 and 79 had a 2.3% infection fatality rate, while those 80 to 89 had an almost 6% fatality rate. Nearly 13% of those over 90 died.

In comparison, those 40 to 49 had a 0.04% fatality rate.

These differing fatality rates can explain the observed higher number of deaths among younger people in New York City. Because the population there is younger than in Italy, more deaths among young people are expected, despite their lower fatality rate. The researchers predict that about 26% of all deaths from COVID-19 in New York City will be among those younger than 65.

The population of Italy, on the other hand, is older, yielding a higher overall fatality rate for the country's population: 0.8%, versus 0.5% for New York. Only 10% of Italian deaths will be younger than 65.

The team also estimated, based on the predicted fatality rate for those infected with the new coronavirus and the positivity rate for those tested for COVID-19 in New York City, that about one-quarter of that city's population has been infected with the virus. This agrees with the recent announcement by New York Gov. Andrew Cuomo of 21% infection.

The team's predicted infection rate for Santa Clara is around 1%, while that for Los Angeles is around 2%, based on current mortality rates.

Given known infection and fatality rates on the Diamond Princess cruise ship, the team also calculated an upper limit on the fatality rate for those infected: about twice the lower limit, or 1%, for New York City and Santa Clara County.

Uncertainty fueled by lack of diagnostic tests

Uncertainty about the fatality rate for those infected by the new virus, dubbed SARS-CoV-2, resulted from delays in testing, due to a shortage of test kits and testing labs. This left public health officials in the dark about the true rate of infection in the general population, which is needed to calculate what percentage of infected people die.

The Stanford study estimated an infection rate in Santa Clara County of between 2.5% and 4.2% of residents, whereas the USC study estimated an infection rate in Los Angeles between 2.8% and 5.6%. Both are much higher than previous estimates, which means the number of confirmed COVID-positive deaths relative to those infected dropped to a low of 0.2%.

Based on these studies, some of the Stanford authors have argued that COVID-19 is little worse than the seasonal flu, casting doubt on decisions to mandate shelter-in-place and the closing of many businesses.

"Of course, it (the infection fatality rate) matters, for policy decisions," Seljak said. "Is this just a bad case of flu, as they would like to claim, or is it something much more serious?"

To answer that question, Seljak and his colleagues mined a previously untapped source of data: the daily death rate for 1,688 towns in Italy between Jan. 1 and April 4 for the years 2015 through 2020, provided by the Italian Institute of Statistics. The excess deaths between January and April of this year, presumably due to COVID-19, can be used to calculate a lower limit for the death rate from the virus.

"The dataset is a treasure trove for statistical analysis of COVID-19 mortality," Seljak said. "For example, it can give mortality rate as a function of age better than any other data out there, a sad consequence of tens of thousands of deaths from COVID-19 in Italy. With this data, we established that if one gets infected and is above 90 years of age, the probability of dying is at least 10%, because that is the fraction of the entire population of Bergamo province in this age group that died. In contrast, the corresponding number for ages 40 to 49 is 0.04%, far lower than previous estimates."

The Lombardy region of Italy, for example, was a viral hotspot, with the province of Bergamo hardest hit: The infection spread to so many people in Bergamo—likely two-thirds of the population, if not the entire population—that it is possible that so-called herd immunity has set in, Seljak said. That means that enough people are immune, at least temporarily, to stanch the spread of the virus among the the uninfected.

With essentially everyone in Bergamo infected, and the known deaths since January—predicted to be more than 6,000 out of a population of 1 million—it was easy to calculate the lowest possible infected fatality rate: 0.56%.

For Lombardy, the researchers estimated that the lowest possible fatality rate was even higher: about 0.84%. They also estimated that 23% of the population of Lombardy was infected, as of April 18—on average, 35 times the number of positive tests in the province.

The team conducted an analysis for all Italian towns that reported daily death data and for all age groups, using a counterfactual analysis: estimating the expected number of deaths daily between January and April 2020, based on the previous five years, and comparing those numbers with reported deaths. The excess is assumed to be due to COVID-19. The researchers employed statistical methods often used in analyzing large sets of data: the Conditional Mean with a Gaussian process (CGP) and a Synthetic Control Method (SCM).

In nearly all towns, the excess deaths in early 2020 exceeded the official count attributed to COVID-19.

The numbers the team came up with are lower limits, the researchers emphasize, since deaths in many Italian towns are not fully up to date.

