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Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
@NickAnderegg
Aug 6, 2024 • 30 tweets • 12 min read • Read on X
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THIS IS BIG. WOW. New paper in PLOS Pathogens has findings about:
- the effect of the SARS-CoV-2 spike protein on cardiac cells (and mitochondrial dysfunction!),
- a treatment to be investigated, and
- how this is NOT caused by mRNA vaccines!

Buckle up, we're diving in...

1/ Published August 5, 2024 in PLOS Pathogens: "SARS-CoV-2 spike-induced syncytia are senescent and contribute to exacerbated heart failure" "Author Summary In this paper, we directly linked SARS-2-S-triggered syncytium [fused cells] formation in the absence of infection with the ensuing induction of cellular senescence and its pathophysiological contribution to heart failure. We propose that both SARS-2-S expression and SARS-2-S protein internalization were sufficient to induce senescence in nonsenescent ACE2expressing cells. This is important because of the persistent existe...
[This paper is an uncorrected proof; it's been peer-reviewed, but not copyedited yet.]

A bit of background: syncytia (sin-sih-sha) are giant cells with multiple nuclei that form from the fusion of multiple cells. Viral infections are a common cause of syncytia.

2/
"Abstract SARS-CoV-2 spike protein (SARS-2-S) induced cell–cell fusion in uninfected cells may occur in long COVID-19 syndrome, as circulating SARS-2-S or extracellular vesicles containing SARS-2-S (S-EVs) were found to be prevalent in post-acute sequelae of COVID-19 (PASC) for up to 12 months after diagnosis. ... Here, we found that the senescent outcome of SARS-2-S induced syncytia exacerbated heart failure progression. We first demonstrated that syncytium formation in cells expressing SARS-2-S delivered by DNA plasmid or LNP-mRNA exhibits a senescence-like phenotype. Extracellular ...
NIH > National Library of Medicine Medical Subject Headings MeSH Descriptor Data 2024 Giant Cells (aka syncytia) Multinucleated masses produced by the fusion of many cells; often associated with viral infections. In AIDS, they are induced when the envelope glycoprotein of the HIV virus binds to the CD4 antigen of uninfected neighboring T4 cells. The resulting syncytium leads to cell death and thus may account for the cytopathic effect of the virus. Entry Term(s): Giant Cells, Multinucleated; Multinucleated Giant Cells; Polykaryocytes; Syncytia; Syncytium;
The authors had two motivations for this study:

1. Cardiac complications are a major feature of COVID.
2. Patients with heart failure tend to experience very poor outcomes from COVID.

Really, it hasn't been entirely clear *how* COVID leads to heart failure... until now?

3/ "Introduction ...Although symptoms resulting from infection typically resolve within weeks, some individuals experience persistent symptoms following the acute phase of COVID-19, the so-called post-acute sequelae of COVID-19 (PASC) or long COVID [2–4]. SARS-CoV-2 infection predominantly offends the respiratory system. Currently, evidence has suggested cardiac complications as one of the important pathogenic features of COVID-19 [5,6]. More importantly, compared with patients without heart failure, those with diagnosed heart failure experienced a longer length of hospital stay, increas...
Syncytia form when the spike protein present on the surface of one cell makes contact with another cell.

This study went a step further by looking at how *extracellular* vesicles containing the spike protein can fuse cells... *without* active infection.

4/ "SARS-CoV-2 syncytium constitutes a hallmark of COVID-19-associated pathology and may potentially contribute to pathology by facilitating viral dissemination, cytopathy, immune evasion, and the inflammatory response [12]. ... In addition to mediate viral-cell fusion, the presence of SARS-2-S on the cell surface is sufficient to mediate cell-cell fusion, a mechanism called fusion from within (FFWI)[14,15]. The fusogenic activity of SARS-2-S is potent, as even undetectable amounts of SARS-2-S can cause cell-cell fusion [14]. In addition to mediating FFWI, viruslike particles or lipid ves...
Why do syncytia matter?

They're a potential route for the spike protein to cause damage even AFTER an active infection has subsided.

Like some other viruses, SARS-CoV-2 can cause cell senescence—which is when the cell replication cycle stops, and the cells degrades.

