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The game contains multiple references to the Resident Evil series, such as the T- and G-viruses, and the Merchant from Resident Evil 4.
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In one of the random encounters, a man runs towards the player and gives them a box. If they decide to open it, the man will repeat the phrase "Whats in the box?" This may be a reference to the famous scene in the movie "Se7en", in which Brad Pitt's character repeats this line.
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The route featured in the game eventually leads to Oregon, just like the game's spiritual predecessor Oregon Trail, which in turn was based on the historical emigrant trail of the same name.
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