In some situations a number of agents each have the ability to undertake an initiative that would have substantial effects on the others. Suppose that each of these agents is purely motivated by an altruistic concern for the common good. We show that if each agent acts on her own personal judgment as to whether the initiative should be undertaken, then the initiative will be undertaken more often than is optimal. We suggest that this phenomenon, which we call the unilateralist’s curse, arises in many contexts, including some that are important for public policy.
To lift the curse, we propose a principle of conformity, which would discourage unilateralist action. We consider three different models for how this principle could be implemented, and respond to an objection that could be raised against it.
[Keywords: The Winner’s Curse, Disagreement, Rationality, Aumann, informative prior, shrinkage, bid shading]
…if an idea comes to mind of artwork I would like to see which doesn’t exist yet, I need to pay real money to commission an artist to do so. In the English-language market, there are quite a few options. These range from art websites such as DeviantArt and FurAffinity, to services which provide you with YCH (Your Character Here) artwork to bid for such as YCH.commishes.
But if you have favourite Japanese artists on services such as Pixiv, then the language barrier may prevent you from outright enquiring whether an artist is taking a commission. This is where Skeb.jp comes in, a Japanese artwork and voice-over commissioning service, which to date has received over 100,000 requests and has thousands of artists taking requests from the public. Like a small but growing number of Japanese artwork sites, English-language support is incorporated into the website. But even more substantial, is the ability for English-writing users to submit requests of their own through the DeepL Translator service.
…Each artist profile provides a direct Yes/No answer around whether they are taking requests, a sample of their public works, approximate rates (minimum and recommended), and the time it takes them to deliver the requested artwork typically. Doing this saves much unreasonable back-and-forth between client and artist about simple information. Instead, the website has you fill out a request form (example below) which allows you to provide specifics and payment. The simple one-page form allows you to enter an overview of the artwork you want to be commissioned (which is translated into English), provide a sum you are happy to pay, determine whether or not you want the artwork to be SFW (Safe for Work) or NSFW (Not Safe for Work) and a few other specifications. Some components of this form (eg. whether NSFW requests are acceptable) can be dictated directly by the artist. Otherwise whichever the client dictates cannot be switched by either party after being submitted. The application is then sent off to the artist, which they have the exclusive right to accept or decline. Depending on the deadline selected, the artist either has 30 days to accept with a delivery deadline of 60 days after submission, or 7 days to take with a delivery deadline of 90 days after submission.
…DeepL is a fantastic machine-learning translator service which I use regularly. But adding to the game of chance, translations can on the odd occasion come out with surreal interpretations. These include instances of こんばんは [“good evening”] being complemented with a dozen exclamation points, to things which don’t match what you wrote at all. Not only do you have the occasional translation issue to deal with, but character limits. Artists can dictate whether they want requests which are 140 characters in length or 1,000 characters in length. In theory, this is great, as it allows artists to dictate whether they want brief requests which will enable them to use their creativity or extended requests that use more of the client’s creativity. But with the 140 character limit, it can get tough to write more than a small sentence or two in English within the count, before they are shortened considerably into Japanese.
By 2009, Harry Hong, a spiky-haired twenty-four-year-old Angeleno, delivered the site’s first certified max-out, and Adam Cornelius, another Tetris enthusiast and a filmmaker, began working on a documentary about the remarkable achievement. When Harrison saw the project on Kickstarter, he donated a few hundred dollars to help complete the film, but added a caveat. “You can’t just talk about Harry Hong”, he recalls writing. “You’ve got to talk about Jonas Neubauer. You’ve got to talk about Thor Aackerlund. You’ve got to get these guys together and have a tournament and see who’s actually the best.”
Some of the players who gathered for the first classic-Tetris tournament, for all their thousands of hours of practice, were in the dark about basic tactics. Hong was stunned to learn that his strategy of scoring Tetrises by dropping long bars into a left-side gap was suboptimal. Due to piece-flipping mechanics, a right-side gap was superior. Dana Wilcox, one of the highest-scoring players on the Twin Galaxies leaderboard, discovered that she’d played for 20 years without knowing that the blocks could be spun in either direction.
…Learning to “hyper-tap” was a priority. Thor had been the first to hyper-tap, but, by 2017, Koryan Nishio, a Japanese programmer in his forties, was the only prominent player using the technique. (“It seemed like a lot of work for a video game”, Vince Clemente, who has co-organized the classic-Tetris tournament since its inception, explained.) To Joseph, though, it was the obvious way to go. To tap quickly, he developed a unique one-handed grip: with his right thumb on the control pad, he flexed his right bicep until his arm shook, pressing down with each tremor, about fifteen times per second. He turned his thumb into a jackhammer.
…Jonas quit his job to stream full-time on Twitch—broadcasting an efficient, battle-tested style for amateurs to emulate. When Joseph won the tournament again, in 2019, he inspired more young players. In 2020 alone, 131 players maxed out; between 1990 and 2019, 87 players had maxed out. Kids had killed the Tetris curve.
These new players see a max-out not as an impossibility, but as a rite of passage. Before even buying the game, most of the rising generation of classic-Tetris players have already watched hours of the best performances, hard-wiring beautiful stacking strategies. As they begin practicing, they often join one of many classic-Tetris servers on Discord, where hundreds of people are online all the time, ready to discuss any aspect of the game. It’s there that they often learn the most common hyper-tapping grip—holding the controller sideways, with the directional pad facing up—and how to properly tense the right arm so that it shakes quickly and consistently. They study the principles of developing a relatively even stack with a built-out left side, and discuss how dropping a pair of tetrominoes in a complementary orientation can reduce the need for a timely T-piece. They can imitate Joseph’s “hyper-tap quick-tap”, in which he sneaks in a left-handed tap among a right-thumb flurry, or watch Jonas’s “Tetris Spin Class” and observe how certain flips can clear a line and make the stack Tetris ready.
