US modelling study estimates impact of school closures for COVID-19 on US health-care workforce and associated mortality

Study estimates 1 in 7 frontline medical workers may miss work to care for their children when US schools are closed to reduce the spread of COVID-19

April 4, 2020

Science Daily/The Lancet

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." 

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." 

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.

 https://www.sciencedaily.com/releases/2020/04/200404155613.htm

Lessons from the Spanish flu: Early restrictions lowered disease, mortality rates

March 30, 2020

Science Daily/Loyola University Health System

A review of published data and analysis on the Spanish flu, found that cities that adopted early and broad isolation and prevention measures had disease and mortality rates that were 30% to 50% lower than other cities.

Large events are cancelled, restaurants and non-essential businesses are closed, and in many states, residents have been asked to shelter in place, all to limit the spread and impact of the COVID-19 virus. But are strict and early isolation and other preventative mandates really effective in minimizing the spread and impact of a disease outbreak?

Stefan E. Pambuccian, MD, a Loyola Medicine cytologist, surgical pathologist and professor and vice chair of the Department of Pathology and Laboratory Medicine at Loyola University Chicago Stritch School of Medicine, has reviewed published data and research from three papers dating back to the 1918-19 Spanish flu pandemic, which infected one-fifth to one-third of the world's population and killed 50 million people.

According to the data and analysis, cities that adopted early, broad isolation and prevention measures -- closing of schools and churches, banning of mass gatherings, mandated mask wearing, case isolation and disinfection/hygiene measures -- had lower disease and mortality rates. These cities included San Francisco, St. Louis, Milwaukee and Kansas City, which collectively had 30% to 50% lower disease and mortality rates than cities that enacted fewer and later restrictions. One analysis showed that these cities also had greater delays in reaching peak mortality, and the duration of these measures correlated with a reduced total mortality burden.

"The stricter the isolation policies, the lower the mortality rate," says Dr. Pambuccian. He studied the Spanish flu, including prevention measures and outcomes, to help develop standards for staffing and safety in the cytology lab, where infectious diseases like the COVID-19 virus are diagnosed and studied at the cellular level. His broader article appeared online this week in the Journal of the American Society of Cytopathology.

Like today, not everyone in 1918 and 1919 thought the strict measures were appropriate or effective at the time.

An estimated 675,000 people died in the U.S. from the Spanish flu, "and there was skepticism that these policies were actually working," says Dr. Pambuccian. "But they obviously did make a difference."

In 1918, the world was still at war "with overcrowded barracks," and much of the U.S. lived with "poverty, poor nutrition, poor hygiene, household/community-level crowding, and a lack of preparation of the population and decision makers due to cognitive inertia and poor medical and insufficient nursing care," says Dr. Pambuccian.

"Although the world is a much different place than it was 100 years ago, the efficacy of the measures instituted during the 1918-19 pandemic gives us hope that the current measures will also limit the impact of the COVID-19 pandemic."

https://www.sciencedaily.com/releases/2020/03/200330110344.htm

'Feeling obligated' can impact relationships during social distancing

March 19, 2020

Science Daily/Michigan State University

In a time where many are practicing "social distancing" from the outside world, people are relying on their immediate social circles more than usual. Does a sense of obligation -- from checking on parents to running an errand for an elderly neighbor -- benefit or harm a relationship? A Michigan State University study found the sweet spot between keeping people together and dooming a relationship.

"We were looking to find whether obligation is all good or all bad," said William Chopik, assistant professor of psychology at MSU and co-author of the study. "When we started, we found that people were responding to types of obligations in different ways. People distinguished between requests that were massive obligations and requests that were simple. There's this point that obligation crosses over and starts to be harmful for relationships."

According to Jeewon Oh, MSU doctoral student and co-author of the study, obligation is sometimes the "glue that holds relationships together," but it often carries negative connotations.

"We found that some obligations were linked with greater depressive symptoms and slower increases in support from friends over time," Oh said. "However, other obligations were linked with both greater support and less strain from family and friends initially."

Chopik and Oh's findings suggest that there's a distinct point at which obligation pushes individuals to the brink of feeling burdened, which can start to harm their relationships.

"The line in our study is when it crosses over and starts to be either a massive financial burden or something that disrupts your day-to-day life," Chopik said. "While engaging in substantive obligation can benefit others and make someone feel helpful, it is still costly to a person's time, energy and money."

Until now, similar research showed inconsistencies in how obligation impacts relationships, which Chopik attributes to the spectrum of obligation. This spectrum ranges from light obligation, like keeping in touch with a friend, to substantive obligation, like lending that friend a considerable amount of money.

"In a way, major obligations violate the norms of friendships," Chopik said. "Interestingly, you don't see that violation as much in relationships with parents or spouses."

