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Hospitals Making Drugs?

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This story from the New York Times got a lot of attention yesterday, and understandably so. It’s fundamentally about the shortage of some generic drugs, a problem that’s been with us for some years now in one form or another. My own belief is that much of this is a regulatory problem, and I note that Scott Gottleib, the current FDA commissioner, has said that he wants to do something about the situation (or these situations, more properly, since there are several factors). One way is to work through what still appears to be a backlog of generic application reviews, so that more companies can get into some of these markets.

But for now, let’s just stipulate that there’s a problem: it’s the solution proposed in the article that’s raised eyebrows:

Now, some of the country’s largest hospital systems are taking an aggressive step to combat the problem: They plan to go into the drug business themselves, in a move that appears to be the first on this scale.

“This is a shot across the bow of the bad guys,” said Dr. Marc Harrison, the chief executive of Intermountain Healthcare, the nonprofit Salt Lake City hospital group that is spearheading the effort. “We are not going to lay down. We are going to go ahead and try and fix it.”

But right off, that runs into the paragraph above: if you’re going to start your own generic manufacturing effort, you have to get in line for the FDA to review your application to sell the compound(s). And that’s one of the logjams – one that will not be fixed by jamming another log into it. The article, though, mixes several problems together. You have the not-enough-players-making-cheap-drugs problem (which can happen through several means, regulatory approval not least among them), and you also have the only-one-manufacturer-eat-my-dust problem, which also takes many forms.

In some cases of the latter, you have old, off-patent, formerly cheap compounds where one supplier has been granted market exclusivity (and the ability to raise prices and drive everyone else out of the market). How does this happen? Deliberately by design of the FDA: there are incentives to bring older drugs into the modern regulatory framework, and if you do the tests needed, you get a very, very nice reward. Too nice, from my point of view, but that’s how the law is written. In other one-manufacturer cases, people have bought up the only supplier of a small drug and then taken it into “restricted distribution”, which basically keeps any other potential competitor from running the comparison trials needed to even get in line at the FDA to sell the drug, too. That’s the Martin Shkreli playbook (although he’s not the only one), and it also takes advantage of FDA regulations about how and why distribution of a drug can be so restricted. Want to change these? Change the law.

The Times, though, doesn’t go into these details, and you have to read closely to even get the sense that there are several different problems here. This is probably the most overt statement:

“We’re seeing an acceleration of both shortages and escalation of prices,” said Dr. Richard Gilfillan, the chief executive of Trinity Health, a large Catholic system that operates in nearly two dozen states and is part of the group. “There’s not been any effective push back on either of these.”

That’s a key distinction. There’s no shortage at all of (say) daraprim (Shkreli’s notorious example) or colchicine, an old drug whose current owner got the modern-regulation reward. It’s just that their prices have gone through the roof. On the other hand, there are a number of other old compounds where there really isn’t enough to go around, because the lone manufacturer has run into sourcing or production problems at some point.

Intermountain executives would not discuss many details of the project, citing fears that competitors could shut them out of the market by quickly dropping the price of the drugs in question, then raising them again later. They said they would focus on drugs whose prices have risen sharply or that have been in short supply.

“We’re going to have to hold that very close to our vest,” Dr. Harrison said. The company will either rely on third-party manufacturers or decide to make the drugs themselves.

Now that’s a big distinction, though. That third-party manufacturer solution is the most straightforward, but in the case of plain-old-shortage drugs, you’re going to be asking them to make something that they’re not making now. They’ll have to get the process going, and everyone will have to get regulatory approval to give it to patients. In the case of expensive restricted drugs, though, this solution would seem to be impossible: the law says that the current manufacturer has exclusivity, or can force exclusivity by denying supplies to competitors. What then?

As far as making the drugs themselves, that’s an even bigger hill to climb. Making even a relatively simple old generic drug is a much different thing than a hospital does, and getting that going will not be simple. And there’s the matter of – yes, yet again – regulatory approval. This is not a process that will alleviate a shortage any time soon, although (as the article correctly notes), the FDA has said that it will give priority to facilities that are working to alleviate such shortages.