What took Jonas years to figure out takes new players minutes. “You don’t need to experiment for hours trying to figure out what works and what doesn’t”, Jacob Huff, a nineteen-year-old who maxed out last March after playing for two months, said. “You can ask someone in the Discord and they’ll tell you every spin that you can do.” Strategies born on Discord are practiced and scrutinized on Twitch, then put to the test in a growing pool of competitions: Classic Tetris Monthly, Classic Tetris League, Classic Tetris Gauntlet, Classic Tetris Brawl. Thanks to hyper-tapping and more efficient stacking, players build higher and higher, almost refusing to accept any line clearance that’s not a Tetris. To the older generation, the style seems reckless. To newer players, it’s simply the best way to play.
…By the quarter-final [of the championship], the entire old guard had vanished. The remaining players were all of the YouTube generation, with many explicitly crediting its algorithm for introducing them to classic Tetris.
“You and Your Research”, (1986-03-07):
[Transcript of a talk by mathematician and Bell Labs manager Richard Hamming about what he had learned about computers and how to do effective research (republished in expanded form as Art of Doing Science and Engineering: Learning to Learn; 1995 video). It is one of the most famous and most-quoted such discussions ever.]
At a seminar in the Bell Communications Research Colloquia Series, Dr. Richard W. Hamming, a Professor at the Naval Postgraduate School in Monterey, California and a retired Bell Labs scientist, gave a very interesting and stimulating talk, ‘You and Your Research’ to an overflow audience of some 200 Bellcore staff members and visitors at the Morris Research and Engineering Center on March 7, 1986. This talk centered on Hamming’s observations and research on the question “Why do so few scientists make substantial contributions and so many are forgotten in the long run?” From his more than 40 years of experience, 30 of which were at Bell Laboratories, he has made a number of direct observations, asked very pointed questions of scientists about what, how, and why they did things, studied the lives of great scientists and great contributions, and has done introspection and studied theories of creativity. The talk is about what he has learned in terms of the properties of the individual scientists, their abilities, traits, working habits, attitudes, and philosophy.
“Toward a Theory of Revolution”, (1962-02):
Revolutions are most likely to occur when a prolonged period of objective economic and social development is followed by a short period of sharp reversal. People then subjectively fear that ground gained with great effort will be quite lost; their mood becomes revolutionary. The evidence from Dorr’s Rebellion, the Russian Revolution, and the Egyptian Revolution supports this notion; tentatively, so do data on other civil disturbances. Various statistics—as on rural uprisings, industrial strikes, unemployment, and cost of living—may serve as crude indexes of popular mood. More useful, though less easy to obtain, are direct questions in cross-sectional interviews. The goal of predicting revolution is conceived but not yet born or mature
2001-garille.pdf: “Stigler's Diet Problem Revisited”, Susan Garner Garille, Saul I. Gass
Obesity is associated with increased mortality, and weight loss trials show rapid improvement in many mortality risk factors. Yet, observational studies typically associate weight loss with higher mortality risk. The purpose of this meta-analysis of randomized controlled trials ( ) of weight loss was to clarify the effects of intentional weight loss on mortality.
2,484 abstracts were identified and reviewed in PUBMED, yielding 15 reporting (1) randomization to weight loss or non-weight loss arms, (2) duration of ≥18 months, and (3) deaths by intervention arm. Weight loss interventions were all lifestyle-based. Relative risks (RR) and 95% confidence intervals (95% CI) were estimated for each trial. For trials reporting at least one death (n = 12), a summary estimate was calculated using the Mantel-Haenszel method. Sensitivity analysis using sparse data methods included remaining trials.
Trials enrolled 17,186 participants (53% female, mean age at randomization = 52 years). Mean body mass indices ranged from 30–46 kg/m2, follow-up times ranged from 18 months to 12.6 years (mean: 27 months), and average weight loss in reported trials was 5.5±4.0 kg. A total of 264 deaths were reported in weight loss groups and 310 in non-weight loss groups. The weight loss groups experienced a 15% lower all-cause mortality risk (RR = 0.85; 95%: 0.73–1.00). There was no evidence for heterogeneity of effect (Cochran’s Q = 5.59 (11 d.f.; p = 0.90); I2 = 0). Results were similar in trials with a mean age at randomization ≥55 years (RR = 0.84; 95% 0.71–0.99) and a follow-up time of ≥4 years (RR = 0.85; 95% 0.72–1.00).
In obese adults, intentional weight loss may be associated with approximately a 15% reduction in all-cause mortality.
Libertarians are an increasingly prominent ideological group in U.S. politics, yet they have been largely unstudied. Across 16 measures in a large web-based sample that included 11,994 self-identified libertarians, we sought to understand the moral and psychological characteristics of self-described libertarians. Based on an intuitionist view of moral judgment, we focused on the underlying affective and cognitive dispositions that accompany this unique worldview. Compared to self-identified liberals and conservatives, libertarians showed (1) stronger endorsement of individual liberty as their foremost guiding principle, and weaker endorsement of all other moral principles; (2) a relatively cerebral as opposed to emotional cognitive style; and (3) lower interdependence and social relatedness. As predicted by intuitionist theories concerning the origins of moral reasoning, libertarian values showed convergent relationships with libertarian emotional dispositions and social preferences. Our findings add to a growing recognition of the role of personality differences in the organization of political attitudes.
