New study highlights scale and impact of long COVID

University of Arizona Health Sciences

In a new review paper, researchers from the Universities of Arizona, Oxford and Leeds analyzed dozens of previous studies into long COVID to examine the number and range of people affected, the underlying mechanisms of disease, the many symptoms that patients develop, and current and future treatments.

Long COVID, also known as Post-COVID-19 condition, is generally defined as symptoms persisting for three months or more after acute COVID-19. The condition can affect and damage many organ systems, leading to severe and long-term impaired function and a broad range of symptoms, including fatigue, cognitive impairment – often referred to as ‘brain fog’ –  breathlessness and pain.

Long COVID can affect almost anyone, including all age groups and children. It is more prevalent in females and those of lower socioeconomic status, and the reasons for such differences are under study. The researchers found that while some people gradually get better from long COVID, in others the condition can persist for years. Many people who developed long COVID before the advent of vaccines are still unwell.

“Long COVID is a devastating disease with a profound human toll and socioeconomic impact,” said Janko Nikolich, MD, PhD, senior author of the paper, director of the Aegis Consortium at the U of A Health Sciences, professor and head of the Department of Immunobiology at the U of A College of Medicine – Tucson, and BIO5 Institute member. “By studying it in detail, we hope to both understand the mechanisms and to find targets for therapy against this, but potentially also other infection-associated complex chronic conditions such as myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia.”

If a person has been fully vaccinated and is up to date with their boosters, their risk of long COVID is much lower. However, 3%-5% of people worldwide still develop long COVID after an acute COVID-19 infection. According to the Centers for Disease Control and Prevention, long COVID affects an estimated 4%-10% of the U.S. adult population and 1 in 10 adults who had COVID develop long COVID.

The review study also found that a wide range of biological mechanisms are involved, including persistence of the original virus in the body, disruption of the normal immune response, and microscopic blood clotting, even in some people who had only mild initial infections.

There are no proven treatments for long COVID yet, and current management of the condition focuses on ways to relieve symptoms or provide rehabilitation. Researchers say there is a dire need to develop and test biomarkers such as blood tests to diagnose and monitor long COVID and to find therapies that address root causes of the disease.

People can lower their risk of developing long COVID by avoiding infection – wearing a close-fitting mask in crowded indoor spaces, for example – taking antivirals promptly if they do catch COVID-19, avoiding strenuous exercise during such infections, and ensuring they are up to date with COVID vaccines and boosters.

“Long COVID is a dismal condition but there are grounds for cautious optimism,” said Trisha Greenhalgh, lead author of the study and professor at Oxford’s Nuffield Department of Primary Care Health Sciences. “Various mechanism-based treatments are being tested in research trials. If proven effective, these would allow us to target particular subgroups of people with precision therapies. Treatments aside, it is becoming increasingly clear that long COVID places an enormous social and economic burden on individuals, families and society. In particular, we need to find better ways to treat and support the ‘long-haulers’ – people who have been unwell for two years or more and whose lives have often been turned upside down.”

The full paper, “Long COVID: a clinical update,” is published in The Lancet.

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Journal

The Lancet

DOI

10.1016/S0140-6736(24)01136-X 

Method of Research

Data/statistical analysis

Subject of Research

People

Article Title

Long COVID: a clinical update

Article Publication Date

31-Jul-2024

COI Statement

In the past 36 months, TG has held research grants from UK National Institute for Health and Care Research, Balvi, Medical Research Council, Health Data Research UK, and Research Council of Norway. She is a Governing Body Fellow at Green Templeton College and a Visitor at the Pitt Rivers Museum, University of Oxford, and was until 2022, a trustee of the Hilda Martindale Charitable Trust (an educational hardship fund). MS has held research grants from National Institute for Health and Care Research, Research England Policy Support Fund, and the Engineering and Physical Sciences Research Council. He is the Editor-in-Chief of the Oxford Handbook of Rehabilitation Medicine. AP has received consulting fees and grants from the US National Institutes of Health and is Chief Medical Officer of Blooming Magnolia (a 501[c]3 non-profit organisation). JŽN acknowledges institutional support from the endowed Bowman Professorship in Medical Science that he holds at the University of Arizona. He holds or has held research grants from the US National Institutes of Health. He holds US patent number 11119103 (serological assays for SARS-CoV-2). TG and MS were funded by the UK National Institute for Health and Care Research (LOCOMOTION study), and JŽN by the US National Institutes of Health. The funders had no role in any aspect of the writing of this Review. The authors were not precluded from accessing any data in the study (which, being a Review, came from publicly available published papers), and they accept responsibility to submit this Review for publication.

