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Adherence and patients experiences with the use of oral anticancer agents

Timmers, L.

2016

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Timmers, L. (2016). Adherence and patients experiences with the use of oral anticancer agents. http://www.ubvu.vu.nl/dissertations/fulltext/11822/529188.pdf

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^ƵŵŵĂƌLJͻϮϭϳ

^ƵŵŵĂƌLJ

/ŶƚƌŽĚƵĐƟŽŶ

^ƵŵŵĂƌLJͻϮϭϵ ĂĚŚĞƌĞŶĐĞǁĂƐĂƐƐĞƐƐĞĚďLJŵĞĂŶƐŽĨĂƚĞůĞƉŚŽŶŝĐƉŝůůĐŽƵŶƚ͕ĂƋƵĞƐƟŽŶŶĂŝƌĞĂŶĚĂƌĞǀŝĞǁ ŽĨƚŚĞƉĂƟĞŶƚ͛ƐŵĞĚŝĐĂůĮůĞĂŶĚƉŚĂƌŵĂĐLJŵĞĚŝĐĂƟŽŶƌĞĐŽƌĚƐ͘WĂƌĂŵĞƚĞƌƐĐŽůůĞĐƚĞĚǁĞƌĞ ƉĂƟĞŶƚƐ͛ ĚĞŵŽŐƌĂƉŚŝĐƐ͕ ƚƌĞĂƚŵĞŶƚ ĐŚĂƌĂĐƚĞƌŝƐƟĐƐ͕ ďĞůŝĞĨƐ ĂŶĚ ĂƫƚƵĚĞ ƚŽǁĂƌĚƐ ĚŝƐĞĂƐĞ ĂŶĚ ŵĞĚŝĐŝŶĞƐ͕ ƐĞůĨͲƌĞƉŽƌƚĞĚ ĂĚŚĞƌĞŶĐĞ͕ ƐŝĚĞͲĞīĞĐƚƐ͕ ƋƵĂůŝƚLJ ŽĨ ůŝĨĞ ĂŶĚ ƐĂƟƐĨĂĐƟŽŶ ĂďŽƵƚŝŶĨŽƌŵĂƟŽŶ͘WĂƟĞŶƚƐŽīƚƌĞĂƚŵĞŶƚĮůůĞĚŽƵƚĂƋƵĞƐƟŽŶŶĂŝƌĞĂďŽƵƚƚŚĞƌĞĂƐŽŶƐĨŽƌ ĚŝƐĐŽŶƟŶƵĂƟŽŶ͘ ůƚŚŽƵŐŚŵŽƐƚƉĂƟĞŶƚƐǁĞƌĞĨƵůůLJĂĚŚĞƌĞŶƚƚŽŽƌĂůĂŶƟĐĂŶĐĞƌĂŐĞŶƚƐ͕ƚŚĞƌĞǁĂƐĂƐƵďƐƚĂŶƟĂů ŶƵŵďĞƌƚĞŶĚŝŶŐƚŽŶŽŶͲĂĚŚĞƌĞŶĐĞ͘dŚĞŵĞĂŶĂĚŚĞƌĞŶĐĞƌĂƚĞ;ZͿ;ŶсϭϳϳͿǁĂƐϵϵ͘ϭйǁŝƚŚ ϮϬ͘ϯйŽĨƉĂƟĞŶƚƐŚĂǀŝŶŐĂƐƵďͲŽƉƟŵĂůZ;фϵϱй͕хϭϬϱйͿĐŽŶƐŝƐƟŶŐďŽƚŚŽĨƵŶĚĞƌͲĂŶĚŽǀĞƌͲ ĂĚŚĞƌĞŶĐĞ͘hƐŝŶŐŵĞĚŝĐĂƟŽŶŝŶĂĐŽŶƟŶƵŽƵƐƌĞŐŝŵĞŶ;ƌĂƚŚĞƌƚŚĂŶĂĐLJĐůŝĐĚŽƐŝŶŐƌĞŐŝŵĞŶͿ͕ ůŝǀŝŶŐĂůŽŶĞĂŶĚďĞŝŶŐůŽǁĞĚƵĐĂƚĞĚŝŶĐƌĞĂƐĞĚƚŚĞĐŚĂŶĐĞƐŽĨƐƵďŽƉƟŵĂůĂĚŚĞƌĞŶĐĞ;KZƐ с ϰ͘ϴϴ͕ ϰ͘ϱϵ ĂŶĚ Ϯ͘ϱϯ͕ ƌĞƐƉĞĐƟǀĞůLJͿ͘ /Ŷ ĂĚĚŝƟŽŶ͕ ŽƉƟŵĂů ĂĚŚĞƌĞŶĐĞ ǁĂƐ ůĞƐƐ ĐŽŵŵŽŶ ŝŶ ƉĂƟĞŶƚƐ ƌĞƉŽƌƟŶŐ ƚƌĞĂƚŵĞŶƚ ĐŽŶƚƌŽů ;KZ с Ϭ͘ϳϳͿ͘ KŶĞ ƚŚŝƌĚ ŽĨ ϳϵ ƉĂƟĞŶƚƐ Žī ƚƌĞĂƚŵĞŶƚ ƌĞƉŽƌƚĞĚƚŚĞŝƌĞdžƉĞƌŝĞŶĐĞĚƐŝĚĞͲĞīĞĐƚƐĂƐŽŶĞŽĨƚŚĞƌĞĂƐŽŶƐĨŽƌĚŝƐĐŽŶƟŶƵĂƟŽŶ͘ ŚĂƉƚĞƌƐϱĂŶĚϲĂƌĞƌĞƉŽƌƚƐŽĨĂƉƌŽƐƉĞĐƟǀĞŵƵůƟĐĞŶƚƌĞƐƚƵĚLJŽŶŵĞĚŝĐĂƟŽŶĂĚŚĞƌĞŶĐĞƚŽ ĞƌůŽƟŶŝď͘ƌůŽƟŶŝďŝƐĂƚLJƌŽƐŝŶĞŬŝŶĂƐĞŝŶŚŝďŝƚŽƌ;d</ͿƚĂƌŐĞƟŶŐƚŚĞĞƉŝĚĞƌŵĂůŐƌŽǁƚŚĨĂĐƚŽƌ ƌĞĐĞƉƚŽƌ;'&ZͿ͘ƚƚŚĞƟŵĞŽĨƚŚĞƐƚƵĚLJ͕ĞƌůŽƟŶŝďŚĂĚďĞĞŶƌĞŐŝƐƚĞƌĞĚĨŽƌƚŚĞƐĞĐŽŶĚͲĂŶĚ ƚŚŝƌĚͲůŝŶĞƚƌĞĂƚŵĞŶƚŽĨŶŽŶͲƐŵĂůůĐĞůůůƵŶŐĐĂŶĐĞƌ;E^>Ϳ͘dŚĞĚƌƵŐŝƐƉƌĞƐĐƌŝďĞĚŽŶĐĞĚĂŝůLJ ŝŶĂĐŽŶƟŶƵŽƵƐƌĞŐŝŵĞŶ͘dŚĞĚĞƐŝŐŶŽĨƚŚĞƐƚƵĚLJŚĂƐďĞĞŶĚĞƐĐƌŝďĞĚŝŶŚĂƉƚĞƌϱ͘WĂƟĞŶƚƐ ƐƚĂƌƟŶŐĞƌůŽƟŶŝďƚƌĞĂƚŵĞŶƚǁĞƌĞĨŽůůŽǁĞĚĨŽƌϰŵŽŶƚŚƐ͘ƚƚŚĂƚƟŵĞƚŚĞƌŽůĞŽĨ'&ZŐĞŶĞ ŵƵƚĂƟŽŶǁĂƐŶŽƚĨƵůůLJƵŶĚĞƌƐƚŽŽĚ͕ĂŶĚĞƌůŽƟŶŝďƉĂƟĞŶƚƐƐƚĂƌƚĞĚƚŚĞƌĂƉLJǁŝƚŚŽƵƚŬŶŽǁůĞĚŐĞ ŽĨƚŚĞ'&ZŵƵƚĂƟŽŶƐƚĂƚƵƐŝŶƚƵŵŽƵƌƟƐƐƵĞ͘ĚŚĞƌĞŶĐĞǁĂƐĂƐƐĞƐƐĞĚƵƐŝŶŐĂŵĞĚŝĐĂƟŽŶ ĞǀĞŶƚŵŽŶŝƚŽƌŝŶŐƐLJƐƚĞŵ;DD^Ϳ͘ƌĞĂƵŶĚĞƌƚŚĞĐƵƌǀĞ;hͿŽĨĞƌůŽƟŶŝďǁĂƐĚĞƚĞƌŵŝŶĞĚ ĨƌŽŵŽŶĞƉůĂƐŵĂƐĂŵƉůĞďLJƉŽƉƵůĂƟŽŶƉŚĂƌŵĂĐŽŬŝŶĞƟĐƐĂŌĞƌŽŶĞ͕ƚǁŽĂŶĚĨŽƵƌŵŽŶƚŚƐ͘ ĞĨŽƌĞƐƚĂƌƚĂŶĚĂƚŵŽŶƚŚůLJŝŶƚĞƌǀĂůƐ͕ƉĂƟĞŶƚƐĮůůĞĚŽƵƚƋƵĞƐƟŽŶŶĂŝƌĞƐŽŶĂĚŚĞƌĞŶĐĞ͕ďĞůŝĞĨƐ ĂďŽƵƚŵĞĚŝĐĂƟŽŶ͕ŝůůŶĞƐƐƉĞƌĐĞƉƟŽŶƐ͕ƋƵĂůŝƚLJŽĨůŝĨĞ͕ƐLJŵƉƚŽŵƐĂŶĚƵƐĞŝŶĚĂŝůLJƉƌĂĐƟĐĞ͘

