More on Science
Michael Hunter, MD
3 years ago
5 Drugs That May Increase Your Risk of Dementia
While our genes can't be changed easily, you can avoid some dementia risk factors. Today we discuss dementia and five drugs that may increase risk.
Memory loss appears to come with age, but we're not talking about forgetfulness. Sometimes losing your car keys isn't an indication of dementia. Dementia impairs the capacity to think, remember, or make judgments. Dementia hinders daily tasks.
Alzheimers is the most common dementia. Dementia is not normal aging, unlike forgetfulness. Aging increases the risk of Alzheimer's and other dementias. A family history of the illness increases your risk, according to the Mayo Clinic (USA).
Given that our genes are difficult to change (I won't get into epigenetics), what are some avoidable dementia risk factors? Certain drugs may cause cognitive deterioration.
Today we look at four drugs that may cause cognitive decline.
Dementia and benzodiazepines
Benzodiazepine sedatives increase brain GABA levels. Example benzodiazepines:
Diazepam (Valium) (Valium)
Alprazolam (Xanax) (Xanax)
Clonazepam (Klonopin) (Klonopin)
Addiction and overdose are benzodiazepine risks. Yes! These medications don't raise dementia risk.
USC study: Benzodiazepines don't increase dementia risk in older adults.
Benzodiazepines can produce short- and long-term amnesia. This memory loss hinders memory formation. Extreme cases can permanently impair learning and memory. Anterograde amnesia is uncommon.
2. Statins and dementia
Statins reduce cholesterol. They prevent a cholesterol-making chemical. Examples:
Atorvastatin (Lipitor) (Lipitor)
Fluvastatin (Lescol XL) (Lescol XL)
Lovastatin (Altoprev) (Altoprev)
Pitavastatin (Livalo, Zypitamag) (Livalo, Zypitamag)
Pravastatin (Pravachol) (Pravachol)
Rosuvastatin (Crestor, Ezallor) (Crestor, Ezallor)
Simvastatin (Zocor) (Zocor)
This finding is contentious. Harvard's Brigham and Womens Hospital's Dr. Joann Manson says:
“I think that the relationship between statins and cognitive function remains controversial. There’s still not a clear conclusion whether they help to prevent dementia or Alzheimer’s disease, have neutral effects, or increase risk.”
This one's off the dementia list.
3. Dementia and anticholinergic drugs
Anticholinergic drugs treat many conditions, including urine incontinence. Drugs inhibit acetylcholine (a brain chemical that helps send messages between cells). Acetylcholine blockers cause drowsiness, disorientation, and memory loss.
First-generation antihistamines, tricyclic antidepressants, and overactive bladder antimuscarinics are common anticholinergics among the elderly.
Anticholinergic drugs may cause dementia. One study found that taking anticholinergics for three years or more increased the risk of dementia by 1.54 times compared to three months or less. After stopping the medicine, the danger may continue.
4. Drugs for Parkinson's disease and dementia
Cleveland Clinic (USA) on Parkinson's:
Parkinson's disease causes age-related brain degeneration. It causes delayed movements, tremors, and balance issues. Some are inherited, but most are unknown. There are various treatment options, but no cure.
Parkinson's medications can cause memory loss, confusion, delusions, and obsessive behaviors. The drug's effects on dopamine cause these issues.
A 2019 JAMA Internal Medicine study found powerful anticholinergic medications enhance dementia risk.
Those who took anticholinergics had a 1.5 times higher chance of dementia. Individuals taking antidepressants, antipsychotic drugs, anti-Parkinson’s drugs, overactive bladder drugs, and anti-epileptic drugs had the greatest risk of dementia.
Anticholinergic medicines can lessen Parkinson's-related tremors, but they slow cognitive ability. Anticholinergics can cause disorientation and hallucinations in those over 70.
5. Antiepileptic drugs and dementia
The risk of dementia from anti-seizure drugs varies with drugs. Levetiracetam (Keppra) improves Alzheimer's cognition.
One study linked different anti-seizure medications to dementia. Anti-epileptic medicines increased the risk of Alzheimer's disease by 1.15 times in the Finnish sample and 1.3 times in the German population. Depakote, Topamax are drugs.
