H5N1

Yong: COVID-19 changed science forever

Via The Atlantic, Ed Yong has another must-read: COVID-19 Changed Science Forever. Excerpt:

in fall of 2019, exactly zero scientists were studying COVID‑19, because no one knew the disease existed. The coronavirus that causes it, SARS‑CoV‑2, had only recently jumped into humans and had been neither identified nor named. But by the end of March 2020, it had spread to more than 170 countries, sickened more than 750,000 people, and triggered the biggest pivot in the history of modern science. Thousands of researchers dropped whatever intellectual puzzles had previously consumed their curiosity and began working on the pandemic instead. In mere months, science became thoroughly COVID-ized. 

As of this writing, the biomedical library PubMed lists more than 74,000 COVID-related scientific papers—more than twice as many as there are about polio, measles, cholera, dengue, or other diseases that have plagued humanity for centuries. Only 9,700 Ebola-related papers have been published since its discovery in 1976; last year, at least one journal received more COVID‑19 papers than that for consideration. By September, the prestigious New England Journal of Medicine had received 30,000 submissions—16,000 more than in all of 2019. 

“All that difference is COVID‑19,” Eric Rubin, NEJM’s editor in chief, says. Francis Collins, the director of the National Institutes of Health, told me, “The way this has resulted in a shift in scientific priorities has been unprecedented.” 

Much like famous initiatives such as the Manhattan Project and the Apollo program, epidemics focus the energies of large groups of scientists. In the U.S., the influenza pandemic of 1918, the threat of malaria in the tropical battlegrounds of World War II, and the rise of polio in the postwar years all triggered large pivots. Recent epidemics of Ebola and Zika each prompted a temporary burst of funding and publications. But “nothing in history was even close to the level of pivoting that’s happening right now,” Madhukar Pai of McGill University told me.

COVID-19: Constantly surprising SARS-CoV-2 virus found to be heat tolerant, self-healing and very resilient in lab tests

Via the South China Morning Post: Coronavirus: constantly surprising virus found to be heat tolerant, self-healing and very resilient in lab tests. Excerpt:

A research team in Hungary pinched the coronavirus with a fine needle to measure how much force it could take before popping like a balloon. 

It did not. 

The native virion of Sars-CoV-2 – a complete virus particle – was only about 80 nanometres wide, and the needle tip was much smaller than that. The tip drove from the top of the virus to the bottom. The virion was squashed, then immediately rebounded as the needle left. 

The researchers repeated the drill 100 times and the same viral particle remained almost intact. 

It is “surprisingly resilient,” said the team led by Dr Miklos Kellermayer of Semmelweis University in Budapest in a non-peer-reviewed paper posted on biorxiv.org on Thursday. 

The new coronavirus has constantly surprised scientists with its unique structure. For instance, a team from Tsinghua University in Beijing released the most detailed structural reconstruction of the virus in the journal Cell this week with the discovery that the virus could pile a large amount of nucleic acid ribbon that carries genetic data into a very tight envelope without the two becoming entangled. 

However, the virus used in this and other previous studies was frozen to obtain a sharp, stable shot for the camera.  

Kellermayer’s team captured how the virus behaved when it was alive. They put the viral particles on a tray coated with a biological binding material. 

The material could fix the virus in position. Under a laser-emitting atomic force microscope, the scientists played around with the virus with a needle to see how it responded to various stimuli.  

A virus usually becomes vulnerable after leaving the host. But according to some studies, Sars-CoV-2 could stay on some everyday surfaces such as cupboards for several days. 

How it managed to survive environmental disturbances remained unclear. 

The Hungarian team found the viral envelope barely gave any resistance as the needle tip landed on the surface. As the tip went further, the resisting force peaked and then quickly diminished to almost non-existent. 

Their experimental data suggested Sars-Cov-2 could be the most physically elastic virus ever known to humans so far, and repeated deformation did not seem to affect the overall structure and the content inside the virus, either. 

“Its mechanical and self-healing properties may ensure adaptation to a wide range of environmental circumstances,” said Kellermayer and colleagues.

