Purging of deleterious burden in the endangered Iberian lynx.

SignificanceThe dynamics of deleterious variation under contrasting demographic scenarios remain poorly understood in spite of their relevance in evolutionary and conservation terms. Here we apply a genomic approach to study differences in the burden of deleterious alleles between the endangered Iberian lynx (Lynx pardinus) and the widespread Eurasian lynx (Lynx lynx). Our analysis unveils a significantly lower deleterious burden in the former species that should be ascribed to genetic purging, that is, to the increased opportunities of selection against recessive homozygotes due to the inbreeding caused by its smaller population size, as illustrated by our analytical predictions. This research provides theoretical and empirical evidence on the evolutionary relevance of genetic purging under certain demographic conditions.

Comparing Survival of Perihilar Cholangiocarcinoma After R1 Resection Versus Palliative Chemotherapy for Unresected Localized Disease.

BACKGROUND: Resection of perihilar cholangiocarcinoma (pCCA) is a complex procedure with a high risk of postoperative mortality and early disease recurrence. The objective of this study was to compare patient characteristics and overall survival (OS) between pCCA patients who underwent an R1 resection and patients with localized pCCA who received palliative systemic chemotherapy. METHODS: Patients with a diagnosis of pCCA between 1997-2021 were identified from the European Network for the Study of Cholangiocarcinoma (ENS-CCA) registry. pCCA patients who underwent an R1 resection were compared with patients with localized pCCA (i.e., nonmetastatic) who were ineligible for surgical resection and received palliative systemic chemotherapy. The primary outcome was OS. RESULTS: Overall, 146 patients in the R1 resection group and 92 patients in the palliative chemotherapy group were included. The palliative chemotherapy group more often underwent biliary drainage (95% vs. 66%, p < 0.001) and had more vascular encasement on imaging (70% vs. 49%, p = 0.012) and CA 19.9 was more frequently >200 IU/L (64 vs. 45%, p = 0.046). Median OS was comparable between both groups (17.1 vs. 16 months, p = 0.06). Overall survival at 5 years after diagnosis was 20.0% with R1 resection and 2.2% with chemotherapy. Type of treatment (i.e., R1 resection or palliative chemotherapy) was not an independent predictor of OS (hazard ratio 0.76, 95% confidence interval 0.55-1.07). CONCLUSIONS: Palliative systemic chemotherapy should be considered instead of resection in patients with a high risk of both R1 resection and postoperative mortality.

Non-invasive prehabilitation to foster widespread fMRI cortical reorganization before brain tumor surgery: lessons from a case series.

PURPOSE: The objective of this prospective, single-centre case series was to investigate feasibility, clinical outcomes, and neural correlates of non-invasive Neuromodulation-Induced Cortical Prehabilitation (NICP) before brain tumor surgery. Previous studies have shown that gross total resection is paramount to increase life expectancy but is counterbalanced by the need of preserving critical functional areas. NICP aims at expanding functional margins for extensive tumor resection without functional sequelae. Invasive NICP (intracranial neuromodulation) was effective but characterized by elevated costs and high rate of adverse events. Non-invasive NICP (transcranial neuromodulation) may represent a more feasible alternative. Nonetheless, up to this point, non-invasive NICP has been examined in only two case reports, yielding inconclusive findings. METHODS: Treatment sessions consisted of non-invasive neuromodulation, to transiently deactivate critical areas adjacent to the lesion, coupled with intensive functional training, to activate alternative nodes within the same functional network. Patients were evaluated pre-NICP, post-NICP, and at follow-up post-surgery. RESULTS: Ten patients performed the intervention. Feasibility criteria were met (retention, adherence, safety, and patient's satisfaction). Clinical outcomes showed overall stability and improvements in motor and executive function from pre- to post-NICP, and at follow-up. Relevant plasticity changes (increase in the distance between tumor and critical area) were observed when the neuromodulation target was guided by functional neuroimaging data. CONCLUSION: This is the first case series demonstrating feasibility of non-invasive NICP. Neural correlates indicate that neuroimaging-guided target selection may represent a valid strategy to leverage neuroplastic changes before neurosurgery. Further investigations are needed to confirm such preliminary findings.

