Culture

ROCKVILLE, Md. - May 28, 2020 - The Association for Molecular Pathology (AMP), the premier global, molecular diagnostic professional society, today released the preliminary results of its April 2020 SARS-CoV-2 Testing Survey for clinical laboratories. The anonymous survey was created and administered to document clinical laboratory efforts and experiences. The results will be used to help inform future advocacy and clinical practice programs related to pandemic responses.

AMP's 67-question survey assessed many important aspects of SARS-CoV-2 molecular diagnostic testing, including methodology, performance, capacity, supply chain, regulatory, and reporting requirements. The preliminary results today included feedback from 118 representatives from US-based academic medical centers, commercial reference laboratories and community hospitals. 85% of these respondents are currently offering SARS-CoV-2 testing to patients, while another 10% are currently in the test validation phase. 90% of the laboratories recognize the need to increase diagnostic testing capacity further, and they are working hard to make this happen in the next few months. However, more than 70% of these laboratories have experienced supply chain interruptions that have resulted in significant delays, in many cases forcing them to validate at least three different diagnostic testing methods at the same time just in case the supply of reagents or materials runs out. These supply shortages have included everything from the RNA extraction kits, primers, probes, and enzymes to the physical sample collection materials, such as the swabs and containers for storage and transportation.

"Clinical laboratories across the country are working hard and being extremely resourceful in order to provide diagnostic SARS-CoV-2 testing to Americans, with the majority running at full staffing/testing capacity seven days a week," said Karen E. Weck, MD, AMP President and Professor of Pathology and Laboratory Medicine, Professor of Genetics and Director of Molecular Genetics and Pharmacogenomics at University of North Carolina Chapel Hill. "However, AMP members know more testing is needed as the country begins to reopen. We are continuing to deploy multiple testing methodologies to overcome supply shortages, increase capacity and improve turnaround times."

Based on the common themes found in the survey results, AMP is recommending that federal, state and local governments:

1. Reassess type and location of SARS-CoV-2 testing services needed: In order to provide acute care, safely reopen businesses and reinvigorate the economy, there should be a reassessment of what type of testing is needed and where.

2. Reprioritize supply allocations based on clinical testing needs, which could change over time: Depending upon the prevalence of SARS-CoV-2 in a community, there may be a shift in testing methodology and related supply needs over time. The need for testing supplies designed for acute care, surveillance, high-throughput, and other clinical needs should be monitored widely to provide real-time feedback to agencies to support data-driven supply allocations.

3. Increase transparency, communication, and real-time transmission of Information between laboratories and suppliers (commercial manufacturers and government): There is a need for laboratories to understand in real-time resource availability and reagent and supply quantities.

4. Real-time coordination amongst laboratories to leverage moments of excess capacity: Based on data regarding testing capacity and demand, there may be an opportunity to coordinate regionally to ensure that any excess test capacity is leveraged to ensure samples get processed as quickly as possible.

5. Standardize agency reporting format and processes for reportable infectious diseases during a pandemic: Complying with multiple agency reporting requirements with variable formats has been burdensome to the clinical laboratories.

AMP will continue to review and analyze the results of the survey as part of its ongoing commitment to share expertise, assess laboratory needs, engage key stakeholders and provide recommendations for improving future pandemic responses and ensuring more patients have access to high-quality testing procedures.

CINCINNATI - A transgenic mouse developed at Cincinnati Children's to model the deadly childhood immune disease HLH (hemophagocytic lymphohistiocytosis) may play a key role in saving lives during the COVID-19 virus pandemic.

One of the genetically engineered mouse strain's inventors--Cincinnati Children's cancer pathologist Gang Huang, PhD-- is co-investigator on a small clinical trial that successfully tested a drug used to treat to HLH (ruxolitinib) to dramatically reverse respiratory and multi-system inflammation in severely ill COVID-19 patients. Data from the Phase II clinical study is published in the Journal of Allergy and Clinical Immunology.

The study involved 43 hospitalized patients diagnosed with severe COVID-19 between February 9 and February 28 in Wuhan, China, believed to be ground zero for the pandemic. The multi-center study was led by Jianfeng Zhou, MD, PhD, Department of Hematology at Tongji Hospital, Tongji Medical College and Huazhong University of Science in Wuhan.

