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Early convalescent plasma use — helpful in avoiding severe COVID — also may lower long COVID risk

Findings from a nationwide, multicenter study led by Johns Hopkins Medicine and the Johns Hopkins Bloomberg School of Public Health suggest that patients…

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Findings from a nationwide, multicenter study led by Johns Hopkins Medicine and the Johns Hopkins Bloomberg School of Public Health suggest that patients with COVID-19 have less chance of developing post-COVID conditions — commonly known as long COVID — if they receive early treatment with plasma from convalescent (recovered) COVID patients that contain antibodies against SARS-CoV-2, the virus that causes COVID-19.

Credit: Will Kirk, Johns Hopkins University

Findings from a nationwide, multicenter study led by Johns Hopkins Medicine and the Johns Hopkins Bloomberg School of Public Health suggest that patients with COVID-19 have less chance of developing post-COVID conditions — commonly known as long COVID — if they receive early treatment with plasma from convalescent (recovered) COVID patients that contain antibodies against SARS-CoV-2, the virus that causes COVID-19.

The new research, first posted online today in mBio, a journal from the American Society for Microbiology, is a follow-up investigation to the 2021 clinical trial that showed convalescent plasma is an effective and safe option as an early outpatient treatment for COVID-19. The latest study looked at the long-term outcomes of a large portion of the participants from the 2021 clinical trial.

“Following our initial study, health care professionals kept SARS-CoV-2 antibody-rich blood plasma available in their blood banks as part of the treatment arsenal against COVID-19 in people who are immunocompromised; and now, our new findings show it also may lower the risk of post-COVID conditions,” says study co-lead author David Sullivan, M.D., professor of molecular microbiology and immunology at the Johns Hopkins Bloomberg School of Public Health with a joint appointment in infectious diseases at the Johns Hopkins University School of Medicine.

The original outpatient early treatment clinical trial was conducted between June 2020 and October 2021. The researchers provided 1,181 randomized participants with one unit each of either polyclonal high-titer convalescent plasma (containing a concentrated mixture of antibodies specific to SARS-CoV-2) or placebo control plasma (with no SARS-CoV-2 antibodies). The participants were 18 and older, and had tested positive for SARS-CoV-2 within eight days prior to transfusion. A successful outcome was defined as not requiring hospitalization within 28 days after plasma transfusion.

The original clinical trial found that 17 participants out of 592 (2.9%) who received the convalescent plasma required hospitalization within 28 days of their transfusion, while 37 out of 589 (6.3%) who received placebo control plasma did. This translated to a relative risk reduction for hospitalization of 54%.

As part of the clinical trial, 882 participants also were evaluated for their levels of 21 different cytokines and chemokines at screening, and at 14 days and 90 days after they received either convalescent plasma or placebo control plasma. Cytokines and chemokines are signaling proteins secreted by cells in response to infection, and as a result, activate specific immune system functions such as inflammation. In turn, excessive or unchecked inflammation is believed to be a key factor in the development of post-COVID conditions.

For the latest study, the researchers used the cytokine and chemokine measurements, along with reports by patients of any post-COVID conditions at the 90-day examination, to determine if there was any association between early convalescent plasma therapy and long COVID symptoms. Statistical analyses were conducted to validate the findings, after adjusting for other factors that could make someone more prone to post-COVID conditions, such as demographics (e.g., age and race), competing diseases (e.g., diabetes) and vaccine status.

At 90 days after receiving either convalescent or control plasma, 590 (66.9%) of the study participants showed no post-COVID conditions, while 292 (33.1%) did. Of the latter group, the most commonly reported symptoms were fatigue and anosmia (loss of smell).

Levels of cytokines and chemokines were elevated at screening for most of the study participants, and decreased more by day 90 in those who had received convalescent plasma,” says study senior author Aaron Tobian, M.D., Ph.D., director of the Transfusion Medicine Division and professor of pathology at the Johns Hopkins University School of Medicine.

Additionally, study participants who had higher-than-normal levels of one particular cytokine, interleukin-6 (IL6), at screening were more likely to be among those with post-COVID symptoms by day 90. IL6 is known to trigger an inflammatory response in humans.

