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The maintenance of road infrastructures is one of the main challenges that transportation authorities must face to guarantee the safe mobility of people and goods. Novel remote monitoring technologies offer advanced solutions for this issue, allowing the inspection of large sections of the network in a time-effective way. In this paper, we introduce a methodology for the detection of cracks on road pavements using point clouds acquired with a mobile laser scanner. First, the points of the cloud are labelled as pavement or cracks based on field annotations, and local geometric features of the points are calculated using principal component analysis. Two different machine learning classifiers, Support Vector Machine (SVM) and Random Forest, are then trained to identify crack points using the point feature data. The crack points predicted by the classifiers are clustered as individual instances and compared to the corresponding ones from a test dataset. Although pointwise performance of the method is modest, it can correctly identify and measure areas of the pavement affected by cracking.

Among a multitude of variables that are involved in self-regulated learning and that define the student’s profile, we find learning strategies and academic motivation. The aim of this study was to analyze relationships between learning strategies, attitude toward study, self-concept, and academic achievement. A total of 519 students from upper primary education in Cantabria (Spain) were participants in this cross-sectional study, which used non-experimental, descriptive, correlational methodology. The results confirmed a tendency for greater use of learning strategies, along with optimal motivation towards schoolwork, to be positively related to overall academic achievement. Moreover, low-medium-high levels of learning strategy use and of academic motivation were differentially associated with academic achievement. This study has confirmed that complementary learning strategies such as group work or extracurricular activities, as well as academic self-concept, are predictive of achievement in the subjects considered, as well as of academic achievement in general. Educational contexts that take into account learning strategies and academic motivation are called for, both as a means and as an end in themselves, in order to achieve meaningful, practical and functional learning that leads to higher academic achievement.

Inherited Retinal Dystrophies (IRDs) are a group of rare diseases with a prevalence of 1:3000-4000 people. They are genetic, primarily affecting retinal photoreceptors and epithelial pigmentary cells, and lead to neurodegeneration and finally apoptosis. In 2021, we published our global results obtained in our registry at the Fundación Jiménez Díaz University Hospital (Madrid, Spain) from 1991 to August 2019. Now, we aimed to update these results until August 2022. Thus, we conducted a retrospective hospital-based cross-sectional study on 4.794 IRD-affected unrelated families from all the Spanish autonomous communities. Families were classified into three phenotypic categories: a) “NON-RP” for cone-dominated phenotypes, b) “RP” (retinitis pigmentosa) for primary rod involvement, and c) “syndromic IRD” when visual plus extra-ocular symptoms are present. Molecular studies included: single-gene studies, clinical exome, whole exome or whole genome sequencing. Overall, 62% (2962/4794) of the families were genetically characterized, in which 1.997 different likely causative variants (5.064 different alleles) were identified in 188 genes. The most common phenotype encountered was RP (59% of families, 2465/4794). Regarding the types of causative alleles, missenses were the most frequent (51%), followed by truncating (nonsense, frameshift, indels and splicing; 44%), while copy number variations were only 2%. The most recurrently mutated genes were PRPH2, ABCA4 and RS1 in autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL) NON-RP families, respectively; RHO, USH2A and RPGR in AD, AR and XL for non-syndromic RP; and MYO7A, USH2A and BBS1 in syndromic IRD. Pathogenic variants ABCA4:p.Arg1129Leu and USH2A:p.Cys759Phe were the most frequent. Our study provides the overall genetic landscape for IRD in Spain, reporting the largest cohort ever presented and a high number of causal genes involved in these diseases. Furthermore, our findings have important implications for genetic diagnosis and counseling, but also for possible therapeutic management

Se reporta formalmente la presencia de Dianema urostriatum (Miranda Ribeiro, 1912), en afluentes del río Putumayo, ampliando de esta forma su distribución geográfica en la cuenca Amazónica. Este registro enriquece la ictiofauna continental peruana.

Although pleural effusion is a frequent finding in clinical practice, determining its aetiology may be challenging, and up to 20% of cases remain undiagnosed. Pleural effusion may occur secondary to a nonmalignant gastrointestinal disease. A gastrointestinal origin is confirmed based on a review of the medical history of the patient, thorough physical examination and abdominal ultrasonography. In this process, it is crucial to correctly interpret findings on pleural fluid obtained by thoracentesis. In the absence of high clinical suspicion, identifying the aetiology of this type of effusion may be difficult. Clinical symptoms will be determined by the gastrointestinal process causing pleural effusion. In this setting, correct diagnosis relies on the specialist's ability to evaluate pleural fluid appearance, test for the appropriate biochemical parameters and determine whether it is necessary or not to send a specimen for culture. The established diagnosis will determine how pleural effusion is approached. Although this clinical condition is self-limited, many cases will require a multidisciplinary approach because some effusions can only be resolved with specific therapies.

