[Challenges and initiatives in the prevention of healthcare associated infections: Expert consensus study]. / Retos e iniciativas en la prevención de las infecciones relacionadas con la asistencia sanitaria: estudio de consenso de expertos.

INTRODUCTION: The objective of the project was to identify new strategies, agreed upon by experts, that help reduce the prevalence of Health Care Related Infections (HAIs) given the increase in their prevalence as a result of the pandemic and improve patient safety. MATERIAL AND METHODS: The project was developed in three phases. The first two are framed in a sequential explanatory mixed model. Phase 1 consisted of a quantitative study (anonymous survey) to find out the perception of healthcare professionals about HAIs, risk factors, preventive measures, protocols, disinfection products and approaches. Phase 2 consisted of a qualitative exploratory study in which a panel of 15 experts analyzed the results, using focus group techniques, integrating both phases through the elaboration of metainferences. Phase 3 consisted of a qualitative descriptive study where, through nominal group techniques, agreed proposals for strategies to prevent HAIs were prepared. RESULTS: The panel of experts defined a total of 51 proposals for new strategies: 15 in hand hygiene, 13 in surface cleaning, 13 in the use of devices, and 10 in HAI prevention training. Of all of them, 13 were agreed upon as preferable (medium-high viability and high impact) and 7 as recommendable (low viability and high impact). CONCLUSIONS: In the prevention of HAIs, experts recommend applying different strategies simultaneously, which include innovative, technological and humanization aspects, both in data collection, intervention and training, prioritizing those with the greatest impact. and feasibility.

The aquaculture supply chain in the time of covid-19 pandemic: Vulnerability, resilience, solutions and priorities at the global scale.

The COVID-19 global pandemic has had severe, unpredictable and synchronous impacts on all levels of perishable food supply chains (PFSC), across multiple sectors and spatial scales. Aquaculture plays a vital and rapidly expanding role in food security, in some cases overtaking wild caught fisheries in the production of high-quality animal protein in this PFSC. We performed a rapid global assessment to evaluate the effects of the COVID-19 pandemic and related emerging control measures on the aquaculture supply chain. Socio-economic effects of the pandemic were analysed by surveying the perceptions of stakeholders, who were asked to describe potential supply-side disruption, vulnerabilities and resilience patterns along the production pipeline with four main supply chain components: a) hatchery, b) production/processing, c) distribution/logistics and d) market. We also assessed different farming strategies, comparing land- vs. sea-based systems; extensive vs. intensive methods; and with and without integrated multi-trophic aquaculture, IMTA. In addition to evaluating levels and sources of economic distress, interviewees were asked to identify mitigation solutions adopted at local / internal (i.e., farm-site) scales, and to express their preference on national / external scale mitigation measures among a set of a priori options. Survey responses identified the potential causes of disruption, ripple effects, sources of food insecurity, and socio-economic conflicts. They also pointed to various levels of mitigation strategies. The collated evidence represents a first baseline useful to address future disaster-driven responses, to reinforce the resilience of the sector and to facilitate the design reconstruction plans and mitigation measures, such as financial aid strategies.

Dataset of working mPEG-alkyne with scCO2.

This article contains data related to the research article entitled "Carbon dioxide sorption and melting behavior of mPEG-alkyne". The presented data gives information on the thermodynamics properties of the solvent and the polymer. The time saturation of mPEG-alkyne in supercritical carbon dioxide (scCO2) was evaluated in a high-pressure variable volume cell in different period of time at different pressure at the same temperature. The effects of pressure and temperature on the density of CO2 when it is above supercritical conditions are determined with Sanchez Lacombe and Bender Equation and compared with the NIST database and values of equation of Bender. The characteristic parameters of CO2 were determined with the equations proposed by Chengyong Wang et al. [1] and the sum of squared error was calculated for each parameter. Furthermore in this work the solubility data of scCO2/polymer mixture were correlated with Sanchez Lacombe Equation of State (SL EOS) and Heuristic model proposed by Irene Pasquali et al. [2]. This work describes the methodology for solving the SL EOS between the polymer and scCO2 and the procedure of determining the solubility parameter with the group contribution method necessary to apply the heuristic model is described.

Harmonizing analytical chemistry and clinical epidemiology for human biomonitoring studies. A case-study of plastic product chemicals in urine.