Chopik explained that friendships are viewed as low-investment, fun relationships that make people feel good.

"Our longest lasting friendships continue because we enjoy them. But if obligations pile up, it might compromise how close we feel to our friends," Chopik said. "Because friendships are a relationship of choice, people can distance themselves from friends more easily than other types of relationships when faced with burdensome obligations."

Additionally, substantive obligations may create strain in a friendship as we try to encourage our friends to do the same even when they might not be able to do so, Oh said.

"Although we may feel good when we do things for our friends, and our friends are grateful to us, we may start to feel like we are investing too much in that relationship," Oh said.

On the other end of the spectrum, light obligation creates what Chopik calls a "norm of reciprocity."

"Those light obligations make us feel better, make us happier and make our relationships stronger," Chopik said. "There's a sense that 'we're both in this together and that we've both invested something in the relationship.'"

That's why, among the best relationships, low-level acts of obligation don't feel like obligations at all. Small acts of kindness, which strengthen the bonds of our relationships, are done without any fuss or burden.

Still, some types of relationships can make even minor obligations seem daunting. If someone doesn't have a great relationship with a parent, a quick phone call to check in isn't enjoyable, it's an encumbrance.

"Even for things we would expect family members to do, some in the study did them begrudgingly," Chopik said.

Chopik and Oh's findings reveal a spectrum of obligations as diverse as the relationships one has in life.

"It's the little things you do that can really enhance a friendship, but asking too much of a friend can damage your relationship," Chopik said.

https://www.sciencedaily.com/releases/2020/03/200319125132.htm

Standardizing COVID-19 data analysis to aid international research efforts

March 27, 2020

Science Daily/Center for Genomic Regulation

Researchers from the Centre for Genomic Regulation (CRG) have launched a new database to advance the international research efforts studying COVID-19.

The publicly-available, free-to-use resource (https://covid.crg.eu) can be used by researchers from around the world to study how different variations of the virus grow, mutate and make proteins.

"Scientists are working round the clock to understand SARS-CoV-2, the virus causing COVID-19, so that we can find its weak spots and beat it. A huge amount of scientific data is being published around the world," says Eva Novoa, a researcher at the CRG in Barcelona.

"However, some of the technologies we use to study SARS-CoV-2, such as nanopore RNA sequencing, are so new that the results of one paper aren't comparable to another due to the patchwork of different standards and methodologies used. We are taking all this data and analyzing it so that it meets a more universally comparable standard. This will help researchers more quickly and accurately spot the strengths and weaknesses of the coronavirus."

To understand how the coronavirus grows, mutates and replicates, scientists have to sequence the RNA of COVID-19. The RNA sequence reveals crucial information about the proteins the virus makes to invade human cells and replicate, which in turn informs governments on the infectiousness and severity of the pandemic.

Traditional sequencing tools can take a long time to provide results. In recent years, sequencing data in real time has become a reality thanks to the use of nanopore sequencing technologies, revolutionizing genomics research and disease outbreak monitoring. Nanopore sequencing provides scientists and clinicians with immediate access to the DNA and RNA sequence information of any living cell in real-time, enabling a rapid response against the threat of a pandemic.

However, the raw data produced by nanopore sequencing is highly complex. Scientists and clinicians currently lack systematic guidelines for the reproducible analysis of the data, limiting the vast potential of the nascent technology.

To standardize the analysis of publicly available SARS-CoV-2 nanopore sequencing data, researchers at the Centre for Genomic Regulation (CRG) in Barcelona are using MasterOfPores, a computer program developed by the group of Eva Novoa and CRG Bioinformatics Unit. The software was first described last week in Frontiers in Genetics.

"The internet and an increasing culture of open science, data sharing and preprints have transformed the research landscape. Infrastructure that would take months to set up to research an emerging virus can now be done in just a few days owing to novel scientific computing approaches," says Julia Ponomarenko, Head of the Bioinformatics Unit at the CRG.

MasterOfPores can be executed on any Unix-compatible OS on a computer, cluster or cloud without the need of installing any additional software or dependencies, and is freely available in Github. The publicly-available, free-to-use resource has currently analysed 3TB of SARS-CoV-2 nanopore RNA sequencing data. The CRG researchers will continue to update the resource with new data as soon as it becomes available.

https://www.sciencedaily.com/releases/2020/03/200327122315.htm

The genetic quest to understand COVID-19

Unlocking the genetic code of the novel coronavirus will help us prevent other diseases

March 26, 2020

Science Daily/University of Sydney

How the novel coronavirus that causes COVID-19 made the leap from animals to humans is a puzzle that scientists are trying to solve as humanity comes to grip with the deadly pandemic sweeping the globe.