Here’s another key part:

Erin Fox, a drug shortage expert at the University of Utah, said the idea of creating a nonprofit drug company is promising. “I think anything that increases the number of suppliers will help,” she said. She added that the trick will be in selecting the right third-party manufacturer to ensure good quality.

Why yes, that will be the trick. And you’ll have to see if you’re actually increasing the number of suppliers when you do that, or just asking an existing one to supply you as well (which you will at least pass on at cost). In some of these cases, said manufacturer might wonder why they should supply you at all, depending on their own situation with the current customer. I’ll watch this proposal with interest, but some of it is on a collision course with reality (not that I’m defending reality, in this case!) A reader of the Times article might get the impression that “Hey guys, let’s just make the drugs!” is the obvious and easy solution, though, and that’s just not quite the case.

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satadru
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The Republican candidate for Pennsylvania's 18th District is a torture advocate who worked at Abu Ghraib

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When Rep Tim Murphy resigned in shame after he was outed for pressuring his mistress to get an abortion while serving on the "House Pro-Life Caucus," it triggered a special election in Pennsylvania's 18th, a rustbelt district in the southwest corner of the state, where a strong Democrat candidate named Conor Lamb is polling high against his Republican opponent, torture advocate Rick Saccone, who served as an Army intelligence support consultant at Abu Ghraib prison after its torture scandal. (more…)

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HarlandCorbin
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Rustbelt? We're far more a new-economy area. Sure there are still old industrial sites here, but they are going the way of the dodo.
satadru
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A randomly generated, totally novel enzyme rescues mutant bacteria

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Proteins are chains of amino acids, and each link in the chain can hold any one of the 20 amino acids that life relies on. If you were to pick each link at random, the number of possible proteins ends up reaching astronomical levels pretty fast.

So how does life ever end up evolving entirely new genes? One lab has been answering that question by making its own proteins from scratch.

Way back in 2016, the same lab figured out that new, random proteins can perform essential functions. And those new proteins were really new. They were generated by scientists who made amino acid sequences at random and then kept any that folded into the stable helical structures commonly found in proteins. These proteins were then screened to see if any could rescue E. coli that were missing a gene essential to survival.

Three proteins succeeded, which indicates that they compensated for the missing gene’s essential function. But they did not do so by acting as a catalyst (meaning they weren’t enzymes).

In a recent paper in Nature Chemical Biology, however, the lab is reporting that one newer protein has acted as a catalyst.

The E. coli used in these experiments lacked the ability to use the iron provided in their medium because of the deletion of a gene that normally provides this function. So the experiments were a test to see if a randomly generated protein would be able to catalyze reactions with iron. The three proteins that had passed this test in 2016, however, simply altered gene activity so that the iron became available through other pathways.

To generate the recent enzyme, the researchers took one of the proteins that already rescued the mutant E. coli and subjected it to random mutagenesis. This ultimately produced an iron-releasing enzyme. Just like the natural enzyme, this synthetic one has a chiral preference for its substrate, meaning that it can only work with one structural form of the molecule and not its mirror image.

But its similarities to the native enzyme end there. The amino acid sequence of this synthetic enzyme bears no relation to the bacterial enzyme it replaces. This made figuring out how it works very difficult. Usually this is done by comparing the protein in question to similar ones from other species: clearly not an option here. The researchers also tried to crystallize it, which would let them figure out its structure, but no deal.

So they started mutating amino acids one by one to see which mutations rendered the enzyme inactive. This told them that the original amino acid that had been replaced must be important. This method revealed five particular amino acids that comprise the likely active site. When software that predicts protein structures was given the protein’s amino acid sequence and told that these five had to be close together, it spit out one structure that seemed the most likely.

And just like the amino acid sequence, the structure looked so totally different from the native enzyme’s that the researchers think the enzyme must work through a completely new mechanism.

