Clinical Trial Designs and Measures in Hereditary Spastic Paraplegias

Hereditary spastic paraplegias (HSPs) are a large group of genetically-diverse neurologic disorders characterized clinically by a common feature of lower extremity spasticity and gait difficulties. Current therapies are predominantly symptomatic, and even then usually provide inadequate relief of symptoms. Going forward, HSP therapeutics development requires a systematic analysis of quantifiable measures and tools to assess treatment response. This review summarizes promising therapeutic targets, assessment measures, and previous clinical trials for the HSPs. Oxidative stress, signaling pathways, microtubule dynamics, and gene rescue/replacement have been proposed as potential treatment targets or modalities. Quantitative evaluation of pre-clinical rodent HSP models emphasize rotarod performance, foot base angle, grip strength, stride length, beam walking, critical speed, and body weight. Clinical measures of HSP in humans include 10-m gait velocity, the Spastic Paraplegia Rating Scale (SPRS), Ashworth Spasticity Scale, Fugl-Meyer Scale, timed up-and-go, and the Gillette Functional Assessment Questionnaire. We conducted a broad search for past clinical trials in HSPs and identified trials that investigated pharmacological agents including atorvastatin, gabapentin, L-threonine, botulinum toxin, dalfampridine, methylphenidate, and baclofen. We provide recommendations for future HSP treatment directions based on these prior research experiences as well as regulatory insight

LMDA Canada: Canadian Caucus Newsletter, November 2000

Contents include: Negotiating Contracts, Letter of Agreement of an Instiutional Dramaturg, What is Dramaturgy (A Few Possibilities), Writers, Scripts and Community, A Case Study in Dramaturgical Allegiance, L.A. in L.A., Dramaturgical Discoveries at NeXtFest, Report from the Chairhttps://soundideas.pugetsound.edu/lmdanewsletter/1028/thumbnail.jp

Risk factors associated with mortality and interventions in 472 neonates with interrupted aortic arch: A Congenital Heart Surgeons Society study

ObjectiveWe sought to determine the prevalence of outcomes and associated patient and management factors for neonates with interrupted aortic arch.MethodsFrom 1987 to 1997, a total of 472 neonates were enrolled prospectively from 33 institutions. Competing risks methodology was used to determine simultaneous risk and associated incremental risk factors for death, initial and subsequent left ventricular outflow tract procedures, and arch reinterventions.ResultsOverall survival was 59% at 16 years after study entry but improved with successive birth cohort. In general, risk factors for death in each of the competing risks analyses included lower birth weight, younger age at study entry, type B interrupted aortic arch, and major associated cardiac anomalies. Of 453 patients who had interrupted aortic arch repair, after 16 years 33% had died and 28% had undergone an arch reintervention. Reintervention was more likely for those who had truncus arteriosus repair, interrupted aortic arch repair by a method other than direct anastomosis with patch augmentation, and the use of polytetrafluoroethylene as either an interposition graft or a patch. From study entry, competing risks after 16 years showed that 28% had died and 34% had undergone an initial left ventricular outflow tract procedure. Initial left ventricular outflow tract procedure was more likely for those with single ventricle, type B interrupted aortic arch, bicuspid aortic valve, or anomalous right subclavian artery. Among those who had undergone an initial left ventricular outflow tract procedure, after 16 years 37% had died and 28% had undergone a second procedure.ConclusionAnatomic features affect mortality and initial left ventricular outflow tract procedures, whereas characteristics of the arch repair affect arch reintervention

LMDA Canada: Canadian Caucus Newsletter, November 1999

Contents include: LMDA Canadian Caucus Membership, Letter from the Editor, Survey Results, Canadian Dramaturtle Goes to Oz, Translation on the St. Lawrence, Experimenting with the Audience, Feeding My Habit or Why I Stopped Being a Dramaturg and Went Back to School, Mini-Conference on Dramaturgy 1999, Canadians in Chicago, War of the Worlds, Dramaturging Dr. Faustus, Inside the Process: A New Angle on the Spring Festival of New Plays, ScriptLab: Millennium Approacheshttps://soundideas.pugetsound.edu/lmdanewsletter/1029/thumbnail.jp

