COVID news & more, 3/16/24

This week, March 11 marked four years since the WHO declared a global pandemic for COVID. Remember the run on toilet paper and cleaning supplies? We have come a long way since then, but COVID is still a serious disease. 

JN.1 and its descendants still make up most COVID cases now. Emergency department visits are down more than 21% this week and hospitalizations are down 13.6% from the week prior. The CDC’s wastewater monitoring shows that the entire United States is down to a “MODERATE” level of wastewater SARS-CoV-2 virus now. We see from Sara Anne Willette’s analysis that Tennessee’s wastewater SARS-CoV-2 levels are extremely high, followed by high levels in Kansas, Virginia and Georgia. Here in the Bay Area, levels have come down in most places to a moderate level.

According to JP Weiland’s March 15th update, COVID infections continue to decrease significantly to “Medium” levels in most places and he calculates that about 1 in every 77 people is currently infected reflecting 430,000 new COVID infections each day in the United States. 

Variants

New variant BA.2.87.1 was found in South Africa and Asia, but it does not have the ability to outcompete dominant variant JN.1. In the future, it may or may not pick up mutations, but for now it does not appear to be a threat. 

There is a new variant called KP.2 that is JN.1 with an additional “FLiRT” (F456L and R346T) mutation in its spike protein that is growing exponentially in some places. According to Mike Honey, “Globally, KP.2 is showing a very strong growth advantage of 14% per day (101% per week)” over JN.1 and other Pirola (BA.2.86) descendants. He predicts that KP.2 could take over as the dominant variant sometime in late March. I am interested to see if the 2023-2024 XBB.1.5 vaccine will protect against KP.2 as it does against JN.1. Some seniors are waiting to get their next booster of the XBB.1.5 COVID vaccine, but it may be wise to get the booster sooner if future studies show that it protects against KP.2.

JP Weiland posted yesterday regarding the evolution of mutations in SARS-CoV-2 variants. He said “What we've seen over the past 2 years is an evolutionary pattern of big saltations (a new variant appears with many new mutations all at once) , then a lot of quick convergent evolution to optimize the new variant. I can't think of another virus that has a similar trend.  Usually they have stepwise mutations.”

Acute COVID infections, General COVID info

With the fourth anniversary of COVID being announced as a global pandemic, some authors have written summary articles of what we have learned over the last 4 years of the COVID pandemic. In a post titled “Covid, 4 years on”, Eric Topol MD looked at partisan gaps in COVID death rates, the evolution of the SARS-CoV-2 virus, and the fact that vaccines protect not only against COVID infections, but also against blood clots, heart attacks, heart failure and strokes in the post-acute phase of the disease (see below). He also reflected on his disappointment with the CDC's March 1st recommendations that tell COVID positive people that they can return to work if they have no fever and have improving symptoms. I wholeheartedly agree that it makes no sense for people with COVID to return to work before they are negative on a rapid antigen test.

COVID infection is known to increase the risk of heart attack, strokes, blood clots and other cardiovascular complications acutely and in the long term. Looking at 10 million vaccinated people vs. 10 million unvaccinated people from the UK, Spain, Estonia, vaccination was found to significantly reduce (by 45–81% in the acute phase and 24-58% in the post-acute phase) the risk of blood clots and cardiac events including heart attack, heart failure and stroke. “If you are vaccinated, your risk of having post-Covid cardiovascular and thromboembolic complications is reduced quite dramatically,” Prieto-Alhambra said.

Figure 2: effect of COVID-19 vaccines on post-COVID-19 cardiac and thromboembolic complications

A group of scientists from the World Health Network reviewed 122 articles on COVID and Long COVID. They looked at how COVID infection can affect different organs in our bodies long term by initially causing asymptomatic organ damage that can lead to new chronic diseases. Long COVID was also discussed. 

Scientists from the University of Pennsylvania looked at immunological imprinting and how past vaccines or infections shape differences in antibodies made by our B cells for current variants. They found that vaccinated people may get breakthrough COVID infections because SARS-CoV-2 continues to accumulate mutations in its spike protein. Each breakthrough infection with a new variant can boost ancestral cross-reactive antibodies and B cells. Baseline immunity imprinting influences the activation of variant-specific SARS-CoV-2 responses in B cells.

People often ask if COVID rapid antigen tests work against the latest variants. The answer is “yes”. An article in The Conversation reviews how “researchers keep ‘testing the tests,’ and they pass”.

People who are at high risk of getting severe acute COVID infections are often given Paxlovid and sometimes iv Remdesivir to help prevent hospitalization. Some hospitals also give COVID convalescent plasma. A new randomized clinical trial shows that unvaccinated people who received high antibody titer COVID convalescent plasma (CCP) early in their infection as outpatients did not need to be hospitalized for their infections.