Is intraoperative mapping of music performance mandatory to preserve skills in professional musicians? Awake surgery for lower-grade glioma conducted from a meta-networking perspective.

OBJECTIVE: In surgery for lower-grade glioma (LGG) in professional musicians, for whom preserving music ability is essential, a critical question has emerged, namely, is it mandatory to include music performance during awake mapping, as proposed in several reports? In fact, music ability is subserved by a mosaic of interactive cognitive and emotional processes that rest on several networks. Therefore, from a meta-network perspective, the authors investigated whether an integrated multimodal monitoring of these cognitive and emotional functions during stimulation mapping could be efficient in maintaining musical skill. Indeed, it could be difficult for a patient to play a musical instrument in the surgical setting in addition to performing other tasks, such as movement and language. METHODS: An awake mapping-guided resection for LGG without intraoperative music performance was performed in 3 professional musicians. Intraoperative tests were tailored to each patient depending on the critical corticosubcortical circuits surrounding the tumor, including not only sensorimotor or language skills but also higher-order functions with a constant multitasking during the resection. RESULTS: Although music skills were not mapped during surgery, all patients resumed their professional activities, preserving the ability to play music and to perform concerts, to teach and to compose music, or to start learning a new instrument. CONCLUSIONS: A connectome-based resection without intraoperative music performance seems effective in achieving maximal glioma removal while preserving crucial networks subserving musical skills, creativity, and music learning. Neurosurgery should evolve toward a meta-networking approach to better understand higher-order functions mediating complex behavior, such as being a professional musician.

CRISPR-Cas9-mediated functional dissection of the foxc1 genomic region in zebrafish identifies critical conserved cis-regulatory elements.

FOXC1 encodes a forkhead-domain transcription factor associated with several ocular disorders. Correct FOXC1 dosage is critical to normal development, yet the mechanisms controlling its expression remain unknown. Together with FOXQ1 and FOXF2, FOXC1 is part of a cluster of FOX genes conserved in vertebrates. CRISPR-Cas9-mediated dissection of genomic sequences surrounding two zebrafish orthologs of FOXC1 was performed. This included five zebrafish-human conserved regions, three downstream of foxc1a and two remotely upstream of foxf2a/foxc1a or foxf2b/foxc1b clusters, as well as two intergenic regions between foxc1a/b and foxf2a/b lacking sequence conservation but positionally corresponding to the area encompassing a previously reported glaucoma-associated SNP in humans. Removal of downstream sequences altered foxc1a expression; moreover, zebrafish carrying deletions of two or three downstream elements demonstrated abnormal phenotypes including enlargement of the anterior chamber of the eye reminiscent of human congenital glaucoma. Deletions of distant upstream conserved elements influenced the expression of foxf2a/b or foxq1a/b but not foxc1a/b within each cluster. Removal of either intergenic sequence reduced foxc1a or foxc1b expression during late development, suggesting a role in transcriptional regulation despite the lack of conservation at the nucleotide level. Further studies of the identified regions in human patients may explain additional individuals with developmental ocular disorders.

Modelling the impact of functionality, cognition, and mood state on awareness in people with Alzheimer's disease.

OBJECTIVES: To investigate the nature of the relationship between cognitive function, mood state, and functionality in predicting awareness in a non-clinically depressed sample of participants with mild to moderate Alzheimer's disease (AD) in Brazil. METHODS: People with AD (PwAD) aged 60 years or older were recruited from an outpatient unit at the Center of AD of the Federal University of Rio de Janeiro, Brazil. Measures of awareness of condition (Assessment Scale of the Psychosocial Impact of the Diagnosis of Dementia), cognitive function (Mini-Mental State Examination), mood state (Cornell Scale for Depression in Dementia), and functionality (Pfeffer Functional Activities Questionnaire) were applied to 264 people with mild to moderate AD and their caregivers. Hypotheses were tested statistically using SEM approach. Three competing models were compared. RESULTS: The first model, in which the influence of mood state and cognitive function on awareness was mediated by functionality, showed a very good fit to the data and a medium effect size. The competing models, in which the mediating variables were mood state and cognitive function, respectively, only showed poor model fit. CONCLUSION: Our model supports the notion that the relationship between different factors and awareness in AD is mediated by functionality and not by depressive mood state or cognitive level. The proposed direct and indirect effects on awareness are discussed, as well as the missing direct influence of mood state on awareness. The understanding of awareness in dementia is crucial and our model gives one possible explanation of its underlying structure in AD.

