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Focused ultrasound (FUS) in combination with systemically injected microbubbles can be used to non-invasively open the blood-brain barrier (BBB) in targeted regions for a variety of therapeutic applications. Over the past two decades, preclinical research into the safety and efficacy of FUS-induced BBB opening has proven this technique to be transient and efficacious, propelling FUS-induced BBB opening into several clinical trials in recent years. However, as clinical trials further progress, the neuroinflammatory response to FUS-induced BBB opening needs to be better understood. In this study, we provide further insight into the relationship of microbubble cavitation and the resulting innate immune response to FUS-induced BBB opening. By keeping ultrasound parameters fixed (i.e. frequency, pressure, pulse length, etc.), three groups of mice were sonicated using a real-time cavitation controller until a target cavitation dose was reached (1 x 107 V2•s, 5 x 107 V2•s, 1 x 108 V2•s). The change in relative gene expression of the mouse inflammatory cytokines and receptors were evaluated at three different time-points (6 h, 24 h, and 72 h) after FUS. At both 6 and 24 h time-points, significant changes in relative gene expression of inflammatory cytokines and receptors were observed across all cavitation groups. However, the degree of changes in relative expression levels and the number of genes with significant changes in expression varied across the cavitation groups. Groups with a higher cavitation dose exhibited both greater changes in relative expression levels and greater number of significant changes. By 72 h post-opening, the gene expression levels returned to baseline in all cavitation dose groups, signifying a transient inflammatory response to FUS-induced BBB opening at the targeted cavitation dose levels. Furthermore, the real-time cavitation controller was able to produce consistent and significantly different BBB permeability enhancement volumes across the three different cavitation dose groups. These results indicate that cavitation monitoring and controlling during FUS-induced BBB opening can be used to potentially modulate or limit the degree of neuroinflammation, further emphasizing the importance of implementing cavitation controllers as FUS-induced BBB opening is translated into the clinic. [Display omitted] • Cumulative cavitation dose can be used as a metric to control focused ultrasound induced-blood-brain barrier opening and the resulting inflammatory response. • The inflammatory response following blood-brain barrier opening was modulated by the cavitation-based controller system. • The measured inflammatory response peaked between the 6-h and 72h time-point after blood-brain barrier opening. • The measured inflammatory response returned to baseline values at the 72-h time-point at all caviation levels. • The cavitation-based controller system with fixed sonication parameters produced distinct blood-brain barrier opening volumes. [ABSTRACT FROM AUTHOR]

Objective: Focused ultrasound (FUS) has emerged as a non-invasive technique to locally and reversibly disrupt the blood-brain barrier (BBB). Here, we investigate the use of diffusion tensor imaging (DTI) as a means of detecting FUS-induced BBB opening at the absence of an MRI contrast agent. A non-human primate (NHP) was repeatedly treated with FUS and preformed circulating microbubbles to transiently disrupt the BBB (n = 4). T1- and diffusion-weighted MRI scans were acquired after the ultrasound treatment, with and without gadolinium-based contrast agent, respectively. Both scans were registered with a high-resolution T1-weighted scan of the NHP to investigate signal correlations. DTI detected an increase in fractional anisotropy from 0.21 ± 0.02 to 0.38 ± 0.03 (82.6 ± 5.2% change) within the targeted area one hour after BBB opening. Enhanced DTI contrast overlapped by 77.22 ± 9.2% with hyper-intense areas of gadolinium-enhanced T1-weighted scans, indicating diffusion anisotropy enhancement only within the BBB opening volume. Diffusion was highly anisotropic and unidirectional within the treated brain region, as indicated by the direction of the principal diffusion eigenvectors. Polar and azimuthal angle ranges decreased by 35.6% and 82.4%, respectively, following BBB opening. Evaluation of the detection methodology on a second NHP (n = 1) confirmed the across-animal feasibility of the technique. In conclusion, DTI may be used as a contrast-free MR imaging modality in lieu of contrast-enhanced T1 mapping for detecting BBB opening during focused-ultrasound treatment or evaluating BBB integrity in brain-related pathologies. [ABSTRACT FROM AUTHOR]

Over the last two decades, it has become clear that classical molecules that regulate neurodevelopment also play an important role in directly regulating the development of the vascular system and vice versa. The prototypical angiogenic ligand vascular endothelial growth factor (VEGF) is by now also regarded as a molecular regulator of different neurodevelopmental processes, such as neuronal progenitor proliferation, migration and differentiation, dendritic and axonal branching and synaptogenesis. The direct effect of other classical angiogenic factors, such as angiopoietins and its receptor Tie2, on neurodevelopmental processes remains less defined. Recent work from our group indicates that the angiopoietin-Tie2 pathway does not only regulate blood vessel formation and stabilization but also simultaneously affect neuronal dendritogenesis in a cell-autonomous manner. In this mini-review, we will integrate our findings within the current understanding of the neurovascular link and within the previous knowledge of the potential effects of angiopoietins in the neuronal context. [ABSTRACT FROM AUTHOR]

We hereby share our perspective and experience regarding hydrogen thermodynamics. The thermodynamic modeling of hydrogen and hydrogen-containing mixtures seen from a historical perspective, beginning in 1979 with the publication of Daubert and Graboski on the modification of SRK EoS to systems containing hydrogen, up to nowadays where different tools as molecular simulations are in place, is shortly presented. The selected milestones are directly connected with the vision of the company to be one of the largest low-carbon hydrogen technology licensors in the world and has been the foundation for the design of safe and reliable chemical manufacturing processes in 8 decades. With our technical knowhow in hydrogen technologies, we are currently further developing and optimizing next gen blue and green technologies, thereby needing thermodynamic tools for a wide range of hydrogen-containing systems, over a wide range of conditions, and for different properties. We see in general a need for standardization and guidelines on how to perform the thermodynamic part of this type of new projects, and embrace all relevant efforts, especially when it comes to properties and fluid behavior related to safety issues. The existing status both in terms of experimental data and thermodynamic models will be discussed and evaluated. Finally, some scientific areas will be mentioned where we see much promise in the future and we believe they can contribute to the modeling of the new processes, from a broader perspective, going "beyond" thermodynamic analysis and allowing a more holistic assessment of new projects. [ABSTRACT FROM AUTHOR]

Parkinson's disease has many symptomatic treatments, but there is no neuroprotective therapy currently available. The evolution of this disease is inexorably progressive, and halting or stopping the neurodegenerative process is a major unmet need. Parkinson's disease motor features at onset are typically limited to 1 body segment, that is, focal signs, and the nigrostriatal degeneration is highly asymmetrical and mainly present in the caudal putamen. Thus, clinically and neurobiologically the process is fairly limited early in its evolution. Tentatively, this would allow the possibility of intervening to halt neurodegeneration at the most vulnerable site. The recent use of new technologies such as focused ultrasound provides interesting prospects. In particular, the possibility of transiently opening the blood-brain barrier to facilitate penetrance of putative neuroprotective agents is a highly attractive approach that could be readily applied to Parkinson's disease. However, because there are currently effective treatments available (ie, dopaminergic pharmacological therapy), more experimental evidence is needed to construct a feasible and practical therapeutic approach to be tested early in the evolution of Parkinson's disease patients. In this review, we provide the current evidence for the application of blood-brain barrier opening in experimental models of Parkinson's disease and discuss its potential clinical applicability. © 2019 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Self-injurious and aggressive behaviors are common in fragile X syndrome (FXS). However, little is known about the persistence of these behaviors and associated risk markers. We established the prevalence and persistence of self-injurious and aggressive behaviors over eight years in males with FXS, and associations with risk markers. Results showed 77% and 69% persistence rates for self-injurious and aggressive behavior, respectively. Baseline levels of repetitive behavior predicted persistent self-injurious behavior. Chronological age, impulsivity and overactivity were associated with persistent aggressive behavior but only impulsivity predicted persistence. This is the first study to document the persistence of self-injurious and aggressive behavior in FXS over the medium to long term and to identify behavioral risk markers that might facilitate targeted early intervention. [ABSTRACT FROM AUTHOR]

