Culture

What The Viewpoint Says: Discussion of recommendations for angiotensin-converting enzyme inhibitor and angiotensin receptor blocker use in patients with or at risk of contracting coronavirus disease 2019 (COVID-19).

Authors: Franz H. Messerli, M.D., of Bern University Hospital in Switzerland, 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/jamacardio.2020.1282)

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.

What The Viewpoint Says: Information on the coronavirus disease 2019 pandemic that is useful for pediatric clinicians is in this article.

Authors: Sonja A. Rasmussen, M.D., M.S., of the University of Florida College of Medicine in Gainesville, 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/jamapediatrics.2020.1224)

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.

A healthcare 'passport' to access NHS and other wellbeing services has been beneficial for the mental health of veterans and provides them with a sense of identity, according to research published in the BMJ Military Health.

The Veterans Universal Passport (VUP) pilot project was developed by Diane Palmer, formerly of the Veterans' Mental Health Transition, Intervention and Liaison Service (TILS) for the Midlands and East of England, and is supported by the Ministry of Defence along with several veterans' charities. It has been independently evaluated by the Veterans and Families Institute for Military Social Research at Anglia Ruskin University (ARU).

Participants in the scheme, who were veterans recently transitioning to civilian life, reported improved continuity of care and promoted a feeling of control over care. The military-specific nature of the VUP also gave participants a sense of identity and helped them negotiate the complexities of the civilian healthcare system.

One veteran who took part in the pilot scheme said: "It's been really great actually. It's got all my information in one place. Instead of me having to keep going backwards and forwards trying to find it. I find it really easy."

Healthcare workers also praised the VUP. One said: "It's a regularity of feeling proactive, engagement, in their own care."

Lead author Dr Lauren Godier-McBard, of ARU, said: "Many ex-service personnel find navigating health and social care services on 'civvy street' daunting and complex. However, it is important that veterans who are in need of these services are not lost in the system and an ongoing healthcare record provides continuity of care and patient empowerment.

"We identified in our research that participants found having a single document to access a number of different services reduced their anxiety and provided them with much-needed structure to their journey through treatment.

"The fact this is a document exclusively for veterans also gave them a sense of pride and identity, further improving their wellbeing."

Surgical masks may help prevent infected people from making others sick with seasonal viruses, including coronaviruses, according to new research that could help settle a fierce debate spanning clinical and cultural norms.

In laboratory experiments, the masks significantly reduced the amounts of various airborne viruses coming from infected patients, measured using the breath-capturing "Gesundheit II machine" developed by Dr. Don Milton, a professor of applied environmental health in the University of Maryland School of Public Health and a senior author of the study published April 3 in the journal Nature Medicine.

Milton has already conferred with federal and White House health officials on the findings, which closely follow statements this week from the head of the Centers for Disease Control and Prevention saying the agency was reconsidering oft-stated advice that surgical masks aren't a useful precaution outside of medical settings. (The debate takes place at a time when clinicians themselves face dangerously inadequate supplies of masks--a shortfall other UMD researchers are scrambling to help solve.)

The question of masks has roiled society as well, with some retailers refusing to let employees wear them for fear of sending negative signals to customers, and cases of slurs and even physical attacks in the United States and elsewhere against Asians or Asian Americans who were wearing masks, a measure some consider a necessity during a disease outbreak.

The study, conducted prior to the current pandemic with a student of Milton's colleagues on the Faculty of Medicine at the University of Hong Kong, does not address the question of whether surgical masks protect wearers from infection. It does suggest that masks may limit how much the infected--who in the case of the novel coronavirus often don't have symptoms--spread diseases including influenza, rhinoviruses and coronaviruses.

Milton, who runs the Public Health Aerobiology, Virology, and Exhaled Biomarker Laboratory in the School of Public Health, demonstrated in a 2013 study that surgical masks could help limit flu transmission. However, he cautions that the effect may not be as great outside of controlled settings.

Nevertheless, he said, the chance they could help justifies taking a new look at whether all people should be encouraged to wear them when they venture out of their houses to stores or other populated locations during the current COVID-19 lockdown.

"In normal times we'd say that if it wasn't shown statistically significant or the effective in real-world studies, we don't recommend it," he said. "But in the middle of a pandemic, we're desperate. The thinking is that even if it cuts down transmission a little bit, it's worth trying."

Previous studies have shown that coronavirus and other respiratory infections are mostly spread during close contact, which has been interpreted by some infectious disease specialists to mean that the disease could spread only through contact and large droplets, such as from a cough or sneeze--a message that has often been shared with the public.

"What they don't understand is that is merely a hypothesis," Milton said. The current study (along with earlier ones) shows, by contrast, that tiny, aerosolized droplets can indeed diffuse through the air. That means it may be possible to contract COVID-19 not only by being coughed on, but by simply inhaling the breath of someone nearby who has it, whether they have symptoms or not. Surgical masks, however, catch a lot of the aerosolized virus as it's exhaled, he said.

The study was conducted at the University of Hong Kong as part of the dissertation research of the lead author, Dr. Nancy Leung, who, under the supervision of the co-senior authors Drs. Cowling and Milton, recruited 246 people with suspected respiratory viral infections. Milton's Gesundheit machine compared how much virus they exhaled with and without a surgical mask.

"In 111 people infected by either coronavirus, influenza virus or rhinovirus, masks reduced detectable virus in respiratory droplets and aerosols for seasonal coronaviruses, and in respiratory droplets for influenza virus," Leung said. "In contrast, masks did not reduce the emission of rhinoviruses."

Although the experiment took place before the current pandemic, COVID-19 and seasonal coronaviruses are closely related and may be of similar particle size. The report's other senior author, Professor Benjamin Cowling, division head of epidemiology and biostatistics, School of Public Health, HKUMed, and co-director of the World Health Organization Collaborating Centre for Infectious Disease Epidemiology and Control, said, "The ability of surgical masks to reduce seasonal coronavirus in respiratory droplets and aerosols implies that such masks can contribute to slowing the spread of (COVID-19) when worn by infected people."

