New details about potentially deadly Covid inflammation

 A recent USC study provides new information about why SARS-CoV-2, the virus behind the COVID-19 pandemic, may elicit mild symptoms at first but then, for a subset of patients, turn potentially fatal a week or so after infection. The researchers showed that distinct stages of illness correspond with the coronavirus acting differently in two different populations of cells.

The study, published in Nature Cell Biology, may provide a roadmap for addressing cytokine storms and other excessive immune reactions that drive serious COVID-19.

The team found that when SARS-CoV-2 infects its first-phase targets, cells in the lining of the lung, two viral proteins circulate within those cells—one that works to activate the immune system and a second that, paradoxically, blocks that signal, resulting in little or no inflammation.

The team also discovered a second pathway the virus sometimes takes to enter immune cells. This alternative pathway both stunts the virus's ability to reproduce and prevents the production of the second immune signal-braking protein. The first protein is then able to spur rampant inflammation linked to severe symptoms.

"There are two stages that work through different signaling pathways," said Rongfu Wang, Ph.D., a professor of pediatrics and medicine at the Keck School of Medicine of USC. "With the normal pathway, everything goes normally, and the virus replicates. When the immune cells pick up the virus, replication is defective, but it produces a lot of inflammatory signaling molecules called cytokines."

In lab experiments, the Keck School of Medicine scientists identified a drug that quelled inflammation in human immune cells infected with SARS-CoV-2 and reduced symptoms in mice, suggesting that it may be possible to prevent deadly cytokine storms.

Exploring inflammation in COVID-19

Wang and his colleagues began with two related core questions: Why is so little inflammation seen with SARS-CoV-2 in lung cells? And, for the people who don't recover in the first seven to 10 days, why do the symptoms get so much worse? The researchers started by screening all SARS-CoV-2 proteins to see which ones regulate the production of cytokines. Their search yielded two results: a protein called NSP14, which causes inflammation, and another called ORF6, which quells it.

The team followed up on this finding with an exhaustive series of experiments encompassing protein-on-protein reactions, human and animal cell lines, lab models, and tissue and fluid samples from COVID-19 patients.

This is the picture that emerged: When the coronavirus enters a cell of the lung lining through its known entry point, the ACE2 protein on the cell's surface, both NSP14 and ORF6, are produced within the cell. ORF6 acts as a guardian at the membrane surrounding the cell nucleus, effectively silencing the inflammatory signal.

"In this population of lung cells, ORF6 overrides NSP14 so that no cytokines are produced," said Wang, who is also the Endowed Chair in Cell Therapy Research at Children's Hospital Los Angeles. "Even if NSP14 takes action, ORF6 doesn't let it get into the cell nucleus. The door is closed, so it's completely blocked for cytokine production."

Discoveries about the coronavirus's direct effect on the body's natural defenses

While it has been suspected that SARS-CoV-2 affects immune cells, to date, there hasn't been a clear view of how this works. The Keck School research team shed substantial light on this topic.

They mapped out the process for how SARS-CoV-2 interacts with immune cells, which generally lack ACE2 proteins on their surface. Wang and his colleagues found that immune cells take the virus inside through a membrane protein called TLR1, which acts as a sort of virus sensor as part of the body's first line of defense. Instead of the coronavirus's well-known spike protein latching onto these cells, SARS-CoV-2 connects using one of the envelope proteins on its surface.

The nature of this separate entrance prevents the production of ORF6, eliminating the anti-inflammatory signal. The pro-inflammatory protein NSP14 then drives immune cells to send out cytokines that can cause the serious, sometimes fatal symptoms seen in later-stage COVID-19.

In one of the most striking pieces of evidence, human immune cells that were genetically engineered so that they lacked the TLR1 protein showed no signs of inflammatory response when infected with SARS-CoV-2. When two other types of cells that normally lack ACE2 were altered so that they had TLR1 on their surface and then exposed to SARS-CoV-2, the coronavirus was able to gain entry

The study not only expanded our understanding of COVID-19 infection but also offered new clues about how to manage the later, serious stage of the disease. In experiments with mice, treating COVID-19 with a drug that blocks TLR1 led to longer survival and less weight loss compared to an untreated control group.

