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This article aims to determine the extent to which job satisfaction and justice at work influence the turnover intention of public transport workers. The power of job satisfaction and justice to predict the turnover intention was studied in employees of a public transportation company in Corumbá, Brazil, and measured using the following validated instruments: Scale of Job Satisfaction, Scale of Perception of Distributive Justice, Scale of Perception of Procedural Justice and Turnover Intention Scale. The article reports a quantitative descriptive study that uses the survey technique. The data was analyzed using descriptive statistics and measures of central tendency. Participants were found to be more satisfied with their colleagues, their boss and the nature of the work, and less satisfied with salaries and promotions. In terms of turnover intention, the survey showed an average result. The data on justice at work showed that distributive justice was perceived more positively than procedural justice. Correlation analysis revealed that job satisfaction and justice were significantly correlated with turnover intention. These results indicate that employees’ intention to leave the company where they work decreases as job satisfaction and the perception of justice at work increase.

Objectives: To illustrate in-depth validation of prediction models developed on multicenter data. Methods: For each hospital in a multicenter registry, we evaluated predictive performance of a 30-day mortality prediction model for transcatheter aortic valve implantation (TAVI) using the Netherlands heart registration (NHR) dataset. We measured discrimination and calibration per hospital in a leave-center-out analysis (LCOA). Meta-analysis was used to calculate I2 values per performance metric from the LCOA and to compute mean and confidence interval (CI) estimates. Case mix differences between studies were inspected using the framework of Debray et al. for understanding external validation. We also aimed to discover subgroups (SGs) with high model prediction error (PE) and their distribution over the centers. Results: We studied 16 hospitals with 11,599 TAVI patients with an early mortality of 3.7%. The models’ area under the curve (AUCs) had a wide range between hospitals from 0.59 to 0.79, and miscalibration occurred in seven hospitals. Mean AUC from meta-analysis was 0.68 (95% CI 0.65-0.70). I2 values were 0%, 74%, and 0% for AUC, calibration intercept and slope, respectively. Between-hospital case-mix differences were substantial, and model transportability was low. One SG was discovered with marked global PE and was associated with poor performance on validation centers. Conclusion: The illustrated combination of approaches provides useful insights to inspect multicenter-based prediction models, and it exposes their limitations in transportability and performance variability when applied to different populations.

Objective: To assess differences in adverse maternal and neonatal outcomes before and after closure of a secondary obstetric care unit of a community hospital in an urban district. Study Design: Retrospective cohort study using aggregated data from National Perinatal Registry of the Netherlands (PERINED) in the very urban region of Amsterdam, consisting of data of five secondary and two tertiary hospitals. We assessed maternal and neonatal outcomes in singleton hospital births between 24 +0 weeks of gestational age (GA) up to 42 +6 weeks. Data of 78.613 births were stratified in two groups: before closure (years 2012–2015) and after closure (2016–2019). Results: Perinatal mortality decreased significantly from 0.84 % to 0.63 % (p = 0.0009). The adjusted odds ratio (aOR) of the closure on perinatal mortality was 0.73 (95 % CI 0.62–0.87). Both antepartum death (0.46 % vs 0.36 %, p = 0.02) and early neonatal death (0.38 % vs 0.28 %, p = 0.015) declined after closure of the hospital. The number of preterm births decreased significantly (8.7 % vs 8.1 %, p=+0 onwards. The mortality decrease coincides with a reduction of preterm deliveries. The increasing trend in asphyxia and postpartum hemorrhage is of concern. Centralization of care and increasing birth volume per hospital may lead to improvement of quality of care. A broad integrated, multidisciplinary maternity healthcare system linked with the social domain can achieve health gains in maternity care for all women.

Objective: To identify whether good birth practices are being carried out for healthy newborns during the COVID-19 pandemic in a university hospital. Method: Multicenter quantitative study, carried out at a University Hospital with 72 women from March to June 2021. Data were analyzed using the PSPP software. Results: 47 (67.1%) newborns were encouraged to breastfeed in the 1st hour of life, 41 (57.7%) had skin-to-skin contact, 37 (52.9%) had timely cord clamping and 9 (12.5%) newborns did not receive any of these practices mentioned in labor and birth care. Conclusion: This study showed that, during the COVID-19 pandemic, good practices at birth and delivery were present in the care provided to healthy newborns still in the delivery room at the University Hospital, as recommended by the Ministry of Health.

