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Defiant is incredible (+5% Heal at the start of every round) for no draw backs.
The Jinx is also really nice - free debuffs on the enemy when your Hero gets hit. Getting this on a Tank is wonderful.
Even though it's a positive quirk, Breacher is just awful. If you get lucky and get it on your normal frontliner/Tank then it's fine; but because it's a positive quirk, you can't get rid of it if you end up getting it mid-run on someone you've built as a backliner (not without some serious luck in getting another positive quirk to replace it). Really doesn't make any sense to me that a positive quirk essentially forces you to adapt to a different (and potentially less optimal) Turn 1 strategy. You could easily fix this by renaming the quirk 'Reckless', making it a negative quirk, and removing the Defence and Strength buffs.
Coward is not bad for someone like grave robber who isn'ts supposed to be in rank 1. If she gets shuffled there (very common in Librarian fight due to the names of the dudes I pick) I'm totally ok if she flies back 3 ranks without using any action points. Thank God actually.
There are a lot of diseases to hate - wasting sickness means no traveling heals means you're probably going to start every battle on the edge of death. The 5% chance to get stunned disease every round really tickles my pickle when it procs. Lots of them reduce max hp which is very scary when you're trying to do deathless runs.
I thought this as well until I rolled it on highwayman at the beginning of the run so I built him around PB shot...let me tell you he carried my team for quite awhile. Being able to start every round with a Crit PB shot was crazy
Luck into the movement pet and put the breacher in the back and get a party damage boost as well
It's definitely manageable, I'm not saying it isn't, I wouldn't end a run if I got it late-run, it's just that it's a quirk that forces you to change your play style (unless it's on a front-liner already), and as others have said it can actually be super terrible if you get it on a Vestal (for example).
For example, breacher on man at arms is ideal. breacher on plague doctor less so.
Anemic is a really bad quirk. -bleed resistance, high chance to be dazed every round, *and* it blocks poultice items at the inn. The Yips sucks as well. Cowardly is bad for obvious reasons, although it's okay if it's on a backline hero.
I haven't seen all the diseases yet, but the most devastating one I've come across so far is Cholera. It nukes healing received by 50% and and tries to daze you every single round. Sepsis seems really bad as well if you let it fester for a while.
Having just got Lost in Time on a Jester I think it is very good, if I'm reading it right then the downsides may only happen if he is allowed to become stressed.
I have it on my HWM and he can one shot most back liners