Control strategies used in lower limb exoskeletons for gait rehabilitation after brain injury: a systematic review and analysis of clinical effectiveness.

BACKGROUND: In the past decade, there has been substantial progress in the development of robotic controllers that specify how lower-limb exoskeletons should interact with brain-injured patients. However, it is still an open question which exoskeleton control strategies can more effectively stimulate motor function recovery. In this review, we aim to complement previous literature surveys on the topic of exoskeleton control for gait rehabilitation by: (1) providing an updated structured framework of current control strategies, (2) analyzing the methodology of clinical validations used in the robotic interventions, and (3) reporting the potential relation between control strategies and clinical outcomes. METHODS: Four databases were searched using database-specific search terms from January 2000 to September 2020. We identified 1648 articles, of which 159 were included and evaluated in full-text. We included studies that clinically evaluated the effectiveness of the exoskeleton on impaired participants, and which clearly explained or referenced the implemented control strategy. RESULTS: (1) We found that assistive control (100% of exoskeletons) that followed rule-based algorithms (72%) based on ground reaction force thresholds (63%) in conjunction with trajectory-tracking control (97%) were the most implemented control strategies. Only 14% of the exoskeletons implemented adaptive control strategies. (2) Regarding the clinical validations used in the robotic interventions, we found high variability on the experimental protocols and outcome metrics selected. (3) With high grade of evidence and a moderate number of participants (N = 19), assistive control strategies that implemented a combination of trajectory-tracking and compliant control showed the highest clinical effectiveness for acute stroke. However, they also required the longest training time. With high grade of evidence and low number of participants (N = 8), assistive control strategies that followed a threshold-based algorithm with EMG as gait detection metric and control signal provided the highest improvements with the lowest training intensities for subacute stroke. Finally, with high grade of evidence and a moderate number of participants (N = 19), assistive control strategies that implemented adaptive oscillator algorithms together with trajectory-tracking control resulted in the highest improvements with reduced training intensities for individuals with chronic stroke. CONCLUSIONS: Despite the efforts to develop novel and more effective controllers for exoskeleton-based gait neurorehabilitation, the current level of evidence on the effectiveness of the different control strategies on clinical outcomes is still low. There is a clear lack of standardization in the experimental protocols leading to high levels of heterogeneity. Standardized comparisons among control strategies analyzing the relation between control parameters and biomechanical metrics will fill this gap to better guide future technical developments. It is still an open question whether controllers that provide an on-line adaptation of the control parameters based on key biomechanical descriptors associated to the patients' specific pathology outperform current control strategies.

Self-care nursing assessment: cross-cultural adaptation and validation of the Spanish version of the Self-care of chronic illness inventory.

BACKGROUND: Self-care is the primary means of caring for a chronic condition. Therefore, it is necessary to assess it by using a good validity and reliability instrument. The Self-Care of Chronic Illness Inventory (SC-CII) is a generic instrument developed to measure self-care processes behaviors using three separate scales in patients with chronic illness. The original cross-cultural assessment concluded the need for future studies sampling patients from different sites to increase the generalizability of the psychometric evaluation results. It was unclear whether this tool had sound psychometrics properties in the context of Spanish culture. The purpose of this study was to cross-culturally adapt the SC-CII, test its psychometric properties and validate its use among Spanish people with chronic diseases. METHODS: A cross-cultural translation of the SC-CII was performed from English to Spanish. The psychometric evaluation was conducted in a sample of 350 patients with chronic conditions through a multicenter cross-sectional study based on the STROBE guideline. Data were collected from face-to-face interviews during 2022. Internal validity was assessed with Confirmatory Factor Analysis, internal consistency reliability with Cronbach alpha for unidimensional scales and McDonald's Omega reliability coefficient for multidimensional scales. RESULTS: Most (63.4%) participants were older adults aged 65 years or older with a mean age of 65.45 ± 14.97. The average number of chronic conditions reported was 2.81%; the most common conditions were hypertension (52.3%), musculoskeletal disorders (46.3%) and diabetes (38.9%). Patients reported adequate self-care behaviors in all three scales of the SC-CII. The Self-Care Maintenance and Management scales were multidimensional, and the Self-Care Monitoring scale was unidimensional. In Confirmatory Factor Analysis, the Self-Care Maintenance and Monitoring scales had satisfactory fit indices. The Self-care Management scale had acceptable fit indices. The Omega reliability coefficient for multidimensional scales was 0.75 (Self-Care Maintenance) and 0.72 (Self-Care Management). The Cronbach alpha coefficient of the Self-Care Monitoring scale was 0.85. Item-total correlations were all significant except one. Test-retest reliability showed an intraclass correlation coefficient of 0.92. CONCLUSIONS: The SC-CII has appropriate psychometrics characteristics and is a culturally suitable and reliable instrument for assessing to the self-care behaviors of patients with chronic disease in Spain. The scale provides a simple and rapid solution to assess the self-care process.

