#phases of Drug Development

[clivaldatabase]

How does pharmacovigilance affect clinical industry, in US, Germany, and India

Pharmacovigilance is an essential branch of clinical industry since it focuses on the safety of drugs and their effectiveness. From the above observations it could be noted that while the principles, laws and the mechanisms of pharmacovigilance in the US, Germany and India are all different, the overall objectives of protecting the public from hazard from medicines are the same. These countries ensure that the monitoring and evaluation of drug safety data is always being done hence helping the world initiatives of making the drugs safer for use.

[superchemistryclasses]

Inside Drug Discovery Chemistry: From Molecules to Modern Medicine

Introduction: Understanding Drug Discovery Chemistry Drug discovery chemistry is the science that helps turn small chemical substances into medicines that people use to treat diseases. It plays a big role in modern healthcare by helping create drugs that are safe, effective, and affordable. The process may sound complex, but don’t worry—we’ll explain everything in a simple way. From the first…

[respectissexy]

Things I find myself telling my teen patients often, in no particular order.

(I am not your therapist and nothing in this post is a substitute for getting your own personal mental health treatment if you need it.)

Being a teenager sucks. Your brain is in a state of development where all your emotions are intensified, and those emotions are frequently bad because being a teenager sucks. You’re basically an adult when it’s convenient for the adults, and a kid when it’s convenient for the adults. This is crazymaking. It is my opinion that critics of “it gets better” messaging do not recall being a teenager very well. I’m not saying being an adult is a picnic. But generally speaking it beats the hell out of being the legal property of your parents while your brain is going brrrrr.

On that note, if you have any kind of mental illness, these may be your worst, most symptomatic years. 

Your brain is also in a stage of development where new habits are more likely to stick. That means that if you and I (33) both started learning Russian tomorrow, you would be more likely to stick with it and get better at Russian faster than me; but if you and I started doing a new drug tomorrow, you would be more likely to get addicted.

It’s normal to hate living with your parents even if you love them. I’m not saying you have to love your parents, but if you do, that doesn’t obligate you to enjoy living under the same roof. MANY adults have loving relationships with parents they would never want to live with again. (It may also take a few years of living apart for you to determine whether you actually hate your parents or whether you just hate living with them. This too is normal.)

There’s nothing wrong with going through phases. If you believe that what you’ve got going on right now is going to be your permanent identity, well, you’d know better than anybody else; but it’s fine if it’s not. “I’m into this right now” is good enough and people should respect it.

How much time you spend on your Screen Device is less predictive of mental health outcomes than what you are actually doing on your Screen Device. Three hours of gaming with your friends beats one hour of watching thinspiration videos on TikTok or arguing with strangers on tumblr about who gets to call themselves a dyke. (Assuming your friends are nice to you.)

Sex is supposed to be fun. If you’re having sex and it isn’t fun, something is wrong – maybe you’re not ready to be having sex yet, maybe you’re having sex with the wrong people, maybe your partner needs to learn your body and preferences better, or maybe you’re having sex for the wrong reasons.

(Obligatory don’t do drugs BUT) if you’re going to do drugs, weed is safer than alcohol.

You may be tempted to assume that the people who treat you like you’re not cool enough to hang out with them are, in fact, the coolest people ever and ultimate arbiters of cool, and expend a lot of energy trying to win them over. I implore you to at least consider the possibility that your friends who actively want to hang out with you are exactly as cool as those people, and quite possibly cooler. 

If you barely eat anything all day and then binge at night, the reason you’re binging at night is because you barely ate all day. If you teach your body that it will not be fed for long periods of time, it will do its best to ensure, whenever you do eat, that you eat as much as possible. This is a feature, not a bug.

Sleep hygiene is unfortunately not bullshit.

“People experience social penalties for not being thin” is extremely true, but “no one will ever love you unless you’re thin” is extremely false.

The world is full of happy, successful, financially solvent adults who did not get into their first choice colleges.

[reasonsforhope]

"A large clinical trial in South Africa and Uganda has shown that a twice-yearly injection of a new pre-exposure prophylaxis drug gives young women total protection from HIV infection.

The trial tested whether the six-month injection of lenacapavir would provide better protection against HIV infection than two other drugs, both daily pills. All three medications are pre-exposure prophylaxis (or PrEP) drugs.

Physician-scientist Linda-Gail Bekker, principal investigator for the South African part of the study, tells Nadine Dreyer what makes this breakthough so significant and what to expect next.

Tell us about the trial and what it set out to achieve

The Purpose 1 trial with 5,000 participants took place at three sites in Uganda and 25 sites in South Africa to test the efficacy of lenacapavir and two other drugs.

Lenacapavir (Len LA) is a fusion capside inhibitor. It interferes with the HIV capsid, a protein shell that protects HIV’s genetic material and enzymes needed for replication. It is administered just under the skin, once every six months.

The randomised controlled trial, sponsored by the drug developers Gilead Sciences, tested several things.

The first was whether a six-monthly injection of lenacapavir was safe and would provide better protection against HIV infection as PrEP for women between the ages of 16 and 25 years than Truvada F/TDF, a daily PrEP pill in wide use that has been available for more than a decade.

Secondly, the trial also tested whether Descovy F/TAF, a newer daily pill, was as effective as F/TDF...

The trial had three arms. Young women were randomly assigned to one of the arms in a 2:2:1 ratio (Len LA: F/TAF oral: F/TDF oral) in a double blinded fashion. This means neither the participants nor the researchers knew which treatment participants were receiving until the clinical trial was over.

In eastern and southern Africa, young women are the population who bear the brunt of new HIV infections. They also find a daily PrEP regimen challenging to maintain, for a number of social and structural reasons.

During the randomised phase of the trial none of the 2,134 women who received lenacapavir contracted HIV. There was 100 percent efficiency.

By comparison, 16 of the 1,068 women (or 1.5%) who took Truvada (F/TDF) and 39 of 2,136 (1.8%) who received Descovy (F/TAF) contracted the HIV virus...

What is the significance of these trials?

This breakthrough gives great hope that we have a proven, highly effective prevention tool to protect people from HIV.

There were 1.3 million new HIV infections globally in the past year. Although that’s fewer than the 2 million infections seen in 2010, it is clear that at this rate we are not going to meet the HIV new infection target that UNAIDS set for 2025 (fewer than 500,000 globally) or potentially even the goal to end Aids by 2030...

For young people, the daily decision to take a pill or use a condom or take a pill at the time of sexual intercourse can be very challenging.

HIV scientists and activists hope that young people may find that having to make this “prevention decision” only twice a year may reduce unpredictability and barriers.

For a young woman who struggles to get to an appointment at a clinic in a town or who can’t keep pills without facing stigma or violence, an injection just twice a year is the option that could keep her free of HIV.

What happens now?

The plan is that the Purpose 1 trial will go on but now in an “open label” phase. This means that study participants will be “unblinded”: they will be told whether they have been in the “injectable” or oral TDF or oral TAF groups.

They will be offered the choice of PrEP they would prefer as the trial continues.

A sister trial is also under way: Purpose 2 is being conducted in a number of regions including some sites in Africa among cisgender men, and transgender and nonbinary people who have sex with men.

