Well, take all of the shortcomings noted for .22 mag and magnify them several times as you descend through .22 long, .22 lr, and .22 short.
The penetration tests were interesting, but not really reflective of most self defense shooting situations, but more of execution shooting. Even then, shortcomings were apparent.
Well, that was a rifle and really wasn't a defensive shooting. She sniped the grizzly from short range, plain and simple. She got to pick and choose her shot, much like Ethan did with his .22 short testing. The problem is that in self defense situations that are often very fluid, people don't often get much of a chance to 'place' their shots where they want them. While they may be hoping to hit a spot, they are realistically happy to be hitting an area of the body...and a lot of shots just outright miss.
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I had a self defense instructor who loved his NAA Mini revolvers. He believed in carrying one as a back-up to his knife. He referred to it as a "Get off me" gun. In some ways, his logic made decent sense. Basically, the notion was that beyond arm reach distance, it was difficult to cock, aim and fire the little gun effectively (hitting the target) while in motion and dealing with a target that is in motion. For him, it was more of a contact distance weapon more so than a standoff weapon, although he said the gun certainly could be fairly accurate at distance. Later, when I purchased mine, I mounted a red dot sight on it (maybe the first every to do so) and managed to hit 3 or 5 or 4 of 5 rounds at a human silhouette at 50 yards. That, of course, was slow fire, aimed shooting, nothing defensive about it except to note that if you missed your intended target, people as far away as at least 50 yards could be harmed by your shot (no doubt much farther).