Disruption of foxc1 genes in zebrafish results in dosage-dependent phenotypes overlapping Axenfeld-Rieger syndrome.

The Forkhead Box C1 (FOXC1) gene encodes a forkhead/winged helix transcription factor involved in embryonic development. Mutations in this gene cause dysgenesis of the anterior segment of the eye, most commonly Axenfeld-Rieger syndrome (ARS), often with other systemic features. The developmental mechanisms and pathways regulated by FOXC1 remain largely unknown. There are two conserved orthologs of FOXC1 in zebrafish, foxc1a and foxc1b. To further examine the role of FOXC1 in vertebrates, we generated foxc1a and foxc1b single knockout zebrafish lines and bred them to obtain various allelic combinations. Three genotypes demonstrated visible phenotypes: foxc1a-/- single homozygous and foxc1-/- double knockout homozygous embryos presented with similar characteristics comprised of severe global vascular defects and early lethality, as well as microphthalmia, periocular edema and absence of the anterior chamber of the eye; additionally, fish with heterozygous loss of foxc1a combined with homozygosity for foxc1b (foxc1a+/-;foxc1b-/-) demonstrated craniofacial defects, heart anomalies and scoliosis. All other single and combined genotypes appeared normal. Analysis of foxc1 expression detected a significant increase in foxc1a levels in homozygous and heterozygous mutant eyes, suggesting a mechanism for foxc1a upregulation when its function is compromised; interestingly, the expression of another ARS-associated gene, pitx2, was responsive to the estimated level of wild-type Foxc1a, indicating a possible role for this protein in the regulation of pitx2 expression. Altogether, our results support a conserved role for foxc1 in the formation of many organs, consistent with the features observed in human patients, and highlight the importance of correct FOXC1/foxc1 dosage for vertebrate development.

De novo transcriptome sequencing of the northern fowl mite, Ornithonyssus sylviarum, shed light on parasitiform poultry mites evolution and its chemoreceptor repertoires.

The northern fowl mite (NFM), Ornithonyssus sylviarum, and the poultry red mite (PRM), Dermanyssus gallinae, are the most serious pests of poultry, both of which have an expanding global prevalence. Research on NFM has been constrained by a lack of genomic and transcriptomic data. Here, we report and analyze the first global transcriptome data across all mite live stages and sexes. A total of 28,999 unigenes were assembled, of which 19,750 (68.10%) were annotated using seven functional databases. The biological function of these unigenes was classified using the GO, KOG, and KEGG databases. To gain insight into the chemosensory receptor-based system of parasitiform mites, we furthermore assessed the gene repertoire of gustatory receptors (GRs) and ionotropic receptors (IRs), both of which encode putative ligand-gated ion channel proteins. While these receptors are well characterized in insect model species, our understanding of chemosensory detection in mites and ticks is in its infancy. To address this paucity of data, we identified 9 IR/iGluRs and 2 GRs genes by analyzing transcriptome data in the NFM, while 9 GRs and 41 IR/iGluRs genes were annotated in the PRM genome. Taken together, the transcriptomic and genomic annotation of these two species provide a valuable reference for studies of parasitiform mites and also help to understand how chemosensory gene family expansion/contraction events may have been reshaped by an obligate parasitic lifestyle compared with their free-living closest relatives. Future studies should include additional species to validate this observation and functional characterization of the identified proteins as a step forward in identifying tools for controlling these poultry pests.