Paxlovid works by inhibiting the main protease (Mpro) of the SARS-CoV-2 virus. But, certain mutations in the SARS-CoV-2 virus could make it become resistant to Paxlovid in the future. Michael Z. Lin’s lab from Stanford reports that they have made a second generation Mpro inhibitor of SARS-CoV-2 called ML2006a4 from boceprevir. ML2006a4 is less sensitive to mutations in the SARS-CoV-2 Mpro, so it may be able to fight future SARS-CoV-2 variants better than first generation Mpro drugs like Paxlovid. 

An article that came out this week in the Lancet’s eClinical Medicine journal sounded too good to be true. Authors reported that giving early combinations of repurposed drugs fluvoxamine, bromhexine, cyproheptadine, and niclosamide led to 0% of patients getting neuro-Long COVID. Mike Hoerger tweeted about the many faults with this study including cherry picking data, attrition bias, and some “audaciously implausible” results. 

Yesterday, March 15th, was Long COVID Awareness Day. People from the Long COVID community posted photos of themselves before and after they got Long COVID. In Australia, people with Long COVID had a Long COVID Awareness lay down in front of Parliament House in Melbourne. People gathered together in many other countries as well. The CN Tower in Canada and the Shipbuilders of Port Glasgow sculptures in Scotland were lit with teal, gray and black representing Long COVID’s ribbon. In the tricolored Long COVID ribbon, teal represents hope and support, gray represents loss and grief, and black loneliness and isolation. 

Bernie Sanders posted a video where he discussed that Long COVID is a hidden public health crisis that we cannot ignore. At least 16 million adults and 1 million children in the U.S. are currently affected by Long COVID. Two to four million Americans are unable to work because of Long COVID which represents $170 Billion in lost wages every year.

Mr. Sanders recommends:

1. Educate medical professionals about Long COVID.

2. Find treatments urgently to lessen the impacts of Long COVID and cures for LC.

3. Increase federal funding to address Long COVID.

4. Prevent Long COVID with vaccinations and the use of masks when needed. He reminded that every new COVID reinfection increases the risk of getting Long COVID.

In honor of Long COVID Awareness Day, the CDC posted a message with a photo of able bodied people standing and hugging on a beach looking at the sun with their backs turned to the viewer. Some Long COVID folks on Twitter said that the picture reflected the CDC turning their backs on people with Long COVID. They also commented that people with Long COVID are not represented by this stock photo as they are at home in bed, too weak to walk on a sandy beach and they wear eye masks because light from the sun hurts their eyes and heads.

On Long COVID Awareness Day, Queensland, Australia’s Chief Health Officer John Gerrard said that the term "Long COVID" is harmful and that long term post-COVID viral symptoms are no different than the flu and other respiratory illnesses. Dr. Putrino responded 

“As a scientist, an Australian and one of the world's leading authorities on Long COVID, I was disgusted to see John Gerrard's irresponsible comments regarding Long COVID in the media. The most prominent scientific journals in the world have published systematic reviews of the literature highlighting the fact that 7-12% of acute SARS-CoV-2 infections result in Long COVID - a chronic disease state that has no approved treatments. 

Long COVID can affect people of any age, gender and health status and according to Dr David Cutler, a leading health economist, it is on track to cost the US government $3.7 Trillion dollars. All consensus science points to the fact that Long COVID is a serious health crisis that requires the immediate attention of public health officials. In John Gerrard's careless, callous and unfounded comments we see a public health official who has failed his people. His dangerous and uninformed comments have placed hundreds of thousands of Queenslanders at risk of severe and permanent disability. He has placed a politically expedient, personal opinion ahead of four years of high-quality scientific research on the topic and if he had any integrity left he would resign.”

In the UK, more than a fifth of adults are not looking for work and long term illness has been cited as the main reason for about one-third of the working age inactive population. A new article in the European Journal of Public Health shows that labor market inactivity, which is defined as neither being in work nor actively seeking it, in the UK is about 40% higher in people with Long COVID. 

Scientific American reposted the interview that The Conversation did with Dr. Ziyad Al-Aly looking at COVID and its effects on the brain. Even mild COVID infections can cause the brain to age the equivalent of seven years. Dr. Al-Aly explained, “To put the finding of the New England Journal of Medicine study into perspective, I estimate that a three-point downward shift in IQ would increase the number of U.S. adults with an IQ less than 70 from 4.7 million to 7.5 million – an increase of 2.8 million adults with a level of cognitive impairment that requires significant societal support.”

Meghan Rosen looked at recent studies of biomarkers for Long COVID. As Dr. Akiko Iwasaki explained, “we are not likely to come up with one biomarker or even one set of biomarkers to distinguish everyone with long COVID. The difficulty is that long COVID is not just one disease.” The article goes on to look at studies showing SARS-CoV-2 viral persistence, complement dysfunction, low cortisol levels, exhausted T cells and elevated interferon-gamma in Long COVID.

