It Was Twenty Years Ago ...

The lecanemab show has jogged yet another memory. Thanks. Just about 20 years ago (first run 2003, likely filmed 2002) there was a L&O:CI episode that dealt with Alzheimer's. The bad guy has the daughter of a recently dead guy killed in order to get his hands on the dead guy's brain. Yuck, I hear you say. Well... the daughter had said that she and the father would spend enough time in cryo to reach the cure for what killed them. Assuming, I suppose, discounting getting one's brains blown out in some way. With the daughter dead, the bad guy keeps the dead guy from ending up in a tube of nitrogen, and the bad guy gets the brain.

Why, you might ask? Easy enough to explain. The dead guy had been a politician who, when in a presidential race in the 70s, would blubber in newscasts. He drops out (like Muskie in that time frame, but wasn't afflicted), of course. It is later learned that he had early on-set Alzheimer's, but recovered and continued on to a brilliant time in Washington.

Enter the bad guy (well, we've seen him already...) with Binky's Brain. His intended use for the neurons is to use them (the dead guy recovered from Alz, of course) to concoct an instant cure for Alz. Did I mention that he runs a medical foundation? And that his son, some 40-ish years old, has early on-set Alz? You see where this is going. Goren and Eames have figured out the gag by now, with just a few minutes to go in the episode. They have the bad guy in the interrogation room, goading him to incriminate himself. And, of course this being teeVee, he does in spades. I can't find a transcript of the episode, so this is mostly correct from my lifelong lousy memory:

Bad guy: my team is working day and night to isolate the APOE4 gene and we'll have cure in no time! (Son is in the room, too)
Goren: so you found E4 in his brain?
Bad guy: yes, yes we have!!

Game over for the bad guy, of course. OK, so what's remarkable? How is it that a police procedural writer in 2002 knows about APOE4?

From the wiki

As of 2012, the E4 variant was the largest known genetic risk factor for late-onset sporadic Alzheimer's disease (AD) in a variety of ethnic groups.[64] However, the E4 variant does not correlate with risk in every population.

Ten years after the episode, it's common knowledge.

So, when was APOE4 proposed as a factor in Alzheimer's? 1993 is the first report of correlation. But that's in the scientific literature. A quick look at the NYT indicates some references in the late 1990s. But that's some left wing fake news, after all.

In the end, watch high brow teeVee and learn something. Well... sort of. The dialog implies that finding E4 in the dead guy's brain is a good thing, the key to the bad guy's team to make a cure for the son's affliction. My memory of the exact dialog between Goren and the bad guy is fuzzy, so it's not clear how finding E4 (which is bad) in the recovered dead guy's brain is good for the bad guy's team making a cure. Poetic license someplace.

Brainiacs

Before the lecanemab show discussed in this morning's post, there was this sitting in the queue. Time to hit Enter, I guess.

There's much ado about the lecanemab results. Here's a thread from Feuerstein and a comment, to wit:

... highly statistically significant loss of brain volume across all Rx groups in their phase-2 study?
-- MadhavThambiset

Hmm, one might say. Moreover, the SAP is Bayesian. Color me suspicious. While it may not happen soon, this drug will fail in real-world practice, same as every other anti-amyloid compound. Mammy Yokum has spoken. Hokum is hokum.

Here's a lengthy report (the great Derek Lowe).

The antibody was dosed at 10mg/kg twice a week, and the [PII] Bayesian trial was set to look for an 80% chance of a 25% or greater decline in disease progression, as measured by ADCOMS, the Alzheimer's Disease Composite Score. It missed that endpoint at the specified 12-month evaluation point, and at the 18-month point it was actually showing weaker effects than it did at 12 months.

Now, the entire point of whispering Bayes is that stat sig will be easier to find since you're only attempting to improve on 'prior knowledge', not starting from scratch

The similarity to some cancer therapies is worth keeping in mind: in oncology, if you die at the about the same time you would have otherwise, but with smaller tumors (and that only confirmed by imaging, not by quality of life), no one cares.

Ouchy!!

And talk about Ouchy!! This is an even more pointed report; may haps a takedown?