The blood-brain barrier (BBB) prevents most drugs from gaining access to the brain parenchyma, which is a recognized impediment to the treatment of neurodegenerative disorders like Parkinson's disease (PD). Focused ultrasound (FUS), in conjunction with systemically administered microbubbles, opens the BBB locally, reversibly and non-invasively. Herein, we show that neither FUS applied over both the striatum and the ventral midbrain, without neurotrophic factors, nor intravenous administration of neurotrophic factors (either through protein or gene delivery) without FUS, ameliorates the damage to the nigrostriatal dopaminergic pathway in the sub-acute MPTP mouse model of early-stage PD. Conversely, the combination of FUS and intravenous neurotrophic (protein or gene) delivery attenuates the damage to the nigrostriatal dopaminergic pathway, by allowing the entry of these agents into the brain parenchyma. Our findings provide evidence that the application of FUS at the early stages of PD facilitates critical neurotrophic delivery that can curb the rapid progression of neurodegeneration while improving the neuronal function, seemingly opening new therapeutic avenues for the early treatment of diseases of the central nervous system. Unlabelled Image [ABSTRACT FROM AUTHOR]

[Display omitted] Monitoring brain responses to ultrasonic interventions is becoming an important pillar of a growing number of applications employing acoustic waves to actuate and cure the brain. Optical interrogation of living tissues provides a unique means for retrieving functional and molecular information related to brain activity and disease-specific biomarkers. The hybrid optoacoustic imaging methods have further enabled deep-tissue imaging with optical contrast at high spatial and temporal resolution. The marriage between light and sound thus brings together the highly complementary advantages of both modalities toward high precision interrogation, stimulation, and therapy of the brain with strong impact in the fields of ultrasound neuromodulation, gene and drug delivery, or noninvasive treatments of neurological and neurodegenerative disorders. In this review, we elaborate on current advances in optical and optoacoustic monitoring of ultrasound interventions. We describe the main principles and mechanisms underlying each method before diving into the corresponding biomedical applications. We identify areas of improvement as well as promising approaches with clinical translation potential. [ABSTRACT FROM AUTHOR]

The low-density lipoprotein receptor-related protein 4 (LRP4) is essential in muscle fibers for the establishment of the neuromuscular junction. Here, we show that LRP4 is also expressed by embryonic cortical and hippocampal neurons, and that downregulation of LRP4 in these neurons causes a reduction in density of synapses and number of primary dendrites. Accordingly, overexpression of LRP4 in cultured neurons had the opposite effect inducing more but shorter primary dendrites with an increased number of spines. Transsynaptic tracing mediated by rabies virus revealed a reduced number of neurons presynaptic to the cortical neurons in which LRP4 was knocked down. Moreover, neuron-specific knockdown of LRP4 by in utero electroporation of LRP4 miRNA in vivo also resulted in neurons with fewer primary dendrites and a lower density of spines in the developing cortex and hippocampus. Collectively, our results demonstrate an essential and novel role of neuronal LRP4 in dendritic development and synaptogenesis in the CNS. [ABSTRACT FROM AUTHOR]

BACKGROUND: The association of ozone exposure with respiratory outcomes has been investigated in epidemiologic studies mainly including asthmatic children. The findings reported had methodological gaps and inconsistencies. OBJECTIVES: We aimed to investigate effects of personal ozone exposure on various respiratory outcomes in school-age children generally representative of the population during their normal activities. METHODS: We conducted a panel study in a representative sample of school-age children in the two major cities of Greece, Athens and Thessaloniki. We followed 188, 10-to 11-y-old, elementary school students for 5 wk spread throughout the 2013-2014 academic year, during which ozone was measured using personal samplers. At the end of each study week, spirometry was performed by trained physicians, and the fractional concentration of nitric oxide in exhaled air (FeNO) was measured. Students kept a daily time-activity-symptom diary and measured PEF (peak expiratory flow) using peak flow meters. Mixed models accounting for repeated measurements were applied. RESULTS: An increase of 10 µg/m³ in weekly ozone concentration was associated with a decrease in FVC (forced vital capacity) and FEV1 (forced expiratory volume in 1 s) of 0:03 L [95% confidence interval (CI): -0:05, -0:01] and 0:01 L (95% CI: -0:03, 0.003) respectively. The same increase in exposure was associated with a 11.10% (95% CI: 4.23, 18.43) increase in FeNO and 19% (95% CI: -0:53, 42.75) increase in days with any symptom. The effect estimates were robust to PM10 adjustment. No inverse association was found between ozone exposure and PEF. CONCLUSIONS: The study provides evidence that airway inflammation and the frequency of respiratory symptoms increase, whereas lung function decreases with increased ozone exposure in schoolchildren. [ABSTRACT FROM AUTHOR]

Drug delivery to subcortical regions is susceptible to the blood–brain barrier (BBB) impeding the molecular exchange between the blood stream and the brain parenchyma. Focused ultrasound (FUS) coupled with the administration of microbubbles has been proved to open the BBB locally, transiently, and noninvasively both in rodents and in nonhuman-primates (NHPs). The development of this disruption technique independent of MRI monitoring is of primordial importance yet restrained to the targeting optimization. This paper establishes the linear relationship of the incidence angle with the volume of BBB opening ( V\mathrm{BBB} ) and the peak negative pressure when sonicating the caudate nucleus and the putamen region of five NHPs. In addition, the effect of central nervous system structures on the opening morphology is evaluated by identification of the gray-to-white-matter ratio at the opening site. Finally, the targeting accuracy is assessed through the estimation of the geometric and angle shift of the opening from the targeted region. Interestingly, results prove a monotonic increase of the opening volume with close to normal incidence angles. Moreover, 80.35% of the opening lies on gray-matter regions compared with only 19.41% attributed to the white matter. The opening was found to be shifted axially, toward the transducer, and laterally with an average angle shift of 4.5°. Finally, we were capable of showing reproducibility of targeting accuracy with the same stereotactic and ultrasonic parameters. This paper documents the a priori prediction of the opening volume through manipulation of the angle and pressure as well as establishing the predictability, accuracy, and safety of FUS-induced BBB opening in NHPs. [ABSTRACT FROM AUTHOR]

