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Kumo desu ga, nani ka? So I'm a Spider, So What?

2018.06.18 12:31 BalefireX Kumo desu ga, nani ka? So I'm a Spider, So What?

Welcome to /KumoDesu, the subreddit for So I'm a Spider, So What?, the hit isekai series about a girl reincarnated as the weakest spider, just trying to survive!

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Everything related to Razorback sports: football, basketball, baseball, track, softball, gymnastics, and so on and so forth.

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2023.06.09 04:29 Bubzoluck [30 min read] The Opioid Epidemic before the Opioid Epidemic - Exploring Morphine Derivatives and the First Opium War (Part 1)

[30 min read] The Opioid Epidemic before the Opioid Epidemic - Exploring Morphine Derivatives and the First Opium War (Part 1)
Hello and welcome back to SAR! I have written and rewritten this post a few times now and I think I have landed on a format I am happy with. When we talk about the impact of medicine on history its important to get the context right, and I think I have found a way to talk about our topic. So what is it? No chemical is more important to the world of medicine than Opium, okay maybe Penicillin, but today we will say its Opium. Principally an analgesic (anti-pain), the Opium Poppy allowed for humans to take away pain in great degrees and further development on the natural chemicals has opened up surgery and post-op recovery. While we tend to look at the recent Opioid Epidemic as the only issue regarding Opiates, history reveals to us a very similar precursor. Also please head over to u/jtjdp post about morphine derivatives here! She does an amazing job explaining the higher level concepts of medicinal chemistry that I just wouldn’t do justice. Alright, enough quibbling, let’s get to the good stuff.
Disclaimer: this post is not designed to be medical advice. It is merely a look at the chemistry of medications and their general effect on the body. Each person responds differently to therapy. Please talk to your doctor about starting, stopping, or changing medical treatment.

How Much do you Know About Pain?

To be alive is to feel pain, and emo sentiments aside, this is one of the biggest biological properties of the central nervous system. When you think about it, how does the body take external stimuli and allow you to recognize it? The answer is the sensory nervous system which is responsible for sensing many different types of stimuli: temperature, pressure, pain, and chemicals. These sensory neurons carry the information from the extremities and transmit it up the spinal cord into the brain for processing. From there the brain alerts you to the issue allowing you to correct whatever problem is causing the pain. Let’s take a look:
  • We call these receptors Nociceptors and activation of these neurons in the periphery leads to a signal being sent towards the spinal cord. Those peripheral nerves eventually complex with the Dorsal Horn of the spinal cord and interface with the central nervous system to transfer the pain signal. This signal is then sent Ascending to the Thalamus where the pain signal is recognized and initiates a response (such as pulling your hand away from the hot stove). But that’s not the full story, the brain also sends signals back down Descending to modify the incoming signal and dampen it. Its this modifying that makes pain fade over time when you aren’t focusing on it—otherwise the brain would be overwhelmed by the repetitive signal and continuously think injury is still happening. Now let’s divide this process into its two parts, first up the Ascending pathway.
  • As the Action Potential travels from the periphery towards the Spine it causes the influx of Calcium into the Presynaptic Neuron. This neuron is what carries the original signal to then transfer into the Spine for further traveling. Eventually we reach the Synapse where the finger-nerve and spine meet and we get the transfer of information via Neurotransmitters. In this case, two chemicals are released: Glutamate and Substance P (which literally stands for Substance Pain). Glutamate will activate two receptors (AMPA and NMDA) which are Excitatory and stimulate the continuation of the pain signal up to the brain. Substance P activates the NK1 receptor which enhances the frequency of the pain signal (the throbbing) and the intensity of the pain burst. So to simplify, Glutamate allows the signal to be passed up to the brain but depending on the strength of the original pain signal more or less Substance P is released which modulates the strength and attention-grabbing nature of it. Okay great, we sent the pain pathway up and it will get processed in multiple different parts of the brain. But the brain can’t have that signal stinging it so it must send information back down to dampen that pain signal. This is where that aforementioned Descending pathway comes in. Above you can see how the blue line reaches down out of the brain and back into the spine to turn ‘off’ the signal. This is the basis of Analgesia or pain relief.
  • Okay so now we have to divide the action of the Descending pathway which acts to dampen and modulate the original signal coming into the brain. Now, normally at rest this Descending neuron is inhibited so any fresh incoming signal is not inhibited from the get go but once that pain signal does come in, we get the good stuff! In response to pain the brain releases substances called Endorphins which activate the mu Opioid Receptor (MOR) located on the Descending pathway. Now MOR are inhibitory in nature so they are inhibiting the inhibitory resting state of neurons, or in other words, are allowing the Descending neuron to activate. And this is an important fact to recognize, Opiates do not inhibit pain, they inhibit the physiology of the nervous system that prevents modulation of the pain signal.
    • Once the inhibition is inhibited, the Descending neuron is free to release two neurotransmitters onto the nerve that was carrying the original pain signal. Both Norepinephrine and Serotonin are released to activate their respective receptors which inhibit the release of Substance P and Glutamate thus decreasing the incoming pain signal. Likewise MOR receptors are found directly on the incoming nerve and further prevent the release of Glutamate and Substance P as well as being found on the Ascending neuron preventing the activation of the NMDA/AMPA and NK1 receptors. The result: dampened incoming signal and decreased pain sense being sent to the brain.

