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Huisie - the vast majority of the Modify ePub options are perfectly safe to "always run", in that they look for a particular condition to be present in the ePub and if found does the option otherwise does nothing.
Personally I have about a dozen options checked that I run on most of the ePubs that I import. And with those options checked I have never had a problem.
However there are a few options that in theory you might not want to do on every epub. For instance "Smarten punctuation" - if the ePub already has smart quotes, I think there is a risk that this option will (due to the flaws that exist in its algorithm) result in some quotes being changed from correct to incorrect.
Certainly options like "Remove all metadata jackets", "Update metadata", removing known artifacts etc should all be perfectly safe to run on any epub...
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