5/ "SARS-CoV-2 elicits the senescence of infected cells, similar to other viruses (virus-induced senescence, VIS). Cellular senescence is a state of stable cell cycle arrest characterized by ... induction of the lysosomal enzyme senescence-associated β-galactosidase (SA-β-gal) and activation of the senescence-associated secretory phenotype (SASP). SARS-CoV-2 infection triggers paracrine senescence and can lead to a hyperinflammatory environment and the onset of acute respiratory disease syndrome. ... Interestingly, isolated recombinant SARS-2-S protein has been shown to increase the SASP...
So before we dive into results, what is the headline?

Although cytokine storm has long been thought the cause of COVID-related cardiac issues, this study found that the SARS-CoV-2 spike protein "led to profound cardiac fibrosis without affecting baseline cariac function."

6/ "Here, we recommend that rescue of cardiac metabolism dysfunction should be taken into consideration in individuals during the acute or post-acute stage of SARS-CoV-2 infection. It should be noted that SARS-CoV-2 infection also induces new onset of multiple cardiovascular diseases and causes long-term cardiovascular sequelae in PACS patients. Cytokine storm was suggested to be a point of convergence in the pathophysiologic process between COVID-19 and heart failure. Here we found that SARS-2-S led to profound cardiac fibrosis without affecting baseline cardiac function. Further studies...
Moreover, they found a drug target that may be able to prevent "the downregulation of mitochondrial metabolism," and it has shown potential promise in treating heart failure overall.

It would treat the "increased risk of developing heart failure and sudden cardiac death"!

7/ "Previous studies have shown that small-molecule inhibition of WNK1 prevents the downregulation of mitochondrial metabolism and improves RV function and survival in pulmonary arterial hypertension. We found that WNK1 inhibition alleviated SARS-2-Saggravated heart failure and reduced serum cTnT and IL-1ß levels. cTnT is released into circulation during injury to cardiac myocytes(51]. Individuals with higher cTnT levels are at an increased risk of developing heart failure and sudden cardiac death. Therefore, through its metabolism-rescue and anti-inflammatory properties, WNK463 may have ...
Let's dive in to the results! I'm going to jump around a bit, because this paper is EXTENSIVE.

First up, when they cultured cells expressing the spike (S) protein and the ACE2 receptor in a 1:1 ratio, the cells started fusing within four hours. Basic premise confirmed!

8/ "...To explore whether SARS-2-S expression was sufficient to induce senescence..., we cocultured SARS-2-S (Wuhan-Hu-1)-expressing A549 cells with ACE2-expressing A549 cells at a 1:1 ratio (S1A and S1B Fig). Syncytial cells rapidly appeared at 4 h post coculture (hpc) and gradually grew in size, as indicated by microscopic analysis (Fig 1A). Notably, SARS-2-S-expressing syncytia (hereafter referred to as SARS-2-S syncytia) with enhanced SA-B-gal staining began to appear at 12 hpc, and the percentage of SA-B-gal-positive syncytia among SARS-2-S syncytia gradually increased during the fus...
In the cultures with SARS-2-S syncytia, the cells secreted more senescence-related cytokines, including IL-6, IL-8, and IL-2, compared to the cells exposed to a mutant spike protein that can't cause senesense!

They found similar syncytia formation in other cell types.

9/ "Real-time PCR (RT-qPCR) revealed significant transcriptional upregulation of senescenceassociated genes (Fig 1B). The upregulation was fusion specific, as SNF , S, ACE2 and SNF +ACE2 cells did not exhibit such upregulation (S1G Fig). Consistently, the conditioned medium of SARS-2-S syncytia at 48 hpc contained significantly more SASP-related cytokines, such as IL-6, IL-8, and IL-2, than that at 0 hpc compared to SARS-2-S NF mutant (Fig 1D). We found that higher increased levels in secreted proteins than mRNA levels of IL-6 and IL-8. This may be due to the continued expression and secr...
They also tested the spike from four Omicron variants (BA.1, BA.5, BA.2.75, BA.2.75.2). Previous work has found BA.1 has a 5x reduction in ability to fuse cells (compared to wild-type), but the others have a 1.2-1.7x reduction.

All formed syncytia, just a bit more slowly.