 

Every rose has its thorns … or does it?

Cold Spring Harbor Laboratory

 

image: 

A rose at the New York Botanical Garden; some varieties grow naturally “thornless.” Jack Satterlee, a postdoc in CSHL’s Lippman lab, turned to the Botanical Garden for help procuring rare plant specimens with and without prickles.

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Credit: Jack Satterlee/Cold Spring Harbor Laboratory

According to Greek mythology, red roses first appeared when Aphrodite pricked her foot on a thorn, spilling blood on a white rose. Since then, roses’ thorns have captured the imaginations of countless poets and forlorn lovers.

But they aren’t the only plants with these dangerous protrusions, technically called prickles. Prickles have evolved independently in species across the plant kingdom. Their main function: warding off herbivores. They’re even present in certain eggplant and rice crops. Yet, for years, it’s been unclear how the trait pops up so frequently in such unrelated species.

Now, in a breakthrough discovery, Cold Spring Harbor Laboratory (CSHL) has found that the same ancient gene family is responsible for prickles across many plants, despite millions of years of evolutionary separation.

CSHL postdoc James Satterlee was inspired to investigate prickles upon touring a field where his advisor, Professor & HHMI Investigator Zachary Lippman, grows hundreds of nightshades. Think tomatoes, potatoes, and eggplants.

“I noticed many had very prominent prickles. So, I asked, ‘What do we know about that? What’s going on with this adaptation?’ It turns out we knew almost nothing," recalls Satterlee. 

With scientists in Spain, Satterlee began analyzing eggplants, which led him to a gene family called LONELY GUY (LOG). LOG genes are normally responsible for making a hormone that causes cell division and expansion. Satterlee discovered that certain LOG mutations also eliminate prickles in eggplants. Lippman and Satterlee wondered: Could LOG-related genes be responsible for prickle gains and losses across multiple plants over millions of years?

The team started combing through prior studies and contacting collaborators around the globe. Satterlee and Lippman worked with the New York Botanical Garden to examine specimens with and without prickles. Collaborators at Cornell University used genome editing to eliminate prickles in desert raisins, a foraged berry native to Australia. Another colleague in France suppressed prickles in roses. In total, the team came to associate prickles with LOG-related genes in about 20 species.

Lippman says while this discovery could be used to engineer plants without prickles, it also has big implications for understanding convergent evolution in all life. That is, how completely different species independently develop similar traits. 

“You’re really asking about life in general—evolution of traits. How do they emerge? How are they modified? What are the underlying mechanisms? What can we learn about things we take for granted?” he explains. 

The answer could someday make lesser-known species like desert raisins a new fruit in supermarkets. At the very least, it should make life easier for horticulturalists plucking roses’ pesky thorns.

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atterlee collaborated with Mohammed Bendahmane, research director at France’s INRAE, to suppress prickle growth in roses. Left: a rose plant exposed to virus-induced gene silencing; note the diminished prickles. Right: a control specimen with fully grown prickles. Image: Mohammed Bendahmane/INRAE, CNRS, Université de Lyon, France

Credit

Mohammed Bendahmane/INRAE, CNRS, Université de Lyon, France

Journal

Science

DOI

10.1126/science.ado1663 

Article Title

Convergent evolution of plant prickles by repeated gene co-option over deep time

Article Publication Date

2-Aug-2024

 

Strengthening global regulatory capacity for equitable access to vaccines in public health emergencies

Georgetown University Medical Center

WASHINGTON – Three high-impact steps could be taken by global health leaders to reshape the global regulatory framework and help address the pressing need for equitable access to diagnostics, therapeutics, and vaccines during public health emergencies, say a Georgetown global health law expert and a medical student.

