Day 9: Costume

an entry for darkest prompts promptober 2022

previous days: 1, 2, 3, 4, 5, 6, 7, 8

now available on ao3 too

Costume NOUN - a set of clothes worn by an actor or performer for a particular role.

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Being a human seemed easy when you were one. What could be so hard in being a man, after all? One head, two arms, two legs, something between them preferably, a bod to hold one's guts. Easy enough! Right? Or at least, it should be. After all, if one was asked if he knew what a man looked like, most would say yes. But if that same lot were asked to describe a man they supposedly knew in detail, suddenly, a lot of issues arose. The same problems Dismas never thought he would have to face - as if the constant bloodlust or the maddening tittering of blood in human bodies wasn't enough already. 

He knew what ailed him just as much as he knew there was no cure - the signs of infection he got when he was battling the cursed sycophants. The same infection now burned in his veins. The same infection that made his teeth fall out and replaced them with conical, twitching fangs, that broke his jaw, shifting it into an impossible maw, capable of opening wider than any human jaw should, that turned his tongue into a contraption of ribbed muscle and sinew tipped with a sharpened bone needle. Existential panic aside, it was extremely noticeable - a feature most unwelcome when one shared a room with a zealous crusader who was hellbent on executing the infected. 

Thankfully, at first, his trusted neckerchief was enough to hide the reddened skin and cracks on his lips. But soon, the highwayman knew, a mere neckerchief wouldn't be enough to survive. Therefore Dismas, being the conman that he was, started faking being human. 

And human face was the first thing he had to learn about. It was an odd thing to start exploring. All the expressions and muscles and tiny twitches that could give away the wrongness in it that he had to not only notice, but also hurriedly re-learn from scratch. He taught himself to fold his new tongue so that it would fit inside the twitching mess he had to call his mouth now. He spent hours learning how to contract new muscles in his jaws to make his teeth press flat against his gums so he could close his mouth fully without cutting into himself. It took weeks of concentration and effort to understand how to pull the infection deeper, leaving only reddened skin and new scars on his lips when he was forced to heal the accidental opening of his jaws further than humans were able to. 

The rogue still wore the neckerchief day in and day out, just to be extra careful. 

The hands were next. Dismas never thought about his hands much - who did? Nimble fingers, hurting wrists, lots of scars and callouses. Hands like any other. It was only when he was forced to recreate them time and time again that he actually started contemplating the intricacies of their design, the complex latticework of muscle and ligaments that made it possible to hold a mug of booze or reload a flintlock. He learned what caused his claws to grow, how to stifle them, and how to bite those out with the unexpected use of his fangs so he'd lose the least blood possible if he ever lost control. 

In some scary, twisted way, he started understanding Paracelsus' obsessions. 

But time passed, and mutations carved more and more out of him, making Dismas fake and hide and pretend to the point of not remembering how to exist without it. He became proficient in being a human much like he was proficient with his dirk and his flintlock - in talking like a human would, in moving as a human could, in looking like a human might. His infected brethren welcomed his finesse, mimicking his success, using his lessons to hide in plain sight, to adapt, to survive, to endure. They were tolerated, but they weren't on his level. They were let out of quarantine, sure, with proper permits and after required checkups and labelling, but none could snuggle to the crusader who orchestrated their elimination with the holy man being none the wiser. The same knight who swore to kill every last blight of Crimson Curse on the face of the world would enthusiastically spill to him all his plans on how to contain and eradicate the disease. Dismas listened closely and nodded, squinting in a certain way that guaranteed to hide the crimson glint in his dark eyes. This was precious intel to mould Hamlet's Hive around, after all, saving the lives of his brethren who were less skilled in hiding. 

Sometimes, when they smoked together, Dismas genuinely forgot about his sickness and simply enjoyed Reynauld's company. Other times he wanted to confess - only to be faced with yet another proposal to the Heiress on how to make infecteds' life a living hell. A prison. 

Then he was sent to hunt bloodsuckers again, and efficiency required removing his human skin for a while - snapping the jaw open, using proboscis as another knife, and utilizing his claws and wings in the most efficient way possible. He was a force to reckon with, one of the oldest surviving infected, the one who was infected for long enough not only to sprout wings but also start developing unique mutations, the co-founder of the Hive. 

But then the hunt ended, and he turned himself inside out, cramming his new, twisted being into his old scarred skin. 

Merely a human. 

Just a highwayman.

Just Dismas in the costume of being himself, the host and the sole guest of the masquerade held in his honour. 

And as the pipe was passed between them, as Rey was cheery and glad that Dismas was "safe from the scourge", the rogue couldn't help but wonder when would the clock hit midnight, and the ball would end. 

THE SALAMANDERS

The third group of elementals is the salamanders, or spirits of fire, who live in that attenuated, spiritual ether which is the invisible fire element of Nature. Without them material fire cannot exist; a match cannot be struck nor will flint and steel give off their spark without the assistance of a salamander, who immediately appears (so the mediæval mystics believed), evoked by friction. Man is unable to communicate successfully with the salamanders, owing to the fiery element in which they dwell, for everything is resolved to ashes that comes into their presence. By specially prepared compounds of herbs and perfumes the philosophers of the ancient world manufactured many kinds of incense. When incense was burned, the vapors which arose were especially suitable as a medium for the expression of these elementals, who, by borrowing the ethereal effluvium from the incense smoke, were able to make their presence felt.

The salamanders are as varied in their grouping and arrangement as either the undines or the gnomes. There are many families of them, differing in appearance, size, and dignity. Sometimes the salamanders were visible as small balls of light. Paracelsus says: "Salamanders have been seen in the shapes of fiery balls, or tongues of fire, running over the fields or peering in houses." (Philosophia Occulta, translated by Franz Hartmann.)

Mediæval investigators of the Nature spirits were of the opinion that the most common form of salamander was lizard-like in shape, a foot or more in length, and visible as a glowing Urodela, twisting and crawling in the midst of the fire. Another group was described as huge flaming giants in flowing robes, protected with sheets of fiery armor. Certain mediæval authorities, among them the Abbé de Villars, held that Zarathustra (Zoroaster) was the son of Vesta (believed to have been the wife of Noah) and the great salamander Oromasis. Hence, from that time onward, undying fires have been maintained upon the Persian altars in honor of Zarathustra's flaming father.

One most important subdivision of the salamanders was the Acthnici. These creatures appeared only as indistinct globes. They were supposed to float over water at night and occasionally to appear as forks of flame on the masts and rigging of ships (St. Elmo's fire). The salamanders were the strongest and most powerful of the elementals, and had as their ruler a magnificent flaming spirit called Djin, terrible and awe-inspiring in appearance. The salamanders were dangerous and the sages were warned to keep away from them, as the benefits derived from studying them were often not commensurate with the price paid. As the ancients associated heat with the South, this corner of creation was assigned to the salamanders as their drone, and they exerted special influence over all beings of fiery or tempestuous temperament. In both animals and men, the salamanders work through the emotional nature by means of the body heat, the liver, and the blood stream. Without their assistance there would be no warmth.

THE SECRET TEACHINGS OF ALL AGES by Manly P. Hall c. 1928

Pic. Source: Amorum emblemata, figuris aeneis incisa by Veen, Otto van, 1556-1629 c. 1608 https://archive.org/details/amorumemblemataf00veen/page/3/mode/1up

Guilty Gear Characters ranked by how high they look in their Accent Core Portrait

To celebrate 4/20, I will be ranking every single Guilty Gear Accent Core portrait from least to most blazed out of their mind!

23.Potemkin

Everyone else got so high that there was no weed left when Potemkin arrived, leaving the Zeppian soldier angry and weedless.

22. Ky Kiske

The illyrian king does not know what weed is and has taken an anti-drug pledge back in highschool. He refuses to even think about anything with caffeine in it, much less actual drugs. He is judging you.

21.Venom

Venom similarly did not get any of the weed, He’s similarly quite miffed about this predicament and is currently going for the kill.

20.Chipp Zanuff

The self declared president refuses to even try a weed, no matter what day it is. He looks down at you with scorn, ready to give you his own personal Drug Psa/Friendship Speech. Winners don’t do drugs, you’ve never seen Goku with a blunt, now have you?

19.Millia Rage

She’s judging you.

18.Zappa

Not actually high, arrived here while the weed was being handed out and got a headache from the smell. Left ASAP. 

17. Jam Kuradoberi

She made weed brownies as a 4/20 special and is currently checking your eyes to see how effective they are. She’s considering calling a doctor.

16. Testament

They are both judging you and trying their very best not to make it noticable that they accidentally ate a weed brownie earlier, because of which they can now see a skeleton dancing in the edge of their vision.

15. Baiken

Similarly judging you for being a lightweight. Took a few brownies herself to make Anji more tolerable. Is suprisingly less stabby than she usually is.

14.A.B.A.

Took her first weed a few hours ago and is currently suffering the after effects. Honestly just wants to go home. Doesn’t remember where she parked Paracelsus.

13. Faust

Got called in by Jam because her weed brownies are too strong. Impossible to tell how high exactly he is due to the bag on his head, however the glowing eye makes it likely that he snuck off with a little snack after he treated his patients.

12.Slayer

Ate the most weed brownies out of everyone but is very easily holding himself together. Has years of experience pretending not to be high. Is patting your back and telling you a story about how he and Nagoriyuki got absolutely blazed in a karaoke bar in the 19th century.

11.Order Sol

Just passed you the bong with an expression that says “here you go my man, this is the good shit.”

10.Johnny

Was right before Order Sol in the blunt rotation. Is currently thinking about women. The sunglasses are hiding it well but he’s completly out of his mind.

9.Anji Mito

Put extra weed in the brownies. Quite stoned himself but knows exactly what he did. Is not sorry for what he did.

8.I-no

Tripping balls. Is currently trying to remember if she turned the stove off before coming here. Is gonna return to a burned down home and an on fire Raven.

7.Robo-Ky

is a bong

6.Eddie

Did not realize corpses could actually get high and scarfed down an entire batch of brownies. Is currently on another planet. Does not remember his own name. Zato-one was never revived, Eddie is still high as of Xrd.

5.Dizzy

First time weed consumer and absolute light weight. Has no idea what’s going on but thinks everything is really nice. has been staring at her own tail swishing back and forth for the better part of an hour now.

4. Axl Low

Chewsday innit

3. May

Snuck off with Johnny’s bong. Can taste colors. Wil try to touch your face.

2. Sol Badguy

Stoned out of his fucking mind. Can’t handle weed as well as he could during his holy order days. Is currently drooling onto himself. There are no thoughts behind that headband.

1.Bridget

My daughter, she is sick. Her face, it is melting.

I read Solomon's script during the past days and I'll summerize something here. I already did the same on my twitter account so it's basically a repost from there but whatever

- Script is 33 pages, each page has three columns

- Nasu leaves notes for CloverWorks in the script. In the Marisbury/Solomon scene he writes "on screen" for Solomon's words because "(you couldn't use Solomon's voice yet)"

- THEY CHANGED ROMAN'S FIRST SCENE HE WAS ASLEEP IN THE SCRIPT LIKE HE WAS IN GAME

- I'm leaving the whole translation of the Lev/Leonardo dialogue because it's AMAZING and she snaps SO HARD against him:

“Roman, in the control room, has no objection and looks at Lev on the monitor with a pensive expression.

Da Vinci, on the other hand, cannot tolerate Lev's sarcasm and refutes it.

Da Vinci: "Of course, of course. You could not have known Romani's humanity. After all, this guy didn't trust anyone until I was summoned to Caldea."

Lev, hearing da Vinci's objection, frowned: "What?”

With anger at Lev and resentment at the life of Roman, Da Vinci speaks.

Roman is surprised by Da Vinci's uncharacteristically emotional response.

Da Vinci: "I don't know why, I don't know who the enemy is. There is no guarantee that it will happen in the first place.” He believed in such a" crisis of mankind "and threw out his entire life."

- Follows a Roman pov placed in his past:

// I keep waiting, believing that something that shouldn't happen will happen.

// I can't let the enemy know that I'm aware.

// So I can't talk to anyone.

// I don't know what to learn for that time (for then it'll come)

// So I'll learn everything I can–

- At the end of the first Servant sequence Nasu literally wrote "depends on the costs it's up to you to decide if they'll speak or not" LMAO

- Nasu really doesn't care about the servants in Solomon. In almost every scene with them he basically goes "ok, you chose what to do, I'll continue writing the important stuff".

I'm not kidding, in the first Servants vs Goetia fight he makes A LIST OF SERVANTS and tells "you choose which of them you want to use for that purpose".

For example, the first Servant purpose is "following Mash running to the throne" and Nasu wrote "Geronimo or Paracelsus" (I'm sad, I would've LOVED to see Paracelsus in the movie!!!)

Another example: purpose is destroying Solomon's magical barrier. Servants in the list are Altera (which was the chosen one) or Kintoki. Same thing for the second Servant vs Goetia fight, but in that one there are some servant that Nasu absolutely wanted in the movie.

The Rider was Ushiwakamaru, the Caster was Amadeus, the Berserker Asterios and THE ARCHER WAS DAVID!!!! I'M HAPPY NASU ACTUALLY ASKED FOR DAVID TO BE THERE 😭😭😭

For other classes, there was a list of 2-3 servants

- another interesting thing I want to clarify is that Baal is there /in the script). It's not just a random Demon Pillar who talks to Goetia, it's Baal. I'm saying this because many people think the next FGO adaptation will be Shinjuku because of Baal

- While Mash and Fujimaru are heading to the Temple there's a dialogue in which Fujimaru says he want to come back to Chaldea with Mash. She doesn't answer. In the script Nasu states she was scared, that's why she doesn't speak

- No servant dialogue in the Seven Servants vs Goetia scene either

- “Mash's voice is quiet but dignified. There is no hostility in it. It is not an attempt to denigrate Goetia, but purely an assertion: "I wanted to live like that".”

- Mash thinking "you're so lonely" when Goetia asks her to understand him

- There's a beautiful Fujimaru pov after Mash's death. I'll leave it here as well:

“He runs to Mash's shield, grasps the grip of the shield to see what remains of Mash, and falls to his knees.

Fujimaru's face is shaking with anger. His hostility towards Goetia and his resentment towards himself are driving him crazy.

(Fujimaru's disappointment is not that he has failed to fulfil his promise to return with her, but that Mash, who has helped him, has told him that she wanted to help him at least once.

She has done more than enough. She has done more than enough for me. She helped me. And yet, in Mash's mind, she had not been able to repay me in any way.)”

- Roman leaving Chaldea is 1:1 to the original game I SWEAR NASU WROTE "FROM HERE IT'S THE SAME AS THE GAME" AND I REALLT DON'T UNDERSTAND WHY

- “Solomon (M) (Actually, after this incinerator was resolved. I dreamed of being able to live freely as a person.)” NASU I HATE YOU

- Ars Nova is VERY WELL explained btw. The movie cut literally everything here, it focuses more on the emotional side (which is also in the script of course)

- The dialogue between Guda and Solomon is 1:1 (movie/script) except for a thing: Guda grabs the hem of Solomon's garment (💔💔)

- The final dialogue between Roman and Da Vinci is REALLY LONG. Nasu wrote that he knows it's long but he tried to shorten it as soon as possible AND IT LASTS THREE PAGES ANYWAY. You can clearly see Nasu loves Roman and his name and it makes me really happy!!! It's the same as the game but with a more detailed description, like Da Vinci's sad smile or Roman trying to be brave

- Also, when Roman explain the meaning of his name (“I wanted to live that way”) Nasu writes a note below:

“//of course, he won't have the freedom to live that way”

I'M CRYING THANK YOU NASU I REALLY HATE YOU WHY DOES ROMAN HAVE TO SUFFER LIKE THIS

- Roman says the most meaningful thing he has done in his life was watch Guda grow up into a reliable Master I CAN'T TAKE THIS ANYMORE

Hypmic OC Crew: Freestyle Angels

so I’ve seen a lot of people posting their Hypmic OCs lately, and that made me want to buckle down and finalize the details for mine!

An all-female team based out of Tokyo’s Minato Ward, the Freestyle Angels are technically an independent crew - they got together to drive out crews who were abusing their claims to the territory, but aren’t interested in winning more territory themselves. (Not that they’d qualify for the DRBs anyway, of course.) Rather, they serve as a foil/rival team to the Chuohku trio.

Sumire Kuino, AKA Queen of Street

“Alone we can do so little; together we can do so much” - Helen Keller

Occupation: Humanitarian aid organizer

Birthday: October 7th

Age: 30

Zodiac: Libra

Height: 6′0″

Weight: 165 lbs

Blood type: AB

Likes: Bargains, fixing things, dogs, birdwatching

Dislikes: Wastefulness, unpaid debts, technology, selfish people

Favorite food: Chazuke

Least favorite food: Fugu

The daughter of a corrupt businessman and his mistress. Her father was an associate of Sairo Tohoten, who helped him flee the country when he got in trouble with the authorities, leaving a young Sumire and her mother behind. Sumire’s mother, only viewing her as another mouth to feed, likewise abandoned her daughter once she’d found a new lover. Frightened at the possibility of ending up in an orphanage, Sumire struggled to fend for herself on the streets until she was taken under the wing of an older homeless man named Takayoshi. He would go on to raise Sumire as his own, with her quickly coming to call him ‘Grandpa’ and taking on his family name. Over the years, Sumire became increasingly protective of him in turn, and he and his circle of friends would jokingly call her ‘queen’ for her assertive, take-charge nature; Sumire was always exasperated by the nickname, but grudgingly grew to accept it.

Takayoshi was the sort of person who was always willing to lend a hand and always kept an eye out for those who needed it, and Sumire followed his example. After he passed away, she became a guardian for anyone with nowhere to go, spending her days building shelters, distributing food, and standing up to whoever threatened the people that depended on her. She had fleeting hopes that the Party of Words would remedy some of the ills plaguing society, but found that little changed once the H Age began. Before the formation of the Dirty Dawg, Minato Ward went through a tumultuous period where it rapidly changed hands between many crews who abused their power. Sumire stole a set of Hypnosis Mics off of one such group and began using it to defend the defenseless, forming a duo with Ageha Hinokuchi called the Rough Diamonds, then a trio once they met Kaori Sakuragi.

Her microphone takes the shape of a street sign, while her speakers are a graffiti-covered castle made from debris. Her ability, Bulwark, decreases the damage done to her allies, albeit at the cost of taking it herself. Her personal rapping style is based off of Hime.

Personality-wise, Sumire’s an incredibly caring person under an intimidating exterior; her default stone-faced expression rarely changes and she speaks very bluntly. She won’t really judge or try to control the choices of those she helps, but if she needs to put her foot down for someone’s own good, her naturally commanding presence makes it hard to not do what she says. She’s a quick learner who can fix up just about anything she puts her hands on (with the exception of hi-tech gadgets) and a highly efficient penny-pincher; show her something with a high price tag and get ready to hear a thorough breakdown of just how many groceries it could buy. Her biggest flaw is that she doesn’t always take care of herself as well as she does others, requiring her teammates to step in and force her to take the occasional break.