Why the COVID-19 pandemic will be a long, long haul

The Tyee has published my article Why the Pandemic Will Be a Long, Long Haul. Excerpt:

When a new disease emerges — SARS, Ebola, COVID-19 — we very rapidly go from total ignorance to knowing quite a lot. A virus or bacteria comes out of nowhere, people get sick and die, and suddenly we have the bug’s whole genome. Research articles on symptoms and therapies, some of them useful, flood the internet. We feel well armed for a swift response.  

But the more we learn, the more we discover how little we really know.  

Nine months after rumours of a SARS-like pneumonia began to leak out of Wuhan, we now know the SARS-CoV-2 virus seems able to attack almost anywhere in the body, not just the lungs. Some of the attacks are rare but truly horrible, but the worst may be the attacks that don’t stop when the virus is gone.  

Doctors call these attacks “sequelae,” and they can be trivial or lifelong chronic disabilities. After the West African Ebola outbreak, researchers found many survivors suffered from eye inflammation, headache, fatigue, muscle pain, joint pain and memory loss. Ebola virus was still in some men’s semen 40 months after they’d recovered. 

Similarly, some COVID-19 survivors may have lifelong souvenirs of their experience. Such survivors call the problem “long COVID,” and call themselves “long-haulers.”

Cytokine levels in critically ill patients with COVID-19 and other conditions

Via JAMA Network: Cytokine Levels in Critically Ill Patients With COVID-19 and Other Conditions.

An abnormally strong proinflammatory response known as “cytokine storm” may play an important role in the pathophysiology of coronavirus disease 2019 (COVID-19), although cytokine storm remains ill defined. Sinha and colleagues reported that although IL-6 levels are elevated in severe COVID-19, they are lower than levels usually observed in (non–COVID-19) acute respiratory distress syndrome (ARDS). However, this comparison is limited by the use of different assays, which are not well standardized. We compared cytokine levels in critically ill patients with COVID-19 vs levels in patients with other critical illnesses.  

Methods 

All patients in this study were admitted to the intensive care unit (ICU) of Radboud University Medical Center. Plasma concentrations of the proinflammatory cytokines tumor necrosis factor (TNF), IL-6, and IL-8 were determined in consecutive mechanically ventilated patients with COVID-19 with ARDS (partial pressure of oxygen/fraction of inspired oxygen ratio <300; sampled within 48 hours after ICU admission), bacterial septic shock with or without ARDS (sampled within 24 hours after septic shock diagnosis), out-of-hospital cardiac arrest (OHCA; sampled within 24 hours after ICU admission), and multiple traumas (sampled within 24 hours after trauma). 

The patients with sepsis and trauma are part of larger published cohorts, whereas data of 14 patients with OHCA were previously published. Sampling occurred between 2010 and 2020 (Table). Patients with immunological insufficiencies were excluded, defined as chronic/concomitant use of immunosuppressive medication, chemotherapy/radiotherapy in the last year or in the past for (non-)Hodgkin lymphoma, or humoral/cellular deficiencies. 

Cytokines in all cohorts were determined using the same methodology (Milliplex assay, Millipore, on a MAGPIX instrument, Luminex Corporation) by the same technician using the same protocol. Patient characteristics were analyzed using Fisher exact or Kruskal-Wallis tests followed by Dunn post hoc tests. Cytokine data are presented as geometric means (95% CIs) and analyzed using 1-way analysis of variance on log-transformed data followed by Dunnett post hoc tests. 

Data were analyzed using Graphpad Prism version 8.3.0 (Graphpad Software). A 2-sided P < .05 was considered statistically significant. The study was carried out in accordance with the applicable rules concerning the review of research ethics committees and informed consent in the Netherlands. All patients or legal representatives were informed about the study details and allowed to abstain from participation. Patients who consented to participate or their next of kin provided oral consent.  

Results 

There were 46 patients with COVID-19 with ARDS, 51 with septic shock with ARDS, 15 with septic shock without ARDS, 30 with OHCA, and 62 with multiple traumas. There were no significant differences in sex or age between patients with COVID-19 and other patient groups (Table). Patients with COVID-19 had a higher body mass index and prevalence of diabetes than patients with OHCA and trauma. In COVID-19, cardiovascular insufficiency was more common, overall disease severity and leukocyte counts were lower, and lung injury was more severe compared with the other groups. 

