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BACKGROUND: RNA modifications are important regulators of transcript activity and an increasingly emerging body of data suggests that the epitranscriptome and its associated enzymes are altered in human tumors. METHODS: Combining data mining and conventional experimental procedures, NSUN7 methylation and expression status was assessed in liver cancer cell lines and primary tumors. Loss-of-function and transfection-mediated recovery experiments coupled with RNA bisulfite sequencing and proteomics determined the activity of NSUN7 in downstream targets and drug sensitivity. RESULTS: In this study, the initial screening for genetic and epigenetic defects of 5-methylcytosine RNA methyltransferases in transformed cell lines, identified that the NOL1/NOP2/Sun domain family member 7 (NSUN7) undergoes promoter CpG island hypermethylation-associated with transcriptional silencing in a cancer-specific manner. NSUN7 epigenetic inactivation was common in liver malignant cells and we coupled bisulfite conversion of cellular RNA with next-generation sequencing (bsRNA-seq) to find the RNA targets of this poorly characterized putative RNA methyltransferase. Using knock-out and restoration-of-function models, we observed that the mRNA of the coiled-coil domain containing 9B (CCDC9B) gene required NSUN7-mediated methylation for transcript stability. Most importantly, proteomic analyses determined that CCDC9B loss impaired protein levels of its partner, the MYC-regulator Influenza Virus NS1A Binding Protein (IVNS1ABP), creating sensitivity to bromodomain inhibitors in liver cancer cells exhibiting NSUN7 epigenetic silencing. The DNA methylation-associated loss of NSUN7 was also observed in primary liver tumors where it was associated with poor overall survival. Interestingly, NSUN7 unmethylated status was enriched in the immune active subclass of liver tumors. CONCLUSION: The 5-methylcytosine RNA methyltransferase NSUN7 undergoes epigenetic inactivation in liver cancer that prevents correct mRNA methylation. Furthermore, NSUN7 DNA methylation-associated silencing is associated with clinical outcome and distinct therapeutic vulnerability.

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Innate immune responses rely on inducible gene expression programmes which, in contrast to steady-state transcription, are highly dependent on cohesin. Here we address transcriptional parameters underlying this cohesin-dependence by single-molecule RNA-FISH and single-cell RNA-sequencing. We show that inducible innate immune genes are regulated predominantly by an increase in the probability of active transcription, and that probabilities of enhancer and promoter transcription are coordinated. Cohesin has no major impact on the fraction of transcribed inducible enhancers, or the number of mature mRNAs produced per transcribing cell. Cohesin is, however, required for coupling the probabilities of enhancer and promoter transcription. Enhancer-promoter coupling may not be explained by spatial proximity alone, and at the model locus Il12b can be disrupted by selective inhibition of the cohesinopathy-associated BET bromodomain BD2. Our data identify discrete steps in enhancer-mediated inducible gene expression that differ in cohesin-dependence, and suggest that cohesin and BD2 may act on shared pathways.

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BACKGROUND: Previous safety issues involving medical devices have stressed the need for better safety signal detection. Various European Union (EU) national competent authorities have started to focus on strengthening the analysis of vigilance data. Consequently, article 90 of the new EU regulation states that the European Commission shall put in place systems and processes to actively monitor medical device safety signals. METHODS: A systematic literature review was conducted to synthesize the current state of knowledge and investigate the present tools used for medical device safety signal detection. An electronic literature search was performed in Embase, Medline, Cochrane, Web of science, and Google scholar from inception until January 2017. Articles that included terms related to medical devices and terms associated with safety were selected. A further selection was based on the abstract review. A full review of the remaining articles was conducted to decide on which articles finally to consider relevant for this review. Completeness was assessed based on the content of the articles. RESULTS: Our search resulted in a total of 20,819 articles, of which 24 met the inclusion criteria and were subject to data extraction and completeness scoring. A wide range of data sources, especially spontaneous reporting systems and registries, used for the detection and assessment of product problems and patient harms associated with the use of medical devices, were studied. Coding is remarkably heterogeneous, no agreement on the preferred methods for signal detection exists, and no gold standard for signal detection has been established thus far. CONCLUSION: Data source harmonization, the development of gold standard signal detection methodologies and the standardization of coding dictionaries are amongst the recommendations to support the implementation of a new proactive approach to signal detection. The new safety surveillance system will be able to use real-world evidence to support regulatory decision-making across all jurisdictions.