She deeply respects Jakurai’s work, but finds Hifumi too flashy for her tastes. She’s also helped Dice a few times in the past, but he finds her kind of terrifying and tries to avoid her. The one person who can immediately make her lose her composure is Rei; plenty of his victims have ended up on the streets, and one of them even committed suicide despite Sumire’s attempts to save them. Unless her teammates stop her, she’ll attack him on sight.

Ageha Hinokuchi, AKA HI-FLYA

“Once freedom lights its beacon in man’s heart, the gods are powerless against him” - Jean-Paul Sartre

Occupation: Fitness & self-defense instructor

Birthday: May 6th

Age: 28

Zodiac: Taurus

Height: 5′6″

Weight: 138 lbs

Blood type: B

Likes: Pro wrestling, action movies, dancing, the beach

Dislikes: Muscle cramps, energy drinks, smoking, conformity

Favorite food: Barbecue

Least favorite food: Sea cucumber

A former member of the Party of Words. As a child, she lost her parents to an armed robbery, leading her to support Otome’s goals of eliminating conventional weapons from Japan. However, she increasingly found herself unable to turn a blind eye to the ways in which the Party manipulated innocent people. Once she learned about the True Hypnosis Microphone, she attempted to sabotage the facility where they were produced, but was discovered. In the fight that followed, a fire broke out; she fell from a great height into the flames and was presumed dead by the Party members who had been trying to apprehend her. However, a friend of hers in the group discovered that she’d survived and smuggled her to safety. After recovering from her wounds, she took on a new name and face, leaving her old identity behind to become Ageha Hinokuchi.

Her goal of stopping the Party of Words remained unchanged, and for a while she was constantly on the move, collecting evidence of their crimes and trying to come up with a way to stand against them. In Minato Ward, she happened to cross paths with Sumire Kuino, who had stolen a set of Hypnosis Microphones and was using them to defend people in need. Though initially reluctant to use one herself, she was forced to when Sumire was outnumbered and lured into a trap. Sumire, who was a firm believer in always repaying what she owed, asked what she could do in exchange for Ageha saving her life. This sparked a deep bond that eventually led to Ageha divulging her past to Sumire, and they formed a duo known as the Rough Diamonds. They later met Kaori Sakuragi and rechristened themselves the Freestyle Angels (incidentally, Ageha came up with both names, the latter because she was a fan of Charlie’s Angels).

Her microphone takes the shape of a portable music player held on an armband and a pair of headphones with butterfly wings on them, while her speaker is a four-sided boxing scoreboard. Her ability, Reverb, allows her to hit her opponent twice in one go, although the second hit isn’t as strong. Her personal style is inspired by Akkogorilla.

In contrast to Sumire, Ageha is fun-loving, always wears a smile, and is overflowing with energy; this is largely due to regretting how she previously lived, as someone blindly obedient who didn’t fully appreciate the joys of life. She can quickly befriend just about anyone and is a bit of a flirt, but only to tease. All of this belies a keen observational eye, though, and she’ll play up being an airhead to make others underestimate her. She knows a wide variety of martial arts, with kickboxing and aikido being her specialties. Because she currently lives and works in Roppongi, she’s also good with foreign languages.

Ageha is a big fan of Sasara’s comedy routines. She's suspicious of Ramuda because she knows he was involved with Chuokhu, but isn’t fully aware of his nature as a clone. Likewise, she detests Rei for having worked on the True Hypnosis Mic, but is much better at hiding it than Sumire.

Kaori Sakuragi, AKA wallflower

“Be not another, if you can be yourself” - Paracelsus

Occupation: Self-employed craftsperson

Birthday: December 5th

Age: 20

Zodiac: Sagittarius

Height: 5′3″

Weight: 116 lbs

Blood type: A

Likes: Homemade things, aromatherapy, reading, gardening

Dislikes: Cameras, busy places, the dentist, controlling people

Favorite food: Croquettes

Least favorite food: Beef tongue

Child-star-turned-idol, lead singer of the wildly popular group ‘Cutie Blooms’, Kaori seemingly vanished off the face of the earth one day. In truth, years of constant media presence, overwork, and pressure to please her demanding stage mother had driven Kaori to have a mental breakdown. Unable to be in the presence of other people without suffering severe panic attacks, she shut herself up in her apartment just before the start of the H Age for two years. When a paparazzi tracked her down and began harassing her for interviews, she fled and became lost on the streets of Minato-ku, but was rescued by Sumire Kuino and Ageha Hinokuchi. Seeing them wield their Hypnosis Mics in her defense reminded her of her original love for singing, and she begged them to make her the third member of their crew.

While her teammates have been helping her work through her trauma, Kaori is still afraid of having her face or voice recognized. She keeps her features obscured by glasses and masks as much as possible, prefers to stay out of sight, and primarily communicates through a tablet that reads out what she writes; she’s very quiet and stammers a lot when she does speak. During her years as a shut-in, she learned to provide for herself in a number of ways, such as growing her own vegetables and making clothes and other handicrafts, the latter of which she sells online.

Her microphone takes the shape of her tablet and stylus, while her speaker is a greenhouse that overflows with more and more flowers as she gains confidence during battle. Her ability, Tongue-Tied, scrambles her opponent’s speech. Her personal style is based off of Haru Nemuri.

Kaori is sensitive, timid, and somewhat pessimistic, but still possesses a very strong determination deep down at her core. She despises the fake persona that was forced upon her by the idol industry and wants to “win back her true self”. The more comfortable she gets around someone, the more she shows her passionate and cheerful side. She’s also very creative and good at memorizing small details, but at the cost of sometimes getting lost in her own thoughts and not noticing what’s going on around her.

She’s an avid reader of Gentaro’s novels, having sent him lots of anonymous fanmail in the past. She’s also recently started listening to Jyushi’s music.

Chapter 3: The Hag

Prologue

Chapter 1: The Necromancer

Chapter 2: The Prophet

Chapter 3: The Hag

Chapter 4: The Brigand Vvulf

Chapter 5: The Brigand’s Cannon

Chapter 6: The Drowned Crew

Chapter 7: The Siren

Chapter 8: The Swine God

Chapter 9: The Formless Flesh

Chapter 10: The Ancestor

Epilogue

The following weeks I was deep in my training as I sent out the heroes I had assembled into the area surrounding the Hamlet. With the dungeon cleared, it was unclear where we needed to focus our efforts next. While I knew any of the immediate surrounding area was bound to hold something, I preferred to have an order of priority.

While they were exploring the area, I met the most peculiar and concerning man in all of existence. When he arrived, he asked for me by name. I met him in the Town Square to ensure that we were seen by all as I did not have the best feeling when I was informed of him. He stood tall with marks all along his bare chest and arms. It seemed like he was always covered in some blood, usually his own, but I was not aware of that yet. As far as I was concerned, someone bloody and vicious was in my Hamlet and I was expecting trouble.

When I arrived, he broke into a grin and greeted me with a booming voice. He informed me that the closest branch of the Church of the Light had sent him. He asked where the Vestal Julia was as she had stopped writing to them and given the contents of her letters, they found it fitting to have someone look into it. Seeing that the man was not a threat and we were about to talk about a much more… sensitive topic I only saw it fit to invite him back to the Estate.

From there, I had the grim duty of informing him and Julia’s demise. The scarred man did not seemed surprised, but simply nodded. He asked if her reports on an undead Necromancer were true and I confirmed that as well. I saw no benefit to lying to him or the Church of Light. My encounters with their kind had shown that lying was a good way to earn their ire. If these lands truly are cursed by something my Ancestor did, I do not wish to lose their support no matter my personal opinions on their faith.

The man then paused and looked around before saying that he would stay to help purge the evil out of these lands. I was taken aback and asked him if he was even allowed to do that. Didn’t he have to return to his Church and report Julia’s death? He said that no, a letter would suffice. He pointed out that she told the Church of her efforts to reestablish the Light in the Hamlet and with her death, it would be to our advantage to have someone tied to the larger church to help revitalize it. I couldn’t provide any argument against this. I was certain Reynauld would appreciate the help so he was not the only person seeing the revival of the church.

I asked the man what he could bring to the group and he informed me that he had a unique talent for sharing the burdens of another person. He went into a frankly terrifying conversation about how pain liberated him of his worries and his burdens, so he shares this joy with others. I decided I wanted to keep a closer eye on this man and instead of placing him in the barracks we had made for the heroes, I decided it was best he remained close. He offered no argument and said that the feeling was mutual. It was not the most reassuring response, but I could hardly blame him, I suppose. I am the owner of a twisted, corrupted land and I did just have a Vestal killed under my care. After our conversation, I lead him through the estate and had him pick his chambers. He picked a humble servant chamber, and I cannot say I was surprised. Still, I ensured the space was clean and showed him where everything he could need was within the house.

Within the following days, I discovered that his name is Damian. He had been close to me since he arrived, seeming keen on discussing either Julia or what has been happening in and around the Hamlet. I admit I am still apprehensive speaking to him. I do not wish to receive a religious lecture about death or about cleansing the lands.

Thankfully, I did not have to wait much longer for news to arrive. Apparently, there were two things that required my attention. The first was the Coves. There were reports of inhabitants entering them and never returning and there is no indication of why they entered in the first place. The second was more concerning, however. There was a strange fungus encroaching from the Wealds. Whenever someone moved to try to harvest it or stamp it out, it released spores that either caused the person to become confused, or it poisoned them. It took a good number of spores to kill someone, but if it was pushing in on the Hamlet, I did not want to take any risks.

Once I had received this news, I devised a plan with Paracelsus to set fire to the fungi from afar as it was the only conceivable way we could think of to eradicate it. With help from the others, it seemed we had a good way of combating the issue and keeping them locked in the Wealds, but I suppose it was only a temporary solution at best as eventually the mushrooms seemed to react to our reagents as well. Poor Boudica needed a rescue party since she was so lost after being confused by a plume of spores.

It seemed luck was eventually on our side again, however. Shortly after our solution started to fail, a woman by the name of Missandei arrived. She is a gifted marksman with a crossbow and while she was more soldier than survivalist, she claimed to have some understanding of the Wealds. While she admitted that she was not familiar with the mushrooms we were struggling with, she still knew enough to lay some poisons by firing them into where they grew the densest. This at least provided us with footpaths where there were no mushrooms so we could move further in and eradicate more of the pests without risking losses.

It was shortly after we started to see a serious decline in the number of hazardous mushrooms that I received a letter from a curious address. The man who delivered it to me could hardly remember how he came upon the letter, much less how he came to my estate to deliver it. My only theory is that he was under the influence of their spores and someone took advantage of that, or that perhaps someone purposefully used them to the same effect. Regardless, the letter came from someone living deep within the Wealds. It seemed like such an impossible notion that someone could live surrounded by the vicious wildlife and that mushrooms, but I was quickly learning that the Hamlet and its surrounding area seemed to thrive on the impossible.

The letter was addressed to my ancestor, the same one who reached out to me and begged that I return to the Hamlet to redeem it. The letter expressed surprise that he had returned and invited him out to their hut in the woods. They said they’d leave him a path so he could arrive unharmed. It was about this point that I received a report that despite our best efforts, the fungi were back in full force. It was at this point that I started to suspect that there was a supernatural element to them and that perhaps whoever wrote this letter would know more. On top of that, if they knew my ancestor personally, I figured they would be able to answer some questions about him.

The following morning, I set out with Paracelsus, Missandei, and Reynauld. We found a path that was clear of mushrooms and I felt that was confirming my suspicions that whoever wrote the letter likely had something to do with them. We pressed cloths to our faces to keep out the spores to the best of our abilities should the need arise and pressed on.

We stuck to this path, being careful that our movements did not set off their spores, or the creatures consumed by them that occasionally moved and walked. The path cut through a Graveyard that once belonged to the Hamlet but had long since been abandoned since it was so far from the town proper to be safe. To our surprise, we were not the only people there. It seemed someone else had noticed the opening and decided to take advantage. A woman in strange clothes paused as she saw us. She almost fled the scene, but thankfully there was only one path she could follow, so catching her was no problem.

I asked this woman why she was digging up the graves and she ever so kindly asked me what I thought. Of course she was robbing graves, there were some rich people buried in that graveyard. No doubt they were buried with their finest jewels and she wanted them. I asked her why she wanted their jewels and she informed that she needed the money, but she also just liked the look of them. Ignoring the second part, I offered her employment instead. There was no sense in having her rob our graves when we could put her to work. The woman was just as surprised as the rest of the group, but reluctantly agreed. Though she said that if she felt she wasn’t receiving fair pay, she would leave and likely take some gold with her. I still let her in.

The grave robber by the name of Audrey then joined us, helping us travel further into the Wealds and to the hut that belonged to the mystery author of the letter. Audrey was mercifully light footed and would often scout the path for us to make sure it was clear, though I am certain it was also to keep some distance from Reynauld as he attempted to lecture her on her grave robbing habits. The humor of him, a known cheating gambler, lecturing someone else on not committing crime was a touch humorous to me, but I refused to explain why I was laughing.

Soon enough we arrived at the location of this hut, unharmed just as promised. The doors opened as we arrived and a woman stepped out to greet us. Though it was clear she was by no means a normal woman as she had plenty of markings on her clothes and there were herbs I knew to be arcane in nature hanging from her belt. She looked confused and baffled once she realized that we were not my ancestor and asked what the meaning of this was, she was very clear about who she wanted to see in her letter. I informed her that to the best of our knowledge, my ancestor was dead. He sent me letter begging me to arrive and no one had seen him since. The woman gave a horrible laugh before shaking her head, saying something about how he “must have finally done it”. I asked her what she meant, but she simply waved her hand, dismissing the question.

She moved to sit near a large cauldron that she had outside her home. As she settled down, she took out a knife and took some of the herbs that were hanging off of her belt and started to cut them into the pot. Finally, after a moment of silent cutting, she asked if I knew what I had been summoned to the Hamlet for. I told her that I had been asked to help cleanse it of whatever evils my ancestor had released. The witch shook her head, her expression becoming grimmer as she said that the cycle begins again with me. At that point I was reminded of what the Prophet had said, and I could feel my veins run cold. I still did not know what this cycle was and yet two separate people mentioned it. It had to be a pattern of some kind and I was no closer to understanding it than I was weeks ago.

I wanted information. I wanted to know just what I had apparently done by existing in this space, so I asked the witch if she could explain what this cycle was, but she did not take kindly to me asking anymore questions. At that point she started to spat about me being ungrateful. As it was, I did arrive to her home uninvited and started to demand answers of her. While I could understand her irritation, I felt I had to press the issue. The idea that I was causing something awful by stepping foot into the Hamlet was too great to ignore, but she told me to find my own answers. She said there had to be plenty around the Hamlet to work with, and she “did not deal with simpletons”.

At this point I was at a loss for words about this issue, so I asked her if I could ask a question on a different subject. She reluctantly said that she would, so I asked her about the mushrooms. How did she know that there would be a path? Did she know what powers them? At that point, she smiled and said that they were hers. She used them for her spells and potions and she always needed lots of them, so she allowed them to spread. I pointed out that the spores were hazardous to humans, but she simply shrugged and said they never bothered her, so it was no problem of hers.

I don’t know where the thought came from, but I was so bold as to ask her if they were tied to her. I asked if the mushrooms would survive without her. She paused, staring me down, challenging me, and said that no, the mushrooms would die with her. There was something dangerous in her voice, but something pushed back, and I lunged. For the longest time, I did not and could not understand what drove me to attack the witch, but one moment I was standing before her, the next I had a sword stuck in her arm where I had missed her chest. She howled in pain and started to attack. My companions, though reluctant, did rush to my aid.

The battle was not long. Though she performed strange, terrible spells that nearly cooked poor Reynauld alive, she was no match for Missandei and Audrey’s amazing shots and Paracelsus’ blight filled bombs. As she fell, it was just as she had promised. We could see the mushrooms in the immediate area begin to whither and fade away. The air was suddenly that much clearer, and we could walk back without fear of losing our way due to the confusing, poisonous spores they released.

As we walked back though, I could not help but replay the words of the Hag and the Prophet in my mind. If there was a cycle, then it had something to do with my ancestor and me. If my ancestor had released something evil, then was I expected to do the same. Was that “something evil” the cause for my outburst or was I growing irritable myself with stress? I didn’t know. I didn’t know which answer was worst for it meant that either I was not in control of my actions, or I was, and I did something I was not proud of.

Regardless, from that day on I decided I needed to watch my actions closer and watch for any signs for something awful lurking within me. I hated the thought but doing anything else felt irresponsible.

Adventures Around A Teacup Pt 3 (Hakuno, Gilgamesh)

Previously: One, Two 

_____

Slowly, carefully; the little king was working to repair the wound on the young heroine that he had chosen for himself. His lips pressed against her face now and then, stealing away the frustration and the pains of what those wounds had done.

That wasn’t to say that the king showed no wounds.

Whenever the woman in his arms would reach to so much as wipe at the blood on the king’s face, the king would pull that hand down or shake his head. His bent and damaged armor only let the wounds bleed worse depending on how he moved. It showed deep wounds in his gut and along his shoulders, where the parts of the armor overlapped.

Their treatment of one another was slow.

Their bond though, that was something that grew remarkably deeper and faster between them. Those brown eyes looked up at the king, those lips moving in the gentlest of ways. The king’s expression widened at the sight, mouth opening only to close one more.

Like the golden armor that the little king wore, despite its tattered shape and history of damage and hurt, the king simply gleamed.

The heroine swayed her love into soon laying down. Those small hands would pull strap after strap loose on the king. She still wept. The king’s hands still soothed. Yet, despite her remaining pains and her need to rest, she continued to treat her king.

Gilgamesh watched the two, watched them adore and care for one another to the depths of their capabilities.

The two had been smacked injured from an onslaught of attacks.

One of the other little chibis had escaped from the lab that Paracelsus had been working in. The purple haired pestilence had gone after his two chibi, somehow managing to find his room.

While they had obviously won, slaughtering the woman and reclaiming their space, it had cost them severely.

Gilgamesh had found them at the end of the battle, having gone to speak to Hakuno. His own heroine had been occupied with Gudako and Mash, discussing what to do about the small beings that Paracelsus had made.

“They could be left on a planet somewhere,” Hakuno had offered.

While that plan was better than their death, he found he didn’t quite care for it either. Something about watching the two was more important than forcing the little ones to establish their own world.

He left tissues and a small jar of ointment open on the book the little heroine and king were laying on. He found the little brunette rushing over, tearing strip after strip of the tissue and returning to her king.

The little one paused.

What did she need?

There was tissue to use as gauze. There was ointment to use for sterilizing and caring for the wound. What could she…

“She is looking for something to hold the tissue in place. Tape or glue perhaps.”

Gilgamesh froze as he heard the voice at his side.

A hand reached forward, putting tiny bits and pieces of what would have been a small amount of tape on the edge of the book. She tapped lightly, watching the little brunette jump a moment before looking. The relief that came to that expression was distinct. She rushed to fetch some of the tape and wrinkled her nose lightly at how sticky the tape seemed to be.