O presente artigo tem por objetivo compreender algumas das principais acepções e concepções sobre uma das mais trágicas secas para os sertanejos nordestinos, especificamente, os sertanejos do interior do estado do Ceará, a seca de 1915, retratada no romance “O Quinze”, da escritora cearense Rachel de Queiroz. O texto busca contextualizar e conceituar as principais abordagens acerca da história/historiografia e literatura das secas, tomando como referencial a seca de 1915, descrita e analisada na obra do gênero literário de romance regionalista referenciada. Trata-se de um estudo teórico de abordagem qualitativa com fundamentação em fontes secundárias por meio de revisão de literatura específica que demonstra a estética da linguagem da literatura e o seu imbricamento com a história/historiografia locais. Como resultados conclusivos, é possível assegurar que “O Quinze” pode e deve ser considerado como um dos romances regionalistas mais consistentes de memória recomendável para a história/historiografia regionalista do nordeste brasileiro, sendo necessário sempre mais estudos a partir deste, visando a compreensão identitária de um Brasil mais profundo.

Cryogenic electron microscopy and data processing enable the determination of structures of isolated macromolecules to near-atomic resolution. However, these data do not provide structural information in the cellular environment where macromolecules perform their native functions, and vital molecular interactions can be lost during the isolation process. Cryogenic focused ion beam (FIB) fabrication generates thin lamellae of cellular samples and tissues, enabling structural studies on the near-native cellular interior and its surroundings by cryogenic electron tomography (cryo-ET). Cellular cryo-ET benefits from the technological developments in electron microscopes, detectors and data processing, and more in situ structures are being obtained and at increasingly higher resolution. In this Review, we discuss recent studies employing cryo-ET on FIB-generated lamellae and the technological developments in ultrarapid sample freezing, FIB fabrication of lamellae, tomography, data processing and correlative light and electron microscopy that have enabled these studies. Finally, we explore the future of cryo-ET in terms of both methods development and biological application.

Introducción: El deporte en los adultos mayores de 35 años, tiene como finalidad, promover la salud y socialización de los participantes. El fútbol es uno de los elegidos. Por tanto, mantener una composición corporal y alimentación adecuada, asegura mejor calidad de vida, rendimiento físico y prevención de lesiones. Objetivo: Analizar la composición corporal y la ingesta calórica de un equipo de fútbol sénior de Santa Fe. Metodología: Estudio con enfoque cuanti-cualitativo, descriptivo, transversal. Se evaluó antropométricamente a 21 deportistas mayores de 35 años. Se estimó ingesta alimentaria utilizando registro alimentario de 3 días, a 14 de ellos. El análisis de datos se realizó mediante Excel Microsoft. Los registros alimentarios, fueron analizados a través de Tablas de Composición Química de Alimentos del Centro de Endocrinología Experimental y Aplicada. Resultados y discusión: El promedio de masa muscular se estimó en 36,5 kg (±7,6), y la masa adiposa en 26,01 kg (±7,07). La ponderación de la primera fue inferior y, de la segunda superior a otros estudios de referencia. La ingesta energética fue menor a 3.000 Kcal en casi todos los futbolistas. El promedio de la ingesta de hidratos de carbono por kg de peso corporal/día fue insuficiente (1,7 g HC/kg PC/día). Respecto a las proteínas, solo 3 jugadores tuvieron un consumo adecuado. El resto tuvo ingestas deficientes. Conclusiones: La ingesta de hidratos de carbono y de proteínas por kilogramos de peso corporal fue insuficiente. Es necesaria la revisión de instrumentos de recolección de datos.

Adipose tissue (AT) is a highly active and plastic endocrine organ. It secretes numerous soluble molecules known as adipokines, which act locally to AT control the remodel and homeostasis or exert pleiotropic functions in different peripheral organs. Aberrant production or loss of certain adipokines contributes to AT dysfunction associated with metabolic disorders, including obesity. The AT plasticity is strictly related to tissue vascularization. Angiogenesis supports the AT expansion, while regression of blood vessels is associated with AT hypoxia, which in turn mediates tissue inflammation, fibrosis and metabolic dysfunction. Several adipokines can regulate endothelial cell functions and are endowed with either pro- or anti-angiogenic properties. Here we address the role of adipokines in the regulation of angiogenesis. A better understanding of the link between adipokines and angiogenesis will open the way for novel therapeutic approaches to treat obesity and metabolic diseases.

The development of direct electron detectors has played a key role in low-dose electron microscopy imaging applications. Monolithic active-pixel sensor detectors are currently widely applied for cryogenic electron microscopy (cryo-EM); however, they have best performance at 300 kV, have relatively low read-out speed and only work in imaging mode. Hybrid pixel detectors can operate at any energy, have a higher detective quantum efficiency (DQE) at lower voltage, have unprecedented high time resolution, and can operate in both imaging and diffraction modes. This could make them well-suited for novel low-dose life-science applications, such as cryo-ptychography, iDPC, and liquid cell imaging. Timepix3 is not frame-based, but truly event-based, and can record individual hits with 1.56 ns time resolution. Here, we present the integration of such a detector into a cryo-EM workflow and demonstrate that it can be used for automated data collection on biological specimens. The performance of the detector in terms of modulation transfer function and DQE has been investigated at 200 kV and we studied the effect of deterministic blur. We describe a single-particle analysis structure of 3 Å resolution and compare it with Falcon3 data collected using the same microscope. These studies could pave the way towards more dose-efficient single-particle techniques.

