Roadmap to DILI research in Europe. A proposal from COST action ProEuroDILINet.

In the current article the aims for a constructive way forward in Drug-Induced Liver Injury (DILI) are to highlight the most important priorities in research and clinical science, therefore supporting a more informed, focused, and better funded future for European DILI research. This Roadmap aims to identify key challenges, define a shared vision across all stakeholders for the opportunities to overcome these challenges and propose a high-quality research program to achieve progress on the prediction, prevention, diagnosis and management of this condition and impact on healthcare practice in the field of DILI. This will involve 1. Creation of a database encompassing optimised case report form for prospectively identified DILI cases with well-characterised controls with competing diagnoses, biological samples, and imaging data; 2. Establishing of preclinical models to improve the assessment and prediction of hepatotoxicity in humans to guide future drug safety testing; 3. Emphasis on implementation science and 4. Enhanced collaboration between drug-developers, clinicians and regulatory scientists. This proposed operational framework will advance DILI research and may bring together basic, applied, translational and clinical research in DILI.

Re-treatment with radium-223: first experience from an international, open-label, phase I/II study in patients with castration-resistant prostate cancer and bone metastases.

BACKGROUND: Six radium-223 injections at 4-week intervals is indicated for patients with castration-resistant prostate cancer and symptomatic bone metastases. However, patients usually develop disease progression after initial treatment. This prospective phase I/II study assessed re-treatment safety and efficacy of up to six additional radium-223 injections. PATIENTS AND METHODS: Patients had castration-resistant prostate cancer and bone metastases and six initial radium-223 injections with no on-treatment bone progression; all had subsequent radiologic or clinical progression. Concomitant agents were allowed at investigator discretion, excluding chemotherapy and initiation of new abiraterone or enzalutamide. The primary endpoint was safety; additional exploratory endpoints included time to radiographic bone progression, time to total alkaline phosphatase and prostate-specific antigen progression, radiographic progression-free survival, overall survival, time to first symptomatic skeletal event (SSE), SSE-free survival, and time to pain progression. RESULTS: Among 44 patients, 29 (66%) received all six re-treatment injections. Median time from end of initial radium-223 treatment was 6 months. Forty-one (93%) reported ≥1 treatment-emergent adverse event. No grade 4-5 hematologic treatment-emergent adverse events occurred. Only one (2%) patient had radiographic bone progression; eight (18%) had radiographic soft tissue tumor progression (three lymph node and five visceral metastases). Median times to total alkaline phosphatase and prostate-specific antigen progression were not reached and 2.2 months, respectively. Median radiographic progression-free survival was 9.9 months (12.8-month maximum follow-up). Five (11%) patients died and eight (18%) experienced first SSEs. Median overall survival, time to first SSE, and SSE-free survival were not reached. Five (14%) of 36 evaluable patients (baseline worst pain score ≤7) had pain progression. After 2 years of follow-up, 28 (64%) patients died, and the median overall survival was 24.4 months. CONCLUSIONS: Re-treatment with a second course of six radium-223 injections after disease progression is well tolerated, with minimal hematologic toxicity and low radiographic bone progression rates in this small study with limited follow-up. Favorable safety and early effects on disease progression indicate that radium-223 re-treatment is feasible and warrants further evaluation in larger prospective trials.

Trajectories of cortical thickness maturation in normal brain development--The importance of quality control procedures.