The scientists made this enzyme not using any kind of rational design or strategy; they were just tooling around with random amino acid sequences and having bacteria determine if they could do what they wanted. In a completely contrived case of convergent evolution, the researchers made a protein that does not share a sequence, structure, or even mechanism with the one evolution hit upon—yet it performs the same function. A thousand-fold slower than the natural one, but it might get better if given further time to evolve.

Nature Chemical Biology, 2018. DOI: 10.1038/NCHEMBIO.2550 (About DOIs).

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satadru
2 days ago
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Wow.
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acdha
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Deep Space Nine’s Revolutionary Look at Black Fatherhood

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As long as there’s been TV, the family has been one of its favorite go-tos. All week long, Vulture is exploring how it’s been represented on our screens.

The arc of American history is undergirded by a continuous, pointed degradation of the black family.

The crux of this is the pervasive mythology surrounding the “missing black father.” At his feet has been laid the blame for poverty, mass incarceration, police brutality, and any number of ills, rather than the real culprit — the systemic, institutionalized racism that defines so much of American life. Despite statistics and studies that contradict this mythology, this archetype continues to cast a shadow on the black community. It’s because of this that the representation of the black father in television holds so much weight.

Recent series like the CW’s superhero adaptations, Black Lightning and The Flash, as well as the beautifully rendered southern drama Queen Sugar, have been showcases for complex depictions of black fatherhood. But the arc of the black father in pop culture is most defined by its representation in beloved sitcoms in the 1970s and 1990s. The sharp-tongued James Evans Sr. in Good Times, the highly successful and caring Uncle Phil in The Fresh Prince of Bel-Air, and the perfect representation of middle-class aspiration, The Cosby Show’s Cliff Huxtable, have become iconic for their blend of familiarity, warmth, and representation of the black nuclear family. These sitcoms have guided our conversations about black fatherhood in television, and they’re important for how they refute the noxious mythology of the missing black father. But their episodic nature, and the need of sitcoms to connect with broad audiences, meant they lacked a certain complexity necessary to consider these ideas with further depth. The series I find to be the most personally moving, narratively complex, and politically potent depiction of black fatherhood also happens to be the most underrated: Star Trek: Deep Space Nine.

When Deep Space Nine premiered in 1993, it was walking in the shadow of its immensely successful predecessor, The Next Generation, which was still on the air. The series was also entering a politically fraught environment on the heels of the Los Angeles riots, and not far removed from the presidency of Ronald Reagan — a politician who framed black people as stark stereotypes of criminals and “welfare queens,” establishing a cultural understanding of black families that America continues to grapple with. In this context, the DS9 producers’ decision to cast its leading commander (and later captain) as a black man was not just a historic first within Star Trek, but politically resonant in ways that have only deepened over the years.

Why Diversity Is So Integral to Star Trek: Discovery

Deep Space Nine would go on to carve a unique path within Star Trek lore, and science fiction as a whole, as a complex, expertly crafted meditation on war and the price of peace that favored multi-season arcs, which amplified its biting approach to Star Trek mythos. In its first season, it was uneven, still getting a hold on the characterization and ideas it would continue to explore. But one aspect of its story immediately felt lived-in and real: the tender relationship between Commander (and later Captain) Benjamin Sisko (a magnetic, theatrical Avery Brooks) and his young son, Jake (Cirroc Lofton).

The pilot, “The Emissary,” artfully lays the groundwork for their relationship, introducing Sisko as a widower reluctant to take the position as commander aboard the space station and shepherd the Bajorans, a highly religious people recently freed from a decades-long occupation by the Cardassians, into joining the Federation. His wife, Jennifer (Felecia M. Bell), died during the Battle of Wolf 359 which was headed by a Borg-assimilated Captain Picard (Patrick Stewart), making their first and only meeting in the series an icy one. Both Sisko and Jake are grieving this loss, clinging to each other for stability and familiarity as they enter a strange new environment. When watching “The Emissary” recently, the chemistry between Brooks and Lofton was immediately apparent. They moved and touched one another with a familiarity that struck me as having a deep, emotional history. They felt like a family with an immediacy I’ve seen few actors able to match on television.