This article explores the challenge of incorporating longer historical time frames into a social semiotic understanding of meaning-making. We focus on museums as complex, multimodal assemblages, and trace the distinct trajectory of museums and their development in China. We illustrate the key differentiating stages of museums in China, and focus on the contemporary Chengdu Tianfu Art Museum (hereby TAM), as a case study exemplifying the intertwined nature of history in aspects of contemporary museum practice. We argue that history is inherently intersected in the making of materiality and meaning, and demonstrate through illustrative Spatial Discourse Analysis how this intersection is materialized in the design and use of TAM. Our analysis shows that TAM is both continuous with, and different from, prior museum practices. In doing so, we reveal connections between semiotic change and social change, and demonstrate that history and materiality cannot be divorced from the politics of representation.

RESUMO O trabalho tem como objetivo analisar a Curva ABC em áreas gerenciais da empresa de papelaria Nishikawa e Cia, localizada no município de Bela Vista - MS. A pesquisa é um estudo de caso, utilizando relatórios quantitativos da empresa para a elaboração das curvas. Ao se aplicar o Princípio de Pareto, os resultados apontaram que: as 2 principais categorias de produtos vendidos, de 14 analisadas, fazem parte da atividade principal da empresa e somaram 51% do faturamento, a estratégia de gestão de estoques não estava alinhada com as vendas, clientes cadastrados foram responsáveis por 37% do faturamento e que a curva que mais se assemelhou a regra 80/20 foi a que comparava vendas com produtos de diferentes fornecedores onde 20% dos fornecedores representaram 81% do valor de produtos vendidos. Palavras-chave: Palavra-1: Gerência. Palavra-2: Curva ABC. Palavra-3: Estudo de Caso. Palavra-4: Princípio de Pareto. Palavra-5: Regra 80/20. Palavra-6: Relatórios quantitativos.

To define the prevalence of subclinical synovitis on magnetic resonance imaging (MRI) in a large cohort of patients with juvenile idiopathic arthritis (JIA) in clinical remission and to evaluate its predictive value in terms of disease flare and joint deterioration.Ninety patients with clinically inactive JIA who underwent a contrast-enhanced (CE)-MRI of a previously affected joint were retrospectively included. Each joint was evaluated for synovitis, tenosynovitis, and bone marrow edema. Baseline and follow-up radiographs were assessed to evaluate structural damage progression.CE-MRI was acquired in 45 wrists, 30 hips, 13 ankles, and 2 knees. Subclinical synovitis was detected in 59 (65.5%) of 90 patients and bone marrow edema in 42 (46.7%) of 90 patients. Fifty-seven of 90 (63.3%) patients experienced a disease flare during follow-up. Forty-four of 59 (74.6%) patients with subclinical synovitis experienced a disease flare versus 13 (41.9%) of 31 patients with no residual synovitis on MRI (P = 0.002). The presence of subclinical synovitis was the best predictor of disease flare on multivariable regression analysis (hazard ratio [HR] 2.45, P = 0.003). Baseline and follow-up radiographs were available for 54 patients, and 17 (31.5%) of 54 patients experienced radiographic damage progression. The presence of bone marrow edema (HR 4.40, P = 0.045) and being17 years old (HR 3.51, P = 0.04) were strong predictors of joint damage progression in the multivariable analysis.MRI-detected subclinical inflammation was present in a large proportion of patients with JIA despite clinical remission. Subclinical synovitis and bone marrow edema have been shown to play a role in predicting the risk of disease relapse and joint deterioration, with potential implications for patients' management of the disease.