2012-shenhav.pdf: “Divine intuition: cognitive style influences belief in God”, (2012; ):
Some have argued that belief in God is intuitive, a natural (by-)product of the human mind given its cognitive structure and social context. If this is true, the extent to which one believes in God may be influenced by one’s more general tendency to rely on intuition versus reflection. Three studies support this hypothesis, linking intuitive cognitive style to belief in God. Study 1 showed that individual differences in cognitive style predict belief in God. Participants completed the Cognitive Reflection Test (CRT; Frederick, 2005), which employs math problems that, although easily solvable, have intuitively compelling incorrect answers. Participants who gave more intuitive answers on the CRT reported stronger belief in God. This effect was not mediated by education level, income, political orientation, or other demographic variables. Study 2 showed that the correlation between CRT scores and belief in God also holds when cognitive ability (IQ) and aspects of personality were controlled. Moreover, both studies demonstrated that intuitive CRT responses predicted the degree to which individuals reported having strengthened their belief in God since childhood, but not their familial religiosity during childhood, suggesting a causal relationship between cognitive style and change in belief over time. Study 3 revealed such a causal relationship over the short term: Experimentally inducing a mindset that favors intuition over reflection increases self-reported belief in God.
[Keywords: reasoning, religion, religiosity, reflection, atheism.]
2000-cook.pdf: “How Complex Systems Fail: Being a Short Treatise on the Nature of Failure; How Failure is Evaluated; How Failure is Attributed to Proximate Cause; and the Resulting New Understanding of Patient Safety”, (2000; ):
- Complex systems are intrinsically hazardous systems.
- Complex systems are heavily and successfully defended against failure.
- Catastrophe requires multiple failures—single point failures are not enough.
- Complex systems contain changing mixtures of failures latent within them
- Complex systems run in degraded mode.
- Catastrophe is always just around the corner.
- Post-accident attribution accident to a ‘root cause’ is fundamentally wrong.
- Hindsight biases post-accident assessments of human performance.
- Human operators have dual roles: as producers & as defenders against failure.
- All practitioner actions are gambles.
- Actions at the sharp end resolve all ambiguity.
- Human practitioners are the adaptable element of complex systems.
- Human expertise in complex systems is constantly changing.
- Change introduces new forms of failure.
- Views of ‘cause’ limit the effectiveness of defenses against future events.
- Safety is a characteristic of systems and not of their components.
- People continuously create safety.
- Failure free operations require experience with failure.
1976-sagan.pdf: “Particles, environments, and possible ecologies in the Jovian atmosphere”, (1976-10-01; ):
The possible existence of indigenous Jovian organisms is investigated by characterizing the relevant physical environment of Jupiter, discussing the chromophores responsible for the observed coloration of the planet, and analyzing some permissible ecological niches of hypothetical organisms. Values of the eddy diffusion coefficient are estimated separately for the convective troposphere and the more stable mesosphere, and equilibrium condensation is studied for compounds containing Na, Cl, or both. The photoproduction of chromophores and nonequilibrium organic molecules is analyzed, and the motion of hypothetical organisms is examined along with the diffusion of metabolites and the consequent growth of organisms. Four kinds of organisms are considered: primary photosynthetic autotrophs (‘sinkers’), larger autotrophs or heterotrophs that actively maintain their pressure level (‘floaters’), organisms that seek out others (‘hunters’), and organisms that live at almost pyrolytic depths (‘scavengers’). It is concluded that ecological niches for sinkers, floaters, and hunters appear to exist in the Jovian atmosphere.
…The eddy diffusion coefficient is estimated as a function of altitude, separately for the Jovian troposphere and mesosphere. The growth-rate and motion of particles is estimated for various substances: the water clouds are probably nucleated by NH4Cl and sodium compounds are likely to be absent at and above the levels of the water clouds. Complex organic molecules produced by the Lα photolysis of methane may possibly be the absorbers in the lower mesosphere which account for the low reflectivity of Jupiter in the near-ultraviolet. The optical frequency chromophores are localized at or just below the Jovian tropopause. Candidate chromophore molecules must satisfy the condition that they are produced sufficiently rapidly that convective pyrolysis maintains the observed chromophore optical depth. Organic molecules and polymeric sulfur produced through H2S photolysis at λ>2300 Å probably fail this test, even if a slow, deep circulation pattern, driven by latent heat, is present. The condition may be satisfied if complex organic chromophores are produced with high quantum yield by NH3 photolysis at λ<2300 Å. However, Jovian photoautotrophs in the upper troposphere satisfy this condition well, even with fast circulation, only biochemical properties of comparable terrestrial organisms are assured. Unless buoyancy can be achieved, a hypothetical organism drifts downward and is pyrolyzed. An organism in the form of a thin, gas-filled balloon can grow fast enough to replicate if (i) it can survive at the low mesospheric temperatures, or if (ii) photosynthesis occurs in the troposphere. If hypothetical organisms are capable of slow, powered locomotion and coalescence, they can grow large enough to achieve buoyancy. Ecological niches for sinkers, floaters, and hunters appear to exist in the Jovian atmosphere.
1997-carter-shotetsu-unforgottendreams.pdf: “Unforgotten Dreams: Poems by the Zen Monk Shōtetsu”, (1997; ):
[This volume presents translations of over 200 poems by Shōtetsu, who is generally considered to be the last great poet of the uta form. Includes an introduction, a glossary of important names and places and a list of sources of the poems.]
The Zen monk Shōtetsu (1381–1459) suffered several rather serious misfortunes in his life: he lost all the poems of his first thirty years—more than 30,000 of them—in a fire; his estate revenues were confiscated by an angry shogun; and rivals refused to allow his work to appear in the only imperially commissioned poetry anthology of his time. Undeterred by these obstacles, he still managed to make a living from his poetry and won recognition as a true master, widely considered to be the last great poet of the classical uta, or waka, tradition. Shōtetsu viewed his poetry as both a professional and religious calling, and his extraordinarily prolific corpus comprised more than 11,000 poems—the single largest body of work in the Japanese canon.
The first major collection of Shōtetsu’s work in English, Unforgotten Dreams presents beautifully rendered translations of more than two hundred poems. The book opens with Steven Carter’s generous introduction on Shōtetsu’s life and work and his importance in Japanese literature, and includes a glossary of important names and places and a list of sources of the poems. Revealing as never before the enduring creative spirit of one of Japan’s greatest poets, this fine collection fills a major gap in the English translations of medieval Japanese literature.