It’s important to conduct trials among different groups because we have seen differences in effectiveness. Whether the sex is anal or vaginal is important and may have an impact on effectiveness.

How long until the drug is rolled out?

We have read in a Gilead Sciences press statement that within the next couple of months [from July 2024] the company will submit the dossier with all the results to a number of country regulators, particularly the Ugandan and South African regulators.

The World Health Organization will also review the data and may issue recommendations.

We hope then that this new drug will be adopted into WHO and country guidelines.

We also hope we may begin to see the drug being tested in more studies to understand better how to incorporate it into real world settings.

Price is a critical factor to ensure access and distribution in the public sector where it is badly needed.

Gilead Sciences has said it will offer licences to companies that make generic drugs, which is another critical way to get prices down.

In an ideal world, governments will be able to purchase this affordably and it will be offered to all who want it and need protection against HIV."

-via The Conversation, July 3, 2024

[felinepipebomb]

Philadelphia’s (democratic) Mayor has enacted this completely fascist plan to forcibly arrest an entire neighborhood of drug users, sex workers, and unhoused people in our city to make way for gentrification and the financial interests of developers, btw.

Phase one: force your citizens into unliveable conditions of abuse and poverty that prompt or increase reliance on opiates

Phase two: increase criminalization and stigma, cutting off any kind of safe supply and forcing people dependent on opiates to turn to drugs cut with xylazine and fentanyl, increasing overdoses and health crises

Phase three: use your power as elected officials to bully, threaten, cut funding for, and ultimately try to remove any harm reduction organizations started by affected people in the area you’ve concentrated them into

Phase four: use taxpayer money to send hundreds of armed & violent pigs into that area to kidnap, arrest, and beat people they profile at a glance as drug users, sex workers, ‘undesirables’ etc

Phase five: attempt to distract from the blood on your hands by having cheap luxury apartment buildings put up

Image description coming when im not exhausted unless someone else wants to add one first

[wisteriasymphony]

Since you know a lot about horror methods of control, (to which I thank you as it is helping with my writing), what are some hypothetical GOSHE methods of controlling a sentimonster other than using their amok (this is a scenario where the amok is broken or not functional, like in Mirelle's case). I already have dr*gg*ng with ketamine, but what would you suggest. Microdosing them with medicines to make them more suggestible?

My suggestion for you would be to study Steven Hassan's BITE model of authoritarian control!!! I learned of it from the first time back when I was in my cults phase back in middle school, but the model is a very digestible way of categorizing controlling behavior, and having that as a starting point is going to be helpful for going forward.

Behavioral and Emotional control is going to be what you want to draw from. Behavioral control is going to be used more for the sentihumans that are already "well-conditioned", and Emotional control for the ones who are trying to be more independent—But there will obviously be an overlap.

So, in addition to drugging with medication, I'd say that sleep deprivation would be a huge way of control. Bribing them and withholding things from them would also be a very simple method of control—Given how stunted the sentihumans are supposed to be (like Ambre, like Adrien), no matter how much they may goof off they will generally listen to whatever authority figures ask of them because they are biologically conditioned to go along with it. Mireille doesn't know that her broken amok means she's able to not follow orders, because she doesn't know that the amok is how people make her follow orders!

For many sentihumans, keeping them suggestible is something you'd only need to do for those that have gotten pretty far in their mental development. Once they've gotten into the routine of doing whatever they're asked, it's going to be something they default to.

[slut-and-falcon]

Wicked Fiyeraba Headcannons:

-Fiyero def sits on Elphaba’s lap

- they call each other Yero and Fae; after the Wicked Witch persona dies, they only go by Yero and Fae so less people will be able to tie them to the dead witch and the missing prince.

- one of Fiyero’s favorite activities is to have Elphaba read to him. He finds it very relaxing, and informative. (Fiyero has dyslexia and that why he doesn’t like reading himself- but dyslexia isn’t a diagnosis in Oz, it hasn’t been recogized)

- they take care of young orphaned Animals, and Fiyero got Elphaba an egg apron so she could put all the kittens/small Animals in the pockets while she was caretaking

- Fiyero likes to draw…he draws a lot of Elphaba (and the Animals, but mostly Elphaba)

- Fiyero likes to purchase Vinkun silk scarves for Elphaba. She uses some for practical embellments in her clothing- like as a belt, shawl or hair covering. Others she keeps as house clothes- like as a night shawl. There’s one though- black with red roses- that is only used during intimacy with Fiyero.

- Elphaba and Fiyero have really complex feelings about Glinda…she was Elphaba’s close and only friend for a while, but Fiyero helped Elphaba realize that Glinda treated her like crap (this is apart from not making the sacrifices to leave with Elphaba). Elphaba also had some romantic feelings towards Glinda, and does not know what to do with those feelings. Fiyero loved Glinda, but wasn’t in love with her. He is highly aware of her faults, but still misses her and feels bad for what happened. Both realize that Glinda was manipulated by the Wizard and Madam Morrible, but both also realize that only Glinda is responsible for Glinda’s actions. And can they forgive her for being an anti-Animal/Anti-Witch propaganda machine? For helping in orchestrating Nessa’s death, and creating a trap for Elphaba? They don’t know. Together, Elphaba and Fiyero write letters to Glinda that are then burned before being sent, allowing them to work through all of these feelings and trauma they have in relation to Glinda.

- Fiyero’s favorite thing todo to annoy Elphaba is to use her butt as a pillow. Elphaba hates it (but will tolerate it) and Fiyero loves it.

-Elphaba is very passionate about a lot of stuff, and has a habit of information dumping, even when it’s considered rude. Fiyero likes it, but has felt the need to coach Elphaba for when the time is appropriate to do so, after she accidentally offended Fiyero’s mother.

- Fiyero and Elphaba do the whole “3 taps means I Love You” thing

-Fiyero likes to comb/take care of Elphaba’s hair

- Fiyero is an addict, he got addicted to a ❄️-like ozian drug while in his rebellion/coping-with-being-royalty phase. He hasn’t always been completely honest with Elphaba about it, but he got clean when he joined the Gale Force. He still had carvings, especially with his chronic pain and stress, and he tries to be as honest as possible with Elphaba about his cravings. They both use 🍃 to deal with chronic pain and stress though, but in moderate amounts.

- After being tortured by the Gale Force- Fiyero develops Narceolpsey. It’s a learning curve for both him and Elphaba.

-Elphaba offered Fiyero an open relationship (not because she wanted one but because she thought he would be unhappy with just her, and the novelty would wear off). Fiyero refused (while he had been poly in the past, he refused because he knew Elphaba’s reasonings were based in her feeling inadequate and self conscious).

Hmm I’ll think of more

[mx-heinous]

BESTIE!!! I love your writing so much??? May we have some thomas Wayne jr headcanons? I love your perspective of him so far and I’d love to know more!!