"Some of my colleagues think that we have been overly conservative, which might be true," Seljak said. "We have just accounted for the people who have died up until today, but people are still dying."

More information: Chirag Modi et al. Total COVID-19 Mortality in Italy: Excess Mortality and Age Dependence through Time-Series Analysis, (2020). DOI: 10.1101/2020.04.15.20067074

Provided by University of California - Berkeley

Engineers develop precision injection system for plants

by David L. Chandler, Massachusetts Institute of Technology

A microinjection device (red) is attached to a citrus tree, providing a way of injecting pesticide or other materials directly into the plant's circulatory system. Credit: Massachusetts Institute of Technology

While the human world is reeling from one pandemic, there are several ongoing epidemics that affect crops and put global food production at risk. Oranges, olives, and bananas are already under threat in many areas due to diseases that affect plants' circulatory systems and that cannot be treated by applying pesticides.

A new method developed by engineers at MIT may offer a starting point for delivering life-saving treatments to plants ravaged by such diseases.

These diseases are difficult to detect early and to treat, given the lack of precision tools to access plant vasculature to treat pathogens and to sample biomarkers. The MIT team decided to take some of the principles involved in precision medicine for humans and adapt them to develop plant-specific biomaterials and drug-delivery devices.

The method uses an array of microneedles made of a silk-based biomaterial to deliver nutrients, drugs, or other molecules to specific parts of the plant. The findings are described in the journal Advanced Science, in a paper by MIT professors Benedetto Marelli and Jing-Ke-Weng, graduate student Yunteng Cao, postdoc Eugene Lim at MIT, and postdoc Menglong Xu at the Whitehead Institute for Biomedical Research.

The microneedles, which the researchers call phytoinjectors, can be made in a variety of sizes and shapes, and can deliver material specifically to a plant's roots, stems, or leaves, or into its xylem (the vascular tissue involved in water transportation from roots to canopy) or phloem (the vascular tissue that circulates metabolites throughout the plant). In lab tests, the team used tomato and tobacco plants, but the system could be adapted to almost any crop, they say. The microneedles can not only deliver targeted payloads of molecules into the plant, but they can also be used to take samples from the plants for lab analysis.

The work started in response to a request from the U.S. Department of Agriculture for ideas on how to address the citrus greening crisis, which is threatening the collapse of a $9 billion industry, Marelli says. The disease is spread by an insect called the Asian citrus psyllid that carries a bacterium into the plant. There is as yet no cure for it, and millions of acres of U.S. orchards have already been devastated. In response, Marelli's lab swung into gear to develop the novel microneedle technology, led by Cao as his thesis project.

The disease infects the phloem of the whole plant, including roots, which are very difficult to reach with any conventional treatment, Marelli explains. Most pesticides are simply sprayed or painted onto a plant's leaves or stems, and little if any penetrates to the root system. Such treatments may appear to work for a short while, but then the bacteria bounce back and do their damage. What is needed is something that can target the phloem circulating through a plant's tissues, which could carry an antibacterial compound down into the roots. That's just what some version of the new microneedles could potentially accomplish, he says.

"We wanted to solve the technical problem of how you can have a precise access to the plant vasculature," Cao adds. This would allow researchers to inject pesticides, for example, that would be transported between the root system and the leaves. Present approaches use "needles that are very large and very invasive, and that results in damaging the plant," he says. To find a substitute, they built on previous work that had produced microneedles using silk-based material for injecting human vaccines.

"We found that adaptations of a material designed for drug delivery in humans to plants was not straightforward, due to differences not only in tissue vasculature, but also in fluid composition," Lim says. The microneedles designed for human use were intended to biodegrade naturally in the body's moisture, but plants have far less available water, so the material didn't dissolve and was not useful for delivering the pesticide or other macromolecules into the phloem. The researchers had to design a new material, but they decided to stick with silk as its basis. That's because of silk's strength, its inertness in plants (preventing undesirable side effects), and the fact that it degrades into tiny particles that don't risk clogging the plant's internal vasculature systems.

They used biotechnology tools to increase silk's hydrophilicity (making it attract water), while keeping the material strong enough to penetrate the plant's epidermis and degradable enough to then get out of the way.

Sure enough, they tested the material on their lab tomato and tobacco plants, and were able to observe injected materials, in this case fluorescent molecules, moving all they way through the plant, from roots to leaves.

