Two decades of Alzheimer's research may be based on deliberate fraud that has cost millions of lives
Over the last two decades, Alzheimer's drugs have been notable mostly for having a 99% failure rate in human trials. It's not unusual for drugs that are effective in vitro and in animal models to turn out to be less than successful when used in humans, but Alzheimer's has a record that makes the batting average in other areas look like Hall of Fame material.
And now we have a good idea of why. Because it looks like the original paper that established the amyloid plaque model as the foundation of Alzheimer's research over the last 16 years might not just be wrong, but a deliberate fraud.
The suspicion that something was more than a little wrong with the model that is getting almost all Alzheimer's research funding ($1.6 billion in the last year alone) began with a fight over the drug Simufilam. The drug was being pushed into trials by its manufacturer, Cassava Sciences, but a group of scientists who reviewed the drug maker's claims about Simufilam believed that it was exaggerating the potential [...] and hired an investigator to provide some support for this position.
[...] In 2006, Nature published a paper titled "A specific amyloid-β protein assembly in the brain impairs memory." Using a series of studies in mice, the paper concluded that "memory deficits in middle-aged mice" were directed caused by accumulations of a soluble substance called "Aβ*56." [...]
That 2006 paper was primarily authored by neuroscience professor Sylvain Lesné and given more weight by the name of well-respected neuroscientist Karen Ashe, both from the robust neuroscience research team at the University of Minnesota. [...]
The results of the study seemed to demonstrate the amyloids-to-Alzheimer's pipeline with a clarity that even the most casual reader could understand, and it became one of—if not the most—influential papers in all of Alzheimer's research.[...]
What intrigued Schrag when he came back to this seminal work were the images. Images in the paper that were supposed to show the relationship between memory issues and the presence of Aβ*56 appeared to have been altered. Some of them appeared to have been pieced together from multiple images. [...]
Now Science has concluded its own six-month review, during which it consulted with image experts. What they found seems to confirm Schrag's suspicions.
They concurred with his overall conclusions, which cast doubt on hundreds of images, including more than 70 in Lesné's papers. Some look like "shockingly blatant" examples of image tampering, says Donna Wilcock, an Alzheimer's expert at the University of Kentucky.
[...] And it seems highly likely that for the last 16 years, most research on Alzheimer's and most new drugs entering trials have been based on a paper that, at best, modified the results of its findings to make them appear more conclusive, and at worst is an outright fraud.
Some interesting stuff between the [...] was cut down for this summary, so I recommend reading the linked story. I also coincidentally just listened to the most recent Science podcast where they go into this in much greater detail and is well worth a listen. [hubie]
(Score: 2) by rigrig on Saturday July 23 2022, @11:58PM (2 children)
Too bad that even if somebody were willing to hand out grants for something as redundant as replicating studies, all the scientists are busy doing research that will get their name in the papers...
No one remembers the singer.
(Score: 5, Informative) by quietus on Sunday July 24 2022, @01:47PM (1 child)
If you had taken care to read the article, you’d have noticed that the manipulation was exposed by a neuro-scientist (Schrag) who himself was hired by a group of scientists who were concerned about the claims about an Alzheimer drug, and decided to take the pharma company producing the drug to court.
After the researcher had tried to notify in vain the National Institute of Health, he contacted Science who put image experts onto the case for independent verification. These image experts were not random nerds, but scientists themselves: the one quoted is a molecular biologist.
(Score: 2) by RS3 on Sunday July 24 2022, @05:27PM
Oh gosh, how will we ever know what to believe anymore?
(Score: 4, Interesting) by PiMuNu on Sunday July 24 2022, @12:27AM (2 children)
Note that if you don't get around to reading TFA, author also notes that senior folks in the NIH names are on the paper as well.
(Score: 2) by quietus on Sunday July 24 2022, @01:55PM (1 child)
And that might be the real issue here: a guy who co-wrote the particular paper, now a top honcho at NIH, clearly shovelling contradictory evidence under the grass ( and instead giving at least one other author bonus money (silence money?)).
As Science suggest when mentioning the prices of Alzheimer drugs based on the principles of this research paper, there might be more dirt to find at the NIH once Congress or Senate start investigative hearings.