Jack Burns
3 years ago
Here's what to expect from NASA Artemis 1 and why it's significant.
NASA's Artemis 1 mission will help return people to the Moon after a half-century break. The mission is a shakedown cruise for NASA's Space Launch System and Orion Crew Capsule.
The spaceship will visit the Moon, deploy satellites, and enter orbit. NASA wants to practice operating the spacecraft, test the conditions people will face on the Moon, and ensure a safe return to Earth.
We asked Jack Burns, a space scientist at the University of Colorado Boulder and former member of NASA's Presidential Transition Team, to describe the mission, explain what the Artemis program promises for space exploration, and reflect on how the space program has changed in the half-century since humans last set foot on the moon.
What distinguishes Artemis 1 from other rockets?
Artemis 1 is the Space Launch System's first launch. NASA calls this a "heavy-lift" vehicle. It will be more powerful than Apollo's Saturn V, which transported people to the Moon in the 1960s and 1970s.
It's a new sort of rocket system with two strap-on solid rocket boosters from the space shuttle. It's a mix of the shuttle and Saturn V.
The Orion Crew Capsule will be tested extensively. It'll spend a month in the high-radiation Moon environment. It will also test the heat shield, which protects the capsule and its occupants at 25,000 mph. The heat shield must work well because this is the fastest capsule descent since Apollo.
This mission will also carry miniature Moon-orbiting satellites. These will undertake vital precursor science, including as examining further into permanently shadowed craters where scientists suspect there is water and measuring the radiation environment to see long-term human consequences.
Artemis 1 will launch, fly to the Moon, place satellites, orbit it, return to Earth, and splash down in the ocean. NASA.
What's Artemis's goal? What launches are next?
The mission is a first step toward Artemis 3, which will lead to the first human Moon missions since 1972. Artemis 1 is unmanned.
Artemis 2 will have astronauts a few years later. Like Apollo 8, it will be an orbital mission that circles the Moon and returns. The astronauts will orbit the Moon longer and test everything with a crew.
Eventually, Artemis 3 will meet with the SpaceX Starship on the Moon's surface and transfer people. Orion will stay in orbit while the lunar Starship lands astronauts. They'll go to the Moon's south pole to investigate the water ice there.
Artemis is reminiscent of Apollo. What's changed in 50 years?
Kennedy wanted to beat the Soviets to the Moon with Apollo. The administration didn't care much about space flight or the Moon, but the goal would place America first in space and technology.
You live and die by the sword if you do that. When the U.S. reached the Moon, it was over. Russia lost. We planted flags and did science experiments. Richard Nixon canceled the program after Apollo 11 because the political goals were attained.
Large rocket with two boosters between two gates
NASA's new Space Launch System is brought to a launchpad. NASA
50 years later... It's quite different. We're not trying to beat the Russians, Chinese, or anyone else, but to begin sustainable space exploration.
Artemis has many goals. It includes harnessing in-situ resources like water ice and lunar soil to make food, fuel, and building materials.
SpaceX is part of this first journey to the Moon's surface, therefore the initiative is also helping to develop a lunar and space economy. NASA doesn't own the Starship but is buying seats for astronauts. SpaceX will employ Starship to transport cargo, private astronauts, and foreign astronauts.
Fifty years of technology advancement has made getting to the Moon cheaper and more practical, and computer technology allows for more advanced tests. 50 years of technological progress have changed everything. Anyone with enough money can send a spacecraft to the Moon, but not humans.
Commercial Lunar Payload Services engages commercial companies to develop uncrewed Moon landers. We're sending a radio telescope to the Moon in January. Even 10 years ago, that was impossible.
Since humans last visited the Moon 50 years ago, technology has improved greatly.
What other changes does Artemis have in store?
The government says Artemis 3 will have at least one woman and likely a person of color.
I'm looking forward to seeing more diversity so young kids can say, "Hey, there's an astronaut that looks like me. I can do this. I can be part of the space program.”
Laura Sanders
3 years ago
Xenobots, tiny living machines, can duplicate themselves.
Strange and complex behavior of frog cell blobs
A xenobot “parent,” shaped like a hungry Pac-Man (shown in red false color), created an “offspring” xenobot (green sphere) by gathering loose frog cells in its opening.