Background: The currently available mortality prediction models (MPM) have suboptimal performance when predicting early mortality (30-days) following transcatheter aortic valve implantation (TAVI) on various external populations. We developed and validated a new TAVI-MPM based on a large number of predictors with recent data from a national heart registry. Methods: We included all TAVI-patients treated in the Netherlands between 2013 and 2018, from the Netherlands Heart Registration. We used logistic-regression analysis based on the Akaike Information Criterion for variable selection. We multiply imputed missing values, but excluded variables with >30% missing values. For internal validation, we used ten-fold cross-validation. For temporal (prospective) validation, we used the 2018-data set for testing. We assessed discrimination by the c-statistic, predicted probability accuracy by the Brier score, and calibration by calibration graphs, and calibration-intercept and calibration slope. We compared our new model to the updated ACC-TAVI and IRRMA MPMs on our population. Results: We included 9144 TAVI-patients. The observed early mortality was 4.0%. The final MPM had 10 variables, including: critical-preoperative state, procedure-acuteness, body surface area, serum creatinine, and diabetes-mellitus status. The median c-statistic was 0.69 (interquartile range [IQR] 0.646–0.75). The median Brier score was 0.038 (IQR 0.038–0.040). No signs of miscalibration were observed. The c-statistic's temporal-validation was 0.71 (95% confidence intervals 0.64–0.78). Our model outperformed the updated currently available MPMs ACC-TAVI and IRRMA (p value < 0.05). Conclusion: The new TAVI-model used additional variables and showed fair discrimination and good calibration. It outperformed the updated currently available TAVI-models on our population. The model's good calibration benefits preprocedural risk-assessment and patient counseling.

Three-dimensionally evaluation of the treatment changes of a Herbst appliance using a lower anchorage unit not touching the lingual surface of the lower incisors. The sample consisted of 23 Class II:1 patients (12 males, 11 females) with a mean age of 15.7±1.7 years treated with a Flip-Lock Herbst® appliance (TP Orthodontics, Inc., La Porte, IN, USA). The lower anchorage unit for the Herbst appliance consisted of two anchor bands connected by a lingual arch with 3mm distance from the incisor’s lingual surface. Treatment changes in mandibular incisor inclination, overjet and overbite were evaluated by means of cone beam computed tomography images (i-CAT® Classic unit, Imaging Sciences International, Hatfield, PA, USA) obtained before and after treatment with the Herbst appliance. On average, there was a statistically significant increase in mandibular incisor inclination (2.6+1.8°) and a reduction in overjet (3.2+2.2mm) and overbite (1.3+0.9mm). Genders did not differ significantly. Incisor proclination was however only seen in 74% of the patients. The changes in mandibular incisor inclination were associated with the changes in overjet (/r/ = 0.1 to 0.5) and overbite (/r/ = 0.3 to 0.7). A Herbst appliance with a mandibular anchorage unit distant from the incisor’s lingual surface results in smaller amounts of mandibular incisor proclination compared to literature. However, as it induces canine anchorage loss, the decreased amount of proclination may not prevail after multibracket treatment. Keywords: Cone-Beam Computed Tomography. Mandibular Advancement. Tooth Movement Techniques. ResumoAvaliação tridimensional das alterações induzidas pelo aparelho Herbst utilizando a unidade de ancoragem inferior afastada da superfície lingual dos incisivos. A amostra incluiu 23 pacientes Classe II:1 (12 masculino, 11 feminino), média de idade 15,7 ± 1,7, tratados com aparelho Herbst Flip-Lock® (TP Orthodontics, Inc., La Porte, IN, EUA). A unidade de ancoragem inferior do aparelho Herbst consistiu-se de duas bandas conectadas por um arco lingual afastado 3mm da superfície lingual do incisivo. As alterações induzidas pelo tratamento na inclinação dos incisivos inferiores, trespasse horizontal e trespasse vertical foram avaliadas por meio de imagens de tomografias computadorizadas de feixe cônico (i-CAT® Classic unit, Imaging Sciences International, Hatfield, PA, USA) obtidas antes e após o tratamento com aparelho Herbst. Na média, houve diferença significativa com aumento da inclinação dos incisivos inferiores (2,6+1,8°) e diminuição do trespasse horizontal (3,2+2,2mm) e do trespasse vertical (1,3+0,9mm). Não houve diferença estatística entre os sexos. No entanto, a vestibularização do incisivo ocorreu em apenas 74% dos pacientes. As alterações na inclinação dos incisivos inferiores apresentam correlação estatisticamente significativa com as alterações no trepasse horizontal (/r/ = 0,1 a 0,5) e no trespasse vertical (/r/ = 0,3 a 0,7). O aparelho Herbst com uma unidade de ancoragem inferior afastada da superfície lingual dos incisivos resulta em menor quantidade de vestibularização do incisivo inferior em comparação com a literatura. Entretanto, como isto induz perda de ancoragem do canino, a diminuição da vestibularização pode não prevalecer ao final tratamento ortodôntico com braquetes. Palavras-chave: Tomografia Computadorizada de Feixe Cônico. Avanço Mandibular. Técnicas de Movimentação Dentária.

