PROJECT SUMMARY/ABSTRACT An interruption in the normal swallowing mechanism due to abnormal neuromuscular function in the esophageal body or the lower esophageal sphincter (LES) is associated with significant morbidity and quality of life impact, as well as increased mortality related to malnutrition, aspiration and cancer. Achalasia is the prototypical esophageal motility disorder and has an incidence of 1-5 per 100,000 and a prevalence of 10-20 per 100,000. Unfortunately, the cause of achalasia is unknown and the current therapies are primarily compensatory in nature and focus on disrupting the LES to improve emptying using either endoscopic dilation or surgical myotomy. Over the last 5 years, there has been an evolution away from dilation and surgery toward per oral endoscopic myotomy (POEM) due to its less invasive approach compared to surgery and its superior efficacy compared to dilation. However, important questions regarding the effectiveness and risks of POEM remain and the impact of the myotomy approach (position, length, depth) on outcomes is also unclear. The standard POEM myotomy is typically 8-10 cm in length, extending 2-3 cm into the cardia and approximately 6-7 cm above the squamocolumnar junction and it is performed with either a transmural or superficial approach targeting only the circular muscle. We recently reported that blown out myotomy (BOM) is a common mechanism of achalasia treatment failure related to focal dilatation along the myotomy site that profoundly impairs emptying. The scientific premise of this study is that the current arbitrary approach to myotomy in POEM is associated with a predilection to increased GERD and BOM formation through its effects on the distal esophagus. We hypothesize that an innovative precision approach with POEM can improve outcomes and reduce complications. Thus, we are proposing a multicenter randomized trial (Aim 1) to test the hypothesis that a short, tailored POEM will be non-inferior to the standard POEM and associated with less reflux disease and a reduction in BOM formation. Additionally, we will also aim to better understand outcomes in jackhammer esophagus and spastic motility disorders through a rigorous prospective study (Aim 2) assessing response to a long tailored myotomy. Using data and samples from study participants, we also aim to refine and validate a new Achalasia Patient Reported Outcome (APRO) measure (Aim 3) and establish a repository of biological specimens to help elucidate the pathophysiology of achalasia. This study will reshape the management of esophageal motility disorders and improve our understanding of the pathogenesis of these disorders by sharing specimens with translational scientists focused on neurogastroenterology.