Multiscale tomographic analysis of heterogeneous cast Al-Si-X alloys.

The three-dimensional microstructure of cast AlSi12Ni and AlSi10Cu5Ni2 alloys is investigated by laboratory X-ray computed tomography, synchrotron X-ray computed microtomography, light optical tomography and synchrotron X-ray computed microtomography with submicrometre resolution. The results obtained with each technique are correlated with the size of the scanned volumes and resolved microstructural features. Laboratory X-ray computed tomography is sufficient to resolve highly absorbing aluminides but eutectic and primary Si remain unrevealed. Synchrotron X-ray computed microtomography at ID15/ESRF gives better spatial resolution and reveals primary Si in addition to aluminides. Synchrotron X-ray computed microtomography at ID19/ESRF reveals all the phases ≥ ∼1 µm in volumes about 80 times smaller than laboratory X-ray computed tomography. The volumes investigated by light optical tomography and submicrometre synchrotron X-ray computed microtomography are much smaller than laboratory X-ray computed tomography but both techniques provide local chemical information on the types of aluminides. The complementary techniques applied enable a full three-dimensional characterization of the microstructure of the alloys at length scales ranging over six orders of magnitude.

Incidence rates and trends of hip/femur fractures in five European countries: comparison using e-healthcare records databases.

Hip fractures represent a major public health challenge worldwide. Multinational studies using a common methodology are scarce. We aimed to estimate the incidence rates (IRs) and trends of hip/femur fractures over the period 2003-2009 in five European countries. The study was performed using seven electronic health-care records databases (DBs) from Denmark, The Netherlands, Germany, Spain, and the United Kingdom, based on the same protocol. Yearly IRs of hip/femur fractures were calculated for the general population and for those aged ≥50 years. Trends over time were evaluated using linear regression analysis for both crude and standardized IRs. Sex- and age-standardized IRs for the UK, Netherlands, and Spanish DBs varied from 9 to 11 per 10,000 person-years for the general population and from 22 to 26 for those ≥50 years old; the German DB showed slightly higher IRs (about 13 and 30, respectively), whereas the Danish DB yielded IRs twofold higher (19 and 52, respectively). IRs increased exponentially with age in both sexes. The ratio of females to males was ≥2 for patients aged ≥70-79 years in most DBs. Statistically significant trends over time were only shown for the UK DB (CPRD) (+0.7% per year, P < 0.01) and the Danish DB (-1.4% per year, P < 0.01). IRs of hip/femur fractures varied greatly across European countries. With the exception of Denmark, no decreasing trend was observed over the study period.

Tolerance to COX-2 inhibitors in children with hypersensitivity to nonsteroidal anti-inflammatory drugs.

BACKGROUND: Hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) can affect children, with the mechanism proposed being inhibition of the cyclooxygenase enzyme-1 (COX-1). In these patients nonchemically related NSAIDs, including COX-2 inhibitors, can induce the reaction, hampering treatment of fever and inflammatory processes. OBJECTIVES: To analyse retrospectively tolerance to etoricoxib, a selective COX-2 inhibitor, and to meloxicam, a preferential COX-2 inhibitor, in children with hypersensitivity to NSAIDs. METHODS: Clinical records of children (aged 1-14 years) diagnosed with hypersensitivity reactions to NSAIDs from January 2006 to January 2013 were included. The diagnosis was confirmed by oral drug provocation test (DPT) with the culprit NSAIDs and acetylsalicylic acid (ASA). Tolerance to paracetamol, etoricoxib and meloxicam was also evaluated. RESULTS: The study included 41 children with a positive DPT with ASA and the culprit NSAID. DPT with paracetamol and etoricoxib was negative in all children, although two (4.9%) children developed a reaction after the administration of meloxicam. CONCLUSIONS: These data indicate that both etoricoxib and meloxicam are good alternatives for treatment in older children with hypersensitivity to NSAIDs.