When Lofton was first cast as Jake, his parents had recently divorced and Brooks became a father figure to him. At a 2013 panel on Deep Space Nine, a black man in the audience spoke eloquently about how watching this relationship, and Brooks’s role in particular, was deeply impactful for him. Lofton later said, “Avery was that same role model for me in real life.” For his part, Brooks has long discussed how the Sisko and Jake dynamic was big part of why he wanted to join Star Trek. “The relationship between Sisko and his son was … very important,” Brooks said in 2012. “That was something else you still don’t often see on air, at least as it concerns black and brown men and their sons. We got to play complicated, emotional and intricate scenes, and we got to have tender and fun moments. It wasn’t a pat relationship or an easy one, and it was very realistic.”

As Deep Space Nine continued over the course of seven seasons, Sisko and Jake’s relationship took on new dimensions. Jake grows into an empathetic young man who inherits his father’s interests in the arts and becomes a writer. Sisko evolved into one of the most complex characters in all of science fiction. He was a wounded widow and, eventually, beloved husband to his second wife, Kasidy (Penny Johnson), a righteously determined Starfleet captain, and a man aware that for this war to be won, he would have to sacrifice his own morality for the sake of progress. Brooks gave Sisko his trademark bombastic intensity and gravitas. He made his monologues feel theatrical while never sacrificing the core of their emotional impact. But there was also something about the quieter moments, where his face would melt into a broad smile whenever he saw a child or held Jake in his arms. Sisko’s love for Jake provided a poignant contrast to the temerity and flinty brio he portrayed as a captain. Ira Steven Behr, who took over as showrunner in 1995, and the inventive writing staff, which included creators like Ronald D. Moore, never lost sight of the fact that the heart of Sisko’s character would always be his love for Jake.

Conversations about representation in pop culture often feel like too much of a number’s game. Whittling the value of a series down to who stars in and who creates these works can be useful when looking at the culture more broadly. But it doesn’t tell us about the soul of the work — how it speaks to its audience, the history it reflects, the artistic risks it’s willing to take in order to not only represent minorities, but to speak to their experience with care. The impact of Deep Space Nine goes beyond the casting of black actors like Brooks and Lofton in these pivotal roles. The series boldly interrogated blackness within the arc of American history through their characterization. Like my maternal family, Sisko was from New Orleans and took pride in his heritage, often cooking Creole recipes from scratch that he learned from his chef father. When I see three generations of the Sisko family onscreen in episodes like the season-four two-parter “Homefront” and “Paradise Lost,” a tinge of wonder rises in me. How often have we seen a black family given such importance, depth, and cultural weight on a television show such as this?

I didn’t fully understand the gravity of the Sisko family until I listened to Brooks in the aforementioned 2013 panel, talking about what made him take the role, beyond being able to play a caring single father. It was “the opportunity to have a conversation about succeeding generations [that] intrigued me,” Brooks said. When considering the lineage of black fatherhood in television, it is one in which our cultural past and present is considered. But rarely have black people in television had the opportunity to examine our future without eschewing the complexity of blackness and its history for allegory. As Robin Greene II wrote for The Atlantic, “For Sisko, a native of New Orleans, history spoke with a powerful, notably African American voice.”