The findings' larger implications suggest that early-stage COVID-19 is best addressed by attempting to stymie viral replication, while later-stage therapy should focus on taming inflammation.

"Inflammation is a major issue in many diseases," Wang said. "If you can control inflammation, you can control a lot of diseases. Depending on the situation, you either want to activate the immune system when something's wrong or calm it when there's nothing else wrong."

More information: Tianhao Duan et al, ACE2-dependent and -independent SARS-CoV-2 entries dictate viral replication and inflammatory response during infection, Nature Cell Biology (2024). DOI: 10.1038/s41556-024-01388-w

https://medicalxpress.com/news/2024-03-covid-reveals-potentially-deadly-inflammation.html

'Study finds few hospitals promoting potentially predatory medical payment products'

 Fifty million Americans are on a financing plan to pay off medical or dental bills, with one-quarter of those bearing some interest. Increasingly, medical payment products (MPPs)—which include credit cards and loans administered by hospitals, physician practices, or third-party companies—have come under scrutiny by the Consumer Financial Protection Bureau, U.S. Department of Health & Human Services, and the Treasury.

The agencies' concern is that the products may be sidestepping a broad range of patient and consumer protections and inflating medical bills with financing costs—but little research exists on the topic.

Researchers with the USC Schaeffer Center for Health Policy & Economics conducted a cross-sectional study to find out how often hospitals were promoting these payment products. Analyzing a nationally representative sample of hospitals, they found few hospitals promote potentially predatory lending on their websites.

Notably, those hospitals that did promote interest-bearing payment products to their patients were more likely to be non-profits and face higher rates of uncompensated care than hospitals that didn't promote these products.

Their study was published in JAMA Health Forum.

"As we started our research, we thought we might uncover widespread promotion of interest-bearing credit cards and loans on hospital websites, but that's not what we found," said study author Erin Duffy, a research scientist and director of research training at the USC Schaeffer Center.

"Fewer than one in ten hospitals promoted interest-bearing medical payment products, and those promoting them were disproportionately non-profit hospitals with more uncompensated care. Based on our study, we suggest regulators take a close look at the financial conditions of hospitals promoting medical payment products before enacting regulation."

Study highlights include the following:

• Of the 670 hospitals in the study sample, 19% offered any MPP.
• 8.5% of hospitals promoted an interest-bearing MPP. Over half of those explicitly described an interest-free promotional period, and the interest rates among the handful that publicly reported them ranged from 5.25% to 29.99%.
• Hospitals offering interest-bearing MPPs were more often non-profit and had higher total unreimbursed and uncompensated care cost as a percent of operating expenses than other hospitals.
• While interest-bearing MPPs were rare, hospital-administered payment plans were common. They were offered by 87% of the hospitals in the sample.

While anecdotal accounts of hospitals partnering with third parties that offer high-interest credit cards have been in the news, researchers say that doesn't appear to be the typical patient experience with third-party medical financing.

The Schaeffer Center study was already underway when the Consumer Financial Protection Bureau, the U.S. Department of Health & Human Services, and the Treasury published a request for information about MPPs. While more research may be needed, given the small number of interest-bearing MPPs included in the sample, the researchers say they are hopeful that the results will inform regulators.

"Our findings suggest that if regulators pursue policies limiting hospitals' ability to promote medical payment products, that may need to be combined with efforts to stabilize hospital finances," said study co-author Erin Trish, Co-Director of the USC Schaeffer Center and Associate Professor at the USC Mann School of Pharmacy and Pharmaceutical Sciences. "Hospitals may be relying on these products when they lack the resources to offer longer-term, interest-free financing."

More information: Samantha Randall et al, Prevalence of Medical Payment Products Promoted on US Hospitals' Websites, JAMA Health Forum (2024). DOI: 10.1001/jamahealthforum.2024.0231 jamanetwork.com/journals/jama- … 816953

https://medicalxpress.com/news/2024-03-hospitals-potentially-predatory-medical-payment.html

Texas appeals court blocks state from probing transgender kids' parents

 A Texas appeals court on Friday upheld a lower court's injunction blocking the state from investigating parents who provide their transgender children with gender-affirming medical treatments, which Governor Greg Abbott has called abusive.