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CD4 and CD8 mark helper and cytotoxic T cell lineages, respectively, and serve as coreceptors for MHC-restricted TCR recognition. How coreceptor expression is matched with TCR specificity is central to understanding CD4/CD8 lineage choice, but visualising coreceptor gene activity in individual selection intermediates has been technically challenging. It therefore remains unclear whether the sequence of coreceptor gene expression in selection intermediates follows a stereotypic pattern, or is responsive to signaling. Here we use single cell RNA sequencing (scRNA-seq) to classify mouse thymocyte selection intermediates by coreceptor gene expression. In the unperturbed thymus, Cd4+Cd8a- selection intermediates appear before Cd4-Cd8a+ selection intermediates, but the timing of these subsets is flexible according to the strength of TCR signals. Our data show that selection intermediates discriminate MHC class prior to the loss of coreceptor expression and suggest a model where signal strength informs the timing of coreceptor gene activity and ultimately CD4/CD8 lineage choice.

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INTRODUCTION: The amount of mandatory data that needs to be analyzed as part of a medical device postmarket surveillance (PMS) system has grown exponentially in recent times. This is a consequence of increasingly demanding and complex regulatory requirements from Health Authorities, aimed at a better understanding of the medical device safety evaluation. Proactive approaches to PMS processes are becoming more necessary as regulators increase the scrutiny of device safety. New technologies have been explored to address some of the challenges associated with this changing regulatory environment. AREAS COVERED: This paper focuses on the different technical aspects of blockchain and how this new technology has the potential to support the ongoing efforts to improve the PMS system for medical devices. EXPERT OPINION: To address these challenges, we suggest to generate a private PMS data permissioned blockchain with a proof-of-authority consensus mechanism, to which only a restricted number of designated and audited participants have authorization to validate transactions and add them to the PMS data blockchain ledger. Blockchain has the potential to support a more efficient approach, which could offer many advantages to the different stakeholders involved in the PMS process, such as supporting with new regulatory initiatives.

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PURPOSE: Recent safety issues involving medical devices have highlighted the need for better postmarket surveillance (PMS) evaluation. This article aims to describe and to assess the quality of the PMS data for a medical device and, finally, to provide recommendations to improve the data gathering process. METHODS: A descriptive analysis of medical device reports (MDRs) on the use of MRA, a specific type of hip implant replacement submitted to the Food and Drug Administration Manufacturer and User Facility Device Experience database from 1 January 2008 to 31 December 2017. The number of reports was described as the number of MDRs per unique MDR number and stratified by different variables. The quality was assessed by the level of completeness of the collected PMS data. RESULTS: The total number of reports related to MRA was 2377, and the number of MDRs per year ranged between 84 in 2009 and 452 in 2017. Most of the reports were reported by manufacturer Depuy Johnson & Johnson and were reported by a physician. In 44.9% of the reports, the device problem was reported as "Unknown." When the device problem was known, in the majority of cases, it was related to an implant fracture. The quality of the collected data was assessed as low due to missing information. CONCLUSION: The underlying data should meet high quality standards to generate more evidence and to ensure a timely signal generation. This case study shows that the completeness and quality of the MDRs can be improved. The authors propose the development of tools to ensure a more dynamic complaint data collection to contribute to this enhancement.

