Modulation of enhancer looping and differential gene targeting by Epstein-Barr virus transcription factors directs cellular reprogramming

Epstein-Barr virus (EBV) epigenetically reprogrammes B-lymphocytes to drive immortalization and facilitate viral persistence. Host-cell transcription is perturbed principally through the actions of EBV EBNA 2, 3A, 3B and 3C, with cellular genes deregulated by specific combinations of these EBNAs through unknown mechanisms. Comparing human genome binding by these viral transcription factors, we discovered that 25% of binding sites were shared by EBNA 2 and the EBNA 3s and were located predominantly in enhancers. Moreover, 80% of potential EBNA 3A, 3B or 3C target genes were also targeted by EBNA 2, implicating extensive interplay between EBNA 2 and 3 proteins in cellular reprogramming. Investigating shared enhancer sites neighbouring two new targets (WEE1 and CTBP2) we discovered that EBNA 3 proteins repress transcription by modulating enhancer-promoter loop formation to establish repressive chromatin hubs or prevent assembly of active hubs. Re-ChIP analysis revealed that EBNA 2 and 3 proteins do not bind simultaneously at shared sites but compete for binding thereby modulating enhancer-promoter interactions. At an EBNA 3-only intergenic enhancer site between ADAM28 and ADAMDEC1 EBNA 3C was also able to independently direct epigenetic repression of both genes through enhancer-promoter looping. Significantly, studying shared or unique EBNA 3 binding sites at WEE1, CTBP2, ITGAL (LFA-1 alpha chain), BCL2L11 (Bim) and the ADAMs, we also discovered that different sets of EBNA 3 proteins bind regulatory elements in a gene and cell-type specific manner. Binding profiles correlated with the effects of individual EBNA 3 proteins on the expression of these genes, providing a molecular basis for the targeting of different sets of cellular genes by the EBNA 3s. Our results therefore highlight the influence of the genomic and cellular context in determining the specificity of gene deregulation by EBV and provide a paradigm for host-cell reprogramming through modulation of enhancer-promoter interactions by viral transcription factors

The Adolescent Depression Rating Scale (ADRS): a validation study

BACKGROUND: To examine the psychometric properties of the Adolescent Depression Rating Scale (ADRS), a new measure was specifically designed to evaluate adolescent depression. METHODS: The 11-item clinician-report and 44-item self-report versions of the ADRS were developed from a qualitative phase involving interviews of experts and adolescents. These two instruments were then administered to 402 French speaking adolescents with and without depressive disorders. Item distribution, internal consistency, convergent validity, discriminant validity and factorial structure were assessed. RESULTS: After reduction procedures, a 10-item clinician version and a 10-item self-report version were obtained. The ADRS demonstrated good internal consistency (alpha Cronbach coefficient >.70). It also discriminated better between adolescents with and without depression than the Hamilton Depressive Rating Scale and the Beck Depression Inventory (BDI-13). CONCLUSION: The ADRS is a useful, short, clinician-report and self-report scale to evaluate adolescent depression. Further studies to replicate our findings and evaluate ADRS sensitivity to effects of treatment and psychometric properties in populations of adolescents with several psychiatric disorders are warranted

Collaborative Brain-Computer Interface for Aiding Decision-Making

We look at the possibility of integrating the percepts from multiple non-communicating observers as a means of achieving better joint perception and better group decisions. Our approach involves the combination of a brain-computer interface with human behavioural responses. To test ideas in controlled conditions, we asked observers to perform a simple matching task involving the rapid sequential presentation of pairs of visual patterns and the subsequent decision as whether the two patterns in a pair were the same or different. We recorded the response times of observers as well as a neural feature which predicts incorrect decisions and, thus, indirectly indicates the confidence of the decisions made by the observers. We then built a composite neuro-behavioural feature which optimally combines the two measures. For group decisions, we uses a majority rule and three rules which weigh the decisions of each observer based on response times and our neural and neuro-behavioural features. Results indicate that the integration of behavioural responses and neural features can significantly improve accuracy when compared with the majority rule. An analysis of event-related potentials indicates that substantial differences are present in the proximity of the response for correct and incorrect trials, further corroborating the idea of using hybrids of brain-computer interfaces and traditional strategies for improving decision making

The association between clinical integration of care and transfer of veterans with acute coronary syndromes from primary care VHA hospitals

