7/12/2018

Biopharma
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There are a lot of tau-focused drugs in the clinic: antibodies, antisense. Which will read out first? Hopefully better luck than amyloid. Probably still too late in the disease process to work, but who knows?

Zogenix has themselves a great drug. I wonder how it works. Maybe just 2B antagonism? Anyone know?

Let’s continue with our R&D productivity analysis. Last time we determined Pfizer would have been better off never investing in R&D, and instead contributing their R&D expense to a hypothetical investment fund earning 5% per year. How about Merck?

Organic Merck R&D: Januvia/Janumet, Fosamax, Zocor, Mevacor, Singulair
Schering-Plough/Organon/Centocor/Johnson & Johnson: Zetia, Vytorin, Remicade, Simponi, Nuvaring, Claritin, Clarinex, Peg-Intron, Bridion, Temodar
To Be Continued…

Papers I’ve Read
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Interpreting Genetic Variants in Titin in Patients with Muscle Disorders. Savarese, et al. JAMA Neurol 2018.
The odyssey of diagnosing a rare disease. Not always easy even when you know what you’re looking for.

Understanding Titin Variants in the Age of Next-Generation Sequencing–A Titanic Challenge. Dr. Carsten Bonnermann. JAMA Neurology 2018.
Editorial doesn’t add anything to the paper.

Genital inflammation undermines the effectiveness of tenofovir gel in preventing HIV acquisition in women. McKinnon et al. Nature Medicine 2018.
Lubricating and antiviral, not bad! Honestly, just take PreP pill. I guess I don’t understand global culture. How about a patch?

H3B-8800, an orally available small-molecule splicing modulator, induces lethality in spliceosome-mutant cancers. Seiler, et al. Nature Medicine 2018. This is really good drug discovery science but I fear really bad chemistry. Structure has ‘natural product’ written all over it and look at that chirality!

Dentate granule cell recruitment of feedforward inhibition governs engram maintenance and remote memory generalization. Guo, et al. Nature Medicine 2018. Fascinating! Not for the uninitiated.

Tau Positron Emission Tomography in Autosomal Dominant Alzheimer Disease: Small Windows, Big Picture. McDade & Bateman. JAMA Neurol 2018. See Tau comments above.

Ertugliflozin for Type 2 Diabetes. JAMA 2018.
Welcome to the dance.

Dabigatran in patients with myocardial injury after non-cardiac surgery (MANAGE): an international, randomised, placebo-controlled trial. Devereaux et al. Lancet 2018;391.
Very nice study as MINS and other postoperative complications are underrecognized.

An Incomplete Prescription. President Trump’s Plan to Address high Drug Prices. Sarpatwari et al. JAMA 2018.
This is a joke. The easiest way to lower drug costs is to allow interchangable biosimilars. Old, off-patent biologics are our biggest drug cost. Not mentioned here. The part that really irks me is the authors’ foolish CPI statistics. Yes, drug costs have outpaced inflation. Why, is the question? Why are consumers demanding these goods so much that their prices are rising? Its not a producer-only phenomenon. It has happened since the 1960s. We care about health. Companies are producing great innovations. We have more disposable income than ever. None of this is bad. What perverse insanity this writing is. Not to mention 90% of medical costs come from two letters and one punctuation mark: Dr.

Flatland by Edwin Abbott – A Modern Vantage Point
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Flatland, though published in 1884, still has a voice that speaks to us today. A satire with a mathematical theme, Abbott not only indicts the backward Victorian-aristocrat thinking of his time but also wisely ruminates on higher dimensions. While Abbott foreshadowed the nearby Einstein (to a very small extent), he’d still be very happy to hear about Minkowski spaces and other manifolds where today’s minds contort themselves to understand higher spatial dimensions and fail. “We have no evidence to support the existence of a fourth spatial dimension, and if they do exist, they exist in a compressed and unobservable state”, a modern thinker might say. Not that Abbott was the first person to contemplate “4D” (Kant had him by a mile), but his narrative form is enchanting and illuminative for the simpler, 80-page readers among us.

What was Abbott saying from a psychosocial perspective? His perspective on heirarchy is timeless. Man’s attempt to find order in the world in relation to other men is futile and forgive me, circular. The sorrowful denizens of Flatland reasonably assign rank by the number of sides their person exhibits. The larger the number of sides, the more they approach the perfection ideal (that of a circle) and are accorded status as such. In today’s world, non-capitalist institutions such as politicians, government employees and the media resemble Flatlanders. Without the laissez-faires simplicity of financial order, the non-capitalists struggle to find order, and therefore, meaning. Capitalists have their own problems with meaning, which is an essay for another day. So, non-capitalists are Flatlanders, searching for a pecking order consisting mostly of who can make laws governing the capitalists, interpret and execute laws governing the capitalists, write stories about the capitalists, and sometimes simply and smugly, judge the capitalists. It’s good to govern (explicity in government and implicitly in the media) those you cannot compete with. This psychogical reordering is comfortable, like the pentagon who outranks the isosceles.

In Flatland, one irony is that large-sided polygons are so circle-like, but can never reach circlehood because they’re actually going backwards in the number of sides required: one. If anything, the lowly women, who are but “two-sided” (and often invisible) are closer to perfection than the 500-sided elder “circle”. So, too, it is with the non-capitalist group I described. What could be more frustrating right now than to be a lifelong politician/”civil servant”? To arrive in 2018 and realize you’ve accomplished nothing: President Trump just decided to become President and you are just some 200-sided shape trying to be 210-sided. The usurping of the aristocracy and the idiocy that created it in the first place is the point of Flatland. We don’t have an aristocracy in America, but we do have a strange edifice resembling some aristocratic properties. The government and media thrives on self-importance. Nothing makes journalists I confront angrier than when I tell them their stories don’t matter. No one reads them, no one believes them. You can call me “the most hated man in America”, but the reality is people cheer me and shake my hand everyday. I’ve gotten hundreds, maybe thousands of fan mail and two pieces of hate mail. Two! I’ve been in federal prison for ten months and have been treated like a hero for confronting media and government. If I’m hated, I’d like to see what loved looks like. Is that what Elizabeth Warren is? Nothing makes politicians/government officials angrier than when I make fun of them, often to their face. Don’t I know who they are? That they could put me in jail!?

