Let's Know Things

This week we talk about HIV, AIDS, and ART.We also discuss HAART, the Berlin Patient, and potential future cures.Recommended Book: Allergic by Theresa MacPhailShow Notes* https://www.unaids.org/en/resources/fact-sheet* https://hivinfo.nih.gov/understanding-hiv/fact-sheets/hiv-treatment-basics* https://clinicalinfo.hiv.gov/en/glossary/antiretroviral-therapy-art* https://www.paho.org/en/topics/antiretroviral-therapy* https://journals.lww.com/jaids/fulltext/2010/01010/declines_in_mortality_rates_and_changes_in_causes.13.aspx* https://link.springer.com/article/10.1007/s13181-013-0325-8* https://academic.oup.com/jac/article/73/11/3148/5055837?login=false* https://journals.lww.com/jaids/fulltext/2016/09010/narrowing_the_gap_in_life_expectancy_between.6.aspx* https://en.wikipedia.org/wiki/Tenofovir_disoproxil* https://en.wikipedia.org/wiki/Management_of_HIV/AIDS* https://www.verywellhealth.com/cart-hiv-combination-antiretroviral-therapy-48921* https://www.cdc.gov/hiv/risk/art/index.html* https://www.freethink.com/health/cured-of-hiv* https://www.jstor.org/stable/3397566?origin=crossref* https://www.nytimes.com/1982/05/11/science/new-homosexual-disorder-worries-health-officials.html* https://pubmed.ncbi.nlm.nih.gov/23444290/* https://my.clevelandclinic.org/health/diseases/4251-hiv-aids* https://web.archive.org/web/20080527201701/http://data.unaids.org/pub/EPISlides/2007/2007_epiupdate_en.pdf* https://www.thelancet.com/journals/lanhiv/article/PIIS2352-3018(23)00028-0/fulltextTranscriptIn mid-May of 1981, the queer community-focused newspaper, the New York Native, published what would become the first-ever article on a strange disease that seemed to be afflicting community members in the city.What eventually became known as AIDS, but which was at the time discussed by medical professionals primarily in terms of its associated diseases, was clinically reported upon for the first time less than a month later, five official cases having been documented in an interconnected group of gay men and users of injectable drugs, who came to the attention of doctors for not being inherently immunocompromised, but still somehow contracting a rare type of pneumonia that only really impacted folks with severely impaired immune systems.In subsequent years, doctors started using a range of different terms for HIV and AIDS, calling them at different times and in different contexts the lymphotophic retrovirus, Kaposi's sarcoma and opportunistic infections, and the 4H disease, referring to heroine users, hemophiliacs, homosexuals, and Haitians, the four groups that seemed to make up almost all of the confirmed afflicted patients.The acronym GRID, for gay-related immune deficiency was also used for a time, but that one was fairly rapidly phased out when it became clear that this condition wasn't limited to the gay community—though those earlier assumptions and the terminology associated with them did manage to lock that bias into mainstream conversation and understanding of AIDS and HIV for a long time, and in some cases and in some locations, to this day.By the mid-80s, two research groups had identified different viruses that seemed to be associated with or responsible for cases of this mysterious condition, and it was eventually determined (in 1986) that they were actually the same virus, and that virus was designated HIV.HIV, short for Human Immunodeficiency Virus, is a retrovirus that, if left untreated, leads to Acquired Immunodeficiency Syndrome, or AIDS, in about 50% of patients within ten years of infection.So HIV is the virus, AIDS is a condition someone with HIV can develop after their immune system is severely damaged by the infection, and there are a bunch of diagnostic differentiations that determine when someone has transitioned from one category to the other, but in general folks with HIV will experience moderate flu- or mono-like symptoms, alongside swollen lymph nodes and rashes and throat problems and sores across their bodies in the early stages of infection, and as things progress, they develop opportunistic infections of the kind that can only really latch onto a human when their immune system is weakened or shut down. While AIDS, arriving after the immune system is well and truly damaged, brings with it a slew of opportunistic infections and associated issues, the afflicted person potentially developing all sorts of cancers, sarcomas, persistent infections, and extreme versions of the flu-like, mono-like symptoms they may have suffered earlier on.We don't know for certain how and where HIV originated—and that's true of both kinds, as there's an HIV-1 and HIV-2 virus, the former of which accounts for most infections, the latter of which is less common, and less overall infectious—but both HIV types seem to have been transmitted to humans from non-human primates somewhere in West-central Africa in the early 20th century, possibly from chimpanzees in southern Cameroon, but that's pretty speculative, and there's some evidence that these diseases may have made the leap several times; so while there's a pretty good chance, based on what we know now, that the disease made it into humans and mutated approximately somewhere in that vicinity, sometime in the early 20th century, possibly via chimps hunted and eaten by locals as bushmeat, we really don't know for certain.There are reports of what were probably HIV as far back as 1959 in the Belgian Congo, but that's a bit speculative, too, and based on imperfect notes from the time.Back then, though, and through the 1980s, folks who contracted HIV and who were not treated would typically die within 11 years of being infected, and more than half of those diagnosed with AIDS in the US from 1981 through 1992 died within 2 years of their diagnosis; such a diagnosis was a death sentence, basically; it was a really horrible and scary time.Today, the outlook for folks who contract HIV is substantially better: the life expectancy of someone who contracts the virus and who is able to get treatment is about the same as someone who is not infected; the disease isn't cured, but the level of HIV virus in the blood of a person receiving treatment is so small that it's no longer transmissible, or even detectable.What I'd like to talk about today is a new therapy that's making those sorts of outcomes possible, how some few people have now been cured of HIV entirely, and what's on the horizon in this space.