10/ "We next compared the senescence potential of four Omicron variants, SARS-2-SBA.1 , SARS-2-SBA.5 , SARS-2-SBA.2.75 , and SARS-2-SBA.2.75.2 , with that of SARS-2-S (S1C Fig). As reported, the Omicron BA.1 variant showed significantly weaker fusogenic activity than SARS-2-S [26] (5× reduction). The fusogenic capacity of BA.5 (1.2× reduction), BA.2.75 (1.7× reduction), and BA.2.75.2 (1.7× reduction) was modestly lower than that of SARS-2-S [27,28]. Notably, the percentage of SA-β-gal-positive syncytia was comparable to that of SARS-2-S, although they formed more slowly (Fig 1F and 1G). .....
Here's where it gets REALLY concerning: Extracellular vesicles—little packets, emitted by cells, containing a protein or some other type of small molecule—have been found carrying the S protein in patients' blood long after initial infection...

11/ "SARS-2-S delivery by EVs or mRNA confers the ability to trigger syncytial senescence Since SARS-2-S was shown to be incorporated into extracellular vesicles circulating in patient blood [29], we then asked if SARS-2-S protein internalization by S-EVs has the ability to trigger syncytium formation and cell senescence in an FFWO-dependent manner. To this end, we first used ultracentrifugation to purify EVs from the supernatant of HeLa- or SARS-2-Sexpressing HeLa cells and confirmed their identity by probing for exosome markers and the EVs were normalized by NTA (S2A-S2C Fig). We next l...
...and they found that these extracellular vesicles, once taken up by a cell, can cause the cell to fuse to another ACE2-expressing cell.

The fused cells then showed signs of senescence (including increased transcription of TNF, IL6, IL8, and CDKN1A genes).

Not great!

12/ "SARS-2-S delivery by EVs or mRNA confers the ability to trigger syncytial senescence ... These cells fused with cells expressing ACE2 at 8 hpc, as indicated by the appearance of multinucleated cells (Fig 2A). Importantly, the fused cells exhibited enhanced SA-ß-gal and p21 staining, with increased transcription of the TNF, IL6, IL8 and CDKN1A genes (Fig 2B), features that are typical of senescence."
What about the mRNA vaccines—they produce a spike protein, so can they also cause this problem? Nope!

The spike design used in the vaccines has a couple of tweaks to make it more stable, and those changes prevent it the vaccine-based spike protein from causing cell fusion!

13/ "Since COVID-19 mRNA vaccines, including Pfizer and Moderna, express S protein antigen by delivering SARS-2-S mRNA, we next asked whether SARS-2-SwT and S-protein-based vaccine (SARS-2-Sv) delivered in the form of encoding mRNA would trigger syncytium formation and cell senescence (S3A Fig). Previous study indicated, compared to SARS-2-SwT, two prolines were added to stabilize the structure's prefusion shape of S-protein in COVID-19 vaccine, this mutation greatly reduces cell fusion of COVID-19 vaccine. ... ... We did not observe syncytial cells formation, signs of senescence and sign...
To be really sure that the S protein can cause this type of syncytial senescence to occur in real organs, they injected mice with a virus that causes them to express human ACE2 in their livers.

When injected with the wild S protein, it induced senescence in their livers!

14/ "Finally, we explored whether cell senescence related to SARS-2-S-mediated cell fusion would also occur in vivo. To this end, we injected AAV-hACE2 constructs into the tail veins of 8-week-old C57BL/6] mice to drive mainly hepatic hACE2 expression. Four weeks later, we intramuscularly administered a single dose of S-mRNA-LNP or LNP to hACE2-expressing mice and examined the induction of senescence. Immunohistochemical analysis revealed robust SARS-2-S expression and the increased appearance of multinucleated cells with at least four nuclei in the livers of S-mRNA-LNP-treated mice compar...
Next up, they looked at mitochondrial regulation.

Long story story, MAVS (mitochondrial antiviral signaling) proteins, which detect foreign double-stranded RNA, cause mitochondrial senescence in response to the SARS-2-S syncytia.

15/
"These data suggest the involvement of RIG-I, the primary sensor of nonself-derived dsRNA [this means it detects double-stranded RNA of a foreign-source (e.g. from a virus)], in functional MAVS aggregation in SARS-2-S syncytia." --- "SARS-2-S syncytia provoke the formation of functional MAVS aggregates ...We then focused on mitochondrial antiviral signalling adaptor protein (MAVS), a mitochondrial adaptor protein that links the cytoplasmic RNA sensor RIG-I to its downstream signalling molecules by forming well-ordered prion-like aggregates. .... Furthermore, MAVS aggregat...
"Fig 3. SARS-2-S syncytia induce the RIG-I-dependent formation of functional MAVS aggregates. Confocal microscopic images of MAVS and mitochondria in A549 cells infected with VSV or A549 cells cocultured for the indicated times. Red, MitoTracker staining for mitochondria; green, MAVS staining; blue, DAPI staining. A magnified view of the boxed region is also shown. Scale bars represent 10 um (whole image) and 1 um (magnified)."
Jumping ahead a bit, they found that "senescent SARS-2-S syncytia exhibit [shrunken] morphology, leading to the activation of WNK1," which is a molecule involved in regulating cell senesence.