Clarity AD had a sole primary endpoint of an effect on CDR-SB versus placebo. CDR-SB is a subjective tool used by doctors to make an initial assessment of a patient's condition, but became an acceptable endpoint when in 2013 the FDA relaxed guidelines, conceding that co-primary cognitive/functional measures might prove impractical in early Alzheimer's.
...
One [question] concerns the extent to which Aria-E occurrence disclosed which patients were on lecanemab and called Clarity AD's result into question. [unblinding the arms]

And, not to ignore the obvious, this is this author's take on the PII. He is not a Bayes fan, either.

Here's the skinny on 'adaptive Bayesian' trials.

By The Numbers - part the twenty fourth

Some oddities in the numbers from last night's lecanemab show. If that means nothing to you: lecanemab is a new monoclonal antibody (MAB) said to remove Aβ from the brains of Alzheimer's patients. The 'amyloid hypothesis' asserts that Aβ accumulation in the brain is the cause of Alzheimer's. That assertion has never been proven, alas. Some in the field assert quite the opposite: that Aβ is a reaction by the immune system to the actual driver (to date unknown) of Alzheimer's.

Aduhelm was, with great controversy, approved by FDA (reportedly over the objections of its scientists and overtly by outside reviewers) last year. It is also a MAB, and is alleged to work by clearing Aβ from the brain. IIRC, Aduhelm was the first anti-Aβ (aka, disease modifying compound) to be approved. All previous therapies have been symptom reduction.

Now comes lecanemab. Two, to my reading, contradictory statements appear in the report.
First:

The researchers found that participants in both groups had a "clinical dementia rating" or CDR-SB score of about 3.2 at the start of the trial. Such a score is consistent with early Alzheimer's disease, with a higher number associated with more cognitive impairment. By 18 months, the CDR-SB score went up 1.21 points in the lecanemab group, compared with 1.66 in the placebo group.

That difference is characterized in the report as a 27% improvement with lecanemab (.45/1.66). Where things get weird is
Second:

Lecanemab, a monoclonal antibody, works by binding to amyloid beta, a hallmark of the degenerative brain disorder. At the start of the study, the participants' average amyloid level was 77.92 centiloids in the lecanemab group and 75.03 centiloids in the placebo group. By 18 months, the average amyloid level dropped 55.48 centiloids in the lecanemab group and went up 3.64 centiloids in the placebo group, the researchers found.

So, nearly 20 times greater scavenging of Aβ by lecanemab leads to a 27% improvement in decline? Color me skeptical. It would seem logical that if Aβ is driving Alzheimer's, then such a massive reduction in it should lead to a hell of a lot more benefit. Time will tell if this abyss is made a big deal of by the medical and pharma fraternity.

By The Numbers - part the twenty third

By now, unless you've been living under a rock with the RRW crowd, you're well aware that the Chinese people are fed up with Xi's 'zero-Covid' protocol. So, let's look at some of the numbers.

Population - 1.412 billion as of 2021
Number vaccinated - "As of June 4, 2022, about 87 percent of people in China had been fully vaccinated against the coronavirus COVID-19."
Number of cases - 25,835/day in last reporting week
Number of cases this date last year - 39/day
Number of cases, Omicron spike 14 April 2022 - 26,469/day
Number of cases, March 2020 to February 2022 - ~100 or fewer per day
Reported deaths - 5,232
Vaccines in use -

Sinopharm BIBP (inactivated virus)
CanSino Biologics shot (viral vector)
CanSino Biologics inhaled (viral vector)
[the wiki has further listings]
Pfizer - not yet approved
Chinese mRNA made but not approved in China

Number of lockdowns since start to 1 June 2022 - ~25
Number of Apple factories impacted by lockdown (as we speak) - 1 (so far, and it's iPhone)

What to make of all these numbers? The Xi protocol of 'zero-Covid' (aka, test/trace/isolate/lockdown) kept cases absurdly low until Covid-ο hit, and even then very low by American/European experience. And now again with the BA variants (it is believed). We know (or think we do) that the B* variants of Covid-ο are less severe than Covid-19 or Covid-ο, so it would be sensible to relax 'zero-Covid', just as the West has done. On the other hand, China does not yet have an mRNA vaccine at all, much less as the principle vaccine. There's been some talk that Xi wants to show he's a real dictator and thus won't budge; might be. Xi, meet Rock and a Hard Place.