Last fall, I went to Syracuse University to speak with a small group of journalism graduate students. I was given the opportunity to host a screening, and I decided on the season-six Deep Space Nine episode “Far Beyond Our Stars,” one of the most stunning installments in Star Trek history for its willingness to push the boundaries of genre to interrogate racism and America’s past, not to mention Brooks’s exceptional work as both director and star of the episode. In the episode, strange visions from the Prophets begin to take over Sisko’s life and he imagines himself as Benny Russell, a science-fiction writer in 1950s New York, writing a story about a space station known as Deep Space Nine. At first, the episode may seem like a clever way to watch the cast members outside of their usual makeup and prosthetics, but it reveals itself to be a sincere meditation on black identity, racism, and how black people have not been allowed to imagine their future selves. In the 1950s plotline, Jake isn’t Sisko’s son, but a slick-talking street hustler known as Jimmy. The episode builds to a gut-wrenching emotional turn that always moves me to tears: Jimmy/Jake is gunned down in the street by cops, sending Benny/Sisko into an emotional breakdown. He barrels toward Jimmy’s lifeless body, covered in blood. When Benny grows angry, the cops take the opportunity to brutalize him. Weeks later, Benny finally decides to go to the office to see his story about Deep Space Nine — which he cherishes because it allows for a hopeful future for black people — first published, only to find out it won’t be going to print. Benny launches into a monologue about the power of his idea with a beautiful intensity that echoes with the voice of every black man beaten down by a system that survives on their suffering.

When the episode finished airing at Syracuse University, I was approached by a black professor who sat in on the screening. He was deeply moved by Brooks’s performance, the audaciousness of his direction, and the political resonance of the story line, which tackled everything from police brutality to the devaluing black creativity. “Why didn’t this man win any Emmys?” he asked ecstatically. We spoke at length about how Sisko and his relationship with Jake is one of the more unsung revolutionary turns in television history and why it cuts so deeply. No series before or since has a portrayed a black father with such complexity, crafting him as a widow, a powerful authority figure, a religious icon, a man whose morals are formed in shades of gray and whose love of his son remained his guiding principle.

The beauty of their relationship is perhaps never better portrayed than in the season-four episode “The Visitor.” The episode is framed by an elderly Jake Sisko (played with touching melancholy by Tony Todd), now a successful writer living in New Orleans, burdened by regret. He reflects on a freak accident aboard the USS Defiant that seemingly took the life of his father when he was young. Sisko is actually stuck in some strange pocket dimension, never growing old and intermittently able to break away to witness his aging son’s life. Jake spends the rest of his life trying to find a way to save Sisko, sacrificing his career as a writer and even his marriage to do so. “The Visitor” brings to the fore what separates Deep Space Nine from the more widely praised representations of black fatherhood: its continued dedication to revealing the emotional vulnerability of the black family at its center. Throughout “The Visitor,” Sisko and Jake laugh, weep, and reveal just how deep their love goes for one another. Seeing black men cry, grapple with the historical importance of their existence, and remain beautifully, dynamically human is something no other science-fiction series on television has done with such panache.

What makes the bond between Sisko and Jake one that is both culturally revolutionary and emotionally resonant is the chemistry between them, brought to life by the actors  and the tenderness of the writing. The family they represent is wholly unique on television: a window into the future of black identity that never forgets the trials of our past or the complexity of our humanity.

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satadru
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Delta Cracking Down on Emotional Support Animals

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Delta announced that starting March 1 they’ll be requiring new advance documentation for passengers bringing ’emotional support animals’ on board their aircraft.

Basically they say the whole fake emotional support thing has gone too far. Delta carries 250,000 service and support animals each year — up 86% since 2016. And we’re not just talking about trained dogs, “[c]ustomers have attempted to fly with comfort turkeys, gliding possums known as sugar gliders, snakes, spiders and more.”

Continue reading Delta Cracking Down on Emotional Support Animals...

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satadru
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How Haiti became poor

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haiti.jpg

In case you missed it, the President of the United States called Haiti, El Salvador, and African countries “shitholes,” then pretended like he didn’t say it, but basically said it all over again.

This matters not just because it’s racist (the President is racist, in fact, he is professionally racist), because it’s vulgar (“shithole,” one of the all-time great swear words, is forever sullied by this), and because it’s catastrophically bad for foreign and domestic relations. It matters in part because of the history of Haiti, and the history of racist discourse about Haiti.

