I like the new 3-batter and extra innings rules, guess it's just me
Starting a game now I am...
1) Trading difficulty at hardest level, Lineup Selection to sabermetric (game options)
2) Universal DH, extra innings rules for all games. Remove Expanded roster.
3) Go owner-crazy on trade rules - no 10/5, injury trades on, draft pick trades on. Advanced draftee signings off.
4) Financials I don't have a set thing, but normally all budget available (instead of team owner decides), maybe revenue sharing to 50%. Contract years at 5 maximum. *Maybe* free agency earlier.
5) Automatic evolutions off for most games. Try and get a balanced schedule with as much interleague as possible (there's a mod forum for schedules that sometimes helps

)
6) Playoffs expand, don't have a set way - right now I like top 2 from each division make it, with best 2 records getting a bye. One best-of-5 then into bo7 against the 'bye' teams.
Think that's about it, is that enough blasphemy?
(one advantage of unifying DH is a possible league realignment the next year too

....)