The Stars Align in the Shape of a Poppy
To start our story about Opiates we need to turn to the great precursor—Opium. Opium itself is not a chemical but rather a really thick liquor (called latex) that contains a high concentration of Morphine (and some Codeine). There are 38 species of Poppy plants but only two produce Opium is great enough supply that it is worth farming them and humans have been cultivating these varieties for as long as we have known about the plants. When humans settled into Mesopotamia (near modern day Iraq), Poppies were one of the few plants grown in plots as large grain or vegetable fields (meaning that they were thought of as valuable as food). Throughout the Greek age of medicine (pre-500 BCE) through the Islamic medicinal revolution (500 BC-1500 AD), Opium was a major component of treatment, assisted suicide, and poison. In fact its through the rise of the Muslim Caliphates that we see the export of Opium to other parts of the world, especially through the Mediterranean Sea once the Crusaders return. Opium trading to the East via the silk roads was an almost continuous affair since time immemorial and Pakistan was a major growing area for the Eastern Poppy trade.
  • By the time after the Crusades (11-13th centuries), we start to see the West’s fixation on Opium. For many reasons Europe didn’t develop many psychoactive plants to the same degree as more humid/hot climates like Africa, the Middle East, and India. This is why the importation of Opium (and also Marijuana) was such a trade commodity and staple in the development of Western medicine. During the Renaissance and the revival of Greek philosophy we start to see the re-fascination with Opium and by the 1600s we see merchants importing Laudanum into Europe for recreational and medicinal use. The standard use of Tincture of Opium (which is Opium dissolved in ethanol, a DEADLY combination) was a particularly favorite preparation which was prescribed to the lowest day-worker all the way up to kings.
    • The importation and use of Opium exploded in the late 1700s once the British conquered a major Poppy growing region of India. This region (western India and most of Pakistan) was originally slated to grow cotton like the American colonies but the region wasn’t wet enough to sustain the plant—it could however grow copious fields of Poppy plants to create Opium. Throughout the 18th century the British Raj became the largest exporter of Opium to Europe and after the discovery that Mercury and Arsenic may not be safe, Opium took over their duties. By 1780 almost all major remedies incorporated the use of Opium in some capacity and with the huge supply, it was incredibly cheap.
  • Poppy wasn’t only important to the British for its medicinal properties but also to bolster the huge amount of loss they were incurring in global trade to one trade partner—China. After she made contact with China in the mid-1500s, Britain starting to import HUGE amounts of tea as the Brits became literally addicted to the substance. By 1800 a full 15% of the ENTIRE British Empire’s revenue was being spent on importing tea, that’s 30 million pounds per YEAR, leading to a massive trade deficit. This means that more money was being sent to China literally enriching a foreign country while the British public was getting their fix on the black stuff. Oh and just in case you think things haven’t changed, Britain still accounts for 42.6% of the world’s tea consumption—seriously Brits, ever heard of coffee? Anyways, all this money leaving the British economy to be spent on non-Empire sustaining commodities was a major national security risk for the British. It would be different if they were importing gunpowder like the Dutch were or Silver as the Spanish had but literally they were consuming the riches they were spending the money on.
    • Remember too that the British were not in the best position by the turn of the 19th century—they had just lost their colonies in the Americas, involvement in the Napoleonic Wars killed a generation of men, and the push to develop industries over public health led to a focus on fast growth rather than smart growth. One of the results of the Napoleonic Wars was the British occupation of the Island of Java which developed a very potent Opium which was traded with Chinese merchants regularly. Soon British merchants realized they could rebalance the trade deficit by selling Javanese Opium into China but the small island was unable to produce enough Poppies to meet the demand. So Britain turned to another one of its colonies, India.
  • India by the end of the 1700s was a bit of a challenge. The British hold on the subcontinent was firm but they couldn’t grow the cash crops they wanted. Indian cotton was nothing compared to Egyptian or Southern American (i.e. Virginia/North Carolina/Georgia) cotton and the Indian tobacco was known for being bitter. But by the 1770s the British government realized that Poppy was an easy crop to grow and the demand across the border with China was an easy market; British traders brought their cargo to small islands off the coast of China where it was sold for silver. Initially the Chinese didn’t mind the sale of Opium in their territory—when the British traders collected the silver from the sale they would almost immediately use it to buy Chinese goods, thus driving tax revenue for the Chinese government.
  • But if you buy Opium, people are going to use that Opium. By the 1810s all trade with foreigners was restricted to just one port, Canton, and slowly the city started to develop a habit for the drug. The use of mind altering substances was curtailed pretty quickly for hundreds of years in China—the Ming Dynasty banned tobacco in 1640 and the Qing banned Madak (a powdered Opium containing tobacco) was similarly banned in 1729. But by 1790 more and more Chinese citizens were becoming addicted to the substance; what started as a recreational drug slowly became a crippling addiction that took hold over Canton. For a rigid society, the crippling Opiate addiction was a moral corruption for the Qing government and forced them to curtail Opium importation in 1780 and then an outright ban in 1796.
  • Knowing just how devastating the Opium was having on the inhabitants of Canton, as well as how it spread further inland, British merchants kept peddling their drug. Older ships with larger hulls were converted into floating warehouses and parked just outside of navigable waters. Once set up, Opium smugglers would pull up, purchase the Opium and avoid any oversight by the Chinese government to prevent the sale of the drug. Following their mother country, American merchants started to sell Turkish Opium, an inferior variety, at a much cheaper rate leading to drug peddling competition with more and more tons of Opium being sent into China. This drove down the price of Opium considerably which ultimately increased the demand.
    • This demand eventually led to reversal of trade, meaning that more silver was leaving China to pay for Opium than the British were using to pay for Chinese goods. American and European traders could show up in Canton with holds full of Opium, sell it off for a profit, and then make a tidy silver profit to bring back to Europe. Likewise the importation of cheap machine-made cotton, furs, clocks, and steel into China driving down domestic profits.