Effectiveness of a game-based educational strategy e-EDUCAGUIA for implementing antimicrobial clinical practice guidelines in family medicine residents in Spain: a randomized clinical trial by cluster.

BACKGROUND: Clinical practice guidelines (CPGs) have teaching potential for health professionals in training clinical reasoning and decision-making, although their use is limited. The objective was to evaluate the effectiveness of a game-based educational strategy e-EDUCAGUIA using simulated clinical scenarios to implement an antimicrobial therapy GPC compared to the usual dissemination strategies to improve the knowledge and skills on decision-making of family medicine residents. Additionally, adherence to e-EDUCAGUIA strategy was assessed. METHODS: A multicentre pragmatic cluster-randomized clinical trial was conducted involving seven Teaching Units (TUs) of family medicine in Spain. TUs were randomly allocated to implement an antimicrobial therapy guideline with e-EDUCAGUIA strategy ( intervention) or passive dissemination of the guideline (control). The primary outcome was the differences in means between groups in the score test evaluated knowledge and skills on decision-making at 1 month post intervention. Analysis was made by intention-to-treat and per-protocol analysis. Secondary outcomes were the differences in mean change intrasubject (from the baseline to the 1-month) in the test score, and educational game adherence and usability. Factors associated were analysed using general linear models. Standard errors were constructed using robust methods. RESULTS: Two hundred two family medicine residents participated (104 intervention group vs 98 control group). 100 medicine residents performed the post-test at 1 month (45 intervention group vs 55 control group), The between-group difference for the mean test score at 1 month was 11 ( 8.67 to 13.32) and between change intrasubject was 11,9 ( 95% CI 5,9 to 17,9). The effect sizes were 0.88 and 0.75 respectively. In multivariate analysis, for each additional evidence-based medicine training hour there was an increase of 0.28 points (95% CI 0.15-0.42) in primary outcome and in the change intrasubject each year of increase in age was associated with an improvement of 0.37 points and being a woman was associated with a 6.10-point reduction. 48 of the 104 subjects in the intervention group (46.2%, 95% CI: 36.5-55.8%) used the games during the month of the study. Only a greater number of evidence-based medicine training hours was associated with greater adherence to the educational game ( OR 1.11; CI 95% 1.02-1.21). CONCLUSIONS: The game-based educational strategy e-EDUCAGUIA shows positive effects on the knowledge and skills on decision making about antimicrobial therapy for clinical decision-making in family medicin residents in the short term, but the dropout was high and results should be interpreted with caution. Adherence to educational games in the absence of specific incentives is moderate. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02210442 . Registered 6 August 2014.

HW/SW Platform for Measurement and Evaluation of Ultrasonic Underwater Communications.

The purpose of this work is to present a flexible system that supports the study of wideband underwater acoustic communications (UAC). It has been developed both to measure channels and to test transmission techniques under realistic conditions in the ultrasonic band. This platform consists of a hardware (HW) part that includes multiple hydrophones, projectors, analog front-ends, acquisition boards, and computers, and a software (SW) part for the generation, reception, and management of acoustic sounding signals and noise. UAC channels are among the most hostile ones and exhibit an important attenuation and distortion, essentially due to both multipath propagation, which results in a very long channel impulse response, and time-varying behavior, which produces a notable Doppler spread. To cope with this challenging medium, sophisticated transmission techniques must be employed. In this sense, adequate signal processing algorithms have been designed aiming not only at the analysis and characterization of underwater communication channels but also at the evaluation of diverse modulation, detection, and coding schemes, from Orthogonal Frequency Division Multiplexing (OFDM) to single-carrier digital modulations with a single-input multiple-output (SIMO) configuration that takes advantage of diversity techniques. Wideband sounding signals, to be injected into the sea from the transmitter side, are created with patterns that allow multiple tests on a batch. With offline processing of the captured data at the receiver side, different trials can be carried out in a very flexible manner. The different aspects of the platform are described in detail: the HW equipment used, the SW interface to control acquisition boards, and the signal processing algorithms to estimate the UAC channel response. The platform allows the analysis and design of new proposals for underwater communications systems that improve the performance of the current ones.

