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I realized that making flush() invalidate keys breaks the final example in the docs, which loops over inbox.iterkeys() and removes messages, doing a pack() after each message.
Which platforms lack file.truncate()? Windows has it; POSIX has it, so modern Unix variants should all have it. Maybe mailbox should simply raise an exception (or trigger a warning?) if truncate is missing, and we should then assume that flush() has no effect upon keys.