Milton pointed to other measures his research has found is even more effective than masks, such as improving ventilation in public places like grocery stores, or installing UV-C lights near the ceiling that works in conjunction with ceiling fans to pull air upwards and destroy viruses and bacteria.

"Personal protective equipment like N95 masks are not our first line of defense," Milton said. "They are our last desperate thing that we do."

It turns out that there may be some limits to the influence of Western culture on the rest of the world, after all. A new paper in Frontiers in Psychology that examined men's attitudes towards and behaviors around muscularity in three countries found than non-Western men were generally less hung up about their body image and pursuing a muscular physique than Western men.

"However, we did still find evidence that men in these populations are influenced by both other men around them and by the media," said lead author Dr. Tracey Thornborrow at the University of Lincoln in the United Kingdom.

Most of the research on sociocultural influences, like media portrayals that shape male ideals and behaviors around muscularity and masculinity, have focused on so-called WEIRD (Western, Educated, Industrialized, Rich, Democratic) populations. That means many of the conclusions around the drive for muscularity and its negative behaviors, such as steroid use and unhealthy dieting, are very Western-centric.

Thornborrow and the other UK scientists on the team wanted to learn if those attitudes translated to countries with different cultural norms, so they compared a cohort of British men against Ugandan and Nicaraguan males.

The study collected and assessed a number of parameters from each group, ranging from demographics and body mass index (BMI) to feelings about media influences and peer pressure on achieving an idealized appearance to personal body goals.

Participants also ranked the perceived level of muscularity of their current body and their ideal body on the Male Adiposity and Muscularity Scale (MAMS). Designed by the Person Perception Lab at the University of Lincoln, the new scale uses two-dimensional images created from 3D software, providing a more realistic range of body types and sizes based on measurements of real people.

The researchers also used a form of artificial intelligence to find patterns in that data that might predict which ethnic groups would be driven toward behaviors to achieve more muscle regardless of country of origin.

"We used machine learning methods because they are good at determining if sociocultural factors, such as media and ethnicity, and a drive for muscularity, make it more likely that men will actively want to change their bodies," said co-author Tochukwu Onwuegbusi, also out of the University of Lincoln, who crunched the numbers on the study.

For example, the data from the current study suggest that being a Caucasian man in the UK or a Miskitu man in Nicaragua means that he would more likely believe that one should be muscular. Such men are more likely to engage in muscle-building activities, such as weight training or drinking protein shakes.

Motivations behind the drive toward a more muscle-bound frame can be complex, Thornborrow noted. For instance, men from certain ethnic groups in Nicaragua who reported being less concerned with physical appearance were still likely to try to increase muscle mass.

These non-media influenced motivations "could include local ideas about masculinity, and a muscular body being a visual indicator of a working man, not a lazy man," Thornborrow explained. "In rural Nicaragua, many men will engage in physical work, such as farming, fishing, and construction, so a muscular body is associated with being a hard-working man."

While there is growing evidence that men in Western countries are experiencing a lot of pressure to conform to stereotypical body ideals, similarly to women, the picture emerging in non-WEIRD populations is less clear. More research is needed to better understand the consequences of these other cultural attitudes and behaviors around body image.

"This study, in particular, shows how there can be variation within groups -- for example, nations or ethnic groups -- and so it becomes more important to ensure any strategies or interventions are tailored to the specific cultural context," Thornborrow said.

PHILADELPHIA - An increased proportion of Indigenous American (IA) ancestry was associated with a greater incidence of HER2-positive breast cancer, according to a study published in Cancer Research, a journal of the American Association for Cancer Research.

"The risk of breast cancer-related mortality varies between different populations, with Latina women having a greater risk of breast cancer-specific mortality than non-Hispanic white women," said Laura Fejerman, PhD, associate professor of medicine at the University of California San Francisco. "Latina women tend to be diagnosed with more aggressive breast cancer subtypes, which may contribute to their greater risk of mortality, among other factors," Fejerman added.

Breast cancers are classified into subtypes based on the status of hormone receptors and the human epidermal growth factor receptor 2 (HER2). These receptors respond to factors outside the cell and promote cellular proliferation. Breast cancers that have higher than normal levels of HER2 are referred to as HER2-positive breast cancers and tend to grow more aggressively than some other subtypes. HER2-positive breast cancers are more common in Latina women than in non-Hispanic white women, but the underlying reasons for this remain unclear.

Previous work from Fejerman and colleagues demonstrated that IA ancestry was associated with a lower incidence of breast cancer. However, the influence of IA ancestry on different breast cancer subtypes remained unclear. A prior study that examined a small cohort of Colombian patients with breast cancer suggested that a higher proportion of IA ancestry was associated with increased expression of the ERBB2 gene, which encodes HER2. This led Fejerman and colleagues to examine whether IA ancestry may be associated with risk of HER2-positive breast cancer.

The Peruvian Genetics and Genomics of Breast Cancer study (PEGEN-BC), led by Fejerman and developed in collaboration with Tatiana Vidaurre, MD, PhD, at the Instituto de Enfermedades Neoplásicas (INEN) in Lima, Peru, recruited 1,842 patients. Participants at INEN were invited to participate in the study if they had received a diagnosis of invasive breast cancer during or after the year 2010 and were between the ages of 21 and 79 years. "Peru is one of the countries in Latin America with extremely high proportions of IA ancestry, which is an understudied genetic component in medical research. The collaboration with Dr. Vidaurre from INEN was fundamental for the realization of this study," Fejerman noted.

The publication reports results from 1,312 patients who had available genome-wide genotype data. HER2-positive breast cancers accounted for 30 percent of cases (18 percent were positive for hormone receptors). On average, participants had approximately 76 percent IA ancestry, with 9.8 percent of patients having greater than 95 percent IA ancestry.

