Aagaardmosley3511

BACKGROUND Long non-coding RNAs (lncRNAs) exhibit highly cell type-specific expression and function, making this class of transcript attractive for targeted cancer therapy. However, the vast majority of lncRNAs have not been tested as potential therapeutic targets, particularly in the context of currently used cancer treatments. Malignant glioma is rapidly fatal, and ionizing radiation is part of the current standard-of-care used to slow tumor growth in both adult and pediatric patients. RESULTS We use CRISPR interference (CRISPRi) to screen 5689 lncRNA loci in human glioblastoma (GBM) cells, identifying 467 hits that modify cell growth in the presence of clinically relevant doses of fractionated radiation. Thirty-three of these lncRNA hits sensitize cells to radiation, and based on their expression in adult and pediatric gliomas, nine of these hits are prioritized as lncRNA Glioma Radiation Sensitizers (lncGRS). Knockdown of lncGRS-1, a primate-conserved, nuclear-enriched lncRNA, inhibits the growth and proliferation of primary adult and pediatric glioma cells, but not the viability of normal brain cells. Using human brain organoids comprised of mature neural cell types as a three-dimensional tissue substrate to model the invasive growth of glioma, we find that antisense oligonucleotides targeting lncGRS-1 selectively decrease tumor growth and sensitize glioma cells to radiation therapy. CONCLUSIONS These studies identify lncGRS-1 as a glioma-specific therapeutic target and establish a generalizable approach to rapidly identify novel therapeutic targets in the vast non-coding genome to enhance radiation therapy.BACKGROUND In highly segmented and complex healthcare organizations social capital is assumed to be of high relevance for the coordination of tasks in healthcare. So far, comprehensively validated instruments on social capital in healthcare organizations are lacking. The aim of this work is to validate an instrument measuring social capital in healthcare organizations. METHODS This validation study is based on a cross-sectional survey of 1050 hospital employees from 49 German hospitals which specialize in breast cancer care. Social capital was assessed by a six-item scale. Reliability analyses and confirmatory factor analyses were conducted to determine the content validity of items within the theory-driven one-dimensional scale structure. The scale's associations with measures of the social aspects of the work environment (identification, social support, open communication climate) were estimated to test convergent validity. Criterion-related validity was evaluated by conducting structural equation modelling to examine the predictive validity of the scale with measures of work engagement, well-being and burnout. RESULTS A one-dimensional structure of the instrument could be identified (CFI = .99; RMSEA = .06). Convergent validity was shown by hypothesis-consistent correlations with social support offered by supervisors and colleagues, a climate of open communication, and employee commitment to the organization. Criterion-related validity of the social capital scale was proved by its prediction of employee work engagement (R2 = .10-.13 for the three subscales), well-being (R2 = .13), and burnout (R2 = .06-.11 for the three subscales). CONCLUSIONS The confirmed associations between social capital and work engagement, burnout as well as well-being stress the importance of social capital as a vital resource for employee health and performance in healthcare organizations. In healthcare organizations this short instrument can be used as an efficient instrument to measure the organizations' social capital.BACKGROUND Microangiopathy in type 2 diabetes (T2D) is associated with cardiovascular disease (CVD), but most relevant studies were performed > 10 years ago. CVD risk factor management has since improved. The aim of this study was to determine whether diabetic retinopathy (DR) and its severity increases stroke and myocardial infarction (MI) risk in a contemporary cohort. METHODS Fremantle Diabetes Study Phase II participants with T2D had DR graded from fundus photography at baseline between 2008 and 2011. Subsequent hospitalizations and mortality for MI or stroke were ascertained through validated data linkage to end-2016. Cox regression modelling identified predictors of first stroke and MI including DR presence and severity. RESULTS The 1521 participants with T2D and known DR status (mean age 65.6 years, 52.1% males, median diabetes duration 9.0 years) were followed for a mean of 6.6 years. After excluding those with prior MI/stroke, there were 126 incident MIs among 1393 eligible participants and 53 incident strokes in 1473 eligible participants, respectively. Moderate non-proliferative DR (NPDR) or worse was significantly and independently associated with an increased risk of incident stroke (adjusted hazard ratio 2.55 (95% CI 1.19, 5.47), p = 0.016). Retinopathy presence and severity increased the risk of incident MI in unadjusted models (p ≤ 0.001), but these associations were no longer statistically significant after adjusting for other risk factors. CONCLUSIONS Moderate NPDR or worse was associated with an increased risk of first stroke in Australians with T2D. Intensified CVD risk factor management should be considered for patients with at least moderate NPDR.BACKGROUND Chronic obstructive pulmonary disease (COPD) is a major public health problem and cause of mortality worldwide. However, COPD in the early stage is usually not recognized and diagnosed. It is necessary to establish a risk model to predict COPD development. METHODS A total of 441 COPD patients and 192 control subjects were recruited, and 101 single-nucleotide polymorphisms (SNPs) were determined using the MassArray assay. With 