Zhou is a longtime collaborator of Huang and colleagues at the Cincinnati Children's HLH Center of Excellence, part of the Cancer and Blood Diseases Institute.

Ruxolitinib Shows Signs of Benefit

Patients taking ruxolitinib were randomly selected to receive two daily 5mg oral doses of the anti-inflammatory drug, plus the standard of care treatment for COVID-19. A randomly selected control group of 21 patients received a placebo along with the standard of care treatment.

"Ruxolitinib recipients had a numerically faster clinical improvement," study authors write in their report. "Significant chest CT improvement, a faster recovery from lymphopenia and favorable side-effect profile in ruxolitinib group were encouraging and informative to future trials to test efficacy of ruxolitinib in a larger population."

Patients treated with ruxolitinib saw a shorter median time to clinical improvement compared to the control group. Patients treated with ruxolitinib saw a shorter median time to clinical improvement compared to the control group. Researchers reported that 90 percent of ruxolitinib patients showed CT scan improvement within 14 days, compared with 61. 9 percent of patients from the control group. Three patients in the control group eventually died of respiratory failure. All the severely ill patients who received ruxolitinib survived.

More clinical testing of the drug is needed. A larger Phase III clinical trial RUXCOVID by Incyte and Novartis is now testing up to 400 severely ill COVID-19 patients with the drug, according to Huang. Preliminary clinical data from the study is expected during the summer, he added.

"This is the first therapy we know of that appears to work effectively to quiet the cytokine storm and inflammation in severe COVID-19 disease, and there are no significant toxicities to patients who take the drug by two pills a day," Huang said. "This is critical until we can develop and distribute enough effective vaccine to help prevent people from becoming infected."

Calming the 'Cytokine Storm'

The so-called cytokine storm that inundates the bodies of severely ill COVID-19 patients with inflammatory cells produced by the immune system is a common feature of children battling secondary HLH, which happens in patients where initial HLH treatment has not worked. Huang, who along with a large portion of the world's scientific community was busy trying to study and find solutions to COVID-19, noticed this common clinical feature of both illnesses.

He also noticed that severe COVID-19 disease clinical manifestations are very similar to those seen in transgenic laboratory mice created to faithfully mimic human secondary HLH in the lab. That preclinical laboratory research, some of it in collaboration with the researchers in Wuhan, China, helped identify the drug ruxolitinib for treating secondary HLH. The anti-inflammatory drug is also used to treat other blood diseases including leukemia.

"I approached our research colleagues in Wuhan and explained our observations and recommended this drug be tested to quiet the cytokine storm in the multi-system inflammation in patients with severe COVID-19 disease," Huang said. "The disease was spreading very rapidly and many people were dying. We believed the existing clinical drug would help save lives. So, we worked to push it forward before there is an effective vaccine for everyone."

Huang said the work with colleagues in China was completed on a compressed timeframe as scientists around the world went on high alert to battle the pandemic in January. During their work, Huang and researchers in China found other clinical studies involving other diseases where ruxolitinib also had worked well at quieting inflammation, and testing on COVID-19 patients proceeded.

Offering a government-sponsored health plan with publicly determined payment rates to people who buy their own insurance could lower the cost of premiums, but on its own it is unlikely to substantially increase the overall number of people with coverage, according to a new RAND Corporation study.

Modeling four scenarios for adding a public option for individual coverage available nationwide, researchers found that premiums for public plans could be 10% to 27% lower than private insurance plans because of lower provider payment rates in the public option.

A public option had much less impact on boosting the number of people with insurance. Under three of the scenarios, the number of uninsured people fell 3% to 8%, while the number of uninsured declined marginally under a fourth scenario studied.

The analysis also found that lower-income people are less likely to benefit from the public option because of the tax credit structure of the federal Affordable Care Act.

"Since higher-income people pay the full cost of insurance on the individual market, they could receive substantial savings under a public option," said Jodi Liu, the study's lead author and a policy researcher at RAND, a nonprofit research organization. "But policymakers should consider how the design of a public option could decrease the tax credits lower-income enrollees receive under the ACA."

