The Brief

For people suffering from long COVID's often disabling symptoms, including intense fatigue, breathing troubles, cognitive issues and heart palpitations, the list of scientific unknowns may sound defeating. There's still no validated treatment or diagnostic test specifically for the condition, although there are many candidates.

Clinicians who treat long COVID are acutely aware of the unsettled nature of the field. "You do sort of feel like you're out in the wilderness," says Dr. Rasika Karnik, medical director of UChicago Medicine's post-COVID clinic.

Karnik first began seeing long COVID patients in the fall of 2020. There's more information to work with now, she says, but doctors' approach still comes down to treating individual symptoms, rather than the underlying cause of the illness. "It's hard to look a patient in the eyes and say 'we're not quite sure yet' and to keep repeating that," she says.

But researchers are making progress in the field, and they presented their recent findings at one of the first major gatherings dedicated to sharing emerging evidence about the possible root cause of long COVID and implications for treatment.

"I know there's been a lot of frustration that there haven't been faster answers," says Dr. Catherine Blish, a professor of medicine at Stanford University and one of the organizers of the conference, held by the nonprofit Keystone Symposia in Santa Fe, N.M., in late August.

"But in all honesty, we are so much further ahead at this relative point than for any other major disease in my lifetime as an infectious disease specialist," she says.

The meeting underscored that scientists have made headway in developing evidence of a clear biological basis for what patients have been reporting for years.

"I've never doubted it — people are suffering," says Harlan Krumholz, a cardiologist at Yale University who's involved in long COVID research. "But we're now seeing imaging evidence, biopsy evidence, physiologic testing evidence of derangements in people who have long COVID."

Here are some of the new findings and promising lines of research highlighted during the three-day gathering.

Narrowing in on some key suspects behind the disease

If long COVID were a crime scene, authorities would have no shortage of leads.

They've pinpointed a handful of possible reasons why patients suffer from an array of chronic symptoms. The tricky thing is disentangling which mechanisms are bystanders and which are actually doing the damage.

"At this point, we have hints and correlative data," says Blish. "We can say we see this finding in a subset of people, but that doesn't mean it's the cause of their problems."

Take the theory of viral persistence: There's now strong evidence that protein and genetic material from SARS-CoV-2 persist in the blood and tissue of some long COVID patients well after their initial illness. Scientists believe these "viral reservoirs" could be driving many of the problems in long COVID patients, although it isn't yet clear exactly how this is happening — and whether the virus itself is replicating.

Dr. Michael Peluso, an infectious disease specialist at the University of California, San Francisco, told conference attendees that his team is now confident in their data showing pieces of viral antigen in the blood of people anywhere from six months to more than a year after they've had COVID-19.

They compared these blood samples to ones collected years before the pandemic to verify their conclusions. "That's a very, very important finding, showing that this is indeed real," he says.

But the story gets more messy from there because these viral reservoirs may not be the primary culprit.

While they are more likely to find viral persistence in the most symptomatic long COVID patients, not everyone with long COVID has it, Peluso notes, "And then really importantly, we're also seeing this in some people who feel totally fine — and we don't know what that means."

Finding activated T cells where they shouldn't be

Other leads have come from imaging technology that traces the activity of T cells, a type of white blood cell, which are part of the body's main antiviral immune response.

"We saw some very unexpected findings," says Dr. Timothy Henrich, an associate professor of medicine at the University of California, San Francisco.

His lab has found activated T cells in the gut wall, lung tissue, certain lymph nodes, the bone marrow, the spinal cord and the brainstem, long after someone's initial infection.

"You really shouldn't have activated T cells in the spinal cord or the brainstem," he says. "We are seeing evidence of this immune response in areas we don't typically see in the setting of an acute viral infection."

Here too the immunological detective work opens up even more questions: This T cell activity is also present in people who've recovered from an infection and have no long COVID symptoms, although Henrich notes the levels appear to be higher in certain tissues of people with long COVID.

So what does this immune response actually indicate about the underlying cause of the disease?

Henrich says T cell activity could be evidence that the immune system is trying to purge the viral reservoirs, or that the immune response has gone awry, possibly in the form of an autoimmune response, and is "doing damage to people, even if the virus has been cleared or is not replicating in those tissues," he says.

