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bb-studies · 2 years ago

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Uncovering the Role of Phase I Studies in Drug Development

Introduction

In drug development, a phase I study is the initial period of testing in humans. This stage is where you can make sure that your new compound is safe and effective enough to warrant further investigation. While it's important to have an effective Phase I program in place, there are several other aspects of clinical trial design and management that should be considered as well. These include designing an optimal dose for Phase II studies and ensuring the safety of your candidate drug.

Designing a clinical trial program for your new compound

Before you begin your early clinical trial program, you need to ensure that your compound is safe and well-tolerated. This can be accomplished with a phase I study. A phase I study is the first step in drug development and helps determine if your drug is safe and effective for humans. In addition to providing insights into whether or not further clinical trials should be pursued, it also provides information about how best to design those trials based on how people respond when given varying amounts of the new drug.

The goal of the phase I clinical trial is to collect information about what happens when an experimental drug is administered at different doses over a range of time periods (e.g., 2 hours versus 4 hours). It's important that each subject receive both high and low doses so that scientists can see how much variation there might be between people taking different amounts of this new compound. The most common way this occurs is through giving participants escalating doses (first small initial dose followed by larger ones as time passes) or by giving them fixed doses every few days until they reach their maximal tolerated dose (MTD), which involves gradually increasing their daily intake until they have taken enough medicine for several days in a row without showing any adverse side effects such as nausea or diarrhea; however, there are other ways as well!

Selecting the optimal dose for Phase II

Phase II studies are designed to assess the efficacy and safety of a compound. A dose escalation study is typically done in this phase, because it is important to determine the effective dose of a drug before proceeding with expensive Phase III trials.

Selecting the optimal dose for Phase II studies can be challenging if you do not have any relevant data from your previous studies (i.e., Phase I). In such cases, you may need to consider using an established approach such as Bayesian statistics or adaptive randomization technique.

Optimizing your clinical program and trial design

As the development of a drug proceeds, it is important to optimize your clinical program and trial design. This will help ensure that you get the most out of your studies and are able to move on to later stage trials in a timely manner.

When planning and conducting Phase I studies, consider:

The trial design and study population

Whether or not the study is scalable for use in later-stage trials

How feasible, ethical, and sustainable will this study be?

Determining the safety of your candidate drug

Phase I studies are the first step in a drug development process. They are designed to test for safety, not efficacy. Phase II studies determine whether a drug has any potential to be effective. Phase III studies test for efficacy and side effects in human subjects.

Phase II studies usually include 100-300 participants; phase III typically includes 2,000-3,000 participants. These phases of testing are very expensive and take several years to complete; they must also be approved by regulators before they can begin testing on humans.

Identifying potential toxicities

In a phase I study, you are given a small dose of your molecule and its effects on the body are observed. If the molecule is toxic and has adverse effects, you will have to do more research and development to come up with a safer product. However, it may be that your drug is not toxic at all, or maybe only one pathway in the body gets affected by it. In either case, if you cannot identify how your compound works and what other pathways might be affected by it in phase I, then any additional work will simply be more expensive in later stages when you need more patients taking larger doses of your drug.

Determining the pharmacokinetic profile of your compound

Pharmacokinetics is the study of how a drug is absorbed, distributed, metabolized, and excreted by the body. The pharmacokinetic profile of your compound will determine whether it has a safe and effective dose range.

These studies are typically done in cells or animals so that you can get answers about how quickly your drug will be broken down by enzymes in the body.

Collecting and analyzing data on your compound's metabolism, disposition, and excretion

In order to correctly interpret the results of your study, you will need to understand the difference between "metabolism," "disposition," and "excretion." If a compound is metabolized into more than one product, then those products are considered metabolites. The sum of all metabolites that arise from a single compound is known as its metabolic profile. The rate at which metabolites are formed from their parent drug depends on the enzyme(s) involved in this process (known as an enzyme-mediated reaction). You can use your Phase I studies to identify enzymes that may be involved in metabolism, including those responsible for making hydroxylated metabolites (e.g., 2-OH form).

Effective phase I studies can ensure that you move into later stages of drug development with confidence.

Phase I studies are essential to drug development. They're small in size, which means they can be completed quickly, and they focus on establishing safety. They're also the first step in clinical trials and don't require many subjects to complete.

Conclusion

The success of a phase I study is not only dependent on the science that goes into designing it, but also on the planning and execution by those involved in its execution. The information gathered during this pivotal stage in drug development can be used to improve future clinical trials and help scientists make better decisions about how their compounds should be developed.

#phase I studies #phase 1 clinical trials #early phase clinical development

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excalculus · 9 months ago

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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.

#rabies #biology #long post #animal death #medicine #original content

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ltash · 2 months ago

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The Bodyguard pt-1

Part 2 & 3 link in the end.

SimonGhostRileyxfemalereader

The boardroom was sleek, modern, and imposing, with dark wood panelling and a sprawling glass table. Sunlight filtered through the floor-to-ceiling windows, casting sharp shadows across the faces of the people who had slowly filed in, each flashing rehearsed smiles in your direction. You leaned back in your chair, absentmindedly chewing on the end of a sleek silver pen, your eyes sharp, taking in every movement, every fake expression.

Five guards stood silently behind you, their presence a subtle but unmistakable reminder of your authority. You were untouchable here, or at least, that's what you needed them to believe. As the CEO and heiress of Aventis Pharmaceuticals, a company built on generational influence, you knew there were black sheep lurking within your empire. You could feel it in the way certain board members avoided your gaze, shifting uncomfortably under your silent scrutiny.

"Let's get started," you said, your voice calm but unyielding as you set the pen down, giving each person a measured look. "I need the details on the latest antinarcotic project we're working on."

There was a pause before the head of R&D, Dr. Marcus Lewin cleared his throat. He looked pale, though you couldn't tell if it was the lighting or nerves. "Ah... of course, Miss Aventis," he began, shuffling some papers before him. "We're in the third phase of clinical trials now. The formula has shown promising results, minimal side effects, with a faster recovery rate compared to the last version."

You raised an eyebrow, watching him squirm slightly. "Minimal side effects?" you repeated. "We're aiming for a groundbreaking product, Dr. Lewin. I expect 'minimal' to be an understatement."

"Yes, of course," he stammered, nodding vigorously. "I, uh, apologize. We're working on further improvements. There's also some data regarding efficacy rates in the latest testing group. I can forward the specifics to you."

You leaned forward slightly, your gaze hardening. "Forward them to me? Dr. Lewin, I'd prefer a comprehensive update now from you. Or are there... issues you'd rather not discuss here?"

A few other board members shifted uncomfortably, casting sidelong glances at one another. But Dr. Lewin managed a stiff smile. "No issues, Miss Aventis. We've been gathering the results carefully. We're confident we can meet the expected deadline and provide a full report for you to review."

You nodded slowly, letting the silence stretch. "Good. I expect nothing less. And, just to be clear," you said, glancing around the table at the assembled members, "I don't tolerate surprises. If there are any... discrepancies, now is the time to disclose them. Otherwise, I expect total transparency."

A hush fell over the room.

Your gaze shifted to Martin Hayes, the company's CFO, a man known for his sharp financial acumen and, at times, slippery ethics. He sat across the table, his fingers tapping nervously against his folder. He offered a tight, polite smile as he looked up to meet your eyes.

"And about our deal with that company?" you asked, your voice cool, with just a hint of impatience.

Martin cleared his throat, adjusting his tie. "Yes, of course, Miss Aventis. The partnership with Arcadia Biotech is progressing as planned. We've secured favourable terms for both manufacturing and distribution, ensuring a significant reduction in costs while increasing production capabilities."

You tilted your head, studying him. "And Arcadia is still unaware of our... competitive projects?"

He hesitated, just for a fraction of a second, but you didn't miss it. "They're completely in the dark," he assured quickly. "We've kept all sensitive projects under strict confidentiality clauses. As far as Arcadia is concerned, they're our exclusive partners in the development and distribution of the existing narcotic treatments."

You tapped your fingers against the table. "Good. I'd like a written assurance from you that our proprietary research won't leak. If Arcadia or any other competitor even hints at knowing about our new product, I'll know who to turn to, won't I, Martin?"

The colour drained slightly from his face. "Absolutely, Miss Aventis. You have my word; I'll have our legal team draft an ironclad document."

"See that you do." You leaned back, giving him a faint smile as if to relieve the tension just slightly. "And remember, gentlemen and ladies," you added, letting your gaze roam around the table, "we're here to lead the industry-not to compete in petty games. I expect only the highest standards of loyalty and discretion."

A murmur of agreement filled the room, the board members nodding.

You leaned forward, placing both hands on the table, and fixed each board member with a piercing stare. The boardroom fell silent, the tension thick in the air.

"Also, remember this," you said, your voice low but unwavering. "I am more than capable of running my father's company. Each of you is here because you're shareholders, yes, but let's not mistake that for immunity."

A flicker of uncertainty crossed a few faces, and you didn't miss a beat.

"If I find out that anyone here has tampered with our formulas, compromised our products, or made any attempt to sabotage the reputation of Aventis Pharma..." You let the threat hang in the air for a moment, letting them feel the weight of your words. "Then you'll all be sinking with me. I won't hesitate to bring down every last one of you along with this company if it comes to that."

