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Siebe. Profile picture
Siebe.
@PatientPersists
🎯 Goal: curing SARS-CoV-2 persistence #LongCovid | No formal biomed education | MA Philosophy | MSc Business | ❤️ nuance | effective altruism
Sep 4 • 11 tweets • 4 min read
How much does public research funding affect drug development & market success?

Two papers have looked at this (h/t @mattsclancy @Atelfo ).

Based on these, I ran some quick calculations for ME/CFS and Long Covid

🧵

1/ Image @mattsclancy @Atelfo Toole (2012) found that 1% increase in NIH funding increases new drugs (17-24y later) by 1.8%. Or about $706M in 2010 USD for 1 drug approval
sciencedirect.com/science/articl…Image
Aug 25 • 16 tweets • 4 min read
What's interesting about these findings, is that they had moderately strong correlation with CPET performance! That's in addition to there being a clean separation between healthy controls vs. LC* & ME

I find these findings really exciting!

Some thoughts & caveats

🧵 Image First, a methodology question

The x-axis appears to be a composite measure of 'CF * COL4 (Lumen)'

(Lumen is the internal space of the capillary, through which the blood flows)

In the caption it's called 'CF*Lumen'

I don't know what CF means. Capillary flow? Collagen fiber? Image
Nov 30, 2024 • 5 tweets • 1 min read
This is an important point: not only patient-reported outcomes (surveys) are susceptible to bias.

Many supposedly "objective" measures are susceptible to 'effort effects': people trying harder because they expect they can do more, expect less PEM, want to please, etc. Some examples with high risk of 'effort effects':
- 6-minute walk test
- grip strength
- any other "simple" exercise performance
- realtime brain activity
Mar 18, 2024 • 14 tweets • 2 min read
If you want to get better at evaluating science, I can highly recommend the book Science Fictions by @StuartJRitchie

I just finished it, and it has really emphasized the many issues with science & I learned a lot!

A few takeaways 🧵 Image The image above illustrates it well: looking only at registered trials & their primary outcomes, only 50% of trials found a positive effect of various depression treatments.

However, through publ. bias, outcome switching, spinning results etc, the literature looks much rosier!
Feb 23, 2024 • 7 tweets • 3 min read
This is a great article, worth reading.

A few graphs I noticed in addition to @yaneerbaryam🧵 S100b

Also found increased in this other study

Image
Feb 14, 2024 • 7 tweets • 3 min read
A great paper on viral persistence, with multiple teams using a variety of methods.

They discovered immune activation, as well as efforts to limit immune activity.

Viral persistence assays (Simoa, nCounter, SPEAR) all pooped out: not finding high levels of antigens or RNA Sample: they focused on the most severe patients, who had at least some measurable biological dysfunctions (POTS, microvascular, endothelial, pulmonary)

I really like this: presumably easier to find abnormalities in extreme population

Severity doesn't seem measured via scale 🫤 Image
Feb 4, 2024 • 5 tweets • 2 min read
To make LC more attractive to pharma we need

1. A surrogate biomarker

2. An international patient registry ➡️ reduces costly recruitment

3. Public precommitment by FDA for accelerated pathways for the first effective drugs

Explained:

#UniteToFight2024 atelfo.github.io/2023/12/23/bio…
1. A surrogate biomarker

Requires increased (and targeted) government spending.

Patient advocacy groups are clearly focused on this
Jan 18, 2024 • 18 tweets • 6 min read
This paper has now been uploaded as preprint, and the data is definitely interesting:

➡️ Evidence suggests viral replication in Long Covid
➡️ In whole blood
➡️ In significant fraction of pwLC

Paper:

A summary with graphs 🧵 medrxiv.org/content/10.110…
Sample: 48 pwLC, 12 matched controls. All (but 1) non-hospitalized.
➡️ Bit of a small control group imo

➡️ Analysis done on whole blood, instead of plasma or serum

✅ Significance levels corrected for multiple tests (via FDR)
Jan 11, 2024 • 12 tweets • 3 min read
The low serotonin findings in LC & POTS can probably not be treated with SSRIs.

According to my literature search, SSRIs increase serotonin (=5-HT) in the brain but *decrease* peripheral serotonin.

MAOi (and 5-HTP?) may be more effective, but have limitations

🧵 Study 1)

Results
" In 64 SSRI users, median concentrations of plasma-free and platelet serotonin were 10-fold and 14-fold lower, respectively, than in 64 matched controls."
journals.sagepub.com/doi/10.1177/00…
Jan 4, 2024 • 9 tweets • 3 min read
A wonderful paper! A couple of takeaways

🧵 1/ Plenty of amyloid containing deposits/microclots, but no signs of hypoxia or clogged capillaries --> energy deficiency likely not caused by this, but by mitochondrial dysfunction.

(Microclots could be consequence, or maybe carry something harmful)

#TeamClots Image
Dec 7, 2023 • 16 tweets • 4 min read
Striking claim by @johanvawe at today's conference:

they found evidence strongly suggesting viral replication (antisense SARS-CoV-2 RNA) via transcriptomics in blood of LC patients!