1990-murphy.pdf: “The Lifetime Risk of Suicide in Alcoholism”, (1990-04-01; ):
Current estimates of the lifetime risk of suicide in alcoholism (11% to 15%) are shown statistically to be untenable. Examination of the mortality from suicide in all published follow-up studies of alcoholics containing the requisite data permits calculation of a much smaller lifetime suicide risk: about 2% in untreated and 2.21% in outpatient-treated probands. Studies of alcoholics identified from hospital admissions yield a lifetime risk of about 3.4% for the United States, the United Kingdom, and other English-speaking countries. It is higher in the Scandinavian and European countries with high suicide rates, but not in those with low national suicide rates. The population at risk is shown to be about half of that commonly estimated, and consists of seriously affected alcoholics. While the annual incidence of suicide in the United States is about 1.3% currently, only that quarter of the population identifiably psychiatrically ill is at substantial risk. Despite the seemingly minuscule lifetime risk of 2% to 3.4%, the likelihood of suicide in conservatively diagnosed alcoholism is between 60 and 120 times that of the non-psychiatrically ill. Such alcoholism contributes about 25% of the suicides.
2011-ziobrowski.pdf: “Abnormal Returns From the Common Stock Investments of Members of the U.S. House of Representatives”, Alan J. Ziobrowski, James W. Boyd, Ping Cheng, Brigitte J. Ziobrowski
2004-ziobrowski.pdf: “Abnormal Returns from the Common Stock Investments of the U.S. Senate”, (2004-12-01; ):
The actions of the federal government can have a profound impact on financial markets. As prominent participants in the government decision making process, U.S. Senators are likely to have knowledge of forthcoming government actions before the information becomes public. This could provide them with an informational advantage over other investors. We test for abnormal returns from the common stock investments of members of the U.S. Senate during the period 1993–1998. We document that a portfolio that mimics the purchases of U.S. Senators beats the market by 85 basis points per month, while a portfolio that mimics the sales of Senators lags the market by 12 basis points per month. The large difference in the returns of stocks bought and sold (nearly one percentage point per month) is economically large and reliably positive.
Common maxims about beauty suggest that attractiveness is not important in life. In contrast, both fitness-related evolutionary theory and socialization theory suggest that attractiveness influences development and interaction. In 11 meta-analyses, the authors evaluate these contradictory claims, demonstrating that (a) raters agree about who is and is not attractive, both within and across cultures; (b) attractive children and adults are judged more positively than unattractive children and adults, even by those who know them; (c) attractive children and adults are treated more positively than unattractive children and adults, even by those who know them; and (d) attractive children and adults exhibit more positive behaviors and traits than unattractive children and adults. Results are used to evaluate social and fitness-related evolutionary theories and the veracity of maxims about beauty.
Volumetric dosing is the process of dissolving a compound in a liquid to make it easier to measure. In the interest of harm reduction, it is important to use volumetric dosing with certain compounds that are too potent to measure with traditional weighing scales. This technique makes it possible to use a cheap $30 scale and still measure accurately to a few milligrams.
Many psychoactive substances, including benzodiazepines and certain psychedelics, are active at less than a single milligram. Such small quantities cannot be accurately measured with common digital scales, so the drug must instead be dosed volumetrically by weighing out larger amounts of the compound and dissolving it in a calculated volume of a suitable liquid.
“I have a slight fascination with sweeteners.”, (2015-04-26):
I have a slight fascination with sweeteners. About five years ago I imported a kilo of “Neotame” sweetener from a chem factory in Shanghai. It was claimed to be 10,000–12,000 times sweeter than sugar. It’s a white powder and came in a metal can with a crimped lid and typically plain chemical labeling. Supposedly it is FDA-approved and a distant derivative of aspartame.
US customs held it for two weeks before sending it on to Colorado with no explanation. When received, the box was covered in “inspected” tape and they had put the canister in a clear plastic bag. The crimped lid looked like a rottweiler chewed it open and white powder was all over the inside of the bag. I unwisely opened this in my kitchen with no respirator as advised by the MSDS which I read after the fact (I am not a smart man).
Despite careful handling of the bag, it is so fine in composition that a small cloud of powder erupted in front of me and a hazy layer of the stuff settled over the kitchen. Eyes burning and some mild choking from inhaling the cloud, I instantly marveled at how unbelievably sweet the air tasted, and it was delicious. For several hours I could still taste it on my lips. The poor customs inspector will have had a lasting memory of that container I’m pretty sure.
Even after a thorough wipe-down, to this day I encounter items in my kitchen with visually imperceptible amounts of residue. After touching it and getting even microscopic quantities of the stuff on a utensil or cup, bowl, plate, whatever, it adds an intense element of sweetness to the food being prepared, sometimes to our delight. I still have more than 900g even after giving away multiple baggies to friends and family (with proper safety precautions).
We have been hooked on it since that first encounter. I keep a 100mL bottle of solution in the fridge which is used to fill smaller dropper bottles. I’ve prepared that 100mL bottle three times over five years, and that works out to about 12g of personal (somewhat heavy) usage for two people in that time. Probably nowhere near the LD50.
I carry a tiny 30mL dropper bottle of the solution for sweetening the nasty office coffee and anything else as appropriate. Four drops to a normal cup of coffee. We sweeten home-carbonated beverages, oatmeal, baked goods (it is heat stable), use it in marinades, and countless other applications.
I don’t know if it’s safe. The actual quantity used is so incredibly tiny that it seems irrelevant. I’d sweeten my coffee with polonium-210 if it could be done in Neotame-like quantities. Between this, a salt shaker loaded with MSG and a Darwin fish on my car, I’m doomed anyway.