Hi, there :D

Idk if you sent this ask to the wrong person (lol), but I'm gonna write down my TJ hcs anyway

He operates under the belief that nothing really matters, that the universe is hopeless, blah blah blah. Because of this, he actually considers Bruce to be "puppies and rainbows" to a certain degree since Bruce holds what he thinks to be, an insanely optimistic (borderline naive) outlook on Gotham's future and people's potential to be good

It confuses the majority of people since his "sunshiney younger brother" is fucking *BATMAN*, who's famous for being the most paranoid person in the planet

100% lets the Batkids do whatever they want. He doesn't really care, but when Bruce scolds them, he takes it as a chance to mess with him, and he brings up all the deranged shit Bruce did in his childhood. (Like that scene in Rick and Morty where Rick shows Beth her concerning childhood toys)

He and Bruce were a nightmare to deal with for Alfred, especially during Bruce's teenage dirtbag years

Tbh, I'm not even sure if he fully grew out of the Teenage Dirtbag phase

When he was younger, he didn't really know what to do with his life, and often asked himself, "What's the point?" It led to him developing a bit of a drug addiction

He's about 10ish years older than Bruce, and after that night in the alley, he decided to go to rehab. He was kind of...a mess at the time, and figured that it would've been better for everyone, Bruce especially, if he just avoided the Manor

His relationship with his parents is...complicated

He didn't wanna be the one to continue the Wayne legacy, and he holds no respect for authority

People take one look at him and immediately clock that he has daddy issues

Was intrigued by the concept of the multiverse and went dimension hopping for a bit. He's definitely Seen Some Shit because of it

Even when Bruce was like 20 already, he still treated him like he was a kid. He learned about the whole Batman thing, and his first thoughts were, "You decided to cosplay that cartoon you watched growing up?"

Mentally compares Bruce's vigilantism to a kid playing superhero. He thinks it's pointless and kinda dumb, but eh, if it makes Bruce happy

Doesn't trust the Justice League. At all. He thinks of them as "Bruce's dumb weird friends." He definitely also has his own plans on how to take them down

Showed up as "Owlman" a few times to make fun of Batman

Has definitely made of Bruce for the Matches Malone thing

Visits like, once a decade. It's mostly to check if everything's gone to shit or not

[clivaldatabase]

Streamline Clinical Trial Phases with Clival Database

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[myeagleexpert]

𝕸𝖞 𝕳𝖔𝖑𝖞 𝕷𝖎𝖌𝖍𝖙

Yandere ex bad boy x reader When a former bad boy gets out of prison and finds you, the light of his life, he decides he would never let you go again.

cw: delusional yandere, creppy, clingy, no use of yn, reader is stressed and doesn't love yandere but is with him just because he's a stress reliever, the straight-laced girl gets involved with an ex badboy, use of pet names “princess , love”, stalking, insecurity, thoughts of getting married, beginning of a relationship, religious themes at the beginning (youth meeting), very soft at the beginning because the longer you stay together the more he develops an obsession.

"I will marry you". You would be grateful to hear this from a long-term relationship….but hearing this on the first day of your first official relationship?? Who would have the audacity to ask you that??

Marc, your new boyfriend. He is of average height, with shaved hair and thin. You met him by inviting him to a youth meeting at your church, and since he wanted to embrace his new good guy phase, he clearly went. And it wouldn't take long for you to regret that decision.

Marc is strangely strange, like a criminal in interrogation, already anticipating the argument he would have with the lawyer. He has an anxious look on his face every time you meet, and the pressure he has placed on his shoulders to be the “perfect boyfriend” requires him to be honest with you. Everyone knows and feels that pleasant and cozy atmosphere when a couple gets to know each other more and more, opening up little by little, leaving themselves vulnerable to the person their heart burns so much but…. I don't want to ruin this phase, but… he opened up about his past and it totally changed your image of him. How messing with delinquent people influenced him, how he left his family and ran away from home, how his other two serious relationships were toxic and abusive and hurt him psychologically, how he spent time in jail when they caught him with drugs , how he abandoned the will to live….

Until he met you and everything changed.

“You are the light of my life” “I only see my future by your side”

Of all the years he appeared in your life, he appeared just when you were killing yourself studying for a place at the college of your dreams! How much sacrifice! So much pressure! So much stress! The year you followed an intense study routine and practically isolated yourself from the world to study was the year he appeared…as a distraction.

You were so stressed that you needed a distraction on your side. After all, you need to live your youth too, don’t you? It won't be anything serious, you don't have time for that princess, it will just be a momentary relief, just a little flig.

Not if it's up to him.

In fact, you "met" in high school, from different classes, he uses and insists on this argument every time you say that you haven't known each other long enough. "But we never spoke….". "But we talked through our eyes!" You swear you can count on the fingers of your left hand how many times you've actually seen him.

Upon leaving the cold and degrading prison and feeling completely lost, he prayed to the heavens about what direction to ask for in life and coincidentally your profile appeared on his Instagram!

"As soon as I saw your profile, I knew you were different and would change my life" he tells the story of how he met his precious girlfriend for the millionth time, with the same dreamy sigh as always.

He spent 8 months just observing you, what you like and what you don't like, following you, your friends and family on all social networks, he discovered your favorite books and read each one of them trying to be the one you admire most, he discovered where you buy your favorite perfumes and bought the ones you liked the most, to know how you felt and all that… thrown out the window. Because every time Marc looks at you, he forgets everything, the world goes blank and his focus is absolutely you.

He forgets the beautiful words he thought when he was going home, he forgets the way the heartthrob in his book convinced the girl to give him an innocent kiss on the cheek, or how he rehearsed in the mirror how to hold her hand and kiss her without looking so awkward, Marc forget that he has to breathe to continue living but frankly he prefers to be in your air, breathe your oxygen. He also forgets that he had other relationships and shouldn't be so nervous around you.

“Then I said-…hey, I can feel your gaze from here.” “Am I staring at you a lot?? Aah sorry, you’re so beautiful that I couldn’t resist.” he says while kissing your cheek and interrupting anything that would come out of your mouth.

Marc desires to be a devoted follower of his goddess, you. But most of the time it fails miserably. He is in such a trance that he forgets everything and even though the eyes of a passionate puppy that he looks at you with seem cute, you are not guilty of feeling offended. He forgets your favorite place to go out, he forgets your favorite snack, he forgets that sweets make you feel calmer in tpm, he forgets that you canceled a date and gets sulky afterwards blaming you, he forgets that you have bigger goals clear and more important than him and most importantly, he forgets that you have a life before him and whenever you mention an ex-boyfriend he's like "What do you mean you had a boyfriend before me? Who is he? Why did they break up?" So that I don't make the same mistakes he did so that I find him and threaten him to never even look at him again.

and for you so I can make you feel guilty for still having his contact so it's just me and you in the world

Marc is strangely strange, have you ever seen a bear hiding behind a lamp post? So is his jealousy. His blood boils every time you mention a name that isn't his, his body screams mine mine mine, to possessively squeeze your waist and his mouth kisses you until the princess's stressed little head forgets that useless name what you just said after all, I'm the one next to you and I bet he can't make you feel good like I do but…. he hides it well, sometimes, when he forces it. But it's so fking hard to disguise it!

"I met a friend of mine today" "Friend, what friend? A man?" "Then he said- "But wait, love - sorry to interrupt you - since when and where have you known him?" Wasn't this friend of yours on his list where he came from? "I met him in my first year of high school, love, he moved away after that, and I met him again now" " And you hugged him? "Of course, like I do with everyone-" "whyyyyyy?" “Marc he’s my friend and-” “And do you remember his name?”- He asked something simple but that had a strong and heavy meaning behind it.

the name. the name is something so simple but so important, isn’t it?