ResumenLa historia de la literatura universal contiene capítulos latinoamericanos vitales, como el del boom. La universalidad y la posibilidad de trascender lo nacional son recursos distribuidos inequitativamente, como argumentará este artículo en discusión con trabajos que decretan la democratización de la literatura. Este artículo analiza las condiciones que hacen posible la circulación latinoamericana del escritor argentino César Aira mediante la reconstrucción de las ediciones de sus libros en México, central para la edición en castellano. Este análisis, en primer lugar, complejiza la polarización del campo editorial; en segundo, indaga en los modos como editoriales distintas responden a la concentración y extranjerización; en tercero, produce conocimiento sobre un escritor con creciente prestigio internacional; y por último, sostiene la productividad metodológica de las trayectorias editoriales de escritores. Se propone que las editoriales son centrales para estudiar los lazos regionales e hipotetiza que las editoriales medianas que apuestan por catálogos de literatura latinoamericana a largo plazo parecen empresas improbables.

Sarcoidosis is a multiorgan granulomatous disease with a variable course.The purpose of this study is to identify the patients that are more likely to experience disease progression.A retrospective study in patients ≥18 years. Pulmonary function and radiological stage (Scadding criteria) were assessed at diagnosis, and at 1, 3 and 5 years. Sarcoidosis progression was established based on deterioration of radiological or pulmonary function (decrease ≥10% of FVC and/or ≥15% of diffusing capacity of the lung (DLCO).The sample included 277 caucasian patients [mean age, 50±13.6; 69.7% between 31-60 years; 56.3% men]. In total, 65% had stage II sarcoidosis, whereas only 8.3% had stage III/IV disease. Mean pulmonary function (FVC, FEVAt 3 years, a third of patients experienced sarcoidosis progression. Age was the only factor associated with disease prognosis.

Triple X syndrome is a sex chromosomal aneuploidy characterized by the presence of a supernumerary X chromosome, resulting in a karyotype of 47,XXX in affected females. It has been associated with a variable cognitive, behavioral, and psychiatric phenotype, but little is known about its effects on brain function. We therefore conducted 7 T resting-state functional magnetic resonance imaging and compared data of 19 adult individuals with 47,XXX and 21 age-matched healthy control women using independent component analysis and dual regression. Additionally, we examined potential relationships between social cognition and social functioning scores, and IQ, and mean functional connectivity values. The 47,XXX group showed significantly increased functional connectivity of the fronto-parietal resting-state network with the right postcentral gyrus. Resting-state functional connectivity (rsFC) variability was not associated with IQ and social cognition and social functioning deficits in the participants with 47,XXX. We thus observed an effect of a supernumerary X chromosome in adult women on fronto-parietal rsFC. These findings provide additional insight into the role of the X chromosome on functional connectivity of the brain. Further research is needed to understand the clinical implications of altered rsFC in 47,XXX.

The growing trend of developing standards of information exchange and management processes is leading to Building Information Models (BIM) being adapted to work with linear infrastructure assets. For this reason, the Industry Foundation Classes (IFC) has developed standards for linear infrastructure such as roads. Furthermore, the usage of remote sensing technologies, such as Mobile Laser Scanning (MLS) systems for infrastructure monitoring is increasingly common. This paper presents an automated methodology that takes as input 3D point cloud tiles from an MLS and its trajectory, and outputs an IFC-compliant file that models the alignment of the road and the width of the roadway along the length of the road. The methodology is evaluated in 48 km of mountain roads, in some cases without road markings, using neither intensity nor colour fields. Agencia Estatal de Investigación | Ref. FJC2018-035550-I Fundación BBVA

Mammalian blastocyst formation involves the specification of trophectoderm followed by the differentiation of the inner cell mass into either epiblast or primitive endoderm. During this time, the embryo maintains a window of plasticity and can redirect its cellular fate when challenged experimentally. In this context, we found that the primitive endoderm alone was sufficient to regenerate a complete blastocyst and continue normal postimplantation development to term. We identify anin vitropopulation similar to the early primitive endodermin vivo, that exhibits the same embryonic and extra-embryonic potency, forming three dimensional embryoid structures. Commitment in early primitive endoderm is suppressed by JAK/STAT signalling, collaborating with OCT4 to safeguard enhancer status enabling multi-lineage differentiation. Our observations support the notion that transcription factor persistence underlies plasticity in regulative development and highlights the importance of primitive endoderm in perturbed development.

