Deciphering Host-Parasite Interplay in Leishmania Infection through a One Health View of Proteomics Studies on Drug Resistance.

Recent efforts in the study of vector-borne parasitic diseases (VBPDs) have emphasized an increased consideration for preventing drug resistance and promoting the environmental safety of drugs, from the beginning of the drug discovery pipeline. The intensive use of the few available antileishmanial drugs has led to the spreading of hyper-resistant Leishmania infantum strains, resulting in a chronic burden of the disease. In the present work, we have investigated the biochemical mechanisms of resistance to antimonials, paromomycin, and miltefosine in three drug-resistant parasitic strains from human clinical isolates, using a whole-cell mass spectrometry proteomics approach. We identified 14 differentially expressed proteins that were validated with their transcripts. Next, we employed functional association networks to identify parasite-specific proteins as potential targets for novel drug discovery studies. We used SeqAPASS analysis to predict susceptibility based on the evolutionary conservation of protein drug targets across species. MATH-domain-containing protein, adenosine triphosphate (ATP)-binding cassette B2, histone H4, calpain-like cysteine peptidase, and trypanothione reductase emerged as top candidates. Overall, this work identifies new biological targets for designing drugs to prevent the development of Leishmania drug resistance, while aligning with One Health principles that emphasize the interconnected health of people, animals, and ecosystems.

Planning traffic surveillance in Spain: How to optimize the management of police resources to reduce road fatalities.

Although traffic police enforcement is widely recognized as a key action in the road safety field, it can be a costly policy to implement. In addition, governments often impose budget constraints that can limit the resources available for activities such as law enforcement and surveillance. To evaluate the impact of human traffic control resources planning on traffic fatalities on Spanish NUTS-3 regions interurban roads, this paper uses an econometric model to investigate the performance of police enforcement intensity by focusing on two crucial traffic law infractions (i.e., speeding and drunk driving). After controlling for a range of economic, demographic, climate, and risk exposure variables, results highlight the relevance of visible, human, and in-person traffic law enforcement through regular vehicle patrols for reducing traffic crashes, with a non-significant effect of automatic enforcement. Our findings have important implications for traffic police resource management regarding the effective maintenance of patrol cars and plans to digitalize and automatize police administrative tasks and procedures.

Analyzing the safety impact of longer and heavier vehicles circulating in the European market.

INTRODUCTION: The European Union (EU) has developed different strategies to internalize the costs of excessive motor traffic in the road freight transport sector. One of these is a relaxation of restrictions on the size and load capacity of trucks that circulate between member States and a proposal has been made for Longer and Heavier Vehicles (LHVs) to be allowed to circulate across borders. LHVs are the so-called "megatrucks" (i.e., trucks with a length of 25 meters and a weight of 60 tonnes). Megatrucks have allowed to circulate for decades in some European countries such as Norway, Finland, and Sweden, world leaders in traffic accident prevention, although the impact that cross-border traffic would have on road safety is still unknown. METHODS: This article provides an econometric analysis of the potential impact on road safety of allowing the circulation of "megatrucks" throughout the EU. RESULTS: The findings show that countries that currently allow megatrucks to circulate present lower traffic accident and fatality levels, on average. CONCLUSIONS: The circulation of this type of vehicle is only advisable in countries where there is a certain degree of maturity and demonstrated achievements in the field of road safety. Practical applications: European countries that have allowed megatruck circulation obtaining better road safety outcomes in terms of accidents, although the accident lethality rate seems to be higher. Consequently, introducing megatruck circulation requires a prior proper preparation and examination.

Looking for traces of the Troika's intervention in European road safety.

The recent economic crisis has required the bailout of some European States by the so-called Troika, with capital injections accompanied by financial austerity. This paper analyzes econometrically the impact of this support programme on road safety for an original panel data (1995-2015). The findings also corroborate the Kuznets curve hypothesis for traffic accidents in the long term. Regarding the impact of intervention in the short term, despite reductions in safety policy budgets due to austerity, financial support, and related austerity measures might have led to an improvement in road safety, reducing both the number of accidents and fatalities. Therefore, it seems that our result is more linked to the austerity measures than to the financial support given by the Troika.

Experimental resistance to drug combinations in Leishmania donovani: metabolic and phenotypic adaptations.