In a random dawn, he realized that the little princess didn't remember people's names very well and when asked, you replied “They're not important to me, just some extras interacting with me” and while you sleepy laughed at theory made on the spot, his heart squeezed as he remembered that you often forgot his name too.

I'm not so important that you remember my name?

In a random dawn, you told him that you had had other relationships before him, but you never felt anything for them, so you ended it and left and forgot about them. Others, which were hidden and you did crazy things in love for them, regretted them and never saw them again. And that he was your first official boyfriend, the first you took home, the first you took to meet your parents and family, the first you took to your hiding place in the house. He. But as quickly as pride filled his heart, his mind fed the uncertainties and insecurities that keep him awake at night.

Would you live love adventures with him too? Would you regret loving him? Do you have feelings for him or is it a one-sided relationship? Would you forget about him? Would you trade it for one night? Would you… leave?

Marc is so strangely strange that he sometimes blurts out strange and chilling phrases every time you try to subtly open his eyes about the relationship, and in his head they are sweet and romantic, passionate and sincere declarations always sealing the promise with kisses and hugs that are increasingly hard and possessive, but they are red signs in your eyes that something is wrong.

“I don’t know if I could handle that either.” You said as you casually gossiped about a breakup between a couple you saw on the internet, without realizing it Marc's eyes darkened when he heard the word breakup "Listen, if we broke up I…"

"Baby, you know that if it's up to me, we'll never breakup, right?" With a determined look, Marc pulled you onto his lap

"Of course, dear, but if what you did…"

"I would come to your house, take you and lock you away from the world. Because if that's the case, you would never leave me."

"Whoa boy, a little bird wasn't meant to be trapped." When you felt the sincerity of Marc's words, you tried to leave your dear boyfriend's lap, demonstrating that you were serious about the matter, this fact did not go unnoticed by him as he smiled at you and with hearts in his eyes, he kissed you madly until you was breathless and again and again and again….he put you in a bridal carry position, pressing you against his chest with such force that it left you sore

"So i cut the bird's wings and we stay together, love, 24 hours a day, 7 days a week. We will never break up, remember what I told you? Let's get married, my beautiful darling."

[reasonsforhope]

"People living with diabetes might have a new hope. Scientists have tested a new drug therapy in diabetic mice, and found that it boosted insulin-producing cells by 700% over three months, effectively reversing their disease.

Beta cells in the pancreas have the important job of producing insulin in response to blood sugar levels, but a hallmark of diabetes is that these cells are either destroyed or can’t produce enough insulin. The most common treatment is regular injections of insulin to manage blood sugar levels.

But a recent avenue of research has involved restoring the function of these beta cells. In some cases that’s started with stem cells being coaxed into new beta cells, which are then transplanted into patients with diabetes. Researchers behind this kind of work have described it as a “functional diabetes cure.”

Now, scientists at Mount Sinai and City of Hope have demonstrated a new breakthrough. Previous studies have mostly involved growing new beta cells in a lab dish, then transplanting them into mice or a small device in humans. But this new study has been able to grow the insulin-producing cells right there in the body, in a matter of months.

The therapy involved a combination of two drugs: one is harmine, a natural molecule found in certain plants, which works to inhibit an enzyme called DYRK1A found in beta cells. The second is a GLP1 receptor agonist. The latter is a class of diabetes drug that includes Ozempic, which is gaining attention lately for its side effect of weight loss.

The researchers tested the therapy in mouse models of type 1 and 2 diabetes. First they implanted a small amount of human beta cells into the mice, then treated them with harmine and GLP1 receptor agonists. Sure enough, the beta cells increased in number by 700% within three months of the treatment. The signs of the disease quickly reversed, and stayed that way even a month after stopping the treatment.

“This is the first time scientists have developed a drug treatment that is proven to increase adult human beta cell numbers in vivo,” said Dr. Adolfo Garcia-Ocaña, corresponding author of the study. “This research brings hope for the use of future regenerative therapies to potentially treat the hundreds of millions of people with diabetes.”

The results are intriguing, but of course being an animal study means there’s still much more work to be done before it could find clinical use. So far, harmine alone has recently undergone a phase 1 clinical trial in humans to test its safety and tolerability, while other DYRK1A inhibitors are planned for trials in humans next year.

Perhaps most importantly, the team will soon experiment with combining beta-cell-regenerating drugs with others that modulate the immune system. Ideally this should help overcome a major hurdle: the immune system will continue attacking new beta cells as they’re produced.

The research was published in the journal Science Translational Medicine."

-via New Atlas, July 14, 2024

[covid-safer-hotties]

Also preserved in our archive (Daily updates!)

By Mary Van Beusekom, MS

New findings from two studies have tied use of the antiviral drug nirmatrelvir-ritonavir (Paxlovid) to a reduction in COVID-19 hospitalizations and death, as well as to faster resolution of symptoms and less use of healthcare resources.

Benefit seen only in older patients For the first study, published in Clinical Microbiology and Infection, a Medical University of Vienna–led research team compared the effectiveness of Paxlovid with that of the antiviral drug molnupiravir (Lagevrio)—and with that of not receiving an antiviral—against hospitalization and all-cause death from January 2022 to May 2023. Participants were adults with mild to moderate infections and one or more risk factors for severe illness caused by the SARS-CoV-2 Omicron variant.

"The oral antivirals nirmatrelvir-ritonavir and molnupiravir are the mainstay treatment for Covid-19 in non-hospitalised adults at increased risk of severe disease," the study authors wrote. "Both oral antivirals were approved at the time of the study period (2022/2023) for the treatment of non-hospitalised patients with mild-to-moderate Covid-19, but the current National Institute of Health guidelines favour nirmatrelvir-ritonavir over molnupiravir."

Of the 113,399 eligible COVID-19 patients in the retrospective cohort study, 10.7% received Paxlovid, 9.5% received molnupiravir, and 80.0% served as untreated controls. Over 96% of participants were previously infected with or vaccinated against COVID-19.

A total of 0.43% of Paxlovid recipients, 1.4% of molnupiravir users, and 1.13% of controls were hospitalized within 28 days (risk difference [RD], -0.7%; Paxlovid vs control RD, 0.26%). No Paxlovid recipients and 0.13% each of molnupiravir users and controls died.

The estimated risk of hospitalization was 0.57% in Paxlovid users and 1.09% in controls (adjusted RD [aRD], -0.53%). The estimated risk of death was 0.0% in the Paxlovid group and 0.13% in controls (aRD, -0.13%).

The number of patients needed to treat to prevent hospitalization and death was 190 in Paxlovid recipients and 792 in controls, respectively. These statistically significant aRDs were seen only among patients 60 years and older.

The estimated risk of hospitalization in the molnupiravir analysis was 1.36% in the molnupiravir group and 1.16% among controls (aRD, 0.2%). The estimated risk of death was 0.12% in molnupiravir recipients and 0.14% in controls (aRD, -0.01%).

"Among outpatients aged ≥60 years with Covid-19 in an Omicron-dominated era, treatment with nirmatrelvir-ritonavir was associated with a lower risk of hospitalisation and all-cause death within 28 days, albeit with wide confidence intervals and high numbers needed to treat," the study authors wrote.