There is an interdisciplinary interface between analytical chemistry and epidemiology studies with respect to the design, execution, and analysis of environmental epidemiology cohorts and studies. Extracting meaningful results linking chemical exposure to human health outcomes begins at study design and spans the entire workflow. Here we discuss analytical experimental design from an exposure science perspective, and propose a reporting checklist for the design of human biomonitoring studies. We explain key analytical chemistry concepts of blanks and limits of reporting and present a case series of plastic product chemical exposure in prenatal urine specimens from the Barwon Infant Study.

New insights about the monomer and homodimer structures of the human AOX1.

Human aldehyde oxidase (hAOX1) is a molybdenum dependent enzyme that plays an important role in the metabolism of various compounds either endogenous or xenobiotics. Due to its promiscuity, hAOX1 plays a major role in the pharmacokinetics of many drugs and therefore has gathered a lot of attention from the scientific community and, particularly, from the pharmaceutical industry. In this work, homology modelling, molecular docking and molecular dynamics simulations were used to study the structure of the monomer and dimer of human AOX. The results with the monomer of hAOX1 allowed to shed some light on the role played by thioridazine and two malonate ions that are co-crystalized in the recent X-ray structure of hAOX1. The results show that these molecules endorse several conformational rearrangements in the binding pocket of the enzyme and these changes have an impact in the active site topology as well as in the stability of the substrate (phthalazine). The results show that the presence of both molecules open two gates located at the entrance of the binding pocket, from which results the flooding of the active site. They also endorse several modifications in the shape of the binding pocket (namely the position of Lys893) that, together with the presence of the solvent molecules, favour the release of the substrate to the solvent. Further insights were also obtained with the assembled homodimer of hAOX1. The allosteric inhibitor (THI) binds closely to the region where the dimerization of both monomers occur. These findings suggest that THI can interfere with protein dimerization.

Integrated chemical exposure assessment of coastal green turtle foraging grounds on the Great Barrier Reef.

The Great Barrier Reef receives run-off from 424,000 km2 catchment area across coastal Queensland, incorporating diffuse agricultural run-off, and run-off point sources of land-based chemical pollutants from urban and industrial development. Marine biota, such as green turtles (Chelonia mydas), are exposed to these diverse chemical mixtures in their natural environments, and the long term effects on turtle and ecosystem health remain unknown. This study was part of a larger multi-disciplinary project characterising anthropogenic chemical exposures from the marine environment and turtle health. The aim of this study was to screen for a wide range of anthropogenic chemical pollutants present in the external and internal environment of green turtles, using a combination of traditional targeted chemical analyses, non-target suspect screening, and effect-based bioassay methods, while employing a case-control study design. A combination of passive (water) and grab (water, sediment) samples were investigated. Three known green turtle foraging sites were selected for sampling: two coastal 'case' sites influenced primarily by urban/industrial and agricultural activities, respectively; and a remote, offshore 'control' site. Water and sediment samples from each of the three sampling locations showed differences in chemical pollutant profiles that reflected the dominant land uses in the adjacent catchment. Targeted mass spectrometric analysis for a range of pesticides, industrial chemicals, pharmaceuticals and personal care products found the greatest detection frequency and highest concentrations in coastal samples, compared to the control. Non-target screening analysis of water showed clear differentiation in chemical profile of the urban/industrial site. In-vitro assays of sediment samples from the control site had lowest induction, compared to coastal locations, as expected. Here we present evidence that turtles foraging in coastal areas are exposed to a range of anthropogenic pollutants derived from the adjacent coastal catchment areas.

Protocol for Computational Enzymatic Reactivity Based on Geometry Optimisation.

Enzymes play a biologically essential role in performing and controlling an important share of the chemical processes occurring in life. However, despite their critical role in nature, attaining a clear understanding of the way an enzyme acts is still cumbersome. Computational enzymology is playing an increasingly important role in this field of research. It allows the elucidation of a complete and detailed mechanism of an enzymatic reaction, including the characterization of reaction intermediates and transition states from both structural and energetic points of view, which is something that no other single experiment can produce alone. In this review, we present a general computational strategy to study enzymatic mechanisms based on adiabatic mapping and free geometry optimization. These methods allow chemical reactions to be studied with high theoretical levels, and allow a more exhaustive exploration of the chemical reactional space than other available methods, albeit being limited to the extent that they explore the enzyme conformational space. Special attention is given to the choice of the theoretical levels, as well as describing the model systems that are currently used to study enzymatic reactions. With this, we aim to provide a good introduction for non-specialised users in this field of research. We also provide a selection of hand-picked examples from our own work that illustrate the power of computational enzymology to study catalytic mechanisms. Some of these studies constitute pioneering work in the field that were later validated by experimental means.