Patients and advocates for people suffering from long COVID and myalgic encephalomyelitis/chronic fatigue syndrome hosted an installation of 300 cots in front of the Washington Monument on the National Mall in Washington, D.C., in May, to represent the millions of people suffering from post-infectious disease.

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Similar questions bedevil researchers pursuing another theory.

Research shows that people with long COVID have high levels of Epstein-Barr antibodies and that an acute COVID infection can trigger reactivation of the virus.

Akiko Iwasaki, a professor of immunobiology at Yale University, says it's well known that this herpesvirus can lead to a "long COVID-like syndrome," but whether or not the reactivation is driving long COVID symptoms — or just an indication of a dysregulated immune system — remains to be seen.

All of those involved in research stress that they don't expect just one answer to long COVID. It's likely that many of these theories about its underlying cause are interrelated. And certain mechanisms may only be causing symptoms in some patients and not others.

Microclots could point the way to treatment

Early in the pandemic, it was recognized that COVID-19 can wreak havoc on the vascular system, in particular causing inflammation and damage to the inner lining of blood vessels, known as endothelial cells.

Resia Pretorius, a medical researcher at Stellenbosch University in South Africa, says the clotting and hyperactivation of platelets in long COVID is essentially a "persistent continuation" of what happens during an acute infection within the blood vessels.

Her research has focused on the role of tiny, harmful blood clots she's seeing in the blood of long COVID patients that appear to have "trapped inflammatory molecules that you might expect inside the blood if you have inflamed [or] damaged endothelial layers."

"It's not unique to long COVID, but long COVID has so much more of these inflammatory molecules in circulation," says Pretorius. "And what makes it so interesting is that the spike protein drives these microclots to form."

As the clots accumulate, they may choke off blood flow, preventing oxygen from reaching tissue.

In Santa Fe, Pretorius shared preliminary data from her team showing that so-called "triple therapy" — a combination of three medications — targeting clotting and platelet hyperactivation could benefit some long COVID patients. The preprint showed that this regime resolved symptoms in the majority of the 91 patients who were followed, although the results are not yet peer-reviewed and the study was not a clinical trial.

The approach is not without risk; many patients reported bruising, some had nosebleeds and one reported a gastrointestinal bleed.

Pretorius says microclots are not necessarily the root cause of long COVID, though.

It could be that viral reservoirs are actually helping trigger this vascular mayhem in the first place. These microclots, if left untreated, could also tie into other problems seen in long COVID patients, perhaps leading some to develop autoimmunity, says Pretorius. "That is a problem to solve because we know autoimmune diseases are notorious for being so, so difficult to treat."

Sex differences may play a role in long COVID risk

In general, males tend to do worse during an acute bout of COVID-19, but studies show that long COVID appears to be more prevalent among females. Yale's Iwasaki says this is also the case for other "post-acute infection syndromes."

This background led Iwasaki's lab to look into sex differences in the immune profiles of long COVID patients, in hopes of finding another path to understanding what could be driving the illness. She says they've found that reactivation of Epstein-Barr virus and the activation of T cells are more prevalent among females, whereas males have different "immune signatures."

"We're already starting to see sex differences in long COVID symptoms, as well as potentially the autoimmunity more associated with female patients," she says. "This insight is critical going forward because now we can separate out long COVID into different clusters. And depending on the driver of the disease, we can start targeting it with proper medicine."

Iwasaki's lab has also zeroed in on the role of hormones.

At the conference, she shared evidence of reduced cortisol levels in long COVID patients and shared a separate, unpublished finding that female long COVID patients tend to have reduced testosterone levels and that males have reduced estradiol levels.

Those who had lower testosterone (compared to the controls who don't have long COVID symptoms) also have higher activation of T cells, whether they're males or females, says Julio Silva, a graduate student in Iwasaki's lab who presented the new findings on testosterone. And this was "associated with higher neurological symptoms and overall higher symptom burden," says Silva.

The impetus to look at testosterone was, in part, because of "anecdotes from trans individuals who were informing us that while on testosterone therapy, their symptoms had improved dramatically," says Silva. While the results are preliminary and need to be replicated, he says they at least raise the question "could hormonal therapy help?"