Gilgamesh glanced to his side as the young woman set to work, paying attention to the much taller version of that young heroine settle at his side.

“You had them here the whole time, didn’t you?” Hakuno asked quietly.

“They merely happened to appear from time to time. I am neither their god nor their maker. What occurs to them is not mine to decide.”

Hakuno nodded, but her eyes drifted to his face. “I found them in here a few days ago. You had fallen asleep and they were.. that is…”

She fell silent.

It must have been one of the times when the two had been doting upon one another. They were very prone to such things, often finding themselves caught up in one another to the point of ignoring the fact that there was food around or a dimming of the lights so he could sleep.

“Did you come to simply bore me with the knowledge of your awareness of them?”

Hakuno shook her head, “I came to ask if you feel anything for me like your chibi self feels for my own.”

His prepared quips had nothing for that.

As usual, Hakuno skipped formalities, danced around pleasantries to simply get to the heart of the matter. It was something worthy of respect, but…

“If I did?”

Those eyes widened, bidding him into leaning closer. That surprised expression coaxed him into coming close to her, pressing a hand to the arm of the chair she sat in.

“Fool, do not ask a question and then give me such a look without explanation. What does it matter to you what words I say? Have my actions not been enough?”

She couldn’t slip away, not when she had scooted her chair in to be close to him and the chibi. She couldn’t simply run like she had before, giving excuse and escaping what strange stirrings they created within one another.

However, she didn’t seem to have any interest in doing anything like that.

He felt her hands press to his cheeks and he watched those eyes drift from meeting his gaze to watching his lips. The stillness of the room intensified, the sounds around them ebbed away until not even a thought could pass through his mind.

Then, he felt her shy embrace.

The most fleeting, soft kiss that she could have ever given him, composed of the most pointed puckering of the lips, was pressed to his lips. He watched her pull back, a pink staining her cheeks before he sniffed quietly.

“You know nothing of pleasure, Hakuno,” he chastised. “You will never feel anything from such infantile affections.”

Before the tiny couple, the great king pressed his hand to the back of Hakuno’s neck, tilting her head back a bit and sealing her lips with his own. His tongue swept over her lips. His mouth stole the very air from her lungs, deepening the embrace and marriage of his lips to hers in a way that made the young maiden stir beneath him.

His maiden- his Hakuno- was always in need of learning more from him.

Thankfully, he was inclined to entertain himself with teaching her.

Epidermolysis Bullosa Market Size, Epidemiology, Leading Companies, Drugs and Competitive Analysis by DelveInsight

(Albany, US) DelveInsight has launched a new report on ‘Epidermolysis Bullosa (EB)-Market Insights, Epidemiology, and Market Forecast–2030’.

DelveInsight’s ‘Epidermolysis Bullosa (EB)-Market Insights, Epidemiology, and Market Forecast–2030’ report deliver an in-depth understanding of the EB, historical and forecasted epidemiology as well as the EB market trends in the United States, EU5 (Germany, France, Italy, Spain, and the United Kingdom) and Japan.

Epidermolysis Bullosa Key Findings

According     to the publisher's, the total prevalent population of EB in seven major     markets ranges was 41,509 in 2017.

The     total diagnosed prevalent cases of EB in the 7MM was 39,433 in 2017.

In     2017, there were 26,104 prevalent cases of EB in the United States. In the     same years, there were a total of 24,799 diagnosed prevalent cases of EB     in the United States.

Epidermolysis     Bullosa is of several types, and three major types of Epidermolysis     bullosa includes Epidermolysis bullosa simplex (EBS), junctional EB (JEB),     and dystrophic EB (DEB). Assessments as perthe publisher's analysts show     that the majority of cases of EB are EBS in the United States. In 2017,     there were 14,879 cases of EBS, 1,240 cases of JEB, and 8,680 cases of DEB     in the United States. DEB is further divided as recessive and dominant.

Out     of 8,680 cases of DEB in the United States in 2017, 4,554 cases were     dominant DEB and 4,126 cases were recessive DEB.

Among     the European countries, the United Kingdom had the highest prevalent     population of EB with 5,037 cases, followed by Germany which had a     prevalent population of 4,919 in 2017. On the other hand, Spain had the     lowest prevalent population of 928 in 2017.

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Epidermolysis Bullosa (EB) Emerging Drugs

Oleogel-S10 (AP-101): Amryt Pharma

Oleogel-S10 (AP-101) is a topical product that is being developed for the treatment of EB. It incorporates a betulin-based active ingredient formulated with sunflower oil. AP-101 acts by promoting the differentiation and migration of keratinocytes (skin cells with wound repair capabilities) as well as transiently increasing the level of proinflammatory mediators (which also promote healing).

AP101 has already received marketing approval for the treatment of partial-thickness wounds (PTWs) in adults from the European Commission in January 2016 under the brand name Episalvan. The company is also developing AP103, a potential treatment for patients with RDEB. Oleogel-S10 is currently in phase III clinical trial and recently reported positive unblinded interim efficacy and safety analyses.

EB-101: Abeona Therapeutics

EB-101 (LZRSE-Col7A1) is an autologous, ex-vivo gene therapy in which the COL7A1 gene is inserted into a patient's skin cells (keratinocytes) for the treatment of the underlying disease in recessive dystrophic epidermolysis bullosa (RDEB). The patient's cell is genetically engineered in the lab to express a missing protein called type VII collagen and then these corrected cells will be transplanted back to the patient. These cells should then make type VII collagen. The process of adding inserting the correct type VII collagen gene into cells is called gene transfer. Post this process i.e. gene transfer the engineered cells are grown in culture into a sheet of cells that look like a plastic film. This sheet is then grafted to wounds.

The company has evaluated the safety of EB-101 in phase I/II trial in which product has shown significant results, wound treated with EB-101 were significantly healed >50% for more than two years post-administration.

CCP-020 (Diacerein 1% Ointment): Castle Creek Pharmaceuticals

CCP-020 (Diacerein 1% Ointment) is a topical ointment that is being developed by Castle Creek Pharmaceuticals for the treatment of EBS. The drug is engineered to potentially block the activity of interleukin-1? (IL-1?), a pro-inflammatory cytokine that is involved in the inflammatory signaling pathway associated with EBS. Blocking of IL-1? reduces the auto-inflammatory effects in the skin of patients with EBS and strengthen epidermal tissue and support healing.

Diacerein is a commercially available medicine used to treat osteoarthritis. Its therapeutic potential in treating blistering in patients with epidermolysis bullosa simplex was initially discovered by a team of researchers at the EB House Austria, University Clinic for Dermatology at the Paracelsus Medical University (PMU). Diacerein is commonly marketed as tablets but for EBS researchers have developed an ointment with 1% of diacerein. Presently Castle Creek is developing CCP-020 is in the phase II stage of development. Earlier a phase II trial of CCP-020 for EBS got terminated because an independent data monitoring committee suggested that the study will not meet statistical objectives.

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Companies Mentioned

Amryt     Pharma

Abeona     Therapeutics

Castle     Creek Pharmaceuticals

RegeneRx

Krystal     Biotech

Fibrocell     Technologies/Castle Creek Pharmaceuticals

RHEACELL     GmbH

Holostem     Terapie Avanzate

StemRim/Shionogi

Phoenix     Tissue Repair (BridgeBio Pharma, Inc)

Menlo     Therapeutics

JCR     Pharmaceuticals

Amicus     Therapeutics

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Key Topics Covered:

1. Key Insights

2. Executive Summary of Epidermolysis Bullosa (EB)

3. Epidermolysis Bullosa (EB) Market Overview at a Glance

3.1. Market Share (%) Distribution of Epidermolysis Bullosa (EB) in 2017

3.2. Market Share (%) Distribution of Epidermolysis Bullosa (EB) in 2030

4. Epidermolysis Bullosa (EB): Disease Background and Overview

4.1. Introduction

4.2. Causes of Epidermolysis Bullosa

4.3. Signs and Symptoms of Epidermolysis Bullosa

4.4. Classification of Epidermolysis Bullosa

4.5. Pathophysiology of Epidermolysis Bullosa

4.6. Genetic Bases of Epidermolysis Bullosa

4.7. Diagnosis of Epidermolysis Bullosa

4.7.1. Diagnostic Guidelines

5. Case Reports

5.1. Dystrophic Epidermolysis Bullosa in Pregnancy: A Case Report of the Autosomal Dominant Subtype and Review of the Literature

5.2. Managing pain in children with epidermolysis bullosa

5.3. Epidermolysis bullosa: a case report

5.4. Newborn Infant with Epidermolysis Bullosa and Ankyloglossia

6. Epidemiology and Patient Population

6.1. Key Findings

6.2. Epidemiology Methodology

6.3. 7MM Total Prevalent Patient Population of Epidermolysis Bullosa

6.4. 7MM Diagnosed Prevalent Patient Population of Epidermolysis Bullosa

6.5. 7MM Type-Specific Diagnosed Prevalence of Epidermolysis Bullosa

7. Country Wise-Epidemiology of Epidermolysis Bullosa

7.1. United States Epidemiology

7.1.1. Assumptions and Rationale

7.1.2. Total Prevalent Cases of Epidermolysis Bullosa in the United States

7.1.3. Diagnosed Prevalence of Epidermolysis Bullosa in the United States

7.1.4. Type-Specific Diagnosed Prevalence of Epidermolysis Bullosa in the United States

7.2. EU5 Epidemiology

7.3. Japan Epidemiology

8. Treatment and Management of Epidermolysis Bullosa (EB)

8.1. Skin and Wound Management

8.2. General Management Principles

8.3. Special Considerations

8.4. Management of Chronic wounds in EB

8.5. Pain care for patients with epidermolysis bullosa: best care practice guidelines

9. Unmet Needs

10. Emerging Drugs

10.1. Key Cross Competition

10.2. Oleogel-S10 (AP-101): Amryt Pharma

10.2.1. Product Description

10.2.2. Other Development Activities

10.2.3. Clinical Development

10.2.4. Clinical Trials Information

10.2.5. Safety and Efficacy

10.2.6. Product Profile

10.3. EB-101: Abeona Therapeutics

10.4. CCP-020 (Diacerein 1% Ointment): Castle Creek Pharmaceuticals

10.5. RGN-137: RegeneRx

10.6. B-VEC (KB103, Beremagene Geperpavec): Krystal Biotech

10.7. FCX-007: Fibrocell Technologies/Castle Creek Pharmaceuticals

10.8. Allo-APZ2-EB: RHEACELL GmbH

10.9. COL7 and LAMB3 gene therapy: Holostem Terapie Avanzate

10.10. KOI2 (Redasemtide/HMGB1 Peptides): StemRim/Shionogi

10.11. PTR-01 (BBP-589): Phoenix Tissue Repair (BridgeBio Pharma, Inc)

10.12. Serlopitant (VPD-737): Menlo Therapeutics

11. Failed Therapies for Epidermolysis Bullosa (EB)

11.1. JR-031: JCR Pharmaceuticals

11.1.1. Product Description

11.1.2. Other Development Activities

11.1.3. Clinical Development

11.1.4. Clinical Trials Information

11.1.5. Product Profile

11.2. Allantoin (Zorblisa): Amicus Therapeutics

12. Epidermolysis Bullosa: Seven Major Market Analysis

12.1. Key Findings

12.2. Market Methodology

12.3. Attribute Analysis

12.4. Market Size of Epidermolysis Bullosa in the 7MM

12.5. Market Size of Epidermolysis Bullosa by Therapies in the 7MM

13. Market Outlook: The United States

13.1. United States Market Size

13.1.1. The Total Market Size of Epidermolysis Bullosa

13.1.2. Market Size of Epidermolysis Bullosa by Therapies in the United States

14. Market Outlook: Europe

15. Market Outlook: Japan

16. Market Drivers

17. Market Barriers

18. SWOT Analysis

19. Reimbursement and Market Access

20. Recognized Establishments

21. Appendix

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Media Contact Company Name: DelveInsight Business Research LLP Contact Person: Ankit Nigam Email: [email protected] Phone: +19193216187 City: Albany State: New York Country: United States Website:https://www.delveinsight.com/

THE „MIRACLE OF KAPUVÁR” The expression above was used by a journalist from Graz, who visited the Angiological Department of Sándor Lumniczer Hospital and Clinic of Kapuvár, to describe the special and unique medical treatment system (carbonic acid gas bath) considered as HUNGARICUM applied to cure patients suffering from peripheral angiopathy. It is well-known that approx 3-400 thousand patients in Hungary, 60-70 million in Europe and ten millions on the other continents are affected by this disease. It can be stated that it is a pandemic disease similarly to tuberculosis or Black Death of the old times.The beneficial effects of this special bath method were already known in the Roman era. Later, in the 16th century Paracelsus took advantage of the method, mainly for curing burns and ulcers. Since the 19th century the utilization of the Transylvanian mofettes by the traditional medicine has been mentioned in several documents. In Europe well-known carbon dioxide baths can be found in Germany, France, the Czech Republic, Slovakia, Austria and Transylvania (Romania). In Hungary at first Dr. Pál Schwartz applied artificial carbon dioxide bath (in bath-tub) in Mihályi in 1940’s. Later he continued the treatments in the hospital of Kapuvár. The carbon dioxide for the treatments was obtained from gas-fields that were exploited in the 1930’s and ‘40’s by deep-boring. Schwartz applied the bath successfully for the treatment of chronic joint diseases. Carbon dioxide is present in our lives: it regulates the respiration and the circulation. Experience proves that it absorbs through the skin and expends the blood vessels locally under the skin. The cardiac functions improve; the superfluous gas leaves through the lung. This determines the indication of the treatment, since it is recommended to patients whose respiratory surface has decreased or the cardiac functions have declined and can not be burdened. The thermal water of 67 °C of Kapuvár, which is qualified as medicinal water, is – according to experts – top quality water in Hungary, the most acknowledged after Hévíz. The water of the thermal well is alkaline hydrogen carbonate and chloride thermal water containing dissolved salt in large volumes (14337 mg/l), and due to its content of iodide and sulphide ion, it can be classified as iodiferous and sulphide thermal water. Besides, the water contains significant concentration of bromide, fluoride, lithium and metasilicic acid.

Safety Based Limits for the Control of Impurities in Drug Substances and Drug Products: A Review-Juniper publishers

Safety based impurity limits are key to the effective reduction and control of impurities in medicinal products. Impurity limits now have a greater focus on daily exposure limits, with the introduction of various approaches, such as permitted daily exposure (PDEs), acceptable intake (AIs), threshold of toxicological control (TTCs) and staged TTCs all aimed at defining a virtually safe dose (VSD). This in turn led to the introduction of less than lifetime (LTL) limits for mutagenic impurities, which is based on an application of Haber's law which states that concentration and exposure times are both critical for assessing likely safety risk to patients. Surprisingly, LTLs have not been applied to the other specific classes of impurities or indeed general impurities.

A recent publication has suggested that a LTL limit for general impurities of 5 mg or 0.7% (whichever is lower), for clinical studies with durations of less than 6 months is warranted. ICH S9 indicated that there was no additional impact on patient safety for impurities where the parent drug substance is extremely toxic and impurity levels (even mutagenic impurities) for oncology products could be controlled at higher levels. However, there has been little regulatory appetite for broadening this entirely pragmatic approach to other therapeutic areas, where life expectancy is equally short, i.e. rare diseases.

Keywords:  Haber's law; Duration of dosing; Safety-based limits; Acceptable daily intakes; Acceptable intakes; Permitted daily exposure; Virtually safe dose; Less than lifetime limits

    Introduction

Paracelsus, the medieval physician, who is often viewed as the father of modern toxicology, was the first person to appreciate that "the dose makes the poison". This essentially means that very toxic materials can be used therapeutically at very low concentrations and conversely even safe materials can be toxic if overdosed. This in turn led to Haber's law, which basically states that, the incidence and/or severity of any toxic effect is dependent on the total exposure to the toxic agent; that is, the exposure concentration (c) rate(or dose) multiplied by the duration time (t) of exposure (i.e. cxt). This law is often utilised in setting exposure limits for toxic components. The major caveat, is that establishing acceptable daily intakes (ADIs) for long-term exposures to a toxic substance when only data from short-term studies are available, does require the use of an uncertainty or safety factor.

For example, cancer risk estimates are typically based on the average lifetime daily dose (LDD), which in turn is derived from the total cumulative exposure, using Haber's law, i.e. cxt. Gaylor [1] proposed a modified Haber’s law to better extrapolate safe levels based on shorter term exposure intervals and this takes the form of:

           c3x t=c’3x t'

where c and t are the known safe exposure levels(c) based on the longer exposure duration (t) and c’ and t' are the projected safe concentration (c’) based on the pre-defined shorter exposure duration (t’). Haber’s law is equally germane to impurities as it is to medicinal products.

Impurities in New Drug Substances and New Drug Products (Ich Q3a/ Ich Q3b)

One of the first international guidance that used safety based limits for impurities was the international conference on harmonization (ICH) Q3A [2]. This provided an overview of the typical impurities that were found in new drug substances and their controls. Impurities were evaluated based on both chemistry considerations, including "classification and identification of impurities, report generation, listing of impurities in specifications, and a brief discussion of analytical  procedures"; and safety considerations, including "specific guidance for qualifying those impurities that were not present, or were present at substantially lower levels, in batches of a new drug substance used in safety and clinical studies"

Impurities were further delineated into identified and unidentified classes, both of which were included as specification tests [3]. This includes unidentified impurities that were known to be present at levels greater than pre-defined reporting, identification and qualification threshold (Table 1). Those unidentified impurities are often defined on the drug substance specification "by an appropriate qualitative analytical descriptive label (e.g., "unidentified A", "unidentified with relative retention of 0.9")"

1. The amount of drug substance administered per day;

2. Reporting Threshold: A limit above (>) which an impurity should be reported. Reporting threshold is the same as reporting level in Q2B (4);

3. Higher reporting thresholds should be scientifically justified;

4. Lower thresholds can be appropriate if the impurity is unusually toxic;

5 Identification Thresholds: A limit above (>) which an impurity should be identified;

6 Qualification Thresholds: A limit above (>) which an impurity should be qualified

The reporting threshold was linked to the capability of the supporting analytical methodology [4]. Identification threshold was the limit where the unknown impurity was required to be identified by appropriate analytical methodology. Whereas, the qualification threshold necessitated acquiring and evaluating pre-clinical safety data that "establishes the biological safety of an individual impurity or a given impurity profile at the level(s) specified".

Interestingly, although the derivation of the reporting threshold was linked to method capability, the derivation of the identification and qualification threshold limits were never fully delineated, apart from linkage with the maximum daily dose of the product. In addition, for those impurities "known to be unusually potent or to produce toxic or unexpected pharmacological effects, the quantitation/detection limit of the analytical procedures should be commensurate with the level at which the impurities should be controlled". Again, the implicit meaning of this statement was never fully articulated, but it was the genesis for the subsequent guidance on mutagenic impurities, initially termed genotoxic impurities [5].

