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I will start troubleshooting by disabling script scan feature of VSE (for testing) and see if this makes any difference.
If yes then please add the internal URLs to VSE script scan whitelist.
I got the server guys to disable script scan, which seems to have helped tremendously on one of the applications which is very AJAX intensive. Not sure if that's what "script scan" refers to, but none the less, that one works great now.
The second application is now spotty. Sometimes it works great, sometimes not. FWIW, it ALWAYS works great when mcshield.exe is disabled. When it hangs up, it seems to be on scaning files that I would think have nothing to do with scripting, e.g. .gif .jpg and .html files. Also, it usually works great the SECOND time when stuff would be presumably cached, but not the first time. Before we disabled script scan it worked horribly EVERY time, which seems odd.
For I/O intensive applications I'd just add the process names to the list of Low-Risk Processes. That's what we do for apps like this. And remove ScriptScan completely, at least on servers.