The digital transformation is having a major impact on the consumer product market, pushing food retailers to foster online sales. To avoid large investments, e-grocers are tending to use their existing physical stores to undertake the online order picking process. In this context, these companies must choose in which traditional stores must prepare online orders. The aim of this study is to identify which store features affect order preparation times. The action research approach has been used at a Spanish e-grocer to analyze the characteristics that differentiate picking stores from each other; furthermore, the preparation times for a sample of online orders have been measured. The data were analyzed statistically using one-way ANOVA to define the optimal store in terms of size, assortment, backroom and congestion. The study shows that three of the four characteristics are significant on the preparation time. Therefore, e-grocers using a store-based model can use this information to focus their efforts on optimizing this process, assigning online order picking to the most appropriate stores. The approach used allows the study to be suitable for different retail context. Moreover, the results serve as support for strategic decision-making of researchers and e-grocers seeking to become more competitive in this continually growing market.

En mercados de aprovisionamientos y distribución cada vez más complejos, volátiles y globales, la gestión sostenible de la cadena de suministro y de sus procesos asociados es, y lo será más en el futuro, un elemento clave de competitividad. En este ámbito sostenible, el diseño de envases y embalajes contribuye de forma activa a esta mejora competitiva de empresas y cadenas de suministro, lo que ha generado diferentes aproximaciones teóricas, entre las que destaca el concepto “Sustainable Packaging Logistics” (SPL). En el marco del desarrollo de este concepto, diferentes autores han identificado el potencial de abordar diferentes actuaciones, entre las que destaca la estandarización de formatos y calidades de envases y embalajes. Por todo ello, este artículo propone y justifica una metodología para la estandarización del sistema de envase y embalaje desde una óptica de eficiencia y sostenibilidad, basada en el rediseño de los envases secundarios. Asimismo, la aplicación de esta metodología se ilustra con el desarrollo de un caso en el sector alimentario que adopta el enfoque “Action Research”. Este artículo se considera de interés a nivel académico y empresarial por cuanto profundiza en la estandarización e integración del sistema combinado envase-embalaje-producto-cadena de suministro como vía de despliegue del enfoque SPL.

The calcineurin pathway is often activated in mycosis fungoides. We aimed to assess the activity and safety of topical pimecrolimus, a calcineurin inhibitor, in patients with early mycosis fungoides.PimTo-MF was a single-arm, multicentre, phase 2 trial done at six medical centres in Spain. Patients (aged ≥18 years) had histologically confirmed early mycosis fungoides (stages IA-IIA) and an Eastern Cooperative Oncology Group performance status of 0-1. Key exclusion criteria included the use of concurrent treatments for mycosis fungoides, including sunbathing, topical or systemic corticosteroids, and other calcineurin inhibitors. Patients applied topical pimecrolimus 1% cream on their skin lesions twice daily for 16 weeks (1 g per 2% of body surface), with subsequent follow-up of 12 months. Dosage modifications were not allowed. To evaluate adherence to the treatment, patients were instructed to return all empty tubes to the hospital (as per drug accountability protocols). The primary endpoint was the overall response ratein the intention-to-treat population. PimTo-MF is registered with EudraCT, 2014-001377-14, and is complete.Between March 1, 2015, and Sept 30, 2016, 39 patients were enrolled. All patients were assessable, with a median age of 51·5 years (IQR 45-62), and the population was predominantly male (24 male [62%], 15 female [38%]). Median follow-up after baseline was 5·7 years (IQR 5·7-6·2). 22 (56%) of 39 patients had an overall response (one complete response, 21 partial responses). Responses were observed across IA (14 [54%] of 26 patients) and IB (eight [73%] of 11 patients) clinical stages, but not IIA. Topical pimecrolimus was well tolerated and no patient required a dose reduction or discontinued treatment because of unacceptable drug-related toxicity. No patients were lost to follow-up or discontinued treatment. 13 (33%) of 39 patients reported adverse events; transitory mild burning or pruritus (grade 1) was the most common, seen in eight (21%) patients. In three (8%) of these patients, the burning or pruritus was considered related to treatment. No grade 4 or 5 adverse events were observed.Pimecrolimus 1% cream seems active and safe in patients with early stage mycosis fungoides. Our findings should be taken with caution until long-term follow-up data are obtained that confirm the safety of this treatment. Further controlled clinical trials are warranted to confirm these results.Instituto de Salud Carlos III and the European Regional Development Fund.For the Spanish translation of the abstract see Supplementary Materials section.