At the frontline of this scientific work is Professor Edward Holmes, an evolutionary virologist who holds a joint position with the School of Life and Environmental Sciences and the School of Medical Sciences at the University of Sydney.

He has been working closely with scientists in China and around the world to unlock the genetic code of SARS-CoV-2, which is the virus that causes COVID-19, to understand its origins and assist in the race other scientists are engaged in to find an effective vaccine.

Their work will also help in the monitoring and prevention of other viruses that could potentially transfer from wildlife into humans, causing what are known as zoonotic diseases.

Already this year, Professor Holmes has co-authored four papers on the novel coronavirus, including two of the earliest descriptions of the virus (published in Nature and The Lancet).

This week he publishes two more.

Brought forward for early publication on Thursday by Nature after peer review, the first paper identifies a similar coronavirus to the one now infecting humans in the Malayan pangolin population of southern China. Professor Holmes, a co-author, is the only non-China based academic on the paper.

Understanding the evolutionary pathway by which this novel coronavirus has transferred to humans will help us not only combat the current pandemic but assist in identifying future threats from other coronaviruses in other species.

This paper is an important part of solving that puzzle.

Professor Holmes said: "The role that pangolins play in the emergence of SARS-CoV-2 (the cause of COVID-19) is still unclear. However, it is striking is that the pangolin viruses contain some genomic regions that are very closely related to the human virus. The most important of these is the receptor binding domain that dictates how the virus is able to attach and infect human cells."

The paper identifies pangolins as possible intermediate hosts for the novel human virus that has emerged. The authors call for these animals and others to be removed from wet markets in order to prevent zoonotic transmission to humans.

Professor Holmes said: "It is clear that wildlife contains many coronaviruses that could potentially emerge in humans in the future. A crucial lesson from this pandemic to help prevent the next one is that humans must reduce their exposure to wildlife, for example by banning 'wet markets' and the trade in wildlife."

Just last week Nature Medicine published research co-authored by Professor Holmes with scientists from Scripps Research Institute in La Jolla California, the University of Edinburgh, Columbia University in New York and Tulane University, New Orleans.

That paper has dispelled the fanciful idea that the novel coronavirus was a manufactured biological agent.

Using comparative analysis of genomic data, the scientists show that SARS-CoV-2 is not a laboratory construct or a purposefully manipulated virus.

Professor Holmes said: "There is simply no evidence that SARS-CoV-2 -- the cause of COVID-19 -- came out of a lab. In reality, this is the sort of natural disease emergence event that researchers in the field like myself have been warning about for many years."

That paper has quickly become the highest ranked academic study of all time as measured by Altmetric, a company that monitors media coverage of research papers.

"The high Altmetric is a strong indication of the remarkable global interest in this topic," Professor Holmes said.

And today, Professor Holmes publishes a commentary in the journal Cell with his colleague Professor Yong-Zhen Zhang from the Shanghai Public Health Clinical Centre and the School of Life Science at Fudan University, Shanghai.

In that article they outline our current knowledge of what the genomic data reveals about the emergence of SARS-CoV-2 virus and discuss the gaps in our knowledge.

This includes taking samples from the Wuhan wet market where it is believed the virus originated. The paper says that "genome sequences of 'environmental samples' -- likely surfaces -- from the market have now been obtained and phylogenetic analysis reveals that they are very closely related to viruses sampled from the earliest Wuhan patients."

However, Professor Holmes and Professor Zhang are quick to point out that as "not all of the early [COVID-19] cases were market associated, it is possible that the emergence story is more complicated than first suspected."

The paper says that the SARS-CoV-2 virus is likely to become the fifth endemic coronavirus in the human population. It concludes that "coronaviruses clearly have the capacity to jump species boundaries and adapt to new hosts, making it straightforward to predict that more will emerge in the future."

How we respond to that will require more research to assist develop public health policy.

They point to policy and other measures to help prevent other coronaviruses becoming a health danger to humans. These include:

- Surveillance of animal coronaviruses in a variety of mammalian species. It is known that bats carry many coronaviruses, we know little about what other species carry these viruses and which has the potential to emerge in humans. 

- Increase action against the illegal wildlife trade of exotic animals

- Removal of mammalian and perhaps avian wildlife from wet markets

https://www.sciencedaily.com/releases/2020/03/200326144357.htm

Modelling study estimates impact of physical distancing measures on progression of COVID-19 epidemic in Wuhan

March 25, 2020

Science Daily/The Lancet

A new study suggests extending school and workplace closures in Wuhan until April, rather than March, would likely delay a second wave of cases until later in the year, relieving pressure on health services.

New modelling research, published in The Lancet Public Health journal, suggests that school and workplace closures in Wuhan, China have reduced the number of COVID-19 cases and substantially delayed the epidemic peak -- giving the health system the time and opportunity to expand and respond.

