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There is an increasing acknowledgment that suicidal behaviors are negatively affected by school failure in adolescents and young adults. However, no systematic reviews with meta-analysis have been performed to evaluate the strength of this association. We assessed the magnitude of association of school failure as risk factor for suicide behavior in adolescents and young adults. Six international databases were searched up until January 2017. Inclusion criteria were: (1) assessment of suicide attempt or suicide; (2) case-control or cohort studies; (3) subjects aged 12-26 years; (4) school failure evaluated, which includes low academic performance, school dropout, school expulsion, and grade repetition. Random effect models were used; population attributable risks (PARs) were estimated. From 26,883 potentially eligible articles, 14 (62,298 individuals) were included. Meta-analyses could only be performed for suicide attempt. A history of school dropout (OR 6.44, 95% CI 3.03-13.65), low academic performance (OR 1.48, 95% CI 1.22-1.81), and school failure (OR 1.98, 95% CI 1.49-2.64) were significant risks of suicide attempts. Highest PAR estimates were 9.9% for school dropout, 5.1% for low academic performance, and 6.7% for any school failure. Only one study has been found for suicide, but results suggest an association with school dropout. Results show that the students who had school failure are at higher risk of suicide attempt and probably for suicide. The development of effective programs to prevent suicidal behaviors in educational settings may be an effective strategy to reduce these behaviors. However, reliable conclusions from this review are limited by the small amount of included studies for analysis.

Objective: SARS-CoV-2 outbreak has a negative psychological impact among general population. Data comparing mental health status before and during the outbreak is needed. The BIOVAL-D-COVID-19 study assess the socio-economic and psychological impact of the COVID-19 pandemic and lockdown in a representative sample of non-institutionalized Spanish adult population, and estimate the incidence of mental health disorders, including suicidal behaviours, and possible related factors. Method: Observational longitudinal study including two online surveys: baseline survey (T0) performed during 2019 and follow-up survey (T1) conducted 12-month later. The latter included nine sections: socio-demographic, health status, mental health, employment conditions and status, material deprivation, use of healthcare services, intimate partner violence and resilience. Four of the nine sections are administered in T0 and T1 assessments. Longitudinal data analyses will estimate adjusted incidence rates of mental health disorders using Poisson regression models. Risk and protective factors will be analysed through multiple logistic regression models. Resumen: Objetivo: el estudio BIOVAL-D-COVID-19 evaluará el impacto socioeconómico y psicológico de la pandemia de COVID-19 y del confinamiento en una muestra representativa de población española adulta no institucionalizada, y estimará la incidencia de trastornos de salud mental, incluida la conducta suicida, y los posibles factores relacionados. Métodos: estudio longitudinal que incluye dos encuestas online: la encuesta basal (T0) realizada durante 2019 y la encuesta de seguimiento (T1) realizada 12 meses después. Esta última tiene nueve secciones: variables sociodemográficas, estado de salud general, salud mental, condiciones laborales y estatus laboral, privación material, uso de servicios de salud, violencia de pareja y resiliencia. Cuatro de las nueve secciones se administran en ambas encuestas (T0 y T1). Se utilizarán modelos de regresión de Poisson para el análisis longitudinal de las tasas de incidencia ajustadas de trastornos de salud mental. Los factores de riesgo y de protección se analizarán mediante modelos de regresión logística múltiple.

ABSTRACT Bacteria have evolved a sophisticated array of signal transduction systems that allow them to adapt their physiology and metabolism to changing environmental conditions. Typically, these systems recognize signals through dedicated ligand binding domains (LBDs) to ultimately trigger a diversity of physiological responses. Nonetheless, an increasing number of reports reveal that signal transduction receptors also bind antagonists to inhibit responses mediated by agonists. The mechanisms by which antagonists block the downstream signaling cascade remain largely unknown. To advance our knowledge in this field, we used the LysR-type transcriptional regulator AdmX as a model. AdmX activates the expression of an antibiotic biosynthetic cluster in the rhizobacterium Serratia plymuthica. AdmX specifically recognizes the auxin phytohormone indole-3-acetic acid (IAA) and its biosynthetic intermediate indole-3-pyruvic acid (IPA) as signals. However, only IAA, but not IPA, was shown to regulate antibiotic production in S. plymuthica. Here, we report the high-resolution structures of the LBD of AdmX in complex with IAA and IPA. We found that IAA and IPA compete for binding to AdmX. Although IAA and IPA binding does not alter the oligomeric state of AdmX, IPA binding causes a higher degree of compactness in the protein structure. Molecular dynamics simulations revealed significant differences in the binding modes of IAA and IPA by AdmX, and the inspection of the three-dimensional structures evidenced differential agonist- and antagonist-mediated structural changes. Key residues for auxin binding were identified and an auxin recognition motif defined. Phylogenetic clustering supports the recent evolutionary emergence of this motif specifically in plant-associated enterobacteria. IMPORTANCE Although antagonists were found to bind different bacterial signal transduction receptors, we are still at the early stages of understanding the molecular details by which these molecules exert their inhibitory effects. Here, we provide insight into the structural changes resulting from the binding of an agonist and an antagonist to a sensor protein. Our data indicate that agonist and antagonist recognition is characterized by small conformational differences in the LBDs that can be efficiently transmitted to the output domain to modulate the final response. LBDs are subject to strong selective pressures and are rapidly evolving domains. An increasing number of reports support the idea that environmental factors drive the evolution of sensor domains. Given the recent evolutionary history of AdmX homologs, as well as their narrow phyletic distribution within plant-associated bacteria, our results are in accordance with a plant-mediated evolutionary process that resulted in the emergence of receptor proteins that specifically sense auxin phytohormones.

