Gene Expression Profiles of Sporadic Canine Hemangiosarcoma Are Uniquely Associated with Breed

The role an individual's genetic background plays on phenotype and biological behavior of sporadic tumors remains incompletely understood. We showed previously that lymphomas from Golden Retrievers harbor defined, recurrent chromosomal aberrations that occur less frequently in lymphomas from other dog breeds, suggesting spontaneous canine tumors provide suitable models to define how heritable traits influence cancer genotypes. Here, we report a complementary approach using gene expression profiling in a naturally occurring endothelial sarcoma of dogs (hemangiosarcoma). Naturally occurring hemangiosarcomas of Golden Retrievers clustered separately from those of non-Golden Retrievers, with contributions from transcription factors, survival factors, and from pro-inflammatory and angiogenic genes, and which were exclusively present in hemangiosarcoma and not in other tumors or normal cells (i.e., they were not due simply to variation in these genes among breeds). Vascular Endothelial Growth Factor Receptor 1 (VEGFR1) was among genes preferentially enriched within known pathways derived from gene set enrichment analysis when characterizing tumors from Golden Retrievers versus other breeds. Heightened VEGFR1 expression in these tumors also was apparent at the protein level and targeted inhibition of VEGFR1 increased proliferation of hemangiosarcoma cells derived from tumors of Golden Retrievers, but not from other breeds. Our results suggest heritable factors mold gene expression phenotypes, and consequently biological behavior in sporadic, naturally occurring tumors

Reconciling the professional and student identities of clinical psychology trainees

The study explored the ways in which qualified and trainee clinical psychologists perceived professional behaviour, as illustrated in a series of short vignettes, in student and clinical practice contexts. Comparisons were made to identify the extent to which ideas of professionalism differed across different learning contexts and between qualified and unqualified staff, with the aim of adding to the literature on which factors influence the development of professional identity in health professionals. An online questionnaire depicting a range of potentially unprofessional behaviours was completed by 265 clinical psychology trainees and 106 qualified clinical psychologists. The data were analysed using a general linear model with simultaneous entry in which rater (trainee vs qualified clinical psychologist), setting (student vs placement) and their interaction predicted acceptability ratings. We found that, in general, trainees and qualified staff agreed on those behaviours that were potentially unprofessional, although where significant differences were found, these were due to trainees rating the same behaviours as more professionally acceptable than qualified clinical psychologists. Despite trainees identifying a range of behaviours as professionally unacceptable, some percentage reported having engaged in a similar behaviour in the past. Irrespective of the status of the rater, the same behaviours tended to be viewed as more professionally unacceptable when in a placement (clinical) setting than in a student (university) setting. Generally, no support was found for a rater by setting interaction. The study suggests that trainee clinical psychologists are generally successful at identifying professional norms, although they do not always act in accordance with these. Conflicting student and professional norms may result in trainees viewing some potentially unprofessional behaviour as less severe than qualified staff. Health professional educators should be aware of this fact and take steps to shape trainee norms to be consistent with that of the professional group

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

The Recognition of and Care Seeking Behaviour for Childhood Illness in Developing Countries: A Systematic Review

Background: Pneumonia, diarrhoea, and malaria are among the leading causes of death in children. These deaths are largely preventable if appropriate care is sought early. This review aimed to determine the percentage of caregivers in low- and middle-income countries (LMICs) with a child less than 5 years who were able to recognise illness in their child and subsequently sought care from different types of healthcare providers. Methods and Findings: We conducted a systematic literature review of studies that reported recognition of, and/or care seeking for episodes of diarrhoea, pneumonia or malaria in LMICs. The review is registered with PROSPERO (registration number: CRD42011001654). Ninety-one studies met the inclusion criteria. Eighteen studies reported data on caregiver recognition of disease and seventy-seven studies on care seeking. The median sensitivity of recognition of diarrhoea, malaria and pneumonia was low (36.0%, 37.4%, and 45.8%, respectively). A median of 73.0% of caregivers sought care outside the home. Care seeking from community health workers (median: 5.4% for diarrhoea, 4.2% for pneumonia, and 1.3% for malaria) and the use of oral rehydration therapy (median: 34%) was low. Conclusions: Given the importance of this topic to child survival programmes there are few published studies. Recognition of diarrhoea, malaria and pneumonia by caregivers is generally poor and represents a key factor to address in attempts to improve health care utilisation. In addition, considering that oral rehydration therapy has been widely recommended for over forty years, its use remains disappointingly low. Similarly, the reported levels of care seeking from community health workers in the included studies are low even though global action plans to address these illnesses promote community case management. Giving greater priority to research on care seeking could provide crucial evidence to inform child mortality programmes