ϮϮϬͻ^ƵŵŵĂƌLJ ůƚŚŽƵŐŚ ĂĚŚĞƌĞŶĐĞ ƚŽ ĞƌůŽƟŶŝď ƚƌĞĂƚŵĞŶƚ ǁĂƐ ŐĞŶĞƌĂůůLJ ŚŝŐŚ͕ ŶŽŶͲĂĚŚĞƌĞŶĐĞ ŵŝŐŚƚ ďĞ ŚŝŐŚůLJƌĞůĞǀĂŶƚŝŶĂĐŽŶƐŝĚĞƌĂďůĞŶƵŵďĞƌŽĨƉĂƟĞŶƚƐĂƐĂĚŚĞƌĞŶĐĞфϵϱйŚĂƐƉƌĞǀŝŽƵƐůLJďĞĞŶ ƐŚŽǁŶƚŽďĞƌĞůĂƚĞĚƚŽƉŽŽƌĞƌƌĂƚĞƐŽĨƌĞƐƉŽŶƐĞƚŽĞƌůŽƟŶŝď͘dŽƐƵƉƉŽƌƚŽƉƟŵĂůĞƌůŽƟŶŝď ŝŶƚĂŬĞ͕ĐůŝŶŝĐŝĂŶƐŶĞĞĚƚŽƚĂŬĞĂĚĞƋƵĂƚĞŵĞĂƐƵƌĞƐƚŽĂŵĞůŝŽƌĂƚĞƐLJŵƉƚŽŵƐĂŶĚƚŽĂĚĚƌĞƐƐ ĂĚŚĞƌĞŶĐĞĂŶĚĐŽƌƌĞĐƚŝŶƚĂŬĞǁŝƚŚŽƵƚĨŽŽĚ͘dŚŝƐƐƚƵĚLJƐŚŽǁĞĚƚŚĂƚĞƐƉĞĐŝĂůůLJŽůĚĞƌƉĂƟĞŶƚƐ ĂŶĚƚŚŽƐĞǁŚŽĞdžƉĞƌŝĞŶĐĞƐƚŽŵĂƟƟƐŵĂLJŶĞĞĚĞdžƚƌĂĂƩĞŶƟŽŶ͘&ŽŽĚŝŶƚĂŬĞĚƵƌŝŶŐƚŚĞƵƐĞ ŽĨĞƌůŽƟŶŝďƐŚŽƵůĚďĞĐĂƌĞĨƵůůLJĂĚĚƌĞƐƐĞĚ͕ŽŶƚŚĞŽŶĞŚĂŶĚƚŽƐƵƉƉŽƌƚƉĂƟĞŶƚƐŝŶĐŽƌƌĞĐƚůLJ ƚĂŬŝŶŐĞƌůŽƟŶŝďŝŶƚŚĞĂďƐĞŶĐĞŽĨĨŽŽĚĂŶĚŽŶƚŚĞŽƚŚĞƌŚĂŶĚƚŽĂǀŽŝĚĂŶŽƌĞdžŝĂ͘ ŚĂƉƚĞƌƐϳĂŶĚϴĂƌĞƌĞƉŽƌƚƐŽĨĂƉƌŽƐƉĞĐƟǀĞŵƵůƟĐĞŶƚƌĞƐƚƵĚLJŽŶŵĞĚŝĐĂƟŽŶĂĚŚĞƌĞŶĐĞ ƚŽĐĂƉĞĐŝƚĂďŝŶĞ͘ĂƉĞĐŝƚĂďŝŶĞŝƐƌĞŐŝƐƚĞƌĞĚĨŽƌĂĚũƵǀĂŶƚƚƌĞĂƚŵĞŶƚŽĨŚŝŐŚͲƌŝƐŬĐŽůŽŶĐĂŶĐĞƌ͕ ƚƌĞĂƚŵĞŶƚŽĨŵĞƚĂƐƚĂƟĐĐŽůŽƌĞĐƚĂůĐĂŶĐĞƌ͕ĂĚǀĂŶĐĞĚŐĂƐƚƌŝĐĐĂŶĐĞƌĂŶĚĨŽƌůŽĐĂůůLJĂĚǀĂŶĐĞĚ ŽƌŵĞƚĂƐƚĂƟĐďƌĞĂƐƚĐĂŶĐĞƌ͘ĂƉĞĐŝƚĂďŝŶĞŝƐĂŶŽƌĂůƉƌŽĚƌƵŐŽĨϱͲŇƵŽƌŽƵƌĂĐŝů;ϱͲ&hͿĂŶĚŚĂƐ ůĂƌŐĞůLJƌĞƉůĂĐĞĚƚŚĞŝŶƚƌĂǀĞŶŽƵƐϱͲ&h͕ƐŝŶĐĞŝƚƐŽƌĂůĂĚŵŝŶŝƐƚƌĂƟŽŶŝƐŵŽƌĞĐŽŶǀĞŶŝĞŶƚ͘dŚĞ ĚƌƵŐŝƐĐŽŶƐŝĚĞƌĞĚĞƋƵĂůůLJĞīĞĐƟǀĞĂƐϱͲ&hĂŶĚ͕ĂƉĂƌƚĨƌŽŵŚĂŶĚͲĨŽŽƚƐLJŶĚƌŽŵĞ;,&^Ϳ͕ŚĂƐĂ ďĞƩĞƌƚŽdžŝĐŝƚLJƉƌŽĮůĞ͘ĂƉĞĐŝƚĂďŝŶĞŝƐĐŽŵŵŽŶůLJƉƌĞƐĐƌŝďĞĚŝŶĂϯͲǁĞĞŬƚƌĞĂƚŵĞŶƚĐLJĐůĞ͕ǁŝƚŚ ƚǁŝĐĞĚĂŝůLJĚŽƐĞƐŽŶĚĂLJƐϭƚŚƌŽƵŐŚϭϰ͕ǁŝƚŚŝŶϯϬŵŝŶƵƚĞƐĂŌĞƌĂŵĞĂůĂŶĚϭϮŚŽƵƌƐĂƉĂƌƚ͕ ĨŽůůŽǁĞĚ ďLJ Ă ϳͲĚĂLJ ƌĞƐƚ ƉĞƌŝŽĚ͘ WŚLJƐŝĐŝĂŶƐ ĂĚũƵƐƚ ƚŚĞ ĐĂƉĞĐŝƚĂďŝŶĞ ĚŽƐŝŶŐ ƌĞŐŝŵĞŶ ǁŚĞŶ ƌĞůĞǀĂŶƚƐŝĚĞͲĞīĞĐƚƐŽĐĐƵƌ͘ƐƐĞƐƐŵĞŶƚŽĨĂĚŚĞƌĞŶĐĞƚŽĐĂƉĞĐŝƚĂďŝŶĞƚƌĞĂƚŵĞŶƚŝƐĐŚĂůůĞŶŐŝŶŐ ďĞĐĂƵƐĞƚŚĞĐŽŵƉůĞdžĚŽƐŝŶŐƌĞŐŝŵĞŶĂŶĚŝŶĚŝǀŝĚƵĂůĂĚũƵƐƚŵĞŶƚƐĚƵƌŝŶŐƚƌĞĂƚŵĞŶƚ͘

