My caliber choice doesn't change unless I'm doing outdoor activities in Bear country over in Idaho and Montana...........357 mag with heavy hard cast slugs in nothing less than a 4" barrel. If I were in Alaska I would raise the bar to 44 mag with similar ammo.
For 2 legged creatures, the only thing that is going to guarantee that a bad guy instantly stops attacking whether it be with fists or a gun is a hit to the CNS which can be done with a 22lr. I wouldn't carry a 22lr for defense because the statistics say that blood loss or fear is what actually ends most altercations involving firearms. While even a bb gun can stop a threat with fear, I won't carry ammo in most handgun calibers that won't reliably expand, as even a small caliber such as the 22 magnum with an expanded bullet will typically cause a faster bleed out than than most ball ammo which merely pushes flesh and arteries to the side as apposed to cutting. For me, this means the smallest calibers I will carry are 22 mag and 380ACP, and I will only carry ammo that reliably expands and meets FBI penetration standards in those calibers. As long as I feel I can rapidly put multiple shots on target with a gun that meets my ammo requirements, I will carry it regardless of what part of town I'm in. While a meth-head or a crack junkie might be more likely to attack you and less likely to back down because of fear, they're going to bleed out just the same if you put bullets through their heart or major arteries. That's my take on it.
For what it's worth, I mostly carry a 9mm loaded with Hornady critical defense when going into high risk areas, but it's because my sub-compact 9mm is far more accurate and holds more ammo than my micro 380 or 22 mag revolver, not because I don't think the gold dots in my 22mag or the hot underwood gold dots in my 380 wouldn't get the job done with good shot placement.