Several reports have described cortical thickness (CTh) developmental trajectories, with conflicting results. Some studies have reported inverted-U shape curves with peaks of CTh in late childhood to adolescence, while others suggested predominant monotonic decline after age 6. In this study, we reviewed CTh developmental trajectories in the NIH MRI Study of Normal Brain Development, and in a second step, evaluated the impact of post-processing quality control (QC) procedures on identified trajectories. The quality-controlled sample included 384 individual subjects with repeated scanning (1-3 per subject, total scans n=753) from 4.9 to 22.3years of age. The best-fit model (cubic, quadratic, or first-order linear) was identified at each vertex using mixed-effects models. The majority of brain regions showed linear monotonic decline of CTh. There were few areas of cubic trajectories, mostly in bilateral temporo-parietal areas and the right prefrontal cortex, in which CTh peaks were at, or prior to, age 8. When controlling for total brain volume, CTh trajectories were even more uniformly linear. The only sex difference was faster thinning of occipital areas in boys compared to girls. The best-fit model for whole brain mean thickness was a monotonic decline of 0.027mm per year. QC procedures had a significant impact on identified trajectories, with a clear shift toward more complex trajectories (i.e., quadratic or cubic) when including all scans without QC (n=954). Trajectories were almost exclusively linear when using only scans that passed the most stringent QC (n=598). The impact of QC probably relates to decreasing the inclusion of scans with CTh underestimation secondary to movement artifacts, which are more common in younger subjects. In summary, our results suggest that CTh follows a simple linear decline in most cortical areas by age 5, and all areas by age 8. This study further supports the crucial importance of implementing post-processing QC in CTh studies of development, aging, and neuropsychiatric disorders.

rs3918242 MMP9 gene polymorphism is associated with myocardial infarction in Mexican patients.

Several studies have demonstrated that matrix metalloproteinases (MMPs) play a major role in atherosclerotic plaque disruption and lead to myocardial infarction (MI). We investigated the association between the MMP1 -1607 1G/2G (rs1799750), MMP3 -1612 5A/6A (rs3025058), and MMP9 -1562 C/T (rs3918242) polymorphisms and the risk of developing MI in a Mexican mestizo cohort. The genotype analysis was performed using the restriction fragment length polymorphism-polymerase chain reaction technique in a group of 236 patients with a history of MI and 285 healthy controls. Similar distributions of rs1799750 and rs3025058 were observed in both groups; however, the MMP9 rs3918242 T allele and the CT genotype were associated with the risk of developing MI (OR = 2.32, pC = 0.02 and OR = 2.40, pC = 0.02, respectively). Multiple logistic analysis was performed between MI patients and controls to estimate the risk, and after adjusting for identified risk factors, the CT + TT genotypes of MMP9 rs3918242 were found to be significantly associated with increased risk of developing MI than those with the CC genotype (OR = 2.88, P < 0.01). In summary, our results reveal that the rs3918242 polymorphism of the MMP9 gene plays a major role in the risk of developing MI.

Complications associated with radiofrequency ablation of pulmonary veins. / Complicaciones asociadas a la ablación mediante radiofrecuencia de venas pulmonares.

OBJECTIVE: Radiofrequency ablation is an efficacious alternative in patients with symptomatic atrial fibrillation who do not respond to or are intolerant to at least one class I or class III antiarrhythmic drug. Although radiofrequency ablation is a safe procedure, complications can occur. Depending on the location, these complications can be classified into those that affect the pulmonary veins themselves, cardiac complications, extracardiac intrathoracic complications, remote complications, and those that result from vascular access. The most common complications are hematomas, arteriovenous fistulas, and pseudoaneurysms at the puncture site. Some complications are benign and transient, such as gastroparesis or diaphragmatic elevation, whereas others are potentially fatal, such as cardiac tamponade. CONCLUSION: Radiologists must be familiar with the complications that can occur secondary to pulmonary vein ablation to ensure early diagnosis and treatment.

Circulating RNA: looking at the liver through a frosted glass.

CONTEXT: The evaluation of the liver condition, based on serum enzymatic activity and biopsies, is insufficient. Therefore, it is a priority to find a correlation between circulating RNAs and liver damage. METHODS: Publications were retrieved by the search terms "circulating RNA AND liver". RESULTS: Although differences exist between studies, a profile of RNAs that repeatedly appeared as indicators of liver damage was identified. DISCUSSION: We highlight those circulating RNAs useful to diagnostic, and discuss the transport mechanisms. CONCLUSION: Several studies have proven that circulating RNAs are useful to establish a diagnostic and a prognosis of liver diseases.