&

Paxlovid reduced all (viral) biomarkers, except for antisense RNA Image This suggests SARS-CoV-2 somehow might evade full shutdown by Paxlovid, and maybe all Mpro inhibitors (like Pax is) need to be coupled with other antiviral therapeutics
Dec 1, 2023 • 10 tweets • 2 min read
Excited about my new mini-project:

setting up a number of prediction questions on prediction market @ManifoldMarkets about Long Covid, e.g.

- predicting outcomes of trials
- other scientific progress
- policy outcomes
- development of new cases

🧵 Betting is done with fake money, but it gives a 'wisdom of the crowds' effect.

Would people be interested in such a prediction market?

@cjmaddison @ahandvanish @AnilvanderZee @chydorina @loscharlos @coco_chatel @RorPreston @postviraltrials @desertdracula @maosbot @cstroeckw
Oct 7, 2023 • 14 tweets • 4 min read
I've been keeping track of covid mab anecdotes/survey data for a while now

I collected about n=40 from surveys, patient groups, and my network. Some may be overlapping.

I believe results are promising

A thread 🧵 Roughly 21 Evusheld anecdotes

4/21 improved (all mild)
1/4 relapsed afterwards
0/21 worsened
Aug 2, 2023 • 12 tweets • 3 min read
UCSF, led by @MichaelPelusoMD, is starting this trial with the anti -SARS-CoV-2 spike antibody cocktail AER002.


Why I'm so excited that this can cure viral persistence in Long Covid:classic.clinicaltrials.gov/ct2/show/NCT05… - AER002 is probably the two mAbs P2G3 LS & P5C3 LS derived from a human, which the inventors of Aerium Therapeutics describe in their paper: ncbi.nlm.nih.gov/pmc/articles/P…
Jun 30, 2023 • 21 tweets • 8 min read
Let's have a look at this paper. The community is very excited about it.

It claims to have found a number of abnormalities, posits a mechanism, and most significantly, claims to have a biomarker for both ME/CFS & #LongCovid

➡️ Imo, all have very significant limitations

A🧵 First some caveats:
- I don't have a biomedical background
- I forgot the details of all my statistics classes
- I have brainfog

Nevertheless, a lot of my criticism doesn't need advanced knowledge, just close reading.

Also, this is a preprint. It hasn't had peer review yet
Jun 7, 2023 • 5 tweets • 1 min read
cell.com/cell-reports/f…

This is such an interesting study (Feb '23), shedding light on neuro-LC. 🧵

- Mice injected with spike had cognitive dysfunction

- It didn't matter where the spike was injected (brain or not)

- dysfunction was delayed (day 30-60), not acute (day 7) - dysfunction improved over time (d60)

- Dysfunction was correlated with synaptic loss, not neuronal

- Dysfunction was caused by microglia (= 'manager cells' in brain) pruning synapses (i.e. neuroinflammation)
Mar 7, 2023 • 5 tweets • 2 min read
Interesting metabolomics paper using #LongCovid chronic headache we phenotype

Sampled 5 times, from acute phase to 3 months out. Small sample!

Mentions a number of familiar things, such as interferons, cytokines, neurotransmitters, arginine.

(Doesn't mention cortisol) One of the more surprising findings to me was that

1) serotonin was upregulated
2) this began already during the acute phase

In fact, for many of the abnormal metabolites, if seems to be off already during the acute phase

SSRI use wouldn't make sense?
Feb 22, 2023 • 13 tweets • 7 min read
Alright, so this study by Klein et al. last year found serum cortisol to be significantly low in #LongCovid

I was surprised at this, and recently looked into the literature.

Tl;dr There are contradictory findings; cortisol doesn't seem a useful biomarker for #LongCovid

🧵 First Klein et al. (2022)
medrxiv.org/content/10.110…

They had 101 LC patients, and found that ~90% had serum cortisol <70ng/ml.

According to some labs, this is below normal, while at others 50-70 might be 'low normal'

CC = convalescent control
HC = healthy control Image
Feb 11, 2023 • 9 tweets • 5 min read
This is super interesting: it looks like researchers found a way SARS-CoV-2 infects cells without full virions/"infectious virus"

The nucleocapsid (N) protein can carry RNA and enter neighbouring cells independent of ACE2.

🧵

rb.gy/jn40v8 This is relevant, because infectious virions largely haven't been found in #LongCovid , which leads some people to conclude the is no actively replicating virus.

However, we know RNA can persist in different ways:
Feb 10, 2023 • 4 tweets • 2 min read
New study:

"the TLR-related receptor LRRC15 as a new spike receptor that can bind and sequester SARS-CoV-2 and limit infection."

The body produces a protein LRRC15 during COVID, where "it lines the airways and may form an innate antiviral barrier"

journals.plos.org/plosbiology/ar…
1/3 "LRRC15 switches fibroblast transcriptional programs from a fibrotic program to an antiviral one"

Collagen production seems decreased while interferon production is increased

2/3
Jan 2, 2023 • 11 tweets • 5 min read
Hopes for the new year: #LongCovid trials I'm excited about

🧵 1) #CPCOV03

Host directed antiviral, induced autophagy

I wrote a thread about it here