Abbott, a Republican, had ordered the state Department of Family Protective Services (DFPS) to carry out child abuse investigations into families whose children were receiving puberty-blocking treatments in February 2022.

A month later, a district court judge imposed a statewide temporary injunction on such investigations, saying the probes endangered children and their families.

The appeals court in Austin upheld the district court judge's injunction in a pair of rulings on Friday, delivering a victory to LGBTQ groups, medical professionals and civil liberties advocates opposing moves by conservative politicians in dozens of states to criminalize the provision of gender-transitioning treatments for trans youth.

"This is a much-needed victory for trans youth and those who love and support them," the American Civil Liberties Union said on X on Friday.

Representatives for Abbott and the DFPS did not immediately respond to a request for comment.

The American Civil Liberties Union (ACLU) and Lambda Legal challenged Abbott's order on behalf of the family of a 16-year-old transgender girl targeted for investigation.

The child had taken puberty-delaying medications and hormone therapy. Her mother was a DFPS employee and was put on paid administrative leave after asking what Abbott's directive would mean for her family.

In 2022, the district court judge said the governor's order could cause "irreparable injury" to families, given the stigma attached to being targets of a child abuse investigation, as well as the loss of livelihood.

Texas restricted gender-affirming care for youth in 2023, making it one of more than a dozen states that currently bars young transgender people from receiving certain puberty-blockers and hormone therapies, according to the Human Rights Campaign tracker.

https://www.yahoo.com/news/texas-appeals-court-blocks-state-214708498.html

Inflation is heading higher again. Is it a 'bump' in the road or something more?

 February's PCE index showed another sharp increase in prices

An uptick in inflation early this year and remarkably strong economic growth are likely to keep U.S. interest rates high, but probably not for long.

Federal Reserve Chair Jerome Powell on Friday said the February report on inflation and consumer spending didn't offer any major surprises.

Put another way, his remarks suggest the Fed is still on track to cut interest rates three times this year - and most economists agree.

What they aren't entirely in agreement on is when.

Some economists and senior Fed officials such as Gov. Chris Waller say inflation will have to slow further - and the economy needs to cool off a bit - before the central bank cuts rates.

For now, Wall Street is betting on June, but July or even later is not out of the question.

"It will take more evidence of inflation moderation in the months ahead to give the Fed the confidence to pull the trigger on its first rate cut this year," said chief economist Scott Anderson of BMO Capital Markets.

The chief worry, of course, is sticky inflation. Prices rose sharply in January and February, reversing a steady decline at the end of last year.

The Fed's preferred inflation gauge, the personal-consumption expenditures (PCE) price index, rose 0.3% in February following a 0.4% gain in January. If inflation continues to come in hot, it could push the yearly rate of inflation back above 3%.

But Powell doesn't seem worried. He said he expects inflation to continue to slow while acknowledging their will be "bumps" on the road to the Fed's goal of 2% annual inflation.

The 12-month rate of PCE inflation isn't actually far from that goal, registering at 2.5% in February. But it's reversed course since December and is running above 3% in the past three months on an annualized basis.

The February PCE inflation report wasn't all bad, though. The cost of services - the bigger driver of recent inflation -slowed after a big increase in January.

What's more, the so-called supercore rate of service inflation posted a small increase. This measure excludes energy and housing and is seen as a proxy for labor costs.

"The notable cooldown in 'supercore' PCE inflation was encouraging," said senior economist Lydia Boussour of EY Parthenon.

The big question is whether that can continue, especially given the strength of the U.S. economy.

Consumer spending jumped 0.8% in February to mark the biggest gain in a year. Gross domestic product, the official scorecard of the economy, is likely to increase around 2% in the first quarter in another demonstration of the economy's resilience.