Martin Hayes shifted uncomfortably, his collar suddenly seeming a little too tight. Dr. Lewin was looking down at his notes, his jaw clenched, while a few others exchanged uneasy glances.

"Now," you continued, sitting back but keeping your gaze sharp, "let's ensure that it never comes to that. We are all on the same side, or we should be. Our success is your success. I expect complete loyalty to the vision my father built and entrusted me to lead."

You let the silence settle, watching them absorb your message. Finally, you smiled, but it was a smile of steel. "Any questions?"

No one spoke up, and you nodded in satisfaction. The boardroom felt smaller, suddenly less crowded with ambition and more attuned to your authority.

The boardroom cleared, and with a curt nod, you dismissed the meeting. Rising from your seat, you walked out with purposeful strides, your five bodyguards falling in line behind you, each scanning the area, their presence, an unspoken wall of security. You exited the building and moved toward the parking lot, where the air was still and quiet, almost eerily so.

Your eyes drifted to a Hummer parked discreetly in the far corner. It felt out of place, like a shadow that didn't belong. You slipped into your sleek sports car, the engine purring to life, but an uneasy feeling gnawed at you. Suddenly, figures emerged from the darkness, men with sharp eyes and cold expressions, each one wielding M14 rifles. Diego Garcia's assassins. The Hummer door stayed shut, but you caught a glimpse of Garcia himself watching from within, his gaze locked on you.

Before you could react, a hail of bullets erupted. Your heart thundered as your bodyguards sprang into action, returning fire, but the assassins moved with ruthless precision. In moments, one by one, your guards went down, each man fighting until his last breath but hopelessly outnumbered. You watched in horror, paralyzed as they fell, each life extinguished in seconds. You barely registered your own scream, choked by terror and fury, as the sounds of gunfire faded, leaving only silence and blood.

Your hands fumbled, trying to unlock the doors, but they were stuck, trapping you in the vehicle like a helpless bystander in a nightmare. You felt your pulse race as the shadows closed in, and then Diego was there, standing right outside your window, his face illuminated in the dim parking lot light. He smiled, a dark, twisted smile that sent chills through you.

"Mine," he whispered through the glass, his voice laced with malice and satisfaction.

A wave of dizziness overtook you, and everything spun. His words echoed in your mind as your vision blurred. Helpless and horrified, you slipped into unconsciousness, the last image seared into your memory: Diego's face, and that sinister smile that promised nothing but darkness.

A week had passed since the attack, but the memory of it still haunted you, flickering at the edge of your thoughts as you sat on the plush velvet sofa in your expansive drawing room. Sunlight poured through the towering windows, casting a warm glow over the gleaming marble floors and the breathtaking view of the Los Angeles skyline stretched beyond, grounding you in the opulence of your mansion. The faint hum of a helicopter faded as it settled on the rooftop, carrying with it your new bodyguard: Lieutenant Simon "Ghost" Riley, a man whose reputation preceded him.

The sound of heavy boots echoed through the hallways, each step precise and deliberate, growing closer until the double doors swung open. You rose from the sofa, instinctively straightening your posture as the figure of Ghost entered the room, his presence consuming it instantly. He was massive, towering over you at 6'4", his muscular frame stretching the fabric of his black t-shirt, every inch of him exuding strength and danger. His broad chest and shoulders were carved with the kind of power that comes only from a life on the battlefield, and his thick, muscular thighs tested the seams of his black cargo pants. A holstered firearm rested against his leg, a stark reminder of the deadly world you were stepping into.

But it was his eyes that struck you the hardest. Deep brown and unwavering, they locked onto yours with an intensity that felt almost physical, as if they could see straight through every secret you held. A skull-patterned bandana covered most of his face, concealing his expression, but his gaze was enough, it was fierce, calculating, and unyielding. His buzz-cut hair, a dirty blonde, caught a hint of sunlight, and a jagged scar traced down his left temple, the brutal souvenir of battles fought and survived.

The contrast between the two of you felt almost surreal, his raw, masculine power against your delicate, fragile beauty. At just five feet tall, your frame seemed almost dainty by comparison, a striking contrast of elegance and strength. The soft material of your dress hugged your figure, emphasizing the curve of your waist and your petite, curvy form, while your brown, doe-like eyes met his with a mixture of curiosity and caution.

"This is Ghost, ma'am," he nodded, his voice low, gravelly, resonant. The sound of it sent a shiver down your spine, filling the room as thoroughly as his presence did.

You hesitated, caught off guard by his intensity, before extending your hand. "Lieutenant Riley," you greeted, your voice steady even as you took in every detail of the man before you. "I've heard a lot about you."

He accepted your hand, his grip firm and respectful, but his eyes stayed sharp and assessing, as if already calculating every risk, every angle of protection.

"Welcome to my mansion. How was your journey?" you asked, settling yourself elegantly on the velvet couch, your posture flawless.

"The journey was fine, ma'am," he replied, his deep voice rumbling through the room. He took a step closer, crossing his arms, his gaze intense and assessing. "The view from the landing pad is quite something, too."

You felt his eyes linger, moving over you, taking in the details of your petite frame and the way your bodycon dress clung to your curves. He tried to keep his focus professional, but it was hard not to notice the finer details.

"Tea, coffee, or whiskey?" you offered.

A faint smirk tugged at the corner of his mouth. "Whiskey," he replied without hesitation, his gaze still fixed on you.

With a small nod, you rose from the sofa and moved to the bar across the room, reaching for the bottle of Kentucky bourbon. His eyes tracked your every movement, lingering on the bare skin between the thin straps of your dress. The dress hugged your form perfectly, and though he kept his face stoic, his attention remained unwavering as you poured the amber liquid into a glass.

You turned, holding the glass in your hand, and extended it to him. He stepped forward, his calloused fingers wrapping around the glass, brushing lightly against yours. The brief contact sent a jolt up your arm, but his face revealed nothing, not a hint of reaction. He lifted the glass to his lips, taking a slow, measured sip, all the while keeping his gaze steady on you.

You leaned back onto the plush sofa, crossing your legs elegantly, watching as he brought the glass of bourbon to his lips, taking a slow sip without breaking eye contact. The slight tension in the room was palpable, each of you sizing up the other, feeling out the boundaries of this unfamiliar relationship.

"So," you murmured, a faint hint of curiosity in your tone, "you wear the skull mask, Ghost..."

His eyes narrowed slightly above the edge of his mask, a flicker of irritation passing through them. He lowered the glass, studying you in silence for a moment before he replied, his tone even. "It's part of the job," he said. "Helps me keep things... impersonal. No one gets to see my face."

You tilted your head, not breaking his gaze. "Not even me?" you asked softly, a subtle challenge in your voice. "Not even the person you're here to protect?"

There was a beat of silence, his eyes dark and unreadable behind the mask. For a moment, you thought he might look away or ignore the question altogether. But then he spoke, his tone a shade more guarded. "Protection is about distance, ma'am. Masks help with that. It's not personal, just how I keep a clear line between my duty and... everything else."

You took a slow breath, absorbing his words. "Clear lines, huh?" You leaned forward, resting your chin on your hand as you studied him, his formidable frame, his stoic face, the shadows that clung to him. "Is that what works best for you, Lieutenant? No attachments, no faces, just the mission?"

He held your gaze, unflinching. "It's what's kept me alive." His answer was calm, unwavering, as though he'd thought it through many times before.

You nodded, acknowledging the harsh reality he lived by. "Well, I suppose I can respect that," you replied, your voice soft but thoughtful. "But you should know, Ghost, this won't be a typical mission. There are things at play here that... don't fit within clear lines."

He didn't respond, but his intense gaze on you seemed to deepen, like he was silently bracing himself for the unknown. Finally, he gave a slight nod, the barest hint of understanding in his eyes.

"Understood," he said, his tone low and resolute. And in that moment, you realized that, for all the distance he wanted to maintain, his presence, steady and unyielding, was exactly what you needed.

"Diego Garcia," you said, your voice quiet but resolute. "The Santiago Cartel."

Ghost's expression darkened. The name carried weight, a reputation steeped in violence. "Diego Garcia," he repeated, his tone grim. "Powerful, ruthless, no ordinary drug lord."

"He's bigger than Valeria Garza. More dangerous than El Sin Nombre."

Ghost's gaze was sharp, intense. "I know. Santiago Cartel is one of the deadliest in Mexico, and Garcia's the head of the snake."

"He's after me," you admitted, feeling the weight of the words as they left your lips.

Ghost's eyes narrowed. "Why?"

"My company produces anti-narcotics," you explained. "We sell the cure. He sells the poison."

Recognition flickered in his eyes. "You're cutting into his profits," he said, understanding dawning. "You make him look weak."

"We're about to launch a new antidote," you continued. "One that blocks the effects of drugs like cocaine, fentanyl. It's still in testing, but it'll be on the market soon."

He nodded slowly, processing it. "The cartel won't let that happen. They'll do whatever it takes to stop you."

You felt a shiver at his words but pushed on. "He's already killed for it. My bodyguards... I watched them die, right in front of me."

A muscle tightened in Ghost's jaw. "He killed them in front of you," he said, his voice low, edged with anger. "Bastard doesn't play by any rules."

"He sent his men. They were armed with M14 rifles. My men didn't stand a chance."

His expression grew grim. "M14s. No wonder your guards didn't make it."