(Score: 2) by quietus on Sunday July 24 2022, @02:09PM
And there you have a further stinky element: the whole of Cassava’s claims about the effectiveness of the drug was based on research done on the basis of 2 NIH grants to the company, resulting in papers with their own image anomalies (see FDA Citizen Petition, linked to by DailyKos).
(Score: 2) by Barenflimski on Sunday July 24 2022, @01:57AM
That's frustrating.
(Score: 2) by bzipitidoo on Sunday July 24 2022, @02:13AM (12 children)
Not the first time there's been fraud in medical research. I am recalling a certain Korean who falsified data and findings about stem cells, publishing in 2004. By 2006, the lies were exposed, and he was fired. And tried and convicted. But this Alz research slid for 16 years?!?! Majorly embarrassing! Where's the peer review? Why didn't peer review catch this?
(Score: 1, Interesting) by Anonymous Coward on Sunday July 24 2022, @02:20AM (4 children)
Because neoliberal ideas have resulted in universities being glorified corporate contractors.
The grant winners who populate all the key positions (since it's the money, Lebowski) don't do science. They lead initiatives. They propose visions. They specialize in sucking govt teat. There aren't any scientists left in universities, except socially decrepit individuals who now clean the equipment for The Serious People.
There's really no difference between industry and university research any more. Why anyone would accept 1/3 the salary to do a postdoc, or even bother doing a PhD, is in question - if you're just fulfilling contracts for stake-holders then might as well go into industry and get paid.
(Score: 3, Insightful) by RS3 on Sunday July 24 2022, @03:18AM
Sadly true. Your post inspired me to think "what about amateur scientists, much like individuals contributing to open-source code projects?" And, so much of science was done by all kinds of people, including individuals, up until sometime early 1900s. And then I remembered: oh yeah, science (medical too) has gotten so complex and intricate that you probably need millions of dollars worth of laboratory equipment and a staff to do anything big. And of course so many scientists work at research facilities and their ideas are owned by the lab's owners. I guess there's still some kind of chance for the little guy, but small.
(Score: 2, Insightful) by khallow on Sunday July 24 2022, @04:25AM (2 children)
"Sucking govt teat" isn't being glorified corporate contractors. That illustrates a different failure mode. Former President Eisenhower in his "military industrial complex" speech near the end of his tenure spoke also of a "scientific technological elite":
Funny how your complaints sound very much like a description of what he warned against.
Unless of course, you're into the government money and easy environment of university research. You don't even have to fulfill contracts.
My take is that glorified corporate contractors would at least be doing something.
(Score: 0) by Anonymous Coward on Sunday July 24 2022, @07:05PM (1 child)
> My take is that glorified corporate contractors would at least be doing something.
I mean, yes. But doing "corporate" work that requires a certain result or kiss your bonus goodbye. It's not the science of the science books.
(Score: 1) by khallow on Monday July 25 2022, @05:41PM
What was that other option? "Sucking govt teat"? That sound like sciencing to you? At least, in the private world, the funding isn't highly centralized.
(Score: 4, Interesting) by RamiK on Sunday July 24 2022, @09:31AM (6 children)
The short-sellers didn't have a financial interest to pay for the peer-review investigation until the drugs were approved by the FDA.
This is a pretty interesting case study for Milton Friedman's argument against the FDA: The original argument said it's possible more people are harmed by the delays the FDA causes in allowing good drugs than by the good they do in blocking bad drugs. Now, we have a fairly complex example showing the an even worse implication of slow and expensive regulations: If the research would have led to early drug development, it would have failed in the market (either short sellers or when being used in the community) and two decades of research wouldn't have been sent down the drain. Sure, some people would have been hurt from the new and useless drugs' side-effects. Maybe there would have even been fatalities. But, two decades of science and a generations of medical research is such a huge loss for any field that it's likely would have been worth it.
Regardless, peer-review, as tool for science, failed.
compiling...
(Score: 4, Interesting) by quietus on Sunday July 24 2022, @02:39PM (5 children)
If you’d take the matter seriously, you might at least have read the dailykos article. The research was ordered when the results of stage II trials were published i.e. long before FDA approval; and if you’d casually checked the involved company’s Wikipedia entry you’d have noticed the company has great difficulty getting such approvals, as in getting no approvals at all in their whole history.
How you get from there to turning the FDA into the villain of the piece is anybody’s guess, but I suspect a copy of Atlas Shrugged and a high dose of opioid painkillers might have done the trick.