Tiny “living machines” made of frog cells can make copies of themselves. This newly discovered renewal mechanism may help create self-renewing biological machines.
According to Kirstin Petersen, an electrical and computer engineer at Cornell University who studies groups of robots, “this is an extremely exciting breakthrough.” She says self-replicating robots are a big step toward human-free systems.
Researchers described the behavior of xenobots earlier this year (SN: 3/31/21). Small clumps of skin stem cells from frog embryos knitted themselves into small spheres and started moving. Cilia, or cellular extensions, powered the xenobots around their lab dishes.
The findings are published in the Proceedings of the National Academy of Sciences on Dec. 7. The xenobots can gather loose frog cells into spheres, which then form xenobots.
The researchers call this type of movement-induced reproduction kinematic self-replication. The study's coauthor, Douglas Blackiston of Tufts University in Medford, Massachusetts, and Harvard University, says this is typical. For example, sexual reproduction requires parental sperm and egg cells. Sometimes cells split or budded off from a parent.
“This is unique,” Blackiston says. These xenobots “find loose parts in the environment and cobble them together.” This second generation of xenobots can move like their parents, Blackiston says.
The researchers discovered that spheroid xenobots could only produce one more generation before dying out. The original xenobots' shape was predicted by an artificial intelligence program, allowing for four generations of replication.
A C shape, like an openmouthed Pac-Man, was predicted to be a more efficient progenitor. When improved xenobots were let loose in a dish, they began scooping up loose cells into their gaping “mouths,” forming more sphere-shaped bots (see image below). As many as 50 cells clumped together in the opening of a parent to form a mobile offspring. A xenobot is made up of 4,000–6,000 frog cells.
Petersen likes the Xenobots' small size. “The fact that they were able to do this at such a small scale just makes it even better,” she says. Miniature xenobots could sculpt tissues for implantation or deliver therapeutics inside the body.
Beyond the xenobots' potential jobs, the research advances an important science, says study coauthor and Tufts developmental biologist Michael Levin. The science of anticipating and controlling the outcomes of complex systems, he says.
“No one could have predicted this,” Levin says. “They regularly surprise us.” Researchers can use xenobots to test the unexpected. “This is about advancing the science of being less surprised,” Levin says.
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Tora Northman
3 years ago
Pixelmon NFTs are so bad, they are almost good!
Bored Apes prices continue to rise, HAPEBEAST launches, Invisible Friends hype continues to grow. Sadly, not all projects are as successful.
Of course, there are many factors to consider when buying an NFT. Is the project a scam? Will the reveal derail the project? Possibly, but when Pixelmon first teased its launch, it generated a lot of buzz.
With a primary sale mint price of 3 ETH ($8,100 USD), it started as an expensive project, with plenty of fans willing to invest in what was sold as a game. After it was revealed, it fell rapidly.
Why? It was overpromised and under delivered.
According to the project's creator[^1], the funds generated will be used to develop the artwork. "The Pixelmon reveal was wrong. This is what our Pixelmon look like in-game. "Despite the fud, I will not go anywhere," he wrote on Twitter. The goal remains. The funds will still be used to build our game. I will finish this project."
The project raised $70 million USD, but the NFTs buyers received were not the project's original teasers. Some call it "the worst NFT project ever," while others call it a complete scam.
But there's hope for some buyers. Kevin emerged from the ashes as the project was roasted over the fire.
A Minecraft character meets Salad Fingers - that's Kevin. He's a frog-like creature whose reveal was such a terrible NFT that it became part of history – and a meme.
If you're laughing at people paying $8K for a silly pixelated image, you might need to take it back. Precisely because of this, lucky holders who minted Kevin have been able to sell the now-memed NFT for over 8 ETH (around $24,000 USD), with some currently listed for 100 ETH.
Of course, Twitter has been awash in memes mocking those who invested in the project, because what else can you do when so many people lose money?
It's still unclear if the NFT project is a scam, but the team behind it was hired on Upwork. There's still hope for redemption, but Kevin's rise to fame appears to be the only positive outcome so far.
[^1] This is not the first time the creator (A 20-yo New Zealanders) has sought money via an online platform and had people claiming he under-delivered. He raised $74,000 on Kickstarter for a card game called Psycho Chicken. There are hundreds of comments on the Kickstarter project saying they haven't received the product and pleading for a refund or an update.
