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There have been a lot of great letters over the years. Standout topics: Writers who complain that they're beautiful, brilliant and misunderstood. Writers whose spouse/partner is sexually withholding or deficient and should the writer stay in the relationship. Struggles with addictions. Llamma ranching.
Replies: There was one a few years ago that had Cary joining the underground and eating good cheese in the current political climate. I think there were a couple that touched on people you meet in your life, some of whom are massively significant but aren't meant to be in your life for long.
And I may think of more, this is off the top of my head.