Summary: The contribution of cross-presenting XCR1+ dendritic cells (DCs) and SIRPα+ DCs in maintaining T cell function during exhaustion and immunotherapeutic interventions of chronic infections remains poorly characterized. Using the mouse model of chronic LCMV infection, we found that XCR1+ DCs are more resistant to infection and highly activated compared with SIRPα+ DCs. Exploiting XCR1+ DCs via Flt3L-mediated expansion or XCR1-targeted vaccination notably reinvigorates CD8+ T cells and improves virus control. Upon PD-L1 blockade, XCR1+ DCs are not required for the proliferative burst of progenitor exhausted CD8+ T (TPEX) cells but are indispensable to sustain the functionality of exhausted CD8+ T (TEX) cells. Combining anti-PD-L1 therapy with increased frequency of XCR1+ DCs improves functionality of TPEX and TEX subsets, while increase of SIRPα+ DCs dampened their proliferation. Together, this demonstrates that XCR1+ DCs are crucial for the success of checkpoint inhibitor-based therapies through differential activation of exhausted CD8+ T cell subsets.

Serrated polyposis syndrome (SPS) is one of the most frequent polyposis syndromes characterized by an increased risk for developing colorectal cancer (CRC). Although SPS etiology has been mainly associated with environmental factors, germline predisposition to SPS could also be relevant for cases with familial aggregation or a family history of SPS/CRC. After whole-exome sequencing of 39 SPS patients from 16 families, we identified a heterozygous germline frameshift variant in the POLD1 gene (c.1941delG, p.(Lys648fs*46)) in a patient with SPS and CRC. Tumor presented an ultra-hypermutated phenotype and microsatellite instability. The POLD1 germline variant segregated in three additional SPS-affected family members. We attempted to create yeast and cellular models for this variant but were no viable. Alternatively, we generated patient-derived organoids (PDOs) from healthy rectal tissue of the index case, as well as from a control donor. Then, we challenged PDOs with a DNA-damaging agent to induce replication stress. No significant differences were observed in the DNA damage response between control and POLD1-Lys648fs PDOs, nor specific mutational signatures were observed. Our results do not support the pathogenicity of the analyzed POLD1 frameshift variant. One possible explanation is that haplosufficiency of the wild-type allele may be compensating for the absence of expression of the frameshift allele. Overall, future work is required to elucidate if functional consequences could be derived from POLD1 alterations different from missense variants in their proofreading domain. To our knowledge, our study presents the first organoid model for germline POLD1 variants and establishes the basis for its use as a model for disease in SPS, CRC and other malignancies.

The persistence of HIV reservoirs, including latently infected, resting CD4+ T cells, is the major obstacle to cure HIV infection. CD32a expression was recently reported to mark CD4+ T cells harboring a replication-competent HIV reservoir during antiretroviral therapy (ART) suppression. We aimed to determine whether CD32 expression marks HIV latently or transcriptionally active infected CD4+ T cells. Using peripheral blood and lymphoid tissue of ART-treated HIV+ or SIV+ subjects, we found that most of the circulating memory CD32+ CD4+ T cells expressed markers of activation, including CD69, HLA-DR, CD25, CD38, and Ki67, and bore a TH2 phenotype as defined by CXCR3, CCR4, and CCR6. CD32 expression did not selectively enrich for HIV- or SIV-infected CD4+ T cells in peripheral blood or lymphoid tissue; isolated CD32+ resting CD4+ T cells accounted for less than 3% of the total HIV DNA in CD4+ T cells. Cell-associated HIV DNA and RNA loads in CD4+ T cells positively correlated with the frequency of CD32+ CD69+ CD4+ T cells but not with CD32 expression on resting CD4+ T cells. Using RNA fluorescence in situ hybridization, CD32 coexpression with HIV RNA or p24 was detected after in vitro HIV infection (peripheral blood mononuclear cell and tissue) and in vivo within lymph node tissue from HIV-infected individuals. Together, these results indicate that CD32 is not a marker of resting CD4+ T cells or of enriched HIV DNA-positive cells after ART; rather, CD32 is predominately expressed on a subset of activated CD4+ T cells enriched for transcriptionally active HIV after long-term ART.

