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Bad weather alone was enough trouble, sometimes it would be too foggy for the boats to travel or too cold to leave camp. Also, rain would cause the instruments to rust so Lewis had to constantly check them and oil them down again. Along the river were mass amounts of mosquitoes which Lewis said "gathered around my face so much so I could not see." Choppy waters would make boat travel difficult and while they made it, there was the constant fear of drowning or the boat capsizing. Hostile natives, disease (men drank from the rivers, and there was a shortage of fruit and vegetables), wild animals, mutiny from members of the expedition, and always the constant danger of falling into one of the rivers, breaking a leg, etc. Bad water would cause the men to suffer from terrible boils on their skin; Lewis would suffer from a bad case of the flu one winter and Clark suffered from a "rheumatism of the neck" which caused him pain for several days. For Clark, Lewis applied a "hot stone wrapped in flannel" to help ease his pain. At one point Lewis was accidentally shot in the left thigh by a near-blind member of the expedition, but managed to make it back safely. During the winter, the men suffered from frostbite, luckily leading to no necessary amputations, but the cold temperatures prevented them from leaving their forts to hunt. Also, several times the men had to keep constant guard on their supplies and natives would follow them and try to steal their horses.

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