High-resolution maps of embryonic development suggest that acquisition of cell identity is not limited to canonical germ layers but proceeds via alternative routes. Despite evidence that visceral organs are formed via embryonic and extra-embryonic trajectories, the production of organ-specific cell types in vitro focuses on the embryonic one. Here we resolve these differentiation routes using massively parallel single-cell RNA sequencing to generate datasets from FOXA2

BACKGROUND There is an increased risk of atherosclerosis in patients with chronic hepatitis C or human immunodeficiency virus, but there is scarce data on hepatitis B virus infection. The hypothesis of this study is that hepatitis B virus infection increases the risk of carotid plaques and subclinical atherosclerosis in naïve hepatitis B e antigen (HBeAg) negative subjects. AIM To assess the rate of carotid plaques and subclinical atherosclerosis in naïve HBeAg negative subjects in comparison with a cohort of healthy controls. METHODS Prospective case-control collaborative study conducted in two tertiary hospitals. Four hundred and two subjects prospectively recruited at the outpatient clinic were included from May 2016 to April 2017: 201 naïve HBeAg-negative hepatitis B virus-infected [49 chronic hepatitis B (CHB) and 152 inactive carriers(ICs)] and 201 healthy controls. Anthropomorphic and metabolic measures, liver stiffness and carotid Doppler ultrasound were performed. Subclinical atherosclerosis was established on an intima-media thickness increase of ≥1.2 mm and/or the presence of carotid plaques. Normally distributed quantitative variables were compared with the Student t test and those with a non-normal distribution with the Mann-Whitney U test. Categorical variables were compared between groups using the χ2 or Fisher exact test. RESULTS Carotid plaques were found more often in CHB (32.7%) than ICs (17.1%) or controls (18.4%) (P = 0.048). Subclinical atherosclerosis was also increased in CHB (40.8%) vsICs (19.1%) or controls (19.4%) (P = 0.003). No differences in the risk of atherosclerosis were observed between controls and ICs. The factors independently associated with the presence of carotid plaques were age [odds ratio(OR) 1.43, P < 0.001] and CHB (OR 1.18, P = 0.004) and for subclinical atherosclerosis, age (OR 1.45, P < 0.001), CHB (OR 1.23, P < 0.001) and diabetes (OR 1.13, P = 0.028). In the subset of young subjects (< 50 years), carotid plaques (12.5% vs 1.1%, P = 0.027) and subclinical atherosclerosis (12.5% vs 2.2%, P = 0.058) were more frequent among CHB than ICs. CONCLUSION Untreated HBeAg-negative CHB is an independent risk factor for carotid plaques and subclinical atherosclerosis, while ICs present a similar risk to controls.

Introducción. Numerosos investigadores muestran los múltiples beneficios de la motivación académica en los procesos educativos, tanto en el ámbito escolar como en el familiar. Una adecuada adquisición y desarrollo de estrategias de aprendizaje durante la ESO resulta clave para la proyección académica futura. El objetivo de este trabajo es profundizar en la relación entre las metas académicas y los estilos educativos parentales respecto de las estrategias de aprendizaje en estudiantes de ESO. Método. Para llevarlo a cabo se administraron tres cuestionarios a una muestra de 358 estudiantes de 1º a 4º de ESO con edades comprendidas entre 11 y 17 años. Resultados. Destacan las diferencias estadísticamente significativas en el nivel más alto de la meta de tarea y del estilo parental democrático respecto de las estrategias cognitivas, metacognitivas y de gestión de los recursos. Esto indica la superioridad estratégico-motivacional de la orientación al aprendizaje y de estilos educativos familiares equilibrados en afecto y control. Discusión y conclusiones. El perfil motivacional-familiar más estratégico responde a la orientación a metas de aprendizaje y en menor medida también de rendimiento, con estilo parental democrático y en segundo lugar autoritario, teniendo en cuenta la influencia negativa de la autoprotección del ego y la evitación de la tarea. Finalmente, se ofrecen conclusiones que serán necesarias en futuros trabajos en esta línea.

The aim of this study was to explore the emotional impact of Covid-19 on healthcare professionals at the Clinical and University Hospital of Valencia (Spain), and to identify the associated variables. A total of 228 professionals completed an ad hoc online survey in May 2020. The healthcare professionals experienced symptoms of stress (32%), depression (26%), anxiety (14%) and intrusive memories (7.5%). A higher frequency of sadness and anxiety was observed in women and in professionals who had presented Covid-19 symptoms. The professional category with the most frequent emotional symptoms was that of auxiliary nurses, and for stress also nurses and residents. The most affected were the first line units. The psychological variables that were negatively associated with the frequency of all symptomatic manifestations were: self-care, self-esteem, resilience, and use of active coping strategies, together with self-efficacy and social support for stress and depression. Despite the limitations of the study, the results may contribute to guide preventive programs for health professionals in future health crises.

Background: A child’s disability can have significant consequences for the family, especially at an emotional level and in day-to-day life. Families must adapt to ever-changing circumstances, frequently leading to stress within the family. Each family member must attempt to cope with these circumstances, drawing on cognitive and behavioral resources to deal with new situations. Objectives: This work aims to study stress, resilience, and satisfaction within the families of children with and without disabilities. It also analyzed these aspects depending on the type of disability (intellectual, physical, autism spectrum disorder, and multiple disabilities). Methods: The sample consisted of 299 families, of whom 178 had a child with a disability and 121 without any disability. The study used the Parenting Stress Index – Short Form (PSI-FS) and the Saavedra-Villalta Resilience Scale (SV-RES). Satisfaction was measured using two items evaluating family satisfaction in general and the perceived satisfaction of the child in particular. Results: The results show that families having a child with a disability reported higher levels of resilience but lower levels of stress and family satisfaction. Moreover, differences were observed depending on the type of disability, with those affected by intellectual disability showing higher levels of stress and lower levels of resilience. Conclusion: The study results show the importance of resilience in dealing with adverse situations that may produce stress. This is an important aspect that must be considered in work and interventions with families of children with disabilities.

