The Black Death was an epidemic of Bubonic Plague that hit Europe in 1346, killing about 30-60% of Europe's population at its peak. It led to social and economic change being greatly accelerated, eventually leading to capitalism, and the church's power was weakened. Medical knowledge was also increased. This devastating plague stopped in 1350, though it kept coming back until the 19th century. What if it appeared a century earlier, in 1246?
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