Although during the initial stages of COVID-19 pandemic, the pediatric population seemed to be less affected, a number of SARS-CoV-2-related manifestations emerged over time, the principal of which is the multisystem inflammatory syndrome in children (MIS-C). Here we provide an update on the main pediatric disorders associated with SARS-CoV-2 infection.MIS-C is novel postinfectious manifestation with clinical features similar to Kawasaki disease and characterized by intense systemic inflammation affecting multiple organs. Many children required intensive care therapy because of circulatory shock, usually of myocardial origin. Appropriate treatment with immunomodulatory therapies led to favorable outcomes in most patients, with recovery of overall health and cardiac dysfunction. In addition to MIS-C, a variety of other complications of COVID-19 in children have been described, including thrombotic events, neurologic manifestations, and chilblain-like lesions. There is still uncertainty about the true prevalence of long COVID in children and its distinction from pandemic-related complaints.The experience gained so far with MIS-C and the other SARS-CoV-2-related complications in children and adolescents will facilitate accurate diagnosis and appropriate treatment. Further studies are needed to elucidate the pathophysiology of MIS-C and to determine the real impact of long-COVID in the pediatric age group.

The current study aimed to investigate the validity of three ActiGraph predictive equations that are available to estimate free-living physical activity energy expenditure (PAEE) in women with severe obesity. The study included 20 women with class III obesity (age: 22-38 years). During 14 days of free-living conditions, total energy expenditure was measured using the doubly labelled water method; in addition, participants wore a triaxial accelerometer (model GT3X+) on the hip. The resting metabolic rate was measured by indirect calorimetry. At group level, the Freedson VM3 Combination was found to be more precise (bias = -61 kcal/day) than the Williams Work-Energy (bias = -283 kcal/day) and the Freedson Combination equations (bias = -186 kcal/day) for estimating PAEE. However, the three predictive equations had a wider limit of agreement (Williams Work-Energy [258, -824 kcal/day], Freedson Combination equations [324, -697 kcal/day] and Freedson VM3 Combination [424, -546 kcal/day]), indicating great uncertainty of the estimate. In conclusion, a wide variation was observed in the performance of different ActiGraph equations in estimating free-living PAEE among women with class III obesity. Therefore, our data do not support the use of these equations, and more studies are needed to improve predictive performance in free-living conditions.

Objective To assess concordance among criteria for inactive disease (ID) and low disease activity (LDA) in juvenile idiopathic arthritis (JIA) and to seek factors driving discordance. Methods The frequency of fulfillment of existing criteria was evaluated in information on 10,186 patients extracted from 3 cross-sectional data sets. Patients were divided up according to the functional phenotypes of oligoarthritis and polyarthritis. Concordance between criteria was examined using weighted Venn diagrams. The role of each individual component in explaining discordance between criteria was assessed by calculating the absolute number and percentage of instances in which the component was responsible for discrepancy between definitions. Results Criteria for ID were met by 28.6–41.1% of patients with oligoarthritis and by 24.0–33.4% of patients with polyarthritis. Criteria for LDA were met by 44.8–62.4% of patients with oligoarthritis and by 44.6–50.4% of patients with polyarthritis. There was a 57.9–62.3% overlap between criteria for ID and a 67.9–85% overlap between criteria for LDA. Parent and physician global assessments and acute-phase reactants were responsible for the majority of instances of discordance among criteria for ID (8.7–15.5%, 10.0–12.3%, and 10.8–17.3%, respectively). Conclusion We found fair concordance between criteria for ID and LDA in JIA, with the main drivers of discordance for ID being physician and parent global assessments and acute-phase reactants. This observation highlights the need for further studies aimed to evaluate the impact of subjective physician and parent perception of disease remission and of laboratory measures of inflammatory activity on the definition of ID.

No Brasil o agronegócio se destaca como uma das atividades de maior geração de renda e impacto nos mercados mundiais. Dentro desse contexto, a pecuária de corte coloca o país como um dos maiores produtores e exportadores de carne bovina e, dentro desta, destaca-se a modalidade de confinamento e semiconfinamento, que vem apresentando crescente adesão por parte dos produtores dadas suas vantagens em relação a forma convencional de criação de bovinos. Neste sentido, o presente estudo possui como objetivo a identificação dos fatores que influenciam na compra de núcleos de composição da dieta de gados confinados. Para tanto, foi desenvolvida uma pesquisa quantitativa descritiva, realizada através da aplicação de questionários estruturados a 83 confinadores de gado da região Centro-Oeste do país. Após a coleta dos dados e caracterização da amostra através de estatística descritiva, foi realizada a Análise Fatorial. Os resultados mostram que a mesma apresentou a possibilidade de identificar fatores latentes a um nível de explicação moderado (58,1%), através da composição de quatro fatores (Reputação do vendedor, Praticidade Técnica, Segurança e Resultado) que são compostos pelas dez variáveis estudadas, indicando que os principais pontos para a definição de compra do produto se vincula a esses itens, ressaltando-se ainda que a variável “Nível de garantia” não se enquadrou em nenhum dos fatores estipulados, de forma que a mesma não se caracteriza como um ponto chave a ser analisado na mensuração do processo de compra.