In their “Perspective” published today in the New England Journal of Medicine, Georgetown School of Health professor Sam Halabi, JD, and George O’Hara, a Georgetown medical student and David E. Rogers Student Fellow, say these reforms aim to enhance the capacity of national regulatory bodies, particularly in low- and middle-income countries to ensure timely and safe access to essential medical products.
The U.S. Food and Drug Administration (FDA) and a select group of national regulatory authorities currently dominate the approval process for medical products. However, this concentration of regulatory capacity in high-income countries has led to bottlenecks and delays in the distribution of critical medical supplies during emergencies, as seen during the COVID-19 pandemic.

A recent analysis highlights that few national regulatory bodies, primarily in high-income countries, meet the World Health Organization's (WHO) stringent criteria for being "highly performing." Approximately three-quarters of WHO member states lack the regulatory maturity to assure their populations of the quality of medical products, including vaccines.

To address these weaknesses, Halabi, who directs the Center for Transformational Health Law at the O'Neill Institute for National and Global Health Law, and O’Hara propose three key measures for the WHO and global health leaders:

1. Expand Regulatory Coordination and Planning: The WHO should actively engage in focused planning with national regulatory authorities that have achieved advanced maturity levels. This includes integrating regulators from countries like Korea, Saudi Arabia, and Singapore into a regional coordination initiative for dossier review and approval during emergencies.
2. Leverage Regional and Multilateral Development Banks: Development banks should agree to extend loans for procuring medical products approved by WHO-listed authorities with a given certification. This would alleviate the bottlenecks and access issues exacerbated by the dependence on WHO's Emergency Use Listing designation during the COVID-19 pandemic.
3. Promote Regulatory Flexibility in Pandemic Agreements: As negotiators finalize a global pandemic agreement, provisions should focus on a coordinated and multilateral approach to leveraging emerging regulatory capacity. By decentralizing regulatory review and expanding the approval process to include authorities from countries with stronger regulatory systems, LMICs can secure vaccine doses earlier in future pandemic responses.

“Together, these steps can drive more cohesive responses to future public health emergencies,” write Halabi and O’Hara.

The WHO has already initiated steps to reduce reliance on the European Medicines Agency and the FDA by creating a new framework of WHO-listed authorities to replace the stringent regulatory authority designation. However, the authors stress the need for additional efforts to ensure greater national control over vaccine supply and reduce dependence on global entities like COVAX.

“Expansion of regulatory pathways would prioritize public health by enabling diagnostics, therapeutics, and vaccines to reach populations sooner,” they write. “By taking incremental but high-impact steps based on the WHO’s classifications of regulatory systems, global health leaders can mount a more equitable and rapid response.”

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O’Hara’s work was supported by a David E. Rogers Student Fellowship Award.

 

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Journal

New England Journal of Medicine

Method of Research

Commentary/editorial

Subject of Research

Not applicable

Article Title

Preparing for the Next Pandemic — Expanding and Coordinating Global Regulatory Capacity

Article Publication Date

3-Aug-2024

York researchers make breakthrough in bid to develop vaccines and drugs for neglected tropical disease

Scientists have developed a new, safe and effective way to infect volunteers with the parasite that causes leishmaniasis and measure the body’s immune response, bringing a vaccine for the neglected tropical disease a step closer.

University of York

Scientists have developed a new, safe and effective way to infect volunteers with the parasite that causes leishmaniasis and measure the body’s immune response, bringing a vaccine for the neglected tropical disease a step closer.  

The breakthrough, by a team from the University of York and Hull York Medical School, is described in the journal Nature Medicine and lays the foundations for vaccine development and for testing new preventative measures.

Controlled human infection studies, where volunteers are exposed to small amounts of the microbes that cause disease, play a vital role in allowing scientists to provide evidence of the safety and efficacy of new vaccines, but their use in the fight against neglected tropical diseases has been limited. 

Leishmaniasis is caused by infection with microscopic Leishmania parasites that are transmitted into the skin during the bite of an infected sand fly. 

The disease affects over one million people every year, the majority developing a slow to heal ulcer at the site of the infection. Though the ulcer eventually heals, the scar has a significant impact on quality of life, especially for women and children and when the infection is on the face. 