An image cytometer based on angular spatial frequency processing and its validation for rapid detection and quantification of waterborne microorganisms.

We introduce a new image cytometer design for the detection of very small particulates and demonstrate its capability in water analysis. The device is a compact microscope composed of off-the-shelf components, such as a light emitting diode (LED) source, a complementary metal-oxide-semiconductor (CMOS) image sensor, and a specific combination of optical lenses that allow, through an appropriate software, Fourier transform processing of the sample volume. Waterborne microorganisms, such as Escherichia coli (E. coli), Legionella pneumophila (L. pneumophila) and phytoplankton, are detected by interrogating the volume sample either in a fluorescent or label-free mode, i.e. with or without fluorescein isothiocyanate (FITC) molecules attached to the micro-organisms, respectively. We achieve a sensitivity of 50 cells per ml, which can be further increased to 0.2 cells per ml by pre-concentrating an initial sample volume of 500 ml with an ad hoc fluidic system. We also prove the capability of the proposed image cytometer of differentiating microbiological populations by size with a resolution of 3 µm and operating in real contaminated water.

Analysis of genetic variability of Fasciola hepatica populations from different geographical locations by ISSR-PCR.

Inter-simple sequence repeats markers were used to determinate the genetic variability of Fasciola hepatica populations recovered from sheep and cattle from Spain (Sp1, Sp2, Sp3 and Sp4), UK (Eng), Ireland (Ir) and Mexico (Mex). Twenty five primers were tested but only five produced 39 reproducible bands, being 71.79% polymorphic bands. This percentage ranged from 10.26% in Sp4 to 48.72% in Sp1, and per host between 28.21 and 48.72% in sheep and between 10.26 and 38.46% in cattle. This relatively low range of genetic diversity within populations, with a mean of 34.40%, implies that a large proportion of variation resided among populations. The population differentiation (Gst = 0.547) indicated that 54.7% of variation is due to differences between populations and 45.3% due to differences within population. The Nei's distance ranged between 0.091 and 0.230 in sheep and between 0.150 and 0.337 in cattle. The genetic relationships between populations and individuals were shown by a UPGMA dendrogram and a principal coordinate analysis; both grouped all populations separately from Sp4, a population of from the Midwest of Spain with the lowest level of diversity. Small genetic distances were observed between Eng and Ir, on the one hand, and Sp1, Sp2, Sp3, from the Northwest of Spain, together with Mex, on the other.

Use of computed tomography as a non-invasive method for diagnosing cephenemyiosis in roe deer (Capreolus capreolus).

This study was conducted to assess the reliability of computed tomography (CT) for diagnosing bot fly infestations by Cephenemyia stimulator (Clark) (Diptera: Oestridae) in roe deer (Capreolus capreolus L.) (Artiodactyla: Cervidae). For this purpose, the heads of 30 animals were analysed, firstly by CT and then by necropsy, which was used as the reference standard method. The prevalence values obtained by both methods were identical; the prevalence of infestation was 40.0% overall, and was higher in males (45.5%) than in females (25.0%). These results highlight the usefulness of CT as an alternative or non-invasive method for diagnosing cephenemyiosis in live-captured roe deer and in hunting trophies or museum collections that cannot be destroyed or damaged.

Intensive care practices in brain death diagnosis and organ donation.

We conducted a multicentre study of 1844 patients from 42 Spanish intensive care units, and analysed the clinical characteristics of brain death, the use of ancillary testing, and the clinical decisions taken after the diagnosis of brain death. The main cause of brain death was intracerebral haemorrhage (769/1844, 42%), followed by traumatic brain injury (343/1844, 19%) and subarachnoid haemorrhage (257/1844, 14%). The diagnosis of brain death was made rapidly (50% in the first 24 h). Of those patients who went on to die, the Glasgow Coma Scale on admission was ≤ 8/15 in 1146/1261 (91%) of patients with intracerebral haemorrhage, traumatic brain injury or anoxic encephalopathy; the Hunt and Hess Scale was 4-5 in 207/251 (83%) of patients following subarachnoid haemorrhage; and the National Institutes of Health Stroke Scale was ≥ 15 in 114/129 (89%) of patients with strokes. Brain death was diagnosed exclusively by clinical examination in 92/1844 (5%) of cases. Electroencephalography was the most frequently used ancillary test (1303/1752, 70.7%), followed by transcranial Doppler (652/1752, 37%). Organ donation took place in 70% of patients (1291/1844), with medical unsuitability (267/553, 48%) and family refusal (244/553, 13%) the main reasons for loss of potential donors. All life-sustaining measures were withdrawn in 413/553 of non-donors (75%).