(Score: 3, Insightful) by RamiK on Sunday July 24 2022, @04:25PM (4 children)
Why does that matter when it took short-traders to start the investigation rather than the FDA or peers? That is, the FDA regulations failed since the FDA only makes sure companies report they've gone through the motions rather than actively try and duplicate their results using FDA run labs while the peer review failed since the original papers were never duplicated by other scientists.
So, all-in-all, the paper-to-market process as going through both peer-review and FDA regulations, is a rubber-stamp.
How did my "interesting case study" turn into villainizing the FDA? All I'm saying is that, where Friedman only (rhetorically) considered how many people die from bad drugs vs. how many people die from waiting for the approval of good drugs, we now have another factor to consider: How much medical science itself suffers when a whole field wastes over a decade on a faulty theories.
But to give a more concrete example of Friedman's argument, imagine how many people would have died if the FDA wasn't ordered to fast-track the COVID-19 inoculations. What if instead of months, it would have taken years? How much damage did the bad J&J and ilk inoculations caused compared to the lives that would have been lost if Moderna and Pfizer would have been delayed? Extending on that, how many years of research would have been lost on old inoculation technologies while waiting?
Eh, while a free market libertarian solution where adversarial labs could be funded and run by shorts traders and competing companies might be an interesting game theory experiment, my solution to the faulty FDA and peer-review process isn't to loosen the regs but to nationalize the whole pharmaceutical industry, peer-review process and approval procedures by having the government directly fund thousands of labs at what would probably be the single greatest expenditure ever. I admit I never took political science classes, but I'm pretty sure that's one step beyond socialism straight into communism.
compiling...
(Score: 3, Informative) by quietus on Sunday July 24 2022, @06:56PM (3 children)
The FDA repeatedly prevented this company bringing drugs to market because they either didn’t consider their research valid or considered the side effects too serious: how can you call that a failure of the FDA?
It is not the role of the peer review process to reproduce the research described in a scientific article: that’s the role of the wider scientific community and the reason why the concept of a hypothesis is central to hard science.
The short-tracking of covid vaccines had little to do with skipping FDA regulations: the only thing what happened is that the different stage trials ran in parallel instead of sequential. The reason these normally run in sequence is to catch negative side effects as early as possible, and not putting larger sample sizes in harm’s way. Pharma companies (J&J, at least) already were thinking aloud of doing this themselves before gov’t started shuffling money towards them.
Finally, it wasn’t professional hedge fund short traders who stirred the proverbial pot here: but a bunch of scientists who bought shorts and paid a piffle amount of money to another scientist to put their complaint against the NIH on solid administrative grounding.
(Score: 2) by RamiK on Sunday July 24 2022, @07:51PM
It's a "The operation was successful, but the patient died" type problem: The FDA and publicist' editors are fulfilling their intended roles, but they're failing at their intended purpose due to how their roles are set out. That is, it's a policy failure. You can compare it to the war on drugs where even if educators, police, judges and prisons are all doing their jobs, the result is a failure because the premise itself is folly. Here, the problem is that the government reached for all the easy pickings, and left the real hard work - providing incentives for research duplication - to the charity and short traders. Worse, the FDA and publications are providing a false sense of assurance regarding the validity of products and research: The reason the FDA managed to stop certain drugs from reaching the markets entirely depends on the results reported by the companies themselves. A bad actor can, and does circumvent the checks. Just like how the opioid overdose epidemic kept claiming lives and everyone shrugged saying they it's not their fault.
Who do you think does all that bioinformatics and engineering consultancy for hedge funds? MBAs, lawyers and stats majors? Hedge funds hire engineers and scientists full-time and contractually-consultancy to review patents as standard practice. Whether these guys are otherwise working academic / private researchers and only do the consultancy and investing as side-gigs makes no difference whatsoever. It's still a market incentive that only barely stopped the FDA's approval and was a good decade too late in taking down the bad paper.
Again, the issue is policy: The research-to-drug system is nothing but useless expensive red tape: Red tape in the form of existing credentials to get a paper publicized by a journal and red tape in the form of money poured into repeat-until-succeed-lab-trials to get the FDA's rubber stamp. All the while, the one factor that can actually stop bad science from getting through - experimental duplication - isn't being funded. And why? Because we're already spending too much on journals and FDA trials. So, yeah, they're not failing at their jobs. It's their jobs that's failing.
compiling...