The design of the study on capecitabine has been described in ŚĂƉƚĞƌϳ͘WĂƟĞŶƚƐƐƚĂƌƟŶŐ ĐĂƉĞĐŝƚĂďŝŶĞ ƚƌĞĂƚŵĞŶƚ ǁĞƌĞ ĨŽůůŽǁĞĚ ƵƉ ƚŽ ĮǀĞ ϯͲǁĞĞŬ ĐLJĐůĞƐ͘ ĚŚĞƌĞŶĐĞ ǁĂƐ ĂƐƐĞƐƐĞĚ ƵƐŝŶŐĂƉŝůůĐŽƵŶƚ͕ƉŚĂƌŵĂĐLJĚĂƚĂĂŶĚŝŶĨŽƌŵĂƟŽŶĨƌŽŵƚŚĞƉĂƟĞŶƚƐ͛ŵĞĚŝĐĂůĮůĞ͘WŚLJƐŝĐŝĂŶƐ͛ ĂĚũƵƐƚŵĞŶƚƐŽĨƚŚĞĚŽƐŝŶŐƌĞŐŝŵĞŶǁĞƌĞƚĂŬĞŶŝŶƚŽĂĐĐŽƵŶƚ͘^ĞůĨͲƌĞƉŽƌƚĞĚĂĚŚĞƌĞŶĐĞǁĂƐ ŵĞĂƐƵƌĞĚ ƵƐŝŶŐ ƚŚĞ DĞĚŝĐĂƟŽŶ ĚŚĞƌĞŶĐĞ ZĞƉŽƌƚ ^ĐĂůĞ ;DZ^Ϳ͘ ƚ ďĂƐĞůŝŶĞ ĂŶĚ ĚƵƌŝŶŐ ǁĞĞŬϮŽĨĐLJĐůĞƐϭ͕ϯĂŶĚϱ͕ƉĂƟĞŶƚƐĮůůĞĚŽƵƚĂƋƵĞƐƟŽŶŶĂŝƌĞŽŶƋƵĂůŝƚLJŽĨůŝĨĞ͕ƐLJŵƉƚŽŵƐ͕ ďĞůŝĞĨƐ ĂďŽƵƚ ŵĞĚŝĐŝŶĞƐ͕ ŝůůŶĞƐƐ ƉĞƌĐĞƉƟŽŶƐ ĂŶĚ ƵƐĞ ŝŶ ĚĂŝůLJ ƉƌĂĐƟĐĞ͘ h ŽĨ ϱ͛ͲĚĞŽdžLJͲϱͲ ŇƵŽƌŽƵƌŝĚŝŶĞ;ϱ͛Ͳ&hZͿ͕ϱͲ&hĂŶĚɲͲŇƵŽƌŽͲɴͲĂůĂŶŝŶĞ;&>ͿĚƵƌŝŶŐǁĞĞŬϮŽĨĐLJĐůĞƐϭ͕ϯĂŶĚ ϱ ǁĂƐ ĚĞƚĞƌŵŝŶĞĚ ďLJ Ă ƉŽƉƵůĂƟŽŶ ƉŚĂƌŵĂĐŽŬŝŶĞƟĐ ŵŽĚĞů ŝŶ EKEDD ĂŶĚ ǀĂůƵĞƐ ǁĞƌĞ ĐŽŵƉĂƌĞĚǁŝƚŚƉĂƟĞŶƚͲƌĞƉŽƌƚĞĚƐLJŵƉƚŽŵƐ͘