Similar guidance was provided for impurities typically found in new drug products. These impurities are usually termed degradation products [6]. There was greater delineation of the thresholds in terms of dose (Table 2). However, it was never fully explained why the various thresholds, in terms of maximum daily dose, could not be aligned. Thus there is the confusing scenario that the reporting thresholds are above or below 1g; whereas, the identification thresholds are divided into four (>2g, >10mg- 2g, 1mg-10mg and <1mg); whilst the qualification thresholds were also divided into four, but were not aligned with the classes defined in the identification thresholds (>2g, >100mg-2g, 10mg- 100mg and <10mg).

1 The amount of drug substance administered per day;

2 Thresholds for degradation products are expressed either as a percentage of the drug substance or as total daily intake (TDI) of the degradation product. Lower thresholds can be appropriate if the degradation product is unusually toxic;

3 Higher thresholds should be scientifically justified.

The other confusing aspect was that the maximum daily dose (mg/day) and the maximum strength of a product (mg) are often not the same value. Thus for instance, the anti-malarial drug quinine sulfate [7] has a maximum therapeutic dose from the product label of 648mg every 8hours, i.e. 1944mg/day; whereas, the highest dose strength are 324mg/capsule. The analysts testing and releasing quinine sulfate capsules will do so on the commercial product (324mg/capsule), not the maximum dose taken by the patient (1944mg/day). In addition, although reporting thresholds are always measured as percentage values and are easily aligned with the data output from the method used by the analyst; identification and qualification thresholds are measured in either percentage values or mg/day values (Table 3).

The other aspect of having safety based limits for impurities is that it does not reflect the duration of treatment use for that drug and results in the same limits being proposed irrespective of whether the drug is proscribed pro ne rata (PRN) or as required, e.g. for constipation, mild pain, etc., or through life time treatments, e.g. for treatment of high blood pressure, etc.

ICH Q3A [2] and Q3B [6] were always intended to be only applicable to marketed products, but the regulatory expectations during clinical development often exceed what is actually required. For example, it isn't unusual to see the following expectations [8]:

"For phase I expect structure (or identifier) and origin For phase II expect Limit of Detection and Quantification and actual impurity levels to be established (aligned with ICH Q3A, Q3B, etc)".

However, by phase II the final synthetic route and process of the drug substance are rarely identified or optimised, and the attrition rate of phase II drugs is still very high [9]. What the regulatory guidance enshrined in ICH M3 [10], actually states with respect to impurities is, "If specific studies are warranted to qualify an impurity or degradant, generally these studies are not warranted before phase 3 unless there are changes that result in a significant new impurity profile (e.g., a new synthetic pathway, a new degradant formed by interactions between the components of the formulation). In these latter cases, appropriate qualification studies can be warranted to support phase 2 or later stages of development"

Residual Solvent Impurities (ICH Q3C)

Although residual solvents are mentioned in ICH Q3A [2], a separate guideline, ICH Q3C [11], was developed to provide safety based guidance on the allowable limits of common residual solvents within pharmaceuticals. As there are "no therapeutic benefits from residual solvents, all residual solvents should be removed to the extent possible to meet product specifications, good manufacturing practices, or other quality based requirements". Additionally, ICH Q3C recommends the use of less toxic solvents. Thus, solvents that are known to be highly toxic (Class 1) should be avoided during the production of drug substances, excipients, and especially drug products, unless their usage can be justified using a risk-benefit assessment [12]. In addition, some solvents with intermediate toxicity (Class 2) should also be limited from a patient safety perspective. Ideally, the least toxic solvents (Class 3) should always be used where practical. Recommended limits for all solvents may change as additional safety data become available. In addition, supporting safety data for new solvents may be added to the guidance.

Although tolerable daily intake (TDI) and acceptable daily intake (ADI) were both in common usage, ICH Q3C (12) introduced a new term, permitted daily exposure (PDE) to avoid confusion of differing values for ADI's for the same substance. In addition to avoidance of class 1 solvents, the concept of "as low as reasonably practicable" (ALARP) was introduced and is applied to class 2 solvents and often to class 3 solvents. Indeed, regulatory agencies will often use process capability arguments to drive down residual solvent levels below the safety based limits [13] derived from ICH Q3C.

Residual Elemental Impurities (ICH Q3D)

Residual elemental impurities were also mentioned in ICH Q3A [2], but again a separate guideline, ICH Q3D (14) was developed to provide safety based guidance on the allowable limits of residual elements within pharmaceuticals. As elemental impurities provide no therapeutic benefit to the patient, "their levels in the drug product should be controlled within acceptable limits" [14].

The ICH Q3D guideline is sub-divided into three parts: the derivation and assessment of toxicity data; the establishment of a PDE for each elemental impurity derived for three different routes of administration (oral, inhaled and parenteral); and application of a risk based approach to control elemental impurities (as per ICH Q9 (12)). One difference from ICH Q3C [11] is that applicants are not expected to tighten the safety based limits based on process capability considerations, as long as the residual elemental impurities do not exceed the PDE values. However, in certain cases, levels below the PDE may be warranted when lower levels have been shown to positively impact on other critical quality attributes (CQAs) of the drug product; for example, element catalyzed drug degradation (this is particularly common with oxidative degradation mechanisms [15]. In addition, for those elements with higher PDEs, lower limits may have to be assessed from a pharmaceutical quality perspective. Residual elements are classified into 5 different categories: class 1, 2a, 2b, 3 and others (Table 4).

ICH Q3D [14] provides a platform for developing an ICH Q9 (12) aligned risk-based control strategy to limit elemental impurities within the drug product. Although, the guidance had highlighted the risk inherent from both drug substance and excipients, the reality based on a multi-product assessment is that the risk is low. Li et al. [16] tested 190 samples from 31 different excipients and 15 samples from eight different drug substances for residual elemental impurities. The results show relatively low levels of elemental impurities are present in the samples tested.

Residual mutagenic impurities (ICH M7)

ICH M7 [5] is focused on DNA reactive impurities that can potentially cause DNA damage, when present at low levels, and thus can potentially cause cancer in man. Importantly, other types of toxic impurities that are non-mutagenic will typically have a threshold mechanism and as such usually do not pose carcinogenic risk in man, at the levels typically seen for impurities.

A Threshold of Toxicological Concern (TTC) approach was introduced to describe an "acceptable intake for any unstudied chemical that poses a negligible risk of carcinogenicity or other toxic effects", this equates to a virtually safe dose (VSD). The methodologies that underpin the TTC are universally considered to be very conservative, as they use a simple linear extrapolation from the TD50 dose (i.e. dose giving a 50% tumor incidence) to a 1 in 106 likelihood of cancer occurrence.

A default TTC value of 1.5μg/day corresponding to a theoretical 10-5 excess lifetime risk of cancer can therefore be justified for mutagenic impurities. Some high potency groups referred to as the "cohort of concern", e.g. aflatoxin-like-, N-nitroso-, and alkyl-azoxy compounds; were identified where the default TTC would still pose a significant carcinogenic risk. These high potency compounds were excluded from the TTC approach.

ICH M7 [5] bases acceptable intakes for mutagenic impurities on established risk assessment approaches (see ICH Q9 [12]. As such, acceptable risk during the early development phase is established at a higher theoretically calculated risk level of approximately one additional cancer incidence per million, i.e. 1 in 106 risk levels. For later stages in development (Phase III) and for commercial products, the risk level is reduced to one in one hundred thousand, i.e. 1 in 105 risk levels. It is worth highlighting, that these risk levels represent a small theoretical increase in risk when compared to the overall lifetime incidence of developing cancer in man, which is greater than 1 in 3.

The initial risk assessment is undertaken on the drug substance synthetic pathway to identify real or potential impurities that may be reactive and thereby mutagenic in nature. In parallel, the formulation and manufacturing process are also assessed for the formation of any reactive degradants (both real and potential), that could be realistically expected to form during long term, real-time storage conditions. In silico structure- based assessments, i.e. Derek Nexus, Sarah Nexus, etc., are used for predicting mutagenicity based upon QSAR (quantitative structure activity relationships) approaches. These findings are then reviewed by toxicology experts to provide any additional understanding as to the relevance of these predictions (both positive and negative), and in the case of contradictory outcomes to understand those differences. Based on this assessment, impurities are categorised into five different classes in order of decreasing regulatory concern (Table 5).

1. For class 1 compounds, i.e. those which are known mutagenic carcinogens, an AI (acceptable intake) or a PDE (permitted daily exposure)approach has been introduced (ICH M7(R1) (17)). These limits are based on either (i) linear extrapolations from TD50 (AI) or (ii) threshold-based PDEs. There are 10 compounds covered by the AI approach and a further 3 covered by the PDE approach.

2. LTL (less than lifetime limits)

3. TTC (Threshold of Toxicological Concern)

It is anticipated that monitoring and control strategies (including analytical methods) will be less developed during earlier clinical phases, where overall development experience is of necessity limited, compared to later clinical phases and commercial manufacture. ICH M7 [17] proposesa control strategy using four control options for mutagenic impurities, of these only one includes control of the mutagenic impurity on the API specification (option 1). Options 2 and 3 define some levels of in-process control; whereas, option 4 is centred on process understanding alone, typically termed "Purge Arguments" [18].

It is should be emphasised that these established cancer risk assessments are based on lifetime exposures, i.e. 75 years. Thus, Less-Than-Lifetime (LTL) exposure based limits can be derived both during development and commercial use. LTLs can have higher acceptable intakes of mutagenic impurities and still maintain comparable risk levels, which is obviously an application of Haber's law. Therefore, the carcinogenic effect is predicated on both duration of exposure and dose. Thus for example, "if the compound specific acceptable intake is 15 |ig/day for lifetime exposure, the less than lifetime limits (Table 6) can be increased to a daily intake of 100 |ig (>1-10 years treatment duration), 200 |ig (>1-12 months) or 1200|ig (<1month)" [5]. This LTL approach may also be appropriate "in diseases with reduced life expectancy, limited therapeutic alternatives or chronic diseases with late onset" [19].

It is worth emphasising that exceeding the default TTC or LTL limits is not necessarily linked with an increased cancer risk in man, given the extremely conservative suppositions employed in the evolution and derivation of the TTC or LTL values. For instance, higher exposure to a potential mutagenic impurity, e.g. formaldehyde, may be reasonable when exposure can be significantly greater from other sources, e.g. endogenous metabolism, food, etc. The most likely increase in cancer incidence is actually much less than 1 in 100,000. In addition, in cases where a mutagenic compound is a non-carcinogen in a rodent bioassay, there would be no predicted increase in cancer risk. Based on all the above considerations, any exposure to an impurity that is later identified as a mutagen is not necessarily associated with an increased cancer risk for patients already exposed to the impurity. A risk assessment would determine whether any further actions would be taken

In principle, ICH M7 does not apply to advanced cancer therapeutic indications (covered by ICH S9 (20)), where the drug is itself genotoxic. ICH M7 does not apply to established excipients, flavouring agents and certain biological products, including herbal medicines. Existing commercial products are also exempted, apart from where there are new safety data (including new mutagenic data) for existing impurities; significantly, structural alerts alone do not trigger regulatory concern. However, ICH M7 does cover changes to marketed products, including new marketing applications and postapproval submissions.

Impurities in oncology products (ICH S9)

ICH S9 [20] was developed to provide guidance for nonclinical studies for the development of anticancer pharmaceuticals used in clinical trials for the treatment of patients with advanced disease and limited therapeutic options. During the development of oncology products, supporting clinical studies often involve cancer patients whose prognosis is poor and projected lifetime is short (<2 years).

As such, the guideline objectives are to facilitate and accelerate the development of these anticancer pharmaceuticals whilst protecting patients from unnecessary adverse effects. In addition, ethical use of animals, in accordance with the 3R principles (reduce/refine/replace) are paramount. Importantly, the principles described in other ICH guidelines need to be considered in the development of oncology products; whereas, those specific situations where requirements for nonclinical testing may diverge from other guidance are described in ICH S9.

Additionally, the dose levels used in these clinical oncology studies are often at the top end of the tolerable range [21] and often result in adverse effect dose levels. Hence, "the type, timing and flexibility called for in the design of nonclinical studies of anticancer pharmaceuticals can differ" significantly from nononcology pharmaceuticals. Historically, limits for impurities (see ICH Q3A [2] and Q3B [6] have been based on a negligible risk to the patient. In oncology products this consideration, whilst important, is not as important as patient wellbeing and exceeding the ICH Q3A [2]/Q3B [6] limits for impurities may be applicable and an appropriate justification should be included in the marketing application.

This explanation should include an overview of the disease being treated, including patient prognosis, the nature of the drug itself (pharmacology, genotoxicity and carcinogenicity, etc.), the total duration of treatment, and the impact of any reduction in impurity levels on manufacturability. Furthermore, the qualification of these impurities may include reflections on the concentration tested in supporting nonclinical studies compared to the levels seen in clinical batches. In addition, TTC, LTL and AI/PDE limits for mutagenic impurities (see ICH M7 [5]) are inappropriate for oncology products and justifications can be used to set higher limits. Interestingly, the guidance does not specifically say that the applicant can default to ICH Q3A [2]/ Q3B [6] limits, although this is often inferred. Impurities that are also metabolites can be considered to be suitably qualified.

Interestingly, regulators have been very unwilling to extend the philosophy of ICH S9 [20] beyond oncology products, for instance into rare diseases [22], where lifetime expectancy can be similarly short, i.e. <2 years and where patient expectations are equally high.

New Reflections on Impurities

Harvey et al. [23] used a variety of chemical databases to demonstrate that the 1mg/day impurity level for an unqualified impurity of unknown toxicity, proposed by ICH Q3A [2] (Table 1) is indeed a robust prediction of a virtually safe dose (VSD) for non-mutagenic impurities. Then using the modified Haber's law, where C=1 mg and t=75 years (i.e., 27375 days) and t is 6 months or 182 days they determined a VSD for this shorter exposure interval of 5 mg/day (i.e. 5 times higher than existing ICH Q3A limit). However, for very potent drugs with effective doses of <1mg, a 5mg/day limit for a related impurity isn't realistic from either a safety or quality perspective. Therefore, the authors also introduced a percentage cut off based on 5x the ICH Q3A qualification threshold of 0.15%; i.e. 0.7%. Thus the proposed limits for drug substances are 5mg or 0.7%, whichever is lower.

This allows applicants to adopt the existing ICH Q3A guideline which were developed for commercial products and apply them to development products, in much the same way that the ICH M7 guidelines allows LTL limits for mutagenic impurities, for early clinical development. For drug products, similar LTL limits for non-mutagenic impurities can be derived based on a modification of Haber’s law. The additional constraint of a percentage limit of 0.7% need not be applied to drug products as the more potent the drug substance becomes, the lower the dose required. The authors therefore suggested a limit of 5 mg or 2%, whichever is lower, for exposure intervals of <6 months, for general drug substance impurities, i.e. non-mutagenic.

In addition to absolute amounts of unknown impurities, the other key focus is those impurities with unusually high and/ or specific toxicities. Whilst it is recognised that mutagenic impurities constitute the greatest threat to patient safety and they have been addressed via ICH M7; there are other classes of non-mutagenic impurities that will still give cause for concern. The three principal classes of toxic impurities are

(i) polyhalogenated, dibenzodioxins, dibenzofurans and biphenyls that are non-mutagenic carcinogens, which have specific regulatory framework with respect to acceptable exposure levels [24],

(ii) organophosphates or carbamates that are neurotoxins and have their own threshold of concern [25] and (iii) β- lactam like impurities that have the potential to cause anaphylaxis and which currently do not have any threshold of concern [23].

It is worth highlighting that

(a) These impurities are extremely rare and do not reflect the typical structure of impurities generated by medicinal research [26,27] and

(b) That these structural motifs (if present) would be highlighted and addressed as part of the ICH M7 risk assessment [5] , as "the findings from any mutagenic risk assessment are also reviewed by toxicology experts"

    Conclusion

Safety based impurity limits are a core consideration of all of the existing ICH Q3 guidance documents. However, there has been an evolution in the approach toward impurities since the publication of the initial guidance [2,6]. Whereas, ICH Q3A [2] and Q3B [6] provide general guidance on impurities in drug substances and drug products, respectively and mainly focus on absolute levels of impurities, i.e. percentage based limits; later guidance focused on individual impurity classes; i.e. residual solvents [11], residual elemental impurities [14] and mutagenic impurities [5] and had a greater focus on daily exposure limits. In the latter cases, this led to the introduction of various impurity specific limits, such as PDEs, Als, TTCs and staged TTCs, all aimed at defining a virtually safe dose (VSD). This in turn led to the introduction of LTL limits for mutagenic impurities.

LTLs are based on an application of Haber's law which states that concentration and exposure times are both critical for assessing likely safety risk to patients. Surprisingly, LTLs have not been applied to the other specific classes of impurities or indeed general impurities. In order to address this deficiency, Harvey et al. [23] have assessed the underpinning data behind the current "1mg or 1%, whichever is lower" limit in ICH Q3A [2] /Q3B [6], and they found this to be based on robust science and they proposed an ancillary LTL for general impurities of 5 mg or 0.7%, whichever is lower, for clinical studies with durations of less than 6 months.

Logically, the toxicity of the parent drug substance also affects how we deal with impurities, even very toxic impurities. Thus, there is limited, if any, additional impact on patient safety for impurities where the parent drug substance is mutagenic, carcinogenic or cytotoxic. Accordingly it was recognised that for oncology products, impurity levels (even mutagenic impurities) could be controlled at higher levels. This "higher level" wasn’t defined but is based on an overview of the disease being treated, including patient prognosis, and the nature of the drug itself. Additionally, from a risk based perspective and an understanding of Haber's law, an overt focus on impurity control makes little sense if the life expectancy of the affected patient is short, i.e. less than 2 years [20]. Interestingly, there has been little regulatory appetite for widening this entirely pragmatic approach to impurity control to other therapeutic areas, where life expectancy is equally short, i.e. rare diseases [22].

    Conflict of Interest

The author is an individual CMC consultant and declares that there are no conflicts of interest.

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The Vagaries of Occult Book Buyers

There are benefits to having made a pact with a spirit who procures books as its very nature. The sideways of having something appear that you never were looking for, but indeed wanted, is particularly helpful.

As it was I have been thinking about the role of the occult bookseller down through the ages. How, from Roman times until now one could purchase a manuscript, and later printed books, of occult lore from a professional seller. In times of suppression there were still those who dealt books of forbidden knowledge, keeping a copy under the counter for those who inquire directly. Booksellers in London have carried the works of Dee and Agrippa for centuries, no less in the 16th century than today.

What a wonderful book it would make, a history of those actual historic persons who sold occult books. A well written story of the occult publishers and bookshops that have existed from the middle ages until the late 19th century would be fantastic. Something very accurately written, well footnoted, and with an extensive bibliography.