Let’s Look at the Drugs a Bit
Stepping away from the history a bit, let’s introduce the Family. Okay so we understand how pain is sent to the brain and how it modulates but there is so much more to the mu Opioid Receptor and that’s not the only kind of Opioid receptor that we have. The two most clinically useful receptors are the Mu and Kappa Opioid Receptors (KOR) because they result in analgesia but there is a Delta Opioid Receptor (DOR) that is worth mentioning. The majority of the Opiates that we know and love are Mu agonists but there are some very interesting Kappa agonists that are worth mentioning as well.
  • Above is a chart that shows the binding affinities of select Opiates to the Mu receptor. The smaller the number is, the more tightly they bond. Now affinity is different than potency—potency is a measure of how much drug (in g) is required to produce the same effect. So even though morphine has a higher affinity than fentanyl, fentanyl has a MUCH more potent effect (which is why it can be so dangerous, you only need a little). Now many of the opiates cause the same effect so I want to spend more time on what makes them all so different:
  • First up we have the 5-Ring Morphinians which are derived from the natural product Morphine. These structures have 5 component parts: an aromatic benzene ring (A), a completely saturated bridge ring (B), a partially unsaturated ring with an alcohol attachment (C), a piperidine heterocycle above the rest of the structure (D) and finally a ether linkage between the top and bottom of the structure to keep it fairly rigid (E). Truthfully we are only going to focus on two locations—firstly the top alcohol (red circle) can be methylated to form Codeine, a natural Prodrug of Morphine. A Prodrug is one that is biologically inactive but goes through an initial metabolism once ingested that makes it active.
  • In fact it’s this initial metabolism of Codeine that makes it very interesting. In order for Codeine to exert any pain relief it needs to be converted to Morphine which actually exerts the desirable properties. This is done by the liver enzyme CYP2D6 which is a pretty minor pathway for Codeine—only about 10% of the Codeine is actually converted to Morphine to have some action. Because of this 2D6 dependent pathway we have to be careful about administering drugs that might inhibit the 2D6 pathway because that would mean we are preventing codeine from being active. Drugs like Fluoxetine (Prozac) and Paroxetine (Paxil) are strong 2D6 inhibitors and so if we administered Codeine to someone taking this drug they’d never get any benefit from the Codeine. In addition there are genetic/ethnic differences that pharmacists can account for such as 2D6 activity. If you are someone with very little 2D6 activity then you would also not convert Codeine to Morphine and thus get no action from the drug—this may be a reason why some people say Codeine doesn’t work for them. Another reason could be that they are Rapid Metabolizers and quickly convert the Codeine to Morphine and thus get a massive hit quickly after ingestion—in that cause you’d need a much smaller dose than another person for the same effect.
  • A different drug that is the opposite of Codeine is Hydromorphone (Dilaudid) which has a Ketone on ring C. This ketone and the lack of the double bond on this ring increases the lipophilicity of the drug and increases its ability to penetrate into the brain and thus have a greater effect. In fact Hydromorphone is 5-10x more potent than Morphine due to its greater ability to penetrate into the brain and increased receptor affinity for the mu receptor. Because the A ring OH is not capped with a methyl group, we don’t need to rely on 2D6 to metabolize Hydromorphone into an active drug form which again increases the activity of this drug compared to Codeine.
  • So combine these two structural changes—the capped OH on ring A as seen in Codeine and the increased affinity found with the ketone in Hydromorphone and we get Hydrocodone (Norco, Lorcet). Well in this case you’d get a drug that has very good affinity for the mu receptor (better than codeine) BUT is still reliant on the small 2D6 pathway for activation (worse than morphine). In this regard only about 10% of Hydrocodone is active at a time. We can see this effect in the relative doses for equivalent effect: to match the effect of 30mg of Morphine, we’d need only 7.5mg of Hydromorphone (more active) but need 200mg of Codeine (less active).
  • This brings us to our last drug of this class, Oxycodone which has a special OH group found on Ring B. What you’ll notice is that Oxycodone has that capped OH on ring A so it requires metabolism through 2D6 just like Codeine and Hydrocodone. When it is uncapped it becomes Oxymorphone which has 3 times as much effect as Morphine BUT that extra OH makes Oxycodone an exclusive Mu receptor agonist. Unlike the other drugs which may go to other receptors causing side effects (more on this later).