Objectives Tocilizumab showed trends for improving skin fibrosis and prevented progression of lung fibrosis in systemic sclerosis (SSc) in randomised controlled clinical trials. We aimed to assess safety and effectiveness of tocilizumab in a real-life setting using the European Scleroderma Trial and Research (EUSTAR) database.Methods Patients with SSc fulfilling the American College of Rheumatology (ACR)/EULAR 2013 classification criteria, with baseline and follow-up visits at 12±3 months, receiving tocilizumab or standard of care as the control group, were selected. Propensity score matching was applied. Primary endpoints were the modified Rodnan skin score (mRSS) and FVC at 12±3 months compared between the groups. Secondary endpoints were the percentage of progressive/regressive patients for skin and lung at 12±3 months.Results Ninety-three patients with SSc treated with tocilizumab and 3180 patients with SSc with standard of care fulfilled the inclusion criteria. Comparison between groups did not show significant differences, but favoured tocilizumab across all predefined primary and secondary endpoints: mRSS was lower in the tocilizumab group (difference −1.0, 95% CI −3.7 to 1.8, p=0.48). Similarly, FVC % predicted was higher in the tocilizumab group (difference 1.5 (−6.1 to 9.1), p=0.70). The percentage of progressive/regressive patients favoured tocilizumab over controls. These results were robust regarding the sensitivity analyses. Safety analysis confirmed previously reported adverse event profiles.Conclusion Although this large, observational, controlled, real-life EUSTAR study did not show significant effectiveness of tocilizumab on skin and lung fibrosis, the consistency of direction of all predefined endpoints generates hypothesis for potential effectiveness in a broader SSc population.

Introduction: Regardless corticosteroids are recommended for the treatment of organizing pneumonia there is limited evidence supporting this practice. Thus, we performed a systematic review of the literature on systemic corticosteroid treatment for organizing pneumonia. Methods: A search was implemented in the PubMed database (Medline) for articles published in the last 20 years. Those studies with incomplete or insufficient data and case reports were excluded. We collected data including: demographics, clinical data, diagnostic procedures, aetiology, treatment regimen (drug, posology, duration, response) and evolution. Results: A total of 135 publications were selected and finally 13 studies with 849 patients were included in the review: 12 retrospective observational studies and a single prospective observational study. Most of the patients were started on treatment with systemic corticosteroids – a total of 627 (30–100% depending on the series), but there was a great heterogeneity regarding drug, doses and duration. On those that started treatment, 226 (36%) presented a relapse of the disease during follow-up. Only one study provided information regarding treatment side-effects. Conclusion: The findings of this systematic review show the low quality data supporting the use of corticosteroids for the treatment of organizing pneumonia. This highlights a need to undertake appropriately designed studies to investigate which is the most appropriate treatment regimen that trades off benefits and risks of prolonged corticosteroid administration. Resumen: Introducción: Aunque los corticosteroides están recomendados para tratar la neumonía organizada, hay pocos datos que respalden esta práctica, por lo cual efectuamos una revisión sistemática de la bibliografía sobre el tratamiento con corticosteroides sistémicos para la neumonía organizada. Métodos: Se hizo una búsqueda en la base de datos PubMed (Medline) de artículos publicados en los últimos 20 años. Se descartaron los estudios con datos y casos clínicos incompletos o insuficientes. Los datos que recabamos abarcaron: datos demográficos, datos clínicos, técnicas diagnósticas, etiología, pauta terapéutica (fármaco, posología, duración, respuesta) y evolución. Resultados: Se eligieron 135 publicaciones en total y se incorporaron finalmente a la revisión 13 estudios con 849 pacientes: 12 estudios observacionales retrospectivos y un solo estudio observacional prospectivo. La mayor parte de los pacientes habían comenzado el tratamiento con corticosteroides sistémicos, un total de 627 (30%-100% en función de la serie), pero la duración, las dosis y el fármaco manifestaron una gran heterogeneidad. Entre los que habían empezado el tratamiento, 226 (36%) presentaron una recidiva de la enfermedad durante el seguimiento. Solo en un estudio se ofreció información sobre los efectos adversos del tratamiento. Conclusión: Los resultados de esta revisión ponen de manifiesto la escasa calidad de los datos sobre el tratamiento de la neumonía organizada con corticosteroides. Este hecho destaca la necesidad de emprender estudios diseñados correctamente para investigar la pauta terapéutica más adecuada que compense los riesgos y beneficios de la administración prolongada de corticosteroides.

This study investigated the role of IL-35 in systemic sclerosis (SSc) patients, focusing on CD4+ T cell response and immunomodulatory cytokine production. By comparing the cytokine levels in healthy donors (HD) and SSc patients using ELISAs, we found a significantly lower plasma IL-35 concentration in the SSc patients (52.1 ± 5.6 vs. 143 ± 11.1, p < 0.001). Notably, the IL-35 levels showed a negative correlation with TGF-β (p < 0.001) and IL-17 (p = 0.04). Assessing the IL-35R expression across cell types in the SSc patients and HDs via flow cytometry, we found higher levels on monocytes (40.7 + 5.7 vs. 20.3 ± 1.9, p < 0.001) and lower levels on CD8+ T cells (61.8 ± 9.2 vs. 83.4 ± 0.8, p < 0.05) in the SSc patients. The addition of recombinant IL-35 to stimulated peripheral blood mononuclear cells reduced the IL-17+CD4+ T cell percentage (9.0 ± 1.5 vs. 4.8 ± 0.7, p < 0.05) and increased the IL-35+CD4+ T percentage (4.1 ± 2.3 vs. 10.2 ± 0.8, p < 0.001). In a Treg:Tresponder cell Sco-culture assay with HD and SSc samples, rIL35 decreased the cell proliferation and levels of IL-17A (178.2 ± 30.5 pg/mL vs. 37.4 ± 6.4 pg/mL, p < 0.001) and TGF-β (4194 ± 777 pg/mL vs. 2413 ± 608 pg/mL, p < 0.01). Furthermore, we observed a positive correlation between the modified Rodnan skin score (mRSS) and TGF-β (p < 0.001), while there was a negative correlation between mRSS and IL-35 (p = 0.004). Interestingly, higher levels of plasmatic IL-35 were detected in individuals with limited disease compared to those with diffuse disease (60.1 ± 8.0 vs. 832.3 ± 4.1, p < 0.05). These findings suggest that IL-35 exhibits anti-inflammatory properties in SSc and it may serve as a marker for disease severity and a therapeutic target.