—Antiretroviral therapy, or ART, typically consists of a combination of drugs based on those that were originally combined in this way in 1996 by researchers who announced their findings at the International AIDS Conference in Vancouver—they called their approach highly active antiretroviral therapy, or HAART, and this combo was based on findings from earlier drugs that addressed one of HIV's seven stages of development—but because they all hit that same, single stage, the virus was rapidly developing an immunity to them, and they were universally pretty toxic, with horrible side-effects.What's more, this drug cocktail increased patients' life expectancy by about 24 months, on average—which is a lot, about two years, but considering all those side effects, which included severe liver problems and anemia, the extra months of life generally weren't very pleasant extra months.In 1995, a class of drugs called protease inhibitors were introduced, which prevented HIV from making copies of itself using the body's structural proteins.That, combined with the effects of other, existing retrovirals, which hindered the virus's ability to hijack the body's cells to make more of itself, turned out to be a substantial improvement over just one or the other approach.The announcement in 1996 was notable because the researchers involved were able to knock the viral load in their patients down to an undetectable level, and then keep it there, by using three drugs from each of those two antiviral classes, those two different approaches.So HAART was a major improvement over what came before, but it was still imperfect; deaths tied to HIV plummeted by 50% in the US and Europe in just three years, but the life expectancy of folks using this therapy was still low compared to other people; someone who contracted HIV in their 20s and went on this therapy was still only expected to live till their early 50s; way better than a two-year increase, but still plenty of room for improvement.In addition to that lifespan duration limitation, the HAART bundle of therapies was just really difficult to maintain.Some people experienced a dramatic redistribution of body fat, some developed heart arrhythmias or insulin resistance or peripheral neuropathy or lactic acidosis—which is basically a toxic buildup of the acid that results from metabolism, which is usually cleared naturally, but when it doesn't, it's potentially deadly.Anything less than absolutely perfect adherence to the treatment schedule was also potentially deleterious to the desired outcomes; it wasn't a forgiving regimen, with some of the drugs requiring three capsules be taken every 8 hours, and there was a chance that if a portion of a dose of one drug was missed, or not administered on time, the virus could develop an immunity to it and the whole thing would fall apart.Consequently, the HAART regimen was generally reserved until things got really bad, and that meant it didn't have a very large effect on the infected population, and those who did benefit from it suffered consequences, alongside those benefits.The change in terminology from HAART to ART arrived in 2001 when a drug called Viread, the brand name for tenofovir disoproxil, was released and added into the mix, replacing some of the most toxic and cumbersome of the previous therapies with a single pill per day, and one that came with far fewer, and far less extreme, side effects.In 2005 it was finally demonstrable, with a bunch of data, that beginning this type of therapy early rather than waiting until things get really bad was worth the trade-offs—researchers showed that if folks received access to ART upon diagnosis, severe HIV associated and non HIV associated illnesses  were reduced by 61%.As of 2016 there was still an average life expectancy gap between folks with HIV who received early care and people who were not infected of about 8 years, but that gap has been steadily closing with the introduction of new, easier to use, less side effect prone drugs—drugs that tend to attack the virus at different stages, and which take different approaches to hindering and blocking it—alongside innovations in how the drugs are delivered, like introducing substances that are converted by the body into the desired drug, which massively cuts the requisite dosage, in turn lessening the strain on the body's organs and the potential side effects associated with taking a higher dose of the drug, itself.We've also seen the advent of fixed-dose combination drugs, which are exactly what they sound like: a single pill containing the entire combination of drugs one must take each day, which makes a combination therapy much easier to administration and stick with, which in turn has substantially reduced the risk of severe side effects, and