^ƵŵŵĂƌLJͻϮϮϭ Žƌ ĚĞůĂLJ ŽĨ ƚŚĞ ŶĞdžƚ ĐLJĐůĞ ;ϯϱйͿ͘ /Ŷ ŵƵůƟǀĂƌŝĂƚĞ ĂŶĂůLJƐŝƐ ƚŚĞ ƉƌŽďĂďŝůŝƚLJ ŽĨ ĂŶ ĂĚũƵƐƚŵĞŶƚ ŝŶĐƌĞĂƐĞĚǁŝƚŚƚŚĞŶƵŵďĞƌŽĨĐŽͲŵĞĚŝĐĂƟŽŶ;KZϭ͘ϭϵͿĂŶĚĂƐƚƌŽŶŐĞƌĞŵŽƟŽŶĂůƌĞƐƉŽŶƐĞ ƚŽƚŚĞĚŝƐĞĂƐĞ;KZϭ͘ϯϮͿ͘hŽĨϱ͛Ͳ&hZǁĂƐĂƐƐŽĐŝĂƚĞĚǁŝƚŚǁĞŝŐŚƚůŽƐƐ;KZϭ͘ϭϬͿ͕hŽĨ &>ǁŝƚŚ,&^;KZϬ͘ϵϬͿ͕ƌŚŝŶŽƌƌŚŽĞĂ;KZϭ͘ϮϭͿǁĞŝŐŚƚůŽƐƐ;KZϭ͘ϬϵͿĂŶĚĚĞƉƌĞƐƐŝŽŶ;KZ Ϭ͘ϵϬͿ͘dŚŝƐƐƚƵĚLJƐŚŽǁĞĚ͕ƚŚĂƚŵĂŶĂŐĞŵĞŶƚŽĨĂĚŚĞƌĞŶĐĞĂƉƉĞĂƌƐƐƉĞĐŝĮĐĂůůLJŝŵƉŽƌƚĂŶƚŝŶ longer term treatment.

,ĞĂůƚŚĐĂƌĞƉƌŽǀŝĚĞƌƐ͛ƉĞƌƐƉĞĐƟǀĞ

WĂƟĞŶƚƐ͛ŵĞĚŝĐĂƟŽŶĂĚŚĞƌĞŶĐĞŝƐŝŶŇƵĞŶĐĞĚďLJŝŶĨŽƌŵĂƟŽŶĂŶĚĐŽŵŵƵŶŝĐĂƟŽŶĨƌŽŵƚŚĞŝƌ ŚĞĂůƚŚĐĂƌĞƉƌŽǀŝĚĞƌƐ;,WƐͿ͘/ŶŚĂƉƚĞƌƐϵĂŶĚϭϬƌĞƐƵůƚƐŽĨĂĐƌŽƐƐͲƐĞĐƟŽŶĂů͕ŵƵůƟͲĐĞŶƚĞƌ ŽďƐĞƌǀĂƟŽŶĂůƐƚƵĚLJĂŵŽŶŐ,WƐŝŶŚĂĞŵĂƚŽͲŽŶĐŽůŽŐLJƐĞƫŶŐƐŝŶƚŚĞEĞƚŚĞƌůĂŶĚƐĂŶĚƚŚĞ ƵƚĐŚͲƐƉĞĂŬŝŶŐƉĂƌƚŽĨĞůŐŝƵŵŚĂƐďĞĞŶĚĞƐĐƌŝďĞĚ͘dŚĞĂŝŵŽĨƚŚŝƐƐƚƵĚLJǁĂƐƚŽĂƐƐĞƐƐ,WƐ͛ ƉĞƌĐĞƉƟŽŶƐ͕ĐƵƌƌĞŶƚĐůŝŶŝĐĂůƉƌĂĐƟĐĞŽĨƐƵƉƉŽƌƟŶŐĂĚŚĞƌĞŶĐĞƚŽKĂŶĚƚŽĞdžƉůŽƌĞĐůƵĞƐ ƚŽŝŵƉƌŽǀĞĂĚŚĞƌĞŶĐĞŵĂŶĂŐĞŵĞŶƚ͘WŚLJƐŝĐŝĂŶƐ͕ŶƵƌƐĞƉƌĂĐƟƟŽŶĞƌƐ͕ŶƵƌƐĞƐĂŶĚƉŚĂƌŵĂĐŝƐƚƐ ĮůůĞĚŽƵƚĂŶĞůĞĐƚƌŽŶŝĐƋƵĞƐƟŽŶŶĂŝƌĞŝŶĐůƵĚŝŶŐƋƵĞƐƟŽŶƐŽŶĂĚŚĞƌĞŶĐĞŵĂŶĂŐĞŵĞŶƚǁŝƚŚ respect to the items ŝŶƐŝŐŚƚŝŶƚŽĂĚŚĞƌĞŶĐĞ͕ƉĂƟĞŶƚƐ͛ĐŽŵŵƵŶŝĐĂƟŽŶ͕ĐĂƉĂďŝůŝƚLJƚŽŝŶŇƵĞŶĐĞ͕