Using mathematical modelling to simulate the impact of either extending or relaxing current school and workplace closures, researchers estimate that by lifting these control measures in March, a second wave of cases may occur in late August, whereas maintaining these restrictions until April, would likely delay a second peak until October -- relieving pressure on the health services in the intervening months.

However, the authors caution that given the large uncertainties around estimates of the reproduction number (how many people an individual with the virus is likely to infect), and how long a person is infected on average, the true impact of relaxing physical distancing measures on the ongoing COVID-19 epidemic cannot be precisely predicted.

"The unprecedented measures the city of Wuhan has put in place to reduce social contacts in school and the workplace have helped to control the outbreak," says Dr Kiesha Prem from the London School of Hygiene & Tropical Medicine, UK, who led the research. "However, the city now needs to be really careful to avoid prematurely lifting physical distancing measures, because that could lead to an earlier secondary peak in cases. But if they relax the restrictions gradually, this is likely to both delay and flatten the peak."

In December 2019, a novel coronavirus (SARS-CoV-2) emerged in Wuhan, China. In mid-January 2020, schools and workplace were closed as part of the Lunar New Year holidays. These closures were then extended to reduce person-to-person contact and prevent the spread of SARS-CoV-2.

In the study, researchers developed a transmission model to quantify the impact of school and workplace closures using information about how often people of different ages mix with each other in different locations, and to assess their effects on bringing the outbreak under control.

Using the latest data on the spread of COVID-19 in Wuhan and from the rest of China on the number of contacts per day by age group at school and work, they compared the effect of three scenarios: no interventions and no holidays (a hypothetical scenario); no physical distancing measures but school winter school break and Lunar New Year holidays as normal; and intense control measures with school closed and only about 10% of the workforce -- eg, health-care personnel, police, and other essential government staff -- working during the control measures (as started in Wuhan in mid-January). They also modelled the impact of lifting control measures in a staggered way, and during different stages of the outbreak (in March and April).

The analyses suggest that the normal school winter break and Lunar New Year holidays would have had little impact on the progression of the outbreak had schools and workplaces opened as usual. However, putting extreme measures in place to reduce contacts at school and workplaces, could reduce case numbers and the size of the epidemic peak, whilst also delaying the peak. The effects of these distancing measures seem to vary by age, with the greatest reductions in new cases among school children and the elderly, and lowest among working-aged adults. However, once these interventions are relaxed, case numbers are expected to rise.

Further analysis suggests that physical distancing measures are likely to be most effective if the staggered return to work commences at the beginning of April -- potentially reducing the median number of new infections by 24% up to the end of 2020, and delaying a second peak until October.

"Our results won't look exactly the same in another country, because the population structure and the way people mix will be different. But we think one thing probably applies everywhere: physical distancing measures are very useful, and we need to carefully adjust their lifting to avoid subsequent waves of infection when workers and school children return to their normal routine. If those waves come too quickly, that could overwhelm health systems," says co-author Dr Yang Liu from London School of Hygiene & Tropical Medicine.

Despite these important findings, the study has some limitations, including that it assumed no difference in susceptibility between children, and that the extreme distancing measures used in Wuhan may have increased the transmission within households. Finally, the model did not capture individual-level differences in contact rates, which could be important in super-spreading events, particularly early on in an epidemic.

Writing in a linked Comment, Dr Tim Colbourn from University College London, UK (who was not involved in the study) says: "The study by Kiesha Prem and colleagues in The Lancet Public Health is crucial for policy makers everywhere, as it indicates the effects of extending or relaxing physical distancing control measures on the coronavirus disease 2019 (COVID-19) outbreak in Wuhan, China."

He continues: "Given many countries with mounting epidemics now potentially face the first phase of lockdown, safe ways out of the situation must be identified... New COVID-19 country-specific models should incorporate testing, contract tracing, and localised quarantine of suspected cases as the main alternative intervention strategy to distancing lockdown measures, either at the start of the epidemic, if it is very small, or after the relaxation of lockdown conditions, if lockdown had to be imposed, to prevent health-care system overload in an already mounting epidemic." 

https://www.sciencedaily.com/releases/2020/03/200325212154.htm

Wuhan study shows lying face down improves breathing in severe COVID-19

March 24, 2020

Science Daily/American Thoracic Society

In a new study of patients with severe COVID-19 (SARS-CoV-2) hospitalized on ventilators, researchers found that lying face down was better for the lungs. The research letter was published online in the American Thoracic Society's American Journal of Respiratory and Critical Care Medicine.