A Methodological Approach for Spatiotemporally Analyzing Water-Polluting Effluents in Agricultural Landscapes Using Partial Triadic Analysis.

Multivariate techniques for two-dimensional data matrices are normally used in water quality studies. However, if the temporal dimension is included in the analysis, other statistical techniques are recommended. In this study, partial triadic analysis was used to investigate the spatial and temporal variability in water quality variables sampled in a northeastern Spain river basin. The results highlight the spatiality of the physical and chemical properties of water at different sites along a river over 1 yr. Partial triadic analysis allowed us to clearly identify the presence of a stable spatial structure that was common to all sampling dates across the entire catchment. Variables such as electrical conductivity and Na and Cl ions were associated with agricultural sources, whereas total dissolved nitrogen, NH-N concentrations, and NO-N concentrations were linked to polluted urban sites; differences were observed between irrigated and nonirrigated periods. The concentration of NO-N was associated with both agricultural and urban land uses. Variables associated with urban and agricultural pollution sources were highly influenced by the seasonality of different activities conducted in the study area. In analyzing the impact of land use and fertilization management on water runoff and effluents, powerful statistical tools that can properly identify the causes of pollution in watersheds are important. Partial triadic analysis can efficiently summarize site-specific water chemistry patterns in an applied setting for land- and water-monitoring schemes at the landscape level. The method is recommended for land-use decision-making processes to reduce harmful environmental effects and promote sustainable watershed management.

Distress and job satisfaction after robbery assaults: a longitudinal study.

BACKGROUND: External/intrusive violence at work can result in psychological distress and can be an important risk to employee health and safety. However, the vast majority of workplace violence studies have employed cross-sectional and correlational research, designed to examine immediate reactions after being assaulted at work. AIMS: To explore whether exposure to robbery as a traumatic event may contribute to the onset of typical symptoms of psychological distress (anxiety depression, dysphoria and loss of confidence) and job dissatisfaction over time. METHODS: We collected data by using a two-wave panel design, in which employees working the days of bank robberies, in an Italian bank, filled in a questionnaire between 48h and 1 week after the robbery (T1) and 2 months after the robbery (T2). We performed structural equation models to evaluate the fit of different models to our data. RESULTS: There were 513 participants at T1 (58% women) and 175 (34%) participants at T2 (62% women). There was a simultaneous association in which psychological distress leads to job dissatisfaction both following robbery and 2 months later. CONCLUSIONS: Our findings support a synchronous effects model and suggest that interventions after suffering physical assaults, apart from helping employees to recover their health, should consider restoring their trust and confidence in the organization. This study contributes to understanding the dynamic relationships between a robbery at work and its outcomes over time, by addressing several methodological deficiencies in previous longitudinal studies.

Flares from a candidate Galactic magnetar suggest a missing link to dim isolated neutron stars.