prevented mutations that might otherwise make a patient's virus more immune to some component of the drug cocktail.Some newer options just use two drugs, too, compared to the previous three-or-more, and most of these have been shown to be just as effective as the earlier, more bodily stressful combinations, and a recent, 2021 drug is injectable, rather than deliverable in pill-form, and can be administered just once a month—though a version of this drug, sold under the name Cabenuva, has been approved for administration every other month.So things in this corner of the medical world are looking pretty good, due new approaches and innovations to existing therapy models.These models remain imperfect, but they're getting better every year, and contracting HIV is no longer a death sentence, nor does it mean you'll always be infectious, or even detectably infected: the amount of HIV virus in one's blood can be kept undetectably low for essentially one's entire life, so long as one is able to get on the right therapy or combination of therapies and stick with it.That said, the global HIV pandemic is far from over, and access to these drugs–many of which are pricy, if you don't have insurance that will cover them—is not equally distributed.As of late-2022, the UN's official numbers indicate that about 39 million people, globally, have HIV, about 1.3 million were infected in 2022, and about 630,000 died from AIDS-related illnesses that year.That said, of those 39 million or so who are infected, nearly 30 million are receiving some kind of antiretroviral therapy, and about 86% of people who are estimated to be infected know their status, so they can seek such therapies, and/or take other precautious to protect themselves and others; though that also means about 5.5 million people, globally, have HIV and don't realize it.Here's a really remarkable figure, though: among people who are infected and know they are infected, about 93% of them were virally suppressed as of 2022.That's astonishing; 93% of people who have HIV and are aware of it are on some kind of therapy that has allowed them to suppress the virus so that it's nearly undetectable—the difference between the two, by the way, is that suppressed means 200 copies of the HIV virus per milliliter of blood, while undetectable is generally considered to be less than 50 copies per milliliter.So huge leaps in a relatively short period of time, and a massive improvement in both duration and quality of life for folks who might otherwise suffer mightily, and then die early, because of this virus and its associated symptoms.That said, there are some interesting, new approaches to dealing with HIV on the horizon, and some of them might prove to be even more impactful than this current batch of incredibly impactful ART options.As of September 2023, five people have been confirmed cured of HIV; not suppressed and not with viral loads at undetectable levels: cured.The first of these cured people, often referred to as the Berlin Patient, received a stem cell transplant from a bone marrow donation database that contained a genetic mutation called CCR5 Delta 32, which makes those who have it essentially immune to HIV infection.Three months after he received the transplant and stopped taking ART, doctors were unable to find any trace of the virus in his blood.He died from cancer in 2020, but there didn't seem to be any HIV in his blood from when he received the stem cell transplant, onward, and that happened in the early 2000s, and was formally announced to the medical community in 2008.At least two other people—two that we know about, anyway—have been cured of HIV using the same method; though at the moment at least, this option is severely limited as it requires that patients have a bone marrow match in donor databases, and that one of those donors have that specific, relatively rare mutation; so with existing science and techniques, at least, this is unlikely to be a widespread solution to this problem—though a 2017 experiment used stem cells derived from umbilical cord blood from a baby with that mutation to treat a woman' leukemia and cure her HIV, so there's a chance other approaches that make use of the same basic concept might be developed, opening this up to more people.Cancer drugs may also help some people with HIV: a drug that's been approved to treat several cancers called Venetoclax seems to also bind to a protein that helps HIV-infected T cells dodge the body's immune system and survive, and that realization has led to a series of experiments that showed HIV was suppressed in mice receiving this drug—though it bounced back a week later, and two weeks later in mice receiving both this drug and ART.This is unlikely to be a solution unto itself, then, but there's a chance either an adjusted version of this drug, or this drug in combination with other therapies, might be effective; and there's a clinical trial testing the efficacy of Venetoclax in human HIV patients at the end of this year, and another in 2024, so we may soon know if its safe and desirable to use this drug alongside ART, and that may, in turn, lead to a better understanding of how to amplify the drug's effects, or apply this method of hindering HIV from a different angle.CRISPR, the gene-editing technology borrowed from bacteria that allows for the cutting and removing and adding of genetic information, has enabled the development of several new potential HIV cures, one of which, called EBT-101, basically enters the body, finds helper T cells, and then cuts out chunks of the HIV virus's DNA, which prevents it from