DC Palter
3 years ago
How Will You Generate $100 Million in Revenue? The Startup Business Plan
A top-down company plan facilitates decision-making and impresses investors.
A startup business plan starts with the product, the target customers, how to reach them, and how to grow the business.
Bottom-up is terrific unless venture investors fund it.
If it can prove how it can exceed $100M in sales, investors will invest. If not, the business may be wonderful, but it's not venture capital-investable.
As a rule, venture investors only fund firms that expect to reach $100M within 5 years.
Investors get nothing until an acquisition or IPO. To make up for 90% of failed investments and still generate 20% annual returns, portfolio successes must exit with a 25x return. A $20M-valued company must be acquired for $500M or more.
This requires $100M in sales (or being on a nearly vertical trajectory to get there). The company has 5 years to attain that milestone and create the requisite ROI.
This motivates venture investors (venture funds and angel investors) to hunt for $100M firms within 5 years. When you pitch investors, you outline how you'll achieve that aim.
I'm wary of pitches after seeing a million hockey sticks predicting $5M to $100M in year 5 that never materialized. Doubtful.
Startups fail because they don't have enough clients, not because they don't produce a great product. That jump from $5M to $100M never happens. The company reaches $5M or $10M, growing at 10% or 20% per year. That's great, but not enough for a $500 million deal.
Once it becomes clear the company won’t reach orbit, investors write it off as a loss. When a corporation runs out of money, it's shut down or sold in a fire sale. The company can survive if expenses are trimmed to match revenues, but investors lose everything.
When I hear a pitch, I'm not looking for bright income projections but a viable plan to achieve them. Answer these questions in your pitch.
Is the market size sufficient to generate $100 million in revenue?
Will the initial beachhead market serve as a springboard to the larger market or as quicksand that hinders progress?
What marketing plan will bring in $100 million in revenue? Is the market diffuse and will cost millions of dollars in advertising, or is it one, focused market that can be tackled with a team of salespeople?
Will the business be able to bridge the gap from a small but fervent set of early adopters to a larger user base and avoid lock-in with their current solution?
Will the team be able to manage a $100 million company with hundreds of people, or will hypergrowth force the organization to collapse into chaos?
Once the company starts stealing market share from the industry giants, how will it deter copycats?
The requirement to reach $100M may be onerous, but it provides a context for difficult decisions: What should the product be? Where should we concentrate? who should we hire? Every strategic choice must consider how to reach $100M in 5 years.
Focusing on $100M streamlines investor pitches. Instead of explaining everything, focus on how you'll attain $100M.
As an investor, I know I'll lose my money if the startup doesn't reach this milestone, so the revenue prediction is the first thing I look at in a pitch deck.
Reaching the $100M goal needs to be the first thing the entrepreneur thinks about when putting together the business plan, the central story of the pitch, and the criteria for every important decision the company makes.
Ray Dalio
3 years ago
The latest “bubble indicator” readings.
As you know, I like to turn my intuition into decision rules (principles) that can be back-tested and automated to create a portfolio of alpha bets. I use one for bubbles. Having seen many bubbles in my 50+ years of investing, I described what makes a bubble and how to identify them in markets—not just stocks.
A bubble market has a high degree of the following:
- High prices compared to traditional values (e.g., by taking the present value of their cash flows for the duration of the asset and comparing it with their interest rates).
- Conditons incompatible with long-term growth (e.g., extrapolating past revenue and earnings growth rates late in the cycle).
- Many new and inexperienced buyers were drawn in by the perceived hot market.
- Broad bullish sentiment.
- Debt financing a large portion of purchases.
- Lots of forward and speculative purchases to profit from price rises (e.g., inventories that are more than needed, contracted forward purchases, etc.).
I use these criteria to assess all markets for bubbles. I have periodically shown you these for stocks and the stock market.
What Was Shown in January Versus Now
I will first describe the picture in words, then show it in charts, and compare it to the last update in January.