  • Next up I want to look at some Mu opioid receptor Antagonists or those than inhibit the function of the opioid receptor. Looking at the first two drugs, Naloxone and Naltrexone, we can see that they have the structure similar to Hydromorphone so they would have incredible brain penetration and affinity for opioid receptors BUT they contain that funky Nitrogen tail. Now normally there is a short methyl tail that is required for the function of Morphine but by adding a bulkier tail the drug is able to fit inside the receptor but prevent activation. What’s most important about these two drugs is that they have much more affinity for the receptor than other opiates. We can see this effect in the graph above: when no Naloxone is present, Fentanyl occupies the opiate receptor about 75% of the time. But as soon as Naloxone is administered that number drops swiftly (within minutes)--this is because Naloxone has a higher affinity for sitting in the receptor than Fentanyl. Think of it like the bully Naloxone coming up and pushing the poor defenseless Fentanyl off the swings so the bully can play on it (except in this instance Fentanyl is causing an overdose and we need to save someone’s life).
  • Buprenorphine is similar but it is a Partial Agonist instead of being a full antagonist. Buprenorphine is not a 5-ring Morphinian byt a 6-ring Oripavine that has a few different modifications. The biggest additions is that it has the bulky Nitrogen tail found in full Antagonists but it has this funky C ring tail which fights the antagonism. The result is a tug of war between the antagonism of the Nitrogen tail and the agonism of this new C-ring tail resulting in Partial agonism—so if you took Buprenorphine you’d notice a markedly decreased pain relieving ability but importantly there is a ceiling effect, its much harder to overdose on Buprenorphine than other full agonists. In addition in the second graph we can see that Buprenorphine has the greatest affinity for the receptor than our other agonists which prevents someone from taking a more potent opiate while taking Buprenorphine. In this case the bully is already sitting on the swing and scaring away the other kids thus preventing them from having a turn (and potentially causing an overdose). This does mean that if someone was taking a more potent drug (like Fentanyl) and then took Buprenorphine, it would cause withdrawal just like Naloxone or Naltrexone.
  • Speaking of withdrawal, let’s take a look at how that happens. Remember that the pain signal is caused by the activation of AMPA and NMDA receptors from the peripheral nerve. AMPA is a type of receptor called a G-Protein Coupled Receptor or GPCR which in this case is linked to an Excitatory G-protein which leads to the activation of the nerve. When AMPA is activated, the G-protein (Ga) activates an enzyme called Adenylate Cyclase (AC) which increases the production of pro-activity cAMP—or in simpler terms—when AMPA is activated, it leads to an increase in levels of pro-pain molecule cAMP. The Opioid receptor is also a GPCR but it is linked to an inhibitory G-protein which prevents the action of Adenylate Cyclase and thus leads to a decrease in cAMP levels. So Opiates prevent pro-pain cAMP signaling from continuing.
    • In the second graph we can see how tolerance forms. Initially (A), Adenylate Cyclase and cAMP levels are not affected by having opiates even though their ability to push along the pain signal is blocked. After a few hours, the leftover cAMP is degraded and cAMP levels start to drop significantly (B). In response to these levels going down, the activity of Adenylate Cyclase starts to increase and increase (C) which raises the level of cAMP. This rise in Adenylate Cyclase activity opposes the action of the opiate which necessitates the need for increased doses of Opiates and is why tolerance forms. As sustained inhibition of Adenylate Cyclase continues, the body upregulates Adenylate Cyclase activity to create more cAMP and to combat this we increase the dose.
    • Now what if after years of taking an Opiate we suddenly administer Naloxone, an Opiate antagonist. Well after weeks to months of taking an Opiate, the level of Adenylate Cyclase activity is WAY above baseline. When you administer the antagonist, suddenly Adenylate Cyclase is able to produce a TON of cAMP that normally is blocked which leads to a MASSIVE amount of downstream signaling. The result is intense nausea and vomiting, stomach cramps, fever, anxiety, insomnia, and cravings. Thankfully the withdrawal process ends after about 72 hours but is one of the worst experiences someone can go through which is why proper down-tapering of Opiates is extremely important.