Differentially expressed genes in IMR5 cells after OTX015 and JQ1 treatment respectively

Mechanisms of reduced cell viability induced by OTX015 are cell line dependent. OTX015 reduces cell proliferation over time and induces cell cycle changes as well as apoptosis. (a) Representative photomicrographs of neuroblastoma cell lines treated with OTX015 for 72 h. Scale bar=200 µm. (b) The slope (1/h) of cell proliferation over time measured using xCELLigence of cell lines treated with OTX015. Significance was measured with the Student's t test. (c) Cell proliferation monitored using the xCELLigence system over time in neuroblastoma cell lines treated with 500 nM OTX015 (black) or DMSO control (grey). (d) Cell lines were treated 72 h with 500 nM OTX015 or DMSO, then fixed and stained with propidium iodide for flow cytometry. The distribution of OTX015-treated cells in different stages of the cell cycle is shown. (e) Fraction of apoptotic cells measured in the cell death ELISA assay after 72 h treatment with 250 nM or 500 nM OTX015 or DMSO control. Significant differences between treated cells versus controls were calculated by Student's t test. * p < 0.05, ** p < 0.01. (f) Cell proliferation measured in the BrdU ELISA after 72 h of treatment with 250 nM or 500 nM OTX015 or DMSO. Significant differences between treatment groups and the controls were calculated by Student's t test.

All H3K27Ac peaks called in non-promoter regions in IMR5

OTX015 has no significant effect on non-malignant human fibroblasts. (a) Representative pictures of human fibroblasts treated for 72 h with 500 nM OTX015 or DMSO control. Scale bar=100 µm. (b) Growth of fibroblasts treated with 500 nM OTX015 (black) or DMSO control (grey) monitored over 96 h using the xCELLigence system. The slope (1/h) of both curves was calculated, and did not show a significant difference (right) using the Student's t test.

Supplemental Figures S7. Supplemental Figures S7. Effects of JQ1 and OTX015 on BRD4 binding to MYD88 promoter region in DLBCL cell lines.

GSEA of gene sets describing general cellular processes after treatment with OTX015 and/or JQ1(GSEA, Broad institute)

BET inhibition preferentially disrupts expression of genes associated with super-enhancers. (a) ChIP-seq profiles for H3K27Ac binding at representative super-enhancer-associated gene loci, including MYCN, NCOR2, BCOR and GLI2, in MYCN-amplified IMR-5 cells. The x-axis shows genomic position and the y-axis the histone mark signal in units of reads per million per base pair (rpm/bp). The gene model is depicted below and scale bars above the binding profiles. (b) The Fisher exact test shows enrichment of super-enhancer associated genes among the downregulated genes (logFC < 0 and q < 0.05) by OTX015 or JQ1 treatment. (c) Cumulative distribution plots of the top 200 super-enhancer-associated genes and their fold-change measured using genes which are differentially regulated in IMR-5 cells by OTX015 treatment, JQ1 treatment or the overlap between these datasets (left to right). Plots show a shift towards negative logFC for super-enhancer associated genes (blue curves) compared to genes not associated with super-enhancers (black curves). (d) Box plots of log2-fold changes in the top 200 genes associated with super-enhancers (SE) and regular enhancers (non-SE) in genes differentially regulated (compared to DMSO-treated controls) in IMR-5 cells treated with OTX015, JQ1 or the overlap from both datasets (left to right). Statistical significance was determined using a two-sided Mann-Whitney test.

GSEA of cancer gene sets after treatment with OTX015 and/or JQ1(GSEA, Broad institute)

BET bromodomain inhibition leads to disruption of MYCN driven gene-expression programs even at high levels of MYCN. (a) Enrichment of the published gene expression signature for JQ1-treated human MYCN-amplified neuroblastoma cell lines (11) in differentially expressed genes in IMR-5 cells after treatment with OTX015, JQ1 or DMSO control. (b) Enrichment of the published gene expression signature for MYC target genes (16) in differentially expressed genes in IMR-5 cells after treatment with OTX015, JQ1 or DMSO control. (c) Enrichment of the published gene expression signature for JQ1-treated human MYCN-amplified neuroblastoma cell lines (11) in differentially expressed genes in mNB-A1 cells after treatment of with OTX015, JQ1 or DMSO control. (d) Enrichment of the published gene expression signature for MYC target genes (16) in differentially expressed genes in mNB-A1 cells after treatment with OTX015, JQ1 or DMSO control (* p < 0.05, ** p < 0.01, *** p < 0.001). (e) GSEA (version 2.0, Broad Institute) of differentially expressed genes in IMR5 cells after treatment with OTX015 or JQ1 using gene sets representing signatures of JQ1 as well as MYC target genes (11, 16).