"Laswell suggested you," you continued, watching him closely. "She said if anyone could handle Garcia, it'd be you."

He met your gaze, a flicker of confidence in his eyes. "She's not wrong. I've dealt with men like him before." His voice was calm, unshaken. "And I'll take him down.

"Let me show you around," you said, motioning for him to follow.

Ghost nodded. "Lead the way."

The mansion was sleek and modern, blending luxury with privacy. As you walked through the marble driveway, you passed the tall, solid wooden door into the living room, its polished granite floors gleaming in the light. To the left, a door opened to the swimming pool area, surrounded by greenery. Above, a glass skywalk connected the house, offering a view of the water below.

A spiral staircase led to the second floor where your master bedroom and its luxurious bathroom were located, complete with a Jacuzzi and a high-tech shower. The back lawn opened up to the underground parking area.

As you walked, Ghost took in everything with a sharp, calculating gaze. The mansion wasn't just a home, it was a fortress. Every detail, from the barbed wire to the strategic location, was a reminder of the protection it offered.

"Like what you see?" you asked, watching his reaction.

Ghost's expression was unreadable, but his voice was steady. "It's secure," he said, eyes flicking over the property. "More than most would need."

"It's still smaller than other mansions here," you countered.

"Smaller, yes. But more secure," he said. "Most billionaires settle for an alarm system. You went further."

"The reason I don't go bigger is security," you replied. "I know Diego could breach it, but it's L.A. He'd think twice."

Ghost nodded. "Smart. L.A.'s dangerous, but Garcia would hesitate."

"Good. Let him be intimidated. Makes my job easier."

He shifted his attention back to you. "What about inside? Armed guards?"

"Outside," you said. "The perimeter's covered."

He raised an eyebrow. "Inside?"

"You..." you trailed off, letting him fill in the rest.

Part 2

Part 3

Pic credit: VhenanVirabelasan

https://www.instagram.com/vhenan_virabelasan?igsh=MWpmdnVzaXN5czYyZg==

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lifewithchronicpain · 5 days ago

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New questions are being raised about the effectiveness of an experimental analgesic and whether it can be a viable alternative to opioid pain medication.

Results from Vertex Pharmaceuticals’ Phase 2 clinical trial show that suzetrigine is essentially no more effective than a placebo in relieving back and hip pain caused by lumbosacral radiculopathy (LSR).

After 12 weeks of treatment with suzetrigine, patients with LSR had a 2.02 average reduction in their pain scores on a rating scale of zero to 10. That compares to an average reduction of 1.98 for patients who received a placebo or sham treatment.

Although the difference between 2.02 and 1.98 is statistically meaningless, Vertex claimed the overall findings were “statistically significant and clinically meaningful” in a press release. The company blamed the lackluster results on the placebo effect and the difficulty of treating lumbosacral radiculopathy. (Read more at link)

I would love if there was a viable option besides opioids, but the fact that they’re pushing forward with this drug despite results like this means they just want to make something they can claim relieves pain so doctors don’t have to prescribe opioids. Studies have shown anti-depressants and gabapentin are not that great either but if you have pain then your doctor is going to prescribe those first these days. As long as new pain relievers are pressured to replace opioids rather than prioritizing pain relief, then we could be setting the stage for really shitty medications forced on patients.

#disability #chronic pain #ableism #spoonies #chronic illness #opioids #pain relief #study #article

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afeelgoodblog · 2 years ago

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1. Girl with incurable cancer recovers after pioneering treatment

A girl’s incurable cancer has been cleared from her body after what scientists have described as the most sophisticated cell engineering to date. Alyssa, whose family do not wish to give their surname, was diagnosed with T-cell acute lymphoblastic leukaemia in May 2021.

Scientists at Great Ormond Street Hospital for Children in London gave her pre-manufactured cells edited using new technology to allow them to hunt down and destroy cancerous T-cells without attacking each other. Less than a month after being given the treatment, she was in remission, and was able to have a second bone marrow transplant.

Can I get a fuck cancer?

2. The UK has made gigabit internet a legal requirement for new homes

Updated regulations require new properties to be built with gigabit broadband connections and make it easier to install into existing blocks of flats across the UK. Connection costs will be capped at £2,000 per home, and developers must still install gigabit-ready infrastructure (including ducts, chambers, and termination points) and the fastest-available connection if they’re unable to secure a gigabit connection within the cost cap

3. US cancer death rate falls 33% since 1991

The rate of people dying from cancer in the United States has continuously declined over the past three decades, according to a new report from the American Cancer Society.

The US cancer death rate has fallen 33% since 1991, which corresponds to an estimated 3.8 million deaths averted, according to the report, published Thursday in CA: A Cancer Journal for Clinicians. Partly due to advances in treatment, early detection and less smoking, report says

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4. Lab-grown retinal eye cells make successful connections, open door for clinical trials to treat blindness

Retinal cells grown from stem cells can reach out and connect with neighbors, according to a new study, completing a “handshake” that may show the cells are ready for trials in humans with degenerative eye disorders.

Over a decade ago, researchers from the University of Wisconsin–Madison developed a way to grow organized clusters of cells, called organoids, that resemble the retina, the light-sensitive tissue at the back of the eye. They coaxed human skin cells reprogrammed to act as stem cells to develop into layers of several types of retinal cells that sense light and ultimately transmit what we see to the brain.

5. The ozone layer is on track to recover in the next 40 years, the United Nations says

The Earth's ozone layer is on its way to recovering, thanks to decades of work to get rid of ozone-damaging chemicals, a panel of international experts backed by the United Nations has found.

The ozone layer serves an important function for living things on Earth. This shield in the stratosphere protects humans and the environment from harmful levels of the sun's ultraviolet radiation. In the latest report on the progress of the Montreal Protocol, the U.N.-backed panel confirmed that nearly 99% of banned ozone-depleting substances have been phased out.

6. Uganda declares an end to Ebola outbreak

The Ugandan government has declared an end to its Ebola outbreak, less than four months after cases were first reported. Since 20 September, 56 people have died from the virus, which is spread through body fluids, and there have been 142 confirmed infections.

The country has reported no new infections in more than 42 days – twice the maximum incubation period of the virus, a World Health Organization benchmark for a country to be declared Ebola-free.

7. Doggy ‘daycare’ bus in Alaska goes viral on TikTok

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#best news of last week

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covid-safer-hotties · 3 months ago

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Also preserved on our archive

By Adam Piore

There’s still no cure for the debilitating condition. But some front-line clinicians are finding ways to help patients feel better.

Until Elizabeth Kenny shuffled into Dr. David M. Systrom’s clinic at Brigham and Women’s Hospital in May 2022, she’d pretty much given up hope.

Two years earlier, the 50-something actress took to her bed with COVID-19, feverish and exhausted, to wait for her body to repair itself. Instead, Kenny’s 101-degree fever lasted 70 days and left behind a series of life-altering symptoms that perplexed every doctor she’d consulted. She’d stopped sweating. Her body fluctuated between feeling hot and freezing cold. She had so much trouble digesting food that she became malnourished. She developed a stutter. Bright lights made her vision blur. The back of her head often felt like someone had whacked it with a frying pan. Her heart raced. But the worst part was the relentless, soul-crushing exhaustion.

Systrom, she recalls, “was the first person that when I was describing my symptoms, wasn’t going ‘weird,’” said Kenny, who lives in Arlington. “He was like, ‘yep.’ And then asking me questions that nobody had asked.” Systrom told her that “obviously” Kenny had long COVID. Then he introduced her to a series of unfamiliar words that she would come to know intimately in the weeks that followed: “dysautonomia,” “small fiber neuropathy,” and “mast cell disorder.” It was the beginning of a new phase in her illness. One with hope.

The US Centers for Disease Control and Prevention estimates almost 7 percent, or close to 18 million Americans, are afflicted with the mysterious condition known as long COVID, a syndrome that is so heterogenous, elusive, and difficult to treat, it took a year for some doctors to even acknowledge it was real. In the years that followed, the federal government has doled out more than $1.6 billion to study it, helping to make it one of the most researched diseases in any four years of recorded history. Yet we have little to show for it.

In July, the National Academies of Science, Engineering, and Medicine, at the behest of the Biden administration, published an official definition of the condition. Long COVID occurs after a COVID-19 infection, lasts for at least 3 months, affects one or more organ systems, and includes hundreds of possible symptoms and diagnosable conditions, scientists wrote. But there are still no approved blood tests to diagnose long COVID, no clinically validated treatments, and no cure.

The news is not all bad. Five years in, a small but growing cadre of front-line clinicians such as Systrom are beginning to unravel some of long COVID’s most vexing mysteries. In the process, they are achieving something that once seemed impossible: they are finding ways to help patients, including Kenny, get their lives back.

Doing so requires improvisation, experimentation, and a willingness to work at the edge of medical knowledge. Systrom and his colleagues discuss promising scientific papers and trade tips at conferences, on Zoom calls, and in email chains. Their growing well of anecdotal experience is pointing the way toward the groundbreaking research and clinical trials that will be needed to develop a standard of care in the years ahead as we grapple with a slow-burning public health crisis that shows no sign of abating. While the incidence of long COVID has dropped from roughly 10 percent at the peak of the pandemic to about 3.5 percent among the vaccinated, only about 25 percent of those who develop the condition recover, according to Systrom and other front-line clinicians.