A Change in Trade Policy
Oh, you’re still here. Neat! So by the 1820s the Qing dynasty was running into many problems regarding Opium. Firstly they needed the Opium taxes to fund their efforts to put down the White Lotus Rebellion and retain power. But after almost 30 years of trade the effects on Chinese communities could not be ignored along with local officials operating under the imperial trade department, the Hong, profiting from bribes to allow Opium. Regardless of initial efforts things were getting out of hand for the Qing government. In 1800, about 4000 chests of Opium or 560,000 pounds entered the country but by 1830 that number exploded to 20,000 chests or about 3 million pounds. But more than the amount of Opium actually entering the country was the incessant rudeness of the British government to open trade.
  • One of the “problems” for the British traders was how clamped down trade was with China. By 1800 all trade was limited to just Canton and the Hong was a strict master of trade. Foreigners were not allowed to appeal decisions made by the Hong and only Chinese traders could sell goods further inland than Canton. Traders chafed against this extreme oversight and sent hundreds of letters to the Hong requesting special dispensations which were summarily denied. Things changed significantly in 1834 when the Chinese trade was de-monopolized away from the East India Company allowing any private trader to get involved in the Eastern trade.
  • In August of 1834, the British sent Lord William John Napier to Macau as superintendent of Chinese trade with the explicit order to follow all Chinese regulations. Thinking he knows best, Napier decided that the restrictive Chinese trade system was too restrictive and sent a letter to the Viceroy of Canton. This was unheard of—NO foreign traders were allowed to speak directly with Chinese officials and the Viceroy refused to accept it. So why not double down by ordering two British ships to BOMBARD two Pearl River forts as a show of force? Luckily Napier died of Typhus almost directly after else it would have resulted in a full blown war.
  • In 1839 the Qing government appointed Lin Zexu as the Opium czar to completely eradicate the Opium trade from China. Lin banned the sale of Opium in China completely, set up rehabilitation centers for those affected by the drug, and put addicts to work to distract them while detoxing. Lin demanded that all Opium supplies must be surrendered to Qing authorities and any Chinese citizen disobeying the order would be punishable by death. He even went as far as closing the Pearl River Channel, trapping British traders in Canton and seizing their Opium warehouse stockpiles.
  • The replacement for Napier was Admiral Sir Charles Elliot who protested the seizure of the Opium stockpile but knew that they could do nothing. He ordered all Opium ships to flee and prepare for battle which caused Lin Zexu to beseige a group of traders inside a Canton warehouse. Elliot convinced the traders to cooperate with the Chinese government and surrender their stock, saying that the British government would compensate for the lost Opium (which he had no authority to do). During April and May 1839 the British (and American) traders to surrender 20,000 chests of Opium which was burned for three days outside Canton. Following the burning, trade resumed to normal except no more Opium was allowed. Like many other instances of the government removing legitimate sale of a drug, the black market increased markedly.
  • In July 1839 a new scandal rocked the British-Chinese trade system; two British sailors became drunk and beat a man death outside of his village. In response, Superintendent Elliot arrested the two men and paid compensation to the villager’s family for the loss of the man but Elliot refused to hand over the sailors to the Qing government. Lin Zexu saw this as a blatant disregard for Chinese law—afterall traders needed to understand that they can’t just come to China and violate Chinese law as they saw fit. Elliot offered to hold a trial on a British ship in front of Chinese officials to show that the men would not get off free. This incident would start the smoldering.
    • On September 4th, Elliot sent two ships to Kowloon to buy food and provisions from Chinese peasants. While approaching the harbor, three Chinese war junks gave permission to the two British ships to trade but that permission was rescinded by the commander of Kowloon fort. Elliot fumed against the slight and said that if the British were not allowed to trade by 3pm, he would fire on the fort. 3pm passed and the British opened fire on the fort causing the Chinese junks to return fire. The fighting continued for 7 hours until nightfall and Elliot had to prevent the British officers from pressing the attack, thus ending the Battle of Kowloon. Having driven off the Chinese ships, the British purchased the supplies they needed while the Kowloon commander claimed that both ships were sunk and 50 British sailors killed.
    • The reaction in Britain was about as much as you expect. Prime Minister Palmerston sent out letters to the Governor General of India to prepare marines to invade China and another letter to the Chinese Emperor telling him that Britain would send a military force. He sent a letter to Superintendent Elliot to set up a blockade on the Pearl River and capture Chusan Island. He also instructed Elliot to accomplish the following objectives:
      • Demand the respect as a British envoy from the Qing Government.
      • Secure the right for British law to be doled out on British subjects
      • Get recompense for destroyed British property, especially the illegal drugs that they destroyed
      • And most important, End the Canton System thus opening up China to free trade for the first time, ever.
Alright this is where we will leave things off for now, on the brink of war with China. Stay tuned!
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2023.06.09 04:27 rrmdp 📢 AdventHealth Redmond is hiring a Certified First Assist Full-Time!