The facade of the aristocracy’s power is what Flatland exposes. The facade is both the frustrated actions the edifice takes to self-perpetuate (laws, journalist output, the miasma of South Parkian smug filling our lungs) and its precious self-delusion, which must also not be shattered. Letting bubble-dwellers enjoy their setting is a reasonable way to handle their existence. Unfortunately, natural entropy occurs and the popping of safe spaces reminds the self-appointed enlightened that the path they chose is dim and foggy. The shape with the fewest sides, indeed, has the sharpest angles.

Personal
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The 13th is my favorite day of the month, as I was remanded on the 13th and it’s easy to count the months. I have about 3 years left exactly. That I’ll spend 5% of my life in isolated study isn’t pleasant but books like Frankel’s “Man’s Search For Meaning” puts things into perspective! Everyone said the biggest downside to jail is boredom. I am not bored… very, very far from it.

What’s the point of free speech? I’m censored from Twitter/Periscope, Twitch, Okcupid (!), Tinder (!!), and other websites. Why say anything if it’s not the consensus? CONSENUS KNOWS BEST.

Glossary
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dyspnea. shortness of breath.
Heart Failure. A progressive and usually fatal cardiovascular illness where the heart cannot pump enough blood to meet the body’s demands.
Chronic Obstructure Pulmonary Disease (COPD). A progressive lung disease affecting millions of people where airways are obstructed.
spirometry. a breath test used to measure pulmonary function, resulting in important values such as FEV, FVC and lung volume.
cytokine (very important, very simple). A signaling protein, usually activates its cognate (matching) receptor (e.g. IL-6 binds IL-6R). Often used to send a pro-inflammatory or autoimmune signal. Target for many medicines including world’s best-selling drugs, the TNF antibodies.
interstitial (adj) / interstitium (n). the space between organs, sometimes called the “Third Space”.
alveoli (n., pl), alveola (n., si), alveolus (n., si), alveolar (adj). the basic, fundamental respiratory unit in the lung where oxygenation occurs.
pneumonia. inflammation of the alveoli

25 thoughts on “7/12/2018”

  1. Great post today Martin. Stay safe, glad your keeping yourself entertained and educated. I mailed you a letter a little while back, hope you read it… For reference drawn on its envelope is a small grey box. Good luck man!

  2. You are beyond your years Martin. Take this time in prison and lash the sentencing court from back to chest with the knowledge you earn in your concrete box!

  3. Hi Martin, I’ve been following you for a few years now. You inspire me everyday to not be human trash and to do something with myself. It would be fair to call you my hero as you helped me (and many others I’m sure) through some awful times. Good luck in there, much love.

  4. You were acting very remorseful before sentencing, speaking of yourself in third person…The past two posts don’t imply that. Was that an act? It’s okay if it was. I, personally, don’t think you did anything wrong. PS. What do you think of Ross Ulbrict?

  5. “The shape with the fewest sides, indeed, has the sharpest angles.” Quotable.

    As an independently wealthy person, being behind bars (but not for a lifetime) is clearly beneficial in some ways. That is, so long as you do not become bitter.

    You are relatively free from distractions. With disciplined study, you may leave not only richer, but stronger and with more potential; the “J-curve effect”.

    Looking forward to further posts.

  6. How do you have access to WSJ and other scientific articles? Is someone sending them to you or they provide you with access to them at the prison?

    1. He probably has someone copy/paste articles into the “jail email” system and he is able to stay updated that way. Imagine he uses it to send these blogs out as well.

  7. Dear Martin,

    May I please have your opinion on Sesen Bio and their drug Vicinium? They recently released 3 month data on their phase 3 for this drug and based on their presentations this could possible serve as a new viable treatment for patients with bladder cancer? Thank you for your time should you choose to read this and look into this company.

  8. Didn’t you get banned from Twitch for doxxing though? I don’t think that’s really protected under free speech lmao

  9. 13 is also taylor swift’s favorite number.

    “Nothing makes journalists I confront angrier than when I tell them their stories don’t matter. No one reads them, no one believes them.”

    truth.

    i remember during one of your streams you told a journalist that if you made some random sh*tpost online, more people would read that than his article… and the guy had no response.

    -jinx

  10. Hi Martin, thank you for continuing to post. I really enjoy reading these and it complements my own learning well. Very much appreciated. Your the best bro.

  11. Flatland is a great read.

    I like your thoughts on the capitalist’s necessity for order and the non-capitalists inability to find it naturally. Reminds me of Jordan Peterson’s defense of the innate human desire for hierarchal societal structures and ‘non-capitalists’ denial and even rebuke of it (often citing patriarchy). Capitalists assign worth by merit/wealth (this laissez-faires simplicity you speak of) while progressives assign it arbitrarily (sympathy/lack of privilege?). In other words, progressives struggle to find order when they deny capitalism, and resort to their own perverted hierarchy like the Flatlanders, and therefore suffer through a meaningless existence haha.

    Also, the relationship you saw between the lowly women being closer to single sided perfection than the n-gon and the futility of a politician pursuing more sides is brilliant.

    -Jesse, MI, 23

  12. I just bought Flatland thanks for the reference. I appreciated your taste in literature and music. You are indeed a gentleman and a scholar. 🙂

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