State and federal lawmakers have expressed interest in creating a public health insurance option, broadly defined as an insurance plan for individuals under age 65 that provides access to publicly determined payment rates.

Four different bills that would create a federal public option were introduced in the Congress in 2019 and several Democratic presidential candidates (including presumptive nominee Joe Biden) included public options in their health reform platforms.

RAND researchers used a microsimulation approach to estimate how the addition of a federal public option for individual market insurance could affect overall insurance coverage, individual market enrollment and premiums for individual market enrollees. About 14 million people buy plans on the individual market each year.

The analysis considered four designs that vary based on what rates providers are paid, whether the public option is considered "on-Marketplace" or "off-Marketplace" coverage that affects premium tax credit amounts under the ACA , and whether premium tax credits are available to higher-income individuals. Researchers assumed that the public option for individual market insurance would offer bronze, silver, gold and platinum tiers of actuarial-based coverage.

Payment rates were set at 79 percent of the current commercial rates (between Medicaid and commercial rates) for two scenarios and at 93 percent of commercial rates (between Medicare and commercial rates) for the other two scenarios.

The analysis assumes that providers are willing to contract at lower payment rates and that adequate provider networks can be formed. (The work was conducted prior to the coronavirus pandemic and does not assess its impact on participating providers and payment rates.)

The findings suggest that most enrollees in the individual market would switch from private plans to public plans in these scenarios.

A relatively small pool of sicker and more-expensive people would remain enrolled on private plans because of assumptions that higher spenders would have lower preference for public plans because of real or perceived access barriers related to lower payments to providers. As a result, researchers found that some individual market premiums increased when they modeled the public plan.

Federal spending fell under all of the scenarios, with savings ranging from $7 billion to $24 billion annually. The savings occur as premium tax credit amounts decline, because the silver-level public option becomes the benchmark for setting subsidy levels in some scenarios and because of changes to the risk pool and competition effects.

To gauge the welfare effects on individuals, researchers estimated the number of people who would be "better off" (becoming newly insured or paying less for an equivalent or more generous plan) or "worse off" (becoming uninsured or paying more for an equivalent or less generous plan) in each scenario. Across the public option scenarios analyzed, 5.1 million to 12.1 million people were better off, and 2.2 million to 6.8 million people were worse off.

Those who were worse off have incomes below 400 percent of federal poverty level. Because tax credits were tied to the public silver premium in most of the RAND scenarios, individuals' tax credits fell when the public plan was introduced. As a result, for many subsidized individuals, the introduction of the public option did not reduce out-of-pocket premiums.

Researchers say that one option to ease this burden would be to reinvest the cost savings from a public option into programs that would benefit lower-income people, such as providing a larger tax credit to lower-income people who buy individual health insurance policies.

WASHINGTON -- The amount of scarring in damaged kidneys as a result of diabetes or acute injury, is a key factor in determining treatment. But it has not been possible, using traditional techniques, to quickly and accurately assess how widespread this kind of wounding extends within the organ. Now, however, a physicist and chemist at Georgetown University Medical Center has shown that a microscope he began developing with colleagues at University of California-Irvine can provide an immediate answer.

His findings, published in the journal Kidney International, suggest that, given further successful testing of this device, it could be adopted in an operating suite using biopsies, usually taken with a needle, from a patient's kidney. These biopsies, which don't need to be stained, will score the degree of tubulointerstitial fibrosis -- progressive scarring due to a failed wound-healing process of kidney tissue after chronic, sustained injury. This score can then be combined with results from traditional pathology to help physicians assess long-term prognosis.

While this kind of approach was developed for cancer prognosis, this study represents "to our knowledge, the first expansion of this type of test to understand human kidney disease and to specifically to characterize disease states," says the study's lead investigator, Suman Ranjit, PhD, assistant professor in Georgetown's Department of Biochemistry and Molecular & Cellular Biology.