By The Numbers - part the twenty second

Don't you just love human geometry? We've made 8 billion of ourselves. Which is to say, all at once now, not just in all of history. 8 billion.

For comparison:
1951 - 2,584,034,261 [I know, why didn't they use 1950??]
1900 - 1,600,000,000
1850 - 1,200,000,000
1804 - 1,000,000,000 [more or less, the USofA beginning]

And the RRW (of all countries, btw) want to run this little blue marble as if it's still the beginning of the 19th century. Slaves and women as chattel and all the rest. Keep on fucking, big daddy.

Ain't geometric growth powerful?

Why Do We Need The Red States, Anyway?

This is the headline on my CNN homepage this morning: "Red and blue America look like two separate nations". Yeah, so what else is new?? It's always been that way.

So, why do we? Well, we don't; they're the welfare queens of the nation. Here's a recent report on the situation. Mind, it's been this way for decades. The Red states want to party like it's 1859, but use cell phones and other accoutrements of Modern Living.

Eight of the 10 states most dependent on the federal government were Republican-voting, with the average red state receiving $1.35 per dollar spent.
The eight states receiving the highest child tax credit per capita were all Republican-voting.

Live free or die?? Not bloody likely, if they can control the Congress and keep Uncle Sugar's moolah flowing.

Somebody's Gotta Do It

It's been years since I've watched an SNL episode all the way through. Until Baldwin took on The Orange Trickster, I seldom watched at all. When HBO returned to Dish, I looked forward to Maher, but he's turned into RRW in Progressive clothing. If it weren't for Oliver, I wouldn't care about HBO. As to the late-night crew, nada. For the longest time, for reasons lost in the mists of time, I thought Kimmel was the RRW of late-night. Then I saw the headlline that he's vowed to quit if the Suits keep him from doing Trump jokes. Well!

So, I don't know if any of that cabal has yet gone here, but someone has to.

What happened to the Red Wave? Turned out to be just a bit of spotting! Which, yet again, proves that the RRW is just a bunch of whiny, bitching pussies.

Dee Feat is in Dee Flation - part the forty fifth

As regular readers well know, these missives (and those by the more famous) have been bleating the case that the post-Covid (if we really are "post", of course) inflation was/is a temporary problem; in the sense that it's not been driven by one or more of the usual suspects: wage push, cost push, demand pull. Yes, one might make a bit of a case for the third, in that about $1 trillion went unspent during much of Covid, and Sleepy Joe and the Democrats did put some bucks into households. But it's been largely a supply problem, particularly due to Xi's stupidity.

Well, we just got the latest inflation numbers (manipulated by the Socialist BLS, of course), and it's abating. One month's data does not a trend make. But we know, for sure, that Putin, Xi, and Salman have been the bad actors through all this. So the NYT writes up the story.

After stripping out food and fuel costs, both of which jump around, prices rose by 6.3 percent on an annual basis, down from 6.6 percent in the prior reading. And that core inflation measure pulled back sharply on a monthly basis, posting its slowest increase in more than a year.

That is hopeful. On the one hand, one would expect food and fuel to lead the inflation number, given: gasoline prices were supposed to kill Sleepy Joe and the Democrats. On the other hand, if the regular parts of the market basket are retreating, then that has to mean supply is closer to meeting demand. And that's what the author points out

The report provides early evidence that the Fed's campaign to slow rapid inflation may be helping to ease price pressures, working alongside recent healing in supply chains.
[my emphasis]

This was Jerome Powell's answer when he began his war on the American economy:

Federal Reserve Chair Jerome Powell told lawmakers Wednesday that rate hikes will not bring down oil and food prices, despite their contributing the lion's share of recent inflation gains.

In an exchange with Sen. Elizabeth Warren (D-Mass.), Powell was blunt in saying that the Fed's efforts to tamp down on higher prices with higher interest rates will not impact either category.

"Chair Powell, will gas prices go down as a result of your interest rate increase?" she asked.
"I would not think so, no," he replied.
Then Warren asked, "Will the Fed's interest rate increases bring food prices down for families?"
Powell said, "I wouldn't say so, no."
He nonetheless stressed that the Fed was equipped to tackle inflation more broadly.
"We have both the tools we need and the resolve it will take to restore price stability on behalf of American families and businesses," he said, during his semiannual testimony to Congress.