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PURPOSE: Recent public health safety issues involving medical devices have led to a growing demand to improve the current passive-reactive postmarket surveillance (PMS) system. Various European Union (EU) national competent authorities have started to focus on strengthening the postmarket risk evaluation. As a consequence, the new EU medical device regulation was published; it includes the concept of a PMS Plan. METHODS: This publication reviewed Annex III Technical Documentation on PMS and Annex XIV Part B: Postmarket clinical follow-up from the new Regulation (EU) 2017/745 of the European Parliament and of the Council on medical devices. RESULTS: The results of the PMS activities will be described in the PMS plan and will be used to update other related documents. A modular approach to structure the contents of the PMS plan will help to consistently update other PMS information. It is our suggestion that the PMS plan should consist of a PMS plan Core and a PMS plan Supplement. The PMS plan Core document will describe the PMS system, and the PMS plan Supplement will outline the specific activities performed by the manufacturer for a particular medical device. CONCLUSIONS: The PMS plan may serve as a thorough tool for the benefit-risk evaluation of medical devices. If properly developed and implemented, it will function as a key player in the establishment of a new framework for proactive safety evaluation of medical devices.

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Cohesin is important for 3D genome organization. Nevertheless, even the complete removal of cohesin has surprisingly little impact on steady-state gene transcription and enhancer activity. Here we show that cohesin is required for the core transcriptional response of primary macrophages to microbial signals, and for inducible enhancer activity that underpins inflammatory gene expression. Consistent with a role for inflammatory signals in promoting myeloid differentiation of hematopoietic stem and progenitor cells (HPSCs), cohesin mutations in HSPCs led to reduced inflammatory gene expression and increased resistance to differentiation-inducing inflammatory stimuli. These findings uncover an unexpected dependence of inducible gene expression on cohesin, link cohesin with myeloid differentiation, and may help explain the prevalence of cohesin mutations in human acute myeloid leukemia.

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Recent safety issues involving non-active implantable medical devices (NAIMDs) have highlighted the need for better pre-market and post-market evaluation. Some stakeholders have argued that certain features of medicine safety evaluation should also be applied to medical devices. Our objectives were to compare the current processes and methodologies for the assessment of NAIMD safety profiles with those for medicines, identify potential gaps, and make recommendations for the adoption of new methodologies for the ongoing benefit-risk monitoring of these devices throughout their entire life cycle. A literature review served to examine the current tools for the safety evaluation of NAIMDs and those for medicines. We searched MEDLINE using these two categories. We supplemented this search with Google searches using the same key terms used in the MEDLINE search. Using a comparative approach, we summarized the new product design, development cycle (preclinical and clinical phases), and post-market phases for NAIMDs and drugs. We also evaluated and compared the respective processes to integrate and assess safety data during the life cycle of the products, including signal detection, signal management, and subsequent potential regulatory actions. The search identified a gap in NAIMD safety signal generation: no global program exists that collects and analyzes adverse events and product quality issues. Data sources in real-world settings, such as electronic health records, need to be effectively identified and explored as additional sources of safety information, particularly in some areas such as the EU and USA where there are plans to implement the unique device identifier (UDI). The UDI and other initiatives will enable more robust follow-up and assessment of long-term patient outcomes. The safety evaluation system for NAIMDs differs in many ways from those for drugs, but both systems face analogous challenges with respect to monitoring real-world usage. Certain features of the drug safety evaluation process could, if adopted and adapted for NAIMDs, lead to better and more systematic evaluations of the latter.

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While evidence is accumulating to support specific neurocognitive deficits as putative endophenotypes for schizophrenia, the heritability of these deficits in healthy subjects and whether they share common genetic influences, is not well established. In the present study, 529 healthy adult twins from two centers within the European Twin Study Network on Schizophrenia (EUTwinsS) were assessed on two domains that are consistently found to be particularly compromised in schizophrenia. Specifically, Intellectual Quotient Score (IQ) and the Letter-Number Sequencing Test (LNS), a measure of working memory, were measured in all twins. Latent variable components were explored through structural equation modeling, and common genetic underpinnings were examined using bivariate analyses. Results showed that the phenotypic correlation between IQ and working memory was almost entirely attributed to shared genetic variance (95.5%). We discuss the potential use of a combined measure of IQ and working memory to improve the power of molecular studies in detecting the genetic mechanisms underlying schizophrenia.