Taken together, Iwasaki says their data strongly suggest there could be problems in the area of the brain that's responsible for regulating these hormones.

Viral persistence offers one possible target for treating long COVID

In the absence of a clear roadmap for treating long COVID, doctors and patients have taken to trying all kinds of therapies — from antivirals to drugs approved for treating addiction.

"All of this research is so critical to understanding the underlying mechanisms of long COVID," says Lisa McCorkell, co-founder of the advocacy group Patient-Led Research Collaborative. "We need to pair that with focusing on clinical trials. We have enough evidence right now to at least try some things."

In Santa Fe, UCSF's Peluso outlined how his team had just launched a small trial using monoclonal antibodies to target the coronavirus spike protein in long COVID patients — one vehicle for testing whether viral persistence is the underlying cause of at least some patients' symptoms. Meanwhile, Iwasaki and Krumholz, both at Yale, have started a clinical trial testing whether a 15-day course of Paxlovid can help alleviate symptoms.

Stanford's Blish points out that as more clinical trials start up, their success will hinge on being deliberate about which patients should be enrolled, since long COVID is a catch-all term for what may be multiple different illnesses.

"We need to understand in detail who's most likely to benefit from those trials, because if we just take everyone, that trial will fail," she says.

Many other trials are in the works, too, but Dr. Jennifer Curtin says those will inevitably take time to produce evidence that trickles down to patient care.

"It's that tough sort of in-between status right now," says Curtin, co-founder of the telehealth clinic RTHM that treats long COVID and other overlapping conditions like myalgic encephalomyelitis/chronic fatigue syndrome, or ME/CFS for short. "So what do you do for the people who are sick and suffering now until we get that data?"

Curtin, who has lived with ME/CFS herself, says their clinic's approach is to perform intensive workups, draw lots of blood and try to identify which symptoms they can treat.

"Treatment is very much individually tailored," she says. "Right now it's a journey that you take with your patients. You're going through this together. You're both learning on this road and it can be tough."

Always in the backdrop at the Santa Fe gathering was the question of whether there would be enough funding — be it from the U.S. Congress or the pharmaceutical industry — to advance the research agenda toward treatments.

"What we really need here is industry engagement. We need funding for clinical trials. And that, to me, is something that's missing," says McCorkell.

President Trump once insisted he had "nothing to do with Project 2025," the right-wing policy plan that became a key flashpoint during the presidential campaign.

The Democrats tried to turn the 900-page Heritage Foundation-led blueprint to remake the government into a political boogeyman, and succeeded to some degree, but it wasn't enough to win the election.

A year later, many of the policies have been implemented, from cracking down on immigration to dismantling the Department of Education.

"A lot of the policies from Day 1 to the last day and in between that the administration has adopted are right out of Project 2025," said Rob Bonta, the attorney general of California, who has used Project 2025 to prepare legal papers against the administration.

Concerns about the project started to bubble up over the spring of 2024, but really caught fire a few months later when actress Taraji P. Henson singled out Project 2025 while hosting the BET awards.

"Pay attention. It's not a secret. Look it up!" she said, speaking directly into the camera during the show. "They are attacking our most vulnerable citizens. The Project 2025 plan is not a game."

'Ridiculous'

Then-candidate Trump tried to dismiss the hysteria, calling the ideas "ridiculous" — and claiming he did not know who was behind it — even though key people involved in developing the plans served in his first administration.
And when it was clear the firestorm would not go away, Trump went on the attack against those allies who wrote the playbook.

"They're a pain in the a--," said Chris LaCivita, a senior adviser to the Trump campaign, who tore into the organizers of Project 2025 at an event hosted by CNN and Politico during the Republican National Convention in Milwaukee.

"Look, I think that in the perfect world, from their perspective, they would love to drive the issue set, but they don't get to do that," he added.

Yet days after winning, Trump tapped Russell Vought, an architect of Project 2025, to lead the Office of Management and Budget — considered the nerve center of the White House. Other contributors followed.
Trump soon unleashed a flurry of orders reshaping the government, many of which were outlined in Project 2025.

"As of today, it will henceforth be the official policy of the United States government that there are only two genders, male and female," he said during his inaugural address.

