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Luis Suarez and Steven Gerrard both played in a 1-0 win over Anzhi on Thursday so will not be as fresh as hoped for what should be another combative Merseyside derby.
Newcastle are without Cheick Tiote due to suspension and Alan pardew will make widespread changes after a second-string side beat Brugge in the Europa League.
Former Saints star Gareth Bale returns from paternity leave to play against his old club, who are in trouble towards the foot of the table.
A huge match at Stamford Bridge sees Chelsea aiming to respond to a Champions League defeat to Shakhtar, while United must do without the injured Shinji Kagawa.