The advanced microscope, called DIVER, uses phasor approach to fluorescence lifetime imaging (FLIM). Simply said, the devices work together to examine the type of molecules that are in an image of the tissue sample captured by the microscope. It uses endogenous fluorescence emitted naturally by the biomolecules, measuring the time it takes for different molecules to stay in the excited state (fluorescence lifetime). The results are pseudo-color mapped, with each color representing specific types and degrees of molecular content that reveal changes in structure and biology of the organ that link to disease severity.

"Using this method, numerous biopsies from a kidney can be examined quickly. The process is automated, eliminating operator bias," says Ranjit. In contrast, traditional biopsies often an hours-long process of staining and pathological examination happens outside of an operating room.

This study examined frozen human kidney biopsy tissues from patients with diabetes, obtained from the University of Chicago. Researchers found that the new method closely replicated findings obtained by pathology analyses.

Ranjit started to work on this clinical project using what he calls his "home built" device while a postdoctoral scholar at UC Irvine's Laboratory for Fluorescence Dynamics, but completed it at Georgetown. He now has applied for federal grants that will help him "shrink" this idea into a small handheld device that could be used in operating rooms, and to further improve automation and imaging speed.

When the device is perfected, Ranjit says it may be possible to use it for assessing disease state in many organs, a process that now depend on cumbersome pathological analysis.

"When widely used this imaging technique will enable physicians to detect early fibrosis, or scarring, in tissues as well as determine the health of kidney, liver and other tissues that are being considered for transplantation," says co-author Moshe Levi, MD, Interim Dean for Research at GUMC and professor of biochemistry and molecular & cellular biology.

Perennial warm-season grasses do not provide high-quality forage during mid to late-summer, which limits yearling stocker cattle from maintaining high rates of growth in the Southern Great Plains. This shortage has resulted in a continual search by researchers for annual legumes that can provide sufficient amounts of nutritious forage during August through September.

In a recently published article in the Agronomy Journal, researchers from USDA-ARS Grazinglands Research Laboratory and Oklahoma State University document the function of tepary bean and guar as potential summer forages under the growing conditions of Southern Great Plains. The two-year field experiment compared the productivity, leaf-to-stem ratios, and chemical composition of forage produced by three cultivars of each of tepary bean and guar with the soybean used as a control.

Results showed that tepary bean consistently offered rapid and better forage yields with a higher leaf-to-stem ratio. In contrast, guar maintained a low leaf-to-stem ratio and soybean possessed the least digestible stems in forage biomass among the tested legumes.

The article suggests tepary bean as an alternate forage option to soybean for producers and encourages further research to define management strategies for growing tepary bean in extensive production settings.

Among dinosaurs of ancient Colorado, scavenging and possibly cannibalism were responses to a resource-scarce environment, according to a study published May 27, 2020 in the open-access journal PLOS ONE by Stephanie Drumheller of the University of Tennessee, Knoxville, and colleagues.

Tooth marks on fossil bones can be excellent evidence of ancient feeding habits, but such marks left by carnivorous dinosaurs (theropods) are typically very rare. The Mygatt-Moore Quarry of Colorado, dating back to the late Jurassic Period around 150 million years ago, is an exception. In this study, Drumheller and colleagues found that nearly 29% of 2,368 examined bones from the quarry bore the bites of theropod dinosaurs.

Examining the damage left by the serrated edges of the dinosaurs' teeth, the authors infer that the bulk of these bites were most likely made by the large predator Allosaurus, the most common theropod found in the quarry. While most of the bites were found on the bones of herbivorous dinosaurs, about 17% were bites that theropods had made on the bones of other theropods--and around half of these bites targeted less nutritious body parts, suggesting the action of scavengers who arrived after the best bits had decomposed or been eaten by earlier carnivores.

The authors suggest this unusual assemblage is the result of an ancient environment where carcasses were buried slowly, providing ample time for scavengers to find them. The high incidence of scavenging may be the result of a stressed ecosystem whose large predators suffered a scarcity of food. Additionally, since many of the presumed Allosaurus bite marks were found on the bones of other Allosaurus, these might represent rare evidence of dinosaur cannibalism, and the first such evidence for the behavior in this famous Jurassic predator.

Dr. Drumheller adds: "Big theropods like Allosaurus probably weren't particularly picky eaters, especially if their environments were already strapped for resources. Scavenging and even cannibalism were definitely on the table."