Purpose Data on the role of prolactin (PRL) in the physiologic range in the female sexual response are scanty. We aimed at investigating the association between PRL and sexual function as assessed by the Female Sexual Function Index (FSFI). We explored the presence of a cut-off level of PRL able to identify Hypoactive Sexual Desire Disorder (HSDD). Methods 277 pre- and post-menopausal women consulting for Female Sexual Dysfunction (FSD) and sexually active were enrolled in an observational, retrospective study. 42 women were used as no-FSD controls. A clinical, biochemical and psychosexual evaluation was performed. The main outcome measures were: FSFI, Female Sexual Distress Scale-Revised, Middlesex Hospital Questionnaire and Sexual excitation/sexual inhibition scale (SIS/SES). Results Normo-PRL FSD women (n = 264) showed lower FSFI Desire score than controls (n = 42), and higher than hyper-PRL FSD women (n = 13). These differences emerged both in pre-menopausal and post-menopausal subjects. In the normo-PRL FSD group, those with PRL in the higher quintile reported higher FSFI Desire scores than those with PRL in the lowest quintile. Women with HSDD presented a lower PRL level than those without (p = 0.032). A ROC curve analysis for PRL showed an accuracy of 0.610 ± 0.044 (p = 0.014) in predicting HSDD. With a threshold of p = 0.006) and lower cortisol levels (p = 0.003) than those with PRL > = 9.83 μg/L. Conclusions Hyper-PRL is associated with low desire; however, among normo-PRL FSD women, those with the lowest levels demonstrated a poorer desire than those with the highest levels. PRL

Background Cancer stem-like cells (CSCs) are a subpopulation of tumor cells responsible for tumor initiation, metastasis, chemoresistance, and relapse. Recently, CSCs have been identified in Uveal Melanoma (UM), which represents the most common primary tumor of the eye. UM is highly resistant to systemic chemotherapy and effective therapies aimed at improving overall survival of patients are eagerly required. Methods Herein, taking advantage from a pan Fibroblast Growth Factor (FGF)-trap molecule, we singled out and analyzed a UM-CSC subset with marked stem-like properties. A hierarchical clustering of gene expression data publicly available on The Cancer Genome Atlas (TCGA) was performed to identify patients’ clusters. Results By disrupting the FGF/FGF receptor (FGFR)-mediated signaling, we unmasked an FGF-sensitive UM population characterized by increased expression of numerous stemness-related transcription factors, enhanced aldehyde dehydrogenase (ALDH) activity, and tumor-sphere formation capacity. Moreover, FGF inhibition deeply affected UM-CSC survival in vivo in a chorioallantoic membrane (CAM) tumor graft assay, resulting in the reduction of tumor growth. At clinical level, hierarchical clustering of TCGA gene expression data revealed a strong correlation between FGFs/FGFRs and stemness-related genes, allowing the identification of three distinct clusters characterized by different clinical outcomes. Conclusions Our findings support the evidence that the FGF/FGFR axis represents a master regulator of cancer stemness in primary UM tumors and point to anti-FGF treatments as a novel therapeutic strategy to hit the CSC component in UM.

Introduction Female Orgasm Disorder and its risk factors are still under-investigated. Objective To describe the psychological, relational and clinical correlates of orgasmic function during partnered sexual activity in women consulting for sexual symptoms. Methods In an observational retrospective study, we collected data from a consecutive sample of 430 heterosexual, sexually active women (mean age 46±12.9 years) consulting for sexual symptoms. All patients underwent a structured interview and a physical, gynecologic and laboratory examination; they completed a series of validated questionnaires, including the Female Sexual Function Index (FSFI), the Female Sexual Distress Scale-Revised (FSDS-R), the Middlesex Hospital Questionnaire (MHQ), the Body Uneasiness Test (BUT-A and BUT-B), the Sexual Inhibition/Excitation Scale (SIS/SES), and the Dyadic Adjustment Scale (DAS). Results 268 subjects (62%) reported a persistent distressing decrease of the frequency of orgasm for at least six months. Among them, 93 (22% of the whole sample) reported a mild decrease, 91 (21%) a severe decrease, and 19% reported anorgasmia. Nine women described Anorgasmia as lifelong. The severe decrease of orgasm frequency during partnered sexual activity was associated with the inability to reach orgasm with masturbation (p=0.009). After adjusting for age and menopausal status, the FSFI Orgasm (FSFI-O) domain was negatively associated with MHQ total score (p=0.001), an index of general psychopathology, and with body image concerns, explored through both BUT-A and BUT-B global measures. The stronger correlation emerged with the BUT-A Avoidance subscale (p=0.005). Among other psychological parameters, significant, negative correlations were observed between FSFI-O and a reported diagnosis of psychiatric disease, including mood disorders (p=0.001), use of antidepressants (p=0.001), chronic stress (p=0.002), and familiar conflicts (p=0.008). Noteworthy, no correlation was observed between FSFI-O and Inhibition/Excitation measures. When exploring sexual and relational parameters, we found that women displaying higher FSFI-O scores were more likely to be engaged in a stable sexual relationship (p=0.003), to report at least three sexual encounters per month (p Conclusions Orgasmic function was correlated with anxiety and depressive symptoms, use of antidepressants, body image concerns, marital conflicts and low partner’s desire, independently of age and menopausal status. Risk factors for severe FOD were psychiatric diseases, abuse history, urinary incontinence and past pelvic surgery. Disclosure No

