Any ideas on why this error would randomly pop up on my portal that I just upgraded from 3.3.7 -> 4.8.2?  I saw some related threads, but didn't see any conclusions drawn.

AssemblyVersion: 04.08.02
PortalID: 0
PortalName: Environmental, Safety & Health, Inc.
UserID: -1
UserName:
ActiveTabID: 36
ActiveTabName: Home
RawURL: /portal/Home/tabid/36/Default.aspx
AbsoluteURL: /portal/Default.aspx
AbsoluteURLReferrer:
UserAgent: Mozilla/4.0 (compatible; MSIE 7.0; Windows NT 5.1; .NET CLR 1.0.3705; .NET CLR 1.1.4322; .NET CLR 2.0.50727; Media Center PC 4.0; .NET CLR 3.0.04506.30; InfoPath.2; .NET CLR 3.0.04506.648)
DefaultDataProvider: DotNetNuke.Data.SqlDataProvider, DotNetNuke.SqlDataProvider
ExceptionGUID: 39b4cb8b-3926-4d3f-8948-84eeb2a32937
InnerException: Attempt to access the method failed.
FileName:
FileLineNumber: 0
FileColumnNumber: 0
Method: System.Reflection.MethodBase.PerformSecurityCheck
StackTrace:
Message: DotNetNuke.Services.Exceptions.PageLoadException: Attempt to access the method failed. ---> System.MethodAccessException: Attempt to access the method failed. at System.Reflection.MethodBase.PerformSecurityCheck(Object obj, RuntimeMethodHandle method, IntPtr parent, UInt32 invocationFlags) at System.Reflection.RuntimeMethodInfo.Invoke(Object obj, BindingFlags invokeAttr, Binder binder, Object[] parameters, CultureInfo culture, Boolean skipVisibilityChecks) at System.Reflection.RuntimeMethodInfo.Invoke(Object obj, BindingFlags invokeAttr, Binder binder, Object[] parameters, CultureInfo culture) at System.Reflection.MethodBase.Invoke(Object obj, Object[] parameters) at System.Web.Handlers.ScriptResourceHandler.EncryptString(String s) at System.Web.Handlers.ScriptResourceHandler.RuntimeScriptResourceHandler.System.Web.Handlers.IScriptResourceHandler.GetScriptResourceUrl(Assembly assembly, String resourceName, CultureInfo culture, Boolean zip, Boolean notifyScriptLoaded) at System.Web.UI.ScriptReference.GetUrlFromName(ScriptManager scriptManager, IControl scriptManagerControl, Boolean zip) at System.Web.UI.ScriptReference.GetUrl(ScriptManager scriptManager, IControl scriptManagerControl, Boolean zip) at System.Web.UI.ScriptManager.RegisterScripts() at System.Web.UI.ScriptManager.OnPagePreRenderComplete(Object sender, EventArgs e) at System.Web.UI.Page.OnPreRenderComplete(EventArgs e) at System.Web.UI.Page.ProcessRequestMain(Boolean includeStagesBeforeAsyncPoint, Boolean includeStagesAfterAsyncPoint) --- End of inner exception stack trace ---
Source:
Server Name: IPSWBZ0005ATL2

Do you have a module on the home page that is adding a ScriptManager to the page?  DNN already has one added.

I think you might have the right theory about medium trust. 

I would like to invite you to future Orlando DotNetNuke® Users Group meetings, since you are so close.  When they resume at the end of the summer, the new location will be closer to you.