It is activated by the fused cells losing their volume.

16/ "...Previous study indicated that with-no-lysine (WNK) kinasel is a molecular crowding sensor that undergoes cell shrinkage-dependent phase separation to restore cell volume, the shrinkage of senescent SARS-2-S syncytia made us wonder whether WNK1 was activated [41]. Notably, we observed a significant shift of WNK1 from a diffuse to punctate distribution in senescent SARS-2-S syncytia of A549 and AC16 cells (Fig 5E-5I), but not in those cells treated with palbociclib (Fig 5J-5M). This phase behaviour appeared as early as 12 hpc in AC16 cells (Fig 5E). Accordingly, WNK1-triggered SPAK p...
They found WNK1 activation led to significantly decreased "mitochondrial oxidative capacity of the cocultured cardiomyocyte"

But "inhibition of WNK1 via WNK463 [which prevents down-regulation of metabolic enzymes] was sufficient to rescue impaired mitochondrial respiration"

17/ "So, we try to study energy metabolism of cardiomyocytes syncytia whether dependent on WNK1 activation [42,43]. We next explored the possibility that senescent SARS-2-S syncytia in cardiomyocytes with WNK1 activation might contribute to impaired metabolism in the setting of heart dysfunction. Compared to non-fusion controls, the mitochondrial oxidative capacity of the cocultured cardiomyocytes was significantly decreased at 48 hpc as indicated by reduced basal respiration, ATP-linked respiration, spare respiratory, and maximal respiration (Fig 6A and 6B). In addition, these senescent c...
Jumping ahead again, we're getting to the headline experiments.

They administered the SARS-2-S protein to some mice that express the human ACE2 receptor, and syncytia formed, as expected.

18/ "Senescent SARS-2-S syncytia exacerbated heart failure To assess whether senescent SARS-2-S syncytium stimulates heart dysfunction in vivo, K18-hACE2 mice were administered with pseudovirus expressing BA.5 spike (SARS-2-Spp) intravenously. Mice were euthanized on the fifth day.... The results showed that the presence of cardiomyocyte syncytia in the hearts of mice infected with the SARS2-SpP. Additionally, fluorescence staining showed that cellular senescence in syncytia expressing the S protein. On the eighth day post administered, mice were performed heart function tests, then eutha...
They concluded that "SARS-2-S promotes fibrosis without causing baseline cardiac abnormalities," and in the mice with pre-existing heart failure, it "exacerbated heart failure progression"

"fibrosis without causing baseline cardiac abnormalities"... not great!

19/ "Functional analysis of hearts, including ejection fraction (EF), fractional shortening (FS), left ventricular internal dimension at end diastole (LVID;d), left ventricular internal dimension at end-systole (LVID;s), as well as serum brain natriuretic peptide (BNP) levels between the two groups were also comparable. Thus, SARS-2-S promotes fibrosis without causing baseline cardiac abnormalities during 7 observational days. We then repeated the above experiment with intraperitoneally (i.p.) injected isoproterenol (ISO) to assess the impact of SARS-2-Spp on cardiac function in mice with ...
Finally, they examined if WNK1 inhibition can "alleviate heart failure exacerbated by SARS-2-S through rescuing metabolic dysfunction." They found positive results, "further supporting the notion that senescent SARS-2-S syncytia contribute to exacerbated heart failure."

20/ "We then wanted to test if WNK1 inhibition by WNK463 can alleviate heart failure exacerbated by SARS-2-S through rescuing metabolic dysfunction. ... Therefore, WNK1 intervention can effectively protect the heart from exacerbated heart failure triggered by SARS-2-S. Additional, to further prove that senescence SARS-CoV-2 syncytia act as a central pathogenic principle provoking heart failure, we attempted to eliminate senescent cells or inhibit fusion by using the senolytic drug dasatinib or the anti-syncytial drug niclosamide. Intriguingly, the administration of dasatinib and niclosamid...
What do they conclude?