The mechanism of the Ser-(cis)Ser-Lys catalytic triad of peptide amidases.

In this paper, we report a theoretical investigation of the catalytic mechanism of peptide amidases that involve a Ser-(cis)Ser-Lys catalytic triad. Previous suggestions propose that these enzymes should follow a distinct catalytic mechanism from the one that is present in the classic Ser-His-Asp catalytic triad. The theoretical and computational results obtained in this work indicate the opposite idea, showing that both mechanisms are very similar and only few differences are observed between both reactions. The results reveal that the different alignment of the Ser-(cis)Ser-Lys catalytic triad in relation to the classical Ser-His-Asp triad may provide a better stabilisation of the reaction intermediates, and therefore make these enzymes catalytically more efficient. The catalytic mechanism has been determined at the M06-2X/6-311++G**//B3LYP/6-31G* level of theory and requires five sequential steps instead of the two that are generally proposed: (i) nucleophilic attack of serine on the carbonyl group of the substrate, forming the first tetrahedral intermediate, (ii) formation of an acyl-enzyme complex, (ii) release of an ammonia product, (iv) nucleophilic attack of a water molecule forming the second tetrahedral intermediate, and (iv) the release of the product of the reaction, the carboxylic acid. The computational results suggest that the rate-limiting step is the first one that requires an activation free energy of 15.93 kcal mol-1. This result agrees very well with the available experimental data that predict a reaction rate of 2200 s-1, which corresponds to a free energy barrier of 14 kcal mol-1.

Amino acid deprivation using enzymes as a targeted therapy for cancer and viral infections.

INTRODUCTION: Amino acid depletion in the blood serum is currently being exploited and explored for therapies in tumors or viral infections that are auxotrophic for a certain amino acid or have a metabolic defect and cannot produce it. The success of these treatments is because normal cells remain unaltered since they are less demanding and/or can synthesize these compounds in sufficient amounts for their needs by other mechanisms. Areas covered: This review is focused on amino acid depriving enzymes and their formulations that have been successfully used in the treatment of several types of cancer and viral infections. Particular attention will be given to the enzymes L-asparaginase, L-arginase, L-arginine deiminase, and L-methionine-γ-lyase. Expert opinion: The immunogenicity and other toxic effects are perhaps the major limitations of these therapies, but they have been successfully decreased either through the expression of these enzymes from other organisms, recombination processes, pegylation of the selected enzymes or by specific mutations in the proteins. In 2006, FDA has already approved the use of L-asparaginase in the treatment of acute lymphoblastic leukemia. Other enzymes and in particular L-arginase, L-arginine deiminase, and L-methioninase have been showing promising results in vitro and in vivo studies.

Concentrations of phthalates and DINCH metabolites in pooled urine from Queensland, Australia.

Dialkyl phthalate esters (phthalates) are ubiquitous chemicals used extensively as plasticizers, solvents and adhesives in a range of industrial and consumer products. 1,2-Cyclohexane dicarboxylic acid, diisononyl ester (DINCH) is a phthalate alternative introduced due to a more favourable toxicological profile, but exposure is largely uncharacterised. The aim of this study was to provide the first assessment of exposure to phthalates and DINCH in the general Australian population. De-identified urine specimens stratified by age and sex were obtained from a community-based pathology laboratory and pooled (n=24 pools of 100). Concentrations of free and total species were measured using online solid phase extraction isotope dilution high performance liquid chromatography tandem mass spectrometry. Concentrations ranged from 2.4 to 71.9ng/mL for metabolites of di(2-ethylhexyl)phthalate, and from <0.5 to 775ng/mL for all other metabolites. Our data suggest that phthalate metabolites concentrations in Australia were at least two times higher than in the United States and Germany; and may be related to legislative differences among countries. DINCH metabolite concentrations were comparatively low and consistent with the limited data available. Ongoing biomonitoring among the general Australian population may help assess temporal trends in exposure and assess the effectiveness of actions aimed at reducing exposures.