Analyses revealed statistically significant differences in the distribution of different breast cancer subtypes among women with different proportions of IA ancestry. The odds of having a HER2-positive tumor were 1.19 times higher for every 10 percent increase in IA ancestry. Conversely, the odds of developing HER2-positive disease decreased with increasing European ancestry. The observed associations were independent of the participant's age at diagnosis, level of African ancestry, height, tumor stage at diagnosis, and region of residence. The findings were replicated with smaller cohorts from Mexico and Colombia. The odds of having a HER2-positive tumor in these cohorts was approximately 1.28 times greater for every 10 percent increase in IA ancestry.

"The association between IA ancestry and HER2 status suggests that population-specific variants of IA origin could be partly contributing to the higher incidence of HER2-positive breast cancer in Latinas," said Fejerman. "Our ongoing research aims to identify the specific germline variants that may lead to this association." This information could eventually be incorporated into a risk prediction model for Latina women to identify those at high risk for certain subtypes, explained Fejerman. Understanding the genetic basis of the observed association could also help researchers understand the biology of the disease, which could eventually lead to new treatments, Fejerman added.

"Even though humans are mostly the same, there are differences between populations that affect disease risk and outcome," said Fejerman. "This study highlights the importance of studying diverse populations and collaborating with other countries. We need to understand diverse populations so that we may someday be able to provide precision cancer prevention and care to everyone, and not just a subset of the population."

A limitation of the study is that it did not include healthy controls. Additionally, the lack of certain epidemiological data and information about environmental exposures or lifestyle behaviors precluded the analysis of all possible factors.

LA JOLLA, CA -- An antibody recovered from a survivor of the SARS epidemic in the early 2000s has revealed a potential vulnerability of the new coronavirus at the root of COVID-19, according to a study from scientists at Scripps Research.

The study, published today in Science, is the first to map a human antibody's interaction with the new coronavirus at near-atomic-scale resolution. Although the antibody was produced in response to an infection of SARS (severe acute respiratory syndrome), which is caused by the SARS-CoV virus, it cross-reacts with the new coronavirus, SARS-CoV-2.

The structural mapping revealed a nearly identical site on both coronaviruses to which the antibody binds, suggesting a functionally important and vulnerable site for this family of coronaviruses.

"The knowledge of conserved sites like this can aid in structure-based design of vaccines and therapeutics against SARS-CoV-2, and these would also protect against other coronaviruses--including those that may emerge in the future," says the study's senior author Ian Wilson, DPhil, Hansen Professor of Structural Biology and Chair of the Department of Integrative Structural and Computational Biology at Scripps Research.

SARS-CoV, which causes SARS, originated in horseshoe bats, but jumped to humans in South China in 2002, eventually infecting more than 8,000 people and killing almost 800 before it was quelled by lockdowns, quarantines and other measures.

SARS-CoV-2, a closely related coronavirus that causes COVID-19, first emerged in the Chinese city of Wuhan in late 2019. Much more infectious than its viral cousin, it has led to a pandemic, causing far more cases of illness and fatalities than SARS. The development of a vaccine or even an effective treatment could significantly ameliorate the crisis.

The Wilson lab is known for its pioneering structural studies of antibodies bound to viruses including HIV and influenza. These studies have been used to inform designs of vaccines and antibody drugs, as well as other therapeutics. Along with hundreds of other labs around the world, Wilson's team is now focused on SARS-CoV-2.

"Our ultimate goal here is to obtain structural information on antibodies and their binding sites, and use that to guide SARS-CoV-2 vaccine design, just as our lab has done with influenza and HIV," says the study's co-first author Nicholas Wu, PhD, a postdoctoral research associate in the Wilson lab.

The new study centers on an anti-SARS-CoV antibody called CR3022 that was originally isolated in 2006 by the pharmaceutical company Crucell Holland B.V. in the Netherlands. A report from Chinese scientists earlier this year indicated that CR3022 cross-reacts against SARS-CoV-2. Wilson's team used their structural mapping expertise to determine how the antibody binds to SARS-CoV-2.

A key finding is that the antibody's binding site is highly similar between the two coronaviruses--differing by just four protein building blocks called amino-acids. That high degree of similarity implies that the site has an important function that would be lost if it mutated significantly.

Yet, the site's function remains mysterious. The Scripps Research analysis found that the antibody binding site is relatively remote from the part of the virus that grabs hold of cell-surface protein receptors in preparation for penetrating cells in our lungs. That suggests that, at least for SARS-CoV, CR3002 neutralizes the virus's ability to infect cells in some indirect way.

Adding to the mystery is the finding that the antibody binding site on these viruses is not normally accessible to antibodies.

"We found that this region is usually hidden inside the virus, and only exposed when that part of the virus changes its structure, as it would in natural infection," says co-first author Meng Yuan, PhD, also a research associate in the Wilson lab.

Despite the slightness of difference between the two coronaviruses, the antibody binds much less tightly to SARS-CoV-2 than it does to the SARS virus, and cannot neutralize SARS-CoV-2 in lab dish tests as it does SARS-CoV.

Still, the findings suggest that the binding site for this antibody on SARS-CoV-2 is a site of vulnerability, and that antibodies binding it more tightly would plausibly succeed in neutralizing the virus. Such neutralizing antibodies, if developed into therapies, could be used to treat COVID-19 patients and to provide temporary protection from the virus to uninfected individuals, for example healthcare workers.

The fact that this binding site is highly conserved between SARS-CoV and SARS-CoV-2 also hints that there may be antibodies, still to be discovered, that can effectively neutralize both viruses--and perhaps in the same way, can neutralize future emergent coronaviruses before they can cause pandemics.

Labs at Scripps Research and throughout the world are currently seeking antibodies, via blood donations, from people who have recovered from COVID-19 for further studies along these lines.