Ascertainment of acute liver injury in two European primary care databases.

PURPOSE: The purpose of this study was to ascertain acute liver injury (ALI) in primary care databases using different computer algorithms. The aim of this investigation was to study and compare the incidence of ALI in different primary care databases and using different definitions of ALI. METHODS: The Clinical Practice Research Datalink (CPRD) in UK and the Spanish "Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria" (BIFAP) were used. Both are primary care databases from which we selected individuals of all ages registered between January 2004 and December 2009. We developed two case definitions of idiopathic ALI using computer algorithms: (i) restrictive definition (definite cases) and (ii) broad definition (definite and probable cases). Patients presenting prior liver conditions were excluded. Manual review of potential cases was performed to confirm diagnosis, in a sample in CPRD (21%) and all potential cases in BIFAP. Incidence rates of ALI by age, sex and calendar year were calculated. RESULTS: In BIFAP, all cases considered definite after manual review had been detected with the computer algorithm as potential cases, and none came from the non-cases group. The restrictive definition of ALI had a low sensitivity but a very high specificity (95% in BIFAP) and showed higher rates of agreement between computer search and manual review compared to the broad definition. Higher incidence rates of definite ALI in 2008 were observed in BIFAP (3.01 (95% confidence interval (CI) 2.13-4.25) per 100,000 person-years than CPRD (1.35 (95% CI 1.03-1.78)). CONCLUSIONS: This study shows that it is feasible to identify ALI cases if restrictive selection criteria are used and the possibility to review additional information to rule out differential diagnoses. Our results confirm that idiopathic ALI is a very rare disease in the general population. Finally, the construction of a standard definition with predefined criteria facilitates the timely comparison across databases.

Antidepressant prescribing in five European countries: application of common definitions to assess the prevalence, clinical observations, and methodological implications.

PURPOSE: Drug utilization studies have applied different methods to various data types to describe medication use, which hampers comparisons across populations. The aim of this study was to describe the time trends in antidepressant prescribing in the last decade and the variation in the prevalence, calculated in a uniform manner, in seven European electronic healthcare databases. METHODS: Annual prevalence per 10,000 person-years (PYs) was calculated for 2001-2009 in databases from Spain, Germany, Denmark, the United Kingdom (UK), and the Netherlands. Prevalence data were stratified according to age, sex, antidepressant type (selective serotonin re-uptake inhibitors [SSRIs] or tricyclic antidepressants [TCAs]) and major indications. RESULTS: The age- and sex-standardized prevalence was lowest in the two Dutch (391 and 429 users per 10,000 PYs) and highest in the two UK (913 and 936 users per 10,000 PYs) populations in 2008. The prevalence in the Danish, German, and Spanish populations was 637, 618, and 644 users per 10,000 PY respectively. Antidepressants were prescribed most often in 20- to 60-year-olds in the two UK populations compared with the others. SSRIs were prescribed more often than TCAs in all except the German population. In the majority of countries we observed an increasing trend of antidepressant prescribing over time. Two different methods identifying recorded indications yielded different ranges of proportions of patients recorded with the specific indication (15-57% and 39-69% for depression respectively). CONCLUSION: Despite applying uniform methods, variations in the prevalence of antidepressant prescribing were obvious in the different populations. Database characteristics and clinical factors may both explain these variations.

Effect of solution heat treatment on the internal architecture and compressive strength of an AlMg4.7Si8 alloy.

The evolution of the microstructure of an AlMg4.7Si8 alloy is investigated by scanning electron microscopy and ex situ synchrotron tomography in as-cast condition and subsequent solution treatments for 1 h and 25 h at 540 °C, respectively. The eutectic Mg2Si phase, which presents a highly interconnected structure in the as-cast condition, undergoes significant morphological changes during the solution heat treatment. Statistical analyses of the particle distribution, the sphericity, the mean curvatures and Gaussian curvatures describe the disintegration of the interconnected seaweed-like structure followed by the rounding of the disintegrated fractions of the eutectic branches quantitatively. The ternary eutectic Si resulting from the Si-surplus to the stoichiometric Mg2Si ratio of the alloy undergoes similar changes. The morphological evolution during solution heat treatment is correlated with results of elevated temperature compression tests at 300 °C. The elevated temperature compressive strength is more sensitive to the degree of interconnectivity of the three dimensional Mg2Si network than to the shape of the individual particles.