Replication of PTPRC as genetic biomarker of response to TNF inhibitors in patients with rheumatoid arthritis.

Genetic biomarkers could be useful for orienting treatment of patients with rheumatoid arthritis (RA), but none has been convincingly validated yet. Putative biomarkers include 14 single nucleotide polymorphisms that have shown association with response to TNF inhibitors (TNFi) in candidate gene studies and that we assayed here in 755 RA patients. Three of them, in the PTPRC, IL10 and CHUK genes, were significantly associated with response to TNFi. The most significant result was obtained with rs10919563 in PTPRC, which is a confirmed RA susceptibility locus. Its RA risk allele was associated with improved response (B=0.33, P=0.006). This is the second independent replication of this biomarker (P=9.08 × 10(-8) in the combined 3003 RA patients). In this way, PTPRC has become the most replicated genetic biomarker of response to TNFi. In addition, the positive but weaker replication of IL10 and CHUK should stimulate further validation studies.

Clinical Decision Support and Palivizumab: A Means to Protect from Respiratory Syncytial Virus.

BACKGROUND AND OBJECTIVES: Palivizumab can reduce hospitalizations due to respiratory syncytial virus (RSV), but many eligible infants fail to receive the full 5-dose series. The efficacy of clinical decision support (CDS) in fostering palivizumab receipt has not been studied. We sought a comprehensive solution for identifying eligible patients and addressing barriers to palivizumab administration. METHODS: We developed workflow and CDS tools targeting patient identification and palivizumab administration. We randomized 10 practices to receive palivizumab-focused CDS and 10 to receive comprehensive CDS for premature infants in a 3-year longitudinal cluster-randomized trial with 2 baseline and 1 intervention RSV seasons. RESULTS: There were 356 children eligible to receive palivizumab, with 194 in the palivizumab-focused group and 162 in the comprehensive CDS group. The proportion of doses administered to children in the palivizumab-focused intervention group increased from 68.4% and 65.5% in the two baseline seasons to 84.7% in the intervention season. In the comprehensive intervention group, proportions of doses administered declined during the baseline seasons (from 71.9% to 62.4%) with partial recovery to 67.9% during the intervention season. The palivizumab-focused group improved by 19.2 percentage points in the intervention season compared to the prior baseline season (p < 0.001), while the comprehensive intervention group only improved 5.5 percentage points (p = 0.288). The difference in change between study groups was significant (p = 0.05). CONCLUSIONS: Workflow and CDS tools integrated in an EHR may increase the administration of palivizumab. The support focused on palivizumab, rather than comprehensive intervention, was more effective at improving palivizumab administration.

The catalytic mechanism of carboxylesterases: a computational study.

The catalytic mechanism of carboxylesterases (CEs, EC 3.1.1.1) is explored by computational means. CEs hydrolyze ester, amide, and carbamate bonds found in xenobiotics and endobiotics. They can also perform transesterification, a reaction important, for instance, in cholesterol homeostasis. The catalytic mechanisms with three different substrates (ester, thioester, and amide) have been established at the M06-2X/6-311++G**//B3LYP/6-31G* level of theory. It was found that the reactions proceed through a mechanism involving four steps instead of two as is generally proposed: (i) nucleophilic attack of serine to the substrate, forming the first tetrahedral intermediate, (ii) formation of the acyl-enzyme complex concomitant with the release of the alcohol product, (iii) nucleophilic attack of a water or alcohol molecule forming the second tetrahedral intermediate, and (iv) the release of the second product of the reaction. The results agree very well with the available experimental data and show that the hydrolytic and the transesterification reactions are competitive processes when the substrate is an ester. In all the other studied substrates (thioester or amide), the hydrolytic and transesterification process are less favorable and some of them might not even take place under in vivo conditions.

Discovery of new druggable sites in the anti-cholesterol target HMG-CoA reductase by computational alanine scanning mutagenesis.