ŬŶŽǁůĞĚŐĞ ŽĨ ĐŽŶƐĞƋƵĞŶĐĞƐ and ŝŶƐŝŐŚƚ ŝŶƚŽ ĐĂƵƐĞƐ͘ sĂůŝĚĂƚĞĚ ƋƵĞƐƟŽŶŶĂŝƌĞƐ ǁĞƌĞ ƵƐĞĚ

ƚŽ ĂƐƐĞƐƐ ďĞůŝĞĨƐ ĂďŽƵƚ ŵĞĚŝĐĂƟŽŶ ĂŶĚ͕ ĨŽƌ ƉŚLJƐŝĐŝĂŶƐ͕ ƐŚĂƌĞĚ ĚĞĐŝƐŝŽŶ ŵĂŬŝŶŐ ;^DͿ͘ /Ŷ ĂĚĚŝƟŽŶ͕ƚŚĞƉĞƌĨŽƌŵĂŶĐĞŽĨϰϳĂĚŚĞƌĞŶĐĞƐƵƉƉŽƌƟǀĞĐĂƌĞĂĐƟǀŝƟĞƐĐĂƚĞŐŽƌŝƐĞĚŝŶƚŽĞŝŐŚƚ ĚŽŵĂŝŶƐ͗ <ŶŽǁůĞĚŐĞ͕ ǁĂƌĞŶĞƐƐ͕ ^ĞůĨͲĞĸĐĂĐLJ͕ /ŶƚĞŶƟŽŶ ĨŽƌŵĂƟŽŶ͕ /ŵƉůĞŵĞŶƚĂƟŽŶ͕ ^ŽĐŝĂů

ƐƵƉƉŽƌƚ͕ AĚǀĞƌƐĞĞǀĞŶƚƐŵĂŶĂŐĞŵĞŶƚ and&ĂĐŝůŝƚĂƟŽŶ was inventoried.

