Agency: What Does It Mean to Be a Human Being?

This paper will look at the results of what has been termed "the crisis of modernism" and the related rise of postmodern perspectives in the 19th and 20th centuries. It concentrates on what is arguably the chief casualty of this crisis - human agency - and the social science that has developed out of the crisis. We argue that modern and postmodern social science ultimately obviate human agency in the understanding of what it means to be a human being. Attention is given to the contemporary intellectual world and the way in which it has been deeply informed by neo-Hegelian and other postmodern scholarly trends, particularly in accounting for how agency has come to play little role in social science understanding of human action. The paper also offers an alternative conception of human agency to the commonly endorsed libertarian model of free choice. Finally, the paper argues that this view of agency preserves meaning and purpose in human action and counters the pervasive social science worldview that sacrifices agency and meaning to powerful invisible abstractions.

Bretylium, a Class III Antiarrhythmic, Returns to the Market.

Bretylium, with an extensive pharmacologic and medicinal history, was approved by the United States Food and Drug Administration in 1986 for "short-term prevention and treatment of ventricular fibrillation (VF) and treatment of life-threatening ventricular arrhythmias and ventricular tachycardia (VT) unresponsive to adequate doses of a first-line antiarrhythmic agent, such as lidocaine." The NDA sponsor withdrew bretylium from the market in 2011, largely due to unavailability of raw materials required for its production; prior to this, bretylium was removed from the 2000 ACLS Guidelines algorithm for VF/pulseless VT given the challenges obtaining raw materials for drug manufacture. Recently, bretylium has been reintroduced into the US market by a generic pharmaceutical company with the same indications as before. This article provides a history of the salient trials evaluating the efficacy and safety of bretylium and looks to the future as bretylium finds its place in the modern day management of ventricular arrhythmia.

Clinical endpoints and adaptive clinical trials in precirrhotic nonalcoholic steatohepatitis: Facilitating development approaches for an emerging epidemic.

Due to the increasing prevalence of nonalcoholic steatohepatitis (NASH) and its associated health burden, there is a high need to develop therapeutic strategies for patients with this disease. Unfortunately, its long and asymptomatic natural history, the uncertainties about disease progression, the fact that most patients are undiagnosed, and the requirement for sequential liver biopsies create substantial challenges for clinical development. Adaptive design methods are increasingly used in clinical research as they provide the flexibility and efficiency for identifying potential signals of clinical benefit of the test treatment under investigation and make prompt preplanned adaptations without undermining the validity or integrity of the trial. Given the high unmet medical need and the lack of validated surrogate endpoints in NASH, the use of adaptive design methods appears reasonable. Furthermore, due to the limited number of patients willing to have multiple liver biopsies and the need for long-term exposure to assess an impact in outcomes, a continuous seamless adaptive design may reduce the overall sample size while allowing patients to continue after each one of the phases. Here, we review strategic frameworks that include potential surrogate endpoints as well as statistical and logistical approaches that could be considered for applying adaptive designs to clinical trials in NASH with the goal of facilitating drug development for this growing medical need. (Hepatology Communications 2017;1:577-585).

Non-Alcoholic Steatohepatitis: Limited Available Treatment Options but Promising Drugs in Development and Recent Progress Towards a Regulatory Approval Pathway.

The prevalence of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is increasing world-wide in parallel to the increase of the obesity epidemic. Insulin resistance (IR) and the accumulation of triglyceride-derived toxic lipid metabolites play a key role in its pathogenesis. Multiple biomarkers are being evaluated for the non-invasive diagnosis of NASH. However, a percutaneous liver biopsy is still the gold standard method; the minimal diagnostic criteria include the presence of >5% macrovesicular steatosis, inflammation, and liver cell ballooning. Several pharmaceutical agents have been evaluated for the treatment of NASH; however, no single therapy has been approved so far. Due to the increasing prevalence and the health burden, there is a high need to develop therapeutic strategies for patients with NASH targeting both those with early-stage disease as well as those with advanced liver fibrosis. There are unique challenges in the design of studies for these target populations. Collaborative efforts of health authorities, medical disease experts, and the pharmaceutical industry are ongoing to align options for a registrational pathway. Several companies pursuing different mechanisms of action are nearing the end of phase II with their candidates. This manuscript reviews those compounds with a variety of mode of actions that have been evaluated and/or are currently being tested with the goal of achieving a NAFLD/NASH indication.