So I mused for several days on this day dreamed book until, after having ordered a volume of the first edition of "Folk-Lore volume 5" 1887, I received something altogether different. Instead of a book of folklore, I received a copy of "Book-Lore, vol 5 1887". In it I found plenty of stories of booksellers, occult and otherwise, but even more so stumbled onto this absolutely fantastic portrayal of occult book collectors. Its such a perfect and spot on assessment of those who would be occultists, yet find the collecting part much more enjoyable than the actual practicalities of magic. As true today as it was 130 years ago when it was written.

I reproduce the full short piece below. I am still waiting for a concise history of occult booksellers to appear, but in the meantime this laugh will do.

  +++

  "The Vagaries of (Occult) Book Buyers - III " from Book-Lore, a Magazine Devoted to Old Time Literature - 1887

Lord Lytton, in that curious and mysterious novel, Zanoni, mentions an old bookseller who, after years of toil, had succeeded in forming an almost perfect library of works on occult philosophy. Poor in everything but a genuine love for the mute companions of his old age, he was compelled to keep open his shop, and trade, as it were, in his own flesh. Let a customer enter and his countenance fell; let him depart empty-handed and he would smile gaily, oblivious for a time of bare cupboard and inward cravings. A purchaser was indeed a deadly enemy to the old man, for every proffered coin was scorching hot, a miserable and inadequate exchange for one drop of purple blood.

It is astonishing what a deep interest some people take in weird and obscurely written books. They will gloat over the mysteries of Hermes, and nervously finger the pages of Agrippa, - that foul magician whose judgment of himself and all his labours is so eloquently portrayed in his Vanitie of Arts and Sciences. No matter, says the devotee, Agrippa was mistaken; he was afraid of the Inquisition, and recanted. He could not have invented the sigils, triangles, and magic circles, without which congregated with horrid eyes the spirits of the Moon and Paymon, the King of the West Wind. Agrippa was afraid of the spectres he had raised; afraid of his own black dog, and of the hell to which it pointed.

The amateur occult philosopher is, however, not afraid - as yet - and every spare moment is occupied in ferreting out the names of ghostly men, who either suffered on the rack or at the stake, for leaguing themselves with the powers of the air, or else tumbled headlong into the talons of besieging hosts of devils, all screaming, as Paracelsus says they sometimes do, " Thy pentacles and thy circle are wrong, thy words are false; come thou with us."

The old bookseller was a type, and, as we think, a type only, of Lytton's own creation; perhaps a reflection of the soul of Lytton himself, ever groping through mists of tale and fable, and ever unsatisfied.

The purchaser of works on occult philosophy is usually exceedingly enthusiastic, so much so that he persists in his so-called studies, notwithstanding the fact that nine-tenths of his books are in Latin, a language of which he knows little or nothing. In a few words, he would become a disciple of Jannes and Jambres, and to this end sets about accumulating materials in the form of huge folios, conscientiously intending, no doubt, to read them when time and opportunity offer.

His course of reading so far has been confined to the Strange Story, which first riveted his attention on fiends and spectres, and to Barrett's Magus, which, being in English, and adorned with a number of weird plates, has proved an excellent stimulant to further exertions. The Bible is ransacked, and the "Witch of Endor and Simon Magus duly weighed in the balance, while such phrases as " Now the magicians of Egypt they also did in like manner with their enchantments," roll off the tongue with unctuous volubility. Presently the aspirant to " horrors fell and grim " stumbles across the treatises of Raphael and Sibly, and sighs to think that his ignorance effectually cuts him off from the delightful contemplations of those obscure authors upon whose diatribes their works are founded.

At this point the average student comes to a full stop, and turns probably to astrology as being a more tangible study, and apparently much easier. His little library swells with the treatises of Lilly, Raphael, Placidus de Titus, and the great Ptolemy, while he rejoices to think that Flamsted believed in the reality of the science, and that old Burton, the "Democritus Junior," hanged himself rather than admit that his own horoscope was out of gear.

The next step is the purchase of a planisphere, which conveniently dispenses with abstruse calculations in spherical trigonometry; and finally the student erects a horoscope all out of his own head, showing plainly enough that he was born when Mercury was retrograde, and at the square of the moon - a never-failing sign of idiocy, proved up to the hilt, be it said, when he is at last actually persuaded to go a-horse-racing with his slender capital, merely because the "quesited" - the famous "Flying Scud" - is in a trine aspect with Jupiter, Lord of the Seventh, and therefore cannot lose. The horse, however, breaks down, and is scratched four-and-twenty hours after the money is staked, and henceforth astrology is a Will-o'-the-wisp that will never again lure our bibliophile to his ruin.

Out of every twenty persons who take up the study of occult philosophy, nineteen are supremely ignorant of the most ordinary branches of knowledge, but the twentieth is a man of very different composition. He, too, began, perhaps, in the same way as his less gifted brethren, and has followed the same paths, and pored over the same books, and would like also to rival the deeds of Albertus Magnus, who had power over the elements; or of Peter of Abono, who raised terrible forms as easily as a market gardener raises cabbages.

He speedily discovers that Barrett's Magus is, in part, at least, a mere translation, and a very bad one, of Agrippa's fourth book, and that Raphael has mutilated the words of every author he quotes. There is no reliable work in English which can possibly be procured, and so he turns to the Latin, beginning with Iamblichus, and his famous book De Mysteriis, printed by Aldus in 1497. This rare and interesting specimen of typography loses, however, all its beauty in the absorbing nature of its contents; and the same observation is applicable to the author's Vita Pythagorae, published at Rome in 1556. These treatises are, it is true, mere introductions which every tyro who hopes hereafter to lift the veil of Isis must read if he wishes to fit himself to meet the petrifying gaze of the "Dweller on the Threshold" but they are also two most useful books, as from them can be gleaned a mass of information which, rightly understood, is declared by the initiated to point to the portals of the world beyond the grave.

With appetite whetted to a swallowing-point perfectly gluttonous in its magnitude, the student next turns to the treatise of the learned Jesuit, Martin Delrio, who, in his Disquisitionum Magicarum, examines the many different systems of magic practised by the professors of his day; to Bodin's De la Demonomanie des Sorciers; and in their turn to Boissardus, Jerome Cardan, Glanvil, Grillandus, Van Helmont, Wierus, and the Malleus Maleficanim of Sprenger and Institor.

All these works, comprehending as they do an assortment of wonders the like of which the world never saw, and perhaps never will see, support one another in a manner that would put a coterie of Old Bailey witnesses to the blush, so precise and seemingly accurate are the expressions used, so consequential the inferences. There is no mincing matters, no equivocation nor contradiction; everything is so orderly and precise that what is usually regarded, in this country at least, as a structure composed entirely of falsehood and fraud, becomes quite natural in appearance, so that, at last, the student finds himself accepting a statement, no matter how foolish, simply because Sprenger affirms it to be true, or Robert Fludd hints that it possibly may be.

All this time money is going out as fast as credulity, for works on occult philosophy are very expensive. The dealers are aware of their patron's feverish anxiety to obtain them when once bitten by the mania, and, as a matter of course, charge accordingly. Thus £3 is, as a rule, demanded for the Opera Omnia of Paracelsus, 1658, 2 vols., folio; seven or eight guineas for the collected works of Cardan, Lugd., 1663; and as much and more for those of Robert Fludd, Oppenheim, 1617-38. Respecting this last author, Isaac D'Israeh, in his Curiosities of Literature, states that in his time as much as £40 had to be given for a single volume, so great in those days appears to have been the anxiety to obtain copies of works of this and a similar class. We can imagine, therefore, how large must have been the value of the unique collection formed by the bookseller to whom Lytton so fondly refers, and we - or at least some of us - may almost participate in his disinclination to have such a splendid assortment broken in upon by the amateur peripatetic philosopher who in all probability cannot read one hundredth part of the treasures he longs to possess.

The modern world has now been revolving for nearly 1,900 years, and during the whole of that time repeated attempts have been made to lift the curtain that shuts out the invisible world. Some few persons - as, for example, Rozencrantz, who founded the Society of the Rosy Cross, and Paracelsus, who is "now living in his tomb, whither he retired disgusted with the vices and follies of mankind " - are credited with having peeped for a few brief moments behind it; but with these and some other exceptions the progress that has been made is admitted by the most ardent devotee to have been nil. Rumour, as chorus, has taken the place of fact, and dreams that of reality, but still the modern occultist cannot be brought to see that he labours in vain. And so he goes on purchasing ponderous volumes, ugly to look at and absolutely useless for every purpose, theoretical as well as practical, until either he is forced by repeated failures to admit that his favourite authors are impostors, or that he himself has, in spite of all his application, failed to reach the road that leads from this world to that which is to come. He and others like him - and there are many even in this century - would outstrip themselves in a desperate race through the darkness of Erebus; they spend a lifetime in learning to walk, only to be afflicted with total paralysis at the last; and when they awake to find their labour has been in vain, they are amazed to think of the fallacy which engulphed years of toil in the futile attempt to discover what they will learn in five minutes after they are dead.

However, be this as it may, the sale of books on occult philosophy goes on apace, and purchasers are very eager to part with their cash, a phenomenon which is observed in very few instances save the one under discussion. Some of these days enterprise may detect money in new editions and translations of Artemidorus on dreams, and Raymond Lully and Artephius on the philosopher's stone; but at present the trade is confined exclusively to old and battered copies which have served generations of investigators, which are now being read, and which will be read, in all probability, until they are thumbed out of recognition.

It is said of the Emperor Nero, that among other studies he ardently followed that of magic. He employed immense sums, wrung from the sweat of Rome, in this pursuit; searched far and wide for professors, - penetrating the remote regions of India and Africa, - and even prowled among the ruined towers of Chaldsea. Rewards were offered, and threats of cruel torture not only lavished but carried into effect, and with what result? Absolutely none, for all the power of Rome could not raise up another Witch of Endor, nor prolong the Emperor's life for a single second. And yet there are in England at this moment thousands of busybodies who think they can, with their limited resources, accomplish what Nero, with all Rome at his back, failed to perform; and so they go on, blinking like owls over distressing paragraphs that no one either in heaven above, nor in the earth beneath, nor in the waters under the earth, can possibly construe into intelligible English. The only consolation is that these good people are out of harm's way, and may perhaps be laying up a store of patience which may serve their end when the fit is over. They are very good customers of the booksellers also, and rejoice exceedingly over one very small piece of silver which they persuade themselves they are on the eve of finding.

- M. A. G.

  Find the rest of this fantastic 19th century magazine of book collecting here:

"The Vagaries of (Occult) Book Buyers - III " from Book-Lore, a Magazine Devoted to Old Time Literature - 1887

Top 10 Craziest Things Scientists Used to Believe

Top 10 Craziest Things Scientists Used to Believe

Throughout history scientists have expressed crazy theories and, more often than not, they turn out to be exactly that – crazy ideas without any logic or scientific evidence to back them up. But that didn’t stop them being used for hundreds of years before someone told them to stop. While it’s easy to look down on some of these scientific theories and wonder just what the hell they were thinking, hopefully our future generations won’t have the same sentiment when they look back at our breakthroughs and endeavours. 10. Homunculus/Preformationism

Hartsoeker /public domain In its simplest form, this is the sperm version of Russian Dolls. Inside a man is sperm which looks like a tiny man, and inside him is a smaller sperm man, and so on and so forth. This theory didn’t just apply to humans but to every living thing, including vegetation. To take it one step further, scientists believed that because all of us were packed into the first load of sperm, all men had existed since the dawn of the universe in the first man, Adam, niftily explaining why we were all born with sin. However, being a spermist didn’t stop just there. It also seemed logical (at least to fellow scientist Paracelsus) that if you were to place human sperm inside a horse womb and feed it blood, you could develop your own tiny-man without the need of a woman. As all features of a baby were believed to come from the father and the mother provided just the womb, it seemed perfectly reasonable that a homunculus would mature in around 40 weeks. 9. Vulcan

Lith. of E. Jones & G.W. Newman – Library of Congress Keen astronomers will note that the planet Mercury has a different orbit to how it should behave under classical mathematical predictions. As a result, a theory circulated that there had to be a planet between the Sun and Mercury, named Vulcan, which was altering its orbit. Being so close to our shining star where the sky is never dark also explained why it was so hard to see. This wasn’t as far fetched as it might seem because it was believed that the solar system ended at Saturn. Uranus was suddenly discovered, opening up the possibility of more planets. This was proven true when Uranus’ orbit suggested an even bigger planet further out there and clever minds were able to perfectly predict the whereabouts and discovery of Neptune. However, when Einstein published his theory of relativity in 1915, it handily explained all the differences observed in Mercury’s orbit and meant that Vulcan was no longer needed. You might think this discovery would put all questions about Vulcan to rest, but this wasn’t the case. Amateur astronomers still claimed to have ‘found’ Vulcan up to the 1970s, until interest in this planet eventually seemed to fade away. The idea of Vulcan lives on thanks to the efforts of Star Trek writers who created a certain pointy-eared member of the Enterprise who hailed from a planet with the same name. 8. Alchemy

For centuries alchemists tried to create the Philosopher’s Stone – a legendary substance which was believed to contain the elixir of life as well as the ability to transform base metals into noble metals (for example the changing of lead into gold). Scientists dedicated their entire lives to the discovery of this fabled rock. Albertus Magnus even claimed he saw the transformation of rock into gold and legend believed that he possessed the stone, although the evidence of this discovery of immortality is somewhat sketchy due to his untimely death. Now debunked as nothing more than a myth, the seemingly magical properties of the Philosopher’s Stone consumed the minds of some of history’s most prolific scientists. Even Isaac Newton spent more of his time as an alchemist than he did into his physics research, which he treated as no more than a hobby. The study of alchemy did contribute in some ways to modern science, but we can’t help but wonder what else Newton may have advanced had he spent less time on this pseudoscience. However, alchemy shouldn’t be completely mocked. It is entirely possible to create gold from almost thin air. All we need to make this happen is a Large Hadron Collider to smash atoms together with incredible power, generating microscopic amounts of gold. The energy used may far, far outweigh the worth of gold produced, but no one said we had to be practical. 7. Humorism

Humorism is a theory which postulates that the human body is made up of four humors; black bile, yellow bile, phlegm and blood. When there is an imbalance, we become ill or suffer from disabilities if they are not treated with haste. The most well known form of humorism is bloodletting, primarily due to physicians believing blood was often the most imbalanced of all humors. As the name suggests, this is the removal of blood to cure or prevent illness, most often by leeches. When it came to how much blood had to be removed, they often waited until the patient fainted as this was a sign that their humors were in balance (and the leeches well fed). It was accepted that almost everything ranging from acne and indigestion to cancer and insanity could be cured due to the imbalance of blood. George Washington had close to 4 litres of blood removed via leeches to cure a sore throat. It didn’t help much as he died several hours later. Humorism was the standard care of practice in Ancient Greece, and it was slowly adopted by the Roman Empire before making its way to Islamic doctors. Whilst this may seem like a very outdated form of medicine, the astounding truth is that this was the primary form of care until the 19th Century when modern medicine began to disprove its usefulness. Granted, there are a few rare cases where bloodletting is a recognised form of treatment (such as high blood pressure), but let’s not go reaching for the leeches just yet. 6. Tobacco

Tobacco has long been used throughout history as a form of trade or to seal a deal through the smoking of a peace pipe. Although one would think that inhaling smoke was a not a good thing, this idea wasn’t accepted by mainstream public until the mid 60s, and it only gathered real steam almost two decades later. With the backing of famous adverts like “’more doctors smoke Camels than any other cigarette!”, physicians would often prescribe the use of tobacco to cure a variety of ailments such as asthma and as aides in weight loss. Perhaps one of the most bizarre health claims of cigarettes was the advisement which claimed pregnant women should smoke as they would give birth to smaller babies. Whilst a smaller size may help in childbirth, in hindsight we now know the pain of a wide birth canal far outweighs the negative effects of smoking during pregnancy. Although it was known that cigarette smoking did cause some problems such as throat irritation, it was stated that this only affected some people, usually those of a sensitive disposition. Instead of not recommending smoking at all, doctors were instead advising to use a different version of cigarettes (such as Lucky Strikes) which were marketed as less irritating to tender throats. Add this together with tobacco enemas and tobacco toothpaste and you might just wonder what health professionals were really smoking back then. 5. Radiation is good for you

It’s hard to believe there was once a time when scientists believed radiation was actually good for you, yet this was true during the early 20th century. As a direct result of this misguided belief, there were many popular radioactive products that were actively marketed as being good for the health, even curing such ailments as arthritis and rheumatism. These ranged from ingesting radioactive water, brushing your teeth with radioactive toothpaste thought to make your teeth shine and sparkle, to even lying down in uranium rich sand to sooth those annoying aches and pains. This practice continued well into the 1950s, with perhaps the most famous case being the Radium Girls. These factory workers were challenged with the task of painting watch dials with radioactive paint to make them glow in the dark. They didn’t just stop there; they would often paint their nails and teeth for fun. As we would now expect, many died or suffered from anemia or necrosis of the jaw, commonly known as radium jaw. One of the outspoken supporters of the safety of radiation was Nobel Prize winner Marie Curie. With her refusal to accept the dangers of radiation, Curie suffered from many chronic illnesses including near blindness induced by cataracts. Due to years of storing test-tubes wherever she felt, often in her coat pocket or desk drawer, her notebooks (and even cookbook) have such high levels of radiation they are considered too dangerous to handle and are stored in lead lined boxes. Nowadays it’s probably for the best that we stick to radiation free glow sticks for our glow-in-the-dark needs. 4. Mercury as a laxative

Despite being insanely toxic and requiring special handling, mercury was once used by scientists in a variety of very different ways. In the early 20th century mercury was often administered regularly as a laxative and dewormer for children as well as being used as an active ingredient in teething powders for young infants. Additionally, traditional medicine saw it being used for all conditions ranging from constipation and toothaches to depression and child-bearing. One of its most famous medical applications is the use of mercury in treating syphilis, which actually does help fight the disease. This is because one of the side effects of being dosed by mercury is a high fever, which syphilis is highly sensitive to. However, mercury poisoning also has the added bonus of frequently causing insanity and death, not dissimilar to the disease it was often used to treat. So before you crack open the thermometer as a home remedy, maybe seek a professional’s opinion first. 3. World Ice Theory (Welteislehre) In 1984 Hanns Horbiger proposed a concept in which all substances in the cosmos came from ice. Ice moons, ice planets and everything ice in between. Unlike most scientists on this list who were perhaps lacking in evidence to disprove them otherwise, Hanns came to this theory with no research, but through a vision. His dream immediately discredited Newton’s Law of Gravity (according to Hans at least). He worked with amateur astronomers to flesh out his theory before happily publishing his ideas. According to the theory, the solar system began when two stars collided. The impact of this caused fragments of the smaller, wetter star to be blasted out into space where it froze into giant blocks of ice; forming what we now know as the Milky Way as well as a bunch of other solar systems. The planets were formed when large chunks of ice collided with each other whilst the smaller blocks are what we know as meteors. When these collide with the Earth, they produce hailstorms. As suspected, academics paid little attention at first to his theory. Nevertheless, a segment of the general public actually began supporting his ideas in such strength that societies were founded, pamphlets were handed out and even a newspaper was published. Strangely enough, it began to spread into politics. Adolf Hitler was a firm believer and even adopted this theory as the Nazi Party’s official cosmological belief. After the end of World War II, this theory pretty much lost any support it once had. But be warned, there is still a small cult of followers out there, trying to melt away all scientific evidence which could leave their beliefs out in the cold. 2. Germ Theory