Levels of all 3 cytokines were significantly lower in patients with COVID-19 than in patients with septic shock with ARDS; the geometric means were 22 pg/mL (95% CI, 18-27) vs 40 pg/mL (95% CI, 30-55) (P < .01) for TNF; 48 pg/mL (95% CI, 35-66) vs 376 pg/mL (95% CI, 190-744) (P < .001) for IL-6; and 27 pg/mL (95% CI, 23-33) vs 215 pg/mL (95% CI, 133-347) (P < .001) for IL-8 (depicted in the Figure on a log scale). Patients with COVID-19 also displayed significantly lower IL-6 and IL-8 concentrations compared with patients with septic shock without ARDS (Figure). TNF levels in patients with COVID-19 were higher than those in trauma patients, whereas no differences between patients with COVID-19 and OHCA or trauma were present for IL-6. For IL-8, lower concentrations were found in patients with COVID-19 compared with patients with OHCA, while no differences vs the trauma group were observed.  

Discussion 

In this study, critically ill patients with COVID-19 with ARDS had circulating cytokine levels that were lower compared with patients with bacterial sepsis and similar to other critically ill patients. These findings are in line with lower leukocyte counts observed in patients with COVID-19, and are possibly due to lower overall disease severity, despite the presence of severe pulmonary injury. 

The findings of this preliminary analysis suggest COVID-19 may not be characterized by cytokine storm. Whether anticytokine therapies will benefit patients with COVID-19 remains to be determined. Limitations of the study include the small sample sizes, single center involved, and the use of different lots of the same assays without data on lot-to-lot variability.

'Wave of silence' spread around world during COVID-19 pandemic

Via The Guardian: 'Wave of silence' spread around world during coronavirus pandemic. Excerpt:

An unprecedented wave of silence spread around the world in the wake of the coronavirus pandemic, according to researchers who found that vibrations from human activity slumped under national lockdowns.  

Records from seismic stations all over the planet show that high frequency noise caused by industrial plants, traffic and other activities fell as much as 50% as country after country imposed restrictions that grounded planes, emptied roads and brought down the shutters on shops and businesses. 

“You can almost see it as a wave,” said Stephen Hicks, a seismologist who worked on the study at Imperial College, London. “You can see the seismic quietening spread over time, starting in China in late January and then moving on to Italy and beyond in March and April.”  

The scientists analysed traces from a network of 268 seismic sensors in 117 countries and found substantial falls in human-generated noise in 185 of them. The largest drops were seen in busy urban centres such as New York and Singapore, but even remote stations in Germany’s Black Forest and in Rundu, Namibia, fell quieter as human activity was curtailed. 

Around universities and schools in the UK and US, seismic vibrations fell around 20% more than the usual drops seen during holidays. In Barbados, high frequency noise fell by 50% in the weeks before lockdown, as flights dried up and tourists already on the island took the final few flights back home. 

“The quietening is unprecedented, at least as far as we can go back in time with continuous seismic data,” said Thomas Lecocq, first author on the study at the Royal Observatory in Belgium. Digital records of seismic activity exist from the 1970s, but paper records go back further. 

The findings, reported in Science, reveal that vibrations from human activity spread further than scientists expected, reaching seismometers in remote outposts or installed deep underground. “We normally try to put seismometers in quiet places, but this shows that it’s hard to get away from the noise,” said Hicks. 

For researchers, the sudden global quietening presents an unexpected opportunity. As the global population grows and cities swell, more people are at risk from earthquakes, volcanoes and landslides driven by the geology that lies beneath them. Human activity increasingly masks the weak seismic waves that indicate slippage on geological fault lines, or early rumblings in a volcano, but during lockdown, such signals are easier to spot.

COVID-19: Chinese virologist Shi Zhengli publishes new paper on pathogen’s evolution

Via the South China Morning Post: Coronavirus: Chinese virologist Shi Zhengli publishes new paper on pathogen’s evolution.

Shi Zhengli, the Chinese virologist whose work has been the subject of controversial theories about the origin of the novel coronavirus, has published new research into Sars-related pathogens and their animal hosts. 