Non-small-cell lung cancer patients with activating epidermal growth factor receptor (EGFR) mutations typically benefit from EGFR tyrosine kinase inhibitor treatment. However, virtually all patients succumb to acquired EGFR tyrosine kinase inhibitor resistance that occurs via diverse mechanisms. The diversity and unpredictability of EGFR tyrosine kinase inhibitor resistance mechanisms presents a challenge for developing new treatments to overcome EGFR tyrosine kinase inhibitor resistance. Here, we show that Akt activation is a convergent feature of acquired EGFR tyrosine kinase inhibitor resistance, across a spectrum of diverse, established upstream resistance mechanisms. Combined treatment with an EGFR tyrosine kinase inhibitor and Akt inhibitor causes apoptosis and synergistic growth inhibition in multiple EGFR tyrosine kinase inhibitor-resistant non-small-cell lung cancer models. Moreover, phospho-Akt levels are increased in most clinical specimens obtained from EGFR-mutant non-small-cell lung cancer patients with acquired EGFR tyrosine kinase inhibitor resistance. Our findings provide a rationale for clinical trials testing Akt and EGFR inhibitor co-treatment in patients with elevated phospho-Akt levels to therapeutically combat the heterogeneity of EGFR tyrosine kinase inhibitor resistance mechanisms.EGFR-mutant non-small cell lung cancer are often resistant to EGFR tyrosine kinase inhibitor treatment. In this study, the authors show that resistant tumors display high Akt activation and that a combined treatment with AKT inhibitors causes synergistic tumour growth inhibition in vitro and in vivo.

Coronavirus disease 2019 (COVID-19) has rapidly expanded worldwide. Currently, there are no biomarkers to predict respiratory worsening in patients with mild to moderate COVID-19 pneumonia. Small studies explored the use of Krebs von de Lungen-6 circulating serum levels (sKL-6) as a prognostic biomarker of the worsening of COVID-19 pneumonia. We aimed at a large study to determine the prognostic value of sKL-6 in predicting evolving trends in COVID-19. We prospectively analyzed the characteristics of 836 patients with COVID-19 with mild lung disease on admission. sKL-6 was obtained in all patients at least at baseline and compared among patients with or without respiratory worsening. The receiver operating characteristic curve was used to find the optimal cutoff level. A total of 159 (19%) patients developed respiratory worsening during hospitalization. Baseline sKL-6 levels were not higher in patients who had respiratory worsening (median {IQR} 315.5 {209–469} vs. 306 {214–423} U/ml p = 0.38). The last sKL-6 and the change between baseline and last sKL-6 were higher in the respiratory worsening group (p = 0.02 and p < 0.0001, respectively). The best sKL-6 cutoff point for respiratory worsening was 497 U/ml (area under the curve 0.52; 23% sensitivity and 85% specificity). sKL-6 was not found to be an independent predictor of respiratory worsening. A conditional inference tree (CTREE) was not useful to discriminate patients at risk of worsening. We found that sKL-6 had a low sensibility to predict respiratory worsening in patients with mild-moderate COVID-19 pneumonia and may not be of use to assess the risk of present respiratory worsening in inpatients with COVID-19 pneumonia.

Abstract Colorectal cancer (CRC) is a complex disease that can be caused by a spectrum of genetic variants ranging from low to high penetrance changes, that interact with the environment to determine which individuals will develop the disease. In this study, we sequenced 20 early-onset CRC patients to discover novel genetic variants that could be linked to the prompt disease development. Eight genes, CHAD, CHD1L, ERCC6, IGTB7, PTPN13, SPATA20, TDG and TGS1, were selected and re-sequenced in a further 304 early onset CRC patients to search for rare, high-impact variants. Although we found a recurring truncating variant in the TDG gene shared by two independent patients, the results obtained did not help consolidate any of the candidates as promising CRC predisposing genes. However, we found that potential risk alleles in our extended list of candidate variants have a tendency to appear at higher numbers in younger cases. This supports the idea that CRC onset may be oligogenic in nature and may show molecular heterogeneity. Further, larger and robust studies are thus needed to unravel the genetics behind early-onset CRC development, coupled with novel functional analyses and omic approaches that may offer complementary insight.