"We think this is a new tool that can be used by plant biologists and bioengineers to better understand transport phenomena in plants," Cao says. In addition, it can be used "to deliver payloads into plants, and this can solve several problems. For example, you can think about delivering micronutrients, or you can think about delivering genes, to change the gene expression of the plant or to basically engineer a plant."

"Now, the interests of the lab for the phytoinjectors have expanded beyond antibiotic delivery to genetic engineering and point-of-care diagnostics," Lim adds.

For example, in their experiments with tobacco plants, they were able to inject an organism called Agrobacterium to alter the plant's DNA—a typical bioengineering tool, but delivered in a new and precise way.

So far, this is a lab technique using precision equipment, so in its present form it would not be useful for agricultural-scale applications, but the hope is that it can be used, for example, to bioengineer disease-resistant varieties of important crop plants. The team has also done tests using a modified toy dart gun mounted to a small drone, which was able to fire microneedles into plants in the field. Ultimately, such a process might be automated using autonomous vehicles, Marelli says, for agricultural-scale use.

Meanwhile, the team continues to work on adapting the system to the varied needs and conditions of different kinds of plants and their tissues. "There's a lot of variation among them, really," Marelli says, so you need to think about having devices that are plant-specific. For the future, our research interests will go beyond antibiotic delivery to genetic engineering and point-of-care diagnostics based on metabolite sampling."

Explore further

Hormone produced in starved leaves stimulates roots to take up nitrogen

More information: Yunteng Cao et al. Precision Delivery of Multiscale Payloads to Tissue‐Specific Targets in Plants, Advanced Science (2020). DOI: 10.1002/advs.201903551

Provided by Massachusetts Institute of Tech

New study finds connection between fault roughness and the magnitude of earthquakes

by McGill University

Credit: McGill University

A new study led by McGill University has found that tectonic plates beneath the Earth's surface can show varying degrees of roughness and could help explain why certain earthquakes are stronger than others.

Earthquakes happen when the rocks beneath the Earth's surface break along geological fault lines and slide past each other. The properties of these faults—such as the roughness of their surface—can have an influence on the size of seismic events, however their study has been challenging because they are buried deep beneath the Earth's surface.

In order to have a better understanding of the characteristics of these faults, researchers from McGill University, the University of California Santa Cruz and Ruhr University Bochum in Germany used high-resolution seismic reflection data to map and measure the roughness of 350 km2 of a plate boundary fault located off the Pacific coast of Costa Rica.

"We already knew that the roughness of a fault was an important factor, but we did not know how rough faults in the subsurface truly are, nor how variable the roughness is for a single fault," says James Kirkpatrick, a professor in McGill's Department of Earth and Planetary Sciences.

Rougher surfaces of faults may explain earthquake magnitude

In a recently published study in Nature Geoscience, Kirkpatrick and his colleagues were able to show that some parts of the studied fault have a rougher surface than others.

Historically, the earthquakes that have occurred in this part of the world have been moderately large (M7) and Kirkpatrick, who is also the study's first author, believes the rough patches they found might be the reason why.

"These rough patches are stronger and more resistant to earthquake slip," he says. "The historical record of earthquakes is relatively short, so we can't say with certainty that larger ones have not occurred. Future seismic events in the area, which will be recorded with modern equipment, should help us determine if they show the same limited magnitude."

Kirkpatrick and his colleagues also hope to apply their methods to other subduction zones where similar geophysical data is available to start to evaluate whether their conclusions are generally applicable.

"This connection between the fault roughness and earthquake magnitude might one day help us understand the size and style of earthquakes most likely to occur a given fault."

Explore further

Seismic biomarkers in Japan Trench fault zone reveal history of large earthquakes
More information: James D. Kirkpatrick et al, Subduction megathrust heterogeneity characterized from 3D seismic data, Nature Geoscience (2020). DOI: 10.1038/s41561-020-0562-9

Journal information: Nature Geoscience

Provided by McGill University

North Atlantic right whales are in much poorer condition than Southern right whales

by Woods Hole Oceanographic Institution

New research by an international team of scientists reveals that endangered North Atlantic right whales are in much poorer body condition than their counterparts in the southern hemisphere.

This alarming research, led by Dr. Fredrik Christiansen from Aarhus University in Denmark, was published this week in the journal Marine Ecology Progress Series. The study is the result of a collaborative effort by scientist from 12 institutions across 5 nations. Among the coauthors are Senior Scientist Peter Corkeron and Associate Scientist Heather Pettis of the Anderson Cabot Center for Ocean Life at the New England Aquarium and Michael Moore and Carolyn Miller of the Woods Hole Oceanographic Institution.