(Score: 2) by Immerman on Monday July 25 2022, @12:40AM (1 child)
>It is not the role of the peer review process to reproduce the research described in a scientific article:
It absolutely is.
>that’s the role of the wider scientific community and the reason why the concept of a hypothesis is central to hard science.
Yes, that is what peer review is.
The review a paper gets before publishing is NOT meaningfully peer review - at best it's a cursory pre-review to reduce the risk of that a journal wastes its readers' time with obviously flawed papers.
(Score: 2) by quietus on Monday July 25 2022, @11:40AM
In a broad sense, you're correct: the actual peer review happens through the scientific community at large through reproduction and extension of previous work. In a narrower sense, however, the term peer review usually refers to editorial review i.e. the reviewing of an article before publishing in a scientific journal. That editorial review is done by sending out the article to a selected group of peers for validation.
(Score: 4, Informative) by Subsentient on Sunday July 24 2022, @03:23AM (6 children)
Sometimes, I lose a little additional faith in humanity that I didn't know I still had. Stomach churningly disgusting and absolutely unforgivable.
"It is no measure of health to be well adjusted to a profoundly sick society." -Jiddu Krishnamurti
(Score: 4, Touché) by c0lo on Sunday July 24 2022, @06:00AM
Keeping into account the "may be based...", your reaction should have been on the line of
You're welcome
(large grin)
https://www.youtube.com/watch?v=aoFiw2jMy-0 https://soylentnews.org/~MichaelDavidCrawford
(Score: 2) by quietus on Sunday July 24 2022, @02:48PM
And yet all that money and influence and pr brought down by a single steady hand: if that doesn’t raise your hopes for humanity, I don’t know what will. Now off into your own lab again, and fire up them image analysis programs before visiting PubPeer.
(Before you go, though: read the full story at Science here: https://www.science.org/content/article/potential-fabrication-research-images-threatens-key-theory-alzheimers-disease [science.org] )
(Score: 0) by Anonymous Coward on Sunday July 24 2022, @05:47PM (3 children)
That is a pure clickbait headline and otherwise stains a pretty decently written article.
Nowhere in the article does the author even mention anything about how this has led to deaths, so it is very irresponsible to even put it in the headline, because it is entirely unjustifiable. The only argument you can make is to suggest that we would have otherwise have come up with a cure for Alzheimer's and it would have been widely approved and disbursed such that millions of people would have been cured with the new treatment.
(Score: 2) by janrinok on Sunday July 24 2022, @06:35PM (1 child)
I am not arguing one way or the other - but if this has been falsely used as a diagnostic then many patients will have been treated for the wrong medical condition. As we cannot know how many people that might be, the the original headline is certainly sensationalist but might also be accurate as an estimate. I agree that we have no way of knowing what that figure is. We feel that our own headline was more 'balanced'.
(Score: 0) by Anonymous Coward on Sunday July 24 2022, @09:34PM
Sorry for the confusion: I meant that it is a clickbait title being used in the Daily Kos article. There should have been some attention given to it in the article if they are going to say that, but if the Daily Kos is set up like a traditional news site, it also might be the case that the article headlines are not written by the article writers.
(Score: 1) by khallow on Tuesday July 26 2022, @01:32AM
What would you call a 16 year delay in research on an illness that kills hundreds of thousands of people a year? Remember you don't see the millions of people who died and will continue to die because of that waste of time. Opportunity costs are invisible.
(Score: -1, Offtopic) by Anonymous Coward on Sunday July 24 2022, @05:25AM (1 child)
It may be. Anyone like to sort through the mess?
(Score: 0) by Anonymous Coward on Sunday July 24 2022, @06:03AM
I wouldn't mind to help, just please remind me who is that Alzheimer that did the research.
(Score: 4, Insightful) by quietus on Sunday July 24 2022, @09:48AM (18 children)
Think statistics for a moment, people. The number of research papers published each year is well over a million. Number of papers offered for review, but not making it to publication, is a multiple of that number.
Correctness of these papers, like all natural phenomena, follows a normal distribution aka a Gauss curve. That means you’ve got at the low end about 5-7% duds through sheer incompetence, and at the high end an equal percentage of duds through outright fraud, even — or especially — after having passed through human review.
