To really mess up big time, to fuck up with massively significant consequences.
On futurama, when Fry, pulled one of the lanterns from the old church, ruining Paul Revere's midnight ride; Professor Farnsworth informed him of his screwup of historical proportions by saying: "Fry, you dope! You've really screwed the granny this time.".
"Fry, you dope! You've really screwed the granny this time."
"You read from the Necronomicon and unleash Lord Cthulhu on Australia?! Well, it looks like you've really screwed the granny on this one."
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