Category Archives: Asked & Answered

Asked & Answered: 15.0

The majority of my readers (I would say vast majority but that would imply a vast number of readers) are of, shall we say, advanced age.  Being of advanced age has its benefits — for instance, my age allows me to completely ignore what passes for pop music these days and no one, except maybe James Corden, will criticize me for it — but advanced age also has its drawbacks.  One of them is the ever-growing list of prescription drugs that people my age find themselves ingesting on a regular basis.

Don’t get me wrong, I’m not anti-medical-science.  In fact I feel fortunate when I consider the array of drugs developed in the last 40, 30, 20, 10 years to address the many maladies of civilized life.  These drugs range from lisinopril (high blood pressure, approved in 1987, generic since 2002) to omeprazole (acid reflux, approved in 1988, generic since 2001) to ropinirole (restless legs, approved in 1997, generic since 2008) to aflibercept (wet macular degeneration, approved in 2011 and now costing Medicare $2.9 billion a year) to apixaban (anti-coagulant for atrial fibrillation, approved in 2012 and costing $10 billion a year).

Being of suitably advanced age and other circumstances, I partake of all of these drugs, and more.  Not like it’s fun, but it would be less fun otherwise.

But what I really want to talk about is how these wondrous pharmacologicals are handled inside our bodies.  We down these pills as if they simply melt in our tummies, magically do their respective jobs for the day, and then discreetly leave the scene.  But that would not be the case at all.

I became interested in how drugs are processed in our bodies after a recent, and brief, trial of the diuretic chlorthalidone, a blood-pressure medicine that has been in use since 1960.  In my case, the drug is unreasonably effective.  In just two days, my blood pressure fell nearly 30 points and I lost about 6 pounds, despite drinking lots of water to stay hydrated.  I had to stop the trial to keep my blood pressure and weight from falling even further.

I wondered how chlorthalidone could have such a drastic, powerful effect on me — could there have been some interaction with another of my several prescription medicines?

• • • 

When drug interactions occur, it’s not because the drugs chemically react with one another in your bloodstream, but typically because they (a) have the same effect, (b) have opposing effects, or (c) use the same metabolic path through your gut or liver– in effect, competing with each other for your body’s metabolic resources.  This is actually pretty common.

Another type of interaction is when you ingest something, drug or otherwise, that thwarts the metabolic process itself.  You’ve probably heard, for example, that drinking grapefruit juice is a bad idea when you are taking certain medications.  This is because…

… grapefruit juice inhibits the CYP3A4 enzyme of the cytochrome P450 system in the intestinal mucosa, increasing the bioavailability of drugs with a high first pass metabolism. [British Journal of Medical Practitioners, 2012]

If I may clarify — and please do, you say!  According to the National Library of Medicine, CYP3A4 is the name of a gene on human chromosome 7.  This gene directs various cells to manufacture an enzyme (one of the P450 enzymes) that is “involved in the metabolism of approximately half the drugs in use today, including acetaminophen, codeine, cyclosporin, diazepam, erythromycin, and chloroquine.  The enzyme also metabolizes some steroids and carcinogens.”

Here, metabolism means the process of breaking down a drug into smaller molecules that can be eliminated by the body.  Simply put, the CYP3A4 enzyme helps us deactivate many toxins and drugs.  In fact, drug manufacturers rely on CYP3A4 to remove their drugs from the bloodstream, which allows medicines to be taken on a daily, high-compliance basis.

If your CYP3A4 enzymes get blocked or disabled, then the drugs that are designed to be broken down by CYP3A4 will circulate in your system at higher levels than the drug-maker intended.  This can in turn produce toxic effects.

The CYP3A4 enzyme (below, per the RCSB Protein Data Bank) looks like a Rorschach test designed by Jackson Pollock:

Drawing of CYP3A4 enzyme

That mammals, over the eons, evolved a way to manufacture a toxin-neutralizing enzyme as complex as this is beyond my comprehension — and also beyond the scope of this post. But clearly, the evolution of CYP3A4 wasn’t shaped by grapefruit juice.  (The chemical in grapefruit juice, bergamottin, that deactivates the CYP3A4 enzyme was not conclusively identified until 2012.)

Grapefruit juice is not the only inhibitor of CYP3A4 (see this list) and is only one of many food-based inhibitors (fresh-ground black pepper is another).  I don’t use much pepper or drink grapefruit juice, so that would not explain any unusual drug responses I might have.  It would be more likely for my medications to be fighting over my CYP3A4 enzymes.