In September 2021, Systrom was among the first clinicians in the nation to demonstrate a measurable change in the physiology of patients suffering from long COVID — and explain how those changes might account for the crushing fatigue that is among its most debilitating symptoms. The study helped establish long COVID as a legitimate condition and overcome the skeptics, said Dr. David Putrino, who runs a long COVID clinic at New York’s Mt. Sinai Hospital.

The study grew out of his experiences with patients: Prior to the arrival of COVID-19, Systrom, a critical care physician who runs a pulmonary clinic at Brigham and Women’s Hospital, had spent years studying chronic fatigue syndrome, also known as myalgic encephalomyelitis, an illness afflicting more than 3 million Americans. When Systrom saw his first long COVID patients — before the condition even had a name — he recognized their symptoms immediately. They were similar if not identical to those reported by patients with chronic fatigue.

To prove it, Systrom had 10 patients don masks and threaded thin, flexible tubes into their jugular veins and major arteries in the forearm to measure the concentration of oxygen absorbed into the lungs, passed into the bloodstream, and taken up by the body’s muscles as they underwent rigorous workouts on stationary bicycles.

Patients who reported symptoms of long COVID absorbed just as much oxygen into their lungs as those without it. But the amount reaching their muscles — oxygen needed to produce the energy required by the exercise — was dramatically reduced, Systrom found.

A growing body of research suggests that both long COVID and chronic fatigue are post-viral syndromes that result in chronic, low-grade inflammation that can damage healthy tissue and, in some cases, the production of auto-antibodies that can attack it.

Systrom and others have begun to catalog the scope of the microscopic carnage caused by the immune system’s friendly fire. Using skin biopsies, Systrom has identified damage to the vast microscopic network of small nerve fibers responsible for sending a wide array of sensory information to the brain. The brain uses that information to regulate involuntary physiologic processes including heart rate, blood flow, temperature, breathing, digestion, and sexual arousal. The result is a condition called “dysautonomia,” a failure of the autonomic nervous system often associated with diabetes as well as autoimmune and degenerative nerve disorders.

They have also identified reductions in mitochondria, the microscopic powerhouses that produce the chemical energy needed to perform basic cellular functions.

For many patients, these findings have been a revelation.

“He’s taken me from feeling completely lost in the woods to at least now just being on the edge of the woods,” Kenny said. “At least now I have a partial understanding of what’s happening to me.” Perhaps more important, Systrom and others have begun to find ways to blunt the condition’s most debilitating symptoms.

Most front-line treatments are still “anecdotal, based on our hunch and experience that we’ve amassed in the clinic over the past several years,” said Ziyad Al-Aly, a clinical epidemiologist at Washington University in St. Louis and leading long COVID researcher, who runs a long COVID clinic.

To tamp down the toxic low-level inflammation, Systrom often prescribes a low dosage of naltrexone, an anti-addiction drug. He and others recently launched a randomized clinical trial to demonstrate the success they have seen in the clinic. He uses Midodrine, a drug that can cause blood vessels to tighten, to increase blood pressure, which can fall dangerously low due to the problems with autonomic nerve signaling. And he offers Mestinon, approved to treat a chronic autoimmune neuromuscular disease called myasthenia gravis, to improve communication between the small nerve fibers and the brain.

Other promising off-label therapies listed by Al-Awy, Putrino, and others include emergency opioid medications that seem to attenuate brain fog, transdermal patches that deliver mitochondrial supplements, and antihistamines, which can be used to tamp down the overactivation of the immune system’s mast cells in tissues.

These treatments have not been validated by the Food and Drug Administration and the success rate varies by patient type, symptoms, and clinical practice. While Putrino and Systrom both believe the transdermal patches have helped their patients with mitochondrial dysfunction, for instance, Al-Awy has less confidence in their efficacy and is thus far less likely to prescribe them.

For Kenny, these medications make a difference. Today, she can move around her house and do things for five hours a day, instead of just two. Her brain fog has lifted enough that she can write for small windows of time. She no longer suffers from intestinal distress so severe she has to use the bathroom five times a day.

Her disease feels like a disability, not a death sentence.

“There’s this huge difference depending on which doctor you end up with,” she said. “I could have just as easily been put with a different doctor who doesn’t have Systrom’s background, who would give me that speech: ‘This is a brand new disease. We don’t know anything. This is all emerging. We still don’t know.’ I got lucky.”

#mask up #covid #pandemic #covid 19 #wear a mask #public health #coronavirus #sars cov 2 #still coviding #wear a respirator

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waytooinvested · 8 months ago

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Forgotten, Not Forgiven - Chapter 11

This and previous chapters are also on AO3

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

Clinical trial for Q-wave brain stimulator.

Trial subject 1. Session 5

First official sleep study: subject agreed to an overnight sleep study, during which two periods of Q-wave treatment are to be applied for 40 minutes each, one commencing during the deep sleep stage and a second at onset of REM sleep.

11.11pm – Deep sleep phase treatment commenced.

11.51pm: First treatment application successfully completed: blurring evidenced on Q-scan slightly extended to 0.7mm

2.07am: Following initial treatment dosage subject was allowed to complete one full sleep cycle at rest, followed by commencement of second treatment application on entering REM sleep

2.19am: Negative effects of Q-waves observed, treatment aborted.

Q-wave brain stimulator trial terminated with immediate effect.

Everything had been proceeding exactly as they had been anticipating. The deep sleep phase had been perfect, and to begin with the REM sleep treatment seemed even more promising, with the blurred patch expanding by 0.4mm within the first seven minutes. Success had seemed inevitable.

Then Lena looked over at Kara and saw the thin ribbon of blood trickling from her nose, and her heart stalled painfully in her chest before thumping back into action at twice its usual pace. She bypassed the dial completely and yanked the plug out of the wall to stop the Q-wave generator, then ran to kneel beside the bed.

‘Kara? Kara, please wake up. Are you okay?’

Kara stirred sleepily, blinking up at her in evident confusion as Lena tugged at the straps and pushed the Q-wave cap off and away with one hand while the other tenderly cradled her head.

‘What is it, did something happen?’

‘Do you feel alright?’

‘Of course, I’m totally fine. I was having the strangest dream though. I was flying, and... I think I was carrying you’.

Lena forced a laugh that might more properly have been called a sob as she remembered saying almost those exact words to Kara after she had been poisoned by Edge.

And after she had saved her life yet again...

It was a piece of real memory, and that Kara had it at all should have been incredible news, but combined with the nosebleed all it did was prove Lex had been serious about the dangers of forcing her to remember.

What if Lena had looked up five minutes later?

What if it had been too late?

Kara could have died tonight because of her.

She could have died.

‘Anyway, I don’t suppose you woke me to hear about my weird subconscious. Is everything alright?’

‘No, I’m afraid it’s not. I’m stopping the trial’.

The bed frame squeaked in protest as Kara sat up abruptly, looking properly alarmed for the first time since her rude awakening.

‘What? No! It’s been going so well, you can’t just stop!’

‘We have to Kara, you had a nose bleed’.

‘Don’t be silly, I never get-’

But the protest died as Kara reached up to touch her face, then examined the smear of red on her fingers.

‘Huh’.

‘I’m so, so sorry, I really thought this was going to be completely safe. I can’t say for sure that it was caused by the Q-waves, but I’m not willing to take that chance. If there is even the slightest possibility that this is hurting you, we are not doing it again’.

‘But it’s only a little one. Couldn’t you just… do some checks on the wave frequency or whatever before we try again? I would feel so awful if you cancel the whole project just because I had one tiny nose bleed, especially when I feel completely fine and it might not even have been caused by what we were doing. Think of all the people you were going to help’.

I was going to help you. That’s all. It was always just you, and now I can’t even do that.

‘No, I just can’t take that risk. I’m sorry Kara, but it’s over. I’ll just- I’ll find another way to continue the work. Come on, we’d better give Alex a call and get you over to the DEO so they can check you out properly’.

It looked like Kara wanted to protest further, but after taking in Lena’s expression for a few moments she apparently decided there was no point, and nodded reluctantly.

‘Alright, if you really think we need to stop, then I trust you. There’s no need to wake up Alex though, she’ll only fuss and there’s nothing wrong with me’.

‘Oh, we’re waking Alex for her sake, not yours. Otherwise she’ll be looking at a life sentence for my murder after she finds out I didn’t tell her about this so she could check you out for herself. What’s a bit of lost sleep compared to that?’

Kara rolled her eyes, a look of fond exasperation on her face that could have been for Alex or Lena or both as she picked up her phone to call her sister.