We all know the importance of washing our hands before preparing food, and we know that this simple task is also very important when it comes to performing surgery. This wasn’t always the case. Once upon a time the common belief amongst doctors and surgeons was that a gentleman’s hands were always clean, thus did not need to be washed. As you can probably guess, mortality rate was quite high. Ignaz Semmelweis, a Hungarian physician, noticed that when it came to birthing, two hospitals had very different death rates. The hospital for the poor, and therefore staffed by midwives, had far fewer cases of puerperal fever than the hospital staffed by the best doctors around. This seemed completely against common sense as the physicians were presumed to better trained than the midwives. He noticed that the physicians were doing autopsies on women who had died during childbirth with puerperal fever and then heading over to the operating room to deliver babies. Semmelweis concluded that the doctors were somehow poisoning the women, and at first he believed it was due to some sort of toxic chemical (we now know as germs). He concluded that the best way to prevent this was by washing the ‘toxin’ off. His theory paid off and mortality rates in the hospitals dropped to nearly the same rate (and also proved the midwives were just as effective as delivering babies as the doctors!). Although this should have made him into a well published scientist, his career didn’t quite go as planned. His ideas were rejected by the medical community when he could offer no acceptable evidence or explanation, and they weren’t excited to be told their hands were in need of a cleaning. His eventual breakdown had him committed into an insane asylum for the remainder of his life. 1. Lost Lands

Lost lands were believed to be continents, islands and regions which supposedly existed during the prehistoric era. It was thought that they had disappeared due to either a huge devastating geological event or because of the rising water level of the Ice Age. Although this now seems like the stuff of legend comparable to the fabled lost city of Atlantis, up until the late 1950s this was the central belief of scientists. When faced with similar fossils which had appeared thousands of miles across oceans, the easiest way to solve the reason for this distance was to draw a sunken bridge between the appropriate land masses on a map. At least six of these bridges were accepted as fact, all of which have since became obsolete and disproved. Alfred Wegener was among the first to observe how the different land masses of the Earth seemed to fit together like giant puzzle pieces, giving birth to the theory of Continental Drift. Whilst he attracted few supporters, his ideas were largely met with criticism and skepticism due to the top geologists being resistant to change and his lack of reason as to why the land masses had moved. The missing evidence he needed was tectonic plates. Like all good discoveries, these were found largely by accident. With the new invention of sonar, submarines during World War II spent a huge amount of time scouring the ocean depths, clearly showing the many plate boundaries. Although Wegener didn’t live long enough to see his theory became widely accepted, we’re sure he’d consider all their disagreements as water under the bridge by now.

https://ift.tt/2qvLBmG . Foreign Articles November 23, 2019 at 06:41PM

300+ TOP HOMEOPATHY Interview Questions and Answers

HOMEOPATHY Interview Questions :-

1. What Is Homeopathy? Homeopathy is a system of medicine which involves treating the individual with highly diluted substances, given mainly in tablet form, with the aim of triggering the body’s natural system of healing. Based on their specific symptoms, a homeopath will match the most appropriate medicine to each patient. 2. What About Historical Context? Homeopaths claim that Hippocrates may have originated homeopathy around 400 BC, when he prescribed a small dose of mandrake root to treat mania, knowing it produces mania in much larger doses. In the 16th century, the pioneer of pharmacology Paracelsus declared that small doses of "what makes a man ill also cures him." 3. What Are The Physical, Mental And Emotional Aspects Of Homeopathy? Homeopathy is based on the philosophy that the body, mind and emotions are not really separate and distinct, but are actually fully integrated. Based on this perspective, a homeopath seeks a remedy that fits all of a patient’s physical and psychological symptoms. Although some people’s symptoms may be complex, a well-trained homeopath will know which symptoms should be specially noted, and can choose an effective, individualized remedy. 4. Explain Level 1: First Aid? Homeopathy can be used in first aid to safely treat common ailments and occurrences, such as sprains and bruises, minor burns, skin irritations and reactions (including poison ivy, diaper rash and insect bites), teething pain, etc. 5. Explain Level 2: Acute Homeopathy? Acute health problems are those in which the symptoms will eventually go away on their own. They are temporary conditions, such as colds, flu, coughs, sprains, etc. A homeopathic remedy can be useful and attractive because it is safe, gentle and has no harmful side effects. Homeopathy can also be used to assist sensitive conditions such as pregnancy. 6. Explain Level 3: Constitutional Homeopathy? Constitutional homeopathy refers to the treatment of a person as a whole, including past and present symptoms. When accurately implemented, homeopathic constitutional care can elicit a profound healing response. Homeopathy can be extremely effective in treating chronic and long-term health problems. Recurrent ear infections, for example, can be treated with a homeopathic remedy for a longer period of time to strengthen the body’s immune system and to prevent future occurrences. 7. What Are The Three Levels Of Homeopathic Therapy? Level 1: First Aid Homeopathy can be used in first aid to safely treat common ailments and occurrences, such as sprains and bruises, minor burns, skin irritations and reactions (including poison ivy, diaper rash and insect bites), teething pain, etc. Level 2: Acute Homeopathy Acute health problems are those in which the symptoms will eventually go away on their own. They are temporary conditions, such as colds, flu, coughs, sprains, etc. A homeopathic remedy can be useful and attractive because it is safe, gentle and has no harmful side effects. Homeopathy can also be used to assist sensitive conditions such as pregnancy. Level 3: Constitutional Homeopathy Constitutional homeopathy refers to the treatment of a person as a whole, including past and present symptoms. When accurately implemented, homeopathic constitutional care can elicit a profound healing response. Homeopathy can be extremely effective in treating chronic and long-term health problems. Recurrent ear infections, for example, can be treated with a homeopathic remedy for a longer period of time to strengthen the body’s immune system and to prevent future occurrences. 8. What Is The Relationship Between Symptoms And Homeopathy? Symptoms are the language of a disease — the body’s attempt to balance itself. Without symptoms, a person could have a potentially life threatening illness with no way of identifying it. There have been many cancer patients who reported that they hadn’t suffered from a cold or flu in years prior to their diagnosis. The explanation was probably not that they didn’t have infections during this period, but more likely that their bodies were unable to fight these infections by producing necessary symptom indications. Many conventional drugs try to inhibit and suppress symptoms — sometimes leading to even more serious symptoms. Conventional (allopathic) physicians do not usually recognize the new series of symptoms as being related to the old. Thus, they treat them as new and unrelated problems. Did you know that a fever is the body’s attempt to activate the immune system’s white blood cells and defend itself from infection? If a person is given a symptom-supressing medication — fighting the fever — too soon, they will be less able to fight the actual infection. Homeopathy does not seek to remove or suppress symptoms. Its goal is to recognize and remove the underlying cause of these symptoms. This is why a homeopath will work toward understanding the whole person — including their body, mind and emotional state — before prescribing a remedy. 9. What Can Such Small Doses Be Effective? Homeopathic remedies are indeed very small doses. However, they are specially prepared doses which undergo a specific process — including dilution of ingredients (called potentization), as well as a vigorous shaking (succussion). Specially formulated homeopathic remedies are thought to resonate with the body, triggering a positive healing response. This response gently, and effectively, heals from the inside out. The documented results from thousands of experienced homeopaths, and from millions of their patients, clearly show that these small, individualized doses produce profound health benefits. 10. How Can The Correct Homeopathic Remedy Be Found? Finding the appropriate homeopathic remedy depends upon gaining a complete understanding of the patient as a whole person. This means that the homeopath must take note of the physical, mental and emotional levels of each person before deciding on a correct remedy. Homeopathic remedies have been described as "designer medicines." While this might seem like a simplistic and trendy view of homeopathy, it is true that remedies are specially "designed" for individuals based upon their unique, and sometimes complex, state of being. Take for example migraine headaches. We could easily demonstrate that one person might have pain on one side of their head, while another person had pain on both sides. Still another person could have nausea accompanying the migraine, and yet another could have dizziness. It is important to recognize that, in addition to the person’s physical symptoms, there are underlying psychological and emotional aspects as well. Homeopathic remedies are only given when the total continuum of physical and psychological symptoms has been identified.

HOMEOPATHY Interview Questions 11. What Is Homeopathy’s Approach? Homeopathy is based on a"whole person" approach. In homeopathy, the remedy or treatment program is customized and individualized to the patient, with the intent of removing the underlying cause. 12. What Is Conventional Medicine’s Approach? Conventional (allopathic) medicine usually relies on treating a patient’s physical symptoms. This treatment might also assume a person’s symptoms need to be controlled, suppressed or eliminated. 13. Explain The Homeopath’s Role As "detective"? It has been said that the work of the homeopath is to observe the patient, process and reflect on the gathered information, and then determine the underlying disturbance. This process can be thought of as a mystery, wherein the homeopathic "detective" attempts to discover where the flow of energy in the body has been blocked or impeded. Each signal/symptom offered by the patient can be thought of as a clue to determine the correct remedy. The patient’s eye contact, body posture, breathing patterns, voice quality, and expressions are also noted as potential clues. Next, the data must be reconstructed, as it might be in a mystery novel or movie. When all of the information about the patient’s physical, mental and emotional symptoms has been documented, then the final search for the answer begins. Unlike a detective — or medical physician for that matter — the homeopath’s goal is not only to remove the symptoms, but also to eliminate the essential causal problem by stimulating the body’s natural curative powers. This is the reason for obtaining such a detailed analysis of the patient. 14. Explain The Homeopathic Treatment? The goal of the homeopathic treatment is to encourage the body to return to a natural state of balance and health. Like the missing pieces of a puzzle, homeopathic medicines help "fill-in" the gaps in the body to stimulate a person’s own healing potential and energies. When this occurs, the person will have access to the body’s natural strength and wisdom, so that more conventional medicines and chemical-based substances may not be needed. 15. Tell Me Is Homeopathy Merely Psychological? If you think you must "believe in" homeopathy for it to work, you need to know that it is not a placebo effect. Here are some powerful examples: Infants: Homeopathic remedies and treatments are successfully used by parents for common infant ailments such as colic, teething pain and some infections. Animals: There are many veterinarians using homeopathic medicines to treat domestic pets such as cats, dogs and birds, as well as barnyard animals like goats, horses and cows. Is it possible to have a placebo effect with animals? Millions of people across the world use and rely on homeopathic remedies. Today there are a rapidly growing number of conventional medical doctors using homeopathic medicines, including: 39% of French family physicians 20% of German physicians 10% of Italian physicians Moreover, in many European countries there is a growing trend of medical doctors referring patients to homeopathic physicians. 16. What Is The Patients Role? Open Communication & Observation: While it is the homeopath's job to elicit relevant information by asking probing questions, the patient can expect a higher chance of receiving an effective homeopathic remedy if he or she is open and truthful in describing their physical and psychological symptoms. It is also important to be observant of the changes taking place in your system. To that end, you might want to keep a journal or notes on any noticeable changes or shifts in your symptoms or health. Substances to Avoid: Another important thing to remember is that it is wise to avoid any substances that might interfere with your remedy. Certain substances have been found to reverse (&qout;antidote") the effects of homeopathic remedies and medicines. It is suggested that you avoid the following substances, practices and items to insure the best response from your remedy: Avoid: Coffee Camphor, or camphorated products including products containing eucalyptus and camphor oils Dental work, teeth cleaning, drilling or anesthetics Electric blankets Mint, or mentholated products Nicotine Recreational drugs Some conventional drugs (Be sure to tell your homeopath what you are taking) X-Rays Stress, which can lower the resonance of a homeopathic remedy 17. Is Homeopathy A Proved Science? It definitely is. Homeopathy is a science based on sound logic and vast experimental data. Homeopathy is the only medicinal science where data has been collected by proving on human beings and not on animals because human beings can communicate their actual feelings during the testing while animals cannot. The principles of Homeopathy have been derived and authenticated by vast clinical experiments and data. The homeopathic medicines are prepared in a standardized manner. The homeopathic pharmacopoeia lists more than 3000 remedies, whose clinical efficiency has been proved in various clinical trials conducted all over the world. 18. What Are Homeopaths Qualified Doctors? Yes. There are more than 180 homeopathic medical colleges in India and about 1000 colleges all over the world recognized by their respective Governments. The degree course is an extensive study encompassing the detailed and thorough study of the human body, Homeopathic pharmacy, Medicine, Gynaecology, Materia Medica, Philosophy, Total patient management etc. In India the full course lasts for four and half years followed by internship for 1year, which includes practical training in hospitals. There are now also postgraduate courses available in India. One must register with the Medical Council to practice legally. 19. Explain Is It True That Homeopathic Medicines Are Only Placebos (sugar Pills)? No. The pills of Homeopathic medicines are made from sugar but they work only as vehicles. Actual liquid medicine prepared from various natural medicinal substances, is poured over the pills and dispensed as medications. Homeopathic medicines are also available in liquid form or tinctures, which can be administered directly or by diluting them in water whenever required. 20. What Does The Homeopath Give The Same White Pills For All Illnesses/patients? What seems so is not true. The white pills which are dispensed from a homeopath are only neutral vehicles or carriers of actual medicines that is sprinkled on them.When the actual drug is poured on these white pills they get coated with the curative power of the drug. Different drugs are usually poured in various differing potencies as to best suit different patients. There are about 3000 medicines and 10 variable potencies (powers of medicines) of each medicine so minimum 30,000 various permutation and combinations are utilized. HOMEOPATHY Interview Questions with Answers 21. What Does One Have To Take The Medicines For A Long Time? Usually not. The duration of the treatment depends upon the nature of the disease and the fighting capacity of the patient's body. The treatment is required for a certain time period so as to improve the resistance of the body to fight diseases. Taking into consideration all these factors the treatment is continued for a certain time frame for the benefit of the patient. Once the patient starts improving we stop the medicines and the natural immunity and control mechanism of the body will take care of the rest of the problems. 22. What Does Homeopathy Take A Long Time To Act? It is a myth that medicines act slowly. Its action is quick and the effect lasts much longer, often forever. The disease is cured from its roots. With most of the other systems of medicine symptoms are merely palliated or at times suppressed while in Homeopathy they are cured for good. The time taken for the cure is proportionate to the chronicity of the ailment. In fact if a patient seeks homoeopathic treatment at the onset of an ailment, he stands great chances of a really quick recovery. Also in acute illnesses homoeopathic medicines act fast and effectively. For e.g. if "X" is suffering from bronchial asthma and he is suffering for the last 14 years and has been to various systems of medicine. Now if you give him homeopathy and say in 2 years time the patient is completely alright - Please tell us which one is slower? 23. Why Detailed History? Detailed history is very essential as homeopathy believes in treating the individual and not the disease. So the physician needs to know the individual and not about his disease. Also the chronic diseases are due to suppression of skin affections or emotions; hence detailed history will reveal whether any past ailments suppressed has lead to the present complaints. Every incidence affects our life, so it is very important to know all the incidences and its impact it had on the patients. Hence a detailed history right from the childhood till date is needed to find the right medicine which suits the patient. If you co-operate and give honest and detailed history we can help you to achieve better and healthy life. 24. What Will The Homeopath Need To Know? The homeopath needs to know every minutest detail about you which characterizes you, something which is unusual about you, so that he can find the right remedy for you. Homeopath needs to understand you, your nature, your complaints and your disturbed mental and emotional state in order to reach to the core of your case. Any peculiar habit that you have, your past medical history, past affairs, about your childhood details, any thing and every thing about you will help the physician to help you. So if you give an honest and correct history to the physician, he can assess your case accurately. Anything that you confide in your physician will be strictly confidential and helpful. 25. Tell Me Do Homeopathic Medicines Have Steroids? No. It is a misconception that has been developing in the recent times. Due in many cases after seeing the improvement in a very short time people think that homeopaths give steroids. All Homoeopathic medicines are prepared by using scientific predefined methods of extracting the medicinal properties from source substances. There is no scope or need to adulterate the derived medicines with any other substances, as this would completely obliterate the curative properties of the same. The prescription of homoeopathic medicines is based on the similarity of the symptoms of the patient with those produced by the drug (in its purest form) when proved (clinical trials) in healthy individuals. So any addition to the original medicine would completely alter its medicinal properties and hence alter it non-curative. Also if steroid is added the medicines will taste bitter. If the patient has any doubts he should check the medicines from a standard laboratory before consuming any quantity. 26. Why Do Homeopaths Do Not Tell The Name Of The Medicines That Has Been Given? The name of the medicine is not disclosed for the benefit of the patient. If the patient after knowing the name of the medicines starts taking it according to his or her whims and fancies; it will distort the disease picture and in the future treatment of the patient will be much more difficult. Also certain medicines have to be changed and given as per the state of the disease and recovery. If the patient wants a copy of case record can be provided to the patient but at the end of the treatment, when patient has completely recovered. 27. Homeopathic Dilutions Cannot Act As Medicines Because Beyond Avogadros Number There Is No Drug Substance Left. Is It Correct? No, they definitely act. This misconception persisted for a very long time and there was no technique to demonstrate the same. But new researches show that dilutions definitely act. For example: When rats are drugged with the substance Arsenic, they excrete the same in the urine to a certain extent. When these rats are given potentised Arsenic the rate of excretion increases considerably; and higher the potency, the faster is the elimination. Another experiment showed that when homeopathic Belladona potentised) was given to guinea pigs, it produced contractions in the ileum (part of intestine); and higher the potency stronger was the contraction. Though this is yet a hypothesis, it seems that beyond Avogadro's number, the molecules in solutions appear to develop a 'stamp' or 'image' of the original substance, which does not get wiped off even in extremely diluted preparations. As the proof of pudding is in eating. Proof of effectiveness of homeopathic medicine is in results. Once you see good results you are convinced about its efficacy. 28. What Are There Any Side Effects Of Homeopathic Medicines? No, there are no side effects of homeopathic medicines. Some times the symptoms may get aggravated for short period of time, but this is a good sign that the homeopathic medicine is right and has started acting. Sometimes you may get cold, skin rash or little discharge after taking homeopathic medicine that means the system is getting cleared. In the same way your old symptoms like constipation, warts or any skin rash may reappear, do not take any medicine to treat these reappearing old symptoms, as these old symptoms will go away in short period of time and you are healed completely and permanently. 29. What Is Cure Possible With Homeopathic Medicines? Homeopathy is curative. It treats the cause (internal malady or the imbalanced energy) and not the expression (diagnostic symptoms specific to the disease) of the disease. The symptoms are only used as an indication to select the right remedy for the individual. It treats the person as a whole and not his individual body parts. Homeopathy takes into account the expressions of an illness characteristic to the individual and a curative remedy chosen on this basis gives a gentle and permanent cure at the earliest. 30. Explain Should One Take Homeopathic Medicines Only From A Qualified Doctor? Yes, he should. There have been instances of miracle cures by lay people practicing homeopathy, but it is always advisable to go to a homeopathic physician, as he is qualified to judge the severity and depth of your illness and thereby prevent undue complications later on, which could be overlooked by a hobby practitioner due to his ignorance of scientific medical knowledge. Only a qualified physician can guide you towards a complete mental, emotional, spiritual, physical and pathological recovery. 31. Explain Does Homeopathy Believe In Disease Diagnosis And The Pathological Investigations? Yes. It is very essential to diagnose a disease, but for the selection of the remedy we require to know the characteristic symptoms of the patient and not the disease symptoms. For e.g. If a person is having an attack of asthma, he will be having wheezing and congestion of the chest and he gets relief only if he throws his head backwards. Wheezing and congestion of chest are symptoms of the disease but for the selection of the remedy the important symptom is 'relief by throwing head backwards'. Hence to differentiate the disease symptoms with the individual characteristic symptoms good knowledge of disease is important. The pathological investigations are also important to judge the improvement, know disease diagnosis and the prognosis. 32. Explain Are There Any Food Restrictions During The Treatment? Yes the patient is only advised to avoid eating or drinking 15 minutes before or after taking homeopathic medication. One has to avoid coffee, raw onion and raw garlic. Also avoid eating mint, camphor and menthol as these can hinder the action of the homeopathic medicine or antidote the effects of the medicine. 33. Tell Me Can Patients Suffering From Diabetes Take Homeopathic Medicines? Yes why not? As the daily dietary intake of sugar by a person would normally far exceed the minuscule quantity consumed in the form of homeopathic pills (Approximately the quantity of sugar consumed with 1 cup of tea is same as being consumed by entire week of Homeopathic medication). The patient also has an option of taking the medicines in liquid form, or by inhalation. Besides this, homeopathic pills are composed of lactose that is not harmful even for diabetes. 34. Tell Me Does One Have To Stop Other Medicines Which The Patient Has Been Taking? No. The patient should not stop the medicines which he has been taking. It should be tapered gradually once the patient is improving but this should be done in consultation with the treating physician. In some cases where the other medicine cannot be discontinued, both the medicines have to be continued for the benefit of the patient. The treatment should be planned and properly implemented. 35. Explain Do Homeopathic Medicines Bring About Aggravation Initially? In some cases there is an initial aggravation of the symptoms but it is a good sign that shows the medicine is right and has started acting. But this happens in a few cases and not all patients will have an aggravation; most of the patients have simple long lasting amelioration. 36. Tell Me Is It Safe To Take Homeopathic Medicines During Pregnancy? Yes. It is always better to take homeopathic medicines from a qualified homeopathic doctor. If the treatment is planned in a proper way it will have lots of benefits to the mother and the child. The child will be much healthier and the medicines will help to fight the hereditary diseases which are carried from generation to generation. In fact if homeopathy is given during pregnancy, the delivery would be normal and easier. The child will be relatively healthier and emotionally well balanced, intellectually sound and physically stronger. 37. In Which Disease Condition Homeopathic Treatment Is More Effective? There is no condition that Homeopathy cannot treat. Conditions from a simple cold to cancer can be treated with Homeopathy. It takes into account the individual symptoms of the patient suffering from any disease and not the diagnosis of the disease. By the virtue of this certain diseases that cannot be diagnosed clinically or even unknown diseases can also be treated. Also in incurable cases where even the modern line of treatment fails to help the patients, homeopathy will prove to be a very good palliative and will improve the last days of life and ease the death. This happens in advanced stages of cancer, we can relieve pain very easily and effectively. 38. Is Homeopathic Treatment Effective For Children, Adults, Woman And Elderly? Homeopathy has no bar for age and sex; it is equally effective for every human being in every stage of their life from birth till death. 39. Tell Us Does Homeopathy Work In Acute Cases? Yes. Homeopathy has wonderful remedies that give prompt relief in acute cases like fever, cough, cold, diarrhea, headaches etc. when the person opts for homeopathy at the onset of the ailment. 40. Tell Me Does Homeopathy Believe In Surgery? Yes, it does. Surgery is a separate branch of medicine. It has to be resorted to in conditions that are beyond the domain of medicine. But one can avoid surgery in certain cases as homeopathy can effectively treat many so called surgical conditions like tonsillitis, piles, warts, kidney stones etc. HOMEOPATHY Questions and Answers Pdf Download Read the full article

