Saving
Manual and quicksaving are disabled. To save your game, you'll need to find a bed and sleep for at least an hour.
Game crashes though
Fast Travel
Fast Travel is disabled. If you wish to be somewhere, you'll have to physically travel there.
Oh god they better make this work with settlement defence quests, currently unless you happen to be nearby it is impossible to get back to help in time unless you fast travel. They are the only time I ever fast travel in the game anyway.
Weighted Ammo
Bullets and shells now all have a small amount of weight, which varies by caliber. Heavier items such as fusion cores, rockets, and mini-nukes can really drag you down.
THANK YOU FINALLY
Crippled Limbs
Crippled limbs will no longer auto-heal after combat and will remain crippled until healed by a Stimpak.
Didn't even realise they auto-healed after combat. This should have gone further and worked like New Vegas' hardcore mode where only Doctor's Bags could heal crippled limbs.
Companions
Companions will no longer automatically get back up if downed during combat and will return home if abandoned without being healed.
Better, but annoying that they don't die outright still.
Enemy and Loot Repopulation
Locations you've cleared will now repopulate enemies and loot at a significantly slower rate.
Yes thank you
No removal of unkillable characters though, was really /really/ hoping that'd make it into survival mode