Company: AdventHealth Redmond
Location: Rome, GA, United States 📍
Date Posted: June 08, 2023 📅
Apply & Description 👉
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2023.06.09 04:27 rrmdp 📢 AdventHealth Redmond is hiring a CT/X-Ray Technologist - Full-Time!

Company: AdventHealth Redmond
Location: Rome, GA, United States 📍
Date Posted: June 08, 2023 📅
Apply & Description 👉
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2023.06.09 04:27 teaforsnail Never backpacked before, any advice welcome!

24F, this is my first time doing extensive travel so I'm thinking I'll try to stick to 4 days in each place? In order, I'm thinking I'll go to Barcelona, Nice, Milan, Prague, then Munich. Alternatively, Amsterdam, Berlin, Warsaw, Kyiv, Bucharest, and Athens. Though the first one sounds much easier for a beginner.
I'll be sticking to hostels, and I'm not too social so nights out aren't a big deal to me. I've seen people mention 40L packs vs rolling a suitcase about, so that's on the checklist too.
If any of you have done a similar trip, about how much did it cost you total? I'm not even sure where to begin on the budget for it.
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2023.06.09 04:26 jkirn05 Please help flash bios

Hey fam, needing help!!! I am upgrading CPU, GPU, and hard drive.
AX370-k3 gaming
Going to website, downloaded newest bios, extracted to new thumb drive, rebooted, presses “end” tried to choose it and got error “invalid bios image” tried the 2 newest others and same problem.
Going from 1700x to 5700x CPU. Any advice or workaround would be AMAZING!!!
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2023.06.09 04:26 LizaBrownAuthor11 They're famous

They're famous
I play Stop 2. The letter was R and for Famous Duos I tried our favorite YouTube couple. It worked.
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2023.06.09 04:24 Rainnetic Is this good Crit Rate and Crit DMG?

Is this good Crit Rate and Crit DMG? submitted by Rainnetic to Ganyu [link] [comments]

2023.06.09 04:23 rheise311 Looking for suggestions on cycling destinations / routes on my (USA) summer road trip

I will have about a week on my own to leisurely make my way from Savannah, GA back home to Maine, and will have my road bike with me. I will likely take a route along the lines of:
Day 1: Savannah, GA to Charlotte, NC Day 2: Charlotte, NC to Norfolk, VA Day 3: Norfolk, VA to Yardley, PA Day 4: Yardley, PA to Hartford, CT Day 5: Hartford, CT to Portland, ME
I was thinking I'd try to get in rides in the Savannah area on Day 1 before I leave, and then something in the Winston-Salem and/or Raleigh-Durham area on Day 2, and along the Delaware coast (Dewey Beach area?) Day 3. I have ridden around Yardley before and like the area. I have not ridden in the Hartford / neighboring suburbs much, but have driven lots of it.
My question is, if I'm going along this route (ish) are there any must-ride areas for scenic / iconic / enjoyable rides? Please let me know any / all thoughts!
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2023.06.09 04:15 Aggressive0909 Que tipo de cara vc acha que mete na laurinha?

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2023.06.09 04:14 Good_Hovercraft5040 globe or converge?

diin mas nami sila duwa ang pldt dw every 2 months ga guba daw wala na pulos...
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2023.06.09 04:14 187gvrrick help: 22y/o Want to join HBAC union GA

This is gonna be all over the place, i hope this is the place to post. I want to know if a union is right for me , currently i’m a server i don’t have any parental help and have been on my own since 16. I rent right now but plan to put down on a home a year from now, so i to be able to support that and im stressing about what to do. i love hands on work and i’ve been told repeatedly that HVAC is the way to go and on other occasions i’ve heard union this union that. i’m looking at “local 72” , but how has your experience been with a union specifically in GA? How was starting out financially through it? Really want to get a kick on my life as i’ve been sober for a couple years and want to keep my life moving on the right track. thankyou in advance for any help/ advice given.
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2023.06.09 04:13 keepitinyourpanties So much

So much submitted by keepitinyourpanties to namesoundalikes [link] [comments]

2023.06.09 04:13 enfueggo OC Fair motor home demolition derby: How early do you need to get in line for GA seating?