In "Lung Recruitability in SARS -- CoV-2 Associated Acute Respiratory Distress Syndrome: A Single-Center, Observational Study," Haibo Qiu, MD, Chun Pan, MD, and co-authors report on a retrospective study of the treatment of 12 patients in Wuhan Jinyintan Hospital, China, with severe COVID-19 infection-related acute respiratory distress syndrome (ARDS) who were assisted by mechanical ventilation. Drs. Qiu and Pan were in charge of the treatment of these patients, who were transferred from other treatment centers to Jinyintan Hospital.

A majority of patients admitted to the ICU with confirmed COVID-19 developed ARDS.

The observational study took place during a six-day period the week of Feb. 18, 2020.

"This study is the first description of the behavior of the lungs in patients with severe COVID-19 requiring mechanical ventilation and receiving positive pressure," said Dr. Qiu, professor, Department of Critical Care Medicine, Zhangda Hospital, School of Medicine, Southeast University, Nanjing, China. "It indicates that some patients do not respond well to high positive pressure and respond better to prone positioning in bed (facing downward)."

The clinicians in Wuhan used an index, the Recruitment-to-Inflation ratio, that measures the response of lungs to pressure (lung recruitability). Members of the research team, Lu Chen, PhD, and Laurent Brochard, PhD, HDR, from the University of Toronto, developed this index prior to this study.

The researchers assessed the effect of body positioning. Prone positioning was performed for 24-hour periods in which patients had persistently low levels of blood oxygenation. Oxygen flow, lung volume and airway pressure were measured by devices on patients' ventilators. Other measurements were taken, including the aeration of their airway passages and calculations were done to measure recruitability.

Seven patients received at least one session of prone positioning. Three patients received both prone positioning and ECMO (life support, replacing the function of heart and lungs). Three patients died.

Patients who did not receive prone positioning had poor lung recruitability, while alternating supine (face upward) and prone positioning was associated with increased lung recruitability.

"It is only a small number of patients, but our study shows that many patients did not re-open their lungs under high positive pressure and may be exposed to more harm than benefit in trying to increase the pressure," said Chun Pan, MD, also a professor with Zhongda Hospital, School of Medicine, Southeast University. "By contrast, the lung improves when the patient is in the prone position.

Considering this can be done, it is important for the management of patients with severe COVID-19 requiring mechanical ventilation."

The team consisted of scientists and clinicians affiliated with four Chinese and two Canadian hospitals, medical schools and universities.

https://www.sciencedaily.com/releases/2020/03/200324202056.htm

Anxious about COVID-19? Stress can have lasting impacts on sperm and future offspring

Study identifies biological mechanism by which stress alters sperm and impacts brain development in next generation

March 23, 2020

Science Daily/University of Maryland School of Medicine

Prolonged fear and anxiety brought on by major stressors, like the coronavirus pandemic, can not only take a toll on a person's mental health, but may also have a lasting impact on a man's sperm composition that could affect his future offspring. That is the finding of a provocative new study published in the journal Nature Communications by researchers at the University of Maryland School of Medicine.

The research outlines a biological mechanism for how a father's experience with stress can influence fetal brain development in the womb. The effects of paternal stress can be transferred to offspring through changes in the extracellular vesicles that then interact with maturing sperm. Extracellular vesicles are small membrane-bound particles that transport proteins, lipids, and nucleic acids between cells. They are produced in large amounts in the reproductive tract and play an integral role in sperm maturation.

"There are so many reasons that reducing stress is beneficial especially now when our stress levels are chronically elevated and will remain so for the next few months," said study corresponding author Tracy Bale, PhD, Professor of Pharmacology and Director of the Center for Epigenetic Research in Child Health & Brain Development at the University of Maryland School of Medicine. "Properly managing stress can not only improve mental health and other stress-related ailments, but it can also help reduce the potential lasting impact on the reproductive system that could impact future generations."

She and her colleagues did not specifically study those who were under stress due to the coronavirus pandemic.

To examine a novel biological role for extracellular vesicles in transferring dad's stress to sperm, the researchers examined extracellular vesicles from mice following treatment with the stress hormone corticosterone. After treatment, the extracellular vesicles showed dramatic changes in their overall size as well as their protein and small RNA content.

When sperm were incubated with these previously "stressed" extracellular vesicles prior to fertilizing an egg, the resulting mouse pups showed significant changes in patterns of early brain development, and as adults these mice were also significantly different than controls for how they responded to stress themselves.

To see if similar differences occurred in human sperm, the researchers recruited students from the University of Pennsylvania to donate sperm each month for six months, and complete questionnaires about their perceived stress state in the preceding month. They found that students who had experienced elevated stress in months prior showed significant changes in the small RNA content of their sperm, while those who had no change in stress levels experienced little or no change. These data confirm a very similar pattern found in the mouse study.