Curious, I made a list of the 11 (yes, that many) medications and supplements that I take on a daily and/or occasional basis, and then searched the web to see how many of them use the CYP3A4 pathway.  I found that 6 of the 11 rely on CYP3A4 for their metabolism, and two of those can even inhibit CYP3A4.  Just to complicate things.

I have no control which drugs have first dibs on my CYP3A4 reserves.  I guess I have to trust that, if I’m not having issues, then my body is doing its best to handle the drug traffic down there.  But it pays to be vigilant, especially when adding or adjusting medicines.

• • • 

What about my not-so-friendly friend, chlorthalidone?  Turns out that CYP3A4 was not a factor here — chlorthalidone is hardly metabolized at all but instead is very slowly filtered out by the kidneys.  By slowly, I mean that it takes over 40 hours to eliminate half of it.

This is probably one reason why, as I just learned, that diuretics like chlorthalidone are on the American Geriatric Society’s Beers List of “potentially inappropriate drugs” for older (sorry, advanced age) adults.

I know now that the dosage of chlorthalidone I was prescribed (25mg) was way too high; as I discovered, it would have been more prudent for my doctor to have started me out on one-quarter of that dose, given my age.  Doctors know a lot of things, but they can’t keep up with everything.  It doesn’t mean you doubt them, but you have more time and energy to research your specific situation than your doctor does — you can add to her knowledge.

If this post has given you a slightly better sense of what goes on inside you after you take your pills, and helps you appreciate the complexities of medical management for seniors, then great.  Thanks for hanging in here until the end.

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Asked and Answered 14.0

If you’re in love with Wordle — as so many of us are ♥ ♥ ♥ ! — wouldn’t it be wise to learn everything you can about your object of desire before you discover something about them that causes you to walk out on the relationship in anger and disappointment?  Of course you would.  That’s why I am here to offer some Wordle relationship advice before it gets to that point… that is, the crying point 💧💧💧.

We all hate falling into those Wordle rabbit holes like SLATE-SPATE-STATE-SKATE or PAINT-SAINT-TAINT-FAINT, games that could end in six guesses just as easily as three.  The games that make you want to dive off a barren, rocky cliff into a cold, turbulent sea.  Well, perhaps I exaggerate.  There could be a patch of grass on that cliff.

Don’t worry, what I’m about to reveal is not going to spoil your Wordle fun, but it might be helpful for you to know something about the set of 2,300 words that are Wordle solutions.  The solution set has been available since Wordle was launched, and some players feel that having the solution set at hand is part and parcel of playing the game.  While I disagree, there are times I would appreciate knowing whether I am on Wordle’s wavelength when considering my next guess.

So, I downloaded the Wordle solution set — without looking at the list of words — and then created a spreadsheet that allowed me to ask and answer five general questions about the nature of the words that are Wordle solutions.  (If you feel that even general knowledge about the solution set would ruin the game for you, then stop reading now.)

My first question was, how many vowels does the typical Wordle word have?  The answer (below) is that about two-thirds of the solutions have two vowels.  Of the remaining third, the solution is more likely to contain a single vowel than three vowels:

FIGURE 1: NUMBER OF VOWELS IN SOLUTION

Pie Chart - the number of vowels in Wordle solutions

Next, I wanted to know the likelihood that a given Wordle solution starts with a vowel, which I always find annoying.  This turns out to be a bit less than one out of seven.  So, once a week we should expect IRATE, ETHER, or ALERT?  As Charlie Brown would say, AAUGH!

FIGURE 2: FIRST LETTER OF SOLUTION

Pie Chart - the starting letter in Wordle solutions

Third, it certainly feels like a substantial number of Wordle words end in E, more so than other vowels and consonants.  I didn’t tally up the endings letter-by-letter, but I did find that about a third of the solutions end in E or Y, with E being a bit more likely:

FIGURE 3: FINAL LETTER OF SOLUTION

Pie Chart - the ending letter in Wordle solutions

Which brings us to the letter frequency of the Wordle solution set.  I was curious to know how often the two most common vowels AE and the four most common consonants LRST appear in Wordle words.  I found that only 5% of the solutions do not contain any of the letters AELRST.  One-third of Wordle solutions contain exactly two AELRST letters, while three-quarters of the solutions contain two, three, four or more.  This means that your Wordle blind date is likely to be bland, letter-wise.  Even STALE.  Or bore you to TEARS.