It is hence inevitable that some “key paper” turns out to be a dud either way. That does not mean, however, that the large majority of papers are frauds, attempts to put the little man down, or attempts to suck the government’s tit(s).
(Score: 2) by c0lo on Sunday July 24 2022, @10:21AM (11 children)
Assuming a Gauss distribution is quite an assertion.
Boltzmann distribution [wikipedia.org] is still a thing and explains quite well why 90% of everything is crap [wikipedia.org] - any explanation you can set forth on why scientific articles would make an exception?
https://www.youtube.com/watch?v=aoFiw2jMy-0 https://soylentnews.org/~MichaelDavidCrawford
(Score: 3, Touché) by quietus on Sunday July 24 2022, @10:53AM (8 children)
If 90% of everything is crap, wouldn’t that imply that 90% of all buildings collapse under their own weight?
Your Boltzmann distribution is about a closed system with only 2 variables. Gauss curves on the other hand are observational and representative of natural phenomena e.g. take a random sample of a 1000 people and put out a frequency distribution of weight, length, skin color or whatever biological property, and you’ll get a normal distribution.
I prefer thousands of these observations over whatever good sounding quip of a single human (and writers often seem to me to be heavily overrated btw: like trusting a news anchor with your investment decisions).
(Score: 0) by Anonymous Coward on Sunday July 24 2022, @02:09PM (4 children)
We're talking about buildings, not piles of rubble, right?
What do the fact that more than 90% of the buildings no longer exist after 100 years, and yet there a enough of them that are valuable enough to be preserved even if they can't stand on their own (like the pyramids or Stonehenge do)?
Oh really? So, that energy can take zillions of forms doesn't matter to you, eh?
And this is in relation with the quality of the scientific publications exactly how?
Are you trying to say that all humans naturally exhibit the metabolic function of producing scientific articles? Or that "weight, length, skin color or whatever biological property" are somehow correlated with the quality of the scientific articles they produce, so we can soundly extrapolate based on this correlation?
You have thousands of observations that in regards with the quality of the scientific articles? Then it shouldn't be too hard to show those numbers.
If you don't, your assertion "is a Gauss distribution" have no basis so far.
(Score: 2) by quietus on Sunday July 24 2022, @02:57PM (3 children)
Enlighten me to the zillions of forms energy can take.
Also: are you saying that the human brain is not biological?
(Score: 2) by c0lo on Monday July 25 2022, @12:27AM (1 child)
Some examples for you, just don't expect to list them all
I can tell you've been nurtured on some degree and your behavior isn't entirely governed by your nature, but I reckon that nurture didn't go far enough. I can say this based on the fact that at least you can write (so you had some nurture) your naive and horrible simplified models of reality on S/N and your propensity of thinking they are adequate.
The bliss of your ignorance likely feels good to you. And, from this "perspective, people" PoV, the same likely happens to the entire cohort of people on this Earth that think their ignorance is as good as the scientists' knowledge.
---
As for the personal reason I chose to debate this very assertion of "Gauss distribution being applicable for professional performance": it reminds me the PHBes of this world using it in rank and yank [wikipedia.org]. It's even more reprehensible to me to see someone outside the area of scientific research using it as the gospel to characterize the quality of scientific papers: it may be so but, if you can't show me the numbers, have some decency and STFU before you draw conclusions based on not verified/demonstrated assumptions
https://www.youtube.com/watch?v=aoFiw2jMy-0 https://soylentnews.org/~MichaelDavidCrawford
(Score: 2) by quietus on Monday July 25 2022, @11:53AM
Oopsie -- there I thought that there were only really 2 forms of enery: potential energy and kinetic energy. I guess I must stand corrected here.
As for the compliments: accepted with gratitude.
(Score: 3, Informative) by PiMuNu on Monday July 25 2022, @06:34PM
To be clear, Boltzmann distribution indeed occurs in nature; it describes the probability distribution of kinetic energy of atoms in a gaseous medium having temperature T.
Boltzmann distribution arises as a probability distribution based on the number of possible states of a gaseous medium. It's not about "forms of energy". I don't think "forms of energy" means anything.
(Score: 0) by Anonymous Coward on Sunday July 24 2022, @05:53PM
Survivorship bias? The buildings you see are the one out of ten that stand. :)
Besides, I wouldn't claim 10% success rate, but his argument does have an example for 25%:
(Score: 2) by hendrikboom on Sunday July 24 2022, @09:34PM
The survival of medieval cathedrals during their construction seems to follow statistics like that. Quite a few fell down before they were finished and had to be redesigned and rebuilt.