Trump ended diversity, equity and inclusion programs. He launched massive immigration enforcement and took the first steps to overhaul the federal workforce.

Bonta, the attorney general of California, said Project 2025 defined Trump's first year back in office. The country's 23 Democratic attorneys general studied Project 2025, consulted with each other and, he said, prepared a response for every potential action should it be taken.

"The existence of Project 2025 was the Trump administration telling us exactly what they were going to do and sending it to us in writing," Bonta said.

Bonta has filed or joined lawsuits that have successfully blocked Trump's policies requiring states like California to join his immigration crackdown, freeze of domestic federal funding and layoffs at agencies such as the U.S. Department of Education.

The White House dismissed concerns about Project 2025, calling them irrelevant theories from Beltway insiders.

"President Trump is implementing the agenda he campaigned on and that the American people voted for," said Abigail Jackson, a White House spokeswoman.

Jackson said the president focused on implementing the agenda he campaigned on — lowering gas prices, accelerating economic growth and securing the border.

Fueling controversy

Trump may have actually fueled the controversy by rejecting Project 2025 during the campaign, said Tevi Troy, a presidential historian and former White House aide to George W. Bush.

"I would say that Project 2025 was largely standard conservative fare, but with a bit more of a MAGA flavor than previously."

Troy sees little difference between what the Heritage Foundation did with Project 2025 and what think tanks on the left and right have been doing for years compiling policy proposals for incoming presidents.

He pointed to the personnel and policy ideas of the Hoover Institution that helped shape the George W. Bush administration and the Center for American Progress' influence on the Obama administration.

"If the Trump campaign had leaned into it and said, 'sure, this is an agenda that has been put out as a think tank. This happens all the time. We will look at them in due time when the election is over,' " said Troy. "By criticizing and disavowing Project 2025, it suddenly became more radioactive."

Paul Dans, the director of Project 2025, says he never took the attacks personally, which he chalked up to political calculus. 

He likened watching the president sign executive orders and directives that first came across his desk to being an animator who watches his or her sketchbook come to life on the big screen.

"I believe the proof is in the pudding," said Dans, who also served in the first Trump administration. "Every day that President Trump rolls out another Project 2025 item, it's really an endorsement of our work, myself and the work of thousands of patriots who came together."

Dans is now highlighting that work in a run for the Senate, against Trump-ally, Republican Lindsey Graham.

Trump did eventually embrace Project 2025 during the shutdown fight last fall.

He boasted of meeting with "Russ Vought, he of PROJECT 2025 Fame," while threatening to dismantle federal agencies.

"I can't believe the Radical Left Democrats gave me this unprecedented opportunity," he said.

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President Trump says his controversial push for U.S. control of Greenland comes after he failed to win the Nobel Peace Prize last year, adding he no longer feels obliged to think only of peace.

In a message to Norway's prime minister Jonas Gahr Støre on Sunday night, Trump criticized the European country for not giving him the prize.

"Considering your Country decided not to give me the Nobel Peace Prize for having stopped 8 Wars PLUS, I no longer feel an obligation to think purely of Peace, although it will always be predominant, but can now think about what is good and proper for the United States of America," Trump said in the message.

"The World is not secure unless we have Complete and Total Control of Greenland," Trump added.

The message was reported by PBS NewsHour, and was later confirmed by Norwegian Prime Minister Jonas Gahr Støre in a statement.

Gahr Støre said he received the message on Sunday in response to a text he and Finland's President Alexander Stubb had sent to Trump, in which they had conveyed opposition to Trump's proposed tariff increases on eight European countries over the recent Greenland dispute.

In their message to Trump, according to The New York Times, which received a copy of the exchange from the Norwegian prime minister's office, Gahr Støre and Stubb wrote: "We believe we all should work to take this down and de-escalate — so much is happening around us where we need to stand together."

The pair suggested a joint call.

"Norway's position on Greenland is clear. Greenland is a part of the Kingdom of Denmark, and Norway fully supports the Kingdom of Denmark on this matter," Gahr Støre said. "We also support that NATO in a responsible way is taking steps to strengthen security and stability in the Arctic."