Abstract Background Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood. Methods We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models. Results In sex-specific MR analyses, higher BMI (per 4.2 kg/m2) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m2) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles. Conclusions Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.

Data in this article provides detailed information on the microbial dynamics and degradation performances in two full-scale anaerobic digesters operated in parallel for 476 days. One of them was kept at 35 °C for the whole experiment, while the other was submitted to sub-mesophilic (25 °C) conditions between days 123 and 373. Sludge samples were collected from both digesters at days 0, 80, 177, 218, 281, 353, and 462. The provided data include the operational conditions of the digesters and the characterization of the sludge samples at the physicochemical level, indicative of the digesters’ degradation performance. It also includes the characterization of the sludge samples at the multiomics level (16S rRNA gene sequencing, metagenomics, and metabolomics profiling), to decipher the changes in the microbial structure and molecular activity. The 16S rDNA gene sequencing, metagenomics, and metabolomics data were generated using an IonTorrent PGM sequencer, an Illumina NextSeq 500 sequencer, and LTQ-Orbitrap XL mass spectrometer respectively. The 16S rDNA gene raw data and the metagenomics data have been deposited in the BioProject PRJEB49115, in the ENA database (https://www.ebi.ac.uk/ena/browser/view/PRJEB49115). The metabolomics data has been deposited at the Metabolomics Workbench, with study id ST002004 (DOI: 10.21228/M8JM6B). The data can be used as a source for comparisons with other studies working with data from full-scale anaerobic digesters, especially for those investigating the effect of the temperature modification. The data is associated with the research article “Metataxonomics, metagenomics, and metabolomics analysis of the influence of temperature modification in full-scale anaerobic digesters” (Puig-Castellví et al [1]).

La protección del bienestar animal es hoy día una preocupación universal. Sin embargo, su garantía sigue siendo una laguna que aún no ha cubierto el derecho internacional. Desde la dimensión ambiental del modelo de paz transformadora, el desarrollo del Buen Vivir es fundamental para entender nuestras relaciones sociales y nuestras interacciones con el resto de seres vivos. Por ello, trataremos de entender qué papel desempeñan los animales y, en concreto, los perros en la cultura de paz. Veremos cómo su labor puede resultar de gran trascendencia en ámbitos de actuación pública esenciales en cualquier modelo de sociedad, como son la sanidad, la salud o las emergencias. Posteriormente, destacaremos algunas experiencias latinoamericanas que ilustran ese cambio en la concepción del bienestar animal y su aportación a las sociedades actuales. Estas experiencias llaman al optimismo y que pueden ser propulsoras del cambio social hacia modelos de convivencia que comporten un beneficio común para animales y humanos, en las interacciones que puedan generarse entre ambos. Finalizaremos exponiendo algunas conclusiones y reflexiones generales que inciten a futuros investigadores a trabajar sobre esta misma materia. Queda mucho camino por recorrer, pero ya hemos empezado a andar.

Physical activity has been linked to lower risks of colorectal and breast cancer. Here, the authors present a Mendelian randomisation analysis supporting a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer.

Mealworm, TM (Tenebrio molitor), and black soldier fly, BSF (Hermetia illucens) are of special interest for food and feed applications due to their environmental benefits such as low water and land requirements, low greenhouse gas emissions, and high feed-conversion efficiency. This study assesses the use of ultrafiltration (UF) to fractionate protein concentrates from TM and BSF (TMPC, BSFPC) in order to enhance emulsifying and foaming properties. A 30 kDa regenerated cellulose acetate membrane enabled the separation of concentrate and permeate fractions for both insect proteins from two different initial feed concentrations (10 and 7.5 g/L). Permeate flux and protein transmission behave differently depending on the insect type and the initial concentration; while for TMPC permeate flux increases with a decrease in the initial protein concentration, it is not affected for BSFPC. The existing membrane cleaning protocols are suitable for recovering water flux after UF of insect proteins, enabling membrane re-use. Emulsifying activity is maintained for all the TMPC fractions, but it is significantly lower for the permeate fractions of BSFPC. Foaming properties are maintained for all the UF fractions of BSFPC and the ones from 7.5 g/L TMPC. Acidic solubilization leads to a fraction with enhanced emulsifying capacity and one with higher foaming capacity than the original for BSFPC. This study opens the door to membrane technology for insect protein fractionation, which has not been studied so far and has already provided useful solutions for other animal and plant proteins.

The present study aims to assess the prevalence of autism spectrum disorder (ASD) in preschool and school-age children following a two-phase procedure. The screening phase was performed on a sample of 5555 children taking into account parent and teacher information. The individual assessment included the ADI-R, ADOS-2 and Wechsler scales. The estimated prevalence was 1.55% in preschoolers and 1.00% in school-age children. Between 1.84 and 2.59% of the children exhibited subclinical diagnosis. The male-to-female ratio was around 4:1. Most of the children exhibited mild and moderate nuclear symptoms, and the girls showed less severe communication problems. Previous diagnosis was found in 62-71% of the children. Prevalence estimates are close to the 1% international ratings and much higher than previous national reports suggested.