"Our study shows that the baby's brain develops differently if the father experienced a chronic period of stress before conception, but we still do not know the implications of these differences," said Dr. Bale. "Could this prolonged higher level of stress raise the risk for mental health issues in future offspring, or could experiencing stress and managing it well help to promote stress resilience? We don't really know at this point, but our data highlight why further studies are necessary."

The research team did find that stress-induced changes in the male reproductive system take place at least a month after the stress is attenuated and life has resumed its normal patterns. "It appears the body's adaptation to stress is to return to a new baseline," Dr. Bale said, "a post-stress physiological state -- termed allostasis."

This research was funded by the National Institute of Mental Health and included co-authors from the Institute for Genome Sciences at the University of Maryland School of Medicine and the Department of Pharmaceutical Science at the University of Maryland School of Pharmacy, as well as the University of Pennsylvania.

"This research represents a critical step in understanding important mechanisms that underlie the field of intergenerational epigenetics," said UMSOM Dean E. Albert Reece, MD, PhD, MBA, who is also the Executive Vice President for Medical Affairs, University of Maryland, and the John Z. and Akiko K. Bowers Distinguished Professor. "Such knowledge is crucial to identify early interventions to improve reproduction and early childhood development down the road."

While the study did not test stress management interventions to determine what effects they might have on attenuating the changes in sperm composition, Dr. Bale, who goes for regular runs to reduce the stress of the current COVID-19 pandemic, contends that any lifestyle habits that are good for the brain are likely good for the reproductive system.

"It is important to realize that social distancing does not have to mean social isolation, especially with modern technologies available to many of us," said Joshua Gordon, Director of the National Institute of Mental Health in his web message about coping with coronavirus. "Connecting with our friends and loved ones, whether by high tech means or through simple phone calls, can help us maintain ties during stressful days ahead and will give us strength to weather this difficult passage."

The Centers for Disease Control and Prevention has tips on "stress and coping" page on their COVID-19 site that recommends the following to "support yourself":

• Take breaks from watching, reading, or listening to news stories, including social media. Hearing about the pandemic repeatedly can be upsetting.

• Take care of your body. Take deep breaths, stretch, or meditate. Try to eat healthy, well-balanced meals, exercise regularly, get plenty of sleep, and avoid alcohol and drugs.

• Make time to unwind. Try to do some other activities you enjoy.

• Connect with others. Talk with people you trust about your concerns and how you are feeling.

https://www.sciencedaily.com/releases/2020/03/200323132410.htm

Median incubation period for COVID-19

March 17, 2020

Science Daily/University of Massachusetts Amherst

A new study calculates that the median incubation period for COVID-19 is just over 5 days and that 97.5% of people who develop symptoms will do so within 11.5 days of infection.

A University of Massachusetts Amherst biostatistician who directs the UMass-based Flu Forecasting Center of Excellence was invited by the White House Coronavirus Task Force to participate Wednesday morning in a coronavirus modeling webinar.

The four-hour, virtual gathering will include 20 of the world's leading infectious disease and pandemic forecasting modelers, from researchers at Harvard, Johns Hopkins and the Centers for Disease Control and Prevention (CDC) in the U.S. to those based at institutions in England, Hong Kong, South Africa and the Netherlands.

According to the White House Coronavirus Task Force coordinator Dr. Charles Vitek, "This webinar is designed to highlight for the Task Force what modeling can tell us regarding the potential effects of mitigation measures on the coronavirus outbreak. The unprecedented speed and impact of the nCoV-19 epidemic requires the best-informed public health decision-making we can produce."

Nicholas Reich, associate professor in the School of Public Health and Health Sciences, heads a flu forecasting collaborative that has produced some of the world's most accurate models in recent years. He and postdoctoral researcher Thomas McAndrew have been conducting weekly surveys of more than 20 infectious disease modeling researchers to assess their collective expert opinion on the trajectory of the COVID-19 outbreak in the U.S. The researchers and modeling experts design, build and interpret models to explain and understand infectious disease dynamics and the associated policy implications in human populations.

Reich is co-author of a new study in the Annals of Internal Medicine that calculates that the median incubation period for COVID-19 is just over five days and that 97.5 percent of people who develop symptoms will do so within 11.5 days of infection. The incubation period refers to the time between exposure to the virus and the appearance of the first symptoms.

The study's lead author is UMass Amherst biostatistics doctoral alumnus Stephen Lauer, a former member of the Reich Lab and current postdoctoral researcher at the Johns Hopkins Bloomberg School of Public Health.

