http://fallout.wikia.com/wiki/hardcoe_mode + http://fallout.wikia.com/wiki/Immobile+ http://fallout.wikia.com/wiki/Tough_Guy_(Fallout_Tactics), original effects of Jet from FO2 as well as other drugs and add more weight to ammo. "hardcoe Extra"
I am not sure if they would be able to do this or not, but I would like to have a bunch of options to choose from at the beginning of the game. That way, even if you are playing Normal difficulty you could still have some challenge. Some examples:
1. Ammo could have weight or be weightless.
2. Carrying too much weight roots you to the spot, or stays like it is in Fallout 3(where you can still move, but can't Fast Travel).
3. Companions are mortal. You can choose whether they become unconcious or worm-food when getting to zero life.
4. Choose whether food, drink, and sleep is implemented like in Fallout 3 or like they are in the hardcoe mode.
5. Tough Guy mode(like Styles mentioned above). If you die, you die. Time to start over. Of course, you should still have emergency saves that would be usable only in the event of glitches/crashes/freezing. The game should be able to tell that your character received lethal damage/radiation/starvation and when it happens, makes it final.
Those are just a few options of course, but to at least have the ability to choose what ones you want and which ones you don't should increase both replayability and up the challenge for those who want it.