‘You two are as bad as each other, you know that?’

~~~~~~~~~~~~~~~~~~~~~~~

After Kara had been checked out, cleared, and taken back to her apartment, the core task force for Project Atlantis (as Operation-get-our-girl-back had become more formally known) gathered for an emergency meeting to discuss what had just happened. Given that Kara had been cleared medically and was now back in her own home none the wiser this probably could have waited until morning, but when Kara had called Alex, Alex called J’onn, and the others were already en route to the DEO after Nia had seen something troubling in her dream, so they had decided not to wait.

J’onn, Nia, Brainy, Alex, and Lena.

There were a few other agents who knew Supergirl’s identity and therefore part of what they were working on, plus James, who was helping to hold things down at Catco, but the five of them were the only ones who knew everything, and Lena was glad she didn’t have to admit her failure to a bigger audience.

She had already presented the progression of the trial and the hopes she had had for the sleep study, and now went on to explain how it had gone wrong shortly after starting the REM treatment stage. For a long minute everyone was quiet as they examined the scan progressions Lena had just given them, then Alex banged a fist on the table and swore.

‘It was going so well. I really thought we had the answer’.

‘The probabilities looked quite promising, I too am surprised that this happened’.

‘So what do we do now? Do we dial back the treatments? Make them shorter, or less frequent?’

Lena had nodded along in commiseration with Alex and Brainy’s comments, but at J’onn’s contribution she stopped, brows drawing into her boardroom “someone just suggested dangerous cost cutting measures at the children’s hospital” expression.

‘Of course not. This is it for the Q-wave stimulator, I’m terminating the trials effective immediately. I assumed that was implied’.

The nosebleed was proof that her premise had been flawed, and it was sheer luck that the whole thing hadn’t ended up a lot worse than it did.

Kara could have died tonight. She could have died. She could have-

‘I’m not certain that is a logical course of action Lena. My calculations show only a 6.3% chance of further injury to Kara if the sessions return to being carried out while she is conscious, and with greater spacing between-’

Now Brainy too?

‘That is 6.3% too much. I’m sorry, but this is not a debate. It’s my device and I am telling you that I will not let any of you use it on Kara again. If I have to smash it to pieces and destroy the schematic to make sure of it I will not hesitate’.

Alex raised her eyebrows, reaching out towards Lena as if she was going to put a soothing hand on her arm, though she stopped short of actually touching her.

‘Woah, hey, there’s no need for that, we’re all on the same side here. But we don’t have another plan – if we can’t use Q-waves, what are we going to do?’

‘For now, nothing, Kara’s brain needs time to heal from the trauma it’s just experienced. Maybe in a few weeks we can think about trying something new, but until then-’

‘A few weeks?’ Alex interrupted, extended hand withdrawing along with the conciliatory tone. ‘We can’t wait that long. We’re barely holding things together as it is without Supergirl.’

At another time Lena might have been sympathetic, but right now the image of blood running down Kara’s face while she lay apparently unconscious (just sleeping in fact, but the seconds when Lena had been unsure if she would ever wake up again had felt like an eternity) was hovering just behind her eyelids ready to ambush her the moment she closed her eyes, and Alex’s protestation seemed flimsy at best.

Kara could have died tonight.

Lena could have killed her.

The roil of panic she was trying not to acknowledge boiled over, and her reply lashed out like a whip.

‘National City survived for years without superheroes. Are you really telling me that you can’t last a couple more months without your little sister holding your hand?’

Alex slammed both hands down on the table, her own tenuous grip on her composure snapping under the weight of Lena’s goading.

‘DAMN it Lena, this is not about me! Do you realise that Kelly nearly died confronting Malefic? He was seconds away from forcing her to cut her own throat. Seconds. I can’t let that happen again!’

‘And I can’t let you risk hurting Kara to make sure it doesn’t!’

‘You think I want to? She’s my sister, I love her more than almost any other person on the planet, but we have to be realistic. Kara is not the only one in danger here!’

They were both standing now, eyes locked, though Lena wasn’t sure when or how that had happened. If the two of them had been alone they would have fought it out until they had vented what they needed to, then calmed back down enough to figure out a new plan together, but they were not alone. J’onn interrupted their glaring match with a stern throat-clear, looking between them like a disappointed teacher with two unruly pupils.

‘That’s enough, both of you. Will you please sit down so we can discuss this rationally?’

Lena was prepared to ignore him and continue their debate to its conclusion, but after a few more seconds of crackling tension Alex flickered her gaze to J’onn and nodded stiffly, a part of her apparently still reacting to the authority of her former boss. She dropped back into her seat looking partially (though not entirely) chastened, and after a moment Lena followed suit more slowly, schooling her own features to avoid showing any hint of similar emotion herself.

It wasn’t that she didn’t care what happened to Kelly.

She was actually the one person connected to this little group that Lena had not entirely cut contact with after she’d found out about Supergirl, and she liked her very much. It was awful to think that she had so nearly been hurt, and if there was anything Lena could do to keep it from happening again, then she would. But she was a scientist, and a researcher, and she could not in good conscience support the continuation of a trial that would put her subject at a greater level of potential harm than was warranted, especially after having assured them that they would be entirely safe.

And she would not allow Kara to be harmed. Not for anyone. Not even if it meant every other person in the city suffered for it.

‘Thank you. Lena, you may be right about continuing any form of physical intervention at this stage, but Alex is also right that we can’t wait too long to do something. So, I suggest we stop trying to break down the barrier with external force and take a different approach entirely’.

J’onn paused, looking round to check he had everyone’s undivided attention, then continued before anyone (Lena) could raise objections.

‘Sometimes Martian powers will kick in without conscious direction when presented with imminent threat to life, and I think a similar instinctive approach could work for Kara. A survival reflex could bring back her powers without having to pass through her conscious mind, allowing the memories to follow after them once the way had been opened up and avoiding the potentially dangerous weakened pathways created by the Q-wave treatment’.

‘Interesting… Like avoiding the locked door in her mind altogether and instead creating a hitherto undiscovered window. I predict that that course of action would have an 84.2% chance of success’.

There was a beat of silence while Lena waited for J’onn to add something that would make his idea sound more sane, but it appeared he was done speaking.

‘Are you actually suggesting that we should put Kara’s life in danger? That’s your safer plan?’

J’onn raised his hands, fending off the argument they both knew was still simmering just below the surface.

‘Controlled danger. Something we could set up and monitor, and bring her out of if needed. She wouldn’t be at any real risk’.

Controlled danger.

Inducing hypothermia until Kara’s muscles gave up shivering and her heart slowed and eventually stopped.

Pressing on her throat to make her fight for air, her eyes wild with terror as she tried to free herself of the constriction.

Submerging her in water and watching her thrash and struggle, breaking the surface only to be drawn back under without having managed to take a breath, water replacing air in her lungs until at last she went limp and sank out of sight, just like-

‘NO’.

Her muscles tensed, ready to jump to her feet again, but Alex broke in before she could manage more than that single, reactive syllable of negation. It was probably lucky that she did, because for all her years of social training, Lena wasn’t at all sure her own response would have been as measured as Alex’s.

‘Sorry J’onn but I’m going to have to side with Lena on this one. We need Supergirl back, but we can’t take the chance on something going wrong with that plan. Even if we made some artificial danger that we could fully control, if it was real enough for survival instincts to kick in, it would also be real enough that something could go really badly wrong. Besides, that still leaves a 15.8% chance of failure for a plan that would be seriously traumatic to Kara, and that is way too high’.

‘It doesn’t have to be real danger. If we put Kara into a simulation-’

‘That doesn’t negate the trauma of thinking she’s dying!’

Lena’s volume was creeping up again, but she managed not to actually shout.

‘Maybe not, but Supergirl is tougher than you’re giving her credit for, and we can’t afford to take a kid glove approach on this one. Kara would want us to try it if it meant reducing the risk to the rest of National City caused by her absence’.

‘Kara has no idea what’s going on, so she can’t really express an informed opinion right now, can she?’

‘Exactly. That’s why we have to make a decision based on what she would want us to do. You’ve worked with Supergirl before, when have you ever known her to choose her own safety over someone else’s?’

J’onn had a point. The Kara Lena thought she had known was someone who had needed her protection, who had stood behind her when danger threatened and let her take the lead. It had made her feel strong, protective, trusted to keep her friend safe, and that trust made her believe she really could be an immovable object between Kara and whatever threatened them, no matter how bad things got. Now she realised with a pang that Kara’s attempts to hide were in reality her trying to slip away to return as Supergirl, and whenever she had she had immediately put her own body between Lena’s and the source of danger, and Lena had let her. Of course she had. Supergirl was the girl of steel.

But right now she was just Kara, and whether she wanted them to or not, all of those old protective instincts surged at the idea of standing back and allowing her to be killed, even if it was only in a simulation.

Lena folded her arms and stared steadily back at J’onn.

‘Well then. Maybe it’s time someone made the decision for Kara that she would make for them.’

‘Maybe… but I think you’re wrong about what that would be.’

She laughed, but there was no humour in it.

‘You’re telling me that Kara wouldn’t keep the truth from someone to protect them, whether they would have chosen that for themselves or not. You’re telling me that.’

J’onn had the grace to look uncomfortable, but he still didn’t rise to the provocation.

‘This situation is different from Kara choosing not to tell you about her Kryptonian identity.’

‘Yes, it is. Because finding out the truth wouldn’t have fucking KILLED me!’