The enzyme 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA-R) is the fundamental target for the treatment of hypercholesterolemia nowadays. The HMG-CoA-R clinical active site inhibitors (statins) are among the most widespread and profitable drugs ever sold but their side effects (myopathies, sometimes severe) still limit their use, which makes the finding of alternatives to statins a field of intense research. In this line, we address here a new strategy for inhibiting the homotetrameric HMG-CoA-R. The enzyme consists of a "dimer of dimers", each dimer having two active sites. We pursue here the inhibition of enzyme oligomerization, through drug binding to the dimer interface. We have computationally mutated 232 interfacial residues by alanine and calculated the loss in binding free energy among the monomers that build up each dimer of the homotetramer. This led to the identification of the (ten) key residues for the formation of the active dimer (Glu528, Ile531, Met534, Tyr644, Glu665, Asn686, Lys692, Lys735, Met742, and Val863). The results show that these residues are located in two specific spots of the protein with a cleft shape, whose shape and size is favorable for small drug binding. It is expectable that small molecules specifically bound to these druggable pockets will have a major effect on the oligomerization of the protein or/and in active site formation. This paves the way for the discovery of new families of inhibitors of HMG-CoA-R.

Structural and dynamics analysis of matrix metalloproteinases MMP-2 complexed with chemically modified tetracyclines (CMTs).

Matrix metalloproteinases (MMPs) play a critical role in physiological processes and pathological conditions such tumor invasion and metastasis. In recent years, a number of MMP inhibitors have been proposed, including the chemically modified tetracyclines (CMTs), which have been evaluated in preclinical cancer models showing promising results. This work provides insights into the structure and dynamics of the MMP-2 catalytic domain complexed with seven CMT (CMT-n), based on the analysis of molecular dynamics trajectories in solution. The comparative analysis of various relevant molecular aspects of the different complexes of MMP-2 and CMT-n derivatives was performed aiming to elucidate the effect of ligands on the enzyme structure. These include the radial distribution function of the water molecules around the catalytic zinc, the solvent accessible surface area for the inhibitors and the root-mean-square fluctuation for all amino acid residues. The results help to understand the differences in the binding modes of related compounds and, therefore, add to further design of novel tetracycline-based inhibitors for MMP enzymes.

Farnesyltransferase inhibitors: a comprehensive review based on quantitative structural analysis.

Farnesyltransferase inhibitors (FTIs) have mainly been used in cancer therapy. However, more recently, investigations on these inhibitors revealed that FTIs can be used for the treatment of other diseases such as Progeria, P. falciparum resistant malaria, Trypnosomatid, etc. Hence the development of novel FTIs is an important task for the drug discovery program. Initially, numerous peptidomimetic FTIs were developed from the template of CAAX (CVIM was the first pharmacophore model used as a peptidomimetic). Later, many non-peptidomimetic FTIs have been discovered with the structural modification of the peptidomimetics. The structural analysis of those developed FTIs by various researchers suggested that the presence of a heterocycle or a polar group in place of the thiol group is required for interaction with the Zn(2+) ion. The bulky naphthyl, quinolinyl, phenyl, phenothazine, etc in this position provide better hydrophobicity to the molecules which interact with the aromatic amino acid moieties in the hydrophobic pocket. A hydrophilic region with polar groups is necessary for the polar or hydrogen bonding interactions with the amino acids or water molecules in the active site. Many FTIs have been isolated from natural products, which possessed inhibitory activity against farnesyltransferase (FTase). Among them, pepticinnamin E (9R), fusidienol (9T), gliotoxin (9V), cylindrol A (9X), etc possessed potential FTase inhibitory activities and their structural features are comparable to those of the synthetic molecules. The clinical studies progressing on FTIs showed that tipifarnib in combination with bortezomib is used for the treatment of patients with advanced acute leukemias. Successful phase I and II studies are undergoing for tipifarnib alone or in combination with other drugs/radiation for the treatment of multiple myeloma, AML, breast cancer, mantle cell lymphoma, solid tumors, non-small cell lung cancer (NSCLC), pancreatic cancer, glioblastoma, etc. Phase I pharmacokinetic (maximum tolerated dose, toxicity) and pharmacodynamic studies of AZD3409 (an orally active double prodrug) is progressing on patients with solid malignancies taking 500 mg once a day. A phase II study is undergoing on lonafarnib alone and in combination with zoledronic acid and pravastatin for the treatment of Hutchinson-Gilford Progeria syndrome (HGPS) and progeroid laminopathies. Lonafarnib therapy improved cardiovascular status of children with HGPS, by improved peripheral arterial stiffness, bone structure and audiological status in the patients. Other important FTIs such as BMS-214662, LB42908, LB42708, etc are under clinical studies for the treatment of various cancers. This review concluded that the quantitative structural analysis report with an elaborative study on the natural product compounds provides ideas for development of novel molecules for the FTase inhibitory activity. The fragment based analysis is also needed to select the substituents, which provides significant inhibitory activities and can also have good pharmacokinetic properties in the clinical studies.