The head of the centre for emerging infectious diseases at the Wuhan Institute of Virology, Shi said in a paper published on the preprint website Biorxiv.org on Thursday that the Chinese horseshoe bat was the natural host for Sars-related coronaviruses (SARSr-CoVs). 

The research, which has not been peer-reviewed, said that the bat carried many coronaviruses with a high degree of genetic diversity, particularly in the spike protein, which suggested they had evolved over time to aid their transmission. 

“All tested bat SARSr-CoV spike proteins had a higher binding affinity to human ACE2 than to bat ACE2, although they showed a 10-fold lower binding affinity to human ACE2 compared with their SARS-CoV counterpart,” the paper said. 

The ACE2, or angiotensin-converting enzyme 2, is a protein that provides the entry point for the coronavirus to hook onto and infect human cells, while the spike protein is the part of the virus that binds to human cells.  

Earlier laboratory research established a strong genetic link between the coronavirus that causes Covid-19 and one found in a horseshoe bat in southeastern China. 

Shi has been the subject of intense speculation over her work at the institute, which includes the discovery of the natural bat reservoir for the Sars (severe acute respiratory syndrome) pathogen that spread through southern China from 2002 to 2003. 

US President Donald Trump last month said he had a high degree of confidence that the novel coronavirus was linked to the Wuhan Institute of Virology, even after US intelligence said that while it was “not man-made or genetically modified”, it was still examining information to determine if the outbreak began from infected animals or a lab accident. 

Shi had weeks earlier denied the pathogen had somehow leaked from her lab. 

“I guarantee with my life that the virus has nothing to do with my lab,” she said in a WeChat post in February. 

She took to social media again this month to dismiss rumours that she had defected from China with her family and taken hundreds of confidential documents with her. 

“No matter how difficult things are, there will not be a ‘defector’ situation as the rumours have said,” she wrote on WeChat. 

On March 9, she took part in an online discussion about the novel coronavirus. 

“I predicted in 2018 that the chances of cross-species infection of the bat Sars-related coronavirus were quite high,” she said. 

“But I didn’t expect it to happen so soon … in the city where I live.”

Ed Yong: The COVID-19 pandemic doesn’t have to be this confusing

I've been hearing about Ed Yong's great article in The Atlantic: The Pandemic Doesn’t Have to Be This Confusing. Now I've finally read it. It's better than great; it's wise. Here are the last three paragraphs:

The coronavirus not only co-opts our cells, but exploits our cognitive biases. Humans construct stories to wrangle meaning from uncertainty and purpose from chaos. We crave simple narratives, but the pandemic offers none. The facile dichotomy between saving either lives or the economy belies the broad agreement between epidemiologists and economists that the U.S. shouldn’t reopen prematurely. The lionization of health-care workers and grocery-store employees ignores the risks they are being asked to shoulder and the protective equipment they aren’t being given. The rise of small anti-lockdown protests overlooks the fact that most Republicans and Democrats agree that social distancing should continue “for as long as is needed to curb the spread of coronavirus.” 

And the desire to name an antagonist, be it the Chinese Communist Party or Donald Trump, disregards the many aspects of 21st-century life that made the pandemic possible: humanity’s relentless expansion into wild spaces; soaring levels of air travel; chronic underfunding of public health; a just-in-time economy that runs on fragile supply chains; health-care systems that yoke medical care to employment; social networks that rapidly spread misinformation; the devaluation of expertise; the marginalization of the elderly; and centuries of structural racism that impoverished the health of minorities and indigenous groups. It may be easier to believe that the coronavirus was deliberately unleashed than to accept the harsher truth that we built a world that was prone to it, but not ready for it. 

In the classic hero’s journey—the archetypal plot structure of myths and movies—the protagonist reluctantly departs from normal life, enters the unknown, endures successive trials, and eventually returns home, having been transformed. If such a character exists in the coronavirus story, it is not an individual, but the entire modern world. The end of its journey and the nature of its final transformation will arise from our collective imagination and action. And they, like so much else about this moment, are still uncertain.

COVID-19 outbreak may have started in September, say British scientists

Via the South China Morning Post: Coronavirus outbreak may have started in September, say British scientists. Excerpt and then a comment:

The first outbreak of the coronavirus could have happened further south than the central Chinese city of Wuhan as early as September, according to a team of scientists led by the University of Cambridge. 