Dr. Michael Peluso and colleagues wrote an excellent review of the dysregulated inflammatory response in Long COVID that involves both innate and adaptive immune cells. They looked at systemic inflammation in Long COVID, elevated IL-6 levels that are associated with increases in other pro-inflammatory cytokines, and reactivation of herpesviruses like EBV in Long COVID. They also discussed that TNFα and IFNγ can increase intestinal permeability which can leak bacteria and toxins into the bloodstream. In addition, they discussed that myeloid cells produce pro-inflammatory cytokines including CCL11, which can activate microglia in the brain and may lead to neurologic conditions like cognitive dysfunction. 

Fig. 2. Summary of immune perturbations associated with LC as covered in this Review. 

Many people with Long COVID suffer from Myalgic Encephalomyelitis /Chronic Fatigue Syndrome (ME/CFS) which is a post-infectious illness that causes exhaustion, post-exertional malaise, and brain fog. A pilot study from the Simmaron Research Institute published in May 2023 showed that the serum of ME/CFS patients with or without orthostatic intolerance (OI) and and small fiber neuropathy (SFN) all had significantly elevated levels of tetrahydrobiopterin (BH4) in their blood. According to Wikipedia, BH4 has multiple roles. The major one is to convert amino acids such as phenylalanine, tyrosine, and tryptophan to precursors of dopamine and serotonin, which are neurotransmitters. BH4 is also important for the conversion of L-arginine (L-Arg) to nitric oxide (NO) in endothelial cells where NO causes dilation of blood vessels. Endothelial dysfunction can be prevented by (1) increasing BH4 synthesis by taking supplements of its precursor (sepiapterin) or by dietary supplementation of L-arginine. Modulation of the arginine-NO pathway by BH4 and arginine is beneficial for ameliorating vascular insulin resistance in obesity and diabetes.

In non-COVID news, Ella Marushchenko posted a scientific article that must have been at least partially written by artificial intelligence (AI) because the human authors and reviewers did not notice that in the first line of the introduction states “Certainly, here is a possible introduction for your topic”.

In an average-risk screening population, a cell-free DNA blood test from Guardant Health called the Shield test had 83% sensitivity for colorectal cancer, 90% specificity for advanced neoplasia, but only 13% sensitivity for advanced precancerous lesions. A next generation DNA stool test called “BLUE-C” from Exact Sciences showed higher sensitivity for colorectal cancer and advanced precancerous lesions than their commercially available fecal immunochemical test (FIT) Cologuard. BLUE-C was found to be 94% sensitive for colon cancer and 43% sensitive for advanced precancerous lesions. BLUE-C had lower specificity than Cologuard however. 

The number of disabled scientists in academia dropped from 2% to 1.3% from 2008 to 2022. In their Op Ed in STAT news, Elizabeth Weaver II and Kiana Jackson request that the NIH work to change this. A new report in the Annals of Internal Medicine of more than 36,000 postmenopausal women showed that taking calcium and vitamin D supplements for more than 20 years lead to a 7% reduction in cancer mortality, but a 6% increase in cardiovascular deaths, with no effect on all-cause mortality. Some Apple Cinnamon Fruit Puree Pouches were voluntarily recalled in October of 2023 because of high levels of lead. This week, the FDA recalled 6 cinnamon brands that also were found to have high levels of lead. GLP-1 agonist Semaglutide (Wegovy) received FDA approval this week for reducing the risk of stroke and heart attack in overweight adults. This may help some patients get insurance approval for the drug.

Have a great rest of your weekend,

Ruth Ann Crystal MD

COVID news notes:

US Variant tracker: https://covid.cdc.gov/covid-data-tracker/#variant-proportions

Variants in locations around the globe: https://outbreak.info/

CDC COVID data tracker: https://covid.cdc.gov/covid-data-tracker/index.html#datatracker-home

CDC COVID Hospitalizations (blue) and Emergency Room (orange) visits tracker: https://covid.cdc.gov/covid-data-tracker/index.html#trends_weeklyhospitaladmissions_7dayeddiagnosed_00

Weekly ED visits for respiratory illnesses, by age and disease: https://www.cdc.gov/ncird/surveillance/respiratory-illnesses/index.html

US Wastewater Monitoring:

CDC wastewater reporting: https://www.cdc.gov/nwss/rv/COVID19-nationaltrend.html

CDC wastewater map: https://www.cdc.gov/nwss/rv/COVID19-currentlevels.html

Very high: Tennessee, Virginia, Kansas

Biobot: https://biobot.io/data/

National SARS-CoV-2 data from Sara Anne Willette: https://iowacovid19tracker.org/

Tennessee wastewater has very high levels of SARS-CoV-2.