The S protein can contribute to heart failure. This is important for acute infections AND long-term complications, because the "persistence of circulating SARS-2-S protein ... increase the likelihood of cell-cell fusion in uninfected cells."

21/ "Discussion ... the SARS-2-S protein mediates fusion between the viral and cellular membranes during particle entry, fusion with uninfected cells and FFWO. ... Here, we directly linked SARS-2-S-triggered syncytium formation with ... its pathophysiological contribution to heart failure progression. We found that both SARS-2-S expression and SARS-2-S protein internalization were sufficient to induce senescence in non-senescent ACE2-expressing cells. In particular, mRNAs-SARS-2-S injection provoked pathways ... in vivo. This was not only important for acute SARS-CoV-2 infection, but the ...
They also note that syncytia expressed senescence-related cytokines, including TNF-alpha, IL-6, and IFN-gamma, among others, and these seem related to the metabolic regulation.

22/ "Nevertheless, we provide evidence of the contribution of RIG-I-MAVS to the regulation of SARS-2-S syncytium fate through TNFa. Using multiplex protein analysis, we identified a burst of SASP-related cytokines, including TNFa, IL-6, IFN-y, and others, in the hACE2 mouse model injected with SARS-2-S mRNA. Although the exact contribution of each cytokine to SARS-2-S syncytium survival and senescence remains unclear, we provide evidence that the central regulation of SARS-2-S syncytium survival and senescence may be dependent on TNFa. Previous studies reported that TNFR2 interacts with th...
And, importantly, the mRNA vaccines CANNOT cause cellular senescence using this mechanism, as they have a couple of mutations which "effectively inhibit the formation of syncytia, mitigate cellular senescence, and prevent the release of" senescence-relate signals.

23/ "Our results have also revealed that the S sequence derived from the COVID-19 mRNA vaccine which harbors mutations in two proline residues. These mutations effectively inhibit the formation of syncytia, mitigate cellular senescence, and prevent the release of SASP. This finding corroborates prior research, affirming that the unique design of the mRNA vaccine mitigates syncytia formation, thus enhancing its safety. Moreover, our findings emphasize the necessity of optimizing vaccine sequences to mitigate the risk of syncytia formation in vaccine design."
Because patients with heart failure show elevated ACE2 expression, while those with Long COVID exhibit "persistent circulating SARS-2-S and EVs harboring SARS-2-S," this combination "may increase the likelihood of syncytium formation."

24/ "With the progression of COVID-19, heart failure appears to be a potential hazard due to SARS-CoV-2 infection, chiefly in elderly patients with hypertension, ischaemic heart disease, and diabetes mellitus. Patients with basic heart failure disease showed elevated ACE2 expression, whereas patients with PACS exhibited persistent circulating SARS-2-S and EVs harbouring SARS-2-S. High ACE2 expression and long SARS-2-S duration may increase the likelihood of syncytium formation. Moreover, the pre-existing inflammatory environment with older age or with chronic disease, especially those with...
This is very much a basic research paper and doesn't have anything directly *usable* in clinical practice. However, it really illuminates the pathophysiology of cardiac complications of SARS-CoV-2 infection—EVEN ASYMPTOMATIC INFECTIONS.

Paper:

25/25journals.plos.org/plospathogens/…
AFAIK, it’s totally a non-issue with the non-mRNA vaccines, because they don’t even have a full spike protein.

And I think their statements about how mRNA vaccines with a different design could have more complications was a veiled reference to one of China’s vaccines

26/25
No idea what to do about denialism at this point, other than continuing to educate and hope it gets through!

That's the goal with my threads: Hopefully, they can help give people the knowledge and language they need to discuss the science directly!

27/25
At this point, it's a *potential* treatment that still needs further study, but it's a solid lead!

- Inhibiting the *WNK1 molecule* with a *WNK463 molecule* is the new option uncovered here
- Two existing preventative drugs should be investigated

28/25

WNK1 inhibition (using WNK463) is the potential new drug target to investigate. Other drugs to investigate include: • the anti-syncytial drug niclosamide • the senolytic (drug that may selectively kill senescent cells) dasatinib as a protective measure against heart failure exacerbation triggered by the SARS-2-S protein.
Glad you asked, because I was conflating previous vector vaccines with ones under development!

