Ambroxol as a novel disease-modifying treatment for Parkinson\u27s disease dementia: Protocol for a single-centre, randomized, double-blind, placebo-controlled trial

© 2019 The Author(s). Background: Currently there are no disease-modifying treatments for Parkinson\u27s disease dementia (PDD), a condition linked to aggregation of the protein α-synuclein in subcortical and cortical brain areas. One of the leading genetic risk factors for Parkinson\u27s disease is being a carrier in the gene for β-Glucocerebrosidase (GCase; gene name GBA1). Studies in cell culture and animal models have shown that raising the levels of GCase can decrease levels of α-synuclein. Ambroxol is a pharmacological chaperone for GCase and is able to raise the levels of GCase and could therefore be a disease-modifying treatment for PDD. The aims of this trial are to determine if Ambroxol is safe and well-tolerated by individuals with PDD and if Ambroxol affects cognitive, biochemical, and neuroimaging measures. Methods: This is a phase II, single-centre, double-blind, randomized placebo-controlled trial involving 75 individuals with mild to moderate PDD. Participants will be randomized into Ambroxol high-dose (1050 mg/day), low-dose (525 mg/day), or placebo treatment arms. Assessments will be undertaken at baseline, 6-months, and 12-months follow up times. Primary outcome measures will be the Alzheimer\u27s disease Assessment Scale-cognitive subscale (ADAS-Cog) and the ADCS Clinician\u27s Global Impression of Change (CGIC). Secondary measures will include the Parkinson\u27s disease Cognitive Rating Scale, Clinical Dementia Rating, Trail Making Test, Stroop Test, Unified Parkinson\u27s disease Rating Scale, Purdue Pegboard, Timed Up and Go, and gait kinematics. Markers of neurodegeneration will include MRI and CSF measures. Pharmacokinetics and pharmacodynamics of Ambroxol will be examined through plasma levels during dose titration phase and evaluation of GCase activity in lymphocytes. Discussion: If found effective and safe, Ambroxol will be one of the first disease-modifying treatments for PDD. Trial registration: ClinicalTrials.gov NCT02914366, 26 Sep 2016/retrospectively registered

Shareholder activism in the UK: types of activists, forms of activism, and their impact on a target’s performance

Considering the recent rapid expansion of shareholder activism phenomenon in the United Kingdom (UK) and the vast amount of resources committed to it by corporations, government and investors, its effectiveness has become a crucial subject for investigation. This article analyzes organizational outcomes of shareholder activism in the UK. This research is based on a unique comprehensive database of shareholder activism events during the period of 1998–2008. We provide a detailed account of different types of activists, activism strategies and shareholder demands associated with the events of activism. Our findings show that the effectiveness of shareholder activism in terms of abnormal stock-market returns varies dramatically depending on its form, type of investor and the nature of investor proposals

A multi-objective reverse logistics model for electronic products considering environmental impacts and Kanban pull system

Technological innovation is exponentially growing at a quick rate, as well as its outputs- electronic products. Because of this, new products quickly replaces older ones, such that the rate of obsolescence is growing in number and the amount of electronic waste (e-waste) generated each year is also increasing with population. Moreover, a huge percentage of this goes to landfill or incineration. Recycling is being performed to prevent the damaging of the environment. However, only a few recycle because of the costs associated with the activities involved with it. The recovery of materials from used electronic products that are already for disposal is referred to as reverse logistics or reverse supply chain. Studies regarding reverse logistics have been done before such as the study of Joaquinlao (2009) and the study of Cruz (2008) however there were some points which they failed to consider such as the relevance of inventory management in the reverse logistics system and the other environmental impacts aside from carbon emissions. One of the areas of concern in the product take back program is the inventory management of returns (Kuik, Dekker, & Fleischmann, 2001). Without proper inventory management, the system will be inefficient in terms of handling the stocks which can result in the recycling facility not being able to satisfy the raw material requirements of the manufacturing facility. If the requirements for raw materials of the manufacturing facility are not met, the tendency is to purchase raw materials from virgin material suppliers which would contribute to the environmental impact category of resource depletion. From this scenario, we can see that inventory management of returns has an indirect effect on the environmental impact generated by the reverse logistics system. In the study, a kanban system was applied to manage the inventory of returns. Also, carbon emission is not the only factor that affects the environmental impact generated by the system. Raw material extraction is also considered in the system because the requirements that recycling facilities can\u27t supply will be taken from the virgin raw material extraction and extracting natural resources is frequently a destructive activity that damages the rainforest ecosystem and causes problems for people living nearby and downstream from mining operations (Butler, 2011).A multi-objective mixed-integer programming model was created to capture operational aspects of the reverse supply chain of electronic waste. It aims to balance the two conflicting objectives, which are to minimize the total operating cost incurred by the system and to minimize the total negative environmental impact contributed by the activities of the supply chain. The model was used to come up with optimal decisions regarding the sourcing of raw materials, and the inventory level to maintain in order to ensure an efficient flow of materials and used products, which would contribute in lowering the environmental impact.Using General Algebraic Mathematical Model System (GAMS), the formulated model was validated to ensure that the model behaves as expected. To identify the significant variables that affect the system, sensitivity analysis was performed using Design of Experiments (DOE). The results of this analysis showed that the consideration of the environment aspect in the reverse supply chain would prefer a low kanban level for finished components and raw materials to maintain in order to have a balance between cost and environmental impact. Also, a higher kanban size for raw materials is preferred when considering the environment because this would ensure that there will be enough recycled materials while decreasing the frequency of replenishment. Recycled materials would be preferred when the processing cost, together with the collection cost, is cheaper compared to the purchasing cost of virgin raw materials. Moreover, if the weight for resource depletion is set to high, the amount of recycled materials to be ordered would be greater than the purchased virgin materials. Lastly, as cost is lowered, environmental impact would increase and vice versa.Suggestions for further research include considering the quality of recycled materials, using other environmental impact assessment methodology, incorporating other recovery options, and closing the supply chain loop