Strategies for the early detection of autism spectrum disorders (ASD) in people with intellectual developmental disorder (IDD) are urgently needed, but few specific tools have been developed. The present study examines the psychometric properties of the EVTEA-DI, a Spanish adaptation of the PDD-MRS, in a large randomized sample of 979 adults with IDD. Factorial solution analysis suggested a three-factor solution (stereotyped behavior, communication, and social behavior). The EVTEA-DI showed good reliability and convergent validity when compared to the Childhood Autism Rating Scale. Discriminative validity analysis resulted in an acceptable global sensitivity of 70% and a high specificity of 90%. The EVTEA-DI proved to be a valid screening tool in ASD assessment of the adult Spanish population with IDD.

E Wayne Ross is professor at the University of British Columbia (Canada). He is interested in the influence of social and institutional contexts on teachers’ practice as well as the role of curriculum and teaching in building a democratic society in the face of antidemocratic impulses of greed, individualism, and intolerance. Xosé Manuel Souto is professor at the University of Valencia (Spain), in the department of social and experimental sciences education. He directs the Gea-Clío educational innovation group that has developed, for the past thirty years, its work in the fields of teacher training, creation of curricular material and educational research.

Critical citizenship education must consider the global and digital context in which we live. Digital media and global processes have a decisive influence on people’s daily lives. However, digital literacy programs rarely go beyond teaching technological skills. Similarly, critical thinking approaches to education focus on developing cognitive skills, omitting the weight of values and emotions in decision making. This research analyses Spanish secondary school students’ narratives and reflections about two publications on Twitter that present biased information to encourage undemocratic attitudes. The results show that most students are far from being critical of the information they read on the internet, and they easily fall into the trap of defending undemocratic discourses.

La didàctica de les ciències socials i la didàctica de la llengua i la literatura estan unides per un fort vincle que es remunta a l’origen d’ambdues àrees. El desenvolupament del pensament crític i de la literacitat crítica ha estat -i segueix sent- un dels elements centrals de les seves línies de recerca. Aquestes sempre han tingut en l’horitzó la formació d’una ciutadania global, reflexiva i crítica, capaç de desmantellar els relats de l’odi presents en els mitjans i en les xarxes socials, llegint més enllà de les línies i de les fonts d’informació, i analitzant textos, imatges, vídeos, i altres productes culturals per tal d’ identificar ideologies i poder comprendre i enfrontar els problemes socials passats i presents, i projectar-se cap al futur

Neuroblastoma is the most common abdominal solid tumour in childhood. Its removal implies a complex surgery that requires surgical experience due to the usual encassement of major abdominal blood vessels. Standard surgical planning is based on CT or MRI images. However, in complex cases, normal anatomy is altered and it is dificult to interpret. 3D virtual planning and 3D Printing (3DP) can overcome this difficulties of comprehension. The most common 3DP technology used for this cases is material jetting. Nevertheless, this technology is very expensive and cannot be widely used. Consequently, its use is limited. The present study seeks to introduce the possibility of reducing costs whilst mantaining the quality of the 3D printed protypes. A full-process of a neuroblastoma case using hybrid manufacturing combining some FFF and some SLS 3D printed parts is presented. The two processes are carried out separately and then joined in a final assembly. The cost of the prototype was 347 €, which is significantly lower than a prototype 3D printed by material jetting.

Using cervical explant models and cervical tissue from ART-suppressed HIV+ women, the authors here show that resident memory T cells (TRM) in the cervical mucosa are preferentially infected and harbor more viral DNA, RNA and protein than non-TRM, suggesting that TRM may serve as viral reservoir in the cervical mucosa.

Here, the authors identify B lymphocyte antigen CD20 as a marker for HIV-infected T cells and provide evidence for the potential use of anti-CD20 antibodies in combination with latency reversing agents for depletion of viral reactivated CD4 T cells in patients on antiretroviral therapy.

Non-small cell lung cancer with EGFR mutations are known to develop resistance to EGFR tyrosine kinase inhibitors. Here, the authors show AURKB activation to be associated with resistance in EGFR mutant lung cancer cells, and that AURKB is a therapeutic target in resistant tumours that lack the p.T790M or other acquired mutations.

Introduction Clozapine is the most effective antipsychotic for treatment resistant schizophrenia but adverse reactions to clozapine include neutropenia. Patients with COVID-19 infection frequently experience lymphopenia, but not neutropenia.The impact of clozapine treatment in the presence of COVID-19 is unknown Objectives Show 2 cases of neutropenia in patients treated with long-term clozapine during COVID-19 infection. Methods Subjects: 48 admitted patients to a long-stay psychiatric unit. COVID-19 infection confirmed by positive nasopharyngeal swab for viral ribonucleic acid of SARS-CoV-2. Hematological controls between March and April 2020. Results 16 patients (33%) treated with clozapine.18 patients (37’5%) had COVID-19 infection, of which 5 (10’4%) were treated with clozapine; 2 presented neutropenia. 1- 56-year-old woman diagnosed with schizophrenia on clozapine since 2009. Begins to have a dry cough and fever with positive COVID-19 swab (day 0). Slight leukopenia without neutropenia was observed on day 1. On day 7, neutropenia was observed with an absolute neutrophil count (ANC) of 1100. We decided to suspend clozapine and to initiate daily hematological controls. The ANC on day 8 was 970. Over the next few days the ANC will progressively improve until neutropenia resolved (day 22). 2- 55-year-old woman who required a transfer to a general hospital because of respiratory complications from COVID-19. She presented significant leukopenia (1’01x 10^3/uL) and neutropenia (ANC 100). Clozapine was not withdrawn. She was treated with granulocyte colony-stimulating factor. Conclusions An urgent full blood count will be required to exclude neutropenia with appropriate action. Further research will be needed to clarify the possible relationship between COVID-19, clozapine and neutropenia. Disclosure No significant relationships.