Transgenic Overexpression of Myocilin Leads to Variable Ocular Anterior Segment and Retinal Alterations Associated with Extracellular Matrix Abnormalities in Adult Zebrafish.

Myocilin is an enigmatic glaucoma-associated glycoprotein whose biological role remains incompletely understood. To gain novel insight into its normal function, we used transposon-mediated transgenesis to generate the first zebrafish line stably overexpressing myocilin [Tg(actb1:myoc-2A-mCherry)]. qPCR showed an approximately four-fold increased myocilin expression in transgenic zebrafish embryos (144 hpf). Adult (13 months old) transgenic animals displayed variable and age-dependent ocular anterior segment alterations. Almost 60% of two-year-old male, but not female, transgenic zebrafish developed enlarged eyes with severe asymmetrical and variable abnormalities in the anterior segment, characterized by corneal limbus hypertrophy, and thickening of the cornea, iris, annular ligament and lens capsule. The most severe phenotype presented small or absent ocular anterior chamber and pupils, due to iris overgrowth along with dysplastic retinal growth and optic nerve hypertrophy. Immunohistochemistry revealed increased presence of myocilin in most altered ocular tissues of adult transgenic animals, as well as signs of retinal gliosis and expanded ganglion cells and nerve fibers. The preliminary results indicate that these cells contributed to retinal dysplasia. Visual impairment was demonstrated in all old male transgenic zebrafish. Transcriptomic analysis of the abnormal transgenic eyes identified disrupted expression of genes involved in lens, muscular and extracellular matrix activities, among other processes. In summary, the developed transgenic zebrafish provides a new tool to investigate this puzzling protein and provides evidence for the role of zebrafish myocilin in ocular anterior segment and retinal biology, through the influence of extracellular matrix organization and cellular proliferation.

Biochemical Evolution of a Potent Target of Mosquito Larvicide, 3-Hydroxykynurenine Transaminase.

A specific mosquito enzyme, 3-hydroxykynurenine transaminase (HKT), is involved in the processing of toxic metabolic intermediates of the tryptophan metabolic pathway. The HKT enzymatic product, xanthurenic acid, is required for Plasmodium spp. development in the mosquito vectors. Therefore, an inhibitor of HKT may not only be a mosquitocide but also a malaria-transmission blocker. In this work, we present a study investigating the evolution of HKT, which is a lineage-specific duplication of an alanine glyoxylate aminotransferases (AGT) in mosquitoes. Synteny analyses, together with the phylogenetic history of the AGT family, suggests that HKT and the mosquito AGTs are paralogous that were formed via a duplication event in their common ancestor. Furthermore, 41 amino acid sites with significant evidence of positive selection were identified, which could be responsible for biochemical and functional evolution and the stability of conformational stabilization. To get a deeper understanding of the evolution of ligands' capacity and the ligand-binding mechanism of HKT, the sequence and the 3D homology model of the common ancestor of HKT and AGT in mosquitoes, ancestral mosquito AGT (AncMosqAGT), were inferred and built. The homology model along with 3-hydroxykynurenine, kynurenine, and alanine were used in docking experiments to predict the binding capacity and ligand-binding mode of the new substrates related to toxic metabolites detoxification. Our study provides evidence for the dramatic biochemical evolution of the key detoxifying enzyme and provides potential sites that could hinder the detoxification function, which may be used in mosquito larvicide and design.

Serum biomarkers and Doppler pulsatile index increases likelihood ratio for prediction of preeclampsia in the second trimester of pregnancy.