“Our study is among the first to show that elevation of IL6 early after the onset of infection is associated with post-COVID conditions,” says study co-lead author Kelly Gebo, M.D., M.P.H., professor of medicine at the Johns Hopkins University School of Medicine. “While cytokine levels decreased throughout the study population from infection to day 90, they dropped more significantly in those who received convalescent plasma early in the course of their illness. So, it appears that when IL6 levels remain elevated during the COVID-19 recovery phase, it likely contributes to post-COVID conditions.”

Future studies, says Gebo, could examine the impact of anti-IL6 agents combined with other treatments against COVID-19 among outpatients.

Because of the large number of co-authors on this study, their names, financial disclosures and conflict-of-interest statements are not listed here. That information may be found in the published paper.

The study was principally funded by the U.S. Department of Defense’s Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense (DOD JPEO-CBRND), in collaboration with the Defense Health Agency (DHA). Initial support was received from the Bloomberg Philanthropies and the state of Maryland, with additional support coming from National Institute of Allergy and Infectious Diseases grant 3R01AI152078-01S1 and the agency’s Division of Intramural Research, National Center for Advancing Translational Sciences grant U24TR001609, the Mental Wellness Foundation, the Moriah Fund, Octapharma Plasma, the HealthNetwork Foundation and the Shear Family Foundation.

The views expressed are those of the authors and should not be construed to represent the positions of the U.S. Army or the U.S. Department of Defense. The data and opinions presented do not reflect the view of the U.S. government.


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Mathematicians use AI to identify emerging COVID-19 variants

Scientists at The Universities of Manchester and Oxford have developed an AI framework that can identify and track new and concerning COVID-19 variants…

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Scientists at The Universities of Manchester and Oxford have developed an AI framework that can identify and track new and concerning COVID-19 variants and could help with other infections in the future.

Credit: source: https://phil.cdc.gov/Details.aspx?pid=23312

Scientists at The Universities of Manchester and Oxford have developed an AI framework that can identify and track new and concerning COVID-19 variants and could help with other infections in the future.

The framework combines dimension reduction techniques and a new explainable clustering algorithm called CLASSIX, developed by mathematicians at The University of Manchester. This enables the quick identification of groups of viral genomes that might present a risk in the future from huge volumes of data.

The study, presented this week in the journal PNAS, could support traditional methods of tracking viral evolution, such as phylogenetic analysis, which currently require extensive manual curation.

Roberto Cahuantzi, a researcher at The University of Manchester and first and corresponding author of the paper, said: “Since the emergence of COVID-19, we have seen multiple waves of new variants, heightened transmissibility, evasion of immune responses, and increased severity of illness.

“Scientists are now intensifying efforts to pinpoint these worrying new variants, such as alpha, delta and omicron, at the earliest stages of their emergence. If we can find a way to do this quickly and efficiently, it will enable us to be more proactive in our response, such as tailored vaccine development and may even enable us to eliminate the variants before they become established.”

Like many other RNA viruses, COVID-19 has a high mutation rate and short time between generations meaning it evolves extremely rapidly. This means identifying new strains that are likely to be problematic in the future requires considerable effort.

Currently, there are almost 16 million sequences available on the GISAID database (the Global Initiative on Sharing All Influenza Data), which provides access to genomic data of influenza viruses.

Mapping the evolution and history of all COVID-19 genomes from this data is currently done using extremely large amounts of computer and human time.

The described method allows automation of such tasks. The researchers processed 5.7 million high-coverage sequences in only one to two days on a standard modern laptop; this would not be possible for existing methods, putting identification of concerning pathogen strains in the hands of more researchers due to reduced resource needs.

Thomas House, Professor of Mathematical Sciences at The University of Manchester, said: “The unprecedented amount of genetic data generated during the pandemic demands improvements to our methods to analyse it thoroughly. The data is continuing to grow rapidly but without showing a benefit to curating this data, there is a risk that it will be removed or deleted.

“We know that human expert time is limited, so our approach should not replace the work of humans all together but work alongside them to enable the job to be done much quicker and free our experts for other vital developments.”

The proposed method works by breaking down genetic sequences of the COVID-19 virus into smaller “words” (called 3-mers) represented as numbers by counting them. Then, it groups similar sequences together based on their word patterns using machine learning techniques.