Wastewater SCAN: https://data.wastewaterscan.org/

California statewide view https://buff.ly/3YObiul

Sewer Coronavirus Alert Network (SCAN) project by Stanford University: https://soe-wbe-pilot.wl.r.appspot.com/charts

Santa Clara County wastewahttps://covid19.sccgov.org/dashboard-wastewater

CDC Respiratory vaccination trends: https://www.cdc.gov/respiratory-viruses/data-research/dashboard/vaccination-trends-adults.html

JP Weiland: https://twitter.com/JPWeiland

https://twitter.com/JPWeiland/status/1768774655542767937

March 15th update:

• Infections continue to recede, back down to "Medium" levels.  

• However,  JN.1 + "FLiRT" (F456L and R346T) are now growing. [KP.2]

• 430,000 new infections/day

• 1 in every 770 became infected today

• 1 in every 77 people currently infected

  

• Michael Hoerger modeling:  http://pmc19.com/data/

https://twitter.com/michael_hoerger

https://twitter.com/michael_hoerger/status/1767779394615906609

Variants 

https://twitter.com/Mike_Honey_/status/1767138269622644835

Mike Honey: 

The new KP.2 lineage of SARS-CoV-2 is showing signs of spread. 

• It was first detected in samples collected in early January from Assam, India. It has since showed up in NZ, across North America, Europe and Asia.

• Samples from India dried up during January, so it's unclear if KP.2 is still spreading there.

• KP.2 adds the Spike R346T mutation to JN.1.11.1. 

• Globally, KP.2 is showing a very strong growth advantage of 14% per day (101% per week) over other BA.2.86.* "Pirola" (including JN.1.*) since February. That predicts a crossover in late March.

• Actually looks roughly 2-3X faster than JN.1 vs EG.5.* at roughly the same point. 

https://twitter.com/JPWeiland/status/1768785704513905147

What we've seen over the past 2 years is an evolutionary pattern of big saltations, then a lot of quick convergent evolution to optimize the new variant.  

I can't think of another virus that has a similar trend.  Usually they have stepwise mutations.

Acute COVID infections, General COVID info

https://twitter.com/yaneerbaryam/status/1768646172661440770

3/15/24 World Health Network: Spectrum of COVID-19: From Asymptomatic Organ Damage to Long COVID Syndrome https://buff.ly/3TEwDEv

• Review of 122 COVID and Long COVID articles, including how COVID infection can affect different body organs and long term chronic diseases increased after COVID infection.

3/15/24 Science Friday on NPR: What We Know After 4 Years Of COVID-19 https://buff.ly/43iXURa

• With Hannah Davis and Akiko Iwasaki

3/13/24 Eric Topol: Covid, 4 years on

Covid, 4 years on

• Partisan gap in death rates, as reflected by counties who voted Republican in the 2020 election.

• Variants, evolution of the virus and BA.2.87.1

• Vaccines protect against COVID infections, against blood clots—deep vein thrombosis and pulmonary embolism, heart attacks, strokes, and heart failure,

• Disappointment with the CDC's March 1 new recommendations

3/14/24 Immunity: Immunological imprinting shapes the specificity of human antibody responses against SARS-CoV-2 variants https://buff.ly/3VkdGt0

• Vaccinated people get breakthrough COVID infections because SARS-CoV-2 continues to accumulate mutations in its spike protein.

• Baseline immunity imprinting influences the activation of variant-specific SARS-CoV-2 responses in B cells.

"Highlights:

• Variant breakthrough infections boost ancestral cross-reactive antibodies and B cells.

• First and second BA.5 exposures fail to elicit variant-specific antibodies and B cells.

• XBB infections and vaccinations elicit XBB-specific responses in some individuals.

• XBB-specific responses correlate with low levels of pre-existing humoral immunity."

3/11/24 NY Times: Four Years On, the Mysteries of Covid Are Unraveling https://buff.ly/3ITKJwN

Rapid antigen tests still work against the latest variants:

3/1/24 The Conversation: COVID-19 rapid tests still work against new variants – researchers keep ‘testing the tests,’ and they pass https://buff.ly/3wMW7HH

Social and Advocacy

Long COVID Awareness Day, March 15, 2024

3/15/24 https://twitter.com/zalaly/status/1768610338377748934

3/15/24 Video from Bernie Sanders

https://twitter.com/SenSanders/status/1768721395721126003

Bernie Sanders discusses that LC is a hidden public health crisis that we cannot ignore. At least 16 million adults and 1 million children in the U.S. are affected by Long COVID. 

2 to 4 million Americans are unable to work which represents $170 Billion in lost wages every year.