Introduction Clozapine is the most effective antipsychotic for treatment resistant schizophrenia. In patients treated with clozapine, COVID-19 infection may result in complications including an increased risk of pneumonia, clozapine toxicity, and disruption to clozapine treatment by COVID-19 induced lymphopenia. Objectives We report 5 cases of elevated clozapine levels occurring in patients with COVID-19 infection who had been previously managed for several years on stable doses. Methods Subjects: 48 admitted patients to a long-stay psychiatric unit. COVID-19 infection confirmed by positive nasopharyngeal swab for viral ribonucleic acid of SARS-CoV-2. Hematological controls between March and April 2020. Results 16 patients (33%) treated with clozapine.18 patients (37’5%) had COVID-19 infection, of which 5 (10’4%) were treated with clozapine. Results are presented in table 1. Increases in plasma clozapine levels were observed in all cases (49’38 to 307.5%). We don’t have the clozapine levels of a patient who presented a pneumonia requiring admission and treatment in the general hospital. Two cases of neutropenia were observed, of which one had to discontinue treatment with clozapine. In the other three patients the dose of clozapine was reduced and they did not present haematological or intoxication complications that required further adjustments. Conclusions Covid-19 infection is associated with increased serum clozapine levels by probably multifactorial mechanisms (systemic infection, reduced smoking). Importance of full clinical assessment of suspected COVID-19 infection in clozapine treated patients, including assessment clozapine level, and full blood count. The general recommendation is to reduce the dose of clozapine in this patients.

Introduction The Cognitive Disorders Unit carries out sessions of Psychoeducational Groups (PG) for caregivers of patients diagnosed with cognitive impairment (CI). The aim is to educate about the disease, improve the caregiver’s self-care and learn how to take better care of the sick. Objectives Analyze the profile of the caregivers that participate in PG and assess changes in their psychological state. Methods Subjects: 110 caregivers of patients diagnosed with mild-moderate CI who have participated in PG. Methodology: sociodemographic data of the caregiver and patient are collected. The following scales are passed: General-Health-Questionnaire (GHQ-12), Global-Deterioration-Scale, Barthel-Index. 5 sessions of 90 minutes are carried out every fortnight. An opinion questionnaire and the GHQ-12 are administered at the end of the sessions. Results 86% of caregivers are women: 37% spouses and 55% daughters; mean age 57; 92% of patients live with the caregiver. 62% of caregivers present some kind of psychological disorder that is significantly reduced (p=0,0003) after some sessions. After PG: 65% of caregivers are able to further enjoy their daily activities 46% improve concentration capacity 42% improve sleeping and mood. Opinion Questionnaire Results: 98% of caregivers are satisfied with the activities, the topics addressed and their applicability. Conclusions The participants in PG were mostly daughters of patients, with average age 57, and living in the same household. Participation in PG improves the information and skills of caregivers, and reduces psychological disorders by improving their mood, their ability to concentrate, their quality of sleep and enjoyment of daily activities.

Introduction Horticultural therapy is a professional practice that is increasingly used in a lot of mental health rehabilitation programs. This therapy was introduced in the Comunitary Rehabilitation Service of INAD, considering its beneficial results in patients with severe mental disorder in combination with the usual rehabilitation program. Objectives We would like to study the benefits of this therapy compared to the usual in our patients. Methods This is an explanatory study for the purpose of establishing the association between the application of a Therapeutic Horticulture Program and the Clinical Symptomatology of Schizophrenia. A research with an experimental design Pre and Post-Test was carried out, by applying a Horticulture Program and evaluating with PANSS after 6 months its effects on the Clinical Symptomatology. The participants of the experimental group were selectively chosen. The only selection criteria were to attend the orchard at least once a week and be diagnosed with a schizophrenic disorder. The control group was chosen according to the number of members that made up the other group, with the criterion that they did not perform any outdoor activities and also had a diagnosis of schizophrenia. Results The comparison of the Pre and Post-Test measures in the case of the experimental group reports the presence of statistically significant differences in the scale of positive symptomatology composite scale and general scale. Conclusions This psychopathological improvement of those participants open a door to possible applications of this therapy as a psychosocial treatment.