No vaccines or drugs are currently available to prevent people from becoming infected with leishmaniasis, in part due to the difficulties and costs associated with conducting clinical trials in the countries where these diseases are most common. 

Lead investigator, Professor Paul Kaye from the Hull York Medical School at the University of York, said: “This is a landmark study that now provides a new approach to test vaccines and preventative measures for leishmaniasis in a rapid and cost-effective way. It also allows us to learn more about how our immune system fights the infection. Thanks to the generosity of the volunteers that took part in our study, we are now well-positioned to bring new hope to those that are affected by this disease.”

Clinical lead for the study, Professor Alison Layton from the Medical School’s Centre for Skin Research, said: “Research on skin diseases that affect people in the UK and in developing countries is a priority at the Medical School. This study, which demonstrates that this infection model is safe and well tolerated by participants, exemplifies our global approach to skin health and has the potential to impact the lives of many millions worldwide.”

The study, which builds on significant achievements by the University of York and its international partners, involved 14 volunteers recruited from around York. 

The volunteers were exposed to sand flies infected with a parasite species that causes one of the mildest forms of leishmaniasis. The researchers followed the development of the lesion at the site of the sand fly bite to evaluate the progress of the infection and then terminated the infection by biopsy of the skin. The scientists then studied the biopsy to examine the immune responses at the site of infection.  

This major new approach uses natural transmission by sand fly to initiate infection and state of the art technologies, allowing the researchers to track the infection and the body’s immune response in real-time. 

The model will accelerate efforts to test new vaccines and understand how immunity to infection arises, the researchers say.

The researchers now hope to use their model to design clinical trials to test a vaccine developed at Hull York Medical School, along with other candidate vaccines available in the future. Controlled human infection models have already been used to support the development of vaccines for cholera, malaria, influenza, dengue fever and most recently COVID-19. 

Parkash et al, Safety and reactogenicity of a controlled human infection model of sand fly-transmitted cutaneous leishmaniasis is published in the journal Nature Medicine. 

The research was a collaboration between the Hull York Medical School, York and Scarborough Teaching Hospitals NHS Trust,  the Department of Parasitology at Charles University in Prague,  the Center for Geographic Medicine and Tropical Diseases at Chaim Sheba Medical Center, Tel Aviv University and the Kuvin Centre for Study of Tropical & Infectious Diseases, Hebrew University-Hadassah Medical School, Jerusalem.

Funding for the research was through a Developmental Pathways Funding Scheme award from the UK Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement and is also part of the EDCTP2 program supported by the European Union.

 

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Journal

Nature Medicine

DOI

10.1038/s41591-024-03146-9. 

Article Title

Safety and reactogenicity of a controlled human infection model of sand fly-transmitted cutaneous leishmaniasis

Article Publication Date

2-Aug-2024

 

U$A FOR PROFIT HEALTHCARE

Health insurers have required prior authorization for services for decades—but have they treated patients equitably?

New study evaluates racial disparities in prior authorization outcomes by a major national insurer

Peer-Reviewed Publication

Texas A&M University

Prior authorization—the process by which a health insurance company denies or approves coverage for a health care service before the service is performed—became standard practice beginning with Medicare and Medicaid legislation in the 1960s.

Although research has uncovered disparities in prior coverage for cancer patients based on race, little has been known to date on the role of prior authorization in increasing or decreasing these disparities.

To learn more about the issue, Benjamin Ukert, PhD, an assistant professor of health policy and management in the Texas A&M University School of Public Health, and a colleague at Penn State conducted a retrospective study of data provided by a major national commercial insurance provider on 18,041 patients diagnosed with cancer between Jan. 1, 2017, and April 1, 2020.

“Data on provider-insurer prior authorization is difficult to access and analyze, but this research could provide valuable information on equity in the prior authorization process in specialty care for patients, health care provers and plan managers, policy makers and employers.”

For the study, Ukert described the racial and ethnic composition of the data used in terms of prior authorization process outcomes for self-insured and fully insured adults diagnosed with the 13 most common cancers other than basal cell carcinomas, which generally do not require a prior authorization. Subjects had at least two Evaluation and Management office visit claims with a cancer diagnosis or one cancer diagnosis during an emergency department or inpatient stay during the study period.

