"For example, how do you start Windows in Safe Mode and add programs one-by-one?"
What start in safe mode does it prevent programs from auto starting with windows.
So once you are in safe mode, with working calibre, you can manually start suspect 1, retry
add books, manually start suspect 2,
retry...
you have 2 suspects. if
add books used to work and we know calibre has
not updated, then look at the 2 things that you know have recently updated... N & A
I still question why you need them, unless you have very dodgy habits, but you don't want that discussion..[ i used XP for years, without N or A - i survived

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