Meta-analysis research studies in psychology aren't always reproducible due to a lack of transparency of reporting in the meta-analysis process, according to a new study published May 27, 2020 in the open-access journal PLOS ONE by Esther Maassen of Tilburg University, the Netherlands, and colleagues.

Meta-analysis is a widely used method to combine and compare quantitative data from multiple primary studies. The statistical approach used in meta-analyses can reveal whether study outcomes differ based on particular study characteristics, and help compute an overall effect size--for instance, the magnitude of a treatment effect--for the topic of interest. However, many steps of a meta-analysis involve decisions and judgements that can be arbitrary or differ by researcher.

In the new study, researchers analyzed 33 meta-analysis articles in the field of psychology. The meta-analytical studies were all published in 2011 and 2012, all had data tables with primary studies, and all included at least ten primary studies. For each meta-analysis, the team searched for the corresponding primary study articles, followed any methods detailed in the meta-analysis article, and recomputed a total of 500 effect sizes reported in the meta-analyses.

Out of 500 primary study effect sizes, the researchers were able to reproduce 276 (55%) without any problems. (In this case, reproducibility was defined as arriving at the same result after reanalyzing the same data following the reported procedures.) However, in some cases, the meta-analyses did not contain enough information to reproduce the study effect size, while in others a different effect than stated was calculated. 114 effect sizes (23%) showed discrepancies compared to what was reported in the meta-analytical article. 30 of the 33 meta-analyses contained at least one effect size that could not be easily reproduced.

When the erroneous or unreproducible effect sizes were integrated into each meta-analysis itself, the team found that 13 of the 33 (39%) meta-analyses had discrepancies in their results, although many were negligible. The researchers recommend adding to existing guidelines for the publication of psychological meta-analyses to make them more reproducible.

The authors add: Individual effect sizes from meta-analyses in psychology are difficult to reproduce due to inaccurate and incomplete reporting in the meta-analysis. To increase the trustworthiness of meta-analytic results, it is essential that researchers explicitly document their data handling practices and workflow, as well as publish their data and code online.

For many patients with a bicuspid aortic valve that needs replacing, transcatheter aortic valve replacement (TAVR) appears to be a safe treatment option with low complication rates, according to a study published in JACC: Cardiovascular Interventions. The study found patients with bicuspid valves who were at increased risk for surgery had a 30-day and one-year mortality rate and stroke rate that was similar to patients with the more common tricuspid valves.

An estimated 2% of the U.S. population has an aortic valve with two leaflets (bicuspid) instead of three (tricuspid). The aortic valve is a one-way valve between the heart and the aorta, the main artery from the heart that distributes oxygen-rich blood to the body. The leaflets, or flaps, normally open widely and close securely to regulate blood flow. This allows blood to flow from the heart to the aorta and prevents blood from flowing backwards into the heart. Having a bicuspid valve requires regular monitoring by a physician since it can lead to an increased risk of heart valve complications. Prior research has shown that up to 20% of people with a bicuspid valve will need replacement at some point.

"No one's valve works as well at age 70 as it does at age 20, but in patients with a bicuspid aortic valve, it's more likely to wear out and require replacement," said study lead author John K. Forrest, MD, director of the Structural Heart Disease Program at Yale University School of Medicine and Yale New Haven Hospital.

Since studies of TAVR have traditionally excluded bicuspid patients, until now it has not been known how these patients fare when they are treated with the procedure. To answer this question, the researchers used data from the STS/ACC TVT Registry, which collects data of all commercial TAVR cases in the U.S. They analyzed 932 patients with bicuspid valve disease who underwent TAVR with one of two valves, the Evolut R or Evolut PRO, between July 2015 and September 2018.

The patients in the study were at increased surgical risk, based on a number of factors including their age and whether they had medical conditions such as diabetes, prior surgery, stroke or peripheral vascular disease. The majority of bicuspid patients in this study were at intermediate or high surgical risk.

These patients were compared to similar patients with tricuspid valve disease who underwent TAVR during that same time period. The study found similar rates of death from any cause at 30 days (2.6% vs. 1.7%) and one year (10.4% vs. 12.1%), as well as the rate of stroke at 30 days (3.4% vs. 2.7%) and one year (3.9% vs. 4.4%).