Safety Based Limits for the Control of Impurities in Drug Substances and Drug Products: A Review-Juniper Publishers

Introduction

Paracelsus, the medieval physician, who is often viewed as the father of modern toxicology, was the first person to appreciate that "the dose makes the poison". This essentially means that very toxic materials can be used therapeutically at very low concentrations and conversely even safe materials can be toxic if overdosed. This in turn led to Haber's law, which basically states that, the incidence and/or severity of any toxic effect is dependent on the total exposure to the toxic agent; that is, the exposure concentration (c) rate(or dose) multiplied by the duration time (t) of exposure (i.e. cxt). This law is often utilised in setting exposure limits for toxic components. The major caveat, is that establishing acceptable daily intakes (ADIs) for long-term exposures to a toxic substance when only data from short-term studies are available, does require the use of an uncertainty or safety factor.For example, cancer risk estimates are typically based on the average lifetime daily dose (LDD), which in turn is derived from the total cumulative exposure, using Haber's law, i.e. cxt. Gaylor [1] proposed a modified Haber’s law to better extrapolate safe levels based on shorter term exposure intervals and this takes the form of:            c3x t=c’3x t'where c and t are the known safe exposure levels(c) based on the longer exposure duration (t) and c’ and t' are the projected safe concentration (c’) based on the pre-defined shorter exposure duration (t’). Haber’s law is equally germane to impurities as it is to medicinal products.Impurities in New Drug Substances and New Drug Products (Ich Q3a/ Ich Q3b)One of the first international guidance that used safety based limits for impurities was the international conference on harmonization (ICH) Q3A [2]. This provided an overview of the typical impurities that were found in new drug substances and their controls. Impurities were evaluated based on both chemistry considerations, including "classification and identification of impurities, report generation, listing of impurities in specifications, and a brief discussion of analytical procedures"; and safety considerations, including "specific guidance for qualifying those impurities that were not present, or were present at substantially lower levels, in batches of a new drug substance used in safety and clinical studies"Impurities were further delineated into identified and unidentified classes, both of which were included as specification tests [3]. This includes unidentified impurities that were known to be present at levels greater than pre-defined reporting, identification and qualification threshold (Table 1). Those unidentified impurities are often defined on the drug substance specification "by an appropriate qualitative analytical descriptive label (e.g., "unidentified A", "unidentified with relative retention of 0.9")"1. The amount of drug substance administered per day;2. Reporting Threshold: A limit above (>) which an impurity should be reported. Reporting threshold is the same as reporting level in Q2B (4);3. Higher reporting thresholds should be scientifically justified;4. Lower thresholds can be appropriate if the impurity is unusually toxic;5 Identification Thresholds: A limit above (>) which an impurity should be identified;6 Qualification Thresholds: A limit above (>) which an impurity should be qualifiedThe reporting threshold was linked to the capability of the supporting analytical methodology [4]. Identification threshold was the limit where the unknown impurity was required to be identified by appropriate analytical methodology. Whereas, the qualification threshold necessitated acquiring and evaluating pre-clinical safety data that "establishes the biological safety of an individual impurity or a given impurity profile at the level(s) specified".Interestingly, although the derivation of the reporting threshold was linked to method capability, the derivation of the identification and qualification threshold limits were never fully delineated, apart from linkage with the maximum daily dose of the product. In addition, for those impurities "known to be unusually potent or to produce toxic or unexpected pharmacological effects, the quantitation/detection limit of the analytical procedures should be commensurate with the level at which the impurities should be controlled". Again, the implicit meaning of this statement was never fully articulated, but it was the genesis for the subsequent guidance on mutagenic impurities, initially termed genotoxic impurities [5].Similar guidance was provided for impurities typically found in new drug products. These impurities are usually termed degradation products [6]. There was greater delineation of the thresholds in terms of dose (Table 2). However, it was never fully explained why the various thresholds, in terms of maximum daily dose, could not be aligned. Thus there is the confusing scenario that the reporting thresholds are above or below 1g; whereas, the identification thresholds are divided into four (>2g, >10mg- 2g, 1mg-10mg and <1mg); whilst the qualification thresholds were also divided into four, but were not aligned with the classes defined in the identification thresholds (>2g, >100mg-2g, 10mg- 100mg and <10mg).1 The amount of drug substance administered per day;2 Thresholds for degradation products are expressed either as a percentage of the drug substance or as total daily intake (TDI) of the degradation product. Lower thresholds can be appropriate if the degradation product is unusually toxic;3 Higher thresholds should be scientifically justified.The other confusing aspect was that the maximum daily dose (mg/day) and the maximum strength of a product (mg) are often not the same value. Thus for instance, the anti-malarial drug quinine sulfate [7] has a maximum therapeutic dose from the product label of 648mg every 8hours, i.e. 1944mg/day; whereas, the highest dose strength are 324mg/capsule. The analysts testing and releasing quinine sulfate capsules will do so on the commercial product (324mg/capsule), not the maximum dose taken by the patient (1944mg/day). In addition, although reporting thresholds are always measured as percentage values and are easily aligned with the data output from the method used by the analyst; identification and qualification thresholds are measured in either percentage values or mg/day values (Table 3).The other aspect of having safety based limits for impurities is that it does not reflect the duration of treatment use for that drug and results in the same limits being proposed irrespective of whether the drug is proscribed pro ne rata (PRN) or as required, e.g. for constipation, mild pain, etc., or through life time treatments, e.g. for treatment of high blood pressure, etc. ICH Q3A [2] and Q3B [6] were always intended to be only applicable to marketed products, but the regulatory expectations during clinical development often exceed what is actually required. For example, it isn't unusual to see the following expectations [8]: "For phase I expect structure (or identifier) and origin For phase II expect Limit of Detection and Quantification and actual impurity levels to be established (aligned with ICH Q3A, Q3B, etc)".However, by phase II the final synthetic route and process of the drug substance are rarely identified or optimised, and the attrition rate of phase II drugs is still very high [9]. What the regulatory guidance enshrined in ICH M3 [10], actually states with respect to impurities is, "If specific studies are warranted to qualify an impurity or degradant, generally these studies are not warranted before phase 3 unless there are changes that result in a significant new impurity profile (e.g., a new synthetic pathway, a new degradant formed by interactions between the components of the formulation). In these latter cases, appropriate qualification studies can be warranted to support phase 2 or later stages of development"Residual Solvent Impurities (ICH Q3C)Although residual solvents are mentioned in ICH Q3A [2], a separate guideline, ICH Q3C [11], was developed to provide safety based guidance on the allowable limits of common residual solvents within pharmaceuticals. As there are "no therapeutic benefits from residual solvents, all residual solvents should be removed to the extent possible to meet product specifications, good manufacturing practices, or other quality based requirements". Additionally, ICH Q3C recommends the use of less toxic solvents. Thus, solvents that are known to be highly toxic (Class 1) should be avoided during the production of drug substances, excipients, and especially drug products, unless their usage can be justified using a risk-benefit assessment [12]. In addition, some solvents with intermediate toxicity (Class 2) should also be limited from a patient safety perspective. Ideally, the least toxic solvents (Class 3) should always be used where practical. Recommended limits for all solvents may change as additional safety data become available. In addition, supporting safety data for new solvents may be added to the guidance.Although tolerable daily intake (TDI) and acceptable daily intake (ADI) were both in common usage, ICH Q3C (12) introduced a new term, permitted daily exposure (PDE) to avoid confusion of differing values for ADI's for the same substance. In addition to avoidance of class 1 solvents, the concept of "as low as reasonably practicable" (ALARP) was introduced and is applied to class 2 solvents and often to class 3 solvents. Indeed, regulatory agencies will often use process capability arguments to drive down residual solvent levels below the safety based limits [13] derived from ICH Q3C.Residual Elemental Impurities (ICH Q3D)Residual elemental impurities were also mentioned in ICH Q3A [2], but again a separate guideline, ICH Q3D (14) was developed to provide safety based guidance on the allowable limits of residual elements within pharmaceuticals. As elemental impurities provide no therapeutic benefit to the patient, "their levels in the drug product should be controlled within acceptable limits" [14].The ICH Q3D guideline is sub-divided into three parts: the derivation and assessment of toxicity data; the establishment of a PDE for each elemental impurity derived for three different routes of administration (oral, inhaled and parenteral); and application of a risk based approach to control elemental impurities (as per ICH Q9 (12)). One difference from ICH Q3C [11] is that applicants are not expected to tighten the safety based limits based on process capability considerations, as long as the residual elemental impurities do not exceed the PDE values. However, in certain cases, levels below the PDE may be warranted when lower levels have been shown to positively impact on other critical quality attributes (CQAs) of the drug product; for example, element catalyzed drug degradation (this is particularly common with oxidative degradation mechanisms [15]. In addition, for those elements with higher PDEs, lower limits may have to be assessed from a pharmaceutical quality perspective. Residual elements are classified into 5 different categories: class 1, 2a, 2b, 3 and others (Table 4).ICH Q3D [14] provides a platform for developing an ICH Q9 (12) aligned risk-based control strategy to limit elemental impurities within the drug product. Although, the guidance had highlighted the risk inherent from both drug substance and excipients, the reality based on a multi-product assessment is that the risk is low. Li et al. [16] tested 190 samples from 31 different excipients and 15 samples from eight different drug substances for residual elemental impurities. The results show relatively low levels of elemental impurities are present in the samples tested.Residual mutagenic impurities (ICH M7)ICH M7 [5] is focused on DNA reactive impurities that can potentially cause DNA damage, when present at low levels, and thus can potentially cause cancer in man. Importantly, other types of toxic impurities that are non-mutagenic will typically have a threshold mechanism and as such usually do not pose carcinogenic risk in man, at the levels typically seen for impurities.A Threshold of Toxicological Concern (TTC) approach was introduced to describe an "acceptable intake for any unstudied chemical that poses a negligible risk of carcinogenicity or other toxic effects", this equates to a virtually safe dose (VSD). The methodologies that underpin the TTC are universally considered to be very conservative, as they use a simple linear extrapolation from the TD50 dose (i.e. dose giving a 50% tumor incidence) to a 1 in 106 likelihood of cancer occurrence.A default TTC value of 1.5μg/day corresponding to a theoretical 10-5 excess lifetime risk of cancer can therefore be justified for mutagenic impurities. Some high potency groups referred to as the "cohort of concern", e.g. aflatoxin-like-, N-nitroso-, and alkyl-azoxy compounds; were identified where the default TTC would still pose a significant carcinogenic risk. These high potency compounds were excluded from the TTC approach.ICH M7 [5] bases acceptable intakes for mutagenic impurities on established risk assessment approaches (see ICH Q9 [12]. As such, acceptable risk during the early development phase is established at a higher theoretically calculated risk level of approximately one additional cancer incidence per million, i.e. 1 in 106 risk levels. For later stages in development (Phase III) and for commercial products, the risk level is reduced to one in one hundred thousand, i.e. 1 in 105 risk levels. It is worth highlighting, that these risk levels represent a small theoretical increase in risk when compared to the overall lifetime incidence of developing cancer in man, which is greater than 1 in 3.The initial risk assessment is undertaken on the drug substance synthetic pathway to identify real or potential impurities that may be reactive and thereby mutagenic in nature. In parallel, the formulation and manufacturing process are also assessed for the formation of any reactive degradants (both real and potential), that could be realistically expected to form during long term, real-time storage conditions. In silico structure- based assessments, i.e. Derek Nexus, Sarah Nexus, etc., are used for predicting mutagenicity based upon QSAR (quantitative structure activity relationships) approaches. These findings are then reviewed by toxicology experts to provide any additional understanding as to the relevance of these predictions (both positive and negative), and in the case of contradictory outcomes to understand those differences. Based on this assessment, impurities are categorised into five different classes in order of decreasing regulatory concern (Table 5).1. For class 1 compounds, i.e. those which are known mutagenic carcinogens, an AI (acceptable intake) or a PDE (permitted daily exposure)approach has been introduced (ICH M7(R1) (17)). These limits are based on either (i) linear extrapolations from TD50 (AI) or (ii) threshold-based PDEs. There are 10 compounds covered by the AI approach and a further 3 covered by the PDE approach.2. LTL (less than lifetime limits)3. TTC (Threshold of Toxicological Concern)It is anticipated that monitoring and control strategies (including analytical methods) will be less developed during earlier clinical phases, where overall development experience is of necessity limited, compared to later clinical phases and commercial manufacture. ICH M7 [17] proposesa control strategy using four control options for mutagenic impurities, of these only one includes control of the mutagenic impurity on the API specification (option 1). Options 2 and 3 define some levels of in-process control; whereas, option 4 is centred on process understanding alone, typically termed "Purge Arguments" [18].It is should be emphasised that these established cancer risk assessments are based on lifetime exposures, i.e. 75 years. Thus, Less-Than-Lifetime (LTL) exposure based limits can be derived both during development and commercial use. LTLs can have higher acceptable intakes of mutagenic impurities and still maintain comparable risk levels, which is obviously an application of Haber's law. Therefore, the carcinogenic effect is predicated on both duration of exposure and dose. Thus for example, "if the compound specific acceptable intake is 15 |ig/day for lifetime exposure, the less than lifetime limits (Table 6) can be increased to a daily intake of 100 |ig (>1-10 years treatment duration), 200 |ig (>1-12 months) or 1200|ig (<1month)" [5]. This LTL approach may also be appropriate "in diseases with reduced life expectancy, limited therapeutic alternatives or chronic diseases with late onset" [19].It is worth emphasising that exceeding the default TTC or LTL limits is not necessarily linked with an increased cancer risk in man, given the extremely conservative suppositions employed in the evolution and derivation of the TTC or LTL values. For instance, higher exposure to a potential mutagenic impurity, e.g. formaldehyde, may be reasonable when exposure can be significantly greater from other sources, e.g. endogenous metabolism, food, etc. The most likely increase in cancer incidence is actually much less than 1 in 100,000. In addition, in cases where a mutagenic compound is a non-carcinogen in a rodent bioassay, there would be no predicted increase in cancer risk. Based on all the above considerations, any exposure to an impurity that is later identified as a mutagen is not necessarily associated with an increased cancer risk for patients already exposed to the impurity. A risk assessment would determine whether any further actions would be takenIn principle, ICH M7 does not apply to advanced cancer therapeutic indications (covered by ICH S9 (20)), where the drug is itself genotoxic. ICH M7 does not apply to established excipients, flavouring agents and certain biological products, including herbal medicines. Existing commercial products are also exempted, apart from where there are new safety data (including new mutagenic data) for existing impurities; significantly, structural alerts alone do not trigger regulatory concern. However, ICH M7 does cover changes to marketed products, including new marketing applications and postapproval submissions.Impurities in oncology products (ICH S9)ICH S9 [20] was developed to provide guidance for nonclinical studies for the development of anticancer pharmaceuticals used in clinical trials for the treatment of patients with advanced disease and limited therapeutic options. During the development of oncology products, supporting clinical studies often involve cancer patients whose prognosis is poor and projected lifetime is short (<2 years).As such, the guideline objectives are to facilitate and accelerate the development of these anticancer pharmaceuticals whilst protecting patients from unnecessary adverse effects. In addition, ethical use of animals, in accordance with the 3R principles (reduce/refine/replace) are paramount. Importantly, the principles described in other ICH guidelines need to be considered in the development of oncology products; whereas, those specific situations where requirements for nonclinical testing may diverge from other guidance are described in ICH S9.Additionally, the dose levels used in these clinical oncology studies are often at the top end of the tolerable range [21] and often result in adverse effect dose levels. Hence, "the type, timing and flexibility called for in the design of nonclinical studies of anticancer pharmaceuticals can differ" significantly from nononcology pharmaceuticals. Historically, limits for impurities (see ICH Q3A [2] and Q3B [6] have been based on a negligible risk to the patient. In oncology products this consideration, whilst important, is not as important as patient wellbeing and exceeding the ICH Q3A [2]/Q3B [6] limits for impurities may be applicable and an appropriate justification should be included in the marketing application.This explanation should include an overview of the disease being treated, including patient prognosis, the nature of the drug itself (pharmacology, genotoxicity and carcinogenicity, etc.), the total duration of treatment, and the impact of any reduction in impurity levels on manufacturability. Furthermore, the qualification of these impurities may include reflections on the concentration tested in supporting nonclinical studies compared to the levels seen in clinical batches. In addition, TTC, LTL and AI/PDE limits for mutagenic impurities (see ICH M7 [5]) are inappropriate for oncology products and justifications can be used to set higher limits. Interestingly, the guidance does not specifically say that the applicant can default to ICH Q3A [2]/ Q3B [6] limits, although this is often inferred. Impurities that are also metabolites can be considered to be suitably qualified.Interestingly, regulators have been very unwilling to extend the philosophy of ICH S9 [20] beyond oncology products, for instance into rare diseases [22], where lifetime expectancy can be similarly short, i.e. <2 years and where patient expectations are equally high.New Reflections on ImpuritiesHarvey et al. [23] used a variety of chemical databases to demonstrate that the 1mg/day impurity level for an unqualified impurity of unknown toxicity, proposed by ICH Q3A [2] (Table 1) is indeed a robust prediction of a virtually safe dose (VSD) for non-mutagenic impurities. Then using the modified Haber's law, where C=1 mg and t=75 years (i.e., 27375 days) and t is 6 months or 182 days they determined a VSD for this shorter exposure interval of 5 mg/day (i.e. 5 times higher than existing ICH Q3A limit). However, for very potent drugs with effective doses of <1mg, a 5mg/day limit for a related impurity isn't realistic from either a safety or quality perspective. Therefore, the authors also introduced a percentage cut off based on 5x the ICH Q3A qualification threshold of 0.15%; i.e. 0.7%. Thus the proposed limits for drug substances are 5mg or 0.7%, whichever is lower.This allows applicants to adopt the existing ICH Q3A guideline which were developed for commercial products and apply them to development products, in much the same way that the ICH M7 guidelines allows LTL limits for mutagenic impurities, for early clinical development. For drug products, similar LTL limits for non-mutagenic impurities can be derived based on a modification of Haber’s law. The additional constraint of a percentage limit of 0.7% need not be applied to drug products as the more potent the drug substance becomes, the lower the dose required. The authors therefore suggested a limit of 5 mg or 2%, whichever is lower, for exposure intervals of <6 months, for general drug substance impurities, i.e. non-mutagenic.In addition to absolute amounts of unknown impurities, the other key focus is those impurities with unusually high and/ or specific toxicities. Whilst it is recognised that mutagenic impurities constitute the greatest threat to patient safety and they have been addressed via ICH M7; there are other classes of non-mutagenic impurities that will still give cause for concern. The three principal classes of toxic impurities are(i) polyhalogenated, dibenzodioxins, dibenzofurans and biphenyls that are non-mutagenic carcinogens, which have specific regulatory framework with respect to acceptable exposure levels [24],(ii) organophosphates or carbamates that are neurotoxins and have their own threshold of concern [25] and (iii) β- lactam like impurities that have the potential to cause anaphylaxis and which currently do not have any threshold of concern [23].It is worth highlighting that(a) These impurities are extremely rare and do not reflect the typical structure of impurities generated by medicinal research [26,27] and(b) That these structural motifs (if present) would be highlighted and addressed as part of the ICH M7 risk assessment [5] , as "the findings from any mutagenic risk assessment are also reviewed by toxicology experts"ConclusionSafety based impurity limits are a core consideration of all of the existing ICH Q3 guidance documents. However, there has been an evolution in the approach toward impurities since the publication of the initial guidance [2,6]. Whereas, ICH Q3A [2] and Q3B [6] provide general guidance on impurities in drug substances and drug products, respectively and mainly focus on absolute levels of impurities, i.e. percentage based limits; later guidance focused on individual impurity classes; i.e. residual solvents [11], residual elemental impurities [14] and mutagenic impurities [5] and had a greater focus on daily exposure limits. In the latter cases, this led to the introduction of various impurity specific limits, such as PDEs, Als, TTCs and staged TTCs, all aimed at defining a virtually safe dose (VSD). This in turn led to the introduction of LTL limits for mutagenic impurities.LTLs are based on an application of Haber's law which states that concentration and exposure times are both critical for assessing likely safety risk to patients. Surprisingly, LTLs have not been applied to the other specific classes of impurities or indeed general impurities. In order to address this deficiency, Harvey et al. [23] have assessed the underpinning data behind the current "1mg or 1%, whichever is lower" limit in ICH Q3A [2] /Q3B [6], and they found this to be based on robust science and they proposed an ancillary LTL for general impurities of 5 mg or 0.7%, whichever is lower, for clinical studies with durations of less than 6 months.Logically, the toxicity of the parent drug substance also affects how we deal with impurities, even very toxic impurities. Thus, there is limited, if any, additional impact on patient safety for impurities where the parent drug substance is mutagenic, carcinogenic or cytotoxic. Accordingly it was recognised that for oncology products, impurity levels (even mutagenic impurities) could be controlled at higher levels. This "higher level" wasn’t defined but is based on an overview of the disease being treated, including patient prognosis, and the nature of the drug itself. Additionally, from a risk based perspective and an understanding of Haber's law, an overt focus on impurity control makes little sense if the life expectancy of the affected patient is short, i.e. less than 2 years [20]. Interestingly, there has been little regulatory appetite for widening this entirely pragmatic approach to impurity control to other therapeutic areas, where life expectancy is equally short, i.e. rare diseases [22].