Gahr Støre also pointed out that while President Trump claimed that Norway "decided not to give me the Nobel Peace Prize," the government of Norway is not responsible for the awarding of the Nobel Peace Prize. The Nobel Peace Prize has been awarded by a five member Norwegian Nobel Committee since 1901.

The Danish navy's inspection ship HDMS Vaedderen sails off Nuuk, Greenland, on Sunday.

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The Peace Prize, which was last awarded to Venezuela's opposition leader Maria Corina Machado, is also awarded for the previous year. That means the most recent prize was awarded for 2024, before President Trump commenced his second term of office. Machado gave Trump her prize last week as a symbolic thank you for his recent actions in Venezuela.

In a phone interview with NBC News on Monday, Trump again claimed that the Norwegian government has control over the Nobel Peace Prize. "Norway totally controls it despite what they say," he said. Trump also said he would follow through on his threats to impose further tariffs. When asked whether he would use force to seize Greenland, the president replied: "No comment."

The European Union is set to hold an emergency summit on Thursday, in which attendees will discuss how to respond to the threats. In a statement on social media, the EU's foreign policy chief Kaja Kallas said the bloc had "no interest to pick a fight" but would "hold our ground."

Trump's message to Gahr Støre comes as tensions rise between Europe and the United States over the status of Greenland, an autonomous territory of the Kingdom of Denmark that is strategically important and rich in resources.

On Monday, the World Economic Forum said officials from Denmark would not be attending the meeting in Davos, Switzerland, this week. "We can confirm that the Danish government will not be represented in Davos this week," a spokesperson, Alem Tedeneke, told NPR.

On Sunday, in a collective rebuke to President Trump, the leaders of Denmark, Finland, France, Germany, the Netherlands, Norway, Sweden and the United Kingdom issued a joint statement condemning recent U.S. tariff threats. The eight countries, which are all members of NATO, said that Trump's proposed tariffs "undermine transatlantic relations and risk a dangerous downward spiral."

On Saturday night, President Trump had written on his Truth Social social media platform that he would impose tariffs on imports from the countries, after they had deployed limited military personnel to Greenland to participate in a Danish-led Arctic exercise known as 'Arctic Endurance.'

Trump said America would levy a 10% tariff on goods from the eight countries starting on Feb. 1, which would rise to 25% on June 1, and remain in place "until such time as a Deal is reached for the Complete and Total purchase of Greenland" by the United States.

The open dispute comes after weeks of increasingly assertive U.S. rhetoric regarding Greenland, in which Trump has repeatedly said that Greenland is strategically vital to U.S. national security, citing its location and untapped mineral deposits.

In his text message, Trump questioned Denmark's right to claim Greenland. "Denmark cannot protect that land from Russia or China, and why do they have a 'right of ownership' anyway? There are no written documents, it's only that a boat landed there hundreds of years ago, but we had boats landing there, also," Trump said.

Trump made similar comments last week, saying "the fact that they had a boat land there 500 years ago doesn't mean that they own the land," drawing mirth on social media, with comedians like Jon Stewart noting on The Daily Show "how do you think we got our land?"

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The Martin Luther King Jr. Day holiday weekend is typically busy for the Inner City Youth Orchestra of Los Angeles. On Monday, the orchestra finished its third performance of the weekend at the California African American Museum, which included a musical rendition of the civil rights leader’s seminal “I Have a Dream Speech.”

It was flautist Tionna LeSassier’s first time playing with the orchestra on the federal holiday. Tionna said she began playing flute when she was 12.

“I feel really relieved that I was able to accomplish such a big performance for a really big holiday,” Tionna, who has been playing flute for more than two years, said. “I cannot believe I’m here playing with these amazing musicians.”

The orchestra’s performance, which included pieces like “We Shall Overcome” and the “Afro-American Symphony,” capped off the museum’s annual “King Day” celebration.

The event is held on the federal holiday that honors the legacy of the Baptist preacher whose nonviolent protests and eloquent speeches helped shift American attitudes about race in the 1960s and beyond and lead to landmark Civil Rights legislation.

Earlier in the day, museumgoers listened to and reflected on a recording by the Rev. Martin Luther King Jr. from 1967. Nearly 60 years later, event participants said, the words still feel fresh.

