A new beginning: an overview of new psychoactive substances

New psychoactive substances are the newest danger trending on the drug market. Though they are defined as substances designed to replicate the effects of traditional illegal drugs such as cocaine, ecstasy, amphetamines and cannabis, it has been suggested that these mimics are extensively more potent than their counterparts. Beyond the limits of current legislation, clandestine chemists have set out to manufacture these substances for profit, whilst benefitting users in areas of affordability, availability and purity. Since the rediscovery of mephedrone in 2003 and more so in recent years, the manufacture and sale of these substances has soared. Due to the rate at which these ever-increasing analogues are being manufactured, and the endless number of combinations available for production, it is unlikely the trade will be reduced in the near future. This review provides an overview of these new substances addressing; what they are, when they were produced, where they are available, how they are manufactured, who is taking them and why users are resorting to these substances over traditional substances. It is clear throughout this review that the lack of information surrounding these substances is leading to increased risks to users, untrained healthcare and forensic professionals and ineffective legislation. Welcome to, a new beginning

Modelling the cost effectiveness of interferon beta and glatiramer acetate in the management of multiple sclerosis

OBJECTIVE: To evaluate the cost effectiveness of four disease modifying treatments (interferon betas and glatiramer acetate) for relapsing remitting and secondary progressive multiple sclerosis in the United Kingdom. DESIGN: Modelling cost effectiveness. SETTING: UK NHS. PARTICIPANTS: Patients with relapsing remitting multiple sclerosis and secondary progressive multiple sclerosis. MAIN OUTCOME MEASURES: Cost per quality adjusted life year gained. RESULTS: The base case cost per quality adjusted life year gained by using any of the four treatments ranged from £42 000 ($66 469; 61 630) to £98 000 based on efficacy information in the public domain. Uncertainty analysis suggests that the probability of any of these treatments having a cost effectiveness better than £20 000 at 20 years is below 20%. The key determinants of cost effectiveness were the time horizon, the progression of patients after stopping treatment, differential discount rates, and the price of the treatments. CONCLUSIONS: Cost effectiveness varied markedly between the interventions. Uncertainty around point estimates was substantial. This uncertainty could be reduced by conducting research on the true magnitude of the effect of these drugs, the progression of patients after stopping treatment, the costs of care, and the quality of life of the patients. Price was the key modifiable determinant of the cost effectiveness of these treatments

Estimating population cardinal health state valuation models from individual ordinal (rank) health state preference data

Ranking exercises have routinely been used as warm-up exercises within health state valuation surveys. Very little use has been made of the information obtained in this process. Instead, research has focussed upon the analysis of health state valuation data obtained using the visual analogue scale, standard gamble and time trade off methods. Thurstone’s law of comparative judgement postulates a stable relationship between ordinal and cardinal preferences, based upon the information provided by pairwise choices. McFadden proposed that this relationship could be modelled by estimating conditional logistic regression models where alternatives had been ranked. In this paper we report the estimation of such models for the Health Utilities Index Mark 2 and the SF-6D. The results are compared to the conventional regression models estimated from standard gamble data, and to the observed mean standard gamble health state valuations. For both the HUI2 and the SF-6D, the models estimated using rank data are broadly comparable to the models estimated on standard gamble data and the predictive performance of these models is close to that of the standard gamble models. Our research indicates that rank data has the potential to provide useful insights into community health state preferences. However, important questions remain

Estimating population cardinal health state valuation models from individual ordinal (rank) health state preference data

Ranking exercises have routinely been used as warm-up exercises within health state valuation surveys. Very little use has been made of the information obtained in this process. Instead, research has focussed upon the analysis of health state valuation data obtained using the visual analogue scale, standard gamble and time trade off methods. Thurstone’s law of comparative judgement postulates a stable relationship between ordinal and cardinal preferences, based upon the information provided by pairwise choices. McFadden proposed that this relationship could be modelled by estimating conditional logistic regression models where alternatives had been ranked. In this paper we report the estimation of such models for the Health Utilities Index Mark 2 and the SF-6D. The results are compared to the conventional regression models estimated from standard gamble data, and to the observed mean standard gamble health state valuations. For both the HUI2 and the SF-6D, the models estimated using rank data are broadly comparable to the models estimated on standard gamble data and the predictive performance of these models is close to that of the standard gamble models. Our research indicates that rank data has the potential to provide useful insights into community health state preferences. However, important questions remain.health state valuation; HUI-2; SF-6D

Estimating population cardinal health state valuation models from individual ordinal (rank) health state preference data

Ranking exercises have routinely been used as warm-up exercises within health state valuation surveys. Very little use has been made of the information obtained in this process. Instead, research has focussed upon the analysis of health state valuation data obtained using the visual analogue scale, standard gamble and time trade off methods. Thurstone’s law of comparative judgement postulates a stable relationship between ordinal and cardinal preferences, based upon the information provided by pairwise choices. McFadden proposed that this relationship could be modelled by estimating conditional logistic regression models where alternatives had been ranked. In this paper we report the estimation of such models for the Health Utilities Index Mark 2 and the SF-6D. The results are compared to the conventional regression models estimated from standard gamble data, and to the observed mean standard gamble health state valuations. For both the HUI2 and the SF-6D, the models estimated using rank data are broadly comparable to the models estimated on standard gamble data and the predictive performance of these models is close to that of the standard gamble models. Our research indicates that rank data has the potential to provide useful insights into community health state preferences. However, important questions remain

Stiff‐Stilbene Ligands Target G‐Quadruplex DNA and Exhibit Selective Anticancer and Antiparasitic Activity