1995-dunitz.pdf: “Disappearing Polymorphs”, (1995; ):
When a compound exhibits polymorphism—the existence of more than one crystal structure—it may be important to obtain a particular polymorph under controlled and reproducible conditions. However, this is not always easy to achieve. Tales of difficulties in obtaining crystals of a particular known form or in reproducing results from another laboratory (or even from one’s own!) abound. Indeed, there are cases where it was difficult to obtain a given polymorphic form even though this had previously been obtained routinely over long time periods. Several monographs contain explicit or passing references to these problems, but much of this lore has gone undocumented, especially in the last 30 years or so. In this Account we present and discuss old and new examples.
“Disappearing Polymorphs Revisited”, (2015-06-01):
Nearly twenty years ago, Dunitz and Bernstein described a selection of intriguing cases of polymorphs that disappear. The inability to obtain a crystal form that has previously been prepared is indeed a frustrating and potentially serious problem for solid-state scientists. This Review discusses recent occurrences and examples of disappearing polymorphs (as well as the emergence of elusive crystal forms) to demonstrate the enduring relevance of this troublesome, but always captivating, phenomenon in solid-state research. A number of these instances have been central issues in patent litigations. This Review, therefore, also highlights the complex relationship between crystal chemistry and the law.
“Perverse Polymorphism”, (2019-11-26):
…as the case of ritonavir shows, you can have a compound that has been worked on for years and produced commercially in bulk that hits upon a more stable solid phase. And since these more stable crystal forms tend to have very different solubilities, the effect on a drug development program (or in ritonavir’s case, a drug that is already rolling off the manufacturing line!) can be extremely unwelcome. When this happens, it can seem as if the original crystal form is going extinct and never to be seen again, an effect that seems almost supernatural. But as these papers note, the “unintentional crystalline seed” hypothesis is surely the explanation.
…What’s more, a given cubic foot of air could easily contain a million or so particles under a half-micron size without anyone noticing at all. Consider also that such too-small-to-see particles can lurk in what looks like a clear solution, and you have plenty of opportunities to spread a given polymorph around by what seems like magic. The 2015 paper tracks down several examples of the spread of such material…It’s also not true that polymorphs can truly go extinct, either, although it’s understandable that it might appear that way. There are always conditions out there to obtain the old crystalline form, although there is no requirement that these be easy to find (!) Indeed, the original form of ritonavir was recovered and brought back into production after a great deal of effort, although not before HIV-positive patients had seen their medicine disappear from the shelves for months (and not before Abbott had lost a quarter of a billion dollars along the way).
…There are compounds for which only one crystalline form has ever been reported, and there are others with two dozen polymorphs (and when that’s happening, you can be pretty sure that there are some others that haven’t shown up yet). Only one polymorph of aspirin was known until 2005, when another turned up.
“The Most Important Scientist You’ve Never Heard Of: For 60 years, American drivers unknowingly poisoned themselves by pumping leaded gasoline into their tanks. Here is the lifelong saga of Clair Patterson—a scientist who helped build the atomic bomb and discovered the true age of the Earth—and how he took on a billion-dollar industry to save humanity from itself.”, (2017-05-17):
[Clair Patterson’s clean-room innovations, reducing bias in chemistry, led to his anti-lead crusade as he discovered that existing data on ‘natural’ lead contamination were useless garbage due to global contamination & corrupt researchers, masking enormous increases, and played a key role in the recognition of its danger and eventual ban.]
…The feds gave lip service to critics like Henderson, advocating that independent researchers should continue investigating leaded gasoline. But it never happened. In fact, independent researchers failed to study leaded gasoline for the next four decades. For 40-plus years, the safety of leaded gasoline was studied almost entirely by Kehoe and his assistants. That entire time, Kehoe’s research on tetraethyl lead was funded, reviewed, and approved by the companies making it. Kehoe and the Ethyl Corporation would maintain this monopoly until Clair Patterson, scratching his head in a Chicago laboratory, wondered why so much lead was fouling his beloved rocks.
…scientists pegged the Earth’s age at 3.3 billion years. However, an aura of mystery and uncertainty still surrounded the number…Brown knew if somebody uncracked the ratio of uranium to lead inside an old rock, he could learn its age. That included Earth itself. Brown worked out a mathematical equation to nail the age of the Earth, but, to solve it, he needed to analyze rock samples 1000× smaller than anybody had ever measured before. Brown needed a protégé, somebody experienced tinkering with a mass spectrometer and uranium, to make it happen…Wanting to ensure that Brown’s formula—and their methods—were correct, the duo started each experiment with the same routine. First they’d crush granite, then Tilton would measure the uranium as Patterson handled the lead. But the numbers always came out goofy…Patterson figured he had the same problem. He tried to remove lead contamination from his samples. He scrubbed his glassware. Too much lead. He used distilled water. Too much lead. He even tested blank samples that, to his knowledge, contained no lead at all. Lead still showed up. “There was lead there that didn’t belong there”, Patterson recalled. “More than there was supposed to be. Where did it come from?”
…As journalist Lydia Denworth describes in her book, Toxic Truth, Patterson went to enormous lengths to rid his lab of contaminants. He bought Pyrex glassware, scoured it, dunked it in hot baths of potassium hydroxide, and rinsed it with double-distilled water. He mopped and vacuumed, dropping to his hands and knees to buff out any traces of lead from the floor. He covered his work surfaces with Parafilm and installed extra air pumps in his lab’s fume hood—he even built a plastic cage around it to prevent airborne lead from hitchhiking on dust. He wore a mask and gown and would later cloak his body in plastic. The intensity of these measures was unusual for the time. It would be another decade before the laminar-flow “Ultra Clean Lab” would be patented. Patterson’s contemporaries simply didn’t know that approximately 3 million microscopic particles floated around the typical lab, each particle a barrier obstructing The Truth. Five years would pass before Patterson finally perfected his own ultraclean techniques…At Caltech, Patterson built the cleanest laboratory in the world. He tore out lead pipes in the geology building and re-wired the walls (lead solder coated the old wires). He installed an airflow system to pump in purified, pressurized air and built separate rooms for grinding rocks, washing samples, purifying water, and analysis. The geology department funded the overhaul by selling its fossil collection. Patterson knighted himself the kingpin of clean. “You know Pigpen, in Charlie Brown’s comic, where stuff is coming out all over the place?” he told Cohen. “That’s what people look like with respect to lead. Everyone. The lead from your hair, when you walk into a super-clean laboratory like mine, will contaminate the whole damn laboratory. Just from your hair.”…He demanded that his assistants scrub the floor with small wipes daily. Later, he’d ban street clothes and require his assistants to wear Tyvek suits (scientific onesies).