En esta introducción queremos repasar algunas de las temáticas esenciales que caracterizaron el trabajo de nuestro maestro Joan Pagès. A Joan el concepto de “maestro” le gustaba, consideraba que era una de las palabras más bonitas y de más alto rango que existen. De hecho, él fue, antes que nada, un maestro y así se definía con orgullo. Su gran preocupación fue siempre cómo mejorar la enseñanza y el aprendizaje de lo social, cómo educar una ciudadanía más crítica, más democrática, más comprometida. Así que haremos un pequeño recorrido por algunas temáticas sobre las que investigó y reflexionó, sobre las que debatió con entusiasmo y a las que hizo aportaciones que tanto nos han ayudado, a quienes creemos que la enseñanza de las ciencias sociales puede servir para lograr un mundo mejor. Recordamos aquí algunas de sus contribuciones más importantes, pero no pretendemos mostrar su obra, que abarca cerca de 400 publicaciones y una gran cantidad de temáticas, desde la enseñanza del tiempo histórico, la memoria y la conciencia histórica, el currículum, la formación del profesorado, la educación económica, jurídica, política, la educación para la ciudadanía, la participación, el trabajo a partir de problemas sociales o cuestiones socialmente vivas, la competencia social y ciudadana, el pensamiento social crítico, entre otras. Solo pretendemos señalar algunos aspectos de su trabajo, como ejemplo de la trascendencia de su obra. Esta introducción sirve de preámbulo a los distintos autores y autoras que han querido participar en este número de REIDICS, y que completan este monográfico de homenaje al maestro.

ObjectivesAnti-TIF-1γ autoantibody detection is important for cancer screening in patients with dermatomyositis. The gold standard for anti-TIF-1γ detection, immunoprecipitation, is only available from a few specialized laboratories worldwide, so commercial ELISA/immunoblot tests have emerged in recent years. To analyze their usefulness in diagnosing cancer-associated dermatomyositis, we compared Euroimmun Euroline profile with our previously validated in-house immunoblot assay with human recombinant TIF-1γ.MethodsWe included 308 adult patients from Hospital de la Santa Creu I Sant Pau and Vall Hebrón Hospital (Barcelona, Spain) tested for anti-TIF-1γ autoantibodies using the Euroline profile and an in-house immunoblot assay.ResultsA total of 27 anti-TIF-1γ were detected by the Euroline and 12 by the in-house assay. Fair agreement was observed between Euroline and the in-house immunoblot Cohen’s kappa 0.3163. Expected prevalence of anti-TIF-1γ autoantibodies was observed for the two methods for dermatomyositis and undifferentiated connective tissue diseases, but unexpectedly high prevalence of anti-TIF-1γ autoantibodies was detected by Euroline compared to the in-house immunoblot for other diseases (16.5% Euroline vs 0.8% in-house immunoblot, p

El presente artículo expone una investigación-acción relativa a una propuesta didáctica denominada ‘Módulo Cabildo Ciudadano’, destinada a fortalecer las competencias ciudadanas y el empoderamiento constituyente de un grupo de futuros docentes de Educación Básica. Para ello, se abordaron el estallido social chileno ocurrido entre 2019 y 2020, así como el consiguiente proceso constitucional desatado, sucesos sincrónicos al desarrollo de las indagaciones. La valoración de la propuesta se realizó desde un enfoque mixto con predominio cualitativo. Se emplearon notas de campo, cuestionarios, entrevistas semiestructuradas y un grupo de discusión. La información obtenida fue procesada mediante un análisis cualitativo de contenido y otro de frecuencias descriptivas. Los resultados apuntan al potencial del abordaje de la realidad social para el desarrollo de competencias ciudadanas y del interés hacia los asuntos públicos. Asimismo, se determinaron una serie de fortalezas y debilidades, además de propuestas a considerar en el rediseño del módulo educativo.

PMR is a common inflammatory rheumatic disease. Although its clinical characteristics are fully recognized, no specific test for its diagnosis has been established to date. Several studies have described a wide variety of diseases that present with polymyalgic symptoms. A 18FDG-PET/CT scan could help to deal with these differential diagnoses. The goal of our study is to describe the findings of the 18FDG-PET/CT scan in a cohort of PMR patients and to detail how the 18FDG-PET/CT scan improves accuracy when diagnosing other underlying conditions. This cross-sectional study enrolled patients with a diagnosis of PMR who underwent to a 18FDG-PET/CT scan to rule out other diagnosis. The 18FDG-PET/CT scan was performed either following clinical criteria at the onset of clinical symptoms or when the patient became PMR steroid resistant. Patients' demographic, clinical and analytical data at the moment of the 18FDG-PET/CT scan were recorded. The final diagnosis was confirmed according to clinical judgement. A total of 103 patients with PMR were included. In 49.51% of patients, the 18FDG-PET/CT scan was ordered to study resistance to steroid therapy. The final diagnoses of patients were PMR in 70.9% patients, large vessel vasculitis in 15.5%, neoplasms 4.8% and another diagnosis in the rest. The 18FDG-PET/CT scan is a very useful technique for the study of Polymyalgia Rheumatica, not only to help in the diagnostic process, but also due to its role in the identification of a variety of PMR-like patrons.

There is evidence of longitudinal atrophy in posterior brain areas in early-onset Alzheimer’s disease (EOAD; aged