Here's how I see this going:
May and Jay are set to have their wedding in #600, but since May not being lonely would remove her and Peter that much more from the angst of Ben's death, I see Otto trying to break up the wedding, and in the ensuing struggle between Otto and Spidey, Jay accidentally gets killed. Otto might actually feel bad (he does seem to genuinely care for May by now, after all), but Peter DEFINITELY will feel bad, because Jonah will blame Spidey for Jay's death, thus renewing his hate-on for Spidey, and so will May, thus leading to a whole NEW reason for Peter to feel guilty, as well as a new justification for why Peter can't tell May that he's Spidey.
I'll be genuinely impressed with the creative team if they don't go down this road, but I'm pretty sure they will, because they realize that they need ZOMG EVAN MOAR EXTREEEM justifications to preserve Peter's status quo.
And the fact that the city turned on Spidey over a BASEBALL GAME? LAME. That's AL BUNDY-level misfortune contrivance.