FIGURE 4: SOLUTIONS CONTAINING LETTERS AELRST

Pie Chart - the number of AELRST letters in Wordle solutions

Lastly, how likely is it that your latest Wordle crush is from a Slavic-European country?  By that I mean, how many of the solutions contain one or more of the rare (according to Words with Friends) letters JKQVXZ?   Surprisingly, the answer is about one in five:

FIGURE 5: SOLUTIONS CONTAINING LETTERS JKQVXZ

Pie Chart - the number of JKQVXZ letters in Wordle solutions

So now you know a little more about the game you’ve been spending so much time with and often grumbling about.  Maybe this will help you find the day’s solution more quickly and put a little more love ♥ ♥ ♥ into your love-hate relationship with Wordle.

_______

Update: One reader commented that her strategy is to start with consonants that did not appear in the previous day’s solution.  (Her rules were actually much more complicated, but too hard for me to analyze.)  So I looked at the solution set in order of publication date to see whether use-fresh-consonants is in fact a good strategy.  Here is the data:

Consonants Found in
Previous Day’s Puzzle
Number of
Puzzles
Percent of
Puzzles
0 1112 48%
1 869 38%
2 289 12%
3 43   2%
4 3 ~0%

Almost half the time, there are no shared consonants between the current solution and the previous day’s solution.  Furthermore, it is rare to have three or four shared consonants. So the odds seem to be definitely in your favor if you re-use zero or maybe one consonant from the previous day.

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Asked & Answered: 13

When I became a Damn Yankee [1] back in the aughts, one of the first things I noticed was the outsize presence of Christian radio here, both AM and FM, and both music and talk.  There are more religious radio stations in the Asheville area (15 within a 30-mile radius) than NPR stations in the entire state of South Carolina (nine) or Tennessee (also nine).

I soon found an easy way to locate (and bypass) Christian stations — just set the car radio to “scan” and listen for giveaway words like righteous, almighty, rejoice, praise, miracle, glory and power, along with the instant-bingos Jesus, Savior and God.  At least one of the above is sure to be heard in any six-second fragment of any Christian radio broadcast here.

The abundance of God’s Radio-Spoken Word in these parts led me to wonder: are there so many religious radio stations here because there is so much sin to stamp out, or because there is so much righteousness to self-congratulate?  Is there any correlation at all between the reach of religious radio in a region and the size of its cesspool of sin?

Before we get to the answer (after all, this is an Asked & Answered article), let’s talk about the possible types of correlation between one thing and another [see illustrations below].

As shown in the first diagram, direct correlation is when one factor increases along with the other.  If sin and religious radio were directly correlated, then one would tend to find more sin in areas that have more religious radio stations.  There would be several ways to explain such a correlation:

(a) Religious broadcasters might be drawn to set up shop in high-sin communities, because that is where The Word is needed the most (cf. the Willie Sutton Rule).

(b) Or it might be that sinners hear the Sunday sermons, feel the full power of the Lord’s forgiveness, and then figure, “Hey, the slate is clean, this gives me a whole new week of sinning to do.”

(c) Or maybe religious broadcasts actually encourage sin!  But that could only be true if they made listeners believe things like vaccinations are deadly, children need to be “delivered” from same-sex households, and if you convert to Islam you may beat your wife.  Since these are all unthinkable, this hypothesis may be a bit shaky.

This brings us to inverse correlation (second diagram) where as one factor rises, the other tends to fall.  If that were the case here, then we could say: the more religious stations, the fewer the citations.  What might explain such a catchy correlation?

(a) Perhaps religious radio broadcasts reach into the hearts of hardened men and subdue their wayward impulses.  Listeners might say to themselves, “Nah, I don’t need to rob that bank today.  It’s Sunday, the Lord’s day, and they’re closed.”

(b) Or it could be that religious radio strengthens the wills of the righteous, who then elect law-and-order politicians, who then pass punitive laws, which mandate long prison terms for sinners, who decide to flee to other states.  Could be that.

But it is also possible there is no correlation at all (third diagram) between the number of religious radio stations and the amount of sinning in a given area.  How would one know?  Asked — and now answered.

METHODOLOGY

I started by selecting fifteen cities at random from five US regions (Northeast, Southeast, Central, Texas-Oklahoma, California) and three population ranges (Large = 3-6 million, Medium = 1-2 million, and Small = 0.5-1.0 million).  The population figures for each area (see table below) were based on the estimated number of residents within a 30-mile radius of city center.  [Sources:  Free Map Tools and MCDC (Missouri Census Data Center).]

Now, I needed a proxy for the amount of sin in a given area, since the true definition of sin is known only to God.  (As we will all find out on Judgment Day, won’t we!)  For my proxy I chose the crimes homicide, robbery and assault — purposely ignoring property crime — and then totaled the respective rates for each city, with each crime given equal weighting.  [My main source here was the FBI although all my other sources cited FBI statistics.]