Purpose Focused Ultrasound (FUS) in conjunction with systemically administered microbubbles has been shown to open the Blood-Brain Barrier (BBB) locally, non-invasively and reversibly in rodents and non-human primates (NHP), suggesting the immense potential of this technique. The objective of this study entailed the investigation of the physiologic changes in the brain following the FUS-induced BBB opening and their relationship with the underlying anatomy. Materials and methods Pharmacokinetic analysis was implemented in NHP's that received FUS at various acoustic pressures. Relaxivity mapping enabled the robust quantitative detection of the BBB opening as well as grey and white matter segmentation. Drug delivery efficiency was measured for pre-clinical validation of the technique. Results Based on our results, the opening volume and the amount of the gadolinium delivered were found mostly contained in the grey matter, while FUS-induced permeability and drug concentration varied depending upon the underlying brain inhomogeneity, and increased with the acoustic pressure. Conclusions Overall, apart from the in vivo protocols for BBB analysis developed here, this study also suggests the important role that FUS can have in efficient drug delivery via localized and transient BBB opening. [ABSTRACT FROM AUTHOR]

The delivery of most therapeutic agents is rendered ineffective for the treatment of brain diseases due to the presence of the blood–brain barrier (BBB). The goal of this study was to investigate the effect of pre-infusion focused ultrasound (FUS) and microbubbles on the distribution of direct brain infusion in vivo. A single-element FUS transducer was used in all sonications, which were carried out immediately prior to direct infusion procedures. Mice received direct infusion of either Gadolinium-labeled albumin (Gd-albumin, 74 kDa) or adeno-associated virus (AAV, ∼4 MDa). The volumes of Gd-albumin at 30 min were deemed comparable (P = 0.334) between the direct infusion (DI)-only group and the FUS + DI group. At 120 min, the FUS + DI group showed significantly higher contrast-enhanced volume (9.76 ± 0.74 mm3) than the DI-only group (7.14 ± 0.34 mm3). For mice infused with AAV, the total volume of transduction was estimated as GFP-positive regions and FUS + DI group demonstrated significantly higher (P = 0.017) transduction efficiency in vivo. In conclusion, enhanced bio-distribution of directly infused agents was observed when the targeted region was pre-conditioned with FUS and microbubbles. Focused ultrasound has the potential, as an adjuvant technique, to significantly enhance direct brain infusion and achieve the desired therapeutic outcomes. [ABSTRACT FROM AUTHOR]

Dew point specifications are of high interest in the natural gas industry. The CPA equation of state (EoS) was previously validated against both water content and phase equilibrium data. Moreover, solid model parameters were estimated for four natural gas main components (methane, ethane, propane, and carbon dioxide). In this study we have extended the use of CPA EoS to perform equilibrium temperature calculations for natural gas main components with (mono-)ethylene glycol (MEG) as an inhibitor. The ternary systems with aqueous MEG solution include methane, ethane, propane, carbon dioxide, and hydrogen sulfide. The quaternary systems with aqueous MEG solution include methane + ethane, methane + propane, methane + n-heptane, and methane + n-octane. Three multicomponent systems (>4 components) were also studied. The temperature range of the literature data is between 241.25-333.15 K, and the pressure range is between 0.1-24.8 MPa. The results in all cases are compared against experimental data, and very good agreement with experimental data is obtained. [ABSTRACT FROM AUTHOR]

We derive optimal-order a posteriori error estimates for fully discrete approximations of initial and boundary value problems for linear parabolic equations. For the discretization in time we apply the fractional-step υ-scheme, and for the discretization in space the finite element method with finite element spaces that are allowed to change with time. The first optimal-order a posteriori error estimates for the norms of L∞ (0, T; L2(Ω)) and L2(0, T;H1(Ω)) are derived by applying the reconstruction technique. [ABSTRACT FROM AUTHOR]

Thereis a need for high-quality experimental phase equilibriumdata in the petroleum and chemical industries, for example, mixturesof oil and gas with gas hydrate inhibitors (methanol, glycols) andorganic acids. This includes a wide range of different systems, whichall deal with processes that rely on phase equilibrium data for optimization.The objective of this work is to provide experimental data for hydrocarbonsystems with polar chemicals such as alcohols, glycols, and water.New vapor–liquid equilibrium data are reported for methane+ water, methane + methanol, and methane + methanol + water for severaltemperatures in the range 284 K to 324 K and in the pressure range(5 to 20) MPa. The Cubic-Plus-Association (CPA) equation of stateis used to model the phase equilibria data measured. A good agreementbetween predictions and experimental data is observed, supportingthe reliability of the new data. [ABSTRACT FROM AUTHOR]

Abstract: We consider fully discrete schemes for linear parabolic problems discretized by the Crank–Nicolson method in time and the standard finite element method in space. We study the effect of mesh modification on the stability of fully discrete approximations as well as its influence on residual-based a posteriori error estimators. We focus mainly on the qualitative, analytical and computational behavior of the schemes and the error estimators. [Copyright &y& Elsevier]

We derive residual-based a posteriori error estimates of optimal order for fully discrete approximations for linear parabolic problems. The time discretization uses the Crank--Nicolson method, and the space discretization uses finite element spaces that are allowed to change in time. The main tool in our analysis is the comparison with an appropriate reconstruction of the discrete solution, which is introduced in the present paper. [ABSTRACT FROM AUTHOR]

Abstract: The adsorption of carbon monoxide on the Pt{110} surface at coverages of 0.5 ML and 1.0 ML was investigated using quantitative low-energy electron diffraction (LEED IV) and density-functional theory (DFT). At 0.5 ML CO lifts the reconstruction of the clean surface but does not form an ordered overlayer. At the saturation coverage, 1.0 ML, a well-ordered p(2×1) superstructure with glide line symmetry is formed. It was confirmed that the CO molecules adsorb on top of the Pt atoms in the top-most substrate layer with the molecular axes tilted by ±22° with respect to the surface normal in alternating directions away from the close packed rows of Pt atoms. This is accompanied by significant lateral shifts of 0.55Å away from the atop sites in the same direction as the tilt. The top-most substrate layer relaxes inwards by −4% with respect to the bulk-terminated atom positions, while the consecutive layers only show minor relaxations. Despite the lack of long-range order in the 0.5 ML CO layer it was possible to determine key structural parameters by LEED IV using only the intensities of the integer-order spots. At this coverage CO also adsorbs on atop sites with the molecular axis closer to the surface normal (<10°). The average substrate relaxations in each layer are similar for both coverages and consistent with DFT calculations performed for a variety of ordered structures with coverages of 1.0 ML and 0.5 ML. [Copyright &y& Elsevier]

