Given a context passage, generate a question from the passage such that its answer is shortest continous span from the passage.

Input: Consider Input: Urgent surgery or life-threatening bleeding requires prompt reversal of the anticoagulant effects of dabigatran. This study assessed the ability of three- and four-factor prothrombin complex concentrate (PCC) and idarucizumab (specific antidote for dabigatran) to reverse the anticoagulant effects of dabigatran in a porcine model of trauma. Twelve animals were given dabigatran etexilate (DE) orally and dabigatran intravenously, before infliction of trauma. Six animals received tranexamic acid plus fibrinogen concentrate 12 minutes post-injury. Six PCCs (each 30 and 60 U/kg) and idarucizumab (30 and 60 mg/kg) were added to blood samples ex vivo. Coagulation was assessed by several coagulation assays. All coagulation parameters were altered after dabigatran infusion (plasma level: 442 138 ng/ml). Both three- and four-factor PCCs mostly or completely reversed the effects of dabigatran on thromboelastometry variables and PT but not on aPTT. Idarucizumab neutralised plasma concentrations of dabigatran, and reversed the effects of the drug on coagulation variables. Thrombin generation showed dose-dependent over-correction following the addition of PCC, implying that elevated levels of thrombin are required to overcome dabigatran-induced coagulopathy. In contrast, treatment with idarucizumab returned thrombin generation to baseline levels. Following trauma, therapy with tranexamic acid plus fibrinogen improved correction of coagulation parameters by PCC, and thromboelastometry parameters by idarucizumab. All investigated PCCs improved dabigatran- and trauma-induced coagulopathy to a similar degree. In conclusion, this study shows that three- and four-factor PCCs are similarly effective for dabigatran reversal. Idarucizumab also reversed the effects of dabigatran and, unlike PCCs, was not associated with over-correction of thrombin generation.

Output: Which drug can be reversed with idarucizumab?


Input: Consider Input: The War of the Spanish Succession was a European conflict of the early 18th century, triggered by the death of the childless Charles II of Spain in November 1700. His closest heirs were members of the Austrian Habsburg and French Bourbon families; acquisition of an undivided Spanish Empire or Monarchy by either threatened the European balance of power. Charles left his throne to Louis XIV's grandson Philip who was proclaimed King of Spain on 16 November 1700. Disputes over the separation of the Spanish and French crowns, division of territories and commercial rights led to war in 1701 between the Bourbons of France and Spain and the Grand Alliance, whose candidate was Archduke Charles, younger son of Habsburg Emperor Leopold. By 1710, fighting was deadlocked; Allied victories in Italy and the Low Countries had driven the French back to their borders but they could not achieve a decisive breakthrough while Philip was secure in Spain. When Archduke Charles succeeded his brother Joseph I as Emperor in 1711, Britain effectively withdrew, forcing its Allies to make peace and leading to the 1713 Treaty of Utrecht, followed in 1714 with Rastatt and Baden. Philip was confirmed as King of Spain and renounced the French throne; Spain retained the bulk of its pre-war territories outside Europe with their European territories divided between Austria, Britain and Savoy. Longer term impacts included Britain's emergence as the leading maritime and commercial power, the beginning of the decline of the Dutch Republic, the creation of a centralised Spanish state and the acceleration of the break-up of the Holy Roman Empire.

Output: Who was Emperor first, Archduke Charles or his brother Joseph I?


Input: Consider Input: Mutations in the K-ras oncogene and in the p53 tumor suppressor gene are commonly identified in sporadic cases of pancreatic adenocarcinoma. Although these genes might serve as useful markers for early diagnosis of pancreatic carcinoma in patients at risk for the development of this disease, familial pancreatic carcinomas have not been studied for these mutations. We recently had the opportunity to examine a pancreas prophylactically removed from a patient with a strong family history of pancreatic carcinoma. This gave us the unique opportunity to study the early events in the development of familial adenocarcinoma of the pancreas. Histopathological examination of the pancreas revealed multifocal papillary and nonpapillary mucinous duct hyperplasia. Seven of these foci were microdissected and analyzed for K-ras and p53 mutations. The K-ras mutations were detected by combined mutant-enriched polymerase chain reaction-restriction fragment length polymorphism analysis and characterized further by allele-specific oligonucleotide hybridization. Five of the seven duct lesions harbored activating point mutations in codon 12 of K-ras; a G to A transition was found in four and a G to C transversion in one. In contrast, these lesions did not harbor detectable p53 mutations as determined by denaturing gradient gel electrophoresis of exons 5 to 8, nor was there overexpression of the p53 protein as determined by immunohistochemistry. These findings suggest that mutations in K-ras represent an early event in the pathogenesis of pancreatic carcinoma. In addition, monitoring of patients with a strong family history of pancreatic carcinoma for K-ras mutations may identify patients at risk for the development of invasive carcinoma.


Output: Which is the molecular mechanism underlying K-ras alterations in carcinomas?