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Steve Borthwick has been dealt a double injury blow, with two England internationals ruled out of his latest squad ahead of the Nations Championship.
Harlequins forward Chandler Cunningham-South and Bristol Bears centre Benhard Janse van Rensburg have both been left out of the 36-man training group.
The pair were unavailable when Borthwick named his England squad on Sunday, with the team now preparing to face Australia at Twickenham on 8 November.
It leaves the England boss with some big decisions to make before the autumn campaign gets underway.
Cunningham-South faces around two months on the sidelines after suffering an ankle injury.
The powerful back-row forward requires surgery, ruling him out of England's upcoming Nations Championship fixtures.
It's a frustrating setback for the 23-year-old, who has become an important option in Borthwick's forward pack.
As Sky Sports reported, the injury means Cunningham-South will miss England's latest training camp.
His absence opens the door for others to stake their claim, with Northampton Saints' Henry Pollock, Exeter Chiefs' Greg Fisilau and Tom Pearson among the back-row options selected.
The injury also comes at a frustrating time for Harlequins, who have already had to manage several fitness concerns this season.
Bristol Bears centre Janse van Rensburg is another significant absentee.
The South African-born midfielder suffered a nasty head injury while playing for Bristol earlier this month and has not been included in the latest squad.
Having made his England debut during the summer, the 29-year-old had been pushing for a bigger role in Borthwick's plans.
His absence comes at a difficult time, with Gloucester centre Seb Atkinson also limited to rehabilitation work.
However, there is some good news for England.
Joe Marchant has earned a recall following his return to English rugby with Sale Sharks, while Gloucester's Will Joseph is also back in the international picture.
Both players have been handed an opportunity to stake their claim, with Borthwick facing some difficult selection calls in midfield.
Meanwhile, Immanuel Feyi-Waboso and Guy Pepper will join Atkinson in camp to continue their rehabilitation.
England face Australia on 8 November before taking on Japan and New Zealand, with the Nations Championship finals weekend to follow.