This study aims to compare the accuracy of risk prediction for preeclampsia (PE) of three calculators during the second trimester of gestation: American College of Obstetricians and Gynaecologists (ACOG), National Institute for Health and Care Excellence (NICE), and Foetal Medicine Foundation (FMF). Complete medical history, mean uterine artery Doppler pulsatile index were performed (PI) and venous blood samples for placental growth factor (PIGF), soluble fms-like tyrosine kinase-1 (sFLT-1), and Endoglin measurements were obtained from 214 women between 20-24 weeks gestation. PE frequency was 8.4% (18/214). Sensitivity and specificity were 94.4% and 37.2% and 44.4% and 74.5% for ACOG and NICE respectively. Sensitivity for FMF was 66.7% and 44.4% at <32 weeks and <36 weeks respectively and specificity was 97.2% and 98.1%. The highest positive likelihood ratio, 22, was obtained for FMF as compared to 1.49 and 1.76 for ACOG and NICE. These findings suggest that the addition of US and serum biomarkers in the FMF calculator increases accuracy for prediction of PE.Impact StatementWhat is already known on this subject? Several strategies have been implemented to evaluate risk for PE. The ACOG and NICE calculators, based on medical and anthropomorphic data, and the FMF calculator, which includes ultrasound and serum biomarkers, have been used for the prediction of PE risk in the first trimester of gestation.What do the results of this study add? Although the identification of markers for the prediction of PE during the first trimester of pregnancy has been of major clinical interest, in many countries women attend their first prenatal visit up until the second trimester of pregnancy. This is the first multicentre study in Latin American population to compare the three risk prediction systems including serum biomarkers during the second trimester of pregnancy.What are the implications of these findings for clinical practice and/or further research? We propose the FMF calculator (including PI and serum biomarkers) as a useful tool for PE risk detection during the second trimester of pregnancy. However, as this study is limited by its small sample size, larger multicenter studies are needed to confirm our findings and assert the usefulness of the FMF calculator.

Psychometric properties of the EQ-5D-5L in patients with major depression: factor analysis and Rasch analysis.

BACKGROUND: The EQ-5D is one of the most recommended questionnaires for cost-effectiveness studies. AIMS: To study the psychometric properties of the EQ-5D-5L in patients with major depression. METHODS: This prospective observational study included 433 patients with major depression who completed the EQ-5D-5L and Patient Health Questionnaire-9 (PHQ-9) questionnaires at baseline, of whom 310 also did six months later. The structural validity was assessed by confirmatory factor analysis, the item functioning by item response analysis, and reliability by Cronbach's alpha. Convergent validity and known-groups validity was studied using the PHQ-9 and a general health question. To assess responsiveness effect sizes were calculated. RESULTS: The results supported the unidimensionality and showed adequate item functioning, with somewhat age-related item differential functioning for the mobility dimension. Cronbach's alpha was 0.77. The EQ-5D-5L showed a high correlation with the PHQ-9 and general health. The more severe the depression level and the poorer the general health, the lower the EQ-5D-5L scores (p < 0.001). Responsiveness parameters showed moderate changes among "improved" patients. CONCLUSIONS: These findings support the adequate psychometric properties of the EQ-5D-5L in patients with major depression. It could be very useful for clinicians and researchers as an outcome measure and for use in economic evaluation.

Health Related Quality of Life in Major Depressive Disorder: evolution in time and factors associated.

Major Depressive Disorder (MDD) is the most prevalent mental disorder. We aimed to analyze which factors were associated to their Health-Related Quality of Life (HRQoL) perception in patients diagnosed of MDD and how they evolved over six months.

Abatacept in monotherapy vs combined in interstitial lung disease of rheumatoid arthritis-multicentre study of 263 Caucasian patients.

OBJECTIVE: To assess the efficacy and safety of abatacept (ABA) in monotherapy (ABAMONO) vs combined ABA [ABA plus MTX (ABAMTX) or ABA plus non-MTX conventional synthetic DMARDs (csDMARDs) (ABANON-MTX)] in RA patients with interstitial lung disease (ILD) (RA-ILD). METHODS: This was a restrospective multicentre study of RA-ILD Caucasian patients treated with ABA. We analysed in the three groups (ABAMONO, ABAMTX, ABANON-MTX) the following outcome variables: (i) dyspnoea; (ii) forced vital capacity (FVC) and diffusion capacity of the lung for the carbon monoxide (DLCO); (iii) chest high-resolution CT (HRCT); (iv) DAS28-ESR; (v) CS-sparing effect; and (vi) ABA retention and side-effects. Differences between basal and final follow-up were evaluated. Multivariable linear regression was used to assess the differences between the three groups. RESULTS: We studied 263 RA-ILD patients (mean ± s.d. age 64.6 ± 10 years) [ABAMONO (n = 111), ABAMTX (n = 46) and ABANON-MTX (n = 106)]. At baseline, ABAMONO patients were older (67 ± 10 years) and took higher prednisone dose [10 (interquartile range 5-15) mg/day]. At that time, there were no statistically significant differences in sex, seropositivity, ILD patterns, FVC and DLCO, or disease duration. Following treatment, in all groups, most patients experienced stabilization or improvement in FVC, DLCO, dyspnoea and chest HRCT as well as improvement in DAS28-ESR. A statistically significant difference between basal and final follow-up was only found in CS-sparing effect in the group on combined ABA (ABAMTX or ABANON-MTX). However, in the multivariable analysis, there were no differences in any outcome variables between the three groups. CONCLUSION: In Caucasian individuals with RA-ILD, ABA in monotherapy or combined with MTX or with other conventional-DMARDs seems to be equally effective and safe. However, a CS-sparing effect is only observed with combined ABA.