Been to a few car demolition derbies at the fair but always bought seats ahead of time. Always wanted to see the motorhome one but looks like I'm too late again and there only a handful of single seats left Wed:
For anybody who has actually gotten free general admissions seats for the motorhome derby, how early did you get in line? Or how early did you get there and you were too late?
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2023.06.09 04:12 keepitinyourpanties So many

So many submitted by keepitinyourpanties to gorillazcirclejerk [link] [comments]

2023.06.09 04:11 187gvrrick 22y/o thinking about union GA

This is gonna be all over the place. I want to know if a union is right for me , currently i’m a server i don’t have any parental help and have been on my own since 16. I rent right now but plan to put down on a home a year from now, so i to be able to support that and im stressing about what to do. i love hands on work and i’ve been told repeatedly that HVAC is the way to go and on other occasions i’ve heard union this union that. i’m looking at “local 72” , but how has your experience been with a union specifically in GA? How was starting out financially through it? Really want to get a kick on my life as i’ve been sober for a couple years and want to keep my life moving on the right track. thankyou in advance for any help/ advice given.
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2023.06.09 04:10 leedia666 Trash cans that can be used as decorations👀

Trash cans that can be used as decorations👀 submitted by leedia666 to SnkrsheadClub [link] [comments]

2023.06.09 04:09 nomoreusernamefam Did anyone receive an email back for partial refund?

I bought the ticket before they reduced the GA pass price. I emailed them to request a partial refund on the price difference but I haven’t heard back from them.
submitted by nomoreusernamefam to electriczoo [link] [comments]

2023.06.09 04:09 NiftWatch Professor u/NiftWatch’s IMAX lecture, part 3.

I got the film celas off eBay.
“Why do 5 perf 70mm and 15 perf 70mm both exist simultaneously if 15 perf 70mm is so much better?”
  1. 5 perf existed before IMAX was born. 5 perf 65/70mm film began its comercial Hollywood use in the 1950’s. Several films were shot and released in 65/70. In 1970, some dudes from Canada turned the film on its side and were like “we can get a huge picture out of this, eh?” and ran it horizontally through the camera 15 perforations per frame at 24 frames per second. Then, they projected it on a huuuuuuuge screen, and they called it “Image Maximum” or IMAX as we know it today.
  2. It’s easier to shoot dialogue scenes on 5 perf. That’s why Dunkirk, Tenet, and Oppenheimer weren’t shot entirely on 15 perf. IMAX 15 perf cameras are too loud.
  3. It’s easier to build a smaller screen to project 5 perf than it is to build a ginormous screen to project 15 perf. Also, it was relatively easy to retrofit standard cinema screens with 5 perf projectors to show The Hateful Eight on 5 perf.
“Why don’t they just project IMAX 15 perf on smaller screens?”
Because that’s ilegal! /s
No, but actually, they used to do that. The 1.90 retrofitted “lieMAX” screens were given a variation of a 15/70 projector with a small footprint and a 1.90 aspect ratio limitation. MPX, for MiltiPleX. These were first installed in 2004, until the IMAX digital Xneon system was born and rolled out in 2008.
And TCL Chinese IMAX in Hollywood, with a 90 foot screen, had Interstellar projected on 15/70, even though their screen isn’t tall enough for 1.43. Oppenheimer is also being projected on 15/70 at TCL.
Ok, study those perforation dots, the unit exam is Thursday. I’ll be in my office if you need me. Office hours are in the syllabus.
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2023.06.09 04:08 Himawari-OPG Yuusha ga Shinda! • The Legendary Hero is Dead! - Episode 10 discussion

submitted by Himawari-OPG to YuushagaShinda [link] [comments]

2023.06.09 04:07 millennial_pinkk Selling 1x 3-day GA wristband to Gov Ball for $200 or best offer - can meet in Manhattan to exchange

PM if interested!
submitted by millennial_pinkk to avesNYC_tix [link] [comments]