G-quadruplex nucleic acid structures have long been studied as anticancer targets whilst their potential in antiparasitic therapy has only recently been recognized and barely explored. Herein, we report the synthesis, biophysical characterization, and in vitro screening of a series of stiff-stilbene G4 binding ligands featuring different electronics, side-chain chemistries, and molecular geometries. The ligands display selectivity for G4 DNA over duplex DNA and exhibit nanomolar toxicity against Trypasanoma brucei and HeLa cancer cells whilst remaining up to two orders of magnitude less toxic to non-tumoral mammalian cell line MRC-5. Our study demonstrates that stiff-stilbenes show exciting potential as the basis of selective anticancer and antiparasitic therapies. To achieve the most efficient G4 recognition the scaffold must possess the optimal electronics, substitution pattern and correct molecular configuration.M.P.O. thanks the Bristol Chemical Synthesis Centre for Doctoral Training, funded by EPSRC (EP/L015366/1) and the University of Bristol for a PhD studentship. J.C.M./P.P. thank Spanish Ministerio de Ciencia Innovación y Universidades (Grants CTQ2015- 64275-P and RTI2018-099036-B-I00). M.C.G. thanks the European Research Council (ERC-COG: 648239

Cocaine trafficking between South America and Greece and methods of concealment

This research investigates the cocaine business between South America and Greece, and its trading methods. Cocaine trafficking is a complex political, social, cultural, and moral challenge that transcends national borders in size and importance. This problem as a phenomenon is global and multidimensional, as it involves, from the point of cultivation to the point of consumption, various people, social strata, huge economic interests, countries and even governments. The engagement of specialists from the maritime sector and individuals from the “higher social strata” who actively participate in the shipment and trafficking of cocaine to West Europe and Greece is highlighted. The cocaine industry in Greece is ‘structured’ by a network of interaction and collaboration involving governmental, commercial, and civil society players, according to information from a range of resources. The largest quantities of cocaine are produced in South American, and in particular in Colombia, Peru, and Bolivia, from where a large percentage of production is destined for European markets. The smuggling business into Europe takes place in large quantities, mainly by sea from coastal areas / ports of South American countries and the Caribbean Islands. Containers are the main transportation method, with quantities being hidden either within the legal cargo or in specially designed crypts. Sailing boats are also a time-honored method of smuggling drugs. The main points of entry of cocaine transported by sea from Latin America to Southern Europe, either directly or through West Africa, via the Mediterranean, is Spain, as well as France, Italy, Portugal, and Greece. Respectively, the cocaine entry points by sea in Northern Europe are mainly the Netherlands, Belgium, and Germany. Then the quantities are shipped to the rest of the European countries. For smaller quantities of cocaine, trafficking to Europe occurs by air from Brazil and other South American countries. Globally, Europe is a major drug market, maintained mainly by drugs smuggled from other parts of the world. Latin America is an important source of drugs entering Europe, which acts as a transit point for cocaine destined for other continents. Additional research is recommended regarding the financial, social, and political interests of the individuals involved in this industry in order to truly evaluate the dynamics of this unlawful trade

Enhanced sampling molecular dynamics simulations correctly predict the diverse activities of a series of stiff-stilbene G-quadruplex DNA ligands

Ligands with the capability to bind G-quadruplexes (G4s) specifically, and to control G4 structure and behaviour, offer great potential in the development of novel therapies, technologies and functional materials. Most known ligands bind to a pre-formed topology, but G4s are highly dynamic and a small number of ligands have been discovered that influence these folding equilibria. Such ligands may be useful as probes to understand the dynamic nature of G4 in vivo, or to exploit the polymorphism of G4 in the development of molecular devices. To date, these fascinating molecules have been discovered serendipitously. There is a need for tools to predict such effects to drive ligand design and development, and for molecular-level understanding of ligand binding mechanisms and associated topological perturbation of G4 structures. Here we study the G4 binding mechanisms of a family of stiff-stilbene G4 ligands to human telomeric DNA using molecular dynamics (MD) and enhanced sampling (metadynamics) MD simulations. The simulations predict a variety of binding mechanisms and effects on G4 structure for the different ligands in the series. In parallel, we characterize the binding of the ligands to the G4 target experimentally using NMR and CD spectroscopy. The results show good agreement between the simulated and experimentally observed binding modes, binding affinities and ligand-induced perturbation of the G4 structure. The simulations correctly predict ligands that perturb G4 topology. Metadynamics simulations are shown to be a powerful tool to aid development of molecules to influence G4 structure, both in interpreting experiments and to help in the design of these chemotypes

Use of cumulative incidence of novel influenza A/H1N1 in foreign travelers to estimate lower bounds on cumulative incidence in Mexico

Background: An accurate estimate of the total number of cases and severity of illness of an emerging infectious disease is required both to define the burden of the epidemic and to determine the severity of disease. When a novel pathogen first appears, affected individuals with severe symptoms are more likely to be diagnosed. Accordingly, the total number of cases will be underestimated and disease severity overestimated. This problem is manifest in the current epidemic of novel influenza A/H1N1. Methods and Results: We used a simple approach to leverage measures of incident influenza A/H1N1 among a relatively small and well observed group of US, UK, Spanish and Canadian travelers who had visited Mexico to estimate the incidence among a much larger and less well surveyed population of Mexican residents. We estimate that a minimum of 113,000 to 375,000 cases of novel influenza A/H1N1 have occurred in Mexicans during the month of April, 2009. Such an estimate serves as a lower bound because it does not account for underreporting of cases in travelers or for nonrandom mixing between Mexican residents and visitors, which together could increase the estimates by more than an order of magnitude. Conclusions: We find that the number of cases in Mexican residents may exceed the number of confirmed cases by two to three orders of magnitude. While the extent of disease spread is greater than previously appreciated, our estimate suggests that severe disease is uncommon since the total number of cases is likely to be much larger than those of confirmed cases