Global standards of Constitutional law : epistemology and methodology

Just as it led the philosophy of science to gravitate around scientific practice, the abandonment of all foundationalist aspirations has already begun making political philosophy into an attentive observer of the new ways in which constitutional law is practiced. Yet paradoxically, lawyers and legal scholars are not those who understand this the most clearly. Beyond analyzing the jurisprudence that has emerged from the expansion of constitutional justice, and taking into account the development of international and regional law, the ongoing globalization of constitutional law requires comparing the constitutional laws of individual nations. Following Waldron, the product of this new legal science can be considered as ius gentium. This legal science is not as well established as one might like to think. But it can be developed on the grounds of the practice that consists in ascertaining standards. As abstract types of best “practices” (and especially norms) of constitutional law from around the world, these are only a source of law in a substantive, not a formal, sense. They thus belong to what I should like to call a “second order legal positivity.” In this article I will undertake, both at a methodological and an epistemological level, the development of a model for ascertaining global standards of constitutional law

An examination of alternative option hedging strategies in the presence of transaction costs

© 2017 Dr Vicky Siew See ChowSubstantial progress has been made in developing option hedging models that account for transaction costs. Previous analyses of option hedging strategies in the presence of transaction costs use a Monte Carlo simulation framework in conjunction with a mean variance rule to compare different strategies. These studies being based on simulated stock price data are essentially theoretical tests. It is not known, however, how various proposed hedging strategies compare in terms of hedging precision and transaction costs when tested using actual market data. In addition, the mean variance rule is subject to certain well-known restrictive assumptions. This thesis aims to fill two gaps in the literature, by: (1) using actual market data to examine hedging performance, and (2) using a stochastic dominance rule as an alternative hedging performance measure. I undertake two studies. The first compares hedging strategies using Monte Carlo simulation together with mean variance and stochastic dominance criteria. Simulation allows us to study the consistency of the hedging outcomes determined by criteria rules in a controlled environment. The second study is a comprehensive empirical investigation of the merits of competing option hedging strategies with transaction costs, using S&P 500 index options. Both studies examine the hedging performance of the delta-neutral hedge. Given the widely documented volatility risk in empirical data, I further supplement the empirical study with a delta–vega-neutral hedge. Consistent with the literature, the Monte Carlo simulation demonstrates that move-based strategies are superior to time-based strategies. In contrast, empirical testing shows time-based strategies, in particular the Black-Scholes discrete time hedging strategy, are the optimal hedging strategies. Empirically, I find that a delta-neutral hedge is sufficient for a hedger to attain the optimal tradeoff between hedging precision and transaction costs paid if the hedger is using time-based strategies. I further demonstrate that a hedger can save a substantial amount of transaction costs by simply switching from a move-based strategy to a time-based strategy. A hedger is able to save an average 46% of the transaction costs associated with a poorly performing hedging strategy by simply switching to the optimal hedging strategy. I also show that mean variance and stochastic dominance comparisons are not always mutually consistent with each other; however, the differences are usually small. The rank of each strategy under either rule is highly dependent on the characteristics of the empirical distribution of the net hedging error. I also show that a stochastic dominance test provides a precise ranking of hedging performance for each hedging strategy only when there are strong dominance relationships among the strategies, that is, when the empirical density functions of net hedging error for each of the strategies are sufficiently different. The comparisons presented in my study strengthen the confidence in the mean variance rule as a performance measure in assessing hedging outcomes in the presence of transaction costs. The findings of my thesis will assist financial institutions in making informed hedging decisions when transaction costs are taken into consideration

354 Lenvatinib and pembrolizumab in advanced endometrial carcinoma (EC): long-term efficacy and safety update from a phase 1b/2 study