IntroductionNew early low-invasive biomarkers are demanded for the management of Oligoarticular Juvenile Idiopathic Arthritis (OJIA), the most common chronic pediatric rheumatic disease in Western countries and a leading cause of disability. A deeper understanding of the molecular basis of OJIA pathophysiology is essential for identifying new biomarkers for earlier disease diagnosis and patient stratification and to guide targeted therapeutic intervention. Proteomic profiling of extracellular vesicles (EVs) released in biological fluids has recently emerged as a minimally invasive approach to elucidate adult arthritis pathogenic mechanisms and identify new biomarkers. However, EV-prot expression and potential as biomarkers in OJIA have not been explored. This study represents the first detailed longitudinal characterization of the EV-proteome in OJIA patients.MethodsFourty-five OJIA patients were recruited at disease onset and followed up for 24 months, and protein expression profiling was carried out by liquid chromatography-tandem mass spectrometry in EVs isolated from plasma (PL) and synovial fluid (SF) samples.ResultsWe first compared the EV-proteome of SF vs paired PL and identified a panel of EV-prots whose expression was significantly deregulated in SF. Interaction network and GO enrichment analyses performed on deregulated EV-prots through STRING database and ShinyGO webserver revealed enrichment in processes related to cartilage/bone metabolism and inflammation, suggesting their role in OJIA pathogenesis and potential value as early molecular indicators of OJIA development. Comparative analysis of the EV-proteome in PL and SF from OJIA patients vs PL from age/gender-matched control children was then carried out. We detected altered expression of a panel of EV-prots able to differentiate new-onset OJIA patients from control children, potentially representing a disease-associated signature measurable at both the systemic and local levels with diagnostic potential. Deregulated EV-prots were significantly associated with biological processes related to innate immunity, antigen processing and presentation, and cytoskeleton organization. Finally, we ran WGCNA on the SF- and PL-derived EV-prot datasets and identified a few EV-prot modules associated with different clinical parameters stratifying OJIA patients in distinct subgroups.DiscussionThese data provide novel mechanistic insights into OJIA pathophysiology and an important contribution in the search of new candidate molecular biomarkers for the disease.

Cell motility—a cellular behavior of paramount relevance in embryonic development, immunological response, metastasis, or angiogenesis—demands a mechanical deformation of the cell membrane and influences the surface motion of molecules and their biochemical interactions. In this work, we develop a fully coupled multi-physics model able to capture and predict the protein flow on endothelial advecting plasma membranes. The model has been validated against co-designed in vitro experiments. The complete picture of the receptor dynamics has been understood, and limiting factors have been identified together with the laws that regulate receptor polarization. This computational approach might be insightful in the prediction of endothelial cell behavior in different tumoral environments, circumventing the time-consuming and expensive empirical characterization of each tumor.

During melanoma progression, malignant melanocytes are reprogrammed into mesenchymal-like cells through to an epithelial–mesenchymal transition (EMT) process associated with the acquisition of an invasive, prometastatic phenotype. The fibroblast growth factor-2 (FGF2)/FGF receptor (FGFR) system plays a pivotal role in melanoma, leading to autocrine/paracrine induction of tumor cell proliferation and angiogenesis. Long pentraxin-3 (PTX3) interacts with FGF2, and other FGF family members, inhibiting FGF-dependent neovascularization and tumor growth. Here, PTX3 protein and the PTX3-derived acetylated pentapeptide Ac-ARPCA-NH2 inhibit FGF2-driven proliferation and downstream FGFR signaling in murine melanoma B16-F10 cells. Moreover, human PTX3-overexpressing hPTX_B16-F10 cells are characterized by the reversed transition from a mesenchymal to an epithelial-like appearance, inhibition of cell proliferation, loss of clonogenic potential, reduced motility and invasive capacity, downregulation of various mesenchymal markers, and upregulation of the epithelial marker E-cadherin. Accordingly, PTX3 affects cell proliferation and EMT transition in human A375 and A2058 melanoma cells. Also, hPTX_B16-F10 cells showed a reduced tumorigenic and metastatic activity in syngeneic C57BL/6 mice. In conclusion, PTX3 inhibits FGF/FGFR-driven EMT in melanoma cells, hampering their tumorigenic and metastatic potential. These data represent the first experimental evidence about a nonredundant role of the FGF/FGFR system in the modulation of the EMT process in melanoma and indicate that PTX3 or its derivatives may represent the basis for the design of novel therapeutic approaches in FGF/FGFR-dependent tumors, including melanoma. Mol Cancer Ther; 12(12); 2760–71. ©2013 AACR.