Critical illness polyneuropathy and myopathy in the vascular patient

Critical illness polyneuropathy and myopathy is a neuromuscular disorder resulting in flaccid tetraparesia and difficulty in extubation that occurs in intensive care unit patients, among patients subjected to vascular surgery. The main risk factor for its appearance is the presence of sepsis and systemic inflammatory response syndrome. Case reports: Two cases of Critical illness polyneuropathy were diagnosed in vascular patients treated for a brachiocephalic trunk aneurysm and an abdominal aortic aneurysm who presented difficulty in extubation and flaccid tetraparesia in the postoperative period. Both died after a prolonged stay in hospital. This pathology is relatively frequent in intensive care unit patients, presenting elevated morbidity and mortality. It is important to suspect its presence as well as to know its prognosis. Furthermore, although specific treatment does not exist, it is important to initiate a rehabilitation programme as soon as possible (AU)

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Protein-ligand docking in the new millennium--a retrospective of 10 years in the field.

Protein-ligand docking is currently an important tool in drug discovery efforts and an active area of research that has been the subject of important developments over the last decade. These are well portrayed in the rising number of available protein-ligand docking software programs, increasing level of sophistication of its most recent applications, and growing number of users. While starting by summarizing the key concepts in protein-ligand docking, this article presents an analysis of the evolution of this important field of research over the past decade. Particular attention is given to the massive range of alternatives, in terms of protein-ligand docking software programs currently available. The emerging trends in this field are the subject of special attention, while old established docking alternatives are critically revisited. Current challenges in the field of protein-ligand docking such as the treatment of protein flexibility, the presence of structural water molecules and its effect in docking, and the entropy of binding are dissected and discussed, trying to anticipate the next years in the field.

Qualitative and quantitative analysis of poly(amidoamine) dendrimers in an aqueous matrix by liquid chromatography-electrospray ionization-hybrid quadrupole/time-of-flight mass spectrometry (LC-ESI-QTOF-MS).

This work introduces a liquid chromatography-electrospray ionization-hybrid quadrupole/time-of-flight mass spectrometry (LC-ESI-QTOF-MS)-based method for qualitative and quantitative analysis of poly(amidoamine) (PAMAM) dendrimers of generations 0 to 3 in an aqueous matrix. The multiple charging of PAMAM dendrimers generated by means of ESI has provided key advantages in dendrimer identification by assignation of charge state through high resolution of isotopic clusters. Isotopic distribution in function of abundance of isotopes (12)C and (13)C yielded valuable and complementarity data for confident characterization. A mass accuracy below 3.8 ppm for the most abundant isotopes (diagnostic ions) provided unambiguous identification of PAMAM dendrimers. Validation of the LC-ESI-QTOF-MS method and matrix effect evaluation enabled reliable and reproducible quantification. The validation parameters, limits of quantification in the range of 0.012 to 1.73 µM, depending on the generation, good linear range (R > 0.996), repeatability (RSD < 13.4%), and reproducibility (RSD < 10.9%) demonstrated the suitability of the method for the quantification of dendrimers in aqueous matrices (water and wastewater). The added selectivity, achieved by multicharge phenomena, represents a clear advantage in screening aqueous mixtures due to the fact that the matrix had no significant effect on ionization, with what is evidenced by an absence of sensitivity loss in most generations of PAMAM dendrimers. Fig Liquid chromatography-electrospray ionization-hybrid quadrupole/time of flight mass spectrometry (LC-ESI-QTOF-MS) based method for qualitative and quantitative analysis of PAMAM dendrimers in aqueous matrix.