Finally, I counted the number of religious radio stations, AM and FM, within 30 miles of the center of each city.  [Source: radio-locator.com.]  I included stations whose format was listed as religious, gospel, Christian contemporary or Spanish Christian (found primarily in California and Texas).  The bar chart below shows the number of religious radio stations (and the percentage of the total they represent) for each metro area, grouped by region.

RESULTS AND COMMENTARY

What surprised me about the radio station data was that most of the selected metro areas had about the same number (12.5 ± 1.3) of religious stations, regardless of population or region.  Cities with significantly more religious stations were Austin (22), Kansas City (23) and Houston (31).  Spanish Christian was by far the dominant religious format in Houston but represented only a handful of the religious stations in Austin and Kansas City.

The percentage of religious-format stations in a given metro area was typically 18-22%, again irrespective of population or region.  The notable outliers were Kansas City (40%), Houston (39%), Austin (33%) and Asheville (33%).  By comparison, religious radio in Chicago (13%) was a bit light, at least on a percentage basis.

Let’s now consider the original question — does religious radio have sin-fighting power?  To get a visual sense of the correlation, if any, I plotted each city’s rate of violent crime (selected crimes per million residents) vs. the prevalence of religious radio (stations per million residents) within 30 miles of city center.  I then calculated the best-fit curve [2] through these data points:

Hallelujah! as Leonard Cohen might say if he were alive today and subscribed to this blog.  It looks like the more religious radio stations per capita, the lower the crime rate, right?  Go tell it on the mountain, people — mount a transmitter on every steeple!

Or maybe not.  On closer inspection, this graph reveals a somewhat different correlation: the large cities are all on the left side of the graph, the medium cities are all in the middle, and the small cities skew to the right.  It is almost as if the rate of violent crime and the concentration of religious radio stations both depend on population density. 

In fact, we already noted that the raw number of religious stations within a 30-mile radius of a city does not depend on its population.  (Perhaps it has more to do with the available frequencies on the radio dial.)  That being the case, small cities will naturally tend to have the greatest concentration of religious radio stations, when expressed in terms of stations per million residents.  So this graph, in many ways, says nothing at all!  Or more precisely, while there are differences in crime rates, there is not a strong correlation between crime and religious radio, at least for this sample of cities.

To be able to say the same thing mathematically, I decided to analyze this data set with a statistical tool called multiple linear regression (MLR).  This tool helps identify which factors are strongly correlated and which are not, so that one can select a model that best fits the data.  I evaluated many models with various combinations and powers of the factors, but none of them fit the data better than the following two-factor model:

C = 64.5 + 1.22 P 2 – 1.04 S

where C is the crime rate (crimes per year per million people), P is the local population (millions) and S is the local concentration of religious radio (stations per million people).  This model suggests that crime rises with the square of the population but falls as the concentration of religious radio increases.

To illustrate the workings of this model, let’s pretend that Chicago doubled the number of religious radio stations in the area, from 12 to 24.  (This means S for Chicago would rise from 2.0 to 4.0.)  The model predicts that this would lead to a 2-point drop in the rate of violent crime, or twelve people a year who are not murdered, robbed or assaulted.  If you lived in Chicago, wouldn’t you want to be one of those twelve?

But before we start building a bunch of radio towers, we need to check the goodness-of-fit of the model to see what its predictions are worth.  According to the MLR analysis, the correlation coefficient for this model is only 0.5 (1.0 would be a perfect fit).  This means there is a weak-to-moderate correlation between the crime rate and the factors proposed to explain it.

Finally, the MLR analysis reports a 91% chance that P is a significant variable, but only a 69% chance that S is significant.  In other words, the religious radio effect is probably just a lot of noise, as you likely suspected before you even read this article.

I hope you at least learned something today that you wouldn’t normally hear on a Sunday.  Now, go thy way, and from henceforth sin no more.

________________

[1]  I learned the local definition of Damn Yankee — a Northener who moves to the South and stays there — when I was only half-jokingly called one in a 2007 job interview here.
[2]  Here I need to insert a note about the crime rate data for Scranton, PA, the town where Joe Biden lived until he was 10.  Whereas the other crime rates in this study were based on the most recently available data (2018 and 2019), the 2018 crime rates in Scranton took an incredible leap — I figured that this must reflect some kind of change in reporting methods or coverage area.  So, even though my graph shows 2018-2019 crime data for Scranton, I used an average of Scranton’s 2016 and 2017 violent crime rates for the purpose of calculating the best-fit curve.
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