PDF - 44KB, Legends to Supplementary Figures S1-S4.

PDF - 37KB, hPTX3 overexpression in B16-F10 cells.

PDF - 117KB, PTX3 expression in human melanoma.

PDF - 114KB, Morphogenic assay on Matrigel.

PDF - 65KB, Matrigel implant assay.

PDF - 33KB, List of oligonucleotide primers utilized for PCR experiments.

Background/Aims International interest in development of treat-to-target (T2T) in both childhood-onset systemic lupus erythematosus (cSLE) and adult-onset SLE (aSLE) is increasing. T2T could facilitate more effective and structured use of treatments, aggressively controlling disease activity, preventing organ damage, and improving health-related quality of life. The first step is the selection of an appropriate target. Remission is deemed the ultimate target, but may not be attainable by all. Low disease activity (LDA), based on the principle of “tolerable” disease activity on stable treatment, with low corticosteroid dosage, may be more appropriate for some patients. The aim of this study was to derive a consensus-based cSLE appropriate definition of LDA, building upon existing aSLE definitions to improve applicability to cSLE, whilst maintaining sufficient unity to ensure that future T2T studies including adolescents and adults together are possible. Methods The International cSLE T2T Task Force, including 18 specialists from paediatric rheumatology/nephrology, and adult rheumatology undertook a series of Delphi surveys, exploring views on aSLE LDA targets. Two virtual consensus meetings were held, utilising a modified nominal group technique to debate, modify, and vote upon topics underpinning the cSLE LDA target and its criteria. Agreement of > 80% was considered consensus. Results The task force agreed that the LDA target should encompass cSLE as a whole and be based upon the aSLE Lupus Low Disease Activity State definition (LLDAS), with modifications to make it more applicable to cSLE (cLLDAS, all 100% agreement). A conceptual definition of cLLDAS was defined: ‘A state, which if sustained, is associated with a low likelihood of adverse outcome (considering disease activity, damage, and medication toxicity)’ (100% agreement). Five cLLDAS criteria were agreed, as detailed within Table 1. The final cLLDAS definition was endorsed by the Paediatric Rheumatology European Society (PReS) Executive Council and PReS cSLE Working Party Chair, on behalf of the Society. Conclusion A cSLE, age-appropriate definition of cLLDAS has been generated, preserving sufficient unity with the aSLE LLDAS definition to encourage life-course research. The development and validation of targets has been a key enabler for T2T trials, therefore this initiative represents a significant step forward for cSLE. Disclosure E.M.D. Smith: None. A. Aggarwal: None. J. Ainsworth: None. E. Al-Abadi: None. T. Avcin: None. L. Bortey: None. J. Burnham: None. C. Ciurtin: None. C.M. Hedrich: None. S. Kamphuis: None. D. Levy: None. L. Lewandowski: None. N. Maxwell: None. E. Morand: None. S. Ozen: None. C. Pain: None. A. Ravelli: None. C. Saad Magalhaes: None. C. Pilkington: None. D. Schonenberg: None. C. Scott: None. K. Tullus: None. M.W. Beresford: None.

Objective: To investigate trends in low 5-minute Apgar scores in (near) term singletons. Design: Nationwide cohort study. Setting: The Netherlands. Population: A cohort of 1,583,188 singletons liveborn between 35 and 42 weeks of gestation in the period 2010-2019 from the Dutch Perinatal Registry. Methods: We studied trends using Cochrane-Armitage trend tests. Risk factors were studied by logistic regression analysis and Population Attributable Risk (PAR) calculation. Main outcome measures: Low 5-minute Apgar score (Results: The proportion of infants with low 5-minute Apgar score Conclusions In the Netherlands, the risk of a low 5-minute Apgar score increased significantly over the last decade, with the highest increase being observed in the obstetric intervention subgroups of instrumental vaginal delivery and emergency caesarean section. Neonatal mortality remained stable over the study period.