The tiny hairs found on plant roots play a pivotal role in helping reduce soil erosion, a new study has found. The research, led by the University of Bristol and published in Communications Biology, provides compelling evidence that when root hairs interact with the surrounding soil they reduce soil erosion and increase soil cohesion by binding soil particles.

Soil erosion can have a devastating impact across the globe and a serious threat for modern agriculture. The increased demand for agriculture has led to forests and natural grasslands being converted to farm fields and pastures.

However, many of the plants grown, such as coffee, cotton and palm oil, can significantly increase soil erosion beyond the soil's ability to maintain and renovate. It can also lead to increased pollution and sedimentation in streams and rivers or, because these areas are often less able to hold onto water, can worsen flooding. This problem is particularly urgent considering the ever-expanding human population and climate change.

Researchers from the Universities of Bristol and Exeter have revealed the crucial function the microscopic roots hairs play in binding and reinforcing soil.

While the larger-scale root properties such as diameter, length and surface area have been extensively studied to understand their role in preventing soil erosion, the effect that micro-scale properties, such as root hairs, has is less well documented.

The research team looked at how wild plants Arabidopsis thaliana, which produced root hairs, compared with an almost identical Arabidopsis with the same root hair structure in reducing soil erosion.

They found that, when planted in sufficient density, plants with root hairs reduced soil loss almost completely - while otherwise identical plants without hairs could not stem the flow of erosion.

Three methods were used to explore the soil retention benefits of root hairs. First, the samples were placed in a sterile gel, in a petri dish, and then subjected to increasing centrifugal force. The study found that the hairless seedlings were easier to remove from the gel compared to seedlings abundant with root hairs.

Second, the study found that root hairs were also shown to stabilise the plant in the soil, as they increased the force needed to uproot the plant.

Third, in the experimental landscapes laboratory at Exeter, root hairs reduced water erosion to almost zero.

Professor Claire Grierson, one of the study's lead authors from Bristol's School of Biological Sciences explained: "These findings could be the key in helping to tackle soil erosion. There are three possible ways root hairs could enhance soil, either the soil might bind directly to root hair surfaces, root hairs might release material that reinforces soil, or root hairs might release material that is processed by microbes into something that can reinforce soil.

"We hope our knowledge about the properties of plants that minimise soil erosion will allow the creation and selection of best-suited agricultural plants."

Professor Quine, an expert in Earth System Science at the University of Exeter, added: "This exciting, truly interdisciplinary project across biology, maths, engineering and environmental science has given us invaluable new insights into the influence of microscopic root structures on the macroscopic behavior of soils.

"I was amazed at the difference that root density made in reducing soil erosion to almost zero, when root density was high, whereas soil loss was still significant when roots at the same density had no hairs.

"We are excited to explore how the hairs exert this extraordinary influence."

The team are now working to distinguish between these hypotheses and identify the molecules involved.

In early February, research teams from Charité - Universitätsmedizin Berlin, München Klinik Schwabing and the Bundeswehr Institute of Microbiology published initial findings describing the efficient transmission of SARS-CoV-2. The researchers' detailed report on the clinical course and treatment of Germany's first group of COVID-19 patients has now been published in Nature*. Based on these findings, criteria may now be developed to determine the earliest point at which COVID-19 patients treated in hospitals with limited bed capacity can be safely discharged.

In late January, a group of patients in the Starnberg area near Munich became Germany's first group of epidemiologically linked cases of COVID-19. Nine patients from this 'Munich cluster' subsequently received treatment at München Klinik Schwabing. "At that point time, we really knew very little about the novel coronavirus which we now refer to as SARS-CoV-2," says one of the study's lead authors, Prof. Dr. Christian Drosten, Director of the Institute of Virology on Campus Charité Mitte. He adds: "Our decision to study these nine cases very closely throughout the course of their illness resulted in the discovery of many important details about this new virus."

"The patients treated at our hospital were all young to middle-aged. Their symptoms were generally mild and included flu-like symptoms like cough, fever and a loss of taste and smell," explains the other lead author, Prof. Dr. Clemens Wendtner, Head of the Department of Infectious Diseases and Tropical Medicine at München Klinik Schwabing, a teaching hospital of LMU Munich. "In terms of scientific significance, our study benefited from the fact that all of the cases were linked to an index case, meaning they were not simply studied based on the presence of certain symptoms. In addition to getting a good picture of how this virus behaves, this also enabled us to gain other important insights, including on viral transmission."

All nine patients underwent daily testing using both nasopharyngeal (nose and throat) swabs and sputum samples. Testing continued throughout the course of their illness and up to 28 days after the initial onset of symptoms. The researchers also collected stool, blood and urine samples whenever possible or practical. All of the samples collected were then tested for SARS-CoV-2 by two separate laboratories working independently of each other: the Institute of Virology on Campus Charité Mitte in Berlin and the Bundeswehr Institute of Microbiology, an institution which forms part of the German Center for Infection Research (DZIF).

According to the researchers' observations, all COVID-19 patients showed a high rate of viral replication and shedding in the throat during the first week of symptoms. Sputum samples also showed high levels of viral RNA (genetic information). Infectious viral particles were isolated from both pharyngeal (throat) swabs and sputum samples. "This means that the novel coronavirus does not have to travel to the lungs to replicate. It can replicate while still in the throat, which means it is very easy to transmit," explains Prof. Drosten, who is also affiliated with the DZIF, and is a professor at the Berlin Institute of Health (BIH). Due to genetic similarities between the new virus and the original SARS virus, the researchers initially assumed that, just like the SARS virus, the novel coronavirus would predominantly target the lungs - thus making human-to-human transmission more difficult. "However, our research involving the Munich cluster showed that the new SARS coronavirus differs quite considerably in terms of its preferential target tissue," says the virologist, and adds: "Naturally, this has enormous consequences for both viral transmission and spread, which is why we decided to publish our initial findings in early February."