Together with vector control, chemotherapy is an essential tool for the control of visceral leishmaniasis (VL), but its efficacy is jeopardized by growing resistance and treatment failure against first-line drugs. To delay the emergence of resistance, the use of drug combinations of existing antileishmanial agents has been tested systematically in clinical trials for the treatment of visceral leishmaniasis (VL). In vitro, Leishmania donovani promastigotes are able to develop experimental resistance to several combinations of different antileishmanial drugs after 10 weeks of drug pressure. Using an untargeted liquid chromatography-mass spectrometry (LC-MS) metabolomics approach, we identified metabolic changes in lines that were experimentally resistant to drug combinations and their respective single-resistant lines. This highlighted both collective metabolic changes (found in all combination therapy-resistant [CTR] lines) and specific ones (found in certain CTR lines). We demonstrated that single-resistant and CTR parasite cell lines show distinct metabolic adaptations, which all converge on the same defensive mechanisms that were experimentally validated: protection against drug-induced and external oxidative stress and changes in membrane fluidity. The membrane fluidity changes were accompanied by changes in drug uptake only in the lines that were resistant against drug combinations with antimonials, and surprisingly, drug accumulation was higher in these lines. Together, these results highlight the importance and the central role of protection against oxidative stress in the different resistant lines. Ultimately, these phenotypic changes might interfere with the mode of action of all drugs that are currently used for the treatment of VL and should be taken into account in drug development.

Can cars and trucks coexist peacefully on highways? Analyzing the effectiveness of road safety policies in Europe.

We examine the impact on the traffic accident rate of the interaction between trucks and cars on Europe's roads using a panel data set that covers the period 1999-2010. We find that rising motorization rates for trucks lead to higher traffic fatalities, while rising motorization rates for cars do not. Empirically, the model we build predicts the positive impact of stricter speed limit legislation for trucks in the reduction of road fatalities. These findings lend support to European strategies and aimed at promoting alternative modes of freight transport, including rail and maritime transport.

Design, synthesis and anti-leishmanial activity of novel symmetrical bispyridinium cyclophanes.

Nine novel symmetrical bispyridinium cyclophanes have been synthesized. They are rigid derivatives with an upper spacer which joins the two exocyclic amino groups, and a lower spacer joining the two positively charged nitrogen atoms. At least one of the two spacers is an aliphatic linker, such as an alkane or oxyalkane fragment. The activity of these compounds has been evaluated against promastigotes and intracellular amastigotes of Leishmania donovani and Leishmania major. All the cyclophanes are more active against L. major, with EC50 in intracellular amastigotes of between 1 and 17 µM, they exhibit very low toxicity against mammalian cells THP-1 and in some cases they present a higher selectivity index than the reference anti-leishmanial drugs amphotericin B and miltefosine. Compound 9 [2,8-Diaza-1,9(4,1)-dipyridinacyclotetradecaphan-1(1),9(1)-bis(ilium) dibromide] is the most active one among cyclophane derivatives against intracellular amastigotes of L. donovani (EC50 7.6 ± 0.2 µM) while L. major amastigotes are 6-fold more susceptible to the compound (EC50 1.26 ± 0.3 µM). Compound 9 produces depolarization of the mitochondrial membrane and a decrease in the ATP levels that leads to death of the parasites. The anti-leishmanial activity of this macrocyclic salts is independent of the Leishmania enzymes ethanolamine kinase and choline/ethanolamine kinase.

Can health public expenditure reduce the tragic consequences of road traffic accidents? The EU-27 experience.

This study uses data for the EU-27 countries in the period 1999-2009 to estimate determinants of road traffic fatality rates. Controlling for country attributes and road safety policy variables, we examine the influence of variables related with the national health systems; the number of hospital beds per square kilometer, and the percentage of health expenditures over gross domestic product. We find evidence that the density of hospital beds contributes to the fall in traffic-related fatalities. Furthermore, the quality of general medical facilities and technology associated with increases in health expenditure may be also a relevant factor in reducing road traffic fatalities.

Can fear of going to jail reduce the number of road fatalities? The Spanish experience.

The goal of this article is to evaluate the impact of the drastic Spanish Penal Code reform on the number of road deaths in Spain and the time that the effects might last. This is achieved by means of multivariate unobserved component models set up in a state space framework estimated using maximum likelihood. In short, with this reform Spain might be considered to be closing the final gap that kept it apart from other developed countries as far as the road accident rate is concerned. We have found two different types of effects on Spanish road traffic fatalities. Initially, a month before the reform was passed there was a 24.7 percent fall in Spanish road deaths. After the Bill had been passed and for the following thirteen months, thereductionstayed at a constant sixteen percent. This reform has reduced Spanish road fatalities by 534 in all between November 2007 and December 2008 and the effects will foreseeably continue during 2009.

An econometric analysis of the effects of the penalty points system driver's license in Spain.

This article seeks to quantify the effects of the penalty points system driver's license during the 18-month period following its coming into force. This is achieved by means of univariate and multivariate unobserved component models set up in a state space framework estimated using maximum likelihood. A detailed intervention analysis is carried out in order to test for the effects and their duration of the introduction of the penalty points system driver's license in Spain. Other variables, mainly indicators of the level of economic activity in Spain, are also considered. Among the main effects, we can mention an average reduction of almost 12.6% in the number of deaths in highway accidents. It would take at least 2 years for that effect to disappear. For the rest of the safety indicator variables (vehicle occupants injured in highway accidents and vehicle occupants injured in accidents built-up areas) the effects disappeared 1 year after the law coming into force.