being able to replicate itself or hide away, reemerging later after another treatment has suppressed it.The benefit of this approach is that it could kill the viral reservoirs that otherwise allow HIV to persist in people who have undergone treatments, and a version of it that targets SIV, which is similar to HIV, but found in non-human primates—performed exactly as they hoped it would, finding and editing the targeted DNA, raising hopes than an HIV-targeting variation may manage similar wonders in human patients.This would be great if it ends up working, as one injection would theoretically clear all HIV from a person's system in relatively short-order, but the trials done so far have been small and on monkeys, and because of the nature of the research, it's not clear the monkeys were cured of HIV—just that the treatment got where it was supposed to go and made some DNA edits.A human trial of EBT-101 will finish up in March of 2025, though the researchers plan to follow up with their subjects for up to 15 years following the trial, to assess any long-term effects from their treatment, since CRISPR and this approach to messing with genes is still such a new thing.So while this may be a solution at some point, there's a good chance it won't be a real-deal, available option for another decade, minimum.So we've come a long way in a very short period of time with HIV and AIDS treatments, and the future is looking pretty good, with even more options and approaches on the horizon, including some actual cures, alongside high-quality, actually useable treatments.But there's still room to grow in terms of infection awareness, there are still distribution issues for some of these drugs, and there's still a fair bit of prejudice, the consequence of ignorance and historical misunderstandings and biases, keeping folks and institutions from doing as much as they otherwise could in many parts of the world; so a lot to be proud of, a lot to look forward to, but still plenty of room for improvement across the board. 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This week we talk about China’s standard map, the nine-dash line, and shoals.We also discuss WWIII, undersea minerals, and realities on the ground.Recommended Book: Outlive by Peter AttiaShow Notes* https://www.chinadaily.com.cn/a/202308/28/WS64ec91c2a31035260b81ea5b.html* https://www.uscc.gov/research/south-china-sea-arbitration-ruling-what-happened-and-whats-next* https://amti.csis.org/island-tracker/china/* https://globalvoices.org/2023/09/05/the-chinese-2023-map-has-nothing-new-but-why-are-chinas-neighbours-mad-about-it/* https://en.wikipedia.org/wiki/Government_of_China* https://www.reuters.com/world/asia-pacific/philippines-taiwan-malaysia-reject-chinas-latest-south-china-sea-map-2023-08-31/* https://theconversation.com/what-is-the-nine-dash-line-and-what-does-it-have-to-do-with-the-barbie-movie-209043* https://en.wikipedia.org/wiki/Republic_of_China_(1912%E2%80%931949)* https://en.wikipedia.org/wiki/Nine-dash_line* https://theconversation.com/what-is-the-nine-dash-line-and-what-does-it-have-to-do-with-the-barbie-movie-209043* https://hir.harvard.edu/vietnam-and-china-conflicting-neighbors-stuck-in-nationalism-and-memory/TranscriptIn the wake of some stunning defeats to European powers in the 19th century, and its place on the winning side of WWII, the Chinese government saw quite a lot of territory disappear, but then gained a fair bit back, following that global conflict, and this necessitated the redrawing of many maps, most of which were substantially outdated, because of the relative rapidity with which their territory was changing during this period—they lost Vietnam as a supplicant state, for instance, but also added a fair number of former Japanese islands to their collection, including Taiwan, which it took from Japan in 1945, and where the former Chinese government fled following Mao's revolution, which is what led to modern day Taiwan as a separate state, by their reckoning, at least, from that of Mainland China, which doesn't agree.And as is the case with Taiwan, not everyone in the area agrees about which other islands and bodies of water belong to whom, and the huge number of islands of varying sizes in the South China Sea are especially fraught, in terms of ownership claims, as many of them are worthless for the purpose of building real-deal settlements, but could be useful in terms of military infrastructure, allowing ships to dock and refuel, serving as weapons platforms for missiles and anti-aircraft equipment; that sort of thing.These island-related controversies have sparked or been components of several recent conflicts in the region, including clashes between the Chinese and Vietnamese militaries in 1974 and 1988, and as an apparent effort to lock-in their claim to some of these territories, the Chinese government, in December of 1947, published a map called the Location Map of South Sea Islands, which showed the South China Sea, along with an eleven-dash line that encompassed a huge, u-shaped portion of the region, with the implication that everything within that line belonged to China, though the Chinese government never outright said "all of this is ours, stay out."Beginning in the early 1950s, this line used only nine dashes, and had changed shape a bit, no longer including the Gulf of Tonkin as a concession to the now-independent North Vietnamese government.But the former Chinese government, the one that was now occupying and governing from Taiwan, continued to use an eleven-dash line on their official map, the implication being that they