For prior authorization data, Ukert analyzed the length of days from the cancer diagnosis to the prior authorization, the decision to deny or approve the service, and if the denial resulted from medical necessity

Independent variables were self-reported race or ethnicity provided by employers and electronic medical records and drawn from the sociodemographic data for covered individuals available from the insurer. Racial categories were non-Hispanic White, non-Hispanic Asian, non-Hispanic Black and Hispanic (either Hispanic-White or Hispanic-Black).

For covariates, Ukert used a large set of sociodemographic control variables identified from the medical claims and the American Community Survey. Others included sociodemographic information, including information about health insurance coverage, and length of health plan enrollment prior to the cancer diagnosis. After measuring the extent of any comorbidities for the six months before the cancer diagnosis, Ukert merged the block group characteristics on household income and education level from the five-year 2017 American Community Survey. He then used linear regression models to evaluate whether disparities by race or ethnicity emerged in prior authorization process outcomes.

The sample was 85 percent White, 3 percent Asian, 10 percent Black, and 1 percent Hispanic, 64 percent were female and the average age was 53. The average prior authorization denial rate was 10 percent and the denial rate specifically due to medical necessity was 5 percent. Those who identified as Hispanic had the highest prior authorization denial rate at 12 percent, while those who identified as Black had the lowest prior authorization denial rate at 8 percent.

“In short, we found no racial or ethnic disparities in prior authorization outcomes for individuals identifying as Black and Hispanic, compared to White,” Ukert said. “In addition, Asian patients had higher rates of prior authorization approvals compared to White patients.”

By Ann Kellett, Texas A&M University School of Public Health

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Journal

Health Services Research

DOI

10.1111/1475-6773.14334 

Article Title

Effects of Affordable Care Act on uninsured hospitalization: Evidence from Texas

 

Turkey vultures fly faster to defy thin air

How large turkey vultures remain aloft in thin air

The Company of Biologists

Mountain hikes are invigorating. Crisp air and clear views can refresh the soul, but thin air presents an additional challenge for high-altitude birds. ‘All else being equal, bird wings produce less lift in low density air’, says Jonathan Rader from the University of North Carolina (UNC) at Chapel Hill, USA, making it more difficult to remain aloft. Yet this doesn’t seem to put them off. Bar-headed geese, cranes and bar-tailed godwits have recorded altitude records of 6000 m and more. So how do they manage to take to the air when thin air offers little lift? One possibility was that birds at high altitude simply fly faster, to compensate for the lower air density, but it wasn’t clear whether birds that naturally inhabit a wide range of altitudes, from sea level to the loftiest summits, might fine-tune their flight speed to compensate for thin air. ‘Turkey vultures are common through North America and inhabit an elevation range of more than 3000 m’, says Rader, so he and Ty Hedrick (UNC-Chapel Hill) decided to find out whether turkey vultures (Cathartes aura) residing at different elevations fly at different speeds depending on their altitude. They publish their discovery in Journal of Experimental Biology that turkey vultures fly faster at altitude to compensate for the lack of lift caused by flying in thin air.

First the duo needed to select locations over several thousand meters’ altitude, so they started filming the vultures flying at the local Orange County refuse site (80 m above sea level); ‘Vultures on a landfill… who would have guessed?’, chuckles Rader. Then they relocated to Rader’s home state of Wyoming, visiting Alcova (1600 m) before ending up at the University of Wyoming campus in Laramie (2200 m). At each location, the duo set up three synchronized cameras with a clear view to a tree that was home to a roosting colony of turkey vultures, ready to film the vultures’ flights in 3D as they flew home at the end of the day. ‘Wyoming is a famously windy place and prone to afternoon thunderstorms’, Rader explains, recalling being chased off the roof of the University of Wyoming Biological Sciences Building by storms and the wind blurring movies of the flying birds as it rattled the cameras.