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This article discusses new latent variable techniques developed by the authors. As an illustration, a new factor mixture model is applied to the monozygotic-dizygotic twin analysis of binary items measuring alcohol-use disorder. In this model, heritability is simultaneously studied with respect to latent class membership and within-class severity dimensions. Different latent classes of individuals are allowed to have different heritability for the severity dimensions. The factor mixture approach appears to have great potential for the genetic analyses of heterogeneous populations. Generalizations for longitudinal data are also outlined.

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Twin registries form an exceptionally rich source of information that is largely unexploited for phenotypic analyses. One obstacle to straightforward phenotypic statistical analysis is the inherent dependency, which is due to the clustering of cases within families. The present simulation study gauges the degree of the bias produced by the dependency of family data on the estimates of standard errors and chi-squared, when they are treated as independent observations in a phenotypic model, and assesses the efficiency of an estimator, which corrects for dependency. When family-clustered data are used for phenotypic analysis, in treating individuals as independent, and using standard maximum likelihood estimation, there is a tendency for the chi-square statistic to be overestimated, and the standard errors of the parameters to be underestimated. The bias increases with family resemblance, due to heritability or shared environment. The source of family resemblance -- either heritability (h(2)) and/or shared environment (c(2)) -- interacts with the composition of the sample. In the absence of c(2), samples with twins, parents and spouses show the lowest bias, whereas in the presence of c(2) samples with only twins show the lowest bias. In all conditions the bias remained below 15%. The use of the 'complex option' available in Mplus (clustering corrected robust maximum likelihood estimation) reduces the bias to the levels observed when only independent cases are considered. Thus with the use of robust estimates the bias due to family dependency becomes practically negligible in all conditions of dependency. In conclusion, the present study shows that the bias due to dependency in family data does not form a serious obstacle to phenotypic data analysis.

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OBJECTIVE: There is a dose-response positive relationship between type A behavior (TABP) and cardiovascular disease-related symptoms. Estimates of heritability for TABP from previous studies vary; this might be explained by limitations in the sizes and compositions of the samples. METHODS: This study combines a large sample size, twin and parental, data from males and females, two generations of young adults and older adults, and the use of structural equation modeling (SEM) and full information maximum likelihood (FIML) estimation. To assess TABP, the Jenkins Activity Survey (JAS) was collected from MZ and DZ twins and their parents (n = 1670 twin families). Structural equation modeling is used to evaluate and estimate the effects of additive and nonadditive genetic effects, nonshared environmental effects, and competitive sibling interaction. RESULTS: Forty-five percent of the variance in TABP was the result of genetic factors (28% were additive and 17% were nonadditive). The remaining 55% of the variance was explained by environmental factors not shared by the members of the same family. Competitive sibling interaction effects were not significant. There was no evidence of sex differences either in variances or means. CONCLUSION: Understanding the sources of variance on TABP is important for therapy and prevention. According to the present results, the relevant environmental factors for the development of TABP are not shared by the members of the same family. The genetic portion of the variance is also worth considering for therapeutic purposes. Although the genetic code cannot be altered, its effects on behavior may be modifiable through the treatment of the biological mediators.

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BACKGROUND: The Child Behavior Checklist-juvenile bipolar disorder phenotype (CBCL-JBD) is a quantitative phenotype that is based on parental ratings of the behavior of the child. The phenotype is predictive of DSM-IV characterizations of BD and has been shown to be sensitive and specific. Its genetic architecture differs from that for inattentive, aggressive, or anxious-depressed syndromes. The purpose of this study is to assess the developmental stability of the CBCL-JBD phenotype across ages 7, 10, and 12 years in a large population-based twin sample and to examine its genetic architecture. METHODS: Longitudinal data on Dutch mono- and dizygotic twin pairs (N = 8013 pairs) are analyzed to decompose the stability of the CBCL-JBD phenotype into genetic and environmental contributions. RESULTS: Heritability of the CBCL-JBD increases with age (from 63% to 75%), whereas the effects of shared environment decrease (from 20% to 8%). The stability of the CBCL-JBD phenotype is high, with correlations between .66 and .77 across ages 7, 10, and 12 years. Genetic factors account for the majority of the stability of this phenotype. There were no sex differences in genetic architecture. CONCLUSIONS: Roughly 80% of the stability in childhood CBCL-JBD is a result of additive genetic effects.