ϮϮϮͻ^ƵŵŵĂƌLJ ŬŶŽǁůĞĚŐĞŽĨƚŚĞĂĚŚĞƌĞŶĐĞŽĨƚŚĞŝƌƉĂƟĞŶƚƐŽƌƚŽďĞĂǁĂƌĞŽĨƉĂƟĞŶƚƐĚŝƐĐƵƐƐŝŶŐĂĚŚĞƌĞŶĐĞ with them. /ŶŚĂƉƚĞƌϭϬƚŚĞĐƵƌƌĞŶƚƐƚĂƚƵƐŽĨĐĂƌĞƉƌŽǀŝĚĞĚƚŽƐƵƉƉŽƌƚƉĂƟĞŶƚƐƚŽŽƉƟŵĂůůLJƵƐĞƚŚĞŝƌ KŚĂƐďĞĞŶĚĞƐĐƌŝďĞĚ͘/ŶƚŽƚĂů͕ϮϬϴ,WƐ;ϭϲйŵĞĚŝĐĂůŽŶĐŽůŽŐŝƐƚƐ͕ϭϲйŚĂĞŵĂƚŽůŽŐŝƐƚƐ͕ ϭϳйŶƵƌƐĞƉƌĂĐƟƟŽŶĞƌƐ͕ϮϵйŶƵƌƐĞƐĂŶĚϮϮйƉŚĂƌŵĂĐŝƐƚƐͿƉĂƌƟĐŝƉĂƚĞĚŝŶƚŚŝƐƉĂƌƚŽĨƚŚĞ ƐƚƵĚLJ͘dŚĞŵĞĚŝĂŶƐĐŽƌĞƐŽŶƚŚĞĐĂƌĞĂĐƟǀŝƟĞƐƉĞƌĚŽŵĂŝŶĨŽƌ͕ƌĞƐƉĞĐƟǀĞůLJ͕ƉŚLJƐŝĐŝĂŶƐ͕ŶƵƌƐĞ ƉƌĂĐƟƟŽŶĞƌƐ͕ŶƵƌƐĞƐĂŶĚƉŚĂƌŵĂĐŝƐƚƐǁĞƌĞ͗<ŶŽǁůĞĚŐĞ͗ϴϲͲϭϬϬͲϳϭͲϮϵй͖ǁĂƌĞŶĞƐƐ͗ϳϱͲϳϱͲ ϲϯͲϬй͖ ^ĞůĨͲĞĸĐĂĐLJ͗ ϲϬͲϴϬͲϱϬͲϬй͖ /ŶƚĞŶƟŽŶ &ŽƌŵĂƟŽŶ͗ ϲϳͲϭϬϬͲϴϯͲϱϬй͖ /ŵƉůĞŵĞŶƚĂƟŽŶ͗ ϮϱͲϱϬͲϮϱͲϬй͖^ŽĐŝĂů^ƵƉƉŽƌƚ͗ϲϳͲϲϳͲϲϳͲϬй͖ĚǀĞƌƐĞǀĞŶƚƐDĂŶĂŐĞŵĞŶƚ͗ϭϬϬͲϭϬϬͲϭϬϬͲϮϵй͖ &ĂĐŝůŝƚĂƟŽŶ͗ϲϰͲϳϯͲϱϱͲϮϳй͘dŚĞƉƌŽǀŝĚĞĚĐĂƌĞĚŝīĞƌĞĚďLJĐŽƵŶƚƌLJ͘ĞůŐŝĂŶƉŚLJƐŝĐŝĂŶƐƌĞƉŽƌƚĞĚ ŵŽƌĞĂĐƟǀŝƟĞƐƚŚĂŶƵƚĐŚƉŚLJƐŝĐŝĂŶƐ͕ǁŚĞƌĞĂƐŝŶƚŚĞEĞƚŚĞƌůĂŶĚƐŶƵƌƐĞƐĂŶĚƉŚĂƌŵĂĐŝƐƚƐ ƌĞƉŽƌƚĞĚ ŵŽƌĞ ĂĐƟǀŝƟĞƐ ƚŚĂŶ ƚŚĞŝƌ ĞůŐŝĂŶ ĐŽůůĞĂŐƵĞƐ͘ dŚĞ ƉĞƌĐĞƉƟŽŶƐ ŽĨ ĂĚŚĞƌĞŶĐĞ ŵĂŶĂŐĞŵĞŶƚǁĞƌĞƌĞůĂƚĞĚƚŽƚŚĞůĞǀĞůŽĨĐĂƌĞƉƌŽǀŝĚĞĚďLJ,W͘^ŚĂƌĞĚĚĞĐŝƐŝŽŶŵĂŬŝŶŐĂŶĚ ĞůŝĞĨƐĂďŽƵƚŵĞĚŝĐĂƟŽŶǁĞƌĞŶŽƚƌĞůĂƚĞĚƚŽƚŚĞůĞǀĞůŽĨƉƌŽǀŝĚĞĚĐĂƌĞ͘,WƐĞŵƉůŽLJĞĚĂ ǁŝĚĞƌĂŶŐĞŽĨĂĐƟǀŝƟĞƐƚŽƐƵƉƉŽƌƚƉĂƟĞŶƚƐ͘DŽƐƚŽŌĞŶƚŚĞŝƌĞīŽƌƚƐǁĞƌĞĂŝŵĞĚƚŽŝŶĐƌĞĂƐĞ ƚŚĞŝƌƉĂƟĞŶƚƐ͛ŬŶŽǁůĞĚŐĞŽĨƚŚĞĚŝƐĞĂƐĞĂŶĚŝƚƐƚƌĞĂƚŵĞŶƚĂŶĚĂĚǀĞƌƐĞĞǀĞŶƚŵĂŶĂŐĞŵĞŶƚ͘ ,ŽǁĞǀĞƌ͕ĂĐƟǀŝƟĞƐĂŝŵĞĚƚŽƐƵƉƉŽƌƚƐĞůĨͲĞĸĐĂĐLJĂŶĚĂĚŚĞƌĞŶĐĞĚƵƌŝŶŐŽŶŐŽŝŶŐƵƐĞǁĞƌĞ ĨƌĞƋƵĞŶƚůLJŵŝƐƐĞĚ͘ƐĂĐŽŶĐůƵƐŝŽŶ͕,WƐŵŝŐŚƚŝŵƉƌŽǀĞĂĚŚĞƌĞŶĐĞďLJĚŝƌĞĐƚůLJĂĚĚƌĞƐƐŝŶŐ ƚŚŝƐŝƐƐƵĞǁŝƚŚƚŚĞƉĂƟĞŶƚ͘ŶŚĂŶĐŝŶŐ,WƐ͛ŬŶŽǁůĞĚŐĞĂŶĚƉĞƌĐĞƉƟŽŶƐŽĨŵĂŶĂŐĞŵĞŶƚŽĨ ĂĚŚĞƌĞŶĐĞ ŵŝŐŚƚ ŚĂǀĞ Ă ƉŽƐŝƟǀĞ ĞīĞĐƚ ŽŶ ƉĂƟĞŶƚ ĐĂƌĞ͘  ŵƵůƟĚŝƐĐŝƉůŝŶĂƌLJ ĂƉƉƌŽĂĐŚ ǁŝƚŚ ƐŚĂƌĞĚŽƉŝŶŝŽŶƐƵƉŽŶƚŚĞƚĂƐŬĂůůŽĐĂƟŽŶŝƐĂĚǀŝƐĞĚŝŶǁŚŝĐŚƚŚĞƌŽůĞŽĨƚŚĞƉŚĂƌŵĂĐŝƐƚĐŽƵůĚ ďĞĞdžƉĂŶĚĞĚ͘

