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BACKGROUND: Previous studies suggest that dietary vitamin C is inversely associated with gastric cancer (GC), but most of them did not consider intake of fruit and vegetables. Thus, we aimed to evaluate this association within the Stomach cancer Pooling (StoP) Project, a consortium of epidemiological studies on GC. METHODS: Fourteen case-control studies were included in the analysis (5362 cases, 11,497 controls). We estimated odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for the association between dietary intake of vitamin C and GC, adjusted for relevant confounders and for intake of fruit and vegetables. The dose-response relationship was evaluated using mixed-effects logistic models with second-order fractional polynomials. RESULTS: Individuals in the highest quartile of dietary vitamin C intake had reduced odds of GC compared with those in the lowest quartile (OR: 0.64; 95% CI: 0.58, 0.72). Additional adjustment for fruit and vegetables intake led to an OR of 0.85 (95% CI: 0.73, 0.98). A significant inverse association was observed for noncardia GC, as well as for both intestinal and diffuse types of the disease. The results of the dose-response analysis showed decreasing ORs of GC up to 150-200 mg/day of vitamin C (OR: 0.54; 95% CI: 0.41, 0.71), whereas ORs for higher intakes were close to 1.0. CONCLUSIONS: The findings of our pooled study suggest that vitamin C is inversely associated with GC, with a potentially beneficial effect also for intakes above the currently recommended daily intake (90 mg for men and 75 mg for women).

Abstract Background Systematic reviews (SRs) are time-consuming and labor-intensive to perform. With the growing number of scientific publications, the SR development process becomes even more laborious. This is problematic because timely SR evidence is essential for decision-making in evidence-based healthcare and policymaking. Numerous methods and tools that accelerate SR development have recently emerged. To date, no scoping review has been conducted to provide a comprehensive summary of methods and ready-to-use tools to improve efficiency in SR production. Objective To present an overview of primary studies that evaluated the use of ready-to-use applications of tools or review methods to improve efficiency in the review process. Methods We conducted a scoping review. An information specialist performed a systematic literature search in four databases, supplemented with citation-based and grey literature searching. We included studies reporting the performance of methods and ready-to-use tools for improving efficiency when producing or updating a SR in the health field. We performed dual, independent title and abstract screening, full-text selection, and data extraction. The results were analyzed descriptively and presented narratively. Results We included 103 studies: 51 studies reported on methods, 54 studies on tools, and 2 studies reported on both methods and tools to make SR production more efficient. A total of 72 studies evaluated the validity (n = 69) or usability (n = 3) of one method (n = 33) or tool (n = 39), and 31 studies performed comparative analyses of different methods (n = 15) or tools (n = 16). 20 studies conducted prospective evaluations in real-time workflows. Most studies evaluated methods or tools that aimed at screening titles and abstracts (n = 42) and literature searching (n = 24), while for other steps of the SR process, only a few studies were found. Regarding the outcomes included, most studies reported on validity outcomes (n = 84), while outcomes such as impact on results (n = 23), time-saving (n = 24), usability (n = 13), and cost-saving (n = 3) were less often evaluated. Conclusion For title and abstract screening and literature searching, various evaluated methods and tools are available that aim at improving the efficiency of SR production. However, only few studies have addressed the influence of these methods and tools in real-world workflows. Few studies exist that evaluate methods or tools supporting the remaining tasks. Additionally, while validity outcomes are frequently reported, there is a lack of evaluation regarding other outcomes.

Abstract Regulators increasingly require clinical outcome assessment (COA) data for approval. COAs can be collected via questionnaires or digital health technologies (DHTs), yet no single resource provides a side-by-side comparison of tools that collect complementary or related COA measures. We propose how to align ontologies for actively collected and passively monitored COAs into a single framework to allow for rapid, evidence-based, and fit-for-purpose measure selection.

The climate change emergency calls for a reduction in energy consumption in all human activities and production processes. The radio broadcasting industry is no exception. However, reducing energy requirements by uniformly cutting the radiated power at every transmitter can potentially impair the quality of service. A careful evaluation and optimization study are in order. In this paper, by analyzing the Italian frequency modulation analog broadcasting service, we show that it is indeed possible to significantly reduce the energy consumption of the broadcasters without sacrificing the quality of the service, rather, even getting improvements.