Background: Particulate matter air pollution has been associated with adverse health effects. The fraction of ambient particles that are mainly responsible for the observed health effects is still a matter of controversy. Better characterization of the health relevant particle fraction will have major implications for air quality policy since it will determine which sources should be controlled. The RUPIOH study, an EU-funded multicentre study, was designed to examine the distribution of various ambient particle metrics in four European cities (Amsterdam, Athens, Birmingham, Helsinki) and assess their health effects in participants with asthma or COPD, based on a detailed exposure assessment. In this paper the association of central site measurements with respiratory symptoms and restriction of activities is examined. Methods: At each centre a panel of participants with either asthma or COPD recorded respiratory symptoms and restriction of activities in a diary for six months. Exposure assessment included simultaneous measurements of coarse, fine and ultrafine particles at a central site. Data on gaseous pollutants were also collected. The associations of the 24-hour average concentrations of air pollution indices with the health outcomes were assessed in a hierarchical modelling approach. A city specific analysis controlling for potential confounders was followed by a meta-analysis to provide overall effect estimates. Results: A 10 µg/m3 increase in previous day coarse particles concentrations was positively associated with most symptoms (an increase of 0.6 to 0.7% in average) and limitation in walking (OR= 1.076, 95% CI: 1.026-1.128). Same day, previous day and previous two days ozone concentrations were positively associated with cough (OR= 1.061, 95% CI: 1.013-1.111; OR= 1.049, 95% CI: 1.016-1.083 and OR= 1.059, 95% CI: 1.027-1.091, respectively). No consistent associations were observed between fine particle concentrations, nitrogen dioxide and respiratory health effects. As for particle number concentrations negative association (mostly non-significant at the nominal level) was observed with most symptoms whilst the positive association with limitation of activities did not reach the nominal level of significance. Conclusions: The observed associations with coarse particles are in agreement with the findings of toxicological studies. Together they suggest it is prudent to regulate also coarse particles in addition to fine particles. [ABSTRACT FROM AUTHOR]

We derive residual-based a posteriori error estimates of optimal order for time discretizations of linear parabolic equations by the fractional-step ϑ-scheme. We first consider the time semidiscrete problem. The main tool of our analysis is an appropriate reconstruction of the piecewise linear interpolant of the approximate solution that leads to a residual of optimal order. Next we extend the above-mentioned results to the case of a full discretization. The theoretical results are justified with numerical experiments. [ABSTRACT FROM PUBLISHER]

Abstract: Mail carriers represent an occupational group suffering from respiratory symptoms and lung function impairment. Although environmental conditions may play role, information on the effects of air pollution exposure in this population is lacking. The present study was conducted in Athens, Greece, in order to investigate the adverse effects of long-term air pollution exposure on respiratory outcomes in mail carriers. A total of 226 mail carriers and 73 office employees were enroled. Information on respiratory symptoms, medical, occupational, residential and smoking history was obtained through a questionnaire. Flow-volume curves were performed in the workplace using a portable spirometer. Individualised personal exposure assessment has been applied based on long-term residential and occupational subject history linked with geographical air pollution distribution. Furthermore, personal measurements were obtained for forty-one mail carriers using NO2 and O3 passive samplers, assuming that current air pollution exposure is sufficiently representative of long-term, previous exposure to make a plausible link with current health status. The analysis based on exposures estimated on the basis of residential and work addresses showed that the most exposed to PM10 postal workers have rhinitis at a higher rate (OR=1.67, 95% CI: 1.01–2.75). In mail carriers there is indication that those exposed to higher concentrations of Ο3 or PM10 have a greater possibility to present rhinitis (OR=1.63, 95% CI: 0.93–2.88 and OR=1.70, 95% CI: 0.96–3.03, respectively). The effect of O3 on rhinitis became even more apparent in the analysis based on exposures assessed by personal measurements (OR=6.74, 95% CI: 1.24–36.55). Exposure to NO2 was significantly associated with decrements in lung function. For office employees the exposure to air pollutants was not associated to any adverse respiratory outcome. Our findings suggest that air pollution is a contributing factor for the occurrence of rhinitis and lung function impairment in mail carriers. [Copyright &y& Elsevier]

The aim of the article is to provide an analysis of the introduction of principles of New Education in Greece in the beginning of the twentieth century. It focuses on the influence of this movement on Greek pedagogues, especially on those who had studied in Germany, and who tried afterwards to introduce them in the didactic sphere and in the pedagogical field. Their ideas and principles related to New Education and the School of Work (Arbeitschule) and their way of putting them into practice inside the educational system are analysed, including the creation of a certain curriculum, the way of teaching some courses, and the use of certain educational/didactical methods. It is also intended to show how the most important issues of pedagogy and didactics were developed and analysed by the most important pedagogical journals of this period. Attention is paid mainly to the difficulties faced by those who attempted to introduce this system in Greece with regard to a series of factors that differentiate the Greek paradigm from similar endeavours in other European countries. Among these factors one should mention the problem of the language and the consequent ideological antithesis, and the educational reforms in relation to the sociopolitical situation in Greece during the aforementioned period. [ABSTRACT FROM AUTHOR]

Abstract: The truncated Perturbed-Chain Polar Statistical Associating Fluid Theory (tPC-PSAFT) is applied to a number of different mixtures, including binary, ternary and quaternary mixtures of components that differ substantially in terms of intermolecular interactions and molecular size. In contrast to most other SAFT versions, tPC-PSAFT accounts explicitly for polar forces. Three pure-component parameters are required for non-polar and non-associating compounds, two additional parameters characterize the association contribution and one parameter is needed to account for polar interactions. The experimental dipole and/or quadrupole moment and/or polarizability of the component are used to calculate polar interactions. Using a temperature-independent interaction parameter k ij for each binary system, tPC-PSAFT provides accurate prediction of multi-component phase behavior over a wide range of conditions. [Copyright &y& Elsevier]

In this paper, we derive a posteriori error estimates for space-discrete approximations of the time-dependent Stokes equations. By using an appropriate Stokes reconstruction operator, we are able to write an auxiliary error equation, in pointwise form, that satisfies the exact divergence-free condition. Thus, standard energy estimates from partial differential equation theory can be applied directly, and yield a posteriori estimates that rely on available corresponding estimates for the stationary Stokes equation. Estimates of optimal order in L∞(L2) and L∞(H1) for the velocity are derived for finite-element and finite-volume approximations. [ABSTRACT FROM PUBLISHER]

In this work, an equation of state (EoS) is developed to predict accurately the phase behavior of ionic liquid CO2systems based on the truncated perturbed chain polar statistical associating fluid theory (tPC-PSAFT) EoS. This EoS accounts explicitly for the dipolar interactions between ionic liquid molecules, the quadrupolar interactions between CO2molecules, and the Lewis acid−base type of association between the ionic liquid and the CO2molecules. Physically meaningful model pure-component parameters for ionic liquids are estimated based on literature data. All experimental vapor−liquid equilibrium data are correlated with a single linearly temperature-dependent binary interaction parameter. The ability of the model to describe accurately carbon dioxide solubility in various 1-alkyl-3-methylimidazolium-based ionic liquids with different alkyl chain lengths and different anions at pressures from 0 to 100 MPa and carbon dioxide fractions from 0 to 75 mol % is demonstrated. In all cases, good agreement with experimental data is obtained. [ABSTRACT FROM AUTHOR]

The perturbed chain statistical associating fluid theory (PC-SAFT) is extended to polar molecular fluids, namely dipolar and quadrupolar fluids. The extension is based on the perturbation theory for polar fluids by Stell and co-workers. Appropriate expressions are proposed for dipole−dipole, quadrupole−quadrupole, and dipole−quadrupole interactions. Furthermore, induced dipole interactions are calculated explicitly in the model. The new polar PC-SAFT model is relatively complex; for this purpose, a truncated polar PC-SAFT model is proposed using only the leading term in the polynomial expansion for polar interactions. The new model is used for the calculation of thermodynamic properties of various quadrupolar pure fluids. In all cases, the agreement between experimental data and model predictions is very good. [ABSTRACT FROM AUTHOR]

