Clinical trial designs of new medicinal products for treating schizophrenia: discussion of EMA's Guideline and a Better Long Term Trial Design

Background and Objectives: Schizophrenia is a severe chronic disease. Endpoint variables lack objectivity and the diagnostic criteria have evolved with time. In order to guide the development of new drugs, European Medicines Agency (EMA) issued a guideline on the clinical investigation of medicinal products for the treatment of schizophrenia. Methods: Authors reviewed and discussed the efficacy trial part of the Guideline. Results: The Guideline divides clinical efficacy trials into short-term trials and long-term trials. The short-term three-arm trial is recommended to replace the short-term two-arm active-controlled non-inferiority trial because the latter has sensitivity issues. The Guideline ultimately makes that three-arm trial a superiority trial. The Guideline discusses four types of long-term trial designs. The randomized withdrawal trial design has some disadvantages. Long-term two-arm active-controlled non-inferiority trial is not recommended due to the sensitivity issue. Extension of the short-term trial is only suitable for extension of the short-term two-arm active-controlled superiority trial. The Guideline suggests that a hybrid design of a randomized withdrawal trial incorporated into a long-term parallel trial might be optimal. However, such a design has some disadvantages and might be too complex to be carried out. Authors suggest instead a three-group long-term trial design, which could provide comparison between test drug and active comparator along with comparison between the test drug and placebo. This alternative could arguably be much easier to carry out compared with the hybrid design. Conclusions: The three-group long-term design merits further discussion and evaluation.

A Better Place to Be: Republicanism as an Alternative to the Authoritarianism-Democracy Dichotomy

ABSTRACT Title of Dissertation: A BETTER PLACE TO BE: REPUBLICANISM AS AN ALTENATIVE TO THE AUTHORITARIANISM-DEMOCRACY DICHOTOMY Christopher Ronald Binetti, Doctor of Philosophy, and 2016 Dissertation directed by: Dr. Charled Frederick Alford, Department of Government and Politics In this dissertation, I argue that in modern or ancient regimes, the simple dichotomy between democracies and autocracies/dictatorships is both factually wrong and problematic for policy purposes. It is factually wrong because regimes between the two opposite regime types exist and it is problematic because the either/or dichotomy leads to extreme thinking in terms of nation-building in places like Afghanistan. In planning for Afghanistan, the argument is that either we can quickly nation-build it into a liberal democracy or else we must leave it in the hands of a despotic dictator. This is a false choice created by both a faulty categorization of regime types and most importantly, a failure to understand history. History shows us that the republic is a regime type that defies the authoritarian-democracy dichotomy. A republic by my definition is a non-dominating regime, characterized by a (relative) lack of domination by any one interest group or actor, mostly non-violent competition for power among various interest groups/factions, the ability of factions/interest groups/individual actors to continue to legitimately play the political game even after electoral or issue-area defeat and some measure of effectiveness. Thus, a republic is a system of government that has institutions, laws, norms, attitudes, and beliefs that minimize the violation of the rule of law and monopolization of power by one individual or group as much as possible. These norms, laws, attitudes, and beliefs ae essential to the republican system in that they make those institutions that check and balance power work. My four cases are Assyria, Persia, Venice and Florence. Assyria and Persia are ancient regimes, the first was a republic and then became the frightening opposite of a republic, while the latter was a good republic for a long time, but had effectiveness issues towards the end. Venice is a classical example of a medieval or early modern republic, which was very inspirational to Madison and others in building republican America. Florence is the example of a medieval republic that fell to despotism, as immortalized by Machiavelli’s writings. In all of these examples, I test certain alternative hypotheses as well as my own.

Building Better Nurse Scheduling Algorithms

The aim of this research is twofold: Firstly, to model and solve a complex nurse scheduling problem with an integer programming formulation and evolutionary algorithms. Secondly, to detail a novel statistical method of comparing and hence building better scheduling algorithms by identifying successful algorithm modifications. The comparison method captures the results of algorithms in a single figure that can then be compared using traditional statistical techniques. Thus, the proposed method of comparing algorithms is an objective procedure designed to assist in the process of improving an algorithm. This is achieved even when some results are non-numeric or missing due to infeasibility. The final algorithm outperforms all previous evolutionary algorithms, which relied on human expertise for modification.

When is bigger better? The effects of group size on the evolution of helping behaviours.

Understanding the evolution of sociality in humans and other species requires understanding how selection on social behaviour varies with group size. However, the effects of group size are frequently obscured in the theoretical literature, which often makes assumptions that are at odds with empirical findings. In particular, mechanisms are suggested as supporting large-scale cooperation when they would in fact rapidly become ineffective with increasing group size. Here we review the literature on the evolution of helping behaviours (cooperation and altruism), and frame it using a simple synthetic model that allows us to delineate how the three main components of the selection pressure on helping must vary with increasing group size. The first component is the marginal benefit of helping to group members, which determines both direct fitness benefits to the actor and indirect fitness benefits to recipients. While this is often assumed to be independent of group size, marginal benefits are in practice likely to be maximal at intermediate group sizes for many types of collective action problems, and will eventually become very small in large groups due to the law of decreasing returns. The second component is the response of social partners on the past play of an actor, which underlies conditional behaviour under repeated social interactions. We argue that under realistic conditions on the transmission of information in a population, this response on past play decreases rapidly with increasing group size so that reciprocity alone (whether direct, indirect, or generalised) cannot sustain cooperation in very large groups. The final component is the relatedness between actor and recipient, which, according to the rules of inheritance, again decreases rapidly with increasing group size. These results explain why helping behaviours in very large social groups are limited to cases where the number of reproducing individuals is small, as in social insects, or where there are social institutions that can promote (possibly through sanctioning) large-scale cooperation, as in human societies. Finally, we discuss how individually devised institutions can foster the transition from small-scale to large-scale cooperative groups in human evolution.