Mr. Sanders recommends:

1. Educate medical professionals about Long COVID.

2. Urgent need: find treatments to lessen the impacts of Long COVID and cures for LC.

3. Increase federal funding to address Long COVID.

4. Prevent Long COVID with vaccinations and the use of masks when needed. Every new COVID reinfection increases the risk of getting Long COVID.

https://twitter.com/MiquetteAbercr2/status/1768485459569868949

https://twitter.com/TourCNTower/status/1768623709160362085

https://twitter.com/meighanstone/status/1768759333901181153

https://twitter.com/CDCgov/status/1768715314517119259

People discussed this picture of the CDC turning their backs on people with Long COVID. They also commented on how this couldn’t be people with Long COVID because they are at home, they cannot walk on a sandy beach, the sun hurts their eyes and heads, etc.

Phi @sophsoph_psd   https://twitter.com/sophsoph_psd/status/1768757715424157841

“Design is so important and all the institutions that have funding are failing. Long Covid doesn’t look like a f***ing chill gathering at the beach ya muppets.”

3/15/24 ABC.net.au: Queensland's Chief Health Officer says it's time to stop using the term 'long COVID' https://buff.ly/3IDilPb

• Queensland's Chief Health Officer John Gerrard said that the term "Long COVID" is harmful and that long term post-COVID viral symptoms are no different than the flu and other respiratory illnesses. 

Response from Dr. Putrino:

https://twitter.com/PutrinoLab/status/1768506640704422062

“This afternoon (US time) I was asked for comment on the recent statements on #LongCOVID in Australia. Here is the statement I provide:

As a scientist, an Australian and one of the world's leading authorities on LongCOVID I was disgusted to see John Gerrard's irresponsible comments regarding #LongCOVID in the media. The most prominent scientific journals in the world have published systematic reviews of the literature highlighting the fact that 7-12% of acute SARS-CoV-2 infections result in Long COVID - a chronic disease state that has no approved treatments. #LongCOVID can affect people of any age, gender and health status and according to Dr David Cutler, a leading health economist, it is on track to cost the US government $3.7 Trillion dollars. All consensus science points to the fact that Long COVID is a serious health crisis that requires the immediate attention of public health officials. In John Gerrard's careless, callous and unfounded comments we see a public health official who has failed his people. His dangerous and uninformed comments have placed hundreds of thousands of Queenslanders at risk of severe and permanent disability. He has placed a politically expedient, personal opinion ahead of four years of high-quality scientific research on the topic and if he had any integrity left he would resign.”

3/12/24 BBC: More than a fifth of UK adults not looking for work https://buff.ly/3Vg7OBc

• It means 9.2 million people aged between 16 and 64 in the UK are not in work nor looking for a job. The total figure is more than 700,000 higher than before the coronavirus pandemic.

• Concerns have been raised over worker shortages affecting the UK economy.

• Long-term illness has been cited as the main reason for about a third of the working-age inactive population not being in the labour force. 

2/29/24 European J of Public Health: Employment outcomes of people with Long Covid symptoms: community-based cohort study https://buff.ly/3Pith8C

• Labor market inactivity, which is defined as neither being in work nor actively seeking it, in the UK is about 40% higher in people with Long COVID. 

• “The main finding of our study is that reporting Long Covid after SARS-CoV-2 infection is associated with increased odds of labour market inactivity and long-term absence compared with pre-infection, with the period of greatest excess risk being 30 to <40 weeks post-infection for inactivity and 18 to <30 weeks post-infection for absence.”

• In March 2023, an estimated 1.9 million people in the UK (2.9% of the population) self-reported Long Covid, with prevalence being highest among working-age people.

Vaccines

3/12/24 Heart: The role of COVID-19 vaccines in preventing post-COVID-19 thromboembolic and cardiovascular complications https://buff.ly/3wQMc3X

https://heart.bmj.com/content/early/2024/01/24/heartjnl-2023-323483

COVID infection is known to increase the risk of heart attack, strokes, blood clots and other cardiovascular complications acutely and in the long term. Looking at 10 million vaccinated people vs. 10 million unvaccinated people from the UK, Spain, Estonia, vaccination significantly reduced (by 45–81% in the acute phase and 24-58% in the post-acute phase) the risk of blood clots and cardiac events including heart attack, heart failure and stroke, especially in the first months after COVID infection.

“if you are vaccinated, your risk of having post-Covid cardiovascular and thromboembolic complications is reduced quite dramatically,” Prieto-Alhambra said.

Figure 2: effect of COVID-19 vaccines on post-COVID-19 cardiac and thromboembolic complications

Antiviral treatments

3/14/24 JCI Insight (In Press Preview): Outpatient COVID-19 convalescent plasma recipient antibody thresholds correlated to reduced hospitalizations within a randomized trial https://buff.ly/3ViXc4e

• COVID-19 convalescent plasma (CCP) viral specific antibody levels that translate into recipient post-transfusion antibody levels sufficient to prevent disease.