Abstract: Polyesters and polyamides are commercially important polymers prepared by polycondensation. The conventional solution to melt polymerization techniques stop at a low or medium molecular weight product, due to problems arising from severe increase of the melt viscosity and operating temperatures. Higher molecular weights may be reached by Solid State Polymerization (SSP) at temperatures between the glass transition and the onset of melting. Polycondensation progresses through chain end reactions in the amorphous phase of the semicrystalline polymer, which in most cases is in the form of flakes (mean diameter>1.0mm) or powder (mean diameter&#60;100μm); reaction by-products are removed by application of vacuum or through convection caused by passing an inert gas. The advantages of SSP include low operating temperatures, which restrain side reactions and thermal degradation of the product, while requiring inexpensive equipment, and uncomplicated and environmentally sound procedures. Disadvantages of SSP focus on low reaction rates, compared to melt phase polymerization, and possible solid particle processability problems arising from sintering. The review begins with a theoretical background regarding SSP, the fundamentals of techniques and equipment, including the use of inert gas in reactive systems. Further, it is explained how SSP progress involves both chemical and physical steps, since it is controlled by reaction kinetics, reactive chain-end mobility in the amorphous phase, and condensate removal through diffusion. The reaction temperature emerges as the most important parameter of SSP rate variation, due to its interaction with all aspects of the process. High prepolymer molecular weight affects positively the SSP rate, since it is accompanied by elevated degrees of crystallinity; this implies more effective confinement of the amorphous phase and, therefore high concentration and homogeneous distribution of reactive chain ends in the non-crystalline regions. Similarly, refinement in reacting particle size distribution and morphology, in conjunction with high gas flow rates, increases the interfacial area per unit volume and the effectiveness of convective by-product elimination. Finally, the SSP rate increases principally by the use of phosphorous catalysts, which also reduce agglomeration. In the following sections of this review, emphasis is on the progress in experimentally determining the intrinsic rate constants of principal relevant chemical reactions. The corresponding kinetic models are either based on the Flory theory, where the rate expressions are in terms of end-group concentrations, or on a power-law description of the rate with respect to reaction time. Recent advances in modeling and large scale simulation of the various physical and chemical processes occurring within a SSP reactor are reported. The goal is to describe the dynamic evolution of all chemical species within the particle and its surroundings, and assess its dependence on basic process variables. Finally, special focus is given on methods of manipulating the molecular weight distribution of the SSP product, by varying prepolymer particle size distribution, initial stoichiometry and condensate content in the surroundings. [Copyright &y& Elsevier]

Implicit–explicit multistep methods for nonlinear parabolic equations were recently analyzed. If the implicit scheme is one of the backward differentiation formulae (BDF) of order up to six, then the corresponding implicit–explicit method of the same order is stable provided the stability constant is less than a specific scheme-dependent constant. Based on BDF, implicit methods are constructed such that the corresponding implicit–explicit scheme of the same order exhibits improved stability properties. [ABSTRACT FROM AUTHOR]

Costa Tsonopoulos was a thermodynamicist with great contributions in applied thermodynamics but also a passion and dedication in using thermodynamics in industrial practice. He is well-known for his widely used methods for estimating the second virial coefficients, but his interests and developments are much wider. They include, among others, experimental measurements for water-hydrocarbons phase equilibrium and many studies on equations of state, especially the cubic equations of state and his conviction on the great role such "rather simple" models play in chemical engineering. "In our opinion cubic EoS are here to stay", he said together with Jack Heidman in 1985. Many decades later, this is still very much true. This manuscript presents a review of Costa Tsonopoulos work related to (cubic and other) equations of state with some contemporary remarks as well as results of two case studies from the petroleum and chemical industries where indeed we may need to go "beyond" cubic equations, but in a controlled and well-balanced fashion. [ABSTRACT FROM AUTHOR]

The article in Lung India discusses a case of a 76-year-old male who developed auto-immune haemolytic anaemia after being treated with moxifloxacin for a lower respiratory tract infection. The patient experienced a decline in haemoglobin levels, jaundice, weakness, and respiratory issues, leading to hospitalisation. Treatment involved discontinuing moxifloxacin, administering methylprednisolone, packed red blood cells, and rituximab, resulting in a positive response. This case highlights the importance of recognizing and managing rare adverse effects of medications like moxifloxacin, emphasizing the need for prompt diagnosis and appropriate treatment. [Extracted from the article]

An introduction to the journal is presented in which the editor discusses the role of gene-environment interactions in obstructive respiratory diseases.

Introduction Controversy exists about the pathogenesis of idiopathic pulmonary fibrosis acute exacerbations (IPF-AEs). According to one hypothesis IPF-AEs represent the development of any etiology diffuse alveolar damage (DAD) upon usual interstitial pneumonia (UIP), whilst other researchers argue that an accelerated phase of the intrinsic fibrotic process of unknown etiology prevails, leading to ARDS. Different cytokines might be involved in both processes. The aim of this study was to assess pro-inflammatory and pro-fibrotic cytokines in the peripheral blood from stable and exacerbated IPF patients. Methods Consecutive IPF patients referred to our department were included. Diagnoses of IPF and IPF-AE were based on international guidelines and consensus criteria. The interleukins (IL)-4, IL-6, IL-8, IL-10, and IL-13 as well as active transforming growth factor-beta (TGF-β) were measured in blood from both stable and exacerbated patients on the day of hospital admission for deterioration. Subjects were followed for 12 months. Mann-Whitney test as well as Tobit and logistic regression analyses were applied. Results Among the 41 patients studied, 23 were stable, and 18 under exacerbation; of the latter, 12 patients survived. The IL-6 and IL-8 levels were significantly higher in exacerbated patients (p = 0.002 and p = 0.046, respectively). An increase in either IL-6 or IL-8 by 1 pg/ml increases the odds of death by 5.6% (p = 0.021) and 6.7% (p = 0.013), respectively, in all patients. No differences were detected for the other cytokines. Conclusion High levels of IL-6 and IL-8 characterize early-on IPF-AEs and an increase in the levels of IL-6 and IL-8 associates with worse outcome in all patients. However, as the most representative pro-fibrotic cytokines, TGF-β, IL-10, IL-4 and IL-13 were not increased and given the dualistic nature, both pro-inflammatory and pro-fibrotic of IL-6 further studies are necessary to clarify the enigma of IPF-AEs etiopathogenesis. [ABSTRACT FROM AUTHOR]