Purpose: In cancer cells, the epigenome is often deregulated, and inhibition of the bromodomain and extra-terminal (BET) family of bromodomain-containing proteins is a novel epigenetic therapeutic approach. Preliminary results of an ongoing phase I trial have reported promising activity and tolerability with the new BET bromodomain inhibitor OTX015.Experimental Design: We assessed the preclinical activity of OTX015 as single agent and in combination in mature B-cell lymphoma models and performed in vitro and in vivo experiments to identify the mechanism of action and the genetic features associated with sensitivity to the compound.Results: OTX015 showed antiproliferative activity in a large panel of cell lines derived from mature B-cell lymphoid tumors with median IC50 of 240 nmol/L, without significant differences among the different histotypes. In vitro and in vivo experiments showed that OTX015 targeted NFKB/TLR/JAK/STAT signaling pathways, MYC- and E2F1-regulated genes, cell-cycle regulation, and chromatin structure. OTX015 presented in vitro synergism with several anticancer agents, especially with mTOR and BTK inhibitors. Gene expression signatures associated with different degrees of sensitivity to OTX015 were identified. Although OTX015 was mostly cytostatic, the compound induced apoptosis in a genetically defined subgroup of cells, derived from activated B-cell–like diffuse large B-cell lymphoma, bearing wtTP53, mutations in MYD88, and CD79B or CARD11.Conclusions: Together with the data coming from the ongoing phase I study, the in vitro and in vivo data presented here provide the basis for further clinical investigation of OTX015 as single agent and in combination therapies. Clin Cancer Res; 21(7); 1628–38. ©2015 AACR.

Supplemental Figures S1-2. Supplemental Figures S1: effects of OTX015 on cell cycle and cell growth in DLBCL cell lines. Supplemental Figures S2: effects of OTX015 on apoptosis in DLBCL cell lines.

Purpose: Targeting BET proteins was previously shown to have specific antitumoral efficacy against MYCN-amplified neuroblastoma. We here assess the therapeutic efficacy of the BET inhibitor, OTX015, in preclinical neuroblastoma models and extend the knowledge on the role of BRD4 in MYCN-driven neuroblastoma.Experimental Design: The efficacy of OTX015 was assessed in in vitro and in vivo models of human and murine MYCN-driven neuroblastoma. To study the effects of BET inhibition in the context of high MYCN levels, MYCN was ectopically expressed in human and murine cells. The effect of OTX015 on BRD4-regulated transcriptional pause release was analyzed using BRD4 and H3K27Ac chromatin immunoprecipitation coupled with DNA sequencing (ChIP-Seq) and gene expression analysis in neuroblastoma cells treated with OTX015 compared with vehicle control.Results: OTX015 showed therapeutic efficacy against preclinical MYCN-driven neuroblastoma models. Similar to previously described BET inhibitors, concurrent MYCN repression was observed in OTX015-treated samples. Ectopic MYCN expression, however, did not abrogate effects of OTX015, indicating that MYCN repression is not the only target of BET proteins in neuroblastoma. When MYCN was ectopically expressed, BET inhibition still disrupted MYCN target gene transcription without affecting MYCN expression. We found that BRD4 binds to super-enhancers and MYCN target genes, and that OTX015 specifically disrupts BRD4 binding and transcription of these genes.Conclusions: We show that OTX015 is effective against mouse and human MYCN-driven tumor models and that BRD4 not only targets MYCN, but specifically occupies MYCN target gene enhancers as well as other genes associated with super-enhancers. Clin Cancer Res; 22(10); 2470–81. ©2015 AACR.

List of all Super-enhancers identified in IMR5 cells

OTX015 effect on cell viability positively correlates with MYCN status. (a) IC50 of the IMR 5, Chp 134, Chp 212, SK N-BE(2), IMR-32, SK-N-BE, NB69, SK N AS and GI-M-EN neuroblastoma cell lines measured using MTT assays. (b) Maximum reduction of viability in IMR 5, Chp 134, Chp 212, SK N-BE(2), IMR-32, SK-N-BE, NB69, SK N AS and GI-M-EN cells treated for 72 h with 6 µM OTX015 and measured using MTT assays. (c) Relative MYCN mRNA (top) and protein (bottom) expression in all analyzed neuroblastoma cell lines. (d/e) The IC50 values of the cell lines shown in (a) were plotted against MYCN mRNA expression (d) or MYCN protein expression (e), which is shown in (c). Both graphs show weak anti-correlative tendencies in both cell lines (MYCN mRNA p=0.22, MYCN protein p=0.16).

