Well, I think people are really trying to get at with "most efficient RPM", load, and throttle is basically volumetric efficency of the engine.
Think about the reasons behind the development and usage of CVT gas-electric hybrids with very high fuel efficiency...
You have the gas engine running at pretty much a constant speed thanks to the CVT. Ideally you want that engine running at a near resonance frequency if possible for a naturally aspirated engine and since this is "ideal" we can even do away with the efficiency drop from a throttle plate. Torque for acceleration is mainly through the electric motors. All of this is increasing engine efficiency and reducing pumping loses, overfueling, severe load, etc.
So if you can reduce anything that takes away engine efficiency, it will probably increase your mpg... at least on a theoritical level. I've seen good mpg gains from the uncorking of the intake and exhaust on most "modern" cars... but for uber-computerized and factory optimized cars, there's less impact since it's fairly efficient from the factory to begin with. So I'm basically reiterating what infosponge stated. Changes to the engine's intake and exhaust do help, I've seen around 2-4mpg on my family's cars depending on modifications done. Yes, you do want to avoid open loop operation but you don't want to be at high load or rpm either for too long either during accleration.
Other reasons why manufacturers overfuel is to try to keep the catalytic converter alive in some cases. In most cases, during closed loop operation the fuel mixture is cycled from rich to lean to allow the catalytic convertors to maximize their ability to "clean" the exhaust due to the optimal operating conditions of different catalyst material. Also, in other cases it does have to do with performance and the design of the engine to prevent fuel detonation/knock.
If you could find out what the Helmholtz resonance frequency of your engine/manifold is and it is possible to find a proper tall gear to reach that rpm without having the throttle plate open too much that it uses too much fuel while maintaining good volumetric efficency and minimal pumping losses...
But in real life, it's probably just easier to drive like a grandma with all your windows closed and all accessories off. Also, a truck isn't exactly knifing through the air like a Porsche... aerodynamic forces can easily become first order on the truck at high speeds... heck for any vehicle. 50ish is probably slow enough for most trucks to not sap too much engine power from wind resistance.
Also, I think this was mentioned before but a lot of cars do have a RPM cutoff at which the engine computer will not enter closed loop operation. So if you have a car that at 75mph is over that rpm threshold, you're just running on the fuel map of the computer and mpg will get worse because of that.