• "In unvaccinated, seronegative COVID-19 convalescent plasma (CCP) recipients, early transfusion of plasma units in the upper 30% of study donors' antibody levels reduced outpatient hospitalizations. High antibody level plasma units, given early, should be reserved for therapeutic use." 

RED FLAGS *** for this article. See below 3/14/24 eClinical Medicine (Lancet): Early treatment with fluvoxamine, bromhexine, cyproheptadine, and niclosamide to prevent clinical deterioration in patients with symptomatic COVID-19: a randomized clinical trial https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(24)00096-8/fulltext#%20

3/14/24 From Tweet thread by Kashif Pirzada on this article about repurposing drugs in combination to help treat acute COVID infections and reduce Long COVID as well

https://twitter.com/KashPrime/status/1768487878454124914

• n=995 patients in Thailand with acute COVID infection in 2021-2022. 96% were partially/fully vaccinated. Open-label outpatient RCT.

• 41% Alpha and Delta variants, 59% Omicron infections.

• 4 older generic drugs were given in combination started within first 48 hours of an acute COVID infection: 

  • Fluvoxamine (FLV), Cyproheptadine, Bromhexine, Niclosamide

  • None of the patients in the combo drug treatment groups developed Long COVID with brain fog, cognitive symptoms or headache.

Rebuttal from Mike Hoerger:

https://twitter.com/michael_hoerger/status/1768514155647005103

Many red flags in the new "repurposed medications for COVID-19" trial of fluvoxamine et al. I believe it should not have been published but am uncertain whether it will be retracted. Red flag #4 is the most concerning to me.

1. Reported outcomes differ from that on http://clinicaltrials.gov meaning the potential for cherry-picking. 

2. Huge attrition bias. 86% of control participants complete the trial, only 44% of intervention participants did. The study was unblinded (participants knew what they were assigned to). Participants will often stick with an intervention if they believe it works, and drop out if it doesn't.

3. The rationale for how Long Covid was measured was problematic. 

4. Some of the results are audaciously implausible. 75% of the control group was hospitalized at 28 days in a sample where people had mild symptomatic acute infections, were vaccinated, and were required to have "no risk of severe diseases" (per online supplement). It sure sounds like they were pretty at-risk. 100% of the control group had Long Covid at 3 months (in a lower risk sample!). One hundred percent. 0% in any treatment group. The results weren't just perfect, they were beyond perfection. 

Also, the Lead author has a financial interest in Fluvoxamine.

3/13/24 Science Translational Medicine (Michael Z. Lin lab): An orally bioavailable SARS-CoV-2 main protease inhibitor exhibits improved affinity and reduced sensitivity to mutations https://buff.ly/3ICJfGR

• Authors made a second generation Mpro inhibitor of SARS-CoV-2 called ML2006a4 from boceprevir. ML2006a4 is less sensitive to mutations in the SARS-CoV-2 Mpro, so it may be less resistant to future SARS-2 variants. 

Long COVID

3/13/24 Sci Am (Z. Al-Aly on the Conversation): COVID-19 Leaves Its Mark on the Brain. Significant Drops in IQ Scores Are Noted. https://buff.ly/43g5fAV

• Research shows that even mild COVID-19 can lead to the equivalent of seven years of brain aging.

• Reprint of this amazing article:

2/28/24 The Conversation by Ziyad Al-Aly: Mounting research shows that COVID-19 leaves its mark on the brain, including with significant drops in IQ scores https://buff.ly/3P4hIls

• "Generally the average IQ is about 100. An IQ above 130 indicates a highly gifted individual, while an IQ below 70 generally indicates a level of intellectual disability that may require significant societal support.

“To put the finding of the New England Journal of Medicine study into perspective, I estimate that a three-point downward shift in IQ would increase the number of U.S. adults with an IQ less than 70 from 4.7 million to 7.5 million – an increase of 2.8 million adults with a level of cognitive impairment that requires significant societal support."

3/4/24 Science News: The blood holds clues to understanding long COVID https://buff.ly/3PdxoTy

Biomarkers for Long COVID

CITATIONS

T. Thaweethai et al. Development of a definition of postacute sequelae of SARS-CoV-2 infection. JAMA. Vol. 22. May 25, 2023, p. 1934. doi: 10.1001/jama.2023.8823.

C. Greene et al. Blood–brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment. Nature Neuroscience. Published online February 22, 2024. doi:.1038/s41593-024-01576-9.

BBB disruption is evident during acute infection and in patients with long COVID with cognitive impairment.