Supplemental Table S4: List of gene-sets associated with the sensitivity to OTX015.

Supplemental Figures S6. Supplemental Figures S6: OTX015 effects on the production of IL-4 and IL-10 in DLBCL cell lines.

OTX015 reduces cell proliferation and induces apoptosis in MYCN amplified human xenografts. (a) Representative pictures of IMR5 xenograft tumor sections stained with hematoxylin/eosin, and immunohistochemical staining for apoptotic cells (cleaved caspase 3) and proliferating cells (Mib-1/Ki 67) are shown. Scale bar=250 µm. The relative fraction of positively stained cells for cleaved caspase 3 (b) and Mib-1 (c) were calculated from three representative images from each xenograft tumor and are shown as box plots. Statistical difference between groups was assessed by Student's t test. * p < 0.05, ** p < 0.01, *** p < 0.001.

Westermann et al. as well as Valentijn et al. MYCN target gene list and expression changes after OTX015 treatment as well as BRD4 binding

List of all genes from hg19 with changes in BRD4 binding using BRD4- ChIP-seq in IMR5 cells with changes after treatment with OTX015

Supplemental Figures S3-5. Supplemental Figures S3: the gene expression changes induced by OTX015 in DLBCL cell lines. Supplemental Figures S4: network of genes affected by OTX015. Supplemental Figures S5: similar biologic effects of OTX015 and JQ1.

Supplemental Table S1: Cell lines and growth medium.

In early mammalian development, cleavage stage blastomeres and cells of the inner cell mass (ICM) of the blastocyst co-express embryonic and extra-embryonic transcriptional determinants. Using a double protein-based reporter we identify embryonic stem cells (ESC) that co-express the extra-embryonic factor GATA6 alongside the embryonic factor SOX2 in specific conditions. Based on single cell transcriptomics we find these population resemble unsegregated ICM, exhibiting enhanced differentiation potential for endoderm while maintaining epiblast competence and suggesting they represent an ideal model to determine how GATA6 and SOX2 influence each other’s DNA binding. To relate this binding to future fate, we describe a complete enhancer set in both ESCs and naïve extraembryonic endoderm stem cells and ask whether SOX2 and GATA6 recognize these elements in ICM-like ESC sub-population. Both factors support cooperative recognition in these lineages, with GATA6 bound alongside SOX2 on a fraction of pluripotency enhancers and SOX2 alongside GATA6 more extensively on endoderm enhancers. Our findings suggest that cooperative binding between these antagonistic factors both supports self-renewal and prepares progenitor cells for later differentiation.

The present paper presents a set of experiences with the use of Xiaomi Mi Band (from version 1 to 5) in different populations but with the purpose of monitoring the daily life and the occupational performance of the participants. Monitoring with wearable sensors is an easy and non-intrusive approach to encourage preventive care by occupational therapists or other health providers to facilitate professional practice.

Background and AimsImmunotherapy with immune checkpoint inhibitors (ICIs) is a pillar of many advanced tumors. However, there is scarce data concerning the rate of viral hepatitis screening in this population or the risk of viral reactivation.MethodsRetrospective–prospective study that includes all patients who began ICIs between January/2019 and December/2020 in a University Hospital. Data on viral hepatitis screening prior to the beginning of ICIs were collected. In subjects lacking information, serological tests were requested prospectively. Among HBsAg, anti-HBc, or anti-HCV positive subjects, reactivation was prospectively assessed.ResultsDuring the 2-year period of study, 595 subjects received ICIs (61.2% male, mean age 63 years). The most prevalent cancers found were 35.5% lung cancer, 12.1% melanoma, and 8.2% head and neck; ICIs schemes were mainly anti-PD1 (65.7%), followed by anti-PD-L1 (19.2%), and combined therapy (13.6%). Prior to immunotherapy, anti-HCV screening was performed in 462 (77.6%) subjects, HBsAg in 462 (77.6%), anti-HBc in 335 (56.3%), and the complete screening in 328 (55.1%). The anti-HBc screening was more frequently ordered among patients treated with concomitant systemic therapy (p = 0.003), especially in the case of chemotherapy (p = 0.015), though HCV screening was more commonly performed in concomitant therapies different from chemotherapy (p = 0.001). Serological tests were completed prospectively in those alive, leading to an overall prevalence for anti-HCV of 3.5%, HBsAg at 1.3%, and anti-HBc of 15.2%. HCV-RNA was detected in 2/19 (both patients with hepatocellular carcinoma), HBV-DNA in 4/7 HBsAg positive, and in 1/75 anti-HBc positive subject. Five out of the 7 HBsAg carriers and 1/75 anti-HBc+ subjects (due to concomitant antiretroviral therapy) received antiviral prophylaxis. Neither cases of HBV reactivation nor changes in HCV viral load were observed.DiscussionHBV and HCV screening prior to immunotherapy is suboptimal. Though the rate of viral hepatitis reactivation seems extremely low, efforts should be made to optimize viral hepatitis screening prior to immunotherapy for the selection of candidates for either antiviral prophylaxis or periodical follow-up.