‘No one is going to let that happen!’

‘You literally just suggested that we should try that exact thing and hope that the barrier breaks in time for Kara to save herself. Tell me J’onn. Would you be saying the same thing if it was Alex’s life? If she lost part of her memory, and the fastest way to get it back also risked giving her a major stroke or a fatal brain hemorrhage, would you do it? Or would you decide that a kid glove approach might be better if we were talking about someone other than Supergirl?’

‘Lena, that’s not f-’ Alex started to protest, so Lena snapped her attention to her instead.

‘How about if it was Kelly? Right now Kara is more vulnerable than a human, so you can’t argue that we should push ahead because she’s Kryptonian and her body can take it. It can’t. Not right now. So would you risk leaving Kelly brain dead for the sake of a few weeks? Brainy, how about you? Would you think a 6.3% chance of killing Nia was acceptable? Or you Nia, if it was Brainy? I know things are difficult in the city right now, but the world is not in immediate danger, and Kara is safe like this.’

There was utter silence around the table, so thick it would have taken a machete to cut through it. Nobody quite met Lena’s eyes.

‘You’ve made your point Lena’. Alex finally said in a subdued voice, fists clenching and unclenching on the table before her.

‘You’re right. We’re used to Kara being physically a lot stronger than she is right now, and we need to take that into account with whatever plan we make. Maybe we should to go right back to the beginning and look over all the test results again – see if there’s anything we missed the first time round and-’

‘Um… Alex? Maybe I could try something else first?’

Everyone turned to Nia, who until now had been silently watching the argument pinging from Alex to Lena to J’onn and back round again like it was a game of ice hockey.

‘What are you thinking Nia?’ Alex asked.

‘Well, I’m not sure, but maybe there’s a way I could reach Supergirl through Kara’s dreams. It would be less direct than the Mind space because dreams aren’t supposed to be literal, it’s all more vague and symbolic there, so she might fight it less. Plus what Lena told us about the flying dream shows that maybe that’s where the cracks are going to appear’.

‘Oh.. yeah, you could be onto something!’

‘An excellent proposal Nia’.

‘I agree, that could be a good compromise’.

They all looked at Lena, waiting to see if she was going to object to this plan too in spite of everyone else’s support for it. And to be honest, she would have been more comfortable continuing to approach the problem with science rather than something as wishy washy and unpredictable as “magic”. But then… so would Lex. He would be much more likely to anticipate and plan for anything she could do with science than Nia’s dream powers, especially when even Nia didn’t entirely understand how they worked. It was by far the best option on the table at the moment, even if it did mean she was going to have to trust Kara’s treatment and welfare to somebody who wasn’t her.

That part was going to be a wrench after all this time feeling so sure she could crack it, but in a way it was also a relief. For the last few weeks Lena had not so much been burning the candle at both ends as throwing the candle into the centre of a blazing fire and keeping it from melting up entirely by sheer force of bloody mindedness. Between working on the Q-wave stimulator, keeping L-Corp running and spending more time than ever with Kara as part of Project Atlantis, not to mention check in meetings with the rest of the task force, it had been weeks since she had had a full night of unbroken sleep, and that was starting to take its toll. She sighed.

‘I’m in too. But if we’re going ahead I think Alex or I should be there during the sessions so we can keep an eye on Kara and bring her out immediately if she starts showing dangerous symptoms. Sorry Nia, it’s not that I don’t trust you to take care of her, but if you’re in a dream state you might not be so aware of what’s going on physically’.

‘Sure, I’d be fine with one of you two being there – it might be easier to explain as a group thing anyway’.

Around the table shoulders visibly relaxed as the tension eased, and the general mood finally began to shift to something more hopeful – optimistic even – as they started discussing how Dreamer should approach the task. Now that their course was decided Lena sat back and let the conversation go on around her, half listening but making no attempt to direct the flow, or even step into it. It wasn’t like she knew much about powers in any case, and she needed a minute to collect herself after what had just happened.

In the heat of the argument she hadn’t cared what bridges she was burning or what the fallout from that might be just as long as she was keeping Kara from being hurt, but now it was over she felt slightly... unbalanced by the experience. She wasn’t sorry that she had stood up against the suggestion that they should suffocate Kara for her own good (or whatever other ridiculously dangerous alternative J’onn would have come up with), but had to admit, if only to herself, that the way she had gone about it might not have been entirely prudent. Because she wasn’t the top-of-the-food-chain CEO here, whose word had to be obeyed by the majority of the people she came into contact with whether they liked it or not. In fact, now that they no longer needed her technology she wasn’t really anything to this group, and the idea that they might realise as much and drop her from the project made bands of panic tighten around her chest all over again.

She couldn’t walk away from this now. She was in too deep for that. She wasn’t ready to say goodbye yet.

Not to Kara, but not to the rest of them either, because somewhere along the way she had stopped thinking of these people as adversaries she was forced to partner with to achieve a shared goal, and started to think of them as… something else. People that she cared about, and whose company she would miss if it suddenly disappeared from her life.

The hours she spent with Brainy working through technical details and swapping jargon-based humour that no one around them understood.

The coffee breaks with Nia when she and Dreamer both had cause to be at the DEO Headquarters, and the conversations they had that had begun, very lightly, to touch on families and the otherness that both of them experienced in their own different ways.

The camaraderie with Alex and mutual needling that increasingly felt like their own private in-jokes, and the fact that despite all the teasing (and even sometimes fighting), she was the first person Lena wanted to call when something well wrong with Project Atlantis, because Alex cared about Kara as deeply as she did.

Even J’onn, despite a somewhat awkward beginning, was becoming a respected colleague that Lena could almost forget had also posed as her best friend while she opened up about her love life and family insecurities…

Alright, that last one still stung, but they had been making progress. She didn’t want to just throw it all away now, no matter that that was exactly what she would have to do sooner or later, when Kara got her memories back.

‘Lena?’

She blinked back into the room, chagrined to have been caught zoning out just when she most needed to justify her presence here.

‘Sorry Alex, what did you say?’

‘I just asked if you could make next Monday instead of Thursday for the next Atlantis meeting’.

‘Oh-’ She was still in then. For now at least. ‘-Yes. I might need to move a couple of things around, but I can make Monday work, definitely’.

That meant there would be a few extra days until the next meeting, and Lena resolved to spend them (or as much of them as wasn’t already taken up by L-Corp) proving that she could still be a valuable asset to the project. Somewhat regretfully she let go of the extra couple of hours sleep per night that she had promised herself following the end of the Q-wave trials, and instead allocated the time to the study of dream interpretation. Because while it was true that Lena was just about as unmagical as it was possible for a person to be, she was excellent at research, and there was bound to be something in the established body of peer-reviewed literature that would begin to explain the mechanics of Nia’s power. If she could only find it then they would be able to take a scientific approach to determining the right way for Dreamer to get through to Supergirl, and that was something Lena could do in her sleep. The bands around her chest loosened, and she took what felt like her first full breath since she had looked up to see Kara’s blood staining her pillow.

‘How long do you think before you’re ready to get started Nia?’

Is there time for me to express ship some pertinent reading material from overseas, or should I only look locally?

‘Well, there is one snag I’m going to have to work out first... It turns out that Kara doesn’t actually know that I’m Dreamer anymore. That memory must have been pretty tied up with her own identity as Supergirl, and she has just blocked the whole thing out. So. I think before I can start on any of this stuff, I’m going to have to come out to Kara’.

#supercorp #kara danvers #lena luthor #supergirl #supercorp fanfic #fyi leaving me a comment on AO3 is a surefire way to instantly become one of my favourite people #if that is something you have any interest in being!#supergirl fanfiction #kara x lena #multi chapter fic #my fic #Forgotten Not Forgiven

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wumblr · 10 months ago

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well, ask your doctor if post-exposure antibiotics may be right for you i guess. i hadn't heard of these actually, and they're still in trial phase and not yet approved for this use, but i suppose asking a doctor might marginally help expedite that if you are able. these trial results look very promising

offhandedly, you might have better luck asking an STI clinic than a general practitioner. and while you're there, get tested if you haven't recently. syphilis/chlamydia/gonorrhea in particular have been on the rise, and at least some 2 out of those 3 are likely included in any free basic panel test

while we're on the topic there are newer meningitis and HPV vaccines that were probably not available during any adult's routine vaccination and may never be administered routinely, but i've heard they're not hard to request (maybe more from a GP or a pharmacy than a clinic, but if a clinic doesn't administer them they can tell you who does)

this does also run the risk of collapsing sexual health practices down to "yeah i take prophylactics" which is, you know, not a robust discussion and not really a good reason to forego condom use. but that's been an ongoing problem for at least a decade

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lambdatherapeutic · 2 years ago

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Late phase clinical trials Companies in India | Lambda

Lambda is a one of the leaders in Late Phase Clinical Research in India, A highly qualified team of executives and specialists leads our Lambda Research and Late Phase Research efforts with years of clinical, observational, and economic research experience. we’re committed to getting the details

#Late Phase clinical trials #late phase clinical trials in india #Clinical Trial Companies In India #phase I clinical trial