"This finding was not observed in molnupiravir users and younger nirmatrelvir-ritonavir users. Future studies are needed to better define target populations that show greater benefit from treatment with nirmatrelvir-ritonavir," they concluded.

Proportion of patients seeking care slashed 73% The second study, a phase 2/3 randomized clinical trial published today in Clinical Infectious Diseases, also found protection against COVID-19 hospitalization and death in adults receiving Paxlovid and demonstrated a faster resolution of symptoms and lower use of healthcare resources compared with a placebo in high-risk patients.

The research was led by researchers from Pfizer, which developed Paxlovid. The drug was given to 977 symptomatic COVID-19 patients, while 989 were given a placebo, at 343 sites in 21 countries from July 2021 through December 2021, a Delta-predominant period.

Paxlovid significantly shortened the time to symptom relief (median, 13 vs 15 days; hazard ratio, 1.27) and resolution (16 vs 19 days; HR, 1.20) through 28 days and cut the number of COVID-related medical visits by 64.3% and the proportion of patients seeking care by 73.2%.

In total, 0.9% of Paxlovid recipients and 6.4% in the placebo group were hospitalized, for a relative risk reduction of 85.5%. Hospitalized Paxlovid recipients had briefer hospital stays, and none required intensive care or mechanical ventilation. Fewer patients in the Paxlovid group needed other COVID-19 treatments, and none died by 6 months, compared with 15 in the placebo group.

"The importance of having effective COVID-19 treatments such as NMV/r [Paxlovid] to reduce burden on healthcare systems, both ambulatory and hospital based, should not be underestimated," the authors wrote.

Study Links: www.clinicalmicrobiologyandinfection.com/article/S1198-743X(24)00508-1/fulltext

academic.oup.com/cid/advance-article/doi/10.1093/cid/ciae551/7889107

[excalculus]

I saw some mentions of rabies going around again and have no clue what's set it off this time, but given recent scientific developments I want to revisit the idea of curing symptomatic rabies.

First things first: there is still no practical way to do this. The famous Milwaukee Protocol fails far more frequently than it succeeds, and even the successes are not making it out in anything like a normal state. It's been argued that it should no longer be considered a valid treatment [1] due to these issues; any continued use is because there's literally nothing else on the table.

However. There are now two separate studies showing it's possible to cure rabies in mice after the onset of symptoms. The lengths you have to go to in order to pull this off are drastic, to put it mildly, and couldn't really be adapted to humans even if you wanted to. But proof of concept is now on the board.

long post under the cut, warnings for animal experimentation and animal death. full bibliography at the end and first mention of each source links to paper.

Quick recap - rabies is a viral disease of mammals usually transmitted through the saliva of an infected animal. From a contaminated bite wound, it propagates slowly for anywhere from days to months until it reaches the central nervous system (CNS). Post-exposure vaccination can head it off during this phase, but once it reaches the CNS and neurological symptoms appear it's game over. There will typically be a prodromal phase where the animal doesn't act right - out at the wrong time of day, disoriented, abnormally friendly, etc. This will then progress to the furious (stereotypical "mad dog" disease) and/or paralytic phases, with death eventually caused by either seizures or paralysis of the muscles needed for breathing.

That's the course we're familiar with in larger animals. Mice, though, are fragile little creatures with fast metabolisms.

In the first study's rabies infection model, lab mice show rabies virus in the spinal cord by day 4 after infection and in the brain by day 5. Weight loss and slower movement start by day 7, paralysis starting from the hind limbs from day 8 on, and if not euthanized first they're dead by day 10-13. [2]

This study (fittingly conducted at the Institut Pasteur) had two human monoclonal antibodies, and wanted to see if there was any possibility they could be used to cure rabies after what we think of as the point of no return.

Injecting the antibodies into muscle saved some mice if done at days 2 or 4, and none if done later, even at high doses of 20 milligrams per kilogram of body weight of each. Conclusion: targeting the virus out in the rest of the body is no use if it's already replicating in the CNS.

Getting a drug past the blood-brain barrier is, to use a highly technical term, really fucking hard. It's the sort of problem that even the best-funded labs and biggest companies in the world routinely fail at. And that's for small molecule drugs, which are puny compared to antibodies.

But this isn't drug development for a clinical trial. This is a very, very early proof-of-concept attempt, which means you're willing to ignore practicality to see if this idea is even remotely workable. So you can do things like brute force the issue by cutting through the skull to implant a microinfusion pump, which lets you deliver the antibodies directly into the normally-protected space around the brain. Combine this with the normal injections, and you can treat both the CNS and the rest of the body at the same time. Here's a survival graph of treated mice. X axis is days, Y axis is percentage of mice in that group still alive.

Figure 2A from reference 2, accessed February 2024

The fact that the blue, green, and purple lines did anything other than sink horribly to zero is unheard of. When the combination treatment was started at day 6, 100% of the mice survived. Started at day 7 (prodromal phase), 5 out of 9 mice recovered and survived. Started at day 8 (solidly symptomatic, paralysis already starting to set in), 5 of 15 mice recovered and survived. And when they say "survived", they kept these mice all the way to day 100 to make sure. Some of them had permanent minor paralysis but largely they were back to being normal mice doing normal mouse things. So, success, but by pretty extreme means.

Enter the second paper [3]. This was a different approach using a single human monoclonal antibody against Australian bat lyssavirus (ABLV - closely related to rabies, similar symptoms in humans) to try for a cure without needing to deliver treatments directly into the CNS. They also made a luminescent version of ABLV that let them directly image viral activity, so they could see both where the virus was replicating and how much there was in a live mouse.

Figure 1 from reference 3, accessed February 2024

Mice infected with ABLV start showing symptoms around day 8. You can see in the figure that at day 3 there's viral replication in the foot at the site of infection, which has shifted into the spine and brain by day 10. So what happens if you give one of these doomed mice one single injection of the antibody into the body?

Done at day 3, the virus doesn't make it to the brain until day 14, and while disease does set in after that around 30% of the mice survive. Days 5 and 7 are much more interesting. Those mice still develop symptoms at day 8, but the imaging shows the amount of virus in their spines and brains never gets anywhere near the levels seen in untreated controls, and within days it starts to decrease. Around 80% of day 5 and 100% of day 7 mice survive.

Okay, sure, you can stop another lyssavirus, but technically you did start treatment before symptoms appeared. What about symptomatic rabies?

The rodent-adapted rabies strain CVS-11 starts causing symptoms as early as day 3 after infection, and untreated mice die between days 8 and 11. The same single dose of antibody saved 67% of mice treated on day 5 and 50% of mice treated on day 7. Without making the luminescent version of the virus there's no real-time imaging of the infection, but you can still track symptoms.

Figure 2 from reference 3, accessed February 2024. CVS-11 is the name of the rodent rabies strain and F11 is the name of the antibody.

Disease score is a combination of several metrics including things like whether the mice are behaving normally and whether they show signs of paralysis. In untreated mice it goes up and up, and then they die. If one of those lines starts coming back down and continues past day 10 or so, that's a mouse that recovered. The success rate isn't as good as against ABLV, but again, this is a rabies strain specifically adapted to rodents and treatment wasn't started until it was well-established in the CNS.