The researchers examined 181 confirmed cases with identifiable exposure and symptom onset windows to estimate the incubation period of COVID-19. They conclude that "the current period of active monitoring recommended by the U.S. Centers for Disease Control and Prevention [14 days] is well supported by the evidence."

https://www.sciencedaily.com/releases/2020/03/200317175438.htm

Individual response to COVID-19 'as important' as government action

March 6, 2020

Science Daily/University of Oxford

How individuals respond to government advice on preventing the spread of COVID-19 will be at least as important, if not more important, than government action, according to a new commentary from researchers at the University of Oxford and Imperial College London in the UK, and Utrecht University and the National Institute for Public Health and the Environment in the Netherlands.

As the UK moves into the "delay" phase of dealing with a possible COVID-19 epidemic, a new commentary, published today in The Lancet, looks at what we know so far about the new virus. The researchers, led by Professor Sir Roy Anderson at Imperial College and Professor Deirdre Hollingsworth at the University of Oxford's Big Data Institute, also suggest what can be done to minimise its spread and its impact.

Professor Hollingsworth said: 'Completely preventing infection and mortality is not possible, so this is about mitigation. Our knowledge and understanding of COVID-19 will change over time, as will the response. High quality data collection and analysis will form an essential part of the control effort. Government communication strategies to keep the public informed will be absolutely vital.'

Vaccine development is already underway, but it is likely to be at least a year before a vaccine can be mass-produced, even assuming all trials are successful. Social distancing is therefore the most important measure, with an individual's behaviour key. This includes early self-isolation and quarantine, seeking remote medical advice and not attending large gatherings or going to crowded places. The virus seems to largely affect older people and those with existing medical conditions, so targeted social distancing may be most effective.

Government actions will be important, including banning large events such as football matches, closing workplaces, schools and institutions where COVID-19 has been identified, and making sure that good diagnostic facilities and remotely accessed advice, like telephone helplines, are widely available. Ensuring the provision of specialist healthcare is also vital. The researchers warn, however, that large-scale measures may only be of limited effect without individual responsibility. All measures, of course, will have an economic impact, and some stricter measures, such as shutting down entire cities, as seen in Wuhan in China, may be less effective in Western democracies.

The aim of these social distancing measures is to "flatten the curve" of the infection, slowing the spread and avoiding a huge peak in the number of new infections.

Flattening the curve can avoid overwhelming health services, keep the impact on the economy to within manageable levels and effectively buy more time to develop and manufacture effective vaccines, treatments and anti-viral drug therapies.

Sir Roy said: 'Government needs to decide on the main objectives of mitigation -- is it minimising morbidity and associated mortality, avoiding an epidemic peak that overwhelms health-care services, keeping the effects on the economy within manageable levels, and flattening the epidemic curve to wait for vaccine development and manufacture on scale and antiviral drug therapies. We point out they cannot achieve all of these -- so choices must be made.'

The researchers highlight that wider support for the health service and health care workers during an epidemic is vital in any case -- during the Ebola epidemic in 2014-15, the death rate from other causes like malaria and childbirth rose sharply due to overwhelmed health services. The number of deaths indirectly caused by Ebola was higher than the number of deaths from Ebola itself.

While much has been made in the media of a number of "superspreading" events, where one infected individual has inadvertently spread the disease to many others, the authors warn that there are superspreading events in every epidemic, and care should be taken not to make too much of these.

Containing the spread of an infectious disease relies on keeping the "reproduction number," R0, the number of people infected by each infected person, below 1, when the pathogen will eventually die out. If R0 rises above 1, i.e. each infected person infects more than one other person, the pathogen will spread. Early data from China suggests that the R0 for COVID-19 could be as high as 2.5, implying that in an uncontained outbreak, 60% of the population could be infected. There are many unknowns in any new virus, however, and with COVID-19, it is not currently clear how long it takes for an infected person to become infectious to others, the duration of infectiousness, the fatality rate, and whether and for how long people are infectious before symptoms appear. It is also not currently clear if there are cases of COVID-19 which are non-symptomatic.

In comparisons with influenza-A (usual seasonal flu) and SARS, it currently seems likely that the epidemic will spread more slowly, but last longer, which has economic implications. Seasonal flu is generally limited by warmer weather, but as it is not known if this will affect COVID-19, the researchers say it will be important to monitor its spread in the Southern Hemisphere. Researchers will continue to collect and analyse data to monitor spread, while ongoing clinical research into treating seriously ill patients is also necessary.

One of the main priorities for researchers and policymakers will be contact tracing, with models suggesting that 70% of people an individual has come into contact with will need to be traced to control the early spread of the disease. The authors say other priorities include shortening the time from symptom onset to isolation, supporting home treatment and diagnosis, and developing strategies to deal with the economic consequences of extended absence from work.