It seems that Novavax and Janssen use the same STABILIZED spike protein as Pfizer and Moderna:

But oddly enough...

29/25
pubs.acs.org/doi/10.1021/ac…

Janssen: "a stabilized variant of the SARS-CoV-2 spike (S) protein."
...it seems that a bunch of Russian viral vector vaccines—and AstraZeneca—used the regular spike protein!?

So that kind of explains the issues with the AstraZeneca vaccine! Weird.

30/25 ncbi.nlm.nih.gov/pmc/articles/P…

AstraZeneca: "containing S protein gene of coronavirus"
CanSino, Gam-COVID-Vac, and Sputnik Light: "the SARS-CoV-2 protein S gene"

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Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
Feb 1
Many people are asking for recommendations about what storage media to buy, so here's a buying guide from an experienced data hoarder (me)

The MOST IMPORTANT thing to know is that SOLID-STATE MEDIA IS NOT DURABLE. Flash drives, SSDs, SD cards, etc. are NOT long-term storage.

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- In a spinning hard drive, the moving parts are the most common point of failure.
- When you burn a DVD, that shit is fairly permanent.

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Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
Jan 9
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You get insurance so that you can replace all of your stuff in the event of a disaster. When the insurance company effectively says "the risk of disaster is so high that insuring you would almost certainly cause us to lose a lot of money," it ALSO means your life is in danger

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Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
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Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
Jan 3
Let's review some major points in the Nukit controversy, since some people are unclear:

- Someone criticized someone's use of Nukit lanterns.
- Nukit attacked the critic because, as noted, this is how they market
- Nukit now demands "mediation" with the community (how??)

1/ @marigoldglitter: "these tools should be used for people who must be in public despite the dangers, not for white men who want to eat in restaurants and maintain the status quo. if this is what you're gonna use these for, give them to a disabled person who can't go to the doctor b/c of risk." Nukit: ""White man" in this case is buying those products from non-white small businesses who are focused on providing the community with effective, tested mitigations at far, far lower costs than anyone else." OP: "Like why are you coming at me with this aggressive...
Nukit: "If you are in the US, and would like to purchase Far-UVC products, we cannot help you at this time. We tried to resolve the issues there, but the US COVID-Aware community was uninterested in mediation or intercession. As a result of that disinterest, a great deal of harm was done. When stock is finished, we will not be selling our products to the Us anymore. If you are in the US and want Nukit products, would like 333 million Americans, many disabled or immune compromised, to be able to access the most affordable Far-UVC on the market, kindly address the people who made it unsa...
So let's look at this a bit more critically. Here is the "evidence" Nukit provided that the didn't say anything racist. First of all, these aren't the comments in question, but it's worth a look anyway.

2/ Ok, I get that "evidence," "citations," and "personal accountability" are going to be called racist, but since people insist on just spewing lie after lie without any pushback- here's what actually happened. @marigoldglitter- a white woman attacked a Nukit customer who was supporting us by showing our products. This is something we rely on to fund research and donations. If our customers do not do this, that money goes to paid advertising. So yes, attacking our customers is attacking our company and directly harming marginalized folks who receive our products. ...
Seems to be framed this way because Nukit knows it's not an adequate explanation, so they're acting like anyone who criticizes them is in the wrong. --- A bigoted comment is a bigoted comment, even if it's not directed at someone who might be personally offended. Of course, Nukit didn't include the comments people actually call racist! --- Nukit is explicitly saying here that they view any criticism as an "attack," because criticisms can potentially hurt their business goals. Fundamentally, Nukit is angry that this usage of their products are being criticized. --- After Nuki...
Let's be clear about what happened here: Someone lamented the unequal access to protective measures and criticized someone who seems to be using a certain device to *maintain the status quo*, and the manufacturer of the device found it unacceptable.

3/
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Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
Oct 9, 2024
NEW STUDY! This exploratory study identifies a SPECIFIC PHENOTYPE OF LONG COVID that appears related to NEUROMUSCULAR DISTURBANCE rather than lung damage—and they've termed it Complex Ventilatory Dysfunction!

Breakdown of the paper (thread written for a general audience!)...