don't recognize the changes to Chinese territory made by the successor Chinese government that usurped them back in the mid-20th century.However many dashes are used, and whatever the specific expanse of them, though, the significance of this line on what's become known as the Chinese standard maps released at a regular cadence by the government have become the topic of furious debate, as the Chinese government has never really clarified what they're saying when they publish these things, allowing the implication to be that this is their home turf, their islands and ocean, but never taking the next step that would be required to formalize that claim.The implication of any territorial barrier is the violence required to defend it, so the presumed rationale here is that, like Taiwan's status, which is in an official sort of superposition right now, the Chinese government claiming it as their own, the Taiwanese government claiming independence, and everyone else just kind of making positive or negative noises while seldom taking a firm stance one way or the other, allows everyone involved to be unhappy and to hold their own opinions, but to not feel like they need to go to war over the issue, because no hands have been forced in that regard; a stronger stance and a more formal declaration of independence by Taiwan, supported by other nations, would presumably necessitate military action from China, while the same sort of concrete move by China to retake the island by force would probably trigger action from its opposition, as well.Leaving things flexible and vague, though, keeps everything nebulous enough that nothing needs to be blown up and no one has to die.The same seems to be true with this larger pseudo-claim of territory from the Chinese government, these maps showing an area that looks a lot like it belongs to China, but the Chinese government never formally saying "this is ours, and thus, if you want to go to these islands, travel these waters, you'll need our permission, and we'll blast you to kingdom come if you step over the line we've drawn here."What I'd like to talk about today are the implications of this sort of intentional geographic uncertainty, and the response to a new standard map the Chinese government recently released.—The 2023 edition of China's standard map, which usually displays its now-famous nine-dash line alongside other information about the country, like its territorial delineations, capitol cities, and the like, has created a moderate uproar throughout the area in part due to the addition of a tenth dash, and in part because it seems to have added to its collection of territory at the expense of many of its neighbors.Among those who are upset about these new visual claims is the Russian government, which has become increasingly close with the Chinese government following its invasion of Ukraine, which has left it a bit of a pariah, globally, and it's been in many ways propped up and sustained economically by trade with China; but even they made a statement of distaste about this map, which seems to show that an island which was previously divided between Chinese and Russian control, is now just China's.India is also pissed that highly disputed areas along its border with China have seemingly been folded into its neighbor's official collection of territories with the advent of this new map, and Vietnam, the Philippines, Malaysia, Indonesia, and of course, Taiwan, have also spoken out against what this new map implies—the latter of which, Taiwan, perhaps more than most, as that additional tenth dash seems to more firmly embrace it than previous maps, implying that Taiwan is becoming more China's than ever before, which in the current geopolitical context represents a potential military threat.But those other nations are also pretty peeved, as islands they claim as their own have been looped into this large u-shaped area, portrayed as being China's and China's alone; and although in many cases that's been true of previous versions of the map, as well, the context surrounding this version's release is substantially different than the context in previous years.So in response to this hubbub of outcries, the Chinese government has said, basically, calm down, this is the same map, what are you all so upset about?And to some degree that's largely true: most of these claims were on previous maps as well, but that additional dash does seem pretty aggressive in a world in which the Chinese government has made pretty clear that it both intends to retake Taiwan at some point, and that it's willing and able to do so, militarily, and in which the government has been feverishly investing in more guns, ships, jets, and missiles, and rapidly building out its military presence in these contested areas, including military bases high in the mountains along its border with India, in territory both nations claim as their own, and the construction of ship docks and turrets and missile launchers on tiny little islands in the middle of the ocean, which other nations claim, as well, but which China is physically occupying, punctuating their map-based claims with real-world threats toward anyone who challenges them; realities on the ground, to use the defense world parlance for building military assets of this kind in contested territory.In 2016, the Permanent Court of Arbitration in The Hague ruled that China's nine-dash line didn't have any basis in international law, and that this region is mostly international waters, usable by anyone, anytime, for any reasons, more or less.China dismissed this ruling and said it