In situ synchrotron tomographic investigation of the solidification of an AlMg4.7Si8 alloy.

The solidification sequence of an AlMg4.7Si8 alloy is imaged in situ by synchrotron microtomography. Tomograms with (1.4 µm)3/voxel have been recorded every minute while cooling the melt from 600 °C at a cooling rate of 5 K min-1 to 540 °C in the solid state. The solidification process starts with the three-dimensional evolution of the α-Al dendritic structure at 590 °C. The growth of the α-Al dendrites is described by curvature parameters that represent the coarsening quantitatively, and ends in droplet-like shapes of the secondary dendrite arms at 577 °C. There, the eutectic valley of α-Al/Mg2Si is reached, forming initially octahedral Mg2Si particles preferentially at the bases of the secondary dendrite arms. The eutectic grows with seaweed-like Mg2Si structures, with increasing connectivity. During this solidification stage Fe-aluminides form and expand as thin objects within the interdendritic liquid. Finally, the remaining liquid freezes as ternary α-Al/Mg2Si/Si eutectic at 558 °C, increasing further the connectivity of the intermetallic phases. The frozen alloy consists of four phases exhibiting morphologies characteristic of their mode of solidification: α-Al dendrites, eutectic α-Al/Mg2Si "Chinese script" with Fe-aluminides, and interpenetrating α-Al/Mg2Si/Si ternary eutectic.

Sub-micrometre holotomographic characterisation of the effects of solution heat treatment on an AlMg7.3Si3.5 alloy.

A strip cast AlMg7.3Si3.5 alloy is investigated by sub-micrometre holotomographic analysis achieving a voxel size of (60 nm)3 by cone beam magnification of the focused synchrotron beam using Kirkpatrick-Baez mirrors. The three-dimensional microstructure of the same specimen volume in the as-cast state is compared with that after exposure to 540 °C for 30 min resolving microstructural features down to 180 nm. The three-dimensional analysis of the architecture of the eutectic Mg2Si and the Fe-aluminides reveals how the as-cast microstructure changes during the solution treatment. The alloy in the as-cast condition contains a highly interconnected seaweed-like Mg2Si eutectic. The level of three-dimensional interconnectivity of the Mg2Si eutectic phase decreases by only partial disintegration during the heat treatment correcting the two-dimensional metallographic impression of isolated round particles. Statistical analyses of the particle distribution, sphericity, mean curvatures and Gaussian curvatures describe quantitatively the architectural changes of the Mg2Si phase. This explains the decrease of the high temperature strength of the alloy by the solution treatment tested in hot compression.

Three-dimensional rigid multiphase networks providing high-temperature strength to cast AlSi10Cu5Ni1-2 piston alloys.

The three-dimensional (3-D) architecture of rigid multiphase networks present in AlSi10Cu5Ni1 and AlSi10Cu5Ni2 piston alloys in as-cast condition and after 4 h spheroidization treatment is characterized by synchrotron tomography in terms of the volume fraction of rigid phases, interconnectivity, contiguity and morphology. The architecture of both alloys consists of α-Al matrix and a rigid long-range 3-D network of Al(7)Cu(4)Ni, Al(4)Cu(2)Mg(8)Si(7), Al(2)Cu, Al(15)Si(2)(FeMn)(3) and AlSiFeNiCu aluminides and Si. The investigated architectural parameters of both alloys studied are correlated with room-temperature and high-temperature (300 °C) strengths as a function of solution treatment time. The AlSi10Cu5Ni1 and AlSi10Cu5Ni2 alloys behave like metal matrix composites with 16 and 20 vol.% reinforcement, respectively. Both alloys have similar strengths in the as-cast condition, but the AlSi10Cu5Ni2 is able to retain ∼15% higher high temperature strength than the AlSi10Cu5Ni1 alloy after more than 4 h of spheroidization treatment. This is due to the preservation of the 3-D interconnectivity and the morphology of the rigid network, which is governed by the higher degree of contiguity between aluminides and Si.