Abstract Digital health technologies (DHTs) should expand access to clinical research to represent the social determinants of health (SDoH) across the population. The frequency of reporting participant SDoH data in clinical publications is low and is not known for studies that utilize DHTs. We evaluated representation of 11 SDoH domains in 126 DHT-enabled clinical research publications and proposed a framework under which these domains could be captured and subsequently reported in future studies. Sex, Race, and Education were most frequently reported (in 94.4%, 27.8%, and 20.6% of publications, respectively). The remaining 8 domains were reported in fewer than 10% of publications. Medical codes were identified that map to each of the proposed SDoH domains and the resulting resource is suggested to highlight that existing infrastructure could be used to capture SDoH data. An opportunity exists to increase reporting on the representation of SDoH among participants to encourage equitable and inclusive research progress through DHT-enabled clinical studies.

Introduction: Basilar artery occlusion (BAO) may be clinically occult due to variable and non-specific symptomatology. We evaluated the qualitative and quantitative determination of a hyperdense basilar artery (HDBA) on non-contrast computed tomography (NCCT) brain for the diagnosis of BAO.Methods: We conducted a case control study of patients with confirmed acute BAO vs a control group of suspected acute stroke patients without BAO. Two EM attending physicians, one third-year EM resident, and one medical student performed qualitative and quantitative assessments for the presence of a HDBA on axial NCCT images. Our primary outcome measures were sensitivity and specificity for BAO. Our secondary outcomes were inter-rater and intra-rater reliability of the qualitative and quantitative assessments.Results: We included 60 BAO and 65 control patients in our analysis. Qualitative assessment of the hyperdense basilar artery sign was poorly sensitive (54%–72%) and specific (55%–89%). Quantitative measurement improved the specificity of hyperdense basilar artery assessment for diagnosing BAO, with a threshold of 61.0–63.8 Hounsfield units demonstrating relatively high specificity of 85%–94%. There was moderate inter-rater agreement for the qualitative assessment of HDBA (Fleiss’ kappa statistic 0.508, 95% confidence interval: 0.435–0.581). Agreement improved for quantitative assessments, but still fell in the moderate range (Shrout-Fleiss intraclass correlation coefficient: 0.635). Intra-rater reliability for the quantitative assessments of the two attending physician reviewers demonstrated substantial consistency.Conclusion: Our results highlight the importance of carefully examining basilar artery density when interpreting the NCCT of patients with altered consciousness or other signs and symptoms concerning for an acute basilar artery occlusion. If the Hounsfield unit density of the basilar artery exceeds 61 Hounsfield units, BAO should be highly suspected.

Los venezolanos constituyen el colectivo de inmigrantes en España que más ha crecido en los últimos años, dirigiéndose a las zonas más urbanizadas del país, sobre todo Madrid, Canarias y Cataluña. El objetivo principal de este trabajo es estudiar y caracterizar el comportamiento y localización de la inmigración venezolana en la ciudad de Madrid, partiendo de la hipótesis de que las características sociales y económicas de dichos migrantes no constituyen un colectivo típico de migración como sucede con otros grupos de inmigrantes en España que migran solo por motivos económicos. La metodología utilizada combina el análisis cuantitativo de los datos estadísticos con técnicas cualitativas. Como aportación principal de la investigación se pueden destacar que las pautas de localización residencial de los venezolanos en Madrid no coinciden con las de los colectivos de inmigrantes con más presencia en la ciudad (ecuatorianos, colombianos, rumanos, marroquíes…), sino que se concentran en barrios de nordeste de la capital, junto con distritos de la almendra central como el de Salamanca.