Magnetars are young neutron stars with very strong magnetic fields of the order of 10(14)-10(15) G. They are detected in our Galaxy either as soft gamma-ray repeaters or anomalous X-ray pulsars. Soft gamma-ray repeaters are a rare type of gamma-ray transient sources that are occasionally detected as bursters in the high-energy sky. No optical counterpart to the gamma-ray flares or the quiescent source has yet been identified. Here we report multi-wavelength observations of a puzzling source, SWIFT J195509+261406. We detected more than 40 flaring episodes in the optical band over a time span of three days, and a faint infrared flare 11 days later, after which the source returned to quiescence. Our radio observations confirm a Galactic nature and establish a lower distance limit of approximately 3.7 kpc. We suggest that SWIFT J195509+261406 could be an isolated magnetar whose bursting activity has been detected at optical wavelengths, and for which the long-term X-ray emission is short-lived. In this case, a new manifestation of magnetar activity has been recorded and we can consider SWIFT J195509+261406 to be a link between the 'persistent' soft gamma-ray repeaters/anomalous X-ray pulsars and dim isolated neutron stars.

[Non-pharmacological steps for the treatment of acute confusional syndrome in the intensive care unit]. / Medidas no farmacológicas para el tratamiento del síndrome confusional agudo en la unidad de cuidados intensivos.

UNLABELLED: The incidence of delirium in intensive care units is high and it has been under-diagnosed and under-treated. OBJECTIVE: To describe the experiences of ICU nurses in the identification and application of non-pharmacological treatments. METHOD: A qualitative phenomenological research study was performed, based on focus groups. INCLUSION CRITERIA: ICU nurses with one year of more of experience were included. Sample Purpose and snowball technique. DATA COLLECTION: Data from the focus groups were transcribed for analysis and a thematic analysis of the texts was performed. RESULTS: Four themes were identified: a) the physical and social structure of the ICU b) family involvement, c) need for training of health professionals, and d) encouraging the sleep-wake cycle. CONCLUSIONS: It is necessary to control the ICU environment to make it more friendly, to change the routine work to promote relaxation, implement training activities and to make visiting hours flexible.

[Consensus document on ultrasound training in Intensive Care Medicine. Care process, use of the technique and acquisition of professional skills]. / Documento de consenso para la formación en ecografía en Medicina Intensiva. Proceso asistencial, uso de la técnica y adquisición de competencias profesionales.

Ultrasound has become an essential tool in assisting critically ill patients. His knowledge, use and instruction requires a statement by scientific societies involved in its development and implementation. Our aim are to determine the use of the technique in intensive care medicine, clinical situations where its application is recommended, levels of knowledge, associated responsibility and learning process also implement the ultrasound technique as a common tool in all intensive care units, similar to the rest of european countries. The SEMICYUC's Working Group Cardiac Intensive Care and CPR establishes after literature review and scientific evidence, a consensus document which sets out the requirements for accreditation in ultrasound applied to the critically ill patient and how to acquire the necessary skills. Training and learning requires a structured process within the specialty. The SEMICYUC must agree to disclose this document, build relationships with other scientific societies and give legal cover through accreditation of the training units, training courses and different levels of training.

[Translated article] The effect of showing preoperative photographs on patient satisfaction following forefoot surgery.

BACKGROUND: Postoperative outcome measurement typically relies on postoperative radiological results and clinical-functional scales; however, there is a growing interest in considering patient satisfaction (including subjective aspects) as part of the success of forefoot surgery. OBJECTIVE: To determine whether showing a preoperative photograph improves satisfaction in postoperative forefoot surgery patients. MATERIAL AND METHODS: An observational, cross-sectional, analytical study was conducted in the foot and ankle unit of our centre. We included 120 participants between 18 and 90 years old who underwent forefoot surgery. The degree of satisfaction was compared using the PSQ-10 questionnaire between a group of patients who received a preoperative foot appearance image at their 3-month postoperative follow-up and those who did not receive it. RESULTS: The overall satisfaction rate was 78.33% at 3 months after the intervention. The 93.6% of patients who received the photograph were satisfied at the postoperative follow-up, while in the control group, it was 86.2% with a p value of 0.218. CONCLUSION: The degree of satisfaction in patients undergoing forefoot surgery is not associated with the presentation of preoperative photographs.

A fast method for the quantitation of key metabolites of the methionine pathway in liver tissue by high-resolution mass spectrometry and hydrophilic interaction ultra-performance liquid chromatography.