As of January, the bubble indicator showed that a) the US equity market was in a moderate bubble, but not an extreme one (ie., 70 percent of way toward the highest bubble, which occurred in the late 1990s and late 1920s), and b) the emerging tech companies (ie. As well, the unprecedented flood of liquidity post-COVID financed other bubbly behavior (e.g. SPACs, IPO boom, big pickup in options activity), making things bubbly. I showed which stocks were in bubbles and created an index of those stocks, which I call “bubble stocks.”
Those bubble stocks have popped. They fell by a third last year, while the S&P 500 remained flat. In light of these and other market developments, it is not necessarily true that now is a good time to buy emerging tech stocks.
The fact that they aren't at a bubble extreme doesn't mean they are safe or that it's a good time to get long. Our metrics still show that US stocks are overvalued. Once popped, bubbles tend to overcorrect to the downside rather than settle at “normal” prices.
The following charts paint the picture. The first shows the US equity market bubble gauge/indicator going back to 1900, currently at the 40% percentile. The charts also zoom in on the gauge in recent years, as well as the late 1920s and late 1990s bubbles (during both of these cases the gauge reached 100 percent ).
The chart below depicts the average bubble gauge for the most bubbly companies in 2020. Those readings are down significantly.
The charts below compare the performance of a basket of emerging tech bubble stocks to the S&P 500. Prices have fallen noticeably, giving up most of their post-COVID gains.
The following charts show the price action of the bubble slice today and in the 1920s and 1990s. These charts show the same market dynamics and two key indicators. These are just two examples of how a lot of debt financing stock ownership coupled with a tightening typically leads to a bubble popping.
Everything driving the bubbles in this market segment is classic—the same drivers that drove the 1920s bubble and the 1990s bubble. For instance, in the last couple months, it was how tightening can act to prick the bubble. Review this case study of the 1920s stock bubble (starting on page 49) from my book Principles for Navigating Big Debt Crises to grasp these dynamics.
The following charts show the components of the US stock market bubble gauge. Since this is a proprietary indicator, I will only show you some of the sub-aggregate readings and some indicators.
Each of these six influences is measured using a number of stats. This is how I approach the stock market. These gauges are combined into aggregate indices by security and then for the market as a whole. The table below shows the current readings of these US equity market indicators. It compares current conditions for US equities to historical conditions. These readings suggest that we’re out of a bubble.
1. How High Are Prices Relatively?
This price gauge for US equities is currently around the 50th percentile.
2. Is price reduction unsustainable?
This measure calculates the earnings growth rate required to outperform bonds. This is calculated by adding up the readings of individual securities. This indicator is currently near the 60th percentile for the overall market, higher than some of our other readings. Profit growth discounted in stocks remains high.
Even more so in the US software sector. Analysts' earnings growth expectations for this sector have slowed, but remain high historically. P/Es have reversed COVID gains but remain high historical.
3. How many new buyers (i.e., non-existing buyers) entered the market?
Expansion of new entrants is often indicative of a bubble. According to historical accounts, this was true in the 1990s equity bubble and the 1929 bubble (though our data for this and other gauges doesn't go back that far). A flood of new retail investors into popular stocks, which by other measures appeared to be in a bubble, pushed this gauge above the 90% mark in 2020. The pace of retail activity in the markets has recently slowed to pre-COVID levels.
4. How Broadly Bullish Is Sentiment?
The more people who have invested, the less resources they have to keep investing, and the more likely they are to sell. Market sentiment is now significantly negative.
5. Are Purchases Being Financed by High Leverage?
Leveraged purchases weaken the buying foundation and expose it to forced selling in a downturn. The leverage gauge, which considers option positions as a form of leverage, is now around the 50% mark.
6. To What Extent Have Buyers Made Exceptionally Extended Forward Purchases?
Looking at future purchases can help assess whether expectations have become overly optimistic. This indicator is particularly useful in commodity and real estate markets, where forward purchases are most obvious. In the equity markets, I look at indicators like capital expenditure, or how much businesses (and governments) invest in infrastructure, factories, etc. It reflects whether businesses are projecting future demand growth. Like other gauges, this one is at the 40th percentile.
What one does with it is a tactical choice. While the reversal has been significant, future earnings discounting remains high historically. In either case, bubbles tend to overcorrect (sell off more than the fundamentals suggest) rather than simply deflate. But I wanted to share these updated readings with you in light of recent market activity.