…Discovering the age of the Earth was one of the greatest scientific accomplishments of the 20th century, yet Patterson couldn’t kick back and relish it. Lead contamination, he learned, was ubiquitous, and nobody else knew it. He was clueless as to where the lead originated. All he knew was that every scientist in the world studying the metal—from the lead in space rocks to the lead in a human body—must be publishing bad numbers.
…Patterson collected samples from all depths and returned to his ultraclean lab. “Then a very bad thing happened”, he recalled. He found that the samples of young water contained about 20 times more lead…His conclusion was dire. The human body probably contained 100 times more lead than natural. “Man himself is severely contaminated”, Patterson said…The [final] results? The modern American contained nearly 600× more lead than his or her ancestors.
…Back in California, Patterson developed stringent protocols to avoid contamination. It could take days to analyze just one sample. He made researchers wrap their bodies in acid-washed polyethylene bags. Each new sample was handled with a new pair of acid-cleaned gloves. The numbers out of Greenland stupefied. The samples showed a “200- or 300-fold increase” in lead from the 1700s to present day. But the most startling jump had occurred in the last three decades. Talk about smoking guns: Lead contamination had rocketed as car ownership—and gasoline consumption—boomed in North America. By more than 300%. Patterson received a bigger surprise, however, when he surveyed the oldest ice samples. The ice from the 1750s wasn’t pure either. Neither was ice from the year 100 BC. Lead pollution was as old as civilization itself…“The same contamination problem that prevented Patterson from dating the Earth for many years also kept scientists, unknowingly, from measuring accurate concentrations of lead”, Cliff Davidson writes in Clean Hands. “There were plenty of values reported in the scientific literature, but they were mostly wrong.”…For decades, most experts rejected Patterson’s work because they carelessly tested corrupted samples and could not verify his data.
…Patterson’s testimony would influence the Clean Air Act of 1970, which granted the EPA authority to regulate additives in fuel—lead included…By that point, legislators were more apt to listen to Patterson. Once a kooky egghead, he had risen to become a mainstream scientific prophet. He was accepted into the National Academy of Science. He won the Tyler Prize, the greatest environmental science award. An asteroid was even named in his honor. In 1986, the EPA called for a near ban of leaded gasoline.
description.html: “Novir Advisory”, (2000; ):
[Set of online resources published by IAPAC summarizing the Norvir disappearing-polymorph AIDS crisis. As summarized by Bučar et al 2015:]
Public relations footnote: As noted, Abbott’s initial encounter with Form II and its inability to produce Form I led to the disappearance of the drug Norvir® from the market, leaving tens of thousands of AIDS patients without medication. This led to a serious public relations problem for Abbott. To allay public concern, the company held a number of interviews and press conferences, at which senior Abbot officials appeared in order to answer questions. The transcripts were originally published on the website42 of the International Association of Physicians in AIDS Care, but no longer appear there. Some excerpts vividly portray the situation that can arise when a disappearing polymorph is encountered:
“There was no gradual trend. Something occurred that caused the new form to occur……There was no early warning.”
“We, quite honestly, have not been able to pinpoint the precise conditions which led to the appearance of the new crystal form. We now know that the new form is, in fact, more stable than the earlier form, so nature would appear to favor it……Form II is new.”
“We did not know how to detect the new form. We did not know how to test for it. We did not know what caused it. We didn’t know how to prevent it. And we kept asking the question, why now?……We did not know the physical properties of the new form……We did not know how to clean it, and we did not know how to get rid of it.”
“……our initial activities were directed toward eliminating Form II from our environment. Then we finally accepted that we could not get rid of Form II. Then our subsequent activities were directed to figuring out how to live in a Form II world.”
“This is why all of us at Abbott have been working extremely hard throughout the summer [of 1998], often around the clock, and sometimes never going home at night. We have been here seven days a week and we will continue to do so. We have cancelled vacations and asked our families for their understanding and support. This is not an issue that we take lightly.”
“There were several sub-teams of three to 600 people per team working full time in different areas. We also called on as many resources as we could.”
“We tried everything. We conducted countless experiments. We reconditioned our facilities. We rebuilt facilities and new lines. We looked at alternative sites. We visited a number of [other] organizations around the world……to see if we could start clean in a new environment free of Form II.”
“In a matter of weeks—maybe five or six weeks, every place the product was became contaminated with Form II crystals.”
Question: “You are a large multinational company. Your scientists are obviously smart. How could this happen?”
Answer: “A company’s size and the collective IQs of their scientists have no relationship to this problem……This obviously has not happened to every drug. But it has happened to other drugs.”
1960-campbell.pdf#page=5: “The Self-Repairing Robot: Disappearing Polymorphs”, (1960; ):
[From Analog Magazine, October 1960 (v66, #2), pg87–88.
Part of a larger article on growing crystals and self-organization. Campbell describes two examples:
- glycerine, where attempts to freeze it per a German chemist’s research failed and resulted only in a glass, until they contacted him for information and he sent a sample of his glycerine back, which ‘contaminated’ their own samples and resulted in frozen glycerine but now never glass.
- EDT: Bell Labs was growing quartz-substitute crystals called EDT which worked perfectly, replacing expensive quartz, until one day a new polymorph showed up, destroying all EDT crystal production. All attempts to recreate EDT failed, but fortunately, the problem of growing quartz had been solved in the mean time, so it was ultimately not a disaster.]