The analyses revealed that individual North Atlantic right whales—juveniles, adults and mothers—were all in poorer body condition than individual whales from the three populations of Southern right whales. This is alarming, since poor body condition for North Atlantic right whales helps explain why too many of them are dying and why they are not giving birth to enough calves. It could also be affecting their growth and delaying juveniles reaching sexual maturity. These combined impacts on individuals help explain why the species is in decline.

Since the cessation of large-scale commercial whaling in the last century, most populations of southern right whales have recovered well. Now there are about 10,000-15,000 southern right whales. Unfortunately, the same cannot be said for the North Atlantic right whales, found today mostly off the east coast of North America. There are now around 410 individuals left, and the species is heading to extinction. Lethal vessel strikes and entanglement in fishing gear continue to kill these whales. Individual North Atlantic right whales also have to cope with the energetic expense and other costs that are caused by frequent entanglements in fishing gear, in particular lobster and crab pots. These burdens, along with a change in the abundance and distribution of the rice-sized plankton that they eat, have left these whales thin and unhealthy, which makes them less likely to have a calf. This, in turn, contributes to the current overall decline of the species. To quantify "thin and unhealthy," Dr. Christiansen and his colleagues investigated the body condition of individual North Atlantic right whales and compared their condition with individuals from three increasing populations of Southern right whales: off Argentina, Australia and New Zealand.

"Good body condition and abundant fat reserves are crucial for the reproduction of large whales, including right whales, as the animals rely on these energy stores during the breeding season when they are mostly fasting," said Dr. Christiansen. Stored fat reserves are particularly important for mothers, who need the extra energy to support the growth of their newly born calf while they are nursing.

The study is the largest assessment of the body condition of baleen whales in the world. The international research team used drones and a method called aerial photogrammetry to measure the body length and width of individual right whales in these four regions around the world. From aerial photographs, the researchers estimated the body volume of individual whales, which they then used to derive an index of body condition or relative fatness.

"This started out as a conversation between a few of us over dinner at a conference in 2015. Now that the results are out, they're quite shocking," said Peter Corkeron of the Anderson Cabot Center for Ocean Life at the New England Aquarium. "We know that North Atlantic right whales as a species are doing poorly, but this work brings home that as individuals, they're also doing poorly. Their decline has been so rapid that we know it's not simply because not enough calves are being born—too many whales are also dying from human-caused injuries. But this study also shows that their decline isn't solely due to these deaths. Their problems are more insidious, and we need to find a way to ensure that the health of all individual whales improves."

"For North Atlantic right whales as individuals, and as a species, things are going terribly wrong. This comparison with their southern hemisphere relatives shows that most individual North Atlantic right whales are in much worse condition than they should be," said Michael Moore from the Woods Hole Oceanographic Institution. "As a veterinarian, I've long been concerned about how entanglements affect the welfare of these whales. Now we are starting to draw the linkages from welfare to this species' decline. Sub-lethal entanglement trauma, along with changing food supplies is making them too skinny to reproduce well, and lethal entanglement and vessel trauma are killing them. To reverse these changes, we must: redirect vessels away from, and reduce their speed in, right whale habitat; retrieve crab and lobster traps without rope in the water column using available technologies; and minimize ocean noise from its many sources."

This work was supported by funding from NOAA, US Office of Naval Research Marine Mammals Program, World Wildlife Fund for Nature Australia, Murdoch University School of Veterinary and Life Sciences, New Zealand Antarctic Research institute, Otago University and New Zealand Whale and Dolphin Trust and Argentina National Geographic Society.

For 40 years, the New England Aquarium's right whale team has extensively researched and tracked individual right whales and curates the North Atlantic Right Whale Catalog. The scientific team monitors the whales' arrival at breeding and feeding grounds, registering new calves, death rates, and also measuring changes in stress and reproductive hormones.

The Woods Hole Oceanographic Institution is dedicated to advancing knowledge of the ocean and its connection with the Earth system through a sustained commitment to excellence in science, engineering and education, and to the application of this knowledge to problems facing society

Lobstering gear could be reduced, changed to save whales

More information: F Christiansen et al. Population comparison of right whale body condition reveals poor state of the North Atlantic right whale, Marine Ecology Progress Series (2020). DOI: 10.3354/meps13299

Journal information: Marine Ecology Progress Series

New research explores the impact of cover crop residues on weed control

by Cambridge University Press

Cover crops have a well-documented role to play in suppressing troublesome weeds. But what happens as those cover crops degrade?