Author Professor Hans Heesterbeek from the Department of Population Health Sciences at the University of Utrecht said: 'Social distancing measures are societally and economically disruptive and a balance has to be sought in how long they can be held in place. The models show that stopping measures after a few months could lead to a new peak later in the year. It would be good to investigate this further.'

https://www.sciencedaily.com/releases/2020/03/200306183353.htm

COVID-19 infections in U.S. may be much higher, new estimates show

But even moderate interventions can help reduce spread, according to study

March 9, 2020

Science Daily/Cedars-Sinai Medical Center

By March 1, 2020, between 1,043 and 9,484 people in the U.S. may have already been infected by the COVID-19 coronavirus, far more than the number that had been publicly reported, according to a new Cedars-Sinai study.

"This suggests that the opportunity window to contain the epidemic of COVID-19 in its early stage is closing," the researchers stated in their paper, which is posted online on a forum where physicians and researchers share information.

The range of possible patients is significantly higher than the number of confirmed and presumptive U.S. cases reported by the federal Centers for Disease Control and Prevention, which stood at 164 as of March 7. Some news media on March 8 were reporting more than 500 total cases. [Editor's note: as of its March 9 update, the CDC put the total number of COVID-19 cases in the U.S. at 423, including both confirmed and presumptive positive cases.]

Cedars-Sinai investigators, who led the study, said they chose "very conservative" methods to estimate the number of coronavirus cases. "This makes our current estimation likely to be an underestimation of the true number of infected individuals in the U.S.," they wrote.

Shlomo Melmed, MB, ChB, executive vice president of Academic Affairs and dean of the medical faculty at Cedars-Sinai, added: "Cedars-Sinai is committed to the global efforts to combat COVID-19 and we believe that early dissemination of this study and the free sharing of the code that underlies the model will help in those efforts."

To arrive at infection estimates for their new study, the researchers modeled only COVID-19 coronavirus cases "imported" directly to the U.S. from the area of Wuhan, China, before Jan. 23, when the Chinese government locked down the city, and they assumed the lockdown stopped all outbound traffic. Potential cases arriving in the U.S. from other parts of China, or other heavily affected countries such as South Korea, Italy or Iran, were not included in the estimate.

The scale of the COVID-19 epidemic in the U.S. was calculated based on: air traffic data between Wuhan and the U.S., totals of confirmed cases publicly released by the CDC and transmission dynamics as estimated from previous research. The study took into account the identification and quarantine of individual domestic cases in the U.S. Among other considerations, the research team assumed the imported cases were no longer spreading infection.

Based on all these assumptions and methods, the investigators estimated the total number of people in the U.S. infected with coronavirus as of March 1 to be between 1,043 and 9,484. The first figure assumed current preventive procedures -- such as quarantines and screening international travelers at airports -- had reduced as much as 25% of the transmissibility in unidentified cases. The second figure assumed no intervention procedures had been undertaken to reduce the transmissibility.

The disparity between the lowest and highest estimates has important implications for controlling the COVID-19 epidemic, said Dermot P. McGovern, MD, PhD, professor of Medicine and Biomedical Sciences at Cedars-Sinai and senior author of the new study.

"Our model suggests that even moderately effective population interventions to reduce transmission can have a profound impact on the scale of the epidemic," McGovern explained. "This finding supports the role of public health interventions in controlling this disease."

But slowing transmission is not an easy task, given that most COVID-19 cases appear to be mild or even asymptomatic, the researchers noted, which can make it difficult to identify infected individuals who may be spreading the virus.

Despite these obstacles, McGovern said, it may still be possible to mitigate the COVID-19 outbreak through steps already suggested by public health experts.These include promoting social distancing and personal hygiene and restricting large-scale gatherings for occasions such as sporting events.

Additionally, performing mass screening for infected individuals, while expensive and logistically challenging, also would potentially help to control the epidemic, said McGovern, who also is director of Translational Research in the Inflammatory Bowel and Immunobiology Research Institute at Cedars-Sinai.

Dalin Li, PhD, the new study's first author and co-corresponding author with McGovern, said the research team is releasing the just-completed study data online before the full study has been accepted in a journal due to the urgency of the COVID-19 outbreak.

"We are making the results public before peer review as it will be important for timely and informed public health decision-making. We are also making the model available to the research community so that others can build upon it." said Li, a research scientist in the Inflammatory Bowel and Immunobiology Research Institute.

The other co-authors of the study were Jonathan Braun, MD, PhD, professor of Medicine, and research operations associate Gregory Botwin from the Inflammatory Bowel and Immunobiology Research Institute at Cedars-Sinai; and Jun Lv, Weihua Cao and Liming Li, all from Peking University Health Science Center in Beijing.

Funding: Research reported in this publication was supported by the National Institutes of Health, the Helmsley Charitable Trust and the F. Widjaja Foundation.

https://www.sciencedaily.com/releases/2020/03/200309110456.htm