So how on earth is this happening? The antibody neutralizes both ABLV and rabies really well in a test tube, but we've already established that there's no way a huge lumbering antibody is making it past the blood-brain barrier without serious help. Something about the immune response is clearly making it in there though. And it turns out that if you start trying this cure in mice missing various parts of their immune systems, mice without CD4+ T cells don't survive even with the treatment. By contrast mice without CD8+ T cells take longer to work through the infection, but they eventually manage it and are immune to reinfection afterwards.

To grossly oversimplify the immune system here, CD4+ are mature helper T cells, which work mostly by activating other immune cells like macrophages (white blood cells) and CD8+ T cells (killer T cells) against a threat.

Normally, T cells are also kept out by the blood-brain barrier, but we know that in certain specific cases including viral infection they can pass it to migrate into the brain. In the brains of the infected mice for which antibody treatment either wasn't given or didn't work, you can find a roughly even mix of CD8+ and CD4+ T cells along with a whole lot of viral RNA. But in the brains of those successfully fighting off the infection, there's less viral RNA and the cells are almost exclusively CD4+. So the antibody doesn't work by neutralizing the virus directly - something about it is activating the animal's own immune system in a way that gives it a fighting chance.

Again, neither of these proof of concept treatments is really workable yet as a real world cure. The first one is almost hilariously overkill and still has a pretty good chance of failure. The second is less invasive but careful sequencing still shows both low-level viral replication and signs of immune response in the brains of the survivors even at day 139, so it may not be truly clearing the virus so much as trading a death sentence for life with a low-level chronic infection. But now we know that 1. curing rabies after symptoms begin is at least theoretically possible, and 2. we have some clues as to mechanisms to investigate further.

Not today. Not tomorrow. But maybe not never, either.

References:

Zeiler, F. A., & Jackson, A. C. (2016). Critical appraisal of the Milwaukee protocol for rabies: this failed approach should be abandoned. Canadian Journal of Neurological Sciences, 43(1), 44-51.

de Melo, G. D., Sonthonnax, F., Lepousez, G., Jouvion, G., Minola, A., Zatta, F., ... & Bourhy, H. (2020). A combination of two human monoclonal antibodies cures symptomatic rabies. EMBO molecular medicine, 12(11), e12628.

Mastraccio, K. E., Huaman, C., Coggins, S. A. A., Clouse, C., Rader, M., Yan, L., ... & Schaefer, B. C. (2023). mAb therapy controls CNS‐resident lyssavirus infection via a CD4 T cell‐dependent mechanism. EMBO Molecular Medicine, 15(10), e16394.

[starrynightsoversunflowers]

I made a rec list for Latin American books that have queer themes

*DISCLAIMER: "Queer" is not a theme per se. Sometimes it's about identity, sexuality, love, horror, violence, etc. All happening around queer characters.

Most of these deal with pretty heavy themes: prostitution, rape, violence, aids, death. Some representations can be considered "problematic" if you're boring. There are different ways to approach queerness.

Feel free to yell at me about these books/ask where to read them/make recommendations/etc. I definetly have favourites. Also some have movie adaptations.

Descriptions and warnings under the cut

La condesa sangrienta (The bloody countess):

The story of countess Erzebeth Báthory, a medieval hungarian countess know for committing more than 650 murders and inspiring the figure of the vampire. There´s no explicit queer relationships here but there´s absolutely some homoerotism in the narrations of torture. Pizarnik was a lesbian also. TW: disturbing, torture, blood, murder, you should not read this in one go.

El lugar sin límites (Hell has no limits):

The story about la Manuela, a homosexual transvestite that owns half a brothel in a small town. Her daughter owns the other half. The novel shows crudely the misery of forgotten towns and the day to day life of prostitution. There's also a movie. TW: prostitution, murder, homo/transphobia.

El mundo alucinante (A Hallucinations):

A fantasy and free version parody of the Memoires of Fray Servando Teresa de Mier. Known for the uses of magical realism and innovative prose.

Cobra:

Two stories meet. The first is of Cobra, a transvestite, and her transformation. The second of her initiation in a band of black jackers. Erotism and death.

Evita vive (Evita lives):

A controversial book around Eva Perón (after her death) who lives among prostitutes and homosexuals, having orgies and living a life of debauchery.

El beso de la mujer araña (The kiss of the spider woman):

The meeting of two prisoners living in the same cell. One, Valentín, is a political prisoner and the other, Molina, is a sexual deviant. During their weeks there, Molina narrates movies to Valentín and their relationship develops. There's also a movie.

Stella Manhattan:

During Brasil's military dictatorship, the apolitical Eduardo, a.k.a. Stella Manhattan, is expelled form his country for his shameful homosexuality. He returns to the surface as a brazilian counsil in New York and is immediately accosted by a military called Colonel Vianna, a sadomasichist known as the "Black Widow", and by the guerrillas seeking his befall.

Antes que anochezca (Before night falls):

Th 7th of december of 1990 the Cuban author Reinaldo Arenas, in a terminal phase of AIDS, would commit suicide, leaving behing this moving and political testimony, which he finished mere days before taking his own life.

Salón de belleza (Beauty salon):

In a large, unnamed city, a strange, highly infectious disease begins to spread, afflicting its victims with an excruciating descent toward death, particularly unsparing in its assault of those on society's margins. Spurned by their loved ones and denied treatment by hospitals, the sick are left to die on the streets until a beauty salon owner, whose previous caretaking experience extended only to the exotic fish tanks scattered among his workstations, opens his doors as a refuge. In the ramshackle Morgue, victim to persecution and violence, he accompanies his male guests as they suffer through the lifeless anticipation of certain death, eventually leaving the wistful narrator in complete, ill-fated isolation.

Bajar es lo peor (Going down is the worst):

With gothic resonances, Enríquez shows crudely the Buenos Aires of the 90's. The confinement and the paranoia of cocaine, sex as a means to escape or survive, political unbelief, mix with a romantic love that never reaches satisfaction. There's also a movie. TW: drugs, prostitution, rape, suicide.

Loco afán (Mad eagerness):

These "chronicles of aids" narrate stories of homosexuality in Latin America, focused on drag, transvestites and AIDS.

Sirena Selena vestida de pena:

Discovered by Martha Divine in the backstreets of San Juan, picking over garbage, drugged out of his mind and singing boleros that transfix the listener, a fifteen year old hustler is transformed into Sirena Selena, a diva whose uncanny beauty and irrisistable voice will be their ticket to fame and fortune. Auditioning for one of the luxury hotels in the Dominican Republic, Selena casts her spell over Hugo Graubel, one of the hotel's rich investors. Graubel is a powerful man in the Republic, married with children. Selena, determined to escape the poverty and abuse s/he suffered as a child, engages Graubel in a long seduction in this mordant, intensely lyrical tragi-comedy - part masque, part cabaret - about identity (class, race, gender) and "the hunger and desire to be other things."