Immunoglobulin E-mediated immediate allergic reactions to dipyrone: value of basophil activation test in the identification of patients.

BACKGROUND: Pyrazolones are a major cause of immediate IgE-mediated reactions to drugs in many countries. OBJECTIVE: The aim of the study was to evaluate a group of patients with this type of reaction by basophil activation test (BAT), focusing on the influence on positivity of the time between the reaction and this study. METHODS: The study included 51 patients with selective immediate allergic reactions to pyrazolones and 56 controls. Patients were defined by skin testing or a drug provocation test and BATs with pyrazolones were carried out in all cases. Patients who were BAT positive were followed-up for 30 months to establish the rate of decline in positive tests. RESULTS: BAT was positive in 28 (54.9%) cases. BAT sensitivity was higher in those who were skin-test positive (85.7%) compared with those who were skin-test negative (33.3%). The time between the initial reaction and this study was significantly shorter in those who were skin-test positive (P=0.005) and those who were BAT positive (P=0.017). Follow-up of the BAT-positive patients showed a decrease over time, with 60% of these patients becoming negative after 6 months. CONCLUSIONS: BAT is a useful complement to skin testing for the evaluation of immediate allergic reactions to pyrazolones. Although not optimal, BAT sensitivity was also positive in patients with a negative skin test and it is a reasonable alternative in patients with severe reactions who may develop symptoms after skin testing. The time of performance of the test is critical to obtain a positive response.

[Adherence to treatment after kidney transplantation as quality indicator of the information received: Longitudinal study of 2 years follow-up]. / Adherencia al tratamiento tras trasplante renal como indicador de calidad de la información recibida: estudio longitudinal con un seguimiento de 2 años.

INTRODUCTION: Transplantation is an optimal form of treatment for end-stage renal disease, but requires lifelong adherence to immunosuppressive therapy. The aim of this study was to longitudinally assess the adherence to treatment after kidney transplant, as well as to compare the amount of information about the treatment received at one month and 18 months post-transplantation, and its influence on adherence to treatment. MATERIAL AND METHODS: The Self-Reported Measure of Medication Adherence was administered at month (T1), 6 months (T2), 12 months (T3), 18 months (T4), and 24 months (T5) post-transplantation. Survey about aspects of knowledge and attitudes about medication, was administered at one month and 18 months post-transplant. Measures of central tendency and non-parametric tests were used to compare the data. RESULTS: The study included a total of 73 patients with a median age of 57 years. The percentage of patients non-adherent to medication was 9.6% (T1), 22.5% (T2), 29.2% (T3), 29.8% (T4), and 28.1% (T5). One month after transplantation "not consulting with the doctor on forgetting to take medication (P=.034) significantly influenced the non-adherence to treatment. At 18 months post- transplantation, none of the issues raised on medication knowledge had an influence on non-adherence to treatment. CONCLUSIONS: Longer times since transplantation increased the non-adherence to treatment. Some issues regarding the information of treatment influenced the non-adherence in the immediate transplant period, but not in the follow-up.

Whole-exome sequencing in obsessive-compulsive disorder identifies rare mutations in immunological and neurodevelopmental pathways.