We developed an assay for the extraction and simultaneous quantitation of five key metabolites of the methionine metabolic pathway in liver tissue. The metabolites included were 5'-methylthioadenosine, methionine, homocysteine, S-adenosyl-L-homocysteine, and S-adenosyl-L-methionine. The metabolites were extracted using a bead-based homogenization method, and quantitation was carried out using hydrophilic interaction chromatography and time-of-flight mass spectrometry. The extraction procedure was optimized by testing the effect of various solvent combinations. The chromatographic method was optimized for peak shape, signal intensity, and carry-over. With a total chromatographic run time of 5 min, this assay is suitable for the analysis of large sample sets. Time-of-flight mass spectrometry provided high mass accuracy which, combined with isotope pattern matching and use of chemical standards, guarantees high specificity. Moreover, by operating the mass spectrometer in enhanced duty cycle mode the signal strength for the analytes increased three- to tenfold in comparison with the generic full-scan mode. For quantitation, a matrix-spiked calibration method was used. The lowest analyte levels detected and quantified using our method were within the range of concentrations found in the liver. The inter-day coefficients of variance for the analytes were between 5 and 15% in pooled tissue samples. Interestingly, the CVs between individual liver tissue aliquots were about twice as high. Additional experiments suggested that this higher variability was caused by uneven distribution of the analytes within the liver. In conclusion, an optimized and robust assay is now available for the extraction and quantification of key metabolites in the methionine metabolic pathway.

Contribution of high-energy conformations to NMR chemical shifts, a DFT-BOMD study.

This paper highlights the relevance of including the high-energy conformational states sampled by Born-Oppenheimer molecular dynamics (BOMD) in the calculation of time-averaged NMR chemical shifts. Our case study is the very flexible glycerol molecule that undergoes interconversion between conformers in a nonrandom way. Along the sequence of structures from one backbone conformer to another, transition states have been identified. The three (13)C NMR chemical shifts of the molecule were estimated by averaging their calculated values over a large set of BOMD snapshots. The simulation time needed to obtain a good agreement with the two signals present in the experimental spectrum is shown to be dependent on the atomic orbital basis set used for the dynamics, with a necessary longer trajectory for the most extended basis sets. The large structural deformations with respect to the optimized conformer geometries that occur along the dynamics are related to a kinetically driven conformer distribution. Calculated conformer type populations are in good agreement with experimental gas phase microwave results.

Effect of lipopolysaccharide (LPS) from Ochrobactrum intermedium on sheep experimentally infected with Fasciola hepatica.

The effects of the lipopolysaccharide (LPS) from Ochrobactrum intermedium was evaluated in sheep experimentally infected with Fasciola hepatica. Animals were divided into four groups: two treated with the LPS (T1/T2) and two controls (C1/C2). T1/C1 were slaughtered at 30 days postinfection (dpi) and T2/C2 at 85 dpi. Body weight and body condition were found higher in T1 and T2 than in controls, although differences were not significant. Treated sheep showed lower cumulative fecal egg count than controls (p < 0.01). Levels of red blood cells (RBC), white blood cells, hemoglobin, and hematocrit (HCT) were higher in T1 and T2. Significant differences (p < 0.05) in RBC and HCT were found between groups at 84 dpi. More severe macrocytic and hypochromic anemia was observed in C1 and C2 than in treated groups. Total protein and albumin values were higher in T1 and T2 (p < 0.01) until 29 dpi. At the end of the trial, no significant differences were observed in hepatic enzymes, although gamma-glutamyl transferase and aspartate aminotransferase values were higher in C2, and alanine aminotransferase was higher in T2. At necropsy, the mean weight of liver, fibrosis in portal triads, and ganglion size were similar in all groups. The number and size of flukes was greater in C2 than in T2 (p < 0.05). The histological examinations revealed a higher degree of parenchymatous fibrosis in T2 compared to C2 (p < 0.05). The administration of LPS from O. intermedium increased the nonspecific resistance against F. hepatica in experimentally infected sheep.