1950-kohman.pdf: “The case of the barnacled crystal”, (1950-01-01; ):
[Bell Labs account of a bizarre chemical problem.
Bell manufactured in substantial volume ethylene diamine tartrate (EDT), a piezoelectric synthetic crystal, which it used as a substitute for scarce quartz in telephone line components. While the crystals were usually easy to grow, simply by slicing up crystals and dunking them in solutions, new crystals were sprouting a different EDT crystal, a kind of crystal which grew well in the existing solution and solutions prepared from scratch and solutions made from the new crystals as well, yet was completely worthless. This had happened despite no changes in the manufacturing process.
Investigation revealed the new crystal was in fact EDT, but a kind with an additional water molecule. This kind was more stable at lower temperatures than the original, and the manufacturing happened to be done slightly under the critical crossover point—and the ‘superior’ EDT form had finally spontaneously happened and now infected all manufacturing. (Because of the instability, any contact with moisture, such cutting crystals with water jets, would make the new form “sprout like fungus growth”.)
The solution was to eliminate moisture as much as possible, and start manufacturing at temperatures above the crossover point, where the new kind is disfavored.]
The Edgewood Arsenal Human Experiments were a series of classified studies conducted by the U.S. Army at the Edgewood Arsenal in Maryland between 1955 and 1975. A wide variety of chemical weapon applications and protections were tested, including the use of psychoactive agents. Unlike MKUltra, which was tested on many people without their consent, the Edgewood Arsenal Experiments were tested on volunteer army personnel. They were not however, prepared for the horrors they would be exposed to. The psychoactive compounds tested in these experiments include a variety of familiar chemicals like LSD, PCP, and various synthetic cannabinoids. Of particular interest however, are anticholinergics that were tested, better known as deliriants, a class of chemicals notorious for inducing hallucinations through a psychosis-like state, where the user has difficulty distinguishing hallucinations from reality.
Some of the deliriants that were tested will be detailed below. Almost all of the information on them comes from a series of summary reports on the experiments published by the National Academy of Medicine from 1982–1985, along with a detailed Memoir by one of the lead scientists behind the project Dr. James S. Ketchum. All of them except BZ were invented for the purpose of being studied and are only known by a codename “EA” (For Edgewood Arsenal) followed by 4 numbers. We will specifically look at BZ, EA-3443, EA-3580, EA-3834, and EA-3167. The effects of these extremely potent drugs are remarkable and terrifying.
…EA-3167 was most notable for its extreme duration, unlike that of any other psychoactive known of any class. Incapacitating effects could last anywhere from 5–10 days, which could sometimes present as a full 3 day long peak of vivid hallucinations, along with drawn out confusion, amnesia, and inhibition of speech and cognition4. Some subjects would not fully recover for almost 20 days4. After two weeks the symptoms experienced by subjects included:
“included increased irritability; mild impairment of memory, judgment, or abstraction; mental sluggishness with occasional confusion; nervousness; and tenseness.”1
Even 6 months later, a few of the subjects exposed to higher doses demonstrated:
“significant increases in the scores on the hypochondriasis, depression, hysteria, psychasthenia, schizophrenia, and mania scales”
Subjects would often have to be exposed to drawn out and extreme cumulative doses of physostigmine (which can be toxic itself at high doses) to stave off lasting delirium4.
…The potency of EA-3167 was in the range of other deliriants studied when given intramuscularly, 4.1 μg/kg (254 μg in an average person)1. The power of this chemical is astounding-around a quarter of a milligram is enough to induce a 10 day marathon of incapacitated delirium, with at least 3 days of full blown delirious hallucinations. That such a compound can exist and that it is even possible to affect the human mind in that way is utterly terrifying.
“This Chemical Is So Hot It Destroys Nerve Endings—in a Good Way: Resiniferatoxin is 10,000 times hotter than the hottest pepper, and has features that make it promising as a painkiller of last resort”, (2018-11-14):
In Morocco there grows a cactus-like plant that’s so hot, I have to insist that the next few sentences aren’t hyperbole. On the Scoville Scale of hotness, its active ingredient, resiniferatoxin, clocks in at 16 billion units. That’s 10,000 times hotter than the Carolina reaper, the world’s hottest pepper, and 45,000 times hotter than the hottest of habaneros, and 4.5 million times hotter than a piddling little jalapeno. Euphorbia resinifera, aka the resin spurge, is not to be eaten. Just to be safe, you probably shouldn’t even look at it.
But while that toxicity will lay up any mammal dumb enough to chew on the resin spurge, resiniferatoxin has also emerged as a promising painkiller. Inject RTX, as it’s known, into an aching joint, and it’ll actually destroy the nerve endings that signal pain. Which means medicine could soon get a new tool to help free us from the grasp of opioids.
…RTX is a capsaicin analog, only it’s between 500 and 1,000 times more potent. When RTX binds to TRPV1, it props open the nerve cell’s ion channel, letting a whole lot of calcium in. That’s toxic, leading to the inactivation of the pain-sensing nerve endings.
This leaves other varieties of sensory neurons unaffected, because RTX is highly specific to TRPV1. “So you gain selectivity because it only acts on TRPV1, which is only on a certain class of fibers, which only transmit pain”, says Yaksh. “Therefore you can selectively knock out pain without knocking out, say, light touch or your ability to walk.” So if you wanted to treat knee pain, you could directly inject RTX into the knee tissue. You’d anesthetize the patient first, of course, since the resulting pain would be intense. But after a few hours, that pain wears off, and you end up with a knee that’s desensitized to pain.
Researchers have already done this with dogs. “It is profoundly effective there, and lasts much, much longer than I might have expected, maybe a median of 5 months before the owners of the dogs asked for reinjection”, says Michael Iadarola, who’s studying RTX at the National Institutes of Health. “The animals went from basically limping to running around.” One dog even went 18 months before its owners noticed the pain had returned…That and you have to take constantly, but not so with RTX. “You give it once and it should last for an extended period of time because it is destroying the fibers”, says Mannes. “But the other thing with this to remember is there’s no reinforcement. There’s no high associated with it, there’s no addiction potential whatsoever.”