In most cases, viral load decreased significantly during the first week of symptoms. While viral shedding in the lungs also decreased, this decline happened later than in the throat. The researchers were no longer able to obtain infectious virus particles from day 8 after the initial onset of symptoms. However, levels of viral RNA remained high in both the throat and lungs. The researchers found that samples with fewer than 100,000 copies of viral RNA no longer contained any infectious viral particles. This allowed the researchers to draw two conclusions: "A high viral load in the throat at the very onset of symptoms suggests that individuals with COVID-19 are infectious very early on, potentially before they are even aware of being ill," explains Colonel PD Dr. Roman Wölfel, Director of the Bundeswehr Institute of Microbiology and one of the study's first authors. "At the same time, the infectiousness of COVID-19 patients appears to be linked to viral load in the throat and lungs. In hospitals with limited bed capacity and the resultant pressure to expedite patient discharge, this is an important factor when it comes to deciding the earliest point at which a patient can be safely discharged." Based on these data, the study's authors suggest that COVID-19 patients with less than 100,000 viral RNA copies in their sputum sample on day 10 of symptoms could be discharged into home-based isolation.

The researchers' work also suggests that SARS-CoV-2 replicates in the gastrointestinal tract. However, the researchers were unable to isolate any infectious virus from patients' stool samples. None of the blood and urine samples tested positive for the virus. Serum samples were also tested for antibodies against SARS-CoV-2. Half of the patients tested had developed antibodies by day 7 following symptom onset; antibodies were detected in all patients after two weeks. The onset of antibody production coincided with a gradual decrease in viral load.

The Munich- and Berlin-based research groups plan to conduct additional research on the development of long-term immunity against SARS-CoV-2, both within the first German cluster and in other patients. This type of research will also play an important role in the development of vaccines.

As a Yale University postdoctoral researcher, economist Jude Bayham studied the potential consequences of a global pandemic that could shutter schools, close businesses, and strain hospitals. That was back in 2013.

Now, as the world grapples with the coronavirus, the Colorado State University economist and a multi-institutional team are turning those prescient modeling exercises into real insights for policymakers.

"We're repurposing models we had done a while back that frankly at the time, people didn't really care about," said Bayham, assistant professor in the Department of Agricultural and Resource Economics. "It's an 'I told you so' moment. I'm not happy about it. It's unfortunate."

In the last several weeks, Bayham and Yale collaborator Eli Fenichel have run a series of analyses illustrating the toll that long-term school closures may have on U.S. health care providers. They're now fielding inquiries from all over the world, from state governments to child care needs assessment professionals, who think the economists' work could help them navigate the here and now. In the last two weeks, the researchers created an interactive dashboard for drilling down statistics on child care needs by state, city and industry sector. Their data were published in The Lancet Public Health April 3.

Bayham and Fenichel have also created another dashboard for viewing COVID-19 complication risk factors in the workforce.

A third of health workers care for young children

For their health care worker analysis, the researchers used data from the U.S. Current Population Survey to show that about a third of health care workers - doctors, nurses, hospital staff - care for children ages 3-12. Fifteen percent of those households don't have other adults or older children who can help with child care.

At the time they did their original analysis, a long-term school closure was a far-off hypothetical. Now, as school districts nationwide shutter for weeks or months, Bayham's work of yore takes on new significance, and the team is scrambling to update it with current figures.

School closures are intended to slow the transmission of the virus. But Bayham and Fenichel find that the toll school closures take on health care workers could potentially negate any mortality benefits from the closures. Their calculations indicate that if the health care workforce declines by 15 percent, due to the workers now having to care for their children, it could lead to an increase in coronavirus deaths, because the workers aren't there to care for sick people. Specifically, they report that assuming a 15 percent loss of the health care labor force, a coronavirus infection mortality rate increase of just 0.35 percentage points would net a greater number of deaths than would be prevented by the closures.

These calculations are just that - calculations, which don't take into account, for example, the potential rollout of state or federal programs to offer child care relief to workers. And the estimates aren't perfect; the researchers don't claim to know, down to a precise number, what one health care worker's absence portends.

"We don't know, in terms of a productivity measure, the estimate of one nurse saving this many lives or reducing mortality," Bayham said. "But we think it's not zero. So essentially we are getting at how productive they need to be for us to be concerned about how school closures would undermine the goal of saving lives."

The work is a sobering reminder of the societal and public-health tradeoffs of large-scale disruptions like long-term school closures.

Forming networks

As the pandemic continues to unfold, Bayham and colleagues at Yale, Northwestern University and other institutions have quickly formed a network of economists and epidemiologists to continue this and other lines of work. They hope to help inform decisionmakers on questions not only of tradeoffs of school closures, but also, strategies for peeling back such restrictive measures when the time is right.

As researchers all over the world converge their expertise around the pandemic, Bayham and colleagues are also jumping into other projects to help. For example, Bayham is serving on a U.S. Forest Service task force that will examine potential outcomes of coronavirus on firefighters as fire season returns.

And along with department colleagues Becca Jablonski and Dawn Thilmany, Rebecca Clary, Rebecca Hill and Alexandra Hill, he is also serving on a Colorado Department of Agriculture-focused task force looking at effects of social distancing measures on food supply chain issues. CSU's vice president for engagement and extension, Blake Naughton, established the CSU Task Force on Colorado Food Supply to conduct research on several key areas: food access and security; designating food retail establishments as "essential services;" food supply chain workforce readiness; and consumer expenditure and farm market access.

US policymakers considering physical distancing measures to slow the spread of COVID-19 face a difficult trade-off between closing schools to reduce transmission and new cases, and potential health-care worker absenteeism due to additional childcare needs that could ultimately increase mortality from COVID-19, according to new modelling research published in The Lancet Public Health journal.

Using the latest data from the US Census Bureau's Current Population Survey to measure the childcare needs of health-care workers if schools are shut, researchers estimate that nationwide, at least one in seven medical workers may have to miss work to care for their children aged 3-12 years old, even after taking into account childcare provided by non-working adults and older siblings within the same household.