1/ Published Oct 7, 2024: "A new phenotype of patients with post-COVID-19 condition is characterised by a pattern of complex ventilatory dysfunction, neuromuscular disturbance and fatigue symptoms" Abstract: Background Patients with post-COVID-19 condition frequently suffer from chronic dyspnoea. The causes and mechanism for dyspnoea in these patients without evidence of structural lung disease are unclear. ... Results ... A pattern of reduced forced vital capacity (FVC), but normal total lung capacity (TLC), termed complex ventilatory dysfunction ... was observed and occurred mo...
Broadly speaking, there are two groups of acute covid outcomes involving dyspnea (shortness of breath) as a long-term symptom:

- Severe cases that may have physical lung damage
- "Mild" cases that now have ME/CFS-like features, but who have no evidence of lung damage!

2/ "Current evidence suggests that cellular damage, a robust innate immune response with inflammatory cytokine production and a procoagulant state induced by SARS-CoV-2 infection are factors potentially contributing to post-COVID-19 sequelae such as dyspnoea, fatigue, and cognitive and mental disturbances... Dyspnoea has been well characterised as a major clinical symptom of post-COVID condition after severe and critical COVID-19 and is correlated with impaired lung function in terms of pulmonary restriction, and with reduced diffusion capacity as a possible consequence of pulmonary remod...
In this study, they explored this distinction further and identified a distinct subset of patients with a pattern of breathing abnormality that they have termed complex ventilatory dysfunction (CVD).

So how did they arrive at this conclusion? Let's dig in!

3/16 "We hypothesise that patients suffering from post-COVID-19 condition who have fatigue and exertional intolerance also have a reduction in respiratory muscle strength, causing a dysfunctional breathing pattern which is distinct from typical pulmonary sequelae after COVID-19 such as obstruction, restriction or impaired diffusion capacity. Based on clinical observations, we describe a new breathing abnormality termed complex ventilatory dysfunction (CVD), defined as total lung capacity (TLC) - forced vital capacity (FVC) >10% predicted value and absence of restriction (TLC ≥ lower limit o...
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Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
Sep 22, 2024
NEW STUDY! It VERY thoroughly supports the hypothesis that SARS-CoV-2 emerged as a zoonotic spillover event in the Huanan Seafood Wholesale Market—using multiple methods!

Breakdown of the paper (written for a general audience!)...

1/many (but it's worth it, I promise!) Published Sep 19, 2024 in Cell: "Genetic tracing of market wildlife and viruses at the epicenter of the COVID-19 pandemic" Highlights: - Common ancestor of SARS-CoV-2 linked to Huanan market matches the global common ancestor - Wildlife mitochondrial DNA identified in samples from stalls positive for SARS-CoV-2 Abstract: "... We demonstrate that market-linked severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genetic diversity is consistent with market emergence and find increased SARS-CoV-2 positivity near and within a wildlife stall. We identify wildlife DNA in...
This paper reanalyzes the same data from the April 2023 paper in Nature that cast doubt on the Huanan Market hypothesis (pictured).

In the new paper published in Cell this week, another group conducted far more detailed (and statistically sound) analyses!

2/
Original paper that analyzed this same data: "Surveillance ofSARS-CoV-2 at the Huanan Seafood Market" "Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019, emerged in December 2019. Its origins remain uncertain. It has been reported that a number of the early human cases of coronavirus disease 2019 had a history of contact with the Huanan Seafood Market...."
"...It should be noted that the selection of shops for sampling was biased because shops selling wildlife as well as shops linked to early cases were prioritized for sampling. The origin of the virus cannot be determined from the analyses available so far. Although gene barcode analysis of animal species in the study suggested that Myotis, Nyctereutes and Melogale-species that have been recognized as potential host species of sarbecoviruses-were present at the market, these barcodes were mostly detected within the SARS-CoV-2 RT-qPCR-negative samples from the environment. It remains pos...
This new paper starts by reviewing the evidence supporting the Huanan Market hypothesis, and some of the details are FASCINATING!

To begin with, of the 174 COVID cases identified with an onset of December 2019, 32% had a link to the Huanan Market.

In a city of 12 million.

3/ "INTRODUCTION Many of the earliest known cases of COVID-19 worked at or visited the Huanan Seafood Wholesale Market ("Huanan market") in the city of Wuhan, a link first made by clinicians at different hospitals throughout the city. Retrospective review of early COVID-19 cases identified 174 patients with onset in December 2019, 32% of whom had an ascertained link to this location, within a city of over 12 million."
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