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The soul can only return to her divine state after having been purified of her earthly desires. Her reason and free will must take part in the sufferings belonging to the material state, until she attains knowledge and becomes free from desires. For this purpose she clothes herself at certain periods in a physical form (reincarnates as a human being), until she has laid off her desires. The more the soul frees herself from her gross external coats the higher can she rise. - PROCLUS The coiled creative life force at the base of the astral spine, kundalini, has always been symbolized as a serpent. When this creative force is "asleep" in delusion, it flows down and outward and feeds all the senses; uncontrolled, its stinging venom causes insatiable lusts. But when the pure kundalini force is "awakened" by the yogi, it rises to the brain and is transformed into the bliss of Spirit. This uplifting serpentine current is Vasuki, the supreme force for human liberation which begets the offspring of divine realization. -Paramahansa Yogananda “And the Lord sent fiery serpents among the people, and they bit the people; and much people of Israel died. Therefore the people came to Moses, and said, We have sinned, for we have spoken against the Lord, and against thee; pray unto the Lord, that he take away the serpents from us. And Moses prayed for the people. And the Lord said unto Moses, Make thee a fiery serpent, and set it upon a pole: and it shall come to pass, that every one that is bitten, when he looketh upon it, shall live. And Moses made a serpent of brass, and put it upon a pole, and it came to pass, that if a serpent had bitten any man, when he beheld the serpent of brass, he lived.” (Numbers 21: 6-9 KJV) Here the word Nachash is translated in two ways; a fiery serpent and a serpent of brass. This is because Nachash is translated as “a shining one”, referring to the shining light of illumination. The people of Israel had turned away from God, because of this they were “bitten” by the fiery serpent. "...the Kundalini serpent actually dissolves into light." -Carl Jung, Letters Vol. 1, Pages 95-97 "They shall take up serpents; and if they drink any deadly thing, it shall not hurt them; they shall lay hands on the sick, and they shall recover." (Mark 16:18) "As Moses raised the Serpent in the desert so shall the Son of Man be lifted." (John 3:14) "The ascent of the Kundalini through the medullar canal is a very slow and difficult process. The path of the igneous serpent, from one vertebra to another, signifies terrible ordeals, trials, frightful sacrifices and supreme purification. We must not only kill desire, but moreover, we must kill the very shadow of desire." ~Samuel Aun Weor, The Yellow Book Alchemical Yoga The secret vessels of the alchemist are the organs of his own body, together with their etheric and astral counterparts. The operation is in fact a chemical one, under the direction of man’s self-conscious intelligence, which begins in Divine Mind, but is realized by means of changes effected in his physical body. In consequence of these changes, he becomes a new creature, able to exercise powers which are unknown to the average being – He attains Self-Mastery. The basis of alchemy, like the basis of yoga, is the idea that man is a direct consequence of the perfectly free, unmodified Spirit whence all things proceed. This is the true essence of his being. The Great Work is the direction of energy derived from that essence according to the perceptions of an awakened intelligence – Divine Mind. The preliminary in alchemy is the same as the preliminary step in yoga – that is, to eradicate all impurities and transmute the body into a holy temple of God, purged from all uncleanness. The fire of alchemy is said to be a secret fire, often compared to a serpent or dragon – a fiery force which yogis say is coiled in the Saturn center at the base of the spine. It is named Kundalini. Yoga practice raises this “serpent” power stage by stage, through the seven chakras which alchemy identifies with metals. Paracelsus, like other sages, declares the Great Work to be performed by the aid of Mercury, and that the only other agencies of the art are the powers of the sun and moon. We recognize the importance of the power personified by Mercury; the object of yoga is something which is to be grasped by the mind alone. "Yoga chitta vritti nirodha." (Patanjali, Yoga Sutra 1.2) They also recognize the other two agencies, one hot and fiery called Prana or Surya (Surya meaning “sun”); the other agency cold and moist, named Rayi, the lunar current. In the Daoist system it's called Kan and Li, Fire and Water. The mind of man, his Mercury, is able to discover principles, and to control by suggestion the forces of the subconscious life. It is able to invent and execute new application of methods not provided by nature, thus bringing about a finer adjustment and organization of both environment and organism. The result is the new kind of being, able to receive the influx of energies which would harm an ordinary human body, fraught with impurities. When he becomes illumined, he perceives directly the Truth that he is living the eternal life of the One Power which brings all things into manifestation, and sustains and governs everything in the universe. At the completion of this Work, his transmuted personality expresses nothing but the inwardly perceived impulses of the One Power. He knows, not merely believes, that all his thoughts, acts, and words are direct expressions of God, the One Will. "The old Adamical flesh of death cometh not to the heavenly flesh: No, it belongeth to the earth, to death; but the eternal flesh is hidden in the old earthly man, and it is in the old man, as the fire in iron, or as the gold in the dark stone. This is the noble stone (Lapis Philosophorum), the Philosopher’s Stone, which the Magi find, which tinctureth nature, and generateth a new son in the old. He who findeth that esteemeth more highly of it than of this outward world. He who hath it, and knoweth it, if he seeketh, he may find all things whatsoever are in heaven and earth. It is the Stone which is rejected of the builders, and is the chief corner stone; upon whatsoever it falleth, it grindeth to powder, and kindleth a fire therein." - Jacob Boehme

Chapter 2: The Prophet

Shorter than Chapter 1, but let’s fucking goooooo

Prologue

Chapter 1: The Necromancer

Chapter 2: The Prophet

Chapter 3: The Hag

Chapter 4: The Brigand Vvulf

Chapter 5: The Brigand’s Cannon

Chapter 6: The Drowned Crew

Chapter 7: The Siren

Chapter 8: The Swine God

Chapter 9: The Formless Flesh

Chapter 10: The Ancestor

Epilogue

Be weary, there is a violent death here.

Our frontline fighters still needed time to recover as they were just as badly burned as I had feared. I knew Reynauld would be fine. He was a young and healthy man and was capable of recovering quickly, but I had to admit that I was worried if Baldwin would come out the other side of this. Burns on top of his condition was a recipe for disaster, but I should not have doubted him. His will is the strongest I have seen in any man and I had to wonder if he was even human.

Still, I did not feel it was right to send them out to battle just yet. I would rather allow them to rest before I ask them to put their lives on the line again. Besides, it seems that until then, they’ve picked up things to do around the Hamlet to keep their mind off of the stress. Some may be a little less than honorable, such as Dismas and Reynauld’s less than honest gambling, but Julia, Baldwin, and Paracelsus have been seen around the Hamlet either aiding repairs or offering service to the townsfolk to help them. It warmed my heart to see the town starting to recover and heal from the tragedies they have seen.

With them out, however, I have been forced to keep a look out for more heroes to aid our quest. One came to us late in the evening. He said his name is Alhazred and that he is an esteemed professor from a distant University. Further research indicated this to be true, but I was not overly familiar with his studies as I never truly even touched occult studies before I arrived at the Hamlet. After our adventures against the Necromancer, however, how could I turn him down? He would know far more on the topic of the arcane and the supernatural than I ever would. The fact that he was capable of combat despite his frail appearance was just another point in his favor.

Once he was hired, he set upon his work, requesting access to the library that my Ancestor had made. I granted this, but I told him there wasn’t much to see that I was aware of. He was understandably disappointed, but still, he has been there every day I have not called upon him, diligently working away. I also managed to get the old books from the dungeon pulled and brought to him. He seemed more satisfied with those, despite being as damaged as they are.

Alhazred was not the only person to arrive to my Hamlet, however. A brash woman who announced herself as Boudica came in one day and loudly challenged Reynauld. He, thankfully, refused, but an older gentleman that had arrived earlier that day that I had not had the chance to meet with just yet. Reynauld told me that the fight was nothing short of awe-inspiring. The man Boudica had challenged is an old war veteran by the name of Barristan, so it was a battle of old knowledge versus young wit. Boudica came out on top, but just barely. Despite blowing through a table (which they mercifully paid for), I allowed both of them to serve the Hamlet. I admit that I was hesitant with Boudica, being as young and brash as she is, however a conversation with her laid my fears to rest. Despite her behavior, it appears she had nowhere else to go and genuinely wished to help. Perhaps she hoped her earn her keep into the Hamlet, and I found it heartless to say no.

With a new crew assembled of Barristan, Boudica, Julia, and Alhazred, we headed for the dungeons once again with the intent of making sure there was nothing undead left behind within them. As we ventured deeper, we did find some more of the cultists. However, since I did not see anymore moving skeletons, I think it is safe to assume that while they do have some dark arcane powers are their beck and call, they are not capable of Necromancy. The idea brought me some peace.

We traveled beyond the chamber we fought the Necromancer and his minions in and found some undead shambling further within, but with no master they were disorganized and disorientated. I was fooled into thinking this was going to be a simple task as we cut through their ranks. By the time we reached the last door that we left unopened in the dungeons, I had put the prophet out of my mind. What a mistake that was.

I opened the doors to a grimy old man sitting upon the floor. His head and one hand were firmly locked inside a stockade. His other was free and was closed in front of him in a gentle fist. I came to the conclusion that he must have been holding something fragile, but at the same time he did not want the world to see what he was holding. When we entered, he lifted his head. There were old wraps that draped from his head and over his eyes. There was blood over where his eyes were, and I had a sinking feeling about what he was holding.

For a moment, his expression was blank before there was a look of contempt on his face. He asked if I knew what I had done the moment I set foot in the Hamlet. I had to admit, I did not know how to respond to such a question and begged for his pardon. This did not seem to be the answer he wanted as he pushed himself onto his sinewy legs. I asked for him to explain further since I was uncertain as to what he was talking about. This irritated the man and he flew into a tirade about how he tried to warn my Ancestor once, but “look what happened now”. He even claimed that short-sightedness must run in my family for me to arrive here.

Then all of a sudden, his rant was done before he gave a sigh. A smile crept upon his face. He claimed that he “would end the cycle”, though at the time, I had no clue what this meant. All I know is that he held out his free hand and exposed his two gouged eyes to us. He claimed that he could see the ceiling of the dungeon caving in and would cause grievous injury. I was about to speak once more when I suddenly felt Barristan rush and grab me. He pulled me close and held his shield over our heads as a boulder collided. I could hear him cry out in pain from the weight, but we were alive.

Julia, on the other hand, was crushed under the weight as Boudica could do nothing but move out of the way before it got the both of them. The sound of her body breaking is not one I would forget anytime soon.

I admit I did not pay much attention to the battle from there as I was so shaken by the death of Julia to notice much. I had experienced loss prior to this, but never something so sudden and violent. I can’t say I know of anyone who was able to process the first time they saw someone die like this. The idea that perhaps I could have done something to protect her played in my mind on a loop despite the fact that I know it was not something I could have prepared for. How could I have known the Prophet had such terrifying abilities?

What I do know is that eventually there was a hand upon my shoulder. Barristan pulled me away from the side of the boulder, away from what I could see of Julia’s body. I looked over and saw the corpse of the Prophet laid open, wondering when the world had moved on without me. He never took his hand off of me as he helped me out, leading me back towards the Hamlet. No one said much of anything during that trip back.

It took me a few days to truly process what had happened. We eventually sent in Reynauld, Boudica, Dismas, and Barristan in to fetch what they could of Julia’s body. Her grave now is by the Abby that she tried her best to tend to. Reynauld picked up that duty in her stead.

As for me, I attended the service, and then I found Barristan and Reynauld and made a request of them. I do not want to leave the heroes I have employed on their own. I plan to travel with them as often as I can as it is my duty to ensure the corruption here in the Hamlet is driven out. I did not want to be dead weight to them any longer. I asked for them to teach me how to use a blade and how to be a tactician. They seemed to understand why I was asking this of them and agreed to my requests.

In the following weeks, Barristan taught me the basics of planning ahead for these types of battles. He taught me how to think about formations, weighing out our fighter’s strengths and weaknesses, and how to read the enemy. Reynauld drilled me in the ways of a sword and helped me be fitted for some basic armor so I would be less of a liability.

While I know that what happened to Julia was not the result of me being inept as a fighter, it did bring me some comfort to know that no one else would die because I couldn’t even raise a blade to defend myself. I suppose a way, it was me trying to do better for everyone in the Hamlet.