These additional childcare obligations could compromise the ability of the US healthcare system to respond to COVID-19 if alternative childcare arrangements are not made, researchers say.

However, the authors caution that the true impact of school closures on overall deaths from COVID-19 cannot be precisely predicted because of large uncertainties around estimates of transmission and infectivity, and to what extent a decline in the health-care workforce impacts the survival of patients with COVID-19.

"Closing schools comes with many trade-offs, and can create unintentional child-care shortages that put a strain on the health-care system", says Professor Eli Fenichel from Yale University in the USA who co-led the research. "Health-care workers spending less time providing patient care to look after their own children can directly influence the development of an epidemic and the survival of those patients. Understanding these trade-offs is vital when planning the public health response to COVID-19 because if the survival of infected patients is sufficiently sensitive to declines in the healthcare workforce, then school closures could potentially increase deaths from COVID-19." [1]

Support for mandatory school closures to reduce cases and mortality from COVID-19 comes from experience with influenza, or models that do not include the effect of school closure on the health-care workforce. Few studies have considered the trade-off between case reduction and disease burden and the potential loss of healthcare workers to childcare obligations.

In the study, researchers analysed data on more than 3 million individuals between January 2018 and January 2020 to assess family structure and probable within-household childcare options for health-care workers. They identified those most likely to require additional childcare for children aged 3-12 years old in the event of school closures by type of health-care occupation nationally and across different states, assuming that early childcare for children aged under 2 years remains open. They also modelled potential declines in the health-care workforce during school closures with estimates of case reductions from school closures to identify the point at which more lives are lost from school closures than are saved.

The analyses suggest that around 29% of US health-care workers need to provide care for children aged 3-12 years old. In households without a non-working adult or a sibling aged 13 years or older to provide care, the researchers estimate that 15% of health-care workers will require childcare--equivalent to around 2.3 million children nationwide--if schools close. However, the authors note that they were unable to account for health-care workers finding alternative methods of care for their children such as babysitters or friends.

School closures will be especially challenging for nurse practitioners (22% will need childcare), physician's assistants (21%), diagnostic technicians (19%), and physicians and surgeons (16%), as well as nearly 13% of the nursing and home health aids who are single parents and part of the group helping the elderly with infection control in nursing homes, researchers say.

The US states likely to have the greatest unmet childcare needs include South Dakota (21% of health-care workers will need childcare), Oregon (21%), and Missouri (21%). In contrast, Washington DC (9% health-care workers with unmet childcare needs), New Mexico (10%), and New Jersey (11%) are least likely to have health-care worker shortages if schools close.

Further analysis suggests that if the case fatality fraction (the share of people who die out of all those infected) rises from 2% to more than 2.4% when the health-care workforce declines by 15%, school closures could lead to a greater number of deaths than those they prevent. However, there is substantial variation across the country. For example, in South Dakota estimates suggest that the case fatality rate must not increase by more than 1.7% before school closures stop saving lives and start increasing overall mortality, whereas in Washington DC it is 4.1%--this is due to the low child care obligations in Washington DC relative to South Dakota.

"The US healthcare system appears disproportionately prone to labour shortages from school closures, particularly among those health-care workers providing infection control in nursing homes", says co-lead author Dr Jude Bayham from Colorado State University, USA. "These potential health-care workforce shortages should be a priority when assessing the potential benefits and costs of school closures, and alternative child care arrangements must be part of the school closure plan." [1]

According to Fenichel, "Closing schools and distancing in general is about bending the curve to stay below hospital capacity and reduce COVID-19 mortality, but how we distance in order to bend the curve can also influence the hospital capacity we need to stay below. We need to account for both."

The authors note some important limitations of the study, including that the authors informed their model based on the influenza virus, to which children are particularly vulnerable--however, early data on COVID-19 suggests children may be less vulnerable, so the benefits of school closures may be smaller than expected. On the other hand, the authors note that closing schools earlier in an outbreak could prevent more cases and lead to less health-care workers being infected and thus able to treat more patients. The study did not include mortality from other conditions that might occur if the health-care workforce declined, which should be taken into consideration when deciding about closing schools, the authors say.

A sponge found in Manado Bay, Indonesia, makes a molecule called manzamine A, which stops the growth of cervical cancer cells, according to a recent publication in the Journal of Natural Products submitted by researchers at the Medical University of South Carolina (MUSC) and their collaborators. Collaborators include students and investigators at the University of South Carolina (UofSC), College of Charleston, Gadjah Mada University in Indonesia and the University of Malaya in Malaysia.

The American Cancer Society estimates that there will be 13,800 new diagnoses of cervical cancer and 4,290 deaths in 2020. Though Pap tests and HPV vaccination have decreased the number of cervical cancer deaths, cervical cancer remains the fourth most common cancer in women.

The MUSC-UofSC study examined the anti-growth and cancer cell-killing effects of manzamine A in four different cervical cancer cell lines. Manzamine A stopped cervical cancer cells from growing and caused some cells to die but did not have the same effects on normal noncancerous cells.

"This is a highly exciting new application for a molecule that has earlier shown significant potential for the control of malaria and has good drug-like properties," said Mark T. Hamann, Ph.D., the SmartState Charles and Carol Cooper Endowed Chair in Pharmacy and professor in the Department of Drug Discovery and Biomedical Sciences at MUSC. Hamann also serves as the co-senior author of the report.

"Natural products have led to the development of most of our antibiotics and anti-cancer therapies and many controls for pain," explained Hamann.

The study's other co-senior author, Dev Karan, Ph.D., was formerly an associate professor at UofSC before moving to the Medical College of Wisconsin, where he is an associate professor in the Department of Pathology.