Within the 9th European Framework programme, since 2021 EUROfusion is operating five tokamaks under the auspices of a single Task Force called ‘Tokamak Exploitation’. The goal is to benefit from the complementary capabilities of each machine in a coordinated way and help in developing a scientific output scalable to future largre machines. The programme of this Task Force ensures that ASDEX Upgrade, MAST-U, TCV, WEST and JET (since 2022) work together to achieve the objectives of Missions 1 and 2 of the EUROfusion Roadmap: i) demonstrate plasma scenarios that increase the success margin of ITER and satisfy the requirements of DEMO and, ii) demonstrate an integrated approach that can handle the large power leaving ITER and DEMO plasmas. The Tokamak Exploitation task force has therefore organized experiments on these two missions with the goal to strengthen the physics and operational basis for the ITER baseline scenario and for exploiting the recent plasma exhaust enhancements in all four devices (PEX: Plasma EXhaust) for exploring the solution for handling heat and particle exhaust in ITER and develop the conceptual solutions for DEMO. The ITER Baseline scenario has been developed in a similar way in ASDEX Upgrade, TCV and JET. Key risks for ITER such as disruptions and run-aways have been also investigated in TCV, ASDEX Upgrade and JET. Experiments have explored successfully different divertor configurations (standard, super-X, snowflakes) in MAST-U and TCV and studied tungsten melting in WEST and ASDEX Upgrade. The input from the smaller devices to JET has also been proven successful to set-up novel control schemes on disruption avoidance and detachment.

Autophagy is essential to endothelial cell homeostasis. Here the authors show that lipophagy in LEC supports fatty acid oxidation to sustain a mitochondrial-Prox1 gene expression circuit and promote response of LEC to lymphangiogenic mediators.

Abstract Background Risk prediction models incorporating single nucleotide polymorphisms (SNPs) could lead to individualized prevention of colorectal cancer (CRC). However, the added value of incorporating SNPs into models with only traditional risk factors is still not clear. Hence, our primary aim was to summarize literature on risk prediction models including genetic variants for CRC, while our secondary aim was to evaluate the improvement of discriminatory accuracy when adding SNPs to a prediction model with only traditional risk factors. Methods We conducted a systematic review on prediction models incorporating multiple SNPs for CRC risk prediction. We tested whether a significant trend in the increase of Area Under Curve (AUC) according to the number of SNPs could be observed, and estimated the correlation between AUC improvement and number of SNPs. We estimated pooled AUC improvement for SNP-enhanced models compared with non-SNP-enhanced models using random effects meta-analysis, and conducted meta-regression to investigate the association of specific factors with AUC improvement. Results We included 33 studies, 78.79% using genetic risk scores to combine genetic data. We found no significant trend in AUC improvement according to the number of SNPs (p for trend = 0.774), and no correlation between the number of SNPs and AUC improvement (p = 0.695). Pooled AUC improvement was 0.040 (95% CI: 0.035, 0.045), and the number of cases in the study and the AUC of the starting model were inversely associated with AUC improvement obtained when adding SNPs to a prediction model. In addition, models constructed in Asian individuals achieved better AUC improvement with the incorporation of SNPs compared with those developed among individuals of European ancestry. Conclusions Though not conclusive, our results provide insights on factors influencing discriminatory accuracy of SNP-enhanced models. Genetic variants might be useful to inform stratified CRC screening in the future, but further research is needed.

To investigate large library docking's ability to find molecules with joint activity against on-targets and selectivity versus antitargets, the dopamine D2 and serotonin 5-HT2A receptors were targeted, seeking selectivity against the histamine H1 receptor. In a second campaign, κ-opioid receptor ligands were sought with selectivity versus the μ-opioid receptor. While hit rates ranged from 40% to 63% against the on-targets, they were just as good against the antitargets, even though the molecules were selected for their putative lack of binding to the off-targets. Affinities, too, were often as good or better for the off-targets. Even though it was occasionally possible to find selective molecules, such as a mid-nanomolar D2/5-HT2A ligand with 21-fold selectivity versus the H1 receptor, this was the exception. Whereas false-negatives are tolerable in docking screens against on-targets, they are intolerable against antitargets; addressing this problem may demand new strategies in the field.