The labor market is also still very strong, potentially keeping wage growth somewhat above the Fed's comfort level. Layoffs remain very low and another solid increase in hiring is expected in March.

The March employment report comes out next week.

Even if inflation doesn't slow as fast as expected, the good news is that the economy remains very sturdy. Were the Fed to keep interest rates high a bit longer to make sure inflation slows, the economy will probably be OK.

"Is the possibility of a recession elevated at the current time? I would say no and I don't see forecasters disagreeing with that," Powell said. "Growth is strong. The economy is in a good place."

Top Wall Street economists agree: Their own forecast calls for steady U.S. growth in 2024.

These top economists also think a further slowdown in inflation won't come as fast as the Fed would like, but they still think the central bank will cut interest three times this year.

The reason: Interest rates are so high now, they contend, that the Fed can afford to reduce them without giving fresh life to inflation.

Are they right? It remains to be seen. Mark down April 10: That's when the next consumer-price index will be released.

https://www.morningstar.com/news/marketwatch/20240329334/inflation-is-heading-higher-again-is-it-a-bump-in-the-road-or-something-more

New Yorkers Silently Worrying Over Ramifications Of Trump Ruling

 by Janice Hisle and Catherine Yang via The Epoch Times (emphasis ours),

Monday’s dramatic bond reduction for former President Donald Trump did nothing to dissipate the dark cloud that his civil-fraud case has cast over New York business deals.

Although investors won’t publicly admit it, the case is having a chilling effect, said Charles Trzcinka, professor of finance at Indiana University-Bloomington.

“If you talk to people in this market, they are very, very upset … and these are people who are neutral or even opposed to Trump,” Mr. Trzcinka told The Epoch Times. “They’re just angry about it.”

In his role at the university, Mr. Trzcinka said he places students in the corporate lending market in New York, making him aware of trends in that sphere.

An appeals court’s decision to slash the bond by about 60 percent, reducing it to $175 million, still left a massive penalty intact while President Trump continues a legal challenge of Justice Arthur Engoron’s ruling.

Judge Engoron ruled that President Trump and his associates fraudulently overvalued their assets. But Mr. Trzcinka said anyone who thinks President Trump’s activities in that case were irregular or fraudulent may lack an understanding of typical New York business transactions.

A source familiar with the case explained to The Epoch Times that, normally, business-related cases are handled in the New York courts’ commercial division.

There, cases are decided by judges who have specific, “sophisticated” knowledge of commercial law and business practices.

But the case didn’t go that route because New York Attorney General Letitia James found a novel way to use New York’s anti-fraud law.

Researchers examined other alleged fraud cases in New York over a 70-year period and found the Trump case stands alone. The Trump Organization was the only company that confronted the possibility of being forced out of business despite no victim suffering major financial harm.

Because of Ms. James’ unusual application of the law, the case was channeled to a court that would rarely, if ever, handle business-related matters.

Thus, the source said, “This case proceeded in just a highly irregular fashion from the start.”

The New York Stock Exchange on Wall Street in New York on March 20, 2024. (Charly Triballeau/AFP via Getty Images)

‘A Degree of Horror’

Legal scholar Jonathan Turley agreed the case is atypical and its repercussions far-reaching.

“This has really done great damage to the New York legal system … Businesses are looking at this with a degree of horror—that a judge could come up with a figure so large you have to sell parts of your business just to get an appeal,” Mr. Turley told Fox News.

However, people who dislike President Trump are cheering on Ms. James. She ran for election on a promise to prosecute the former president if she won the post of attorney general.

Before the court-ordered bond reduction, the original $464 million bond amount included a $363 million judgment that Judge Engoron levied against President Trump and his associates, plus 9 percent interest.

Speaking to reporters after the March 25 appellate court’s decision, President Trump called Judge Engoron’s original decision a “disservice” to New York.

“Businesses are fleeing,” he said.

The case promises to continue discouraging investors from doing business in the Empire State, Mr. Trzcinka and two other knowledgeable sources told The Epoch Times.

That’s not only because of the crippling dollar amounts involved, the sources said, but also because President Trump and his associates were behaving within the bounds of normal business practice and victimized no one.