In this work we propose a nonlinear blending of two low-order stabilisation mechanisms for the convection–diffusion equation. The motivation for this approach is to preserve monotonicity without sacrificing accuracy for smooth solutions. The approach is to blend a first-order artificial diffusion method, which will be active only in the vicinity of layers and extrema, with an optimal order local projection stabilisation method that will be active on the smooth regions of the solution. We prove existence of discrete solutions, as well as convergence, under appropriate assumptions on the nonlinear terms, and on the exact solution. Numerical examples show that the discrete solution produced by this method remains within the bounds given by the continuous maximum principle, while the layers are not smeared significantly. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is considered the most common form of autoimmune arthritis. The disease's prevalence is around 0.5–1% worldwide, but it seems to vary among different populations. The aim of this study was to estimate the prevalence of self-reported diagnosed RA in the general adult population in Greece. The data were derived from the Greek Health Examination Survey EMENO, a population-based survey performed between 2013 and 2016. Of the 6006 participants (response rate 72%), 5884 were eligible for this study. Prevalence estimates were calculated according to the study design. Prevalence of self-reported RA was estimated to be overall 0.5% (95% CI 0.4–0.7) being approximately three times higher in women than in men (0.7% vs 0.2%, p value = 0.004). A decrease in the prevalence of RA was observed in urban areas of the country. In contrast, higher disease rates were reported in individuals with lower socioeconomic status. Multivariable regression analysis showed that gender, age, and income were related to the occurrence of the disease. Osteoporosis and thyroid disease were the two comorbidities observed at statistically significant higher rates in individuals with self-reported RA. The prevalence of self-reported RA in Greece is similar to that reported in other European countries. Gender, age, and income are the main factors related to the disease's prevalence in Greece. [ABSTRACT FROM AUTHOR]

Presents a clinical case study of recurrent pneumonia in conjunction with symptoms or signs of tracheal stenosis. Overview of the patient's symptoms; Findings of chest computed tomography; Cause of recurrent pneumonia.

Background: The coronavirus disease (COVID-19) pandemic has posed an unprecedented challenge to health systems, and has significantly affected the healthcare of lung cancer patients. The aim of our study was to assess the impact of COVID-19 on early lung cancer patients' surgical treatment. Methods: All consecutive patients with early-stage non-small cell lung cancer eligible for surgical treatment stage I/II and resectable stage III, referred to our department during the first wave of COVID-19 between February to May 2020, were included and compared with those on the exact corresponding quarter in 2019, one year before the pandemic. Waiting time to surgical treatment, increase of tumor's size and increase on lung cancer stage were recorded and compared. All subjects were followed up for 12 months. Multiple linear and logistic regression models were applied to assess the differences in the management of the studied groups adjusting for potential confounders. Results: Sixty-one patients with early-stage lung cancer were included in the study; 28 (median age 67 years, SD: 7.1) during the pandemic and 33 (median age 67.1 years, SD: 7.5) one year earlier. A significantly longer period of waiting for treatment and an increase in tumor size were observed during the pandemic compared to before the pandemic [median time 47 days, interquartile rate (IQR): 23–100] vs. [median time 18 days, IQR: 11–23], p < 0.001. No significant differences were detected in the increase of the stage of lung cancer between the subgroups. Conclusion: The COVID-19 pandemic had a significant impact on surgical and oncological care, leading to significant delays on treatment and an increase in tumor size in early-stage lung cancer patients. [ABSTRACT FROM AUTHOR]

Intrafusal fibers of muscle spindles are innervated in the central region by afferent sensory axons and at both polar regions by efferent γ-motoneurons. We previously demonstrated that both neuron-muscle contact sites contain cholinergic synapse-like specialisation, including aggregates of the nicotinic acetylcholine receptor ( AChR). In this study we tested the hypothesis that agrin and its receptor complex (consisting of LRP4 and the tyrosine kinase Mu SK) are involved in the aggregation of AChRs in muscle spindles, similar to their role at the neuromuscular junction. We show that agrin, Mu SK and LRP4 are concentrated at the contact site between the intrafusal fibers and the sensory- and γ-motoneuron, respectively, and that they are expressed in the cell bodies of proprioceptive neurons in dorsal root ganglia. Moreover, agrin and LRP4, but not Mu SK, are expressed in γ-motoneuron cell bodies in the ventral horn of the spinal cord. In agrin- and in Mu SK-deficient mice, AChR aggregates are absent from the polar regions. In contrast, the subcellular concentration of AChRs in the central region where the sensory neuron contacts the intrafusal muscle fiber is apparently unaffected. Skeletal muscle-specific expression of miniagrin in agrin−/− mice in vivo is sufficient to restore the formation of γ-motoneuron endplates. These results show that agrin and Mu SK are major determinants during the formation of γ-motoneuron endplates but appear dispensable for the aggregation of AChRs at the central region. Our results therefore suggest different molecular mechanisms for AChR clustering within two domains of intrafusal fibers. [ABSTRACT FROM AUTHOR]

Muscle spindles are complex stretch-sensitive mechanoreceptors. They consist of specialized skeletal muscle fibers, called intrafusal fibers, which are innervated in the central (equatorial) region by afferent sensory axons and in both polar regions by efferent γ-motoneurons. We show that AChRs are concentrated at the γ-motoneuron endplate as well as in the equatorial region where they colocalize with the sensory nerve ending. In addition to the AChRs, the contact site between sensory nerve ending and intrafusal muscle fiber contains a high concentration of choline acetyltransferase, vesicular acetylcholine transporter and the AChR-associated protein rapsyn. Moreover, bassoon, a component of the presynaptic cytomatrix involved in synaptic vesicle exocytosis, is present in γ-motoneuron endplates but also in the sensory nerve terminal. Finally, we demonstrate that during postnatal development of the γ-motoneuron endplate, the AChR subunit stoichiometry changes from the γ-subunit-containing fetal AChRs to the ε-subunit-containing adult AChRs, similar and approximately in parallel to the postnatal subunit maturation at the neuromuscular junction. In contrast, despite the onset of ε-subunit expression during postnatal development the γ-subunit remains detectable in the equatorial region by subunit-specific antibodies as well as by analysis of muscle spindles from mice with genetically-labeled AChR γ-subunits. These results demonstrate an unusual maturation of the AChR subunit composition at the annulospiral endings and suggest that in addition to the recently described glutamatergic secretory system, the sensory nerve terminals are also specialized for cholinergic synaptic transmission, synaptic vesicle storage and exocytosis. [ABSTRACT FROM AUTHOR]

Abstract: Monomer fraction (fraction of non-hydrogen bonded molecules) data obtained from spectroscopy are available for a few associating compounds. Such data can be used for testing the performance of association models like CPA and SAFT or alternatively be employed in the model development. But how accurate and how useful are such data today and how successful is their use in the context of association models? In this work we attempt to answer these questions in the case of the CPA model and for ethanol. CPA has been already successfully used to describe thermodynamic properties of many ethanol containing mixtures, using an ethanol parameter set that was adjusted to experimental vapor pressure and liquid density data. We present in this work a new parameter set for ethanol which is estimated using experimental vapor pressure, liquid density data as well as the experimental monomer fractions for liquid ethanol. Using both the existing (“old”) and the new parameter sets, we perform an extensive comparison of CPA results for a wide range of ethanol-containing systems, with water and alkanes as well as multicomponent water–ethanol–hydrocarbon liquid–liquid equilibria and hydrate curves with different ethanol content as inhibitor. There are some differences in the performance of CPA with the two sets but on average the results are similar. This may indicate that monomer fraction data are not very useful in this case or that ethanol monomer fraction data are not accurate and both possibilities are discussed. [Copyright &y& Elsevier]