Studies of rare genetic variation have identified molecular pathways conferring risk for developmental neuropsychiatric disorders. To date, no published whole-exome sequencing studies have been reported in obsessive-compulsive disorder (OCD). We sequenced all the genome coding regions in 20 sporadic OCD cases and their unaffected parents to identify rare de novo (DN) single-nucleotide variants (SNVs). The primary aim of this pilot study was to determine whether DN variation contributes to OCD risk. To this aim, we evaluated whether there is an elevated rate of DN mutations in OCD, which would justify this approach toward gene discovery in larger studies of the disorder. Furthermore, to explore functional molecular correlations among genes with nonsynonymous DN SNVs in OCD probands, a protein-protein interaction (PPI) network was generated based on databases of direct molecular interactions. We applied Degree-Aware Disease Gene Prioritization (DADA) to rank the PPI network genes based on their relatedness to a set of OCD candidate genes from two OCD genome-wide association studies (Stewart et al., 2013; Mattheisen et al., 2014). In addition, we performed a pathway analysis with genes from the PPI network. The rate of DN SNVs in OCD was 2.51 × 10(-8) per base per generation, significantly higher than a previous estimated rate in unaffected subjects using the same sequencing platform and analytic pipeline. Several genes harboring DN SNVs in OCD were highly interconnected in the PPI network and ranked high in the DADA analysis. Nearly all the DN SNVs in this study are in genes expressed in the human brain, and a pathway analysis revealed enrichment in immunological and central nervous system functioning and development. The results of this pilot study indicate that further investigation of DN variation in larger OCD cohorts is warranted to identify specific risk genes and to confirm our preliminary finding with regard to PPI network enrichment for particular biological pathways and functions.

Seasonal changes in prescribing of long-acting beta-2-agonists-containing drugs.

BACKGROUND: For patients with asthma, COPD, or asthma-COPD overlap syndrome (ACOS), inter-country comparisons of seasonal changes in drug prescriptions are scarce or missing. Hence, we aimed to compare seasonal changes in prescription rates of long-acting beta-2-agonist (LABA) in four European countries. METHODS: A common study protocol was applied to six health care databases (Germany, Spain, the Netherlands (2), and the UK (2)) to calculate age- and sex-standardized point prevalence rates (PPRs) of LABA-containing prescriptions by the 1st of March, June, September, and December of each year during the study period 2002-2009. Seasonal variation of PPRs was quantified using seasonal indexes (SIs; based on the ratio-to-moving-average-method) and SIs averaged over the study period (aSI) stratified by sex, age, and indication (asthma, COPD, or ACOS). RESULTS: There was a moderate seasonal change in LABA-containing prescriptions which was more pronounced in asthma or COPD patients compared to ACOS patients. For asthma and ACOS patients, highest seasonal variation was found for patients living in Spain (aSI: 87.3-110.7, aSI: 93.2-103.1) whereas for COPD highest seasonal variation was revealed for the NPCRD database (the Netherlands) (aSI: 92.2-105.6). Regarding age and sex, highest seasonal variation was found in Spanish boys under 10 years of age having a diagnosis of asthma. CONCLUSIONS: By applying a common analysis in six databases, we could observe moderate overall seasonal changes in LABA-containing prescription rates in patients with asthma, COPD, or ACOS.

The effect of coarse intermetallic particles on the fracture process in forged 7000 alloys.

The effect of coarse intermetallic particles on the fracture process in 7000 alloy forgings was investigated using three alloys with different (Fe + Si) impurity levels. The intermetallic particles were identified by selective etching and energy dispersive spectroscopy analysis conducted on a scanning electron microscope. Their geometrical parameters were estimated by image analysis and then correlated with area fractions of different fracture modes on the broken fracture toughness test specimens. It was found that the dominant fracture mode varies with the (Fe + Si) content. The coarse voiding at large intermetallic particles increases systematically with an increase of the impurity level, which in turn increases the amount and size of particles containing Fe and Si while decreasing their spacing. That the crack nucleation and propagation are accelerated by these particles was revealed by in situ scanning electron microscopy observation of the fracture process.