5 clinical features as well as SNPs, 6 predictive models were established and evaluated in the training set and test set by the confusion matrix AU-ROC, AU-PRC, sensitivity (recall), specificity, accuracy, F1 score, MCC, PPV (precision) and NPV. The selected features were ranked. RESULTS Nine SNPs were significantly associated with COPD. Among them, 6 SNPs (rs1007052, OR = 1.671, P = 0.010; rs2910164, OR = 1.416, P  less then  0.037; rs473892, OR = 1.473, P  less then  0.044; rs161976, OR = 1.594, P  less then  0.044; rs159497, OR = 1.445, P  less then  0.045; and rs9296092, OQCI, age, and BMI had the greatest impact on the predictive abilities of the models, while SNPs, sex and smoking were less important. CONCLUSIONS The KNN, LR and XGboost models showed excellent overall predictive power, and the use of machine learning tools combining both clinical and SNP features was suitable for predicting the risk of COPD development.BACKGROUND Epigenetic modifications, including DNA methylation, play an important role in gene silencing and genome stability. CD532 clinical trial Consequently, epigenetic dysregulation can cause several diseases, such as cancer, obesity, diabetes, autism, and imprinting disorders. RESULTS We validate three methods for the generation of epigenome-edited mice using the dCas9-SunTag and single-chain variable fragment-TET1 catalytic domain. We generate model mice for Silver-Russell syndrome (SRS), an imprinting disorder, by target-specific DNA demethylation in the H19 differentially methylated region. Like SRS patients, these mice show H19 upregulation and Igf2 downregulation, leading to severe intrauterine and postnatal growth retardation. CONCLUSION This is the first report of an imprinting disease model animal generated by targeted demethylation of specific loci of the epigenome in fertilized eggs. Epigenome-edited animals are also useful for exploring the causative epimutations in epigenetic diseases.BACKGROUND Digital assessment is becoming more and more popular within medical education. To analyse the dimensions of this digital trend, we investigated how exam questions (items) are created and designed for use in digital medical assessments in Germany. Thus, we want to explore whether different types of media are used for item creation and if a digital trend in medical assessment can be observed. METHODS In a cross-sectional descriptive study, we examined data of 30 German medical faculties stored within a common assessment platform. More precise, 23,008 exams which contained 847,137 items were analysed concerning the exam type (paper-, computer- or tablet-based) and their respective media content (picture, video and/or audio). Out of these, 5252 electronic exams with 12,214 questions were evaluated. The media types per individual question were quantified. RESULTS The amount of computer- and tablet-based exams were rapidly increasing from 2012 until 2018. Computer- and tablet-based written exams showed we for the creation of medical assessments. Moreover, the choice of media type seems to depend on the respective question type.BACKGROUND Klebsiella pneumoniae is a public health concern because of its ability to develop multidrug resistance and hypervirulent genotypes, of those capsular types K1 and K2 cause community and nosocomial life-threatening infections. This study aimed to determine the antibiotic susceptibility patterns and genotypic traits of a collection of Klebsiella spp. isolates. Furthermore, the clonal relatedness of blaNDM producing strains was investigated. METHODS During a 19-months  surveillance study, 122 Klebsiella spp. isolates were cultured from extraintestinal specimens of patients admitted to the tertiary referral hospital in Semnan, Iran. Isolates were identified using biochemical tests and subjected to determination of phylogroups, capsular types and virulence/resistance genes content. Hypervirulent K. pneumoniae (hvKp) strains were detected genotypically, and Enterobacterial Repetitive Intergenic Consensus (ERIC)-PCR fingerprinting was used to determine the clonality of blaNDM producing strains. RESULTS Mucer and one hvKp sequence type 86 (ST86) were carbapenem resistant. Among carbapenem resistant isolates, CC147 strains harboured higher rates of siderophores iutA and ybtS. CONCLUSION The present findings showed a hospital circulation of CC147 blaNDM-1 or blaNDM-1/OXA-48 producing strains, disseminated in different wards. The hvKp/ST86 strain expressing K2 capsular type and carbapenem resistant phenotype wasn't reported from Iran so far. So, it seems that we must be aware of the emergence and spread of new K. pneumoniae clones associated with resistant and hypermucoviscous phenotypes.BACKGROUND Accessibility of health care to students with disabilities is a global concern. This is no less important in Ghana, however, to date, no study has been undertaken regarding access to health care to students with disabilities. This study, therefore, aims to explore the accessibility of health care to students with disabilities, in the quest of achieving universal health coverage in Ghana. METHODS Qualitative methods, involving in-depth interviews were employed to collect data from 54 participants (29 students with disabilities, 17 health workers and 8 school mothers), selected through purposive sampling. Thematic analysis was used to analyze the data. RESULTS The study identified three themes - accessibility, adequacy, and affordability. The study findings highlighted that universal health coverage for students with disabilities has not been achieved due to barriers in accessing health care. The barriers faced by students with disabilities were unfriendly physical environments, structures, equipment, limited support services and poor health insurance policy to finance health care.