Tengo miedo torero (My tender matador):

It is the spring of 1986, and Chilean dictator Augusto Pinochet is losing his grip on power. In one of Santiago’s many poor neighborhoods, a man known as the Queen of the Corner embroiders linens for the wealthy. A hopeless and lonely romantic, he listens to boleros to drown out the gunshots. Then he meets Carlos, a young, handsome man who befriends the aging homosexual and uses his house to store mysterious boxes and hold clandestine meetings. And as the relationship between these two very different men blossoms, they find themselves caught in a revolution that could doom them both. There's also a movie.

Adiós mariquita linda (Goodbye pretty pansy):

Chronicles of ire, delation, passion, resentment and loves. Stories of different cities and travels.

Sexografías (Sexographies):

In fierce and sumptuous first-person accounts, renowned Peruvian journalist Gabriela Wiener records infiltrating the most dangerous Peruvian prison, participating in sexual exchanges in swingers clubs, traveling the dark paths of the Bois de Boulogne in Paris in the company of transvestites and prostitutes, undergoing a complicated process of egg donation, and participating in a ritual of ayahuasca ingestion in the Amazon jungle--all while taking us on inward journeys that explore immigration, maternity, fear of death, ugliness, and threesomes. Fortunately, our eagle-eyed voyeur emerges from her narrative forays unscathed and ready to take on the kinks, obsessions, and messiness of our lives. Sexographies is an eye-opening, kamikaze journey across the contours of the human body and mind.

Los topos (The moles):

The son of missing persons of the Dictatorship casually meets a half-brother who poses as a transvestite to investigate ex repressors and cops.

La virgen cabeza (Slum virgin):

When the Virgin Mary appears to Cleopatra, she renounces sex work and takes charge of the shantytown she lives in, transforming it into a tiny utopia. Ambitious journalist Quity knows she’s found the story of the year when she hears about it, but her life is changed forever once she finds herself irrevocably seduced by the captivating subject of her article.

Falsa liebre (False hare):

The darkness at the port engulfs everything. Pachi and Vinicio go deeper into the beach, approaching an improvised party. They are looking for something to numb their bodies, something to finally erase themselves. Summer has been long, and that day was much worse. Not far from there, Zahir fantasizes about his next travel to the capital city or the northern part of Mexico, away from the aunt who keeps asking him for money, controls him through physical violence, and has driven his little brother, Andrik, to run away from the family home and end up in another: a man’s house, who caresses Andrik and then strikes him with the same hand. Now Zahir must not only convince Andrik to start a new life, but make sure they find a way out of that seemingly endless beach. TW: rape, prostitution, violence.

Ladrilleros (Brickmakers):

Oscar Tamai and Elvio Miranda, the patriarchs of two families of brickmakers, have for years nursed a mutual hatred, but their teenage sons, Pájaro and Ángelito, somehow fell in love. Brickmakers begins as Pájaro and Marciano, Ángelito’s older brother, lie dying in the mud at the base of a Ferris wheel. Inhabiting a dreamlike state between life and death, they recall the events that forced them to pay the price of their fathers’ petty feud. The Tamai and Miranda families are caught, like the Capulets and the Montagues, in an almost mythic conflict, one that emerges from stubborn pride and intractable machismo. Like her heralded debut, The Wind That Lays Waste, Selva Almada’s fierce and tender second novel is an unforgettable portrayal of characters who initially seem to stand in opposition, but are ultimately revealed to be bound by their similarities. TW: violence.

Cuerpo a tierra (Body to the ground):

We aren't always owners of our own decisions, sometimes we´re pulled by an irrecognizable impulse and, sometimes, the only truth is that of the body. Betrayal and deception, love and heartbreak, love and search are the protagonists of these stories.

Temporada de huracanes (Hurricane season):

The Witch is dead. And the discovery of her corpse has the whole village investigating the murder. As the novel unfolds in a dazzling linguistic torrent, with each unreliable narrator lingering on new details, new acts of depravity or brutality, Melchor extracts some tiny shred of humanity from these characters—inners whom most people would write off as irredeemable—forming a lasting portrait of a damned Mexican village. There will be a movie by the end of the year. TW: rape, paedophilia, prostitution.

Pelea de gallos (Cockfight):

Ampuero sheds light on the hidden aspects of the home: the grotesque realities of family, coming of age, religion, and class struggle. A family’s maids witness a horrible cycle of abuse, a girl is auctioned off by a gang of criminals, and two sisters find themselves at the mercy of their spiteful brother. With violence masquerading as love, characters spend their lives trapped reenacting their past traumas. Heralding a brutal and singular new voice, Cockfight explores the power of the home to both create and destroy those within it. TW: rape, incest, violence.

Las aventuras de la China Iron (The adventures of China Iron):

1872. The pampas of Argentina. China is a young woman eking out an existence in a remote gaucho encampment. After her no-good husband is conscripted into the army, China bolts for freedom, setting off on a wagon journey through the pampas in the company of her new-found friend Liz, a settler from Scotland. While Liz provides China with a sentimental education and schools her in the nefarious ways of the British Empire, their eyes are opened to the wonders of Argentina’s richly diverse flora and fauna, cultures and languages, as well as to the ruthless violence involved in nation-building.

Mandíbula (Jawbone):

Fernanda and Annelise are so close they are practically sisters: a double image, inseparable. So how does Fernanda end up bound on the floor of a deserted cabin, held hostage by one of her teachers and estranged from Annelise? When Fernanda, Annelise, and their friends from the Delta Bilingual Academy convene after school, Annelise leads them in thrilling but increasingly dangerous rituals to a rhinestoned, Dior-scented, drag-queen god of her own invention. Even more perilous is the secret Annelise and Fernanda share, rooted in a dare in which violence meets love. Meanwhile, their literature teacher Miss Clara, who is obsessed with imitating her dead mother, struggles to preserve her deteriorating sanity. Each day she edges nearer to a total break with reality. TW: violence, cannibalism.

Las malas (Bad girls):

A trans woman's coming-of-age tale about finding a community among fellow outcasts. Born in the small Argentine town of Mina Clavero, Camila is designated male but begins to identify from an early age as a girl. She is well aware that she's different from other children and reacts to her oppressive, poverty-stricken home life, with a cowed mother and abusive, alcoholic father, by acting out-with swift consequences. Deeply intelligent, she eventually leaves for the city to attend university, slipping into prostitution to make ends meet. And in Sarmiento Park, in the heart of Córdoba, she discovers the strange, wonderful world of the trans sex workers who dwell there. Taken under the wing of Auntie Encarna, the 178-year-old eternal whose house shelters this unconventional extended family, Camila becomes a part of their stories-of a Headless Man who fled his country's wars, a mute young woman who transforms into a bird, an abandoned baby boy who brings a twinkle to your eye. TW: rape, prostitution, transphobia, murder, child death.

Nuestra parte de noche (Our share of the night):

A young father and son set out on a road trip, devastated by the death of the wife and mother they both loved. United in grief, the pair travel to her ancestral home, where they must confront the terrifying legacy she has bequeathed: a family called the Order that commits unspeakable acts in search of immortality. For Gaspar, the son, this maniacal cult is his destiny. As the Order tries to pull him into their evil, he and his father take flight, attempting to outrun a powerful clan that will do anything to ensure its own survival. But how far will Gaspar’s father go to protect his child? And can anyone escape their fate? Moving back and forth in time, from London in the swinging 1960s to the brutal years of Argentina’s military dictatorship and its turbulent aftermath.