'ĞŶĞƌĂůĚŝƐĐƵƐƐŝŽŶ

ŚĂƉƚĞƌϭϭ includes a general discussion on the studies presented in this thesis.

^ƵŵŵĂƌLJͻϮϮϯ ĚŚĞƌĞŶĐĞƚŽƚƌĞĂƚŵĞŶƚǁŝƚŚKŝƐŐĞŶĞƌĂůůLJŚŝŐŚ͗ƚŚĞŵĞĂŶĂĚŚĞƌĞŶĐĞƌĂƚĞĂŵŽƵŶƚƐƚŽ ϵϱͲϭϬϬй͘EĞǀĞƌƚŚĞůĞƐƐ͕ĂĐŽŶƐŝĚĞƌĂďůĞŶƵŵďĞƌŽĨƉĂƟĞŶƚƐŝƐƐƵďͲŽƉƟŵĂůůLJĂĚŚĞƌĞŶƚĂƚĂůĞǀĞů ƚŚĂƚŵŝŐŚƚŚĂǀĞĐůŝŶŝĐĂůƌĞůĞǀĂŶĐĞ͘/ŶĐĂŶĐĞƌƚƌĞĂƚŵĞŶƚŚŝŐŚĂĚŚĞƌĞŶĐĞƐĞĞŵƐŵĂŶĚĂƚŽƌLJƚŽ ĂĐŚŝĞǀĞĂƐƵĐĐĞƐƐĨƵůůŽŶŐͲƚĞƌŵŽƵƚĐŽŵĞ͘dŚĞŶĞŐĂƟǀĞĐŽŶƐĞƋƵĞŶĐĞƐŽĨĂŶĂĚŚĞƌĞŶĐĞƌĂƚĞ фϵϱйŽŶĐůŝŶŝĐĂůƌĞƐƉŽŶƐĞŚĂƐďĞĞŶƐŚŽǁŶĨŽƌŝŵĂƟŶŝďŝŶĐŚƌŽŶŝĐŵLJĞůŽŝĚůĞƵŬĂĞŵŝĂ͕ĞƌůŽƟŶŝď ŝŶE^>ĂŶĚϲͲŵĞƌĐĂƉƚŽƉƵƌŝŶĞŝŶĂĐƵƚĞůLJŵƉŚŽďůĂƐƟĐůĞƵŬĂĞŵŝĂ͘ůƚŚŽƵŐŚůĞƐƐĨƌĞƋƵĞŶƚ͕ ŽǀĞƌƵƐĞĚĞƐĞƌǀĞƐĂƩĞŶƟŽŶĂƐǁĞůů͘dŚŝƐĂůƐŽŚŽůĚƐƚƌƵĞĨŽƌƌĞĐŽŵŵĞŶĚĂƟŽŶƐŽŶƚŚĞŵŽŵĞŶƚ ŽĨŵĞĚŝĐĂƟŽŶŝŶƚĂŬĞƌĞůĂƟǀĞƚŽƚŚĞŝŶƚĂŬĞŽĨĨŽŽĚ͘DĞĚŝĐĂƟŽŶĂĚŚĞƌĞŶĐĞǁĂƐĚĞĐůŝŶĞĂůƌĞĂĚLJ ďĞŐŝŶŶŝŶŐŝŶƚŚĞĮƌƐƚŵŽŶƚŚƐŽĨƚƌĞĂƚŵĞŶƚ͘DĂŶĂŐĞŵĞŶƚŽĨĂĚŚĞƌĞŶĐĞĂƉƉĞĂƌƐƐƉĞĐŝĮĐĂůůLJ important in longer term treatment.