Researchers investigating the virus’ origin analysed a large number of strains from around the world and calculated that the initial outbreak occurred in a window between September 13 and December 7. 

“The virus may have mutated into its final ‘human-efficient’ form months ago, but stayed inside a bat or other animal or even human for several months without infecting other individuals,” University of Cambridge geneticist Peter Forster said on Thursday. 

“Then, it started infecting and spreading among humans between September 13 and December 7, generating the network we present in [the journal] Proceedings of the National Academy of Sciences [PNAS].”

The team analysed the strains using a phylogenetic network – a mathematical algorithm that can map the global movement of organisms through the mutation of their genes. 

They were still trying to pinpoint the location of patient zero, and were hoping for help from scientists in China, but some early signs were prompting them to look into areas to the south of Wuhan, where coronavirus infections were first reported in December. 

“What we reconstruct in the network is the first significant spread among humans,” Forster said.

The Cambridge team recently made international headlines with a paper about the virus’ evolutionary history. Published in PNAS this month, it found that most of the strains sampled in the United States and Australia were genetically closer to a bat virus than the strains prevalent in patients from across East Asia, and the major European type of the virus was a descendant of the East Asian variant. 

But that paper looked only at the first 160 strains collected after late December. The small sample size limited the researchers’ ability to determine when and where the first outbreak actually started.

In their new study, which has not been peer-reviewed, Forster and his colleagues from several institutes including the Institute of Forensic Genetics in Munster, Germany, expanded the database to include 1,001 high-quality full genome sequences released by scientists across the globe. 

The more strains analysed, the more precisely they could trace the origin of the virus’ global spread. By counting the mutations, they could get closer to working out when the first person was infected by a strain that was closest to bat virus.  

Sars-CoV-2, the virus that causes Covid-19, originated from bats. It has been found to share 96 per cent identical genes with a coronavirus isolated by Chinese scientists from bat droppings in the southwestern province of Yunnan in 2013. 

But there were hundreds of mutations between Sars-CoV-2 and the one in Yunnan, and a coronavirus usually acquires one mutation per month. Some scientists have therefore suspected the virus may have been spreading quietly in host animals and humans for years to gradually evolve to a highly adaptive form that could infect humans. 

The first outbreak could be a recent event involving the last few mutations that completed the leap from harmless strain to deadly pathogen, according to the Cambridge team.

I can't find the medRxiv paper (yet), but I'll keep looking.

COVID-19: Editor of Science blasts Trump

An editorial by H. Holden Thorp, editor of the Science journals: Do us a favor.

“Do me a favor, speed it up, speed it up.” This is what U.S. President Donald Trump told the National Association of Counties Legislative Conference, recounting what he said to pharmaceutical executives about the progress toward a vaccine for severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19). 

Anthony Fauci, the long-time leader of the National Institute of Allergy and Infectious Diseases, has been telling the president repeatedly that developing the vaccine will take at least a year and a half—the same message conveyed by pharmaceutical executives. Apparently, Trump thought that simply repeating his request would change the outcome. 

China has rightfully taken criticism for squelching attempts by scientists to report information during the outbreak. Now, the United States government is doing similar things. Informing Fauci and other government scientists that they must clear all public comments with Vice President Mike Pence is unacceptable. This is not a time for someone who denies evolution, climate change, and the dangers of smoking to shape the public message. 

Thank goodness Fauci, Francis Collins [director of the U.S. National Institutes of Health (NIH)], and their colleagues across federal agencies are willing to soldier on and are gradually getting the message out.  

While scientists are trying to share facts about the epidemic, the administration either blocks those facts or restates them with contradictions. Transmission rates and death rates are not measurements that can be changed with will and an extroverted presentation. 

The administration has repeatedly said—as it did last week—that virus spread in the United States is contained, when it is clear from genomic evidence that community spread is occurring in Washington state and beyond. That kind of distortion and denial is dangerous and almost certainly contributed to the federal government’s sluggish response. After 3 years of debating whether the words of this administration matter, the words are now clearly a matter of life and death.  