Background: Monogenic and polygenic inheritances are evidenced for idiopathic pulmonary fibrosis (IPF). Pathogenic variations in surfactant protein-related genes, telomere-related genes (TRGs), and a single-nucleotide polymorphism in the promoter of MUC5B gene encoding mucin 5B (rs35705950 T risk allele) are reported. This French-Greek collaborative study, Gen-Phen-Re-GreekS in inheritable IPF (iIPF), aimed to investigate genetic components and patients' characteristics in the Greek national IPF cohort with suspected heritability. Patients and Methods: 150 patients with familial PF, personal-family extrapulmonary disease suggesting short telomere syndrome, and/or young age IPF were analyzed. Results:MUC5B rs35705950 T risk allele was detected in 103 patients (90 heterozygous, 13 homozygous, allelic frequency of 39%), monoallelic TRG pathogenic variations in 19 patients (8 TERT, 5 TERC, 2 RTEL1, 2 PARN, 1 NOP10, and 1 NHP2), and biallelic ABCA3 pathogenic variations in 3. Overlapping MUC5B rs35705950 T risk allele and TRG pathogenic variations were shown in 11 patients (5 TERT, 3 TERC, 1 PARN, 1 NOP10, and 1 NHP2), MUC5B rs35705950 T risk allele, and biallelic ABCA3 pathogenic variations in 2. In 38 patients, neither MUC5B rs35705950 T risk allele nor TRG pathogenic variations were detectable. Kaplan-Meier curves showed differences in time-to-death (p = 0.025) where patients with MUC5B rs35705950 T risk allele alone or in combination with TRG pathogenic variations presented better prognosis. Conclusion: The Gen-Phen-Re-GreekS in iIPF identified multiple and overlapping genetic components including the rarest, underlying disease's genetic "richesse," complexity and heterogeneity. Time-to-death differences may relate to diverse IPF pathogenetic mechanisms implicating "personalized" medical care driven by genotypes in the near future. [ABSTRACT FROM AUTHOR]

Chirality at surfaces has become a strong focus within the surface science community. A particular motivation is the prospect of using heterogeneous catalysis over chiral solid surfaces for asymmetric synthesis, a prospect which has clear relevance to the pharmaceutical industry. Small amino acids adsorbed on Cu surfaces have emerged as important model systems for studying the interaction of chiral molecules with metal surfaces. In this article, we review the current state of knowledge of these systems, and present the results of new experimental studies of alanine overlayers on Cu{311} and {531} surfaces. Our work on Cu{311} helps us to understand the interplay between different manifestations of chirality, especially 'footprint chirality', in the overlayers. Cu{531} is an intrinsically chiral surface orientation; our data reveal strongly enantiospecific alanine-induced restructuring of this surface. This points the way towards a promising route for obtaining strongly enantiospecific interactions with chiral adsorbates. [ABSTRACT FROM AUTHOR]

Background: Stroke incidence and case-fatality are reported to decline in high-income countries during the last decades. Epidemiological studies are important for health services to organize prevention and treatment strategies. Aims: The aim of this population-based study was to determine temporal trends of stroke incidence and case-fatality rates of first-ever stroke in Arcadia, a prefecture in southern Greece. Methods: All first-ever stroke cases in the Arcadia prefecture were ascertained using the same standard criteria and multiple overlapping sources in three study periods: from November 1993 to October 1995; 2004; and 2015–2016. Crude and age-adjusted to European population incidence rates were compared using Poisson regression. Twenty-eight days case fatality rates were estimated and compared using the same method. Results: In total, 1315 patients with first-ever stroke were identified. The age-standardized incidence to the European population was 252 per 100,000 person-years (95% CI 231–239) in 1993/1995, 252 (95% CI 223–286) in 2004, and 211 (192–232) in 2015/2016. The overall age- and sex-adjusted incidence rates fell by 16% (incidence rates ratio 0.84, 95% CI: 0.72–0.97). Similarly, 28-day case-fatality rate decreased by 28% (case fatality rate ratio = 0.72, 95% CI: 0.58–0.90). Conclusions: This population-based study reports a significant decline in stroke incidence and mortality rates in southern Greece between 1993 and 2016. [ABSTRACT FROM AUTHOR]

Background: Urban air pollution is involved in the progress of idiopathic pulmonary fibrosis (IPF). Its potential role on the devastating event of Acute Exacerbation of IPF (AE-IPF) needs to be clarified. This study examined the association between long-term personal air pollution exposure and AE- IPF risk taking into consideration inflammatory mediators and telomere length (TL).Methods: All consecutive IPF-patients referred to our Hospital from October 2013-June 2019 were included. AE-IPF events were recorded and inflammatory mediators and TL measured. Long-term personal air pollution exposures were assigned to each patient retrospectively, for O3, NO2, PM2.5 [and PM10, based on geo-coded residential addresses. Logistic regression models assessed the association of air pollutants' levels with AE-IPF and inflammatory mediators adjusting for potential confounders.Results: 118 IPF patients (mean age 72 ± 8.3 years) were analyzed. We detected positive significant associations between AE-IPF and a 10 μg/m3 increase in previous-year mean level of NO2 (OR = 1.52, 95%CI:1.15-2.0, p = 0.003), PM2.5 (OR = 2.21, 95%CI:1.16-4.20, p = 0.016) and PM10 (OR = 2.18, 95%CI:1.15-4.15, p = 0.017) independent of age, gender, smoking, lung function and antifibrotic treatment. Introduction of TL in all models of a subgroup of 36 patients did not change the direction of the observed associations. Finally, O3 was positively associated with %change of IL-4 (p = 0.014) whilst PM2.5, PM10 and NO2 were inversely associated with %changes of IL-4 (p = 0.003, p = 0.003, p = 0.032) and osteopontin (p = 0.013, p = 0.013, p = 0.085) respectively.Conclusions: Long-term personal exposure to increased concentrations of air pollutants is an independent risk factor of AE-IPF. Inflammatory mediators implicated in lung repair mechanisms are involved. [ABSTRACT FROM AUTHOR]

INTRODUCTION School-based tobacco control programs exhibit great variety. Our study aimed to evaluate the effectiveness of an experiential learning smoking prevention program in facilitating knowledge acquisition, forging healthy attitudes, and decreasing intention to smoke. METHODS A school-based intervention-control study was implemented during the 2016--2017 academic year among middle-school students in Athens, Greece. The experiential learning intervention was delivered using an interdisciplinary approach, bridging excerpts from ancient classical Greek myths, Aesop fables and ancient classical literature (Aristotle, Herodotus, Plutarch, Xenophon, Homer's Epics), with their decoded archetypal symbols applied in a smoking and tobacco control paradigm. An anonymous selfadministered questionnaire was used at baseline and at follow-up at 3 months to evaluate program effectiveness. RESULTS A total of 351 students participated in our study; 181 (51.6%) in the intervention group and 170 (48.4%) in the control group. The mean age of student participants was 13 years (SD=0.96). Students in the intervention group were more likely to improve their knowledge of the adverse effects of smoking, develop attitudes against smoking and report a negative intention to smoke in the first year following the intervention, compared to the control group. CONCLUSIONS This study provides evidence that school-based experiential learning smoking prevention programs improve smoking-related knowledge, enhance anti-smoking attitudes and reinforce negative intentions toward tobacco products. [ABSTRACT FROM AUTHOR]