2023.06.09 04:06 Efficient_Ad1992 Halloween Ends - Extended Cut

So I'm basically going by the kill count from the novelization and extending some of it so it can be like a extended cut. The storyline from the novel is the same except for a few changes. For example, here's a few reminders:
  1. Have Michael Myers be supernatural and not too weak. 2 Add all the deleted scenes into the movie.
  2. Add Laurie's reaction to Karen's death and having trouble moving on from the inside.
  3. Have Allyson not forget that Michael killed her parents.
  4. Remove Sondra from the movie and have her actually die in Halloween Kills.
  5. Instead of Corey stealing Michael's mask, he uses his scarecrow mask to become his own evil version of The Shape and continues to help Michael regain more of his strength.
  6. Michael keeps the same rusty knife from the sewers and uses it on Halloween (2022).
  7. Have the final showdown between Michael and Laurie longer than 5 minutes and add a showdown between Corey and Allyson.
  8. After killing Doug, Michael is no longer staying in the sewers.
Since Halloween Ends has been nothing but a terrible movie of missed opportunities, here's the kill count which would've been better than what we got if it went by the novel. Let me know your thoughts on this. If you like it, awesome! If you don't like it, then let me know so I can understand and fix the problem.
Halloween (2018, during Halloween Kills)
Jeremy Allen: accidentally killed by Corey Cunningham
November 1st (2018, after Halloween Kills)
Ozzy: killed by Michael Myers 🎃🔪
Hugo: killed by Michael Myers 🎃🔪
November 1st (2018)
Little girl: infected by Michael's evil to kill her abusive father, killed by Michael Myers 🎃🔪
Halloween (2019)
Ryan Couper: killed by Michael Myers 🎃🔪
Kimberly Hart: killed by Michael Myers 🎃🔪
Halloween (2020)
Meredith: killed by Michael Myers 🎃🔪
Halloween (2021)
2 teenage graffiti artists: killed by Michael Myers 🎃🔪
After being dragged in the sewers by Nelson Christopher, Corey encounters Michael and gets infected by his evil.
Nelson Christopher: killed by Corey Cunningham
Doug Muleny: killed by Michael Myers 🎃🔪
Dr. Mathis' house
Dr. Tanner Mathis: killed by Corey Cunningham
Deb Jennings: pinned to the wall, killed by Michael Myers 🎃🔪
Halloween (2022)
During the gas station scene, Michael stalks the bullies before he follows them while Corey lures them to the junkyard.
Billy: killed by Corey Cunningham
Stacy: killed by Corey Cunningham
Ronald Prevo: accidentally killed by Terry Tramer
Terry Tramer: killed by Michael Myers 🎃🔪
Margo: killed by Michael Myers 🎃🔪
Radio Station
Susan (Radio Receptionist): pinned to the wall, killed by Corey Cunningham
Willy the Kid: killed by Michael Myers 🎃🔪
After the radio station kills, Michael and Corey go on their own sprees as they continue killing.
Corey's house
Joan Cunningham: killed by Michael Myers 🎃🔪
Michael arrives at Velkovsy's and stalks Lindsey Wallace and Frank Hawkins. He notices Danny McBride taking a crap at the side of the bar. Michael attacks him as he turns Danny around, stabbing him in the stomach and twisting his knife around it as he begins to bleed out. Lindsey hears something outside as she goes out to investigates. She finds Danny dead at the side. Suddenly appearing, Michael attacks Lindsey as they have fight once again like in Halloween Kills. Michael gets the upper hand and kills Lindsey. Frank goes outside and sees Lindsey lying dead on the floor. He looks back up to see Michael standing above her. Michael does recognize him from 1978 and 2018. Frank pleads to Michael about his partner McCabe being killed by accident, realizing long ago that he should've killed him in 1978. Just like Dr. Loomis in Halloween 4, Frank shoots at Michael, but he mysteriously vanishes.
Danny McBride: killed by Michael Myers 🎃🔪
Lindsey Wallace: killed by Michael Myers 🎃🔪
Theresa Allen: killed by Corey Cunningham
At his demolished home, Michael stalks 7th graders who are dressed up as him. They want to summon Michael Myers to get rid of the people that were mean to them. Michael does appear as he stands where his sister's bedroom once stood, stalking the 7th graders. As a few cops arrive, they tell him Michael Myers was here, but he's already gone.
Myers House
7th Graders: Stalked by Michael Myers 🎃🔪
Laurie's house - The Final Showdown: Michael Myers vs Laurie Strode & Corey Cunningham vs Allyson Nelson
Corey Cunningham: shot twice by Laurie Strode, shot 4 times in the chest and a 5th time in the head and fell out of the window of Laurie's office, killed by Allyson Nelson
Laurie Strode: killed by Michael Myers 🎃🔪
Michael Myers: "killed" by Allyson Nelson
After Allyson defeats Michael, she goes over to her dying grandmother as Laurie says her last words "Evil will never die... It changes shape..." As Laurie dies, Allyson mourns for her grandmother before turning back to see Michael gone. Outside the house, Michael looks down at Corey as he grabs his neck, removing the evil inside him. He tilts his head before leaving the house. After Michael leaves the house, Frank, Sheriff Barker, and the cops arrive as they find Laurie and Corey dead. They found Allyson still alive as they take her outside. Allyson exit the house and looks over at Corey's body. Michael's heavy breathing is heard everywhere in Haddonfield before the screen cuts to black as the Halloween theme plays and the credits roll.
submitted by Efficient_Ad1992 to u/Efficient_Ad1992 [link] [comments]

2023.06.09 04:06 KELSIS2416 Family Dollar elves

Family Dollar elves
Found a WHITE ELF!!!!
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