In the last decade, TAVR has become an increasingly popular way to replace aortic valves. TAVR is a minimally invasive procedure in which a catheter is used to deliver a replacement valve to the site of the old valve, thus avoiding open-heart surgery. While initially reserved for patients whose poor health makes an open-heart valve replacement too risky, recent studies have shown that in patients with tri-leaflet aortic stenosis, TAVR is a viable option even for low-risk patients.

"This study suggests TAVR is a viable option for patients with bicuspid valve disease who are at increased surgical risk," Forrest said. "It will be very important to continue to monitor these patients to see how the valves perform in 10 or 15 years."

What The Study Did: Researchers looked at trends in diversity by sex and race/ethnicity among applicants to U.S. surgical residency and fellowship programs from 2008-2018 to see if diversity was increasing.

Authors: Issam Koleilat, M.D., of the Montefiore Medical Center in New York, is the corresponding author.

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

(doi:10.1001/jamasurg.2020.1018)

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

PHILADELPHIA -- The majority of commercially insured patients who visited the emergency department (ED) for an opioid overdose didn't receive the timely follow-up care known to help prevent a future overdose or death, according to a new study from researchers at the Perelman School of Medicine at the University of Pennsylvania. Of nearly 6,500 patients treated in EDs nationwide for an overdose or other opioid-related medical complications, only 16 percent accessed opioid use disorder (OUD) medications or another form of treatment within three months of the ED visit. The study was published today in JAMA Network Open.

The lack of care was most pronounced among black patients, who were half as likely to receive post-overdose treatment as whites, even after adjusting for type of overdose (prescription or heroin), and other clinical characteristics. Timely follow-up treatments are known to significantly reduce the risk of death among patients suffering from opioid use disorders who are admitted to the ED.

"The ED encounter has been seen as a critical opportunity to engage a patient and connect them to the right care that gives them the best chance for recovery," said the study's first author Austin Kilaru, MD, an emergency department physician and a fellow in the National Clinician Scholars Program at Penn. "However, even with commercially insured patients, who likely have superior ability to access care, we see these low treatment rates, particularly for minorities. There's more work to be done, and these findings give us a comprehensive picture of the gaps and disparities that could help inform those efforts moving forward."

The team analyzed administrative insurance claims under a large commercial insurer filed between October 2011 and September 2016. Researchers defined follow-up treatments as the prescription of medication for opioid use disorder (MOUD)--buprenorphine and naltrexone--or an outpatient or inpatient opioid treatment encounter, which could include behavioral health services or primary care visits. While the study did include two MOUDs shown to reduce the risk of death and overdoses, it did not capture the use of methadone, another common MOUD, because the insurer did not cover it at the time.

Of the 6,451 adult patients treated in EDs nationwide, 4,555 overdosed from prescription opioids and 1,896 overdosed from heroin. Nearly 75 percent of the patients identified as non-Hispanic white and about 10 percent identified as black. Within that group, only 1,069 received follow-up care after being discharged from the ED. Most notably, black patients were half as likely to obtain treatment following overdose compared with white patients (6.1 percent versus 12.1 percent). Hispanic and female patients were also less likely to receive treatments.

Researchers found that patients who had received treatment prior to being admitted to ED were more likely to receive follow-up care. In fact, more than 62 percent of patients who had received prior treatment for an overdose received the follow-up care. Among patients who did not receive treatment 90 days prior to the ED visit (5,769), only about 10 percent--or 643--received follow-up care.

The findings demonstrate that there are barriers to follow-up care beyond being underinsured or uninsured and other factors limiting access that warrant further attention.

Increased adoption of pathways to initiate buprenorphine in the ED, more coordinated communication between EDs and outpatient clinics, and direct conversations between physicians and patients around treatments may help improve that access. These interventions, the authors said, must seek to reduce racial, ethnic, and gender disparities to ensure expanded and equitable access to treatment following overdose.

Since the study time period ended, some hospitals across the country have implemented changes to help address this issue. For example, Penn established its Center for Opioid Recovery and Engagement (CORE), which has helped improve the pathway to recovery for many patients, regardless of insurance status, by implementing such efforts and more.

