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Everton manager David Moyes has lost midfielder Orel Mangala for the remainder of the season and striker Dominic Calvert-Lewin for several weeks after injury setbacks struck the club again.
Belgium international Mangala, 26, suffered an anterior cruciate ligament knee injury late on during Saturday's 1-0 win at Brighton.
He has made 22 appearances for the Blues since joining on a season-long loan from Lyon last summer but must see a specialist "to determine the next step for his recovery", Everton said.
Moyes described it as a "bad injury" and there was a further blow for the Toffees boss when Calvert-Lewin sustained a hamstring injury in the same game.
The 27-year-old hobbled off after 12 minutes and will require a "specialist opinion", with the forward expected to be out of action "for a number of weeks".
Calvert-Lewin, who has scored three goals this season, has entered the final six months of his contract at Goodison Park and has yet to sign a new deal which has been on the table since May.
Approaching Monday's transfer deadline, the injury situation complicates Everton's transfer plans but underlines the need to bring in reinforcements.
Chelsea loanee Armando Broja suffered an ankle injury against Peterborough on 9 January which Moyes forecast would keep him out for about 12 weeks.
Everton have been attempting to come to an arrangement with Chelsea about cutting short striker Broja's season-long loan, which Moyes said was "a possibility".
Premier League clubs are permitted to register a maximum of two domestic loan signings and Everton are at the limit, with Leeds United's Jack Harrison also on their books.
Chelsea may ask for a large fee to terminate the Broja agreement early, considering the Albanian has not scored this term and the danger of his transfer value dropping.
With Youssef Chermiti already out with a thigh problem, it leaves Portuguese Beto as the club's only fit senior striker.
Everton are also without midfielder Dwight McNeil, who has missed the last eight games because of a knee injury, and is likely to need surgery.
The Toffees sit 16th in the Premier League, seven points clear of the relegation zone.