A new study featured in the journal Weed Science explores whether cover-crop residues help to suppress summer annual weeds and promote greater crop yields. Researchers planted single cover-crop treatments of cereal rye, hairy vetch, crimson clover and forage radish in the fall, as well as two-way and three-way mixtures. Each was followed by corn and soybean crops.

The team tracked the biomass of each cover crop and the residual components produced—uncovering several key trends. They found that cover-crop biomass and the ratio of carbon to nitrogen influenced weed suppression and its duration. For example, a 9 to 1 ratio of carbon to nitrogen suppressed pigweed by 50 percent at four weeks after treatment, while a 20 to 1 ratio delivered the same level of control eight weeks after treatment.

Similarly, a cover-crop biomass of 2,800 kg per hectare was needed for 50 percent suppression four weeks after treatment, while a biomass of 6,610 kg per hectare was needed for the same level of suppression at eight weeks after treatment.

In fields where the cover crop was the only weed control measure used, corn and soybean yields increased as both cover crop biomass and carbon to nitrogen ratios increased.

Researchers found that most mixtures of cover crops produced more biomass than individual cover crops alone. Carbon to nitrogen ratios produced by cereal rye and a cereal rye-forage radish mixture were 36 to 1—greater than all the other cover crop treatments. Hairy vetch and crimson clover had ratios of 12 to 1 and 17 to 1, which were the lowest ratios produced by any of the cover crops.

"Our study shows that the biomass of the cover crop isn't all that matters," says Kara Pittman of Virginia Tech, lead researcher for the study. "The composition of the residues the cover crop leaves behind are also important to weed control."

Impacts of cover crop planting dates on soil properties after 4 years

More information: Kara B. Pittman et al, Cover crop residue components and their effect on summer annual weed suppression in corn and soybean, Weed Science (2020). DOI: 10.1017/wsc.2020.16

The basis of glyphosate resistance in amaranth

by American Society of Plant Biologists

William T. Molin (U.S. Department of Agriculture-Agricultural Research Service, Stoneville, MS) teamed up with Allison Yaguchi, Mark Blenner, and Christopher A. Saski (Clemson University, SC) to sequence and dissect the structure of the extrachromosomal DNA replicon that underlies the molecular and biochemical basis of resistance to the herbicide glyphosate in Palmer amaranth (Amaranthus palmeri). This work aids our understanding of adaptive evolution in plants and has implications for optimizing pesticide use in the environment.

Glyphosate is a widely used broad-spectrum herbicide that targets both broadleaf plants and grasses (dicots and monocots). It kills plants by inhibiting the enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS), found only in plants and in some bacteria. EPSPS is a key enzyme for the biosynthesis of essential amino acids and is an ideal target for herbicides because animals and humans use another enzyme that is insensitive to glyphosate to fulfill the same function. Some plants, including A. palmeri, can develop resistance to glyphosate toxicity by massively raising the expression of the EPSPS gene during glyphosate stress, essentially flooding the system with extra EPSPS enzyme and thereby counteracting the effects of the herbicide.

Making more copies of a gene is one possible means to increase gene expression: the phenomenon of amplification of genes or gene clusters is a common stress-avoidance mechanism in animals, plants, and microorganisms and is at play here. The amplified genes are often contained within extrachromosomal circular DNA (eccDNA) fragments known as replicons, circles of DNA that are maintained and replicated outside of the normal linear chromosomes in an organism. In humans, eccDNA is a prevalent feature of many cancers and a variety of diseases associated with developmental defects and premature aging. In such cases, eccDNAs carry oncogenes and other genes that may boost the survival and proliferation of diseased cells.

Molin et al. provide the complete sequence of the eccDNA replicon responsible for glyphosate resistance in A. palmeri, reveal its structural organization and genomic content, and examine some of the features that enable it to replicate and persist in the genome through multiple generations. The eccDNA replicon was found to contain 59 genes, a subset of which (including the EPSPS gene) show higher expression after treatment of the resistant plants with glyphosate. In addition to the presence of amplified genes, the eccDNA structure consists of a complex arrangement of repeated sequences and mobile genetic elements—so-called transposable elements—that might play a role in its maintenance and replication based on analogy with other eccDNAs. Author Christopher Saski noted that "the DNA content of the eccDNA replicon is sophisticated. Sequencing this element was difficult, and this complete assembly became possible only when DNA sequencing technology advanced to the single-molecule level, such as developed by Pacific Biosciences" (the biotechnology company that pioneered these methods, based in Menlo Park, CA).