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There is great interest in the relationships between memory span tasks and cognitive abilities. However, the causes underlying their correlation remain unknown. In the present article, five key data sets were reanalyzed according to two criteria: They must consider complex span tasks (so-called working memory [WM] tasks) and simple span tasks (so-called short-term memory [STM] tasks), and they must comprise cognitive ability measures. The obtained results offer several points of interest. First, memory span tasks should be conceived from a hierarchical perspective: They comprise both general and specific components. Second, the general component explains about four times the variance explained by the specific components. Third, STM and WM measures are closely related. Fourth, STM and WM measures share the same common variance with cognitive abilities. Finally, the strong relationship usually found between memory span tasks and cognitive abilities could be tentatively interpreted by the component shared by STM and WM--namely, the capacity for temporarily preserving a reliable memory representation of any given information.

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The knowledge of the causes and development of anger is still scarce. Previous studies on the sources of variance on Type A Behavior Pattern (TABP) related measures found variable heritability estimates ranging from 0.12 to 0.68, and large differences between MZ and DZ correlations. Some authors considered dominance genetic effects, competitive sibling interaction and sex differences as possible mechanisms to explain the results, but most studies lacked power. The present study uses a large sample of more than 2,500 families, with longitudinal data from MZ and DZ pairs as well as their parents, to disentangle the sources of variance on anger. Model Fitting results showed that the sources of variance differ across sexes. For males 23% of the variance is due to additive genetic effects, and 26% to dominance genetic effects. For females 34% of the variance is due to additive genetic effects, and no dominance effects are found. There was no consistent evidence to confirm the presence of competitive sibling interaction as an alternative explanation for the low correlations in DZ males. The focus of research on the prediction of coronary heart disease (CHD) risk through psychological characteristics has recently changed from the multidimensional TABP to its emotional component: Anger. Understanding the sources of individual differences on anger can help to clarify the mechanisms that link it with CHD and its possible implications for treatment and prevention.

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Despite the increasing importance of the ability-level differentiation hypothesis, no study has been conducted to clarify the role played by sex regarding this issue. A battery of cognitive tests was administered to a sample of 10,247 participants (6,068 males and 4,179 females). Results show a differentiation effect in males (around 2%) but not in females. Therefore, the ability-level differentiation hypothesis is substantiated for males only (AU)

A pesar de la importancia creciente de la hipótesis de la diferenciación por nivel, ningún estudio se ha dirigido a clarificar el papel que la variable sexo juega con respecto a este asunto. En el presente estudio, una batería de pruebas cognitivas se administró a una muestra de 10.247 participantes (6.068 varones y 4.179 mujeres). Se encuentra un efecto de diferenciación en hombres (alrededor de un 2 por ciento), que no se replica en mujeres. Por consiguiente, la hipótesis de la diferenciación por nivel de habilidad sólo se mantiene en la muestra de varones (AU)

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BACKGROUND AND OBJECTIVE: The Health Utilities Index Mark III (HUI-3) is a psychometric instrument developed to assign utilities to patients' health states. We present its Spanish adaptation and validation. Moreover, we estimate its utility in the Spanish population and compare it to Canadian patients. PATIENTS AND METHOD: The Adaptation process has been carried out following the original protocol by Furlong. A panel of experts was selected in order to warrant the process, the questionnaire translation and the training of interviewers. Two different samples were used: a modelling sample to develop the Multi Attribute Utility function (MAUF) and a directed measure sample to validate the MAUF. Both samples are representative of the Spanish population according to gender and age quota. In order to estimate the utilities associated with each health state, Visual Analogue Scale (VAS) and Standard Gamble (SG) procedures were used. The instrument's dimensionality was assessed by means of Factor Analysis, and the convergent validity was checked against EuroQoL. RESULTS: The HUI-3 Spanish version is feasible (< 2% missing values and 7.34 1.27 minutes completion time) and reliable (Cronbach's (= 0.792 in modelling sample, 0.707 in direct measure sample, and 0.760 as a whole), showing a good test-retest correlation (0.909, p < 0.001). Convergent validity is good (correlation with EuroQoL: within 0.788 and 0.793). Factor solution met 5 factors: Speech & Dexterity, Ambulation & Pain, Vision, Emotion & Cognition, and Hearing. The Spanish and Canadian utility function differed significantly; 0.07 pts, p < 0.001). CONCLUSIONS: This questionnaire can be applied to individuals or collectively, either self-administered or through an interview. Psychometric indexes are good. Differences between Spanish and Canadian utility functions suggest the need of using the specific function for each population.

