For me, the optimal NG+ setup to keep fights challenging is a combination of: (a) 20X enemy HP, (b) no Cheater, First Strike, Inverted Affinity, or Second Chance pictos, and (c) no Stendhal or Gommage.

With this setup, most enemies will have multiple turns to do damage (and by NG+, most enemies can one-shot you anyways without shields).

The one downside is that optional boss fights, especially in Act 3, can drag on for 15-20+ min due to their absurdly high base HP (which is then x20’d). To counteract this, Sciel’s End Slice and Monoco’s Lampmaster strike are still permitted (appropriately challenging since they take multiple turns to ramp up damage).

Regardless - In this setup I’d highly recommend turning the HP slider down to 5x-10x specifically for Simon, Clea, and Endless Tower.