“All the parties under this civil case were satisfied,” Mr. Trzcinka said. Yet Ms. James “brought a case without a victim” and secured a judgment approaching $500 million.

“I have never heard of a victimless civil case that even won $500,” he said.

Former President Donald Trump speaks to the media during a pre-trial hearing in New York City on March 25, 2024. (Top R) New York Attorney General Letitia James (C) watches the start of former Presdient Donald Trump's civil fraud trial in New York City on Oct. 2, 2023.

Silently Worrying

Businesspeople are afraid to express concerns about the ramifications aloud. Doing so would paint targets on their backs—an underlying reason why President Trump was unable to persuade bonding companies or banks to cover the original $464 million bond, Mr. Trzcinka and the sources said.

“I don’t think a bonding company [or a bank] is willing to be associated with Donald Trump … because the attorney general could turn around and sue them, go after them,” Mr. Trzcinka said.

Judge Engoron ruled that President Trump and his associates committed fraud by overvaluing his properties.

Parties involved in real estate transactions tend to exaggerate values in one way or the other, and they “hit each other over the head” with dueling appraisals, Mr. Trzcinka said.

And, in a case such as this one, “everyone had the same information and just came to different conclusions” as to the valuations, he said. Then the parties negotiated figures and agreed to them.

Unaffordable for a Multi-Billionaire?

Even before interest was added, Judge Engoron slapped President Trump with “the largest penalty in history” for a case of its kind, said Mr. Trzcinka.

He had never heard of such a high penalty imposed for a “syndicated loan,” which involves civil contracts between a corporate borrower and corporate lenders.

About $355 million of the total order specifically applied to President Trump. In addition, the judge ordered $4 million to be recovered from each of his sons, Eric Trump and Donald Trump Jr., and $1 million from former Trump Organization finance chief Allen Weisselberg.

Even the ultra-wealthy would rarely, if ever, have rapid access to hundreds of thousands of dollars in liquid assets, Mr. Trzcinka and other financial experts say.

Marshaling that much cash to post the bond in just 30 days proved to be a daunting task for President Trump; the appellate court’s ruling granted him 10 more days to post a reduced $175 million bond.

That decision moved the amount from “the realm of the impossible” into a different category; “it’s expensive but it’s feasible,” a source said.

A number of bonding companies said that the most they could shoulder would be $100 million, President Trump’s lawyers said in court filings, adding that many people worked countless hours to find possible solutions to the former president’s predicament.

https://www.zerohedge.com/political/new-yorkers-silently-worrying-over-ramifications-trump-ruling

More Americans say they are worried about illegal immigration, terrorism in 2024

 The number of Americans who say they are worried about illegal immigration and future terrorist attacks rose over the past year, according to a recent poll.

The Gallup survey, released Friday, found there was a 7 percent increase in those who are worried “a great deal” about the surge in illegal immigration. The number was comparable to those who said the same about possible terrorist attacks, per the report.

Roughly 48 percent of those surveyed said they are worried “a great deal” about the impact of illegal immigration, up from 41 percent in March 2023. The poll also found that 43 percent of people are worried about the likelihood of future terrorist attacks, up from 36 percent at this time last year.

The increase in those worried about illegal immigration is likely related to a rise in concern among Democrats. The latest survey shows 27 percent of Democrats are worried about the issue, compared to 14 percent in 2023.

On the other side, Republicans saw a 1 percent decrease in concern over illegal immigration, going from 74 percent concern in 2023 to 73 percent in the most recent survey. There was also a slight rise in concern among independent voters, up to 44 percent in 2024, compared to 39 percent in 2023.

Concern over future terrorist attacks was highest among Republicans at 59 percent, compared to independent voters at 41 percent and Democrats at 32 percent in the latest poll.

The data comes from the Gallup Poll Social Series on Environment, conducted each March.

Results were based on telephone interviews conducted between March 1-20, with a random sample of 1,016 adults. The margin of sampling error is 4 percentage points.