Using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), we show BBB disruption in patients with long COVID-associated brain fog. Transcriptomic analysis of peripheral blood mononuclear cells revealed dysregulation of the coagulation system and a dampened adaptive immune response in individuals with brain fog. Accordingly, peripheral blood mononuclear cells showed increased adhesion to human brain endothelial cells in vitro, while exposure of brain endothelial cells to serum from patients with long COVID induced expression of inflammatory markers. Together, our data suggest that sustained systemic inflammation and persistent localized BBB dysfunction is a key feature of long COVID-associated brain fog.

B. A. Krishna et al. Spontaneous, persistent, T cell–dependent IFN-γ release in patients who progress to Long Covid. Science Advances. Published online February 21, 2024. doi: 10.1126/sciadv.adi9379.

K. Baillie et al. Complement dysregulation is a prevalent and therapeutically amenable feature of long COVID. Med. Published online February 14, 2024. doi: 10.1016/j.medj.2024.01.011.

C. Cervia-Hasler et al. Persistent complement dysregulation with signs of thromboinflammation in active long COVID. Science. Vol. 383. January 19, 2024. doi: 10.1126/science.adg7942.

K. Yin et al. Long COVID manifests with T cell dysregulation, inflammation and an uncoordinated adaptive immune response to SARS-CoV-2. Nature Immunology. Vol. 25. January 11, 2024, p. 218. doi:10.1038/s41590-023-01724-6.

J. Klein et al. Distinguishing features of long COVID identified through immune profiling. Nature. Vol. 623. September 25, 2023, p. 139. doi:10.1038/s41586-023-06651-y.

M.J. Peluso et al. Multimodal molecular imaging reveals tissue-based T cell activation and viral RNA persistence for up to 2 years following COVID-19. medRxiv.org. Posted July 31, 2023. doi: 10.1101/2023.07.27.23293177.

E.R. Praff et al. Coding long COVID: characterizing a new disease through an ICD-10 lens. BMC Medicine. Vol 21. February 16, 2023. doi: 10.1186/s12916-023-02737-6.

H.E. Davis et al. Long COVID: major findings, mechanisms and recommendations. Nature Reviews Microbiology. Vol 21. January 13, 2023, p. 133. doi: 10.1038/s41579-022-00846-2. 

L. Au et al. Long COVID and medical gaslighting: Dismissal, delayed diagnosis, and deferred treatment. SSM Qualitative Research in Health. Vol. 2. December 2022, p. 100167. doi:10.1016/j.ssmqr.2022.100167.

3/2024 Seminars in Immunology (Peluso et al): Systems analysis of innate and adaptive immunity in Long COVID https://buff.ly/3T2q8L2

• Systemic inflammation in LC: 

• The inflammatory marker most consistently associated with LC is (an elevated level of) IL6.

  • Overall, when IL6 is elevated, other pro-inflammatory markers are elevated too.

• Herpesvirus reactivation

  • EBV, but not CMV, can drive autoimmunity through molecular mimicry, specifically through similarity between the EBV protein EBNAa and the central nervous system (CNS) protein GlialCAM [73]

• Inflammatory cytokines such as TNFα and IFNγ can increase intestinal permeability [45], [46], which can lead to leakage of microbes and their byproducts into the bloodstream. 

• Myeloid cells are major producers of pro-inflammatory cytokines and have also been implicated in neurological complications: plasma levels of CCL11, a chemokine that activates microglia (resident myeloid cells of the brain.

• Excessive microglia activity in neurological manifestations of LC [56].

• The overall theme emerging from immunological studies of LC to date is that of an over exuberant and dysregulated inflammatory response, involving both innate and adaptive immune cells, that fails to resolve, as summarized in Fig. 2. 

Fig. 2. Summary of immune perturbations associated with LC as covered in this Review. 

• Cytokines upregulated during LC include pro-inflammatory cytokines, particularly IL6. 

• Innate immune cell perturbations reported in the context of LC include myeloid cells and neutrophils, along with their progenitors (HSPC). The role of NK cells in LC is less studied. 

• LC individuals generally exhibit an increase in antibody responses against SARS-CoV-2. 

• Some herpesvirus antibody responses are elevated (EBV) while others appear to be suppressed (CMV) during LC. 

• Autoantibodies have been reported to be elevated, not different, or increased during LC. 

• Perturbations in both CD4+ and CD8+ T cells have been reported in the context of LC, resulting in overall T cell dysregulation. 

• LC also manifests with a discoordination between the humoral and cellular arms of adaptive immunity.

AI:

https://twitter.com/Ella_Maru/status/1768262888110580132

Other news:

ME/CFS

People with ME/CFS that was not triggered by COVID (triggered by something else) are needed for this study. Must live within 50 miles of NYC.

5/13/23 Int J Molecular Science: Detection of Elevated Level of Tetrahydrobiopterin (BH4) in Serum Samples of ME/CFS Patients with Orthostatic Intolerance (OI): A Pilot Study https://buff.ly/3wWYI1O 

• The bioavailability of tetrahydrobiopterin (BH4), an essential cofactor of endothelial nitric oxide synthase (eNOS) enzyme, is tightly coupled with cardiovascular health and circulation. 