"The period after an overdose is so high risk that we need to be able to use that key window of opportunity," Kilaru said. "Payers and policymakers should push for strategies that encourage, help, and incentivize health systems to deliver the timely follow-up care we know can save more lives."

What The Study Did: Clinical characteristics of patients with asymptomatic or symptomatic COVID-19 are described in this case series from Wuhan, China.

Authors: Yong Xiong, Ph.D., of Wuhan University in China, is the corresponding author.

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

(doi:10.1001/jamanetworkopen.2020.10182)

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

What The Viewpoint Says: How psychiatrists can contribute to diminish the effects of the COVID-19 pandemic is discussed.

Authors: Jurjen J. Luykx, M.D., Ph.D., of University Medical Center Utrecht and Utrecht University in the Netherlands, is the corresponding author.

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

(doi:10.1001/jamapsychiatry.2020.1225)

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

A new understanding of our planet's deepest earthquakes could help unravel one of the most mysterious geophysical processes on Earth.

Deep earthquakes -- those at least 300 kilometers below the surface -- don't typically cause damage, but they are often widely felt. These earthquakes can provide vital clues to understanding plate tectonics and the structure of the Earth's interior. Due to the extremely high temperature and pressures where deep earthquakes occur, they likely stem from different physical and chemical processes than earthquakes near the surface. But it's hard to gather information about deep earthquakes, so scientists don't have a solid explanation for what causes them.

"We can't directly see what's happening where deep earthquakes occur," said Magali Billen, professor of geophysics in the UC Davis Department of Earth and Planetary Sciences.

What's driving deep earthquakes?

Billen builds numerical simulations of subduction zones, where one plate sinks below another, to better understand the forces controlling plate tectonics. Her recent work helps explain the distribution of deep earthquakes, showing that they most often strike in regions of "high strain" where a sinking tectonic plate bends and folds.

"These models provide compelling evidence that strain rate is an important factor in controlling where deep earthquakes occur," she said.

The new understanding that deformation is a major factor in deep earthquakes should help scientists resolve which mechanisms trigger deep earthquakes and can provide new constraints on subduction zone structure and dynamics, Billen said.

"Once we understand deep earthquake physics better, we will be able to extract even more information about the dynamics of subduction, the key driver of plate tectonics," she said.

Her findings were published May 27 in the journal Science Advances.

New way to study deep earthquakes

Deep earthquakes occur in subduction zones -- where one of the tectonic plates floating on the surface of the Earth dives under another and is "subducted" into the mantle. Within the sinking slabs of crust, earthquakes cluster at some depths and are sparse in others. For example, many slabs exhibit large gaps in seismic activity below 410 kilometers in depth.

The gaps in seismicity line up with regions of the slab that are deforming more slowly in the numerical models, Billen said.

"Deformation is not the same everywhere in the plate," Billen said. "That's really what's new here."

Billen's research was not originally intended to investigate deep earthquakes. Rather, she was trying to understand the slow back-and forth motion of deep ocean trenches, where plates bend downward in subduction zones.

"I decided out of curiosity to plot the deformation in the plate, and when I looked at the plot, the first thing that popped in my mind was 'wow, this looks like the distribution of deep earthquakes,'" she said. "It was a total surprise."

Mimicking the deep Earth

Billen's model incorporates the latest data about phenomena such as the density of minerals, different layers in the sinking plate, and experimental observations of how rocks behave at high temperatures and pressures.

"This is the first model that really brings together the physical equations that describe the sinking of the plates and key physical properties of the rocks," Billen said.

The results cannot distinguish between possible causes for deep earthquakes. However, they do provide new ways to explore what causes them, Billen said.

"Taking into account the added constraint of strain-rate should help to resolve which mechanisms are active in the subducting lithosphere, with the possibility that multiple mechanisms may be required," she said.

The project was supported by a fellowship from the Alexander von Humboldt Foundation and an award from the National Science Foundation. The Computational Infrastructure for Geodynamics supports the CitcomS software used for the numerical simulations.