(Score: 1) by khallow on Thursday July 28 2022, @11:33AM
You won't get normal distributions, let us note. Human height, for example, has a sexual dimorphism that isn't covered by a normal distribution. Further, just consider biological gender itself. That basically consists of two large slots and a few weird side cases that are much less frequent. It's not even a continuous parameter that can be modeled by a normal distribution. You're deep in not-even-wrong territory here.
(Score: 3, Interesting) by hendrikboom on Sunday July 24 2022, @09:30PM (1 child)
I wonder what the energy and temperature of the correctness of a paper are.
(Score: 2) by c0lo on Monday July 25 2022, @01:08AM
Substitute the correctness for energy and the amount of grant money for the temperature and it may make sense? (large grin)
Look, I didn't say it is Boltzmann, I'm saying that Gauss is likely a wrong choice as it doesn't explain the Sturgeon's law - the later imply a skewness of the distribution that is not visible on very fine symmetrical shape of the Gauss bell.
Maybe it's a Pareto distribution [wikipedia.org]. Or maybe Poisson distribution is adequate to describe the chances of the number of crap papers being published any given year (I have my hunches it is not).
My point was why should I trust the poster that:
https://www.youtube.com/watch?v=aoFiw2jMy-0 https://soylentnews.org/~MichaelDavidCrawford
(Score: 2) by PiMuNu on Sunday July 24 2022, @05:53PM
No need to guess. It has been well studied
https://en.wikipedia.org/wiki/Replication_crisis [wikipedia.org]
> In psychology ... 97 of the original studies had significant effects, but out those 97, only 36% of the replications yielded significant findings (p value below 0.05).
> In medicine ... Out of 49 medical studies from 1990 to 2003 with more than 1000 citations, 92% found that the studied therapies were effective.... 16 % were contradicted ... 44 % were replicated ... [the rest unclear]
> In medicine ... only 11% of 53 pre-clinical cancer studies had replications that could confirm conclusions from the original studies
Note that I believe the expected rate of disagreement between two having p-value 0.05, one passing and one failing, is given by the union of (possibility that the original test was a false positive) OR (possibility that the check was a false negative), which should be about 10 % of results do not get confirmed (to be precise 1-0.95^2). The wikipedia article doesn't go into details about the stats.
In medicine, a p-value of 0.05 seems to be requirement for a "discovery".
(Score: 1) by khallow on Tuesday July 26 2022, @05:51PM (4 children)
Unless you have policies in place to aggressively increase the cost of such (and weaker stuff like p-hacking) you'll get substantially increased representation of fraud in your high impact papers.
In particular there's no symmetry of a normal distribution here. Papers so low quality that they barely get published tell you nothing about the amount of fraud at the other end.
(Score: 2) by quietus on Wednesday July 27 2022, @12:45PM (3 children)
Those pesky p-values you find in research papers are based on a normal distribution, khallow, as anyone with a scientific or engineering background knows.
Brownie points for creativity in trying to shoe-horn statistical results in a Boltzmann curve, but I kindly suggest you return to that call-girl's belly button and whatever cocaine remains there.
(Score: 1) by khallow on Wednesday July 27 2022, @02:01PM (2 children)
(Score: 2) by quietus on Wednesday July 27 2022, @02:22PM (1 child)
The earth is flat and really supported by a pile of tortoises? There's a chain of pizza restaurants keeping kiddies in the basement for whatever?
(Score: 1) by khallow on Thursday July 28 2022, @11:30AM
The problem with the original supposition is that it is wrong. For a glaring example, no strictly positive valued natural phenomena are normally distributed by definition. A normal distribution infinitely extends into negative territory. Second, you can easily break a normal distribution merely by adding another with a normal peak at a different point. For example, even if the strictly positive variable of male and female human height (both natural phenomena, right?) were normally distributed, you have the peaks at different points. Thus, the category of all human heights, both male and female, would not be normally distributed.
(Score: 2) by Opportunist on Sunday July 24 2022, @10:22AM (1 child)
We can just forget about using that paper?
(Score: 3, Funny) by TrentDavey on Sunday July 24 2022, @03:46PM
Use it. In the outhouse.