In earlier work, Hamann's group identified sponge-derived compounds effective against melanoma as well as prostate and pancreatic cancers. Manzamine A is also effective against the parasite responsible for malaria, leading to a single-dose cure in rodents. Some analogs of this unique class of drugs are candidates for the control of COVID-19, the disease caused by the new coronavirus.

In the current report, manzamine A reduced expression levels of a protein known to be highly expressed in a number of cancers, including cervical cancer, and to contribute to poorer patient outcomes.

Computer modeling showed that manzamine A shares similar structures with known inhibitors of the protein, yet manzamine A is 10 times more potent in blocking the problematic proteins.

Several patents have been filed on manzamine A, and a startup company is in the works.

Next steps are to establish its clinical relevance, according to Hamann.

"The goal now is to make sure that it works in animals and then try to advance it into clinical applications and further development," said Hamann.

While these molecules can be synthesized in the laboratory, Hamann doesn't think that's the best process.

"Most of the starting materials for lab-based synthesis are derived from petroleum," he explained. "In contrast, sponges in their natural habitat can be successfully farmed, and unlike other forms of aquaculture, clean the environment."

Therefore, production of these molecules from sponges growing in the environment would likely be the best source while providing opportunities for economic development in rural Indonesia.

However, the potential to find new therapeutic uses like this one for natural products hinges on species diversity, according to Hamann.

"The preservation of species diversity is extremely important, as is the diversity of the chemicals they produce and the opportunities for treating cancer that they offer," explained Hamann. "If 50 years of climate change remains unchecked, projections are that we may lose one-third of the global species diversity. So with that will go opportunities like this."

A drug already tested against lung disease could potentially inhibit COVID-19 by reducing the coronavirus load that enters the lungs and other organs. That is according to a study in human cell cultures and organoids by researchers at Karolinska Institutet in Sweden and the University of British Columbia (UBC) in Canada, published in the journal Cell.

The results could be promising for the treatment of COVID-19 patients who are in the early stages of infection, according to the researchers.

"Our study provides new insights into how SARS-CoV-2 infects the cells of the body, including in blood vessels and kidneys," says Ali Mirazimi, adjunct professor at the Department of Laboratory Medicine at Karolinska Institutet and one of the study's corresponding authors. "We hope that our results can contribute to the development of a novel drug treatment that can help patients with COVID-19."

The researchers used tissue samples from a patient with COVID-19 to isolate and cultivate SARS-CoV-2, the virus that causes the disease COVID-19. In cell cultures, they were able to show how the spike protein in SARS-CoV-2 binds to a cell surface receptor called angiotensin converting enzyme 2 (ACE2) in order to enter our cells. It is the same mechanism that the original SARS-virus from 2003 used to bind to our cells, and which has been described by several of the researchers in previous studies.

By adding a genetically modified variant of this protein, called human recombinant soluble angiotensin-converting enzyme 2 (hrsACE2), the researchers wanted to test if the virus could be stopped from infecting the cells.

The result now published shows that hrsACE2 reduced viral growth of SARS-CoV-2 by a factor of 1,000 to 5,000 in cell cultures. The result was dose dependent, meaning it varied depending on the total amount of virus in relation to the total amount of hrsACE2. The authors were also able to verify these data from regular cell cultures in engineered miniature replicas of blood vessels and kidneys, so-called organoids grown from human stem cells.

"We believe adding this enzyme copy, hrsACE2, lures the virus to attach itself to the copy instead of the actual cells," Mirazimi says. "It distracts the virus from infecting the cells to the same degree and should lead to a reduction in the growth of the virus in the lungs and other organs."

The research has so far been limited to cell cultures and engineered miniature organs, but the biotech company Aperion Biologics, which develops the drug APN01 with the active substance, is planning to conduct a clinical pilot study on infected COVID-19 patients in China. The same drug has already been tested against lung disease in a clinical phase II study.

The researchers note that the current study only examined the drug's effect during the initial stages of infection and that further research is needed to determine if it is also effective during later stages of disease development.

ACE2 usually helps lungs and other organs to maintain normal function but when viruses bind to the protein they could damage the cells. This could, according to the researchers, explain why some COVID-19 patients suffer severe lung disease and multi-organ failure.

With the help of the organoids, the researchers were also able to show that the virus can directly infect and multiply itself in blood vessels and kidneys. This provides important information on the development of the disease and the fact that severe cases of COVID-19 present with multi-organ failure and evidence of cardiovascular damage. hrsACE2 also reduced the SARS-CoV-2 infection in these engineered human tissues.

"The virus causing the COVID-19 is a close sibling to the first SARS virus," says Josef Penninger, professor in UBC's faculty of medicine and co-corresponding author of the study. "Our previous work has helped to rapidly identify ACE2 as the entry gate for SARS-CoV-2, which explains a lot about the disease. Now we know that a soluble form of ACE2 that catches the virus away, could indeed be a very rational therapy that specifically targets the gate the virus must take to infect us."

An international team led by University of British Columbia researcher Dr. Josef Penninger has found a trial drug that effectively blocks the cellular door SARS-CoV-2 uses to infect its hosts.

The findings, published today in Cell, hold promise as a treatment capable of stopping early infection of the novel coronavirus that, as of April 2, has affected more than 981,000 people and claimed the lives of 50,000 people worldwide.

The study provides new insights into key aspects of SARS-CoV-2, the virus that causes COVID-19, and its interactions on a cellular level, as well as how the virus can infect blood vessels and kidneys.

"We are hopeful our results have implications for the development of a novel drug for the treatment of this unprecedented pandemic," says Penninger, professor in UBC's faculty of medicine, director of the Life Sciences Institute and the Canada 150 Research Chair in Functional Genetics at UBC.

"This work stems from an amazing collaboration among academic researchers and companies, including Dr. Ryan Conder's gastrointestinal group at STEMCELL Technologies in Vancouver, Nuria Montserrat in Spain, Drs. Haibo Zhang and Art Slutsky from Toronto and especially Ali Mirazimi's infectious biology team in Sweden, who have been working tirelessly day and night for weeks to better understand the pathology of this disease and to provide breakthrough therapeutic options."