Electronic Cigarettes Trigger an Inflammatory Response That May Set the Stage for Gum Disease

The oral microbiomes of 25 otherwise healthy participants who use e-cigarettes daily closely match those seen in patients with gum disease, a new study shows. The results suggest that e-cigarettes trigger a proinflammatory response, coating commensal bacteria in the mouth with a layer of slime that makes them unrecognizable to the body and prevents the sequential colonization of other bacteria that form a healthy community. Sukirth Ganesan and colleagues conclude that the glycerol/glycol vehicle in e-cigarettes appears to drive these changes. E-cigarettes have grown wildly popular among Americans, with six percent of the country's population - including 2.5 million high schoolers - puffing on the products nine years after their introduction to the United States. But while these e-cigarettes contain potentially toxic substances, including volatile organic compounds and metals, much remains unknown their long-term effects on human health. To gain insight into how e-cigarettes affect the oral microbiome, Ganesan et al. recruited 123 otherwise healthy individuals, including 25 smokers, 25 nonsmokers, 20 e-cigarette users, 25 former smokers currently using e-cigarettes, and 28 smokers who also use e-cigarettes. They created a catalog of bacterial genes in the microbial communities of e-cigarette users based on plaque samples collected from their teeth, finding that variations arose based on the duration of e-cigarette use, but were not tied to variations in the concentration of nicotine or the type of flavoring. The researchers also observed that while both smoking and e-cigarette use cause inflammation, they do so through different molecular pathways. "I am hoping this research will drive some level of policymaking about the harm we are seeing," said Purnima Kumar, a coauthor of the study, in an interview, challenging the popular perception that e-cigarettes provide a safer alternative to smoking. "If we can see changes in people who are otherwise healthy and have nothing wrong with them, then we should start seriously considering why would you put their lives and their wellbeing at risk."

Melanoma is a malignant tumour resulting from the transformation of melanocytes, the cells in the skin that undertake to synthesise melanin, a complex polymer which protects us from the negative effects of solar radiation. Although melanoma is the least common among skin cancers, it is the one with the highest mortality rate, largely because of its high potential for metastasis.

Once a patient has been diagnosed with advanced-stage melanoma, an assessment is made as to whether he or she stands to benefit from adjuvant therapy with BRAF inhibitors. To do this, clinical laboratories analyse whether or not the patient has a specific mutation in the BRAF gene, specifically the BRAF-V600E mutation, which is one of the most common in melanoma and is regarded as a "driver" mutation, in other words, a mutation that provides an advantage in the onset of tumour transformation and growth.

However, it is becoming increasingly clear that tumours are highly heterogeneous and that there are subpopulations of cells with different mutations and behaviours within the same tumour. "So we believe that quantifying the mutation provides much more information that just trying to detect it (positive or negative). This quantification can be made by means of biopsies using a novel technique known as digital PCR," explained Arrate Sevilla, a researcher in salonsoLab (Evolutionary Human Biology Group), in the UPV/EHU's Department of Genetics, Physical Anthropology and Animal Physiology.

In the study the mutational load was analysed in biopsies of 78 patients and the load of the BRAF-V600E mutation was found to inversely correlate with the stage of the patients, which suggests that it could be useful as a prognosis marker. But in addition, the most interesting thing is that in patients in stage II it correlated inversely with the development of metastasis. That means that the patients who had developed metastasis also tended to have a lower percentage of the mutation in their primary tumours. So by means of predictive analyses based on machine learning, the mutational load of BRAF-V600E was found to be capable of categorizing stage II patients under metastatic and non-metastatic ones in a slightly more accurate way than the routinely used marker: the Breslow thickness marker.

According to the analyses made by this group, which besides the UPV/EHU has had the intervention of scientists from the Biocruces Bizkaia Institute, Onkologikoa and Ikerbasque, the mutation load appears to be linked to the prognosis. "In stage II patients, at least, it could be a predictor of progress to metastasis," said Sevilla.

These results are preliminary ones, so this possible marker would need to be validated in a much bigger cohort of patients. "However, we believe that our discovery is on the right track, it is novel and opens up the door to additional studies on the evolutionary mechanisms of this tumour," added the researcher.