Ebony Elizabeth Thomas, a professor of education and scholar who’s closely studied these narratives, writes:

The reason why White nationalists like 45 always name Haiti because the Haitian nation & people are unique. Haiti defeated Napoleon, threw off the chains of slavery, and exposed the lie of White supremacy & European imperialism. So there’s no end to their hatred for Haiti.

Jonathan Katz, a journalist and former AP correspondent in Haiti who wrote The Big Truck That Went By about Haiti’s 2010 earthquake and the cholera epidemic that followed, has a longer thread spelling out how these narratives about Haiti were generated and how they work. Here’s a thick excerpt:

In order to do a victory lap around the GDP difference between, say, Norway and Haiti, you have to know nothing about the history of the world. That includes, especially, knowing nothing real about the history of the United States… You’d have to not know that the French colony that became Haiti provided the wealth that fueled the French Empire — and 2/3 of the sugar and 3/4 of the coffee that Europe consumed…

You’d have to not realize that Haiti was founded in a revolution against that system, and that European countries and the United States punished them for their temerity by refusing to recognize or trade with them for decades. You’d have to not know that Haiti got recognition by agreeing to pay 150 million gold francs to French landowners in compensation for their own freedom. You’d have to not know that Haiti paid it, and that it took them almost all of the 19th century to do so.

You’d then have to not know that Haiti was forced to borrow some money to pay back that ridiculous debt, some of it from banks in the United States. And you’d have to not know that in 1914 those banks got President Wilson to send the US Marines to empty the Haitian gold reserve… [You’d] have to not know about the rest of the 20th century either—the systematic theft and oppression, US support for dictators and coups, the US invasions of Haiti in 1994-95 and 2004…

In short, you’d have to know nothing about WHY Haiti is poor (or El Salvador in kind), and WHY the United States (and Norway) are wealthy. But far worse than that, you’d have to not even be interested in asking the question. And that’s where they really tell on themselves… Because what they are showing is that they ASSUME that Haiti is just naturally poor, that it’s an inherent state borne of the corruption of the people there, in all senses of the word.

And let’s just say out loud why that is: It’s because Haitians are black.

Racists have needed Haiti to be poor since it was founded. They pushed for its poverty. They have celebrated its poverty. They have tried to profit from its poverty. They wanted it to be a shithole. And they still do.

If Haiti is a shithole, then they can say that black freedom and sovereignty are bad. They can hold it up as proof that white countries—and what’s whiter than Norway—are better, because white people are better. They wanted that in 1804, and in 1915, and they want it now.

The history of Haiti is weird because it is absurdly well-documented, yet totally poorly known. It’s hard not to attribute that to ideology. We don’t teach the Haitian Revolution the way we teach the American, or the French, or the Mexican, because it’s a complicated story. Kids are more likely to hear variations of “Haiti formed a pact with the devil to defeat Napoleon” (this is real thing, I swear) than Toussaint Louverture’s or Jean-Jacques Dessalines’s names.

Also, while Haiti’s revolution was an early, signature event in world history-the first time a European power would be overthrown by an indigenous army (but not the last)-the causes of Haiti’s poverty are basically identical with those of almost every poor nation around the world: a history of exploitation, bad debt, bad geopolitics, and bad people profiting off of that poverty (almost all of them living elsewhere). And this is basically true about poverty in American cities as well (with all the same attendant racist myths).

Some recommended reading:

Tags: Donald Trump   Ebony Elizabeth Thomas   Haiti   Jonathan Katz   poverty
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notadoctor
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satadru
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jsled
10 days ago
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«This matters not just because it’s racist (the President is racist, in fact, he is professionally racist), because it’s vulgar (“shithole,” one of the all-time great swear words, is forever sullied by this), and because it’s catastrophically bad for foreign and domestic relations. It matters in part because of the history of Haiti, and the history of racist discourse about Haiti.»
South Burlington, Vermont
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