Tesis sobre una domesticación (Thesis about a domestication):

A single transvestite is enough to undermine the foundations of a house, to untie the knots of compromise, to break a promise, to give up a life. The familiy clings to brief moments of happiness without noticing it´s been defeated since the start.

La hija única (Still born):

Alina and Laura are independent and career-driven women in their mid-thirties, neither of whom have built their future around the prospect of a family. Laura is so determined not to become a mother that she has taken the drastic decision to have her tubes tied. But when she announces this to her friend, she learns that Alina has made the opposite decision and is preparing to have a child of her own. Alina's pregnancy shakes the women's lives, first creating distance and then a remarkable closeness between them. When Alina's daughter survives childbirth – after a diagnosis that predicted the opposite – and Laura becomes attached to her neighbor's son, both women are forced to reckon with the complexity of their emotions, their needs, and the needs of the people who are dependent upon them. TW: child disease, family violence.

Huaco retrato (Undiscovered):

In an ethnographic museum in Paris, Gabriela Wiener is confronted with her unusual inheritance. She is visiting an exhibition of pre-Columbian artefacts, the spoils of European colonial plunder. As she peers through the glass, she sees sculptures of Indigenous faces that resemble her own - but the man responsible for pillaging them was her own great-great-grandfather, Austrian colonial explorer Charles Wiener. In the wake of her father's death, Gabriela begins delving into all she has inherited from her paternal line. From the brutal trail of racism and theft that Charles left behind to revelations of her father's infidelity, she traces a legacy of abandonment, jealousy and colonial violence, in turn reframing her own struggles with desire, love and race. Seeking relief from these personal and historical wounds, Gabriela turns to the body and desire as sources of both constraint and potential freedom.

Sacrificios humanos (Human sacrifices):

An undocumented woman answers a job posting only to find herself held hostage, a group of outcasts obsess over popular boys drowned while surfing, and two girls suspect sinister behavior from the missionaries lodging in their home. Simultaneously terrifying and exquisite, Human Sacrifices is "tropical gothic" at its finest. Ampuero considers the decay and oppression beneath the surface of our humid and hostile world, where those on the margins must pay the price for the comfort and safety of the elite. These twelve stories contemplate the nature of exploitation and abuse, illuminating the realities of those society consumes and leaves behind.

Soy una tonta por quererte (I'm a fool to want you):

In the 1990s, a woman makes a living as a rental girlfriend for gay men. In a Harlem den, a travesti gets to know none other than Billie Holiday. A group of rugby players haggle over the price of a night of sex, and in return they get what they deserve. Nuns, grandmothers, children, and dogs are never what they seem. These 9 stories are inhabited by extravagant and profoundly human characters who face an ominous reality in ways as strange as themselves.

Las indignas (The unworthy):

A searing, dystopian tale about climate crisis, ideological extremism, and the tidal pull of our most violent, exploitative instincts. TW: death, animal death, rape, cults.

[sciderman]

Kelly's TASM issue 3 dropped and so did the quality (Ba-Dum-Tsss)...but it partly canonized your Peters goth phase by suddenly retconning in a pair of delinquent rebel friends that turned Peter into a punk.

Who customized Bens old army jacket...

Also quick question, was Itsy always trying to uh...bed, Peter? Or is that a new development?

(like...what the absolute FUCK, Kelly?! That's... Peter is drugged, powerless, and literaly not into it....)

The writing is SO bad, just SO bad.

fuck it up punk peter! i wish we could've known each other under better circumstances

as for the rest

[ahamkara-apologist]

Crossposting this over from Bluesky almost verbatum bc its Late but I can't stop thinking about Revenant so this goes here too. I really really love the little worldbuilding detail about the Eliksni being so technologically advanced, yet still relying on apothecaries for medical care because of how long-lived they are; this makes sense to me is mostly bc technology advances exponentially fast while medical development builds very slowly and cautiously, oftentimes with great reluctance to move away from what already works. There's a much higher risk factor regarding faliure one vs the other, and more limitations placed upon medicinal advancement by default, so it makes sense that a long-lived artisan race would have been leaps and bounds ahead in robotics and digital tech while still sticking to ancient medicinal techniques. It's not about innovation, it's about improving what already works, and a long-lived people are more likely going to want to stick with the safety net of reliable, known medications vs racing to get better tools because they're perpetually aware of just how much their current ones can be improved.

Additionally, when age isn't a limiting factor, innovative engineers can continually build and expand on their prototypes/ideas to develop new, effective tech easier, but it also means that the apothocaries would also build on their old, traditional medicinal knowledge, leading to a preservation of the more ancient rites of using tonics. The means of advancement are on two different paths/development curves. Then you've also got the fact that the Eliksni seemed to have a different, positive cultural view on gene editing (aka eco-Splicers), so that means herbs could be edited to be much more potent and effective much more quickly, thus maintaining the tonic system vs advancing drug development into different delivery mechanisms to work around those limitations. You don't find an alternative or a workaround, you just smash through the wall limiting you in the first place by editing the plants themselves to yield what you need directly. It's like how mammals went through a huge phase of adaptive radiation to fill in all the different niches left behind by the dinosaurs after the Cretaceous extinction, but crocodilians retained roughly the same bodyshape they had for millions of years, just tweaking it a bit to fit the newer circumstances- if it ain't broke, don't fix it!

Biology likely also played a factor as well. If the Eliksni had a lower body temperature than humans do, then they may be more tolerant to bacterial infections on account of simply being poorer hosts (or they're less suceptible to infections outside of parasites deliberately evolved to live in them). Our very warm, nutrient-rich mammal bodies mean that bacteria can multiply rapidly, but if the Eliksni were conditional ectotherms (or just had lower body temperature), then bacteria would likely multiply at a slower rate, giving their immune system more time to recognize and eliminate the threat before reaching a point where medicine is needed. Being able to moult/regenerate limbs also drastically simplifies the healing process. Ecdysis is a very effective tool to cure wounds or shed external parasites, and if a limb gets infected, it may be the safest/easiest option to cut it off with sterile tools and regrow it rather than risk the bacteria spreading to the rest of the body (though it would be ether-costly). If it's too damaged to regenerate properly, then the rapid technological advancements with prosthetics + higher neuroplasticity from limb regeneration also make it much easier to treat infected limbs by Simply Not Bothering and chopping them off. This means that stuff like reconstructive/restorative surgeries might be less advanced than our own, simply because there was no real need for it. I do think that vaccines would have been a thing, because it's always much better to prevent than to cure, but tonics would have remained the most viable option for getting medicine into an Eliksni, esp. if they did stuff like bolster bone regeneration or limb regrowth. Hence, the very wide range of specific tonics at different potencies being used to cure various ailments, and the copious amounts of artificial limbs on Eliksni survivors, even accounting for the whole 'we-fled-our-apocalypse-and-promptly-waged-war-and-destroyed-the-last-vestiges-of-our-old-civilization' shtick

I don't know how Eido's tonics turned us into chickens, however. Or plants. Or frogs. That one I'm going to rule out as a guardian-induced confounding factor on account of their paracausal nature, bc I don't think there were chicken-transformation tonics on Riis XD