Stefan Güttel, Professor of Applied Mathematics at the University of Manchester, said: “The clustering algorithm CLASSIX we developed is much less computationally demanding than traditional methods and is fully explainable, meaning that it provides textual and visual explanations of the computed clusters.”

Roberto Cahuantzi added: “Our analysis serves as a proof of concept, demonstrating the potential use of machine learning methods as an alert tool for the early discovery of emerging major variants without relying on the need to generate phylogenies.

“Whilst phylogenetics remains the ‘gold standard’ for understanding the viral ancestry, these machine learning methods can accommodate several orders of magnitude more sequences than the current phylogenetic methods and at a low computational cost.”


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International

There will soon be one million seats on this popular Amtrak route

“More people are taking the train than ever before,” says Amtrak’s Executive Vice President.

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While the size of the United States makes it hard for it to compete with the inter-city train access available in places like Japan and many European countries, Amtrak trains are a very popular transportation option in certain pockets of the country — so much so that the country’s national railway company is expanding its Northeast Corridor by more than one million seats.

Related: This is what it's like to take a 19-hour train from New York to Chicago

Running from Boston all the way south to Washington, D.C., the route is one of the most popular as it passes through the most densely populated part of the country and serves as a commuter train for those who need to go between East Coast cities such as New York and Philadelphia for business.

Veronika Bondarenko captured this photo of New York’s Moynihan Train Hall. 

Veronika Bondarenko

Amtrak launches new routes, promises travelers ‘additional travel options’

Earlier this month, Amtrak announced that it was adding four additional Northeastern routes to its schedule — two more routes between New York’s Penn Station and Union Station in Washington, D.C. on the weekend, a new early-morning weekday route between New York and Philadelphia’s William H. Gray III 30th Street Station and a weekend route between Philadelphia and Boston’s South Station.

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According to Amtrak, these additions will increase Northeast Corridor’s service by 20% on the weekdays and 10% on the weekends for a total of one million additional seats when counted by how many will ride the corridor over the year.

“More people are taking the train than ever before and we’re proud to offer our customers additional travel options when they ride with us on the Northeast Regional,” Amtrak Executive Vice President and Chief Commercial Officer Eliot Hamlisch said in a statement on the new routes. “The Northeast Regional gets you where you want to go comfortably, conveniently and sustainably as you breeze past traffic on I-95 for a more enjoyable travel experience.”

Here are some of the other Amtrak changes you can expect to see

Amtrak also said that, in the 2023 financial year, the Northeast Corridor had nearly 9.2 million riders — 8% more than it had pre-pandemic and a 29% increase from 2022. The higher demand, particularly during both off-peak hours and the time when many business travelers use to get to work, is pushing Amtrak to invest into this corridor in particular.

To reach more customers, Amtrak has also made several changes to both its routes and pricing system. In the fall of 2023, it introduced a type of new “Night Owl Fare” — if traveling during very late or very early hours, one can go between cities like New York and Philadelphia or Philadelphia and Washington. D.C. for $5 to $15.

As travel on the same routes during peak hours can reach as much as $300, this was a deliberate move to reach those who have the flexibility of time and might have otherwise preferred more affordable methods of transportation such as the bus. After seeing strong uptake, Amtrak added this type of fare to more Boston routes.

The largest distances, such as the ones between Boston and New York or New York and Washington, are available at the lowest rate for $20.

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International

The next pandemic? It’s already here for Earth’s wildlife

Bird flu is decimating species already threatened by climate change and habitat loss.

I am a conservation biologist who studies emerging infectious diseases. When people ask me what I think the next pandemic will be I often say that we are in the midst of one – it’s just afflicting a great many species more than ours.

I am referring to the highly pathogenic strain of avian influenza H5N1 (HPAI H5N1), otherwise known as bird flu, which has killed millions of birds and unknown numbers of mammals, particularly during the past three years.

This is the strain that emerged in domestic geese in China in 1997 and quickly jumped to humans in south-east Asia with a mortality rate of around 40-50%. My research group encountered the virus when it killed a mammal, an endangered Owston’s palm civet, in a captive breeding programme in Cuc Phuong National Park Vietnam in 2005.

How these animals caught bird flu was never confirmed. Their diet is mainly earthworms, so they had not been infected by eating diseased poultry like many captive tigers in the region.