The Gallup survey’s results come less than a week after a Harvard CAPS-Harris poll found immigration was a chief concern for voters ahead of November’s general election, with 36 percent of voters saying it was the most important issue facing the country.

Inflation and price increases followed closely behind, with 33 percent of voters calling it the most important issue facing the U.S., per the poll.

https://thehill.com/blogs/blog-briefing-room/4564228-more-americans-say-worried-illegal-immigration-terrorism-2024-survey/

AI Identifies Two Natural Bioactive GLP-1 Compounds

 Artificial intelligence (AI) has identified two plant-based bioactive compounds with potential as glucagon-like-peptide-1 receptor (GLP-1R) agonists for weight loss as possible alternatives to pharmaceutical weight-loss drugs, but with potentially fewer side effects and oral administration.

Using AI, the work aimed to identify novel, natural-derived bioactive compounds that may activate the GLP-1R, which is the site of action of existing weight loss pharmaceutical drugs including semaglutide (Wegovy, Novo Nordisk) and dual agonist tirzepatide (Zepbound, Eli Lilly).

Presenter Elena Murcia, PhD, of the Structural Bioinformatics and High-Performance Computing Research Group & Eating Disorders Research Unit, Catholic University of Murcia, Murcia, Spain, will be sharing her work at the upcoming European Congress on Obesity (ECO 2024) in May.

Although GLP-1 agonists have shown effectiveness in trials, "there are some side effects associated with their use — gastrointestinal issues such as nausea and vomiting, as well as mental health changes like anxiety and irritability. Recent data has also confirmed that when patients stop treatment, they regain lost weight," she said.

In addition, there is the issue of having to inject the drugs rather than taking them orally due to the peptide nature of existing GLP-1 agonists that risk degradation by stomach enzymes before they exert the required effect.

"Drugs that aren't peptides may have fewer side effects and be easier to administer, meaning they could be given as pills rather than injections," said Murcia.

Other recent research has highlighted two promising non-peptide compounds, TTOAD2 and orforglipron. "These are synthetic, and we were interested in finding natural alternatives," she added.

Natural Versions of Compounds That Activate GLP-1Rs

Drawing on recent understanding around the TTOAD2 and orforglipron compounds, the present work focuses on using AI to identify new non-peptidic, natural-derived bioactive compounds to activate the GLP-1R, according to the researcher in her abstract and a preconference press release from ECO.

Using advanced AI techniques (an in silico approach that entails experimentation by computer), Murcia selected natural molecules as bioactive compounds with GLP-1R agonist activity in a stepwise process that initially used ligand and structure-based virtual screening of over 10,000 compounds, followed by additional visual analysis of the top 100 compounds with the highest similarity to determine their degree of interaction with amino acids on the GLP-1 receptors. Arriving at a shortlist of 65, the researchers synthesized these data to identify the compounds with the highest potential as GLP-1R agonists, and two of these, referred to as Compound A and Compound B — both plant-derived — were found to bind strongly to the key amino acids in a similar way to TTOAD2 and orforglipron.

"These compounds are currently being further investigated for their efficacy in obesity treatment through in vitro analysis," wrote Murcia and her colleagues in their abstract.

Asked to comment on the work, Felix Wong, PhD, postdoctoral fellow at the Broad Institute of MIT and Harvard, Cambridge, Massachusetts, who recently discovered a new class of antibiotics with activity against methicillin-resistant Staphylococcus aureus using deep learning, told Medscape Medical News that, "The promise of AI for drug discovery has increasingly been realized, and just recently we have seen the discoveries of new antibiotics, senolytics, and anti-fibrotic compounds, among others."

"This study, which is based on molecular docking, suggests that similar computational methods can be applied to popular therapeutic areas like GLP-1R agonist discovery," he said, adding that "the study will need experimental validation given that computational predictions can lead to false positives and that natural products are often promiscuous."

Murcia has declared no relevant conflicts. Wong has declared he is cofounder of Integrated Biosciences, an early-stage biotechnology company.

https://www.medscape.com/viewarticle/ai-identifies-two-natural-bioactive-glp-1-compounds-2024a10005ze