Scottish Independence, ‘YES’ or ‘NO’ From the ‘NO’ Side Scotland is Better Together with the United Kingdom

If the people of Scotland favour independence, the split will create high level of uncertainty, and this component of risk will be extremely difficult to deal with.

A framework for better understanding drinking-water quality in Happy Valley-Goose Bay, Labrador: Implications for optimization and protection of municipally supplied water

This research project was driven by the recurring complaints and concerns voiced in the media by residents living in the Valley area of the community of Happy Valley-Goose Bay, Labrador. Drinking water in this town is supplied by two water treatment plants (a municipality treatment plant and a DND treatment plant), which use raw water from two different sources (groundwater from multiple wells versus surface water from Spring Gulch brook) and use two different processes of drinking-water treatment. In fact, the drinking water supplied in the Valley area has a unique distribution arrangement. To meet demand, the Valley area is served by a blend of treated waters from a storage reservoir (Sandhill reservoir), which is fed by both water treatment plants. Most of the time, treated water from the municipal treatment plant dominates in the mixture. As water travels through the distribution system and household plumbing, specific reactions can occur either in the water itself and/or at the solid–liquid interface at the pipe walls; this is strongly influenced by the physical and chemical characteristics of the water. These reactions can introduce undesirable chemical compounds and/or favor the growth of bacteria in the drinking water, causing the deterioration of the quality of water reaching the consumer taps. In the distribution system in general, these chemical constituents and bacteria may pose potential threats to health or the water’s aesthetic qualities (smell, taste or appearance). Drinking water should be not only safe, but also palatable.

SSF guidelines: better understanding needed

The Near East and North Africa Regional Consultation on SSF Guidelines focused on raising awareness and support for implementation of the guidelines.

Building Better Nurse Scheduling Algorithms

The aim of this research is twofold: Firstly, to model and solve a complex nurse scheduling problem with an integer programming formulation and evolutionary algorithms. Secondly, to detail a novel statistical method of comparing and hence building better scheduling algorithms by identifying successful algorithm modifications. The comparison method captures the results of algorithms in a single figure that can then be compared using traditional statistical techniques. Thus, the proposed method of comparing algorithms is an objective procedure designed to assist in the process of improving an algorithm. This is achieved even when some results are non-numeric or missing due to infeasibility. The final algorithm outperforms all previous evolutionary algorithms, which relied on human expertise for modification.

Building Better Nurse Scheduling Algorithms

The aim of this research is twofold: Firstly, to model and solve a complex nurse scheduling problem with an integer programming formulation and evolutionary algorithms. Secondly, to detail a novel statistical method of comparing and hence building better scheduling algorithms by identifying successful algorithm modifications. The comparison method captures the results of algorithms in a single figure that can then be compared using traditional statistical techniques. Thus, the proposed method of comparing algorithms is an objective procedure designed to assist in the process of improving an algorithm. This is achieved even when some results are non-numeric or missing due to infeasibility. The final algorithm outperforms all previous evolutionary algorithms, which relied on human expertise for modification.

Towards a better understanding of granular material processes: The coupling of a computational fluid dynamics framework with micro-mechanical models

Abstract not available

Estudio a nivel Colombia de la influencia del aditivo better mix en estado fresco, semi endurecido y endurecido del concreto estructural

Bogotá (Colombia): Universidad de La Salle. Facultad de Ingeniería. Programa de Ingeniería Civil

Rebuilding a Better Response

What is one thing in the world that we have little control over? Mother Nature. We as humans have tried to alter our natural environment countless times, and she has fought back twice as strong, leaving trails of devastation behind. The number of natural disasters has drastically increased, especially in the Southeast Asian region. The aftermath of a tsunami has left a large number of people homeless and lives forever changed. The current recovery process is chaotic and leaves affected individuals stranded without the means of rebuilding for long periods of time. This thesis aims to re-evaluate the recovery relief procedures and provide a better means of rebuilding their lives and community.

Why are some cyano-based ionic liquids better glucose solvents than water?

Among different classes of ionic liquids (ILs), those with cyano-based anions have been of special interest due to their low viscosity and enhanced solvation ability for a large variety of compounds. Experimental results from this work reveal that the solubility of glucose in some of these ionic liquids may be higher than in water – a well-known solvent with enhanced capacity to dissolve mono- and disaccharides. This raises questions on the ability of cyano groups to establish strong hydrogen bonds with carbohydrates and on the optimal number of cyano groups at the IL anion that maximizes the solubility of glucose. In addition to experimental solubility data, these questions are addressed in this study using a combination of density functional theory (DFT) and molecular dynamics (MD) simulations. Through the calculation of the number of hydrogen bonds, coordination numbers, energies of interaction and radial and spatial distribution functions, it was possible to explain the experimental results and to show that the ability to favorably interact with glucose is driven by the polarity of each IL anion, with the optimal anion being dicyanamide.