Background Lenvatinib is a multikinase inhibitor of VEGFR 1–3, FGFR 1–4, PDGFRα, RET, and KIT. Pembrolizumab is an anti-programmed death-1 monoclonal antibody. We previously reported results from a cohort of 108 patients with metastatic EC (data cutoff date, January 10, 2019) who received lenvatinib + pembrolizumab as part of an ongoing multicenter, open-label, phase 1b/2 study evaluating the combination treatment in patients with selected solid tumors (NCT02501096). Lenvatinib + pembrolizumab showed a tolerable safety profile and promising antitumor activity per immune-related (ir) Response Evaluation Criteria In Solid Tumors (RECIST) by investigator assessment, including an objective response rate (ORR) of 38.9% (95% confidence interval [CI], 29.7–48.7), median progression-free survival (PFS) of 7.4 months (95% CI, 5.3–8.7), and median overall survival (OS) of 16.7 months (95% CI, 15.0-not estimable).1 Here we present updated efficacy and safety data (data cutoff date: August 18, 2020). Methods Patients included in the EC cohort had histologically confirmed, measurable metastatic EC and had received ≤2 prior chemotherapies (unless discussed with the sponsor). Patients received lenvatinib (20 mg orally once daily) and pembrolizumab (200 mg intravenously once every 3 weeks). The phase 2 efficacy endpoints included ORR, PFS, OS, and duration of response. Tumor assessments for primary and secondary endpoints were evaluated by investigators per irRECIST. Results The 108 patients from the key efficacy analysis set for the previously reported results were all included in these updated analyses. Median follow-up duration for the study was 34.7 months. Efficacy outcomes are summarized in table 1. Treatment-related adverse events (TRAEs) occurred in 104 (96%) patients (94 [87%] grade ≤3, 10 [9%] grade ≥4). TRAEs led to study-drug interruption of 1 or both drugs in 80 (74.1%) patients and dose reductions of lenvatinib in 73 (67.6%) patients; 23 (21.3%) patients discontinued 1 or both drugs due to a TRAE. The most common grade ≥3 TRAEs were hypertension (33.3%), lipase increased (9.3%), fatigue (8.3%), and diarrhea (7.4%). VIEW INLINE VIEW POPUP DOWNLOAD POWERPOINT Abstract 354 Table 1 Conclusions With extended follow-up, our updated efficacy analysis continued to show clinical benefit in patients with metastatic EC who received lenvatinib + pembrolizumab. Moreover, the combination had a manageable safety profile that was generally consistent with the established safety profiles of the individual monotherapies. No new safety signals were detected. A phase 3 study of lenvatinib + pembrolizumab versus treatment of physician’s choice in advanced endometrial cancer further supports the lasting clinical benefits observed in our study.2 Trial Registration www.clinicaltrials.gov NCT0250109

A standardized approach to the Fugl-Meyer assessment and its implications for clinical trials.

BackgroundStandardizing scoring reduces variability and increases accuracy. A detailed scoring and training method for the Fugl-Meyer motor assessment (FMA) is described and assessed, and implications for clinical trials considered.MethodsA standardized FMA scoring approach and training materials were assembled, including a manual, scoring sheets, and instructional video plus patient videos. Performance of this approach was evaluated for the upper extremity portion.ResultsInter- and intrarater reliability in 31 patients were excellent (intraclass correlation coefficient = 0.98-0.99), validity was excellent (r = 0.74-0.93, P < .0001), and minimal detectable change was low (3.2 points). Training required 1.5 hours and significantly reduced error and variance among 50 students, with arm FMA scores deviating from the answer key by 3.8 ± 6.2 points pretraining versus 0.9 ± 4.9 points posttraining. The current approach was implemented without incident into training for a phase II trial. Among 66 patients treated with robotic therapy, change in FMA was smaller (P ≤ .01) at the high and low ends of baseline FMA scores.ConclusionsTraining with the current method improved accuracy, and reduced variance, of FMA scoring; the 20% FMA variance reduction with training would decrease sample size requirements from 137 to 88 in a theoretical trial aiming to detect a 7-point FMA difference. Minimal detectable change was much smaller than FMA minimal clinically important difference. The variation in FMA gains in relation to baseline FMA suggests that future trials consider a sliding outcome approach when FMA is an outcome measure. The current training approach may be useful for assessing motor outcomes in restorative stroke trials

The BabybreatheTM trial: Protocol for a randomised controlled trial of a complex intervention to prevent postpartum return to smoking

Introduction: Many people quit smoking during pregnancy, but postpartum smoking relapse is common. Maintaining smoking abstinence achieved during pregnancy is key to improving maternal and child health. There are no evidence-based interventions for preventing postpartum smoking relapse. This trial aims to determine whether an intervention to prevent post-partum relapse is effective and cost-effective. Methods and analysis: A randomised controlled trial of a complex intervention to prevent postpartum smoking relapse (BabybreatheTM), with internal pilot, economic and process evaluations. Participants are adults who are pregnant who report having quit smoking in the twelve months before, or during pregnancy. Participants are eligible if they read and understand English, and provide informed consent. Following consent and biochemical validation of smoking abstinence, participants are randomised to intervention or usual care/control (no specific relapse prevention support). The BabybreatheTM intervention consists of manualised advice from a trained member of the health visiting service, health information leaflets for participants and partners, access to the BabybreatheTM website and app. At the time of birth, participants are posted the Babybreathe box, and support is provided by text message for up to 12 months postpartum. Target sample size is 880, recruiting across midwifery services at four hubs in England and Scotland, and through remote advertising in England, Scotland, Wales and Northern Ireland. Outcomes are collected at 6 and 12 months. The primary outcome is self-reported sustained smoking abstinence at 12 months, carbon monoxide verified. Secondary outcomes include self-reported abstinence, time to relapse, partner smoking status and quality of life. Ethics and dissemination: The trial was approved by the North West Preston Research Ethics committee (21/NW/0017). Dissemination will include publication in peer reviewed journals, presentation at academic and public conferences including PPI, and to policy makers and practitioners