Hard mode makes some enemies move slightly differently. Enemies shoot more and different types of bullets. Master mode then speeds up battles by 33% including your character, enemies, the intro and outro, and enemies deal double damage. In all difficulties, enemies have the same health and you deal the same amount of damage.

The final door in Normal requires 60 hearts. Collecting all the chest hearts is certainly fastest.

The final door in Hard/Master requires 75 hearts, which is all but 3 hearts up to that point. There are various doors in the run that require all but a couple hearts, so it's probably fastest to clear things as you pass them. Unfortunately this makes any% very similar to 100%.

I recommend getting the chocolate box extra power for the final boss on Hard/Master but not Normal.

100% does not require keys. 101% requires you open no chests prior to opening the Jealous Chest in Moon Town. On all difficulties this allows skipping exactly one battle.

Regen may be useful in Master 101%, but it's probably worthless in all other difficulties.

If you hold right on the difficulty selection screen for 5 seconds you unlock a pointless difficulty that just kills you every battle.

Whichever seems fun to you. Any% Normal, any% Master, 101% Normal, and 101% Master seem to offer the most variance. It also depends whether you prefer skipping the long encounters or playing all encounters.

Any% Normal: Minimalist. 100% Normal: Somewhat minimalist then cleanup most extra content at end-game. 101% Normal: Slower early game.

Any% Hard: Get everything on the way, skip 3 battles. 100% Hard: Get everything on the way, skip 3 battles until the end. (Very similar to Any% Hard) 101% Hard: Harder early game.

Any% Master: Get everything on the way, skip 3 battles. Die a lot. 100% Master: Get everything on the way, skip 3 battles until the end. Die a lot. 101% Master: I hope you enjoy dying in Spider Cave.

I'm running any% Normal and it seems like a couple of the top runs are on different versions. Which version should I be running? Because the earlier patches seem to be a bit faster. Thanks in advance!

I haven't played in some months. I assume the latest on Steam was fine. I think there were just small dialog changes or something. Let us know if there's anything major that was changed that affects timing and we can look in more detail. I'm not really sure of any specifics you're mentioning.