Since the introduction of glyphosate in the 1970s, the rise of glyphosate-resistant weeds has been a growing problem in agricultural settings. The original glyphosate-resistant amaranth weedy plant that started this project was collected from a soybean field that had been routinely sprayed with the herbicide for a decade. The origin of this eccDNA replicon is unknown but is likely a result of transposable element activation and genomic shuffling that might have been pushed along by the use of glyphosate. That is, plants like A. palmeri that contain the eccDNA are able to survive and propagate where glyphosate is used frequently; additionally, glyphosate stress might contribute to the activation of the transposable elements that influence eccDNA formation and activity. Understanding the complete genomic structure and function of the eccDNA replicon will aid our knowledge of how glyphosate resistance develops and evolves in plants and help to further refine herbicide treatment strategies and combat the rise of resistant weeds.

The authors also identified structural features consistent with tethering of the eccDNA to chromosomes, which may facilitate maintenance of the fragment during normal cellular mitosis. Future work will focus on how the eccDNA self-replicates in plant cells, and identifying the essential functional elements of the replicon. This discovery could lead to "new approaches to genome engineering and the possibility of expressing useful agronomic traits outside of the nuclear genome," said Saski.Researchers make breakthrough in glyphosate resistance in pigweeds

More information: Plant Cell, DOI: 10.1105/tpc.20.00099

Journal information: Plan Cell

Provided by American Society of Plant Biologists

Supreme Court rejects EPA's narrow view of Clean Water Act

by Mark Sherman

The Supreme Court ruled Thursday that sewage plants and other industries cannot avoid environmental requirements under landmark clean-water protections when they send dirty water on an indirect route to rivers, oceans and other navigable waterways.

Rejecting the Trump administration's views, the justices held by a 6-3 vote that the discharge of polluted water into the ground, rather than directly into nearby waterways, does not relieve an industry of complying with the Clean Water Act.

"We hold that the statute requires a permit when there is a direct discharge from a point source into navigable waters or when there is the functional equivalent of a direct discharge," Justice Stephen Breyer wrote for the court.

The decision came in a closely watched case from Hawaii about whether a sewage treatment plant needs a federal permit when it sends wastewater deep underground, instead of discharging the treated flow directly into the Pacific Ocean. Studies have found the wastewater soon reaches the ocean and has damaged a coral reef near a Maui beach.

The Environmental Protection Agency under President Donald Trump reversed the agency's position that Breyer noted has appeared to work well for more than 30 years. That's among many actions the administration has taken to change course on environmental regulations, including making official just days ago a sweeping rollback of the Clean Water Act that would end federal protection for many of the nation's millions of miles of streams, arroyos and wetlands. Public health and environmental groups and some Western states, among other opponents, say the rollback would leave the waterways more vulnerable to pollution from development, industry and farms, and they have promised court fights.

In the Hawaii case, Justices Samuel Alito, Neil Gorsuch and Clarence Thomas dissented. "Based on the statutory text and structure, I would hold that a permit is required only when a point source discharges pollutants directly into navigable waters," Thomas wrote.

David Henkin, a lawyer for the environmental group Earthjustice who argued the case in the high court, said, "This is unquestionably a win for people who are concerned about protecting clean water in the United States."

Sewage plants and other polluters must get a permit under the Clean Water Act when pollutants go through a pipe from their source to a body of water. The question in this case was whether a permit is needed when the pollutant first passes through the soil or groundwater.

Maui injects 3 million to 5 million gallons a day of treated wastewater into wells beneath the Lahaina Wastewater Reclamation Facility, which sits about a half-mile from the Pacific shoreline. Environmental groups in Hawaii sued Maui after studies using dyes to trace the flow showed more than half the discharge from two wells was entering the ocean in a narrow area. They won a ruling from the federal appeals court based in San Francisco.

Breyer raised concerns during arguments in November that a ruling for Maui would provide a "road map" for polluters to evade federal permit requirements.

Still, the court did not go as far as the federal appeals court, which adopted a standard that would have brought even more groundwater discharges under the clean water law.

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