Response Mapping Methods to Estimate the EQ-5D-5L From the Western Ontario McMaster Universities Osteoarthritis in Patients With Hip or Knee Osteoarthritis.

OBJECTIVES: The mapping technique can estimate generic preference-based measure scores through a specific measure that cannot be used in economic evaluations. This study compared 2 response mapping methods to estimate EQ-5D-5L scores using the Western Ontario McMaster Universities Osteoarthritis (WOMAC). METHODS: The sample consisted of 758 patients with the hip or knee osteoarthritis recruited in baseline. Bayesian networks (BN) and multinomial logistic regression (ML) were used as response mapping models. Predictions were obtained using the 6-month follow-up as a validation sample. The mean absolute error, mean squared error, deviation from the root mean squared error and intraclass correlation coefficient were calculated as precision measures. RESULTS: There was 5.5% of missing data, which was removed. The mean age was 69.6 years (standard deviation = 10.5), with 61.6% of women. The BN model presented lower mean absolute error, mean squared error, root mean squared error and higher intraclass correlation coefficient than the ML model. Only the WOMAC items pain and physical function items were related with the EQ-5D-5L dimensions. CONCLUSION: BN response mapping models are more robust methods, with better prediction results, than ML models. The BN model also provided a graphic representation of the dependency relationships between the EQ-5D-5L dimensions and the different WOMAC items that could be useful in the clinical investigation of patients with hip or knee osteoarthritis.

Half-Sandwich Ru(p-cymene) Compounds with Diphosphanes: In Vitro and In Vivo Evaluation As Potential Anticancer Metallodrugs.

Ruthenium(II) complexes are currently considered attractive alternatives to the widely used platinum-based drugs. We present herein the synthesis and characterization of half-sandwich ruthenium compounds formulated as [Ru(p-cymene)(L)Cl][CF3SO3] (L = 1,1-bis(methylenediphenylphosphano)ethylene, 1; L = 1,1-bis(diphenylphosphano)ethylene, 2), which were characterized by elemental analysis, mass spectrometry, 1H and 31P{1H} NMR, UV-vis and IR spectroscopy, conductivity measurements and cyclic voltammetry. The molecular structures for both complexes were determined by single-crystal X-ray diffraction. Their cytotoxic activity was evaluated using the MTT assay against human tumor cells, namely ovarian (A2780) and breast (MCF7 and MDA-MB-231). Both complexes were active against breast adenocarcinoma cells, with complex 1 exhibiting a quite remarkable cytotoxicity in the submicromolar range. Interestingly, at concentrations equivalent to the IC50 values in the MCF7 cancer cells, complexes 1 and 2 presented lower cytotoxicity in normal human primary fibroblasts. The antiproliferative effects of 1 and 2 in MCF7 cells might be associated with the induction of reactive oxygen species (ROS), leading to a combined cell death mechanism via apoptosis and autophagy. Despite the fact that in vitro a partial intercalation between complexes and DNA was observed, no MCF7 cell cycle delay or arrest was observed, indicating that DNA might not be a direct target. Complexes 1 and 2 both exhibited a moderate to strong interaction with human serum albumin, suggesting that protein targets may be involved in their mode of action. Their acute toxicity was evaluated in the zebrafish model. Complex 1 (the most toxic of the two) exhibited a lethal toxicity LC50 value about 1 order of magnitude higher than any IC50 concentrations found for the cancer cell models used, highlighting its therapeutic relevance as a drug candidate in cancer chemotherapy.