1997-appendino.pdf: “Euphorbium: Modern research on its active principle, resiniferatoxin, revives an ancient medicine”, (1997-01-31; ):
Resiniferatoxin, an ultrapotent capsaicin analog present in the latex of Euphorbia resinifera, interacts at a specific membrane recognition site (referred to as the vanilloid receptor), expressed by primary sensory neurons mediating pain perception as well as neurogenic inflammation. Desensitization to resiniferatoxin is a promising approach to mitigate neuropathic pain and other pathological conditions in which sensory neuropeptides released from capsaicin-sensitive neurons play a crucial role. Clinical trials to evaluate the potential of topical resiniferatoxin treatment to relieve pain associated with diabetic polyneuropathy and postherpetic neuralgia are in progress. Though resiniferatoxin was isolated only two decades ago, the dried latex of Euphorbia resinifera, called Euphorbium, has been in medicinal use since the time of recorded history. This review highlights the most important events in the history of this ancient medicine, from the first written record of the therapeutic potential of Euphorbium (at the time of the reign of the Roman Emperor Augustus) to the identification of its active principle as resiniferatoxin in 1975. A brief overview of the enormous contribution of resiniferatoxin to our current understanding of the anatomical localization, function, and pharmacology of vanilloid receptors is provided. Lastly, the mechanisms are summarized by which capsaicin and resiniferatoxin, despite sharing receptors, may have dissimilar biological actions.
[Keywords: euphorbium, resiniferatoxin, capsaicin, vanilloid receptors]
…Only a few fragments of King Juba’s treatise are left6, thus information on the medicinal use of Euphorbium in this period is rather scanty. Subsequently, Euphorbium is mentioned both in the Greek (eg. Dioscorides) and Latin (eg. Pliny the Elder) medical literature as a stemutative (nose irritation) as well as vesicant (skin irritation) agent9. It was also used in the treatment of lethargy: patients could be awakened by “touching their nostrils with a solution of Euphorbium in vinegar”10, with dramatic results, no doubt about it. Other uses of Euphorbium, mentioned by Pliny7, are, however, puzzling, such as the instillation of Euphorbium solutions into the eyes to sharpen sight, or its generalized use against poisons and snake bites. In this case the cure sounds almost worse than the disease: according to Pliny7, no matter where the bite is, an incision is to be made on the skull and the medicament should be inserted there!…During the Renaissance, Euphorbium was widely used as a stemutatory (to provoke sneezing), until its popularity was overshadowed by tobacco5.
…The irritancy of Euphorbium was legendary. Matthiolus in his above mentioned Pedacio Dioscorides reports that pharmacists refused to pulverize it, leaving this task to “facchini o altre persone vili et mecaniche” (that is, to blue collar workers, in today’s lingo)15. Two hundred years later, powdering Euphorbium was still left to “paysans ou gens de basse condition” (ie., to peasants and other folks of low social standing)18. No wonder that Euphorbium soon enjoyed a sinister fame among the makers of practical jokes. For example, balls were disrupted by the general sneezing that followed the spreading of Euphorbium powder on the floor23. Such (mis)use of Euphorbium even found its way into the dramatic literature: Panurge, the merry and cowardly companion of Pantagruel in Rabelais’ play, entitled “Gargantua et Pantagruel”, makes fun of a young girl by giving her a beautiful handkerchief sprinkled with Euphorbium powder. The effect is quite dramatic, to Panurge’s highest delight, the poor victim sneezes “quatre heures sans repos” (ie., four hours without rest).
…In 1975 Hecker’s group in Germany isolated the active principle in Euphorbium and named it resiniferatoxin (RTX)28. During the drying process, the concentration of RTX in the latex diminishes due to oxidation29, which might explain why “young” samples of Euphorbium were not considered suitable for medicinal purposes. As noted by Matthiolus, “Quello che non passa un anno, per la sua molta attivita non e da usare” (ie., samples less than one year old should not be used because they are too powerful)15.
“Are humans constantly but subconsciously smelling themselves?”, (2020-04-20):
All primates, including humans, engage in self-face-touching at very high frequency. The functional purpose or antecedents of this behaviour remain unclear. In this hybrid review, we put forth the hypothesis that self-face-touching subserves self-smelling. We first review data implying that humans touch their faces at very high frequency. We then detail evidence from the one study that implicated an olfactory origin for this behaviour: This evidence consists of statistically-significantly increased nasal inhalation concurrent with self-face-touching, and predictable increases or decreases in self-face-touching as a function of subliminal odourant tainting. Although we speculate that self-smelling through self-face-touching is largely an unconscious act, we note that in addition, humans also consciously smell themselves at high frequency. To verify this added statement, we administered an online self-report questionnaire. Upon being asked, approximately 94% of approximately 400 respondents acknowledged engaging in smelling themselves. Paradoxically, we observe that although this very prevalent behaviour of self-smelling is of concern to individuals, especially to parents of children overtly exhibiting self-smelling, the behaviour has nearly no traction in the medical or psychological literature. We suggest psychological and cultural explanations for this paradox, and end in suggesting that human self-smelling become a formal topic of investigation in the study of human social olfaction.
2004-distasi.pdf: “Stability of Resiniferatoxin Stock Solutions”, (2004-03-26; ):
Researchers have reported degradation of RTX [resiniferatoxin] solution stored in various plastic containers. Therefore, we investigated the stability of stock solutions stored in a commonly used plastic material and in glass, under differing conditions of temperature, light and dark…it clearly emerges that: (a) both room temperature and light exposure affect RTX stability and the combined effect of these factors is additive; (b) RTX degradation, if present, falls to a nadir at 48 hours; (c) At low temperatures, in the dark, plastic storage affords better stability than glass.