Back in North Carolina, Rader reconstructed 2458 bird flights from the movies, calculating their flight speed before converting to airspeed, which ranged from 8.7 to 13.24m/s. He also calculated the air density at each location, based on local air pressure readings, recording a 27% change from 0.89kg/m3 at Laramie to 1.227 kg/m3 at Chapel Hill. After plotting the air densities at the time of flight against the birds’ airspeeds on a graph, Rader and Hedrick could see that the birds flying at 2200m in Laramie were generally flying ~1m/s faster than the birds in Chapel Hill. Turkey vultures fly faster at higher altitudes to remain aloft. But how do they achieve these higher airspeeds?

Rader returned to the flight movies, looking for the tell-tale up-and-down motion that would indicate when they were flapping. However, when he compared how much each bird was flapping with the different air densities, the high-altitude vultures were flapping no more than the birds nearer to sea level, so they weren’t changing their wingbeats to counteract the effects of low air density. Instead, it is likely that the 2200 m high birds were flying faster simply because there is less drag in thin air to slow them down, allowing the Laramie vultures to fly faster than the Chapel Hill birds to compensate for generating less lift in lower air density.

 

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REFERENCE: Rader, J. A. and Hedrick, T. L. (2024). Turkey vultures tune their airspeed to changing air density. J. Exp. Biol. 227, jeb246828. doi:10.1242/jeb.246828

DOI: 10.1242/jeb.246828

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Journal

Journal of Experimental Biology

DOI

10.1242/jeb.246828 

Method of Research

Experimental study

Subject of Research

Animals

Article Title

Turkey vultures tune their airspeed to changing air density

Article Publication Date

1-Aug-2024

 

Flamingos don’t preen more than other waterbirds

University of Exeter

 

image: 

Caribbean flamingo preening

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Credit: Dr Paul Rose

Despite their famously fancy feathers, flamingos don’t spent more time preening than other waterbirds, new research shows.

Scientists watched five of the world’s six flamingo species to see how they spend their time.

While preening time varied, overall flamingos were roughly average compared to existing studies of other waterbirds.

The researchers also examined time spent standing on one leg – finding that captive flamingos most often do this indoors and in water.

The study was carried out by the University of Exeter and WWT Slimbridge Wetland Centre.

“It is widely believed – even among zookeepers – that flamingos spend more time than other birds preening their feathers,” said Dr Paul Rose, from Exeter’s Centre for Research in Animal Behaviour.

“But this hadn’t been tested until now – and we were surprised to find they are roughly ‘middle of the road’ among waterbirds.

“The waterbirds that spend the most time preening are actually Pelecaniformes such as pelicans, gannets and cormorants – which makes sense, as these birds spend the most time in water, and therefore need to maintain feathers for waterproofing.

“Even so, we expected flamingos to be top of the preening charts, as lush pink feathers are so important in their courtship displays.”

The study also found that captive waterbirds spend more time preening than wild birds.

Like many birds, flamingos stand on one leg to save energy and to allow half of their brain to sleep. By doing so in water, flamingos reduce heat loss (only one foot loses heat to the water, rather than two).

Rachael Kinnaird, who worked on the study as part of an MSc in Animal Behaviour at Exeter, said: “Our study shows the value of observing animals to understand their behaviour.

“In this case, a widely held belief about flamingos preening more than other waterbirds didn’t hold true.”

Commenting on the wider importance of the study, Dr Rose said: “By understanding why flamingos behave in certain ways, we can predict how climate and habitat change might affect them.

“At present, greater flamingos are seeing their range expand due to climate change. Meanwhile, mountain species such as Chilean and Andean flamingos are really suffering.

“Studying captive flamingos can help us understand what their wild counterparts need.

“We hold so many species in zoos around the world – so the opportunities to study them, to learn how and why they have evolved, are huge.”

The paper, published in the journal Applied Animal Behaviour Science, is entitled: “What influences feather care and unipedal resting in flamingos? Adding evidence to clarify behavioural anecdotes.”

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Chilean flamingo preening

hadean flamingo standing on one leg

Credit

Dr Paul Rose

Journal

Applied Animal Behaviour Science

DOI

10.1016/j.applanim.2024.106364 

Subject of Research

Animals

Article Title

What influences feather care and unipedal resting in flamingos? Adding evidence to clarify behavioural anecdotes

Article Publication Date

1-Aug-2024