And although the steps required to produce a vaccine could possibly be made more efficient, many of them depend on biological and chemical processes that are essential. So the president might just as well have said, “Do me a favor, hurry up that warp drive.” 

I don’t expect politicians to know Maxwell’s equations for electromagnetism or the Diels-Alder chemical reaction (although I can dream). But you can’t insult science when you don’t like it and then suddenly insist on something that science can’t give on demand. 

For the past 4 years, President Trump’s budgets have made deep cuts to science, including cuts to funding for the Centers for Disease Control and Prevention and the NIH. With this administration’s disregard for science of the Environmental Protection Agency and the National Oceanic and Atmospheric Administration, and the stalled naming of a director for the Office of Science and Technology Policy—all to support political goals—the nation has had nearly 4 years of harming and ignoring science.  

Now, the president suddenly needs science. But the centuries spent elucidating fundamental principles that govern the natural world—evolution, gravity, quantum mechanics—involved laying the groundwork for knowing what we can and cannot do. The ways that scientists accumulate and analyze evidence, apply inductive reasoning, and subject findings to scrutiny by peers have been proven over the years to give rise to robust knowledge. These processes are being applied to the COVID-19 crisis through international collaboration at breakneck, unprecedented speed; Science published two new papers earlier this month on SARS-CoV-2, and more are on the way. 

But the same concepts that are used to describe nature are used to create new tools. So, asking for a vaccine and distorting the science at the same time are shockingly dissonant. 

A vaccine has to have a fundamental scientific basis. It has to be manufacturable. It has to be safe. This could take a year and a half—or much longer. Pharmaceutical executives have every incentive to get there quickly— they will be selling the vaccine after all—but thankfully they also know that you can’t break the laws of nature to get there.  

Maybe we should be happy. Three years ago, the president declared his skepticism of vaccines and tried to launch an antivaccine task force. Now he suddenly loves vaccines. 

But do us a favor, Mr. President. If you want something, start treating science and its principles with respect.

Coronavirus may have spread in US for weeks, gene sequencing suggests

Via The New York Times: Coronavirus May Have Spread in U.S. for Weeks, Gene Sequencing Suggests. Excerpt::

Researchers who have examined the genomes of two coronavirus infections in Washington State say the similarities between the cases suggest that the virus may have been spreading in the state for weeks. 

Washington had the United States’ first confirmed case of coronavirus, announced by the Centers for Disease Control and Prevention on Jan. 20. Based on an analysis of the virus’s genetic sequence, another case that surfaced in the state and was announced on Friday probably was descended from that first case. 

The two people live in the same county, but are not known to have had contact with one another, and the second case occurred well after the first would no longer be expected to be contagious. So the genetic findings suggest that the virus has been spreading through other people in the community for close to six weeks, according to one of the scientists who compared the sequences, Trevor Bedford, an associate professor at the Fred Hutchinson Cancer Research Center and the University of Washington. 

Dr. Bedford said it was possible that the two cases could be unrelated, and had been introduced separately into the United States. But he said that was unlikely, however, because in both cases the virus contained a genetic variation that appears to be rare — it was found in only two of the 59 samples whose sequences have been shared from China, where the virus originated.

A scientist who was not involved in the analysis said he agreed with the conclusion that the second case was connected to the original Washington case. “I think he’s right,” said Andrew Rambaut, professor of molecular evolution at the University of Edinburgh, referring to Dr. Bedford. “It’s extremely unlikely that two viruses coming from outside the U.S.A. independently would arrive in the same geographical area and be genetically related unless they were connected.” 

State and local health officials have been hamstrung in their ability to test widely for the coronavirus. Until very recently, the C.D.C. had insisted that only its test could be used, and only on patients who met specific criteria — those who had traveled to China within 14 days of developing symptoms or had contact with a known coronavirus case. 

If the virus has been spreading undetected in Washington since mid-January, that could mean that anywhere from 150 to 1,500 people may have it, with about 300 to 500 people the most likely range, said Dr. Mike Famulare, a principal research scientist at the Institute for Disease Modeling in Bellevue, Wa., who performed the analysis. These people “have either been infected and recovered, or currently are infected now,” he said. 

Many of those people would now be in the early stages of incubating the virus, and might not yet be contagious, Dr. Famulare said.