Membrane contact sites (MCS) between organelles of eukaryotic cells provide structural integrity and promote organelle homeostasis by facilitating intracellular signaling, exchange of ions, metabolites and lipids and membrane dynamics. Cataloguing MCS revolutionized our understanding of the structural organization of a eukaryotic cell, but the functional role of MSCs and their role in complex diseases, such as cancer, are only gradually emerging. In particular, the endoplasmic reticulum (ER)-mitochondria contacts (EMCS) are key effectors of non-vesicular lipid trafficking, thereby regulating the lipid composition of cellular membranes and organelles, their physiological functions and lipid-mediated signaling pathways both in physiological and diseased conditions. In this short review, we discuss key aspects of the functional complexity of EMCS in mammalian cells, with particular emphasis on their role as central hubs for lipid transport between these organelles and how perturbations of these pathways may favor key traits of cancer cells.

Abstract Tobacco smoking is the largest risk factor for developing chronic obstructive pulmonary disease (COPD), and is associated with hyperresponsiveness of airway smooth muscle (ASM). Chronic exposure to cigarette smoke (CS) leads to airway inflammation and remodelling. However, the direct effect of gaseous CS or CS extract (CSE) on human airway smooth muscle cell (hASMC) function remains poorly understood. This study investigated the acute effect of CS/CSE on calcium homeostasis, a key regulator of ASM physiology and pathophysiology. Primary hASMC were isolated from non-smoking donor lungs, and subjected to Ca2+ imaging studies. We found that both CS, and CSE, rapidly elevated cytosolic Ca2+ in hASMC through stimulation of plasmalemmal Ca2+ influx, but excluded store-operated and L-type Ca2+ channels as mediators of this effect. Using a specific pharmacological inhibitor, or shRNA-driven knockdown, we established that both CS and CSE stimulated Ca2+ influx in hASMC through the neurogenic pain receptor channel, transient receptor potential ankyrin 1 (TRPA1). CS/CSE-dependent, TRPA1-mediated Ca2+ influx led to myosin light-chain phosphorylation, a key process regulating ASM contractility. We conclude that TRPA1 is likely an important link between CS/CSE exposure and airway hyperresponsiveness, and speculate that acute CS/CSE-induced Ca2+ influx could lead to exacerbated ASM contraction and potentially initiate further chronic pathological effects of tobacco smoke.

Abstract Orai1 is a ubiquitously‐expressed plasma membrane Ca2+ channel that is involved in store‐operated Ca2+ entry (SOCE): a fundamental biological process that regulates gene expression, the onset of inflammation, secretion, and the contraction of airway smooth muscle (ASM). During SOCE, Ca2+ leaves the endoplasmic reticulum, which then stimulates a second, amplifying wave of Ca2+ influx through Orai1 into the cytoplasm. Short Palate LUng and Nasal epithelial Clone 1 (SPLUNC1; gene name BPIFA1) is a multi‐functional, innate defense protein that is highly abundant in the lung. We have previously reported that SPLUNC1 was secreted from epithelia, where it bound to and inhibited Orai1, leading to reduced SOCE and ASM relaxation. However, the underlying mechanism of action is unknown. Here, we probed the SPLUNC1‐Orai1 interactions in ASM and HEK293T cells using biochemical and imaging techniques. We observed that SPLUNC1 caused a conformational change in Orai1, as measured using Forster resonance energy transfer (FRET). SPLUNC1 binding also led to Nedd4‐2 dependent ubiquitination of Orai1. Moreover, SPLUNC1 internalized Orai1 to lysosomes, leading to Orai1 degradation. Thus, we conclude that SPLUNC1 is an allosteric regulator of Orai1. Our data indicate that SPLUNC1‐mediated Orai1 inhibition could be utilized as a therapeutic strategy to reduce SOCE.

Morphine is an alkaloid from the opium poppy used to treat pain. The potentially lethal side effects of morphine and related opioids-which include fatal respiratory depression-are thought to be mediated by μ-opioid-receptor (μOR) signalling through the β-arrestin pathway or by actions at other receptors. Conversely, G-protein μOR signalling is thought to confer analgesia. Here we computationally dock over 3 million molecules against the μOR structure and identify new scaffolds unrelated to known opioids. Structure-based optimization yields PZM21-a potent Gi activator with exceptional selectivity for μOR and minimal β-arrestin-2 recruitment. Unlike morphine, PZM21 is more efficacious for the affective component of analgesia versus the reflexive component and is devoid of both respiratory depression and morphine-like reinforcing activity in mice at equi-analgesic doses. PZM21 thus serves as both a probe to disentangle μOR signalling and a therapeutic lead that is devoid of many of the side effects of current opioids.

