Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis

The leishmaniases are diseases that affect millions of people across the world, in particular visceral leishmaniasis (VL) which is fatal unless treated. Current standard of care for VL suffers from multiple issues and there is a limited pipeline of new candidate drugs. As such, there is a clear unmet medical need to identify new treatments. This paper describes the optimization of a phenotypic hit against Leishmania donovani, the major causative organism of VL. The key challenges were to balance solubility and metabolic stability while maintaining potency. Herein, strategies to address these shortcomings and enhance efficacy are discussed, culminating in the discovery of preclinical development candidate GSK3186899/DDD853651 (<b>1</b>) for VL

Comparing political futures: the rise and use of scenarios in future-oriented area studies

The predictive ability of scholars of politics has long been a subject of theoretical debate and methodological development. In theoretical debate, prediction represents a central issue regarding the extent to which the study of politics is scientific. In methodological development, much effort and resource have been devoted to a diverse range of predictive approaches, with varying degrees of success. Expectations that scholars forecast accurately come as much from the policy and media worlds as from the academy. Since the end of the Cold War, scenario development has become prevalent in future-oriented research by area studies scholars. This approach is long due critical re-assessment. For all its strengths as a policy tool, scenario development tends towards a bounded methodology, driving the process of anticipating futures along predetermined paths into a standardised range of options, and paying insufficient attention to theoretical and contextual understandings available within the relevant scholarly disciplines

European survey on efficacy and safety of duty-cycled radiofrequency ablation for atrial fibrillation

Duty-cycled radiofrequency ablation (RFA) has been used for atrial fibrillation (AF) for around 5 years, but large-scale data are scarce. The purpose of this survey was to report the outcome of the technique. A survey was conducted among 20 centres from seven European countries including 2748 patients (2128 with paroxysmal and 620 with persistent AF). In paroxysmal AF an overall success rate of 82 [median 80, interquartile range (IQR) 7490], a first procedure success rate of 72 [median 74 (IQR 5983)], and a success of antiarrhythmic medication of 59 [median 60 (IQR 3972)] was reported. In persistent AF, success rates were significantly lower with 70 [median 74 (IQR 6092)]; P 0.05) as well as the first procedure success rate of 58 [median 55 (IQR 4781)]; P 0.001). The overall success rate was similar among higher and lower volume centres and were not dependent on the duration of experience with duty-cycled RFA (r 0.08, P 0.72). Complications were observed in 108 (3.9) patients, including 31 (1.1) with symptomatic transient ischaemic attack or stroke, which had the same incidence in paroxysmal and persistent AF (1.1 vs. 1.1) and was unrelated to the case load (r 0.24, P 0.15), bridging anticoagulation to low molecular heparin, routine administration of heparin over the long sheath, whether a transoesophageal echocardiogram was performed in every patient or not and average procedure times. Duty-cycled RFA has a self-reported success and complication rate similar to conventional RFA. After technical modifications a prospective registry with controlled data monitoring should be conducted to assess outcom

Deep into the mud: ecological and socio-economic impacts of the dam breach in Mariana, Brazil.

Made available in DSpace on 2018-08-03T00:56:13Z (GMT). No. of bitstreams: 1 1s2.0S1679007316301104main.pdf: 3842180 bytes, checksum: 114f6d73ea48a614146a9f67588338ad (MD5) Previous issue date: 2017-02-06bitstream/item/180810/1/1-s2.0-S1679007316301104-main.pd

Deep into the mud : ecological and socio-economic impacts of the dam breach in Mariana, Brazil.

We review the ecological and socio-economic impacts ofthe catastrophic dam failure in Mariana, Brazil. Tailing management practices by Samarco mining company ultimately caused a dam breach that abruptly discharged between 55 and 62millionm3 of tailings into the Doce River watershed. On November 5th, 2015, a tsunami of slurry engulfed the small district of Bento Rodrigues, loading the Doce River and its estuary with toxic tailings along a 663.2 km trajectory, extending impacts to the Atlantic coast. Acute ecological impacts will adversely affect livelihoods of more than 1 million people in 41 riparian municipalities by reducing local access to fisheries resources, clean water, crop production sites, hydroelectric power generation and raw materials. The threats to riverine human communities are particularly critical for the disadvantaged populations from remote areas that rely on subsistence agriculture and fisheries, and are uniquely vulnerable to long-term heavy metal exposure. At the landscape scale, we predict multiple negative impacts, ranging from alterations of the genetic diversity of fish populations to long-term vegetation loss and poor regeneration in contaminated areas. Consequently, compromised soil stability and runoff control will increase the risk of further geomorphologic disturbance, including landslides, bank failure and mass movements. We propose spatially explicit long-term monitoring frameworks and priority mitigation measures to cope with acute and chronic risks. We posit that, from a national perspective, disastrous impacts like that of Doce River may become more frequent, given the recent regulatory changes that undermine both institutional governance structures and enforcement of environmental regulation