Forty-Year Analysis of Colonoscopic Surveillance Program for Neoplasia in Ulcerative Colitis: An Updated Overview

C.R.C. was funded by the Derek Willoughby Fund for Inflammatory Research. A.L.H. and T.A.G. were funded by Higher Education Funding Council of England

Results of matching valve and root repair to aortic valve and root pathology

ObjectiveFor patients with aortic root pathology and aortic valve regurgitation, aortic valve replacement is problematic because no durable bioprosthesis exists, and mechanical valves require lifetime anticoagulation. This study sought to assess outcomes of combined aortic valve and root repair, including comparison with matched bioprosthesis aortic valve replacement.MethodsFrom November 1990 to January 2005, 366 patients underwent modified David reimplantation (n = 72), root remodeling (n = 72), or valve repair with sinotubular junction tailoring (n = 222). Active follow-up was 99% complete, with a mean of 5.6 ± 4.0 years (maximum 17 years); follow-up for vital status averaged 8.5 ± 3.6 years (maximum 19 years). Propensity-adjusted models were developed for fair comparison of outcomes.ResultsThirty-day and 5-, 10-, and 15-year survivals were 98%, 86%, 74%, and 58%, respectively, similar to that of the US matched population and better than that after bioprosthesis aortic valve replacement. Propensity-score–adjusted survival was similar across procedures (P > .3). Freedom from reoperation at 30 days and 5 and 10 years was 99%, 92%, and 89%, respectively, and was similar across procedures (P > .3) after propensity-score adjustment. Patients with tricuspid aortic valves were more likely to be free of reoperation than those with bicuspid valves at 10 years (93% vs 77%, P = .002), equivalent to bioprosthesis aortic valve replacement and superior after 12 years. Bioprostheses increasingly deteriorated after 7 years, and hazard functions for reoperation crossed at 7 years.ConclusionsValve preservation (rather than replacement) and matching root procedures have excellent early and long-term results, with increasing survival benefit at 7 years and fewer reoperations by 12 years. We recommend this procedure for experienced surgical teams

LMDA Review, volume 11, issue 2

Contents include: A Letter to the Membership from the LMDA Board Chair, Dixon to the Guthrie, Office Update, Technology Notes, News from CEAD Montreal, LMDA Affiliates with ATHE, ATHE 2001 Practice, Theory, Technology and the New Student, Report on Canadian Caucus, Note to the Editor, The Experiment Tradition, Community and the Development of Scripts for Stage and Screen, A Collaborative Workshop, An Intern on Internships, Spotlight on Early Career Dramaturgs, Exciting News from the West Coast, Coming this Way, and Playscripts.com.https://soundideas.pugetsound.edu/lmdareview/1021/thumbnail.jp

Persistent risk of subsequent procedures and mortality in patients after interrupted aortic arch repair: A Congenital Heart Surgeons' Society study

ObjectiveMultiple subsequent procedures directed at the arch and/or the left ventricular outflow tract are frequently required after interrupted aortic arch repair. We the investigated patterns and factors associated with these subsequent procedures and mortality.MethodsWe reviewed the data from 447 patients with interrupted aortic arch at 33 institutions enrolled from 1987 to 1997. We classified the subsequent procedures by type (catheter-based or surgical) and focus (arch, left ventricular outflow tract, and “other” cardiovascular lesions). We used competing risks and modulated renewal analysis to explore subsequent procedures.ResultsThere were 158 subsequent arch and 100 left ventricular outflow tract procedures. Freedom from death at 21 years was 60% overall. The risk of additional subsequent arch procedures decreased after the first subsequent arch procedure in the acute phase, but did not significantly change in the chronic phase. The risk of additional subsequent left ventricular outflow tract procedures increased after the first subsequent left ventricular outflow tract procedure in the chronic phase. The risk factors for subsequent arch procedures and mortality, but not for subsequent outflow track procedures, were related in a complex way to previous procedures and their timing.ConclusionsInterrupted aortic arch is a chronic disease in which patients often undergo multiple subsequent procedures with persistent risk for additional intervention and mortality. The risk factors are related to the nature and timing of previous procedures and to the morphology and details of the index procedure. Interrupted aortic arch should be considered a chronic disorder