would ignore it, basically, so while other nations in the area, like the Philippines, have continued to fish in traditional areas, like the shoals surrounding the Spratly Islands, located between them and Malaysia and Vietnam in the South China Sea, China has been building artificial islands atop coral reefs on this island chain, dredging sand onto the reefs and then pouring concrete over that sand, allowing it to build permanent military structures and install radar systems, missile silos, and aircraft hangers, where it also now bases military aircraft.This has been a huge investment and a lot of work for the Chinese government, but it's allowing them to convert the soft, vague claims printed on their maps into hard realities in the real-world; the international arbitrators in The Hague would not honor what they considered to be their historic, national territorial claims, so they went out and made them real; the equivalent of putting up fences around land with unclear ownership on a parcel near your home—it might still be legally debatable who owns that land, but it becomes very clear who has control over it and access to it and who can use it after a fence is put up; and that's even more the case when you begin to deny others access and imply that you are willing and able to defend it if someone decides to step into what is now, on a very practical level, your turf.This carving out of new territory from international waters and in contested regions by the Chinese government has become an even more substantial issue over the past decade or so as the race to claim and develop undersea resources has become more frantic, with governments around the world scrambling to secure the minerals and other raw materials that will inform the next, post-fossil fuel paradigm, and many of these resources, from lithium to nickel to cobalt, are contained in hard-to-reach areas, like, in some cases, underwater continental shelves.So just as the Arctic has become a hotbed for exploration and infrastructural development, everyone with borders touching the Arctic Ocean doing what they can to build-out their ship-based capacity, military bases, and knowledge of what's underneath all that water, for if and when they can eventually justify stepping in to start building and harvesting those raw materials, the South China Sea is also rich with such assets, and this line on this map, and all this real-world building and hardening of military defenses in the area, is meant to allow China, if and when it wants, to start claiming these resources as its own, as it will have already established clear ownership of the territory surrounding these stockpiles, and the ability to defend these assets if anyone else challenges their claim.Physical conflict related to such claims has already broken out a few times, mostly related to fishing at the moment—the Chinese Coast Guard shooting high-powered water cannons at vessels owned by Philippines-based companies and Vietnamese fishing boats in order to drive them away and again, implicitly, partition-off these rich areas, over time redefining them as being for exclusive Chinese use.But the big concern is that at some point these measures might become more serious and deadly, and this type of conflict, if it escalates, could spiral into something truly global.The disagreement between China and Taiwan about who owns the island and whether the Taiwanese government is legit or not is generally seen as one of the most volatile hot-spots on the planet, in terms of the potential to accidentally set off WWIII, because of who's allied with whom, and what everyone involved has to gain or lose by engaging in such a conflict.It's possible, though, that something seemingly lower-level, like a scuffle over fishing grounds, or the development of undersea mineral extraction infrastructure could be what sets off such a fight, as China defending international waters as if they are their own, putting up a fence on public property, basically, and then shooting anyone who approaches, becomes a test of the international system, and that could lead to a direct conflict between China and let's say the Philippines, and that could pull other regional entities like Vietnam and Indonesia, and maybe even India into the fight, which in turn would potentially bring the US and EU into the conflict, directly or indirectly, alongside Russia and Iran on China's side, again, directly or indirectly.All of which could compound into something incredibly devastating, all because China is attempting to expand in a manner that is considered illegal by international bodies, because what we might think of as the Western bloc, the US and EU and India and its allies, are trying to box China in, as a response, which China doesn't like and which is probably amplifying their efforts in this regard, and because all of that is making this area a potential tinderbox for conflict—no one wanting to give ground, everyone aware the world is changing around them, economically, climactically, and so on, and everyone trying to set themselves up to be in the best possible position mid-century or so, doing the math and maybe even deciding a big conflict would be worth it, so long as that would make them a bigwig in the rapidly impending, next-step geopolitical paradigm. 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The podcast discusses the life and legacy of a famous singer, explores the challenges of gerontocracy in positions of power, and raises concerns about the performance of Mitch McConnell due to his age.

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