This discovery prompted us to collate all confirmed reports of fatal infection with bird flu to assess just how broad a threat to wildlife this virus might pose.

This is how a newly discovered virus in Chinese poultry came to threaten so much of the world’s biodiversity.

H5N1 originated on a Chinese poultry farm in 1997. ChameleonsEye/Shutterstock

The first signs

Until December 2005, most confirmed infections had been found in a few zoos and rescue centres in Thailand and Cambodia. Our analysis in 2006 showed that nearly half (48%) of all the different groups of birds (known to taxonomists as “orders”) contained a species in which a fatal infection of bird flu had been reported. These 13 orders comprised 84% of all bird species.

We reasoned 20 years ago that the strains of H5N1 circulating were probably highly pathogenic to all bird orders. We also showed that the list of confirmed infected species included those that were globally threatened and that important habitats, such as Vietnam’s Mekong delta, lay close to reported poultry outbreaks.

Mammals known to be susceptible to bird flu during the early 2000s included primates, rodents, pigs and rabbits. Large carnivores such as Bengal tigers and clouded leopards were reported to have been killed, as well as domestic cats.

Our 2006 paper showed the ease with which this virus crossed species barriers and suggested it might one day produce a pandemic-scale threat to global biodiversity.

Unfortunately, our warnings were correct.

A roving sickness

Two decades on, bird flu is killing species from the high Arctic to mainland Antarctica.

In the past couple of years, bird flu has spread rapidly across Europe and infiltrated North and South America, killing millions of poultry and a variety of bird and mammal species. A recent paper found that 26 countries have reported at least 48 mammal species that have died from the virus since 2020, when the latest increase in reported infections started.

Not even the ocean is safe. Since 2020, 13 species of aquatic mammal have succumbed, including American sea lions, porpoises and dolphins, often dying in their thousands in South America. A wide range of scavenging and predatory mammals that live on land are now also confirmed to be susceptible, including mountain lions, lynx, brown, black and polar bears.

The UK alone has lost over 75% of its great skuas and seen a 25% decline in northern gannets. Recent declines in sandwich terns (35%) and common terns (42%) were also largely driven by the virus.

Scientists haven’t managed to completely sequence the virus in all affected species. Research and continuous surveillance could tell us how adaptable it ultimately becomes, and whether it can jump to even more species. We know it can already infect humans – one or more genetic mutations may make it more infectious.

At the crossroads

Between January 1 2003 and December 21 2023, 882 cases of human infection with the H5N1 virus were reported from 23 countries, of which 461 (52%) were fatal.

Of these fatal cases, more than half were in Vietnam, China, Cambodia and Laos. Poultry-to-human infections were first recorded in Cambodia in December 2003. Intermittent cases were reported until 2014, followed by a gap until 2023, yielding 41 deaths from 64 cases. The subtype of H5N1 virus responsible has been detected in poultry in Cambodia since 2014. In the early 2000s, the H5N1 virus circulating had a high human mortality rate, so it is worrying that we are now starting to see people dying after contact with poultry again.

It’s not just H5 subtypes of bird flu that concern humans. The H10N1 virus was originally isolated from wild birds in South Korea, but has also been reported in samples from China and Mongolia.

Recent research found that these particular virus subtypes may be able to jump to humans after they were found to be pathogenic in laboratory mice and ferrets. The first person who was confirmed to be infected with H10N5 died in China on January 27 2024, but this patient was also suffering from seasonal flu (H3N2). They had been exposed to live poultry which also tested positive for H10N5.

Species already threatened with extinction are among those which have died due to bird flu in the past three years. The first deaths from the virus in mainland Antarctica have just been confirmed in skuas, highlighting a looming threat to penguin colonies whose eggs and chicks skuas prey on. Humboldt penguins have already been killed by the virus in Chile.

A colony of king penguins.
Remote penguin colonies are already threatened by climate change. AndreAnita/Shutterstock

How can we stem this tsunami of H5N1 and other avian influenzas? Completely overhaul poultry production on a global scale. Make farms self-sufficient in rearing eggs and chicks instead of exporting them internationally. The trend towards megafarms containing over a million birds must be stopped in its tracks.

To prevent the worst outcomes for this virus, we must revisit its primary source: the incubator of intensive poultry farms.

Diana Bell does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.

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