BACKGROUND: Few studies report on the effect of organizational factors facilitating transfer between primary and tertiary care hospitals either within an integrated health care system or outside it. In this paper, we report on the relationship between degree of clinical integration of cardiology services and transfer rates of acute coronary syndrome (ACS) patients from primary to tertiary hospitals within and outside the Veterans Health Administration (VHA) system. METHODS: Prospective cohort study. Transfer rates were obtained for all patients with ACS diagnoses admitted to 12 primary VHA hospitals between 1998 and 1999. Binary variables measuring clinical integration were constructed for each primary VHA hospital reflecting: presence of on-site VHA cardiologist; referral coordinator at the associated tertiary VHA hospital; and/or referral coordinator at the primary VHA hospital. We assessed the association between the integration variables and overall transfer from primary to tertiary hospitals, using random effects logistic regression, controlling for clustering at two levels and adjusting for patient characteristics. RESULTS: Three of twelve hospitals had a VHA cardiologist on site, six had a referral coordinator at the tertiary VHA hospital, and four had a referral coordinator at the primary hospital. Presence of a VHA staff cardiologist on site and a referral coordinator at the tertiary VHA hospital decreased the likelihood of any transfer (OR 0.45, 95% CI 0.27–0.77, and 0.46, p = 0.002, CI 0.27–0.78). Conversely, having a referral coordinator at the primary VHA hospital increased the likelihood of transfer (OR 6.28, CI 2.92–13.48). CONCLUSIONS: Elements of clinical integration are associated with transfer, an important process in the care of ACS patients. In promoting optimal patient care, clinical integration factors should be considered in addition to patient characteristics

Interpreting the role of de novo protein-coding mutations in neuropsychiatric disease

Pedigree, linkage and association studies are consistent with heritable variation for complex disease due to the segregation of genetic factors in families and in the population. In contrast, de novo mutations make only minor contributions to heritability estimates for complex traits. Nonetheless, some de novo variants are known to be important in disease etiology. The identification of risk-conferring de novo variants will contribute to the discovery of etiologically relevant genes and pathways and may help in genetic counseling. There is considerable interest in the role of such mutations in complex neuropsychiatric disease, largely driven by new genotyping and sequencing technologies. An important role for large de novo copy number variations has been established. Recently, whole-exome sequencing has been used to extend the investigation of de novo variation to point mutations in protein-coding regions. Here, we consider several challenges for the interpretation of such mutations in the context of their role in neuropsychiatric disease

An SNP selection strategy identified IL-22 associating with susceptibility to tuberculosis in Chinese

Recent studies showed that IL-22 plays a protective role in the host defense. However, the contribution of polymorphisms of the IL-22 gene to human TB susceptibility remains untested. We have designed a computational approach to select functional SNPs in the IL-22 gene and genotyped them in a two-stage case-control study in Chinese (479 cases and 358 controls). We found that rs2227473, an SNP in the promoter region of IL-22, is associated with TB susceptibility at both stages of our study. The SNP shows associations with p-values of 0.028 and 0.034 respectively, and a combined p-value of 0.0086, with odds ratio at 0.65 (95% confidence interval 0.45–0.90). We further validated the association with an independent cohort (413 cases and 241 controls in Chinese). Our functional studies showed that patients with A allele have significantly higher IL-22 expression than those without A allele under both non-specific and specific stimulations

High prevalence of chronic kidney disease in Iran: a large population-based study

<p>Abstract</p> <p>Background</p> <p>Chronic kidney disease (CKD) is a global public health threat, associated with an alarming increase in morbidity and mortality. The importance is the worldwide increase in its incidence and prevalence.</p> <p>Methods</p> <p>In this cross-sectional study, we estimate the prevalence and determine the associated factors of chronic kidney disease in a representative sample of 10063 participants aged over 20 years, in Tehran, Iran. Chronic kidney disease was defined as estimated glomerular filtration rate less than 60 mL/min/1.73 m2. Glomerular filtration rate was estimated from abbreviated prediction equation provided by the Modification of Diet in Renal Disease study (MDRD).</p> <p>Results</p> <p>Overall prevalence of CKD with the abbreviated MDRD equation was 18.9% (95% confidence interval (CI) 18.2, 20.6). Age adjusted prevalence of CKD was 14.9% (95%CI 14.2, 15.6). Factors associated to CKD include age(years)(odds ratio(OR) 1.1, 95% CI 1.0 to 1.2), female gender (OR 3.1, 95% CI 2.6, 3.7), BMI (BMI 25 to <30 OR 1.5, 95% CI 1.3, 1.8 and BMI ≥ 30 OR 1.6, 95% CI 1.3, 2.0), high waist circumference (OR 1.2, 95% CI 1.1, 1.4), hypertension (OR 1.2, 95% CI 1.1, 1.4), and dyslipidemia (OR 1.3, 95% CI 1.1, 1.5).</p> <p>Conclusion</p> <p>CKD with its high prevalence poses a definite health threat in Iran.</p

Ethnic minority disparities in progression and mortality of pre-dialysis chronic kidney disease : a systematic scoping review