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FUNDAMENTO Y OBJETIVO: El Health Utilities Index Mark 3 (HUI-3) es un instrumento que permite atribuir utilidades a los estados de salud. Se presenta la adaptación y validación al castellano, así como la estimación de las utilidades en la población española comparándola con la canadiense. PACIENTES Y MÉTODO: El proceso de adaptación se ha realizado siguiendo el protocolo de Furlong. Se seleccionó un panel de expertos para garantizar el proceso, la traducción del cuestionario y el entrenamiento de los entrevistadores. Se han utilizado dos muestras: una de modelado destinada a desarrollar la función de utilidad multiatributo (MAUF) y una de medición directa para validar la MAUF. Ambas muestras son representativas de la población española. Para estimar las utilidades asociadas a cada estado de salud se han utilizado: la Escala Visual Analógica y la Apuesta Normalizada o Juego Estándar. La dimensionalidad del instrumento se ha analizado mediante análisis factorial y la validez convergente se ha comprobado con el EuroQoL. RESULTADOS: La versión española del HUI-3 es factible (< 2 per cent de valores perdidos con tiempo de ejecución de 7,34 [1,27] min) y fiable ( -Cronbach de 0,792 en la muestra de modelado; 0,707 en la de medición directa y 0,760 en la muestra total), presentando una buena correlación test-retest (0,909; p < 0,001). Posee buena validez convergente (las correlaciones con EuroQoL oscilaron entre 0,788 y 0,793). La solución factorial obtenida presenta 5 factores: habla y destreza; deambulación y dolor; visión, emoción y cognición, y audición. La función de utilidad española difirió significativamente de la calculada para la población canadiense (0,07 puntos, p < 0,001). CONCLUSIONES: El cuestionario puede aplicarse de forma individual o colectiva y de forma autoadministrada o mediante entrevista. Los índices psicométricos obtenidos son buenos. Las diferencias encontradas entre las funciones de utilidad española y canadiense hacen necesario utilizar como referente las funciones específicas de cada población (AU)

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Las puntuaciones en los tests de inteligencia declinan con la edad, aunque el grado de declive depende de la naturaleza, fluida o cristalizada, de los tests. Sin embargo, pocas investigaciones han abordado la pregunta de qué aptitudes cognitivas son responsables de tal declive. El presente estudio se centra en esta cuestión. La combinación del análisis factorial jerárquico (procedimiento Schmid-Leiman) y el método de vectores correlacionados permite responder a esta pregunta. Ambos procedimientos han sido utilizados para analizar la muestra de estandarización española del WAIS-III. Los resultados muestran que tanto g como el factor manipulativo son responsables del declive en las puntuaciones. El factor verbal (Gc) no da cuenta de tal declive. Por lo tanto, estos resultados suponen una matización del modelo de aptitudes vulnerables y sostenibles propuesto por Horn (AU)

Intelligence test’s scores decline with age, but such decline change for fluid and crystallized tests. However, little effort has been put to investigate what cognitive abilities are responsible for such decline. The present paper focuses on that issue. A hierarchical factor analysis (performed through the Schmid-Leiman transformation) followed by the method of correlated vectors let us to answer that question. Both procedures were applied to the Spanish standardization sample of the WAIS-III. Results show that g and performance factors are responsible for the decrease on the scores. The verbal factor (Gc) does not account for such decline. Therefore, results draw a more fined-grained view about the Horn’s model distinguishing vulnerable and sustainable cognitive abilities (AU)

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