“When machines and computers, profit motives and property rights are considered more important than people, the giant triplets of racism, economic exploitation and militarism are incapable of being conquered,” King said in “The Three Evils of Society,” his keynote address at the National Conference on New Politics in Chicago.

Cameron Shaw, executive director of the Exposition Park museum, told LAist on Monday that the speech has “incredible relevance to the political and social moment and what we’re going through as a people today.”

In a brief discussion after the speech, one attendee spoke about the need to interrogate racism as a systematic ill, not just as one-off acts, and another commented on the importance of standing up to injustice.

Shaw says the museum’s celebration on Martin Luther King Jr. Day has evolved over the last several years, but one of the main throughlines she sees is the continued message of “speaking truth to power.”

“When we celebrate Dr. King today, we celebrate all of the folks past and present who have been brave enough to speak truth to power,” Shaw said. “That is something we truly need.”

Monday’s event also featured a faux stained glass workshop inspired by an exhibition the museum has on display about architect Amaza Lee Meredith.

The museum’s King Day event was one of several celebrating the Civil Rights leader this weekend in L.A.

In South L.A., an annual parade drew thousands of people, with a march concluding in Leimert Park. "It was a wonderful and powerful tribute to Dr. King’s memory to march down MLK Boulevard alongside so many friends and community members in the historic Leimert Park neighborhood," L.A. Mayor Karen Bass said in a statement.

A report of a stabbing marred the end of the event. Bass' statement said city officials were investigating and ensuring people got home safe. She added that "Los Angeles has zero tolerance for this type of violence."

Italian fashion designer Valentino died Monday at his Roman residence. He was 93. His foundation announced his death on Instagram.

Dubbed an "international arbiter of taste" by Vogue, notable women wore his designs at funerals and weddings, as well as on the red carpet. He dressed the likes of Audrey Hepburn and Jackie Onassis, as well as modern stars, including Anna Wintour to Gwyneth Paltrow and Zendaya.

The image of style and lavish living, Valentino's signature features included crisp suits and a "crème brûlée" complexion — due to his fervor for tanning. He was heavily inspired by the stars he saw on the silver screen and had a lifelong fixation with glamour.

"I love a beautiful lady. I love a beautiful dog. I love a beautiful piece of furniture. I love beauty. It's not my fault," he said in The Last Emperor, a 2008 documentary about him.

In the world of haute couture, Valentino embraced sophistication, elegance and traditional femininity through his dresses and trademarked a vibrant red hue. His work embodied romance, luxury and an aristocratic lifestyle.

He was born Valentino Garavani and named after the silent movie star Rudolph Valentino. A self-described spoiled child, the designer acquired a taste for the expensive from a young age; his shoes were custom-made, and the stripe, color and buttons of his blazers were designed to his specifications.

His father, a well-to-do electrical supplier, and his mother, who appreciated the value of a well-made garment, catered to their young son's refined palate and later supported his fashion endeavors, sending him to school and financing his early work.

Growing up in the small town of Voghera, Italy, he learned sewing from his Aunt Rosa in Lombardy. After high school, he moved to Paris to study fashion and take on apprenticeships.

Valentino owed much of his success to his former lover and business partner, Giancarlo Giammetti. The two met in a café on the famed Via Condotti in Rome in 1960, where Valentino had opened his first couture studio.

They founded Valentino Company the same year, and its first ready-to-wear shop opened in Milan in 1969. Together, the pair built a fashion empire over five decades.

They separated romantically when Valentino was 30 but remained business partners and close friends. Valentino knew little about business and accounting before meeting Giammetti; together, they formed two parts of a whole — Giammetti the business mind, and Valentino the creative force.

"Valentino has a perfect vision of how a woman should dress," Giammetti told Charlie Rose in 2009. "He looks for beauty. Women should be more beautiful. His work is to make women more beautiful."

They sold the Valentino company in 1998 for nearly $300 million. It made $1.36 billion in revenue in 2021, according to Reuters.

Even after his retirement in 2008, he couldn't completely leave fashion behind and continued to design dresses for opera productions.

Once the fashion world became more accessible to the public, millions of aspiring fashionistas bought jeans, handbags, shoes, umbrellas and even Lincoln Continentals with his gleaming "V" monogram. By the peak of his career, Valentino's popularity would rival that of the pope's in Rome.

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