Background: There are a growing number of studies on ethnic differences in progression and mortality for pre-dialysis chronic kidney disease (CKD), but this literature has yet to be synthesised, particularly for studies on mortality. Methods: This scoping review synthesized existing literature on ethnic differences in progression and mortality for adults with pre-dialysis CKD, explored factors contributing to these differences, and identified gaps in the literature. A comprehensive search strategy using search terms for ethnicity and CKD was taken to identify potentially relevant studies. Nine databases were searched from 1992 to June 2017, with an updated search in February 2020. Results: 8059 articles were identified and screened. Fifty-five studies (2 systematic review, 7 non-systematic reviews, and 46 individual studies) were included in this review. Most were US studies and compared African-American/Afro-Caribbean and Caucasian populations, and fewer studies assessed outcomes for Hispanics and Asians. Most studies reported higher risk of CKD progression in Afro-Caribbean/African-Americans, Hispanics, and Asians, lower risk of mortality for Asians, and mixed findings on risk of mortality for Afro-Caribbean/African-Americans and Hispanics, compared to Caucasians. Biological factors such as hypertension, diabetes, and cardiovascular disease contributed to increased risk of progression for ethnic minorities but did not increase risk of mortality in these groups. Conclusions: Higher rates of renal replacement therapy among ethnic minorities may be partly due to increased risk of progression and reduced mortality in these groups. The review identifies gaps in the literature and highlights a need for a more structured approach by researchers that would allow higher confidence in single studies and better harmonization of data across studies to advance our understanding of CKD progression and mortality

Renal Function and Risk Factors of Moderate to Severe Chronic Kidney Disease in Golestan Province, Northeast of Iran

Introduction: The incidence of end-stage renal disease is increasing worldwide. Earlier studies reported high prevalence rates of obesity and hypertension, two major risk factors of chronic kidney disease (CKD), in Golestan Province, Iran. We aimed to investigate prevalence of moderate to severe CKD and its risk factors in the region. Methods: Questionnaire data and blood samples were collected from 3591 participants (≥18 years old) from the general population. Based on serum creatinine levels, glomerular filtration rate (GFR) was estimated. Results: High body mass index (BMI) was common: 35.0 of participants were overweight (BMI 25-29.9) and 24.5 were obese (BMI ≥30). Prevalence of CKD stages 3 to 5 (CKD-S3-5), i.e., GFR &lt;60 mL/min/1.73 m2, was 4.6. The odds ratio (OR) and 95 confidence interval (95 CI) for the risk of CKD-S3-5 associated with every year increase in age was 1.13 (1.11- 1.15). Men were at lower risk of CKD-S3-5 than women (OR = 0.28; 95 CI 0.18-0.45). Obesity (OR = 1.78; 95 CI 1.04-3.05) and self-reported diabetes (OR = 1.70; 95 CI 1.00-2.86), hypertension (OR = 3.16; 95 CI 2.02-4.95), ischemic heart disease (OR = 2.73; 95 CI 1.55-4.81), and myocardial infarction (OR = 2.69; 95 CI 1.14-6.32) were associated with increased risk of CKD-S3-5 in the models adjusted for age and sex. The association persisted for self-reported hypertension even after adjustments for BMI and history of diabetes (OR = 2.85; 95 CI 1.77-4.59). Conclusion: A considerable proportion of inhabitants in Golestan have CKD-S3-5. Screening of individuals with major risk factors of CKD, in order to early detection and treatment of impaired renal function, may be plausible. Further studies on optimal risk prediction of future end-stage renal disease and effectiveness of any screening program are warranted. © 2010 Najafi et al

Benefits of ICU admission in critically ill patients: Whether instrumental variable methods or propensity scores should be used

<p>Abstract</p> <p>Background</p> <p>The assessment of the causal effect of Intensive Care Unit (ICU) admission generally involves usual observational designs and thus requires controlling for confounding variables. Instrumental variable analysis is an econometric technique that allows causal inferences of the effectiveness of some treatments during situations to be made when a randomized trial has not been or cannot be conducted. This technique relies on the existence of one variable or "instrument" that is supposed to achieve similar observations with a different treatment for "arbitrary" reasons, thus inducing substantial variation in the treatment decision with no direct effect on the outcome. The objective of the study was to assess the benefit in terms of hospital mortality of ICU admission in a cohort of patients proposed for ICU admission (ELDICUS cohort).</p> <p>Methods</p> <p>Using this cohort of 8,201 patients triaged for ICU (including 6,752 (82.3%) patients admitted), the benefit of ICU admission was evaluated using 3 different approaches: instrumental variables, standard regression and propensity score matched analyses. We further evaluated the results obtained using different instrumental variable methods that have been proposed for dichotomous outcomes.</p> <p>Results</p> <p>The physician's main specialization was found to be the best instrument. All instrumental variable models adequately reduced baseline imbalances, but failed to show a significant effect of ICU admission on hospital mortality, with confidence intervals far higher than those obtained in standard or propensity-based analyses.</p> <p>Conclusions</p> <p>Instrumental variable methods offer an appealing alternative to handle the selection bias related to nonrandomized designs, especially when the presence of significant unmeasured confounding is suspected. Applied to the ELDICUS database, this analysis failed to show any significant beneficial effect of ICU admission on hospital mortality. This result could be due to the lack of statistical power of these methods.</p