La educación constituye uno de los pilares fundamentales de la sociedad y se ve afectada de forma compleja por los fenómenos migratorios. Esto supone un doble reto, tanto para el sistema educativo del país receptor como para los propios estudiantes y sus familias. En este trabajo se evalúa si el éxito educativo español es diferente según el lugar de origen y si los distintos colectivos de jóvenes de origen inmigrante sufren una estigmatización en relación con su probable progresión académica por parte de la sociedad, en general, y del profesorado, en particular. La metodología utilizada ha sido una aproximación multimétodo; utilizando datos recabados del INE y el informe PISA (2015, 2018), los cuales se han analizado con técnicas estadísticas básicas, pruebas de normalidad de las variables, así como el contraste de hipótesis de la τ de Student de comprobación de igualdad de medias. Se trabajó, con técnicas cualitativas de observación participante y entrevista a personal de la comunidad educativa para valorar el nivel de integración de los inmigrantes en el sistema educativo español y su grado de satisfacción. Los resultados obtenidos muestran que el fracaso escolar de los jóvenes inmigrantes es un fenómeno que se da en todo el ámbito nacional. El profesorado presenta dificultades para enseñar en aulas donde hay mayor número de alumnos con problemas de comprensión del idioma, con niveles educativos más dispares, mayores diferencias culturales y, sobre todo, una cierta tendencia a la formación de grupos de alumnos de la misma nacionalidad con problemas de integración en el aula. Las políticas públicas deberían responder a esta problemática de fracaso escolar, discriminación e integración en las aulas y las investigaciones deberían profundizar en esta línea. Abstract Education is one of the fundamental pillars of society and it’s affected complexly by the migratory phenomenon. This is a double challenge for the education system of the host country as it is the students themselves and their families. In this project, we evaluated whether the Spanish educational success is different according to the place of origin and whether the different groups of young of immigrants suffer any stigma in relation to their likely progression academically on behalf of the society, in general, and from teachers, in particular. The methodology used has been a multi-method approach; using data collected from the INE and the PISA report (2015, 2018), which have been analyzed with basic statistical techniques, tests of normality of the variables, as well as the hypothesis contrast of the τ of Student of equality of means. We worked with qualitative techniques of participant observation and interviews with staff of the education community to assess the level of integration of immigrants in the Spanish education system and their degree of satisfaction. The results obtained show that the school failure of young immigrants is a phenomenon that occurs throughout the country. The teaching staff show difficulties in teaching in classrooms where there are more students with language comprehension problems, with dramatically varying education levels, greater cultural differences and, above all, a certain tendency towards the formation of groups of students of the same nationality with problems of integration in the classroom. Public policies should respond to this problem of school failure, discrimination and integration in classrooms and research should be more extensive in this area.

Metastatic cells can mimic many of the phenotypic behaviors of embryonic cells. Here, the authors generate a melanoblast-specific transcriptome using a genetically engineered mouse model and identify KDELR3 as a pro-metastasis gene in melanoma.

We recently reported that the ER stress kinase PERK regulates ER-mitochondria appositions and ER– plasma membrane (ER-PM) contact sites, independent of its canonical role in the unfolded protein response. PERK regulation of ER-PM contacts was revealed by a proximity biotinylation (BioID) approach and involved a dynamic PERK-Filamin A interaction supporting the formation of ER-PM contacts by actin-cytoskeleton remodeling in response to depletion of ER-Ca 2+ stores. In this report, we further interrogated the PERK BioID interactome by validating through co-IP experiments the interaction between PERK and two proteins involved in Ca 2+ handling and ER-mitochondria contact sites. These included the vesicle associated membrane (VAMP)-associated proteins (VAPA/B) and the main ER Ca 2+ pump sarcoplasmic/endoplasmic reticulum Ca ATPase 2 (SERCA2). These data identify new putative PERK interacting proteins with a crucial role in membrane contact sites and Ca 2+ signaling further supporting the uncanonical role of PERK in Ca 2+ signaling through membrane contact sites (MCSs).