ACE2 -- a protein on the surface of the cell membrane -- is now at centre-stage in this outbreak as the key receptor for the spike glycoprotein of SARS-CoV-2. In earlier work, Penninger and colleagues at the University of Toronto and the Institute of Molecular Biology in Vienna first identified ACE2, and found that in living organisms, ACE2 is the key receptor for SARS, the viral respiratory illness recognized as a global threat in 2003. His laboratory also went on to link the protein to both cardiovascular disease and lung failure.

While the COVID-19 outbreak continues to spread around the globe, the absence of a clinically proven antiviral therapy or a treatment specifically targeting the critical SARS-CoV-2 receptor ACE2 on a molecular level has meant an empty arsenal for health care providers struggling to treat severe cases of COVID-19.

"Our new study provides very much needed direct evidence that a drug -- called APN01 (human recombinant soluble angiotensin-converting enzyme 2 - hrsACE2) -- soon to be tested in clinical trials by the European biotech company Apeiron Biologics, is useful as an antiviral therapy for COVID-19," says Dr. Art Slutsky, a scientist at the Keenan Research Centre for Biomedical Science of St. Michael's Hospital and professor at the University of Toronto who is a collaborator on the study.

In cell cultures analyzed in the current study, hrsACE2 inhibited the coronavirus load by a factor of 1,000-5,000. In engineered replicas of human blood vessel and kidneys -- organoids grown from human stem cells -- the researchers demonstrated that the virus can directly infect and duplicate itself in these tissues. This provides important information on the development of the disease and the fact that severe cases of COVID-19 present with multi-organ failure and evidence of cardiovascular damage. Clinical grade hrsACE2 also reduced the SARS-CoV-2 infection in these engineered human tissues.

"Using organoids allows us to test in a very agile way treatments that are already being used for other diseases, or that are close to being validated. In these moments in which time is short, human organoids save the time that we would spend to test a new drug in the human setting," says Núria Montserrat, ICREA professor at the Institute for Bioengineering of Catalonia in Spain.

"The virus causing COVID-19 is a close sibling to the first SARS virus," adds Penninger. "Our previous work has helped to rapidly identify ACE2 as the entry gate for SARS-CoV-2, which explains a lot about the disease. Now we know that a soluble form of ACE2 that catches the virus away, could be indeed a very rational therapy that specifically targets the gate the virus must take to infect us. There is hope for this horrible pandemic."

New York, NY (April 2, 2020)--A new study from Columbia University Irving Medical Center and the Herbert Irving Comprehensive Cancer Center suggests a compound in development for a rare kidney stone disease may have potential against pancreatic cancer. The compound starves tumors of an amino acid, cysteine, which was found to be critical to the survival of pancreatic cancer cells.

The study, conducted in mice with pancreatic cancer, was published online today in the journal Science.

"We're very encouraged by these results," says Kenneth P. Olive, PhD, associate professor of medicine at Columbia University Vagelos College of Physicians and Surgeons, member of the HICCC, and senior author of the study. "Pancreatic cancer is a uniquely lethal disease, with an average survival rate of just six months after diagnosis. We're in desperate need of new treatments."

Most pancreatic tumors ramp up the production of oxidants that can kill many normal cells. Yet, pancreatic tumors thrive under these toxic conditions by importing large amounts of cysteine into their cells. All cells, including pancreatic tumor cells, use cysteine to manufacture molecules that detoxify oxidants.

"Since pancreatic tumors appear to depend on cysteine import for their survival, we hypothesized that it might be possible to slow tumor growth by selectively targeting this amino acid," Olive said.

That strategy of starving the pancreatic cancer cells of cysteine worked. When the gene that controls cysteine import was knocked out in mice with pancreatic cancer closely resembling human tumors, cutting off the cancer's supply of cysteine, the tumors stopped growing and median survival time doubled.

The researchers achieved similar results when the mice were treated with cysteinase--an experimental drug that breaks down cysteine in blood. (Cysteinase is currently being developed by researchers at the University of Texas Southwestern Medical Center for the treatment of cystinuria, a rare genetic disorder in which high levels of cysteine concentrate in the urine, causing kidney and urinary tract stones.)

Human pancreatic cancer cells also appear to be dependent on cysteine, the researchers found. When cysteinase was added to human pancreatic cancer cells in tissue culture, cancer cells died.

Role of Ferroptosis in Pancreatic Cancer

When starved of cysteine, the pancreatic cancers cells are killed by a process called ferroptosis, the researchers also found. Ferroptosis is a form of programmed cell death that results from oxidation damage to cell membranes. Recently discovered by Columbia University researcher Brent Stockwell, professor of biological sciences, a coauthor on the new paper, ferroptosis may also be harnessed against other types of cancer.

Olive's team also worked with a group from the University of Michigan, led by Dr. Costas Lyssiotis, and a group from the Salk Institute, led by Dr. Geoffrey Wahl, to explore the detailed cellular and molecular mechanisms of ferroptosis in pancreatic cancer, in hope that this understanding might lead to additional therapeutic approaches.

Olive's team is now planning to test whether the effect of cysteinase can be magnified by combining it with other treatments, including immunotherapy.

"Though it is not yet known if pancreatic cancers in patients are also susceptible to ferroptosis from cysteine depletion," Olive says, "the clinical development of cysteinase for treatment of the metabolic disorder cystinuria may allow us to test the idea soon."

One of the most exciting aspects of the new study is that cysteine depletion did not appear to harm healthy, normal cells. "You might imagine that all the cells of your body need every amino acid equally, but we knew from prior studies that most normal cells need only very low levels of cysteine," says Olive. "Our whole goal in targeting this difference between normal cells and cancer cells is to develop a treatment that is toxic to cancer and gentle on the rest of the body."