Background: Epidemiological evidence indicates that diets rich in plant foods are associated with a lower risk of ischaemic heart disease (IHD), but there is sparse information on fruit and vegetable subtypes and sources of dietary fibre. This study examined the associations of major plant foods, their subtypes and dietary fibre with risk of IHD in the European Prospective Investigation into Cancer and Nutrition (EPIC).Methods: We conducted a prospective analysis of 490 311 men and women without a history of myocardial infarction or stroke at recruitment (12.6 years of follow-up, n cases = 8504), in 10 European countries. Dietary intake was assessed using validated questionnaires, calibrated with 24-h recalls. Multivariable Cox regressions were used to estimate hazard ratios (HR) of IHD.Results: There was a lower risk of IHD with a higher intake of fruit and vegetables combined [HR per 200 g/day higher intake 0.94, 95% confidence interval (CI): 0.90-0.99, P-trend = 0.009], and with total fruits (per 100 g/day 0.97, 0.95-1.00, P-trend = 0.021). There was no evidence for a reduced risk for fruit subtypes, except for bananas. Risk was lower with higher intakes of nuts and seeds (per 10 g/day 0.90, 0.82-0.98, P-trend = 0.020), total fibre (per 10 g/day 0.91, 0.85-0.98, P-trend = 0.015), fruit and vegetable fibre (per 4 g/day 0.95, 0.91-0.99, P-trend = 0.022) and fruit fibre (per 2 g/day 0.97, 0.95-1.00, P-trend = 0.045). No associations were observed between vegetables, vegetables subtypes, legumes, cereals and IHD risk.Conclusions: In this large prospective study, we found some small inverse associations between plant foods and IHD risk, with fruit and vegetables combined being the most strongly inversely associated with risk. Whether these small associations are causal remains unclear. [ABSTRACT FROM AUTHOR]

Background: Nutrition and lifestyle have been long established as risk factors for colorectal cancer (CRC). Modifiable lifestyle behaviours bear potential to minimize long-term CRC risk; however, translation of lifestyle information into individualized CRC risk assessment has not been implemented. Lifestyle-based risk models may aid the identification of high-risk individuals, guide referral to screening and motivate behaviour change. We therefore developed and validated a lifestyle-based CRC risk prediction algorithm in an asymptomatic European population.Methods: The model was based on data from 255,482 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) study aged 19 to 70 years who were free of cancer at study baseline (1992-2000) and were followed up to 31 September 2010. The model was validated in a sample comprising 74,403 participants selected among five EPIC centres. Over a median follow-up time of 15 years, there were 3645 and 981 colorectal cancer cases in the derivation and validation samples, respectively. Variable selection algorithms in Cox proportional hazard regression and random survival forest (RSF) were used to identify the best predictors among plausible predictor variables. Measures of discrimination and calibration were calculated in derivation and validation samples. To facilitate model communication, a nomogram and a web-based application were developed.Results: The final selection model included age, waist circumference, height, smoking, alcohol consumption, physical activity, vegetables, dairy products, processed meat, and sugar and confectionary. The risk score demonstrated good discrimination overall and in sex-specific models. Harrell's C-index was 0.710 in the derivation cohort and 0.714 in the validation cohort. The model was well calibrated and showed strong agreement between predicted and observed risk. Random survival forest analysis suggested high model robustness. Beyond age, lifestyle data led to improved model performance overall (continuous net reclassification improvement = 0.307 (95% CI 0.264-0.352)), and especially for young individuals below 45 years (continuous net reclassification improvement = 0.364 (95% CI 0.084-0.575)).Conclusions: LiFeCRC score based on age and lifestyle data accurately identifies individuals at risk for incident colorectal cancer in European populations and could contribute to improved prevention through motivating lifestyle change at an individual level. [ABSTRACT FROM AUTHOR]

Background: While Helicobacter pylori (H. pylori) is the major cause of gastric cancer, it has also been suggested to be involved in colorectal cancer development. However, prospective studies addressing H. pylori and colorectal cancer are sparse and inconclusive. We assessed the association of antibody responses to H. pylori proteins with colorectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Methods: We applied H. pylori multiplex serology to measure antibody responses to 13 H. pylori proteins in prediagnostic serum samples from 485 colorectal cancer cases and 485 matched controls nested within the EPIC study. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariable conditional logistic regression to estimate the association of H. pylori overall and protein-specific seropositivity with odds of developing colorectal cancer. Results: Fifty-one percent of colorectal cancer cases were H. pylori seropositive compared with 44% of controls, resulting in an OR of 1.36 (95% CI, 1.00-1.85). Among the 13 individual H. pylori proteins, the association was driven mostly by seropositivity to Helicobacter cysteine-rich protein C (HcpC; OR: 1.66; 95% CI, 1.19-2.30) and Vacuolating cytotoxin A (VacA) (OR: 1.34; 95% CI, 0.99-1.82), the latter being nonstatistically significant only in the fully adjusted model. Conclusions: In this prospective multicenter European study, antibody responses to H. pylori proteins, specifically HcpC and VacA, were associated with an increased risk of developing colorectal cancer. Impact: Biological mechanisms for a potential causal role of H. pylori in colorectal carcinogenesis need to be elucidated, and subsequently whether H. pylori eradication may decrease colorectal cancer incidence. [ABSTRACT FROM AUTHOR]

Purpose: In this study, we aimed to study the correlation between acute and habitual intakes of flavonols, their main food sources and their 24-h urinary concentrations in an European population. Methods: A 24-h dietary recall (24-HDR) and 24-h urine samples were collected on the same day from a convenience subsample of 475 men and women from four countries (France, Italy, Greece and Germany) of the European Prospective Investigation into Cancer and Nutrition (EPIC) study. A standardized 24-HDR software and a country/centre-specific validated dietary questionnaire (DQ) were used to collect acute and habitual dietary data, respectively. The intake of dietary flavonols was estimated using the Phenol-Explorer database. Urinary flavonols (quercetin, isorhamnetin, and kaempferol) were analysed using tandem mass spectrometry with a previous enzymatic hydrolysis. Results: Weak partial Spearman correlations between both dietary acute and habitual intake and urinary concentrations of quercetin (both Rpartial ~ 0.3) and total flavonols (both Rpartial ~ 0.2) were observed. No significant correlations were found for kaempferol and isorhamentin. Regarding flavonol-rich foods, weak correlations were found between urinary concentrations of quercetin and total flavonols and the acute intake of onions and garlics, fruits, tea, and herbal tea (all Rpartial ~ 0.2). For habitual intake, statistically significant correlations were only found between urinary quercetin concentration and herbal tea (Rpartial = 0.345) and between urinary total flavonol concentration and tea, and herbal tea consumption (Rpartial ~ 0.2). Conclusions: Our results suggest that urinary quercetin level can be used as potential concentration biomarkers of both acute and habitual quercetin intake, while urinary concentrations of flavonols are unlikely to be useful biomarkers of individual flavonol-rich foods. [ABSTRACT FROM AUTHOR]