• To explore the role of BH4 in ME/CFS, serum samples of CFS patients (n = 32), CFS patients with OI only (n = 10; CFS + OI), and CFS patients with both OI and small fiber polyneuropathy (n = 12; CFS + OI + SFN) were subjected to BH4 ELISA. 

• Interestingly, our results revealed that the BH4 expression is significantly high in CFS, CFS + OI, and CFS + OI + SFN patients compared to age-/gender-matched control BIOMARKER?

• Finally, a ROS production assay in cultured microglial cells indicated that elevated BH4 in serum samples of CFS + OI patients might be associated with the oxidative stress response.

• These findings suggest that the regulation of BH4 metabolism could be a promising target for understanding the molecular mechanism of CFS and CFS with OI.

  

(A) Control serum and CFS + OI serum-supplemented media was applied on DCFDA-transfected HMC3 human microglial cells for 90 min and then assayed for ROS using the fluorometric method [Ex:Em = 485 nm/535 nm]. n = 10 Control and n = 10 CFS + OI subjects were included. The significance of mean was tested by unpaired t-test between the two groups at * p < 0.05 (=0.0205). 

Other other news:

3/14/24 Lancet Neurology: Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021 https://buff.ly/4cfMf9O

3/14/24 A Cell-free DNA Blood-Based Test for Colorectal Cancer Screening | NEJM https://buff.ly/4aehVe0

A blood test from Guardant Health looking at cell-free DNA from Colon Cancers detected 87.5% of cancers that were at an early and curable stage. The false positive rate was 10%.

Detected only 14% of advanced precancerous lesions.

via Daniel Kraft

3/14/24 NEJM: Next-Generation Multitarget Stool DNA Test for Colorectal Cancer Screening https://buff.ly/3x31z9r

• Fecal next gen DNA with 93.9% sensitivity for colon cancer, 43% for advanced precancerous lesions.

• The next-generation multitarget stool DNA test showed higher sensitivity for colorectal cancer and advanced precancerous lesions than commercially available fecal immunochemical test (FIT) but also showed lower specificity. 

3/11/24 STAT news Op Ed: Disabled scientists are often left out of academia. The NIH can help change that https://buff.ly/3Tzp8zP

• "the representation of disabled principal investigators in academia has declined, dropping from 2% to 1.3% between 2008 and 2022, even though disabled workers’ overall labor force participation rate increased during that period. The NIH needs to use its power over the scientific ecosystem — and its newly published set of landmark recommendations on disability inclusion — to reverse this trend." 

The Los Angeles Department of Public Health warns re: cinnamon products with high levels of Lead. The FDA has recalled these cinnamon products.

https://twitter.com/lapublichealth/status/1767588846697628079

3/7/24 NY Times: F.D.A. Urges Recall of Cinnamon Brands Tainted by Lead https://buff.ly/4acPEoa

3/12/24 Annals of Internal Medicine: Long-Term Effect of Randomization to Calcium and Vitamin D Supplementation on Health in Older Women: Postintervention Follow-up of a Randomized Clinical Trial https://buff.ly/4ab00Vc

• >36,000 postmenopausal women 

• “Calcium and vitamin D supplements seemed to reduce cancer mortality (by 7%) and increase CVD mortality (by 6%) after more than 20 years of follow-up among postmenopausal women, with no effect on all-cause mortality.”

https://www.npr.org/2024/03/08/1237133257/fda-approves-wegovy-heart-attack-stroke-risk

3/8/23 CNN: Semaglutide (Wegovy) gets FDA approval for reducing the risk of stroke and heart attack https://buff.ly/3Iw5cYe

• The FDA added cardiovascular benefits to the medicine’s label, making it the first weight-loss drug to also be cleared to reduce the risk of heart attack, stroke or heart-related death in people at higher risk of these conditions. This may help with insurance coverage.

• “The approval is based on a 17,000-patient study that showed that people taking Wegovy, the sister drug to the better-known Ozempic, had a 20% lower risk of a cardiac event than those taking a placebo.”

• “Wegovy is indicated for people with a body mass index of at least 30 – considered to have obesity – or those with a BMI of at least 27 – considered overweight – and at least one “weight-related” health condition like high blood pressure or cholesterol. Ozempic is approved for type 2 diabetes. Both use the active ingredient semaglutide, part of a class of drugs known as GLP-1 receptor agonists.” 

5/21/19 PNAS Plus (Esfandyarpour R, Ron Davis): A nanoelectronics-blood-based diagnostic biomarker for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) https://buff.ly/3viWnhc

2/21/24 Nature: Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome - Nature Communications https://buff.ly/3UNabLx