And to close out this episode, here he is (you've seen it before as a week's quote)

It's not good to have monetary policy be the main game in town, let alone the only game in town. -- Jerome Powell/2019

At least, so far, he's not been a laughing Laffer.

Canary Sing To Me - part the third

If you look around widely enough, and often enough, you can spot the next Canary in the coal mine.

It's been widely believed that economic growth is a product of reproduction of humans. The tribe that begets the most wins. For decades, likely from the start, it's been an article of faith amongst Israel's right-wing tribe. Today's NYT reports

Sluggish birthrates among secular Israelis, coupled with high rates among the religious, who tend to lean right, have also gradually tipped the balance of voter demographics.

What in the USofA equates to: the great unwashed in the empty places out-breed the educated city dwellers. The Israeli problem has been documented for decades. No solution has been identified.

Oddly, or not, within the same pages is a report that the Jordan river is nearly dry.

Population growth, diminished water supplies and climate change have all taken their toll, while damaged and inefficient infrastructure and the considerable challenges posed by Jordan's geography and topography have only made things worse. The resulting shortages serve as a warning of what the future might hold for the region and the world beyond it.

Gee?? Ya think. In a moment of unpleasant serendipity, this week carried the obit of an anti-growth (population growth) economist.

And, of course, there were recent reports (I didn't follow past the headlines) that 'foreign' owned farms are harvesting water from our desertifying Southwest and shipping it back home. Where's MAGA when you really need it?

Out screwing your neighbor/enemy was a valid technique to win wars. More bodies, more boys, more soldiers, more wins. 2,000 and 3,000 years ago, that plan didn't run up against limited resources the way we have it today. At 2,000 years ago ~170 million all told. At 3,000 years ago ~40 million. Admittedly, 'resources' back then didn't encompass, for instance, petrochemical fertilizers and diesel powered tractors or Abrams tanks. Still, out fucking your enemy could be effective.

About time we figured out how to survive a depleting Mother Earth. We've only got the one, and there's not another one within the distance of chemical rockets. May be none anywhere. "The Martian" was a movie, not a plan.

Musk Ox - part the second

You know, Musk is the epitome of the Right Wingnut hypocrite. from today's news:

"Twitter has had a massive drop in revenue, due to activist groups pressuring advertisers, even though nothing has changed with content moderation and we did everything we could to appease the activists," he said in a tweet. "Extremely messed up! They're trying to destroy free speech in America."

Musk elides the obvious: he has stated, repeatedly, that he doesn't want moderation. Since he now owns the joint, lock stock and barrel, he'll turn it into a "a free-for-all hellscape" as soon as he thinks he can get away with it. Ya can't make money on the innterTubes without advertisers; well, unless you're Amazon.

Just days after Elon Musk assured advertisers that Twitter would not become "a free-for-all hellscape," the social media site was swamped with an outpouring of racist, sexist and antisemitic posts, along with election disinformation and bizarre conspiracy theories. The ugliest of these conspiracies were amplified by Musk himself.

Ya, he's just some anonymous apolitical bidnezzman.

As many predicted, Musk's pro-Trumpian bleeting going back years, and worse since his campaign to have Twitter, has led to a jailbreak. What did he think would happen? Is he so demented that he really believes that most Americans are MAGAists??? I guess if you grow up white in South Africa, you've no truck with those who look like they come from shithole countries. MAGA really means Make America White Again. Or, The South Shall Rise Again.

While he has naturalized, he doesn't get the Constitution. It only prohibits The Damn Gummint from restricting speech, but private enterprise is not so restricted. No one could have sued, and won against, Twitter etc. for banning them for hate speech. That pesky First Amendment has other text, which the MAGAists tend to ignore. There's that bit about no State religion; only White Evangelicals need apply. (Wouldn't be the first time. We've been through this shit before. Twice, even.) Tell that to the Thomas clan. Oh, and Jews will not replace us???? Batshit J. Moron tried his damnedest not to piss off the KKK.

Oh Canada!

Aren't Canadians said to be such nice people? Does it track that the MAGA crowd should import one to assassinate Crooked Nancy?? Well, I guess. At the least, he isn't from one of those shithole countries that Dear Leader Yo! Semite of Thigh Land just can't stand.