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javierpena-inatacvestnotifs · 3 months ago

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Questions Game!

Thanks for the tag @greenwitchfromthewoods 🥰

Do you make your bed? Normally my husband does since he works from home every day, but on the days I do, I will! I am a neat freak so I can't rest unless the bed is made

Favorite number? 2- I was born on April 2nd, started dating my husband on August 2nd, got married on July 22nd, 2 was always the jersey number I would pick whenever I played sports, 2 has just always been my favorite number!

What's your job? I work as a clinical research associate for a company that sponsors phase 1 trials of new cancer drugs! I basically just input a lot of data to a lot of different platforms so trials can stay up and running! I used to be an elementary school teacher, which there are parts that I really miss, but I'm glad to have a job that lets me keep my sanity a lot more 😅

If you could go back to school, would you? I have a masters and no money, so no, I'm good 🫡 If I could go back to the concept of college where you went to 2 classes a day, worked a part time job and had endless amounts of free time, then yes 😂

Can you parallel park? Don't ask me to parallel park or I will have a mental breakdown

Do you think aliens are real? Absolutely???? If you don't think so then????

Can you drive a manual car? No, and again, please don't ask me to, I will sob (can u tell I am an anxious driver)

What's your guilty pleasure? Drinking pop 😩 (or soda for all you non-midwesterners) I know it's so bad for you, and I barley ever have it, but when I do? Lord have mercy, I could drink like 17. Nothing slaps harder than a McDonald's coke

Tattoos? No, I am a big baby when it comes to pain and the most indecisive person I know, I don't think I could ever commit to something permanent on my body. I love tattoos on other people, though!!!

Favorite color? Yellow and sage green!

Do you like puzzles? Yes, but if they're not like, crazy complicated??

Any phobias? I'm an ✨anxious girlie✨ I don't really have an specific phobias, but I just worry a lot about something bad happening at any given moment?? Like yesterday at the gym, I was worried my house was going to set on fire because I was running the dryer while I was gone??? (yay intrusive thoughts!!!)

Favorite childhood sport? I played every sport under the sun as a kid- soccer, basketball, baseball, hockey, golf, swimming, gymnastics, dance, snowboarding, wakeboarding- I'd like to think I'm pretty athletic and I'm also very competitive 😬 I think my favorites were always baseball and hockey! Fun Madeline lore- I was a HUGE tomboy growing up and convinced my parents to let me play in a boy's baseball league from 4th to 8th grade. I was the only girl, and was actually pretty decent, but once everyone hit puberty and could throw 70 mph fastballs, I was like "yeah, I'm out" 😂

Do you talk to yourself? A concerning amount?? I am such a non-confrontational person, that any arguments I need to get off my chest, I just have with myself

NP tags: @honeyedmiller @raspberrybesitos @morallyinept @tightjeansjavi @itsokbbygrl

#tag games!!

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reasonsforhope · 8 months ago

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"In a first-ever human clinical trial, an mRNA cancer vaccine developed at the University of Florida successfully reprogrammed patients’ immune systems to fiercely attack glioblastoma, the most aggressive and lethal brain tumor.

The results in four adult patients mirrored those in 10 pet dog patients suffering from brain tumors whose owners approved of their participation.

The discovery represents a potential new way to recruit the immune system to fight treatment-resistant cancers using an iteration of mRNA technology and lipid nanoparticles, similar to COVID-19 vaccines, but with two key differences: use of a patient’s own tumor cells to create a personalized vaccine, and a newly engineered complex delivery mechanism within the vaccine.

“Instead of us injecting single particles, we’re injecting clusters of particles that are wrapping around each other like onions,” said senior author Elias Sayour, M.D., Ph.D., a UF Health pediatric oncologist who pioneered the new vaccine, which like other immunotherapies attempts to “educate” the immune system that a tumor is foreign.

“These clusters alert the immune system in a much more profound way than single particles would.”

Among the most impressive findings was how quickly the new method spurred a vigorous immune-system response to reject the tumor, said Sayour, principal investigator at the University’s RNA Engineering Laboratory and McKnight Brain Institute investigator who led the multi-institution research team.

“In less than 48 hours, we could see these tumors shifting from what we refer to as ‘cold’—very few immune cells, very silenced immune response—to ‘hot,’ very active immune response,” he said.

“That was very surprising given how quick this happened, and what that told us is we were able to activate the early part of the immune system very rapidly against these cancers, and that’s critical to unlock the later effects of the immune response,” he explained in a video (below).

Glioblastoma is among the most devastating diagnoses, with median survival around 15 months. Current standard of care involves surgery, radiation and some combination of chemotherapy.

The new report, published May 1 in the journal Cell, is the culmination of seven years of promising studies, starting in preclinical mouse models.

In the cohort of four patients, genetic material called RNA was extracted from each patient’s own surgically removed tumor, and then messenger RNA (mRNA)—the blueprint of what is inside every cell, including tumor cells—was amplified and wrapped in the newly designed high-tech packaging of biocompatible lipid nanoparticles, to make tumor cells “look” like a dangerous virus when reinjected into the bloodstream to prompt an immune-system response.

The vaccine was personalized to each patient with a goal of getting the most out of their unique immune system...

While too early in the trial to assess the clinical effects of the vaccine, the patients either lived disease-free longer than expected or survived longer than expected. The 10 pet dogs lived a median of 4.5 months, compared with a median survival of 30-60 days typical for dogs with the condition.

The next step, with support from the Food and Drug Administration and the CureSearch for Children’s Cancer foundation, will be an expanded Phase I clinical trial to include up to 24 adult and pediatric patients to validate the findings. Once an optimal and safe dose is confirmed, an estimated 25 children would participate in Phase 2."

-via Good News Network, May 11, 2024

youtube

-video via University of Florida Health, May 1, 2024

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princesscolumbia · 6 months ago

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https://www.furinkan.com/features/articles/pregnant.html

About a week-ish ago, the above link was posted to the r/Ranma subreddit. I took a look at the article and the tl;dr seems to be as follows:

Once upon a time there was a person who put forth the question to Rumiko Takahashi on whether Ranma's transformation from boy-to-girl was complete enough that Ranma could experience all the consequences of such a transformation, the logical conclusion being, "Can Ranma get pregnant?" The rather infamous 'quote' of "I don't think about that, and neither should you," is purported to come from this question, which told the audience one thing: Don't fucking ask about Ranma's sex life or by Kami-sama, Takahashi-sensei will gut you! This stood as an uncontested truth until the pandemic when someone decided to try and track down the exact source of the quote, at which point they realized this was NOT said at a convention (as had initially been circulated via rumor at the time), but in an editorial that stood in lieu of a an interview that took place over a sit-down dinner between Takahashi and an editor who would wind up garnering a reputation for ginning up drama for its own sake. It's likely a heavily 'interpreted' quote that probably didn't have the intent to come across as cutting or biting and likely had a LOT of questions left on the table that could have been asked as a follow-up. So now that we've answered the question of whether Takahashi-san was actually a rude bitch or not (likely not), if you want to know whether Ranma can get pregnant you are a smelly sex pervert who most likely has cooties and should just drop dead and save us all the trouble of shunning you.

Am I taking liberty with my summary? FU~HUH~HUH~UCK YES! If you want to see what they actually say, follow the link and read. It's not tremendously long and, save for the author's unconscious purity cult bias, is a pretty solid piece of reportage into the infamous "quote," even if the question isn't actually answered. What follows is what I posted to Reddit in the comments section for that link:

I take issue with the foundational premise that the question of whether or not Ranma could get pregnant is inherently puerile or vulgar, which is not only the foundation of the original misquote but also the basis of the article's author's premise. Guess what, people f*ck, including at least two people you (yes, YOU) know. This should not be controversial. Now, I'll grant that, maybe...maybe in the 1990s when the question came up it might have been one of those giggle-behind-a-hand-in-shock kind of things, but we're entering a phase in world culture where uterus transplants for transwomen are being put through clinical trials to allow them to get pregnant. The rights of trans and gender-non-conforming folk are being trampled on the world over. Some transmen are choosing to become pregnant and have children. The hypocrisy of "cis het people get to talk about pregnancy without everyone assuming the question is about f*cking, but you'd better not talk about someone who's even a little bit trans or you're clearly doing it to be filthy, nasty perverts" is being exposed for the comp-het that it is. Asking "does this character who, canonically, transitions back and forth between one biological set of sex organs and secondary sex characteristics multiple times per day have to deal with all the concerns, consequences, and benefits of both forms?" is no longer the automatic, "You can't say that on TV!" that is used to be (and, honestly, never should have been). Soun, canonically, has f*cked. Nodoka, canonically, has f*cked. Genma, canonically (goddess help us all), has fucked. The operational premise of the primary conflict of the series is whether or not Ranma and Akane are going to, eventually, f*ck. The question of "What happens if Ranma gets pregnant?" should only ever be problematic if Takahashi at some point declares that Ranma is an ace transwoman and never wants to birth children, at which point it would be a thing that shouldn't be considered for hard/soft canon purposes because it would violate Ranma's choices in the matter. IMHO, in the reboot I think an episode where Ranma has to deal with attending both the boy's and the girl's sex ed classes would be tremendously funny. It would also have the knock-on effect getting people to think about things like "consent" and "consequences," something our current culture rather lacks.