This essay poses a question about the identity of Latin American literature in the 21st century. In the 1960s and 1970s, the Latin America Boom received recognition both locally and internationally, becoming the dominant means of defining Latin American literature up to the present. This essay explores new ways to understand this notion of Latin America in the literary scene. The case of the Argentine writer César Aira is relevant for analyzing alternative publishing circuits that connect various points of the region. These publishing houses foster a defiant way of establishing the value of literature.

O cultivo de morango é caracterizado pelo uso indiscriminado de agrotóxicos, o que pode causar não apenas contaminação alimentar, mas também o acúmulo de resíduos no ambiente e no homem. Técnicas que minimizem as concentrações residuais nos produtos e no ambiente são desejadas. Assim, este trabalho visou avaliar a utilização de lodo biológico de estações de tratamento de esgoto doméstico no cultivo de morango na degradação do fungicida tebuconazol (TEB) no solo, sua influência nas concentrações residuais e na atividade microbiana no solo. O experimento foi feito usando um planejamento experimental do tipo central composite design (CCD) com 10 tratamentos, sendo: fatoriais (combinações dos níveis +1 e -1), centrais (nível 0) e pontos axiais (+1,41 e -1,41). Foram realizadas análises físico-químicas e microbiológicas no solo e análises cromatográficas para detecção de resíduos de TEB no solo e no morango. Os resultados evidenciaram que maiores dosagens de TEB aplicadas ao cultivo de morango resultaram em maiores concentrações residuais desse fungicida no solo, porém não afetaram os teores residuais no fruto. A adição de lodo biológico ao solo durante o cultivo de morango resultou em maior atividade da biomassa microbiana, melhorando a estabilidade do solo. A destinação de lodo biológico ao solo durante o cultivo de morango mostrou-se adequada e resultou em melhoria na atividade microbiana do solo, o que pode proporcionar benefícios ambientais e econômicos.

Data on the prevalence and mortality of paediatric sepsis in resource-poor settings are scarce. We aimed to assess the prevalence and in-hospital mortality of severe sepsis and septic shock treated in paediatric intensive care units (PICUs) in Brazil, and risk factors for mortality.We performed a nationwide, 1-day, prospective point prevalence study with follow-up of patients with severe sepsis and septic shock, using a stratified random sample of all PICUs in Brazil. Patients were enrolled at each participating PICU on a single day between March 25 and 29, 2019. All patients occupying a bed at the PICU on the study day (either admitted previously or on that day) were included if they were aged 28 days to 18 years and met the criteria for severe sepsis or septic shock at any time during hospitalisation. Patients were followed up until hospital discharge or death, censored at 60 days. Risk factors for mortality were assessed using a Poisson regression model. We used prevalence to generate national estimates.Of 241 PICUs invited to participate, 144 PICUs (capacity of 1242 beds) included patients in the study. On the day of the study, 1122 children were admitted to the participating PICUs, of whom 280 met the criteria for severe sepsis or septic shock during hospitalisation, resulting in a prevalence of 25·0% (95% CI 21·6-28·8), with a mortality rate of 19·8% (15·4-25·2; 50 of 252 patients with complete clinical data). Increased risk of mortality was associated with higher Pediatric Sequential Organ Failure Assessment score (relative risk per point increase 1·21, 95% CI 1·14-1·29, p0·0001), unknown vaccination status (2·57, 1·26-5·24; p=0·011), incomplete vaccination status (2·16, 1·19-3·92; p=0·012), health care-associated infection (2·12, 1·23-3·64, p=0·0073), and compliance with antibiotics (2·38, 1·46-3·86, p=0·0007). The estimated incidence of PICU-treated sepsis was 74·6 cases per 100 000 paediatric population (95% CI 61·5-90·5), which translates to 42 374 cases per year (34 940-51 443) in Brazil, with an estimated mortality of 8305 (6848-10 083).In this representative sample of PICUs in a middle-income country, the prevalences of severe sepsis or septic shock and in-hospital mortality were high. Modifiable factors, such as incomplete vaccination and health care-associated infections, were associated with greater risk of in-hospital mortality.Fundação de Amparo à Pesquisa do Estado de São Paulo and Conselho Nacional de Desenvolvimento Científico e Tecnológico.For the Portuguese translation of the abstract see Supplementary Materials section.