This was auto-banned on Reddit because, apparently, saying the word "fuck," even with the self-censoring and used in the appropriate context, is a bridge too far for a subreddit attended by people old enough to know what sex is.

This isn't the first time I've encountered problematic behavior on the r/Ranma subreddit. When I pointed out that Ranma's basically saying that s/he just plain forgot about their gender and they only wanted the cure for Akane's sake, this is basically Ranma declaring that they don't care about their 'curse' and is genderfluid/NB, just lacking in the language that we have for those gender presentations (or non-presentation, as the case may be) that we have today, I got the clapback of, "NUH-UH! You're wrong! Ranma's a cis guy!".

(Yes, a cis guy. A cis guy who has 'his' own bras and likely has to carry around period products "just in case" and grows at least a cup-size canonically over the course of the show's run as commented on by Nabiki...and don't tell me Nabiki's not at least bi!)

This was on a conversation about whether Ranma was trans, which is a challenging question given the best word at the time for what Ranma is was 'newhalf,' a term that has come to be associated with sex workers and holds the same cultural niche as "sh*male" in American culture; it's a bit derogatory and is considered to be a slur that is used specifically in a sexual connotation. Couple this with the anime and manga being, at best, parallel continuities (there's SO many places where the two are different timelines I could probably do an entire series of posts just breaking down the differences) AND the fans stitching the two together to create fused variant timelines for their derivative works means that we just don't, at this point, have a solid answer.

Thanks to THAT episode of the anime:

Am I... Pretty? Ranma's Declaration of Womanhood (Peacock link)

...pretty much no transwoman on the planet is going to question that anime Ranma is a transgirl. The parallels to our own experiences that (femme)Ranma talks about during her dissociative state hit entirely too close to home and if a member of the writing team for that episode wasn't part of the queer community I will eat my bra with spaghetti sauce.

It's important to note, as well, that because of the anime, Takahashi is NO LONGER THE FINAL AUTHORITY ON ALL THINGS RANMA. If 'death of the author' is a thing, Takahashi committed honorable sepuku and gave creative control over to a writing and directorial team that is not her.

For the original manga, because Takahashi was unwilling to tackle those questions that give Purity Cultists hives (though why she'd shy away from the pregnancy angle when she was perfectly happy showing Ranma and her mirror clone working as prostitutes is a question I will probably never get answered), it's "open to interpretation" as to Ranma's Genderfluid/NB status, though IMHO the text is as clear as you can get it for the language of the time.

(In retrospect, it's obvious; she should be in the club)

In the anime, though, Shampoo and Ukyo are bi (and fuckin'), Ranma is a transwoman, and Akane is either lesbian or bi and strangled by comp-het to an obvious degree. Ryoga may well be trans as well, though his pig-related curse makes the matter questionable given his lamentations could be either about not having a girl body like Ranma does OR having a pig body, which would suck and result in severe dysmorphia either way.

This is because the anime team chose to tackle those questions, at least tangentially. Rumiko Takahashi, for all she is to be thanked for giving the world Ranma 1/2 (...and a few other things), handed off the baton to other creators. If we want the answers to the questions like, "Can Ranma get pregnant?", Takahashi is NOT the source for that.

That said, if she and I had the chance to sit down over a meal in San Diego during a convention, I'd apologize on behalf of the community for the monstrous tool who misquoted her and ask the questions like another content creator, not some asshat who just wants to stir up trouble for decades to come.

#ranma #saotome ranma #ranma ½ #ranma saotome #ranma 1/2 #akane tendo #ukyo kuonji #ryoga hibiki #rankane #shampoo #akane #tendo #tendo akane #THAT question #reddit #source: reddit

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lookofhisoceaneyes · 5 months ago

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Fics that I read the last weeks, that are Per-fect!

Some fics that I have read recently and that I liked and can recommend.

Marvel Fandom

1. A Year in the Life of Sarge's Person by BlueSimplicity

A Year in the Life of Sarge's Person - Chapter 1 - BlueSimplicity - Captain America (Movies) [Archive of Our Own]

This is the tale of a year in the life of Sarge’s person, AKA James Buchanan Barnes, as he tries to recover from everything that’s happened to him over the past eighty years. During that time, he is forced to deal with bad therapists, people with their own agendas, memories he doesn’t want, horrible losses from his past and almost insurmountable odds.

But this is also the story of all the crazy people Bucky meets along the way, who help him when he’s at his lowest, point him in the right direction when he feels lost, make him laugh, grow to love him for who he is, and most importantly, give him hope when he needs it most.

It’s a long and difficult journey, as Bucky works not just to let go of his past, but to also rebuild his own identity and a future for himself. And with Sarge at his side, Bucky slowly comes to realize that not everything he once loved is lost, and if he can just have enough faith in himself and those around him, he might, just might, get his very own happy ending.

Bucky IS Sarge’s person after all. As the once abandoned puppy Bucky saved one night from freezing to death, he knows, more than anyone, just how much Bucky deserves it.

—

Main Ship: Steve Rogers/James “Bucky” Barnes

Oh my, I loved this so so much!

I love fics that involve dogs (or animals). Bucky has a horrible therapist at the beginning, but not later on. His character development is so beautifully written, from the mechanical Winter Soldier to Bucky Barnes. The supporting characters are also great and not existing characters from the Marvel Universe but original characters from the author. Loved it!

2. The Trials and Tribulations of the Watermelon Werewolf by BlueSimplicity

The Trials and Tribulations of the Watermelon Werewolf - Chapter 1 - BlueSimplicity - Captain America (Movies) [Archive of Our Own]

It’s not easy being a werewolf, but Steve Rogers knows he’s lucky. Lehigh's doing well under his care, the humans and werewolves thriving. He doesn't have a mate, but a bonding like that is rare, and with all the members of his Pack already mated, he knows it’s not going to happen for him.

Until the day it does, the realization literally knocking him on his ass.

That’s fine; he can deal. He’s an alpha after all, and while there are rules to courting when one’s mate is human, he knows he can prove his worth. Except no one told him how hard it would be. And Steve is really bad at this. Really, REALLY bad.

After a couple of rough years, Bucky Barnes is back on his feet and ready to start a new phase of his life. He’s been given a second chance and while Lehigh might not be as big as NYC, he loves his apartment, chonk of a cat, new job and crazy neighbors.

Except things have started to get weird. Maybe it’s because of all the werewolves in town, although he’s never had a problem before. Yet he can’t help but notice things have changed, with people staring at him wherever he goes, asking him strange questions, and stealing his lunch.

And it all started when a watermelon was left on his doorstep.

—

Main Ship: Steve Rogers/James “Bucky” Barnes

I liked the worldbuilding so much! Rarely read such a cool werewolf fic. Steve doesn't appear in the first few chapters because we get to know Bucky first. I loved it so much, I read it so quickly. Definitely worth reading!

3. Empire by Isnt_it_pretty_to_think_so

Empire - Chapter 1 - Isnt_it_pretty_to_think_so - Multifandom [Archive of Our Own]

Natasha and Steve go to couple’s therapy. There are a few complications. Their counseling clinic is a front for a Hydra cell that’s seized northern Manhattan. More importantly, they’re definitely not dating.

Also, Steve may or may not be in love with Natasha.

OR:

“I resent being compared to Peggy Carter,” Nat tells their therapist. “Yes, Steve— I assassinated a few people and committed every war crime in the book. That doesn’t make me a bad person.”

Steve knows this is all scripted, but he finds himself getting angry for no logical reason.

“I don’t think you’re a bad person.” His voice rises. “If I did, I wouldn’t be dating you. This isn’t about Peggy."

“It’s always about Peggy.” Nat flips her gaze to the therapist. “He says her name in bed sometimes."

Steve’s hands clench into fists. She’s going off script, damn it, and now he has to go off script, too.

“Nat cheated on me with Tony and Thor,” he improvises. “That’s what she was doing while I was checking my pal Bucky into a rehabilitation clinic. She's emotionally distant.”

“Once again, Mr. Rogers.” The therapist sounds tired. “Let's try our best to keep this constructive.”

—

Main Ship: Steve Rogers/Natasha Romanov

I don't read Steve/Natasha that often, but this was such a great fanfic! I love therapy fics and I thought this was so great! Definitely read it, I highly recommend it.

JjK Fandom

4. No Surprises, Please by vroomvroommic

No Surprises, Please - vroomvroommic - 呪術廻戦 | Jujutsu Kaisen (Manga) [Archive of Our Own]

omotesando queen @ nobanova

why did u give me a fucking b on the midterm. @ nanaminluver69

494 Likes

ily nanamin <3 @ nanaminluver69

Please refer to my rubric for grading guidelines. All further grade disputes will be reviewed upon my return to Tokyo. Best, Gojo Satoru.

omotesando queen @ nobanova

@ nanaminluver69 I will fucking end u

54 Likes

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Main Ship: Haibara Yu/Nanami Kento, other Side Ships

I love, love well written Twitter fics. They are a weakness of mine. I enjoyed them very much and also liked the normal text in between.

Percy Jackson Fandom

5. a rose by any other name by IzzyMRDB

a rose by any other name - IzzyMRDB - Multifandom [Archive of Our Own]

It wasn't Poseidon who met Sally on that beach on Montauk, but rather a far older, much more ancient version of him.

Percy is born far older and younger than he should be.

Percy Jackson & Poseidon

I love darker Percy Jackson and this was so well written. Give it a shot!

Hannibal Fandom

6. shadowing by StratsWrites, YouAreMyDesign

shadowing - StratsWrites, YouAreMyDesign - Hannibal (TV) [Archive of Our Own]

“I’m very strict with my interns,” the doctor says slowly, his eyes on Will’s, never drifting. “In fact, I had asked them not to assign me any more. Unfortunately, I was the only surgeon available to take on extra duties. My expectations for you and your behavior will be high. I have fired interns before, and while I didn’t relish the experience, I won’t hesitate to do so again.”

Main Ship: Will Graham/Hannibal Lecter

I'm having trouble finding Hannigram fics, because the characters are misrepresented or simply because the show has already done such a good portrait of the two. I liked the fanfic. At the end Will is in Heat, so check out the tags. But I liked it for in between.

#hannigram #ao3 fanfic #fanfic #marvel #natasha romanoff #steve rogers #bucky/steve #bucky barnes #percy jackson

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